· WHO Library Cataloguing-in-Publication Data Guidelines for intensified tuberculosis...

Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource- constrained settings

Annexes (for web posting and CD-Rom distribution in tandem

with the guidelines document)

Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource- constrained settings

Department of HIV/AIDS

Stop TB Department

World Health Organization, Geneva, Switzerland

Annexes (for web posting and CD-Rom distribution in tandem with the guidelines document)

WHO Library Cataloguing-in-Publication Data

Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in resource-constrained settings.

1.Tuberculosis - prevention and control. 2.Tuberculosis - diagnosis. 3.HIV infections - complications. 4.Isoniazid - therapeutic use. 5.Predictive value of tests. 6.Developing countries. 7.Guidelines. I.World Health Organization. Stop TB Dept. II.World Health Organization. Dept of HIV/AIDS.

ISBN 978 92 4 150070 8 (NLM classification: WF 220)

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Summary of declarations of interest All members of the Guidelines Group were asked to complete a World Health Organization (WHO) declaration of interest form and only two declared a conflict of interest. These were discussed within the WHO steering group and then with the Guidelines Group before the deliberations. Alison Grant declared receiving financial support of GB£ 200 from Roche to attend the International AIDS Conference, Sydney, 2007 when the aeroplane she was flying in broke down and the GB£ 200 was paid for a flight deviation. Helen Ayles declared receiving financial support amounting to US$ 15 000 from the Bill and Melinda Gates Foundation, US$ 50 000 from Senter Novum and €150 000 from Delft Imaging Systems to conduct research on intensified TB case-finding and isoniazid preventive therapy for TB, and the development of computer-aided diagnostics for TB/HIV. The Guidelines Group discussed these and concluded that there was no conflict of interest. Declarations of interest were collected from all non-WHO peer reviewers. No peer reviewer declared a conflict of interest. All declarations of interest are on electronic file with the Department of HIV/AIDS of WHO.

AcknowledgementsThe development of these guidelines was financially supported by the Joint United Nations Programme on HIV/AIDS Unified Budget and Workplan (UNAIDS UBW) and the US President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) and United States Agency for International Development (USAID).

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Contents

Annex 1: WHO guidelines meeting on preventive therapy and case-finding for TB in people living with HIV: list of participants

Annex 2: WHO guidelines group

Annex 3: WHO meeting on preventive therapy and case-finding for TB among people living with HIV: meeting agenda

Annex 4: Report on the consultation for the revision of the WHO/UNAIDS policy statement on preventive therapy against TB for people living with HIV

Annex 5: Summary of findings and quality of evidence evaluation: intensified TB case-finding for adults and adolescents living with HIV

Annex 6: Summary of findings and quality of evidence evaluation: preventive therapy for adults and adolescents living with HIV

Annex 7: Summary of findings and quality of evidence evaluation: secondary prophylaxis

Annex 8: Summary of findings and quality of evidence: tuberculin skin test (TST)

Annex 9: Summary of findings and quality of evidence evaluation: interferon gamma release assays (IGRA)

Annex 10: Summary of findings and quality of evidence: INH resistance

Annex 11: Summary of finding and quality of evidence: adherence to preventive therapy

Annex 12: Summary of findings and quality of evidence: cost effectiveness

Annex 13: Summary of findings and quality of evidence evaluation: intensive TB case-finding for children living with HIV

Annex 14: Summary of findings and quality of evidence: preventive therapy for children living with HIV

Annex 15: Research gaps

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25–27 January 2010Helen Ayles Department of MedicineP.O. Box 50697Ridgeway Campus, Nationalist RoadLusakaZambia

Draurio BarreiraPrograma Nacional de Controle da Tuberculose DEVEP/SVS/MSSCS Quadra 4 Bloco AEdif. Principal 3º andar70.304-000 Brasília - DF

François-Xavier BlancAgence Nationale de Recherche sur le SIDA et les Hépatites virales101 rue de Tolbiac, 75013 ParisFrance

Charlene BrownTechnical Leadership & Research DivisionOffice of HIV/AIDSUS Agency for International DevelopmentUnited States of America

Kevin CainInternational Research and Programs Branch Division of Tuberculosis Elimination Centers for Disease Control and Prevention 1600 Clifton Rd., MS-E-10 Atlanta, GA 30333United States of America

Rolando A. CedillosProyecto Regional VIH SIDA Centroaméricamerica Av. El Espino 65 Urbanizacion Madre SelvaAntiguo Cuscatlan, La LibertadEl Salvador

Richard Chaisson Consortium to Respond Effectively to the AIDS and TB EpidemicJohns Hopkins UniversityCenter for Tuberculosis Research1503 E. Jefferson Street21231-1003, BaltimoreUnited States of America

Mean Chhivun National Center for HIV/AIDS Dermatology and STD – Ministry of Health No 266, St 1019, SK Phnom Penh Thmey Khan RoesseykeoPhnom Penh Cambodia

Anupong ChitwarakornHIV/STI/TB) Bureau of AIDS/TB/STIDepartment of Disease ControlMinistry of Public Health1100 – NonthaburiThailand

Gavin ChurchyardAurum Institute for Health ResearchP.O. Box 61587, 2107, MarshalltownRepublic of South Africa

Mark CottonStellenbosch UniversityDepartment of Paediatrics and Child HealthFaculty of Health SciencesP.O. Box 19063, 7505 TygerbergRepublic of South Africa

Anand DateGlobal AIDS Program, TB/HIV Team, HIV Care and Treatment BranchCenters for Disease Control and Prevention1600 Clifton Road, N.E. Mailstop E-04Atlanta, GA 30333United States of America

Kevin De Cock (Co-chair)Centers for Disease Control and PreventionP.O. Box 54840-00200Kenya

Dmytro DonchukState Medical University Ukraine

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Annex 1

Wafaa El-SadrInternational Center for AIDS Care and Treatment ProgramsMailman School of Public HealthColumbia University 722 West 168th Street, Room 715New York, NY 10032United States of America

Peter Godfrey-Faussett Department of Infection & Tropical DiseasesLondon School of Hygiene & Tropical MedicineKeppel Street, WC1E 7HT, LondonUnited Kingdom of Great Britain and Northern Ireland

Olga Petrovna FrolovaTB/HIV Health Care Centre of Ministry of Health and Social Development107014, Moscow,3, Barbolina StreetRussian Federation

Paula FujiwaraInternational Union Against Tuberculosis & Lung Disease68 boulevard Saint-Michel, 75006Paris France

Alison GrantClinical Research UnitLondon School of Hygiene & Tropical MedicineKeppel StreetLondon WC1E 7HTUnited Kingdom of Great Britain and Northern Ireland

Mark HarringtonTreatment Action Group611 Broadway, Suite 612New York, NY 10012United States of America

Catherine HewisonMédecins Sans Frontières8 Rue Saint-Sabin75011, ParisFrance

Maureen Kamene Kimenye Ministry of Public HealthP.O. Box 10016Nairobi Kenya

Michael KimerlingBill and Melinda Gates FoundationPO Box 23350Seattle, WA 98102USA

Steve LawnInstitute of Infectious Diseases and Molecular Medicine, Faculty of HealthDesmond Tutu HIV CentreAnzio RoadObservatory 7925Cape TownRepublic of South Africa

Gary MaartensUniversity of Cape Town, Faculty of Health SciencesDivision of Clinical Pharmacology Department of MedicineObservatory 7925Republic of South Africa

Barbara Jean MarstonGlobal AIDS Program, Care and Treatment BranchCenters for Disease Control and Prevention 1600 Clifton Road, N.E. Mailstop E‐04Atlanta, GA 30333United States of America

Thombile MbengasheNational AIDS Programme Cluster National Department of HealthPrivate Bag X828Pretoria 0001Republic of South Africa

Zenebe MelakuInternational Center for AIDS Care and Treatment ProgramsAddis Ababa Ethiopia

Peter Mgosha Ministry of Health and Social WelfareNational AIDS Control ProgrammeP.O. Box 11578Tanzania

Muhamed MulongoTropical Medical and Maternity Center District P.O. Box 17, Sironko Uganda

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Sharon NachmanHealth Science Center State University New York Stony BrookNY 11794-8111United States of America

Alasdair ReidHIV/TB AdviserUNAIDS20 Avenue AppiaCH -1211 Geneva 27Switzerland

Stewart ReidCentre for Infectious Disease Research in ZambiaP.O. Box 34681Plot 2374 , Counting House Square Thabo Mbeki RoadLusaka Zambia

Taraz SamandariCenters for Disease Control and Prevention 1600 Clifton Road MS-E-10 Atlanta, GA 30333United States of America

Paula Isabel Samo GudoNational Tuberculosis ProgramMinistry of Public HealthMozambique

Mauro SchechterHospital Universitario Clementino Fraga Filho Universidade Federal do Rio de Janeiro Rua Professor Rodolpho Paulo Rocco, nº 255 – Ilha do Fundão – Rio de Janeiro – RJ Brazil – 21941.590

Holger SchünemannDepartment of Clinical Epidemiology & BiostatisticsMcMaster University of Health Sciences Centre Room 2C10B, 1200 Main Street WestHamilton, ON, L8N 3Z5Canada

Wim VandeveldeEuropean Community Advisory Board European AIDS Treatment Group Place Raymond Blyckaerts 13B-1050 BrusselsBelgium

Eric van PraagFamily Health InternationalOff Haile Selassie RoadPlot No. 8/10, OysterbayPO Box 78735 Dar es SalaamTanzania

Jay K. Varma U.S. CDC International Emerging Infections ProgramCDC-GAP China Office 23 Dongzhimenwai Dajie Beijing 100600 People’s Republic of China

Fujie Zhang Fujie Zhang National Center for AIDS/STD Control and PreventionChinese CDCNo. 27 Nanwei Road Beijing, P.R. China 100050

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AFROFrank Lule AMRORafael Lopez Olarte

WPROMassimo Ghidinelli

SEAROPuneet Dewan

Christopher Akolo9040 I Steinberg WayLaurelMD 29723United States of America

Martina PenazzatoVia E. Forcellini 4335128 PadovaItaly

Georgina Russell 16 Oliphant Street, London W10 4EGUnited Kingdom of Great Britain and Northern Ireland

Caoimhe SmythWHO HIV/AIDS Department

Léopold BlancSTOP TB Department

Siobhan CrowleyHIV/AIDS Department

Colleen DanielsSTOP TB Department

Andrew DoupeHIV/AIDS Department Haileyesus Getahun (Guidelines Coordinator)STOP TB Department

Sandy GoveHIV/AIDS Department

Reuben Granich (Guidelines Coordinator)HIV/AIDS Department

Teguest GuermaHIV/AIDS Department

Malgorzata GrzemskaSTOP TB Department

Christian GunnebergSTOP TB Department

Suzanne Hill (Co-chair)Policy, Access and Rational Use

Ying-Ru LoHIV/AIDS Department

Lulu MuheChild and Adolescent Health

Eyerusalem NegussieHIV/AIDS Department

Rose PraySTOP TB Department

Mario RaviglioneSTOP TB Department

Delphine SculierSTOP TB Department

Yves Souteyrand HIV/AIDS Department

Diana WeilSTOP TB Department

WHO REGIONAL OFFICES

WHO CONSULTANTS

WHO SECRETARIAT, HEADQUARTERS

Annex 1

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Helen Ayles (ZAMBART Project, Zambia), Draurio Barreira (National TB Program, Brazil), François-Xavier Blanc (Agence Nationale de Recherche sur le SIDA et les Hépatites virales, France), Charlene Brown (US Agency for International Development [USAID], United States of America [USA]), Kevin Cain (Centers for Disease Control and Prevention [CDC], USA), Rolando Cedillos (Proyecto Regional VIH SIDA para Centroamérica, El Salvador), Richard Chaisson (Johns Hopkins University, USA), Mean Chhivun (National AIDS Programme, Cambodia), Anupong Chitwarakorn (Ministry of Public Health, Thailand), Gavin Churchyard (Aurum Institute for Health Research, Republic of South Africa), Mark Cotton (Stellenbosch University, Republic of South Africa), Anand Date (CDC, USA), Dmytro Donchuk (State Medical University, Ukraine), Wafaa El-Sadr (International Center for AIDS Programs, Columbia University, USA), Peter Godfrey-Faussett (London School of Hygiene and Tropical Medicine, UK), Olga Petrovna Frolova (Ministry of Health and Social Development, Russian Federation), Paula Fujiwara (International Union Against Tuberculosis and Lung Disease [The Union], France), Alison Grant (London School of Hygiene and Tropical Medicine, UK), Mark Harrington (Treatment Action Group, USA), Catherine Hewison (Medecins sans Frontieres [MSF], France), Maureen Kamene Kimenye (Ministry of Public Health, Kenya), Michael Kimerling (Bill and Melinda Gates Foundation, USA), Stephen D. Lawn, (University of Cape Town, South Africa), Gary Maartens (University of Cape Town, South Africa), Barbara Jean Marston (CDC, USA), Thombile Mbengashe (National Department of Health, Republic of South Africa), Zenebe Melaku (International Center for AIDS Care and Treatment Programs [ICAP], Ethiopia), Peter Mgosha (Ministry of Health and Social Welfare, Tanzania), Muhamed Mulongo (Tropical Medical and Maternity Centre, Uganda), Sharon Nachman (Stony Brook University Medical Center, USA), Alasdair Reid (Joint United Nations Programme on HIV/AIDS [UNAIDS], Geneva), Stewart Reid (Centre for Infectious Disease Research in Zambia [CIDRZ], Zambia), Taraz Samandari (CDC, USA), Paula Isabel Samo Gudo (Ministry of Public Health, Mozambique), Mauro Schechter (AIDS Research Laboratory, Brazil), Wim Vandevelde (European Community Advisory Board, European AIDS Treatment Group, Belgium), Eric van Praag (Family Health International, Tanzania), Jay K. Varma (CDC, USA), Fujie Zhang (National Center for AIDS/STD Control and Prevention, Peoples’ Republic of China)

Peer reviewers Jesus Maria Garcia Calleja (HIV/AIDS Department, WHO), Jacob Creswell (Stop TB Department, WHO), Irina Eramova (WHO EURO), Robert Gie (University of Stellenbosch, South Africa), Steve Graham (The Union, Australia), Prakash Kudur Hanumaiah (Karnataka Health Promotion Trust, India), Cathy Hewisson (MSF, France), Charles Mwansambo (Kamuzu Central Hospital, Malawi), Nguyen Viet Nhung (National TB programme, Viet Nam), Carla Obermeyer (HIV/AIDS Department, WHO), Ikushi Onozaki (Stop TB Department, WHO), Cyril Pervilhac (HIV/AIDS Department, WHO), Renee Ridzon (Bill and Melinda Gates Foundation, USA), Matji Rifiloe (Ministry of Health, South Africa), Quaid Saeed (WHO EMRO), Fabio Scano (WHO WPRO), Sahu Suvanand (Stop TB Partnership), Risard Zaleskis (WHO EURO)

WHO Headquarters and Regional officesLéopold Blanc (Stop TB Department, WHO), Colleen Daniels (Stop TB Department, WHO), Puneet Dewan (WHO SEARO), Massimo Ghidinelli (WHO WPRO), Sandra Gove (HIV/AIDS Department, WHO), Malgorzata Grzemska (Stop TB Department, WHO), Teguest Guerma (HIV/AIDS Department, WHO), Christian Gunneberg (Stop TB Department, WHO), Rafael Lopez Olarte (WHO AMRO), Frank Lule (WHO AFRO), Eyerusalem Negussie (HIV/AIDS Department, WHO), Rose Pray (Stop TB Department, WHO), Mario Raviglione (Stop TB Department, WHO)

Coordinated byHaileyesus Getahun and Reuben Granich

Annex 2: WHO guidelines group

The following group represents experts from the fields of HIV, TB, HIV/TB, sexually transmitted infections, child health, infectious and tropical diseases, clinical research, maternal health, infectious disease research, clinical epidemiology and biostatistics.

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Annex 3: WHO guidelines meeting on preventive therapy and case-finding for TB in people living with HIV: meeting agenda

25–27 January 2010, Geneva, Switzerland

Day 1: 25 January 201008:30–09:00 Registration09:00–09:15 Welcome remarks T. Guerma

M. Raviglione09:15–09:30 Meeting overview and introductions K. De Cock

(Co-chair)H. Shünemann(Co-chair)

09:30–09:50 Rationale and review process of guidelines R. GranichH. Getahun

09:50–10:00 Overview of GRADE methodology and review of PICOT questions for systematic reviews of scientific evidence

M. Penazzato

10:00–10:30 Coffee break10:30–11:30 GRADE profiles, systematic reviews and draft recommendations for

PICOT Question 1: Define the optimal duration and drug regimen (e.g. INH, rifampicin, etc.) for treatment of LTBI to reduce the risk of developing TB

Community commentary: W. Vandevelde, Belgium

Country/national programme commentary: A. Chitwarakorn, Thailand

Discussion: Open to the floor

M. Penazzato

11:30–12:30 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 2: Define the optimal time to start considering IPT (i.e. should immune status be considered and should IPT be started with ART).


Country/national programme commentary: N. Muraguri, Kenya


M. Penazzato

12:30–14:00 Lunch14:00–15:00 GRADE profiles, systematic reviews and draft recommendations for

PICOT Question 3: Determine whether people living with HIV who had received TB treatment in the past should be provided secondary treatment for LTBI to prevent reinfection or recurrence of tuberculosis.

Community commentary: M. Harrington, United States of America

Country/national programme commentary: T. Mbengashe, Republic of South Africa


A. Sharma

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Annex 3: WHO meeting on preventive therapy and case-finding for TB in people living with HIV: meeting agenda

15:00–16:30 Working group session Group A/PICOT 1 Optimal duration/drug regimenGroup B/PICOT 2 Optimal time to startGroup C/PICOT 3 Secondary treatment of LTBI

16:30–17:30 Report back from Groups A, B, C:Group A/PICOT 1 (15’) Optimal duration/drug regimen Group B/PICOT 2 (15’) Optimal time to startGroup C/PICOT 3 (15’) Secondary treatment of LTBI

K. De Cock(Co-chair)H. Shünemann(Co-chair)

18:00 Reception:Cafeteria, WHO/UNAIDS D Building

Day 2: 26 January09:00–09:10 Overview of Day 2 K. De Cock

(Co-chair)H. Shünemann(Co-chair)

09:10–10:00 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 8: Determine the best combination of signs, symptoms and diagnostic procedures (e.g. radiography, serum-based tests such as IGRA, etc.) that can be used as screening tools to determine eligibility for LTBI treatment and to diagnose TB among people living with HIV (feasibility considerations included).


Country/national programme commentary: Z. Melaku, Ethiopia


A. Date

10:00–10:30 Coffee break10:30–12:30 GRADE profiles, systematic reviews and draft recommendations

for PICOT Question 4: Determine whether treatment for LTBI among people living with HIV leads to significant development of mono-resistance against the drugs used for LTBI treatment.


Country/national programme commentary: R. Cedillos, El Salvador


A. Sharma

12:00–12:30 GRADE profiles, systematic reviews and draft recommendations for PICOT Question 7: TST in resource-limited settings


Country/national programme commentary: D. Barreria, Brazil


C. Akolo

12:30–13:30 Lunch15:30–15:45 Working coffee

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Annex 3

Day 3: 27 January09:00–09:15 Overview of Day 3 K. De Cock

(Co-chair)S. Hill(Co-chair)

09:15–10:00 Paediatrics and IPT S. NachmanM. Cotton

10:00–10:15 Coffee break10:15–11:15 Review of recommendations K. De Cock

(Co-chair)11:15–12:00 Research priorities:

Report back from each group of research issues that emerged from working group discussions

Group A (5’)Group B (5’)Group C (5’)

K. De Cock (Co-chair)S. Hill (Co-chair)

12:00–12:15 Wrap-up of major conclusions, recommendations R. GranichH. Getahun

12:15–12:30 Closing and Next steps T. GuermaM. Raviglione

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15:45–17:00 Working group session (contd)Group A/PICOT 4+5Group B/PICOT 6+7Group C/PICOT 8

17:00–18:30 Report back from Groups A, B, C:Group A/PICOT 4 +5 (20’) Resistance Group B/PICOT 6+7 (20’) TSTGroup C/PICOT 8 (20’) Signs, symptoms/diagnostics

K. De Cock(Co-chair)S. Hill(Co-chair)

Consultation for the Revision of the WHO/UNAIDS Policy Statement on Preventive Therapy againstTB for People Living with HIV

16 November–11 December 2009

Annex 4: Report on the consultation for the revision of the

WHO/UNAIDS policy statement on preventive therapy against TB for people living with HIV



Global Network of People Living with HIV

December 2009

Contents

ContentsAcknowledgments

Executive Summary

Introduction

Methodology

Results and findings

Survey

Introduction

Design

Implementation


Conclusions and Recommendations

Annexes

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Acknowledgements

Executive summary

The Global Network of People living with HIV (GNP+) would like to thank and acknowledge the following people for their assistance in

and contributions to making this e-consultation a success: Rose Bradbury; Georgina Caswell; Chris Mallouris; Thomas Paterson; all of the people

living with HIV who donated their time and made valuable contributions to this consultation; and the World Health Organization (WHO) for its support.The e-consultation and report was coordinated and written by Jason Farrell, CEO, Harm Reduction Consulting Services, Inc.

This report represents the key findings and recommendations that emerged during an online e-consultation to revise the WHO/UNAIDS policy

statement on preventive therapy against TB for people living with HIV. GNP+ organized an e-consultation (three weeks) as well as an online survey to solicit comments and recommendations from people living with HIV on the WHO/UNAIDS policy statement.

The online e-consultation organized by GNP+ and hosted by NAM was held between 16 November and 6 December 2009. The GNP+ e-consultations were designed to gather the perspectives and recommendations from people living with HIV.Each week, the consultation focused on a different topic with several questions that covered various aspects of the guidelines:• Week 1: (16–22 November) Treatment initiation

and adherence• Week 2: (23–29 November) Access to treatment

for people living with HIV• Week 3: (30 November–6 December) Resolving

barriers and building support for expanded treatment

GNP+ invited 306 advocates among people living with HIV to participate in the consultation via e-mail. Approximately 53 registered, representing 52 countries. Of those who registered, four were male, 30 female and 19 others chose not to identify their gender.Based on the numerous responses we received, a few critical key points stood out. What was strongly agreed to by a significant number of PLHIV advocates was that WHO’s overall goal should be to eliminate TB infection worldwide; deal more efficiently with poor outcomes of treatment; and make all efforts to provide TB diagnosis and treatment as early as possible.

More importantly, we found that responses to our consultation reflected many of the prerequisites for

preventive therapy as indicated in the 1998 Policy statement on preventive therapy against TB for people living with HIV.

As suggested in 1998, today we find that the provision of co-located and integrated TB/HIV care should be made available where and when possible, and there should be an appropriate number of skilled and efficient medical providers knowledgeable in current diagnostics, treatment and care.

Many of the GNP+ contributors felt that the quality of care tends to vary between doctors, nurses and counsellors. It was suggested that all medical providers working with people living with HIV should have a standardized level of current knowledge on TB prevention and treatment.

In addition to the e-consultation, GNP+ also developed a survey to capture information on how being diagnosed with TB, participating in medical treatment and maintaining TB treatment impacts the daily living situation of someone with TB. The survey was designed to provide us with a better understanding of the quality of care being provided and how the relationship between the medical provider and patient can impact treatment outcomes.

The GNP+ survey was posted during the last week of the e-consultation (30 November–7 December 2009) using the survey monkey program. Forty HIV-positive advocates filled out the survey. The findings showed that having a supportive relationship with the medical provider as well as with a family member, friend or spouse is critical to successful TB treatment including treatment adherence. Many of those who participated in the survey reported being HIV-positive for an average of 10–15 years and were in a good medical condition, indicating that they had undetectable viral loads and did not have significant side-effects from medications for TB prevention and/or treatment.

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Annex 4. Report on the consultation for the revision of the WHO/UNAIDS policy statement on preventive therapy against TB for people living with HIV

Annex 4

Introduction

Methodology


The online e-consultation organized by GNP+ and hosted by NAM was conducted from 16 November to 6 December 2009. GNP+

e-consultations were designed to gather perspectives and recommendations from people living with HIV.

Each week, the e-consultation focused on a different topic, with several questions that covered various aspects of the guidelines:

• Week 1: (16–22 November) Treatment initiation and adherence

• Week 2: (23–29 November) Access to treatment for people living with HIV

• Week 3: (30 November–6 December) Resolving barriers and building support for expanded treatment

GNP+ invited 306 HIV-positive advocates to participate in the consultation via e-mail. Approximately 53 registered, representing 52 countries. Of those who registered, four were male, 30 female and 19 others chose not to identify their gender.

Building on the experience of undertaking e-consultations, GNP+ employed a user-friendly, accessible and interactive web-

based tool to gain the views and experiences of people living with HIV globally on TB. The GNP+ e-consultation included a range of questions and issues requested by WHO. All questions were open-ended and aimed at gathering qualitative information on the experiences and perspectives of people living with HIV.

During a three-week period, a series of questions were made available to HIV-positive advocates through the use of a password and user name for an online access system. Each week, a different set of questions was posted to obtain responses from those who had registered. To ensure timely responses to questions and concerns regarding the consultation, GNP+ engaged a consultant to moderate the site and discussions, and respond to any problem or question pertaining to TB policy and the consultation process.

While responding to each week’s questions, participants shared similar opinions and/or beliefs as to what constitutes acceptable and

appropriate treatment. Keeping in mind that all those who responded came from different geographical locations/regions and varied types of settings and/or delivery systems for medical care, it is the quality and provision of care that is a cause for concern among many of the participants. In addition to the quality and provision of care, stigma due to their having TB and lack of acceptance by others remain barriers for many who are interested in seeking screening diagnosis, treatment and maintaining ongoing medical care.

Not only were concerns regarding the quality of care and stigma consistently noted among our participants, but it was also strongly suggested that TB screening be co-located within HIV testing sites. Combination treatment should be client-centred, and tailored to the patient’s specific needs such as living conditions as well as the potential adverse effects of combining

TB medications with other prescribed medications and/or any illicit drugs taken.

One of our participants reported that “I would prefer to receive treatment at a hospital as this creates the way to incorporate other services while being treated and this would also prevent some amount of stigma and discrimination... in my country, this exists a lot so the hospital setting would be perfect for me.” As stigma can deter many from accessing care even in facilities with integrated care systems, anonymity of service provision needs to be taken into consideration. Therefore, medical centres or facilities need to be inconspicuous and not identifiable as HIV or TB clinics.

As stigma was mentioned throughout the consultation, we want to draw attention to the provision of comprehensive care. When we asked what are the most essential outcomes sought from TB preventive therapy, not only did we receive many responses

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that TB should be eradicated worldwide, but we also received a number of responses identifying the need to assess and treat mental health conditions. “I know many people living with HIV in my country and other countries in the xxx region who have suffered from TB, and have been treated very badly by the health-care providers and some of them died after few days. I think, as people living with HIV, when they got TB, they faced a double stigma from their surroundings which forced them into a depressive period and really affected their status.”

Therefore, as we focus on the provision of comprehensive care and treatment adherence, there

is clearly an identified need for attention to be devoted to mental health support and establishing social support systems for patients. Without appropriate support systems, recently diagnosed individuals and patients currently engaged in preventive therapy are at high risk for developing depression and terminating treatment and/or making any contact with medical providers as well as family and friends. This is especially the case when treating adolescents. As reported in our consultation, adolescents are subjected to peer pressure and stigma. These as well as economic status can adversely affect treatment or outcomes of preventive therapy.

Survey

In addition to the e-consultation, GNP+ developed a survey to capture information on how being diagnosed with TB – participating in preventive

therapy, continuing with ongoing medical treatment and treatment adherence – impacts the daily living situation of people living with HIV. Additionally, the goal of our survey was to gain a better understanding of the provision of care, specifically the quality of care, and how the relationship between the patient and medical provider impacts treatment outcomes.

Our survey was posted during the last week of the e-consultation (30 November–7 December 2009)

using the survey monkey program. Forty HIV-positive advocates joined us in filling out the survey questionnaires. Based on the survey findings, having a supportive relationship with the medical provider as well as with a family member, friend or spouse is critical to successful TB treatment, including treatment adherence. Many of those who participated in the survey reported being HIV-positive for an average of 10–15 years, and were in a good medical condition, indicating that they had undetectable viral loads and did not have significant side-effects from TB prevention and/or treatment medications.

The concept of conducting a survey was based on the desire to gain a better understanding of how TB affects or impacts the lifestyle of

people living with HIV. The e-consultation questions were primarily based on WHO interests, focused more on clinical issues such as preventive therapy and treatment adherence. Therefore, we felt that offering an alternative, less clinical approach would be successful in garnering a broad range of pertinent viewpoints and opinions from the community of people living with HIV.

Many of the questions included in the survey were designed to elicit information on how the doctor–patient relationship can effect treatment; what support systems are needed or are beneficial for maintaining treatment adherence, and who becomes the primary source of support for and information on TB.

The survey consisted of five sections: demographic information; risk information; medical provider information; TB treatment and care information; and social support information.

Introduction

Design


15

Annex 4

The survey prepared by GNP+ was made available during the last week of our e-consultation (30 November–7 December).

HIV-positive advocates were invited to participate in the survey by using the same password and user

name provided for the e-consultation questions. The survey was conducted by using the survey monkey program to rank the critical outcomes that people living with HIV seek from TB preventive therapy.

Our survey provided interesting results. Basic demographic information of the survey respondents showed that:

• Those taking part in the survey were mostly from Africa, Asia, Europe and Eastern Europe. Of them, 54% were male and 46% female.

• Many reported being HIV-positive for 10–15 years and were predominately between 40 and 50 years of age.

• Of those who completed the survey, 54% indentified as being men who have sex with men (MSM), 29% as drug users and 17% had a history of incarceration.

• Individuals who reported drug use did not mention if they had notified their medical provider about this due to fear of the treatment being terminated or a change in the relationship between them.

• Regarding the quality of medical care, 54% of survey participants reported receiving medical care regularly on a monthly basis and were happy with their medical provider.

• Surprisingly, 55% reported having a mutually respectful relationship with their medical provider and, of those individuals, eighty-five per cent took HIV medications and had undetectable viral loads.

• Fifty per cent of survey respondents said that the relationship with the medical provider was helpful for treatment adherence and, because of this relationship, they felt comfortable disclosing when medication doses were missed.

• Of those who reported taking TB medications, none reported any side-effects that required discontinuation or switching of medications.

The survey findings showed that having a respectful and/or good relationship with the medical provider is critical for successful treatment outcomes. Individuals who disclosed taking TB medications also reported having undetectable viral loads and were clinically in a good medical condition. They self-reported that this increased the benefits they

obtained from preventive therapy. Additionally, all survey participants reported having a family member, spouse or friend to provide support, and all were stably housed.

These four elements of having (1) a good relationship with the medical provider, (2) responding well to HIV treatment, (3) having support systems, and (4) stable housing are key factors for successful treatment outcomes.

However, as substantiated by the findings of the survey, it is apparent that the individuals who participated were well connected to medical care and all of them indicated that they had support either from the family, spouse or friends. Because of these key factors, many responded well to HIV treatment and preventive therapy for TB. Further consultations and additional funding are required to obtain information from individuals who are not connected to care and support systems.

The population of people living with HIV which does not have internet access or computers need to be reached. This target group consists of individuals who are at high risk for and vulnerable to resistant strains of TB, poor care, unstable housing and substance use. Therefore, we need to obtain information from the population that we could not connect with.

The information obtained clearly shows that if there is a good relationship with the doctor, and a supportive family environment, people will respond well to any medical treatment. It would thus be worthwhile for WHO consider providing additional funding to conduct specific outreach efforts targeting the unreached community of people living with HIV at risk for TB, and to conduct focus groups designed to obtain the information required to develop appropriate interventions to successfully connect this group with comprehensive preventive therapy.

Implementation


16

GNP+ recommends that future consultations with people living with HIV be designed and implemented such that they draw on the experiences of HIV-positive people at the community level, people who may not have been reached through the GNP+ e-consultation referred to in this document.

Networks of people living with HIV and/or TB-related organizations at country and/or regional level may have to be supported to develop appropriate methodologies to collect, analyse and present the recommendations from people living with HIV at the community level.

We provide WHO with the following recommendations and highlight key issues for further discussion.

The provision of preventive therapy for TB needs to be offered in a safe, “stigma-free” environment that is not identified as a TB/HIV clinic. The anonymity of the patient needs to be taken into consideration at all times.

HIV testing locations must have on-site screening and preventive therapy for TB available. Opportunities for early TB screening must be sought whenever possible.

The quantity of medication provided to each patient should be based solely upon the doctor’s prescription, and the distance from medical provider/clinic. Those who live near a clinic should receive a one-month supply and those who live at a greater distance should receive a three-month supply.

Regional and/or local HIV treatment adherence rates should not be used to determine if TB preventive services should be made available. They should be used to examine why adherence rates are low and this information should be used to improve adherence to TB treatment.

An individual’s state of health should be taken into consideration to determine the best time and health condition to start treatment for better results and fewer problems from side-effects.

Personal perceptions regarding treatment efficacy and its benefits can impact adherence and overall treatment outcomes. Therefore, mental health screening should be conducted to determine if depression and/or personal perception could affect treatment outcome and overall well-being.

In addition to standard testing to determine if the prescribed TB prevention medication is working efficiently, additional testing such as polymerase chain reaction (PCR) HIV viral load tests should be provided to determine if TB has been eradicated entirely from the patient.

Treatment outcomes for adolescents can be affected by peer support/pressure as well as stigma and economic status.

When treating injecting drug users and those who use other drugs, drug interactions need to be discussed and monitored. Bioavailability and safety issues pertaining to interactions between TB medications and illicit drugs were noted as a concern.

The number of pills required for TB prevention and/or treatment can present significant barriers to successful treatment.

Substance use among individuals who have been prescribed TB preventive therapy has not been reported as a barrier to successful treatment. However, each person’s substance use situation can vary and should be assessed based on the individual’s stability.

Conclusions and Recommendations


17

AnnexesAnnex 1: e-Consultation questions

Week 1: Treatment initiation and adherence

1. What do you think are the most essential outcome or outcomes from TB preventive therapy?

2. In your opinion what do you think the best TB preventive treatments would be: isoniazid (INH), rifampicin (RIF), or pyrazinamide (PZA)?

3. How long do you think would be the best number of days/months needed to take it?

4. Are there benefits of shorter treatment time periods versus potential risks of developing drug-resistant TB?

5. Would providing a three-month supply of medication as opposed to a one-month supply each month improve treatment adherence?

6. What are the acceptable and unacceptable uncertainties relating to TB preventive therapy? (e.g. starting too early; not having long-term safety data on drug contraindications with antiretroviral drugs; hepatitis coinfection and liver toxicity)

7. What have been some of your fears and uncertainties about TB drug resistance, both of being (re)infected with resistant TB and developing drug resistance while taking TB preventive therapy?

Week 2: Access to treatment for people living with HIV

1. What issues or problems, if any, do you think affect people living with HIV who may be diagnosed with TB or are taking TB preventive therapy?

2. Should people living with HIV who received TB treatment in the past be given secondary treatment for latent TB infection to prevent reinfection or recurrence of TB?

3. What would be the best time to start considering preventive therapy (isoniazid preventive treatment; IPT)?

4. Should the condition of a person’s immune status be considered as a factor for when to start? (e.g. T4/T8 cell count, HIV viral load)

5. Should preventive therapy (IPT) be started at the same time as ART? What would you see as personal and medical treatment benefits and trade-offs between earlier and later start of IPT?

6. Do you think low adherence rates to TB preventive therapy should be a barrier to implementation of TB prevention programmes among people living with HIV?

7. What is the level and quality of TB-related health care you receive from your HIV-related health-care provider? (e.g. doctors, nurses, counsellors, home-based care providers, community and peer outreach workers, etc.)

8. Where would you prefer to receive TB preventive treatment services? (e.g. home, TB clinic, HIV clinic, general services clinic)

Week 3: Resolving barriers and building support for expanded treatment

1. Do you think people’s perceptions regarding screening for and diagnosis of TB will have any impact regarding interest of people living with HIV in receiving TB screening? (e.g. health-care workers, family, work colleagues, friends, community perceptions, etc.) What are those perceptions? And what is their impact?

2. Do you think people’s perceptions regarding adherence to TB preventive therapy will have any impact on adherence rates among people living with HIV? What are those perceptions? And what impact?

3. What issues or problems, if any, do you think affect children who may be taking TB preventive therapy?

4. What issues or problems, if any, do you think affect adolescents in taking TB preventive therapy?

5. What issues or problems, if any, do you think affect injection drug users and other drug users including those who may use stimulants (yaba, crystal, etc.) in taking TB preventive therapy?

18

6. What can be or have been barriers to you or someone you know to successfully taking TB preventive therapy? (e.g. number of pills, pill burden, important drug interactions, side-effects, need for toxicity monitoring, etc.)

Annex 2: TB patient survey 2009

Recommendations for preventive therapy against tuberculosis for people living with HIV

1. Demographic information:

Gender: O Male O Female O Lesbian

Race: O White O Asian O African O Latin

Country of residence: O Africa O North America O South America

In the past six months where did you live most of the time?O Your house or apartment O Parents’ house or apartment O Relatives’ house or apartment O Someone else’s house or apartment O Hotel, rooming house or shelter O In a “squat” O On the streets O In jail

How would you consider your housing situation?O Permanent O Temporary O Transitional O Homeless

2. Risk information:

What TB risk group do you identify with? Check all that apply.O Drug user O MSM O Prison/jail history O All

Past and current drug use:O Never O Less than six times O Weekly O 2–3 times per week O 3x or more daily O Monthly O 2–3 times per month

In past 30 days what drugs were used?

In past six months what drugs were used?

Do you live in a country that has a high rate of TB and HIV? Please indicate country.

Do you know how you contracted TB?


19

Annexes

3. Medical provider information

When was the last time you received any medical services?

O Past 30 days O 6 months to a year ago O 1–2 years ago O 2+ years ago O Other

Where did your medical visit take place?O Clinic/doctor’s office O Walk-in clinic O Emergency room O Other

How would you rate your last medical visit?O Excellent O Good O Fair O Poor

Do you see a health professional (doctor, nurse, etc.) for regular check-ups?O Yes O No O Don’t know

If no, why don’t you see a health professional for regular check-ups?O They are disrespectful O They assume any/all health problems are due to drug use O They always tell me to get drug treatment O No health insuranceO Don’t know of a doctor O Other

If you use illicit drugs does your doctor know?O Yes O No O Don’t know

If your health professional knows about your drug use has it affected you treatment?O Yes O No

In what way has it affected your treatment?O Provider became hostile O Stopped treatment/referred to other provider O Presumed all symptoms caused by drug use O Always talked about stop using O No difference/no impact on treatment O Other

When did you find out you were HIV-positive?

Where were you tested?O HIV testing site O Doctor’s office/clinic/jail O Other

How many years have you been living with HIV infection?O Less than one year O 1–5 years O 5–10 years O 10–15 years O 15+ years

What is your current viral load?

What is your current T-cell count?

Are you taking any HIV medications?O Yes O No

If taking HIV medication, what medications are you taking?

Has your doctor informed you about new treatments?O Yes O No

Would you recommend your doctor to a friend?O Yes O No

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4. TB treatment and care information

Upon noticing TB-related symptoms how long did you wait until you went to a doctor?O 1 week O 30 days O 2 months O 3–6 monthsO 6–9 months O 9–12 months O 1 year +

During the doctor’s visit did he or she offer any information or explanation about TB diagnosis and treatments? O Yes O No

What type of testing was provided to determine TB infection?O Blood tests O Chest X-ray O Both O Other

How much information did the doctor provide?O As much as I asked for O Just enough O Very little O None

If the doctor did not offer information, where did you find TB treatment information? O Friends O Family O Partner/boyfriend/girlfriend O Husband/wife O Internet O Educational pamphlets O Outreach workers O Other

How was the relationship with your medical provider?O Very good O Good O Acceptable O Not acceptable O Poor

Was your medical provider respectful?O Very respectful O Somewhat respectful O Reasonable O Tolerable O Disrespectful

Did your relationship with medical provider affect treatment adherence?O Yes O No

Were you comfortable telling the medical provider when you missed taking medication?O Yes O No

Did the number of pills required to be taken make it difficult to manage treatment?O Yes O No

What TB medications where you taking? For treatment or prevention? Please list.

Did you develop any side-effects from TB medications? Describe.

Did the side-effects at any time cause you to discontinue or miss treatment?O Yes O No

If side-effects caused missing medication how long was it before you started again?O 1–3 days O 3–7 days O 1–2 weeks O 1 month O 1–2 months

Did you take any drugs aside from those prescribed to help with side-effects?O Yes O No


21

Annexes

If yes, what illicit drugs did you take for relief from side-effects?

Did you ever switch TB medications to reduce side-effects?O Yes O No

If yes, what medication did you stop taking and switch to with less side-effects?

Stopped taking

Switched to

5. Social support information

Did you inform others about your TB diagnosis?O Yes O No

How long after being diagnosed with TB did you feel comfortable telling others?O 1–3 days O 3–7 days O 1–2 weeks O 1 month O 1–2 months

Who were the first people or first person you disclosed your TB infection?O Boyfriend O Girlfriend O Mother O Husband O Wife O All listed Why were these people the first you disclosed?O Trusted them O Would receive support O Offered information O All

How supportive was your family?O Very supportive O Supportive O Somewhat supportive O Barely supportive O Not supportive

Was your husband, wife, boyfriend, girlfriend, best friend or employer supportive?O Yes O No

If not how did they react to your TB diagnosis and treatment period?O Avoided you due to fear of exposure O Stopped talking to youO Embarrassed/ashamed to know you O Disclosed diagnosis without consentO Used different plates and utensils O Cleaned/wiped everything you touchedO Discontinued/ended relationship O Other

Did friends, family, spouse, and/or employer support help with treatment adherence?O Yes O No

How would or does support from friends family, spouse, and/or employer help with treatment adherence? Please describe.

When you meet people, do you feel comfortable disclosing that you have/had TB?O Yes O No

If not, why, did people discriminate or make you uncomfortable?O Yes O No

Did the people who knew you had/have TB treat you differently? If yes, please describe.O Yes O No

22

Please describe. It is important for us to document all discrimination and mistreatment.


23

Annex 5: Summary of findings and quality of evidence evaluation: intensified TB case-finding for adults and adolescents living with HIV

PICOT Question: What is the best combination of symptoms (with or without abnormal chest radiograph findings) that can be used as a screening tool to identify

adults living with HIV who are eligible for treatment of latent TB infection (LTBI) and for diagnostic work-up of active TB?

Population: Adults and adolescents living with HIVIntervention: Combination of signs and symptoms and diagnostic tools that can be used as a screening tool to identify adults and adolescents living with HIV who are eligible for treatment of LTBI and diagnosis of active TB

Comparison: TB prevalence without interventionOutcomes: Negative predictive value, sensitivity, specificity, positive predictive valueTimeline: 1–2 months during work-up for TB

1. Outcomes of interest

Outcomes Relative importance(rank 1 9 most critical)

Comment

Negative predictive value (to identify those eligible for treatment of LTBI)

9 Critical

Sensitivity (to identify patients for further diagnostic work-up)

9 Critical

Specificity 6 ImportantPositive predictive value 6 Important

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Search criteria

2. Literature search strategy and information retrieval

PubMed Search (“Tuberculosis”[Mesh]) AND “HIV”[Mesh]) AND “(Diagnosis”[Mesh]) OR (TB screening, intensified case-finding, active case-finding, HIV, tuberculosis)

Leading researchers in the area were also contacted to provide any unpublished data fulfilling the search criteria.

LimitsClinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial,

multicentre study, adolescent: 13–18 years, adult: 19–44 years, middle-aged: 45–64 years, middle-aged + aged: 45+ years, aged: 65+ years, 80 and over: 80+ years

articles2119

A primary data meta-analysis entitled “Development of a standardized screening rule for tuberculosis in people living with HIV in

resource constrained settings: individual participant data meta-analysis of observational studies” was used to identify the best symptoms to screen a person living with HIV for treatment of LTBI. The meta-analysis was conducted in collaboration with WHO, CDC and principal investigators of 12 studies that met the inclusion criteria [1–12]. The inclusion criteria for the meta-analysis included: systematic collection of sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Studies which looked at the performance of individual or a combination of symptoms with or without chest X-ray as a screening tool were also examined but they were not considered for evidence retrieval as their participants were limited to TB suspects (cough >2 weeks) or only smear-negative TB patients or they did not use culture as the gold standard [13–20].

Twelve studies [1–12] were included in the primary data meta-analysis [20]. In addition to these studies, other studies were found, which examined the role of symptoms, individually or in combination with or

without chest radiology, as a screening tool for TB [14, 15–19]. Of these, two studies [14,15] collected information on signs and symptoms only among TB suspects, defined as patients with cough >2/3 weeks’ duration. Many studies have demonstrated that cough alone is not a sensitive screening tool and would miss a large number of potential TB cases. Hence, these studies would have missed a large number of TB cases even before assessing the utility of other symptoms and would not have allowed proper assessment of the role of symptoms or their combination. Three studies [14, 16, 18] did not use culture as a gold standard for the entire or a part of their study population. One study [18] focused only on smear-negative TB, thus limiting their findings to patients with smear-negative disease only. Findings from one study [13] were presented at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) as a poster and had not yet been published in a peer-reviewed journal at the time the guidelines were developed. The poster did not provide details of the symptoms used other than cough. The findings of the study for combination of symptoms with abnormal findings on chest X-ray were similar to the results of the primary patient meta-analysis.

Annex 5. Summary of findings and quality of evidence: Intensified TB case finding for adults and adolescents living with HIV

25

258

53

21

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By title

Of interest

By abstract

Annex 5

T he primary patient meta-analysis and other studies were examined using GRADE criteria. Although all the studies included in the meta-

analysis were observational; all the studies except two [6,9] met the criteria (population of interest, uncertain diagnosis, consecutive enrolment and comparison with a gold standard), and therefore qualified as being of the highest quality before other factors for determining the final strength of the evidence were considered [21]. The primary patient meta-analysis showed that at a TB prevalence of 5%, which is commonly found in many heavily impacted settings, absence of all of current cough, night sweats, fever and weight loss could identify a subset of people living with HIV who have a very low probability of having TB disease (negative predictive value 0.97 [95% CI: 0.97, 0.98]) and could be considered for treatment of LTBI based on their eligibility. Using this screening tool, more than

half of the patients would screen negative and could be considered for treatment of LTBI. Of these 4375 individuals, 107 (2.4%) TB patients might be wrongly put on treatment for LTBI as the negative predictive value is not 1. This screening rule had a sensitivity of 0.79 (95% CI: 0.58, 0.91) with a specificity of 0.49 (95% CI: 0.29, 0.70). Using the combination of symptoms proposed in a population of people living with HIV with a 5% TB prevalence requires the investigation of 11 extra cases for every TB case detected; a ratio of TB suspects to a TB case identified that is not much different from what national TB control programmes target in the general population. The meta-analysis also showed that the addition of chest radiography with abnormal findings to the combination increased the sensitivity substantially from 0.79 to 0.90; however, the specificity reduced by 11% (from 50% to 39%). There was no significant gain in the negative predictive value.

GRADE profile table 1: TB screening for adults and adolescents: What is the best combination of symptoms with or without radiology that can be used as a screening tool to identify people living with HIV who are eligible for treatment of LTBI and diagnostic work-up for active TB?

Any one of current cough, fever, night sweats, weight loss as the best combination of symptoms for screeningValues and uncertainty around these Number of participants (studies) Quality of evidence ImportanceNegative predictive value 0.97 (95% CI: 0.97, 0.98) 8148 (9 studies) Moderate CriticalSensitivity0.79 (95% CI: 0.75, 0.82) 8148 (9 studies) Moderate CriticalSpecificity0.49 (95% CI: 0.29, 0.70) 8148 (9 studies) Moderate Important

Any one of current cough, fever, night sweats, weight loss and abnormal chest X-ray findings as the best combination of symptoms for screeningValues and uncertainty around these Number of participants (studies) Quality of evidence ImportanceNegative predictive value 0.98 (95% CI: 0.97, 0.99) 2805 (4 studies) Moderate CriticalSensitivity0.90 (95% CI: 0.66, 0.97) 2805 (4 studies) Moderate CriticalSpecificity0.38 (95% CI: 0.12, 0.73) 2805 (4 studies) Moderate Important

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3. Findings and GRADE profile

Adults and adolescents living with HIV who do not have current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered isoniazid preventive therapy (IPT)Population: Adults and adolescents living with HIVIntervention: Symptom screening using a combination of symptoms comprising current cough, fever, night sweats or weight loss as a screening toolFactor Decision Explanation Quality of evidence Moderate The GRADE assessment of the evidence relies on a primary

patient meta-analysis of 12 studies including over 8000 patients. The meta-analysis assessed a combination of different symptoms (with or without abnormal X-ray findings). The four-symptom rule has a negative predictive value of 98% and the probability of disease among those who screen negative is very low.

Benefits or desired effects

Strong (Benefits outweigh risks)

• Identifies people living with HIV eligible for treatment of LTBI (and potential for reduced TB-related morbidity/transmission).

• Identifies people living with HIV not in need of treatment for active TB.

• Identifies people living with HIV not in need of further evaluation with diagnostic tests for active TB disease.

• Increases health-care worker focus on screening. Risks or undesired effects • Some patients with active TB may not be given treatment

for TB.• Some patients with active TB may be given treatment for

LTBI (see discussion on scientific evidence of low risk for developing drug resistance).

Values and preferences • Improved quality of HIV care• Access to treatment for LTBI• Prevention of life-threatening disease and transmission to

family, friends and the larger communityCosts Strong Increased by:

• Additional staff time required for screening• Cost of supplying isoniazid and pyridoxineReduced by:• Limited resources needed for symptom screening among

persons who regularly attend clinical services for HIV• Avoiding costs of additional diagnostic tests including chest

X-ray• Avoiding costs that would have been associated with

treatment of TBFeasibility Moderate Implementation of symptom screening would be feasible as

• Screening tool includes common TB-associated symptoms and health-care workers are familiar with these

• Avoids the need for repeat follow up and/or additional diagnostic tests

But• Would need improved coordination between TB and HIV

programmes• Would need operational aspects of implementing IPT to be

worked out.Overall ranking of recommendation

Strength of recommendationStrong

4. Risk and benefit assessment


27

Adults and adolescents living with HIV who have any one symptom of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases. Population: Adults and adolescents living with HIV Intervention: Symptom screening using a combination of symptoms comprising current cough, fever, night sweats or weight loss as a screening tool Factor Decision Explanation Quality of evidence Moderate The GRADE assessment of the evidence relies on a primary

patient meta-analysis of 12 studies including over 8000 patients. The meta-analysis assessed a combination of different symptoms (with or without abnormal X-ray findings). The four-symptom rule has a negative predictive value of 98% and the probability of disease among those who screen negative is very low.


Conditional

• Early identification of TB suspects followed by treatment of identified TB cases reduces TB-associated morbidity and mortality among people living with HIV.

• Identification and treatment of non-tuberculous pulmonary infections

• Increase in demand for availability of clinical and diagnostic services

• Increased volume and attention to importance of TB may result in improved quality of TB diagnostic services.

Risks or undesired effects • Because about half of all HIV-infected patients in high HIV/TB prevalence settings will have symptoms, there could be a substantial burden on clinical and diagnostic services.

• If total diagnostic capacity is compromised, then increased demand could result in the displacement of patients in greatest need of diagnostics.

• Volume may negatively influence the quality of laboratory diagnostic services, which might lead to missed diagnoses.

• Not all patients with a positive screen will have TB so, for some patients, there will be inconvenience/cost of tests without benefit.

Values and preferences Strong • Patients generally desire an accurate diagnosis of disease and may be willing to undergo diagnostic evaluation or treatment in an effort to prevent morbidity/mortality and transmission.

Costs Conditional Increased by:• Routine screening will require increased staff time.• Additional diagnostic evaluations (staff, reagents, transport,

laboratory capacity) • Increased quality assurance of diagnostic servicesReduced by:• Using a relatively low-cost screen to identify persons in

need for further diagnostic evaluation avoids the costs of using more expensive tests more broadly

Feasibility • An additional burden of diagnostic tests will be placed on already overburdened laboratories.

• It requires an increased need for referral and a better system for tracking of referrals, which is already compromised.

• Diagnostic services for those identified as TB suspects might not be available.

• Quality of diagnostic services needs to be improved.• Although conducting a symptom screen may be more feasible

than some other diagnostic interventions, it still requires time from already overburdened health-care workers.

Overall ranking of recommendation


Annex 5

28

In resource-limited settings where chest radiology is easily available and affordable, chest X-ray should be added to the screening tool to improve the sensitivity of screening for TB among adults and adolescents living with HIV. Population: Adults and adolescents living with HIV Intervention: Screening using a combination of symptoms comprising current cough, fever, night sweats, weight loss or abnormal chest X-ray as a screening tool Factor Decision Explanation Quality of evidence Moderate The GRADE assessment of the evidence relies on a primary

patient meta-analysis of 12 studies including over 8000 patients. The meta-analysis assessed a combination of different symptoms (with or without abnormal X-ray findings). The GRADE assessment of the evidence showed that the addition of abnormal chest radiograph findings to the four symptom-based rule increases the sensitivity from 79% to 91% with a drop in specificity from 50% to 39%.


Conditional

• Increase in the number of patients identified and evaluated as being likely to have TB disease who might have been missed by symptom screening alone

• Early identification of TB suspects among HIV-infected people followed by appropriate treatment of identified TB cases which, in turn, can reduce TB-associated morbidity and mortality among people living with HIV.

• Identification and treatment of non-tuberculous pulmonary infections

Risks or undesired effects • Substantial burden on the radiology technicians and radiologists reading the X-rays

• Issues with reading of X-rays and inter-reader variability• In an effort to identify all patients with TB, screening could

result in the displacement of patients in greatest need of diagnostics if the total diagnostic capacity is limited.

• Not all patients who screen positive will have TB so, for some patients, there will be inconvenience, unnecessary exposure to radiation, and cost of tests without benefit.

Values and preferences • Patients generally desire an accurate diagnosis of disease and may be willing to undergo diagnostic evaluation or treatment in an effort to prevent morbidity/mortality and TB transmission to family, friends and the community.

Costs Weak (very costly) Increased by:• Routine screening will require staff time. • Chest X-ray for every patient will require additional

resources.• Identification of additional persons requiring diagnostic

evaluation will require resources (staff, reagents, transport, laboratory capacity).

Reduced by:• Treatment benefits patients and the society.

Feasibility Conditional • Feasible only if enough financial and human resourcesOverall ranking of recommendation



29

No Yes

FOOTNOTES TO ADULT ALGORITHM* Every adult and adolescent needs to be evaluated for eligibility to receive antiretroviral therapy (ART) and infection control measures should be prioritized to reduce M. tuberculosis transmission in all settings that provide care.Ɨ Chest radiography can be done if available, but it is not required to classify patients into TB and non-TB groups. In high HIV-prevalence settings with a high TB prevalence among people living with HIV, strong consideration must be given to performing additional sensitive investigations.ǂ Contraindications include: active hepatitis (acute or chronic) or regular and heavy alcohol consumption or symptoms of peripheral neuropathy. Past history of TB and current pregnancy should not be contraindications for starting IPT. Although not a requirement for initiating IPT, tuberculin skin testing (TST) may be done as part of eligibility screening in some settings. § Investigations for TB should be done in accordance with existing national guidelines.

Figure 1. Algorithm for TB screening in adults and adolescents living with HIV in HIV-prevalent and resource-constrained settings

Adults and adolescents living with HIV*

Positive screen for TB with any one of the following:Ɨ

Current coughFever

Weight lossNight sweats

Assess for contraindications to IPTǂ

Screen for TB regularly at each encounter with a health worker or visit to a health facility

No

Give IPT Defer IPT

Yes

Investigate for TB and other diseases§

Not TB

Follow up and

consider IPTTreat for TB

Other diagnosis

Give appropriate

treatment and consider IPT

TB

Annex 5

30

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14. Burgess AL et al. Integration of tuberculosis screening at an HIV voluntary counselling and testing centre in Haiti. AIDS, 2001, 15(14):1875–1879.

15. Espinal MA et al. Screening for active tuberculosis in HIV testing centre. Lancet, 1995, 345(8954):890–893.16. Samb B et al. Methods for diagnosing tuberculosis among in-patients in eastern Africa whose sputum smears are

negative. International Journal of Tuberculosis and Lung Disease, 1997, 1(1):25–30.17. Tamhane A et al. Predictors of smear-negative pulmonary tuberculosis in HIV-infected patients, Battambang,

Cambodia. International Journal of Tuberculosis and Lung Disease, 2009, 13(3):347–354.18. Were W et al. A simple screening tool for active tuberculosis in HIV-infected adults receiving antiretroviral treatment

in Uganda. International Journal of Tuberculosis and Lung Disease, 2009, 13(1):47–53.19. Wilson D et al. Diagnosing smear-negative tuberculosis using case definitions and treatment response in HIV-

infected adults. International Journal of Tuberculosis and Lung Disease, 2006, 10(1):31–38.20. Getahun H et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource

constrained settings: individual participant data meta-analysis of observational studies. PLoS Medicine, 2010, 8(1): e1000391. doi:10.1371/journal.pmed.1000391.

21. Schunemann HJ et al. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. British Medical Journal, 2008, 336(7653):1106–1110.


31


PICOT Question: What is the optimal duration of and drug regimen (e.g. INH, rifampicin [RIF], pyrazinamide

[PZA], etc.) for the treatment of LTBI to reduce the risk of developing TB among people living with HIV/AIDS?

Population: Adults and children living with HIVIntervention: IPT (any regimen)Comparison: No IPTOutcomes: Active TB incidence, mortality, progression of HIV disease, adverse effects (AEs), adherence, TB drug resistance, interval to active TB (Atb), interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (6 months’ INH)Comparison: No IPTOutcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (INH+RIF)Comparison: No IPTOutcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (RIF+pyrazinamide [PZA])Comparison: No IPTOutcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (INH+RIF+PZA)Comparison: No IPTOutcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (6 months’ INH)Comparison: IPT (12 months’ INH)Outcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (continuous INH)Comparison: IPT (6 months’ INH)Outcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

6.1 Optimal duration of and drug regimen for the treatment of latent TB infection (LTBI)

Efficacy

Q6.1.1

Q6.1.2

Q.6.1.3

Q6.1.4

Q6.2 Optimal duration (a)

Q6.2 Optimal duration (b)

Population: Adults living with HIVIntervention: IPT (6 months’ INH)Comparison: Any other regimenOutcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Q6.3 Optimal regimen

32

Population: Adults living with HIVIntervention: IPT (6 months’ INH)Comparison: RIF+PZA Outcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (6 months’ INH)Comparison: INH+RIF Outcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: IPT (6 months’ INH)Comparison: INH+RIF+PZAOutcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: INH+RIF Comparison: INH+RIF+PZA Outcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Q6.3.1

Q6.3.2

Q6.3.3

Q6.3.4

Population: Adults living with HIVIntervention: INH+RIF Comparison: RIF+PZA Outcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Population: Adults living with HIVIntervention: INH+RPT Comparison: INH Outcomes: Active TB incidence, mortality, progression of HIV disease, AEs, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Q6.3.5

Q6.3.6

1. Outcomes of interestOutcomes Relative importance

(rank 1 9 most critical)Comment

Active TB incidence (suspected, probable, confirmed) 9 CriticalConfirmed TB 9 CriticalMortality 9 CriticalProgression of HIV disease 8 CriticalAdverse events 8 CriticalAdherence 7 Critical (addressed by Annex 11)TB drug resistance 7 Critical (addressed by Annex 10)Cost-effectiveness 7 Critical (addressed by Annex 12)Interval to active TB 6 Less criticalInterval to death 6 Less critical



33



2.1 Pubmed Search (“Tuberculosis”[Mesh] AND “HIV Infections”[Mesh]) AND “Therapeutics”[Mesh]

LimitsClinical trial, meta-analysis, randomized controlled trial, review, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial, multicentre study,

adolescent: 13–18 years, adult: 19–44 years, middle-aged: 45–64 years, middle-aged + aged: 45+ years, aged: 65+ years, 80 and over: 80+ years

International conferences (CROI [Conference on Retroviruses and Opportunistic Infections], International AIDS Society [IAS], Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], World AIDS conference), excluding published papers: ICAAC 2009 and previous 0IAS conferences 9CROI 2009 and previous 4

1375

219

19

16

30By title

By abstract

Of interest

Annex 6

34

articles

T he WHO Guidelines Group reviewed the evidence on a wide range of regimens and their duration for TB prevention among

people living with HIV, including results from three unpublished trials. The evidence reviewed studies of drug combinations used for prevention including INH, rifampicin, pyrazinamide and rifapentine. A total of seven studies [1–7] compared INH alone with other regimens, and found that regimens which included pyrazinamide, rifampicin and rifapentine were as

efficacious as INH alone, but were associated with higher rates of toxicity (Table 1). The WHO Guidelines Group concluded that INH at a dose of 300 mg/day remains the drug of choice for chemotherapy to prevent TB in adults living with HIV. The WHO Guidelines Group reviewed and graded the evidence on the duration and durability of effect of IPT in people living with HIV. The critical outcome of interest considered was the efficacy of IPT in preventing active TB, relapse, reinfection and toxicity.

T he WHO Guidelines Group considered the existing evidence on the optimal duration of IPT (6, 9, 12 and 36 months). Although nine months

of IPT is supported by evidence and recommended in some guidelines, there are no studies that have directly compared six and nine months of IPT. Therefore, the discussion focused on the choice between a six- versus 12-month duration of IPT, which showed no significant difference in efficacy. This led the Guidelines Group to strongly recommend the six-month duration. The durability of effect of IPT ranges from six months to five years. The Guidelines Group also reviewed unpublished evidence from two studies that suggest increased benefit with a 36-month or longer duration of IPT, particularly in people who are TST positive.[8,9] The Guidelines Group considered at least 36 months’ duration as a surrogate for lifelong treatment and emphasized the potential benefit of this regimen for people living with HIV in settings with a background of high TB prevalence and transmission. Given the preliminary nature of the evidence, feasibility concerns and potential adverse events, the Guidelines Group conditionally recommends 36 months’ duration of IPT for people living with HIV in settings with high TB prevalence and transmission.

The Guidelines Group reviewed available data on the initiation of IPT and immune status, including concomitant use with ART. Six studies were examined [4,9–13] and showed contrasting results regarding the reduction of TB risk by immune status.

Additional protective benefits of concomitant use of IPT with ART were demonstrated in two observational studies from Brazil and South Africa [12,13], other studies from South Africa [4,12,14,15], and a sub-analysis of data from an unpublished randomized clinical trial from Botswana. Based on this evidence and the potential benefit of concomitant use of IPT with ART, the Guidelines Group strongly recommend that IPT be given irrespective of immune status and whether or not the person is on ART. IPT initiation or completion should not delay commencement of ART in eligible people living with HIV. However, the Guidelines Group recognizes the absence of evidence on whether concomitant initiation of IPT with ART or delayed initiation of IPT is better in terms of efficacy and reduction in toxicity.

Pregnant women living with HIV are at risk for TB, which can impact on maternal and perinatal outcomes, ranging from death of the mother and the newborn, to prematurity and low birth weight. The Guidelines Group stressed the importance of screening pregnant women living with HIV for active TB using the standard clinical algorithm for adults and adolescents as listed in Annex 5. The Group concluded that existing evidence and experience in the pre-HIV and HIV era suggest that IPT is safe in pregnant women. Therefore, the Guidelines Group strongly recommends that pregnancy should not exclude women living with HIV from symptom-based screening for TB and receiving IPT.

Table 1: Comparison of the efficacy of different drug regimens

Intervention Comparator RR (95% Cl) Quality of evidenceINH Rifampicin and pyrazinamide 1.03 (0.75–1.4) ModerateINH INH and rifampicin 0.97 (0.52–1.83) ModerateINH INH, rifampicin and pyrazinamide 0.69 (0.23–1.57) LowINH and rifampicin INH, rifampicin and pyrazinamide 0.75 (0.21–1.82) ModerateINH and rifapentine INH 1.05 (0.56–1.97) Moderate


35

The Guidelines Group reviewed the evidence and discussed the use of IPT as secondary prophylaxis for people who have previously been successfully treated for TB. The evidence was analysed using the GRADE process. Evidence from four studies including three randomized controlled trials and one observational study showed the value of providing IPT immediately after successful completion of TB treatment. The WHO Guidelines Group strongly recommends that adults and adolescents living with

HIV who have successfully completed TB treatment should continue to receive INH for six months and should conditionally receive it for 36 months based on the local situation and existing national guidelines. As there was no evidence on the potential role of IPT for a patient who had successfully completed treatment for multidrug-resistant (MDR) or extensively drug-resistant (XDR) TB, the Guidelines Group has not made any recommendation on the use of IPT after successful treatment for MDR or XDR TB.

2. Pubmed Search ((“Child”[Mesh] OR “Child, Preschool”[Mesh]) OR “Infant”[Mesh]) AND “Tuberculosis”[Mesh] AND “HIV Infections”[Mesh] AND “Therapeutics”[Mesh])

LimitsClinical trial, meta-analysis, randomized controlled trial, review, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial, evaluation studies,

multicentre study, Medline, PubMed Central, all infants: birth–23 months, newborn: birth–1 month, infant: 1–23 months, preschool child: 2–5 years, child: 6–12 years

187

54

8By title

articles

3By

abstract

1

Of interest

International conferences (CROI, IAS, ICAAC, World AIDS conference) excluding published papers:ICAAC 2009 and previous 1IAS conferences 2CROI 2009 and previous 1

Annex 6

36

T wo studies [14,16] were considered for the GRADE analysis. One study suggested significant benefits for children receiving INH

for six months, in particular, with regard to significant reductions in mortality. However, findings from a randomized controlled trial [14] conducted in South Africa showed that when HIV-infected infants with no known exposure to a TB source case are identified in the first three to four months of life, given rapid access to ART and carefully monitored for new TB exposure or disease on a monthly basis, there is no benefit from IPT.

Therefore, based on this, the Guidelines Group recommends that all children more than 12 months of age who are living with HIV and who are unlikely to have active TB should receive six months of IPT as part of a comprehensive package of HIV care.

For children less than 12 months of age, only those with a history of contact with a TB case should receive six months of IPT. In contrast to adults and adolescents, there is no evidence to support the use of INH for longer than six months in children. Therefore, the Guidelines Group concludes that until more data are available, INH for children could not be recommended for more than six months. Similarly, there is no evidence on whether repeating a course of IPT is beneficial for children.

INH should be given at a dose of 10 mg/kg of body weight/per day and it is desirable that 25 mg of vitamin B6 be supplied daily with INH. All available data to date suggest that INH is not toxic for children, even in those receiving ART. The following table shows a simplified dosing schedule for INH at a dose of 10 mg/kg/day.

T he Guidelines Group noted that there is no evidence on the use of IPT in children after successful completion of TB treatment.

However, like adults, children living with HIV are exposed to reinfection and recurrence of TB. Therefore, the Group recommends that children who have been successfully treated for TB and are living in settings with high TB transmission should receive IPT for an additional six months. IPT can be started immediately following the last doses of antituberculosis therapy. TB screening should be carried out regardless of a history of TB treatment during each contact of the child with a health-care worker.

The Guidelines Group also concluded that there are no data regarding the efficacy of IPT for children stratified by the degree of immunosuppression. However, the Group noted that there is biological plausibility in extrapolating what is known for adults and adolescents to children. Therefore, it conditionally recommends the combined use of IPT with ART for all children. The Group emphasizes that ART should not be delayed while starting or completing a course of IPT.

Table 2: Dosing schedule for INH in children

Weight range (kg) Number of 100 mg tablets of INH to be administered per dose

Dose given (mg)

<5 ½ tablet 50 5.1–9.9 1 tablet 10010–13.9 1 ½ tablet 15014–19.9 2 tablets 20020–24.9 2 ½ tablets 250>25 3 tablets or one adult tablet 300


37

1 Con

ceal

men

t of a

lloca

tion

was a

dequ

ate

in fiv

e st

udie

s and

unc

lear

in th

e re

mai

ning

seve

n; in

seve

n tri

als b

oth

prov

ider

s and

par

ticip

ants

wer

e bl

inde

d; th

e in

clusio

n of

rand

omize

d pa

rticip

ants

was

ade

quat

e in

all t

he in

clude

d tri

als;

inte

ntio

n-to

-trea

t (IT

T) a

nalys

is ha

s be

en p

erfo

rmed

in 1

0 tri

als;

par

ticip

ants

’ loss

to fo

llow

up ra

nged

from

0 to

31%

. Moh

amm

ed

et a

l. 20

07 w

as n

ot p

ower

ed to

ass

ess

the

effe

ctive

ness

of I

PT.

2 A d

iffere

nt T

ST s

tatu

s wa

s co

nsid

ered

acr

oss

the

stud

ies;

how

ever

, TST

-neg

ative

pat

ient

s we

re c

onsid

ered

onl

y in

set

tings

with

>30

% o

f LTB

I. 3 F

our o

ut o

f nin

e st

udie

s pr

ovid

ed a

n op

posit

e di

rect

ion

of th

e ef

fect

.

Q 1

.1 E

ffica

cy

Q 1

.1.1

AN

Y TB

DR

UG

A. Q

uest

ion:

Sho

uld

prev

entiv

e th

erap

y (a

ny T

B d

rug)

be

used

in p

eopl

e liv

ing

with

HIV

with

any

PPD

sta

tus?

Setti

ngs:

Any

TB/

HIV

pre

vale

nce

Bib

liogr

aphy

: Pap

e et

al.

1993

; Wha

len

et a

l. 19

97; H

awke

n et

al.

1997

; Mw

inga

et a

l. 19

98; F

itzge

rald

et a

l. 20

01; G

ordi

n et

al.

1997

; Moh

amm

ed e

t al.

2007

; R

iver

o et

al.

2003

; Gor

din

et a

l. 20

00; H

asle

y et

al.

1998

; Mar

tinez

et a

l. 20

00; R

iver

o 20

07

3. Findings and GRADE profiles

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

incid

ence

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r acid

-fast

bac

illi [A

FB])

12R

ando

miz

ed tr

ials

Serio

us1

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ss2

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

4R

ando

miz

ed tr

ials

No

serio

us

limita

tions

1N

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

2N

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)9

Ran

dom

ized

tria

lsSe

rious

1Se

rious

3N

o se

rious

in

dire

ctne

ss2

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Adve

rse

drug

reac

tion

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

8R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

Prev

entiv

e th

erap

y (a

ny T

B dr

ug)

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

142/

3728

(3.8

%)

129/

2034

(6.3

%)

2% 50%

RR

0.6

8 (0

.54–

0.85

)20

few

er p

er 1

000

(from

10

few

er to

29

few

er)

M

OD

ERAT

EC

RIT

ICAL

6 fe

wer

per

100

0 (fr

om 3

few

er to

9

few

er)

160

few

er p

er 1

000

(from

75

few

er to

230

fe

wer

)

50/1

547

(3.2

%)

47/1

026

(4.6

%)

2% 40%

RR

0.7

3 (0

.49–

1.08

)12

few

er p

er 1

000

(from

23

few

er to

4

mor

e)H

IGH

CR

ITIC

AL

5 fe

wer

per

100

0 (fr

om 1

0 fe

wer

to 2

m

ore)

108

few

er p

er 1

000

(from

204

few

er to

32

mor

e)

633/

3728

(17%

)42

7/20

34 (2

1%)

2% 50%

RR

0.9

4 (0

.85–

1.05

)13

few

er p

er 1

000

(from

31

few

er to

10

mor

e)

LOW

CR

ITIC

AL

1 fe

wer

per

100

0 (fr

om 3

few

er to

1

mor

e)30

few

er p

er 1

000

(from

75

few

er to

25

mor

e)

41/1

84 (2

2.3%

)43

/272

(15.

8%)

1% 50%

RR

0.8

8 (0

.6–1

.28)

19 fe

wer

per

100

0 (fr

om 6

3 fe

wer

to 4

4 m

ore)

HIG

HC

RIT

ICAL

1 fe

wer

per

100

0 (fr

om 4

few

er to

3

mor

e)60

few

er p

er 1

000

(from

200

few

er to

14

0 m

ore)

140/

3602

(3.9

%)

33/1

923

(1.7

%)

RR

2.5

5 (1

.7–3

.85)

27 m

ore

per 1

000

(from

12

mor

e to

49

mor

e)H

IGH

CR

ITIC

AL

0%0

mor

e pe

r 100

0 (fr

om 0

mor

e to

0

mor

e)

Annex 6

38

B. Q

uest

ion:

Sho

uld

prev

entiv

e th

erap

y (a

ny T

B d

rug)

be

used

in T

ST-p

ositi

ve p

eopl

e liv

ing

with

HIV

?Se

tting

s: D

iffer

ent T

B/H

IV p

reva

lenc

es

Bib

liogr

aphy

: Pap

e et

al.

1993

; Wha

len

et a

l. 19

97; H

awke

n et

al.

1997

; Mw

inga

et a

l. 19

98

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

incid

ence

(pos

sible

, pro

babl

e or

con

firm

ed) (

follo

w up

1–3

yea

rs; c

linica

l exa

min

atio

n, c

hest

X-ra

y, sp

utum

for A

FB)

4R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

Serio

us2

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)4

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

3N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

Prev

entiv

e th

erap

y (a

ny T

B dr

ug)

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

39/1

760

(2.2

%)

46/6

18 (7

.4%

)

2% 50%

RR

0.3

8 (0

.25–

0.57

)46

few

er p

er 1

000

(from

32

few

er to

56

few

er)

HIG

HC

RIT

ICAL

12 fe

wer

per

100

0 (fr

om 9

few

er to

15

few

er)

310

few

er p

er 1

000

(from

215

few

er to

37

5 fe

wer

)

2/10

1 (2

%)

4/60

(6.7

%)

2% 50%

RR

0.3

0 (0

.06–

1.57

)47

few

er p

er 1

000

(from

63

few

er to

38

mor

e)

LOW

CR

ITIC

AL

14 fe

wer

per

100

0 (fr

om 1

9 fe

wer

to 1

1 m

ore)

350

few

er p

er 1

000

(from

470

few

er to

28

5 m

ore)

195/

1760

(11.

1%)

84/6

18 (1

3.6%

)

5% 50%

RR

0.8

0 (0

.63–

1.02

)27

few

er p

er 1

000

(from

50

few

er to

3

mor

e)

M

OD

ERAT

EC

RIT

ICAL

10 fe

wer

per

100

0 (fr

om 1

9 fe

wer

to 1

m

ore)

100

few

er p

er 1

000

(from

185

few

er to

10

mor

e)

6/38

(15.

8%)

11/2

5 (4

4%)

5% 50%

RR

0.3

6 (0

.15–

0.85

)28

2 fe

wer

per

100

0 (fr

om 6

6 fe

wer

to 3

74

few

er)

HIG

HC

RIT

ICAL

32 fe

wer

per

100

0 (fr

om 7

few

er to

43

few

er)

320

few

er p

er 1

000

(from

75

few

er to

425

fe

wer

)

1 Onl

y on

e st

udy

is av

aila

ble

to a

ddre

ss th

is ou

tcom

e.2 S

mal

l sam

ple

size

and

wide

con

fiden

ce in

terv

al3 O

ne o

f the

four

stu

dies

sho

wed

an o

ppos

ite d

irect

ion

of th

e ef

fect

.


39

1 Thr

ee s

tudi

es o

ut o

f eig

ht s

howe

d a

diffe

rent

dire

ctio

n of

the

effe

ct.

2 One

of t

he th

ree

stud

ies

avai

labl

e pr

esen

ted

an o

ppos

ite d

irect

ion

of th

e ef

fect

. 3 T

he d

irect

ion

of e

ffect

was

diffe

rent

acr

oss

the

stud

ies.

4 O

ppos

ite d

irect

ion

of th

e ef

fect

C. Q

uest

ion:

Sho

uld

prev

entiv

e th

erap

y (a

ny T

B d

rug)

be

used

in T

ST-n

egat

ive

peop

le li

ving

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: F

itzge

rald

et a

l. 20

01; G

ordi

n et

al.

1997

; Haw

ken

et a

l. 19

97; M

oham

med

et a

l. 20

07; M

win

ga e

t al.

1998

; Pap

e et

al.

1993

; Riv

ero

et a

l. 20

03; W

hale

n et

al.1

997

– an

ergy

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

incid

ence

(fol

low

up 1

–3 y

ears

; clin

ical p

rese

ntat

ion,

che

st X

-ray,

sput

um fo

r AFB

, res

pons

e to

TB

treat

men

t)8

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)3

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

2N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs)

8R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us3

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

4N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

Prev

entiv

e th

erap

y (a

ny T

B dr

ug)

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

75/1

677

(4.5

%)

60/1

243

(4.8

%)

2% 50%

RR

0.8

9 (0

.64–

1.24

)5

few

er p

er 1

000

(from

17

few

er to

12

mor

e)

M

OD

ERAT

EC

RIT

ICAL

2 fe

wer

per

100

0 (fr

om 7

few

er to

5

mor

e)55

few

er p

er 1

000

(from

180

few

er to

12

0 m

ore)

22/8

53 (2

.6%

)15

/500

(3%

)

2% 40%

RR

0.7

4 (0

.38–

1.45

)8

few

er p

er 1

000

(from

19

few

er to

14

mor

e)

M

OD

ERAT

EC

RIT

ICAL

5 fe

wer

per

100

0 (fr

om 1

2 fe

wer

to 9

m

ore)

104

few

er p

er 1

000

(from

248

few

er to

18

0 m

ore)

387/

1677

(23.

1%)

316/

1243

(25.

4%)

2% 50%

RR

1.0

1 (0

.89–

1.14

)3

mor

e pe

r 100

0 (fr

om 2

8 fe

wer

to 3

6 m

ore)

M

OD

ERAT

EC

RIT

ICAL

0 m

ore

per 1

000

(from

2 fe

wer

to 3

m

ore)

5 m

ore

per 1

000

(from

55

few

er to

70

mor

e)

35/1

46 (2

4%)

32/1

46 (2

1.9%

)

2% 50%

RR

1.1

0 (0

.72–

1.1)

22 m

ore

per 1

000

(from

61

few

er to

22

mor

e)

M

OD

ERAT

EC

RIT

ICAL

2 m

ore

per 1

000

(from

6 fe

wer

to 2

m

ore)

50 m

ore

per 1

000

(from

140

few

er to

50

mor

e)

Annex 6

40

1 Opp

osite

dire

ctio

n of

the

effe

ct

D. Q

uest

ion:

Sho

uld

prev

entiv

e th

erap

y (a

ny T

B d

rug)

be

used

in p

eopl

e liv

ing

with

HIV

with

unk

now

n TS

T st

atus

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

win

ga e

t al.

1998

; Haw

ken

et a

l. 19

97

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

incid

ence

(fol

low

up 1

–3 y

ears

; clin

ical p

rese

ntat

ion,

che

st X

-ray,

sput

um fo

r AFB

, res

pons

e to

TB

treat

men

t)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

No

serio

us

indi

rect

ness

Serio

us1

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

Prev

entiv

e th

erap

y (a

ny T

B dr

ug)

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

28/2

91 (9

.6%

)23

/173

(13.

3%)

2% 50%

RR

0.8

1 (0

.49–

1.34

)25

few

er p

er 1

000

(from

68

few

er to

45

mor

e)

LOW

CR

ITIC

AL

4 fe

wer

per

100

0 (fr

om 1

0 fe

wer

to 7

m

ore)

95 fe

wer

per

100

0 (fr

om 2

55 fe

wer

to

170

mor

e)

26/5

93 (4

.4%

)28

/466

(6%

)

2% 40%

RR

0.7

9 (0

.47–

1.32

)13

few

er p

er 1

000

(from

32

few

er to

19

mor

e)H

IGH

CR

ITIC

AL

4 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 6

m

ore)

84 fe

wer

per

100

0 (fr

om 2

12 fe

wer

to

128

mor

e)

51/2

91 (1

7.5%

)37

/173

(21.

4%)

2% 50%

RR

0.8

4 (0

.58–

1.24

)34

few

er p

er 1

000

(from

90

few

er to

51

mor

e)H

IGH

CR

ITIC

AL

3 fe

wer

per

100

0 (fr

om 8

few

er to

5

mor

e)80

few

er p

er 1

000

(from

210

few

er to

12

0 m

ore)


41

1 Thr

ee o

ut o

f eig

ht s

howe

d an

opp

osite

dire

ctio

n of

the

effe

ct.

2 Diffe

rent

dire

ctio

n of

the

effe

ct a

cros

s th

e st

udie

s

Q 1

.1.2

INH

vs

PLA

CEB

OA

. Que

stio

n: S

houl

d IN

H p

roph

ylax

is b

e us

ed in

peo

ple

livin

g w

ith H

IV w

ith a

ny T

ST s

tatu

s?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: P

ape

et a

l. 19

93; W

hale

n et

al.

1997

; Haw

ken

et a

l. 19

97; M

win

ga e

t al.

1998

; Fitz

gera

ld e

t al.

2001

; Gor

din

et a

l. 19

97; R

iver

o et

al.

2003

; Wha

len

et

al.1

997

– an

ergy

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

incid

ence

( pr

obab

le, p

ossib

le, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)8

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

5R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)7

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

2N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

2N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Adve

rse

drug

reac

tion

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

7R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

85/2

152

(3.9

%)

123/

1984

(6.2

%)

2% 50%

RR

0.6

7 (0

.51–

0.87

)20

few

er p

er 1

000

(from

8 fe

wer

to 3

0 fe

wer

)H

IGH

CR

ITIC

AL

7 fe

wer

per

100

0 (fr

om 3

few

er to

10

few

er)

165

few

er p

er 1

000

(from

65

few

er to

245

fe

wer

)

34/1

037

(3.3

%)

47/1

026

(4.6

%)

2% 50%

RR

0.7

2 (0

.47–

1.11

)13

few

er p

er 1

000

(from

24

few

er to

5

mor

e)H

IGH

CR

ITIC

AL

6 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 2

m

ore)

140

few

er p

er 1

000

(from

265

few

er to

55

mor

e)

427/

2152

(19.

8%)

419/

1984

(21.

1%)

5% 50%

RR

0.9

5 (0

.85–

1.06

)11

few

er p

er 1

000

(from

32

few

er to

13

mor

e)

M

OD

ERAT

EC

RIT

ICAL

3 fe

wer

per

100

0 (fr

om 7

few

er to

3

mor

e)25

few

er p

er 1

000

(from

75

few

er to

30

mor

e)

41/1

84 (2

2.3%

)43

/272

(15.

8%)

10%

50%

RR

0.8

8 (0

.6–1

.28)

30 fe

wer

per

100

0 (fr

om 1

01 fe

wer

to 7

0 m

ore)

M

OD

ERAT

EC

RIT

ICAL

12 fe

wer

per

100

0 (fr

om 4

0 fe

wer

to 2

8 m

ore)

60 fe

wer

per

100

0 (fr

om 2

00 fe

wer

to

140

mor

e)

56/2

026

(2.8

%)

33/1

873

(1.8

%)

0% 20%

RR

1.6

6 (1

.09–

2.51

)12

mor

e pe

r 100

0 (fr

om 2

mor

e to

27

mor

e)H

IGH

CR

ITIC

AL

0 m

ore

per 1

000

(from

0 m

ore

to 0

m

ore)

132

mor

e pe

r 100

0 (fr

om 1

8 m

ore

to 3

02

mor

e)

Annex 6

42

1 Onl

y on

e st

udy

was

avai

labl

e to

add

ress

this

outc

ome.

2 Sm

all s

ampl

e siz

e an

d wi

de C

I3 M

wing

a et

al.

repo

rted

an o

ppos

ite d

irect

ion

of th

e ef

fect

.

B. Q

uest

ion:

Sho

uld

INH

pro

phyl

axis

be

used

in T

ST-p

ositi

ve p

eopl

e liv

ing

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: P

ape

et a

l. 19

93; W

hale

n et

al.

1997

; Haw

ken

et a

l. 19

97; M

win

ga e

t al.

1998

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

incid

ence

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)4

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

Serio

us2

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)3

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy3

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

18/6

93 (2

.6%

)46

/618

(7.4

%)

2% 50%

RR

0.3

6 (0

.22–

0.61

)48

few

er p

er 1

000

(from

29

few

er to

58

few

er)

HIG

HC

RIT

ICAL

13 fe

wer

per

100

0 (fr

om 8

few

er to

16

few

er)

320

few

er p

er 1

000

(from

195

few

er to

39

0 fe

wer

)

0/52

(0%

)4/

60 (6

.7%

)

2% 50%

RR

0.1

3 (0

.01–

2.32

)58

few

er p

er 1

000

(from

66

few

er to

88

mor

e)

LOW

CR

ITIC

AL

17 fe

wer

per

100

0 (fr

om 2

0 fe

wer

to 2

6 m

ore)

435

few

er p

er 1

000

(from

495

few

er to

66

0 m

ore)

71/6

93 (1

0.2%

)84

/618

(13.

6%)

2% 50%

RR

0.7

4 (0

.55–

1)35

few

er p

er 1

000

(from

61

few

er to

0

mor

e)H

IGH

CR

ITIC

AL

5 fe

wer

per

100

0 (fr

om 9

few

er to

0

mor

e)13

0 fe

wer

per

100

0 (fr

om 2

25 fe

wer

to

0 m

ore)

6/11

(54.

5%)

38/2

5 (1

52%

)

10%

50%

RR

0.3

6 (0

.15–

0.85

)97

3 fe

wer

per

100

0 (fr

om 2

28 fe

wer

to

1292

few

er)

M

OD

ERAT

EC

RIT

ICAL

64 fe

wer

per

100

0 (fr

om 1

5 fe

wer

to 8

5 fe

wer

)32

0 fe

wer

per

100

0 (fr

om 7

5 fe

wer

to 4

25

few

er)


43

1 Fitz

gera

ld e

t al.

and

Hawk

en e

t al.

show

ed a

n op

posit

e di

rect

ion

of th

e ef

fect

.2 D

iffere

nt d

irect

ion

of th

e ef

fect

acr

oss

the

stud

ies

3 Opp

osite

dire

ctio

n of

the

effe

ct

C. Q

uest

ion:

Sho

uld

INH

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

who

are

TST

-neg

ativ

e?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: F

itzge

rald

et a

l. 20

01; G

ordi

n et

al.

1997

; Haw

ken

et a

l. 19

97; M

win

ga e

t al.

1998

; Pap

e et

al.

1993

; Riv

ero

et a

l. 20

03; W

hale

n et

al.1

997

– an

ergy

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)7

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

3R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us2

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)7

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

3N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

49/1

297

(3.8

%)

54/1

193

(4.5

%)

2% 50%

RR

0.8

6 (0

.59–

1.26

)6

few

er p

er 1

000

(from

19

few

er to

12

mor

e)H

IGH

CR

ITIC

AL

3 fe

wer

per

100

0 (fr

om 8

few

er to

5

mor

e)70

few

er p

er 1

000

(from

205

few

er to

13

0 m

ore)

12/5

21 (2

.3%

)15

/500

(3%

)

2% 50%

RR

0.7

6 (0

.36–

1.61

)7

few

er p

er 1

000

(from

19

few

er to

18

mor

e)

M

OD

ERAT

EC

RIT

ICAL

5 fe

wer

per

100

0 (fr

om 1

3 fe

wer

to 1

2 m

ore)

120

few

er p

er 1

000

(from

320

few

er to

30

5 m

ore)

328/

1297

(25.

3%)

298/

1193

(25%

)

2% 50%

RR

1.0

2 (0

.9–1

.16)

5 m

ore

per 1

000

(from

25

few

er to

40

mor

e)H

IGH

CR

ITIC

AL

0 m

ore

per 1

000

(from

2 fe

wer

to 3

m

ore)

10 m

ore

per 1

000

(from

50

few

er to

80

mor

e)

35/1

46 (2

4%)

32/1

46 (2

1.9%

)

10%

50%

RR

1.1

0 (0

.72–

1.69

)22

mor

e pe

r 100

0 (fr

om 6

1 fe

wer

to 1

51

mor

e)

M

OD

ERAT

EC

RIT

ICAL

10 m

ore

per 1

000

(from

28

few

er to

69

mor

e)50

mor

e pe

r 100

0 (fr

om 1

40 fe

wer

to

345

mor

e)

Annex 6

44

1 Opp

osite

dire

ctio

n of

the

effe

ct

D. Q

uest

ion:

Sho

uld

INH

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

unk

now

n TS

T st

atus

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

win

ga e

t al.

1998

; Haw

ken

et a

l. 19

97

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

18/1

62 (1

1.1%

)23

/173

(13.

3%)

2% 50%

RR

0.8

6 (0

.48–

1.52

)19

few

er p

er 1

000

(from

69

few

er to

69

mor

e)

M

OD

ERAT

EC

RIT

ICAL

3 fe

wer

per

100

0 (fr

om 1

0 fe

wer

to 1

0 m

ore)

70 fe

wer

per

100

0 (fr

om 2

60 fe

wer

to

260

mor

e)

22/4

64 (4

.7%

)28

/466

(6%

)

2% 50%

RR

0.7

9 (0

.46–

1.36

)13

few

er p

er 1

000

(from

32

few

er to

22

mor

e)H

IGH

CR

ITIC

AL

4 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 7

m

ore)

105

few

er p

er 1

000

(from

270

few

er to

18

0 m

ore)

28/1

62 (1

7.3%

)37

/173

(21.

4%)

2% 50%

RR

0.8

1 (0

.52–

1.27

)41

few

er p

er 1

000

(from

103

few

er to

58

mor

e)H

IGH

CR

ITIC

AL

4 fe

wer

per

100

0 (fr

om 1

0 fe

wer

to 5

m

ore)

95 fe

wer

per

100

0 (fr

om 2

40 fe

wer

to

135

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


45

1 Onl

y on

e st

udy

is av

aila

ble

for t

his

outc

ome.

2 Sm

all s

ampl

e siz

e an

d wi

de C

I

Q 1

.1.3

INH

+RIF

vs

PLA

CEB

OA

. Que

stio

n: S

houl

d IN

H+R

IF p

roph

ylax

is b

e us

ed in

peo

ple

livin

g w

ith a

ny T

ST s

tatu

s?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: W

hale

n et

al.

1997

; Riv

ero

et a

l. 20

03

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

Serio

us2

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Adve

rse

drug

reac

tion

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RIF

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

12/6

38 (1

.9%

)25

/541

(4.6

%)

2% 50%

RR

0.4

1 (0

.21–

0.81

)27

few

er p

er 1

000

(from

9 fe

wer

to 3

7 fe

wer

)H

IGH

CR

ITIC

AL

12 fe

wer

per

100

0 (fr

om 4

few

er to

16

few

er)

295

few

er p

er 1

000

(from

95

few

er to

395

fe

wer

)

3/82

(3.7

%)

4/77

(5.2

%)

0% 50%

RR

0.7

0 (0

.16–

3.05

)16

few

er p

er 1

000

(from

44

few

er to

106

m

ore)

LOW

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

mor

e)15

0 fe

wer

per

100

0 (fr

om 4

20 fe

wer

to

1025

mor

e)

61/6

38 (9

.6%

)75

/541

(13.

9%)

10%

50%

RR

0.6

9 (0

.5–0

.95)

43 fe

wer

per

100

0 (fr

om 7

few

er to

69

few

er)

HIG

HC

RIT

ICAL

31 fe

wer

per

100

0 (fr

om 5

few

er to

50

few

er)

155

few

er p

er 1

000

(from

25

few

er to

250

fe

wer

)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

28/6

38 (4

.4%

)1/

541

(0.2

%)

0%

RR

16.

72 (3

.29–

84.8

9)29

mor

e pe

r 100

0 (fr

om 4

mor

e to

155

m

ore)

HIG

HC

RIT

ICAL

0 m

ore

per 1

000

(from

0 m

ore

to 0

m

ore)

Annex 6

46

1 Onl

y on

e st

udy

addr

esse

d th

is ou

tcom

e.2 N

o ex

plan

atio

n wa

s pr

ovid

ed.

B. Q

uest

ion:

Sho

uld

INH

+RIF

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

who

are

TST

-pos

itive

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: W

hale

n et

al.

1997

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

dise

ase

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

0N

o ev

iden

ce

avai

labl

eN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

2N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RIF

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

9/55

6 (1

.6%

)21

/464

(4.5

%)

2% 50%

RR

0.3

6 (0

.17–

0.77

)29

few

er p

er 1

000

(from

10

few

er to

38

few

er)

M

OD

ERAT

EC

RIT

ICAL

13 fe

wer

per

100

0 (fr

om 5

few

er to

17

few

er)

320

few

er p

er 1

000

(from

115

few

er to

41

5 fe

wer

)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

57/5

56 (1

0.3%

)64

/464

(13.

8%)

10%

50%

RR

0.7

4 (0

.53–

1.04

)36

few

er p

er 1

000

(from

65

few

er to

6

mor

e)

M

OD

ERAT

EC

RIT

ICAL

26 fe

wer

per

100

0 (fr

om 4

7 fe

wer

to 4

m

ore)

130

few

er p

er 1

000

(from

235

few

er to

20

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


47

1 Onl

y on

e st

udy

addr

esse

d th

is ou

tcom

e.

2 Sm

all s

ampl

e siz

e an

d wi

de C

I3 N

o ex

plan

atio

n wa

s pr

ovid

ed.

C. Q

uest

ion:

Sho

uld

INH

+RIF

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

who

are

TST

-neg

ativ

e?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: R

iver

o et

al.

2003

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssSe

rious

2N

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

Serio

us2

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

3N

o se

rious

in

dire

ctne

ssSe

rious

2N

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RIF

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

3/82

(3.7

%)

4/77

(5.2

%)

2% 50%

RR

0.7

0 (0

.16–

3.05

)16

few

er p

er 1

000

(from

44

few

er to

106

m

ore)

LOW

CR

ITIC

AL

6 fe

wer

per

100

0 (fr

om 1

7 fe

wer

to 4

1 m

ore)

150

few

er p

er 1

000

(from

420

few

er to

10

25 m

ore)

3/82

(3.7

%)

4/77

(5.2

%)

2% 50%

RR

0.7

0 (0

.16–

3.05

)16

few

er p

er 1

000

(from

44

few

er to

106

m

ore)

LOW

CR

ITIC

AL

6 fe

wer

per

100

0 (fr

om 1

7 fe

wer

to 4

1 m

ore)

150

few

er p

er 1

000

(from

420

few

er to

10

25 m

ore)

4/82

(4.9

%)

11/7

7 (1

4.3%

)

10%

50%

RR

0.3

4 (0

.11–

1.03

)94

few

er p

er 1

000

(from

127

few

er to

4

mor

e)

CR

ITIC

AL

66 fe

wer

per

100

0 (fr

om 8

9 fe

wer

to 3

m

ore)

330

few

er p

er 1

000

(from

445

few

er to

15

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

D. Q

uest

ion:

Sho

uld

INH

+RIF

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

unk

now

n TS

T st

atus

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: N

o st

udie

s av

aila

ble

Annex 6

48

1 Jo

hnso

n et

al.

2001

pro

vided

dat

a on

long

-term

follo

w up

. 2 O

nly

one

stud

y is

avai

labl

e to

ass

ess

this

outc

ome.

3 O

nly

TST-

posit

ive s

ubje

cts

were

con

sider

ed.

4 No

expl

anat

ion

was

prov

ided

.

Q 1

.1.4

INH

+RIF

+PZA

vs

plac

ebo

A. Q

uest

ion:

Sho

uld

INH

+RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

any

TST

sta

tus?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: Wha

len

et a

l. 19

97 Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

1 ; cli

nica

l exa

min

atio

n, c

hest

X-ra

y, sp

utum

for A

FB)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us2

Serio

us3

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us2

Serio

us3

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs1 ;

revie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

2Se

rious

4N

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Adve

rse

drug

reac

tion

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us2

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RIF

+PZA

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

10/4

62 (2

.2%

)21

/464

(4.5

%)

2% 50%

RR

0.4

8 (0

.23–

1)24

few

er p

er 1

000

(from

35

few

er to

0

mor

e)

LOW

CR

ITIC

AL

10 fe

wer

per

100

0 (fr

om 1

5 fe

wer

to 0

m

ore)

260

few

er p

er 1

000

(from

385

few

er to

0

mor

e)

58/4

62 (1

2.6%

)64

/464

(13.

8%)

2% 50%

RR

0.9

1 (0

.65–

1.27

)12

few

er p

er 1

000

(from

48

few

er to

37

mor

e)

LOW

CR

ITIC

AL

2 fe

wer

per

100

0 (fr

om 7

few

er to

5

mor

e)45

few

er p

er 1

000

(from

175

few

er to

13

5 m

ore)

58/4

62 (1

2.6%

)64

/464

(13.

8%)

13.8

%

RR

0.6

9 (0

.5–0

.95)

12 fe

wer

per

100

0 (fr

om 4

8 fe

wer

to 3

7 m

ore)

O

OLO

WC

RIT

ICAL

12 fe

wer

per

100

0 (fr

om 4

8 fe

wer

to 3

7 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

26/4

62 (5

.6%

)1/

464

(0.2

%)

0%

RR 2

6.11

(3.5

6–19

1.63

)54

mor

e pe

r 100

0 (fr

om 6

mor

e to

411

m

ore)

M

OD

ERAT

EC

RIT

ICAL

0 m

ore

per 1

000

(from

0 m

ore

to 0

m

ore)


49

1 Onl

y on

e st

udy

is av

aila

ble

to a

sses

s th

is ou

tcom

e.

B. Q

uest

ion:

Sho

uld

INH

+RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

who

are

TST

-pos

itive

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: W

hale

n et

el.

1997

C. Q

uest

ion:

Sho

uld

INH

+RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

who

are

TST

-neg

ativ

e?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: N

o st

udie

s av

aila

ble

D. Q

uest

ion:

Sho

uld

INH

+RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

unk

now

n TS

T st

atus

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: N

o st

udie

s av

aila

bleQua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RIF

+PZA

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

10/4

62 (2

.2%

)21

/464

(4.5

%)

2% 50%

RR

0.4

8 (0

.23–

1)24

few

er p

er 1

000

(from

35

few

er to

0

mor

e)

M

OD

ERAT

EC

RIT

ICAL

10 fe

wer

per

100

0 (fr

om 1

5 fe

wer

to 0

m

ore)

260

few

er p

er 1

000

(from

385

few

er to

0

mor

e)

58/4

62 (1

2.6%

)64

/464

(13.

8%)

2% 50%

RR

0.9

1 (0

.65–

1.27

)12

few

er p

er 1

000

(from

48

few

er to

37

mor

e)

M

OD

ERAT

EC

RIT

ICAL

2 fe

wer

per

100

0 (fr

om 7

few

er to

5

mor

e)45

few

er p

er 1

000

(from

175

few

er to

13

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

50

1 Opp

osite

dire

ctio

n of

the

effe

ct

Q 1

.1.5

RIF

+PZA

vs

plac

ebo

A. Q

uest

ion:

Sho

uld

RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

any

TST

sta

tus?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: Mw

inga

et a

l. 19

98; R

iver

o et

al.

2003

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Adve

rse

drug

reac

tion

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

RIF

+PZA

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

26/4

28 (6

.1%

)48

/427

(11.

2%)

2% 50%

RR

0.5

4 (0

.34–

0.86

)52

few

er p

er 1

000

(from

16

few

er to

74

few

er)

HIG

HC

RIT

ICAL

9 fe

wer

per

100

0 (fr

om 3

few

er to

13

few

er)

230

few

er p

er 1

000

(from

70

few

er to

330

fe

wer

)

13/4

28 (3

%)

19/4

27 (4

.4%

)

0% 50%

RR

0.6

9 (0

.34–

1.38

)14

few

er p

er 1

000

(from

29

few

er to

17

mor

e)H

IGH

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

mor

e)15

5 fe

wer

per

100

0 (fr

om 3

30 fe

wer

to

190

mor

e)

73/4

28 (1

7.1%

)69

/427

(16.

2%)

10%

50%

RR

1.0

4 (0

.77–

1.41

)6

mor

e pe

r 100

0 (fr

om 3

7 fe

wer

to 6

6 m

ore)

M

OD

ERAT

EC

RIT

ICAL

4 m

ore

per 1

000

(from

23

few

er to

41

mor

e)20

mor

e pe

r 100

0 (fr

om 1

15 fe

wer

to

205

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

27/4

28 (6

.3%

)3/

427

(0.7

%)

0%

RR 7

.84

(2.6

–23.

67)

48 m

ore

per 1

000

(from

11

mor

e to

159

m

ore)

HIG

HC

RIT

ICAL

0 m

ore

per 1

000

(from

0 m

ore

to 0

m

ore)


51

1 Onl

y on

e st

udy

avai

labl

e to

add

ress

this

outc

ome

2 Sm

all s

ampl

e siz

e an

d wi

de C

I

B. Q

uest

ion:

Sho

uld

RIF

+PZA

pro

phyl

axis

be

used

in T

ST-p

ositi

ve p

eopl

e liv

ing

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

win

ga e

t al.

1998 Q

ualit

y as

sess

men

t

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

) 1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

Serio

us2

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssSe

rious

2N

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

RIF

+PZA

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

2/49

(4.1

%)

11/6

0 (1

8.3%

)

2% 50%

RR

0.2

2 (0

.05–

0.96

)14

3 fe

wer

per

100

0 (fr

om 7

few

er to

174

fe

wer

)

M

OD

ERAT

EC

RIT

ICAL

16 fe

wer

per

100

0 (fr

om 1

few

er to

19

few

er)

390

few

er p

er 1

000

(from

20

few

er to

475

fe

wer

)

2/49

(4.1

%)

4/60

(6.7

%)

2% 50%

RR

0.6

1 (0

.12–

3.2)

26 fe

wer

per

100

0 (fr

om 5

9 fe

wer

to 1

47

mor

e)

LOW

CR

ITIC

AL

8 fe

wer

per

100

0 (fr

om 1

8 fe

wer

to 4

4 m

ore)

195

few

er p

er 1

000

(from

440

few

er to

11

00 m

ore)

9/49

(18.

4%)

4/60

(6.7

%)

10%

50%

RR

2.7

6 (0

.9–8

.41)

117

mor

e pe

r 100

0 (fr

om 7

few

er to

494

m

ore)

LOW

CR

ITIC

AL

176

mor

e pe

r 100

0 (fr

om 1

0 fe

wer

to 7

41

mor

e)88

0 m

ore

per 1

000

(from

50

few

er to

37

05 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

52

1 Opp

osite

dire

ctio

n of

the

effe

ct

C. Q

uest

ion:

Sho

uld

RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

who

are

TST

-neg

ativ

e?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

win

ga e

t al.

1998

; Riv

ero

et a

l. 20

03

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

) 2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

RIF

+PZA

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

14/2

50 (5

.6%

)21

/243

(8.6

%)

2% 50%

RR

0.6

4 (0

.34–

1.23

)31

few

er p

er 1

000

(from

57

few

er to

20

mor

e)H

IGH

CR

ITIC

AL

7 fe

wer

per

100

0 (fr

om 1

3 fe

wer

to 5

m

ore)

180

few

er p

er 1

000

(from

330

few

er to

11

5 m

ore)

7/25

0 (2

.8%

)9/

243

(3.7

%)

2% 50%

RR

0.7

6 (0

.28–

2.01

)9

few

er p

er 1

000

(from

27

few

er to

37

mor

e)

M

OD

ERAT

EC

RIT

ICAL

5 fe

wer

per

100

0 (fr

om 1

4 fe

wer

to 2

0 m

ore)

120

few

er p

er 1

000

(from

360

few

er to

50

5 m

ore)

41/2

50 (1

6.4%

)39

/243

(16%

)

10%

50%

RR

1.0

2 (0

.68–

1.52

)3

mor

e pe

r 100

0 (fr

om 5

1 fe

wer

to 8

3 m

ore)

M

OD

ERAT

EC

RIT

ICAL

2 m

ore

per 1

000

(from

32

few

er to

52

mor

e)10

mor

e pe

r 100

0 (fr

om 1

60 fe

wer

to

260

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


53

1 Onl

y on

e st

udy

is av

aila

ble

to a

ddre

ss th

is ou

tcom

e.

D. Q

uest

ion:

Sho

uld

RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

unk

now

n TS

T st

atus

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

win

ga e

t al.

1998 Q

ualit

y as

sess

men

t

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

RIF

+PZA

prop

hyla

xis

Con

trol

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

10/1

29 (7

.8%

)16

/124

(12.

9%)

2% 50%

RR

0.6

0 (0

.28–

1.27

)52

few

er p

er 1

000

(from

93

few

er to

35

mor

e)

M

OD

ERAT

EC

RIT

ICAL

8 fe

wer

per

100

0 (fr

om 1

4 fe

wer

to 5

m

ore)

200

few

er p

er 1

000

(from

360

few

er to

13

5 m

ore)

4/12

9 (3

.1%

)6/

124

(4.8

%)

2% 50%

RR

0.6

4 (0

.19–

2.22

)17

few

er p

er 1

000

(from

39

few

er to

59

mor

e)

M

OD

ERAT

EC

RIT

ICAL

7 fe

wer

per

100

0 (fr

om 1

6 fe

wer

to 2

4 m

ore)

180

few

er p

er 1

000

(from

405

few

er to

61

0 m

ore)

23/1

29 (1

7.8%

)26

/124

(21%

)

10%

50%

RR

0.8

5 (0

.51–

1.41

)31

few

er p

er 1

000

(from

103

few

er to

86

mor

e)

M

OD

ERAT

EC

RIT

ICAL

15 fe

wer

per

100

0 (fr

om 4

9 fe

wer

to 4

1 m

ore)

75 fe

wer

per

100

0 (fr

om 2

45 fe

wer

to

205

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

54

1 Diffe

rent

dire

ctio

n of

the

effe

ct a

cros

s th

e st

udie

s 2 G

ordi

n et

al.

2000

sho

wed

an o

ppos

ite d

irect

ion

of th

e ef

fect

.

Q 1

.2 O

PTIM

AL

REG

IMEN

Q.1

.2.1

INH

vs

RIF

+PZA

A. Q

uest

ion:

Sho

uld

INH

vs

RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

any

TST

sta

tus?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: Gor

din

et a

l. 20

00; H

alse

y et

al.

1998

; Mw

inga

et a

l. 19

98; R

iver

o et

al.

2007

; Riv

ero

et a

l. 20

03

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)4

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

4R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us2

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)4

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy2

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Adve

rse

drug

reac

tions

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

5R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+P

ZApr

ophy

laxi

sR

elat

ive

risk

(95%

CI)

Abso

lute

77/1

705

(4.5

%)

75/1

704

(4.4

%)

2% 50%

RR

1.0

3 (0

.75–

1.4)

1 m

ore

per 1

000

(from

11

few

er to

18

mor

e)

M

OD

ERAT

EC

RIT

ICAL

1 m

ore

per 1

000

(from

5 fe

wer

to 8

m

ore)

15 m

ore

per 1

000

(from

125

few

er to

20

0 m

ore)

43/1

597

(2.7

%)

42/1

599

(2.6

%)

2% 50%

RR

1.0

2 (0

.67–

1.55

)1

mor

e pe

r 100

0 (fr

om 9

few

er to

14

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 m

ore

per 1

000

(from

7 fe

wer

to 1

1 m

ore)

10 m

ore

per 1

000

(from

165

few

er to

27

5 m

ore)

299/

1597

(18.

7%)

283/

1540

(18.

4%)

10%

50%

RR

1.0

3 (0

.89–

1.19

)6

mor

e pe

r 100

0 (fr

om 2

0 fe

wer

to 3

5 m

ore)

HIG

HC

RIT

ICAL

3 m

ore

per 1

000

(from

11

few

er to

19

mor

e)15

mor

e pe

r 100

0 (fr

om 5

5 fe

wer

to 9

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

73/1

705

(4.3

%)

114/

1704

(6.7

%)

0%

RR 0

.63

(0.4

8–0.

84)

25 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 3

5 fe

wer

)H

IGH

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


55

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+P

ZApr

ophy

laxi

sR

elat

ive

risk

(95%

CI)

Abso

lute

77/1

705

(4.5

%)

75/1

704

(4.4

%)

2% 50%

RR

1.0

3 (0

.75–

1.4)

1 m

ore

per 1

000

(from

11

few

er to

18

mor

e)

M

OD

ERAT

EC

RIT

ICAL

1 m

ore

per 1

000

(from

5 fe

wer

to 8

m

ore)

15 m

ore

per 1

000

(from

125

few

er to

20

0 m

ore)

43/1

597

(2.7

%)

42/1

599

(2.6

%)

2% 50%

RR

1.0

2 (0

.67–

1.55

)1

mor

e pe

r 100

0 (fr

om 9

few

er to

14

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 m

ore

per 1

000

(from

7 fe

wer

to 1

1 m

ore)

10 m

ore

per 1

000

(from

165

few

er to

27

5 m

ore)

299/

1597

(18.

7%)

283/

1540

(18.

4%)

10%

50%

RR

1.0

3 (0

.89–

1.19

)6

mor

e pe

r 100

0 (fr

om 2

0 fe

wer

to 3

5 m

ore)

HIG

HC

RIT

ICAL

3 m

ore

per 1

000

(from

11

few

er to

19

mor

e)15

mor

e pe

r 100

0 (fr

om 5

5 fe

wer

to 9

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

73/1

705

(4.3

%)

114/

1704

(6.7

%)

0%

RR 0

.63

(0.4

8–0.

84)

25 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 3

5 fe

wer

)H

IGH

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

1 Diffe

rent

dire

ctio

n of

the

effe

ct a

cros

s th

e st

udie

s

2 One

out

of t

he th

ree

stud

ies

show

ed a

n op

posit

e ef

fect

.

B. Q

uest

ion:

Sho

uld

INH

vs

RIF

+PZA

pro

phyl

axis

be

used

in T

ST-p

ositi

ve p

eopl

e liv

ing

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: G

ordi

n et

al.

2000

; Hal

sey

et a

l. 19

98; M

win

ga e

t al.

1998

; Riv

ero

et a

l. 20

07

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)4

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

3R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us2

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs)

3R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us2

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+P

ZApr

ophy

laxi

sR

elat

ive

risk

(95%

CI)

Abso

lute

51/1

322

(3.9

%)

51/1

325

(3.8

%)

2% 50%

RR

1 (0

.68–

1.47

)0

few

er p

er 1

000

(from

12

few

er to

18

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 6

few

er to

9

mor

e)0

few

er p

er 1

000

(from

160

few

er to

23

5 m

ore)

31/1

214

(2.6

%)

31/1

220

(2.5

%)

2% 50%

RR

1 (0

.62–

1.63

)0

few

er p

er 1

000

(from

10

few

er to

16

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 8

few

er to

13

mor

e)0

few

er p

er 1

000

(from

190

few

er to

31

5 m

ore)

238/

1214

(19.

6%)

219/

1220

(18%

)

10%

50%

RR

1.0

9 (0

.93–

1.29

)16

mor

e pe

r 100

0 (fr

om 1

3 fe

wer

to 5

2 m

ore)

M

OD

ERAT

EC

RIT

ICAL

2 m

ore

per 1

000

(from

1 fe

wer

to 6

m

ore)

45 m

ore

per 1

000

(from

35

few

er to

145

m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

56

C. Q

uest

ion:

Sho

uld

INH

vs

RIF

+PZA

pro

phyl

axis

be

used

in T

ST-n

egat

ive

peop

le li

ving

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

win

ga e

t al.

1998

; Riv

ero

et a

l. 20

03

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+P

ZApr

ophy

laxi

sR

elat

ive

risk

(95%

CI)

Abso

lute

17/2

61 (6

.5%

)14

/250

(5.6

%)

2% 50%

RR

1.1

7 (0

.59–

2.32

)10

mor

e pe

r 100

0 (fr

om 2

3 fe

wer

to 7

4 m

ore)

HIG

HC

RIT

ICAL

3 m

ore

per 1

000

(from

8 fe

wer

to 2

6 m

ore)

85 m

ore

per 1

000

(from

205

few

er to

66

0 m

ore)

9/26

1 (3

.4%

)7/

250

(2.8

%)

2% 50%

RR

1.2

4 (0

.47–

3.28

)7

mor

e pe

r 100

0 (fr

om 1

5 fe

wer

to 6

4 m

ore)

HIG

HC

RIT

ICAL

5 m

ore

per 1

000

(from

11

few

er to

46

mor

e)12

0 m

ore

per 1

000

(from

265

few

er to

11

40 m

ore)

42/2

61 (1

6.1%

)41

/191

(21.

5%)

2% 50%

RR

0.8

0 (0

.54–

1.17

)43

few

er p

er 1

000

(from

99

few

er to

36

mor

e)H

IGH

CR

ITIC

AL

4 fe

wer

per

100

0 (fr

om 9

few

er to

3

mor

e)10

0 fe

wer

per

100

0 (fr

om 2

30 fe

wer

to 8

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


57

1 Onl

y on

e st

udy

is av

aila

ble

to a

sses

s th

is ou

tcom

e.

D. Q

uest

ion:

Sho

uld

INH

vs

RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

unk

now

n TS

T st

atus

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

win

ga e

t al.

1998 Q

ualit

y as

sess

men

t

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

-3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+P

ZApr

ophy

laxi

sR

elat

ive

risk

(95%

CI)

Abso

lute

9/12

2 (7

.4%

)10

/129

(7.8

%)

2% 50%

RR

0.9

5 (0

.4–2

.26)

4 fe

wer

per

100

0 (fr

om 4

7 fe

wer

to 9

8 m

ore)

M

OD

ERAT

EC

RIT

ICAL

1 fe

wer

per

100

0 (fr

om 1

2 fe

wer

to 2

5 m

ore)

25 fe

wer

per

100

0 (fr

om 3

00 fe

wer

to

630

mor

e)

3/12

2 (2

.5%

)4/

129

(3.1

%)

0%

RR

0.7

9 (0

.18–

3.47

)7

few

er p

er 1

000

(from

25

few

er to

77

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

mor

e)

19/1

22 (1

5.6%

)23

/129

(17.

8%)

10%

50%

RR

0.8

7 (0

.5–1

.52)

23 fe

wer

per

100

0 (fr

om 8

9 fe

wer

to 9

3 m

ore)

M

OD

ERAT

EC

RIT

ICAL

13 fe

wer

per

100

0 (fr

om 5

0 fe

wer

to 5

2 m

ore)

65 fe

wer

per

100

0 (fr

om 2

50 fe

wer

to

260

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

58

Q 1

.2.2

INH

vs

INH

+RIF

A. Q

uest

ion:

Sho

uld

INH

vs

RIF

+IN

H p

roph

ylax

is b

e us

ed in

peo

ple

livin

g w

ith H

IV w

ith a

ny T

ST s

tatu

s?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

artin

ez e

t al.

2000

; Riv

ero

et a

l. 20

07; R

iver

o et

al.

2003

; Wha

len

et a

l. 19

97

1 Mar

tinez

et a

l. 20

00 s

howe

d an

opp

osite

dire

ctio

n of

the

effe

ct.

2 One

out

of t

he th

ree

stud

ies

show

ed a

n op

posit

e di

rect

ion

of th

e ef

fect

.3 S

mal

l sam

ple

size

and

wide

CI

4 In

Mar

tinez

et a

l. 20

00 R

R wa

s no

t est

imab

le fo

r lac

k of

eve

nts.

5 Diffe

rent

dire

ctio

n an

d siz

e of

the

effe

ct a

cros

s st

udie

s6 M

artin

ez e

t al.

2000

foun

d an

opp

osite

dire

ctio

n of

the

effe

ct.

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)3

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

3R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us2

No

serio

us

indi

rect

ness

Serio

us3

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)3

Ran

dom

ized

tria

lsSe

rious

4Se

rious

5N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Adve

rse

drug

reac

tions

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

4R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

y6N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+I

NH

prop

hyla

xis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

18/7

91 (2

.3%

)19

/810

(2.3

%)

2% 50%

RR

0.9

7 (0

.52–

1.83

)1

few

er p

er 1

000

(from

11

few

er to

19

mor

e)

M

OD

ERAT

EC

RIT

ICAL

1 fe

wer

per

100

0 (fr

om 1

0 fe

wer

to 1

7 m

ore)

15 fe

wer

per

100

0 (fr

om 2

40 fe

wer

to

415

mor

e)

7/14

7 (4

.8%

)5/

151

(3.3

%)

2% 50%

RR

1.4

9 (0

.49–

4.5)

16 m

ore

per 1

000

(from

17

few

er to

116

m

ore)

LOW

CR

ITIC

AL

10 m

ore

per 1

000

(from

10

few

er to

70

mor

e)24

5 m

ore

per 1

000

(from

255

few

er to

17

50 m

ore)

71/6

83 (1

0.4%

)67

/702

(9.5

%)

10%

50%

RR

1.0

9 (0

.8–1

.5)

9 m

ore

per 1

000

(from

19

few

er to

48

mor

e)

LOW

CR

ITIC

AL

9 m

ore

per 1

000

(from

20

few

er to

50

mor

e)45

mor

e pe

r 100

0 (fr

om 1

00 fe

wer

to

250

mor

e)

31/0

(0%

)40

/0 (0

%)

0%

RR

0.7

9 (0

.5–1

.23)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

HIG

HC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


59

B. Q

uest

ion:

Sho

uld

INH

vs

RIF

+IN

H p

roph

ylax

is b

e us

ed in

TST

-pos

itive

peo

ple

livin

g w

ith H

IV?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: Mar

tinez

et a

l. 20

00; R

iver

o et

al.

2007

; Wha

len

et a

l. 19

97

1 Mar

tinez

et a

l. 20

00 s

how

ed a

n op

posi

te d

irect

ion

of th

e ef

fect

.2 O

nly

one

stud

y is

ava

ilabl

e to

add

ress

this

out

com

e.3 S

mal

l sam

ple

size

and

wid

e C

I4 I

n M

artin

ez e

t al.

2000

the

RR

was

not

est

imab

le.

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)3

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

3R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us2

No

serio

us

indi

rect

ness

Serio

us3

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

4N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+I

NH

prop

hyla

xis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

14/6

65 (2

.1%

)15

/685

(2.2

%)

2% 50%

RR

0.9

7 (0

.52–

1.83

)1

few

er p

er 1

000

(from

12

few

er to

21

mor

e)

M

OD

ERAT

EC

RIT

ICAL

1 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 1

9 m

ore)

15 fe

wer

per

100

0 (fr

om 2

65 fe

wer

to

485

mor

e)

3/21

(14.

3%)

1/26

(3.8

%)

2% 50%

RR

3.7

1 (0

.42–

33.1

5)10

4 m

ore

per 1

000

(from

22

few

er to

12

37 m

ore)

LOW

CR

ITIC

AL

54 m

ore

per 1

000

(from

12

few

er to

643

m

ore)

1355

mor

e pe

r 100

0 (fr

om 2

90 fe

wer

to

1607

5 m

ore)

58/5

57 (1

0.4%

)57

/577

(9.9

%)

10%

50%

RR

1.0

6 (0

.75–

1.49

)6

mor

e pe

r 100

0 (fr

om 2

5 fe

wer

to 4

8 m

ore)

M

OD

ERAT

EC

RIT

ICAL

6 m

ore

per 1

000

(from

25

few

er to

49

mor

e)30

mor

e pe

r 100

0 (fr

om 1

25 fe

wer

to

245

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

60

C. Q

uest

ion:

Sho

uld

INH

vs

RIF

+IN

H p

roph

ylax

is b

e us

ed in

TST

-neg

ativ

e pe

ople

livi

ng w

ith H

IV?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: Mar

tinez

et a

l. 20

00; R

iver

o et

al.

2007

1 Sm

all s

ampl

e si

ze a

nd w

ide

CI

2 Opp

osite

dire

ctio

n of

the

effe

ct

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

Serio

us1

Non

e

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssSe

rious

1N

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

2N

o se

rious

in

dire

ctne

ssSe

rious

1N

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sR

IF+I

NH

prop

hyla

xis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

4/12

6 (3

.2%

)4/

125

(3.2

%)

2% 50%

RR

0.9

9 (0

.25–

3.87

)0

few

er p

er 1

000

(from

24

few

er to

92

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 1

5 fe

wer

to 5

7 m

ore)

5 fe

wer

per

100

0 (fr

om 3

75 fe

wer

to

1435

mor

e)

4/12

6 (3

.2%

)4/

125

(3.2

%)

2% 50%

RR

0.9

9 (0

.25–

3.87

)0

few

er p

er 1

000

(from

24

few

er to

92

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 1

5 fe

wer

to 5

7 m

ore)

5 fe

wer

per

100

0 (fr

om 3

75 fe

wer

to

1435

mor

e)

13/1

26 (1

0.3%

)10

/125

(8%

)

2% 50%

RR

1.2

9 (0

.59–

2.84

)23

mor

e pe

r 100

0 (fr

om 3

3 fe

wer

to 1

47

mor

e)

LOW

CR

ITIC

AL

6 m

ore

per 1

000

(from

8 fe

wer

to 3

7 m

ore)

145

mor

e pe

r 100

0 (fr

om 2

05 fe

wer

to

920

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

D. Q

uest

ion:

Sho

uld

INH

vs

RIF

+IN

H p

roph

ylax

is b

e us

ed in

peo

ple

livin

g w

ith H

IV w

ith u

nkno

wn

TST

stat

us?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: No

stud

ies

avai

labl

e


61

D. Q

uest

ion:

Sho

uld

INH

vs

RIF

+IN

H p

roph

ylax

is b

e us

ed in

peo

ple

livin

g w

ith H

IV w

ith u

nkno

wn

TST

stat

us?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: No

stud

ies

avai

labl

e

Q 1

.2.3

INH

vs

INH

+RIF

+PZA

A. Q

uest

ion:

Sho

uld

INH

vs

INH

+RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

any

TST

sta

tus?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: Wha

len

et a

l. 19

97

1 Onl

y on

e st

udy

asse

ssed

this

outc

ome.

2 Onl

y TS

T-po

sitive

pat

ient

s

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

) 1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1Se

rious

2N

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1Se

rious

2N

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Adve

rse

drug

reac

tions

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sIN

H+R

IF+P

ZApr

ophy

laxi

sR

elat

ive

risk

(95%

CI)

Abso

lute

7/53

6 (1

.3%

)10

/462

(2.2

%)

2% 50%

RR

0.6

0 (0

.23–

1.57

)9

few

er p

er 1

000

(from

17

few

er to

12

mor

e)

LOW

CR

ITIC

AL

8 fe

wer

per

100

0 (fr

om 1

5 fe

wer

to 1

1 m

ore)

200

few

er p

er 1

000

(from

385

few

er to

28

5 m

ore)

58/5

36 (1

0.8%

)58

/462

(12.

6%)

2% 50%

RR

0.8

6 (0

.61–

1.21

)18

few

er p

er 1

000

(from

49

few

er to

26

mor

e)

M

OD

ERAT

EC

RIT

ICAL

3 fe

wer

per

100

0 (fr

om 8

few

er to

4

mor

e)70

few

er p

er 1

000

(from

195

few

er to

10

5 m

ore)

58

/536

(10.

8%)

58/4

62 (1

2.6%

)

10%

50%

RR

0.8

6 (0

.61–

1.21

)18

few

er p

er 1

000

(from

49

few

er to

26

mor

e)

LOW

CR

ITIC

AL

14 fe

wer

per

100

0 (fr

om 3

9 fe

wer

to 2

1 m

ore)

70 fe

wer

per

100

0 (fr

om 1

95 fe

wer

to

105

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

3/53

6 (0

.6%

)26

/462

(5.6

%)

2% 50%

RR

0.1

0 (0

.03–

0.33

)51

few

er p

er 1

000

(from

38

few

er to

55

few

er)

M

OD

ERAT

EC

RIT

ICAL

18 fe

wer

per

100

0 (fr

om 1

3 fe

wer

to 1

9 fe

wer

)45

0 fe

wer

per

100

0 (fr

om 3

35 fe

wer

to

485

few

er)

Annex 6

62

B. Q

uest

ion:

Sho

uld

INH

vs

INH

+RIF

+PZA

pro

phyl

axis

be

used

in T

ST-p

ositi

ve p

eopl

e liv

ing

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: W

hale

n et

al.

1997

1 Onl

y on

e st

udy

asse

ssed

this

outc

ome.

C. Q

uest

ion:

Sho

uld

INH

vs

INH

+RIF

+PZA

pro

phyl

axis

be

used

in T

ST-n

egat

ive

peop

le li

ving

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: N

o st

udie

s av

aila

ble

D. Q

uest

ion:

Sho

uld

INH

vs

INH

+RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

unk

now

n TS

T st

atus

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: N

o st

udie

s av

aila

bleQua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

revie

w of

hos

pita

l rec

ords

) 1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(clin

ical a

nd im

mun

olog

ical c

riter

ia)

0N

o ev

iden

ce

avai

labl

eN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pr

ophy

laxi

sIN

H+R

IF+P

ZApr

ophy

laxi

sR

elat

ive

risk

(95%

CI)

Abso

lute

7/53

6 (1

.3%

)10

/462

(2.2

%)

2% 50%

RR

0.6

0 (0

.23–

1.57

)9

few

er p

er 1

000

(from

17

few

er to

12

mor

e)

M

OD

ERAT

EC

RIT

ICAL

8 fe

wer

per

100

0 (fr

om 1

5 fe

wer

to 1

1 m

ore)

200

few

er p

er 1

000

(from

385

few

er to

28

5 m

ore)

58/5

36 (1

0.8%

)58

/462

(12.

6%)

2% 50%

RR

0.8

6 (0

.61–

1.21

)18

few

er p

er 1

000

(from

49

few

er to

26

mor

e)

M

OD

ERAT

EC

RIT

ICAL

3 fe

wer

per

100

0 (fr

om 8

few

er to

4

mor

e)70

few

er p

er 1

000

(from

195

few

er to

10

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


63

Q 1

.2.4

INH

+RIF

vs

INH

+RIF

+PZA

A. Q

uest

ion:

Sho

uld

INH

+RIF

vs

INH

+RIF

+PZA

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

any

TST

sta

tus?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: Wha

len

et a

l. 19

97

1 Onl

y on

e st

udy

is av

aila

ble

to a

sses

s th

is ou

tcom

e.2 O

nly

TST-

posit

ive p

atie

nts

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1Se

rious

2N

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)0

No

evid

ence

av

aila

ble

Non

e

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1Se

rious

2N

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Adve

rse

drug

reac

tions

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

usN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RIF

prop

hyla

xis

INH

+RIF

+PZA

prop

hyla

xis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

9/55

6 (1

.6%

)10

/462

(2.2

%)

2% 50%

RR

0.7

5 (0

.31–

1.82

)5

few

er p

er 1

000

(from

15

few

er to

18

mor

e)

LOW

CR

ITIC

AL

5 fe

wer

per

100

0 (fr

om 1

4 fe

wer

to 1

6 m

ore)

125

few

er p

er 1

000

(from

345

few

er to

41

0 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

57

/556

(10.

3%)

58/4

62 (1

2.6%

)

10%

50%

RR

0.8

2 (0

.58–

1.15

)23

few

er p

er 1

000

(from

53

few

er to

19

mor

e)

LOW

CR

ITIC

AL

18 fe

wer

per

100

0 (fr

om 4

2 fe

wer

to 1

5 m

ore)

90 fe

wer

per

100

0 (fr

om 2

10 fe

wer

to 7

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

13/5

56 (2

.3%

)26

/462

(5.6

%)

0%

RR

0.4

2 (0

.22–

0.8)

33 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 4

4 fe

wer

)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

64

B. Q

uest

ion:

Sho

uld

INH

+RIF

vs

INH

+RIF

+PZA

pro

phyl

axis

be

used

in T

ST-p

ositi

ve p

eopl

e liv

ing

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: R

iver

o et

al.

2007

1 Onl

y on

e st

udy

is av

aila

ble

to a

sses

s th

is ou

tcom

e.

C. Q

uest

ion:

Sho

uld

INH

+RIF

vs

INH

+RIF

+PZA

pro

phyl

axis

be

used

in T

ST-n

egat

ive

peop

le li

ving

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: W

hale

n et

al.

1997

D. Q

uest

ion:

Sho

uld

INH

+RIF

vs

RIF

+PZA

+IN

H p

roph

ylax

is b

e us

ed in

peo

ple

livin

g w

ith H

IV w

ith u

nkno

wn

TST

stat

us?

Setti

ngs:

Hig

h TB

pre

vale

nce

setti

ngs

(>30

% L

TBI)

Bib

liogr

aphy

: No

stud

ies

avai

labl

eQua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(pos

sible

, pro

babl

e, c

onfir

med

) (fo

llow

up 1

–3 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

0N

o ev

iden

ce

avai

labl

eN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

1–3

yea

rs; c

linica

l and

imm

unol

ogica

l crit

eria

)0

No

evid

ence

av

aila

ble

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RIF

prop

hyla

xis

INH

+RIF

+PZA

prop

hyla

xis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

9/55

6 (1

.6%

)10

/462

(2.2

%)

2% 50%

RR

0.7

5 (0

.31–

1.82

)5

few

er p

er 1

000

(from

15

few

er to

18

mor

e)

M

OD

ERAT

EC

RIT

ICAL

5 fe

wer

per

100

0 (fr

om 1

4 fe

wer

to 1

6 m

ore)

125

few

er p

er 1

000

(from

345

few

er to

41

0 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

57

/556

(10.

3%)

58/4

62 (1

2.6%

)

10%

50%

RR

0.8

2 (0

.58–

1.15

)23

few

er p

er 1

000

(from

53

few

er to

19

mor

e)

M

OD

ERAT

EC

RIT

ICAL

18 fe

wer

per

100

0 (fr

om 4

2 fe

wer

to 1

5 m

ore)

90 fe

wer

per

100

0 (fr

om 2

10 fe

wer

to 7

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


65

Q 1

.2.5

INH

vs

rifap

entin

e (R

PT)+

INH

A. Q

uest

ion:

Sho

uld

INH

+RPT

vs

INH

pro

phyl

axis

be

used

in T

ST-p

ositi

ve p

eopl

e liv

ing

with

HIV

?Se

tting

s: H

igh

TB p

reva

lenc

e se

tting

s (>

30%

LTB

I)B

iblio

grap

hy: M

artin

son

et a

l. 20

09

1 Onl

y on

e tri

al is

ava

ilabl

e to

add

ress

this

outc

ome

and

com

paris

on.

2 Cal

cula

ted

on th

e ba

sis o

f TB

incid

ence

(per

100

per

son-

year

s)

3 Cal

cula

ted

on c

rude

num

bers

4 C

alcu

late

d on

the

basis

of d

eath

incid

ence

(per

100

per

son-

year

s)

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(fol

low

up m

edia

n 3.

91 y

ears

; clin

ical e

xam

inat

ion,

che

st X

-ray,

sput

um fo

r AFB

)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

med

ian

3.91

yea

rs; c

ultu

re-p

rove

n)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Mor

tality

(any

cau

se) (

follo

w up

med

ian

3.91

yea

rs; r

evie

w of

hos

pita

l rec

ords

and

pat

ient

s’ file

s)1

Ran

dom

ized

tria

lN

o se

rious

lim

itatio

nsSe

rious

1N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

(follo

w up

3.9

1 ye

ars)

0N

o ev

iden

ce

avai

labl

eN

one

Adve

rse

drug

reac

tion

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

med

ian

3.91

yea

rs; c

linica

l and

labo

rato

ry m

onito

ring)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

+RPT

prop

hyla

xis

INH

prop

hyla

xis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

24/3

29 (7

.3%

)22

/328

(6.7

%)

2% 50%

RR

1.0

5 (0

.56–

1.97

)23

mor

e pe

r 100

0 (fr

om 3

0 fe

wer

to 6

5 m

ore)

M

OD

ERAT

EC

RIT

ICAL

1 m

ore

per 1

000

(from

9 fe

wer

to 1

9 m

ore)

25 m

ore

per 1

000

(from

220

few

er to

48

5 m

ore)

20/3

29 (6

.1%

)17

/328

(5.2

%)

2% 50%

RR

0.8

5 (0

.45–

1.59

)38

few

er p

er 1

000

(from

29

few

er to

31

mor

e)

M

OD

ERAT

EC

RIT

ICAL

3 fe

wer

per

100

0 (fr

om 1

1 fe

wer

to 1

2 m

ore)

75 fe

wer

per

100

0 (fr

om 2

75 fe

wer

to

295

mor

e)

17/2

50 (6

.8%

)25

/241

(10.

4%)

10%

50%

RR

0.6

6 (0

.33–

1.26

)435

few

er p

er 1

000

(from

70

few

er to

27

mor

e)

M

OD

ERAT

EC

RIT

ICAL

34 fe

wer

per

100

0 (fr

om 6

7 fe

wer

to 2

6 m

ore)

170

few

er p

er 1

000

(from

335

few

er to

13

0 m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

4/24

0 (1

.7%

)4/

208

(1.9

%)

0%

RR

0.8

7 (0

.22–

3.42

)32

few

er p

er 1

000

(from

15

few

er to

47

mor

e)

M

OD

ERAT

EC

RIT

ICAL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

mor

e)

Annex 6

66

Q 1

.3 D

urat

ion

Q1.

3.1

6 m

onth

s IN

H v

s 36

mon

ths

INH

A. Q

uest

ion:

Sho

uld

cont

inuo

us IN

H v

s 6

mon

ths

INH

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

any

TST

sta

tus?

Setti

ngs:

Hig

h TB

/HIV

pre

vale

nce

setti

ngs

Bib

liogr

aphy

: Mar

tinso

n et

al.

2009

; Sam

anda

ri et

al.

2009

1 The

Sow

eto

trial

was

not

a h

ead-

to-h

ead

com

paris

on b

ut a

four

-arm

stu

dy d

esig

ned

to c

ompa

re th

e ef

ficac

y of

diffe

rent

regi

men

s as

wel

l.2 T

he S

owet

o tri

al c

onsid

ered

TST

-pos

itive

patie

nts

while

the

BOTU

SA tr

ial e

nrol

led

thos

e wi

th T

ST+/

- 3 M

ean

CD4

coun

t at b

asel

ine

was

>500

cel

ls/m

m3 i

n th

e So

weto

tria

l and

aro

und

200

cells

/mm

3 in

the

BOTU

SA tr

ial.

4 The

Sow

eto

trial

enr

olle

d pa

tient

s wh

o we

re n

ot e

ligib

le fo

r ART

, whi

le in

the

BOTU

SA tr

ial a

bout

40%

of t

he p

atie

nts

had

star

ted

ART.

5 Sub

-ana

ylsis

on th

is ou

tcom

e is

expe

cted

to b

e pe

rform

ed s

oon.

6 The

diffe

renc

e in

the

size

of th

e ef

fect

is la

rge.

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

( po

ssib

le, p

roba

ble,

con

firm

ed) (

follo

w up

mea

n 36

mon

ths;

clin

ical a

sses

smen

t, ch

est X

-ray,

sput

um fo

r AFB

)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

ns1

No

serio

us

inco

nsis

tenc

ySe

rious

2,3,

4N

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

mea

n 36

mon

ths;

cul

ture

-pro

ven)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

ySe

rious

No

serio

us

impr

ecis

ion

Non

e

Mor

tality

(any

cau

se) (

follo

w up

36

mon

ths;

revie

w of

hos

pita

l rec

ords

and

pat

ient

s’ file

s)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

ns1

No

serio

us

inco

nsis

tenc

ySe

rious

2,3,

4N

o se

rious

im

prec

isio

nN

one

HIV

dise

ase

prog

ress

ion

05N

o ev

iden

ce

avai

labl

eN

one

Adve

rse

drug

reac

tions

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

36

mon

ths;

labo

rato

ry m

onito

ring

and

clini

cal a

sses

smen

t)2

Ran

dom

ized

tria

lsN

o se

rious

lim

itatio

nsSe

rious

6N

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

Con

tinuo

us IN

Hpr

ophy

laxi

s6

mon

ths

INH

prop

hyla

xis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

20/9

97 (2

%)

46/1

150

(4%

)

2% 50%

RR

0.5

0 (0

.29–

0.84

)20

few

er p

er 1

000

(from

6 fe

wer

to 2

8 fe

wer

)

M

OD

ERAT

EC

RIT

ICAL

10 fe

wer

per

100

0 (fr

om 3

few

er to

14

few

er)

250

few

er p

er 1

000

(from

80

few

er to

355

fe

wer

)

14/9

97 (1

.4%

)33

/115

0 (2

.9%

)

2% 50%

RR

0.4

8 (0

.26–

0.9)

15 fe

wer

per

100

0 (fr

om 3

few

er to

21

few

er)

M

OD

ERAT

EC

RIT

ICAL

10 fe

wer

per

100

0 (fr

om 2

few

er to

15

few

er)

260

few

er p

er 1

000

(from

50

few

er to

370

fe

wer

)

15/9

97 (1

.5%

)40

/115

0 (3

.5%

)

10%

50%

RR

0.4

3 (0

.24–

0.78

)20

few

er p

er 1

000

(from

8 fe

wer

to 2

6 fe

wer

)

M

OD

ERAT

EC

RIT

ICAL

57 fe

wer

per

100

0 (fr

om 2

2 fe

wer

to 7

6 fe

wer

)28

5 fe

wer

per

100

0 (fr

om 1

10 fe

wer

to

380

few

er)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

70/9

83 (7

.1%

)12

/846

(1.4

%)

1%

RR

5.0

2 (2

.74–

9.19

8)57

mor

e pe

r 100

0 (fr

om 2

5 m

ore

to 1

16

mor

e)

M

OD

ERAT

EC

RIT

ICAL

40 m

ore

per 1

000

(from

17

mor

e to

82

mor

e)


67

Q 1

.3.2

INH

6 m

onth

s vs

12

mon

ths

A. Q

uest

ion:

Sho

uld

6 m

onth

s of

INH

vs

12 m

onth

s of

INH

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

any

TST

sta

tus?

Setti

ngs:

Hig

h TB

/HIV

pre

vale

nce

setti

ngs

Bib

liogr

aphy

: Pap

e et

al.

1993

; Wha

len

et a

l. 19

97; H

awke

n et

al.

1997

; Mw

inga

et a

l. 19

98; F

itzge

rald

et a

l. 20

01; G

ordi

n et

al.

1997

; Riv

ero

et a

l. 20

03; G

ordi

n et

al.

2000

; Mar

tinez

et a

l. 20

00; H

alse

y et

al.

1998

; Riv

ero

et a

l. 20

07

1 Not

est

imab

le d

ue to

the

lack

of e

vent

s in

the

12 m

onth

s gr

oup

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

( po

ssib

le, p

roba

ble,

con

firm

ed) (

follo

w up

1–3

yea

rs; c

linica

l ass

essm

ent,

ches

t X-ra

y, sp

utum

for A

FB)

8R

ando

miz

ed tr

ials

Very

ser

ious

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssN

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

0N

o ev

iden

ce

avai

labl

eN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

and

pat

ient

s’ file

s)2

Ran

dom

ized

tria

lsVe

ry s

erio

usN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

0N

o ev

iden

ce

avai

labl

eN

one

Adve

rse

drug

reac

tions

lead

ing

to tr

eatm

ent i

nter

rupt

ion

(follo

w up

1–3

yea

rs; l

abor

ator

y m

onito

ring

and

clini

cal a

sses

smen

t)8

Ran

dom

ized

tria

lsVe

ry s

erio

usN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

No

serio

us

impr

ecis

ion

Non

e

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

6 m

onth

s of

INH

pro

phyl

axis

12 m

onth

s of

INH

pro

phyl

axis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

57/1

806

(3.2

%)

10/1

84 (5

.4%

)

2% 50%

RR

0.5

8 (0

.3–1

.12)

23 fe

wer

per

100

0 (fr

om 3

8 fe

wer

to 7

m

ore)

LOW

CR

ITIC

AL

8 fe

wer

per

100

0 (fr

om 1

4 fe

wer

to 2

m

ore)

210

few

er p

er 1

000

(from

350

few

er to

60

mor

e)

0/0

(0%

)0/

0 (0

%)

0% 0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

37

5/18

06 (2

0.8%

)24

/184

(13%

)

10%

50%

RR

1.5

9 (1

.085

–2.3

4)77

mor

e pe

r 100

0 (fr

om 1

1 m

ore

to 1

75

mor

e)

LOW

CR

ITIC

AL

59 m

ore

per 1

000

(from

9 m

ore

to 1

34

mor

e)29

5 m

ore

per 1

000

(from

43

mor

e to

670

m

ore)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

56/1

968

(2.8

%)

0/58

(0%

)

0%

RR

0 (0

to 0

)10

few

er p

er 1

000

(from

0 fe

wer

to 0

fe

wer

)

LOW

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

68

B. Q

uest

ion:

Sho

uld

6 m

onth

s of

INH

vs

12 m

onth

s of

INH

pro

phyl

axis

be

used

in p

eopl

e liv

ing

with

HIV

with

a p

ositi

ve T

ST s

tatu

s?Se

tting

s: H

igh

TB/H

IV p

reva

lenc

e se

tting

s B

iblio

grap

hy: P

ape

et a

l. 19

93; W

hale

n et

al.

1997

; Haw

ken

et a

l. 19

97; M

win

ga e

t al.

1998

1 Ver

y sm

all s

ampl

e siz

e in

the

12 m

onth

s gr

oup

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

( po

ssib

le, p

roba

ble,

con

firm

ed) (

follo

w up

1–3

yea

rs; c

linica

l ass

essm

ent,

ches

t X-ra

y, sp

utum

for A

FB)

4R

ando

miz

ed tr

ials

Very

ser

ious

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssSe

rious

1N

one

Confi

rmed

TB

(follo

w up

1–3

yea

rs; c

ultu

re-p

rove

n)

0N

o ev

iden

ce

avai

labl

eN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

and

pat

ient

s’ file

s)4

Ran

dom

ized

tria

lsVe

ry s

erio

usN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

Serio

us1

Non

e

HIV

dise

ase

prog

ress

ion

0N

o ev

iden

ce

avai

labl

eN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

6 m

onth

s of

INH

pro

phyl

axis

12 m

onth

s of

INH

pro

phyl

axis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

16/6

55 (2

.4%

)2/

38 (5

.3%

)

2% 50%

RR

0.4

6 (0

.11–

1.95

)28

few

er p

er 1

000

(from

47

few

er to

50

mor

e)VE

RY L

OW

CR

ITIC

AL

11 fe

wer

per

100

0 (fr

om 1

8 fe

wer

to 1

9 m

ore)

270

few

er p

er 1

000

(from

445

few

er to

47

5 m

ore)

0/0

(0%

)0/

0 (0

%)

0% 0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

68

/655

(10.

4%)

3/38

(7.9

%)

10%

50%

RR

1.3

1 (0

.43–

3.98

)24

mor

e pe

r 100

0 (fr

om 4

5 fe

wer

to 2

35

mor

e)VE

RY L

OW

CR

ITIC

AL

31 m

ore

per 1

000

(from

57

few

er to

298

m

ore)

155

mor

e pe

r 100

0 (fr

om 2

85 fe

wer

to

1490

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


69

C. Q

uest

ion:

Sho

uld

6 m

onth

s of

INH

vs

12 m

onth

s of

INH

pro

phyl

axis

be

used

in T

ST -n

egat

ive

peop

le li

ving

with

HIV

?Se

tting

s: H

igh

TB/H

IV p

reva

lenc

e se

tting

s B

iblio

grap

hy: W

hale

n et

al.

1997

; Haw

ken

et a

l. 19

97; M

win

ga e

t al.

1998

; Fitz

gera

ld e

t al.

2001

; Gor

din

et a

l. 19

97; R

iver

o et

al.

2003

; Wha

llen

et a

l. 19

97 –

ane

rgy

1 Sam

ple

size

in th

e 12

mon

ths-

grou

p wa

s m

uch

smal

ler t

han

that

in th

e 6

mon

ths

grou

p

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

( po

ssib

le, p

roba

ble,

con

firm

ed) (

follo

w up

1–3

yea

rs; c

linica

l ass

essm

ent,

ches

t X-ra

y, sp

utum

for A

FB)

7R

ando

miz

ed tr

ials

Very

ser

ious

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ssSe

rious

1N

one

Confi

rmed

TB

(cul

ture

-pro

ven)

0N

o ev

iden

ce

avai

labl

eN

one

Mor

tality

(any

cau

se) (

follo

w up

1–3

yea

rs; r

evie

w of

hos

pita

l rec

ords

and

pat

ient

s’ file

s)7

Ran

dom

ized

tria

lsVe

ry s

erio

usN

o se

rious

in

cons

iste

ncy

No

serio

us

indi

rect

ness

Serio

us1

Non

e

HIV

dise

ase

prog

ress

ion

0N

o ev

iden

ce

avai

labl

eN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

6 m

onth

s of

INH

pro

phyl

axis

12 m

onth

s of

INH

pro

phyl

axis

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

41/1

151

(3.6

%)

8/14

6 (5

.5%

)

2% 50%

RR

0.6

5 (0

.31–

1.36

)19

few

er p

er 1

000

(from

38

few

er to

20

mor

e)VE

RY L

OW

CR

ITIC

AL

7 fe

wer

per

100

0 (fr

om 1

4 fe

wer

to 7

m

ore)

175

few

er p

er 1

000

(from

345

few

er to

18

0 m

ore)

0/0

(0%

)0/

0 (0

%)

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

30

7/11

51 (2

6.7%

)24

/146

(16.

4%)

10%

50%

RR

1.6

2 (1

.11–

2.37

)10

2 m

ore

per 1

000

(from

18

mor

e to

225

m

ore)

VERY

LO

WC

RIT

ICAL

62 m

ore

per 1

000

(from

11

mor

e to

137

m

ore)

310

mor

e pe

r 100

0 (fr

om 5

5 m

ore

to 6

85

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

Annex 6

70


Adults and adolescents living with HIV, who have an unknown or positive TST status and are unlikely to have active TB, should receive at least six months of IPT as part of a comprehensive package of HIV care. This includes individuals irrespective of degree of immunosuppression, those on ART, those who have previously been treated for TB and pregnant women.

TST is not a requirement for initiating IPT among people living with HIV. Where feasible, TST can be used as people with a positive test benefit more from IPT than those with a negative test. Population: Adults and adolescents living with HIVIntervention: At least six months of IPT (300 mg plus vitamin B6 25 mg daily)Factor Decision Explanation Quality of evidence High Provision of IPT reduces active TB incidence by:

• 33% regardless of TST status (GRADE high) • 64% in TST-positive persons (GRADE high)• 14% in TST-negative persons (GRADE high)• 14% in those with unknown TST status (GRADE moderate)• IPT has been shown to be equally efficacious but less toxic

than multidrug regimens in preventing active TB disease (GRADE low/moderate)


Strong

• Reduction in TB morbidity• Reduction in TB transmission• Reduction in mortality (even if there is no evidence of a

direct effect in terms of death – GRADE moderate)• Potential reduction in generation of MDR and XDR TB by

reducing TB incidence • Reduction in prevalence of non-INH mono/drug-resistant

strains in the community (e.g. mono-RIF)• Avoidance of side-effects of TB treatment• Reduction in drug–drug interaction in patients on ART and

TB treatment• Improved TB infection control in health-care and community

settings (particularly in HIV clinics)• Fewer side-effects than with a preventive combination

regimen (GRADE high)• Less drug–drug interaction caused by alternative preventive

regimens containing RIF• Potential increase in adherence to other treatment (ART,

co-trimoxazole, etc.)Risks or undesired effects • Longer regimen compared to a combination preventive

regimen• Potential for development of greater resistance compared to

a combination prevention regimen• Increase in number of persons receiving unnecessary

treatment (especially when TST is not performed or in case of false-positive TST where TST is performed)

• Potential INH toxicity• Potential development and transmission of INH-resistant

strains by treating undiagnosed active TB• Potential reduction in adherence to other treatment (ART,

co-trimoxazole, etc.)

71


Values and preferences Strong • Less pill burden than in other preventive combination regimens

• Fewer side-effects than in other preventive combination regimens

• Easier to take treatment • Avoids active TB disease, deaths and transmission to other

family members• Health-care workers would be less exposed to active TB

cases and would feel more protected• Infection control benefits for patients, family and the

community both in terms of preventing TB and also in preventing infection and/or reinfection

• Avoids potential need for long TB treatment with a high pill burden and significant side-effects

Patients would feel protected against TB, adding value to HIV care servicesBUT• Longer regimen • RIF would make it easier to monitor adherence• May be concerns regarding the side-effects of INH • Pill burden• Stigma• Increase in number of people attending clinics • Adds burden to supply chain

Costs Weak Increased by:• Longer provision as compared to other shorter preventive

regimens• Costs of INH (including storage, supply and transportation)• Potential laboratory monitoring (in case of toxicity)• Additional staff time in overburdened HIV care settings • Second-line TB treatment needed in case INH resistance

occurs and is transmitted• Treatment of rare INH-related toxicity (blood tests,

hospitalization, patients’ loss of earning)• Additional costs of providing vitamin B6Decreased by:• Less expensive regimen as compared to other preventive

regimens• Avoids treatment costs of active TB• Less hospitalization costs• Reduction in social costs and loss of earnings• Reduction in costs due to treatment of secondary cases

including in health-care workers, which may improve staff retention

• Reduction in costs related to TB–ART co-treatment which often includes more expensive regimens

• Reduction in drug–drug interaction from TB treatment in patients on ART

• Potential reduction in generation of MDR and XDR TB by reducing the incidence of TB

72

Annex 6

Feasibility Strong • Clear clinical and public health benefit with strong evidence base

• Less monitoring needed as compared to other preventive regimens

• Drug easily available and inexpensive• Administration of IPT fits well with the schedule of HIV

programmes• Does not require laboratory monitoring• Health-care workers are already familiar with the drugBUT• Longer-term intervention when compared to other

preventive regimens• Would mean adding an intervention to an overburdened

system• May increase clinic visits and require more staff time• Space required for storage and difficulties in procurement• INH as a single formulation less commonly available

compared to fixed-dose combination (FDC) TB medicines• Opinion leaders are reluctant to use IPT in the face of

scientific evidence• Requires additional training of health-care workers on

benefits of IPT and TB screening Overall ranking of recommendation

Strong

Adults and adolescents living with HIV who have successfully completed their TB treatment should be provided secondary INH prophylaxis for at least six months (strong recommendation) or at least 36 months (conditional recommendation) Population: People living with HIV who have successfully completed TB treatmentIntervention: Secondary INH prophylaxis Factor Decision Explanation Quality of evidence Moderate • Evidence is available from three randomized trials and one

observational study. One randomized trial compared INH with rifampicin after successful TB treatment.

• Adverse events and mortality were not addressed (critical outcome)

• (moderate grade of evidence for recurrent TB outcome)

Benefits or desired effects Strong • Reduction in incidence of recurrent TB • Reduction in TB transmission• Potential reduction in generation of MDR strains by reducing

TB incidence• Improved TB infection control in health-care settings by

reducing active TB and also preventing new infections or reinfection (particularly in HIV clinics)

Risks or undesired effects • Pill burden• Reduction in compliance with other treatments (ART, co-

trimoxazole, etc.)Values and preferences Weak • Lack of motivation in patients as they have already been

treated for TB• Lack of confidence in efficacy of TB drugs

Costs Strong • Costs are unlikely to increase as it can easily be incorporated into routine care for people living with HIV

• Cost-saving implications through preventing development of recurrent TB

Feasibility Strong • It will be part of routine care for people living with HIVOverall ranking of recommendation

Strength of recommendationStrong (at least 6 months)Conditional (at least 36 months)

73


References

1. Fitzgerald DW et al. No effect of isoniazid prophylaxis for purified protein derivative-negative HIV-infected adults living in a country with endemic tuberculosis: results of a randomized trial. Journal of Acquired Immune Deficiency Syndromes, 2001, 28:305–307.

2. Gordin FM et al. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. Terry Beirn Community Programs for Clinical Research on AIDS. New England Journal of Medicine, 1997, 337:315–320.

3. Hawken MP et al. Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial. AIDS, 1997, 11:875–882.

4. Mwinga A et al. Twice weekly tuberculosis preventive therapy in HIV infection in Zambia. AIDS, 1998, 12:2447–2457.

5. Pape JW et al. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet, 1993, 342:268–272.

6. Rivero A et al. [Randomized trial of three regimens to prevent tuberculosis in HIV-infected patients with anergy]. Enfermedades infecciosas y microbiologia clinica, 2003, 21:287–292.

7. Whalen CC et al. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. Uganda–Case Western Reserve University Research Collaboration. New England Journal of Medicine, 1997, 337:801–808.

8. Martinson N et al. Novel regimens for treating latent TB in HIV-infected patient adults in South Africa: a randomized clinical trial. In: Proceedings of the 16th Annual Conference on Retroviruses and Opportunistic Infections, Montreal, Canada, 8–11 February 2009.

9. Samandari T et al. Preliminary results of the Botswana Isoniazid Preventive Therapy (IPT) Clinical Trial (6 months vs 36 months). Union World Lung Conference, Cancun, on behalf of BOTUSA IPT Study; 2009.

10. Akolo C et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of Systematic Reviews, 2010, (1):CD000171.

11. Churchyard GJ et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy? AIDS, 2003, 17:2063–2070.

12. Golub JE et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS, 2009, 23:631–636.

13. Golub JE S et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2007, 21:1441–1448.

14. Madhi SA et al. Lack of efficacy of primary isoniazid (INH) prophylaxis in increasing tuberculosis (TB) free survival in HIV-infected (HIV+) South African children. 48th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, 25–28 October 2008.

15. Martinez Alfaro EM et al. [Evaluation of 2 tuberculosis chemoprophylaxis regimens in patients infected with human immunodeficiency virus. The GECMEI Group]. Medicina clinica (Barc), 2000, 115:161–165.

16. Zar HJ t al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomized controlled trial. British Medical Journal, 2007, 334:136.

17. Mohammed A et al. Randomised controlled trial of isoniazid preventive therapy in South African adults with advanced HIV disease. International Journal of Tuberculosis and Lung Disease, 2007, 11:1114–1120.

18. Johnson JL et al.; for the Uganda–Case Western Reserve University Research Collaboration. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS, 2001, 15:2137–2147.

19. Gordin F et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-Infected persons. An international randomized trial. Journal of the American Medical Association, 2000, 283:1445–1450.

20. Halsey NA et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet, 1998, 351:786–792.

21. Rivero A et al. A randomized clinical trial investigating three chemoprophylaxis regimens for latent tuberculosis infection in HIV-infected patients. Enfermedades infecciosas y microbiologia clinica, 2007, 25:305–310.

74

Annex 6

6.2. Timing of initiation: Define the optimal time to start considering IPT (i.e. should immune status be considered and should IPT be started with ART?).

PICOT Question: What is the optimal time to start considering IPT (i.e. should immune status

be considered and should IPT be started with ART)?

Population: People living with HIVIntervention: Starting IPT if immune suppression not severe (CD4 count >200 cells/mm3)Comparison: Starting IPT if immune suppression severe (CD4 count <200 cells/mm3)Outcomes: Active TB incidence, mortality, AEs, progression of HIV disease, adherence, TB drug resistance, interval to active TB (Atb), interval to deathTimeline: Lifetime

Population: People living with HIVIntervention: Starting IPT and ART at the same timeComparison: Starting ART first followed by IPT Outcomes: Active TB incidence, mortality, AEs, progression of HIV disease, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

6.2.1 Immune status Q6.2.2 (b) ART

Population: People living with HIVIntervention: Starting IPT and ART at the same timeComparison: Starting IPT first followed by ART Outcomes: Active TB incidence, mortality, AEs, progression of HIV disease, adherence, TB drug resistance, interval to Atb, interval to deathTimeline: Lifetime

Q6.2.2 (a) ART


Active TB incidence (suspected, probable, confirmed) 9 CriticalConfirmed TB 9 CriticalMortality 9 CriticalProgression of HIV disease 8 CriticalAdverse events 8 CriticalAdherence 7 Critical (addressed by Annex 11)TB drug resistance 7 Critical (addressed by Annex 10)Cost-effectiveness 7 Critical (addressed by Annex 12)Interval to active TB 6 Less criticalInterval to death 6 Less critical

75


2. Literature search and information retrieval

1. Pubmed Search (“Tuberculosis”[Mesh] AND “HIV Infections”[Mesh]) AND “Therapeutics”[Mesh]

LimitsClinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical

trial, multicentre study, adolescent: 13–18 years, adult: 19–44 years, middle-aged: 45–64 years, middle-aged + aged: 45+ years, aged: 65+ years, 80 and over: 80+ years

1375

219

30By title

articles

19By

abstract

4Of

interest

Evidence retrieval findingsThe Guidelines Group reviewed the available data regarding the initiation of IPT and immune status, including concomitant use with ART. Six studies [1–6] were examined and showed contrasting results on the reduction of TB risk by immune status. Additional protective benefits of concomitant use of IPT with ART were demonstrated in two [3,4] observational studies from Brazil and South Africa, and a sub-analysis of data from an unpublished randomized clinical trial from Botswana. Based on this evidence and the potential benefit of concomitant use of IPT with ART, the Guidelines Group strongly recommends that IPT be given irrespective of immune status and whether or not the person is on ART. IPT initiation or completion

should not delay commencement of ART in eligible people living with HIV. However, the Guidelines Group recognizes the absence of evidence as to whether concomitant initiation of IPT with ART or delayed initiation of IPT is better in terms of efficacy and toxicity.

A large, randomized controlled study (TEMPRANO study) is currently ongoing in Ivory Coast and will provide data on patients randomized to IPT before ART versus simultaneous initiation of IPT and ART. However, relevant studies providing stratifications/sub-analysis or some kind of guidance in terms of optimal time of initiation have been selected as follows:

76

Annex 6

STUDIES BRIEF DESCRIPTION OF RELEVANT FINDINGSMwinga et al. 1998 [5] Protection against TB was limited to those with total lymphocyte count of 2x109/l or

higherRRs for TB stratified by TST and lymphocyte count are most marked in those with a lymphocyte count of 2x109/l or more, and TST reading of 5 mm or more. The rate of TB was 6/56 = 10.71 per 100 person-years in the placebo group and 2/95 = 2.10 per 100 person-years in the INH and RIF+PZA groups combined (RR = 0.19, 95%CI: 0.04–0.94, P = 0.026)

Churchyard et al. 2003 [2]

No significant difference in the efficacy of IPT by CD4 stratum (above or below 200 cells/mm3) though absolute TB recurrence rates were substantially higher in the group with CD4 count <200 cells/mm3 as one would expect.

Golub et al. 2007 [4]Brazil

The subjects included 11 026 HIV-infected patients receiving medical care at 29 public clinics in Rio de Janeiro, Brazil, between 1 September 2003 and 1 September 2005 Data were collected through a retrospective medical records review.The combination of IPT and ART was associated with significant reduction in incidence of TB for patients with both advanced and early HIV disease. In the population of patients with advanced HIV disease (CD4 cell count <350 cells/mm3), over a period of two years, ART alone was associated with a significantly reduced incidence of TB, whereas IPT alone was not.In patients with a CD4 cell count >350 cells/mm3 at baseline, ART significantly reduced the risk of TB, IPT reduced the risk but not at a statistically significant level, whereas the combination reduced the risk substantially.The overall incidence of TB was 2.28 cases/100 person-years (95%CI: 2.06–2.52). Among patients who received neither ART nor IPT, the incidence was 4.01/100 person-years. Patients who received ART had a TB incidence of 1.90/100 person-years (95% CI: 1.66–2.17) and those treated with IPT had a rate of 1.27/100 person-years (95%CI: 0.41–2.95). The incidence among patients who received ART and IPT was 0.80/100 person-years (95% CI: 0.38–1.47). Multivariate Cox proportional hazards modelling revealed a 76% reduction in TB risk among patients receiving both ART and IPT (adjusted relative hazard 0.24; P<0.001) after adjusting for age, previous diagnosis of TB, and CD4 cell counts at baseline.

Samandari et al. 2009 [6]Botswana

Cox regression model that included IPT, baseline CD4 count, baseline TST and ART as a continuous time-dependent variable was performed. For each extra day of ART, the risk of TB decreased by 0.3% (P = 0.018). If provided for 300 days, the risk of TB was reduced by 56%.Overall mortality 1.4% per annum with 2% in the first yearMortality if starting ART: First year: 2.3%Second year: 0.6%Third year: 1.1%From sub-analysis of TST result:Only ART benefits TST-negative persons with a 56% reduction in TB incidence.While ART is important for many reasons, it added only slightly to TB reduction in TST-positive persons receiving continuous IPT.

Akolo et al. 2010 [1]Cochrane Review

Among the papers reviewed, the single placebo-controlled trial that assessed the effect of INH by stage of HIV/AIDS at baseline found no difference (with AIDS [RR 0.96, 95% CI: 0.79 to 1.17] and without AIDS [RR 1.07, 95% CI: 0.84 to 1.35]). (Gordin et al. 1997)

Churchyard et al. 2010 [2]

(Personal communication) Observational study: IPT started within three months of starting ART substantially reduces the risk of death within the first year compared to ART alone, adding further support to the benefits of combining IPT with ART.

77



HIV-infected adults and children, who are unlikely to have active TB, should receive IPT as soon as possible irrespective of their degree of immunosuppression.Population: Adults, adolescents and children living with HIV who are on or not on ARTIntervention: IPT (10–20 mg/kg for children, 300 mg for adults, plus vitamin B6 25 mg daily)Factor Decision Explanation Quality of evidence Moderate • No direct evidence available (likely to be available soon from

ongoing randomized controlled trials)• Indirect evidence supports the concomitant use of IPT and

ART as a more effective intervention than the two alone (Golub et al. 2007; Samandari et al. 2010)


Weak

• Reduction in early mortality (first three months)

Risks or undesired effects

• Patients with advanced disease present additional challenges for diagnosis and potential onset of immune reconstitution inflammatory syndrome (IRIS).

• The Botswana trial reported a statistically non-significant 1.6-fold increase in hepatitis due to INH in people who concomitantly received ART.

Values and preferences Strong • Increased pill burden at ART initiationCosts Strong • Not likely to increase cost unless poorer adherence

compromises the efficacy of first-line regimen inducing failure

• Additional costs of toxicityFeasibility Strong • Administration fits well with the schedule of HIV

programmes.Overall ranking of recommendation



The GRADE profile was not done since none of the available studies directly assessed the question of interest.

78

Annex 6

No Yes

FOOTNOTES TO ADULT ALGORITHM* Every adult and adolescent needs to be evaluated for eligibility for ART. Infection control measures should be prioritized to reduce M. tuberculosis transmission in all settings providing care.Ɨ Chest radiography can be done if available, but is not required to classify patients into TB and non-TB groups. In high HIV-prevalence settings with a high TB prevalence among people living with HIV (e.g. greater than 10%), strong consideration must be given to conducting additional sensitive investigations.ǂ Contraindications include: active hepatitis (acute or chronic) or regular and heavy alcohol consumption or symptoms of peripheral neuropathy. Past history of TB and current pregnancy should not be contraindications for starting IPT. Although not a requirement for initiating IPT, TST may be done as a part of eligibility screening in some settings. § Investigations for TB should be done in accordance with existing national guidelines.

Figure 1. Algorithm for TB screening in adults and adolescents living with HIV in HIV-prevalent and resource-constrained settings

Adults and adolescents living with HIV*

Screen for TB with any one of the following:Ɨ

Current coughFever

Weight lossNight sweats


Screen for TB regularly at each encounter with a health worker or visit to a health facility

No

Give IPT Defer IPT

Yes


Not TB

Follow up and


Other diagnosis

Give appropriate


TB

References

1. Akolo C et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of Systematic Reviews, 2010, (1):CD000171.


3. Golub JE et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS, 2009, 23:631–636.

4. Golub JE et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2007, 21:1441–1448.


6. Samandari T et al.; on behalf of BOTUSA IPT study. Preliminary results of the Botswana IPT Trial: 36 months vs. 6 months isoniazid for TB prevention in HIV-infected adults. 40th Union World Lung Conference, Cancun, 2009.

79



PICOT Question: Should secondary treatment of LTBI be provided to prevent recurrence of TB among

people living with HIV who had received TB treatment in the past?

Population: Adults living with HIV who have received TB treatmentIntervention: IPT (6–12 months’ INH) or any regimenComparison: No IPT or any other regimen immediately after TB treatment

Outcomes: Recurrent TB incidence, mortality, progression of HIV disease, AEs, adherence, interval to recurrent TB, interval to deathTimeline: Lifetime



Comment

Recurrent TB (suspected, probable, confirmed)

9 Critical

Recurrent confirmed TB 9 CriticalMortality 9 CriticalProgression of HIV disease 8 CriticalAdverse events 8 CriticalInterval to active TB 6 Less criticalInterval to death 6 Less critical

Following the GRADE approach, the key outcomes that needed to be considered in making recommendations were chosen and ranked in order

to identify the data that had to be sought from the process of evidence retrieval.

80


2.1 Google Scholar and PubMed were used with the following search strategy (“Tuberculosis”[Mesh] AND “HIV Infections”[Mesh]) AND “”([TB treatment

in the past{Mesh}] or ([Recurrence{Mesh}] or ([Relapse{Mesh}] or ([Reinfection{Mesh}] or ([secondary treatment{Mesh}])

LimitsClinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial,

multicentre study, adolescent: 13–18 years, adult: 19–44 years, middle-aged: 45–64 years, middle aged + aged: 45+ years, aged: 65+ years, 80 and over: 80+ years

The studies of interest include those that compared people living with HIV who had undergone previous treatment for TB and were put on IPT

for a duration of six to 12 months with those who did not receive IPT. The Guidelines Group reviewed the evidence and discussed IPT as secondary prophylaxis for people who had previously been successfully treated for TB. GRADE evidence from four studies [1–4] including three randomized controlled trials and one observational study showed the value of providing IPT immediately after successful completion

of TB treatment. The WHO Guidelines Group strongly recommends that adults and adolescents living with HIV who have successfully completed their TB treatment should continue receiving INH for six months and should conditionally receive it for 36 months based on the local situation and existing national guidelines. No evidence was available on the potential role of IPT for a patient who had successfully completed treatment for MDR or XDR TB. Therefore, the Guidelines Group did not make any recommendation on the use of IPT after successful treatment for MDR or XDR TB.

1456

72

57By title

articles

5By

abstract

4Of

interest

81



Perriens et al. 1995 Haller et al. 1999 Fitzgerald et al. 2000

Churchyard et al. 2003

Methods/design Randomized trial Randomized trial Randomized trial Observational study

Population Kinshasa, Zaire. 335 HIV-positive persons with TB => 260 completed TB treatment => 240 enrolled in further prophylaxis study

280 HIV-positive persons, >15 years old, completed TB treatment, two years’ follow up (192 person years’ treatment vs 142 person-years

Port au Prince, Haiti, >18 years old, HIV-positive, diagnosed and treated for first TB episode, given prophylaxis or placebo after that. Mean follow up 25 months

South Africa, HIV-positive gold miners with documented successful completion of TB treatment

Intervention Of 260 who completed TB treatment => 121 RIF + INH prophylaxis

263 eligible HIV-positive persons => 134 INH + co-trimoxazole

Of 354 with TB => 274 completed treatment => 233 randomized. Of 142 HIV-positive persons => 68 assigned IPT

338 had received secondary preventive therapy

Comparison Of 260 who completed TB treatment => 119 were given placebo

Of 263=> 129 patients

Of 142 => 74 were given placebo

221 had no secondary preventive therapy

Treatment regimen Six months, twice weekly RIF 600 mg/450 mg, INH 15 mg/kg

Placebo

INH, 300 mg once daily plus sulphadoxine–pyrimethamine (S, 500 mg/P, 25 mg once weekly), up to 24 months

No treatment

12-month INH 300 mg + vitamin B6 40 mg

Vitamin B6 40 mg

INH 300 mg/daily

Co-trimoxazole prophylaxis if their CD4 T cell count was <250x106 cells/l and if symptomatic or <200x106 cells/l regardless of symptoms

Outcome Recurrent TB Recurrent TB Recurrent TB Recurrent TBInformation on recurrence

1/73 had relapse in prophylaxis group (48 lost to follow up) vs 9/83 who relapsed in placebo group (36 lost to follow up)

4/134 in prophylaxis group vs 10/129 in control group. The incidence of TB was 2.1 (0.6–3) observations/100 person-years in the prophylaxis group and 7.0 (3.4–12.6) observations/100 person-years in the control group (relative risk 0.30 [0.09–0.94]).

IPT patients 1.4/100 person-years vs placebo 7.8/100 person-years (relative risk 0.18 [0.04–0.83], P=0.010)

Incidence rates 8.6 (INH group) and 19.1 (no treatment group) per 100 person-years; incidence rate ratio, 0.45; 95% confidence interval 0.26–0.78 55% reduction in prophylaxis group

82

Annex 7

Perriens et al. 1995 Haller et al. 1999 Fitzgerald et al. 2000

Churchyard et al. 2003

Comment HIV-seropositive patients followed for relapse; there was no difference in survival between those assigned to RIF plus INH and those assigned to placebo (P = 0.95).The life-table estimate of relapse rate 18 months after completion of six-month treatment was 1.9% for HIV-positive prophylaxis patients – lower than the rate of 9% in HIV-positive placebo patients (P<0.01).At 24 months, the HIV-seropositive patients who received extended treatment had a relapse rate of 1.9%, as compared with 9% among the HIV-seropositive patients who received placebo for the second six months (P<0.01). Extended treatment did not improve survival, however.

The TB recurrence rate was significantly lower among the HIV-1-positive patients receiving INH than among the HIV-1-positive patients receiving placebo.

Limited population – miners

83


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stio

n 5:

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e us

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r peo

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errie

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1995

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for s

ix m

onth

s in

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d of

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2 Sm

all n

umbe

rs

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nsIn

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ssIm

prec

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ther

co

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ions

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nce

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l) (fo

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n

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us

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e

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ive

risk

(95%

CI)

Abso

lute

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38 (8

.3%

)23

/221

(10.

4%)

RR

0.4

5 (0

.26–

0.78

)57

few

er p

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000

(from

23

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Annex 7

84


People living with HIV who have successfully completed their TB treatment should be provided secondary INH prophylaxis. Population: People living with HIV who have successfully completed TB treatmentIntervention: Secondary INH prophylaxis Factor Decision Explanation Quality of evidence Moderate • Only three randomized trials and one observational study.

One randomized trial compared provision of INH with rifampicin after successful TB treatment.

• Adverse events and mortality were not addressed (critical outcome).

• Moderate grade of evidence for recurrent TB outcomeBenefits or desired effects

Strong • Reduced recurrent TB incidence• Reduced TB transmission and improved TB infection control

in health-care settings (particularly in HIV clinics)• Reduced chances of reinfection• Potential reduction in generation of MDR strains by reducing

TB incidenceRisks or undesired effects

• Pill burden• Reduced adherence to other treatment (ART, co-

trimoxazole, etc.)Values and preferences Weak • Lack of motivation among patients as they had just been

treated for TB• Lack of familiarity with and confidence in efficacy of IPT

Costs Strong • Costs are unlikely to increase as INH can easily be incorporated into routine care for people living with HIV.

• Cost-saving implications through prevention of new infections and development of recurrent TB

Feasibility Strong • It will be part of routine care for people living with HIV.Overall ranking of recommendation


References


2. Fitzgerald DW et al. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet, 2000, 356:1470–1474.

3. Haller L et al. Isoniazid plus sulphadoxine–pyrimethamine can reduce morbidity of HIV-positive patients treated for tuberculosis in Africa: a controlled clinical trial. Chemotherapy, 1999, 45:452–465.

4. Perriens JH et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6 or 12 months. New England Journal of Medicine, 1995, 332:779–784.

85



PICOT Question: Is it feasible to perform TST for all people living with HIV before treatment of LTBI in resource-poor settings?

Population: Adults and adolescents living with HIVIntervention: Feasibility of using TST in resource-constrained settings

Comparison: Using IPT without TST Outcomes: Access to IPT vs minimal or no accessTimeline: 5–40 years



Comment

Cost associated with TST 9 CriticalFailure to return for results 9 CriticalStability of purified protein derivative (PPD) and need for cold chain

9 Critical

Measurement issues and interpersonal variability

9 Critical

Access to TST 9 Critical

Studies to date indicate that people living with HIV who are TST-positive are most likely to benefit from preventive therapy.

[1] However, TST implementation poses some

challenges for programmes in resource-poor settings. We evaluated the evidence regarding the feasibility of using TST testing before providing IPT for LTBI in resource-constrained settings.


The key feasibility issues assessed were the following:

• Cold chain/stability of tuberculin• Production quality of tuberculin• Price/costs associated with TST• Measurement issues/inter-reader variability• Loss to follow up/failure to return for TST result• Anergy

PubMed and Embase were considered as the principal databases. Additional studies were identified by searching reference lists of primary studies and review articles. Web sites and package inserts were also checked for relevant information. Additionally, experts in the field of HIV/TB were consulted for relevant articles. Although each of above issues was not separately searched for, each one was included in the overall review of each possible study/article included.

86

Reports were identified:

By reading titles:

By reading abstract:

By reading paper:

Articles/reports of interest:

3. Findings

3.1 Search terms (((“Tuberculin”[MeSH terms] OR “Tuberculin”[all fields]) OR TST (all fields) OR PPD[all fields]) AND (“hiv”[MeSH terms] OR “HIV”[all fields]) AND (TB[all fields] AND (“prevention and control”[subheading] OR (“prevention”[all fields] AND “control”[all

fields]) OR “prevention and control”[all fields] OR (“preventive”[all fields] AND “therapy”[all fields]) OR “preventive therapy”[all fields])) “PPD” and “cold chain”, “PPD” and “cost” OR “price”, “tuberculin” and “stability”.

Studies/articles/reports included were those that evaluated the technical aspects of TST in the general population and HIV-infected

individuals, and were conducted either in high-income or low-income countries.

184

85

45

29

23

87

references

references

references

references

references


3.2 Stability of PPD and need for cold chain

One of the important conditions for maintaining the potency of tuberculin is the need for it to be transported and stored at the appropriate

temperature. Preparations of PPD are stable until the indicated date of expiry, if they are kept continuously cold between +2°C and +8°C and protected from light.[2,3] PPD solution can be adversely affected by exposure to light; therefore, the product should be stored in the dark except when doses are actually being withdrawn from the vial.[2,3] Failure to store and handle PPD as recommended will result in a loss of potency and inaccurate test results.[4] Some studies suggest the possibility of PPD remaining stable even at temperatures outside those recommended.[5–7]

Another report from India showed that on comparing the mean values of PPD test results obtained by using vials at room temperature with those of refrigerated vials, the differences were not significant although the data from this study pertain to non-refrigeration up to 96 hours only and require further validation under rigorous control conditions.[5] Magnus et al. reported that PPD dilutions can be stored at 20°C for some months without significant loss of potency.[7] Although it is possible that PPD solutions can remain stable for at least one year even at 37°C, [5,6] performance may still be jeopardized and the recommended temperatures for storage should still be used.

Tuberculin testing costs less than US$ 10 per person,[8,9] but the prevalence of true positive results is relatively low, and screening may

cost up to US$ 4500 per person eligible for treatment with isoniazid, and US$ 350 000 per case of TB prevented,[8,9] given the added cost associated with the investigation of false-positive reactions,

as well as the costs of treatment and follow up.[10] Though most studies did not state clearly how much cost is associated with TST, the test may also add more costs in terms of the increased workload on personnel, need for patients to return for results to be read and cost of consumables.

3.3 Costs associated with TST

TST/PPD cost Company Dose Cost/dose (US$) Cost/100 000 doses (US$)*A 1 4.7 470 000

B 1 8.9 890 000

C 1 6.1 610 000

D 1 4–9 490 000

E 1 8.7 870 000

F 1 5.8 580 000

Price range/100 000 doses: US$ 470 000–890 000*Excluding shipping

Example: Cost of shipment to KenyaCompany Type of shipment

(shipping takes 5–10 days)Cost/1000 doses (US$) Cost/100 000 doses (US$)

G Courier 85 8 500

G Air freight 177 17 700

F Air freight 125 12 500

NB: Refrigerated item incurs additional shipping charge based on shipping zone.

88

Annex 8

F actors such as variability between and within readers, need for trained personnel to administer and read the test, and the need

for the subjects to be seen a second time so that test results can be read all impact the usefulness of TST.[16] With regard to interpersonal variability in reading the TST, the available evidence shows that groups of health-care workers can be trained to accurately interpret TSTs with a minimum of

variability.[18–21] Evidence that supports other modes of measuring the response is also available, such as the use of flexible calipers.[20] However, measurement methods are imprecise and a number of factors including the time that the results are read after placement of the test may affect the results. The feasibility of training large numbers of health-care workers to place and accurately read TSTs on a large scale is unknown.

Before TST can be used to screen for LTBI, it must first be made available to programmes providing HIV prevention, care and treatment

services. The global supply may not be sufficient to meet the demand. According to a report from India, good-quality tuberculin in various strengths is seldom

available.[16] Reports from South Africa also found difficulty in keeping tuberculin for the test in stock.[22] However, it is possible that manufacturers could scale up production to meet the demand but that would largely depend on market forces.

TST has been used for decades to detect LTBI, but is not entirely reliable due to its low specificity and sensitivity.[23] This is particularly important

in persons with LTBI and immunosuppression. Because of their depressed cell-mediated immunity, people living with HIV may not be able to mount a response to TST. Thus, a negative TST in a person living with HIV may be due to true absence of infection with Mycobacterium tuberculosis or an inability to mount a response due to immunosuppression.[24]

Anergy is defined as absence of induration in response to three antigens (PPD, Candida albicans and parotiditis antigen) applied by the Mantoux method.[25] It has

been recommended that other cutaneous allergens be used to differentiate between the presence of non-reactivity to tuberculin due to an absence of infection or due to anergy.[26] However, anergy testing is not an ideal field test as it requires a repeat visit 48–72 hours after placement of the test and handling injectable materials (syringe, cold chain, etc.), as well as a cadre of trained personnel.[27] A study by Garcia et al. reported that the use of tetanus toxoid and Candida antigen were not useful in differentiating between the absence of reactivity to tuberculin caused by HIV-associated immunodeficiency and that due to absence of latent M. tuberculosis infection.[28] Tuberculin and anergy skin testing have a low predictive value

3.5 Measurement issues and interpersonal variability

3.6 Access to TST

3.7 Anergy

89

The use of TST in identifying patients who might benefit from ITP adds further time and expense, and is an additional step where

patients are lost to follow up.[11] Most of the included studies showed that about 11–21% of patients who had TST did not return for their results to be read.[12–14] The burden of having to return to the health-care facility after 48–72 hours of undergoing TST is particularly a great challenge in many resource-poor settings. However, the study by Aisu et al. suggested that the rate of return for TST to be read increased after HIV counsellors were retrained in HIV and TB.[12] This finding may support the suggestion that

field experience in the care of HIV-infected patients may be the best predictor of physician adherence with a recommended TST procedure.[15] However, the feasibility of having to retrain a large population of health-care providers in resource-poor settings on the use of TST also needs to be considered. It has been reported that the need for subjects to be seen a second time so that test results can be read limit the usefulness of TST.[16] Therefore, while useful, there are considerable feasibility challenges around the need for follow up. In addition, accurate interpretation of the results is occasionally not possible, particularly among people with HIV and low CD4 counts.[17]

3.4 Failure to return



TST is not a requirement for initiating IPT for people living with HIV. Where feasible, TST can be used as people with a positive test result benefit more from IPT than those with a negative test result.Population: People living with HIVIntervention: TSTFactor Decision Explanation Quality of evidence High • Provision of IPT reduces active TB incidence by:

• 33% (GRADE high) regardless of TST status • 64% in TST-positive persons (GRADE high)• 14% in TST-negative persons (GRADE high)• 14% in those with unknown TST results (GRADE moderate)• Therefore, TST is useful in identifying the population who

would benefit most from IPT.Benefits or desired effects

Weak

Benefits:• Early identification of LTBI• Increase in numbers of people diagnosed with LTBI• Minimizes number to be exposed to INH• Correctly identifies people who will benefit from IPT


• Risk of adverse reaction to PPD• Risk of false-negative results (HIV anergy, reader error, poor

product), false-positive results, interaction with BCG)Values and preferences Strong • Patients may not want to have TST

• Concerns regarding returning for results• TST not a form of treatment• Risk of adverse effects

Costs Strong Reduced by:• Increased demand for TST may lower cost of PPD• Reduction in the number of patients on INH (related toxicity

management and follow up)Increased by:• Procurement of PPD/need for storage• Training of workers• Time spent by health-care worker for test• Travel cost for follow-up visits by the patient• Cost associated with further screening for TB

Feasibility Strong • Not many studies in resource-poor settings examined the major issues

• Need for refrigeration and cold chain maintenance• Considerable loss to follow up• Need for training of health-care workers• Increased workload of health-care workers• Need for more training on the use of TST in clinical and

public health practiceBut:• Cost of PPD could be offset by the TB cases prevented• PPD could remain stable at room temperature


Strong

in detecting M. tuberculosis infection in HIV-infected persons, and therefore such testing has a limited role in identifying HIV-infected persons who may benefit from preventive therapy programmes for TB.[29] The usefulness of anergy testing has been questioned and

its use to guide administration of TB chemoprophylaxis has been discontinued in the United States.[30] Until well-designed studies of anergy testing as an adjunct to tuberculin testing are conducted, it is safest to discourage anergy testing.

Annex 8

90

References1. Akolo C et al. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database of Systematic

Reviews, 2010, (1):CD000171.2. Landi S, Held HR. Effect of light on tuberculin purified protein derivative solutions. American Review of Respiratory

Disease, 1975, 111:52–61.3. Medsafe. Tuberculin purified protein derivative (Mantoux) diagnostic antigen. 2007. Available from: http://www.

medsafe.govt.nz/profs/datasheet/t/Tubersolinj.htm (accessed on 12 November 2010).4. Landi S, Held HR. Stability of a dilute solution of tuberculin purified protein derivative at extreme temperatures.

Journal of Biological Standardization, 1981, 9:195–199.5. Ladha A. Effect of refrigeration on Mantoux test result. Indian Pediatrics, 1995, 32:1036. 6. Landi S, Held HR. Stability of dilute solutions of tuberculin purified protein derivative. Tubercle, 1978, 59:121–133.7. Magnus K et al. Stability of purified tuberculin in high dilution. Bulletin of the World Health Organization, 1958,

19:765–782.8. Price LE, Rutala WA, Samsa GP. Tuberculosis in hospital personnel. Infection Control, 1987, 8:97–101.9. Raad I et al. Annual tuberculin skin testing of employees at a university hospital: a cost–benefit analysis. Infection

Control and Hospital Epidemiology, 1989, 10:465–469.10. Menzies D et al. Tuberculosis among health care workers. New England Journal of Medicine, 1995, 332:92–98.11. Hawken MP, Muhindi DW. Tuberculosis preventive therapy in HIV-infected persons: feasibility issues in developing

countries. International Journal of Tuberculosis and Lung Disease, 1999, 3:646–650.12. Aisu T et al. Preventive chemotherapy for HIV-associated tuberculosis in Uganda: an operational assessment at a

voluntary counselling and testing centre. AIDS, 1995, 9:267–273.13. Antonucci G et al. Guidelines of tuberculosis preventive therapy for HIV-infected persons: a prospective, multicentre

study. GISTA (Gruppo Italiano di Studio Tubercolosi e AIDS). European Respiratory Journal, 2001, 18:369–375.14. Sackoff JE et alB. Purified protein derivative testing and tuberculosis preventive therapy for HIV-infected patients in

New York City. AIDS, 1998, 12:2017–2023.15. DeRiemer K, Daley CL, Reingold AL. Preventing tuberculosis among HIV-infected persons: a survey of physicians’

knowledge and practices. Preventive Medicine, 1999, 28:437–444.16. Mohan A, Sharma SK. In search of a diagnostic test for tuberculosis infection: where do we stand? Indian Journal

of Chest Disease and Allied Sciences, 2006, 48:5–6.17. Syed J. TB diagnostics: a crisis for people living with HIV/AIDS worldwide. 2006. Available from: http://www.thebody.

com/content/art1760.html (accessed on 12 November 2010).18. Carter ER, Lee CM. Interpretation of the tuberculin skin test reaction by pediatric providers. Pediatric Infectious

Disease Journal, 2002, 21:200–203.19. Ozuah PO et al. Assessing the validity of tuberculin skin test readings by trained professionals and patients. Chest,

1999, 116:104–106.20. Perez-Stable EJ, Slutkin G. A demonstration of lack of variability among six tuberculin skin test readers. American

Journal of Public Health, 1985, 75:1341–1343.21. Villarino ME et al. Comparable specificity of 2 commercial tuberculin reagents in persons at low risk for tuberculous

infection. Journal of the American Medical Association, 1999, 281:169–171.22. Smart T. Continuous isoniazid preventive therapy (IPT) superior to short course in TST-positive HIV patients – but

only in those with a positive tuberculin skin test (TST). HIV & AIDS Treatment in Practice (HATIP), 2009, 151.Available from: http://www.stoptb.org/wg/tb_hiv/assets/documents/hatip151.pdf (accessed on 13 November 2010).

23. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG and non-tuberculous mycobacteria? International Journal of Tuberculosis and Lung Disease, 2006, 10:1192–1204.

24. Markowitz N et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Pulmonary Complications of HIV Infection Study Group. Annals of Internal Medicine, 1993, 119:185–193.

25. Rivero A et al. [Randomized trial of three regimens to prevent tuberculosis in HIV-infected patients with anergy]. Enfermedades Infecciosas y Microbiología Clínica, 2003, 21:287–292.

26. Arnadottir T et al. Guidelines for conducting tuberculin skin test surveys in high prevalence countries. Tubercle and Lung Disease, 1996, 77 (Suppl 1):1–19.

27. Jones-Lopez EC et al. Delayed-type hypersensitivity skin test reactivity and survival in HIV-infected patients in Uganda: should anergy be a criterion to start antiretroviral therapy in low-income countries? American Journal of Tropical Medicine and Hygiene, 2006, 74:154–161.

28. Garcia-Garcia ML et al. Underestimation of Mycobacterium tuberculosis infection in HIV-infected subjects using reactivity to tuberculin and anergy panel. International Journal of Epidemiology, 2000, 29:369–375.

29. Yanai H et al. Utility of tuberculin and anergy skin testing in predicting tuberculosis infection in human immunodeficiency virus-infected persons in Thailand. International Journal of Tuberculosis and Lung Disease, 1997, 1:427–434.

30. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. Morbidity and Mortality Weekly Report, 1998, 47(RR-20):36–41.


91


PICOT Question: What is the role of IGRA in identifying adults and children who would benefit from treatment for LTBI or active TB?

Population: Adults and children living with HIVIntervention: Use of IGRA in identifying adults and children who would benefit from treatment for LTBI or active TBComparison: No identification of LTBI; TST

Outcomes: Negative predictive value, sensitivity, specificity, positive predictive valueTimeline: One week during work-up to exclude TB before starting IPT




Comment

Predictive value for identification of persons at risk for developing TB

9 Critical

Specificity for identification of persons at risk for developing TB

9 Critical

Sensitivity for identification of persons with active TB

4 Important

Specificity for identification of persons at low risk for TB

4 Important

Degree of agreement between results of IGRA and results of TST

5 Important

PubMed Search (“Tuberculosis”[Mesh]) AND “HIV”[Mesh]) AND “Diagnosis”[Mesh]) OR (IGRA, interferon gamma release assay, Quantiferon gamma Gold In-Tube, T-SPOT, ELISPOT, T-cell based assay, whole blood Quantiferon gamma

release assay, TB, HIV).Leading researchers in the area were also contacted to provide any unpublished data fulfilling the search criteria.

Search criteria

92

225

68By title

58By

abstract

28

Of interest

Studies of interest Twenty-six abstracts/articles [1–26] provided information about sensitivity/specificity of IGRA among the HIV-infected population or performance of IGRA in comparison to TST. Two articles [27,28] specifically provided information on the cost and feasibility of IGRA.Studies evaluating IGRA that are commercially available (T-SPOT, Quantiferon Gold In Tube [QFN G IT]) and their pre-commercial predecessors (ELISPOT based on antigens included in T-SPOT) were included but assays based on alternate antigens were eliminated.

Information was specifically abstracted on: predictive value of IGRA among persons who developed TB (incident TB) and persons with HIV and prevalent active TB (including information about the performance of IGRA in persons with active TB disaggregated by category of CD4 cell count, if available). We also extracted results of IGRA and TST among persons with HIV and no evidence of active TB, including information on the numbers of patients with positive, negative or indeterminate results of each test, and reported kappa values for the degree of agreement between TST and IGRA.

Three studies [2,6,8] considered the ability of IGRA to predict development of TB over time (IGRA Table 1.1). The results of one of these

studies [8] were disregarded because only a CD4 cell count-corrected measure of interferon-gamma (IFN-γ) release was reported. One study [2] reported that among 822 HIV-positive persons in Austria without active TB who were tested with QFN G IT (results: 37 positive, 738 negative, 47 indeterminate), three developed active TB during follow up, all three

of whom had a positive QFN G IT test at baseline. The other study [6] followed 20 people living with HIV with no respiratory symptoms, but with positive ELISPOT; two developed active TB at three and 10 months of follow up.

Eight studies [1–3,13,17,23,25,26] evaluated the performance of QFN G IT assay among adults with HIV in whom prevalent active TB was confirmed by a combination of signs, symptoms, AFB smear and



93

LimitsClinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase

IV, comparative study, controlled clinical trial, multicentre study.

684articles

mycobacterial culture (IGRA Table 2.1). All studies were in settings with high TB and HIV prevalence. The reported sensitivity of QFN G IT ranged from 30% to 83% with a pooled sensitivity of 0.63 (95% CI: 0.57–0.68). The number of persons included in most studies was small (range 8–105), and the total number of persons evaluated was 339.

One study [22] evaluated the sensitivity of QFN G IT among HIV-infected children with active TB. Among 36 children with HIV and active TB, 17 had positive QFN G IT tests; the reported sensitivity for QFN G IT was 0.47 (0.31–0.64).

Five studies [5,6,9,13,18] reported the sensitivity of a T-SPOT assay among HIV-infected adults in whom active TB was confirmed by a combination of signs, symptoms, AFB smear and mycobacterial culture (IGRA Table 2.2), although one of these [9] reported only disaggregated sensitivity for subgroups with lower and higher CD4 cell counts and was not included in the pooled estimate. In the remaining four studies [5,6,13,18] reported sensitivity ranged from 0.89 to 0.90 and the pooled sensitivity was 0.90 (0.84–0.96). The total number of persons included in these studies was 109.

Two studies [7,14] reported the sensitivity of T-SPOT among HIV-infected children with active TB, confirmed by a combination of signs, symptoms, AFB smear and mycobacterial culture (IGRA Table 2.2). The pooled sensitivity was 0.69 (95% CI: 0.57–0.82). The total number of children studied was 52. One study [13] reported on rates of positive IGRA among 10 individuals considered to be at low risk for TB (IGRA Table 3). The number of persons with positive tests were 0 (QFN G IT) and one (with T-SPOT). Ten studies [4,10,12,13,15,16,19,20,22,24] compared the results of QFN G IT with those of TST in HIV-infected persons without evidence of active TB (IGRA Table 4).

In five studies [4,9,12,16,22], the number of persons with positive QFN G IT tests was greater than the number with positive TST and, in the remaining five [10,15,19,20,22], the number of persons with positive TST was greater than the number with positive QFN G IT. Eight studies (IGRA Table 4) compared the results of T-SPOT or ELISPOT with those of TST [9,11,13,16,19,20,22,24]; in six, a larger proportion of patients had positive T-SPOTs [9,11,13,16,19,22], in two, a larger proportion of patients had positive TST.[20,24]

In addition to comparing the proportions of persons positive based on each type of test, many studies reported kappa values for correlation between tests (IGRA Table 4). Reported kappa values varied widely; from –0.02 to 0.43 for agreement between T-SPOT and TST, and between 0.23 and 0.59 for agreement between QFN G IT and TST. These values would be considered by some to be consistent with a range between no and moderate agreement.

The performance of QFN G IT was compromised among HIV-infected people compared with HIV-negative persons. Rates of indeterminate test results for QFN G IT were significantly higher in persons with HIV compared with persons without HIV, and in persons with low CD4 cell counts compared with persons with higher CD4 cell counts. QFN G IT sensitivity was significantly reduced among patients with low CD4 counts. While most studies found no impact of low CD4 count on T-SPOT sensitivity, at least one study [24] found that low CD4 count was associated with an increased risk of indeterminate test results.

Importantly, because there are few longitudinal studies [2,6,8] and no accurate gold standard for LTBI, it is difficult to assess the trade-offs that would occur between sensitivity and specificity using different levels of IFN-γ gamma release to define positive tests.

Annex 9

Reference Test Design Limitations Consistency Directness Precision Overall quality

Total no. with positive results followed up

Predictive value

No. of persons with active TB in whom test was

+ ve - ve indeterminate

1 study QFN G IT Observational –1 –1 –1 –1 Very low

36 0.8 (0.02–0.21)

3 0 0

1 study T-SPOT Observational –1 –1 –1 –1 Very low

20 0.1 (0.01–0.31)

2 0 0

GRADE table

IGRA Table 1.1: Predictive value of IGRA among persons with HIV who developed TB during follow up (incident TB)

94

Reference Test Design Limitations Consistency Directness Precision Total no. with positive results followed up

Predictive value



Aichelburg et al.

QFN G IT Observational 10 unclear –1 –1 36 0.8 (0.02–0.21)

3 0 0

Clark et al. T-SPOT Observational 10 unclear –1 –1 20 0.1 (0.01–0.31)

2 0 0

Summary table

Aichelburg et al.: 18 months of follow up (radiology, culture for TB confirmation)Clark et al.: median follow up of 12 months

QUADAS Quality Assessment of Diagnostic Accuracy Studies


N (with active TB)

Sensitivity (CI)



8 studies (adults)

QFN G IT Observational –1 –1 OK –1 Very low

339 0.63 (0.57–0.68)

212 65 62

1 study (children)

QFN G IT Observational –1 –1 –1 –1 Very low

36 0.47 (0.31–0.64)

17 10 9


N (with active TB)

Sensitivity (CI)



4 (adults) * T-SPOT Observational –1 –1 OK –1 Very low

109 0.9 (0.84–0.96)

98 7 4

2 (children) T-SPOT Observational OK –1 OK –1 Very low

52 0.69 (0.57–0.82)

36 15 1

Reference Test Design Limitations (QUADAS)

Consistency Directness Precision N (with active TB)

Sensitivity (CI)



Aabye et al. QFN G IT Observational 4 and 10 OK OK 68 0.65 (0.53–0.76)

44 9 (13%)

15 (22%)

Aichelburg et al.

QFN G IT Observational 10 not clear –1 –1 8 0.88 (0.64–1)

7 1 (12%)

0

Baba et al.(confirmed)

QFN G IT Observational 10 not clear OK pleural –1 12 0.58 (0.3–0.9)

7 1 (6%)

4 (33%)

Baba et al. (probable)

QFN G IT Observational 10 not clear OK pleural –1 12 0.83 (0.62–1)

10 0 2 (17%)

Kabeer et al. QFN G IT Observational 10 not clear OK OK 105 0.65 (0.56–0.74)

68 19 (18%)

18 (17%)

Leidl et al. QFN G IT Observational 10 not clear OK –1 19 0.68 (0.47–0.89)

13 6 0

Raby et al. QFN G IT Observational 10 not clear OK OK 59 0.63 (0.5–0.78)

37 10 (17%)

12 (20%)

Tsiouris et al. QFN G IT Observational 10 not clear OK –1 26 0.65 (0.46–0.81)

17 4 5

Veldsman et al. QFN G IT Observational None OK –1 30 0.30 (0.14–0.46)

9 15 6

Stavri et al. (children)

QFN G IT Observational 4,10 not clear –1 –1 36 0.47 (0.31–0.64)

17 10 9

GRADE table for QFN G IT

GRADE table for T-SPOT

Summary table for QFN G IT

IGRA Table 2.1: Sensitivity of IGRA among persons with HIV and active TB at baseline (prevalent TB)

IGRA Table 2.2: Sensitivity of IGRA among persons with HIV with active TB at baseline (prevalent TB)


95

*Overall sensitivity/raw numbers not available for one study (Jiang et al.)

Reference Test Design Limitations Consistency Directness Precision N (with active TB)

Sensitivity (CI) No. of persons with active TB in whom test was


Clark et al. T-SPOT Observational 10 not clear

–1 –1 30 0.90 (0.79–1) 27 1 2

Chapman et al. T-SPOT Observational 10 No OK ? 39 0.9 (0.80–0.99) 35 4 0

Jiang et al.* T-SPOT - OK –1 18* 66.7 (CD4 <200)

85.7 (CD4 ≥200)

Leidl et al. T-SPOT Observational 10 not clear

OK –1 19 0.89 (0.75–1) 17 0 2

Rangaka et al. T-SPOT None OK –1 21 0.9 (0.78–1) 19 2 0

Davies et al. (children)

T-SPOT Observational OK OK 22 0.67 (0.43–0.85) 14 7 1

Liebeschuetz et al.(children)

T-SPOT Observational OK OK –1 30 0.73 (0.54–0.88) 22 8 0

Summary table for T-SPOT

Annex 9

96

Summary GRADE table

IGRA Table 3: Specificity of IGRA in HIV-positive persons at low risk for TB

IGRA Table 4: Agreement between results of IGRA and TST


No. with no risk for TB

Sensitivity No. of persons with active TB in whom test was


Leidl et al. QFN G IT Observational –1 –1? –1 Very low

10 0 0 10 0

Leidl et al. T-SPOT Observational –1 –1? –1 Very low

10 0.9 1 9 0

Study N Setting HIV/TB burden

T-SPOT +ve (N)

T-SPOT +ve (%)

T-SPOT indeter (N)

T-SPOT indeter (%)

TST +ve (N)

TST +ve (%)

QFN G IT +ve (N)

QFN G IT +ve (%)

QFT N IT indeter (N)

QFN G IT indeter (%)

Kappa T-SPOT vs TST

Kappa QFN G IT vs TST

Kappa T-SPOT QFN G IT

Jiang et al. 68 High 46 67.6 0 0.0 28 41.2

Karam et al. 247 High 125 50.6 0 53 21.5 0.23

Leidl et al. 109 High 59 54.1 4 3.7 42 47.2 74 67.9 4 3.7 0.37 0.34 0.17

Mandalakas et al. (adults)

20 High 13 65.0 2 10.0 10 50.0 11 55.0 3 15.0 0.43 0.46

Rangaka et al. 74 High 38 52 1 1 35 52 32 43.2 7 5 0.6 0.58

Richeldi et al. 116 Low 4 3.4 0 0 6 5.1 5 4.3 7 6 0.16 0.52 0.19

Stephan et al. 275 Low 66 24.0 8 2.9 33 12.0 52 18.9 0 0 0.2 0.33 0.15

Talati et al. 336 Low 14 4.2 5 1.5 7 9.3 9 2.7 5 1.5 0.16 0.23

Balcells 109 Low 11 10.1 17 15.6 0 0.0 0.59

Jones et al. 201 Low 13 6.5 11 5.5 10 5.0 0.38

Kimura et al. 167 Low 16 9.6 32 19.2 0 0.0 0.28

Luetkemeyer et al.

296 Low 19 9.3 25 8.4 15 5.1 0.37

Mandalakas et al. (children)

23 High 12 52.2 0 0.0 6 26.1 2 16.7 0 0.0 -0.02 0.44


Recommendation: There is currently insufficient evidence to support the use of IGRA to identify persons living with HIV (adults and children) who are eligible for IPT. Population: HIV-infected adults and childrenIntervention: Use of IGRA to identify people eligible for treatment of LTBIFactor Decision Explanation Quality of evidence High The quality of evidence on the role of IGRA in correctly identifying

people eligible for treatment of LTBI is very high. While there is some information about test performance in persons with active TB or at low risk for TB, longitudinal data are very limited. Overall, the evidence does not support the use of IGRA at this time.


Strong

• Sensitivity of T-SPOT may be higher than that of TST • IGRA may require fewer return visits than TST • Risk of adverse events with IGRA may be less than that of

TST • Potential for boosting (with TST) eliminated with IGRA


• Insufficient information to determine whether IGRA can differentiate between LTBI and active TB disease

• Insufficient information to determine whether IGRA can identify persons likely to benefit from LTBI treatment

• IGRA performance is affected by immunosuppression (increased rate of indeterminate results in persons with low CD4 counts).

• IGRA requires a blood draw.• There is a chance of failed phlebotomy, especially in

children.Values and preferences • Patients may prefer to avoid visible reaction to TST.

• Patients may prefer to avoid blood draw.Costs Strong Increased by:

• Need to establish well-equipped laboratory• Need to procure equipment and supplies for IGRA

performance and quality assurance• Need for staff training

Feasibility Strong • Need for well-established laboratories• Need for careful handling and processing of blood samples

to ensure accuracy of tests• Availability of well-trained staff or staff that can be trained




97

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assay in patients with pulmonary tuberculosis. PLoS One, 2009, 4:e4220.2. Aichelburg MC et al. Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma

release assay in HIV-1-infected individuals. Clinical Infectious Diseases, 2009, 48:954–962.3. Baba K et al. Evaluation of immune responses in HIV infected patients with pleural tuberculosis by the QuantiFERON

TB-Gold interferon-gamma assay. BMC Infectious Diseases, 2008, 8:35.4. Balcells ME et al. A comparative study of two different methods for the detection of latent tuberculosis in HIV-positive

individuals in Chile. International Journal of Infectious Diseases, 2008, 12:645–652.5. Chapman AL et al. Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by

enumeration of Mycobacterium tuberculosis-specific T cells. AIDS, 2002, 16:2285–2293.6. Clark SA et al. Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot

technology in human immunodeficiency virus (HIV)-1 patients with advanced disease. Clinical and Experimental Immunology, 2007, 150:238–244.

7. Davies MA et al. Detection of tuberculosis in HIV-infected children using an enzyme-linked immunospot assay. AIDS, 2009, 23:961–969.

8. Elliott JH et al. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution inflammatory syndrome during early antiretroviral therapy. Journal of Infectious Diseases, 2009, 200:1736–1745.

9. Jiang W et al. High-sensitive and rapid detection of Mycobacterium tuberculosis infection by IFN-gamma release assay among HIV-infected individuals in BCG-vaccinated area. BMC Immunology, 2009, 10:31.

10. Jones S et al. Utility of QuantiFERON-TB Gold in-tube testing for latent TB infection in HIV-infected individuals. International Journal of Tuberculosis and Lung Disease, 2007, 11:1190–1195.

11. Karam F et al. Sensitivity of IFN-gamma release assay to detect latent tuberculosis infection is retained in HIV-infected patients but dependent on HIV/AIDS progression. PLoS One, 2008, 3:e1441.

12. Kimura M et al. Comparison between a whole blood interferon-gamma release assay and tuberculin skin testing for the detection of tuberculosis infection among patients at risk for tuberculosis exposure. Journal of Infectious Diseases, 1999, 179:1297–1300.

13. Leidl L et al. Relationship of immunodiagnostic assays for tuberculosis and numbers of circulating CD4+ T-cells in HIV infection. European Respiratory Journal, 2009, 35:619–626.

14. Liebeschuetz S et al. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective cohort study. Lancet, 2004, 364:2196–2203.

15. Luetkemeyer AF et al. Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected individuals. American Journal of Respiratory and Critical Care Medicine, 2007, 175:737–742.

16. Mandalakas AM et al. High level of discordant IGRA results in HIV-infected adults and children. International Journal of Tuberculosis and Lung Disease, 2008, 12:417–423.

17. Raby E et al. The effects of HIV on the sensitivity of a whole blood IFN-gamma release assay in Zambian adults with active tuberculosis. PLoS One, 2008, 3:e2489.

18. Rangaka MX et al. Clinical, immunological, and epidemiological importance of antituberculosis T cell responses in HIV-infected Africans. Clinical and Infectious Diseases, 2007, 44:1639–1646.

19. Rangaka MX et al. Effect of HIV-1 infection on T-cell-based and skin test detection of tuberculosis infection. American Journal of Respiratory and Critical Care Medicine, 2007, 175:514–520.

20. Richeldi L et al. Performance of tests for latent tuberculosis in different groups of immunocompromised patients. Chest, 2009, 136:198–204.

21. Stavri H et al. Comparison of tuberculin skin test with a whole-blood interferon gamma assay and ELISA, in HIV positive children and adolescents with TB. Roumanian Archives of Microbiology and Immunology, 2009, 68:14–19.

22. Stephan C et al. Comparing QuantiFERON-tuberculosis gold, T-SPOT tuberculosis and tuberculin skin test in HIV-infected individuals from a low prevalence tuberculosis country. AIDS, 2008, 22:2471–2479.

23. Kabeer BSA et al. Role of interferon gamma release assay in active TB diagnosis among HIV infected individuals. PLoS One, 2009, 4:e5718.

24. Talati NJ et al. Poor concordance between interferon-gamma release assays and tuberculin skin tests in diagnosis of latent tuberculosis infection among HIV-infected individuals. BMC Infectious Diseases, 2009, 9:15.

25. Tsiouris SJ et al. Sensitivity analysis and potential uses of a novel gamma interferon release assay for diagnosis of tuberculosis. Journal of Clinical Microbiology, 2006, 44:2844–2850.

26. Veldsman C et al. QuantiFERON-TB GOLD ELISA assay for the detection of Mycobacterium tuberculosis-specific antigens in blood specimens of HIV-positive patients in a high-burden country. FEMS Immunology and Medical Microbiology, 2009, 57:269–273.

27. Burgos JL et al. Targeted screening and treatment for latent tuberculosis infection using QuantiFERON-TB Gold is cost-effective in Mexico. International Journal of Tuberculosis and Lung Disease, 2009, 13:962–968.

28. Dewan PK et al. Feasibility, acceptability, and cost of tuberculosis testing by whole-blood interferon-gamma assay. BMC Infectious Diseases, 2006, 6:47.

Annex 9

98


PICOT Question: Does treatment for LTBI among people living with HIV lead to significant development of mono-resistance against the drugs used for LTBI?

Population: Adults living with HIV who received treatment for LTBIIntervention: IPT (6–12 months INH) or any rifampicin-containing preventive treatment regimenComparison: No IPT or any other regimen

Outcomes: Occurrence of mono-isoniazid resistance in TB isolates from people who have received the intervention compared with those who did not receive the interventionTimeline: Lifetime




Comment

Mono-resistance to IPT (IPT versus no treatment/placebo)

9 Critical

Mono-resistance to IPT vs rifampicin (IPT intervention vs rifampicin as control)

9 Less critical

Following the GRADE approach, the key outcomes that needed to be considered in making recommendations have been chosen

and accordingly ranked in order to identify the data that had to be sought from the process of evidence retrieval.

(HIV[MeSH Terms]) AND (Tuberculosis[MeSH Terms]) AND (Antitubercular Agents[MeSH Terms]) OR (“latent”[Title/Abstract]) OR (“isoniazid”[Title/Abstract]) OR (“prevent*”[Title/Abstract]) OR (“resist*”[Title/Abstract])

Concerns regarding the development of isoniazid resistance during IPT in people who develop and/or have active TB while

on preventive treatment is the dominant reason offered for not implementing IPT. Although the

study design of this issue is difficult, a review of the existing data suggests that there is little scientific evidence to support concerns regarding the development of mono-isoniazid resistance and/or multidrug resistance.

2.1 PubMed Search

99

Leading researchers in the field and WHO staff were contacted and provided with the articles reviewed in this study. They were requested

to advise on any other unpublished data or further articles that were not identified by the search strategy.

The major HIV/AIDS and TB conference web sites were also reviewed for abstracts that satisfied the above search criteria.

Limits activated

Studies of interest:

Humans, clinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial,

phase IV, comparative study, controlled clinical trial, evaluation studies, technical report, validation studies

Seventeen articles of original research including abstracts from conferences [1–17] provided some information about the incidence of resistance among

people living with HIV who had latent TB and were provided preventive therapy.

Net studies reviewed for grading of evidence:14 studies7 – IPT versus placebo, randomized trials3 – IPT versus rifampicin, randomized trials4 – IPT versus placebo, observational

220

17studies

3abstracts

from conferences

Of interest

95studies

(including 36 reviews)

articles

+

2.2 Inclusion and exclusion criteria

T he patients in the studies had to meet specific criteria for being diagnosed with HIV and not suffering from active TB at the time of the

study, or being on antitubercular medication prior

to the study. Latent TB or no previous history of TB was noted by the studies. Observational studies and trials were analysed separately for GRADE purposes.

Annex 10

100

Mwinga et al. 1998 – randomized trial excluded – of 96 TB cases, only 12 tested for sensitivitiesKawai et al. 2006 – observational, no numerical dataMugisha et al. 2006 – observational, no placebo group comparison

The studies of interest include those that compared people living with HIV who had undergone previous treatment for TB and were

put on IPT, with no IPT, or a rifampicin-containing regimen for a duration of six to 12 months and/or a shorter duration of the rifampicin regimen.

Study Campos et al. Churchyard et al. Golub et al. Gordin et al. Halsey et al. Hawken et al.

Publication year 2003 2003 2008 2000 1998 1997

Methods/design Case–control – retrospective observational

Observational study Cohort retrospective Randomized controlled trial

Randomized prospective unmasked trial

Randomized double-blind placebo-controlled trial

Data collection Feb 1999–Jan 2000 From 1998 to July 2001

Mar 1990–Mar 1998 Sept 1991–May 1996 Apr 1990–July 1992 Apr 1992–Mar 1994

Population Lima and Callao, Peru Adults >18 years, 80/81 male

South Africa, gold miners, HIV-positive, documented successful completion of TB treatment1

Injecting drug users Baltimore, US, adults, TST-positive with active TB- (by symptom review and chest X-ray)

Outpatients in clinics, US/Mexico/Haiti/Brazil, age >13 years

Haiti, age 16–77 years, HIV-1-positive, TST-positive >5 mm, normal chest X-ray, median follow up 2.5 years

Kenya, HIV-positive, 14–65 years, no past/current TB, clinic or voluntary counselling and testing (VCT) attendees

Sample size 415 HIV-positive with new TB -> 258 reviewed -> 135 TB culture positive -> TB Drug susceptibility tested on 81 => 35 MDR TB-positive

338 had received secondary preventive therapy

800 HIV-positive => 649 TST => 102 TST-positive => 60 IPT started => 36 completed IPT (35% of TST-positives completed IPT), 26-week course

1583 HIV-positive, TST-positive (>5 mm, non-active TB), no past treatment for TB >2 months 35.8% vs 36.8% on ART in the 2 treatment groups

750 HIV-positive => 332 on IPT

342 INH

Comparison group Vs 46 MDR TB-negative HIV-positive patients vs 38 MDR TB-positive of 965 HIV-negative patients

221 had no secondary preventive therapy

1576 HIV-negative => 1104 TST => 434 TST-positive => 239 IPT started => 129/434 IPT completed (30%)

636 completed RIF/PZA vs 544 INH therapy, 36 months’ follow up

333 on RIF prophylactic therapy

342 controls

TB – latent/nil New TB History of TB Latent Latent Latent No TB history

Treatment regimen “TB prophylaxis” MDR TB-positive – 6.7±5 months vs MDR TB-negative 4.4±3.3 months of prophylaxis (P=0.27)

INH 300 mg/daily IPT INH 300 mg/day + pyridoxine HCl 12 months (N=792)

IPT 24 weeks – INH 800 mg/pyridoxine 25 mg bi-weekly

6 months INH 300 mg daily

Control No treatment RIF 600 mg/day + PZA 20 mg/kg/day for 2 months (N=791)

RIF 450 mg/day + PZA 2000 mg for 2 months, bi-weekly

Placebo

Outcomes MDR TB Resistant TB Culture-confirmed TB, adverse events

Resistant TB Culture-confirmed TB

Resistance information

MDR TB in HIV-infected patients was not associated with previous TB therapy or prophylaxis.

51 cases of TB were diagnosed, 28 (8.3%) among the IPT cohort and 23 (10.4%) among the control cohort.

There was no significant difference in the prevalence of isoniazid resistance between the IPT and control cohorts (20% [2/10] and 23% [3/13], respectively, (P=1.0).

No INH resistance detected among TB cases who had received any duration of IPT

No IPT 20 TB cases/24 585 person-years (incidence ratio 0.81 [0.50–1.26]/1000 person-years) vs all starting IPT 2 TB cases/4185 person-years (IR 0.48 [0.06–1.72]/1000 person-years), IPT 30 days 1 TB/3358 person-years (IR 0.29 [0.01–1.66]), completing IPT 0/2385 person-years (IR 0 [0–1.55])

IPT group 24/26 TB cases susceptibility tested – 2 with INH monoresistance, 1 MDR; RIF/PZA group 19/19 TB cases tested – 0 RIF monoresistance, 2 MDR

14 (3.8%) IPT and 19 (5.0%) RIF preventive therapy patients developed TB. Seven had suspectibility testing, 2 resistant to INH, not signficantly different from the 180 other MTB isolates from TB patients without preventive therapy.

19 INH culture-positive patients vs 22 culture-positive controls, 2 resistant/17 tested (INH) vs 0 resistant/21 tested (control) – risk for resistant TB/1000 – 10.05 vs 1.46 (RR 6.88 [0.01–3882.85])



101

Study Johnson et al. Kawai et al. Mosimaneotsile et al.

Moreno et al. Mugisha et al. Mwinga et al.

Publication year 2001 2006 2009 1997 2006 1998

Methods/design Randomized placebo-controlled trial

Retrospective review of MDR TB in a prospective TB treatment trial

Cohort prospective – no placebo group, part of ongoing trial

Historical cohort, not blinded

Retrospective IPT review – feasibility of service provision study

Randomized double-blind placebo-controlled trial

Data collection Mar 1993–Apr 1995 Feb 1999–July 2000 2004–2006 1985–1994 Sep 2001–Sep 2003 (25-month period)

Aug 1992–Jul 1994

Population Uganda, HIV-positive, 18–50 years, TST±, no history of TB

Peru, TB patients identified and treated. Risk factors for MDR TB retrospectively reviewed

Botswana, HIV-positive

Spain, 121 HIV-positive and PPD-positive

Uganda Zambia, HIV-positive, no TB treatment history, both TST-positive and -negative patients; 1.8 years’ median follow up

Sample size 2736 TST-positive and -negative HIV-positive adults, 2018 TST-positive => 536 INH prophylaxis => 459 completed and evaluated

224 patients diagnosed with TB, commenced on TB directly observed treatment, short-course (DOTS)

1995 (72% female, age 18–70 years, no TST criteria

29 INH (median follow up 89 months)

6305 HIV-positive => 3366 TST => 894 TST-positive => 506 IPT => 335 completed

Of 2063 HIV-positive => 1053 subjects => 350 INH

Comparison group Of 2018 TST-positive => 464 placebo => 318 completed and evaluated

No control, part of ongoing trial

92 no treatment (median follow up 60 months)

351 on RIF/352 on placebo

TB – latent/nil Latent Current TB No/latent TB (not treated in past)

Latent Latent No TB and latent TB

Treatment regimen INH 6 months, INF+RIF 3 months, INH+RIF+ PZA 3 months, or placebo 6 months

INH 6 months + pyridoxine 25 mg

9–12 months of INH 9 months in a 12-month period INH 300 mg/25 mg pyridoxine

6 months’ INH twice a week

?? No placebo/no review

No treatment RIF + PZA twice/week, OR placebo

Outcomes 3 definite, 2 possible incident, 3 possible deaths

Resistance information

TB cases INH vs control = 36 vs 46, resistant/total tested – 5/20 vs 1/24

MDR TB is associated with previous TB treatment; found an association with previous IPT

0 out of 3 culture-confirmed TB cases were resistant to INH

3 TB cases INH vs 39/43 tested in no treatment group. Resistance 2 out of 2 tested INH vs 0/12 tested no treatment. Risk for resistance 118.64 vs 5.41 (21.95 [0.04–11 582.31])

5/533 on IPT developed TB; 4 had been on treatment for many months

96 TB cases in all three groups, culture results 26 => sensitivity results for 12 only. One placebo patient resistant to INH

Findings/comments Risk for resistant TB/1000 13.69 vs 3.39 (RR 4.04 [0.50–32.80]) INH vs placebo

At the infectious diseases unit where all patients were HIV-positive, 30 (47%) of them had MDR TB. Multiple regression analysis revealed that MDR TB was associated with previous TB preventive therapy (hazard ratio [HR] 16, 95% CI: 2.8–85, P < 0.002)

Eighty-six per cent (1710/1995) were adherent to the entire 6-month course of IPT

Median survival was more than 111 months in patients who received isoniazid compared with 75 months in patients who did not receive isoniazid (P < 0.001).

The prevalence of INH resistance in Uganda was 6.7% in previously untreated cases in surveillance from 1996 to 1997, --portion of IPT patients will develop disease – IPT would not be expected to be effective.

Annex 10

102

Study Pape et al. Rivero et al. Saenghirunvatta et al.

Zar et al. le Roux et al.

Publication year 1993 2003 1996 2007 2009

Methods/design Randomized clinical trial

Randomized clinical trial

Prospective trial Prospective double-blind placebo-controlled trial

Prospective trial

Data collection 1986–1989 Jun 1994–Dec 1998 1994–1995 Jan 2003–May 2004 December 2002–March 2008

Population Haiti, asymptomatic HIV-positive 18–65 years, no TB history, 118 enrolled (77% female)

Madrid and Andalusia, Spain, HIV-positive patients 18–65 years with TST anergy, no TB history/treatment

Thailand, HIV-positive

South Africa, HIV-positive children >8 weeks (median age 24.7 months), average 5.7 months’ follow up

South Africa, children >8 weeks, median age 25.9 months, average 25 months’ follow up

Sample size 58 on INH+B6 Of 319 HIV-positive => 83 on 6 months’ INH

46 HIV-positive => 10 IPT

263 HIV-positive => 132 IPT

276 patients 171 prophylaxis, 105 placebo

Comparison group 60 vitamin B6 alone 82 3 months’ RIF/ 77 in 2 months’ RIF+PZA / 77 in no treatment group (follow up 88 person-years INH for six months group / 96 person-years RIF 3 months / 81 RIF plus PZA 2 months / 126 person-years no treatment group)

36 controls – no therapy

131 placebo 105 placebo

TB – latent/nil No TB history No TB history If previous TB, placed on therapy, and once completed, placed on trial

No TB history

Treatment regimen 12 months daily INH 300 mg+ pyridoxine (50 mg)

INH 6 months 12 months 300 mg INH daily

INH three times/week

INH daily 43%, 3x per week 57%

Comparison 12 months’ pyridoxine only

RIF + INH 3 months / RIF 2 months / no treatment

No treatment Placebo three times/week

Placebo daily 49%, 3x per week 51%

Outcomes

Resistance informationComments

11/60 vit B6 and 4/58 INH patients had TB; 0 out of 15 TB patients had any drug resistance (all responsive to TB therapy)

11 cases TB overall, 2/3 in INH group resistant to INH, 0/3 in RIF 3 months, 1/1 resistant to INH PZA+RIF in 2-month RIF group, 4/4 resistant to INH+Strep in no treatment group

Small numbers

0/10 AND 1/36 cases TB, no resistance

Small sample size2

TB incidence INH 5/132 vs placebo 13/131. Incidence of resistant M. tuberculosis infection did not increase in children on prophylaxis.

At enrolment, 9% on HAART, by end 31%

22/41 children who were diagnosed with TB were taking daily prophylaxis (P = 0.53). Two diagnosed with MDR TB; both were on daily prophylaxis and had mean adherence below 90%.


103

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Annex 10

104


Providing IPT for people living with HIV who are unlikely to have active TB does not significantly increase the risk of developing INH-resistant TB. Therefore, concerns regarding the development of isoniazid resistance should not be a barrier to implementing IPT programmes. Population: People living with HIV Intervention: Programmatic implementation of IPT for people living with HIV in resource-constrained settingsAction: Concerns regarding the development of isoniazid resistance should not be a barrier to implementing IPT programmes.Factor Decision Explanation Quality of evidence Moderate • Direct evidence from a number of studies and meta-analyses

• Comparison of those on IPT with those receiving placebo shows no significantly increased risk.


Strong

• IPT prevents active TB in people living with HIV. • IPT can be given with no significant risk of developing INH-

resistant TB.• The rare patients who do develop INH mono-resistance can

be treated successfully with routine TB treatment.• Treating mono-RIF resistant LTBI with IPT can prevent

future MDR (INH- and RIF-resistant) TBRisks or undesired effects

• Minimal risk that patients will develop TB while on IPT • Minimal risk that those who develop TB will develop INH-

resistant TB• Minimal risk that those who develop INH resistance will be

untreatable • Minimal risk of transmission of INH resistance • Minimal risk of development of MDR TB due to using IPT in

the face of pre-existing mono-RIF resistant TB • High INH resistance may reduce efficacy of IPT

Values and preferences Strong • IPT is a valuable TB prevention intervention with considerable potential to prevent morbidity, mortality and TB transmission.

Costs Strong • Minimal risk of INH resistance not likely to increase cost as the majority of patients will not develop TB and those who do will likely be successfully treated with routine treatment

• MDR rare but potentially costly event (e.g. laboratory testing, second-line treatment, extended duration)

Feasibility • May be difficult to overcome health-care workers’ concerns regarding development of TB drug resistance

• Evidence and experience strongly supports implementation.Overall ranking of recommendation



105

References1. Campos PE et al. Multidrug-resistant Mycobacterium tuberculosis in HIV-infected persons, Peru. Emerging Infectious

Diseases, 2003, 9:1571–1578.2. Churchyard GJ et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans:

time to change policy? AIDS, 2003, 17:2063–2070.3. Golub JE et al. Long-term effectiveness of diagnosing and treating latent tuberculosis infection in a cohort of HIV-

infected and at-risk injection drug users. Journal of Acquired Immune Deficciency Syndromes, 2008, 49:532–537.4. Gordin F et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an

international randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS, the Adult AIDS Clinical Trials Group, the Pan American Health Organization, and the Centers for Disease Control and Prevention Study Group. Journal of the American Medical Association, 2000, 283:1445–1450.

5. Halsey NA et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet, 1998, 351:786–792.

6. Hawken MP et al. Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial. AIDS, 1997, 11:875–882.

7. Johnson JL et al. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS, 2001, 15:2137–2147.

8. Kawai V et al. Tuberculosis mortality, drug resistance, and infectiousness in patients with and without HIV infection in Peru. American Journal of Tropical Medicine and Hygiene, 2006, 75:1027–1033.

9. le Roux SM et al. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules. BMC Medicine, 2009, 7:67.

10. Moreno S, et al. Isoniazid preventive therapy in human immunodeficiency virus-infected persons. Long-term effect on development of tuberculosis and survival. Archives of Internal Medicine, 1997, 157:1729–1734.

11. Mosimaneotsile B et al. Isoniazid tuberculosis preventive therapy in HIV-infected adults accessing antiretroviral therapy: a Botswana experience, 2004–2006. Journal of Acquired Immune Deficiency Syndromes, 2009, 54:71–77.

12. Mugisha B et al. Tuberculosis case finding and preventive therapy in an HIV voluntary counseling and testing center in Uganda. International Journal of Tuberculosis and Lung Disease, 2006, 10:761–767.



15. Rivero A et al. [Randomized trial of three regimens to prevent tuberculosis in HIV-infected patients with anergy]. Enfermedades Infecciosas y Microbiología Clínica, 2003, 21:287–292.

16. Saenghirunvattana S. Effect of isoniazid prophylaxis on incidence of active tuberculosis among Thai HIV-infected individuals. Journal of the Medical Association of Thailand, 1996, 79:285–287.

17. Zar HJ et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. British Medical Journal, 2007, 334:136.

Annex 10

106

Annex 11: Summary of findings and quality of evidence: adherence to preventive therapy

PICOT Question: Will low adherence rates to treatment for LTBI be a barrier to the implementation of LTBI treatment among people living with HIV?

Population: Adults living with HIV/AIDS in areas where TB prevalence is >30%Intervention: Good adherence to LTBI treatment (>80% medication taken)Comparison: Poor adherence, i.e. <80%Outcomes: Consider only outcomes graded critical in the table belowTimeline: Lifetime (although no study has lifetime follow up)

Population: Children (<15 years) living with HIV/AIDS in areas where TB prevalence is >30%Intervention: Good adherence to LTBI treatment (>80%) Comparison: Poor adherence, i.e. <80%Outcomes: Consider only outcomes graded critical in the table below Timeline: Lifetime (although no study has lifetime follow up)



Outcomes for individuals Relative score Severity index Prevention of deaths from TB 8 CriticalPrevention of TB transmission 8 CriticalReduction in incidence of TB 9 CriticalAcceptably low rate of adverse effects 7 CriticalOutcomes for programmesService uptake justifies staff allocation 8 CriticalResource allocation 8 CriticalTime allocation 7 Less critical

Medline and Embase were used to locate appropriate articles. Keywords: latent TB infection treatment, adherence, HIV PLWHA, isonazid prophylaxis

Adults

Children

Inclusion criteriaTrials (randomized controlled trials/observational studies) that involved LTBI treatment in an unselected HIV population (adult or child) and commented on adherence with reference to how it was monitored,

outcome with regard to adherence (if possible), and made qualitative and quantitative statements with regard to achieving good adherence.

107

Search strategy

Articles identified:

Selected by title:

Selected by abstract:

After reading:

Additional material:

Reviewed:

63

47

24

6

9

15


Unlike treatment for TB which, if unsuccessful, could result in severe morbidity, death and further TB transmission, IPT is a preventive

measure, and whether an individual is adherent and the degree to which they are adherent primarily only directly impacts their personal risk for TB. There are a variety of perspectives on adherence including how many people are lost to follow up, or

how many complete treatment, and how many take most of their tablets. It has been suggested that taking >80% of a course of IPT can be considered successful completion of treatment.[1] This has been interpreted in a number of ways: taking six months’ treatment within nine months, collecting more than 80% of tablets, taking >80% of the regimen. We have specified how adherence has been measured

Annex 11

108

Study/author and year Population Location Regimen Method of adherence measurement (good adherence)

Adherence rates

Randomized controlled trial (RCT)/observational study (OS); Halsey et al. Lancet 1998 [3]

784 Haiti INH twice weekly 6/12 or PZA+RIF twice weekly 2/12

Clinic visit attended (>80%)

74% patients taking RIF+PZA

RCT/OS; Hawken et al. AIDS 1997 [2]

1053 Uganda INH twice weekly 6/12 or RIF+PZA twice weekly for 2/12

Pill collection/self-report/return within one month of last dose (collect 80–100% tablets, self-report taking >80% tablets)

74%

OS; Lugada et al. Int J Tuberc Lung Dis 2002 [15]

98 Uganda INH daily 6/12 Self-report/pill collection/urine (collect pills within 2 weeks of end of last prescription or positive urine)

88% by urine, 76% by pill collection

OS; Munseri et al. Int J Tuberc Lung Dis 2008 [8]

565 Tanzania INH daily 6/12 Not documented 87% (NB: 4% physician terminated)

OS; Mohammed et al. Int J Tuberc Lung Dis 2007 [6]

118 Cape Town INH daily 12/12 if TST-positive or randomized to INH despite TST-negative or placebo if randomized to that and TST-negative

Pill counts, supervisor tick sheet (not given)

Median percentage of doses taken per subject 81.2–91.7% (placebo – open label INH)

in the studies reviewed for the guidelines. Studies examining the effect of individual adherence at a population level have not been performed; this is not surprising as any study designed to evaluate the effect of poor adherence on community levels of TB or latent TB would involve very large numbers with long-term follow up and, as yet, there are few places implementing IPT on such a large scale to allow this to be accurately and meaningfully studied.

There are few studies that look at the effect of individual adherence on individual outcome. One study [2] attempts to link adherence with outcome (note, though, that the study [probably due to inadequate power] does not show the overall benefit of IPT over placebo in preventing TB, see GRADE proforma attached). If the definition of poor adherence is not finishing the course of treatment then those patients lost to follow up in the studies represent poor adherence; and the outcomes of patients who default would answer the question of the effect of adherence on individual outcomes – there are no studies on this issue for patients with HIV. It is sometimes assumed that those who default are equivalent to those untreated, that the non-adherer returns to baseline TB risk and that the question of poor adherence affecting individual outcome is the same as asking whether treatment for LTBI is efficacious. However, this is by no means certain as it may depend on the amount of IPT taken—it is biologically plausible that even some IPT may be better than none.

There are no studies that show the graded response of adherence to individual outcome, e.g. outcome by “adherent patient months”, which would be

interesting. For example, is adherence to five months of IPT equivalent to not taking the medication and/or what is the difference between adherence to six months or nine months of treatment? If there is a graded response on an individual basis to varying levels of adherence, this may have a knock-on effect on population transmission, but again, this has not been studied.

There has been some discussion in the literature suggesting that if adherence to an LTBI prevention programme is low it may reduce the enthusiasm of staff to run one and will potentially raise unit costs. However, this is not reported by the studies as an outcome measure and is often written from a TB programme’s perspective where the traditional focus has been treatment of active TB. HIV services, having experience with long-term prophylaxis such as co-trimoxazole, may have a different chronic or preventive care perspective. The issue of adherence and drug resistance is often raised. Despite a thorough review, no study has been identified that assesses this theoretical risk.

Although data are not available, the assumption is that good adherence will lead to better outcomes and the search brought up a number of studies that examined factors that affect adherence including social, personal, clinical and programmatic interventions. If IPT is offered as part of chronic care for people living with HIV then it may benefit from other efforts to improve adherence. The table below provides a summary of adherence and an approximation of how it has been measured by both the randomized controlled trials (RCTs) and observational studies (OS) that looked at adherence.


109

Study/author and year Population Location Regimen Method of adherence measurement (good adherence)

Adherence rates

Data review; Rowe et al. Int J Tuberc Lung Dis 2005 [10]

87 South Africa INH daily 6/12 Collection of pills (collect 6 months medicines in 9/12 period)

47%

OS; Szakacs et al. BMC Infect Dis 2006 [12]

301 South Africa INH daily long term Urine dipstick one-off 72%

OS; Ngamvithaypong et al. AIDS 1997 [9]

412 Thailand 9/12 daily INH Monthly pill count 67.5%

OS: Mosimaneotsile et al. JAIDS 2009 [7]

1995 Botswana 6/12 INH 2-monthly pill count and clinic attendance

86%

OS: De Souza et al. MIOC 2009 [16]

138 Brazil 6/12 INH Pill count 87.7%

RCT; Whalen et al. N Engl J Med 1997 [17]

2018 Uganda INH+RIF 3/12 or INH+RIF+PZA 3/12 or INH 6/12

Self-report and clinic attendance

Antonnucci et al. Eur Respir J 2001 [18]

40 Italy INH 6/12 Self-report 34.5% 100% compliant

RCT; le Roux et al. BMC Med 2009 [5]

324 children South Africa INH daily or 3 x week 6/12

Pill count and self-report 94.7%

Summary

There is no evidence available to accurately answer whether low adherence rates to treatment for LTBI should be a barrier to

implementation of treatment for LTBI among people living with HIV. However, some useful information can be derived from the published studies that include adherence information. Firstly, adherence data vary between studies (47–94%). However, the studies that achieved higher adherence rates are not always feasible models for scaling up service; they may provide transportation fees to attend clinic appointments [4,6] or incentives on arrival. There is also mention of ineligibility for IPT due to the possibility of poor adherence, which would mean adherence rates are higher than would be achieved in routine programme conditions. It is noticeable that adherence in observational studies that reviewed retrospective adherence in a non-trial setting have lower rates of adherence.[10,12,18] The only published data [2] that linked adherence to LTBI treatment in an HIV-infected population to risk of TB found no increased risk of TB in poor adherers compared with those who

adhered well.[2] This supports the proposal that even if adherence is less than desirable, individual outcomes are not affected. There are no published data suggesting a link between poor adherence and the development of mono-isoniazid resistance. The factors addressed in the research setting, however, are not those that subjects comment on as reasons for poor adherence in the qualitative assessments reported. Side-effects or toxicity are also not mentioned as a risk factor for poor adherence. These conclusions compare favourably with the community consultation document [see Annex 4] and represent opportunities for programme implementation to improve adherence in the design and running of an LTBI programme. Additional research is needed on operationalizing IPT in a patient-centred manner which can improve adherence; however, it must also be recognized that IPT is a preventive measure and non-adherence impacts the individual’s future risk of developing TB. The Guidelines Group made a strong recommendation that concerns regarding adherence should not be a barrier to implementing treatment for LTBI.

Annex 11

110


Concerns regarding adherence should not be considered a barrier to implementing treatment for LTBI.Population: People living with HIV Intervention: Implementation of IPT regardless of adherence concernsAction: HIV programmes should implement IPT Factor Decision Explanation Quality of evidence Low • Studies where adherence is not a measured outcome

• Observational studies with limited patient numbers• Qualitative assessments by interviews with small numbers

of patients (adherent and non-adherent)• Wide variety of adherence-related factors suggesting that

local context is important Benefits or desired effects

Strong

Adherence will:• Reduce TB transmission• Reduce morbidity and mortality secondary to TB • Improve overall impact of the programme


• Extra work for clinic staff• Extra cost in terms of patient information materials

Values and preferences Strong • People living with HIV will appreciate a complete package of HIV/TB care.

• People living with HIV will benefit from lack of active TB disease as a result of IPT.

Costs Strong Increased by:• Initiation of a programme that is not currently running

will entail extra costs in terms of staff, equipment, drugs, storage space, clinic time, patient time

Decreased by:• Overall costs decrease by efficacy of LTBI treatment

programme • Community involvement in programme• Less spending on treatment of active TB (initial or

secondary cases)Feasibility Strong • Fits well within HIV care structure

• Drug staff are familiar with its use • ART programmes are familiar with focusing on adherence

issuesOverall ranking of recommendation



111

References1. De Cock KM, Grant A, Porter JD. Preventive therapy for tuberculosis in HIV-infected persons: international

recommendations, research, and practice. Lancet, 1995, 345:833–836.2. Hawken MP et al. Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized

controlled trial. AIDS, 1997, 11:875–882.3. Halsey NA et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in

HIV-1 infection. Lancet, 1998, 351:786–792.4. Hiransuthikul N et al. INH preventive therapy among adult HIV-infected patients in Thailand. International Journal of

Tuberculosis and Lung Disease, 2005, 9:270–275.5. le Roux SM et al. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial

comparing two dosing schedules. BMC Medicine, 2009, 7:67.6. Mohammed A et al. Randomised controlled trial of isoniazid preventive therapy in South African adults with advanced

HIV disease. International Journal of Tuberculosis and Lung Disease, 2007, 11:1114–1120.7. Mosimaneotsile B et al. Isoniazid tuberculosis preventive therapy in HIV-infected adults accessing antiretroviral

therapy: a Botswana experience, 2004–2006. Journal of Acquired Immune Deficiency Syndromes, 2009, 54:71–77.8. Munseri PJ et al. Completion of isoniazid preventive therapy among HIV-infected patients in Tanzania. International

Journal of Tuberculosis and Lung Disease, 2008, 12:1037–1041.9. Ngamvithayapong J et al. Adherence to tuberculosis preventive therapy among HIV-infected persons in Chiang Rai,

Thailand. AIDS, 1997, 11:107–112.10. Rowe KA et al. Adherence to TB preventive therapy for HIV-positive patients in rural South Africa: implications for

antiretroviral delivery in resource-poor settings? International Journal of Tuberculosis and Lung Disease, 2005, 9:263–269.

11. Scardigli A et al. Responding to the challenge of patients adherence to IPT: experience of an urban ART facility in Mozambique. PEPFAR Implementing Meeting, Namibia, 11 June 2009.

12. Szakacs TA et al. Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa. BMC Infectious Diseases, 2006, 6:97.

13. WHO, UNAIDS. Consultation for the revision of WHO/UNAIDS policy statement on Preventive Therapy against TB for PLWHIV. 2010. [Annex 4]


15. Lugada ES et al. Operational assessment of isoniazid prophylaxis in a community AIDS service organisation in Uganda. International Journal of Tuberculosis and Lung Disease, 2002, 6:326–331.

16. Souza CT et al. Effectiveness and safety of isoniazid chemoprophylaxis for HIV-1 infected patients from Rio de Janeiro. Memórias do Instituto Oswaldo Cruz, 2009, 104:462–467.


18. Antonucci G et al. Guidelines of tuberculosis preventive therapy for HIV-infected persons: a prospective, multicentre study. GISTA (Gruppo Italiano di Studio Tubercolosi e AIDS). European Respiratory Journal, 2001, 18:369–375.

Annex 11

112


PICOT Question: Is the treatment of LTBI in people living with HIV cost effective?

Population: Adults living with HIV in areas where the prevalence of LTBI is >30%Intervention: Treatment for LTBI

Comparator: No treatment for LTBIOutcome: See belowTimeline: Lifetime



Outcomes Relative score Severity status Cost of screening for and treating LTBI related to the cost of treating active TB that would occur in the absence of treatment for LTBI

9 Critical

Cost of treatment of LTBI related to the cost of treating active TB, i.e. does not take screening costs into account

8 Critical

The Medline and Embase databases were used.

Keywords: IPT, latent TB infection treatment, PLWHA, HIV, latent TB treatment, preventive TB treatment, cost-efficacy, cost-effectiveness, cost analysis

Inclusion criteria: LTBI programme in HIV-positive individuals, clearly defined cost inclusive of screening for eligibility for preventive therapy, and estimate made of savings, again clearly defining where costings estimated from and documenting assumptions with regard to TB and programme implementation

Previous PICOT discussions have shown LTBI treatment to be efficacious, safe and an important tool for preventing TB in people living

with HIV. However, there are significant demands on limited funds within HIV programmes, which raise the issue of the cost effectiveness of treatment for LTBI.

113

Articles identified:

Selected by title:

Selected by abstract:

After reading:

Additional articles supplied by Guidelines Committee or sourced from references in other articles

Reviewed:

113

50

14

13

13

8

There were no studies on cost efficacy specifically related to children. There were also no studies on cost efficacy in a population with HIV living in an area with low TB prevalence.

Annex 12

114


The GRADE system is designed to review interventions scored on a number of outcomes. Cost efficacy can be an outcome; however,

the articles that deal directly with cost-efficacy do not specifically have an outcome or control group

and are therefore difficult to assess within the GRADE approach. Therefore, GRADE software and methodology has not been used to answer this particular question.[1]

Published literature on cost-efficacy of IPT in HIV-infected populations

Although the GRADE software has not been used to review the published literature, the principles encompassed within GRADE

(transparent assessment looking at directness, consistency, precision) can be applied. This allows for an assessment of the quality of evidence available and a strength of recommendation that is possible to make from the available studies. Cost considerations are very situation specific – cost of human resources, transportation, training, inpatient care and investigations varies widely between locations; this means that any comparison has to be based on cost relative to an outcome. However, the limited literature does not use a standardized

measure to assess cost. Some studies chose to measure cost per quality-adjusted life year (QALY), some cost per TB case averted, some cost of TB in the person receiving IPT, some cost per averted TB case and averted secondary cases. There is also the issue of economic perspective: cost to the health-care system, cost to the patient, cost inclusive of screening for TB prior to treatment (by a variety of means), and cost of screening for HIV (see tables below). This variability renders direct comparison between studies difficult. Each study is best assessed on its individual merits and the results accumulated in order to formulate a recommendation.

Trial Setting and set-up Assumptions Outcomes Directness Precision Comment

Foster et al.AIDS, 1997, 11:919–925

Zambia district hospital, 6 months’ IPT after initial HIV test, clinical examination, smear, chest X-ray, confirmatory HIV test.Cost of IPT vs cost of treating TB (2/12 in hospital, drugs, diagnostics, lost earnings, health service costs)1000 patients, spreadsheet model

Efficacy of IPT 45–75%Adherence 50–80%Likelihood of developing TB 25–40%Secondary cases 2–5Costs taken from 1997 programmatic costs, no data on where assumptions come from, TB and HIV incidence from local data

Measured in benefit–cost ratio 0.38–3.86 or including patients’ lost wages0.86–6.12(greatest being most efficacious with maximal infectivity)

Relevant setting BUT a model, i.e. not based on reality, and in terms of population assumed around 30% HIV seropositivity with costs inclusive of 2 HIV tests

Wide variability given assumptions. Note benefit–cost ratio significantly >1 only when patient earnings taken into account

Initial population not all HIV-positive

Shrestha et al. Int J Tuberc Lung Dis, 2007, 11:747–754

Urban Uganda (VCT centre). No HAART. Cost of IPT includes screening with questionnaire, smear, chest X-ray, physical examination, TST or treat all, i.e. no TST. Also included staff, training, equipment, space costs with decline over years of programme, no start-up cost. IPT means either 6 or 9 months of INH. Cost discount rate of 3% per year. Markov cohort simulation

Costs supplied from programmatic costs with a range. TST sensitivity 0.2–0.9TST specificity 0.65–0.98Adherence 0.445–0.99Risk of developing TB in controls 0.034–0.1All-cause mortality per year 0.047–0.141Adverse events 0.014–0.041Protection provided by IPT 1–5 yearsFor QALY, survival of HIV-infected individual estimated

Expected QALY with no intervention 498, with targeted TST testing 509 and with a treat-all strategy 539. Cost per QALY of targeted testing averaged $102, cost per QALY gained for treat all $106 (NB: if TST sensitivity is less than 0.52 as might be expected in advanced HIV, then target testing becomes more expensive at $115 per QALY)

Modelled so by necessity not completely transferable

Wide range of results, given variable assumptions. Consistent

Authors comment on non-HAART population.


115


Hausler et al. Bull WHO, 2006, 84:528–536

Part of ProTEST, Cape Town PHC, STI, CHC clinics. Costs from clinic data note cost of ICF/IPT included screening for active TB with smear, TST, chest X-ray, physical examination, also included personnel time and start-up, building, vehicle and coordination costs. Rated against number of cases of TB prevented.

Each case of TB infects 1–14 cases per year.ICF decreases infectious period from 9.6 months by 30%, so for every 100 cases picked up by ICF, 25 cases of TB are prevented. For IPT, the assumed incidence of TB decreases by 60% for 2 years if TST-positive (if adherence 60–80%)1, annual incidence of TB in TST-positive HIV-positive individuals is 8% and each case causes one other. Therefore, for every 100 people completing IPT using TST, 19 cases of TB are averted.

Cost per case of TB prevented by IPT $486–962 (PHC-CHC) but a 36% reduction if chest X-ray removed from screening equation. Removing TST reduces cost by 60% but cost per case prevented by only 4% as IPT is less efficacious.

The assumptions made are from generally well accepted data. The population studied is relevant. Specific costs are of course site- and country-specific (note significant variation from PHC to CHC in same location)

Consistent and plausible variation in cost due to different site.

Note: authors argue cost-effective with TST, and could be more so without chest X-ray.

Bell et al. AIDS, 1999, 13:1549–1556

Model based on reported costings in the literature and using assumptions for the literature. Modelled the effect of 3 preventive therapy strategies: INH 6/12, INH + RIF 3/12, twice weekly RIF+PZA for 2/12. Used a Markov model with 3% discount rate and costs inclusive of indirect social costs and well as cost of secondary cases of infection.2 Cost of preventive therapy included screening costs (with chest X-ray, smear, TST, drug cost, personnel in case of RIF+PZA includes cost of DOT and nutrition supplementation). Measured cost per case prevented and cost per QALY

TB rate if TST-positive 3.4–10% per annumSecondary cases 2–10 Efficacy of preventive therapy duration 1.5 years to lifetimeEfficacy of INH 23–86%, efficacy for INH +RIF 14–82%, efficacy for RIF+PZA 30–90%, adverse events mild/severe 0.25 per month–0.99 per day

Taking all extremes of assumptions and varying costs (halving or doubling) does little to change overall outcome. Compared with cost of treating TB, preventive therapy is cost saving only if social costs are included. However, all regimens are cost reducing in terms of cost of treating TB if incidence of secondary infection is >2.4

Translatable to answer the question

Wide variability in costings and efficacy data exists and are used; however, does not alter overall outcomes.

In a sense, a meta-analysis of cost-efficacy data

Masobe et al. S Afr Med J, 1995, 85:75–81

South Africa predominantly high TB prevalence area. Costs included TST in those from low-prevalence background, cost of drug (INH), clinical services, treatment of INH hepatitis, transportation and breakthrough TB compared with cost of treating TB and secondary TB cases.Costs estimated in 1993 SA Rand with 4% discount rate taken from consensus view of functional TB programme. Estimate 8-year follow up

Assumed 97.2% of patients from high-risk TB background, 2.8% from low risk. TST-positive in 5%. Assume risk of 4.68 adult and 3.2 child secondary cases per active TB case and 6% of contacts develop TB. Annual rate of TB in HIV-positive 5–8%, INH efficacy 90%, compliance 68.5% and INH hepatitis rate 0.48%.

Over 8 years’ cost saving of R 40 551 952(assumed prevent 21 800 cases of active TB)If compliance only 41% then saving only R10.5 million

Translatable to answer the question Direct in terms of applicable setting

Some sensitivity analysis commented on in terms of compliance, 41–68% and sensitivity analysis in terms of discount rate. Still cost-saving

1 Bucher et al. Isonazid prophylaxis for TB in HIV infection: a meta-analysis of randomized controlled trials. AIDS, 1999, 13:501-507.2 Cost taken from Saunderson. Social Science and Medicine, 1995, 40:1203-1212, Foster et al., AIDS, 1997,11:919-925, Aisu et al., AIDS, 1995, 9:267-273.

Annex 12

116


Observational studies of cost (not always compared with outcomes)

Sutton et al.Int J Tuberc Lung Dis,, 2009, 13:713–718.

Cambodia analysis of figures from 2003 to 2006 of running programme. Cost of IPT includes drugs (INH 9/12) and transportation of drugs, cost of patient transportation, cost of screening X-ray and clinical time, capital cost, human resource costs including training and education. Number of patients from their centre, cost from the centre. Compliance (completion rate) 86%

Assume annual TB incidence in HIV-positive population (where TST result not known) is 8%, assume that IPT reduces TB incidence by 60% for 2 years. Assume 17/100 patients taking IPT are the number of TB cases prevented. Estimate that there is 1 secondary case in an HIV-positive person per active case.

Cost per TB case prevented $955 (if 13/100 cases prevented), cost per case prevented $1274 but if 25/100 then falls to $764

Study direct, relative Costs similar to those reported in other studies

Note 88% of patients without active TB were deemed ineligible for IPT (pregnant,alcoholic liver disease, poor adherence likely)

Terris-Prestholt et al. Cost Effectiveness and Resource Allocation, 2008, 6:2

Zambia ProTEST initiative facilitating care programme. Cost of running programme (not clear exactly what included) from 3 sites, cost of IPT does not specify if includes screening. Costs from 2007 converted to USD.

All real-time costs, i.e. no estimate of efficacy or protection but sensitivity analysis performed to look at variation of compliance

Cost per person completing IPT $29–38 (NB: cost per person starting IPT $7–18)overall though altering compliance has less than 10% effect on unit costs

Real-time costings Similar in terms of cost to other studies

No attempt to analyse in terms of efficacy

The Guidelines Group made a strong recommendation that, while there is significant variation between the studies assessed, the

literature suggests that treatment for LTBI is likely to be cost effective. In some studies, there are a number of factors that must be taken into consideration to justify this conclusion. For example, one study [2] argues that the intervention is cost efficacious only if the social cost of having TB and treating TB are taken into consideration, and another study [3] discovered that the intervention becomes cost effective only if each TB case creates five secondary cases, all of which need treatment. In some studies, there are interesting programmatic alterations that dramatically affect cost. A study [4] found that the inclusion of chest X-ray in screening reduced cost efficacy; another study [5] found that the use of

TST reduced the cost of IPT. Yet another study [6] showed that reduction in patient compliance reduced the overall cost savings. None of the studies have been conducted in a population that was also on ART, and this would potentially change costs as well as the additional efficacy of IPT, and the number of secondary active TB cases among people living with HIV. There is considerable room for further research in this area, particularly given the recent improvements in HIV services and the emphasis on an integrated approach to TB and HIV prevention, care and treatment. The strong recommendation supports the overall recommendation for the wide use of IPT within comprehensive HIV prevention, care and treatment services, both as a measure of good clinical practice and as a likely cost-effective measure.

Annex 12Annex 12: Summary of findings and quality of evidence: cost effectiveness

117


Treatment of LTBI should be considered cost effective in people living with HIV.Population: People living with HIV Intervention: Implementation of IPT programme Action: HIV programmes should not avoid the addition of LTBI treatment to their service on cost grounds Factor Decision Explanation Quality of evidence Low • Limited number of studies with inconsistent outcomes

means that cumulative evidence is weak.• Studies are hypothetical with variable assumptions made

with regard to TB incidence, transmission and efficacy of IPT.

• All studies report IPT to be cost effective.Benefits or desired effects

Strong

• Will allow programmes to start LTBI treatment programmes as part of a package of HIV care

• Will save money within HIV and TB programmes which can be re-allocated to other parts of the programme

• Considering LTBI treatment cost effective and therefore initiating IPT programmes will reduce TB transmission, active TB in the individual and potentially realize the benefits listed for recommendation of IPT


• Initial costs will be higher since all studies show cost efficacy over >2-year period and not in the first year of a programme.

• Given the limited data from studies, it is possible that a universal roll-out of IPT may have unforeseen costs (not accounted for on a smaller scale).

Values and preferences Strong • For the individual, it is likely that cost efficacy is unimportant.

• For programmes, being able to justify IPT provision as cost effective will satisfy donors and financial backers.

Costs Strong Increased by:• Use of chest X-ray• Poor adherence• Longer regimen• Use of RIF+PZADecreased by:• Use of TST • Good adherence• Symptom screening

Feasibility Strong • The incremental cost in excess of HIV programme would be limited and feasibility improved as it would be an add-on to existing programmes and no capital investment would be needed.



Annex 12

118

References1. GRADE Working Group. Grading quality of evidence and strength of recommendations. British Medical Journal,

2004, 328:1490–1499.2. Aisu T et al. Preventive chemotherapy for HIV-associated tuberculosis in Uganda: an operational assessment at a

voluntary counselling and testing centre. AIDS, 1995, 9:267–273.3. Foster S, Godfrey-Faussett P, Porter J. Modelling the economic benefits of tuberculosis preventive therapy for

people with HIV: the example of Zambia. AIDS, 1997, 11:919–925.4. Shrestha RK et al. Cost-utility of tuberculosis prevention among HIV-infected adults in Kampala, Uganda. International

Journal of Tuberculosis and Lung Disease, 2007, 11:747–754.5. Shrestha RK et al. Cost-effectiveness of including tuberculin skin testing in an IPT program for HIV-infected persons

in Uganda. International Journal of Tuberculosis and Lung Disease, 2006, 10:656–662.6. Masobe P, Lee T, Price M. Isoniazid prophylactic therapy for tuberculosis in HIV-seropositive patients–a least-cost

analysis. South African Medical Journal, 1995, 85:75–81.7. Hausler HP et al. Costs of measures to control tuberculosis/HIV in public primary care facilities in Cape Town, South

Africa. Bulletin of the World Health Organization, 2006, 84:528–536.8. Bell JC, Rose DN, Sacks HS. Tuberculosis preventive therapy for HIV-infected people in sub-Saharan Africa is cost-

effective. AIDS, 1999, 13:1549–1556.9. Bucher HC GLGGS. Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled

trials. AIDS, 1999, 13:501–507.10. Saunderson P. An economic evaluation of alternative programme designs for tuberculosis control in rural Uganda.

Social Science and Medicine, 1995, 40:1203–1212.11. Sutton BS et al. The cost of intensified case finding and isoniazid preventive therapy for HIV-infected patients in

Battambang, Cambodia. International Journal of Tuberculosis and Lung Disease, 2009, 13:713–718.12. Terris-Prestholt F et al. Integrating tuberculosis and HIV services for people living with HIV: costs of the Zambian

ProTEST Initiative. Cost Effectiveness and Resource Allocation, 2008, 6:2; doi:10.1186/1478-7547-6-2.


119


PICOT Question: What is the best combination of signs and symptoms and diagnostic tools that can be used as a screening tool to identify children living with HIV who are eligible for treatment of LTBI and diagnosis of active TB?

Population: People living with HIV, children living with HIVIntervention: Combination of signs and symptoms and diagnostic tools that can be used as a screening tool to identify children living with HIV who are eligible

for treatment of LTBI and diagnosis of active TBComparison: TB prevalence without interventionOutcomes: Negative predictive value, sensitivity, specificity, positive predictive valueTimeline: 1–2 months during work-up for TB


Outcomes Relative score(rank 1 9 most critical)

Severity status

Negative predictive value (to identify children eligible for treatment of LTBI)

9 Critical

Sensitivity (to identify children for further diagnostic work-up)

9 Critical

Specificity 6 ImportantPositive predictive value 6 Important

120

International conferences: CROI, IAS, International AIDS conferenceCROI 2008, 2009: 0IAS 2009: 2IAC 2008: 2Abstracts of interest: 1

Search criteria:PubMed Search (“Child”[Mesh] OR “Child, Preschool”[Mesh]) OR “Infant”[Mesh]) AND “Tuberculosis”[Mesh]) AND “HIV Infections”[Mesh]) AND “Diagnosis”[Mesh]) OR (TB screening, Children, HIV)


(+ 17 added)

(+10 added from references)

57

20

By title

articles

By abstract

15

Of interest

Limits:Clinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial, evaluation studies, multicentre study, Medline, PubMed Central, all infant: birth–23 months, newborn: birth–1 month, infant: 1–23 months, preschool child: 2–5 years, child: 6–12 years

546

161


121

Annex 13

Studies of interest: A total of 16 articles/abstracts provided information on the clinical presentation of TB among HIV-infected children, or the utility of the TB scoring system in HIV-infected children, or a combination of signs and symptoms or diagnostic tests among HIV-infected children.[1–16]

Information available:There was only one study by Song et al. that looked at the combination of signs, symptoms and diagnostic tests among HIV-infected children.[1] Most of the identified studies presented information on the clinical presentation of TB among HIV-infected children and gave the frequency of various symptoms or the results of tests such as TST and chest X-ray among HIV-infected children with TB.[2–14] Two other studies evaluated the potential role of scoring systems for identification of TB in HIV-infected children.[15,16] Some review articles have summarized the difficulty in diagnosing

TB among HIV-infected children.[17,18] The WHO–CDC meta-analysis focused only on adults and adolescents and did not address children.[19]

An important challenge was the identification of an appropriate gold standard for the confirmation of TB among HIV-infected children. Among children with active TB, both sample collection and the yield of positive culture are generally thought to be low. Reviewed studies [2–16] used bacteriological confirmation of Mycobacterium tuberculosis by culture alone or in combination with radiological findings, TST reaction or response to antituberculosis therapy as the standard for comparison of the yield of various tests or symptom combinations. However, the difficulties encountered in confirming TB, even with the best available tests and technologies, severely limit the ability to identify practical approaches to the identification of TB in children.


Most of the studies [2–14] identified reported on the clinical presentation of TB among HIV-infected children or positivity of different tests

(such as TST or chest X-ray). However, they did not report on the best combination of symptoms or tests that could be used as a screening tool to identify TB among HIV-infected children.

Some studies [15,16] assessed the utility of scoring systems or consistency of different scoring systems in HIV-infected children. These scoring systems are limited by the absence of standard symptom definitions and adequate validation. Therefore, in their current form, their utility among HIV-infected children is limited. The scoring system used in Brazil worked equally well as the clinical algorithm for diagnosis of TB among HIV-infected children; however, its utility in high HIV- and TB-prevalence settings has not been tested and is uncertain.

A study by Marais et al.[7] suggested that an algorithm based only on signs and symptoms was a poor predictor of a diagnosis of TB among HIV-infected children. The presence any one symptom of persistent, non-remittent cough for more than two weeks, objective weight loss in the preceding three months, or reported fatigue reached a sensitivity

of only 0.56 and thus would fail to identify a large proportion of HIV-infected children with TB if used as a screening tool for diagnosis of TB in this population. This combination of symptoms had a specificity of 0.62.

A study by Song et al.[1] reported on the evaluation of TB screening among 303 HIV-infected children in Rwanda using a combination of signs and symptoms and diagnostic tests. The results of screening tests were compared to a gold standard of microbiological confirmation or chest radiograph findings characteristic of TB. Absence of cough for two weeks or more, failure to thrive and fever had a negative predictive value of 0.99. Half the children were found to have a negative symptom screen and would not need further evaluation. Only two children were found to have a false-negative test result when compared with the gold standard. The combination had a sensitivity of 0.90 and specificity of 0.65 for identifying children for further diagnostic evaluation of active TB. Addition of a positive TST to the combination increased the sensitivity to 0.95 with a slight reduction in specificity to 0.59. Thus, 95% of children likely to have TB would be identified by this combination and sent for further evaluation. However, 5% of children likely to have the disease would still be missed.

122

What is the best combination of symptoms and diagnostic tools that can be used as a screening tool to identify children for further diagnostic evaluation of active TB?Cough ≥2 weeks ± failure to thrive ± fever ± positive TST

Values and uncertainty around these Number of participants (studies) Quality of evidenceNegative predictive value

0.99 303 (1 study) LowSensitivity

0.95 303 (1 study) LowSpecificity

0.59 303 (1 study) LowPositive predictive value

0.14 303 (1 study) Low

Quality assessment

No. ofstudies

Design/no. of participants

Limitations Inconsistency Indirectness Imprecision Other considerations

Quality

Any one of cough ≥2 weeks, fever, or failure to thrive Negative predictive value 0.99

1 Observational study/303

Serious limitation*

No serious inconsistency

No serious indirectness

No serious imprecision#

Low

Sensitivity 0.90


Serious limitation*




Low

Specificity 0.651 Observational

study/303Serious

limitation*No serious

inconsistencyNo serious

indirectnessNo serious

imprecision#Low

Positive predictive value 0.14


Serious limitation*




Low

GRADE profile and summary of findingsWhat is the best combination of symptoms and diagnostic tools that can be used as a screening tool to identify HIV-infected children who are eligible for treatment of LTBI?

Culture and radiological appearance were used as a gold standard, which is not a perfect gold standard. Being an observational study and not having a well-defined gold standard, the study did not qualify for the highest quality of evidence. * The reference standard used is unlikely to correctly classify all the children with disease as having the disease. Moreover, sputum was collected only from children with signs and symptoms suggestive of TB or abnormal chest X-rays. # Confidence intervals for the sensitivity and specificity were not reported.


123

What is the best combination of symptoms and diagnostic tools that can be used as a screening tool to identify children for further diagnostic evaluation of active TB?Cough ≥2 weeks ± failure to thrive ± fever ± positive TST

Values and uncertainty around these Number of participants (studies) Quality of evidenceNegative predictive value

0.99 303 (1 study) LowSensitivity

0.95 303 (1 study) LowSpecificity

0.59 303 (1 study) LowPositive predictive value

0.14 303 (1 study) Low


Children living with HIV without poor weight gain,* fever and current cough are unlikely to have active TB and should be offered IPT.

Children living with HIV who are more than 12 months of age and who are unlikely to have active TB should receive six months of INH preventive therapy (10 mg/kg/day) as part of a comprehensive package of HIV care services.

After successful completion of treatment for TB disease, all children living with HIV who are more than 12 months of age should receive INH for an additional six months.

All children with a history of contact with a TB case should receive six months of IPT.

* Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than –3 z-score), or underweight (weight-for-age less than –2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flattening.

Population: Children living with HIV Intervention: Careful history-taking and clinical assessment Factor Decision Explanation Quality of evidence Moderate The quality of evidence is low and comes from one study by Song

et al.Benefits or desired effects

Strong

• Simplifies screening and limits the number of radiological and laboratory investigations

• Identifies children who can benefit from IPT (and thus reduces morbidity/mortality due to TB)


• A small number of children with active TB might be given monotherapy

• Increase in time spent by health-care workers in screening for TB

Values and preferences Strong • Parents would like their children to be protected from TB by provision of IPT, especially in settings with a high TB burden.

Costs Weak/conditional Increased by:• Training of clinicians and nurses to perform clinical

assessment and correctly determine poor weight gain• Additional staff required due to increase in time spent by

existing staff for screeningReduced by:• Limited resources needed for symptom screening among

children already regularly attending clinical services for HIV• Avoiding costs of additional diagnostic tests including chest

X-ray• Avoiding costs that would have been associated with

treatment of TB (if LTBI is effectively treated)Feasibility Weak History-taking and clinical assessment would be feasible

but would require additional training and time from already overburdened staff.


Strength of recommendationStrong (initial IPT for six months)Conditional (post TB treatment)

Annex 13

124

Children living with HIV with any one of the following: poor weight gain, fever or current cough may have active TB and should be evaluated for TB and other diseases.Population: Children living with HIV Intervention: Careful history-taking and clinical assessmentFactor Decision Explanation Quality of evidence Low The quality of evidence is low and comes from one study by Song

et al. Benefits or desired effects

Weak

• Early identification of TB suspects followed by appropriate treatment of identified TB cases can reduce TB-associated morbidity and mortality among children living with HIV.


• Increased demand for clinical and laboratory investigations• This approach would result in a larger number of children

undergoing diagnostic testing, including possible risks (generally not high) associated with sample collection (e.g. from lymph nodes or gastric aspirates)

Values and preferences • Patients/parents generally desire accurate diagnosis of disease and may be willing to undergo diagnostic evaluation or treatment in an effort to prevent morbidity/mortality.

Costs Weak Increased by:• Increase in number of children requiring diagnostic

evaluation for TB will require resources (staff, reagents, transport, laboratory capacity)

• Increased need for quality assurance of diagnostic services• Need for additional drugs due to increase in number of

casesDecreased by:• Decreased costs of managing severely ill or dying children if

TB is recognizedFeasibility Weak • May require some additional training and time from

overburdened health-care workers, laboratory workers and families of affected children




125

No Yes

FOOTNOTES TO ALGORITHM FOR CHILDREN * All children and infants less than one year of age should be provided with IPT if they have a household contact history with a TB case. Ɨ Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than –3 z-score), or underweight (weight-for-age less than –2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flattening.ǂ Contraindications include: active hepatitis (acute or chronic) and symptoms of peripheral neuropathy. Past history of TB should not be a contraindication for starting IPT. Although not a requirement for initiating IPT, TST may be done as part of eligibility screening in some settings. § Investigations for TB must be done in accordance with existing national guidelines.

Figure 2. Algorithm for TB screening in children more than one year of age and living with HIV

Child more than 12 months of age and living with HIV*

Screen for TB with any one of the following:Poor weight gain†

FeverCurrent cough

Contact with a TB case


Screen regularly for TB

No

Give IPT Defer IPT

Yes


Not TB

Follow up and


Other diagnosis

Give appropriate


TB

Annex 13

126

References1. Song R et al. Evaluation of TB screening approaches among HIV-infected children – Rwanda, 2008. 5th IAS

conference on HIV pathogenesis and treatment, 19–22 July 2009 [Abstract no TUPEB132].2. Hesseling AC et al. Outcome of HIV infected children with culture confirmed tuberculosis. Archives of Disease in

Childhood, 2005, 90:1171–1174.3. Iriso R et al. The diagnosis of childhood tuberculosis in an HIV-endemic setting and the use of induced sputum.

International Journal of Tuberculosis and Lung Disease, 2005, 9:716–726.4. Jeena PM et al. Impact of HIV-1 co-infection on presentation and hospital-related mortality in children with culture

proven pulmonary tuberculosis in Durban, South Africa. International Journal of Tuberculosis and Lung Disease, 2002, 6:672–678.

5. Kiwanuka J et al. Diagnosis of pulmonary tuberculosis in children in an HIV-endemic area, Malawi. Annals of Tropical Paediatrics, 2001, 21:5–14.

6. Madhi SA et al. HIV-1 co-infection in children hospitalised with tuberculosis in South Africa. International Journal of Tuberculosis and Lung Disease, 2000, 4:448–454.

7. Marais BJ et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics, 2006, 118:e1350–1359.

8. Mukadi YD et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis among children in Abidjan, Cote d’Ivoire. AIDS, 1997, 11:1151–1158.

9. Palme IB et al. Impact of human immunodeficiency virus 1 infection on clinical presentation, treatment outcome and survival in a cohort of Ethiopian children with tuberculosis. Pediatric Infectious Disease Journal, 2002, 21:1053–1061.

10. Ramirez-Cardich ME et al. Clinical correlates of tuberculosis co-infection in HIV-infected children hospitalized in Peru. International Journal of Infectious Diseases, 2006, 10:278–281.

11. Sassan-Morokro M et al. Tuberculosis and HIV infection in children in Abidjan, Cote d’Ivoire. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1994, 88:178–181.

12. Schaaf HS et al. Culture-confirmed childhood tuberculosis in Cape Town, South Africa: a review of 596 cases. BMC Infectious Diseases, 2007,7:140.

13. Van Rheenen P. The use of the paediatric tuberculosis score chart in an HIV-endemic area. Tropical Medicine and International Health, 2002, 7:435–441.

14. Walters E et al. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. BMC Pediatrics, 2008, 8:1.

15. Edwards DJ, Kitetele F, Van Rie A. Agreement between clinical scoring systems used for the diagnosis of pediatric tuberculosis in the HIV era. International Journal of Tuberculosis and Lung Disease, 2007, 11:263–269.

16. Pedrozo C et al. Clinical scoring system for paediatric tuberculosis in HIV-infected and non-infected children in Rio de Janeiro. International Journal of Tuberculosis and Lung Disease, 2009, 13:413–415.

17. Marais BJ et al. Diagnostic and management challenges for childhood tuberculosis in the era of HIV. Journal of Infectious Diseases, 2007, 196 (Suppl 1):S76–S85.

18. WHO. Guidance for national tuberculosis programmes on the management of tuberculosis in children. Geneva, World Health Organization, 2006 [WHO/HTM/TB/2006.37; WHO/FCH/CAH/2006.7].

19. Getahun H et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource constrained settings: individual participant data meta-analysis of observational studies. PLoS Medicine, 2011, 8(1): e1000391. doi:10.1371/journal.pmed.1000391.


127


PICOT Question: What is the optimal duration and drug regimen (e.g. INH, RIF, etc.) for treatment of LTBI to reduce the risk of TB developing among children living with HIV/AIDS?

Population: Children living with HIVIntervention: IPT (6 months’ INH)Comparison: No IPTOutcomes: Active TB incidence, mortality,

progression of HIV disease, adverse events, adherence, TB drug resistance, interval to active TB, interval to deathTimeline: Lifetime


Outcomes Relative score(rank 1 9 most critical)

Comment

Active TB incidence (suspected, probable, confirmed)

9 Critical

Confirmed TB 9 CriticalMortality 9 CriticalProgression of HIV disease 8 CriticalAdverse events 8 CriticalAdherence 7 Critical (addressed by

Annex 11)TB drug resistance 7 Critical (addressed by

Annex 10)Cost effectiveness 7 Critical (addressed by

Annex 12)Interval to active TB 6 Less criticalInterval to death 6 Less critical

128


Pubmed Search (“Child”[Mesh] OR “Child, Preschool”[Mesh]) OR “Infant”[Mesh]) AND “Tuberculosis”[Mesh]) AND “HIV Infections”[Mesh]) AND “Therapeutics”[Mesh]

187

Limits:Clinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II, clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial, evaluation studies, multicentre study, Medline, PubMed Central, all infant: birth–23 months, newborn: birth–1 month, infant: 1–23 months, preschool child: 2–5 years, child: 6–12 years

8

54

3

1

By title

articles

By abstract

Of interest

International conferences: (CROI, IAS, ICAAC, World AIDS conference) excluding published papers:ICAAC 2009 and previous: 1IAS conferences: 2CROI 2009 and previous: 1

Overall, two studies were considered for the grade analysis.[1,12] One study suggested significant benefits for children receiving INH

for six months, in particular, with regard to significant reductions in mortality.[12] However, findings from a randomized controlled trial conducted in South Africa showed that when HIV-infected infants with no known exposure to a TB source case are identified in the first three to four months of life, given rapid access to ART and carefully monitored for new TB exposure or disease on a monthly basis, there is no benefit from IPT.[1]

Therefore, based on this, the Guidelines Group recommends that all children more than 12 months of age who are living with HIV and who are unlikely to have active TB should receive six months of IPT as part of a comprehensive package of HIV care. For those children less than 12 months of age, only those with a history of contact with a TB case should receive six months of IPT. In contrast to adults and adolescents, there is no evidence to support the use of INH for longer than six months in children. Therefore, the Guidelines Group concludes that until more data are available, INH for children could not


129

Annex 14

The Guidelines Group noted that there is no evidence on the use of IPT in children after successful completion of TB treatment.

However, like adults, children living with HIV are exposed to reinfection and recurrence of TB. Therefore, the Group conditionally recommends that children who have been successfully treated for TB and are living in settings with high TB transmission should receive IPT for an additional six months. IPT can be started immediately following the last dose of antituberculosis therapy. Regardless of a history of TB treatment, TB screening should be carried out

during each contact of the child with a health-care worker.

The Guidelines Group also concludes that there are no data regarding the efficacy of IPT for children stratified by degree of immunosuppression. However, it noted that there is biological plausibility in extrapolating what is known for adults and adolescents to children. Therefore, the Group conditionally recommends the combined use of IPT with ART for all children. The Group emphasizes that ART should not be delayed while starting or completing a course of IPT.

Weight range (kg) Number of 100 mg tablets of INH to be administered per dose

Dose given (mg)

<5 ½ tablet 50 5.1–9.9 1 tablet 10010–13.9 1 ½ tablet 15014–19.9 2 tablets 20020–24.9 2 ½ tablets 250>25 3 tablets or one adult tablet 300

be recommended for more than six months. Similarly, there is no evidence on whether repeating a course of IPT is beneficial for children.

INH should be given at a dose of 10 mg/kg body weight daily and it is desirable that vitamin B6 be supplied

with INH at a dose of 25 mg daily. All available data to date suggest that INH is not toxic for children, even in those receiving ART. The following table shows a simplified dosing schedule for INH 10 mg/kg/day.

130

Q3.

1 Ef

ficac

y in

chi

ldre

nQ

uest

ion:

Sho

uld

INH

pro

phyl

axis

(six

mon

ths)

vs

plac

ebo

be u

sed

in H

IV-in

fect

ed c

hild

ren

(PPD

-pos

itive

or T

B-ex

pose

d)?

Setti

ngs:

Hig

h H

IV/T

B pr

eval

ence

cou

ntry

Bib

liogr

aphy

: Zar

et a

l. 20

07; M

adhi

et a

l. 20

08

3. GRADE profiles and summary of findings

1 Opp

osite

dire

ctio

n of

the

effe

ct.

2 P10

41 (M

adhi

et a

l.) re

pres

ents

an

optim

al H

IV c

are

setti

ng, w

ith c

apac

ity to

dia

gnos

e in

fect

ious

dise

ases

and

goo

d fa

cilitie

s to

rule

out

ac

tive

TB: c

hild

ren

were

you

nger

, hea

lthie

r and

pre

sent

ed in

a le

ss a

dvan

ced

stag

e of

the

dise

ase.

The

stu

dy b

y Za

r et a

l. re

pres

ents

the

mos

t com

mon

cond

ition

in ru

ral a

reas

with

a la

ter d

iagn

osis,

child

ren

pres

entin

g in

a m

ore

adva

nced

stag

e of

the

dise

ase

and

chal

leng

ing

TB d

iagn

osis.

3 O

ne tr

ial a

vaila

ble

4 Wid

e co

nfide

nce

inte

rval

s 5 R

aw d

ata

are

miss

ing

for P

1041

(but

no

signi

fican

t diffe

renc

e wa

s re

porte

d be

twee

n th

e tw

o gr

oups

).

3. GRADE profiles and summary of findings

Qua

lity

asse

ssm

ent

No.

of

stud

ies

Des

ign

Lim

itatio

nsIn

cons

isten

cyIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Activ

e TB

(fol

low

up 5

.7–9

mon

ths;

clin

ical a

lgor

ithm

crit

eria

, che

st X

-ray,

bact

erio

logi

cal is

olat

es fr

om a

ny s

ite)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

2N

o se

rious

im

prec

isio

nN

one

Confi

rmed

TB

(follo

w up

5.7

–9 m

onth

s; c

ultu

re-p

rove

n)

1R

ando

miz

ed tr

ial

No

serio

us

limita

tions

Serio

us3

No

serio

us

indi

rect

ness

Serio

us4

Non

e

Mor

tality

(all c

ause

s) (f

ollo

w up

5.7

–9 m

onth

s; re

view

of h

ospi

tal r

ecor

ds a

nd p

atie

nts’

files)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

Serio

us1

No

serio

us

indi

rect

ness

2N

o se

rious

im

prec

isio

nN

one

Adve

rse

reac

tions

(gra

de 3

or 4

toxic

ity) (

follo

w up

5.7

–9 m

onth

s; c

linica

l and

labo

rato

ry m

onito

ring)

2R

ando

miz

ed tr

ials

No

serio

us

limita

tions

No

serio

us

inco

nsis

tenc

yN

o se

rious

in

dire

ctne

ss5

No

serio

us

impr

ecis

ion

Non

e

HIV

dise

ase

prog

ress

ion

0N

o ev

iden

ce

avai

labl

eN

one

Sum

mar

y of

find

ings

Impo

rtanc

eN

o. o

f pat

ient

sEf

fect

Qua

lity

INH

pro

phyl

axis

(6

mon

ths)

Plac

ebo

Rel

ativ

e ris

k(9

5% C

I)Ab

solu

te

44/3

58 (1

2.3%

)45

/357

(12.

6%)

5%

RR

0.9

7 (0

.660

9–1.

4384

)4

few

er p

er 1

000

(from

43

few

er to

55

mor

e)

M

OD

ERAT

EC

RIT

ICAL

1 fe

wer

per

100

0 (fr

om 1

7 fe

wer

to 2

2 m

ore)

3/22

6 (1

.3%

)3/

226

(1.3

%)

0.9%

RR

1.5

(0.2

5–8.

89)

7 m

ore

per 1

000

(from

10

few

er to

105

m

ore)

LOW

CR

ITIC

AL

4 m

ore

per 1

000

(from

7 fe

wer

to 7

1 m

ore)

26/3

58 (7

.3%

)31

/357

(8.7

%)

10%

RR

0.8

4 (0

.51–

1.37

)14

few

er p

er 1

000

(from

43

few

er to

32

mor

e)

M

OD

ERAT

EC

RIT

ICAL

16 fe

wer

per

100

0 (fr

om 4

9 fe

wer

to 3

7 m

ore)

5/13

2 (3

.8%

)8/

131

(6.1

%)

0%

RR

0.6

2 (0

.21–

1.85

)23

few

er p

er 1

000

(from

48

few

er to

52

mor

e)H

IGH

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

mor

e)

0/0

(0%

)0/

0 (0

%)

0%

RR

0 (0

–0)

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)

CR

ITIC

AL

0 fe

wer

per

100

0 (fr

om 0

few

er to

0

few

er)


131


HIV-infected children who are unlikely to have active TB should receive six months of IPT.Population: HIV-infected children Intervention: 6–9 months of IPT (10–20 mg/kg plus vitamin B6 25 mg daily)Action: Concerns regarding the development of isoniazid resistance should not be a barrier to implementing IPT programmes.Factor Decision Explanation Quality of evidence Moderate • The evidence for provision of IPT in children is still

inconclusive (GRADE moderate) • 6–9 months of INH prophylaxis is the only regimen that has

been investigated so far in this specific population.• No specific biological reasons to think that IPT in children

would be less effective than in adultsBenefits or desired effects

Strong

• Reduction in TB incidence• Reduction in TB transmission (even if children are less likely

to transmit)• Reduction in mortality (Zar et al. GRADE moderate)

especially in children with advanced disease in whom TB may remain undiagnosed

• Avoids side-effects of TB treatment• Reduction in drug–drug interactions between drugs for TB

treatment and ARVs in children on ART• Improved TB infection control in health-care and community

settings (particularly in HIV clinics)Risks or undesired effects

• Increase in unnecessary treatment (especially when TST is not performed or in case of false-positive TST where TST is performed)

• Potential INH toxicity (even if both randomized controlled trials are reassuring on this)

• Potential development and transmission of INH-resistant strains by treating undiagnosed TB (especially in children with more advanced disease where ruling out TB might be even more challenging)

• Reduction in compliance with other treatment (ART, co-trimoxazole, etc.)

Values and preferences Strong • Avoids active TB disease as well as deaths and disease transmission to other family members

• Health-care workers would be less exposed to active TB cases and would feel more protected (less of a problem in children as they are considered to be less contagious)

• Infection control for patient (less of a problem in children as they are considered to be less contagious)

• Avoids all the daily implications of long TB treatment with high pill burden and significant side-effects

• Parents would feel their children were protected against TB, adding value to HIV programmes

BUT• May be worried about side-effects of INH• Pill burden• Stigma

Annex 14

132

Factor Decision Explanation Costs Weak Increased by:

• Costs of diagnosing LTBI (TST)• Costs of INH (including storage, supply and transportation)• Monitoring liver function tests (if standard monitoring or in

case of toxicity)• Additional staff in ART settings are already overloaded by

routine activities• Need for second-line TB treatment in case INH resistance

occurs and is transmitted• Costs for INH-related toxicity (blood tests, hospitalizations,

parents’ loss of earning)• Additional costs of providing vitamin B6Decreased by:• Avoiding active TB treatment costs• Less cost of hospitalizations • Reduction in social costs and loss of parents’ earnings• Reduction in costs due to treatment of secondary cases

including in health-care workers, improving “staff retention”• Reduction in costs achieved by preventing TB–ART co-

treatment including potential need for a more expensive regimen and possible ART failure

• Dose adjustment would require more frequent follow up Feasibility Strong • Drug easily available and cheap

• Administration fits well with the schedule of HIV programmes

• Does not require strict monitoring (laboratory)• Health-care workers would already be familiar with the drugBUT• Lack of child-friendly formulation for infants and very small

children• Would mean adding an intervention to an overburdened

system• May increase clinic visits and require more staff• Space required for storage and difficulties in procurement • INH single formulation less easily available compared to

fixed-dose combinations (FDCs)• Difficult to overcome health-care workers’ reluctance to use

IPT• Health-care workers need to be trained in conducting and

reading TST or IGRA• Dose adjustment would require more frequent follow up




133

No Yes

FOOTNOTES TO ALGORITHM FOR CHILDREN * All children and infants less than one year of age should be provided with IPT if they have a household contact history with a TB case. Ɨ Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than –3 z-score), or underweight (weight-for-age less than –2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flatteningǂ Contraindications include: active hepatitis (acute or chronic) and symptoms of peripheral neuropathy. Past history of TB should not be a contraindication for starting IPT. Although not a requirement for initiating IPT, TST may be done as part of eligibility screening in some settings. § Investigations for TB must be done in accordance with existing national guidelines.

Figure 2. Algorithm for TB screening in children more than one year of age and living with HIV

Child more than 12 months of age and living with HIV*

Screen for TB with any one of the following:Poor weight gain†

FeverCurrent cough

Contact with a TB case


Screen for TB regularly

No

Give IPT Defer IPT

Yes


Not TB

Follow up and


Other diagnosis

Give appropriate


TB

References1. Madhi SA et al.; and the P1041 Team. Lack of efficacy of primary isoniazid (INH) prophylaxis in increasing tuberculosis

(TB) free survival in HIV-infected (HIV+) South African children. 48th ICAAC/IDSA 46th annual meeting, 2008 [G2-1346a].

2. Martinez Alfaro EM, et al. [Evaluation of 2 tuberculosis chemoprophylaxis regimens in patients infected with human immunodeficiency virus. The GECMEI Group]. Medicina Clinica (Barc), 2000, 115:161–165.

3. Martinson NB et al. Novel regimens for treating latent TB in HIV-infected adults in South Africa: a randomized clinical trial. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, 8–11 February 2009 [Paper 36bLB].

4. Mohammed A et al. Randomised controlled trial of isoniazid preventive therapy in South African adults with advanced HIV disease. International Journal of Tuberculosis and Lung Disease, 2007, 11:1114–1120.



7. Quigley MA et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS, 2001, 15:215–222.

8. Rivero A et al. [A randomized trial of three regimens to prevent tuberculosis in HIV-infected patients with anergy]. Enfermedades Infecciosas y Microbiologia Clinica, 2003, 21:287–292.

9. Rivero A et al. [Randomized clinical trial investigating three chemoprophylaxis regimens for latent tuberculosis infection in HIV-infected patients]. Enfermedades Infecciosas y Microbiologia Clinica, 2007, 25:305–310.

10. Samandari T et al.; on behalf of BOTUSA IPT study. Preliminary results of the Botswana IPT Trial: 36 months vs. 6 months isoniazid for TB prevention in HIV-infected adults. 40th Union World Lung Conference, Cancun, 2009.


12. Zar HJ et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial. British Medical Journal, 2007, 334:136.

Annex 14

134

Annex 15: Summary of findings and quality of evidence evaluation: selected research gaps

• The optimal timing for starting IPT and whether/when to combine it with ART should be further investigated, with particular attention to the possible benefits and risks for patients already on ART. In addition, the possibility of discontinuing INH once immunological recovery has been achieved would be of great interest.

• The efficacy, safety and tolerability of a longer regimen of INH prophylaxis should be addressed in the paediatric population.

• Potential co-formulation of INH with co-trimoxazole should be made available and longitudinal data on its effectiveness collected.

• The potential impact of INH monoresistance on IPT and possible efficacy of subsequent TB treatment should be assessed.

• Operational research should be conducted on scaling up the implementation of IPT.

• Programmes implementing IPT as part of HIV prevention and care should be monitored and evaluated.

• Mathematical modelling to evaluate the effectiveness of IPT should be planned, including examination of the risks and benefits with particular attention to benefits stratified by TST status.

• A proper cost-effectiveness analysis addressing different strategies for provision of IPT and TST should be performed.

• The optimal frequency of screening people with HIV for active TB with a symptom questionnaire and the timing of repeat TST in HIV-positive individuals receiving ART should be addressed.

• The algorithm for intensive case-finding in children should be validated.

• Limited studies have evaluated the clinical utility of IGRA in persons with HIV and, to date, no evidence is available to warrant its programmatic use in resource-limited settings as a screening test before IPT. There is a clear need for longitudinal studies that assess the ability of IGRA to identify people at high risk for

developing active TB or those who would benefit from treatment of LTBI. Because of concerns about the impact of immunosuppression on the performance of IGRA, it would be most useful if such studies included persons with both high and low CD4 cell counts and provided results stratified by CD4 cell count. Longitudinal assessment with serial measures is required to elucidate the clinical significance of discordant IGRA and TST, and the predictive value of IGRA for M. tuberculosis infection among HIV-infected persons.

• Better diagnostics for children should be identified. Prospective studies using cases of bacteriologically confirmed TB and appropriate controls including children not suspected of having TB would be needed to evaluate the diagnostic value of TB symptoms.

• Although some studies have evaluated different aspects of the TST in the general population and among HIV-infected persons, very few studies have provided information on the feasibility of using TST in resource-poor settings. No studies have evaluated the actual costs involved in large-scale TST screening among people with HIV infection, and the overall burden of performing TST on already overstretched health systems in resource-poor settings.

• The stability of tuberculin from the point of manufacture to the point of use should be assessed, especially under natural environmental conditions in developing countries where facilities for refrigeration are not readily available.

• The reliability of other categories of health-care professionals in reading TST results, particularly in the HIV-infected population, needs to be evaluated. Efforts are currently being made in the area of task-shifting with the overall goal of scaling up HIV prevention, care and treatment activities. Different strategies are also needed to reduce the proportion of patients who fail to return for the TST results to be read.

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