Challenges of HIV-TB CoinfectionSinata Koulla Shiro (MD)ANRS Satellite Meeting, IAC 2012Washington DC, 23 July 2012

OUTLINEContext

◦ HIV-TB Global Epidemiology Challenges

◦ Diagnosis◦ Combining HIV/TB Treatment

WHO TB/HIV collaborative ProgrammeTB/HIV programme integration◦ The three I’s (Intensified TB case finding,

IPT and early ART, TB Infection Control) Research Perspectves

TB/HIV Global Epidemiology

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· HIV has greatly contributed to resurgence and increased incidence of TB worldwide

· 14 million people are co-infected with TB and HIV worldwide

· In some regions in Africa 75% of TB patients are co-infected with HIV

· TB is the most common cause of death among AIDS patients worldwide

· TB causes at least 11% of AIDS death and possibly as many as 50% in some countries

· MDR-Tuberculosis among HIV patients can cause nosocomial infections

· Rifampicine resistance is also found among HIV infected patients with tuberculosis

TB/HIV Global Epidemioloy

• Hiv testing of TB Patients now standard practice in many countries

• 2.1 million/6.2million(34%) of notified TB patients knew their HIV status in 2010

• 10 Times greater than 3.7% in 2003

TB/HIV Global Epidemiology

• Over 75% in 68 countries including 22 in Africa knew their status

• The coverage of HIV test washighest in Africa (80%) as compared to Europe (59%)

• 23% of TB patients tested + at global level

•44% in Africa tested +

HIV Testing for TB Patients By Country

Global TB/HIV Epidemiology

• Prevalence rates ranged from 8% in Congo to over 50% in South Africa, Botswana, Zambia,Malawi, Uganda

•Prevalence rate was up to 82% in Swaziland

Impact of HIV on TB

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· Increases rate of TB re-activation and progression

· PLWHiv have 20 to 30 times higher life time risk of developing active TB compared with people without HIV

· Increases TB morbidity

· Increases TB mortality (5-14 fold)

· Alters clinical manifestations of TB

· Creates diagnostic challenges

· Complicates treatment

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Incidence of TB after seroconversion among South African Adults, 1991-1997

IncidenceFor 100 Patient-years

RR*

HIV-negative 0.80 RefHIV-positiveTime since seroconversion

< 1 yr 1.62 2.021-2 yrs 2.00 2.502-3 yrs 3.61 4.50

Sonnenberg, JID 2005

* Relative risks HIV+ versus HIV-, all significantly superior to 1

The risk of tuberculosis increases rapidly after HIV

primary infection

Impact of TB on HIV

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· TB infection activates T-cells, indirectly supporting HIV replication

· Active TB is associated with

Increased HIV-1 viral load

Rate of progression to AIDS

Mortality

· HIV viral load decreases with successful TB therapy

· TB therapy when combined with ARV has potential for drug-drug interactions and side effects

Treament Outcomes of TB Patients according to HIV status

challenges

Other Diagnosis challenges

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· CultureSpecific but ensuring access to high

sputum not availableXpert MTB/RIF Assay: Specific, major

breakthrough, more sensitive than AFB on Sptum smear but limited access 1st report on negative results of Mtbc

culture positives· Empiric anti-TB treatment may be

warranted in many circumstances

Sensitivity (with 95% confidence intervals) of Xpert MTB/RIF for diagnosing human immunodeficiency virus–associated tuberculosis during screening of patients before

antiretroviral therapy, stratified by CD4 cell count and sputum smear status.

Lawn S D et al. Clin Infect Dis. 2012;54:1071-1079

Challenge:• 42% and 28% of culture + tested Xpert – respectively in 1 or 2 samples•Sensitivity lower in less advanced HIV Patients

•How to address implication of false negative results of Xpert MTB/RIF

Earlier ART in context of TB/HIV: Why is it still challenging in real practice?

• Major cause of early mortality in patients using ART in RLS (TB as a priority population for earlier ART)

• ART significant reduce the occurrence of TB disease, but in RLS the need to treat both diseases at same time is very common …

• TB still an important condition, even in patients using ART and higher CD4 cell count

–

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ART rapidly decreases the incidence of TB

0

5

10

15

20

25

0-3 mois 3-6 mois 6-12 mois 12-24 mois

Lawn, AIDS 2006 Temps sous ARV

Incidence per 100 patient-years of tuberculosis under ARTs inSouth Africa

Incidence and risks factors of paradoxical tuberculosis-

associated IRIS in HIV-infected adults enrolled in the CAMELIA

clinical trialANRS 1295/CIPRA KH001

D. Laureillard, O. Marcy, Y. Madec, S. Chan, L. Borand, N. Prak, C. Kim, K.K. Lak, C. Hak, B. Dim, E. Nerrienet, T. Sok, A.E. Goldfeld, F.X.

Blanc 6th IAS Conference, Rome, 20 July 2011

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Study profile

661 HIV-infected adults enrolled in Camelia trial

64 patients were excluded: - 16 non tuberculous mycobacteria - 37 deaths before ART initiation - 2 withdrawal before ART initiation - 9 without follow-up after start of ART

597 patients enrolled in this analysis

155 developed paradoxical TB-IRIS

442 did not developparadoxical TB-IRIS

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Conclusions• High frequency (26%) of paradoxical TB-IRIS in

HIV-infected patients with advanced immunodeficiency

• Double the risk of developing TB-IRIS (HR 2.23) when ART initiated at 2 weeks

• Median time of TB-IRIS occurrence: 2 weeks, irrespective of early or late ART initiation

• Low mortality directly related to TB-IRIS: 6/155 (3.9%) in accordance with published data

During the first weeks following ART initiation, clinicians should be vigilant to recognize signs of TB-IRIS (lymph nodes, fever, abdominal pain…).

However TB-IRIS should not be a barrier against early ART initiation in severely immunosuppressed patients.

Overlapping Side Effect Profiles of ARV and Anti-TB drugs

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Side Effect Anti-TB drugs ARV drugsSkin rash PZA, rifampicin, rifabutin, INAH NVP, DLV, EFV, ABCNausea, vomiting PZA, rifampicin, rifabutin, INAH AZT, RTV, AMP, IDVHepatitis PZA, rifampicin, rifabutin, INAH NVP, PILeucopenia, anaemia Rifampicin, rifabutin AZT

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La résistance aux anti-TB est un problème • Définition

– « Multirésistance » (MDR-TB) = résistance à au moins RMP et INH

– « Ultrarésistance » (XDR-TB) = résistance à RPM et INH, et fluroroquinolones et au moins un antiTB injectable de 2ème ligne (Kanamycine, amikacine, capreomycine) *

• Fréquence 2000-2004 (MMWR 2006 )– Mondiale, sur 17690 souches : 20% MDR, 2% XDR-TB – en Afrique : 23% MDR, 1% XDR

• Epidémie de XDR-TB en Afrique du Sud (Ghandi, Lancet 2006) – 1539 souches, 544 M tuberculosis, 41% MDR-TB– 53 patients XDR +, VIH+ 100% sur ceux testés, létalité

98%

* Définition WHO Global Task Force on XDR-TB, Octobre 2006

WHO guidelines recommend 12 collaborative TB/HIV activities

A. Establish and Strengthen Mechanisms for delivering integrated TB/HIV services

• TB/HIV coordinating body• Determine HIV prevalence in TB patients and TB prevalence among PLWH• Joint TB/HIV planning• Monitoring and evaluation 2012

B. Reduce Burden of TB among PLWH and Initiate early ART (Three I’s for HIV/TB)

• Intensified TB case finding (ICF) • TB preventive therapy (IPT) and early ART• TB infection control (IC)

C. Reduce Burden of HIV in presumptive and diagnosed TB patients

• HIV testing and counselling• HIV prevention• HIV/AIDS care and support• Co-trimoxazole Prophylaxis (CTXp)• Antiretroviral therapy (ART)

2004

Integration of TB-HIV Services

Establishing the mechanisms for collaboration

1. TB/HIV coordinating bodies2. HIV surveillance among TB patient3. TB/HIV joint planning4. TB/HIV monitoring and evaluation

Which model of integration ?TB

HIV/Aids

TB + ARVHIV/AIDS

TB TB/HIV

Infectious disease chronic care unit

Tb patients

ARV follow-up

One stop service for TB-HIV co-infected

Health Systems

Community

involvement Decentralizati

on

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Challenges of the three I’s

IPT among HIV + patients• Proven efficacy

– 9 randomized studies ( 4 in Africa)– Risk to active TB decreased by 2 fold

(méta-anlayse: Bucher, AIDS 1999 )• Recommanded by WHO since 1993…

– INH 5 mg/Kg/j 6 mois– After ruling out active TB

• Low IPT completion rates • Questions on durability of INH protection • Fear of resistance• Questions on adherence support to achieve high rates

• : Implication of major changes among care providers(Johnson, AIDS 2001)(Quigley, AIDS 2001)

Challenges of the three I’s :Intensified TB case finding through simplified clinical algorithm Four symptom-based screeningHX of current cough (>15days) Fever Weight loss Night sweats Will permit identification of

patients elligible for IPT

Tuberculosis (TB) screening questionnaire (modified from [11]).

Howard A A , El-Sadr W M Clin Infect Dis. 2010;50:S238-S244

Early initiation of ART:Coverage of ART among TB-HIV Patients