HIV and TB in my Region: Is Anyone Listening?

Soumya Swaminathan, MDDirector, National Institute for Research in

Tuberculosis, ChennaiIndia

WHO Report 2013Global Tuberculosis Control

Worldwide, 8.6 million new incident cases of TB in 2012; 1.3 million TB deaths

~1.13 million (13%) HIV+TB cases;320,000 HIV+TB deaths in 2012

Top Causes of YLL in 1990 and 2013: Global Burden of Disease Study

HIV-Associated TB: Challenges and Key issues

• One-third of the 35 million people living with HIV worldwide are infected with latent TB.

• Persons co-infected with TB and HIV are 30 times more likely to develop active TB disease

• TB is the most common presenting illness among people living with HIV, including those who are taking antiretroviral treatment.

• TB is the leading cause of death among people living with HIV, accounting for one in five HIV-related deaths.

• People living with HIV are facing emerging threats of multi-drug resistant (MDR-TB) and extensively drug resistant TB (XDR-TB)

Percentage of TB patients with known HIV status, 2004 - 2012

Estim HIV +ve incident TB Cases

% notified TB pts tested for HIV

% tested TB pts HIV +ve

% HIVTB pts started on CPT

% HIVTB pts started on ART

Number of HIV +ve people screened for TB

Number of HIV +ve people provided with IPT

AFR 830 74 43 79 55 2392 473

SEAR 170 39 6.2 89 61 1352 <0.01

WPR 24 34 3.1 79 56 308 8.6

GLOBAL

1100 46 20 80 57 4095 519

HIV testing, treatment for HIV+ TB patients and prevention of TB among people living with

HIV, 2012

Collaborative TB/HIV activities 2004-2012SEARO

Teste

d for H

IV

HIV-positive CPT

ART

Scree

ned fo

r TB

IPT -

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1,600,000

2004

2005

2006

2007

2008

2009

2010

2011

2012

Collaborative TB/HIV activities 2004-2012WPRO

Teste

d for H

IV

HIV-positive CPT

ART

Scree

ned fo

r TB

IPT -

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

450,000

500,000

2004

2005

2006

2007

2008

2009

2010

2011

2012

Trends in Number (%) of registered TB patients with known HIV status, 4q08- 1q14, India

4q08

1q09

2q09

3q09

4q09

1q10

2q10

3q10

4q10

1q11

2q11

3q11

4q11

1q12

2Q12

3Q12

4Q12

1Q13

2Q13

3Q13

4Q13

1Q14

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

11%14%17%

21%25%

30%33%35%39%40%

43%47%

51%58%

52%57%

60%63%63%64%62%

69%

Known HIV status Unknown HIV status Proportion with known HIV status

Proportion of TB patients with known HIV Status

• 56% of 13072 of microscopy centres have co-located HIV testing facilities

Northern States • Low HIV Prevalence• Limited HIV Testing

and Care Facilities

Nation-wide, 63% of TB patients with known HIV status

Proportion with known HIV status

0%- 30%31% - 50%51% - 70%> 70%

Clinical Challenges in HIV/TB• How to suspect and diagnose TB earlier

among HIV+ persons?• Treatment – drug interactions, IRIS• MDRTB – new drugs, better regimens• TB in HIV+ children • How to prevent TB among HIV+ persons?• Service integration

Diagnostic Issues

• More extra-pulmonary, disseminated TB

• Active case-finding required

• Smear negative TB more common: sputum culture or more sensitive diagnostics for M.tuberculosis needed– 504 patients with cough and negative sputum smears

– Cough > 2 weeks had sensitivity of 97%, specificity of 6%

– CXR had a sensitivity and specificity of 72% and 57%

• Normal x-ray does not rule out TB – sputum culture positive in 7% of patients with normal CXR vs 21% with abnormal CXR

• “Smear neg. TB” could be other OI’s – need facilities for additional investigations

Swaminathan et al IJTLD 2004, AIDS 2003;17:1398-400, Padmapriyadarsini et al JAIDS 2013,

Top 5 Best Performing Rules in all Subjects with suspected TB (n = 8173), Getahun et al Plos Med 2011

Combination Rule

Sen(%) 

Spe  (%)

LR-

NPV (95% CI)

5% TB Prevalence

CC, F, NS, WL 85 53 0.29 98.5 (98.1 - 98.8)

H, F, NS, WL 82 56 0.32 98.4 (97.9 - 98.7)

CC, F, WL 81 57 0.33 98.3 (97.9 - 98.6)

CC, NS, WL 81 57 0.34 98.3 (97.9 - 98.6)

H, F, NS, WL 81 62 0.31 97.4 (98 - 98.7)CC: Cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

Cepheid GeneXpert MTB/RIF• Molecular beacons

target rpoB gene that covers mutations in > 99.5% of RIF-resistant isolates– Sensitivity in HIV+ 78%– Specificity 98%– Good for extrapulm

specimens (except PF)– Now recommended by

WHO as preferred diagnostic test in smear negative TB, HIV+ persons and children

Lawn, et al. PLoS Med 2011; Theron, et al. Am J Resp Crit Care Med 2011; Scott, et al. PLoS Med 2011; Boehme et al. Lancet 2011; Cochrane Review 2014, WHO guidance 2014

Sensitivity and specificity of Xpert MTB/RIF for detection of PTB in HIV-positive individuals with symptoms (16 studies)

CB-NAAT for TB Diagnosis in Programmatic Settings: Feasibility Study in India

o Objectives: Establish the feasibility and impact of decentralized deployment of routine CBNAAT testing of all pulmonary TB & DR-TB suspects in selected geographic areas

• Approach: Programmatic demonstration: Before & after comparison from same sites; Phased implementation

• ~9 million population, 18 sites

Courtesy: FIND India

Performance among HIV+ and Pediatric Patients

Urine Lipoarabinomannin ELISA

• Meta-analysis of LAM studies (Flores LL, et al. Clin Vaccine Immunol 2011; 18:1616-27)

– Pooled sensitivity 47% in HIV(+) vs. 14% in HIV(-); specificity 96%-97%

– Highest sensitivity in those with CD4 < 50 (67%-85%) (Lawn S, et al. AIDS 2009; Shah M, et al. JAIDS 2009)

Sensitivity of Urine MTB/RIF in Sputum Scarce HIV-Infected Patients

Assay All MTB Cx (+)

Sputum ScarceMTB Cx (-)

HIV/CD4 > 200 HIV/CD4 < 200

AFB Smear 52% N/A 58% 50%

Urine MTB/RIF 48% 40% 31% 54%

Urine LAM ELISA 58% 60% 27% 69%

Urine LAM Strip 48% 45% 27% 69%

Urine LAM ELISA + Urine MTB/RIF

68% 70% 38% 79%

Urine LAM ELISA + AFB Smear

74% N/A 58% 80%

Peter JG, et al. PLoS One 2012; 7:e39966

TB in HIV-infected children• 2678 HIV-infected children over 13 year period in TREAT Asia

pediatric HIV cohort – 457 developed pulmonary TB (period prevalence 17%), 1/3rd of those tested bacteriologically confirmed

• 21 deaths, 4.3%• Median CD4 9%, 185 cells/mm3• 82% favourable outcomes• In ART Clinics in India, incidence of TB among HIV+ children (80% on

ART) was 2.4/100py (poster• TB common in Asian HIV-infected children, especially if

immunosuppressed• Diagnosis is challenging, training needed in specimen collection and

CXR reading• IRIS – mostly paradoxical type. Little information on incidence, risk

factors, management and preventionSudjaritruk et al. AIDS Patient Care and STDs 2013 Dec, Bhavani PK etal, IAS 2014

Pulmonary TB in HIV-infected or severely malnourished children with pneumonia

• Reviewed studies that confirmed the etiology of acute pneumonia in < 5 years children with SAM (WAZ z score <-3) or HIV infection

• Specimens collected by gastric lavage, BAL, percutaneous lung aspirate or induced sputum

• 6 studies, 747 children included – 93 (12%) had active TB• Of 610 HIV+ children (s Africa), 10% had TB• Pulmonary TB more common than suspected in acute

pneumonia with SAM or HIV infection• In children < 2 years, severe extrapulmonary manifestations

eg TB meningitis common

Chisti et al. J Health Popul Nutr 2013 Sep

New TB Cases Previously treated TB cases

Year Coverage Percentage Year Coverage

percentage

Australia 2012 National 1.9 2012 National 6.5Cambodia

2007 National 1.4 2007 National 11

China 2007 National 5.7 2007 National 26 Japan 2002 National 0.7 2002 National 9.8

Mongolia 2007 National 1.4 2012 National 26 Philippines

2004 National 4 2004 National 21

Republic of Korea

2004 National 2.7 2004 National 14

Viet Nam

2006 National 2.7 2006 National 19

Measured % of TB cases with MDRTB, WPRO

Measured % of TB cases with MDRTB, SEANew TB Cases Previously treated TB cases

Year Coverag Percentage

Year Coverag

percentage

Bangladesh

2011 National 1.4 2011 National

29

India 2001,2004,2006, 2009

Sub National

2.2 2006,2009

Sub National

15

Indonesia 2004, 2006,2010

Sub National

1.9 2006,2010

Sub National

12

Myanmar 2008 National 4.2 2008 National

10

Nepal 2011 National 2.3 2011 National

15

Sri Lanka 2006 National 0.18 2011 National

2.2

Thailand 2006 National 1.7 2006 National

35

Baseline Isoniazid Resistance and HIV are Strong Risk Factors for Acquired Rifampicin Resistance: Analysis of

3 Cohorts Treated with 3/weekly anti-TB treatment (Narendran etal CID in press)

For MDRTB, Prevention is Best Policy…

• MDRTB prevalence similar to HIV- populations

• Drug resistance testing (molecular methods) at initiation of treatment

• Treat HIVTB patients with appropriate anti-TB regimen

• Early HAART• Ensure adherence and determine

outcome• New TB drugs – Delamanid and

Bedaquiline approved

• Treatment: > 20 months with 2nd line drugs (6K,Emb,Eth,Z,Levo,Cyclo/14-18Emb,Eth,Levo, Cyclo)

• Favourable outcome in MDRTB 50-60%, XDRTB ~25%

Prevention of TB: Immune Status is Key

• Prevalent TB at the time of HIV diagnosis was 10% in THRio study sites, Brazil

• After adjustment for sex, age, baseline CD4 and baseline viral load, risk of death was significantly higher among prevalent TB cases, aHR=1.72(CI 95% 1.2-2.5)

• Best method of TB prevention is to prevent immune deficiency earlier HIV diagnosis and treatment

Saraceni et al JAIDS 2014 Jun

TB Incidence by HAART Status and CD4 Counts

<200 200-350 >350

No ART

ART

CD4 Count

M.Badri, D.Wilson, R.Wood. Lancet 2002

Preventive Therapy – More than Treatment of Latent TB Infection

• BOTUSA trial: 36H more efficacious than 6H, especially among TST+ and those receiving ART

• S Africa: 6H, lifelong H, 3RH2 and 3RifHow had similar efficacy• India: 6EH and 36H similar efficacy• Rangaka: 12H reduced incidence of TB in patients on HAART,

both TST+ and TST-• Among s African miners, incidence of TB in population not

reduced by IPT, though individual protection +• In Brazil, implementation of package (intensified case finding,

TST and IPT) reduced TB incidence in ART clinics• Limited experience in Asia-PacificSamandari, Lancet 2011, Martinson et al NEJM 2011, Swaminathan Plos One 2012, Rangaka Lancet 2014, Churchyard NEJM 2013, Durovni Lancet 2013

Elimination of TB will require attention to Latent TB Infection also

CHILDREN

• Children < 6 years in contact with infectious TB

• Regardless of TST result• Regimen: INH 10 mg/kg

daily for 6 mo• Shorter regimens needed to

improve compliance• Currently, only 15-20% of

child contacts being screened and initiated on IPT

HIV-INFECTED PERSONS• HIV+ persons without active

TB • Simple 4 symptom screen

high NPV• INH daily for 6 or 36 months

- shorter regimens in trial• Regardless of TST result and

ART status• Vietnam, Cambodia, India

scaling up IPT

Integrating Services – TB, ART, MCH, OST….

• ART integration into MNCH facilities and TB treatment settings led to coverage and mortality

• Integration and decentralization did not lead to adverse outcomes

• Partial decentralization led to reduced attrition in care

• Newer models – community/home provision of ARV, couriering of drugs need assessment

Suthar AIDS 2014 Mar, Kredo Cochrane Database Syst Rev 2013 Jun

Research Needs

• Strategies for Reduction of mortality in TB/HIV• Strategies for prevention of TB in HIV+ adults and

children, including research on biomarkers to predict disease progression from LTBI

• Pharmacokinetics of 2nd line and new anti-TB drugs in children and adults with HIV

• Optimize treatment for HIVTB children < 3 years, including Rifabutin dosage

• Shorter, safer and more convenient TB treatment regimens for DS and DRTB

• Service integration, more patient-friendly services for HIVTB: different models of care

Acknowledgements

• My colleagues at NIRT, Chennai• Dr Havlir, Getahun and others for informative

discussions over the years• Dr BB Rewari, Dept AIDS Control• Dr KS Sachdeva, Central TB Division• Patients and their families