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HIV and TB in my Region: Is Anyone Listening? Soumya Swaminathan, MD Director, National Institute for Research in Tuberculosis, Chennai India.

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Presentation on theme: "HIV and TB in my Region: Is Anyone Listening? Soumya Swaminathan, MD Director, National Institute for Research in Tuberculosis, Chennai India."— Presentation transcript:

1 HIV and TB in my Region: Is Anyone Listening? Soumya Swaminathan, MD Director, National Institute for Research in Tuberculosis, Chennai India

2 WHO Report 2013 Global 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

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

4 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)

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

6 Number of HIV-positive TB patients globally enrolled on co-trimoxazole preventive therapy (CPT) and antiretroviral therapy (ART) 2004 - 2012

7 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 830744379552392473 SEAR 170396.289611352<0.01 WPR 24343.179563088.6 GLOBAL 1100462080574095519 HIV testing, treatment for HIV+ TB patients and prevention of TB among people living with HIV, 2012

8 Collaborative TB/HIV activities 2004-2012 SEARO

9 Collaborative TB/HIV activities 2004-2012 WPRO

10 % of TB patients with known HIV status Year % of TB pts with known HIV status Patients notified (New and retreat) Number of HIV-Positive TB pts SEASEA 20051.61 947 6037 025 2010232 332 77952 519 2011332 358 12755 608 2012392 331 45556 093 WPWP 20052.41 383 1972 221 2010201 364 65212 502 2011251 387 74113 794 2012321 410 83514 181 HIV testing improving, but incomplete 2005- 2012

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

12 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

13 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

14 Diagnostic Issues More extra-pulmonary, disseminated TBMore extra-pulmonary, disseminated TB Active case-finding requiredActive case-finding required Smear negative TB more common: sputum culture or more sensitive diagnostics for M.tuberculosis neededSmear 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 CXRNormal 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“Smear neg. TB” could be other OI’s – need facilities for additional investigations Swaminathan et al IJTLD 2004, AIDS 2003;17:1398-400, Swaminathan et al IJTLD 2004, AIDS 2003;17:1398-400, Padmapriyadarsini et al JAIDS 2013,

15 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, WL85530.2998.5 (98.1 - 98.8) H, F, NS, WL82560.3298.4 (97.9 - 98.7) CC, F, WL81570.3398.3 (97.9 - 98.6) CC, NS, WL81570.3498.3 (97.9 - 98.6) H, F, NS, WL81620.3197.4 (98 - 98.7) CC: Cough in the last 24 hours; F: Fever; H: Haemoptysis; NS: Night sweats; WL: Weight loss

16 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

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

18 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

19 Performance among HIV+ and Pediatric Patients


21 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)

22 Sensitivity of Urine MTB/RIF in Sputum Scarce HIV-Infected Patients AssayAll MTB Cx (+) Sputum Scarce MTB Cx (-) HIV/CD4 > 200HIV/CD4 < 200 AFB Smear52%N/A58%50% Urine MTB/RIF48%40%31%54% Urine LAM ELISA58%60%27%69% Urine LAM Strip48%45%27%69% Urine LAM ELISA + Urine MTB/RIF 68%70%38%79% Urine LAM ELISA + AFB Smear 74%N/A58%80% Peter JG, et al. PLoS One 2012; 7:e39966

23 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%), 1/3 rd 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 prevention Sudjaritruk et al. AIDS Patient Care and STDs 2013 Dec, Bhavani PK etal, IAS 2014

24 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

25 TB Immune Reconstitution Syndrome in Children: Systematic Review 13 studies – 9 from Africa, 3 Asia, 1 LA 303 cases of TB-IRIS described: 270 were unmasking type, 12 paradoxical Age at initiation of ART: 1mo-16 years Interval between ART and IRIS: 8 days to 16 weeks Deaths rare Steroids mentioned as treatment in 2 studies Research needed for incidence, risk factors, case fatality, optimal management and prevention of IRIS in children Link-Gelles et al. PIDJ May 2014

26 New TB CasesPreviously treated TB cases YearCoveragePercentageYearCoveragepercentage Australia2012National 1.9 2012National 6.5 Cambodi a 2007National 1.4 2007National 11 China2007National 5.7 2007National 26 Japan2002National 0.7 2002National 9.8 Mongolia2007National 1.4 2012National 26 Philippine s 2004National 4 2004National 21 Republic of Korea 2004National 2.7 2004National 14 Viet Nam2006National 2.7 2006National 19 Measured % of TB cases with MDRTB, WPRO

27 Measured % of TB cases with MDRTB, SEA New TB CasesPreviously treated TB cases YearCoveragPercentageYearCoveragpercentage Banglades h 2011National 1.4 2011National 29 India2001,200 4, 2006, 2009 Sub National 2.2 2006, 2009 Sub National 15 Indonesia2004, 2006,201 0 Sub National 1.9 2006, 2010 Sub National 12 Myanmar2008National 4.2 2008National 10 Nepal2011National 2.3 2011National 15 Sri Lanka2006National 0.18 2011National 2.2 Thailand2006National 1.7 2006National 35

28 Perfect Breeding Ground for Drug Resistance….Urban Slums Overcrowding, poor ventilation Pollution – indoor and outdoor Undernutrition Ignorance Delayed health seeking Inefficient diagnostics Irrational treatment practices Irregular treatment

29 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)

30 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 2 nd line drugs (6K,Emb,Eth,Z,Levo,Cyclo/14- 18Emb,Eth,Levo, Cyclo) Favourable outcome in MDRTB 50-60%, XDRTB ~25%

31 Number (%) of HIV-infected TB patients receiving ART during TB treatment, India


33 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 <200200-350>350 No ART ART CD4 Count M.Badri, D.Wilson, R.Wood. Lancet 2002

34 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, 3RH 2 and 3RifH ow 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-Pacific Samandari, Lancet 2011, Martinson et al NEJM 2011, Swaminathan Plos One 2012, Rangaka Lancet 2014, Churchyard NEJM 2013, Durovni Lancet 2013

35 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

36 More Questions Than Answers What regimen? – Isoniazid downside peripheral neuropathy and hepatitis – Ongoing trials of Rifapentine include 3HP (12 doses), HP daily for 1 month and PK studies of Rfp with ART How long? – 1 month, 3 mo, 6 mo, 12 mo or lifelong? Best model? – Pre-ART, at ART initiation, post TB treatment? Cost-effectiveness? – 6 mo more cost-effective than 36 mo – Will depend on local TB epidemiology and ART access Pho et al. Plos One 2012

37 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

38 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 2 nd 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

39 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

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