INH Prophylaxis Therapy (IPT) should NOT be implemented for all HIV patients in the Asia Pacific

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1 INH Prophylaxis Therapy (IPT) should NOT be implemented for all HIV patients in the Asia Pacific Thuy Le, MD DPhil Duke University School of Medicine, USA Oxford University Clinical Research Unit Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam No conflicts of interest

2 TB is the number one killer of HIV patients, accounting for more than 25% of HIV-associated deaths. The risk of reactivated and new TB infection is times higher in HIV than in non-hiv-infected individuals The strategies to prevent TB in HIV include early ART and the three Is: Intensive Case Finding, IPT, and Infection Control. IPT has been recommended by the WHO for all HIV-infected individuals including pregnant women and children, regardless of CD4 count, ART status, and previous TB treatment since Strong Recommendation, High Quality of Evidence. Global IPT uptake and implementation remain very slow (1/30 millions PLHIV in 2016)

3 IPT does NOT have the same benefit/harm ratios for all HIV patients in the Asia Pacific Stable, high CD4 count, virologically suppressed, TST/IGRA (-) Starting ART, high CD4 count, TST/IRGA (-) Starting ART, low CD4 count,

4 Cases 45 year old man, ex IDU, on first-line ART for 8 years who has been well and stable, viral load undetectable for 5 years under my care. He has no prior history of TB. CD4 count of year old woman with a history of TB meningitis, history treatment failure on 2 nd line ART with LPV/r for over 3 years, stable, viral load undetectable, CD4 count year old man who completed a 6 month course of pulmonary TB 6 months ago, viral load undetectable, CD4 is 200.

5 Distribution of HIV patients along the TB risk spectrum 50% Asymptomatic starting ART, TST/IRGA (-) Asymptomatic starting ART, TST/IRGA (+) Symptomatic Starting ART Virologically suppressed on long-term ART TST/IRGA (-)

6 Important barriers to implementation in the Asia Pacific region Concerns of INH hepatotoxicity, given the high burden of viral hepatitis coinfection and alcoholic hepatitis in the region, pill burden, adherence, and INH resistance development Uncertainty of efficacy in the setting of very high INH resistance (up to 25%) compared to Africa (<5%) Lack of evidence of benefits in patients who are virologically suppressed on long-term ART with high CD4 counts and those who are TST negative

7 64% of TB cases in 2015 occur in the Asia Pacific region

8 Cochrane of 12 placebo controlled RCT in IPT TB incidence All caused mortality TST (+) TST (-) TST unknown From: Treatment of latent tuberculosis infection in HIV infected persons Akolo C, Adetifa I, Shepperd S, Volmink J.. Cochrane Database Syst Rev Jan 20;(1):CD

9 Systematic review of 41 studies on ITP Use of Isoniazid Preventive Therapy for Tuberculosis Prophylaxis Among People Living With HIV/AIDS: A Review of the Literature Briggs, Melissa A. et al. JAIDS 2015

10 Reduction of TB incidence is observed in TST (+) but not in TST (-) individuals TST (+) TST (-)

11 No evidence for a mortality benefit in TST (+) or (-) individuals

12 TEMPRANO trial and post-trial follow up design

13 Temprano trial results NEJM 2015 Morbidity benefit is driven primarily by Early ART

14 Temprano long-term follow up results IPT: 16 deaths No IPT: 23 deaths Lancet Global Health 2017

15 Temprano: mortality by IGRA test IGRA (+) IGRA (-) There was a clear mortality benefit during the first 30 month (duration of main trial) in IGRA (+) but not in IGRA (-) patients

16 JAIDS. April 2016

17 Meta-analysis of 13 studies N=18,095 in INH group, N=17,985 in control group Only 158 isolates in the INH group and 328 isolates in the control group were available RR for resistance was 1.45 (95% CI: ) Studies from USA, Africa (Kenya, Uganda, Zambia), and Europe (Spain) Emerg Infec Dis. CDC. May 2006

18 IPT should NOT be implemented for all HIV patients in the Asia Pacific There are no clear benefits of IPT in TST negative HIV patients, particularly those who are virologically suppressed on long-term ART Intensive Case Finding (ICF) should include ICF of latent TB infections, just as recommended for non-hiv infected individuals RCTs should be done in countries with high TB/HIV prevalence in the Asia Pacific to inform policy in the region TST is feasible in rural and urban settings and should be implemented now in a diagnostic-driven approach to IPT to reduce TB incidence and to improve treatment acceptability, reducing unneccessary treatment, toxicity, and costs

19 I advocate for Diagnostic driven approach to IPT, with yearly testing for latent TB in HIV patients who are stable on ART Placebo controlled RCTs conducted in the Asia Pacific region: comparing a diagnostic driven approach vs. the WHO mass treatment approach evaluating long morbidity, mortality, tolerability, drug resistance, and cost effectiveness Comparing different TB regimens, combination/short course therapy vs. INH