Isoniazid preventive therapy for HIV+: Controversial topics Gary Maartens Division of Clinical Pharmacology UNIVERSITY OF CAPE TOWN IYUNIVESITHI YASEKAPA UNIVERSITEIT VAN KAAPSTAD
Risk of TB disease after infection HIV -ve 5-10% per lifetime HIV +ve 5-10% per year
TB incidence doubled within the first year of HIV infection (adjusted RR, 2.1 [95% CI, 1.4 3.1]) JID 2005;191:150
TB per 100 py Incidence of TB by CD4 count 20 15 10 Pulmonary Extrapulmonary PTB EPTB 5 0 <50 50-200 200-350 >350 CD4 Holmes JAIDS 2006;42:464-9
Tests for diagnosing LTBI: IFN-γ release assays vs Mantoux Rangaka, Am J Respir Crit Care Med 2007;175:514
TB risk increases exponentially as CD4 declines Tuberculin skin test more likely to be negative in HIV, especially with lower CD4 Therefore TST should not be useful in deciding which HIV+ patients need preventive therapy
Preventive Rx & TST status TST status Relative risk (95%CI) Positive 0.38 (0.25, 0.57) Negative 0.89 (0.64, 1.24) Combined 0.68 (0.54, 0.85) Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD000171
We did not find any association between INH preventive therapy and reductions in incident TB among TST-negative adults with advanced HIV disease
INH transiently increased interferon- producing T cells JID 2006;193:354
DOH May 2010 Where tuberculin tests are feasible and can be performed, IPT should only be offered to those who are TST positive. However, the practicalities and logistics of doing a tuberculin skin test are often an obstacle for provision of TB preventive therapy. Therefore the tuberculin skin test is no longer required to identify HIV infected people eligible for IPT.
INH tolerability in HIV+ Adverse events severe enough to stop therapy INH 3.56% Placebo 2.21% RR 1.66 (1.09-2.51) Woldehanna 2007
How to rule out active TB?
Ruling out TB Simple symptoms effectively rule out TB (NPV 98%) Perform best clinic & with low CD4 Chest x ray not necessary (abnormal CXR increased sensitivity of symptoms by 11.7%, but reduced specificity by 10.7%)
IPT duration of benefit in HIV+ Zambia Benefit lost at 18 months Uganda Benefit lost at 1 year Both post hoc analyses (under-powered) Quigley 2001 Johnson 2001
Lancet 2011;277:1588
BOTUSA study 98%not on ART at start 834 1995 821 Samandari Lancet 2011
Benefit lost after 6 months TB TST+ HR 0.08 (0.01 0.61) TST- HR 0.86 (0.38 1.89) Death TST+ HR 0.28 (0.08 1.03) TST- HR 2.99 (1.27 7.04) Severe AEs >6 months 1% placebo 1.3% INH
Longer duration IPT -Soweto trial HIV+ not needing ART, all TST+ 4 arms: INH continuous (n=164) INH 6 months (n=327) INH + Rifampicin 3 months (n=329) INH + Rifapentine 3 months (n=328) NEJM 2011;365:11
Longer duration IPT -Soweto trial 2 No difference in TB incidence by arm IRR 0.74 (0.29-1.73; P=0.48) H long term vs 6 months Long term INH not well tolerated Grade 3/4 ALT/AST 5.5% vs 28% H 6 months vs long term On treatment analysis showed benefit for long term INH for combined endpoint TB or death (P=0.02) NEJM 2011;365:11
ART plus IPT?
Effect of ART on TB 67% reduction (95% CI 61 73%) Lawn Lancet ID 2010;10:489
TB incidence (/100 py) on ART Lawn AIDS 2009
IPT & ART: Retrospective cohorts 1 Treatment Brazil TB/100 PY (95% CI) South Africa TB/100 PY (95% CI) No ART or IPT 4.01 (3.4-4.69) 7.1 (6.2 8.2) ART 1.90 (1.66 2.17) 4.6 (3.4 6.2) IPT 1.27 (0.41 2.95) 5.2 (3.4 7.8) IPT + ART* 0.80 (0.38 1.47) 1.1 (0.02 7.6) *SA study all IPT then ART, not clear in Brazil study AIDS 2007;21:1441 AIDS 2009;23:631
IPT & ART: Retrospective cohorts 2 SA gold mines Group not given IPT significant differences: More advanced disease (lower CD4, higher viral load, more WHO stage 3 & 4) Started ART earlier years Fewer on cotrimoxazole Lower Hb Adjusted HR death 0.51 (0.32, 0.80) AIDS 2010;24 (Suppl 5):S5
IPT & ART - BOTUSA 1 year of ART reduced TB by 50%. No significant additional effect in TST+ on 36 months INH
IPT + ART, risk:benefit Number needed to treat with IPT to prevent 1 case of TB is about 50 (TST not done) without ART likely to be higher on ART Number needed to harm with IPT about 100 may be more toxic with ART RCT underway Khayelitsha (ends Dec 2011) 12 months INH/placebo n=1368 Starting ART or already on ART Sub-study 82% returned for TST reading Funders: DoH, MSF, Wellcome Trust Rangaka Eur Resp J in press
Conclusions If possible TST should be done as it determines who benefits Start pre-art (unless RCT shows benefit) Benefit is short-lived Operational research needed on long term IPT, only if TST+
IPT-ART study