UZ-UCSF Annual Research Day Empiric TB therapy does not decrease early mortality compared to Isoniazid Preventive therapy in adults with advanced HIV initiating ART: Results of ACTG A5274 (REMEMBER study) UZ-UCSF Annual Research Day April 08, 2016 W.Samaneka MBChB,MSc For the A5274 Study Team Thank you for inviting the A5274 team to present the findings of the REMEMBER study. I’d like to acknowledge the core protocol team and sites

Background Early Mortality and Morbidity within ART programs remains a significant problem in resource-limited settings TB is a major cause of early morbidity and mortality in these settings One of the early observations of ART programs in RLS was high early mortality. Even with modifications of eligibility criteria, those presenting with advanced disease remain vulnerable to early mortality. In these same settings, we know there is high HIV-TB mortality and morbidity. These points set the stage for why this study was conducted. Let’s review this in more detail. Braistein Lancet 2006, Keiser PLoS Med 2008,Castelnuovo CID 2009

1 Year Mortality 50 published cohort studies by region Mortality proportion, median (range) Sub-saharan Africa (n=35) 17% (11-24%) Asia (n=5;China, Cambodia, Thailand) 11% (10-13%) Americas (n=2; Haiti, Peru) 7% (1%-20%) Multiregional (n=5; Asia including India, Africa, South America, Caribbean) 8% (6-10%) Here, based on a systematic review, we can see the mortality rates in resource limited settings across different regions ranging from 7% in the America’s versus 17% in SSA. Gupta et al PLOS One 2011

Mortality by baseline CD4 cell count (ART-LINC and ART-CC) Sub-Saharan Africa Europe & North America 30 < 25 cells/µL 25-49 cells/µL 25 50-99 cells/µL 100-199 cells/µL 20 > 200 cells/µL Cumulative mortality (%) 15 10 IN this Graph, again comparing Resource Rich and Resource Poor setting, we see that starting CD4 count dictates the mortality rates. Among those with CD4 < 25, mortality reaches nearly 20% by 12 months. 5 12 24 36 48 12 24 36 48 Months after starting ART

Incidence of TB after ART Pulmonary TB ranged from 4.8/100 py in Cameroon to 17.7/100py in Kenya TB is difficult to diagnose due to limited diagnostic tools, particularly in those with advanced disease. TB diagnostics are evolving but sensitivity, specificity issues, access, cost, implementation and quality issues are faced with these diagnostics Notably, at the same time, we see high rates of Incident TB that occurs in ART programs. Pulmonary TB ranged from 4.8/100py in Cameroon to 17.7/100py in Kenya. The vast majority of this TB was diagnosed in the first 3 months of ART. Bonnet,et al. AIDS 2006, 20: 1275-1279

Hypothesis Empiric TB treatment will be associated with a decreased rate of death compared to the standard approach among participants with advanced HIV disease at high risk for mortality who are initiating ART in resource-limited settings with high incidence of TB.

ACTG 5274 Phase IV open label strategy trial Reducing Early Mortality & Early Morbidity by Empiric Tuberculosis Treatment Regimens (REMEMBER) ACTG 5274 HIV infected, CD4<50 cells, no active tuberculosis ART + Pre-emptive TB therapy “EMPIRIC” ART+ IPT + TB therapy upon diagnosis “IPT” ART initiated within 3 days of randomization and ATT or IPT within 7 days

Selected Eligibility Criteria Inclusion Exclusion HIV positive > 13 years CD4 < 50 cells/mm3 AST/ALT <=2.5 ULN CrCl >=30 ml/min HBsAg result available Negative pregnancy Karnofsky >30 Suspected or Active TB Single dose NVP within 24 months Current receipt or receipt of >14 days treatment for active TB within 96 weeks of entry > 30 days of INH prophylaxis within 48 weeks > 7days of ARV (except PMTCT) Grade 2 or greater neuropathy History of MDR TB

Stratification Randomization Stratified by CD4 <25 or >=25 cells/mm3 Prognosis: none vs. at least one of: recent hospitalization, low BMI (<18.5), anemia (<8.0g/dL)

Evolving Screening Guidelines Initial screening was TB symptom screen, targeted physical exam (e.g. lymph nodes) and allowing site to perform additional evaluations as per standard of care With Xpert rollout occurring during the study period, all sites were asked to perform single Xpert, AFB, and send for culture in 2013

Study Regimen EMPIRIC IPT Fixed dose HRZE x 8 wks then, Fixed dose HR x 16 wks IPT IPT 300mg once daily x 24 wks ART- BOTH ARMS Study provided: Efavirenz plus Truvada (Tenofovir/Emtricitibine) OR locally available 2 drug NRTI

Primary Objective To compare survival probability between the two study arms 24 weeks after randomization Primary Endpoint: Death or Unknown Status at 24 weeks

Selected Secondary Objectives Time to death Time to AIDS progression or death Rates of safety and tolerability of ART and TB treatment at 24 weeks including: cause of death, including TB-specific mortality, between the two arms. TB incidence

Statistical Analysis Primary Analysis Intent-to-treat analysis Kaplan-Meier estimator was used to estimate the primary event rates for both arms and the z-test was used to compare the primary event rates between the arms.

CONSORT Chart 1368 screened 850 enrolled (62% of those screened) EMPIRIC 424 850 Enrolled IPT 426 578 Excluded 192 (33%) High CD4 182 (31%) Active Disease 87 (15%) Lab out of range 117 (20%) Other 1368 screened 850 enrolled (62% of those screened) Accrual between October 2011-June 2014 Reasons for screen failure 32% Active Infection (primarily TB) 33% CD4 count too high Repeat at accredited lab too high Screening approach before CD4 assessment 15% Other lab exclusion criteria No significant decrease in enrollment with the change in screening procedures (Xpert, Culture)

Baseline Characteristics n=850 Empiric (%) IPT (%) Sex Male 53% Female 47% Race/ethnicity Black 90% 91% Indian 4% 3% Other 6% Age, years Median (IQR) 36 (30-42) 35 (30-42) HIV RNA, log copies/ml 5.4 (5.0, 5.7) 5.3 (4.9, 5.7) CD4 count cells/mm3 18 (9, 31) 19 (9, 33) % <25 63% 61% MODIFY to SHOW BY ARM

Proportion of A5274 participants by country 18 Sites in 10 countries

Absolute Risk Difference Primary Endpoint Empiric IPT Deaths (%) 20 (4.8%) 22 (5.2%) Unknown Vital Status (%) 2 (<0.5%) 0 (0%) Total endpoint events (%) 22 (5.3%) Absolute Risk Difference -0.06% (95% CI: -3.05%- 2.94%), p=0.97

Time to Primary Endpoint (Death or Unknown Vital Status) by Treatment Strategy

Sensitivity Analysis For Mortality Study Population and Stratification Factors No. of Patients Number (%) of Deaths or Unknown Survival 95% CI for Difference in Rates   P Value Empiric IPT All Patients 850 22 (5.2) -3.05, 2.94 0.97 Stratification Factors Pre-Mandated Sputum Xpert 444 13 (5.8) 13 (5.9) NA 0.96 Post-Mandated Sputum Xpert 398 9 (4.6) 9 (4.4) CD4 < 25 cells/mm3 504 17 (6.9) 17 (6.6) 0.92 CD4 ≥ 25 cells/mm3 338 5 (2.9) 5 (3.0) Poor Prognostic Factor 284 13 (9.4) 8 (5.5) 0.94 No Poor Prognostic Factor 558 9 (3.2) 14 (5.0)

Causes of Death Primary Cause of Death Empiric n (%) IPT HIV infection or HIV- related diagnosis 17 (89%) 11 (50%) Non-HIV diagnosis 0 (0%) 5 (23%) Toxicity 1 (5%) No information available 2 (11%) 4 (18%) Other, specify

Time to Death or AIDS progression

Time to Confirmed or Probable TB

Incident Tuberculosis Diagnoses Specific Category of TB cases Empiric IPT Externally Verified TB cases 33 19 Extra pulmonary tuberculosis - clinical diagnosis 11 8 Pulmonary tuberculosis - confirmed 4 Pulmonary tuberculosis - probable 3 Extra pulmonary tuberculosis - probable 5 Pulmonary tuberculosis-clinical diagnosis 1 Extra pulmonary tuberculosis - confirmed Here we see the description of the incident cases of Tuberculosis. All of these cases were verified by external reviewers to assure they met the diagnostic criteria. Overall, there were more TB cases in the Empiric arms. For both arms, the majority of cases were clinical diagnoses of EPTB.

Secondary Outcomes at 24 wks Empiric IPT HIV RNA <400 copies/ml 84% 85% Median CD4 change (IQR) 96 (55-147) 102 (60-159) Any Grade 3 or 4 sign or symptom 12% 11% Any Grade 3 or 4 lab toxicity 23% New “Diagnoses” 49% 51% TB IRIS 2% We reviewed a number of secondary outcomes and the results are similar across the arms. Here you can see the viral suppression, median CD4 change are simliar. Toxicity in terms of Grade 3 or 4 signs, symptoms or lab toxicity are similar. And new diagnoses were very common in both arms, occuring in approximately half of the participants. TB IRIS rates were also similar. Similar Self Reported High adherence to ART and TB medications reported at all visits across arms

Conclusions Empiric TB therapy did not reduce mortality at 24 weeks compared to INH Mortality low in both arms No differences across arms by stratification factors Incident Tuberculosis more common in the Empiric TB arm Possibly in part explained by adherence Possibly by chance as more TB early in empiric arm

Conclusions Empiric TB therapy had similar safety to INH Adverse events similar New HIV-related morbidities common but similar HIV RNA and CD4 trends similar Adherence to ART and TB medication similar

Discussion Current WHO policy advocating routine TB screening and IPT use is sufficient. No added benefit of empiric TB treatment in settings of systematic TB screening. More is not better to prevent mortality

Acknowledgments Lynne Jones Alex Benns, Luann Borowski A5274 Study team and site staff Study participants A. Moses (Malawi CRS, Malawi) C. Riviere (GHESKIO ,Haiti) F.K. Kirui (KEMRI, Kenya) S. Badal-Faesen (Wits, South Africa) D. Lagat (Eldoret, Kenya) M. Nyirenda (Blantyre CRS, Malawi) K. Naidoo (CAPRISA, South Africa) J. Hakim (Zimbabwe) P. Mugyenyi (JCRC, Uganda) G. Henostroza (CIDRZ, Zambia) P.D. Leger (GHESKIO, Haiti) J.R. Lama (Peru) L. Mohapi (South Africa) J. Alave (Peru) V. Mave (Pune, India) V.G. Veloso (Brazil) S. Pillay (Durban, South Africa) N. Kumarasamy (YRGCare, India) Pharmaceutical Support Provided by Gilead Sciences Inc. Merck & Co., Inc. Urine LAM kits- Alere