1. UZ-UCSF Annual Research Day
Reducing Early Mortality and Early Morbidity by Empiric Tuberculosis Treatment Regimens: 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

2. 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

3. 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

4. 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
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

5. 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:

6. 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.

7. 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

8. 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

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

10. 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

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

12. 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

13. 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.

14. 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)

15. 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

16. Proportion of A5274 participants by country
18 Sites in 10 countries

17. 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

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

19. 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)

20. 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

21. Time to Death or AIDS progression

22. Time to Confirmed or Probable TB

23. 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.

24. 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

25. 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

26. 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

27. 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

28. 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