Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2016 Mar 19;387(10024):1198-209.
doi: 10.1016/S0140-6736(16)00546-8.

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial

Mina C Hosseinipour  1 , Gregory P Bisson  2 , Sachiko Miyahara  3 , Xin Sun  3 , Agnes Moses  4 , Cynthia Riviere  5 , Fredrick K Kirui  6 , Sharlaa Badal-Faesen  7 , David Lagat  8 , Mulinda Nyirenda  9 , Kogieleum Naidoo  10 , James Hakim  11 , Peter Mugyenyi  12 , German Henostroza  13 , Paul D Leger  5 , Javier R Lama  14 , Lerato Mohapi  15 , Jorge Alave  14 , Vidya Mave  16 , Valdilea G Veloso  17 , Sandy Pillay  18 , Nagalingeswaran Kumarasamy  19 , Jing Bao  20 , Evelyn Hogg  21 , Lynne Jones  22 , Andrew Zolopa  23 , Johnstone Kumwenda  9 , Amita Gupta  24 ; Adult AIDS Clinical Trials Group A5274 (REMEMBER) Study Team
Collaborators, Affiliations
Randomized Controlled Trial

Empirical tuberculosis therapy versus isoniazid in adult outpatients with advanced HIV initiating antiretroviral therapy (REMEMBER): a multicountry open-label randomised controlled trial

Mina C Hosseinipour et al. Lancet. .

Abstract

Background: Mortality within the first 6 months after initiating antiretroviral therapy is common in resource-limited settings and is often due to tuberculosis in patients with advanced HIV disease. Isoniazid preventive therapy is recommended in HIV-positive adults, but subclinical tuberculosis can be difficult to diagnose. We aimed to assess whether empirical tuberculosis treatment would reduce early mortality compared with isoniazid preventive therapy in high-burden settings.

Methods: We did a multicountry open-label randomised clinical trial comparing empirical tuberculosis therapy with isoniazid preventive therapy in HIV-positive outpatients initiating antiretroviral therapy with CD4 cell counts of less than 50 cells per μL. Participants were recruited from 18 outpatient research clinics in ten countries (Malawi, South Africa, Haiti, Kenya, Zambia, India, Brazil, Zimbabwe, Peru, and Uganda). Individuals were screened for tuberculosis using a symptom screen, locally available diagnostics, and the GeneXpert MTB/RIF assay when available before inclusion. Study candidates with confirmed or suspected tuberculosis were excluded. Inclusion criteria were liver function tests 2·5 times the upper limit of normal or less, a creatinine clearance of at least 30 mL/min, and a Karnofsky score of at least 30. Participants were randomly assigned (1:1) to either the empirical group (antiretroviral therapy and empirical tuberculosis therapy) or the isoniazid preventive therapy group (antiretroviral therapy and isoniazid preventive therapy). The primary endpoint was survival (death or unknown status) at 24 weeks after randomisation assessed in the intention-to-treat population. Kaplan-Meier estimates of the primary endpoint across groups were compared by the z-test. All participants were included in the safety analysis of antiretroviral therapy and tuberculosis treatment. This trial is registered with ClinicalTrials.gov, number NCT01380080.

Findings: Between Oct 31, 2011, and June 9, 2014, we enrolled 850 participants. Of these, we randomly assigned 424 to receive empirical tuberculosis therapy and 426 to the isoniazid preventive therapy group. The median CD4 cell count at baseline was 18 cells per μL (IQR 9-32). At week 24, 22 (5%) participants from each group died or were of unknown status (95% CI 3·5-7·8) for empirical group and for isoniazid preventive therapy (95% CI 3·4-7·8); absolute risk difference of -0·06% (95% CI -3·05 to 2·94). Grade 3 or 4 signs or symptoms occurred in 50 (12%) participants in the empirical group and 46 (11%) participants in the isoniazid preventive therapy group. Grade 3 or 4 laboratory abnormalities occurred in 99 (23%) participants in the empirical group and 97 (23%) participants in the isoniazid preventive therapy group.

Interpretation: Empirical tuberculosis therapy did not reduce mortality at 24 weeks compared with isoniazid preventive therapy in outpatient adults with advanced HIV disease initiating antiretroviral therapy. The low mortality rate of the trial supports implementation of systematic tuberculosis screening and isoniazid preventive therapy in outpatients with advanced HIV disease.

Funding: National Institutes of Allergy and Infectious Diseases through the AIDS Clinical Trials Group.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Figure 1.a Consort Diagram Figure 1.b Screening Methods for Enrolled and Ineligible Participants
Figure 1
Figure 1
Figure 1.a Consort Diagram Figure 1.b Screening Methods for Enrolled and Ineligible Participants
Figure 2
Figure 2. Kaplan Meier plots for time to primary and secondary endpoint
a) Time to primary endpoint (death or unknown status) by treatment strategy b) Time to death or AIDS progression by treatment strategy c) Time to confirmed or probable Tuberculosis by treatment strategy d) Time to death or AIDS progression (Excluding confirmed and probable TB) by treatment strategy
Figure 2
Figure 2. Kaplan Meier plots for time to primary and secondary endpoint
a) Time to primary endpoint (death or unknown status) by treatment strategy b) Time to death or AIDS progression by treatment strategy c) Time to confirmed or probable Tuberculosis by treatment strategy d) Time to death or AIDS progression (Excluding confirmed and probable TB) by treatment strategy
Figure 2
Figure 2. Kaplan Meier plots for time to primary and secondary endpoint
a) Time to primary endpoint (death or unknown status) by treatment strategy b) Time to death or AIDS progression by treatment strategy c) Time to confirmed or probable Tuberculosis by treatment strategy d) Time to death or AIDS progression (Excluding confirmed and probable TB) by treatment strategy
Figure 2
Figure 2. Kaplan Meier plots for time to primary and secondary endpoint
a) Time to primary endpoint (death or unknown status) by treatment strategy b) Time to death or AIDS progression by treatment strategy c) Time to confirmed or probable Tuberculosis by treatment strategy d) Time to death or AIDS progression (Excluding confirmed and probable TB) by treatment strategy
See this image and copyright information in PMC

Comment in

References

    1. UNAIDS. How AIDS changed everything: MDG 6: 15 YEARS, 15 LESSONS OF HOPE FROM THE AIDS ESPONSE. [accessed July 14 2015 2015];Fact Sheet. 2015 http://www.unaids.org/sites/default/files/media_asset/20150714_FS_MDG6_R....
    1. Gupta A, Nadkarni G, Yang WT, et al. Early Mortality in Adults Initiating Antiretroviral Therapy (ART) in Low- and Middle-Income Countries (LMIC): A Systematic Review and Meta-Analysis. PLoS ONE. 2011;6(12):e28691. - PMC - PubMed
    1. Gupta A, Wood R, Kaplan R, Bekker LG, Lawn SD. Prevalent and incident tuberculosis are independent risk factors for mortality among patients accessing antiretroviral therapy in South Africa. PLoS One. 2013;8(2):e55824. - PMC - PubMed
    1. Lawn SD, Badri M, Wood R. Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS. 2005;19(18):2109–16. - PubMed
    1. Brinkhof MW, Egger M, Boulle A, et al. Tuberculosis after initiation of antiretroviral therapy in low-income and high-income countries. Clin Infect Dis. 2007;45(11):1518–21. - PMC - PubMed

Publication types

Associated data