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

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 ?L. 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 ?L (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.

SUBMITTER: Hosseinipour MC

PROVIDER: S-EPMC4931281 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Hosseinipour Mina C MC Bisson Gregory P GP Miyahara Sachiko S Sun Xin X Moses Agnes A Riviere Cynthia C Kirui Fredrick K FK Badal-Faesen Sharlaa S Lagat David D Nyirenda Mulinda M Naidoo Kogieleum K Hakim James J Mugyenyi Peter P Henostroza German G Leger Paul D PD Lama Javier R JR Mohapi Lerato L Alave Jorge J Mave Vidya V Veloso Valdilea G VG Pillay Sandy S Kumarasamy Nagalingeswaran N Bao Jing J Hogg Evelyn E Jones Lynne L Zolopa Andrew A Kumwenda Johnstone J Gupta Amita A

Lancet (London, England) 20160301 10024

<h4>Background</h4>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.<h4>Methods ...[more]

PMID: 27025337

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Project description:BackgroundIn sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only.MethodsWe did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16-18 kg/m2 or BMI-for-age Z scores <-3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary outcomes included absolute changes in weight, BMI, and mid-upper-arm circumference (MUAC). Safety was analysed in all randomly assigned participants. Follow-up was 48 weeks. This trial is registered with ClinicalTrials.gov (NCT01825031) and the ISRCTN registry (43622374).FindingsBetween June 18, 2013, and April 10, 2015, we randomly assigned 1805 participants to treatment: 897 to RUSF and 908 to no-RUSF. 56 (3%) were lost-to-follow-up. 96 (10·9%, 95% CI 9·0-13·1) participants allocated to RUSF and 92 (10·3%, 8·5-12·5) to no-RUSF died within 24 weeks (hazard ratio 1·05, 95% CI 0·79-1·40; log-rank p=0·75), with no evidence of interaction with the other randomisations (both p>0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45).InterpretationIn severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present.FundingJoint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).

Project description:BackgroundClinical studies suggest that isoniazid contributes rapid bacterial killing during the initial two days of tuberculosis treatment but that isoniazid's activity declines significantly after day three. We conducted a 14-day phase IIa open label, randomized trial to assess the essentiality of isoniazid in standard tuberculosis therapy.MethodsA total of 69 adults with newly diagnosed sputum-positive tuberculosis from the South African Western Cape region were enrolled and randomized to a four-arm parallel assignment model. Participants were followed for 14 days as inpatients at either the University of Cape Town Lung Institute or at the TASK Applied Science clinical research organization. All arms received standard daily rifampicin, ethambutol, and pyrazinamide but differed as follows: isoniazid only on days one and two (n=17), isoniazid on days one and two then moxifloxacin on days three through 14 (n=16), no isoniazid (n=18), and a control group that received isoniazid for all 14 days (standard therapy, n=18). The primary endpoint was the rate of colony forming unit (CFU) decline during the first 14 days of treatment.ResultsFor 62 participants analyzed, the initial 14-day mean daily fall in log10 CFU (95% CI) was 0·14 (0·11, 0·18) for participants receiving isoniazid for two days only; 0·13 (0·09, 0·17) for participants receiving isoniazid for two days followed by moxifloxacin; 0·12 (0·08, 0·15) for those not receiving isoniazid; and 0·13 (0·09, 0·16) for the standard therapy group.ConclusionsThe 14 day EBA for the combination rifampicin, ethambutol, and pyrazinamide was not significantly changed by the addition of isoniazid for the first two days or for the first 14 days of treatment. In a post hoc analysis, significantly higher day-two EBAs were observed for all groups among participants with higher baseline sputum CFUs. Our finding that INH does not contribute to EBA suggests that INH could be replaced with another drug during standard treatment to improve efficacy and decrease rates of resistance to first-line drugs. (Funded by the NIH AIDS Clinical Trial Groups and NIH; A5307 ClinicalTrials.gov number, NCT01589497).

Project description:BackgroundNonadherence to HIV medications is a serious unsolved problem and is a major cause of morbidity and mortality in the HIV-positive population. Although treatment efficacy is high if compliance is greater than 90%, about 40% of people with HIV do not meet this threshold.ObjectiveThis study aimed to test a novel approach to improve medication adherence by using a low-cost virtual reality (VR) experience to educate people with HIV about their illness. We hypothesized that people with HIV would be more likely to be compliant with the treatment following the 7-minute experience and, therefore, should have decreasing viral load (VL), increasing cluster of differentiation 4+ (CD4+) cell counts, and improved self-reported adherence.MethodsWe showed the VR experience to 107 participants with HIV at a county hospital in Los Angeles, California. Participants were asked to self-report how often they take their medications on a Likert-scale. The self-reported question (SRQ) was given before and at least 2 weeks after the VR experience. We also compared VL and CD4+ cell counts before and on average 101 days after the experience. VL and CD4+ were obtained per the clinic's standard care protocol. Two-tailed paired t tests were performed on the initial and follow-up SRQ scores, VL, and CD4+. We restricted the CD4+ analysis to participants who had a pre-CD4+ below normal (defined as 500 cells/mm3). To reduce the possibility that VL were trending down and CD4+ were trending up regardless of the VR experience, 2 serial VL and CD4+ obtained before the experience were also compared and analyzed. Immediately following the VR experience, participants were given a 4-question Likert-type postexperience questionnaire (PEQ) that assessed their opinions about the experience.ResultsSRQ scores improved from pre to post experience with high significance (P<.001). VL decreased from pre to post experience by 0.38 log10 copies/mL (95% CI 0.06-0.70; P=.02). In contrast, the 2 serial VL obtained before the experience showed no statistically significant changes. There was also a statistically significant increase in CD4+ (95% CI -3.4 to -54.3 cells/mm3; P=.03). Analysis of the PEQ revealed that VR was comfortable for almost all of the participants and that most participants believed the experience to be educational and that it would improve their medication adherence.ConclusionsThe findings suggest that the low-cost VR experience caused an increased rate of antiretroviral therapy adherence that resulted in a decrease of VL and an increase of CD4+. Further studies are required to explore the duration of this effect and whether these results are generalizable to other treatment settings and populations.

Dataset Information

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

Publications

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

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