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Opportunistic diseases diminish the clinical benefit of immediate antiretroviral therapy in HIV-tuberculosis co-infected adults with low CD4+ cell counts.

ABSTRACT: INTRODUCTION:HIV-tuberculosis (TB) co-infection remains an important cause of mortality in sub-Saharan Africa. Clinical trials have reported early (within 2 weeks of TB therapy) antiretroviral therapy (ART) reduces mortality among HIV-TB co-infected research participants with low CD4 cell counts, but this has not been consistently observed. We aimed to evaluate the current WHO recommendations for ART in HIV-TB co-infected patients on mortality in routine clinical settings. METHODS:We compared two cohorts before (2008-2010) and after (2012-2013) policy change on ART timing after TB and examined the effectiveness of early versus delayed ART on mortality in HIV-TB co-infected participants with CD4 cell count 100?cells/?l or less. We used inverse probability censoring-weighted Cox models on baseline characteristics to balance the study arms and generated hazard ratios for mortality. RESULTS:Of 356 participants with CD4 cell counts 100?cells/?l or less, 180 were in the delayed ART cohorts whereas 176 were in the early ART cohorts. Their median age (32.5 versus 32 years) and baseline CD4 cell counts (26.5 versus 26?cells/?l) respectively were similar. There was no difference in mortality rates of both cohorts. The risk of death increased in participants with a positive Cryptococcal antigen (CrAg) test in both the early ART cohort (aHR?=?2.6, 95% CI 1.0-6.8; P?=?0.045) and the delayed ART cohort (aHR?=?4.2, 95% CI 1.9-9.0; P?

SUBMITTER: Worodria W

PROVIDER: S-EPMC6136949 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Opportunistic diseases diminish the clinical benefit of immediate antiretroviral therapy in HIV-tuberculosis co-infected adults with low CD4+ cell counts.

Worodria William W Ssempijja Victor V Hanrahan Coleen C Ssegonja Richard R Muhofwa Abdallah A Mazapkwe Doreen D Mayanja-Kizza Harriet H Reynolds Steven J SJ Colebunders Robert R Manabe Yukari C YC

AIDS (London, England) 20180901 15

<h4>Introduction</h4>HIV-tuberculosis (TB) co-infection remains an important cause of mortality in sub-Saharan Africa. Clinical trials have reported early (within 2 weeks of TB therapy) antiretroviral therapy (ART) reduces mortality among HIV-TB co-infected research participants with low CD4 cell counts, but this has not been consistently observed. We aimed to evaluate the current WHO recommendations for ART in HIV-TB co-infected patients on mortality in routine clinical settings.<h4>Methods</h4 ...[more]

PMID: 30005014

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Project description:BackgroundImmediate initiation of antiretroviral therapy (ART) in asymptomatic adults with CD4 counts higher than 500 cells per μL, as recommended, might not always be possible in resource-limited settings. We aimed to identify subgroups of individuals who would benefit most from immediate treatment.MethodsThe START trial was a randomised controlled trial in asymptomatic, HIV-positive adults previously untreated with ART. Participants with CD4 counts higher than 500 cells per μL were randomly assigned to receive immediate ART or to defer ART until CD4 counts were lower than 350 cells per μL. The primary endpoint of the study was serious AIDS-defining illnesses or death from AIDS and serious non-AIDS illnesses or non-AIDS-related death. In this post-hoc analysis, we estimated event rates and absolute risk reduction with immediate versus deferred ART, overall and by subgroup. Subgroups were prespecified in the study protocol or formed post hoc on the basis of baseline characteristics associated with morbidity and mortality in people with HIV. For continuous characteristics, approximate terciles were chosen as subgroup cutoff points, unless different cutoffs were clinically meaningful (eg, age ≥50 years). We estimated the number needed to treat immediately with ART for 1 year to prevent one primary event. Heterogeneity in the absolute risk reduction between subgroups was assessed with bootstrap tests. The START trial is registered with ClinicalTrials.gov, number NCT00867048.FindingsBetween April 15, 2009, and Dec 23, 2013, we enrolled 4684 participants from 35 countries across five continents, of whom 2325 were assigned to immediate ART and 2359 were assigned to deferred ART. The primary endpoint occurred in 42 participants in the immediate ART group (0·58 events per 100 person-years) and 100 participants in the deferred ART group (1·37 events per 100 person-years). The absolute risk reduction was 0·80 (95% CI 0·48-1·13) per 100 person-years with immediate treatment, and the number needed to treat immediately to prevent one event was 126 (95% CI 89-208). Significant heterogeneity in absolute risk reduction with immediate ART was found across subgroups according to age (p=0·0022), CD4 to CD8 ratio (p=0·0007), and plasma HIV RNA viral load (p=0·033) at baseline. The highest absolute risk reductions and the lowest numbers needed to treat were found in participants aged 50 years or older, those with CD4 to CD8 ratios of less than 0·5, and those with plasma HIV RNA viral loads of 50 000 copies per mL or higher.InterpretationAsymptomatic, ART-naive adults with CD4 counts higher than 500 cells per μL who are older, have a low CD4 to CD8 ratio, or a high plasma HIV RNA viral load benefit most from immediate initiation of ART and should be prioritised for treatment.FundingUS National Institute of Allergy and Infectious Diseases.

Project description:BackgroundCD4 cell counts is widely used as a biomarker for treatment progression when studying the efficacy of drugs to treat HIV-infected patients. In the past, it had been also used in determining eligibility to initiate antiretroviral therapy. The main aim of this was to model the evolution of CD4 counts over time and use this model for an early prediction of subject-specific time to cross a pre-specified CD4 threshold.MethodsHospital based retrospective cohort study of HIV-infected patients was conducted from January 2009 to December 2014 at University of Gondar hospital, Northwest Ethiopia. Fractional polynomial random effect model is used to model the evolution of CD4 counts over time in response to treatment and to estimate the individual probability to be above a pre-selected CD4 threshold. Human subject research approval for this study was received from University of Gondar Research Ethics Committee and the medical director of the hospital.ResultsA total of 1347 patients were included in the analysis presented in this paper. The cohort contributed a total of 236.58 per 100 person-years of follow-up. Later the data were divided into two periods: the first is the estimation period in which the parameters of the model are estimated and the second is the prediction period. Based on the parameters from the estimation period, model based prediction for the time to cross a threshold was estimated. The correlations between observed and predicted values of CD4 levels in the estimation period were 0.977 and 0.982 for Neverapine and Efavirenz containing regimens, respectively; while the correlation between the observed and predicted CD4 counts in the prediction period are 0.742 and 0.805 for NVP and EFV, respectively.ConclusionsThe model enables us to estimate a subject-specific expected time to cross a CD4 threshold and to estimate a subject-specific probability to have CD4 count above a pre-specified threshold at each time point. By predicting long-term outcomes of CD4 count of the patients one can advise patient about the potential ART benefits that accrue in the long-term.

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Opportunistic diseases diminish the clinical benefit of immediate antiretroviral therapy in HIV-tuberculosis co-infected adults with low CD4+ cell counts.

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Opportunistic diseases diminish the clinical benefit of immediate antiretroviral therapy in HIV-tuberculosis co-infected adults with low CD4+ cell counts.

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