Effect of immediate initiation of antiretroviral therapy on risk of severe bacterial infections in HIV-positive people with CD4 cell counts of more than 500 cells per μL: secondary outcome results from a randomised controlled trial

Jemma O'Connor,Michael J Vjecha,Andrew N Phillips,Brian Angus,David Cooper,Beatriz Grinsztejn,Gustavo Lopardo,Satyajit Das,Robin Wood,Aimee Wilkin,Hartwig Klinker,Pacharee Kantipong,Karin L Klingman,David Jilich,Elbushra Herieka,Eileen Denning,Ibrahim Abubakar,Fred Gordin,Jens D Lundgren

doi:10.1016/s2352-3018(16)30216-8

Abstract

SummaryBackgroundThe effects of antiretroviral therapy on risk of severe bacterial infections in people with high CD4 cell counts have not been well described. In this study, we aimed to quantify the effects of immediate versus deferred ART on the risk of severe bacterial infection in people with high CD4 cell counts in a preplanned analysis of the START trial.MethodsThe START trial was a randomised controlled trial in ART-naive HIV-positive patients with CD4 cell count of more than 500 cells per μL assigned to immediate ART or deferral until their CD4 cell counts were lower than 350 cells per μL. We used Cox proportional hazards regression to model time to severe bacterial infection, which was defined as a composite endpoint of bacterial pneumonia (confirmed by the endpoint review committee), pulmonary or extrapulmonary tuberculosis, or any bacterial infectious disorder of grade 4 severity, that required unscheduled hospital admissions, or caused death. This study is registered with ClinicalTrials.gov, number NCT00867048.FindingsPatients were recruited from April 15, 2009, to Dec 23, 2013. The data cutoff for follow-up was May 26, 2015. Of 4685 HIV-positive people enrolled, 120 had severe bacterial infections (immediate-initiation group n=34, deferred-initiation group n=86; median 2·8 years of follow-up). Immediate ART was associated with a reduced risk of severe bacterial infection compared with deferred ART (hazard ratio [HR] 0·39, 95% CI 0·26–0·57, p<0·0001). In the immediate-initiation group, average neutrophil count over follow-up was 321 cells per μL higher, and average CD4 cell count 194 cells per μL higher than the deferred-initiation group (p<0·0001). In univariable analysis, higher time-updated CD4 cell count (0·78, 0·71–0·85, p=0·0001) was associated with reduced risk of severe bacterial infection. Time-updated neutrophil count was not associated with severe bacterial infection. After adjustment for time-updated factors in multivariable analysis, particularly the CD4 cell count, the HR for immediate-initiation group moved closer to 1 (HR 0·84, 0·50–1·41, p=0·52). These results were consistent when subgroups of the severe bacterial infection composite were analysed separately.InterpretationImmediate ART reduces the risk of several severe bacterial infections in HIV-positive people with high CD4 cell count. This is partly explained by ART-induced increases in CD4 cell count, but not by increases in neutrophil count.FundingNational Institute of Allergy and Infectious Diseases National Institutes of Health, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales, Bundesministerium für Bildung und Forschung, European AIDS Treatment Network, Australian National Health and Medical Research Council, UK National Institute for Health Research and Medical Research Council, Danish National Research Foundation.

Highlights

The Strategic Timing of AntiRetroviral Treatment (START) trial, in people with CD4 counts of more than 500 cells per μL and who were naive to antiretroviral therapy (ART), revealed a 57% reduction in risk of AIDS and non-AIDS morbidity and mortality in participants randomly assigned to immediate ART initiation compared with those allocated to deferred initiation.[1]
We found no substantive randomised trial evidence published about the effect of antiretroviral therapy (ART) on risk of severe bacterial infections in people with HIV and high CD4 cell count (>500 cells per μL) before this study
Our aim was to investigate whether the reduction in severe bacterial infection observed in the immediate-initiation group could be explained by possible increases in neutrophil counts, and the increases in CD4 cell counts that were observed in this group, and to investigate other factors associated with the incidence of severe bacterial infection

Summary

Introduction

The Strategic Timing of AntiRetroviral Treatment (START) trial, in people with CD4 counts of more than 500 cells per μL and who were naive to antiretroviral therapy (ART), revealed a 57% reduction in risk of AIDS and non-AIDS morbidity and mortality in participants randomly assigned to immediate ART initiation compared with those allocated to deferred initiation.[1]. The primary article for the START study reported a reduced risk of bacterial infectious disorder events and incidence of tuberculosis in the immediate-initiation group. Characterisation of the effect of early ART on the incidence of bacterial infections is important because these events are common in people living with HIV.[5,6,7,8,9,10]. In the START study, most serious AIDS-related events, serious non-AIDS-related events, or deaths occurred in patients with CD4 counts above 500 cells per μL and the treatment effect was only partly mediated by changes in Lancet HIV 2017; 4: e105–112.

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