A trial of early antiretrovirals and isoniazid preventive therapy in Africa
Abstract
Background
In sub-Saharan Africa, the burden of human immunodeficiency virus (HIV)–associated tuberculosis is high. We conducted a trial with a 2-by-2 factorial design to assess the benefits of early antiretroviral therapy (ART), 6-month isoniazid preventive therapy (IPT), or both among HIV-infected adults with high CD4+ cell counts in Ivory Coast.
Methods
We included participants who
had HIV type 1 infection and a CD4+ count of less than 800 cells
per cubic millimeter and who met no criteria for starting ART
according to World Health Organization (WHO) guidelines.
Participants were randomly assigned to one of four treatment
groups: deferred ART (ART initiation according to WHO criteria),
deferred ART plus IPT, early ART (immediate ART initiation), or
early ART plus IPT. The primary end point was a composite of
diseases included in the case definition of the acquired
immunodeficiency syndrome (AIDS), non–AIDS-defining
cancer, non–AIDS-defining invasive bacterial disease, or
death from any cause at 30 months. We used Cox proportional
models to compare outcomes between the deferred-ART and
early-ART strategies and between the IPT and no-IPT strategies.
Results
A total of 2056 patients
(41% with a baseline CD4+ count of ≥500 cells per cubic
millimeter) were followed for 4757 patient-years. A total of 204
primary end-point events were observed (3.8 events per 100
person-years; 95% confidence interval [CI], 3.3 to 4.4),
including 68 in patients with a baseline CD4+ count of at least
500 cells per cubic millimeter (3.2 events per 100 person-years;
95% CI, 2.4 to 4.0). Tuberculosis and invasive bacterial
diseases accounted for 42% and 27% of primary end-point events,
respectively. The risk of death or severe HIV-related illness
was lower with early ART than with deferred ART (adjusted hazard
ratio, 0.56; 95% CI, 0.41 to 0.76; adjusted hazard ratio among
patients with a baseline CD4+ count of ≥500 cells per cubic
millimeter, 0.56; 95% CI, 0.33 to 0.94) and lower with IPT than
with no IPT (adjusted hazard ratio, 0.65; 95% CI, 0.48 to 0.88;
adjusted hazard ratio among patients with a baseline CD4+ count
of ≥500 cells per cubic millimeter, 0.61; 95% CI, 0.36 to
1.01). The 30-month probability of grade 3 or 4 adverse events
did not differ significantly among the strategies.
Conclusions
In this African country,
immediate ART and 6 months of IPT independently led to lower
rates of severe illness than did deferred ART and no IPT, both
overall and among patients with CD4+ counts of at least 500
cells per cubic millimeter.
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