Background
In sub-Saharan Africa, among patients with advanced human
immunodeficiency virus (HIV) infection, the rate of death from infection
(including tuberculosis and cryptococcus) shortly after the initiation of
antiretroviral therapy (ART) is approximately 10%.
Methods
In this factorial open-label trial conducted in Uganda, Zimbabwe,
Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of
age or older who had not received previous ART and were starting ART with a
CD4+ count of fewer than 100 cells per cubic millimeter. They underwent
simultaneous randomization to receive enhanced antimicrobial prophylaxis or
standard prophylaxis, adjunctive raltegravir or no raltegravir, and
supplementary food or no supplementary food. Here, we report on the effects
of enhanced antimicrobial prophylaxis, which consisted of continuous
trimethoprim–sulfamethoxazole plus at least 12 weeks of
isoniazid–pyridoxine (coformulated with
trimethoprim–sulfamethoxazole in a single fixed-dose combination
tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose
of albendazole, as compared with standard prophylaxis
(trimethoprim–sulfamethoxazole alone). The primary end point was
24-week mortality.
Results
A total of 1805 patients (1733 adults and 72 children or adolescents)
underwent randomization to receive either enhanced prophylaxis (906
patients) or standard prophylaxis (899 patients) and were followed for 48
weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells
per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly
symptomatic. In the Kaplan–Meier analysis at 24 weeks, the rate of
death with enhanced prophylaxis was lower than that with standard
prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95%
confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127
(14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI,
0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had
significantly lower rates of tuberculosis (P=0.02), cryptococcal infection
(P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause
(P=0.03), and new hospitalization (P=0.03). However, there was no
significant between-group difference in the rate of severe bacterial
infection (P=0.32). There were nonsignificantly lower rates of serious
adverse events and grade 4 adverse events in the enhanced-prophylaxis group
(P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and
adherence to ART were similar in the two groups.
Conclusions
Among HIV-infected patients with advanced immunosuppression, enhanced
antimicrobial prophylaxis combined with ART resulted in reduced rates of
death at both 24 weeks and 48 weeks without compromising viral suppression
or increasing toxic effects. (Funded by the Medical Research Council and
others; REALITY Current Controlled Trials number, ISRCTN43622374.)
