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.