Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa

Abstract

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 .).

Figure 1. Enrollment and Randomization.

Patients could have more than one reason for exclusion; they could also be lost to follow-up without withdrawal of consent and vice versa, so the total numbers of patients with exclusions and discontinuations are lower than the sums of the individual categories. Details regarding the patients’ adherence to treatment are provided in Figure S1 in the Supplementary Appendix.

Figure 2. Overall Mortality and Cause of Death at 48 Weeks.

Panel A shows the results of a Kaplan–Meier analysis of death over 48 weeks in the enhanced-prophylaxis group and the standard-prophylaxis group. The inset shows the same data on an expanded y axis, with Kaplan–Meier estimates of mortality at 24 and 48 weeks. Panel B shows the predominant causes of death in the two groups over 48 weeks.

Figure 3. Secondary and Other Outcomes at 48 Weeks.

Secondary outcomes included death, new tuberculosis, new cryptococcal infection, new candida infection, presumptive severe bacterial infection, serious adverse event, hospitalization, grade 4 adverse event, and adverse event leading to prophylaxis drug modification. IRIS denotes immune reconstitution inflammatory syndrome, and WHO World Health Organization.

Figure 4. Reduction in HIV Viral Load, Increase in CD4+ Count, and Increase in Body-Mass Index at 48 Weeks.

Shown is the percentage of patients with an HIV viral load of fewer than 50 copies per milliliter (Panel A), the CD4+ count (Panel B), and the body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) (Panel C), according to the week since randomization. Below the graphs, the percentages of patients with an HIV viral load of fewer than 50 copies per milliliter are shown in Panel A, and the mean changes from baseline in the CD4+ count and BMI are shown in Panels B and C. The I bars indicate 95% confidence intervals.