Primary and Secondary Outcomes
The primary outcome was death from any cause occurring from randomization to 24 weeks. Secondary outcomes, which were evaluated through 48 weeks, were death from any cause; serious adverse events, grade 4 adverse events, and adverse events leading to modification of ART or other trial drugs; mechanisms of each intervention, including a change in the CD4+ count; incidence of tuberculosis, cryptococcal infection, candidiasis (esophageal or oral), and severe bacterial infections; changes in weight or BMI; hospitalization; and patient-reported adherence to and acceptability of the ART regimen. Adverse events were graded according to the criteria of the National Institutes of Health.19,20 Other outcomes included WHO stage 3 or 4 events.18 An end-point review committee whose members were unaware of trial-group assignments and trial drugs received used protocol-defined criteria and grading tables19,20 to adjudicate all the secondary clinical outcomes that were reported by the trial physicians, along with determining the relatedness of the outcome to a trial drug and compatibility with IRIS. (Details regarding the trial outcomes are provided in the Methods section in the Supplementary Appendix.)
Economic Analysis and Quality of Life
We performed economic analyses to estimate costs and health outcomes during the 48-week trial using data on resources used in the trial and published unit costs for each country. Health was measured on the basis of quality-adjusted life-years, according to the three-level EuroQol Group 5-Dimension Self-Report Questionnaire, which the patients completed at each nurse visit. The value of each health state was assigned with the use of a Zimbabwean value set.21
Statistical Analysis
We determined that the enrollment of 1800 adults and children would provide a power of more than 80% to detect a rate of death from any cause that was 50% lower in the enhanced-prophylaxis group than in the standard-prophylaxis group at 24 weeks (a reduction in mortality from 7.0% to 3.5%) at a two-sided alpha level of 0.05, allowing for a 5% loss to follow-up. An independent data and safety monitoring committee used the Haybittle–Peto approach to review interim data at three annual meetings. We used the intention-to-treat principle to compare the randomized groups using log-rank tests or competing-risks methods for time-to-event outcomes, exact tests for binary outcomes, and generalized estimating equations with independent working correlation for global tests of repeated measures. The primary analyses were stratified according to the factors used to stratify the randomization, with no adjustment for multiple testing. All the analyses were performed with the use of Stata software, version 14.2.
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Results
Trial Patients
A total of 1805 patients underwent randomization to receive enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) (Fig. 1). The baseline characteristics of the patients were well balanced in the two groups (Table 1, and Table S1 in the Supplementary Appendix). The median age was 36 years; 72 patients (4.0%) were 5 to 17 years of age. The median CD4+ count was 37 cells per cubic millimeter, and 1300 of 1763 patients (73.7%) had a viral load of at least 100,000 copies per milliliter. Despite these findings, 854 patients (47.3%) were asymptomatic or mildly symptomatic (WHO clinical disease stage, 1 to 2).
Before randomization, 174 patients (9.6%) were receiving isoniazid treatment and 196 (10.9%) were receiving fluconazole treatment; 3 (0.2%) and 9 (0.5%), respectively, were receiving the drugs as prophylaxis. More patients in the standard-prophylaxis group than in the enhanced-prophylaxis group were prescribed fluconazole, azithromycin, or other antibiotics at randomization, a difference that probably reflected additional use for treating oral candidiasis or minor bacterial infections. All the patients initiated ART at a median of 5 days after screening, predominantly with first-line tenofovir, emtricitabine, and efavirenz.
A total of 56 patients (3.1%) — 24 in the enhanced-prophylaxis group and 32 in the standard-prophylaxis group — were lost to follow-up (i.e., no clinic attendance for >91 days) (P=0.28). At last follow-up, 1765 patients (97.8%) were still receiving first-line ART, of whom 119 (6.6%) had made within-class substitutions. There was no significant between-group difference in the percentage of patients who missed at least one scheduled visit before death or loss to follow-up (11.6% [105 patients] in the enhanced-prophylaxis group and 11.9% [107 patients] in the standard-prophylaxis group, P=0.84).
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