This multi-country trial examined outcomes among treatment-naïve adults and children with CD4 counts below 100 who were given enhanced antimicrobial prophylaxis including trimethoprim-sulfamethoxazole, isoniazid-pyridoxine, fluconazole, azithromycin, and albendazole in addition to antiretroviral therapy (ART). Among the 1,806 patients enrolled in the trial, 906 were randomized to the enhanced prophylaxis group and 899 were randomized to the standard prophylaxis group. At 12 weeks, patients in the enhanced prophylaxis group reported lower adherence to prophylaxis, but adherence at 24 and 48 weeks was similar between the groups. ART adherence was also similar in both groups. At 24 weeks, 8.9 percent of patients in the enhanced prophylaxis group had died, compared to 12.2 percent in the standardized prophylaxis group. At 48 weeks, 11 percent of patients in the enhanced prophylaxis group had died, versus 14.4 percent in the standardized prophylaxis group. This translated to a 27 percent and 24 percent reduction in death rates at 24 and 48 weeks, respectively. Participants in the enhanced prophylaxis group experienced significantly fewer hospitalization days, deaths, World Health Organization stage 3 or 4 occurrences, new tuberculosis diagnoses, and cryptococcal or candidiasis infections. There were also fewer immune reconstitution inflammatory events. The authors concluded that enhanced prophylaxis offers increased survival rates, has a low pill burden, is relatively low cost, has few side effects, and is easily implemented.