Background: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have high mortality (10%) from infections shortly after starting antiretroviral therapy (ART). Methods: The REALITY factorial open-label trial (ISRCTN43622374) randomized Ugandan/Zimbabwean/Malawian/Kenyan ART-naïve HIV-infected adults and children ≥5 years with CD4<100 cells/mm3 to ART with either enhanced-prophylaxis (continuous co-trimoxazole plus ≥12-weeks isoniazid/pyridoxine (co-formulated scored fixed-dose-combination tablet), 12-weeks fluconazole, 5-days azithromycin, single-dose albendazole), or standard-of-care co-trimoxazole. Two other randomizations investigated 12-week adjunctive raltegravir and supplementary food. The primary endpoint was 24-week mortality. Results: 1733(96.0%) adults and 72(4.0%) children/adolescents (median 36 years; 961(53.2%) male) were randomized to enhanced-prophylaxis (n=906) or standard-prophylaxis (n=899) and followed for 48 weeks (56(3.1%) lost-to-follow-up). Median baseline CD4 count was 37 cells/mm3 (IQR 16-63) but 854(47.3%) were asymptomatic or mildly symptomatic (stage 1/2 using the WHO clinical disease staging). 80(8.9%) individuals on enhanced-prophylaxis versus 108(12.2%) on standard-prophylaxis died before 24 weeks (hazard ratio[HR]=0.73 (95% CI 0.55-0.98) p=0.03), and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (HR=0.76 (0.58-0.99) p=0.04, number-needed-to-treat=29), with no evidence of interaction with other randomizations (p>0.7). Enhanced-prophylaxis significantly reduced cases of tuberculosis (p=0.02), cryptococcal disease (p=0.01), oral/oesophageal candidiasis (p=0.02), deaths of unknown cause (p=0.03), and new hospitalisations (p=0.03) but not presumed severe bacterial infections (p=0.32). Serious (p=0.08) and grade-4 (p=0.09) adverse events were marginally less common with enhanced-prophylaxis. Viral suppression (p=0.80) and ART adherence (p=0.31) were similar between groups. Conclusions: Enhanced infection prophylaxis at ART initiation reduced mortality among HIV-infected individuals with advanced immunosuppression, without compromising viral suppression or increasing toxicity. </p
