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Background: Mortality from infections is high in the first 6 months of antiretroviral therapy (ART) among HIV-infected adults and children with advanced disease in sub-Saharan Africa. Whether an enhanced package of infection prophylaxis at ART initiation would reduce mortality is unknown.
Methods: The REALITY 2x2x2 factorial open-label trial (ISRCTN43622374) randomised ART-naïve HIV-infected adults and children >5 years with CD4< 100 cells/mm3. This randomisation compared initiating ART with enhanced prophylaxis (continuous cotrimoxazole plus 12 weeks isoniazid/pyridoxine (anti-tuberculosis) and fluconazole (anti-cryptococcal/candida), 5 days azithromycin (anti-bacterial/protozoal) and single-dose albendazole (anti-helminth)), versus standard-of-care cotrimoxazole. Isoniazid/pyridoxine/cotrimoxazole was formulated as a scored fixed-dose-combination. Two other randomisations investigated 12-week adjunctive raltegravir or supplementary food. The primary endpoint was 24-week mortality.
Results: 1805 eligible adults (n=1733;96.0%) and children/adolescents (n=72;4.0%) (median 36 years; 53.2% male) were randomised to enhanced (n=906) or standard prophylaxis (n=899) and followed for 48 weeks (3.8% loss-to-follow-up). Median baseline CD4 was 36 cells/mm3 (IQR 16-62) but 47.3% were WHO stage 1/2. 80(8.9%) enhanced versus 108(12.2%) standard prophylaxis died before 24 weeks (adjusted hazard ratio[aHR]=0.73 (95% CI 0.54-0.97) p=0.03; Figure) and 98(11.0%) versus 127(14.4%) respectively died before 48 weeks (aHR=0.75 (0.58-0.98) p=0.04), with no evidence of interaction with the two other randomisations (p>0.8). Enhanced prophylaxis significantly reduced incidence of tuberculosis (p=0.02), cryptococcal disease (p=0.01), oral/oesophageal candidiasis (p=0.02), deaths of unknown cause (p=0.02), and (marginally) hospitalisations (p=0.06) but not presumed severe bacterial infections (p=0.38). Serious and grade 4 adverse events were marginally less common with enhanced prophylaxis (p=0.06). CD4 increases and VL suppression were similar between groups (p>0.2).

All-cause mortality
[All-cause mortality]


Conclusions: Enhanced infection prophylaxis at ART initiation reduces early mortality by 25% among HIV-infected adults and children with advanced disease. The pill burden did not adversely affect VL suppression. Policy-makers should consider adopting and implementing this low-cost broad infection prevention package which could save 3.3 lives for every 100 individuals treated.