Background: Early mortality after initiating antiretroviral therapy (ART) is high among HIV-infected adults and children with advanced disease in Sub-Saharan Africa. Intensifying ART with an integrase inhibitor should reduce viral load (VL) faster, but whether this reduces early 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 from Kenya, Malawi, Uganda and Zimbabwe. This randomisation compared initiating ART with 2NRTI+NNRTI with or without 12-week raltegravir intensification. Two other randomisations investigated 12-week enhanced infection prophylaxis 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 raltegravir-intensified (n=903) or standard (n=902) ART and followed for 48 weeks (3.8% loss-to-follow-up). Median baseline CD4 was 36 cells/mm3 (IQR 16-62) and VL 230,000 c/ml (72.5%≥100,000 c/ml). At 4, 12, 24 and 48 weeks, VL was < 50 c/ml in 42.8%, 74.1%, 77.2% and 82.9% in 12-week raltegravir-intensified versus 14.5%, 54.6%, 76.0% and 79.5% standard ART (p< 0.001, < 0.001, 0.59, 0.12, respectively) (Figure). CD4 increases through 24 weeks were similar (p=0.82), although a small difference became apparent at 48 weeks (+163 cells/mm3 intensified versus +148 cells/mm3 standard, p=0.04). 97(10.9%) intensified versus 91(10.2%) standard ART died before 24 weeks (adjusted hazard-ratio[aHR]=1.09 (95% CI 0.82-1.46) p=0.54); 110(12.4%) versus 115(13.0%) respectively died before 48 weeks (aHR=0.98 (0.75-1.27) p=0.86), with no evidence of interaction with the two other randomisations (p>0.7). There was no difference in time to first WHO 3/4 event or death (p=0.31). Serious adverse events (AEs), grade 3/4 AEs and drug-related AEs (adjudicated blind to randomisation) were similar in both groups (p>0.3).

VL and CD4
[VL and CD4]

Conclusions: 12-week raltegravir-intensified ART was well tolerated, resulted in faster VL reduction through 24 weeks and increased CD4 at 48 weeks, but did not reduce mortality or WHO 3/4 events.