Kityo, C;
Szubert, A;
Siika, A;
Heyderman, R;
Bwakura-Dangarembizi, M;
Lugemwa, A;
Mwaringa, S;
... Pett, S; + view all
(2018)
Raltegravir-intensified initial antiretroviral therapy in advanced HIV in Africa: a randomized controlled trial.
PLoS Medicine
, 15
(12)
, Article e1002706. 10.1371/journal..
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Abstract
BACKGROUND: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have high mortality (10%) shortly after starting antiretroviral therapy (ART). This group also have the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster, and hence reduce early mortality, although this strategy could also risk more IRIS events. METHODS AND FINDINGS: In a 2x2x2 factorial open-label parallel-group trial, treatment-naïve HIV-infected adults, adolescents and children >5 years with CD4 <100 cells/mm3 from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, Zimbabwe were randomised 1:1 to initiate standard triple-drug ART with or without 12-weeks raltegravir-intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed following intention-to-treat. Of 2356 individuals screened for eligibility, 1805 were randomized between 18 June 2013-10 April 2015. 961 (53.2%) participants were male; 72 (4.0%) were children/adolescents; median age was 36 years, CD4 37 cells/mm3, and plasma viraemia 249,770 copies/ml. 56 (3.1%) were lost-to-follow-up at 48-weeks. 97/902 (10.9%) raltegravir-intensified-ART vs 91/903 (10.2%) standard-ART participants died before 24-weeks (adjusted hazard-ratio (aHR)=1.10 (95%CI 0.82-1.46) p=0.53), with no evidence of interaction with other randomizations (pheterogeneity>0.7), and despite significantly greater VL suppression with raltegravir-intensified-ART at 4-weeks (343/836 (41.0%) vs 113/841 (13.4%) standard-ART, p<0.001) and 12-weeks (567/789 (71.9%) vs 415/803 (51.7%) standard-ART, p<0.001). Through 48-weeks there was no evidence of differences in mortality (aHR=0.98 (95%CI 0.76-1.28) p=0.91); serious (aHR=0.99 (0.81-1.21) p=0.88), grade-4 (aHR=0.88 (0.71-1.09) p=0.29) or ART-modifying (aHR=0.90 (0.63-1.27) p=0.54) adverse events (the latter occurring in occurring in 59 (6.5%) raltegravir-intensified-ART vs 66 (7.3%) standard-ART); in events judged compatible with IRIS (occurring in 89 (9.9%) raltegravir-intensified-ART vs 86 (9.5%) standard-ART, p=0.79) or hospitalizations (aHR=0.94 (95%CI 0.76-1.17) p=0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance respectively. At 48 weeks, the NRTI mutation K219E/Q (p=0.004), and the NNRTI mutations K101E/P (p=0.03) and P225H (p=0.007), were less common in raltegravir-intensified-ART, with weak evidence of less intermediate or high-level resistance to tenofovir (p=0.06), abacavir (p=0.08) and rilpivirine (p=0.07). Limitations were limited clinical, radiological and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes. CONCLUSIONS: Although 12-weeks raltegravir-intensification was well-tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events, and is not warranted. There was no excess of IRIS-compatible events, suggesting integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immuno-compromised individuals.
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