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Raltegravir-intensified initial antiretroviral therapy in advanced HIV in Africa: a randomized controlled trial

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.. Green open access

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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.

Type: Article
Title: Raltegravir-intensified initial antiretroviral therapy in advanced HIV in Africa: a randomized controlled trial
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.
Publisher version: https://doi.org/10.1371/journal. pmed.1002706
Language: English
Additional information: Copyright: © 2018 Kityo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. .
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute for Global Health > Infection and Population Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10060135
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