%0 Journal Article
%T Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial
%A A. Sarah Walker
%A Abbas Lugemwa
%A Abraham Siika
%A Alexander J. Szubert
%A Anna Griffiths
%A Chatu Rajapakse
%A Cissy Kityo
%A Diana M. Gibb
%A Ennie Chidziva
%A Godfrey Musoro
%A Immaculate Nkanya
%A James Abach
%A James Hakim
%A Kusum Nathoo
%A Linda Nyondo-Mipando
%A Moira J. Spyer
%A Mutsa Bwakura-Dangarembizi
%A Nigel Klein
%A Priscilla Wavamunno
%A Robert Heyderman
%A Sarah L. Pett
%A Shalton Mwaringa
%A Sheila Kabahenda
%A Simon Wachira
%A Timothy Etyang
%A on behalf of the REALITY trial team
%J -
%D 2018
%R 10.1371/journal.pmed.1002706
%X Background In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has 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 2℅2℅2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82每1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76每1.28], p = 0.91); in serious (aHR = 0.99 [0.81每1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71每1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63每1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%]
%K Antiretroviral therapy
%K Death rates
%K HIV
%K Viral load
%K HIV infections
%K Reverse transcriptase inhibitors
%K Adverse events
%K Inflammation
%U https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002706