PMID- 30513108 OWN - NLM STAT- MEDLINE DCOM- 20190501 LR - 20230816 IS - 1549-1676 (Electronic) IS - 1549-1277 (Print) IS - 1549-1277 (Linking) VI - 15 IP - 12 DP - 2018 Dec TI - Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial. PG - e1002706 LID - 10.1371/journal.pmed.1002706 [doi] LID - e1002706 AB - 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 2x2x2 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 0.82-1.46], 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 0.76-1.28], p = 0.91); in 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 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%] with standard ART, p = 0.79) or in hospitalisations (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 nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with 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 of the study include 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 of 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 in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT01825031. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number ISRCTN 43622374. FAU - Kityo, Cissy AU - Kityo C AUID- ORCID: 0000-0002-9286-7052 AD - Joint Clinical Research Centre, Kampala, Uganda. FAU - Szubert, Alexander J AU - Szubert AJ AUID- ORCID: 0000-0002-2082-0861 AD - Medical Research Council Clinical Trials Unit at University College London, University College London, London, United Kingdom. FAU - Siika, Abraham AU - Siika A AD - Moi University School of Medicine, Eldoret, Kenya. FAU - Heyderman, Robert AU - Heyderman R AD - Department/College of Medicine, University of Malawi, and Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi. AD - Division of Infection and Immunity, University College London, London, United Kingdom. FAU - Bwakura-Dangarembizi, Mutsa AU - Bwakura-Dangarembizi M AD - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe. FAU - Lugemwa, Abbas AU - Lugemwa A AD - Joint Clinical Research Centre, Mbarara, Uganda. FAU - Mwaringa, Shalton AU - Mwaringa S AD - KEMRI Wellcome Trust Research Programme, Kilifi, Kenya. FAU - Griffiths, Anna AU - Griffiths A AD - Medical Research Council Clinical Trials Unit at University College London, University College London, London, United Kingdom. FAU - Nkanya, Immaculate AU - Nkanya I AD - Joint Clinical Research Centre, Kampala, Uganda. FAU - Kabahenda, Sheila AU - Kabahenda S AD - Joint Clinical Research Centre, Fort Portal, Uganda. FAU - Wachira, Simon AU - Wachira S AD - Moi University School of Medicine, Eldoret, Kenya. FAU - Musoro, Godfrey AU - Musoro G AD - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe. FAU - Rajapakse, Chatu AU - Rajapakse C AD - Medical Research Council Clinical Trials Unit at University College London, University College London, London, United Kingdom. FAU - Etyang, Timothy AU - Etyang T AD - KEMRI Wellcome Trust Research Programme, Kilifi, Kenya. FAU - Abach, James AU - Abach J AD - Joint Clinical Research Centre, Gulu, Uganda. FAU - Spyer, Moira J AU - Spyer MJ AD - Medical Research Council Clinical Trials Unit at University College London, University College London, London, United Kingdom. FAU - Wavamunno, Priscilla AU - Wavamunno P AUID- ORCID: 0000-0001-5064-024X AD - Joint Clinical Research Centre, Kampala, Uganda. FAU - Nyondo-Mipando, Linda AU - Nyondo-Mipando L AUID- ORCID: 0000-0002-3572-3810 AD - Department/College of Medicine, University of Malawi, and Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi. FAU - Chidziva, Ennie AU - Chidziva E AD - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe. FAU - Nathoo, Kusum AU - Nathoo K AD - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe. FAU - Klein, Nigel AU - Klein N AUID- ORCID: 0000-0003-3925-9258 AD - University College London Great Ormond Street Institute of Child Health, University College London, London, United Kingdom. FAU - Hakim, James AU - Hakim J AD - University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe. FAU - Gibb, Diana M AU - Gibb DM AUID- ORCID: 0000-0002-9738-5490 AD - Medical Research Council Clinical Trials Unit at University College London, University College London, London, United Kingdom. FAU - Walker, A Sarah AU - Walker AS AUID- ORCID: 0000-0002-0412-8509 AD - Medical Research Council Clinical Trials Unit at University College London, University College London, London, United Kingdom. FAU - Pett, Sarah L AU - Pett SL AD - Medical Research Council Clinical Trials Unit at University College London, University College London, London, United Kingdom. AD - Institute for Global Health, University College London, London, United Kingdom. AD - Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, Australia. CN - REALITY trial team LA - eng SI - ClinicalTrials.gov/NCT01825031 SI - ISRCTN/ISRCTN43622374 GR - MC_EX_G1100693/MRC_/Medical Research Council/United Kingdom GR - MC_UU_12023/23/MRC_/Medical Research Council/United Kingdom GR - MC_EX_UU_G1100693/MRC_/Medical Research Council/United Kingdom GR - 203077/Z/16/Z/WT_/Wellcome Trust/United Kingdom GR - MC_UU_12023/17/MRC_/Medical Research Council/United Kingdom GR - D43 TW010060/TW/FIC NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - G1100693/MRC_/Medical Research Council/United Kingdom GR - MC_UU_12023/26/MRC_/Medical Research Council/United Kingdom GR - 101113/Z/13/Z/WT_/Wellcome Trust/United Kingdom PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20181204 PL - United States TA - PLoS Med JT - PLoS medicine JID - 101231360 RN - 0 (Anti-HIV Agents) RN - 0 (Anti-Retroviral Agents) RN - 43Y000U234 (Raltegravir Potassium) SB - IM MH - Adolescent MH - Adult MH - Africa/epidemiology MH - Anti-HIV Agents/*administration & dosage MH - Anti-Retroviral Agents/*administration & dosage MH - Child MH - Child, Preschool MH - *Disease Progression MH - Drug Administration Schedule MH - Female MH - Follow-Up Studies MH - HIV Infections/diagnostic imaging/*drug therapy/*epidemiology MH - Health Services Accessibility/trends MH - Humans MH - Kenya/epidemiology MH - Malawi/epidemiology MH - Male MH - Raltegravir Potassium/*administration & dosage MH - Uganda/epidemiology MH - Young Adult MH - Zimbabwe/epidemiology PMC - PMC6279020 COIS- I have read the journal's policy and the authors of this manuscript have the following competing interests: the institution of ASW has received funding from Janssen and Gilead Sciences for DSMB membership and lectures; JH has received funding for advisory board membership from Mylan Pharmaceuticals; all other authors have no other relationships or activities that could appear to have influenced the submitted work. EDAT- 2018/12/05 06:00 MHDA- 2019/05/02 06:00 PMCR- 2018/12/04 CRDT- 2018/12/05 06:00 PHST- 2018/05/11 00:00 [received] PHST- 2018/10/29 00:00 [accepted] PHST- 2018/12/05 06:00 [entrez] PHST- 2018/12/05 06:00 [pubmed] PHST- 2019/05/02 06:00 [medline] PHST- 2018/12/04 00:00 [pmc-release] AID - PMEDICINE-D-18-01613 [pii] AID - 10.1371/journal.pmed.1002706 [doi] PST - epublish SO - PLoS Med. 2018 Dec 4;15(12):e1002706. doi: 10.1371/journal.pmed.1002706. eCollection 2018 Dec.