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Risks of cardiovascular or central nervous system adverse events and immune reconstitution inflammatory syndrome, for dolutegravir versus other antiretrovirals

meta-analysis of randomized trials

Hill, Andrew M.a; Mitchell, Nikkitab; Hughes, Sophieb; Pozniak, Anton L.c

Current Opinion in HIV and AIDS: March 2018 - Volume 13 - Issue 2 - p 102–111
doi: 10.1097/COH.0000000000000445
HOTTEST TOPICS IN HIV INFECTION: Edited by Giuseppe Pantaleo and David A. Cooper

Purpose of review Results from nonrandomized cohort studies suggest higher risks of CNS adverse events for dolutegravir, versus other ARVs. There have been two case reports of myocarditis on dolutegravir. Integrase inhibitors have been associated with IRIS in two cohort studies. Meta-analysis of randomized trials can be used to cross-check potential safety signals. This systematic review of drug safety used an EMBASE and MEDLINE search combined with serious adverse event (SAE) reports on the website Cardiovascular, CNS or IRIS-associated adverse events were analysed for dolutegravir versus other ARVs. Relative risks for the comparison between dolutegravir and other antiretrovirals were calculated for each adverse event. Meta-analyses applied Mantel–Haenszel random-effects models.

Recent findings There was a higher risk of Grade 1–4 insomnia adverse events for DTG (6.1%) versus other ARVs (4.5%; P = 0.02). There was no significant difference between DTG and other ARVs in the risk of cardiovascular serious adverse events. In the SINGLE and SPRING-1 trials comparing DTG with efavirenz, there were 5/465 patients with reported suicidality SAEs on DTG (1.1%) versus 6/469 (1.3%) on EFV. In other studies, serious adverse events of suicidality were reported for 15/2250 patients on DTG (0.7%) versus 9/2257 patients on other ARVs (0.4%). Risks of IRIS were low, but event rates were low and the main trials excluded CDC stage C disease.

Summary In this meta-analysis, there was no significant effect of dolutegravir on the risk of cardiac, IRIS or suicide-related serious adverse events. There was a higher risk of insomnia for DTG. Other completed randomized trials should be included in new evaluations of DTG safety. Continued pharmacovigilance, with regular meta-analyses, should be used to monitor safety.

aDepartment of Translational Medicine, University of Liverpool, Liverpool

bFaculty of Medicine, Imperial College

cSt Stephens AIDS Trust, Chelsea and Westminster Hospital, London, UK

Correspondence to Dr. Andrew M. Hill, Department of Translational Medicine, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK. Tel: +44 7834 364 608; fax: +44 208 675 1716; e-mail:

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