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Meta-analysis Finds Little Evidence of
Worse Side Effect Rates With Dolutegravir

  16th European AIDS Conference, October 25-27, 2017. Milan
Mark Mascolini
Meta-analysis of randomized trials involving dolutegravir (DTG) found little evidence of worse adverse event rates with this integrase inhibitor than with other antiretrovirals [1]. The only exception was grade 1 to 4 insomnia, which proved more frequent with DTG than with other antiretrovirals.
Researchers from the University of Liverpool and Imperial College London conducted this meta-analysis to provide greater scrutiny of the side effect potential with this potent integrase inhibitor. Previous reports, they noted, suggested higher risk of central nervous system side effects with DTG than with other antiretrovirals; case reports of myocarditis with DTG and cohort studies linking the drug to immune reconstitution inflammatory syndrome (IRIS) also raised concern.
The researchers combined data from EMBASE and MEDLINE searches, serious adverse event reports at www.clinicaltrials.gov, and cardiac serious adverse event case reports from ViiV Healthcare, maker of DTG. They used Cochrane Mantel-Haentzel tests with random effects to compare adverse event rates with dolutegravir versus other antiretrovirals. The investigators focused on potential adverse events brought to light in observational studies.
The meta-analysis involved 6647 patient-years of follow-up. Insomnia was the only adverse event more common with DTG than other antiretrovirals. The researchers counted 165 cases of grade 1 to 4 insomnia in 2716 people taking DTG and 124 cases in 2727 people taking comparator agents (6.1% versus 4.5%, relative risk [RR] 1.30, P = 0.02).
In two trials, SINGLE and SPRING-1, 5 of 465 people taking DTG and 6 of 469 taking efavirenz had evidence of suicidality (1.1% versus 1.3%, RR 0.87, not significant). In seven other trials, suicidality affected 15 of 2250 people taking DTG and 9 of 2257 taking other antiretrovirals (0.7% versus 0.4%, RR 1.58, not significant). Analysis of other central nervous system side effects found statistically similar rates with DTG and other antiretrovirals.
The cardiac event analysis included participants in eight DTG trials. Fifteen of 2202 people randomized to DTG and 8 of 2215 randomized to other antiretrovirals had cardiac serious adverse events (0.7% and 0.4%, RR 1.69, not significant). Researchers in the original trials considered only 1 of 25 cardiac serious adverse events possibly related to DTG. Case data from 19 people with serious cardiac events found underlying cardiac risk factors in 17 of them (89%).
The Liverpool/University College investigators identified IRIS cases in 1 of 414 people assigned to DTG and 2 of 419 assigned to efavirenz in the SINGLE trial (0.2% versus 0.5%); in 6 of 354 on DTG versus 3 of 361 on raltegravir in the SAILING trial (1.7% versus 0.8%); and in 1 of 411 versus 0 of 411 on raltegravir in the SPRING-2 trial (0.2% versus 0%). IRIS did not appear in any other analyzed trials of DTG. None of the noted differences in reported rates was statistically significant, though the researchers noted that event rates were low in these randomized trials, which excluded people with AIDS diseases.
The researchers concluded that the trials they reviewed yielded evidence of only one adverse event more frequent with DTG than other antiretrovirals--grade 1 to 4 insomnia. They called the analysis of suicidality "currently inconclusive." The Liverpool/Imperial College team noted that overall adverse event risks were lower with DTG than with efavirenz in SINGLE, lower than with darunavir/ritonavir in FLAMINGO, and lower than with atazanavir/ritonavir in ARIA. They added that more recently concluded randomized trials should be added to the analysis--DAWNING, SWORD 1 and 2, Gilead trial 1489, and Gilead trial 1490.
1. Hill A, Mitchell N. Meta-analysis of the safety of DTG versus other ARVs in randomised trials: analysis of cardiovascular, CNS and IRIS endpoints. 16th European AIDS Conference. October 25-27, 2017. Milan. Abstract PE12/17.