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New Integrase Inhibitor Controls Toughest Raltegravir-Resistant Virus
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Twice-daily dolutegravir (S/GSK1349572), an investigational integrase inhibitor, controlled replication of raltegravir-resistance in a phase 2 trial, including virus bearing Q148 resistance mutations [1]. In an earlier part of this study, once-daily dolutegravir at 50 mg was less effective against Q148 mutants than against other resistant virus. Researchers designed the new trial with 50 mg of dolutegravir twice daily instead of 100 mg once daily because of pharmacokinetic data indicating that 100 mg once daily would not achieve concentrations possible with 50 mg twice daily.
VIKING enrolled people in whom raltegravir failed and who had virus resistant to drugs in at least three antiretroviral classes, including integrase inhibitors. Everyone had to have one or more fully active antiretrovirals available for a background regimen. This presentation focused on VIKING Cohort II, the people who took 50 mg of dolutegravir twice daily after VIKING Cohort I data showed that once-daily dolutegravir had diminished activity against mutations at integrase position Q148, usually with two or more other integrase mutations.
Everyone in both cohorts added dolutegravir to their failing regimen for 11 days (replacing raltegravir if that regimen included raltegravir). After day 11, study participants replaced other drugs in their failing regimen with an optimized background combination. The primary endpoint was the proportion of people with a viral load below 400 copies on day 11 or at least a 0.7-log viral load decline at that point.
Cohort II included 24 people, 18 of them men, with a median age of 47 years. Median CD4 count stood at 202 and median viral load at 20,000 copies. Twenty people were taking a failing raltegravir regimen when they started dolutegravir; median raltegravir duration in all Cohort II members was 29 months. Eleven people starting dolutegravir had a Q148 mutation plus one or more additional integrase mutations. About half of these people had already taken etravirine, enfuvirtide, and darunavir/ritonavir, and 38% had taken maraviroc.
Of the 24 people in Cohort II, 23 (96%) achieved the primary virologic endpoint, including all 11 people with a Q148 mutation. Thirteen people (56.5%) had a viral load below 400 copies 11 days after starting dolutegravir as functional monotherapy. Viral load dropped by an average 1.8 log in these 24 people.
The investigators analyzed 15 paired viral isolates from day 1 and day 11. Three of these 15 had additional raltegravir-associated mutations on day 11, but all 3 achieved protocol-defined treatment success by attaining at least a 0.7-log drop in viral load. Susceptibility to dolutegravir changed 3-fold and 5-fold in 2 people.
After 30 to 172 days of treatment, no one in Cohort II stopped dolutegravir because of adverse events or lab toxicities. There was only one side effect worse than grade 1 or 2, a case of grade 3 diabetes. Four people (17%) had grade 3 lab toxicities emerge while taking dolutegravir. Two serious adverse events--diabetes and demyelinating polyneuropathy--were not attributed to study drugs.
Compared with Cohort I, people in Cohort II had a better day 11 response rate (96% versus 78%) and a significantly larger drop in viral load (1.8 log versus 1.5 log). Safety profiles were similar in Cohort I and Cohort II. The 50-mg twice-daily dose will be used in phase 3 trials that enroll people with integrase inhibitor-resistant virus.
Reference
1. Eron J, Kumar P, Lazzarin A, et al. DTG in subjects with HIV exhibiting RAL resistance: functional monotherapy results of VIKING study cohort II. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 151LB.
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