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 HIV and Coverage of the
18th Conference on Retroviruses and
Infections (CROI 2011)
 February 27 - March 2, 2011, Boston, MA
Experimental Integrase Inhibitor Dolutegravir Looks Promising for People with Resistant HIV

SUMMARY: The second-generation integrase inhibitor dolutegravir (formerly known as S/GSK1349572 or simply GSK572) demonstrated potent activity with a favorable tolerability profile for HIV patients with highly resistant virus in the second cohort of the VIKING study, researchers reported at the 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011) this month in Boston. Results indicate that the drug works better when taken twice rather than once daily.

By Liz Highleyman

Joseph Eron
(Photo: Liz Highleyman)

Dolutegarvir, being developed jointly by Shionogi and ViiV Healthcare, is an oral integrase inhibitor that can be taken once daily without a booster. In laboratory and early clinical studies it demonstrated good bioavailability, potent antiviral activity, and little potential for drug-drug interactions.

At CROI, Joseph Eron from the University of North Carolina at Chapel Hill presented interim findings from Cohort II of the Phase 2b VIKING study, a group that received 50 mg dolutegravir twice-daily.

VIKING is an open-label, single-arm trial evaluating the safety and efficacy of dolutegravir in treatment-experienced patients with pre-existing resistance to raltegravir (Isentress) -- the sole approved integrase inhibitor -- and any 3 antiretroviral drug classes.

Based on previous studies, participants were categorized into 2 groups depending on their pattern of raltegravir resistance mutations: 1) Q148 pathway mutation plus at least 1 secondary mutation ("Q148+"), which significantly reduces susceptibility to dolutegravir; or 2) Q148 mutation alone, or N155 or Y143 pathway mutations, which confer minimal change in dolutegravir susceptibility.

As previously reported at the International AIDS Conference this past summer in Vienna, Cohort I of the study enrolled 27 patients on failing antiretroviral therapy (ART) who added dolutegravir at a dose of 50 mg once-daily; people who had raltegravir in their failing regimen stopped that drug when they added dolutegravir. For the first 10 days dolutegravir was used as "functional monotherapy," meaning it was likely the only active drug in the regimen; on day 11 background regimens were optimized and treatment continued through week 24.

Since once-daily dolutegravir did not work as well for people with Q148+ mutations, investigators then enrolled a second cohort to receive 50 mg dolutegravir twice-daily. Due to the drug's pharmacokinetics, they decided it was not feasible to increase drug concentrations by upping the dose to 100 mg once-daily, despite the drug's long half-life.

Cohort II included 24 participants on failing ART with a variety of resistance profiles at baseline; about half had Q148+ mutations. The study protocol for Cohort II was similar, except participants were reuired to have at least 1 other fully active drug available to start when treatment was optimized on day 11 -- a "challenging" patient population to find, Eron said, given that nearly half had already tried other newer antiretrovirals including etravirine (Isentress), enfuvirtide (Fuzeon), darunavir (Prezista), and maraviroc (Selzentry).

Three-quarters of the participants were men, the same proportion was white, and the median age was 47 years. They had relatively advanced HIV disease, with a median CD4 cell count of about 200 cells/mm3.


96% of Cohort II participants achieved either viral load < 400 copies/mL or at least a 0.7 log drop in HIV RNA by day 11 (the dual primary endpoint), compared with 78% in Cohort I.
57% reached the < 400 copies/mL endpoint.
All Cohort II participants with Q148+ mutations experienced virological response, compared with just one-third (3 out of 9) in Cohort I.
At day 11, the average viral load reduction was 1.76 log in Cohort II, compared with 1.45 in Cohort I.
Among participants with Q148+ mutations, the corresponding percentages were 1.57 and 0.72, respectively.
Dolutegravir was well-tolerated overall, with similar side effects whether taken once or twice daily.
The most common adverse event was mild-to-moderate diarrhea (6 patients, or 25%).
1 participant experienced 2 severe adverse events, which were considered unrelated to the study drug.
No patients discontinued dolutegravir due to adverse events.

Based on these findings, the investigators concluded, "Dolutegravir continued to show activity against raltegravir-resistant virus and was generally well tolerated at a higher dose in this advanced population."

VIKING II is ongoing, and researchers will evaluate longer-term efficacy at 24 weeks. Based on findings to date, twice-daily dosing has been chosen for forthcoming Phase 3 trials.

Dolutegravir has also been studied as first-line therapy for treatment-naive patients, showing better early efficacy than efavirenz (Sustiva) in combinations that also include tenofovir/emtricitabine (Truvada) or abacavir/lamivudine (Epzicom). In addition, Viiv has said it is working on a single-tablet regimen, dubbed "572-Trii," consisting of dolutegravir/abacavir/lamivudine.

Investigator affiliations: Univ of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC; Georgetown Univ, Washington, DC; San Raffaele Sci Inst, Milan, Italy; Fort Lauderdale, FL; Inst de Salud Carlos III, Madrid, Spain; GlaxoSmithKline, Mississauga, Canada; GlaxoSmithKline, Research Triangle Park, NC; GlaxoSmithKline, Stockley Park, Uxbridge, UK.


J Eron, P Kumar, A Lazzarin, 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 (CROI 2011). Boston. February 27-March 2, 2011. Abstract 151LB.
























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