Integrase Inhibitor Dolutegravir Looks Promising for People with Resistant
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.
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.
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.
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.
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
(Prezista), and maraviroc
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.
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.
reached the < 400 copies/mL endpoint.
Cohort II participants with Q148+ mutations experienced virological
response, compared with just one-third (3 out of 9) in Cohort I.
day 11, the average viral load reduction was 1.76 log in Cohort
II, compared with 1.45 in Cohort I.
participants with Q148+ mutations, the corresponding percentages
were 1.57 and 0.72, respectively.
was well-tolerated overall, with similar side effects whether taken
once or twice daily.
most common adverse event was mild-to-moderate diarrhea (6 patients,
1 participant experienced 2 severe adverse events, which were considered
unrelated to the study drug.
patients discontinued dolutegravir due to adverse events.
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,
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