- Category: HIV Treatment
- Published on Thursday, 13 October 2011 00:00
- Written by Liz Highleyman
The novel integrase inhibitor dolutegravir is among the most potent antiretroviral agents studied to date, but treatment-experienced individuals with raltegravir resistance need to take it twice-daily in order to achieve optimal concentrations, according to findings presented at the 13th European AIDS Conference (EACS 2011) this week in Belgrade.
Dolutegravir (formerly S/GSK1349572 or GSK572)is a next generation integrase inhibitor that remains active against HIV that has developed resistance to the sole approved drug in its class, raltegravir (Isentress).
In the original VIKING study (Cohort I), previously treated patients with extensive drug resistance were treated with 50 mg once-daily oral dolutegravir as "functional monotherapy" for 10 days (meaning it was the only active drug in their regimen), then added an optimized background regimen and continued through week 24.
Although viral suppression was good overall, pharmacokinetic modeling suggested better response might be achieved with higher drug exposure, especially for people with a specific unfavorable pattern of raltegravir resistance mutations.
Drug concentrations reached a plateau when researchers tried to administer larger once-daily doses, however, leading them to instead test 50 mg twice-daily administration in a second group of patients (Cohort II). Again, participants received dolutegravir for 10 days then added an optimized regimen through week 24.
As described by Vincent Soriano from Hospital Carlos III in Madrid, this open-label, single-arm trial enrolled 24 participants on failing antiretroviral therapy with pre-existing resistance to raltegravir and any 2 other antiretroviral classes. They were required to have at least 1 fully active drug available for regimen optimization.
Most participants (75%) were men and the median age was 47 years. They were generally similar to people in the original Cohort I, except they had less advanced HIV disease and were more likely to be coinfected with hepatitis B or C (about 20%). The median CD4 cell count was about 200 cells/mm3. They had been taking antiretrovirals for a median of 15 years and had used a median of 15 different drugs; half were already resistant to the newest available agents.
Participants were divided into 2 groups based on integrase resistance pattern at baseline:
- 46% had the Q148 mutation plus at least 1 secondary mutation, which significantly reduces susceptibility to dolutegravir;
- 54% had all other mutation patterns combined.
Findings from the 11-day dosing period were presented at this year's Conference on Retroviruses and Opportunistic Infections (CROI 2011). Soriano presented 24-week data at EACS.
- At 24 weeks 75% of participants receiving twice-daily dolutegravir achieved undetectable viral load below 50 copies/mL, compared with just 41% of those who took the drug once-daily in Cohort I.
As expected, people with more available active drugs for optimization did better (67% undetectable with 1 active drug, 79% with 2 active drugs).
- 6 participants I Cohort II were classified as nonresponders:
- 4 never suppressed viral load through week 24;
- 1 did so but then experienced viral rebound;
- 1 protocol violation;
- No discontinuations due to adverse events or death.
- Dolutegravir was well-tolerated overall, with the most common side-effect being mild diarrhea.
In a multivariate analysis of Cohort I and Cohort II combined, factors that independently predicted response to dolutegravir at 24 weeks included:
- Unfavorable baseline integrase resistance mutation pattern;
- Availability of other active drugs for optimization;
- Higher baseline CD4 cell count;
- Higher dolutegravir concentration in the blood at day 10.
Based on these findings, 50 mg twice-daily dolutegravir was chosen for further evaluation in a Phase 3 trial. Soriano said an expanded access program is expected to begin in early 2012.
Since raltegravir must also be give twice-daily, this dosing frequency does not put dolutegravir as a disadvantage in an era when people with HIV and their clinicians favor once-daily therapy.
Data from the SPRING-1 study showed that once-daily dolutegravir is adequate for treatment-naive individuals, however, suggesting that this is another drug that will likely be dosed differently depending on prior treatment history.
Investigator affiliations: Hospital Carlos III, Madrid, Spai; Montreal General Hospital, Montreal, Canada; Center for AIDS Research Clinical Care, UNC School of Medicine, Chapel Hill, NC; George Town University, Washington, DC; Hôpital de La Pitié-Salpêtrière, Paris, Franc; San Raffaele Scientific Institute, Milan, Italy; Hôpital Sainte Marguerite, Marseille, France; GlaxoSmithKline, Stockley Park, London, UK; Shionogi & Co., Ltd, Osaka, Japan; GlaxoSmithKline, Toronto, Canada; GlaxoSmithKline, Research Triangle Park, NC.
V Soriano, J Cox, JJ Eron, et al. Dolutegravir (DTG, S/GSK1349572) Treatment of Subjects with Raltegravir (RAL) Resistance: Viral Suppression at Week 24 in the Viking Study. 13th European AIDS Conference (EACS 2011). Belgrade, October 12-15, 2011. Abstract PS1/2.