CROI 2013: Dolutegravir Helps Highly-resistant Treatment-experienced People on Failing ART

The next-generation integrase inhibitor dolutegravir proved more beneficial than raltegravir (Isentress) for highly treatment-experienced people with resistance to 2 or more antiretroviral drug classes, researchers reported in a poster presented at the20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) this week in Atlanta.

Although new antiretroviral agents and treatment strategies are no longer the primary focus of the conference, there is still a need for new and better options for people with extensive treatment experience and very resistant virus.

Integrase inhibitors work by preventing HIV from inserting its genetic material into host cell chromosomes. Because they do not interfere with known human cellular processes, they tend to have less toxicity than some other types of antiretrovirals. Their different mechanism remains active against virus that has developed resistance to earlier drug classes, for example due to prior use of suboptimal drugs or functional monotherapy.

Dolutegravir (formerly S/GSK1349572), being developed by ViiV/Shionogi, was submitted for regulatory approval in the U.S., Canada, and Europe in late 2012 and has been granted FDA priority review status.

Dolutegravir is taken once daily, does not requiring pharmacokinetic boosting, and has stacked up favorably against existing drugs in the long-term VIKING trials of treatment-experienced patients and the SPRING and SINGLE studies of previously untreated individuals.

At this year's meeting Anton Pozniak from Chelsea and Westminster Hospital in London and colleagues presented findings from the Phase 3 SAILING study, evaluating dolutegravir vs the sole approved integrase inhibitor, raltegravir (Isentress) in treatment-experienced people on failing therapy.

The study included 715 participants with ongoing viral replication despite being on treatment. Unlike VIKING -- which evaluated dolutegravir in treatment-experienced patients with pre-existing raltegravir resistance mutations as well as resistance to any 3 antiretroviral classes -- SAILING compared the 2 integrase inhibitors in people who had developed resistant to 2 or more classes but had never used integrase drugs.

About two-thirds of participants were men, half were white, about 40% were of African descent, and the median age was about 42 years. The median CD4 T-cell count was approximately 200 cells/mm³, 30% had high baseline viral load (>50,000 copies/mL), and 15% were coinfected with hepatitis B or C.They had been on antiretroviral therapy for a median of about 6 years and half were resistant to 3 or more drug classes.

Participants wererandomised (1:1) to receive either 50 mg once-daily dolutegravir or 400 mg twice-daily raltegravir for 48 weeks, along with an investigator-selected background regimen that included no more than 2 other agents, including 1 that was fully active. The poster presented results from a planned interim analysis at 24 weeks.

Results

• At 24 weeks, 79% of participants receiving dolutegravir achieved undetectable viral load (<50 copies/mL) compared with 70% of those taking raltegravir, reaching the threshold for statistically superiority.
• The difference was greater (70% vs 53%) among people with high baseline viral load.
• However, the difference was not significant among participants taking the protease inhibitor darunavir (Prezista)(80% vs 81%).
• Median CD4 cell gains were similar, at 99 and 93 cells/mm³, respectively.
• Fewer people on dolutegravir were virological non-responders (15% vs 24%) and they had fewer protocol-defined virologic failures (4% vs 9%).
• Dolutegravir recipients were also less likely to show evidence of integrase inhibitor resistance after treatment failure (0.6% vs 2.8%).
• Dolutegravir was generally safe and well tolerated, with about 20% of participants reporting drug-related adverse events in both arms.
• 2% of dolutegravir recipients and 4% of raltegravir recipients discontinued treatment due to adverse events.
• Gastrointestinal symptoms were the most common side effects, occurring with similar frequency in both groups.
• People with hepatitis B or C coinfection were more likely to experience liver enzyme flares attributed to immune reconstitution inflammatory syndrome (IRIS).

Dolutegravir "demonstrated superior efficacy" to raltegravir, with differences driven by a lower rate of virological failure in patients on dolutegravir, the researchers concluded. The dose studied "was well tolerated with a wide variety of background regimens in treatment-experienced subjects."

3/8/13

Reference

A Pozniak, H Mingrone, A Shuldyakov, et al.  Dolutegravir vs raltegravir in ART-experienced, integrase-naive subjects: 24-week interim results from SAILING (ING111762). 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, March 3-6, 2013. Abstract 179LB.

Other Source

ViiV Healthcare. ViiV Healthcare presents data from Phase III study of dolutegravir vs raltegravir in treatment-experienced adults with HIV-1. Press release. March 6, 2013.