AIDS 2012: Dolutegravir Matches Raltegravir for People Starting HIV Treatment

The novel integrase inhibitor dolutegravir worked as well as raltegravir (Isentress) at 48 weeks for treatment-naive people in the Phase 3 SPRING-2 study, according to a late-breaker presentation at the 19th International AIDS Conference (AIDS 2012) this week in Washington, DC.

HIV integrase inhibitors prevent the virus from inserting its genetic material into host cells. The sole approved drug in this class, twice-daily raltegravir, has demonstrated long-term efficacy with low toxicity and few drug interactions, though it has a relatively low barrier to resistance.

Dolutegravir (formerly S/GSK1349572), produced by ViiV/Shionogi, is taken once-daily with no need for pharmacokinetic boosting. In early studies it appeared well-tolerated, had low potential for drug interactions, and had a distinct resistance profile.

Francois Raffi from the University of Nantes in France, presented results from the SPRING-2 trial (ING113086), a multicenter, double-blind, non-inferiority study comparing 50 mg once-daily dolutegravir vs 400 mg twice-daily raltegravir, both in combination with an investigator-selected dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone of either tenofovir/emtricitabine (the drugs in Truvada), chosen by 60%, or abacavir/lamivudine (the drugs in Epzicom), chosen by 40%.

The analysis included 822 participants in Australia, Canada, Europe, and the U.S. who had not been not previously treated for HIV.

About 85% were men, a similar proportion were white, and the median age was 36 years. At baseline 28% had high HIV viral load above 100,000 copies/mL. The median baseline CD4 T-cell count was about 360 cells/mm³, without just over 10% having < 200 cells/mm³. About 10% had hepatitis C coinfection and 2% had hepatitis B.

Results

• After 48 weeks on treatment, 88% of participants taking dolutegravir achieved HIV RNA below 50 copies/mL, compared with 85% in the raltegravir arm in a "snapshot" analysis.
• The adjusted difference between the 2 arms was 2.5% in favor of dolutegravir, well within the margin for considering the new drug non-inferior.
• Among people with HIV RNA > 100,000 copies/mL, 48-week response rates were 82% with dolutegravir and 75% with raltegravir.
• For people with lower viral load levels, the corresponding rates were 90% and 89%, respectively.
• Virological suppression was rapid in both groups, with about 80% achieving undetectable viral load by 8 weeks.
• Participants in both groups saw a median CD4 cell gain of 230 cells/mm³ at 48 weeks.
• Protocol-defined virological failure was seen in 5% of dolutegravir recipients and 8% of raltegravir recipients.
• At the time of failure, no one in the dolutegravir arm and 1 person in the raltegravir arm had evidence of integrase resistance mutations.
• 11% of people taking dolutegravir and 14% taking raltegravir discontinued treatment due to adverse events and 2% in each arm did so due to lack of efficacy.
• The most common side effects were nausea, headache, nasopharyngitis, and diarrhea, with similar frequencies in both treatment arms.
• Participants in both arms also had similar rates of serious side effects (7% vs 8%, respectively), grade 3-4 laboratory abnormalities, and discontinuations due to adverse events (2% in both arms).
• Dolutegravir recipients saw smaller gains in total cholesterol (3.9 vs 7.7 mg/dL, respectively) and triglycerides (0.9 vs 6.2 mg/dL).
• Dolutegravir recipients had higher serum creatinine levels and lower creatinine clearance, but changes were similar in both arms and there were no discontinuations due to kidney-related events (dolutegravir is known to inhibit tubular secretion of creatinine in the kidneys, which alter estimated but not actual glomerular filtration rate).

Based on these findings, the researchers concluded, "In this well-powered, double-blind placebo study, once-daily dolutegravirwas as effective as twice-daily raltegravir, when co-administered with 2 NRTIs over 48 weeks."

7/27/12

Reference

F Raffi, A Rachlis, HJ Stellbrink,et al. Once-daily dolutegravir (DTG; S/GSK1349572) is non-inferior to raltegravir (RAL) in antiretroviral‑naive adults: 48 week results from SPRING-2 (ING113086). XIX International AIDS Conference. Washington, DC, July 22-27, 2012. Abstract THLBB04.