Novel integrase inhibitor dolutegravir still potent at 96 weeks

The next generation integrase inhibitor dolutegravir maintains viral suppression and remains safe after two years of use, according to a small study presented Wednesday at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

HIV integrase inhibitors prevent the virus from inserting its genetic material into host cells. The sole approved drug in this class, raltegravir (Isentress), has demonstrated long-term efficacy, has few interactions, and is among the best-tolerated antiretrovirals, encouraging development of more agents of this type.

Dolutegravir (formerly S/GSK1349572), produced by ViiV/Shionogi, is taken once daily with no need for boosting and no food requirements. Prior studies showed low potential for drug interactions and a distinct resistance profile.

Hans-Jürgen Stellbrink presented the latest data from the Phase 2b SPRING-1 trial (ING112276), a four-arm, dose-ranging study designed to select an optimal dolutegravir dose for Phase 3 trials.

This multinational study included 205 treatment-naive participants. Most (86%) were men, 80% were white, and the median age was 37 years. The average CD4 cell count at baseline was 324 cells/mm³ and one-fifth of patients had high viral load above 100,000 copies/ml.

Participants were randomly assigned to receive dolutegravir at once-daily doses of 10, 25, or 50mg, or else 600mg efavirenz (Sustiva or Stocrin), all in combination with tenofovir and emtricitabine (the drugs in Truvada; 67%) or abacavir and lamivudine (the drugs in Kivexa or Epzicom; 33%).

Findings from an unusual 16-week primary analysis and the typical 48-week analysis were presented at last summer's International AIDS Society conference (IAS 2011) in Rome. To assess longer-term safety and durability of response, researchers continued to follow patients in all arms through 96 weeks. The 50mg does was chosen for Phase 3 studies of treatment-naive people, now enrolling.

Results

• Dolutegravir was associated with more rapid viral load decline than efavirenz, but rates evened out.
• At 48 weeks, virological response rates (< 50 copies/ml) were 88 to 91% in the dolutegravir arms compared with 82% in the efavirenz arm, not a statistically significant difference.
• At 96 weeks, rates of undetectable HIV RNA were 88% for 50mg dolutegravir, 78% for 25mg dolutegravir, and 79% for 10mg dolutegravir, compared with 72% for efavirenz.
• No cases of protocol-defined virological failure (confirmed viral load > 400 copies/ml) were seen in the 50mg dolutegravir arm through 96 weeks; one, two, and one patient(s), respectively, in the other thee arms experienced failure.
• Several patients experienced early viral rebound while on therapy but re-suppressed HIV RNA while maintaining the same regimen; this was seen more often with dolutegravir than efavirenz.
• The median CD4 cell increase from baseline was slightly greater in the combined dolutegravir arms (339 vs 301 cells/mm³), but the difference did not reach statistical significance.
• No genotypic or phenotypic evidence of integrase or non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was observed in any arm through 96 weeks.
• No new safety issues were identified between 48 and 96 weeks.
• There continued to be fewer moderate-to-severe drug-related adverse events with dolutegravir than with efavirenz (11% vs 24%, respectively).
• Fewer participants discontinued the study due to adverse events in the dolutegravir arms (3% vs 10%, respectively).
• Some patients experienced small changes in serum creatinine (a potential biomarker of kidney dysfunction), but this did not progress over time and there was no evidence of renal damage.

"Dolutegravir administered once daily with two NRTIs was associated with good treatment response at all doses", the researchers concluded. "Fewer subjects treated with dolutegravir discontinued therapy due to adverse events when compared to efavirenz.

Dolutegravir has also demonstrated good outcomes among heavily treatment-experienced patients in the VIKING study, though people with pre-existing raltegravir resistance may require twice-daily dosing.