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AIDS 2012: Once-daily Elvitegravir Suppresses HIV as well as Raltegravir at 96 weeks

The investigational HIV integrase inhibitor elvitegravir taken once-daily continued to perform as well as twice-daily raltegravir (Isentress) at 96 weeks for treatment-experienced people with extensive drug resistance, according to data presented last week at the 19th International AIDS Conference (AIDS 2012) in Washington, DC.

HIV integrase inhibitors prevent the virus from inserting its genetic material into the chromosomes of a host cell, a necessary step for viral replication.The sole approved drug in this class, raltegravir, has demonstrated long-term efficacy and minimal toxicity, though it has a relatively low barrier to resistance.

Gilead Sciences' next-generation integrase inhibitor elvitegravir is used with a boosting agent -- either ritonavir (Norvir) or Gilead's novel pharmacoenhancer cobicistat -- to enable once-daily dosing.

Richard Elion from Whitman-Walker Health presented long-term data from a head-to-head Phase 3 randomized controlled trial comparing 150 mg elvitegravir once-daily vs 400 mg raltegravir twice-daily, both in combination with a fully active boosted protease inhibitor plus a third active drug.

Study 145 included 712 treatment-experienced participants in the U.S., Europe, and Australia; 702 were included in the efficacy analysis. Just over 80% were men, 60% were white, and the average age was 45 years. The mean baseline CD4 T-cell count was approximately 220 cells/mm³, with about 45% having fewer than 200 cells/mm³; 26% had high viral load (>100,000 copies/mL).

Although all participants had used -- and a majority had developed resistance to -- at least 2 antiretroviral drug classes, they were able to construct viable regimens using a ritonavir-boosted protease inhibitor and an active third agent such as etravirine (Intelence), maraviroc (Selzentry), or a nucleoside/nucleotide reverse transcriptase inhibitor. The most frequently used protease inhibitors were boosted darunavir (Prezista) at nearly 60%, lopinavir/ritonavir (Kaletra) at 19%, and boosted atazanavir (Reyataz) at 16%.

Primary 48-week results, presented last summer at the International AIDS Society meeting in Rome, showed that elvitegravir was well-tolerated and non-inferior to raltegravir in efficacy, with 59% vs 58% of participants in the 2 arms, respectively, achieving undetectable viral load. Blinded comparison continued through 96 weeks, and Study 145 has since moved into an open-label observation phase.

Results

• By 96 weeks, 41% of elvitegravir recipients and 42% of raltegravir recipients had discontinued treatment.
• The most common reasons for stopping were poor adherence (39 vs 34 participants, respectively), withdrawal of consent (30 vs 17), loss to follow-up (29 vs 31), lack of efficacy (17 vs 21), adverse events (11 vs 15) and protocol violations (11 vs 14).
• Efficacy of elvitegravir and raltegravir remained comparable at 96 week, with 48% and 45%, respectively, having HIV RNA <50 copies/mL in an intent-to-treat TLOVR analysis.
• 26% and 29% of participants, respectively, experienced virological failure (never suppressed, viral rebound, or drug discontinuation due to non-efficacy).
• CD4 cell gains were also similar, at approximately 200 cells/mm³ in both arms.
• Elvitegravir and raltegravir were both well-tolerated overall, with few participants discontinuing due to side-effects (3% vs 4%, respectively).
• Grade 2-4 adverse events (68% in both arms), serious adverse events (20% vs 23%, respectively), and grade 3-4 laboratory abnormalities (37% vs 42%, respectively) were also generally similar.
• More elvitegravir recipients reported diarrhea (13% vs 8%), while more raltegravir recipients had elevated liver enzymes (approximately 2% vs 6%).
• Among the one-quarter of participants who underwent resistance testing due to suboptimal response or viral rebound, 7% in each arm showed evidence of primary integrase resistance mutations.

The researchers concluded that at week 96, once-daily elvitegravir in combination with a fully active boosted protease inhibitor and another agent in treatment-experienced patients "continues to be non-inferior to twice-daily raltegravir in efficacy with excellent tolerability."

Elvitegravir has been submitted for U.S. Food and Drug Administration approval for treatment-experienced patients. Elvitegravir and cobicistat (along with tenofovir/emtricitabine) are part of a single-tablet regimen known as the Quad that is under regulatory review for treatment-naive people.

7/30/12

Reference

R Elion, J-M Molina, J-R Arribas-Lopez, et al. Efficacy and safety results from a randomized, double blind, active controlled trial of elvitegravir (once-daily) versus raltegravir (twice-daily) in treatment-experienced HIV-positive patients: long term 96-week data. XIX International AIDS Conference (AIDS 2012).  Washington, DC, July 22-27, 2012. Abstract TUAB0105.