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Elvitegravir Not Inferior to Raltegravir in Treatment-Experienced: Phase 3
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6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
Once-daily elvitegravir matched twice-daily raltegravir in virologic response rate, CD4 gains, and safety in a 48-week phase 3 noninferiority trial that enrolled antiretroviral-experienced people [1]. Response rates to both elvitegravir and raltegravir were similar to the 48-week response to raltegravir in a previous trial that enrolled people with triple-class resistance in whom the current regimen failed [2], though entry criteria were more stringent in the BENCHMRK trials of raltegravir [2] than in the new study.
The elvitegravir-raltegravir trial signed up people with a viral load of 1000 copies or higher and either resistance to two or more antiretroviral classes or more than 6 months of experience with two or more classes [1]. Researchers randomized study participants to elvitegravir or raltegravir, both with a fully active ritonavir-boosted protease inhibitor (PI) and a second agent chosen by the investigator. Elvitegravir needs a boost from ritonavir or another boosting agent, while raltegravir does not. The second background regimen agent (after the boosted PI) could be a nucleoside, the nonnucleoside etravirine, maraviroc, or enfuvirtide. The elvitegravir dose was 85 mg once daily with atazanavir/ritonavir or lopinavir/ritonavir and 150 mg once daily with any other boosted PI. Raltegravir was taken at the standard 400 mg twice daily.
The 702 people included in the intention-to-treat analysis averaged 45 years in age, 82% were men, 45% had a CD4 count below 200, 26% had a viral load above 100,000 copies, and 63% had resistance to drugs in two or more antiretroviral classes. Rates of baseline resistance mutations were 72% for nucleosides, 61% for nonnucleosides, and 33% for PIs. The combination given most often with elvitegravir or raltegravir was darunavir/ritonavir plus tenofovir, in 24% of study participants.
Eighty-five people (24%) dropped out of the elvitegravir arm by week 48, 21 because of poor adherence, 9 for lack of efficacy, and 8 for adverse events. Eighty-three people (24%) quit the raltegravir arm by week 48, 17 because of poor adherence, 9 for lack of efficacy, and 12 for adverse events.
The primary endpoint was the proportion of people with a viral load below 50 copies at week 48 in a time-to-loss-of-virologic-response (TLOVR) analysis. Virtually the same proportion taking elvitegravir (207 of 351, 59%) and raltegravir (203 of 351, 58%) reached that endpoint. These results mean elvitegravir fulfilled the study's noninferiority criteria compared with raltegravir (95% confidence interval for difference -6.0% to 8.2%, P = 0.001 for noninferiority). In a per-protocol analysis, sub-50-copy response rates were 75% with elvitegravir and 73% with raltegravir.
Virologic failure rates were 20% in the elvitegravir group (11% rebounds, 8% never suppressed, 1% switched background regimen) and 22% in the raltegravir group (16% rebounds, 5% never suppressed, 1% switched background regimen).Among 60 people whose virus was genotyped after elvitegravir failure, 16 (27%) had detectable integrase mutations, compared with 15 of 72 people (21%) in whom raltegravir failed. PI mutation rates were 7% with elvitegravir and 4% with raltegravir, and nucleoside mutation rates were 12% with elvitegravir and 13% with raltegravir. (from Jules: I recall the presenter saying the profile was cross-resistant)
CD4 counts rose by an average 138 cells in the elvitegravir group and 147 cells in the raltegravir group.
Nine of 354 people taking elvitegravir (3%) and 15 of 358 (4%) taking raltegravir stopped treatment because of adverse events. Rates of grade 3 or 4 adverse events were 19% with elvitegravir and 22% with raltegravir, and rates of serious adverse events were 16% and 21%. Diarrhea was the most common problem, affecting a significantly higher proportion on elvitegravir than raltegravir (12% versus 7%, P = 0.023). More people taking raltegravir than elvitegravir had elevations of three liver markers: alanine aminotransferase (5% versus 2%, P = 0.020), aspartate aminotransferase (5% versus 1%, P = 0.009), and gamma-glutamyltransferase (6% versus 3%, P = 0.039).
In the placebo-controlled BENCHMRK trials, which established the value of raltegravir in people with antiretroviral experience, all study participants had documented phenotypic or genotypic resistance to at least one drug in each of the first three antiretroviral classes [2]. In contrast, in the elvitegravir-raltegravir trial [1], 63% had resistance to drugs in two or more antiretroviral classes. Among people taking raltegravir in BENCHMRK, 63% had a viral load below 50 copies at week 48 in a discontinuation-equals-failure analysis.
Elvitegravir is being studied in a once-daily fixed-dose formulation with cobicistat (a nonritonavir booster), tenofovir, and emtricitabine [3] in antiretroviral-naive people.
References
1. Molina JM, LaMarca A, Andrade Villanueva J, et al. Elvitegravir once-daily is non inferior to raltegravir twice-daily in treatment experienced patients: 48 week results from a phase 3 multicenter, randomized, double blind study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract WELBB05.
2. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359:339-354. http://www.nejm.org/doi/full/10.1056/NEJMoa0708975.
3. Cohen C, Elion R, Ruane P, et al. Randomized, phase 2 evaluation of two single-tablet regimens elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus efavirenz/emtricitabine/tenofovir disoproxil fumarate for the initial treatment of HIV infection. AIDS. 2011;25:F7-F12.
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