Emma Hitt, PhD

July 21, 2011

July 21, 2011 (Rome, Italy) — Elvitegravir, a novel oral integrase inhibitor being evaluated for the treatment of HIV-1 infection, appears to be noninferior to the integrase inhibitor raltegravir after 48 weeks of therapy in treatment-experienced patients, according to findings from the pivotal Study 145.

Jean-Michel Molina, MD, from the Hôpital Saint-Louis, in Paris, France, presented the findings during a late-breaking session here at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention.

"These are the first data in a large set of patients that confirm the efficacy and safety of elvitegravir," Dr. Molina told Medscape Medical News. "These findings suggest that elvitegravir is as good as raltegravir, the only approved integrase inhibitor, and can be given once daily, which is not the case with raltegravir, according to findings of the recent QDMRK trial," he said.

Dr. Jean-Michel Molina

Study 145 randomized 351 patients to receive ritonavir-boosted once-daily elvitegravir 150 mg (or 85 mg in those receiving a background protease inhibitor of either atazanavir or lopinavir) and 351 patients to receive ritonavir-boosted twice-daily raltegravir 400 mg. Each agent was given in combination with an optimized background regimen; 24% of patients received tenofovir and ritonavir-boosted darunavir.

After 48 weeks of treatment, using the time to loss of virologic response algorithm, 59% of elvitegravir-treated patients achieved and maintained a viral load of below 50 copies/mL, compared with 58% of raltegravir-treated patients (intention-to-treat population; noninferiority P = .001; 95% confidence interval, –6.0% to +8.2%).

In addition, the mean increases in CD4 cell counts from baseline to week 48 with elvitegravir and raltegravir were comparable (138 vs 147 cells/mm3).

Adverse events were similar between the elvitegravir and raltegravir groups, and discontinuation of treatment was also similar (3% vs 4%). Adverse events included upper respiratory tract infection, bronchitis, back pain, depression, sinusitis, arthralgia, nausea, and urinary tract infection. The incidence of diarrhea was slightly higher in the elvitegravir group than in raltegravir group (12% vs 7%).

Most grade 3 or 4 laboratory markers were similar between treatment groups, with the exception of gamma glutamyl transpeptidase and the aspartate and alanine liver aminotransferases, for which elevations were more common in the raltegravir group.

Drug resistance rates were similar: 16 of 60 patients who experienced virologic failure exhibited integrase resistance in the elvitegravir group, compared with 15 of 72 patients in the raltegravir group.

"Treatment-experienced patients who need an integrase inhibitor for optimizing their regimen could use once-daily elvitegravir with a boosted protease inhibitor, instead of raltegravir, with similar efficacy and, potentially, if one considers hepatic toxicity, better safety," Dr. Molina said.

He pointed out that the best drugs to use in combination with elvitegravir remain unclear, and it still needs to be determined whether elvitegravir can be used in treatment-naïve patients.

In a January 10 press release, Gilead announced an amendment to the design of Study 145, extending the blinded randomized period from the originally planned 48 weeks to 96 weeks, to obtain longer-term safety and efficacy data. "Based on the achievement of the noninferiority end point, patients will continue to receive the regimen to which they were randomized in a blinded fashion," it says.

"As clinical data for elvitegravir continue to emerge, this drug will likely be added to our armamentarium of antiretrovirals that can be used in treatment-experienced patients, provided they do not have a history of integrase resistance," said independent commentator Olga Klibanov, MD, associate professor of pharmacy at Wingate University School of Pharmacy, in North Carolina, who specializes in HIV and infectious diseases.

"These were 48-week results, so it will be important to determine elvitegravir's long-term efficacy and toxicity," she told Medscape Medical News. "Drug–drug interactions should also be investigated, as this drug is metabolized by the CYP-450 system," she added.

According to Dr. Klibanov, phase 3 clinical trials in treatment-naïve patients are currently underway, in which elvitegravir is coformulated with cobicistat (a pharmacokinetic booster), tenofovir, and emtricitabine in a single tablet. "Efficacy and safety results of these trials are highly anticipated by clinicians," she said.

The study was funded by Gilead. Dr. Molina reports being a member of the Gilead global advisory board. Dr. Klibanov has disclosed no relevant financial relationships.

6th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention: Abstract WELBB05. Presented July 20, 2011.