By Liz Highleyman

Raltegravir (Isentress) is the first HIV integrase inhibitor, approved for treatment-experienced patients in October 2007. As previously reported the drug has also demonstrated potent suppression of HIV with minimal adverse events and good tolerability through 48 weeks in previously untreated individuals. In a presentation at the XVII International Conference on AIDS, taking place this week in Mexico City, researchers reported longer-term treatment-naive data, though 96 weeks.

Martin Markowitz and an international team of colleagues conducted a multicenter randomized Phase II study to evaluate the efficacy, safety, and tolerability of raltegravir at doses of 100, 200, 400, or 600 mg twice-daily, versus efavirenz (Sustiva), both combined with tenofovir (Viread) plus lamivudine (3TC; Epivir) in treatment-naive HIV patients. A total of 198 participants were randomized and treated, 160 in the raltegravir arms and 38 in the efavirenz arm. All had an HIV viral load of at least 5000 copies/mL and a CD4 count of at least 100 cells/mm3.

Patients were initially treated for 48 weeks, after which all participants receiving raltegravir were given the 400 mg dose, as there was little difference in response or adverse events among the various dose groups. Follow-up then continued through 96 weeks.

Results

• At 48 weeks, raltegravir and efavirenz produced similar rates of viral suppression, and this was sustained through longer-term follow-up.

• At 96 weeks, in an intent-to-treat, non-completer = failure analysis, 84% of participants in both the raltegravir and efavirenz arms achieved HIV RNA < 400 copies/mL.

• 83% and 84%, respectively, achieved a viral load < 50 copies/mL.

• In an as-treated analysis looking only at patients who completed 96 weeks of treatment, 92% and 91%, respectively, achieved HIV RNA < 50 cells/mm3.

• Patients in both the raltegravir and efavirenz arms achieved similar CD4 cell increases (220 vs 232 cells/mm3, respectively).

• 2 individuals -- 1 in each arm -- met the protocol definition of virological failure after week 48.

• Discontinuation rates were similar (around 16%) in both arms.

• Drug-related clinical adverse events (AEs) were less frequent in the raltegravir arm compared with the efavirenz arm (51% vs 74%, respectively).

• The most common drug-related AEs overall, occurring in > 10% of all patients, were nausea, dizziness, and headache.

• Neuropsychiatric AEs, such as insomnia and abnormal dreams, were half as frequent in the raltegravir arm compared with the efavirenz arm (16% vs 32%, respectively).

• Raltegravir demonstrated no adverse effect (and less than efavirenz) on total or LDL ("bad") cholesterol or on triglycerides, but also produced a smaller increase in HDL ("good") cholesterol.

• Laboratory AEs were infrequent overall, though there were some cases of severe (grade 4) creatinine phosphokinase elevation in the raltegravir arm.

• No known raltegravir resistance mutations were observed during follow-up.

Based on these findings, the investigators concluded that in antiretroviral-naive patients, "raltegravir with [tenofovir/lamivudine] had potent antiretroviral activity, which was similar to [efavirenz/lamivudine/tenofovir] and was sustained to week 96."

"Raltegravir was generally well tolerated," they added, and "drug-related AEs were observed to be less frequent in patients treated with raltegravir compared to efavirenz."

Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY; Merck Research Laboratories, West Point, CT; Hospital Nacionale Cayetano Heredia and Hospital Nacionale Edgardo Rebagliati, Lima, Peru; Siriraj Hospital, Bangkok, Thailand; Canadian Immunodeficiency Research Collaborative, Toronto, Canada.

8/08/08

Reference
M Markowitz, B-Y Nguyen, E Gotuzzo, and others. Sustained antiretroviral efficacy of raltegravir as part of combination ART in treatment-naive HIV-1 infected patients: 96-week data. XVII International Conference on AIDS (AIDS 2008). Mexico City. August 3-8, 2008. Abstract TUAB0102. (Abstract)