HIV/AIDS Reviews

Abstract

This multicenter study, conducted from June 2005 to October 2006, addresses the safety and efficacy of raltegravir, a putative new anti-HIV-1 agent belonging to a new class of anti-HIV-1 drugs, the integrase inhibitors. One hundred and ninety eight antiretroviral naive HIV-1-infected subjects were analyzed to compare the 100-, 200-, 400-, and 600-mg twice daily doses of raltegravir with efavirenz 600 mg/day, both in combination with two approved nucleoside reverse transcriptase inhibitors, tenofovir 300 mg/day and 3TC 300 mg/day, over 48 weeks. Participants were ≥18 years of age and had an HIV viral load (VL) ≥5,000 copies/ml and ≥100 CD4+ T cells/mm3. The study was double-blinded, randomized, and conducted in two parts. Part I (cohort I) comprised 35 patients receiving raltegravir monotherapy for 10 days. Part II (cohort II) enrolled 171 patients in addition to 30 from cohort I. At screening, randomization was stratified by the HIV-1 RNA level (VL ≤50,000 RNA copies/ml vs. >50,000 RNA copies/ml). Patients who received raltegravir in cohort I received the same dose in cohort II, whereas those who received placebo in cohort I received efavirenz in cohort II. HIV-1 RNA level and CD4+ T cell counts were analyzed and compared in the efavirenz and raltegravir groups at five time points over 48 weeks of therapy. Pharmacokinetic assessments were done at day 10 (cohort I) and week 2 (cohort II). Patients who showed viral failure (HIV-1 RNA level >4,000 copies/ml at week 24) or virologic relapse (two consecutive VL >400 copies/ml after an initial value <400 copies/ ml) were discontinued from the study. Comprehension genotyping and phenotyping were done for tenofovir, lamivudine, and efavirenz and genotyping integrase coding was used to evaluate raltegravir resistance. Safety was evaluated for all patients who took raltegravir at any dose, and the efficacy was estimated at weeks 24 and 48. At week 24, there was a decrease of VL levels to <400 copies/ml in 82 to 100% of cohort II and in 85 to 98% in cohort (I + II). VL <50 copies and changes from baseline CD4+ T count were comparable for these groups. The mean increase in CD4+ T-cells was comparable in the efavienz and raltegravir groups at weeks 24 and 48. Of note, patients receiving raltegravir at any dose had a greater likelihood of achieving an HIV-1 RNA level <50 copies/ml at weeks 2, 4, and 8 than patients receiving efavirenz (p < 0.05). These differences diminished over time, and by week 24, all groups had similar proportions of patients with suppressed VLs. Virologic failure was low (3%) and comparable in the efavirenz and raltegravir groups. A novel resistance mutation, a N155H amino acid substitution in the integrase region, was detected in the raltegravir groups. The incidence of serious adverse events was similar in the efavirenz and raltegravir groups, but drug-related adverse events were more frequently seen with the efavirenz combination regimen than the raltegravir one (p = 0.04 for 100-, 400-, and 600-mg groups and p = 0.07 for the 200-mg group).