Steigbigel RT, Cooper DA, Kumar PN, et al. N Engl J Med. 2008;359(4):339–354
PURPOSE OF THE STUDY. As described above, there are compelling reasons for expanding the anti-HIV armamentarium. Raltegravir is an inhibitor of HIV integrase, an enzyme essential in the cycle of HIV replication. Because it belongs to a novel class of antiretroviral agents, the drug should be effective against HIV that is resistant to other antiretroviral drugs. The purpose of this study was to evaluate the safety and effectiveness of raltegravir in adults with multidrug-resistant virus.
STUDY POPULATION. HIV-infected patients ≥16 years of age were eligible if they had plasma HIV RNA levels of >1000 copies per mL and documented resistance to ≥1 drug in each of the 3 classes of antiretroviral drugs (ie, nucleoside transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors).
METHODS. Two identical trials in different geographic regions were conducted to evaluate raltegravir versus placebo in combination with optimized background anti-HIV therapy. Patients were randomly assigned to receive raltegravir or placebo, in a 2:1 ratio. Clinical status was assessed regularly during the trial, and protocol-mandated laboratory studies were performed at a central laboratory. The primary end point of the study was the proportion of patients achieving HIV RNA levels of <400 copies per mL after 16 weeks of study therapy.
RESULTS. Subjects (N = 699) were enrolled in studies in the different geographic locations. Because results were very consistent between the 2 substudies, combined results are presented. Subjects receiving raltegravir were well matched to the subjects receiving placebo. Seventy-eight percent of subjects receiving raltegravir achieved the primary end point of <400 copies of HIV RNA per mL, compared with ∼42% for those receiving placebo. This difference persisted through week 48 of the study (72% vs 37%). HIV RNA suppression to <50 copies per mL at 48 weeks was achieved by 62% of raltegravir-treated subjects, compared with 33% of placebo recipients. Raltegravir was very well tolerated. The most common drug-related laboratory adverse events were increased serum cholesterol, triglyceride, and aminotransferase levels in the raltegravir group and increased cholesterol and creatinine levels and decreased neutrophil counts in the placebo group. Clinical adverse events were similar between groups, and rates of discontinuation because of drug-related events were also similar in the raltegravir and placebo groups.
CONCLUSIONS. In heavily pretreated, HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than did optimized background therapy alone for ≥48 weeks.
REVIEWER COMMENTS. Since 1995, it has been apparent that treatment of HIV with single agents does not result in complete viral suppression. In that year, given the drugs that were available at the time, ≥3 antiretroviral agents were required to suppress HIV RNA levels to <50 copies per mL. It is clear from the raltegravir and maravirock studies that the addition of a single active agent, regardless of potency or mechanism of action, is not sufficient to achieve this end. However, given the new agents now available, patients with multidrug-resistant HIV have excellent chances of achieving viral suppression, often with 2 active agents. The availability of potent new agents active against multidrug-resistant HIV is welcome news to clinicians and patients still facing the daunting task of maintaining control over a remarkably resilient microbe.
- Copyright © 2009 by the American Academy of Pediatrics