Raltegravir: Integrase inhibitor approved in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients

FDA approved raltegravir on October 12, 2007, for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication and HIV-1 strains that are resistant to multiple antiretroviral agents.

Key Points

Raltegravir is an HIV integrase strand transfer inhibitor. By inhibiting the catalytic activity of HIV-1 integrase, raltegravir prevents the covalent integration of unintegrated linear HIV-1 DNA into the host cell genome, thus preventing the formation of the HIV-1 provirus and thereby preventing propagation of the viral infection. This agent was approved in combination with other antiretroviral agents on October 12, 2007, for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication and HIV-1 strains that are resistant to multiple antiretroviral agents.

Efficacy. The efficacy of raltegravir was assessed in 2 randomized, double-blind, placebo-controlled trials (BENCHMRK 1 and BENCHMRK 2), which are ongoing. The trials enrolled antiretroviral treatment-experienced adult (aged ≥16 years) patients with HIV-1 infection and with documented resistance to ≥1 drug in each of 3 classes of antiretroviral therapies (nonnucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors). Patients were randomized to receive raltegravir 400 mg BID plus optimized background therapy (OBT) or placebo plus OBT. After 24 weeks of treatment, 216 of 286 patients (75.5%) who received raltegravir plus OBT demonstrated HIV-1 RNA <400 copies/mL versus 59 of 150 patients (39.3%) treated with placebo plus OBT. Additionally, 179 of the raltegravir-treated patients (62.6%) demonstrated HIV-1 RNA <50 copies/mL versus 50 patients (33.3%) who received placebo plus OBT. Patients treated with raltegravir plus OBT demonstrated a mean change from baseline in plasma HIV-1 RNA of –1.85 log10 copies/mL versus –0.84 log10 copies/mL in patients treated with placebo plus OBT. Raltegravir-treated patients demonstrated a mean increase from baseline in CD4+ cell counts of 89 cells/mm3 versus 35 cells/mm3 among patients treated with placebo plus OBT.

Safety. When treatment is initiated, patients may develop immune reconstitution syndrome, an inflammatory response to indolent or residual opportunistic infections. Serious drug-related reactions observed in patients treated with raltegravir in clinical trials included hypersensitivity, anemia, neutropenia, myocardial infarction (MI), gastritis, hepatitis, herpes simplex, toxic nephropathy, renal failure, chronic renal failure, and renal tubular necrosis. Myopathy and rhabdomyolysis were also reported in clinical trials; the possible relationship between these events and raltegravir treatment is unknown. The most common adverse events observed in raltegravir-treated patients include diarrhea, nausea, headache, and pyrexia.

Pricing. The wholesale acquisition cost of raltegravir is expected to be approximately $27 per day, or approximately $9,855 per year.