This inhibitor of human immunodeficiency virus type 1 (HIV-1) protease selectively inhibits the cleavage of HIV-encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.
Protease inhibitor receives approval in treatment-experienced patients
Efficacy. The efficacy of darunavir was evaluated in 2 ongoing, randomized, controlled trials in antiretroviral treatment-experienced HIV-1-infected adult patients (N=637). Patients received either darunavir/rtv (600/100 mg BID) plus an optimized background regimen (OBR) or an investigator-selected PI plus an OBR. The OBR consisted of at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) with or without enfuvirtide. Efficacy analyses were based on patients who had completed 24 weeks of treatment or discontinued earlier. Virologic response (confirmed at least 1 log10 HIV-1 RNA below baseline through Week 24) was achieved by 69.5% of patients receiving darunavir/rtv plus an OBR compared with 21.0% of patients receiving a comparator PI plus an OBR. Through 24 weeks of treatment, the proportion of patients with HIV-1 RNA <400 copies/mL (<50 copies/mL) in the darunavir arm was 63% (45%) versus 19% (12.1%) in the comparator arm. The proportion of patients experiencing virologic failure in the darunavir arm was 26.0% compared with 71.0% in the comparator arm. Additional efficacy data for darunavir have been obtained in 2 nonrandomized trials of treatment-experienced subjects (N=246). In these 2 studies, 65% of patients treated with the darunavir regimen experienced virologic response as defined as a decrease of at least 1.0 log10 in plasma viral load versus baseline and 40% of the patients reached <50 HIV-1 RNA copies/mL.
Safety. As darunavir and rtv are both potent inhibitors of CYP3A, coadministration of darunavir/rtv is contraindicated with drugs that are extensively metabolized CYP3A, including: astemizole, terfenadine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, pimozide, midazolam, and triazolam. Darunavir contains a sulfonamide moiety and should therefore be used with caution in patients with a known sulfonamide allergy. Severe skin rash, including erythema multiforme and Stevens-Johnson Syndrome, has been reported in association with darunavir therapy. In some cases, fever and elevations of transaminases have also been reported. New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported in patients receiving therapy with PIs. Because darunavir is primarily metabolized by the liver, caution should be exercised when darunavir/rtv is administered to patients with hepatic impairment. There are reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with PIs. The most common adverse events reported in association with darunavir/rtv include diarrhea, nausea, headache, and nasopharyngitis.
Dosing. The recommended oral dose of darunavir is 600 mg (two 300-mg tablets) twice daily taken with rtv 100 mg twice daily and food. Darunavir must be coadministered with rtv and food to exert its therapeutic effect.