Nelfinavir

Abstract

Nelfinavir (Viracept®) is an orally administered protease inhibitor. In combination with other antiretroviral drugs (usually nucleoside reverse transcriptase inhibitors [NRTIs]), nelfinavir produces substantial and sustained reductions in viral load in patients with HIV infection. Nelfinavir may be used in the treatment of adults, adolescents and children aged ≥2 years with HIV infection. It can also be used in pregnancy. Resistance to nelfinavir may develop, but the most common mutation (D30N, appearing mainly in HIV-1 subtype B) does not confer resistance to other protease inhibitors, thereby conserving these agents for later use. Although less effective than lopinavir/ritonavir, the preferred first-line treatment in US guidelines, nelfinavir is positioned as an alternative agent for the treatment of adults and adolescents with HIV infection and is an option for those unable to tolerate other protease inhibitors. Nelfinavir also has a role in the management of pregnant patients as well as paediatric patients with HIV infection. Nelfinavir is a selective, nonpeptidic competitive inhibitor of the HIV-1 protease. The drug shows good in vitro activity against HIV-1 strains, including strains resistant to zidovudine or non-nucleoside reverse transcriptase inhibitors. The activity of the major metabolite of nelfinavir (M8) against HIV-1 in vitro is similar to that of the parent drug. Additive activity against HIV-1 is observed with nelfinavir in combination with stavudine, didanosine or saquinavir; synergistic activity against HIV-1 is observed with nelfinavir in combination with zidovudine, lamivudine or zalcitabine. Resistance to nelfinavir is mediated most commonly via a substitution at residue 30 (D30N) in HIV protease and has been identified in clinical isolates of HIV from patients receiving treatment with the drug in combination with other agents. This mutation appears to be unique to nelfinavir. Less commonly, a substitution at residue 90 (L90M) may occur during treatment with nelfinavir; this mutation can confer resistance to several other protease inhibitors. Nelfinavir produces beneficial effects on immune function with increases in CD4+ cell counts observed in patients treated with nelfinavir-containing combination regimens. Treatment with nelfinavir was associated with a decrease in Fas expression and Fas-mediated apoptosis and an increase in CD4+ cell counts in patients with HIV infection. The absorption of nelfinavir from the currently available oral formulations is increased when the drug is administered after food, compared with the fasted state. Both nelfinavir and its active metabolite M8 are highly bound to serum proteins and nelfinavir shows extensive tissue distribution. Transplacental passage of the drug appears limited. Nelfinavir is metabolised in the liver by multiple cytochrome P450 (CYP) enzymes. M8 is its major metabolite. The plasma terminal half-life of nelfinavir ranges from 3.7 to 5.3 hours. Almost 90% of the drug is eliminated via the faeces; 1–2% is recovered in urine mostly as unchanged drug. In children, systemic exposure to nelfinavir is highly variable. Clearance in this population is increased by ≈2–3 times compared with that in adults. However, in children aged 2–13 years, adequate systemic exposure to the drug is achieved at recommended dosages. Plasma concentrations of nelfinavir are markedly lower in pregnant women with HIV infection during the third trimester than concentrations in nonpregnant patients. A dosage of 1250mg twice daily produces adequate plasma concentrations in pregnant women, whereas plasma concentrations in recipients of 750mg three times daily may be lower and more variable. Nelfinavir interacts with a number of other drugs via induction or inhibition of CYP isoenzymes in the liver. The efficacy of oral nelfinavir has been investigated in HIV-infected, antiretroviral therapy (ART)-naive or -experienced patients, including adults, adolescents, children and pregnant women. Key clinical trials were ≤48 weeks in duration and measured plasma HIV RNA levels as a virological surrogate marker of disease progression. ART-naive adults and adolescents: In randomised, double-blind or open-label, multicentre studies, nelfinavir demonstrated similar virological efficacy at both recommended dosage levels (750mg three times daily or 1250mg twice daily) when administered as a component of triple therapy (with zidovudine and lamivudine). Treatment with the regimen containing nelfinavir 750mg three times daily resulted in significantly better virological and/or immunological outcomes compared with the placebo-containing regimen. Administered as part of triple therapy in randomised, double-blind, partially blind or open-label, multicentre studies, nelfinavir 750mg three times daily or 1250mg twice daily showed virological efficacy similar to that of atazanavir 200–600mg and was noninferior to fosamprenavir/ritonavir 1400mg/200mg once daily in the SOLO trial. In the NEAT trial, which was also a noninferiority trial, a larger proportion of fosamprenavir than nelfinavir recipients achieved HIV RNA levels of <400 copies/mL at the end of treatment. Nelfinavir was less effective than lopinavir/ritonavir 400mg/100mg twice daily, each given in combination with lamivudine and stavudine. Approximately one-half to two-thirds of the nelfinavir-treated patients in these studies had undetectable viral loads (<400 copies/mL) after 48 weeks of treatment (various intent-to-treat analyses). Immunological responses were similar for each of these protease inhibitor-based regimens. Quadruple regimens containing nelfinavir have also shown efficacy in therapy-naive patients with HIV infection. Triple therapy with efavirenz, zidovudine and lamivudine was the optimal regimen in a study comparing three- and four-drug regimens...