Nelfinavir

Abstract

Nelfinavir is one of several currently available protease inhibitors used to limit viral replication and improve immune function in HIV-infected individuals. It is administered in combination with other antiretroviral agents. Nelfinavir has been evaluated as first-line therapy with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment-naive patients, or as an additional antiretroviral agent in protease inhibitor-naive patients already receiving NRTIs. These studies have shown good efficacy in terms of HIV viral load reduction and increased CD4+ cell counts. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 750mg 3 times daily. The more convenient twice-daily dosage schedule, which is now approved in the US, may be beneficial in improving patient adherence to therapy. Nelfinavir has also been used successfully in combination with non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors, with or without NRTIs. Resistance to nelfinavir has been observed in vitro and in clinical isolates from patients experiencing insufficient or waning viral suppression during treatment. Nelfinavir primarily selects for the D30N mutation, which is not seen with other protease inhibitors, and alone does not cause resistance to other protease inhibitors in vitro. Several studies have shown that patients who experience virological failure while receiving nelfinavir can respond to salvage therapy with other protease inhibitors. Diarrhoea is the most frequent adverse event in patients receiving nelfinavir-based combination therapy, but was generally mild and resulted in minimal discontinuation of therapy in clinical trials. Diarrhoea can usually be controlled with drugs that slow gastrointestinal motility. Metabolic disturbances associated with protease inhibitor use (hypercholesterolaemia, hyperglycaemia and lipodystrophy) have also been reported with nelfinavir. Nelfinavir is associated with a number of clinically significant drug interactions and coadministration of some drugs (e.g. astemizole, cisapride, triazolam) is contraindicated. Coadministration of nelfinavir with other protease inhibitors generally resulted in favourable pharmacokinetic interactions (usually increased area under the concentration-time curve for both drugs). Conclusion: Nelfinavir, in combination with reverse transcriptase inhibitors and/or other protease inhibitors, is effective in limiting HIV replication and increasing CD4+ cell counts in HIV-infected adults and children. The convenience of its dosage administration, the low incidence of adverse events, and the potential for salvage therapies indicate that nelfinavir (as part of combined antiretroviral therapy regimens) should be considered as a first-line option in protease inhibitor-naive patients and in those unable to tolerate other protease inhibitors. Nelfinavir is a nonpeptidic, competitive HIV protease inhibitor that interferes with the processing of viral gag and gagpol polyprotein products into viral enzymes and structural proteins. Inhibition of this process blocks the production of mature infectious virus particles in both acutely and chronically infected cells. Nelfinavir exhibited activity against HIV-1 protease in vitro with an inhibition constant (K _i) of 1.7 nmol/L; other human aspartic proteases were not significantly inhibited. The mean nelfinavir concentration producing 95% inhibition of viral replication (IC₉₅) in a variety of in vitro HIV infection models was 59 nmol/L (range 7 to 130 nmol/L). Nelfinavir inhibited replication of HIV-1 and -2 strains in acutely infected primary macrophages and peripheral blood mononuclear cells (PBMCs) and caused accumulation of gag and gagpol polyprotein intermediates in chronically infected T cell lines. Synergistic antiviral effects were observed in vitro when nelfinavir was combined with the nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine, lamivudine and zalcitabine, and additive effects were seen when combined with stavudine and didanosine. Antiviral synergism was also observed with the dual protease inhibitor combination of nelfinavir and ritonavir. A slightly antagonistic interaction was noted between nelfinavir and indinavir. Nelfinavir induced minimal in vitro cellular toxicity either alone or in combination with other protease inhibitors. Nelfinavir in combination with reverse transcriptase inhibitors (RTIs) reduced HIV replication in compartmental viral reservoirs including CSF, semen and cervicovaginal mucosa. HIV-infected CD4+ T cells undergo accelerated apoptosis leading to severe immunodeficiency. T cell apoptosis was reduced by 23% in PBMCs cultured from patients treated with nelfinavir in combination with RTIs for 48 weeks. Protease inhibitor-naive patients treated with nelfinavir and RTIs generally showed sustainable increases in CD4+ cell counts for the duration of clinical trials (up to 96 weeks). An HIV variant with 7-fold resistance to nelfinavir was isolated in vitro after repeated passages of virus with increasing concentrations of the drug. This variant contained a mutation at HIV protease residue 30 (D30N), a substitution not selected by other protease inhibitors. This was subsequently identified as the predominant mutation in clinical isolates from patients who failed to respond to nelfinavir-based therapies. Although the isolates exhibited high level resistance to nelfinavir, susceptibility to other protease inhibitors (indinavir, ritonavir, saquinavir or amprenavir) was not substantially diminished. In vitro, nelfinavir inhibited epithelial barrier function, an effect possibly related to the diarrhoea reported by patients receiving nelfinavir therapy. Nelfinavir interacts with the multidrug transporter protein MDR1, an efflux pump protein which limits uptake of drugs into major organs and...