Drugs

, Volume 65, Issue 15, pp 2209–2244

Nelfinavir

A Review of its Use in the Management of HIV Infection

Authors

  • Caroline M. Perry
    • Adis International Limited
  • James E. Frampton
    • Adis International Limited
  • Paul L. McCormack
    • Adis International Limited
  • M. Asif A. Siddiqui
    • Adis International Limited
  • Risto S. Cvetković
    • Adis International Limited
Adis Drug Evaluation

DOI: 10.2165/00003495-200565150-00015

Cite this article as:
Perry, C.M., Frampton, J.E., McCormack, P.L. et al. Drugs (2005) 65: 2209. doi:10.2165/00003495-200565150-00015

Summary

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.

Pharmacological Properties

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.

Therapeutic Efficacy

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 containing nelfinavir and/or efavirenz in combination with either stavudine and didanosine or zidovudine and lamivudine.

ART-experienced adults and adolescents: Quadruple therapy containing nelfinavir 750mg three times daily plus efavirenz 600mg once daily and triple therapy containing efavirenz 600mg once daily generally resulted in higher rates of viral suppression than triple therapy containing nelfinavir 750mg three times daily in a randomised, partially blinded, multicentre study. Quadruple therapy produced the most durable virological response. In other randomised studies in ART-experienced patients, nelfinavir 750mg three times daily or 1250mg twice daily demonstrated similar virological efficacy to ritonavir 400mg twice daily, indinavir 800mg three times daily and delavirdine 400mg twice daily, when each drug was administered as a component of triple therapy, and similar long-term clinical efficacy (expressed in terms of the incidence of AIDS-defining conditions/death) to ritonavir 600mg twice daily.

Paediatric patients: Triple therapy with nelfinavir, administered twice or three times daily, plus zidovudine and stavudine (all dosages unspecified) was more effective than placebo in children aged ≥2 years (but not in those aged <2 years) in a randomised, double-blind trial. Approximately one-quarter of the nelfinavir-treated patients in this study had an undetectable viral load (<400 copies/mL) after 48 weeks of treatment, compared with around one-third to one-half of the children who received three- and four-drug regimens containing nelfinavir in an open-label study.

Tolerability

Nelfinavir, as part of combination therapy, was generally well tolerated by adults and adolescents with HIV infection in clinical trials; a small proportion of patients (4%) discontinued treatment due to adverse events. Diarrhoea, generally of mild to moderate intensity and manageable, was the most common adverse event (incidence 20% in two randomised trials) in ART-naive adults and adolescents who received recommended dosages of nelfinavir (750mg three times daily or 1250mg twice daily).

In 48-week, randomised, comparative trials in ART-naive patients, recommended dosages of nelfinavir were usually as well tolerated as atazanavir 200–600mg once daily, fosamprenavir 1400mg twice daily, fosamprenavir/ ritonavir 1400mg/200mg once daily, lopinavir/ritonavir 400mg/100mg twice daily, nevirapine 200mg twice daily and abacavir 300mg twice daily, when each of these agents was administered as a component of a three-drug regimen. Likewise, quadruple and triple therapies containing nelfinavir and/or efavirenz had similar adverse event profiles when evaluated in HIV-infected, ART-experienced patients. However, nelfinavir was better tolerated than indinavir 800mg three times daily and ritonavir 600mg twice daily in terms of the treatment discontinuation rate, when each of these protease inhibitors was assessed as part of combination therapy in ART-experienced patients. A retrospective meta-analysis indicated that nelfinavir was associated with the lowest rate of occurrence of hepatotoxicity relative to indinavir, saquinavir, ritonavir and saquinavir/ ritonavir.

The tolerability profile of nelfinavir in paediatric patients was similar to that in adults. Diarrhoea was the most common, drug-related adverse event. A postmarketing adverse event review did not reveal any unexpected safety concerns relating to the use of nelfinavir in paediatric patients.

The first study with sufficient power to detect a two-fold increase in the risk of overall birth defects with nelfinavir found no such increase. Triple therapy containing nelfinavir was well tolerated by HIV-infected, pregnant women.

1. Introduction

The use of protease inhibitor-containing highly active antiretroviral therapy (HAART) regimens as standard treatment for patients with HIV infection has dramatically improved outcomes for patients with HIV infection. HAART regimens have been shown to produce profound and durable decreases in plasma HIV RNA levels, increases in CD4+ cell counts and a marked decrease in disease-related morbidity and mortality.[1] Boosted protease inhibitor-based or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination regimens are standard first-line HAART regimens.[2] Nelfinavir (Viracept®)1[figure 1], an orally administered protease inhibitor, has been widely used in the treatment of HIV infection for almost a decade.
https://static-content.springer.com/image/art%3A10.2165%2F00003495-200565150-00015/MediaObjects/40265_2012_65152209_Fig1.jpg
Fig. 1

Chemical structure of nelfinavir.

This article provides an overview of the pharmacology of nelfinavir and focuses on its clinical profile and role in the management of adults, adolescents and children (aged ≥2 years) with HIV infection, in line with its approved indications in the US.[3] A review of nelfinavir in the management of HIV infection was published previously in Drugs in 2000.[4]

2. Pharmacodynamic Properties

This section provides a summary of data on the pharmacodynamic profile of nelfinavir. Although some information is derived from early studies of the drug, much of the data on resistance and cross resistance has been published during the last 5 years.

Nelfinavir is a selective, nonpeptidic, peptidomimetic, competitive inhibitor of the HIV-1 protease.[4] The drug mimics the peptide structure at the cleavage site of the substrate protein and competes with natural substrate for binding to the catalytic site of the protease.[5] The homodimeric HIV-1 aspartic protease is responsible for cleaving the viral gag (p55) and gag-pol (p160) polyprotein products into functional core proteins and viral enzymes during post-translational processing as part of a late-stage maturation step in the retroviral life cycle.[6] Inhibition of this critical maturation process, which occurs during or immediately after budding of immature virions from infected cells, results in the production of noninfectious virus.[3]

2.1 Antiviral Activity

Nelfinavir is a potent inhibitor of HIV-1 protease with an in vitro inhibition constant (Ki) of 1.7 nmol/L.[7] It had no significant activity against human aspartic proteases, such as pepsin, renin and gastricin, at concentrations up to 1000 nmol/L, but was shown to have very weak affinity for cathepsin D (Ki = 435 nmol/L) and cathepsin E (Ki = 74 μmol/L).[7]

Nelfinavir protected cultured cells (CEM-SS, MT-2, macrophages or peripheral blood mononuclear cells) against in vitro infection with various strains of HIV-1.[7] The HIV-1 strains tested included strains resistant to zidovudine (HIV-1 G910-6) or NNRTIs (HIV-1 A17). Nelfinavir shows good activity against various strains of HIV-1. The 50% effective concentration (EC50) ranged from 10 to 60 nmol/L against the HIV-1 strains. The mean 95% effective concentration was 59 nmol/L (range 7–130 nmol/L).[7] The 50% cytotoxic concentration of nelfinavir against HIV-1 for CEM-SS and MT-2 cells was 23–28 μmol/L, indicating a high therapeutic index range of 526–916 for the drug. Resumption of HIV-1 proteolytic processing of the gag polyprotein (p55) to processed capsid protein (p24) was prevented for up to 36 hours after removal of nelfinavir from the culture medium.[7]

The major circulating metabolite of nelfinavir, M8 (hydroxy-t-butylamide nelfinavir) [section 3.2], had in vitro antiviral activity similar to that of the parent drug.[8] In HIV-1-infected CEM-SS cells, EC50 values of nelfinavir and M8 were 30.1 and 34.2 nmol/L, whereas in HIV-1-infected MT-2 cells EC50 values were 60.2 and 85.6 nmol/L, respectively. M8 was less cytotoxic than nelfinavir, resulting in a 3-fold higher therapeutic index in CEM-SS cells and a 6-fold higher therapeutic index in MT-2 cells.[8] The main minor oxidative metabolite, M1 (3′-methoxy-4′-hydroxy nelfinavir), had 5- to 11-fold less activity than nelfinavir.[8]

Combining nelfinavir with nucleoside reverse transcriptase inhibitors (NRTIs) resulted in additive (stavudine or didanosine) or synergistic (zidovudine, lamivudine or zalcitabine) in vitro antiviral activity in HIV-1 RF-infected CEM-SS cells, with little or no cellular cytotoxicity.[9] The combination of nelfinavir with zidovudine and lamivudine also produced synergistic activity without cytotoxicity. In combination with other protease inhibitors, nelfinavir was additive with saquinavir, weakly antagonistic with indinavir and additive with ritonavir, but with a trend towards antagonism.[9]

2.2 Resistance and Cross-Resistance

Point mutations in the gene coding for the HIV protease that result in amino acid substitutions can rapidly produce drug-resistant viral strains during monotherapy with protease inhibitors.[10] Therefore, protease inhibitors are usually combined with at least two NRTIs, so that emerging HIV strains with reduced susceptibility to one drug are eliminated by one or more of the other drugs, assuming that patient compliance is sufficient to maintain inhibitory concentrations of the drugs.[10]

2.2.1 Resistance to Nelfinavir

Resistance to nelfinavir appears to develop along one of two mutually exclusive pathways involving either an initial aspartic acid (D) to asparagine (N) substitution at residue 30 (D30N) in the amino acid sequence of the protease or a leucine (L) to methionine (M) substitution at amino acid position 90 (L90M), each of which reduces the binding of nelfinavir and directly decreases susceptibility to the drug.[11,12] The D30N substitution appears to be unique to nelfinavir, while the L90M substitution is seen in association with resistance to several other protease inhibitors.[12,13]

The D30N substitution is the most common primary mutation associated with resistance to nelfinavir and occurs in 27–55% of isolates,[3,1417] although some studies have indicated a very low incidence for the mutation (<3%).[18,19]

The selection of the D30N mutation may differ between HIV-1 subtypes, with subtype B, but not subtype C, preferentially selecting the mutation.[20] The D30N mutation markedly impaired the replication of subtype C virus compared with that of subtype B.[21] Similarly, baseline polymorphisms, such as R57K, may be specific to a viral subtype and facilitate the D30N nelfinavir resistance pathway.[22] The presence of the D30N substitution in the HIV protease was associated with a 5- to 93-fold increase in the EC90 of nelfinavir, while HIV strains without the D30N substitution were not significantly resistant to nelfinavir (<5-fold increase in EC90).[17]

The L90M substitution is less frequent and generally occurs in <4–44% of isolates.[3,11,15] HIV strains containing both the D30N and L90M substitutions are rare, usually occurring in <1% of isolates.[15,16]

Previous antiretroviral experience may influence the development path for HIV-1 resistance to nelfinavir. For instance, in patients previously treated with a protease inhibitor (other than nelfinavir) and failing on nelfinavir-containing therapy (n = 43), the L90M substitution was 2-fold more frequent than the D30N substitution (44% vs 23% of patients).[11] However, the D30N substitution arose 2-fold more frequently than the L90M substitution (40% vs 20%) in protease inhibitor-naive patients failing on nelfinavir-containing therapy (n = 45).[11]

Primary mutations on their own often produce only minor changes in drug sensitivity.[10] The degree of viral resistance to protease inhibitors is generally a function of the cumulative number of mutations.[23] The accumulation of secondary (compensatory) mutations can lead to high-level resistance and often to cross-resistance between different protease inhibitors. Common secondary resistance mutations associated with nelfinavir include substitutions at amino acid positions 10, 35, 36, 46, 71, 77 and 88.[13,17] Substitution at positions 48, 82 and 84, which are commonly associated with cross-resistance to other protease inhibitors, are less frequent secondary mutations with nelfinavir.[3,24] Secondary mutations alone, in the absence of a primary mutation, usually do not affect viral sensitivity to the protease inhibitor. In one study, 2.6% of HIV-1 isolates from protease inhibitor-naive patients failing on nelfinavir-containing therapy were found to contain only secondary mutations or polymorphisms in the absence of D30N or L90M.[15]

The incidence of genotypic resistance to nelfinavir-based therapy was higher than that for ritonavir-boosted lopinavir therapy (45% vs 0% of isolates after 108 weeks; p < 0.001).[16] In the SOLO trial (section 4.1.2), 50% of recipients of nelfinavir-based combination therapy experiencing virological failure had viral isolates with resistance mutations, whereas no protease resistance mutations were identified in isolates from patients treated with fosamprenavir boosted with low-dose ritonavir (p < 0.001).[25] D30N, N88D/S and L90M mutations were identified in viral isolates from 6 (23%) of 26 patients failing treatment with nelfinavir, abacavir and lamivudine in the NEAT trial (section 4.1.2). Mutations consistent with resistance to amprenavir were observed in 5 (17%) of 29 patients experiencing virological failure while receiving fosamprenavir, abacavir and lamivudine.[26]

The incidence of phenotypic resistance to nelfinavir was similar to that of indinavir in a retrospective analysis of a large cohort database (13% vs 16%).[27]

2.2.2 Cross-Resistance Between Protease Inhibitors

The D30N primary mutation (with or without secondary mutations) in HIV-1 protease produces resistance specific to nelfinavir and does not normally result in cross-resistance to indinavir, ritonavir, saquinavir, lopinavir, fosamprenavir or amprenavir.[12,17,24,28,29] By contrast, indinavir, saquinavir and ritonavir induce certain mutations producing relatively high levels of cross-resistance with other protease inhibitors, including nelfinavir.[12,23]

The L90M substitution generally confers broad cross-resistance to other protease inhibitors and is associated (as a primary mutation) with resistance to saquinavir.[11,13,17] However, in one study, the L90M substitution (along with A71V) in 5 of 18 patients failing nelfinavir-containing therapy was not statistically associated with an increased probability of failure following initiation of a salvage saquinavir/ritonavir-containing regimen.[24] Conversely, the L90M substitution in patients failing protease inhibitor therapy other than nelfinavir was associated with phenotypic cross-resistance to nelfinavir in another study.[23] The L90M substitution was present in 46% of nelfinavir-resistant and 6% of nelfinavir-susceptible isolates, and subsequent clinical failure on a salvage nelfinavir-containing regimen correlated with the presence of the L90M substitution.[23]

The majority of HIV isolates resistant to nelfinavir remained susceptible to fosamprenavir and lopinavir (boosted with ritonavir or unboosted) in a genotypic resistance study.[28] The isolates were from 300 patients who had received previous protease inhibitor-containing HAART regimens for 97 weeks (mean); 90 of the 300 patients had been treated with nelfinavir. Independent predictor of resistance to fosamprenavir or lopinavir was prior indinavir exposure; prior saquinavir exposure was an independent predictor of resistance to lopinavir, whereas nelfinavir was protective against resistance to both fosamprenavir and lopinavir.[28] Similarly, in the 48-week CONTEXT trial[29] in protease inhibitor-experienced patients experiencing virological failure, both lopinavir and fosamprenavir, each boosted with ritonavir, showed good virological efficacy (≈95% response rate) in patients infected with HIV-1 harbouring the D30N mutation (section 4.2.3).

Resistance to atazanavir occurred in 38% of tested HIV isolates with the D30N mutation (as well as other mutations).[30] In a trial in ART-experienced patients treated with atazanavir/ritonavir (n = 110) or lopinavir/ritonavir (n = 113), 6 (75%) of 8 atazanavir/ritonavir recipients and 3 (50%) of 6 lopinavir/ritonavir recipients with at least 3 baseline mutations (including D30N) had virological responses to treatment.[30]

2.3 Effects in Patients with HIV Infection

A correlation between plasma nelfinavir concentrations in patients with HIV infection and plasma HIV RNA levels has been demonstrated.[31,32] In a subgroup of 29 antiretroviral-naive patients with HIV infection participating in an open-label clinical trial of a quadruple antiretroviral regimen (nelfinavir, saquinavir, stavudine and lamivudine), there was a direct correlation between median nelfinavir plasma exposure and HIV-1 RNA clearance from plasma. Univariate analysis indicated a significant positive correlation with both nelfinavir (p = 0.001) and saquinavir (p = 0.016), while multivariate analysis showed a significant (p < 0.05) correlation only with nelfinavir.[31] A retrospective analysis of data from 33 HIV-infected patients receiving nelfinavir-containing HAART three times daily for at least 4 months showed a significant inverse correlation (r = 0.43; p = 0.011) between trough plasma nelfinavir concentrations (8 hours post-administration) and the concomitant viral load (plasma HIV RNA level).[32] The trough efficacy thresholds for nelfinavir were 0.5 mg/L and 0.65 mg/L for raw and time-corrected trough plasma concentration values.[32]

Results of a study in paediatric patients suggest that P-glycoprotein (P-gp) may be involved in the virological response to nelfinavir and pharmacokinetics (section 3.3.1) of nelfinavir-containing HAART regimens.[33] Analysis of data from 71 children who participated in the Paediatric AIDS Clinical Trials Group (PACTG) 382 trial showed that those with the multidrug-resistance transporter gene (MDR1)-3435-C/T genotype (n = 33) had a better virological response (plasma HIV-RNA levels <400 copies/mL) to nelfinavir-containing combination therapy at week 8 than 31 children with the C/C genotype (91% vs 59%; p = 0.01). Responses in the seven children with the T/T genotype were similar to those in children with the C/C genotype.[33]

HIV infection results in severe immunodeficiency characterised by depletion of CD4+ cells as a result of the induction of apoptosis, most likely mediated by the Fas ligand.[34] Antiretroviral therapy (ART) facilitates immunological recovery and HIV protease inhibitors, in particular, significantly inhibit CD4+ and CD8+ cell apoptosis.[35] In patients with HIV infection, combination regimens containing nelfinavir have been shown to reduce Fas receptor expression on CD4+ cells[36] and to reduce Fas-mediated apoptosis in CD4+ and CD8+ cells.[37] In parallel, increases in CD4+ cell counts[36,37] and a reduction in HIV RNA levels were observed.[37] Treatment of 23 protease inhibitor-naive HIV-infected patients with nelfinavir and NRTIs for 48 weeks produced a 24% reduction (p < 0.006) in spontaneous T cell apoptosis in cultured peripheral blood mononuclear cells.[38] The reduction in apoptosis correlated with a reduction in plasma HIV RNA of 1.8 log10 copies/mL.

Nelfinavir in combination with two NRTIs produced more rapid and complete immune reconstitution in patients with primary[39] or primary early-stage HIV infection[40] than in patients with chronic[39] or late-stage primary[40] HIV infection.

3. Pharmacokinetic Properties

The pharmacokinetic properties of nelfinavir have been reviewed previously in detail; this section provides an overview and includes data that have become available since the previous review.

Nelfinavir pharmacokinetics have been examined in adults (sections 3.1 and 3.2), including pregnant women (section 3.3.2), and children (section 3.3.1). However, there is generally a lack of data in the elderly and in patients with renal or hepatic impairment (section 3.3). No substantial differences have been observed in nelfinavir pharmacokinetics between healthy volunteers and patients with HIV infection.[3]

Pharmacokinetic parameters of nelfinavir after administration of single or multiple doses of the 250mg tablet formulation are summarised in table I. The pharmacokinetics of nelfinavir administered as a twice-daily regimen are broadly similar to those seen with a three-times-daily regimen.[41] Importantly, over the entire dosage interval, the nelfinavir trough exposures with both regimens are maintained at a level ≥20 times higher than the mean nelfinavir 95% inhibition concentration.[41]
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Table I

Pharmacokinetic parameters of nelfinavir (NFV) administered as 250mg tablets

3.1 Absorption and Distribution

Nelfinavir exposure is increased and pharmacokinetic variability improves when the drug is administered with food in healthy volunteers.[3,42] In healthy volunteers, two formulations (the 250mg tablet and the 625mg tablet) of nelfinavir were not bioequivalent in the fasted state, but may achieve bioequivalence in the fed state.[3,42] Administered with a meal, the 625mg tablet showed better bioavailability than the 250mg tablet and produced higher systemic nelfinavir concentrations in a multiple-dose study in 15 healthy individuals not infected with HIV.[44] Nelfinavir concentrations after administration of a single 750mg dose after food in healthy volunteers were similar for the 250mg tablet and the oral powder.[3]

Both nelfinavir and its major active hydroxy-t-butylamide metabolite, M8 (section 3.2), are highly bound to serum proteins (≥98%).[3,8] In humans, oral nelfinavir has a volume of distribution of 2–7 L/kg,[3] indicating extensive tissue distribution. However, like other highly bound protease inhibitors, transplacental passage of nelfinavir is limited and the drug is unlikely to provide any direct protection from HIV infection to the newborn.[45]

Nelfinavir shows significant intracellular accumulation in peripheral blood mononuclear cells,[46,47] with the mean intracellular maximum concentration, minimum concentration and area under the concentration-time curve from time zero to 12 hours (AUC12) being 15-, 5- and 9-fold higher, respectively, than those in the plasma (all p < 0.001).[47] Similarly, intracellular accumulation of M8, although less than that of the parent drug, has also been demonstrated.[46] For both nelfinavir and M8, the time to maximum concentrations and half-life (t½) values in the intracellular compartment and plasma were generally similar.[46,47]

3.2 Metabolism and Elimination

Nelfinavir is metabolised by multiple cytochrome P450 (CYP) enzymes, including CYP3A and CYP2C19, resulting in the formation of one major and several minor oxidative metabolites.[3] M8, the major metabolite formed by CYP2C19-mediated oxidation of the parent drug, has an in vitro antiretroviral activity similar to that of nelfinavir (section 2.1).[8] The majority (82–86%) of radioactivity in plasma of healthy volunteers receiving a single oral dose of 14C-nelfinavir 750mg was due to the parent drug;[3,8] the remainder apparently comprised nelfinavir metabolites.[8]

Nelfinavir terminal t½ in plasma is <6 hours (table I).[3,42,43] After administration of a single oral 750mg dose, most (87%) of 14C-labelled nelfinavir is excreted in faeces, with unchanged nelfinavir and its oxidative metabolites accounting for 22% and 78% of faecal radioactivity.[3] A small proportion of the dose (1–2%) is recovered in urine, mainly as unchanged nelfinavir.[3]

3.3 Special Populations

Several studies have investigated the pharmacokinetics of nelfinavir in paediatric patients (newborn to 13 years of age) [section 3.3.1] and in pregnant women (section 3.3.2). It is anticipated that renal impairment would have a minimal effect on nelfinavir elimination because <2% of the drug is excreted via this route.[3] Because of the high protein binding of nelfinavir (sections 3.1), drug concentrations in blood are not expected to be significantly affected by dialysis.[3]

Nelfinavir AUC values increased by 49–75% in a single-dose (750mg) study in HIV-negative volunteers with varying degrees of hepatic impairment (Child-Turcotte classes A, B and C) compared with that in healthy volunteers; the M8 : nelfinavir AUC ratio decreased from 24 to ≤4.[48] In another study in 119 HIV-infected patients with hepatitis C virus (HCV) coinfection receiving nelfinavir plus NRTIs for ≥1 month, a significant (p < 0.05) decrease in clearance in HCV-positive patients resulted in approximately 2.5 or 1.3 times higher nelfinavir AUC values in cirrhotic and noncirrhotic HCV-positive than in HCV-negative patients (both p < 0.05); M8 AUCs were reduced by approximately 50% and 30% (not significant).[49] Most (74%) of these patients were receiving nelfinavir 1250mg twice daily.[49]

There are no gender-related differences in the pharmacokinetics of nelfinavir.[3] Specific studies have not been conducted to evaluate the effect of race or age on nelfinavir pharmacokinetics.[3] The clearance of nelfinavir was not significantly affected by bodyweight, age, gender or race in a population pharmacokinetic analysis in 174 HIV-infected patients.[4]

3.3.1 Paediatric Patients

In general, nelfinavir exposure is highly variable in children, who also have an increased (≈2–3 times)[41,50,51] clearance compared with that in adults[3,41] and consequently require a higher bodyweight-based dosage to attain the desired plasma concentrations.[3] Increased clearance, inconsistent food intake and compliance issues in this patient population further exacerbate an already significant problem of unpredictable drug exposure.[3] Nevertheless, the AUC24 readily exceeds the target value (≥30 mg ⋅ h/L)[50] at the recommended dosages in patients aged 2–13 years, but is lower in those aged <2 years[3,51] even at considerably higher dosages (figure 2).[3]
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Fig. 2

Nelfinavir (NFV) exposure (area under the concentration-time curve from time zero to 24 hours [AUC24]) in paediatric patients after administration of the drug in various dosage regimens.[3] Doses given are those specified in the protocol. The dotted line shows the target NFV AUC24, extrapolated as the tenth percentile of the value in adults receiving NFV 750mg three times daily (tid).[50] bid = twice daily.

P-gp may have an important role in the pharmacokinetics of nelfinavir in children.[33] Data from the PACTG 382 trial showed that children with the MDR1-3435-C/T genotype (n = 33) [section 2.3] receiving nelfinavir-containing HAART had significantly (p = 0.02) higher plasma nelfinavir concentrations (8 hours post-dose) and lower (p = 0.04) clearance rates at week 8 than those with the C/C genotype. Results for children with the T/T genotype were similar to those with the C/C genotype.[33]

3.3.2 Pregnant Patients

Plasma nelfinavir concentrations are markedly decreased during pregnancy, especially in the third trimester,[52,53] compared with the nonpregnant state.[5254] This may be due to increased hepatic elimination (the result of hepatic enzyme induction during pregnancy) as well as decreased plasma protein-binding ability.[52] Nevertheless, while nelfinavir 1250mg twice daily produces adequate drug concentrations in pregnant women, nelfinavir 750mg three times daily may be associated with more variable and low concentrations.[2] In 30 pregnant HIV-positive women, the AUC target (AUC8 >10 mg ⋅ h/L) was achieved antepartum and postpartum in three of nine and five of seven women receiving nelfinavir 750mg three times daily; by comparison, 17 of 21 and 16 of 17 women receiving nelfinavir 1250mg twice daily reached their target (AUC12 >15 mg ⋅ h/L).[53]

A strong correlation has been found between nelfinavir concentration ratio (ratio of measured concentration to time-matched population value) <0.90 and an elevated risk of virological failure in pregnant patients.[52]

3.4 Drug Interactions

As with the antiretroviral agents in general, pharmacokinetic interactions between nelfinavir and other drugs are generally mediated via the induction or inhibition of CYP isoenzymes in the liver.[2] Since nelfinavir is metabolised primarily by CYP3A and CYP2C19, drugs that induce or inhibit, or are substrates for, these enzymes have the potential for interaction with nelfinavir.[2,3] Also, nelfinavir is an inhibitor of CYP3A and can therefore alter the pharmacokinetics of drugs metabolised by this isoenzyme.[3] Nelfinavir is not expected to inhibit other CYP isoforms at plasma concentrations achieved in the therapeutic range.[3]

Table II summarises the drug interactions for which specific pharmacokinetic data are available, along with clinical recommendations on their coadministration, where available. Most of the formal drug interaction studies with nelfinavir have been performed using the 250mg tablet formulation as a single 750mg dose or in a 750mg three-times-daily dosage regimen.[3] Therapeutic monitoring of plasma drug concentrations is advisable for patients receiving nelfinavir in combination with drugs that are likely to interact with it. Therapeutic drug monitoring may be used as a means of managing drug-associated toxicities in patients with HIV infection.[2]
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Table II

Clinically significant pharmacokinetic (PK) interactions between oral nelfinavir (NFV) and coadministered drugs.[3] The table excludes interactions for which specific PK data are not readily available and/or those not resulting in clinically significant PK alterations (section 3.4). The prescribing information should be consulted for more information. All parameters are geometric mean values

Coadministration of nelfinavir is contraindicated with amiodarone, quinidine, pimozide, midazolam, triazolam, lovastatin, simvastatin, ergot derivatives, terfenadine, astemizole and cisapride.[3,41] These drugs are highly dependent on CYP3A4 for clearance and their elevated plasma concentrations are associated with serious and/or life-threatening events. Likewise, nelfinavir should be avoided or used with extreme caution with other substrates for CYP3A4 with narrow therapeutic windows, such as terfenadine, astemizole, cisapride.[41] Concomitant use of nelfinavir with the herbal product St John’s wort (Hypericum perforatum) is not recommended as it may substantially reduce plasma nelfinavir concentrations.[2,3,41] Similarly, coadministration with the anticonvulsants carbamazepine and phenobarbital may result in subtherapeutic nelfinavir concentrations.[2,3]

Concomitant administration with nelfinavir may increase the plasma concentrations of some other drugs that are substrates for CYP3A (e.g. calcium channel antagonists, including bepridil, immunosuppressants, including tacrolimus, sirolimus and ciclosporin, and erectile dysfunction agents), resulting in toxicities.[2,3,41]

A clinically relevant drug interaction is not expected when nelfinavir is coadministered with other specific inhibitors of CYP3A (e.g. fluconazole, itraconazole, clarithromycin and erythromycin), inhibitors of CYP2C19 (e.g. fluconazole, fluoxetine, paroxetine, omeprazole, lansoprazole, imipramine, amitriptyline and diazepam), dapsone or co-trimoxazole.[3,41] However, caution and/or careful monitoring of the patient may be needed as the possibility of such an interaction cannot be ruled out. Nelfinavir does not exhibit a clinically significant interaction with amprenavir, tenofovir,[5557] lamivudine, stavudine, zidovudine, didanosine, nevirapine, efavirenz, mefloquine,[58] bupropion,[59] cannabinoids,[60] caspofungin[61] or ketoconazole.[3,41] An interaction between nelfinavir and azithromycin resulting in an increase in azithromycin AUC values of >100% may have been the result of inhibition of p-glycoprotein by nelfinavir.[62]

4. Therapeutic Efficacy

The efficacy of nelfinavir in combination with other antiretroviral agents has been investigated in numerous studies in ART-naive (section 4.1) and in ART-experienced (section 4.2) patients with HIV infection. Several of these trials have been reviewed previously.[4] Most trials were well designed and those selected for review in this section enrolled at least 100 patients. In combination with two other agents (usually two NRTIs), nelfinavir has been compared with other protease inhibitors, NNRTIs and abacavir. Nelfinavir has also been evaluated as a component of quadruple therapy in ART-naive or -experienced patients. Data on the long-term (up to 8 years) efficacy of nelfinavir-containing regimens have also been reported.

Trials in ART-experienced patients have included those evaluating nelfinavir-based regimens in patients switching from another protease inhibitor-based regimen for reasons of drug intolerance (section 4.2.1) or virological failure (section 4.2.2); studies of salvage therapy with other protease inhibitors after nelfinavir failure have also been performed (section 4.2.2). Adolescents were eligible for enrolment in some studies that enrolled ART-naive[6568] or -experienced[69] patients, whereas women of child-bearing potential who were pregnant, breast-feeding or were not using effective contraception were excluded from these trials.[6573] Studies of nelfinavir in ART-naive and -experienced children (section 4.3) are discussed separately.

4.1 Antiretroviral Therapy (ART)-Naive Patients

4.1.1 Placebo-Controlled and Dosage Comparison Studies

Three randomised, multicentre, registrational trials of nelfinavir in ART-naive adults or adolescents (Study 511,[65] AVANTI-3[74] and Study 542) are reviewed in the manufacturer’s prescribing information.[3] Study 511[65] and AVANTI-3[74] were double-blind comparisons of nelfinavir with placebo; Study 511 also compared one of the two recommended nelfinavir dosages (750mg three times daily) with a lower dosage of 500mg three times daily.[65] Study 542 was an open-label comparison of both recommended dosages (750mg three times daily or 1250mg twice daily).[3] Study 511[65] and AVANTI-3[74] have been published in full, whereas results from Study 542 are available only as abstracts (see review by Bardsley-Elliot and Plosker[4]) or from the US manufacturer’s prescribing information[3] (presented here). The dosages of nelfinavir and other antiretroviral drugs used in these studies are included in table III.
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Table III

Efficacy of oral nelfinavir (NFV), in combination with two other antiretroviral agents, in the treatment of antiretroviral therapy (ART)-naive adult and adolescent patients (pts)a with HIV infection.b The randomised trials were conducted at multiple centres; two studies[65,74] were double-blind placebo (PL) comparisons (including one NFV dosage comparison[65]), whereas the third trial[3] was an open-label NFV dosage comparison. The primary efficacy endpoints (where stated/known) were quantitative reductions in plasma HIV RNA levels[65,74] and CD4+ cell counts[65] c

Eligible patients in the placebo-controlled trials were aged ≥13[65] or ≥18[74] years, and had a plasma HIV RNA level of ≥15000 HIV RNA copies/mL[65] or a CD4+ count of between 150 and 500 cells/μL[74] at baseline. Those enrolled in Study 542[3] were aged 18–83 (median 36) years. All patients were protease inhibitor-naive and had received minimal or no treatment with other antiretroviral drugs (table III).

After double-blind treatment for 24[65] or 28[74] weeks, nelfinavir 750mg three times daily was superior to placebo (each administered in combination with zidovudine or lamivudine) with regard to the time-averaged reduction in viral load from baseline,[65,74] the proportion of patients with HIV RNA <400 copies/mL[65] and the increase in CD4+ cell count from baseline[74] (table III). Both studies included an extension phase; virological responses were maintained in patients originally randomised to nelfinavir 750mg three times daily who continued their treatment through 48 weeks.[65,74] Moreover, virological response rates increased markedly and CD4+ cell counts continued to rise in patients originally randomised to placebo who switched from double therapy to triple therapy after adding nelfinavir 750mg three times daily to their regimen at 24[65] or 28[74] weeks. The 750mg three times daily dosage of nelfinavir was more effective than the 500mg three times daily dosage, based on the proportion of patients with HIV RNA <400 or <50 copies/mL after 24 (intent-to-treat; table III) and 48 weeks (as treated; data not shown), and produced a markedly more durable response (p = 0.0007).[65] The reduction in viral load in nelfinavir 750mg three times daily recipients was not significantly greater than that in nelfinavir 500mg three times daily recipients at 24 weeks, whereas it was at 48 weeks (as treated analysis; data not shown).[65] The twice-daily and three-times-daily regimens of nelfinavir demonstrated similar virological efficacy in Study 542 (table III).

4.1.2 Comparisons with Protease Inhibitors

Randomised, multicentre, double-blind, partially blind or open-label comparative trials of nelfinavir, administered as a component of triple ART, include comparisons with other protease inhibitors (lopinavir/ritonavir [M98-863 study[66]]; fosamprenavir, with or without ritonavir [SOLO[75] and NEAT[67] studies]; ritonavir [CPCRA 042/CTN 102[69]]; and atazanavir [AI424-007[73] and -008[71] studies]).

The majority of studies assessed virological efficacy over a 48-week period;[66,67,7173,75,76] the numbers of patients involved, the dosages of nelfinavir and other antiretroviral drugs, and the primary endpoints and efficacy analyses used in these trials are presented in table IV. Eligible patients were aged from 12[66] or 13[67] years, with (where stated) a plasma HIV RNA level >400,[66] ≥1000[72,75] (and ≤500 000[72]), >1500,[76] ≥2000,[71] ≥5000[67,73] (and ≤750 000[73]) and CD4+ count of ≥100 cells/μL[71] at baseline. All patients were protease inhibitor-naive and had received little or no treatment with other antiretroviral drugs (table IV). Baseline viral loads and CD4+ cell counts (mean/median values) are shown in table IV.
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Table IV

Comparative efficacy of oral nelfinavir (NFV), as part of triple antiretroviral therapy (ART), in the treatment of ART-naive adult or adolescent patients (pts)a with HIV infection.b The 48-wk, randomised trials were conducted at multiple (international[66,67,71,73,75,76]) centres; and were of double-blind,[66] partially blind[71,73] c or open-label[67,72,75,76] design. The primary efficacy endpoints were the reduction from baseline in plasma HIV RNA at 48wk[71,73] or the proportion of pts with plasma HIV RNA <400 copies/mL at 24[66] or 48[67,75] wk, <200 copies/mL at 12mo,[76] or <50 copies/mL at 48wk[72] d

As a component of combination therapy, nelfinavir showed good efficacy and produced marked and sustained virological improvements.[66,67,71,73,75] In comparative studies, the virological efficacy of nelfinavir 750mg three times daily[66,73] or 1250mg twice daily[66,71,75] at 48 weeks was, in general, similar to that of atazanavir 200–600mg once daily (AI424-007[73]/-008[71] studies), noninferior to fosamprenavir/ritonavir 1400mg/200mg once daily (SOLO study[75]) and less than that of lopinavir/ritonavir 400mg/100mg twice daily (M98-863 study[66]), when each protease inhibitor was administered as part of triple therapy (table IV). 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) [table IV]. The immunological response was similar for nelfinavir and the comparator protease inhibitor in each of these studies (table IV).

Nelfinavir recipients in the NEAT (noninferiority) study[67] had lower rates of viral suppression at 48 weeks relative to fosamprenavir recipients in intent-to-treat analyses, but not in a per-protocol analysis (table IV). The 95% CIs reported (2%, 28%) were to the right of zero, suggesting a true difference between the two treatment groups for the primary endpoint. However, the study was not powered to detect a difference in the primary study endpoint, namely the proportion of patients achieving a viral load <400 copies/mL. Moreover, the nelfinavir arm in this trial was only half the size of the fosamprenavir arm; this may have been a factor contributing to the observed viral response with nelfinavir, which was somewhat lower than that previously reported for the drug.[67] In contrast, the SOLO study[75] was powered to detect a difference in the primary endpoint, although the proportions of nelfinavir-treated and fosamprenavir/ritonavir-treated patients who achieved a viral load <400 copies/mL at 48 weeks were almost identical (table IV). Both studies were, however, designed as noninferiority trials; fosamprenavir was noninferior to nelfinavir in the NEAT study[67] for the secondary endpoint of viral load reduction from baseline (upper limit of the 95% CI for the between-group difference 0.169 log10 copies/mL [noninferiority threshold 0.5 log10 copies/mL]) and in the SOLO study[75] for the primary endpoint (lower limit of the 95% CI for the between-group difference −6% [noninferiority threshold −12%] intent-to-treat rebound/discontinuation = failure). Of note, more nelfinavir recipients than fosamprenavir (boosted or unboosted) recipients in these studies experienced virological failure (NEAT[67] 28% vs 14%; SOLO 17% vs 7% [intent-to-treat rebound or discontinuation = failure]). In the SOLO trial, at 48 weeks, a numerically higher proportion of patients with HIV RNA levels >500 000 copies/mL at baseline treated with fosamprenavir/ritonavir achieved plasma HIV RNA levels of <400 copies/mL than recipients of nelfinavir (73% vs 53%).[75]

Unlike in the NEAT study,[67] the viral response with nelfinavir in the M98-863 study[66] was similar to that previously reported for the drug. This notwithstanding, lopinavir/ritonavir resulted in higher rates of viral suppression than nelfinavir, both at 24 and 48 weeks (see table IV). It also resulted in a more durable virological response; Kaplan-Meier estimates of the proportion of patients with a persistent response (<400 copies/mL) through 48 weeks were 84% for lopinavir/ritonavir versus 66% for nelfinavir (p < 0.001).[66] The superiority of lopinavir/ritonavir relative to nelfinavir did not appear to reflect differences in adherence, which was similar in both treatment groups (86% vs 83%). In an earlier study that examined the development of resistance to lopinavir/ritonavir and nelfinavir in this trial, adherence to treatment was lower in patients with HIV RNA levels >400 copies/mL than in treatment responders at 24 weeks in both treatment groups.[77]

Nelfinavir also showed good efficacy when administered as a component of quadruple therapy in trials that compared nelfinavir-containing regimens with regimens that included ritonavir and/or saquinavir (table V).[68,70] The nelfinavir quadruple regimen evaluated was, however, no more effective than comparator triple regimens (though the virological response was more durable) in one study.[68] In the other study,[70] a quadruple regimen including nelfinavir and nevirapine produced higher rates of virological suppression than a quadruple regimen that included ritonavir and saquinavir.
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Table V

Efficacy of oral nelfinavir (NFV), as part of quadruple antiretroviral therapy (ART), in the treatment of ART-naive[68,70] or ART-experienced[78] patients (pts)a with HIV infection. The 48-wk, randomised trials were conducted at multiple (international[68,78]) centres; and were of partially blind[78] or open-label[68,70] design. The primary efficacy endpoints were the proportion of pts with plasma HIV RNA <500 copies/mL at 16wk,[78] <50 copies/mL at 16 and 48wk,[68] or ≤20 copies after 48wk[70] b

4.1.3 Comparisons with Other Drugs

Nelfinavir has been compared with the NNRTIs (nevirapine [COMBINE study[76]] and efavirenz [AIDS Clinical Trials Group {ACTG} 384 study[79,80]]) and with an NRTI (abacavir [CNAF3007 study[72]]).

The virological and immunological efficacy of nelfinavir (750mg three times daily[72] or 1250mg twice daily[76]) at 48 weeks was similar to that of abacavir 300mg twice daily (CNAF3007 study)[72] or nevirapine 200mg twice daily (COMBINE study),[76] when each of these drugs was administered with co-formulated lamivudine/zidovudine 300mg/150mg twice daily (table IV). The COMBINE study was designed as a noninferiority trial and, according to the authors, the results suggested that nevirapine was at least as effective as nelfinavir.[76] However, formal noninferiority analyses were not presented.

Triple and quadruple therapies containing nelfinavir and/or efavirenz, combined with either stavudine and didanosine or zidovudine and lamivudine, were assessed in a randomised, partially double-blind, multicentre study (ACTG 384; n = 980) with a median follow-up of 2.3 years.[79,80] The results indicated that, as an initial treatment strategy, quadruple therapy showed no benefit over two sequential triple therapies, the first of which contained either nelfinavir or efavirenz, in terms of the duration of successful HIV treatment.[79,80] Furthermore, triple therapy consisting of efavirenz, zidovudine and lamivudine was identified as the optimal initial therapy among the three- and four-drug strategies evaluated in this study.[79,80]

Initial therapy with a three-drug/two-class regimen that included efavirenz was reported to be superior to nelfinavir-containing regimens (stavudine and didanosine were the backbone) for virological outcomes (but not CD4+ response), according to 3-year results of the INITIO trial (n = 915 ART-naive patients).[81]

4.1.4 Long-Term Efficacy

Nelfinavir-containing regimens have been shown to produce prolonged (72 weeks to ≈8 years) suppression of HIV RNA levels in ART-naive patients in several trials.[8284] In nelfinavir-treated patients, plasma HIV RNA levels remained <400 copies/mL in 82.2% of patients at 72 weeks in the PSIRENE trial (n = 1185),[83] in 62% of 55 patients (intent-to-treat results) at 4 years in study 511[84] and were <50 copies/mL in 95% of 60 patients in study AG1343-1260 at a median of 257 weeks (range 119–439 weeks).[82] Sustained increases in CD4+ cell counts were reported in all three trials.[8284] Patients were also found to have a stable health-related quality of life (HR-QOL) [assessed by the Medical Outcomes Study (MOS)-HIV Health Survey] and high adherence to therapy.[83]

4.2 ART-Experienced Patients

The ACTG 364 study[78] (table V) enrolled 195 ART-experienced patients (mean age 40–43 years) who had previously received NRTI therapy only and had a plasma HIV RNA level ≥500 copies/mL; median baseline viral loads and CD4+ cell counts are shown in table V. Quadruple therapy containing nelfinavir 750mg three times daily plus efavirenz 600mg once daily and triple therapy containing efavirenz 600mg once daily resulted in higher rates of viral suppression than triple therapy containing nelfinavir 750mg three times daily, both in the short-term (16 weeks) and in the long term (40–48 weeks), based on plasma HIV RNA measurements using sensitive (<500 copies/mL) and/or ultrasensitive (<50 copies/mL) assays (table V). However, triple therapy containing efavirenz did not demonstrate superiority over triple therapy containing nelfinavir for the primary study endpoint (<500 copies/mL at 16 weeks) and was less effective than quadruple therapy at 40–48 weeks, according to the ultrasensitive assay (table V). Quadruple therapy also produced the most durable virological response: Kaplan-Meier estimates of the proportion of patients with a persistent response (<200 copies/mL using the ultrasensitive assay) through 48 weeks were 79% for quadruple therapy (p ≤ 0.01 vs triple therapy containing nelfinavir or efavirenz), 58% for triple therapy containing efavirenz (p = 0.04 vs triple therapy containing nelfinavir) and 36% for triple therapy containing nelfinavir. Increases in CD4+ counts were similar in all three treatment groups, both in the short term (data not shown) and long term (table V).[78]

Notably, nelfinavir 750mg three times daily or 1250mg twice daily versus ritonavir 600mg twice daily demonstrated similar efficacy in a randomised, open-label, multicentre study (CPCRA 042/CTN102; n = 775),[69] which was the first trial to provide long-term clinical endpoint data. The rates of AIDS-defining conditions/death after a median of 52 months of follow-up were 12.7 and 11.0 per 100 person years for nelfinavir and ritonavir recipients, respectively (hazard ratio 1.16; 95% CI 0.92, 1.46). This study enrolled patients (mean age 39 years; median duration of prior ART 16 months) who were naive to protease inhibitors (except hard-gel saquinavir) and had a CD4+ count <200 cells/μL; at baseline, the plasma HIV RNA level was 4.9 log10 copies/mL and the CD4+ count was 58 cells/μL (mean values). Background treatment consisted of (unspecified) NRTIs; use of NNRTIs was also permitted. Patients who were intolerant to ritonavir were switched to indinavir (or to nelfinavir if indinavir was contraindicated).[69]

In other randomised[85,86] (open-label[85]) studies in ART-experienced patients, nelfinavir (750mg three times daily) demonstrated similar virological efficacy to ritonavir (400mg twice daily) and delavirdine (400mg twice daily), when each drug was administered in combination with saquinavir soft-gel capsules (400 or 800mg twice daily) plus stavudine (40mg twice daily),[86] and also to indinavir (800mg three times daily), when both drugs were administered in combination with lamivudine (150mg twice daily) plus stavudine (30–40mg twice daily).[85] Moreover, adequate adherence (defined as the patient [i] keeping their appointment, [ii] reporting taking >80% of their medication, and [iii] having a plasma HIV RNA level ≥1.5 log10 below the pre-treatment level) on nelfinavir was superior (p ≤ 0.03) to that on indinavir, as assessed after 6 months (70% vs 48%) and 9 months (59% vs 35%) of treatment.[85]

4.2.1 Switch Therapy

Several small, nonrandomised studies (n = 11–52)[8793] most available as abstracts only[8792] have shown that patients with undetectable HIV RNA (<400 or 500 copies) switching to a twice daily or three times daily nelfinavir-based regimen from another protease inhibitor-based regimen typically experience continued suppression of viral load for at least 12,[87,88,93] 24,[8991] or 36[92] weeks. Reasons for switching included intolerance issues relating to the existing protease inhibitor (indinavir,[8789,92] ritonavir,[88,90,91] saquinavir[88] or ritonavir/saquinavir[93]) and, interestingly, physician preference for nelfinavir due to the possibility of a better defined, successful salvage regimen[93] (see section 4.2.2). Results of several studies (n = 19–126) suggest that nelfinavir-treated patients can switch from a three-times-daily to a twice daily regimen,[94,95] or from the 250mg to a 625mg tablet formulation (both dosed at 1250mg twice daily)[96] without loss of virological efficacy.

4.2.2 Salvage Therapy for Virological Failure

The efficacy of nelfinavir (750mg three times daily) as part of salvage therapy in patients experiencing virological failure while receiving another protease inhibitor (indinavir) has been investigated in two randomised, partially double-blinded, multicentre trials (ACTG 359[97] and ACTG 372B[98]). Both studies enrolled NNRTI-naive patients aged ≥16 years; in one study, the median duration of prior use of indinavir was 14.4 months.[97] The primary endpoints were the proportion of patients with plasma HIV RNA <500 copies/mL[97] or reaching a composite treatment-failure endpoint, which included virological failure, discontinuation of study medication and loss to follow-up or death.[98] The primary analysis timepoint was at 16 weeks, although follow-up was continued for 24[97] or 48[98] weeks.

In the larger study (n = 277),[97] patients received nelfinavir or ritonavir in combination with soft-gel saquinavir plus delavirdine and/or adefovir dipivoxil. Salvage regimens containing nelfinavir produced a similar virological response to those containing ritonavir, with 33% of nelfinavir recipients versus 28% of ritonavir recipients having an undetectable viral load (<500 copies/mL) [pooled data]. Of note, the combination of nelfinavir with saquinavir 800mg three times daily and delavirdine 600mg twice daily yielded the highest proportion of patients with ≤500 HIV RNA copies/mL, both at 16 weeks (47% [20 of 43 patients]) and at 24 weeks (41% [15 of 37]). The corresponding results at 16 and 24 weeks for the combination of ritonavir 400mg twice daily with saquinavir 400mg twice daily and delavirdine 600mg twice daily were 33% (14 of 42 patients) and 30% (11 of 37).[97]

In the smaller study (n = 94),[98] the proportion of patients experiencing treatment failure at 16 weeks was significantly reduced when salvage regimens containing nelfinavir, efavirenz, adefovir dipivoxil and either abacavir or other NRTIs were compared with the same regimens but without nelfinavir (56% vs 78%, p = 0.02). At 48 weeks, however, there was no significant between-group difference in the proportion of patients with plasma HIV RNA ≥500 copies/mL (59% with nelfinavir vs 71% without nelfinavir).[98]

Similar to the experience in randomised studies, several small, nonrandomised studies (n = 19–47)[99103] have shown that nelfinavir-containing salvage regimens benefit some patients experiencing virological failure on another protease inhibitor. Typically, around 20–50% of those receiving regimens containing three or more drugs for up to 1 year have <500 HIV RNA copies/mL.[99103] The preliminary results of a large, multicentre, observational study[104] (n = 853) suggested that patients experiencing failure on saquinavir (with or without ritonavir) responded better to nelfinavir-based salvage therapy compared with patients experiencing failure on regimens containing indinavir and/or ritonavir, or indinavir and saquinavir with or without ritonavir.

Not unexpectedly, the preliminary results of a smaller, multicentre, observational study[105] (n = 77) indicated that nelfinavir combined with two NRTIs was effective as a salvage therapy in protease inhibitor-naive patients experiencing failure on (or intolerant to) NNRTIs; 80% had an undetectable viral load (<400 copies/mL) at 48 weeks.

4.2.3 Salvage After Nelfinavir Failure

Since the resistance profile of nelfinavir differs from that of other protease inhibitors, patients developing resistance to the drug may remain susceptible to other protease inhibitors (section 2.2).[4] In one prospective study,[24] the majority (71%) of 24 evaluable patients who had previously experienced virological failure on nelfinavir-containing regimens had a sustained reduction in viral load to an undetectable level (<500 copies/mL) 24 weeks after switching to a salvage regimen consisting of ritonavir 400mg, saquinavir 400mg, stavudine 40mg and lamivudine 150mg (all twice daily); ten patients (59%) achieved plasma HIV RNA <50 copies/mL. Similar results have been seen in retrospective[106108] (or not stated) studies, which also included small numbers of evaluable nelfinavir failures (n = 6–79).[106108]

A recent retrospective analysis of data from the CONTEXT trial (section 2.2.2) showed that ART-experienced patients with the D30N mutation (among other mutations) at baseline could be treated successfully with either boosted fosamprenavir or lopinavir/ritonavir; suppression of viral load to <400 copies/mL was achieved in 95% and 94% of patients with the D30N mutation, respectively.[29] At baseline, the most common protease mutations (n = 210) were L90M (30%), M46I/L (23%) and D30N (21%) respectively.

4.3 Paediatric Patients

Nelfinavir has also shown efficacy in paediatric patients with HIV infection. The FDA has reviewed five clinical trials of nelfinavir in paediatric patients aged 2–13 years with HIV infection.[109] Much of the following discussion focuses on the two largest studies, the results of which have been published in full (PACTG 377 [n = 181][110] and/or are available from the FDA summary[109] and the US manufacturer’s prescribing information[3] (PACTG 377[110]) and Study 556 [n = 141][109]).

These randomised studies were of double-blind, placebo-controlled[109] or open-label[110] design, and enrolled HIV-infected, ART-naive[109] or -experienced[110] patients who ranged in age from 3 months to 17 years (mean[109]/median[110] 3.9[109]/6.2 years[110]). Study 556[109] evaluated three-times-daily nelfinavir in combination with zidovudine plus didanosine (no further details available), whereas PACTG 377[110] assessed four regimens including three-times-daily nelfinavir 27–33 mg/kg (maximum dose 1250mg) in combination with twice-daily stavudine (1 mg/kg [<30kg bodyweight], 30mg [≥30 but <60kg] or 40mg [≥60kg]) plus twice-daily lamivudine 4 mg/kg and/or nevirapine 120 mg/m2 daily for 14 days, then 120 mg/m2 twice daily. In addition, a substudy of PACTG 377 (PACTG 725) assessed twice daily nelfinavir ≈55 mg/kg (maximum dose 1500mg) in combination with stavudine and lamivudine.[110] Baseline plasma HIV RNA levels were 5.0[109] and 4.4[110] log10 copies/mL; the corresponding baseline CD4+ counts were 886[109] and 696[110] cells/μL.

The US manufacturer’s prescribing information,[3] but not the US FDA summary,[109] presents results for different age groups in Study 556. In children aged ≥2 years, nelfinavir, as a component of triple combination therapy, was superior to placebo in terms of the proportion of patients achieving and maintaining an undetectable viral load (<400 copies/mL) at 48 weeks (figure 3).[3] In children aged <2 years, however, only 2 (10%) of 20 nelfinavir recipients, compared with 1 (4%) of 27 placebo recipients, maintained an undetectable viral load at 48 weeks.[3] According to the FDA summary, nelfinavir-treated children also achieved a longer median time to loss of virological response, compared with placebo recipients (122 vs 0 days; p = 0.0026).[109]
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Fig. 3

Virological efficacy of oral nelfinavir (NFV), in combination with other antiretroviral drugs, in antiretroviral-naive paediatric patients (aged ≥2–12 years) with HIV infection (mean baseline HIV RNA level was 5 log10 copies/mL).[3] Proportion of children achieving and maintaining plasma HIV RNA <400 copies/mL after 48 weeks of treatment with a triple therapy regimen consisting of NFV (three times daily) plus didanosine (ddI) and zidovudine (ZDV) in a randomised, double-blind, placebo (PL)-controlled trial (Study 556; n = 141). Data taken from the manufacturer’s prescribing information;[3] no further antiretroviral drug dosage and administration details are available. * p = 0.0008 vs PL/ddI/ZDV.

In PACTG 377,[110] quadruple therapy consisting of nelfinavir plus stavudine, lamivudine and nevirapine produced a higher long-term virological response (≤400 copies/mL at 48 weeks) than triple therapy consisting of nelfinavir plus stavudine and nevirapine (52% [n = 42] vs 30% [n = 44]; p = 0.048), but not triple therapy consisting of nelfinavir plus stavudine and lamivudine (42% [n = 50]) or twice-daily ritonavir 400 mg/m2 plus stavudine or nevirapine (41% [n = 41]). Virological response (and failure) rates were similar in children receiving twice-daily nelfinavir in PACTG 725, compared with children receiving three times daily nelfinavir in PACTG 377.[110] Patients in this study had previously received only NRTI therapy.[110]

Combination therapy with nelfinavir, stavudine, lamivudine and nevirapine resulted in long-term suppression of plasma HIV RNA levels in infants (aged ≤3 months at the start of treatment; median baseline HIV RNA level 5.3 log10 copies/mL) in an open-label, multicentre phase I/II trial (PACTG 356; n = 52).[111] Plasma HIV RNA levels were <400 copies/mL in 50% of study participants at week 48 and remained at this level in 88% of these patients after 200 weeks of therapy. At 48 weeks and 200 weeks, significantly higher proportions of infants treated with nelfinavir, stavudine, lamivudine and nevirapine had plasma HIV RNA levels <400 copies/mL (83% [p ≤ 0.001 for both comparisons] and 72% [p = 0.01 for both comparisons]) than infants who received zidovudine, lamivudine and nevirapine (24% week 48; 29% week 200), or zidovudine, lamivudine, nevirapine and abacavir (41% week 48; 29% week 200) [intent-to-treat analysis; posthoc pairwise comparisons]. At baseline, all patients had received <10 weeks’ previous NRTI therapy and were protease inhibitor and NNRTI therapy-naive.[111] Combination therapy with nelfinavir, efavirenz and at least one NRTI also showed good virological efficacy in the treatment of HIV-infected children in two noncomparative trials.[112,113] After 24 weeks’ treatment, plasma HIV RNA levels were <400 copies/mL in 63%[113] and 76%[112] of patients (intent-to-treat analysis). Children had been previously treated with NRTIs but had not received protease inhibitors or NNRTIs.[112,113]

In small (n = 11[114] and 35[115]), retrospective[114] or unspecified[115] studies of children who had previously failed protease inhibitor-based treatment, nelfinavir (with[114] or without[115] saquinavir), as a component of salvage therapy, had a less pronounced effect on viral load, compared with lopinavir/ritonavir[115] and ritonavir plus saquinavir,[114] and resulted in fewer patients achieving undetectable viral loads, compared with lopinavir/ritonavir (<20% vs >50%; p < 0.05).[115]

5. Tolerability

The tolerability of nelfinavir alone or in combination with other antiretroviral drugs has been studied in >5000 patients.[3] The drug was generally well tolerated; adverse events were, in the majority of cases, of mild intensity[3] and led to the discontinuation of treatment in only a small proportion of patients (4% in phase II/III clinical studies).[4] However, the concomitant administration of other antiretroviral agents complicates the analysis of adverse events occurring during treatment with nelfinavir.

5.1 General Profile

Table VI presents drug-related adverse events of moderate or severe intensity reported in ≥2% of patients enrolled in two randomised, double-blind, registrational studies of nelfinavir (Study 511 and Study 542) [section 4.1.1].[3]
https://static-content.springer.com/image/art%3A10.2165%2F00003495-200565150-00015/MediaObjects/40265_2012_65152209_Tab6.jpg
Table VI

Most frequently reported drug-related adverse events of moderate or severe intensity and laboratory abnormalitiesa in two randomised, double-blind nelfinavir (NFV) trials[3]

Diarrhoea, generally of mild-to-moderate intensity, is the most common adverse event with nelfinavir and was reported in 20% of patients receiving approved dosages of the drug in Study 511 and Study 542 (table VI).[3] Step-wise dietary and pharmacological intervention consisting of nutritional counselling, psyllium, lactase, calcium carbonate and loperamide can be effective in the management of nelfinavir-associated diarrhoea.[116] Coadministration of probiotics, soluble fibre and glutamine has also been reported to significantly improve nelfinavir-induced diarrhoea in HIV-infected individuals.[117,118]

The US manufacturer’s prescribing information[3] states that the incidence of nelfinavir-associated diarrhoea may be increased in patients receiving the newer 625mg tablet formulation available in the US and Canada, compared with the older 250mg tablet formulation, due to the increased bioavailability of the former.

Metabolic, including hepatic, disturbances with nelfinavir (in relation to those with other antiretroviral agents) are discussed in section 5.2. Triple therapy regimens containing nelfinavir and two NRTIs (either zidovudine and stavudine or lamivudine and didanosine) had no effect on bone mineral density in a long-term (40-month) longitudinal study.[119]

5.2 Comparative Studies

5.2.1 Comparisons with Other Protease Inhibitors

In comparative studies with other protease inhibitors in ART-naive patients (see table IV), nelfinavir 750mg three times daily[66,73] or 1250mg twice daily[66,67,71,75] as a component of a three-drug regimen was, in general, as well tolerated as atazanavir 200–600mg once daily,[71,73] fosamprenavir 1400mg twice daily,[67] fosamprenavir/ritonavir 1400mg/200mg once daily[75] and lopinavir/ritonavir 400mg/100mg twice daily[66] over a 48-week period. The number of patients discontinuing treatment as a result of adverse events was similar in the nelfinavir and comparator arms of these trials (4–7% vs 3–9%).[66,67,71,73,75] The adverse event profiles were also similar across the treatment groups, although diarrhoea was more common with nelfinavir than with atazanavir (56% vs 15–20%[71] and 61% vs 23–30%[73] ; both p < 0.0001), fosamprenavir (18% vs 5%; p = 0.002) and fosamprenavir/ritonavir (16% vs 9%; p = 0.008), whereas jaundice (0% vs 6–12%[73] and 0% vs 11–20%[71] ; p < 0.03 and < 0.0001, respectively) and scleral icterus (0% vs 2–6%[73] and 0% vs 9–12%;[71] p-value not reported and ≤ 0.002, respectively) were more frequent with atazanavir. The results of a retrospective cohort analysis (n = 453)[120] suggested that nelfinavir-treated patients were more likely to have diarrhoea than lopinavir/ritonavir-treated patients (49% vs 17%; p < 0.001); however, a similar incidence of diarrhoea was seen when these agents were directly compared in the larger, prospective, double-blind M98-863 study (n = 653) [17.1% vs 15.6%].[66]

Nelfinavir was better tolerated than other commonly used protease inhibitors when each of these drugs was administered in combination with NRTIs in comparative studies in HIV-infected, ART-experienced patients.[69,85] In one trial,[85] the number of patients discontinuing treatment as a result of adverse events was lower with nelfinavir 750mg three times daily than with indinavir 800mg three times daily (12% vs 34%; p = 0.0073). Diarrhoea was more common with nelfinavir (27% vs 0%; p < 0.0001), whereas renal colic was more frequent with indinavir (0% vs 21%; p = 0.0003).[85] Similarly, discontinuations (including those due to adverse events, 14% vs 47%) occurred later in patients randomised to nelfinavir 750mg three times daily or 1250mg twice daily than in patients randomised to ritonavir 600mg twice daily in another study (p = 0.0001).[69] Two-thirds of the patients assigned to nelfinavir and about half of the patients assigned to ritonavir (or indinavir if intolerant to ritonavir) were still receiving this treatment after 12 months of follow-up.

Laboratory Abnormalities

The laboratory abnormality profile of nelfinavir was similar to that of atazanavir, fosamprenavir (with or without ritonavir) or lopinavir-ritonavir in the aforementioned comparative studies in ART-naive patients,[66,67,71,73,75] with the exception that elevations of bilirubin occurred more often with atazanavir than with nelfinavir (20–49% vs 1%[73] and 41–58% vs 4%[71] ; p-values not reported). Grade 3 or 4 elevations in hepatic transaminase levels, a marker of hepatotoxicity, were similar in patients receiving nelfinavir or the comparator protease inhibitor in the majority of these trials (3–8% vs 2–6%).[66,67,71,75] Moreover, nelfinavir, as part of a treatment regimen, was associated with the lowest rate of occurrence of severe hepatotoxicity relative to four other commonly used protease inhibitors, including one 2-protease inhibitor combination.[121] The results of this meta-analysis (n = 4268) of three prospective and retrospective clinical trials and one prospective cohort study indicated that the rate of occurrence of severe hepatotoxicity (based on combined estimates of liver enzyme level increases) with nelfinavir (2.9% [n = 563]) was numerically lower than that with indinavir (3.6% [n = 2319]) and significantly lower than that with saquinavir (5.4% [n = 1112]; p = 0.01), ritonavir (9.6% [n = 619]; p < 0.0001) and ritonavir/saquinavir (11.9% [n = 234]; p < 0.0001).[121] Of note, definitions of outcomes differed among the studies included in this analysis.[121] Similar results were seen in the subgroup of patients co-infected with hepatitis viruses.[121]

Dyslipidaemia and Lipodystrophy

As a class, protease inhibitors have been associated with various metabolic disturbances, including hypercholesterolaemia, hyperglycaemia and a syndrome of hyperlipidaemia, insulin resistance and lipodystrophy.[4] Through 48 weeks, median increases from baseline in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol and triglycerides were similar in patients receiving nelfinavir or fosamprenavir in the NEAT study[67] and nelfinavir or fosamprenavir/ritonavir in the SOLO study.[75] No median fasting cholesterol values in either of these studies met levels where clinical intervention would be recommended, based on the National Cholesterol Education Program (NCEP) guidelines;[67,75] however, the full report of the NEAT study[67] also stated that 18% of patients in both the nelfinavir and fosamprenavir groups had LDL-cholesterol levels ≥160 mg/dL, the threshold for intervention. As exemplified by study AI424008,[71] the mean percentage increases from baseline in fasting total cholesterol (48 weeks, 25% vs 5–6%), LDL-cholesterol (56 weeks, 23% vs 5–7%) and triglycerides (48 weeks, 50% vs 7–8%) [all p < 0.01] were higher in nelfinavir recipients than in atazanavir recipients, whereas increases in HDL-cholesterol were similar for both treatments. By contrast, the mean increase from baseline to week 48 in triglycerides was lower in nelfinavir-treated patients than in lopinavir/ritonavir-treated patients in the M98-863 study (0.5 vs 1.4 mmol/L; p < 0.001); however, these results must be interpreted with caution, since measurements were made without regard to fasting.[66]

The effects of nelfinavir and other commonly used protease inhibitors and 2-protease inhibitor combinations on the lipid profile of HIV-infected patients have also been investigated in a prospective observational study (n = 7483).[122] Compared with indinavir (n = 2354), ritonavir (n = 515) and 2-protease inhibitor combinations containing (n = 1464) or excluding (n = 174) ritonavir, nelfinavir (n = 2574) was associated with numerically lower values for triglycerides, total cholesterol and total cholesterol : HDL-cholesterol ratio, but a higher value for HDL-cholesterol. However, compared with saquinavir (n = 576), nelfinavir was associated with numerically higher values for all these lipid parameters.[122]

Consistent with the above results in general, patients switching from nelfinavir to atazanavir experienced improvements in fasting total cholesterol, LDL-cholesterol and triglycerides,[123] whereas patients switching from indinavir, ritonavir or ritonavir/saquinavir to nelfinavir (with or without saquinavir) experienced an improvement in triglyceride levels.[90,124] All patients in these studies received protease inhibitors as part of triple combination therapy; where indicated, all drugs were administered at recommended dosages.[90,123,124]

The clinical significance of elevations in lipid levels with nelfinavir in particular and protease inhibitors more generally in terms of increased cardiovascular risk is unknown [71] and longer-term follow-up studies are required.[66] A recent analysis based on the AI424008 study findings estimated a 50% increase in the 10-year risk of coronary heart disease for nelfinavir versus atazanavir.[125] However, the study authors also acknowledged the lack of convincing clinical data showing an increase in cardiovascular outcomes in HIV-infected patients receiving protease inhibitors.[125]

No difference in the rate of adverse events consistent with the presence of lipodystrophy or lipoatrophy was observed between nelfinavir recipients and lopinavir/ritonavir recipients through 48 weeks in the M98-863 study (6% vs 5%).[66] Likewise, no difference in the rate of body fat changes was seen in patients treated with nelfinavir or lopinavir/ritonavir through 48 weeks (5% vs 5%) and 96 weeks (14% vs 15%), according to a meta-analysis of four clinical trials (n = 835).[126] The incidence of lipodystrophy was similar in patients receiving nelfinavir or atazanavir in the AI424007/008 studies (2–3% vs 2–9%); although there is currently no case definition, the majority of these events were reported as grade 1 or 2.[71,73] High plasma concentrations of nelfinavir are associated with an increased risk of lipodystrophy.[127] A retrospective analysis of the US manufacturer’s clinical and safety databases (n = 2904; year of publication 2000) suggested that nelfinavir had a low propensity to induce physical or metabolic changes associated with lipodystrophy.[128]

5.2.2 Comparisons with Other Drugs

In comparisons of different antiretroviral classes in ART-naive patients, nelfinavir was generally as well tolerated as nevirapine 200mg twice daily[76] and abacavir 300mg twice daily,[72] when each drug was administered with co-formulated lamivudine/zidovudine 300mg/150mg twice daily. Diarrhoea was more common with nelfinavir than with nevirapine (35.7% vs 0%; p < 0.0001), whereas rash (1.4% vs 13.9%; p = 0.005) and two laboratory abnormalities (increased neutrophils [14.3% vs 36.1%; p = 0.003] and alkaline phosphatase levels [40% vs 61.1%; p = 0.01]) were more frequent with nevirapine. Fasting cholesterol increased from baseline by a similar (significant: p ≤ 0.002) amount in both treatment arms, although no cases of lipodystrophy were reported.

Quadruple and triple therapies containing nelfinavir and/or efavirenz in combination with two NRTIs had a similar adverse event profile when evaluated in ART-experienced patients[78] and a similar effect on fasting lipids when assessed in ART-naive patients (data available in an abstract).[129]

5.3 Paediatric Patients

The US manufacturer’s prescribing information[3] states that ≈400 paediatric patients aged from birth to 13 years have received nelfinavir in clinical trials. The tolerability profile of the drug in this population was similar to that in adults;[3] the US FDA review[109] reached a similar conclusion, based on a slightly smaller database of 302 patients, also aged from birth to 13 years, who received nelfinavir (in combination with other antiretroviral agents) for up to 96 weeks in four paediatric treatment trials, including Study 556 and PACTG 377/725 (section 4.3).

As in adults, diarrhoea was the most common drug-related adverse event in paediatric patients; this adverse event, regardless of causality, was reported in 39% of patients in the nelfinavir arm of Study 556, compared with 43% of patients in the placebo arm of this trial.[109] According to the US manufacturer’s prescribing information,[3] the incidence of diarrhoea in the other large paediatric treatment trial (presumably PACTG 377/725) was 47%; however, the full publication of this trial[110] indicates only that moderate or worse (grade ≥2) ‘gastrointestinal’ adverse events occurred in 18–27% of patients receiving triple or quadruple therapies containing nelfinavir administered twice or three times daily.

In comparison, leukopenia/neutropenia, the most common drug-related, treatment-emergent, laboratory abnormality, was reported in 9–23% of patients receiving three- or four-drug regimens containing nelfinavir administered three times daily in PACTG 377 (44–52), but in no patient receiving triple therapy containing nelfinavir administered twice daily in PACTG 725 (n = 11).[110] The FDA review determined that leukopenia/neutropenia occurred more frequently in paediatric studies than in adult clinical trials, although no data are presented in the FDA summary.[109]

Notably, drug exposure-response relationships for diarrhoea and neutropenia/leukopenia could not be identified due to the marked variability in nelfinavir exposure in paediatric studies (section 3).[109]

A recent 1-year, post-paediatric, exclusivity postmarketing adverse event review did not reveal any unexpected safety concerns relating to the use of nelfinavir in paediatric patients.[130] In this review, the FDA Adverse Event Reporting System (AERS) database was searched: at the time of the search, there were 377 paediatric reports.[130]

5.4 Pregnant Patients

Nelfinavir (in ‘pregnancy category B’ in the manufacturer’s prescribing information[3]) is the recommended[2] and most commonly reported[131] protease inhibitor in pregnancy. Against this background, it is notable that the first study with sufficient power to detect a two-fold increase in the risk of overall birth defects found no such increase with nelfinavir.[131] Using data from the International Antiretroviral Pregnancy Registry (a commercially sponsored, but scientifically independent, prospective, cohort study), the prevalence of birth defects among 301 live births to women who were exposed to nelfinavir during the first trimester of pregnancy was 3.0% (95% CI 1.4, 5.6); this figure was not significantly different from the expected rate according to the US Centers for Disease Control and Prevention’s population-based birth defects surveillance system (3.1 per 100 live births [95% CI 3.1, 3.2]).[131]

The adverse event profile of nelfinavir in pregnant vs nonpregnant women has been compared with that of nevirapine when each drug was administered in combination with two NRTIs, in a retrospective, multicentre study of 372 HIV-infected, ART-naive women.[132] Both nelfinavir and nevirapine were well tolerated during pregnancy; however, nelfinavir was associated with higher incidences of gastrointestinal disturbances (29.7% [n = 128] vs 6.6% [n= 91]) and hyperglycaemia (defined as blood glucose ≥7.8 mmol/L; 15.6% vs 2.2%) [both p < 0.001], and nevirapine with higher incidences of hepatotoxicity (defined as AST/ALT ≥3 × upper limit of normal; 19.0% [n = 58] vs 4.2% [n = 95]) and hyperglycaemia (8.6% vs 1.1%) [p = 0.003 and 0.019, respectively), than in the non-pregnant state. The 186 pregnant women (age 27 years; plasma HIV RNA level 6270 copies/mL; CD4+ count 360 cells/μL [baseline median values]) enrolled in this study who received nelfinavir- or nevirapine-based therapy delivered at >20 weeks gestation; the 186 nonpregnant controls (34 years; 63686 copies/mL; 216 cells/μL) were followed-up for a 6-month period after the start of their treatment.[132]

In the PACTG 1022 study in which 38 ART-naive pregnant women (10–30 weeks’ gestation) were randomised to receive either nelfinavir or nevirapine, each given in combination with zidovudine plus lamivudine, toxicity was reported in 5% (1 of 21) nelfinavir recipients and in 29% (5 of 17) nevirapine recipients (p = 0.07).[133] In the nevirapine treatment group, one patient developed Stevens-Johnson syndrome and another developed fulminant hepatic failure and died. The only patient with an adverse event in the nelfinavir treatment group had a CD4+ count of <250 cells/μL, whereas the five adverse events documented in the nevirapine recipients and leading to treatment discontinuation occurred in patients with CD4+ counts >250 cells/μL (p = 0.04).[133]

Consistent with these findings, separate searches of the AERS database[130] found no obvious evidence of fetal toxicity following transplacental exposure to nelfinavir (n = 24 cases)[130] and suggested that hepatotoxicity was a more common occurrence in HIV-infected pregnant women receiving nevirapine than in those receiving nelfinavir or another protease inhibitor.[134] In the latter study[134] 28 hepatic adverse events were reported by nevirapine recipients (since 1998), compared with seven such occurrences in nelfinavir recipients. Six women died as a result of hepatic failure during pregnancy (n = 5) or in the immediate postpartum period (n = 1); five received triple therapy containing nevirapine and one received triple therapy containing nelfinavir.[134]

6. Dosage and Administration

This section provides a brief summary of information on the dosage and administration of nelfinavir. The manufacturer’s prescribing information should be referred to for more details on dosages, warnings, precautions and contraindications.[3] In the US, the recommended dosage of nelfinavir for the treatment of adults with HIV infection is 1250mg (five 250mg tablets or two 625mg tablets) twice daily or 750mg (three 250mg tablets) three times daily.[3] The 625mg tablet formulation is available in the US and Canada. Nelfinavir should be taken with meals to ensure maximal absorption (section 3.1). The tablets may be swallowed whole or dispersed in water if preferred. According to the manufacturer, nelfinavir should be used in the treatment of pregnant women only if clearly needed.[3]

Nelfinavir is also approved in the US for the treatment of paediatric patients aged ≥2 years. A powder formulation is available for children unable to swallow tablets. The recommended dosage for children aged 2–13 years is 45–55 mg/kg twice daily or 25–35 mg/kg three times daily with food.[3] Further guidance on dosages in paediatric patients (based on bodyweight) is provided in the manufacturer’s prescribing information.[3]

7. Place of Nelfinavir in the Management of HIV Infection

The main goals of HAART therapy for patients with HIV infection are maximal and durable suppression of viral load as well as restoration and preservation of immunological function, improvement in HR-QOL, and a reduction in disease-related morbidity.[2] Many different combinations of antiretroviral drugs have been evaluated in ART-naive or -experienced patients with HIV infection; triple combination therapy with various combinations is currently the recommended first-line treatment strategy.[2] Key to the successful management of an ART-naive or -experienced patient is the selection of a combination of three antiretroviral drugs that produce substantial and durable reductions in viral load, display favourable resistance profiles with a low propensity to produce cross-resistance, and have pharmacokinetic and tolerability profiles that will promote good adherence to treatment.

US,[2,135,136] British[137] and European[138] guidelines for the use of antiretroviral drugs in patients with HIV infection are in broad agreement that initial protease inhibitor-based therapy regimens for ART-naive patients should include a boosted protease inhibitor in combination with dual NRTI therapy. Administered in combination with zidovudine plus lamivudine or emtricitabine, lopinavir/ritonavir (i.e. lopinavir boosted with ritonavir to improve its potency[135]) is the preferred first-line protease inhibitor in the US Department of Health and Human Service (DHHS)[2] and International AIDS Society (IAS) [US Panel][135] guidelines for the treatment of adolescents[2] and adults[2,135] with HIV infection; atazanavir/low-dose ritonavir, saquinavir/low-dose ritonavir and indinavir/low-dose ritonavir are also preferred first-line options in the IAS guidelines.[135] In the DHHS guidelines for adolescents and adults with HIV infection,[2] nelfinavir is recommended as one of several alternative (second-line) protease inhibitors; others include atazanavir, fosamprenavir/ritonavir, fosamprenavir and indinavir/ritonavir. Nelfinavir 1250mg twice daily (for optimal systemic exposure), as a component of triple therapy, is positioned as a first-line option (saquinavir soft-gel capsule is the alternative protease inhibitor) for the initial treatment of pregnant women with HIV infection.[2] Nelfinavir also has a firm position in the DHHS paediatric guidelines where (in common with lopinavir/ritonavir and ritonavir) it is strongly recommended as a first-line protease inhibitor (in combination with two NRTIs) in the treatment of paediatric patients with HIV infection.[139]

As a single agent and in combination with other antiretroviral drugs, nelfinavir shows good activity against HIV-1 in vitro. Importantly, its resistance profile differs from that of the other available protease inhibitors. The most common mutation in HIV protease conferring resistance to nelfinavir is at D30N. This distinctive mutation can develop over time in HIV-infected patients receiving nelfinavir in combination with other antiretroviral agents (section 2) but alone is unlikely to confer cross-resistance to other protease inhibitors. The selection of the D30N mutation may differ between HIV-1 subtypes, with subtype B, but not subtype C, preferentially selecting the mutation (section 2.2.1). Because the presence of the D30N mutation does not appear to impair the activity of other available protease inhibitors against HIV, other protease inhibitors can subsequently be used should D30N-associated failure of nelfinavir treatment occur, providing a rationale for the early use of nelfinavir in the treatment of HIV infection. Of interest, clinical isolates of HIV with protease mutations at D30N and N88S have been shown to be hypersusceptible to certain protease inhibitors.[140] Less frequently, the L90M mutation may emerge during nelfinavir treatment; in contrast to the D30N mutation, this is likely to result in cross-resistance to other protease inhibitors[140] although this has not been demonstrated consistently (section 2.3.2). Other secondary mutations associated with nelfinavir and possibly resulting in cross-resistance to other protease inhibitors include substitutions at positions 10, 35, 36, 46, 71, 77 and 88.

Systemic exposure to nelfinavir is boosted when it is taken with food; thus, in contrast to other available protease inhibitors, concomitant ‘ritonavir boosting’ is not required. The new 625mg tablet formulation, available in the US and Canada, can be administered as a convenient (two tablets) twice-daily regimen contributing to good treatment adherence. For patients who find it difficult to swallow tablets, the tablets can be dispersed in water, providing an alternative mode of administration. Although nelfinavir shows variable bioavailability in children, adequate plasma concentrations are achieved with recommended dosages (section 3). A palatable oral powder is available for use in paediatric patients which should facilitate adherence to treatment.

Nelfinavir shows extensive tissue distribution, although transplacental passage is limited. Like other protease inhibitors, nelfinavir has a propensity to interact with some coadministered drugs via induction or inhibition of CYP enzymes. The drug interaction profile of nelfinavir has, however, been widely studied and comprehensive data are available on clinically significant interactions affecting nelfinavir and/or the coadministered drug (section 3). Among the currently available protease inhibitors, nelfinavir is the most extensively studied agent with respect to pharmacokinetics in pregnant women.[2]

Extensive clinical experience with nelfinavir has shown that, as a component of triple antiretroviral drug regimens (usually including two NRTIs), it effectively reduces plasma HIV RNA levels in adults, adolescents and paediatric patients with HIV and increases CD4+ cell counts (section 4). Improvements in virological and immune status are durable, with one long-term study showing sustained virological efficacy over a period of 8 years. Nelfinavir-containing quadruple regimens have also shown virological efficacy in HIV-infected patients.

As a component of triple therapy regimens in ART-naive patients in 48-week trials, the virological efficacy of nelfinavir was similar to that of atazanavir and was noninferior to fosamprenavir/ritonavir 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. Of note, the SOLO trial was adequately powered for the primary efficacy endpoint of viral load reduction from baseline, whereas the NEAT trial was not. Nelfinavir was less effective than a regimen that included lopinavir/ritonavir 400mg/100mg twice daily. Regimens containing efavirenz tended to be more effective than nelfinavir-containing combination regimens. The superior virological efficacy of lopinavir/ritonavir-containing therapy compared with nelfinavir-containing therapy is consistent with the relative positioning of these agents in the DHHS guidelines.[2] It should also be noted that lopinavir/ritonavir has a high barrier to the development of viral resistance, which makes it an option for salvage therapy.[141]

In other randomised trials, nelfinavir showed virological efficacy similar to that of abacavir or nevirapine, each given in combination with lamivudine/zidovudine (section 4.1). In addition, nelfinavir-containing combination regimens appear beneficial in the treatment of patients switching from another protease inhibitor (usually due to drug intolerance) [section 4.2]. Salvage regimens including nelfinavir as a component have also been shown to be of benefit in patients failing treatment with indinavir (section 4.2), although nelfinavir is more appropriately positioned as initial therapy than as a component of salvage regimens.

The tolerability profile of nelfinavir has been well defined during almost a decade of clinical use. The drug is generally well tolerated, with (manageable) diarrhoea the most common adverse event, usually occurring at a higher incidence with nelfinavir versus comparator protease inhibitors in several randomised trials (section 5). In most other respects, nelfinavir was as well tolerated as comparator protease inhibitors in ART-naive patients (e.g. similar proportions of patients discontinued treatment because of adverse events) and was better tolerated than indinavir in ART-experienced patients (section 5.2). As a class, the protease inhibitors, including nelfinavir, are associated with various metabolic disturbances (e.g. hyperlipidaemia, lypodystrophy, fat redistribution). There are, however, no clinical trial data clearly demonstrating an increase in cardiovascular morbidity associated with protease inhibitors in general.[125] Nelfinavir had a low propensity to produce metabolic changes associated with lipodystrophy in a retrospective analysis and appeared to compare favourably with indinavir and ritonavir (and less favourably with saquinavir) in terms of lipid profile changes in an observational study of >7000 HIV-infected patients (section 5.2). Of note, compared with saquinavir, ritonavir and ritonavir/saquinavir, nelfinavir was associated with the lowest rate of hepatotoxicity in a meta-analysis of data from >4000 patients (section 5.2). Nelfinavir is also the most extensively studied protease inhibitor in pregnant women with respect to safety and there is no published evidence of human teratogenicity.[2]

The importance of individualising HAART regimens is emphasised in several sets of guidelines and is central to the effective management of patients with HIV infection. Certain protease inhibitors may be unsuitable for some patients for a number of reasons; these include drug-related toxicity and intolerance, and the presence in HIV isolates of mutations conferring drug resistance. Treatment selection will depend on factors such as tolerability, suitability for the treatment of the patient population (e.g. paediatric patient, pregnant patient), and the effect of initial protease inhibitor use on possible later treatment options. Some key differences in the individual tolerability profiles of the protease inhibitors are noted in the DHHS guidelines.[2] For example, atazanavir is associated with indirect hyperbilirubinaemia, fosamprenavir and fosamprenavir/ritonavir with skin rash, saquinavir with gastrointestinal intolerance and indinavir/ritonavir with the potential for a higher incidence of nephrolithiasis than with indinavir alone.[2] Hyperlipidaemia is reported as a disadvantage of lopinavir/ritonavir in the DHHS guidelines; diarrhoea and gastrointestinal intolerance may also occur in recipients of this combination.[2] As mentioned previously, diarrhoea is the most common adverse effect associated with nelfinavir use occurring in 20% of protease inhibitor-naive adults receiving treatment with the drug at approved dosages (section 5.1).[3] A higher incidence of diarrhoea (30–40%) with nelfinavir is reported in the DHHS guidelines.[2]

Cost considerations are clearly important when selecting a protease inhibitor and the relative cost effectiveness of agents with similar clinical profiles may be pivotal when deciding between agents with broadly similar clinical profiles. Pharmacoeconomic data for nelfinavir are however limited at present. Similarly, there is as yet little information published available on the effects of treatment with nelfinavir on health-related quality of life.

In conclusion, nelfinavir, in combination with other antiretroviral drugs (usually NRTIs), 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.

Footnotes
1

The use of trade names is for product identification purposes only and does not imply endorsement.

 

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