- 47 Downloads
Nelfinavir (Viracept®) is an orally administered protease inhibitor. In combination with other antiretroviral drugs (usually nucleoside reverse transcriptase inhibitors [NRTIs]), nelfinavir produces substantial and sustained reductions in viral load in patients with HIV infection. Nelfinavir may be used in the treatment of adults, adolescents and children aged ≥2 years with HIV infection. It can also be used in pregnancy. Resistance to nelfinavir may develop, but the most common mutation (D30N, appearing mainly in HIV-1 subtype B) does not confer resistance to other protease inhibitors, thereby conserving these agents for later use. Although less effective than lopinavir/ritonavir, the preferred first-line treatment in US guidelines, nelfinavir is positioned as an alternative agent for the treatment of adults and adolescents with HIV infection and is an option for those unable to tolerate other protease inhibitors. Nelfinavir also has a role in the management of pregnant patients as well as paediatric patients with HIV infection.
Nelfinavir is a selective, nonpeptidic competitive inhibitor of the HIV-1 protease. The drug shows good in vitro activity against HIV-1 strains, including strains resistant to zidovudine or non-nucleoside reverse transcriptase inhibitors. The activity of the major metabolite of nelfinavir (M8) against HIV-1 in vitro is similar to that of the parent drug. Additive activity against HIV-1 is observed with nelfinavir in combination with stavudine, didanosine or saquinavir; synergistic activity against HIV-1 is observed with nelfinavir in combination with zidovudine, lamivudine or zalcitabine.
Resistance to nelfinavir is mediated most commonly via a substitution at residue 30 (D30N) in HIV protease and has been identified in clinical isolates of HIV from patients receiving treatment with the drug in combination with other agents. This mutation appears to be unique to nelfinavir. Less commonly, a substitution at residue 90 (L90M) may occur during treatment with nelfinavir; this mutation can confer resistance to several other protease inhibitors.
Nelfinavir produces beneficial effects on immune function with increases in CD4+ cell counts observed in patients treated with nelfinavir-containing combination regimens. Treatment with nelfinavir was associated with a decrease in Fas expression and Fas-mediated apoptosis and an increase in CD4+ cell counts in patients with HIV infection.
The absorption of nelfinavir from the currently available oral formulations is increased when the drug is administered after food, compared with the fasted state. Both nelfinavir and its active metabolite M8 are highly bound to serum proteins and nelfinavir shows extensive tissue distribution. Transplacental passage of the drug appears limited. Nelfinavir is metabolised in the liver by multiple cytochrome P450 (CYP) enzymes. M8 is its major metabolite. The plasma terminal half-life of nelfinavir ranges from 3.7 to 5.3 hours. Almost 90% of the drug is eliminated via the faeces; 1–2% is recovered in urine mostly as unchanged drug. In children, systemic exposure to nelfinavir is highly variable. Clearance in this population is increased by ≈2–3 times compared with that in adults. However, in children aged 2–13 years, adequate systemic exposure to the drug is achieved at recommended dosages.
Plasma concentrations of nelfinavir are markedly lower in pregnant women with HIV infection during the third trimester than concentrations in nonpregnant patients. A dosage of 1250mg twice daily produces adequate plasma concentrations in pregnant women, whereas plasma concentrations in recipients of 750mg three times daily may be lower and more variable. Nelfinavir interacts with a number of other drugs via induction or inhibition of CYP isoenzymes in the liver.
The efficacy of oral nelfinavir has been investigated in HIV-infected, antiretroviral therapy (ART)-naive or -experienced patients, including adults, adolescents, children and pregnant women. Key clinical trials were ≤48 weeks in duration and measured plasma HIV RNA levels as a virological surrogate marker of disease progression.
ART-naive adults and adolescents: In randomised, double-blind or open-label, multicentre studies, nelfinavir demonstrated similar virological efficacy at both recommended dosage levels (750mg three times daily or 1250mg twice daily) when administered as a component of triple therapy (with zidovudine and lamivudine). Treatment with the regimen containing nelfinavir 750mg three times daily resulted in significantly better virological and/or immunological outcomes compared with the placebo-containing regimen.
Administered as part of triple therapy in randomised, double-blind, partially blind or open-label, multicentre studies, nelfinavir 750mg three times daily or 1250mg twice daily showed virological efficacy similar to that of atazanavir 200–600mg and was noninferior to fosamprenavir/ritonavir 1400mg/200mg once daily in the SOLO trial. In the NEAT trial, which was also a noninferiority trial, a larger proportion of fosamprenavir than nelfinavir recipients achieved HIV RNA levels of <400 copies/mL at the end of treatment. Nelfinavir was less effective than lopinavir/ritonavir 400mg/100mg twice daily, each given in combination with lamivudine and stavudine.
Approximately one-half to two-thirds of the nelfinavir-treated patients in these studies had undetectable viral loads (<400 copies/mL) after 48 weeks of treatment (various intent-to-treat analyses). Immunological responses were similar for each of these protease inhibitor-based regimens. Quadruple regimens containing nelfinavir have also shown efficacy in therapy-naive patients with HIV infection. Triple therapy with efavirenz, zidovudine and lamivudine was the optimal regimen in a study comparing three- and four-drug regimens 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.
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.
- 2.Department of Health and Human Services (US). Guidelines for the use of antiretroviral agents in HIV infected agents in HIV-1 infected adults and adolescents [online]. Available from URL: http://aidsinfo.nih.gov/guidelines/adult/AA_040705.pdf [Accessed 2005 Aug 19]Google Scholar
- 3.Agouron Pharmaceuticals Inc. Viracept® (nelfinavir mesylate) tablets and oral powder: US prescribing information [online]. Available from URL: http://www.pfizer.com/pfizer/download/ uspi_viracept.pdf [Accessed 2005 Aug 1]Google Scholar
- 5.Speck RR, Flexner C, Tian C-J, et al. Comparison of human immunodeficiency virus type 1 Pr55Gag and Prl60Gag-Pol processing intermediates that accumulate in primary and transformed cells treated with peptidic and nonpeptidic protease inhibitors. Antimicrob Agents Chemother 2000 May; 44(5): 1397–403PubMedCrossRefGoogle Scholar
- 9.Patick AK, Boritzki TJ, Bloom LA. Activities of human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro. Antimicrob Agents Chemother 1997 Oct; 41(10): 2159–64PubMedGoogle Scholar
- 19.Eshleman SH, Krogstad P, Brooks Jackson JB, et al. Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377). J Infect Dis 2001 Jun 15; 183: 1732–8PubMedCrossRefGoogle Scholar
- 22.Masquelier B, Droz C, Dary M, et al. R57K polymorphism in the human immunodeficiency virus type 1 protease as predictor of early virological failure in a cohort of antiretroviral-naive patients treated mostly with a nelfinavir-containing regimen. Antimicrob Agents Chemother 2003 Nov; 47(11): 3623–6PubMedCrossRefGoogle Scholar
- 26.MacManus S, Yates P, White S, et al. GW433908 in ART-naive subjects: absence of resistance at 48 weeks with boosted regimen and APV-like resistance profile with unboosted regimen [abstract no. 598 plus poster]. 10th Conference on Retroviruses and Opportunistic Infections; 2003 Feb 10–14; Boston (MA)Google Scholar
- 28.De Luca A, Di Giambenedetto S, Bacarelli A, et al. Genotypic resistance to boosted (fos)amprenavir and lopinavir in clinical isolates from patients failing protease inhibitors-containing HAART regimens: prevalence and predictors [abstract no. P99]. 7th International Congress on Drug Therapy in HIV Infection; 2004 Nov 14–18; GlasgowGoogle Scholar
- 29.Elston R, Yates P, Tisdale M, et al. GW433908 (908)/ritonavir (r): 48 week results in PI-experienced subjects: a retrospective analysis of virological response based on baseline genotype and phenotype [abstract no. MoOrB1055]. 15th International AIDS Conference; 2004 Jul 11–16; BangkokGoogle Scholar
- 30.Bristol-Myers Squibb Company. Reyataz® (atazanavir sulfate) capsules prescribing information, 2005 Jun [online]. Available from URL: http://www.bms.com [Accessed 2005 Sep 30]Google Scholar
- 36.Victorino R, Sousa A, Chaves AF. Effects of triple antiretroviral therapy on the expression of Fas antigen in patients with HIV1 infection [abstract no. 31178]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; GenevaGoogle Scholar
- 39.Kaufmann G, Zaunders J, Cunningham P, et al. Comparison of immune reconstitution in subjects treated with HAART during primary and chronic HIV-1 infection [abstract no. 345]. 7th Conference Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco (CA)Google Scholar
- 40.Smith DE, Kaufmann GR, Kahn JO, et al. Greater reversal of CD4+ cell abnormalities and viral load reduction after initiation of antiretroviral therapy with zidovudine, lamivudine, and nelfinavir before complete HIV type 1 seroconversion. AIDS Res Hum Retroviruses 2003 Mar; 19: 189–99PubMedCrossRefGoogle Scholar
- 41.Roche Products Limited. UK Summary of product characteristics: Viracept (nelfinavir) 250mg film-coated tablets [online]. Available from URL: http://emc.medicines.org.uk/ [Accessed 2005 Aug 5]Google Scholar
- 44.Hsyu P, Petersen C, Pun E, et al. Increased bioavailability of nelfinavir 625 mg tablet and the potential impact on adverse experiences [abstract no. 116 plus poster]. Antivir Ther 2003 Aug 4; 8: L77–8Google Scholar
- 48.Hsyu PH, Lillibridge JH, Beeby S, et al. Pharmacokinetics of nelfinavir and metabolite M8 in patients with liver impairment after a single oral 750mg dose of viracept. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2000 Sep 17–20; Toronto, 337Google Scholar
- 53.Mirochnick M, Bryson Y, Stek A, et al. Pharmacokinetics of nelfinavir and its M8 metabolite in pregnant HIV-infected women and their infants: PACTG 353 [abstract no. 1891]. Pediatr Res 2003 Apr; 53 (Pt 2): 331Google Scholar
- 56.Kruse G, Esser S, Stocker H, et al. Tenofovir (TDF) does not impair the steady-state pharmacokinetics of nelfinavir (NFV) in HIV-infected patients [poster A-446]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2004 Oct 30–Nov 2; Washington, DCGoogle Scholar
- 57.Boffito M, Pozniak A, Kearney B, et al. Lack of a drug interaction between tenofovir DF and nelfinavir [poster]. 7th International Conference on Drug Therapy in HIV; 2004 Nov 14–18; GlasgowGoogle Scholar
- 63.Kurowski M, Molto J, Breske A, et al. Atazanavir (ATV) enhances trough concentrations of nelfinavir (NFV) and its M8 metabolite in a treatment regimen without ritonavir (RTV) [poster 8.2]. 6th International Workshop of Clinical Pharmacology of HIV Therapy; 2005 Apr 28–30; QuebecGoogle Scholar
- 64.Stocker H, Kruse G, Arasteh K, et al. Pharmacokinetic interaction between saquinavir/r and nelfinavir in HIV-infected patients [poster A-454]. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2004 Oct 30–Nov 2; Washington, DCGoogle Scholar
- 67.Rodriguez-French A, Boghossian J, Gray GE, et al. The NEAT Study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antire-troviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 2004 Jan 1; 35(1): 22–32PubMedCrossRefGoogle Scholar
- 73.Sanne I, Piliero P, Squires K, et al. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 2003; 32: 18–29PubMedCrossRefGoogle Scholar
- 77.Bernstein B, Kempf D, Moseley M, et al. Lack of resistance to ABT-378/ritonavir (ABT-378/R) observed after 24 weeks of therapy in antiretroviral-naive subjects [abstract no. P325]. Int Cong Drug Therapy HIV. AIDS 2000; 14 Suppl. 4: S110Google Scholar
- 81.Cooper D, Yeni P. Virological and immunological outcomes at 3 years following initiation of ART with regimens containing a NNRTI or PI or both: the INITIO Trial [abstract no. 165LB]. 12th Conference on Retroviruses and Opportunistic Infections; 2005 Feb 22–25; Boston (MA)Google Scholar
- 82.Daniels E, Clotet B, Clax P, et al. Long-term efficacy of nelfinavir, impact on adverse events and lipodystrophy [poster 100]. Antivir Ther 2004; 9(6): L57Google Scholar
- 83.Fumaz C, Lopez Aldeguer J, Lozano F, et al. Clinical and psychological impact of prolonged nelfinavir-containing regimens. PSIRENE study [abstract no. P54]. 7th International Congress on Drug Therapy in HIV Infection; 2004 Nov 14–18; GlasgowGoogle Scholar
- 84.Gathe J, Chu A, Yuen N, et al. Durability of nelfinavir combination therapy after 4 years: 3-year extension data from Agouron Study 511 [poster LB10]. 8th European Conference on Clinical Aspects and Treatment of HIV-Infection; 2001 Oct 28–31; Athens, GreeceGoogle Scholar
- 87.Bahrani A, Oldfield IEC. Substitution of nelfinavir (NV) for indinavir (IV) in patients on combination therapy and the effect on viral loads [abstract no. I-241]. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1998 Sep 24–27; San Diego (CA), 440Google Scholar
- 88.Trylesinski A, Dohin E, Delmas C, et al. Alleviating protease inhibitor constraints and for a viral load maintained below the limit of quantification for the long term efficacy, tolerance and compliance: the nelfinavir switch solution [abstract no. P114]. AIDS 1998 Nov; 12 Suppl. 4: S45Google Scholar
- 89.Lefebvre E, Shafran S. Maintenance of virological suppression in patients switched from indinavir (IDV) to nelfinavir (NFV) [abstract no. P62]. AIDS 2000 Oct; 14 Suppl. 4: S34Google Scholar
- 91.Starrett B, Connor S. Maintenance of viral suppression and improvement of metabolic parameters after replacing ritonavir with nelfinavir in a HAART regimen [abstract]. 7th Conference on Retroviruses and Opportunistic Infections; 2000 Jan 30–Feb 2; San Francisco (CA)Google Scholar
- 92.Knechten H, Lippok B, Knickmann M. Switch from indinavir (IDV) to nelfinavir (NFV) in patients on antiviral therapy with stavudine (d4T) and lamivudine (3TC) [abstract P123]. AIDS 1998 Nov; 12 Suppl. 4: S47Google Scholar
- 94.Post J, Williams C. An open label, randomized trial switching nelfinavir dosing from tid to bid: 84 week report [abstract no. TuPeB3224]. 13th International AIDS Conference; 2000 Jul 9–14; Durban, 362Google Scholar
- 95.Dhingra R, Munsiff A. Twice daily nelfinavir results in greater durability and higher CD4 counts than TID dosing [abstract no. WePeB4118]. 13th International AIDS Conference; 2000 Jul 9–14; Durban, 59Google Scholar
- 97.Gulick RM, Hu XJ, Fiscus SA, et al. Randomized study of saquinavir with ritonavir or nelfinavir together with delaviridine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. J Infect Dis 2000 Nov; 182: 1375–84PubMedCrossRefGoogle Scholar
- 102.Casado JL, Dronda F, Garcia-Aratia I, et al. Efficacy and tolerability of the combination of nevirapine, nelfinavir and saquinavir after ritonavir or indinavir failure [abstract no. 529]. 7th European Conference on Clinical Aspects and Treatment of HIV-Infection; 1999 Oct 23–27; Lisbon, 112Google Scholar
- 103.Arrizabalaga J, Iribarren JA, Rodriguez-Arrondo FJ, et al. Salvage therapy with ddI + hydroxyurea (HU) + efavirenz (EFV) + nelfinavir (NFV) in patients who had previously failed indinavir (IDV)/ritonavir (RIT) regimens. 24 weeks follow-up [abstract no. 2206]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco (CA), 537Google Scholar
- 104.Santos J, Palacios R, Ruiz I, et al. Efficacy of nelfinavir as salvage therapy for protease inhibitors failures [abstract no. P65]. 8th European Conference on Clinical Aspects and Treatment of HIV-Infection; Athens 2001 Oct 28–31, 70Google Scholar
- 105.Viciana P, Perez R, Hernadez Quero J, et al. NNRTI salvage therapy with nelfinavir in PI naive patients [abstract plus poster 7.4/15]. 9th European AIDS Conference and 1st EACS Resistance and Pharmacology Workshop; 2003 Oct 25; Warsaw, 57Google Scholar
- 107.Zolopa A, Tebas P, Gallant J, et al. The efficacy of ritonavir (RTV)/saquinavir(SQV) antiretroviral therapy (ART) in patients who failed nelfinavir (NEV): a multicentre cohort study [abstract no. 2065]. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy; 1999 Sep 26–29; San Francisco (CA), 527Google Scholar
- 108.Cavorus A, Thompson CE, Salvato PD. Salvage therapy for antiretroviral failure in HIV+ patients [abstract no. 22402]. 12th World AIDS Conference; 1998 Jun 28–Jul 3; Geneva, 344Google Scholar
- 109.Center of Drug Evaluation and Research of the US Food and Drug Administration. Clinical review for NDA [online]. Available from URL: http://www.fda.gov/cder/foi/esum/2004/ 20778se5-022,20779se5-042,21503se5-001_viracept_clinical _bpca.pdf [Accessed 2005 Aug 19]Google Scholar
- 116.Rachlis A, Gill M, Baril Jeal. Step-wise intervention for the management of nelfinavir (NFV)-associated diarrhoea [abstract plus poster no. 747]. Antivir Ther 2003; 8 Suppl. 1: S392Google Scholar
- 123.Murphy R, Thiry A, Mancini M, et al. Switch to atazanavir from nelfinavir associated with cholesterol and triglyceride improvement: 12 wk results from BMS AI424-044 [abstract LBPEB9013 plus poster]. 14th International AIDS Conference; Barcelona 2002 Jul 7–12, 38Google Scholar
- 126.da Silva B, ing M, Cernohous P, et al. Risk factors for body fat composition changes in patients treated with lopinavir/ ritonavir or nelfinavir [abstract no. 99]. Antivir Ther 2003 Aug 4; 8: L68Google Scholar
- 129.Dube M, Zackin R, Parker R, et al. Prospective study of glucose and lipid metabolism in antiretroviral-naive subjects randomized to receive nelfinavir, efavirenz, or both combined with zidovudine+lamivudine or didanosine+stavudine: A5005s, a substudy of ACTG 384 [abstract no. 74]. 11th Conference on Retroviruses and Opportunistic Infections; 2004 Feb 8–11; San Francisco (CA), 2Google Scholar
- 130.Center for Drug Evaluation and Research for the US Food and Drug Administration. One year post-pediatric exclusivity post-marketing adverse event review: drug use data — nelfinavir mesylate [online]. Available from URL: http://www.fda.gov/ ohrms/dockets/ac/05/briefing/2005-4089bl_06_02_ Nelfinavir.pdf [Accessed 2005 Aug 19]Google Scholar
- 134.Baylor M, Gibbs N. Hepatotoxicity during pregnancy: a review of the FDA adverse event reporting system (AERS) database [abstract and poster 944]. 1 lth Conference on Retroviruses and Opportunistic Infections; 2004 Feb 8–11; San FranciscoGoogle Scholar
- 137.The British HIV Association. BHIVA guidelines for the treatment of HIV-infected adults with antiretroviral therapy 2005 [online]. Available from URL: http://www.bhiva.org/guidelines/2005/HIV/index.html [Accessed 2005 Aug 29]Google Scholar
- 139.Department of Health and Human Services (US). Guidelines for the use of antiretroviral agents in pediatric HIV infection [online]. Available from URL: http://aidsinfo.nih.gov/guidelines/pediatric/PED_032405 [Accessed 2005 Aug 01]Google Scholar