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Nevirapine

A Review of its Use in the Prevention and Treatment of Paediatric HIV Infection

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Summary

Abstract

Nevirapine is a highly specific inhibitor of HIV-1 reverse transcriptase (RT), an important therapeutic target for the treatment of HIV infection. It was the first non-nucleoside RT inhibitor (NNRTI) to be approved for use in HIV-infected individuals, including children.

Nevirapine inhibits replication of multiple HIV-1 strains and clinical isolates in cultured human T cells, but has no activity against other retroviral RTs (including HIV-2 RT) or endogenous human DNA polymerases. Monotherapy with nevirapine rapidly selects for high level drug resistance conferred by a single amino acid substitution in the HIV RT gene. The pattern of resistance mutations selected by nevirapine overlaps with those of other NNRTIs, but is distinct from those of nucleoside analogue RT inhibitors and protease inhibitors.

The pharmacokinetics of nevirapine are characterised by rapid and nearly complete oral absorption, an apparently even distribution throughout all organs and tissues in the body, and a long elimination half-life. Nevirapine is both metabolised by and induces the activity of cytochrome P450 isoenzymes. Caution is required when coadministering nevirapine with other drugs metabolised by this system, including HIV protease inhibitors.

As a single dose therapy given to pregnant women in labour and to neonates shortly after birth, nevirapine reduced the rate of perinatal HIV transmission by 47% compared with a short course of intrapartum and neonatal zidovudine in a randomised trial in breastfeeding women in Uganda. Nevirapine was more cost effective than zidovudine-based regimens for the prevention of perinatal HIV transmission in a cost-effectiveness model in sub-Saharan Africa.

Nevirapine has shown antiretroviral efficacy as part of combination therapy with zidovudine and either didanosine or lamivudine in small numbers of paediatric patients in phase I/II trials. Triple therapy of nevirapine, zidovudine and didanosine was moderately effective in a randomised, nonblind trial in patients with advanced disease.

The most frequent adverse event associated with nevirapine is rash, which occasionally develops into severe rash or Stevens-Johnson syndrome. Elevations in liver enzyme levels can occasionally lead to severe complications in patients receiving multiple dose nevirapine.

Conclusion: Single dose nevirapine appears to be the most cost-effective of available options for the prevention of perinatal HIV transmission suitable for use in developing countries. In addition, preliminary clinical trial data suggest that nevirapine adds to the efficacy of combination therapy for the treatment of HIV infection in infants and children, and is reasonably well tolerated.

Pharmacodynamic Properties

The dipyridodiazepinone nevirapine is a non-nucleoside inhibitor (NNRTI) of HIV-1 reverse transcriptase (RT). Nevirapine binds directly to HIV-1 RT, slowing the rate of viral DNA synthesis prior to insertion into the host cell genome and thereby inhibiting viral replication in acutely infected cells.

Nevirapine inhibited in vitro replication of multiple HIV-1 strains and clinical isolates in cultured human T cells with a 50% inhibitory concentration (IC50) of approximately 40 nmol/L (10.6 μg/L) as determined by inhibition of viral cytopathic effect. It did not inhibit other retroviral RTs, including HIV-2 RT, or endogenous human DNA polymerases. Nevirapine exhibited extremely low cytotoxicity in uninfected human cells.

Complete suppression of viral replication was achieved when nevirapine was added to cultured cells within 24 hours of infection with HIV-1, but activity was limited when the drug was added later. This is consistent with inhibition of an early step in the retroviral life cycle and activity against acute HIV infection. Administration of a short course of nevirapine in chimpanzees beginning just prior to inoculation with HIV-1 was sufficient to protect animals against developing productive or chronic infection, although evidence of proviral integration was observed.

The antiretroviral activity of nevirapine was synergistic with zidovudine, lamivudine or stavudine against wild-type HIV-1 in vitro. Nevirapine was effective alone or synergistically with lamivudine or stavudine against a zidovudineresistant viral strain.

Nevirapine reduced the accumulation of HIV-1 reverse transcripts in cell-free virions, which appear to be needed for efficient virion infectivity. This activity has implications for the control of HIV transmission via cell-free virions in physiological fluids such as semen, cervicovaginal secretions, blood plasma and breast milk.

NNRTIs, including nevirapine, are associated with the rapid emergence of drug-resistant viral mutants when used in monotherapy regimens in HIV-infected patients, or after limited passage of HIV-1 in the presence of inhibitor in vitro. The most common HIV-1 RT mutation selected by nevirapine both in vitro and in vivo is a tyrosine to cysteine change at residue 181 (Y181C). This variant is over 100 times less susceptible to nevirapine than wild-type virus and also confers cross-resistance to other NNRTIs. Acquisition of the Y181C mutation causes zidovudine-resistant HIV variants to regain susceptibility to the NRTI. Nevirapineresistant variants selected in a background of zidovudine resistance contained a valine-to-alanine change at residue 106 (V106A) instead of Y181C. This viral variant is resistant to both nevirapine and zidovudine.

Nevirapine resistance mutations in the HIV RT gene have also been observed at codons 103, 108, 188 and 190 in clinical isolates from patients treated with nevirapine. Amino acid substitutions resulting in reduced susceptibility to nevirapine are all associated with the nevirapine binding site, which is close to but distinct from the RT polymerase catalytic site. The pattern of resistance mutations selected by nevirapine overlaps with those of other NNRTIs, but is distinct from nucleoside analogue reverse transcriptase inhibitors and protease inhibitors.

HIV-1 isolates with high level nevirapine resistance (30- to 2000-fold less sensitive than wild-type virus) were obtained from peripheral blood mononuclear cells from children receiving nevirapine monotherapy as early as day 14. Nevirapine resistance mutations also developed in previously untreated, pregnant, HIV-infected Ugandan women after a single dose of nevirapine 200mg in a phase I/II study of prevention of perinatal transmission. The women acquired the K103N mutation rather than the more common Y181C. The clinical significance of this resistance is not yet known.

Pharmacokinetic Properties

Nevirapine pharmacokinetics in adults are characterised by rapid and nearly complete oral absorption, an apparently even distribution throughout all organs and tissues in the body, and a long elimination half-life (t1/2) of approximately 40 hours.

The recommended adult dosage of nevirapine 200mg twice daily produced an average steady-state plasma concentration of 5.5 mg/L in healthy volunteers. An oral suspension of nevirapine has shown bioavailability similar to that of the tablet in doses up to 200mg. Nevirapine suspension was rapidly absorbed after administration of single oral doses of 7.5 to 120 mg/m2 in 9 HIV-infected children. Maximum plasma concentrations (Cmax) were achieved within 4 hours and reached 0.3 to 2.9 mg/L (1 to 10 μmol/L), up to 273 times higher than the nevirapine IC50 for wild-type virus.

Nevirapine enhances its own metabolism through induction of cytochrome P450 (CYP) isoenzymes (mainly CYP3A). This results in an approximately 2-fold increase in systemic nevirapine clearance in both adult and paediatric patients over 2 to 4 weeks of multiple dose administration. Young children (<6 years of age) appear to clear nevirapine more rapidly than older children, suggesting that dosage adjustments based on age are necessary. Population kinetic analyses suggested that twice daily nevirapine 7 mg/kg or 150 mg/m2 in children <8 years and 4 mg/kg or 120 mg/m2 in children ≥8 years and over would produce nevirapine concentrations approximating those in adults taking 200mg twice daily.

Radiolabelling studies in healthy male volunteers showed that approximately 81.3% of a total nevirapine oral dose was recovered in urine and 10.1% in faeces, mainly as hydroxylated glucuronide metabolites.

Nevirapine was found to cross the placenta efficiently after a single oral 200mg dose to the mother at the onset of labour. This resulted in cord blood nevirapine concentrations well above the target concentration of 100 μg/L (10 times the in vitro IC50 for HIV-1) thought to be necessary for prevention of perinatal HIV transmission. The median t1/2 of nevirapine in the mothers was 61.3 to 65.7 hours. In infants, median t1/2 was 45.4 to 72.1 hours for elimination of the maternal nevirapine dose, and 36.8 to 46.5 hours for elimination of a single 2 mg/kg neonatal dose.

Because nevirapine undergoes extensive hepatic metabolism by CYP3A4 and also induces CYP isoenzyme activity, interactions with other drugs metabolised by this system are expected. Caution is required during coadministration with HIV protease inhibitors, the plasma concentrations of which may be reduced to subtherapeutic levels when coadministered with nevirapine. Protease inhibitors do not appear to affect the pharmacokinetics of nevirapine.

Coadministration of nevirapine with ketoconazole reduced ketoconazole plasma concentrations but increased nevirapine plasma concentrations. Rifampicin decreased nevirapine concentrations but was not itself affected by coadministration with nevirapine.

Clinical Efficacy

Prevention of Perinatal HIV Transmission: The favourable pharmacokinetic profile of nevirapine has prompted its evaluation as a single dose therapy to prevent late in utero and intrapartum perinatal transmission of HIV. HIVNET 012, a phase IIB/III randomised nonblind study, assessed the efficacy of nevirapine or ultrashort course zidovudine for the prevention of HIV transmission from infected pregnant women (n = 626) to their neonates. The nevirapine regimen consisted of a single 200mg oral tablet taken by the mother at the onset of labour, and a single oral dose of nevirapine suspension (2 mg/kg) given to the neonate within 72 hours of birth (median 24 to 30 hours). The zidovudine regimen began with 600mg orally at labour onset, followed by 300mg every 3 hours during labour. The neonate was given oral zidovudine syrup (4 mg/kg) twice daily for 7 days after birth. At 6 to 8 and 14 to 16 weeks after delivery, significantly more babies in the zidovudine than the nevirapine group were HIV-infected (25.1 vs 13.1%). HIV-free survival at 14 to 16 weeks was correspondingly higher in the nevirapine group than in the zidovudine group (85.6 vs 72.4%). The risk to the infant of perinatal HIV infection or death in the first 4 months was thus lowered by 47% by nevirapine treatment in this predominantly (98.8%) breastfed population.

Treatment of Paediatric HIV Infection: Although the antiviral efficacy of nevirapine has been demonstrated in randomised, controlled trials in adult patients, studies of its therapeutic use in children are more limited.

One randomised, nonblind trial of nevirapine has included paediatric patients (ACTG 245). Antiretroviral therapy-experienced patients with advanced disease (aged 6 months to 20 years; n = 432) were randomised to receive triple therapy with nevirapine, zidovudine and didanosine, or double therapy with either nevirapine and didanosine or zidovudine and didanosine (dosages not reported). An interim analysis in 136 patients found that the triple therapy group achieved a significantly greater mean reduction in plasma HIV RNA levels than either double therapy group over a 48-week period. Triple therapy also resulted in sustained reduction of viral load in cerebrospinal fluid in patients with HIV-associated encephalopathy.

Initiation of triple therapy with nevirapine, zidovudine and didanosine before the age of 4 months in asymptomatic or mildly symptomatic perinatally HIV-infected infants produced substantial reductions in viral load in a phase I/II nonblind study. Plasma HIV RNA levels decreased by 1.5 log10 copies/ml in 5 of the 6 infants within 2 to 4 weeks of the start of therapy, and remained below baseline levels through the entire 6 months of therapy. Another phase I/II study demonstrated the efficacy of triple therapy with nevirapine, zidovudine and lamivudine in producing viral load reductions of ≥2log10 copies/ml which were sustained for 12 weeks in 12 of 15 paediatric patients.

Nevirapine monotherapy in dosages of 120 to 400 mg/m2/day inhibited HIV p24 antigen production in paediatric patients with mild to moderate HIV disease, although antiviral activity diminished rapidly at nevirapine dosages below 240 mg/m2/day.

Pharmacoeconomic Considerations

A cost-effectiveness model was used to evaluate the single dose HIVNET 012 nevirapine regimen (200mg orally at the onset of labour, and 2 mg/kg to the neonates within 72 hours of birth) for prevention of perinatal HIV transmission in a hypothetical cohort of 20 000 pregnant women in sub-Saharan Africa. This regimen was compared with other short course antiretroviral interventions including universal administration of the HIVNET 012 regimen (without prior counselling or HIV testing), and several zidovudine-based regimens which have shown efficacy in reducing the rate of HIV perinatal transmission in clinical trials.

Costs were analysed from a public sector healthcare payer perspective, assuming that the payer pays all costs for voluntary counselling and testing and for the treatment itself. Relative to other antiretroviral regimens, which varied in drug acquisition costs and efficacy, the nevirapine regimen was by far the most cost effective, although comparison with other treatments was limited by differences in trial design. By single-variable sensitivity analyses, the cost effectiveness of the targeted HIVNET 012 intervention remained below $US50 per disability-adjusted life-year saved under almost all plausible scenarios, except when the cost of voluntary counselling and testing was high ($US18.50 vs $US7.30 in the base case) and HIV seroprevalence was 15%. The study concluded that a single dose nevirapine regimen for women and neonates was more cost effective than zidovudine-based regimens in reducing perinatal HIV transmission in sub-Saharan Africa.

Tolerability

Nevirapine was reasonably well tolerated in children at dosages of 240 to 400 mg/m2/day in clinical trials. Drug-related adverse events reported in children in nevirapine trials were similar to those reported in adults. Rash, the most frequently reported adverse event, was observed in 17% of adult patients in controlled phase II/III trials and occasionally progressed to serious or life-threatening rash (Stevens-Johnson syndrome/toxic epidermal necrolysis). Rash occurred in 24% of paediatric patients in small clinical studies. Most cases developed within the first 6 weeks of therapy; a reduced lead-in dosage (in children, 120 mg/m2/day) for the first 2 to 4 weeks has been shown to decrease the incidence of rash during the period of nevirapine metabolic autoinduction in both adults and children.

Granulocytopenia was the second most frequently reported adverse event in children (16% incidence); this was the only adverse event that differed from those commonly reported in adults. Other frequently reported (≥5%) adverse events in paediatric clinical trials were vomiting, fatigue, nausea, nervousness, headache, dizziness, somnolence, abdominal pain, diarrhoea, fever and hyperkinesia. Severe or life-threatening hepatotoxicity has also occurred in patients treated with nevirapine, indicating a need for careful monitoring of liver function during nevirapine therapy.

Among women and infants receiving single dose nevirapine for the prevention of perinatal HIV transmission, no serious drug-related adverse events were reported. The incidence of rash in mothers was low (<2%), and no serious cases of rash were reported.

Dosage and Administration

For prevention of perinatal HIV transmission, HIV-infected pregnant women who have had no prior antiretroviral therapy can be administered a single oral 200mg nevirapine dose during labour. A single 2 mg/kg dose of oral nevirapine suspension should then be given to the HIV-exposed neonate within 72 hours of delivery.

Nevirapine is available as an oral suspension for use in paediatric patients. The recommended dosage for children 2 months to 8 years of age is 4 mg/kg of bodyweight once daily for 2 weeks, followed by 7 mg/kg twice daily thereafter. For children 8 years and older the recommended dosage is 4 mg/kg once daily for 2 weeks followed by 4 mg/kg twice daily thereafter.

Dosage adjustments are not necessary in patients with renal impairment who are not receiving dialysis. Patients on dialysis should be monitored for antiviral efficacy, as nevirapine AUC was reduced by 41% in this group. Hepatic impairment decreases the clearance of nevirapine, and patients with liver disease should be carefully monitored for nevirapine-related adverse events.

Patients experiencing moderate or severe elevations in liver enzymes should stop nevirapine therapy until the elevations have returned to baseline. Nevirapine should be discontinued if patients experience severe rash or a rash accompanied by constitutional symptoms.

Drugs suspected to interact with nevirapine should be used only with careful monitoring. These include HIV protease inhibitors, rifampicin (rifampin) and rifabutin, sedative-hypnotics (e.g. triazolam, midazolam), oral anticoagulants, digoxin, phenytoin and theophylline. Ketoconazole should not be administered concomitantly with nevirapine.

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Bardsley-Elliot, A., Perry, C.M. Nevirapine. Paediatr Drugs 2, 373–407 (2000). https://doi.org/10.2165/00128072-200002050-00005

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