Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

Boehringer Ingelheim

Nevirapine was approved by the FDA in 1996 for use in combination with nucleoside analogues in adults with HIV infection. Approval was based on studies showing that the combination of nevirapine with zidovudine + didanosine was more effective in increasing CD4 T-lymphocyte counts and decreasing HIV viral load than a regimen of zidovudine + didanosine alone.(1) Nevirapine was approved for pediatric use in 1998, and an extended-release formulation for adults was approved in 2011.

The FDA has approved several generic formulations of nevirapine for use in the United States. It has granted "tentative approved" status to number of other generic formulations, making them eligible for purchase and use as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries.

Nevirapine is available in immediate-release tablets, extended-release tablets, and oral suspension.

Dosing of Nevirapine Adult Immediate-release (IR) tablet or oral suspension: 200 mg QD for 14 days, then 200 mg BID Extended-release (XR) tablet: 400 mg QD If initiating treatment with nevirapine: start with IR tablet, 200 mg QD for 14 days; then change to XR tablet, 400 mg QD If switching from nevirapine IR formulation (200 mg BID) to XR formulation: start XR tablet, 400 mg QD (without lead-in dosage adjustment) Nevirapine should not be initiated in women with CD4 counts of >250 cells/µL or men with CD4 counts of >400 cells/µL, unless the benefit clearly outweighs the risk* Pediatric Age 15 days-adolescence 150 mg/m2 QD for the first 14 days, then 150 mg/m2 BID; maximum total daily dose: 400 mg Prevention of Mother-to-Child Transmission See Mother-to-Child Transmission Guidelines

Key to abbreviations: QD, once daily; BID, twice daily. * Higher rates of hepatotoxicity in women with CD4 counts of >250 cells/µL and men with CD4 counts of >400 cells/µL prior to initiation of nevirapine. In these patients, nevirapine should be initiated only if the benefit outweighs the risk.

		There are no food restrictions.

		Nevirapine interacts with a number of antiretroviral medications; see nevirapine/other antiretroviral interaction table for information on recommended dosing adjustments.

		No dosage adjustment is necessary in renal insufficiency.

		Please consult product labeling for detailed dosing information.

		FDA Pregnancy Category B.

Nevirapine has been studied in several combination regimens for the treatment of HIV infection. Early trials comparing nevirapine-containing regimens with regimens of established potency were relatively small. In one small study, initial therapy with nevirapine + didanosine + stavudine compared favorably with the combination of efavirenz with the same 2 nucleoside analogues at 48 weeks of therapy.(2) A larger comparison of nevirapine with efavirenz, each combined with lamivudine + stavudine in initial therapy, found no significant difference between treatment arms in rates of virologic suppression or CD4 increase at 48 weeks.(3) This study also compared once-daily dosing of nevirapine with standard twice-daily dosing and found no significant differences in treatment outcomes between the two nevirapine arms. A large trial comparing once-daily extended release nevirapine with twice-daily immediate release formulation, each given in combination with emtricitabine + tenofovir in initial therapy, found comparable rates of HIV RNA suppression at 48 weeks.(4)

Small studies of initial treatment have found that the combination of nevirapine with several dual-nucleoside analogue backbones (emtricitabine + tenofovir, didanosine + stavudine, or lamivudine + zidovudine) compares favorably with atazanavir/ritonavir,(5) indinavir, (6) or nelfinavir (7) plus the same nucleoside analogues. In a small study, the combination of didanosine + tenofovir + nevirapine has demonstrated high rates of early virologic failure in treatment-naive individuals.(8) It is not yet known why this regimen resulted in high failure rates; pending further investigation, this combination should be avoided.

Nevirapine induces metabolism by the cytochrome P450 3A (CYP3A) enzyme system, affecting the levels of many coadministered drugs, including other antiretrovirals. For example, coadministration with nevirapine significantly reduces levels of the protease inhibitors fosamprenavir, indinavir, lopinavir, and saquinavir, as well as the NNRTI efavirenz. Similarly, drugs that induce the CYP3A system, such as rifampin and rifabutin, can decrease levels of nevirapine, whereas those that inhibit CYP3A activity (such as ketoconazole, cimetidine, and macrolide antibiotics) can increase nevirapine levels. Information on drug interactions should be consulted, as dose adjustments are frequently required and some combinations are contraindicated.

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate nevirapine, in combination with tenofovir/emtricitabine or zidovudine/lamivudine, as "acceptable" regimens for use in initial treatment of HIV infection. They also designate nevirapine plus abacavir/lamivudine as a regimen that "may be acceptable but more definitive data are needed."

Because females and patients with higher pretreatment CD4 levels are at increased risk of hepatotoxicity (see "Factors Affecting Adherence," below), it is recommended that nevirapine should not be initiated in adult females with CD4 counts of >250 cells/µL or in adult males with CD4 counts of >400 cells/µL unless the benefit outweighs the risk.(9)

The choice of protease inhibitor vs NNRTI in initial therapy is controversial. Treatment with an NNRTI usually consists of fewer pills, and may cause fewer chronic side effects, than treatment with a protease inhibitor. NNRTIs are therefore appealing for patients in whom convenience and tolerability are necessary for adherence. However, several resistance mutations are necessary to confer resistance to all protease inhibitors, whereas only a single mutation (K103N) is required to confer resistance against all first-generation NNRTIs. For this reason, poor adherence may result in more rapid failure of an NNRTI-based regimen, with more severe consequences for future treatment, than may be the case for a protease inhibitor-based regimen. On the other hand, the long half-lives of nevirapine and efavirenz may allow for occasional missed doses without serum levels falling enough to allow viral replication and selection of resistance.

Data on the effectiveness of nevirapine in subsequent regimens are limited. Subsequent regimens using NNRTIs appear most effective in individuals who have not previously experienced virologic failure while using drugs of this class.

A number of studies (for example 10) have found that switching from a protease inhibitor to nevirapine in the setting of a fully suppressive regimen (with undetectable viral load at the time of switching) does not increase the risk of virologic failure. However, this risk may be increased in antiretroviral-experienced individuals.(11)

Because virus resistant to all available NNRTIs is rapidly selected during failure of an NNRTI-containing regimen, it is important to assess patient motivation and discuss possible side effects and strategies for their management before treatment with nevirapine is initiated.

The most common symptomatic side effect of nevirapine is rash, usually occurring in the first 6 weeks of treatment. Nevirapine-associated skin reactions usually are mild to moderate but in some cases are severe and life threatening. Rash may also accompany hepatotoxicity (see below). Patients with rash should be evaluated carefully for signs of severe skin reaction and for liver toxicity. Women tend to be at higher risk than men for developing nevirapine-associated rash. Likelihood of rash is reduced by the recommended initiation of nevirapine at half treatment dose, with increase to full dose if no rash is present after 2 weeks. When this dose escalation is used, prophylactic corticosteroids do not appear to reduce the risk of rash.(12)

Symptomatic liver toxicity occurs in approximately 4% of patients taking nevirapine for treatment of HIV infection; this may be accompanied by rash. Because life-threatening hepatoxicity has occurred, transaminases should be monitored closely, especially during the first 18 weeks of treatment. The risk of hepatotoxicity is higher in females than in males, and higher in patients with higher CD4 counts (>250 cells/µL in women, and >400 cells/µL in men) at initiation of nevirapine therapy. Women with CD4 >250 cells/µL and men with CD4 >400 cells/µL prior to initiation of nevirapine should start nevirapine only if the potential benefit outweighs the risk.(9) Patients with chronic hepatitis B or C infection also appear to be at higher risk for hepatic events. It does not appear that single doses of nevirapine cause symptomatic liver toxicity in mothers and children who are given this drug for prevention of perinatal HIV infection.

In case of severe skin, liver, or hypersensitivity reaction, nevirapine must be discontinued permanently.

In individuals receiving methadone, nevirapine may precipitate symptoms of withdrawal by lowering blood levels of methadone through a pharmacokinetic interaction.(13) Increases in methadone dose should be considered when nevirapine therapy is initiated.

Resistance to nevirapine is associated with the selection of 1 or more of several resistance mutations.

Implications of nevirapine resistance for treatment with other antiretrovirals

Resistance mutations selected by nevirapine are typically associated with resistance to delavirdine and efavirenz, and also may result in resistance to etravirine.

Implications of resistance to other antiretrovirals for nevirapine treatment

Resistance to other NNRTIs usually is associated with resistance to nevirapine.

In a trial done in Uganda,(14) a perinatal regimen of nevirapine (single oral dose to the mother at onset of labor, followed by a single oral dose to the newborn) showed a dramatic reduction, comparable or superior to an oral zidovudine regimen, in mother-to-child transmission of HIV. However, HIV resistant to NNRTIs was detected in the blood of participating mothers 6 weeks following the single dose of nevirapine. Nevirapine-resistant virus was also detected in infants for whom the regimen did not prevent HIV transmission.(15) The resulting drug resistance can contribute to failure of subsequent NNRTI-containing treatment regimens.(16)