Nonnucleoside reverse transcriptase inhibitor
| Clinical Use|
| Use in Initial vs Subsequent Therapy|
Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services designate regimens containing nevirapine in combination with specified 2-nucleoside analogue backbones as "other" regimens for use in initial treatment of HIV infection.
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.
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 9) 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.(10)
| Potential Adverse Effects|
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 of 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.(11)
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 counts of >250 cells/µL and men with CD4 counts of >400 cells/µL prior to initiation of nevirapine should start nevirapine only if the potential benefit outweighs the risk.(12) Patients with chronic hepatitis B or C infection also appear to be at higher risk of 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.
Because virus resistant to all available NNRTIs can be selected rapidly during failure of a nevirapine-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.
| Interactions with Other Drugs|
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 most protease inhibitors (darunavir is an exception), as well as numerous other medications including some hormonal contraceptives and statins, phenytoin, phenobarbital, and methadone. 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 dosage adjustments are frequently required and some combinations are contraindicated.
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 and rilpivirine.
| Implications of resistance to other antiretrovirals for nevirapine treatment|
Resistance to other NNRTIs usually is associated with resistance to nevirapine.
| Special Uses|
Nevirapine has been used in various prophylaxis protocols to reduce risk of perinatal HIV transmission, for women who did not receive suppressive antiretroviral therapy during pregnancy, and their newborns. A regimen consisting of a single oral dose given to an HIV-infected mother at onset of labor, followed by a single oral dose to the newborn, showed a dramatic reduction in HIV transmission.(13) However, HIV resistant to NNRTIs was detected in the blood of participating mothers 6 weeks following the single dose of nevirapine, and nevirapine-resistant virus also was detected in infants for whom the regimen did not prevent HIV transmission.(14) The resulting drug resistance can contribute to failure of subsequent NNRTI-containing treatment regimens.(15) Other regimens that include nevirapine with nucleoside analogue tails have been used to further decrease the risk of HIV transmission while preventing the development of resistance to nevirapine. Nevirapine has also been given to breast feeding infants of HIV-infected mothers to prevent HIV transmission via breast milk.(16) These approaches may be indicated in resource-constrained settings, but combination maternal and infant antiretroviral prophylactic regimens are recommended, where available.
|| || D'Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med 1996;124:1019-30.|
|| ||Nunez M, Soriano V, Martin-Carbonero L, et al. The SENC trial: a randomized, open-label study comparing efavirenz versus nevirapine. Results at 48 weeks. The XIV International AIDS Conference, Barcelona, July, 2002. Abstract TuPeB4441.|
|| || van Leth F, Phanuphak P, Ruxrungtham K, et al; 2NN Study Team. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004 Apr 17;363(9417):1253-63.|
|| ||Gathe J, Bogner J, Santiago S, et al. Comparison of 48 week efficacy and safety of 400mg QD nevirapine extended release formulation (Viramune XR) versus 200mg BID nevirapine immediate release formulation (Viramune IR) in combination with Truvada in antiretroviral (ARV) naive HIV-1 infected patients (VERxVE). In: Program and abstracts of the XVIII International AIDS Conference; July 18-23, 2010; Vienna. Abstract THLBB202.|
|| ||Soriano V, Koppe S, Migrone H, et al. Prospective randomised comparison of Nevirapine and Atazanavir/ritonavir both combined with Tenofovir DF/Emtricitabine in treatment-naive HIV-1 infected patients: ARTEN Study week 48 results. In: Program and abstracts of the 5th International AIDS Congress; July 19-22, 2009, Cape Town, South Africa. Poster LBPEB07.|
|| || van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line combination therapy with or without a protease inhibitor in HIV-1-infected patients. AIDS 2003; 17(7):987-999.|
|| || Podzamczer D, Ferrer E, Consiglio E, et al. A randomized clinical trial comparing nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients (the Combine Study). Antivir Ther. 2002 Jun;7(2):81-90.|
|| || Leon A, Martinez E, Mallolas J, et al. Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine. AIDS 2005;28;19(2):213-5.|
|| || Negredo E, Cruz L, Paredes R, et al. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with human immunodeficiency virus infection and long-lasting viral suppression. in Infect Dis. 2002 Feb 15;34(4):504-10.|
|| ||Raffi F, Esnault JL, Reliquet V, et al. The Maintavir Study, Substitution of a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) for a Protease Inhibitor (PI) in Patients with Undetectable Plasma HIV-1 RNA: 18 Months Follow-Up. Abstract 474. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2000; Toronto.|
|| || Knobel H, Miro JM, Domingo P, et al; GESIDA 09/99 Study Group. Failure of a short-term prednisone regimen to prevent nevirapine-associated rash: a double-blind placebo-controlled trial: the GESIDA 09/99 study. J Acquir Immune Defic Syndr. 2001 Sep 1;28(1):14-8.|
|| ||Viramune (nevirapine) package insert, Boehringer Ingelheim Pharmaceuticals.|
|| || Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795-802.|
|| || Eshleman SH, Becker-Pergola G, et al. Impact of human immunodeficiency virus type 1 (hiv-1) subtype on women receiving single-dose nevirapine prophylaxis to prevent hiv-1 vertical transmission (hiv network for prevention trials 012 study). J Infect Dis. 2001 Oct 1;184(7):914-7.|
|| || Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al; Perinatal HIV Prevention Trial Group. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med. 2004 Jul 15;351(3):229-40.|
|| ||Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. July 31, 2012. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.|
|| || Clarke SM, Mulcahy FM, Tjia J, et al. Pharmacokinetic interactions of nevirapine and methadone and guidelines for use of nevirapine to treat injection drug users. Clin Infect Dis. 2001 Nov 1;33(9):1595-7.|