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
Non-Nucleoside Reverse Transcriptase Inhibitors
Nevirapine (Viramune, NVP)
(Last updated:7/31/2012; last reviewed:7/31/2012)
Nevirapine (Viramune, NVP) is classified as FDA Pregnancy Category B.
Animal carcinogenicity studies
Nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. Hepatocellular adenomas and carcinomas were increased at all doses in male mice and rats and at higher doses in female mice and rats. Systemic exposure at all doses studied was lower than systemic exposure in humans receiving therapeutic nevirapine doses. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is unknown.
Evidence of impaired fertility was seen in female rats at nevirapine doses providing systemic exposure comparable to human therapeutic exposure.
Teratogenic effects of nevirapine have not been observed in reproductive studies with rats and rabbits at systemic exposures approximately equivalent to or 50% greater than the recommended human dose (based on AUC). In rats, however, a significant decrease in fetal weight occurred at doses producing systemic concentrations approximately 50% higher than human therapeutic exposure.
In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to nevirapine in humans have been monitored to be able to detect at least a 1.5-fold increase in risk of overall birth defects and a 2-fold increase in risk of birth defects in the more common classes, cardiovascular and genitourinary systems. No such increase in birth defects has been observed with nevirapine. Among cases of first-trimester nevirapine exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.7% (28 of 1,020 births; 95% CI, 1.8%–4.0 %) compared with a total prevalence of 2.7% in the U.S. population, based on Centers for Disease Control and Prevention surveillance.1
Placental and breast milk passage
Nevirapine crosses the placenta and achieves neonatal blood concentrations equivalent to that in the mother (cord-to-maternal blood ratio approximately 0.90).2 Nevirapine is excreted into human breast milk; the median concentration in 4 breast milk samples obtained from 3 women during the first week after delivery was approximately 76% (range 54%–104%) of serum levels.2 In 19 women receiving combination therapy with nevirapine, lamivudine, and zidovudine, breast milk nevirapine concentration was 6,795 ng/mL, which was 0.67 times that of maternal serum.3 Median nevirapine breast milk concentration was 4,564 ng/mL in a Kenyan study of 67 HIV-infected nursing mothers receiving a combination of zidovudine, lamivudine, and nevirapine.3 The median nevirapine concentration was 734 ng/mL in the infants who received the drug only via breast milk.
Human studies in pregnancy
Short-Term Peripartum Prophylaxis:
A Phase I study (PACTG 250) evaluated the safety and PKs of nevirapine administered to infected pregnant women as a single 200-mg dose at the onset of labor and as a single 2-mg/kg dose to infants aged 48 to 72 hours.2 No adverse effects were seen in the women or the infants.
The PK parameters of intrapartum nevirapine were similar in pregnant women and in non-pregnant adults, but variability was increased during pregnancy. Nevirapine elimination was prolonged in the infants. The regimen maintained serum concentrations associated with antiviral activity in the infants for the first week of life.
The safety, toxicity, and PKs of nevirapine were also studied in HIV-infected pregnant women beginning chronic therapy late in the third trimester and their infants.4 Initial-dose PK profiles in pregnant women were similar to those seen in non-pregnant adults. Serum nevirapine concentrations fell below the 100 ng/mL target concentration by Day 7 of life in four of eight infants, suggesting that nevirapine elimination was accelerated in infants whose mothers received chronic nevirapine administration compared with newborns whose mothers received only a single intrapartum dose.
The HIVNET 012 study in Uganda compared nevirapine (200 mg orally to the mother at the onset of labor and 2 mg/kg to the neonate within 72 hours of birth) with zidovudine (600 mg orally to the mother at the onset of delivery and 300 mg every 3 hours until delivery, and 4 mg/kg orally twice daily for the first 7 days of life to the neonate). In this study, nevirapine lowered the risk of transmission of HIV by nearly 50% during the first 14 to 16 weeks of life compared with zidovudine.5 However, the women in this African trial were not receiving any other ARV drugs.
In the United States, most infected women who know their HIV status during pregnancy receive combination ARV prophylaxis regimens, usually including zidovudine, as well as intravenous zidovudine during delivery, with 6 weeks of zidovudine given to their infant. A Phase III perinatal trial (PACTG 316) conducted in the United States, Europe, the Bahamas, and Brazil evaluated whether the HIVNET 012 single-dose nevirapine regimen in combination with standard combination prophylaxis regimens (at minimum the PACTG 076 zidovudine regimen; 77% of women in the trial received combination ARV regimens) would provide additional benefits in reducing transmission. Transmission was not significantly different between those who received single-dose nevirapine (1.4%) and those who did not (1.6%).6 Therefore, use of the single-dose nevirapine regimen is not recommended in women receiving combination regimens in the United States.
Longer Term Antenatal Combination Therapy (See also Nevirapine and Hepatic/Rash Toxicity):
The PKs of nevirapine have been evaluated in pregnant women receiving nevirapine as part of ART during pregnancy. A study that determined nevirapine PKs in 26 women during pregnancy (7 second trimester, 19 third trimester) and again in the same women 4 to 12 weeks after delivery found that pregnancy did not alter nevirapine PK parameters.7 In contrast, nevirapine clearance was 20% greater, AUC was 28% lower, and maximum plasma concentration was 30% lower in 16 pregnant women compared with 13 non-pregnant women, based on nevirapine PK data from a therapeutic drug monitoring program that included 12-hour sampling.8
Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure and severe, life-threatening hypersensitivity skin reactions, including Stevens-Johnson syndrome, have been reported in HIV-infected patients receiving nevirapine in combination with other drugs for treatment of HIV disease and in a small number of individuals receiving nevirapine as part of a combination regimen for post-exposure prophylaxis of nosocomial or sexual exposure to HIV.9 These toxicities have not been reported in women or infants receiving two-dose nevirapine (the HIVNET 012 regimen) for prevention of perinatal transmission. The greatest risk of severe rash or hepatic events occurs during the first 6 to 18 weeks of therapy, although the risk of toxicity continues past this period and monitoring should continue at frequent intervals.
Incidence of severe nevirapine-associated skin rash has been reported to be 5.5 to 7.3 times more common in women than men and has been reported in pregnant women.10-12 Other studies have found that hepatic adverse events with systemic symptoms (often rash) were 3.2-fold more common in women than men.13 Several studies suggest that the degree of risk of hepatic toxicity varies with CD4 T-lymphocyte (CD4-cell) count. In a summary analysis of data from 17 clinical trials of nevirapine therapy, women with CD4 counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4-cell counts to experience symptomatic, often rash-associated, nevirapine-related hepatotoxicity.13 Higher CD4-cell counts have also been associated with increased risk of severe nevirapine-associated skin rash.11 Rates of hepatotoxicity and rash similar to those in U.S. studies have been seen in international cohorts of non-pregnant women but not in association with CD4-cell counts >250 cells/mm3.14 In general, in controlled clinical trials, clinical hepatic events, regardless of severity, occurred in 4.0% (range 2.5%–11.0%) of patients who received nevirapine; however, the risk of nevirapine-associated liver failure or hepatic mortality has been lower, in the range of 0.04% to 0.40%.13,15 Severe or life-threatening rash occurs in approximately 2% of patients receiving nevirapine.15
Although deaths as a result of hepatic failure have been reported in HIV-infected pregnant women receiving nevirapine as part of a combination ARV regimen, it is uncertain if pregnancy increases the risk of hepatotoxicity in women receiving nevirapine or other ARV drugs.16 In an analysis of two multicenter prospective cohorts, pregnancy itself was a risk factor for liver enzyme elevations (RR 4.7; 95% CI, 3.4–6.5), although nevirapine use was not, regardless of pregnancy status.17 Additional data from the same cohorts did not show any increased risk of hepatotoxicity in HIV-infected pregnant women receiving nevirapine-based ART versus non-nevirapine-based ART.18In a cohort of 612 pregnant and non-pregnant women starting nevirapine-based therapy, CD4-cell count at initiation of therapy but not liver enzyme elevation was a predictor of rash; pregnancy was not an independent risk factor for the development of toxicity.19 These data suggest that nevirapine is no more toxic in pregnant women than in non-pregnant women.
Women initiating nevirapine with CD4-cell counts >250 cells/mm3, including pregnant women receiving ARV drugs solely for prevention of transmission, are at increased risk of developing symptomatic, often rash-associated, nevirapine-related hepatotoxicity, which can be severe, life threatening, and in some cases fatal.20 Therefore, nevirapine should be used as a component of a combination regimen in this setting only if the benefit clearly outweighs the risk. Women with CD4-cell counts <250/mm3 can receive nevirapine-based regimens, and women who become pregnant while taking nevirapine and who are tolerating their regimens well can continue therapy, regardless of CD4-cell count. Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission of HIV.
Because pregnancy itself can mimic some of the early symptoms of hepatotoxicity, health care providers caring for women receiving nevirapine during pregnancy should be aware of this potential complication. Frequent and careful monitoring of clinical symptoms and hepatic transaminases (that is, alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) is necessary, particularly during the first 18 weeks of therapy. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through 4 months, and every 1 to 3 months thereafter (Adult Antiretroviral Guidelines); in patients with pre-existing liver disease, monitoring should be performed more frequently when initiating therapy and monthly thereafter.21 Transaminase levels should be checked in all women who develop a rash while receiving nevirapine. Patients who develop suggestive clinical symptoms accompanied by elevation in serum transaminase levels (ALT and/or AST) or have asymptomatic but severe transaminase elevations should stop nevirapine and not receive the drug in the future.
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available at http://www.APRegistry.com.
- Mirochnick M, Fenton T, Gagnier P, et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. Pediatric AIDS Clinical Trials Group Protocol 250 Team. J Infect Dis. Aug 1998;178(2):368-374. Available at http://www.ncbi.nlm.nih.gov/pubmed/9697716.
- Shapiro RL, Holland DT, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis. Sep 1 2005;192(5):720-727. Available at http://www.ncbi.nlm.nih.gov/pubmed/16088821.
- Mirochnick M, Siminski S, Fenton T, Lugo M, Sullivan JL. Nevirapine pharmacokinetics in pregnant women and in their infants after in utero exposure. Pediatr Infect Dis J. Aug 2001;20(8):803-805. Available at http://www.ncbi.nlm.nih.gov/pubmed/11734746.
- 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. Sep 4 1999;354(9181):795-802. Available at http://www.ncbi.nlm.nih.gov/pubmed/10485720.
- Dorenbaum A, Cunningham CK, Gelber RD, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA. Jul 10 2002;288(2):189-198. Available at http://www.ncbi.nlm.nih.gov/pubmed/12095383.
- Capparelli EV, Aweeka F, Hitti J, et al. Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med. Apr 2008;9(4):214-220. Available at http://www.ncbi.nlm.nih.gov/pubmed/18366444.
- von Hentig N, Carlebach A, Gute P, et al. A comparison of the steady-state pharmacokinetics of nevirapine in men, nonpregnant women and women in late pregnancy. Br J Clin Pharmacol. Nov 2006;62(5):552-559. Available at http://www.ncbi.nlm.nih.gov/pubmed/17061962.
- Patel SM, Johnson S, Belknap SM, Chan J, Sha BE, Bennett C. Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-HIV-infected individuals. J Acquir Immune Defic Syndr. Feb 1 2004;35(2):120-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/14722442.
- Mazhude C, Jones S, Murad S, Taylor C, Easterbrook P. Female sex but not ethnicity is a strong predictor of non-nucleoside reverse transcriptase inhibitor-induced rash. AIDS. Jul 26 2002;16(11):1566-1568. Available at http://www.ncbi.nlm.nih.gov/pubmed/12131201.
- Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin Infect Dis. Jan 2001;32(1):124-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/11118391.
- Knudtson E, Para M, Boswell H, Fan-Havard P. Drug rash with eosinophilia and systemic symptoms syndrome and renal toxicity with a nevirapine-containing regimen in a pregnant patient with human immunodeficiency virus. Obstet Gynecol. May 2003;101(5 Pt 2):1094-1097. Available at http://www.ncbi.nlm.nih.gov/pubmed/12738113.
- Stern JO, Robinson PA, Love J, Lanes S, Imperiale MS, Mayers DL. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr. Sep 2003;34(Suppl 1):S21-33. Available at http://www.ncbi.nlm.nih.gov/pubmed/14562855.
- Peters PJ, Stringer J, McConnell MS, et al. Nevirapine-associated hepatotoxicity was not predicted by CD4 count >/=250 cells/muL among women in Zambia, Thailand and Kenya. HIV Med. Nov 2010;11(10):650-660. Available at http://www.ncbi.nlm.nih.gov/pubmed/20659176.
- Boehringer-Ingelheim Pharmaceuticals Inc. Viramune drug label. Revised March 25, 2011. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201152s000lbl.pdf. Accessed on June 25, 2012.
- Lyons F, Hopkins S, Kelleher B, et al. Maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy. HIV Med. May 2006;7(4):255-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/16630038.
- Ouyang DW, Shapiro DE, Lu M, et al. Increased risk of hepatotoxicity in HIV-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. AIDS. Nov 27 2009;23(18):2425-2430. Available at http://www.ncbi.nlm.nih.gov/pubmed/19617813.
- Ouyang DW, Brogly SB, Lu M, et al. Lack of increased hepatotoxicity in HIV-infected pregnant women receiving nevirapine compared with other antiretrovirals. AIDS. Jan 2 2010;24(1):109-114. Available at http://www.ncbi.nlm.nih.gov/pubmed/19926957.
- Aaron E, Kempf MC, Criniti S, et al. Adverse events in a cohort of HIV infected pregnant and non-pregnant women treated with nevirapine versus non-nevirapine antiretroviral medication. PLoS One. 2010;5(9):e12617. Available at http://www.ncbi.nlm.nih.gov/pubmed/20838641.
- Grimbert S, Fisch C, Deschamps D, et al. Effects of female sex hormones on mitochondria: possible role in acute fatty liver of pregnancy. Am J Physiol. Jan 1995;268(1 Pt 1):G107-115. Available at http://www.ncbi.nlm.nih.gov/pubmed/7840191.
- Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. Semin Liver Dis. May 2003;23(2):173-182. Available at http://www.ncbi.nlm.nih.gov/pubmed/12800070.