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
General Principles Regarding Use of Antiretroviral Drugs during Pregnancy
Nevirapine and Hepatic/Rash Toxicity
(Last updated:3/28/2014; last reviewed:3/28/2014)
- Nevirapine-based regimens should be initiated in women with CD4 T lymphocyte (CD4) cell counts >250 cells/mm3 only if the benefits clearly outweigh the risks because of the drug’s potential for causing hepatic toxicity/hypersensitivity reaction (AII).
- Women who become pregnant while receiving nevirapine-containing regimens and who are tolerating the regimen well can continue on the therapy regardless of CD4 cell count (AII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
Increases in hepatic transaminase levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) associated with rash or systemic symptoms may be observed during the first 18 weeks of treatment with nevirapine. Signs and symptoms of systemic toxicity may be nonspecific and can include fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, or hepatomegaly with or without initially abnormal hepatic transaminases.1 Development 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.2,3 Other studies have found that hepatic adverse events with systemic symptoms (predominantly rash) were 3.2-fold more common in women than in men.4,5 The degree of risk of rash and hepatic toxicity also appears to vary with CD4 T lymphocyte (CD4) cell count. In a summary analysis of data from 17 clinical trials of nevirapine therapy, women with CD4 cell counts >250 cells/mm3 were 9.8 times more likely than women with lower CD4 cell counts to experience symptomatic, rash-associated, nevirapine-related hepatotoxicity;4 a single-center study also found higher CD4 cell counts to be associated with increased risk of severe nevirapine-associated skin rash.2 CD4 cell counts >250 cells/mm3 predicted rash illness, but not liver enzyme elevation, among pregnant and non-pregnant women initiating nevirapine-based combination antiretroviral therapy (cART) in 3 U.S. university clinics.6 Other international cohorts of non-pregnant women have experienced hepatotoxicity and rash at similar rates as in U.S. studies, but not in association with CD4 cell counts >250 cells/mm3.7 In general, in controlled clinical trials, hepatic events, regardless of severity, have occurred in 4.0% (range 0% to 11.0%) of patients who received nevirapine; severe or life-threatening rash has occurred in approximately 2% of patients receiving nevirapine.8
Several early reports of death due to hepatic failure in HIV-infected pregnant women receiving nevirapine as part of cART raised concerns that pregnant women might be at increased risk of hepatotoxicity from nevirapine compared with other antiretroviral (ARV) drugs.9,10 However, more recent data challenge the notion that nevirapine is uniquely associated with increased hepatotoxicity during pregnancy.11-13 A meta-analysis of data from 3,582 pregnant women included in 20 studies did not find any evidence of increased risk of nevirapine-related adverse events in pregnant women compared with non-pregnant adults. Nevertheless, if nevirapine is used in pregnancy, health care providers should be aware of potential hepatotoxicity with or without rash and should conduct frequent and careful monitoring of clinical symptoms and hepatic transaminases (i.e., ALT and AST), particularly during the first 18 weeks of nevirapine use. Some clinicians measure serum transaminases at baseline, every 2 weeks for the first month, monthly through Month 4, and every 1 to 3 months thereafter (see the Hepatotoxicity section of the table on Antiretroviral Therapy-Associated Common and/or Severe Adverse Effects in the Adult and Adolescent Antiretroviral Guidelines). In patients with pre-existing liver disease, ARV medications other than nevirapine should be considered. If nevirapine is selected, monitoring should be performed more frequently when initiating nevirapine and monthly thereafter.1 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 who have asymptomatic but severe transaminase elevations (i.e., more than 5 times the upper limit of normal) should stop nevirapine and not receive nevirapine again in the future.
Hepatic toxicity has not been seen in women receiving single-dose nevirapine during labor for prevention of perinatal transmission of HIV.14 Women who enter pregnancy on nevirapine-containing regimens and are tolerating them well can continue therapy, regardless of CD4 cell count.
- Kontorinis N, Dieterich DT. Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. Semin Liver Dis. 2003;23(2):173-182. Available at http://www.ncbi.nlm.nih.gov/pubmed/12800070.
- Bersoff-Matcha SJ, Miller WC, Aberg JA, et al. Sex differences in nevirapine rash. Clin Infect Dis. 2001;32(1):124-129. Available at http://www.ncbi.nlm.nih.gov/pubmed/11118391.
- 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. 2002;16(11):1566-1568. Available at http://www.ncbi.nlm.nih.gov/pubmed/12131201.
- Baylor MS, Johann-Liang R. Hepatotoxicity associated with nevirapine use. J Acquir Immune Defic Syndr. 2004;35(5):538-539. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15021321.
- 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. 2003;34 Suppl 1:S21-33. Available at http://www.ncbi.nlm.nih.gov/pubmed/14562855.
- 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.
- 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. 2010;11(10):650-660. Available at http://www.ncbi.nlm.nih.gov/pubmed/20659176.
- Food and Drug Aministration. Viramune drug label. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020933s028,020636s037lbl.pdf. Last accessed on February 25, 2014.
- Lyons F, Hopkins S, Kelleher B, et al. Maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy. HIV Med. 2006;7(4):255-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/16630038.
- Hitti J, Frenkel LM, Stek AM, et al. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. J Acquir Immune Defic Syndr. 2004;36(3):772-776. Available at http://www.ncbi.nlm.nih.gov/pubmed/15213559.
- 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. 2009;23(18):2425-2430. Available at http://www.ncbi.nlm.nih.gov/pubmed/19617813.
- Ford N, Calmy A, Andrieux-Meyer I, Hargreaves S, Mills EJ, Shubber Z. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis. AIDS. 2013. Available at http://www.ncbi.nlm.nih.gov/pubmed/23299174.
- Ouyang DW, Brogly SB, Lu M, et al. Lack of increased hepatotoxicity in HIV-infected pregnant women receiving nevirapine compared with other antiretrovirals. AIDS. 2010;24(1):109-114. Available at http://www.ncbi.nlm.nih.gov/pubmed/19926957.
- McKoy JM, Bennett CL, Scheetz MH, et al. Hepatotoxicity associated with long- versus short-course HIV-prophylactic nevirapine use: a systematic review and meta-analysis from the Research on Adverse Drug events And Reports (RADAR) project. Drug Saf. 2009;32(2):147-158. Available at http://www.ncbi.nlm.nih.gov/pubmed/19236121.