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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:3/28/2014; last reviewed:3/28/2014)

Nevirapine 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.

Reproduction/Fertility

Evidence of impaired fertility was seen in female rats at nevirapine doses providing systemic exposure comparable to human therapeutic exposure.

Teratogenicity/Developmental Toxicity

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 area under the curve [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 (APR), 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 more commonly seen classes of birth defects in the 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 APR, the prevalence of birth defects was 3.0% (31 of 1,049 births; 95% CI, 2.0% to 4.2 %) 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 demonstrates rapid and effective placental transfer, achieving near equivalent concentrations in maternal and cord blood (cord to maternal blood ratio ranging from 0.60–1.02).2,3 Nevirapine has also been shown to be excreted into human breast milk. In a study of 57 Malawian women receiving postpartum nevirapine-based therapy, breast milk to maternal serum concentration ratio was approximately 0.6; detectable nevirapine concentrations were found in the breastfeeding infants (intra-quartile range 0.54–1.06 ug/mL).4 In data from 15 breastfeeding women receiving nevirapine-based therapy in Botswana, median maternal plasma concentration at 1 month postpartum was 6.71 ug/mL and median maternal breast milk concentration was 1.83 ug/mL, for a median maternal breast milk to plasma ratio of 0.27.5 Infant exposure was measured at 1 month in nine infants; all infants had biologically significant detectable nevirapine concentrations in their blood, with a median level of 0.37 ug/mL (range, 0.24–1.2 ug/mL), representing approximately 6% of median maternal value. Similar data were reported in a study of 67 mothers receiving nevirapine-based therapy in Kenya; the median concentration of nevirapine in breast milk was 4.55 ug/mL, with median concentrations at 2, 6, and 14 weeks postpartum in breastfeeding infants of 0.99 ug/mL, 1.03 ug/mL and 0.73 ug/mL, respectively.6

Human Studies in Pregnancy

The pharmacokinetics (PKs) of nevirapine have been evaluated in pregnant women receiving nevirapine as part of combination antiretroviral therapy (cART) 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; they also reported high variability in plasma nevirapine concentrations.8 A Dutch study reported a non-significant trend toward lower nevirapine exposure during pregnancy, with steady-state nevirapine concentrations of 5.2 ug/mL in 45 pregnant women compared to 5.8 ug/mL in 152 non-pregnant women (P = 0.08).9 No dose adjustment during pregnancy is currently recommended for nevirapine.

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—has 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 cART for post-exposure prophylaxis of nosocomial or sexual exposure to HIV.10 In general, in controlled clinical trials, clinical hepatic events, regardless of severity, occurred in 4.0% (range 2.5% to 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%.11,12 Risk of severe or life-threatening adverse events occurs in approximately 2% of patients receiving nevirapine.11 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.13-15 Other studies have found that hepatic adverse events with systemic symptoms (often rash) were 3.2-fold more common in women than men.12 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 cell 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.12 Higher CD4 cell counts have also been associated with increased risk of severe nevirapine-associated skin rash.14 Rates of hepatotoxicity and rash similar to those in U.S. studies have been seen in international cohorts of non-pregnant women, although not all have reported an association with CD4 cell counts >250 cells/mm3.16 In a study of 359 non-pregnant women randomized to nevirapine-based therapy in sub-Saharan Africa, higher nevirapine exposure was associated with development of severe skin toxicity, and baseline CD4 cell counts ≥250 cells/mm3 was associated with nevirapine-related liver toxicity and drug discontinuation.17 Some researchers have suggested that genetic variation in drug metabolism polymorphisms (e.g., CYP2B6 variants) and immune human leukocyte antigen loci may be associated with higher risk of nevirapine-associated adverse events and that the relationship between genetic variants and adverse effects may vary by race.18,19 

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 whether pregnancy increases the risk of hepatotoxicity in women receiving nevirapine or other antiretroviral drugs.20 In a systematic review of 20 studies including 3,582 pregnant women from 14 countries, the pooled proportion of women experiencing a severe hepatotoxic event was 3.6% (95% CI, 2.4% to 4.8%) and severe rash was 3.3% (95% CI, 2.1% to 4.5%); overall 6.2% of women stopped nevirapine due to an adverse event (95% CI, 4.0% to 8.4%).21 These results were comparable to published frequencies in the general adult population and frequencies comparable to non-pregnant women within the same cohorts. These data suggest that the frequency of adverse events associated with nevirapine during pregnancy is not higher than reported for nevirapine in the general population, consistent with data from two multicenter prospective cohorts in which pregnancy was not associated with an increased risk of nevirapine-associated hepatic toxicity.22,23

In the systematic review, there was a non-significant trend toward an increased likelihood of cutaneous events (OR 1.1, 95% CI, 0.8–1.6) and severe cutaneous adverse events in pregnant women with CD4 cell counts ≥250 cell/mm3 (OR 1.4, 95% CI 0.8-2.4).21 A separate systematic review of 14 studies did report a significant association of increased toxicity risk with initiation of nevirapine-based therapy during pregnancy in women with CD4 cell counts ≥250 cells/mm3.24 Nevirapine should be used as a component of a combination regimen in pregnant women with CD4 cell counts ≥250 cells/mm3 only if the benefit clearly outweighs the risk. Women with CD4 cell counts <250 cells/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.

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 (i.e., 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, and then monthly for the first 18 weeks (Adult and Adolescent Antiretroviral Guidelines); in patients with pre-existing liver disease, monitoring should be performed more frequently when initiating therapy and monthly thereafter.25 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.

References

  1. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2013. 2013. Available at http://www.APRegistry.com. Accessed March 5, 2014.
  2. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the fetal compartment (placenta and amniotic fluid). Antivir Ther. 2011;16(8):1139-1147. Available at http://www.ncbi.nlm.nih.gov/pubmed/22155898.
  3. Benaboud S, Ekouevi DK, Urien S, et al. Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates. Antimicrob Agents Chemother. 2011;55(1):331-337. Available at http://www.ncbi.nlm.nih.gov/pubmed/20956588.
  4. Palombi L, Pirillo MF, Andreotti M, et al. Antiretroviral prophylaxis for breastfeeding transmission in Malawi: drug concentrations, virological efficacy and safety. Antivir Ther. 2012;17(8):1511-1519. Available at http://www.ncbi.nlm.nih.gov/pubmed/22910456.
  5. Shapiro RL, Rossi S, Ogwu A, et al. Therapeutic levels of lopinavir in late pregnancy and abacavir passage into breast milk in the Mma Bana Study, Botswana. Antivir Ther. 2013;18(4):585-590. Available at http://www.ncbi.nlm.nih.gov/pubmed/23183881.
  6. Mirochnick M, Thomas T, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. Antimicrob Agents Chemother. 2009;53(3):1170-1176. Available at http://www.ncbi.nlm.nih.gov/pubmed/19114673.
  7. Capparelli EV, Aweeka F, Hitti J, et al. Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med. 2008;9(4):214-220. Available at http://www.ncbi.nlm.nih.gov/pubmed/18366444.
  8. 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. 2006;62(5):552-559. Available at http://www.ncbi.nlm.nih.gov/pubmed/17061962.
  9. Nellen JF, Damming M, Godfried MH, et al. Steady-state nevirapine plasma concentrations are influenced by pregnancy. HIV Med. 2008;9(4):234-238. Available at http://www.ncbi.nlm.nih.gov/pubmed/18366447.
  10. 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. 2004;35(2):120-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/14722442.
  11. Food and Drug Administration. Nevirapine Drug Label. 2011. Accessed on February 14, 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201152s000lbl.pdf
  12. 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.
  13. 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.
  14. 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.
  15. 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. 2003;101(5 Pt 2):1094-1097. Available at http://www.ncbi.nlm.nih.gov/pubmed/12738113.
  16. 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.
  17. Dong BJ, Zheng Y, Hughes MD, et al. Nevirapine pharmacokinetics and risk of rash and hepatitis among HIV-infected sub-Saharan African women. AIDS. 2012;26(7):833-841. Available at http://www.ncbi.nlm.nih.gov/pubmed/22301417.
  18. Yuan J, Guo S, Hall D, et al. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent. AIDS. 2011;25(10):1271-1280. Available at http://www.ncbi.nlm.nih.gov/pubmed/21505298.
  19. Carr DF, Chaponda M, Jorgensen AL, et al. Association of human leukocyte antigen alleles and nevirapine hypersensitivity in a malawian HIV-nfected population. Clin Infect Dis. 2013;56(9):1330-1339. Available at http://www.ncbi.nlm.nih.gov/pubmed/23362284.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. Bera E, Mia R. Safety of nevirapine in HIV-infected pregnant women initiating antiretroviral therapy at higher CD4 counts: a systematic review and meta-analysis. S Afr Med J. 2012;102(11 Pt 1):855-859. Available at http://www.ncbi.nlm.nih.gov/pubmed/23116743.
  25. 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.