Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine (Viramune, NVP)

Summary

• No dose adjustments are required for nevirapine (NVP) during pregnancy.
• First-trimester exposure to NVP is not associated with increased risk of congenital anomalies.
• Data are conflicting regarding the risk of hepatotoxicity in pregnancy. Skin reactions appear to be increased with NVP use during pregnancy.

Human Studies in Pregnancy

Pharmacokinetics

The pharmacokinetic (PK) studies in pregnant women who received NVP as part of antiretroviral therapy (ART) during pregnancy demonstrate varied results. A study of 26 women during their second and third trimesters did not find altered PK parameters compared to the postpartum period¹; however, two other studies found up to 30% lower exposure in pregnancy.^2,3 No dose adjustment is recommended currently for NVP during pregnancy.

Placental and Breast Milk Passage

NVP demonstrates rapid and effective placental transfer, achieving near-equivalent concentrations in maternal and cord blood (cord blood–to–maternal plasma ratio ranges from 0.60 to 1.02).^4,5

NVP also has been shown to be excreted into human breast milk, with breast milk–to–maternal plasma ratios of 0.27 to 0.6 and detectable NVP concentrations in breastfeeding infants.^6-8

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to NVP to detect at least a 1.5-fold increase in risk of overall birth defects and a twofold increase in risk of birth defects in the cardiovascular and genitourinary systems (the most common classes of birth defects in the general population). No such increase in the risk of birth defects has been observed with NVP. Among the cases of first-trimester NVP exposure that have been reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 3.1% (36 of 1,178 live births; 95% confidence interval [CI], 2.1% 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.⁹ Similarly, the French Perinatal Cohort reported no association between exposure to NVP and birth defects, with 71% power to detect a 1.5-fold increase.¹⁰ During 2013 and 2014, at one KwaZulu hospital, one-time nurse-performed exams found a significantly higher risk ratio of total congenital malformations in infants with first-trimester NVP exposure (relative risk = 9.28, 2.27–37.94); 2 out of 52 infants with NVP exposure versus 29 out of 7,592 without NVP exposure.¹¹

Other Safety Information

The risk of NVP-associated severe, life-threatening, and (in some cases) fatal hepatotoxicity—including fulminant and cholestatic hepatitis; hepatic necrosis; hepatic failure; and severe, life-threatening hypersensitivity skin reactions, including Stevens-Johnson syndrome—ranges from 0.04% to 0.40%.^12,13 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 patients should be monitored regularly for signs of toxicity.

Incidence of severe NVP-associated skin rash has been reported to be 5.5 times to 7.3 times more common in women than men. In 17 clinical trials of NVP therapy, women with CD4 counts >250 cells/mm³ were 9.8 times more likely to experience symptomatic, often rash-associated, NVP‑related hepatotoxicity than women with lower CD4 counts.¹³ Higher CD4 counts also have been associated with an increased risk of severe, NVP-associated skin rash.¹⁴

Rates of hepatotoxicity and rash similar to those in U.S. studies have been seen in international cohorts of nonpregnant women, although not all studies have reported an association between rates of hepatotoxicity and rash and CD4 counts >250 cells/mm³. Some researchers have suggested that genetic variation in drug metabolism polymorphisms (e.g., cytochrome P450 Family 2 Subfamily B Member 6 [CYP2B6] variants), tumor necrosis factor receptor–associated factor proteins, and immune human leukocyte antigen loci may be associated with a higher risk of NVP-associated adverse events and that the relationship between genetic variants and adverse events may vary by race.^15-18 Published literature reports rash and hyperbilirubinemia in infants exposed to NVP through breast milk.¹²

Data are conflicting regarding the increased risk of hepatotoxicity in pregnant women receiving NVP.¹⁹ In a systematic review of 20 studies that included 3,582 pregnant women from 14 countries who initiated NVP while pregnant, the pooled proportion of women who experienced a severe hepatotoxic event was 3.6% (95% CI, 2.4% to 4.8%), and the proportion of women who experienced severe rash was 3.3% (95% CI, 2.1% to 4.5%); overall, 6.2% of women stopped taking NVP because of an adverse event (95% CI, 4.0% to 8.4%).²⁰ These results were comparable to published frequencies in the general adult population and comparable to frequencies in nonpregnant women within the same cohorts; publications by Ouyang and colleagues echo these results.^21,22 In contrast, an analysis of data collected in the United Kingdom and Ireland from 2000 to 2011 evaluated 3,426 women, one-quarter of whom were pregnant, and found that pregnant women who were taking efavirenz, maraviroc, or NVP had an increased risk of liver enzyme elevation.²³

Two systematic reviews and a small case-control study additionally indicate that pregnancy appears to increase the risk of cutaneous events, such as Stevens-Johnson syndrome. The systematic review discussed above also reported nonsignificant trends toward increased risk of cutaneous events (odds ratio [OR] 1.1; 95% CI, 0.8–1.6) and severe cutaneous adverse events in pregnant women with CD4 counts ≥250 cell/mm³ (OR 1.4; 95% CI, 0.8–2.4).²⁰ Another systematic review²⁴ reported a significant association between increased toxicity risk and the initiation of NVP-based ART therapy in pregnant women with CD4 counts ≥250 cells/mm³. A case-control study (6 cases, 30 controls) in South Africa reported that pregnancy increased the risk of Stevens-Johnson syndrome (OR 14.28; P = 0.006; 95% CI, 1.54‍–‍131.82).²⁵ NVP (as a component of a combination regimen) should be initiated in pregnant people with CD4 counts ≥250 cells/mm³ only if the benefit clearly outweighs the risk. Pregnant patients with CD4 counts <250 cells/mm³ can receive NVP-based regimens, and patients who become pregnant while taking NVP and who are tolerating their regimens well can continue using those regimens, regardless of their CD4 counts.

Because pregnancy itself can mimic some of the early symptoms of hepatotoxicity (i.e., pregnancy-related nausea and vomiting), health care providers caring for pregnant patients who are receiving NVP should be aware of this potential complication. Frequent and careful monitoring of clinical symptoms and hepatic transaminases (i.e., alanine aminotransferase and aspartate aminotransferase) 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; in patients with pre‑existing liver disease, monitoring should be performed more frequently when initiating therapy and monthly thereafter.²⁶ Transaminase levels should be checked in all patients who develop a rash while receiving NVP. Patients who develop suggestive clinical symptoms accompanied by elevation in serum transaminase levels or who have asymptomatic but severe transaminase elevations should stop taking NVP and not receive the drug in the future.

In a retrospective study at eight government hospitals in Botswana, women who received ART that contained NVP were more likely to experience certain adverse events than women on ART that did not contain NVP. Such events include hypertension (30% vs. 16%), severe hypertension (3.3% vs. 1.2%), gestational hypertension (18% vs. 10%), and early gestational hypertension (12% vs. 7%).²⁷

Animal Studies

Carcinogenicity

NVP showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. Hepatocellular adenoma and carcinomas are increased at all doses of NVP in mice and rats; however, given the lack of genotoxic activity of NVP, it is unclear if this is relevant to humans.¹²

Reproduction/Fertility

Female rats showed impaired fertility at systemic NVP exposures comparable to human therapeutic exposures.¹²

Teratogenicity/Adverse Pregnancy Outcomes

In studies of rats and rabbits, no teratogenic effects of NVP have been observed other than a significant decrease in fetal weight in rats at systemic concentrations 50% higher than human therapeutic exposure.¹²

Excerpt from Table 14

References

1. 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: https://pubmed.ncbi.nlm.nih.gov/18366444.
2. 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: https://pubmed.ncbi.nlm.nih.gov/17061962.
3. 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: https://pubmed.ncbi.nlm.nih.gov/18366447.
4. 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: https://pubmed.ncbi.nlm.nih.gov/22155898.
5. 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: https://pubmed.ncbi.nlm.nih.gov/20956588.
6. 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: https://pubmed.ncbi.nlm.nih.gov/22910456.
7. 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: https://pubmed.ncbi.nlm.nih.gov/23183881.
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9. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989–31 January Morrisville, NC: Registry Coordinating Center; 2023.Available at:https://www.apregistry.com.
10. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French Perinatal Cohort Study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at: https://pubmed.ncbi.nlm.nih.gov/24781315.
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13. Stern JO, Robinson PA, Love J, et al. 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: https://pubmed.ncbi.nlm.nih.gov/14562855.
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: https://pubmed.ncbi.nlm.nih.gov/11118391.
15. 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: https://pubmed.ncbi.nlm.nih.gov/21505298.
16. Carr DF, Chaponda M, Jorgensen AL, et al. Association of human leukocyte antigen alleles and nevirapine hypersensitivity in a Malawian HIV-infected population. Clin Infect Dis. 2013;56(9):1330-1339. Available at: https://pubmed.ncbi.nlm.nih.gov/23362284.
17. Ciccacci C, Rufini S, Mancinelli S, et al. A pharmacogenetics study in Mozambican patients treated with nevirapine: full resequencing of TRAF3IP2 gene shows a novel association with SJS/TEN susceptibility. Int J Mol Sci. 2015;16(3):5830-5838. Available at: https://pubmed.ncbi.nlm.nih.gov/25775161.
18. Carr DF, Chaponda M, Cornejo Castro EM, et al. CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations. J Antimicrob Chemother. 2014;69(12):3329-3334. Available at: https://pubmed.ncbi.nlm.nih.gov/25147095.
19. 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: https://pubmed.ncbi.nlm.nih.gov/16630038.
20. Ford N, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine use in pregnancy: a systematic review and meta-analysis. AIDS. 2013;27(7):1135-1143. Available at: https://pubmed.ncbi.nlm.nih.gov/23299174.
21. 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: https://pubmed.ncbi.nlm.nih.gov/19926957.
22. 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: https://pubmed.ncbi.nlm.nih.gov/19617813.
23. Huntington S, Thorne C, Anderson J, et al. Does pregnancy increase the risk of ART-induced hepatotoxicity among HIV-positive women? J Int AIDS Soc. 2014;17(4 Suppl 3):19486. Available at: https://pubmed.ncbi.nlm.nih.gov/25393995.
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: https://pubmed.ncbi.nlm.nih.gov/23116743.
25. Dube N, Adewusi E, Summers R. Risk of nevirapine-associated Stevens-Johnson syndrome among HIV-infected pregnant women: the Medunsa National Pharmacovigilance Centre, 2007-2012. S Afr Med J. 2013;103(5):322-325. Available at: https://pubmed.ncbi.nlm.nih.gov/23971123.
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27. Zash R, Williams P, Jacobson D, et al. Increased risk of hypertension in pregnancy among women on nevirapine--‐based regimens. Poster 803. Presented at: Conference on Retroviruses and Opportunistic Infections; 2018. Boston, Massachusetts. Available at: https://www.croiconference.org/abstract/increased-risk-hypertension-pregnancy-among-women-nevirapine-based-regimens/.