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Third-Trimester Maternal Toxicity With Nevirapine Use in Pregnancy

From the ¹Department of Obstetrics and Gynecology, ²Pharmacy Practice and Administration, ³Department of Pediatrics, and ⁴Division of Infectious Diseases, Colleges of Medicine and Pharmacy, Ohio State University, Columbus, Ohio.

	ABSTRACT

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OBJECTIVE: Nevirapine-based therapy is associated with increased frequency of adverse events among women with CD4⁺ cell count of 250 cells/µL or greater. We evaluated the safety of nevirapine-based antiretroviral therapy in human immunodeficiency virus (HIV)-1-infected pregnant women.

METHODS: We retrospectively evaluated 23 pregnancies managed with nevirapine-based regimens from July 2001 to April 2005. The incidence of adverse events was determined and analyzed by CD4⁺ cell count of either less than or greater than or equal to 250 cells/µL, and gestational age when nevirapine was initiated. Liver function abnormality was graded according to the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity guidelines.

RESULTS: Five of 23 patients (21.7%) started nevirapine-based therapy after 27 weeks of gestation. All 3 cases of adverse events occurred in this group within 6 weeks of initiating therapy and with CD4⁺ cell count greater than 250 cells/µL. A significant difference was noted in the proportion of patients who developed toxicity while starting nevirapine in the third trimester (3/5, 60%; 95% confidence interval 14.66–94.73) compared with those starting nevirapine earlier in pregnancy (0/18, 0%; 95% confidence interval 0.0–18.53; P < .006). Two patients developed rash, eosinophilia, and liver function abnormality, with one developing clinical hepatitis and renal failure. A third patient had abnormal elevation of liver enzymes but was asymptomatic.

CONCLUSION: The incidence of adverse events with nevirapine may be lower than previously reported (13% versus 29%) and may be primarily noted with initiating the drug late in pregnancy. Further study of nevirapine in larger cohorts of HIV-infected pregnant women is warranted to determine the relationship between nevirapine hepatotoxicity and trimester use.

LEVEL OF EVIDENCE: II-3

The use of combination antiretroviral regimens is now routinely recommended in pregnant HIV-1–infected women to improve maternal health and reduce perinatal HIV-1 transmission by maximally suppressing maternal viral load.³ Nevirapine, a potent nonnucleoside reverse transcriptase inhibitor, is well absorbed after oral administration, possesses a long half-life (25–30 hours), and distributes readily across the placenta.⁴ The favorable pharmacokinetic profile of nevirapine permits a simplified dosage and inexpensive regimen to prevent perinatal transmission, especially in developing countries.^5,6 The HIV Network for Prevention Trial (HIVNET) 012 demonstrated that a short-course oral therapy of nevirapine 200 mg administered to the mothers at the onset of labor and 2 mg/kg to breastfed babies further reduced the risk of HIV-1 transmission by 47% up to age 14–16 weeks compared with zidovudine.⁵ Additionally, the single-dose nevirapine regimen has not been shown to have any major safety concerns.^5,7,8

In the United States, the combination of nevirapine and 2 nucleoside reverse transcriptase inhibitors has been commonly used for HIV-infected pregnant women. Recent data based on large numbers of nonpregnant women have raised concerns of serious nevirapine-associated hepatotoxicity, often rash-associated, among women with CD4 cell counts of 250 cells/µL or greater.⁹ Additionally, a recent report from the Pediatric AIDS Clinical Trial Group 1022 study identified nevirapine as being associated with higher rates of maternal toxicity in pregnancy than previously observed.¹⁰ Our objective was to retrospectively examine the safety of nevirapine-based antiretroviral therapy in HIV-1-infected pregnant women in our center.

	MATERIALS AND METHODS

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The Ohio State University Medical Center implemented the HIV High-Risk Pregnancy Clinic in collaboration with the Ohio State University Infectious Diseases Division and AIDS Clinical Trials Unit and Family with AIDS Clinical and Education Services at Children’s Hospital of Columbus to provide comprehensive care to pregnant women with HIV-1 infection. The Institutional Review Board approved the study to collect and analyze patient demographic information, virologic, immunologic, and laboratory results, and maternal, pregnancy, and newborn outcomes. We reviewed the records of all HIV-1–infected pregnant women treated at the HIV High-Risk Pregnancy Clinic from July 2001 to April 2005 to identify all pregnant women treated with nevirapine-based antiretroviral therapy during the antepartum period. Maternal outcomes after delivery were collected from reviewing clinical charts among women with nevirapine-associated toxicities. The incidence of cutaneous and/or hepatic toxicity was estimated according to the National Institute of Allergy and Infectious Diseases Division of AIDS toxicity grading scales.^10,11 Patients were stratified by CD4⁺ cell counts of either less than or equal to or greater than 250 cells/µL and the gestational age at the start of nevirapine-based regimens for data analysis. Laboratory results were compared between baseline (before nevirapine-based antiretroviral therapy) and after initiation of therapy. Severity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were graded in accordance with the National Institute of Allergy and Infectious Diseases toxicity guidelines as follows: grade 0, less than 1.25 x upper normal limit; grade 1, 1.25–2.5 x upper normal limit; grade 2, 2.5–5 x upper normal limit; grade 3, 5–10 x upper normal limit; and grade 4, more than 10 x upper normal limit.^10,11 Because current Public Health Service guidelines do not recommend continuation of antiretroviral therapy in patients with high CD4⁺ cell counts and low viral loads, postpartum data regarding hepatotoxicity were not available, with most patients stopping antiretroviral therapy at delivery.¹² A systematic PubMed search of literature in English was conducted from January 1980 to the July 2005 using the MeSH key words, "DRESS syndrome," "hepatotoxicity," "nevirapine," "third trimester," and "pregnancy." Statistical differences between groups were evaluated with a 2-tailed Fisher exact test.

	RESULTS

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Since July 2001, we have managed 55 HIV-1–infected pregnant women. At the time of manuscript preparation, 7 patients remain undelivered. Of the 48 delivered patients, 23 patients (48.9%) received antepartum chemoprophylaxis with nevirapine-based antiretroviral therapy. The demographic and clinical characteristics of these nevirapine recipients are summarized in Table 1. Seventeen of 23 (73.9%) HIV-1–infected pregnant women were antiretroviral treatment–naïve with all being nevirapine-naïve. Twenty patients (87%) had entry CD4⁺ counts greater than 250 cells/µL. Only one patient presented with oral and esophageal candidiasis at the initial prenatal care clinic visit. All patients had normal baseline ALT and AST levels at the start of nevirapine therapy. One patient (4.4%) started the nevirapine-containing regimen preconceptionally, whereas the other 22 started during pregnancy: 7 patients (30.4%) at less than 14 weeks, 10 patients (43.5%) between 14 weeks and less than 27 weeks, and 5 patients (21.7%) between 27 and 32 weeks. The fixed-dose combination, zidovudine 300 mg + lamivudine 150 mg (Combivir; GlaxoSmithKline, Brentford, Middlesex, UK), given twice daily, was the most common dual nucleoside analogue drug prescribed during pregnancy. Oral nevirapine was administered at 200 mg daily for the first 2 weeks, then increased to twice daily. Adverse events were observed in 3 (13%) of the 23 subjects. Two patients developed drug rash, eosinophilia, and systemic symptoms, with more than grade 2–3 ALT and AST elevation. One of these 2 patients developed clinical hepatitis and renal failure. The clinical hepatitis resolved 12 weeks after discontinuing nevirapine therapy.¹³ Although the third patient was asymptomatic, she had elevated AST (grade 2) and ALT (grade 3) that returned to baseline while continuing on nevirapine-containing therapy (Table 2). Concurrent medication at the onset of nevirapine-associated adverse events in all 3 patients included only prenatal multivitamin and 2 nucleoside reverse transcriptase inhibitor backbone combinations. None of the 3 patients had a commonly recognizable complication of pregnancy including preeclampsia, hemolysis elevated liver enzymes, and low platelets (HELLP) syndrome, pruritic urticarial papules and plaques of pregnancy (PUPP) syndrome, or acute fatty liver of pregnancy. All adverse events occurred within the first 6 weeks after initiation of nevirapine, and in women with CD4⁺ count greater than 250 cells/µL when nevirapine was started during the third trimester. A significant difference was noted in the fraction of women starting nevirapine in the third trimester who developed hepatic toxicity (3/5) compared with those who started nevirapine in the first or second trimester (0/18) (P < .006). The estimated proportion and the 95% exact binomial confidence interval (CI) for nevirapine-associated hepatic toxicity during first or second trimesters and third trimester are 0/18, 0% (95% CI 0.00–18.53) and 3/5, 60% (95% CI 14.66–94.73), respectively. None of these patients with hepatic toxicity had a medical history (antibody-negative) of hepatitis B or C.

	DISCUSSION

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The Pediatric AIDS Clinical Trial Group 1022 study¹⁰ reported that nevirapine was associated with increased toxicity among five of 17 HIV-1–infected pregnant women (29%) who had CD4⁺ counts greater than 250 cells/µL. Our data show that, while hepatic toxicity may occur with nevirapine, the incidence may be lower (3 of 23 [13%] patients) and may be primarily noted with initiating late in pregnancy. Other studies have shown a similar lower incidence of nevirapine-associated toxicity, but this third-trimester association with nevirapine has not previously been reported in the literature (Kramer F, Stek A, Du WB, Kovacs A. Nevirapine tolerability in HIV-infected women in pregnancy [abstract 923]. ROI 2004 (Retroviruses Opportunistic Infections), Available at: www.retroconference.org. Retrieved January 10, 2005; Bershoff-Matcha SJ, Mundy LM, Henry JV. Adverse events to nevirapine therapy during pregnancy [abstract 939]. ROI 2004 (Retroviruses Opportunistic Infections), Available at: www.retroconference.org. Retrieved January 10, 2005).¹⁴

The occurrence of hepatic toxicity may be more frequent within the first 8 weeks of initiating nevirapine therapy (Kramer et al [abstract]; Bershoff-Matsha et al [abstract]). In a recent study, 49/121 (37%) patients received nevirapine after 24 weeks of pregnancy, and 25/121 (20.9%) women had an adverse reaction to nevirapine (Kramer et al [abstract]). However, information was not available as to the percentage that initiated nevirapine therapy in the third trimester and subsequently developed an adverse event. Of note, only 3/121 (2.5%) had severe toxicity (grade 3), and only 1/121 (0.8%) had a grade 2 rash. In an earlier study of 46 women treated with nevirapine in pregnancy, hepatic toxicity occurred in 4.3%. The association with trimester use and toxicity was not reported (Bershoff-Matsha et al [abstract]). Finally, the tolerability and safety of nevirapine-containing regimens were compared between nonpregnant and pregnant women.¹⁴ Of the 153 HIV-infected women who received nevirapine therapy, 58 (37.9%) were pregnant and 95 (62.1%) were nonpregnant. Hepatotoxicity was defined as more than 3 x the upper normal limit of ALT and AST. No difference in the occurrence of rash was observed between pregnant and nonpregnant women taking nevirapine-containing regimens (8.6% versus 10.5%, 95% CI 0.8 [0.3–2.5], P = .701). Nevirapine therapy was associated with significantly more hepatotoxicity in pregnant than nonpregnant HIV-infected women (19.0% versus 4.2%, 95% CI 5.3 [1.6–17.6], P = .003). Equal rates for hepatitis C and/or hepatitis B were reported in both treatment groups. Unfortunately, no information was provided regarding gestational age at the start of nevirapine use among pregnant HIV-infected women.¹⁴

In the Pediatric AIDS Clinical Trial Group 1022 study, only 1 patient of 5 with an adverse event started nevirapine in the third trimester.¹⁰ Unfortunately, this patient suffered the most severe reaction, with fulminant hepatic failure and maternal death. Two of their 5 cases of adverse events occurred postpartum. Three of their 5 cases of adverse events occurred within 5 weeks of initiating therapy. Nevirapine-induced hepatitis remains a major concern, given several case reports that reveal a rapid progression to hepatic failure and death (Langlet P, Guillaume MP, Devriendt J, Deprez C, Vokaer A, De Koster E, et al. Fatal liver failure associated with nevirapine in a pregnant HIV patient: the first reported case [abstract 6623]. Gastroenterology 2000;118:A1461; Lyons F, Hopkins S, McGeary A, Sheehan G, Bergin C, Mulcahy F. Nevirapine tolerability in HIV infected women in pregnancy – a word of caution [abstract LB27]. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, 2003. Available at: www.ias.se/abstract/show.asp?abstract_id=11081. Retrieved January 10, 2005).¹⁰

The exact mechanism for nevirapine-induced rash and hepatotoxicity remains unknown. The reported risk factors include female sex and higher baseline CD4⁺ count ( 250 cells/µL).^3,15 Our finding on the association of third-trimester use of nevirapine and maternal hepatotoxicity, with or without rash, is intriguing. Serious liver diseases of pregnancy, such as intrahepatic cholestasis, acute fatty liver, and preeclampsia-eclampsia, commonly occur during the third trimester.^16,17 We cannot determine whether there is a link in the timing of starting nevirapine in the third trimester with pregnancy-related liver diseases because our patients with nevirapine-associated adverse events clinically improved after discontinuation of nevirapine. If these cases were related to liver disease of pregnancy, the symptoms and findings would have continued to worsen despite discontinuation of nevirapine.

Nevirapine undergoes extensive hydroxylation by primarily CYP3A4 and CYP2B6, and to lesser extents, CYP2D6 and CYP2C9.¹⁸ The metabolism of nevirapine is slow, with a mean elimination half-life (t_1/2ß) of 40 hours after initial doses, but the mean elimination half-life is decreased to 20–30 hours after long-term dosing, suggesting an autoinduction of the metabolic pathway by nevirapine.^19,20 The recommended dosage schedule for nevirapine is 200 mg once daily for the first 2 weeks, followed by 200 mg twice daily. The rationale for the dose escalation is to prevent high nevirapine plasma levels and cutaneous and other toxicities during the induction phase.

A possible relationship between nevirapine plasma levels and adverse events has been reported. In a study of nevirapine monotherapy, an increased incidence of skin rash was noted with the high-dose (400 mg/day) compared with the low-dose (200 mg/day) nevirapine therapy. Similar association was also noted among pediatric patients receiving nevirapine. In the initial clinical trials of nevirapine treatment in HIV-infected children, a 24% incidence of rash was reported in those receiving high-dose nevirapine therapy.²¹ The incidence of rash decreased to 4.7% when a 2-week lower dose "lead in" period was studied.²² In patients with chronic hepatitis C virus coinfection, nevirapine concentrations of more than 6 µg/mL were associated with a 92% risk of hepatotoxicity compared with control.²³

Pregnancy is associated with profound physiologic changes that may affect drug disposition. Numerous studies have reported altered activity of CYP 2D6 and CYP 3A4 with advancing pregnancy compared with the nonpregnant state.^24,25 Longitudinal changes in the steady-state peak concentration (C_max) and area under the curve (AUC) of nevirapine during second- and third-trimester pregnancy and postpartum were recently reported as part of the Pediatric AIDS Clinical Trial Group 1022 study (Aweeka F, Lizak P, Frenkel L, Au S, Watts H, McNamara J, et al; PACTG 1022 Study Team. Steady state nevirapine pharmacokinetics during second and third trimester pregnancy and postpartum: PACTG 1022 [abstract 932]. ROI 2004 (Retroviruses Opportunistic Infections). Available at: www.retroconference.org. Retrieved January 10, 2005). A decrease in the C_max and AUC was observed during the second, compared with the third trimester and postpartum. The mean peak concentrations of nevirapine at second and third trimesters and postpartum were 5.3, 7.0, and 7.0 µg/mL, respectively (Aweeka et al [abstract]). This relative increase of nevirapine during the third trimester may suggest a decrease in the hepatic metabolism of nevirapine. This reported C_max of nevirapine during the third trimester is greater than the nevirapine concentration associated with a risk of hepatotoxicity in other studies (Aweeka et al [abstract]).²³ These pharmacokinetic findings may support the association between third-trimester nevirapine use and increased adverse events.

It is important to note that the most recent Public Health Service Task Force "Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States" (February 24, 2005)³ state that "Nevirapine should be initiated in pregnant women with CD4⁺ cell counts > 250 cells/µL only if benefit clearly outweighs risks, due to the increased risk of potentially life-threatening hepatotoxicity in women with high CD4⁺ cell counts. Women who enter pregnancy on nevirapine regimens and are tolerating them well may continue therapy, regardless of CD4⁺ cell counts." Given the findings of Pediatric AIDS Clinical Trial Group 1022 and the current "Black-Box" warning in the nevirapine (Viramune; Boehringer-Ingelheim, Ridgefield, CT) package insert documenting the increased risk for hepatotoxicity in HIV-infected women with CD4⁺ cell counts greater than 250 cells/µL, it is unlikely that significant studies will be conducted to inform clinicians about how to manage HIV-infected patients who become pregnant while being successfully and safely managed on a nevirapine-containing regimen or who have infection that is resistant to HIV-1 protease inhibitors.

Limitations of our study include the small sample size and retrospective data collection, but it should be noted that the Pediatric AIDS Clinical Trial Group 1022 had a similar number of participants.¹⁰ Our findings reveal a lower incidence (13%) of nevirapine-associated toxicity, consistent with other recent reports, and provide evidence that support previously identified risks for hepatic toxicity in HIV-infected pregnant women (Kramer et al [abstract]; Bershoff-Matsha et al [abstract]).¹⁶ Furthermore, all of our cases of adverse events occurred when nevirapine was initiated in the third trimester in women with CD4⁺ cell counts greater than 250 cells/µL. The availability of a safe nonnucleoside reverse transcriptase inhibitor would be valuable for HIV-infected women with high CD4⁺ cell counts who are intolerant of or have infection resistant to HIV-1 protease inhibitor–containing regimens. Close monitoring of nevirapine-associated adverse events is prudent, especially if nevirapine use is initiated during the third trimester. Specific reasons for the increased nevirapine-associated adverse events during the third trimester remain to be elucidated. Well-designed pharmacokinetic studies of nevirapine in larger cohorts of HIV-infected pregnant women are warranted to determine the risks and relationship between nevirapine hepatic toxicity and third-trimester use.

	Footnotes

 
Supported, in part, by Health Resources and Services Administration Ryan White Title IV grant H12HA00032120 and National Institute of Allergy and Infectious Diseases grant AI25924 to the Ohio State University’s AIDS Clinical Trials Unit.

Presented at the Society for Gynecologic Investigation Annual Clinical Meeting, Los Angeles, California, March 26, 2005.

Corresponding author: Patty Fan-Havard, PharmD, Division of Pharmacy Practice and Administration, College of Pharmacy, 500 West 12th Avenue, Columbus, OH 43210-1291; e-mail: havard.1{at}osu.edu.

doi:10.1097/01.AOG.0000180182.00072.e3

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Joy, S. Articles by Fan-Havard, P. Search for Related Content PubMed PubMed Citation Articles by Joy, S. Articles by Fan-Havard, P.