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Maternal Toxicity With Continuous Nevirapine in Pregnancy: Results From PACTG 1022
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JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 36(3) 1 July 2004
Hitti, Jane MD*; Frenkel, Lisa M. MD*; Stek, Alice M. MD†; Nachman, Sharon A. MD‡; Baker, David MD‡; Gonzalez-Garcia, Adolfo MD§; Provisor, Arthur MD?; Thorpe, Edwin M. MD¶; Paul, Mary E. MD#; Foca, Marc MD**; Gandia, Jorge MD††; Huang, Sharon MS‡‡; Wei, Lee-Jen PhD‡‡; Stevens, Laura M. BS§§; Watts, D. Heather MD¶¶; McNamara, James MD¶¶; for the PACTG 1022 Study Team
From the *University of Washington, Seattle, WA; †University of Southern California, Los Angeles, CA; ‡State University of New York, Stony Brook, NY; §University of Miami, FL; ?Columbus Regional Healthcare System, Columbus, GA; ¶University of Tennessee Health Science Center, Memphis, TN; #Baylor College of Medicine, TX; **Columbia University, New York, NY; ††City Hospital of San Juan, Puerto Rico; ‡‡Harvard School of Public Health, Boston, MA; §§Frontier Science and Technology Research Foundation, Buffalo, NY; and ¶¶National Institutes of Health, Bethesda, MD.
Received for publication March 31, 2004; accepted May 14, 2004.
This study was supported in part by the Pediatric AIDS Clinical Trials Group of the National Institute for Allergy and Infectious Diseases, the Pediatric/Perinatal HIV-1 Clinical Trials Network of the National Institute of Child Health and Development, and the General Clinical Research Center Units funded by the National Center for Research Resources. Agouron Pharmaceuticals: A Pfizer Company, Boehringer-Ingelheim Pharmaceuticals and GlaxoSmithKline Company donated the study medications.
"...These observations of hepatic toxicity in pregnancy, in our study and other published case reports agree with a recent meta-analysis suggesting that non-pregnant women with CD4 cell counts greater than 250 cells who receive continuous nevirapine are at increased risk for hepatic toxicity including fulminant hepatic failure and death. Men with higher CD4 cell counts are also at increased risk for hepatic toxicity, but at a greater CD4 threshold (400 cells/mL) compared with women. Thus, there appears to be an interaction between gender and immunologic status as risk factors for rash-associated hepatic toxicity with continuous nevirapine. While the exact mechanism for nevirapine-associated hepatic toxicity is not understood, an immune-mediated hypersensitivity component is postulated..."
Potent antiretroviral therapy is commonly prescribed for pregnant women to reduce maternal viral load and thereby minimize the risk of mother-to-child transmission of HIV-1, as well as to treat maternal HIV-1 disease when indicated. However, the relative safety and efficacy of specific antiretroviral medications have not been well defined in pregnancy. We initiated a prospective randomized trial, Pediatric AIDS Clinical Trials Group (PACTG) 1022, to evaluate the safety and efficacy of two frequently prescribed antiretroviral regimens for HIV-1-infected pregnant women. Enrollment into this trial was suspended after greater than expected toxicity was observed, and in response to changes in nevirapine prescribing information. The objectives of this report are to compare the protocol-defined treatment-limiting toxicities associated with nelfinavir compared with nevirapine, and to explore the association of nevirapine toxicity with initiation of HAART among women with higher CD4 cell counts.
Abstract
Objective: To compare the safety of nelfinavir and nevirapine-based antiretroviral treatment in HIV-1-infected pregnant women.
Methods: In Pediatric AIDS Clinical Trials Group Protocol 1022, 38 antiretroviral-naive pregnant women at 10-30 weeks' gestation were randomized to nelfinavir or nevirapine with zidovudine plus lamivudine. The study was suspended because of greater than expected toxicity and changes in nevirapine prescribing information. The incidence of treatment-limiting hepatic or cutaneous toxicity was compared between groups for all subjects and for the subset with CD4 cell counts greater than 250 cells/mL at study entry.
Results:
Twenty-one subjects were randomized to the nelfinavir arm and 18 subjects to the nevirapine arm for a total of 39 subjects. One subject in the nevirapine arm withdrew before treatment was dispensed. This report includes follow-up data on the remaining 38 subjects through January 1, 2004. baseline demographic and clinical characteristics were similar for each treatment group. Of note, 74% of subjects had an entry CD4 cell count greater than 250 cells, and all subjects were asymptomatic with respect to HIV-1. The median length of follow-up as of January 1, 2004 was 38 weeks and was similar between treatment arms.
Toxicity was seen in 1 (5%) of 21 subjects randomized to nelfinavir and 5 (29%) of 17 subjects randomized to nevirapine (P = 0.07). Within the nevirapine group, 1 subject developed fulminant hepatic failure and died, and another developed Stevens-Johnson syndrome. The one adverse event associated with nelfinavir occurred in a subject with a CD4 cell count less than 250 cells. All 5 events among subjects with a CD4 cell count greater than 250 cells were associated with nevirapine (P = 0.04).
Among the subset of participants with an entry CD4 cell count greater than 250 cells, 0 of 14 in the nelfinavir group and 5 (36%) of 14 in the nelfinavir (I think this is misprint, & they meant nevirapine) arm had toxicity leading to treatment discontinuation (P = 0.04). These adverse events occurred at 6 weeks on nelfinavir and at 2-26 (median 5) weeks on nevirapine.
Nevirapine-associated treatment-limiting toxicity included one subject with Stevens-Johnson syndrome, two subjects with an increase in ALT accompanied by non-specific symptoms thought by the managing clinicians to be possibly consistent with clinical hepatitis (Subjects 3 and 4), one subject with Grade 3 ALT without symptoms (Subject 5), and 1 subject with fulminant hepatic failure and death (Subject 6). The woman who died was a 33-year-old African American woman, gravida 2 para 1, who began study medications at 29 weeks' gestation. At study entry she had no laboratory evidence of hepatitis B or C, a normal ALT (59 U/L), an AST just above normal limits (49 U/L), and an entry CD4 cell count of 330 cells/mL (22%). Her other medications at study entry included prenatal vitamins, iron and pseudoephedrine as needed for sinus congestion. Two weeks later, her ALT and AST were 34 and 20 U/L, respectively. Four weeks after entry, she reported a transient facial rash that had resolved by the time of her study visit. Her ALT and AST had increased to 177 and 244 U/L. Six days later she presented with nausea, malaise, and jaundice, and she had an ALT of 1851 U/L and AST of 3288 U/L. She stopped all antiretroviral medications, was admitted to the hospital and 3 days later had a cesarean delivery of a viable 34-week male infant. She subsequently developed multi-system organ failure and died 3 days after delivery. A postmortem liver biopsy showed diffuse hepatic necrosis without steatosis or fibrosis. A full autopsy was not performed.
Conclusions: Continuous nevirapine may be associated with increased toxicity among HIV-1-infected pregnant women with CD4 cell counts greater than 250 cells/mL, as has been observed in non-pregnant women.
HIV-1 infected antiretroviral-naive pregnant women between 10-30 weeks' gestation were randomized to either nelfinavir (1250 mg twice daily) or nevirapine (200 mg once daily for two weeks and then 200 mg twice daily), which were administered with zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) in an open-label trial design. Eligibility criteria included an HIV-1 viral load greater than 1,000 copies/mL and the intention to continue antiretroviral therapy after delivery. Prior zidovudine monotherapy, limited to <8 weeks, was allowed. There was no restriction as to CD4 cell count at study entry. Women with a baseline alanine amino-transferase (ALT) greater than 2.5 times the upper limit of normal, active hepatitis B or C or other serious concurrent illness were not eligible to enroll in the trial.
The study protocol included stringent toxicity management guidelines that were applied uniformly across all centers. Abnormal ALT and aspartate aminotransferase (AST) values were graded according to the Division of AIDS toxicity guidelines for adults: Grade 0 < = 1.25 times the upper limit of normal; Grade 1 = 1.25-2.5 times the upper limit of normal; Grade 2 = 2.5-5.0 times the upper limit of normal; Grade 3 = 5.0-10.0 times the upper limit of normal; and Grade 4 = >10 times the upper limit of normal. Study treatment was stopped for a confirmed Grade 3 or 4 ALT or AST, any symptoms possibly consistent with clinical hepatitis at any grade ALT, or rash accompanied by urticaria, mucous membrane involvement or constitutional symptoms. Study personnel at each site were responsible for deciding whether non-specific symptoms were possibly consistent with clinical hepatitis and merited treatment discontinuation.
Enrollment was suspended in August 2003 because of greater than expected toxicity and changes in nevirapine prescribing information that recommended caution for women with CD4 cell counts greater than 250 cells. These events led to a previously unscheduled intent-to-treat interim analysis comparing the incidence of treatment-limiting toxicity by arm, for all subjects and also for the subset of women with an entry CD4 cell count greater than 250 cells. A 2-tailed Fisher exact test was used to determine statistical significance.
Author Discussion
We observed greater than expected toxicity associated with nevirapine during the first phase of this randomized trial. All of the adverse events in the nevirapine group occurred among women with an entry CD4 cell count greater than 250 cells. The hepatic necrosis seen on liver biopsy from the subject who died is consistent with drug-induced hepatic toxicity, possibly direct hepatocellular injury or an immunoallergic response. The absence of significant hepatic steatosis at the time of death, and the onset occurring early after initiation of HAART makes nucleoside analogue-associated hepatic steatosis unlikely.
The maternal death observed in this trial is similar to three other case reports of maternal death on nevirapine/zidovudine/lamivudine. Two additional cases of maternal mortality associated with nevirapine in pregnancy have been noted, beyond those cited above (Jorge Pinto, Escola de Medicina, Universidade Federal de Minas Gerais, personal communication; Patrick Robinson, Boehringer-Ingelheim Pharmaceuticals, personal communication).The common features of all 6 cases include fulminant hepatic failure presenting 4-5 weeks after starting nevirapine-based antiretroviral therapy, in antiretroviral-naive subjects with previously normal ALT and no history of hepatitis B or C. Four of these 6 cases occurred in women with a baseline CD4 cell count greater than 250 cells. Furthermore, in these cases hepatitis progressed rapidly to hepatic failure and death despite discontinuation of nevirapine and close clinical and laboratory monitoring. There is one additional published case report of severe but non-fatal hepatitis associated with nevirapine in a pregnant woman with an initial CD4 cell count greater than 600 cells/mL. These cases are also similar to reports of severe hepatic toxicity among HIV-1-negative individuals receiving nevirapine for post-exposure prophylaxis.
These observations of hepatic toxicity in pregnancy, in our study and other published case reports agree with a recent meta-analysis suggesting that non-pregnant women with CD4 cell counts greater than 250 cells who receive continuous nevirapine are at increased risk for hepatic toxicity including fulminant hepatic failure and death. Men with higher CD4 cell counts are also at increased risk for hepatic toxicity, but at a greater CD4 threshold (400 cells/mL) compared with women. Thus, there appears to be an interaction between gender and immunologic status as risk factors for rash-associated hepatic toxicity with continuous nevirapine. While the exact mechanism for nevirapine-associated hepatic toxicity is not understood, an immune-mediated hypersensitivity component is postulated.
It is difficult to estimate the true incidences of treatment-limiting toxicity and fulminant hepatic failure associated with continuous nevirapine use in pregnancy. At present, there are no reliable mechanisms to consistently identify and tabulate severe but non-fatal toxicity associated with antiretroviral therapy in pregnancy occurring outside of the context of a clinical trial. Thus, it is unknown whether pregnancy poses an additional risk for nevirapine-associated hepatic toxicity beyond the risk associated with female gender. It is also not possible to determine the incidence of fulminant hepatic failure and death associated with continuous nevirapine use in pregnancy, because the number of pregnant women who have received nevirapine-containing antiretroviral therapy is unknown.
The data from this and other reports should not be extrapolated to the use of single-dose intrapartum nevirapine to prevent mother-to-child HIV-1 transmission. In three large randomized trials, over 1,600 pregnant women received a single intrapartum dose of nevirapine without any increase in maternal toxicity. Similarly, this report does not imply that women who initiate nevirapine and tolerate it well should then discontinue nevirapine if they experience immune reconstitution. There is no evidence to suggest that immune reconstitution increases the risk of nevirapine-associated toxicity, regardless of pregnancy status. It is also not known whether antiretroviral-experienced women with immune reconstitution who switch to a nevirapine-containing regimen would have an increased risk of hepatic toxicity.The major limitation of this study is its small sample size, which could lead to an overestimate of the incidence of hepatic toxicity associated with nevirapine during pregnancy. It is possible that the increased incidence of nevirapine-associated hepatic adverse events observed in this trial will not be confirmed in larger data sets. In addition, since the majority of subjects in both treatment arms were asymptomatic and had CD4 cell counts greater than 250 cells, this study does not provide information about nevirapine-associated toxicity among pregnant women with more advanced HIV-1 disease and lower CD4 cell counts. However, the toxicities observed thus far in this small randomized trial may be clinically relevant even though the sample size is small. The single case of fulminant hepatic toxicity leading to death in our study, together with similar published case reports involving other pregnant women raise concern about the safety of continuous nevirapine in pregnancy in women with CD4 cell counts greater than 250 cells. Since these observations agree with much larger data sets from non-pregnant women, it would seem prudent to be cautious in the use of continuous nevirapine in pregnant women with CD4 greater than 250 cells. The safety of nevirapine-containing antiretroviral regimens for pregnant women with lower CD4 cell counts deserves additional investigation, especially since continuous nevirapine-containing antiretroviral treatment is rapidly becoming a first-line regimen for pregnant women in resource-limited countries.
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