In developed countries, the use of highly active antiretroviral

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1 RAPID COMMUNICATION Antiretroviral-Associated Toxicity Among HIV-1 Seropositive Pregnant Women in Mozambique Receiving Nevirapine-Based Regimens Lilia Jamisse, MD, MPH,* Jennifer Balkus, MPH, Jane Hitti, MD, MPH, Steve Gloyd, MD, MPH, Rolanda Manuel, MD,* Nafissa Osman, MD, PhD, k Martinho Djedje, MD, PhD,* and Carey Farquhar, MD, MPH Objective: To assess toxicities associated with highly active antiretroviral therapy (HAART) among HIV-1 infected pregnant women treated with nevirapine-based regimens according to Mozambican national guidelines. Study Design: Prospective cohort study. Methods: HIV-1 infected antiretroviral-naive pregnant women with CD4 counts #350 cells/ml were initiated on nevirapine, lamivudine, and stavudine or zidovudine and followed monthly. Severe hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels $5-fold the upper limit of normal. Analyses were stratified by baseline CD4 count (,250 vs cells/ml). Results: Among 146 pregnant women, 75 (52%) began nevirapine, lamivudine, and zidovudine and 71 (48%) began nevirapine, lamivudine, and stavudine. Overall, 79 (54%) women had CD4 counts,250 cells/ml, 7 (5%) had grade II hepatotoxicity, and 4 (3%) had severe (grade III or IV) hepatotoxicity. All 4 women with severe hepatotoxicity had baseline CD4 counts $250 cells/ml (P = 0.02). Rates of skin toxicity, anemia, and peripheral neuropathy did not differ by CD4 cell count group. Overall, 12 (8%) women changed or discontinued HAART as a result of drug toxicity. Received for publication August 18, 2006; accepted December 28, From the *Ministry of Health, Maputo, Mozambique; Department of Health Services, University of Washington, Seattle, WA; Department of Obstetrics and Gynecology, University of Washington, Seattle, WA; Department of Epidemiology, University of Washington, Seattle, WA; k Central Hospital of Maputo, Maputo, Mozambique; and {Department of Medicine, University of Washington, Seattle, WA. Supported by the University of Washington s AIDS International Training and Research Program (AITRP) funded by the US National Institutes of Health, Fogarty International Center grant D43 TW000007, and the Office of Research on Women s Health. L. Jamisse and J. Balkus were AITRP scholars. C. Farquhar received support from National Institute of Child Health and Human Development grant K23 HD Written informed consent was obtained from all study participants. This study received ethical approval from the University of Washington s Institutional Review Board and the National Review Board and Ethics Committee in Mozambique and was conducted according to the guidelines set forth by the US Department of Health and Human Services. Reprints: Carey Farquhar, MD, MPH, 325 Ninth Avenue, University of Washington, PO Box , Seattle, WA ( cfarq@u. washington.edu). Copyright Ó 2007 by Lippincott Williams & Wilkins Conclusions: Severe hepatotoxicity from nevirapine-containing HAART in this cohort of pregnant women was more common at higher CD4 counts (6% vs. 0% among women with CD4 counts $250 cells/ml and CD4 counts,250 cells/ml, respectively), suggesting that laboratory monitoring is necessary when administering nevirapine-containing regimens to pregnant women with CD4 counts $250 cells/ml. Key Words: hepatotoxicity, highly active antiretroviral therapy, mother-to-child HIV-1 transmission, nevirapine, pregnancy (J Acquir Immune Defic Syndr 2007;44: ) In developed countries, the use of highly active antiretroviral therapy (HAART) for prevention of mother-to-child transmission (MTCT) of HIV-1 has been shown to reduce rates of in utero and intrapartum transmission effectively to,2%. 1 4 With the introduction of the World Health Organization s (WHO) 3 by 5 initiative, 5 antiretroviral therapy has become more widely available, thus making HAART an option for HIV-1 infected pregnant women in resource-limited settings. At a recent WHO technical meeting on MTCT, it was recommended that HAART be considered for persons with CD4 cell counts,350 cells/ml who have stage I or II clinical disease. 6 For HIV-1 infected pregnant women meeting these clinical criteria, HAART can be initiated at any point during pregnancy. 6,7 One of the primary concerns regarding the use of HAART among pregnant women is antiretroviral-associated toxicity. Nevirapine (NVP)-associated toxicity (hepatotoxicity or skin toxicity), although uncommon, is more likely to occur in women than in men, 8 and some studies have found that it is more common in women with relatively elevated CD4 counts (.250 cells/ml). 9,10 In addition, more frequent hepatotoxicity has been observed among pregnant women compared with nonpregnant women taking NVP-based HAART regimens. 11 When this study was initiated, Mozambican guidelines followed those of the WHO and recommended an NVPcontaining HAART regimen as first-line therapy for pregnant women. The objective of the current study was to evaluate the use of an NVP-containing HAART regimen to prevent MTCT of HIV-1 in an urban resource-limited setting, specifically examining associations between toxicity and maternal CD4 cell count. J Acquir Immune Defic Syndr Volume 44, Number 4, April 1,

2 Jamisse et al J Acquir Immune Defic Syndr Volume 44, Number 4, April 1, 2007 METHODS Study Design and Enrollment of Participants We conducted a prospective cohort study of HIV-1 infected pregnant women and their infants in Maputo, Mozambique. The country has an established integrated health network for the detection, prevention, and treatment of HIV/AIDS. Activities in this study followed the standard referral system and adhered to procedures established at the national level for medical treatment. Antiretroviral therapy used in this study was provided in accordance with established Mozambican national guidelines, which state that all HIV-1 infected women with CD4 cell counts #350 cells/ml should begin HAART during pregnancy and continue treatment postpartum, regardless of their clinical status. 12 Currently, the first regimen offered to pregnant women through national programs includes NVP. Women seeking antenatal care were offered voluntary counseling and testing for HIV-1 (opt-in approach), and HIV- 1 seropositive women of any gestational age were referred to the study hospital, where they received CD4 cell count testing. Written informed consent was obtained from those interested in participating who met the following eligibility criteria: HIV- 1 seropositive,.16 weeks of gestation at enrollment, $18 years old, HAART naive, and CD4 count #350 cells/ml. Women who had previously used single-dose NVP for the prevention of MTCT of HIV-1 were eligible to participate. Women with CD4 counts.350 cells/ml or with clinical conditions that could be aggravated by antiretroviral therapy, such as elevated baseline liver transaminases ($grade III); severe anemia (hemoglobin,7.0 g/ml), and psychiatric disorders were not eligible for the study. Those who were not eligible or who did not consent to be enrolled were referred to other appropriate services for treatment or prophylaxis. Thus, all HIV-1 seropositive women with CD4 counts #350 cells/ml had access to prevention of MTCT services regardless of their participation in the study. Study Procedures At enrollment, an oral questionnaire was administered by a trained study nurse to collect demographic, socioeconomic, and health information. A physical examination was conducted by the study physician, which included an assessment of pregnancy status, overall health, and AIDS disease stage using WHO guidelines. Baseline blood tests included a complete blood cell count (including hemoglobin); aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine measurements, urinalysis, and syphilis testing. All study participants were given iron, folate, multivitamins, and mebendazole and women with symptomatic sexually transmitted infections (STIs) were treated according to the national guidelines using a syndromic approach. Study participants were asked to return 2 weeks after enrollment to begin HAART and were treated with a first-line regimen of NVP, lamivudine (3TC), and zidovudine (ZDV). For women with moderate or severe anemia at enrollment (hemoglobin,8.5 g/ml), stavudine (d4t) was substituted for ZDV. Not all women initiated d4t because of baseline anemia, however. ZDV was periodically unavailable as a result of inconsistent drug distribution, and in these instances, women were treated with d4t regardless of baseline hemoglobin. In cases of contraindication or toxicity, NVP was replaced by nelfinavir (NLF). Participants were seen 1 to 2 weeks after initiating HAART to assess adherence and side effects. Subsequent antenatal follow-up visits took place monthly until 34 weeks of gestation, after which they occurred every 2 weeks until delivery. All study participants were referred to the Central Hospital of Maputo for delivery. Data were collected on the duration of pregnancy and the mode, complications, and outcome of delivery. Postpartum visits occurred 1 week after delivery and then monthly thereafter for 6 months from the time of HAART initiation. At each follow-up visit (antenatal and postnatal), information was collected regarding disease status, side effects, and adverse clinical events. Blood samples were collected to test for liver function and anemia (ALT, AST, and hemoglobin) at 1 to 2 weeks, 1 month, 3 months, and 6 months after HAART initiation. Follow-up CD4 cell counts were performed between 3 and 6 months after starting HAART. Definition of Toxicities Side effects and toxicities were managed according to national guidelines. 12 The regimen was changed if there was severe hepatotoxicity, skin toxicity, peripheral neuropathy, or anemia. Severe hepatotoxicity (grade III or IV) was defined as AST or ALT concentration $5 times the upper limit of normal; moderate (grade II) and mild (grade I) hepatotoxicity were defined as.2.5 times and.1.25 times the upper limit of normal, respectively. Severe skin toxicity was defined as the occurrence of Stevens-Johnson syndrome, confirmed by at least 2 physicians. Severe anemia was defined as hemoglobin,7.0 g/ml and moderate anemia as hemoglobin,8.5 g/ml. Severe neuropathy was defined as acute numbness or pain of the fingertips and toes, including distal paresthesias, as determined by a physician. Laboratory Assays HIV-1 antibody testing was conducted using 2 rapid HIV-1 enzyme-linked immunosorbent assay (ELISA) tests that were performed sequentially. The initial test was conducted using the Determine HIV-1 EIA test (Abbott Laboratories, Abbott Park, IL), with the Uni-Gold Recombigen HIV-1 EIA test (Trinity Biotech, Bray, Wicklow, Ireland) for confirmation of positive samples. CD4 T-cell counts, liver enzymes, and hemoglobin measurements were carried out at the Central Hospital of Maputo using standard assays. Statistical Analysis Our analysis examined associations between CD4 cell count at baseline and the following toxicities: hepatotoxicity, skin toxicity, anemia, and peripheral neuropathy. The Pearson x 2 test was used to examine associations between CD4 cell count groups (CD4 count,250 vs. CD4 $250 and #350 cells/ml) and categoric demographic and toxicity data. The Wilcoxon rank sum test with unequal variances was used to examine this association with continuous variables. These analyses were performed using STATA version 9.0 (Stata Corporation, College Station, TX). 372 q 2007 Lippincott Williams & Wilkins

3 J Acquir Immune Defic Syndr Volume 44, Number 4, April 1, 2007 Antiretroviral Toxicity in Pregnancy RESULTS Enrollment, Follow-Up, and Cohort Characteristics From August 2004 to June 2005, we enrolled 163 HIV- 1 seropositive pregnant women from a peripheral hospital in Maputo, Mozambique. Of these 163 women, 12 (7%) never returned to begin HAART and 2 (1%) were lost to follow-up after initiating HAART (Fig. 1). In addition, 3 women did not begin HAART until after delivery: 1 because of severe anemia (hemoglobin = 5.5 g/ml), 1 because of elevated liver enzymes (ALT = 208 IU/L), and 1 as a result of delays in the health system. These women were excluded from this analysis, leaving 146 HIV-1 seropositive pregnant women who started HAART antenatally (see Fig. 1). Demographic and health characteristics at enrollment are displayed in Table 1. The median age for this cohort was 27 years (interquartile range [IQR]: years), 93 (64%) study participants were married or had a regular partner, and 73 (50%) had completed secondary school or higher education. The median gestational age at enrollment was 26 weeks (IQR: weeks), and the median CD4 count was 231 cells/ml (IQR: cells/ml). Despite CD4 counts #350 cells/ml, our study population was relatively healthy, with most (57%) participants having WHO stage I or II disease. Fifty-nine (40%) women were categorized as having stage III disease, and 4 (3%) had stage IV disease (see Table 1). On average, study participants initiated HAART 24 days (IQR: days) after enrollment. Seventy-five (52%) women began NVP, 3TC, and ZDV, and 71 (48%) women began NVP, 3TC, and d4t. The median duration of follow-up from the initiation of HAART was 39 weeks (range: 9 58 weeks), and the duration of follow-up did not vary by CD4 cell count or initial HAART regimen (P = 0.3 and P = 0.8, respectively). FIGURE 1. Enrollment and follow-up. 1 One woman was lost to follow-up 2 weeks after initiating HAART, and 1 woman moved away 2 months after initiating HAART. TABLE 1. Demographic and Health Characteristics at Enrollment for 146 HIV-1 Seropositive Pregnant Women,250 Cells/mL (n = 79) Number (%) or Median (IQR) $250 Cells/mL (n = 67) Number (%) or Median (IQR) Age (y) 27 (24 30) 27 (24 30) Gestational age (wk) 26 (21 30) 27 (23 32) Secondary school education or greater 37 (47) 36 (55) Married or has regular partner 48 (61) 45 (67) HAART regimen d4t/3tc/nvp 41 (52) 30 (45) ZDV/3TC/NVP 38 (48) 37 (55) Duration of follow-up (wk) 38 (32 48) 40 (28 49) Hemoglobin,8.5 g/ml 13 (16) 6 (9) ALT $1.25-fold upper normal limit 4 (5) 2 (3) WHO disease stage Stage I 32 (40) 31 (46) Stage II 11 (14) 9 (13) Stage III 34 (43) 25 (37) Stage IV 2 (3) 2 (3) HAART-Associated Hepatotoxicity The frequency of hepatotoxicity and skin toxicity by CD4 cell count is displayed in Table 2. Eleven (8%) women experienced some degree of hepatotoxicity ($grade II) during follow-up, and 4 of these women experienced severe TABLE 2. Toxicity and Side Effects of Women Taking HAART During Follow-Up,250 Cells/mL (n = 79) Number (%) $250 Cells/mL (n = 67) Number (%) Hepatic toxicity* 5 (6) 6 (9) 0.55 Severe 0 (0) 4 (6) 0.02 Changed regimen 4 (6) Skin toxicity 8 (10) 6 (9) 0.81 Severe 1 (1) 3 (5) 0.23 Changed regimen 1 (1) 3 (5) Anemia 15# (23) 10** (16) 0.37 Severe k 6 (9) 2 (3) 0.18 Changed regimen 2 (3) 2 (3) Peripheral neuropathy 14 (18) 12 (18) 0.97 Severe{ 1 (1) 0 (0) 0.35 Changed regimen 0 (0) *ALT or AST $2.5-fold upper normal limit. ALT or AST $5-fold upper normal limit. Stevens-Johnson syndrome. Hemoglobin,8.5 g/ml. k Hemoglobin,7.0 g/ml. {Severe numbness of fingertips and toes, including distal paresthesias, as determined by a physician. #N = 66. **N = 61. P q 2007 Lippincott Williams & Wilkins 373

4 Jamisse et al J Acquir Immune Defic Syndr Volume 44, Number 4, April 1, 2007 hepatotoxicity. Clinical information for study participants with severe hepatotoxicity is displayed in Table 3. All 4 women who experienced severe hepatotoxicity had baseline CD4 counts $250 and #350 cells/ml (P = 0.02), and none developed a rash. The median time from initiation of HAART to diagnosis of severe hepatotoxicity was 4.5 weeks (IQR: 4 10 weeks). Three women changed to a NLF-based regimen, and 1 woman stopped all antiretroviral therapy (see Table 3). HAART-Associated Skin Toxicity and Peripheral Neuropathy Skin toxicity was less frequent in this cohort, with 14 (10%) women experiencing some level of skin toxicity. Four (3%) women were diagnosed with Stevens-Johnson syndrome, and these women switched to NLF-based regimens. The median time from HAART initiation to diagnosis of Stevens- Johnson syndrome was 5 weeks (IQR: weeks), and a greater proportion of Stevens-Johnson syndrome was observed among women with CD4 counts $250 cells/ml (see Table 2); however, this difference was not statistically significant (5% vs. 1%; P = 0.23). In this cohort, 26 (18%) women experienced peripheral neuropathy during follow-up and rates of neuropathy did not differ between CD4 cell count groups. The frequency of neuropathy was not statistically different among women taking the ZDV regimen compared with women taking the d4t regimen (22% vs. 15%, respectively; P = 0.27). Only 1 woman was diagnosed with severe neuropathy (grade IV) 9 weeks after initiating the ZDV regimen. Development of Anemia on HAART Twenty-five (20%) of 127 women who had normal hemoglobin levels at baseline developed moderate to severe anemia during follow-up, with the median time to diagnosis of severe anemia being 5 weeks (IQR: 2 9 weeks). The frequency of severe anemia was greater among women with CD4 counts,250 cells/ml; however, this association was not statistically significant (9% vs. 3%, respectively; P = 0.18; see Table 2). Additional Toxicities and Regimen Changes In addition to these reported toxicities, gastrointestinal complaints, including vomiting and diarrhea, were common in this cohort. These were reported by 15% of women and were more common among women with CD4 counts,250 cells/ml (22% vs. 7%, respectively; P = 0.01). No women changed regimens as a result of gastrointestinal symptoms. Overall, 15 (10%) women changed or discontinued HAART during the course of the study; 12 (8%) did so as a result of severe drug toxicity (see Table 3), and 3 women discontinued HAART for other reasons. No side effects or toxicities were reported among those women taking NLFbased regimens, and only 1 woman was diagnosed with more than 1 severe toxicity. This subject experienced severe anemia TABLE 3. Clinical Information for 16 Women Diagnosed With Severe Toxicities* Subject No. Regimen Weeks of Gestation Starting HAART Weeks on Treatment at Onset Entry CD4 Count (Cells/mL) ALT (Grade) Hemoglobin (g/ml) Comment Hepatotoxicity Entry Onset Entry Onset 1 d4t (0) 690 (4) Changed to NLF 2 d4t (0) 413 (4) Stopped HAART 3 ZDV (0) 460 (4) Change to NLF 4 d4t (0) 261 (3) Changed to NLF Skin toxicity 5 ZDV (0) 14 (0) Stopped NVP 6 ZDV (0) 8 (0) Changed to NLF 7 d4t (0) 16 (0) Changed to NLF 8 ZDV (0) 7 (0) Changed to NLF Anemia 2 ZDV (0) 28 (0) Changed to d4t 9 ZDV (0) 13 (0) Changed to d4t 10 d4t (0) 15 (0) No change 11 ZDV (1) 13 (0) Changed to D4T 12 d4t (0) 9 (0) No change 13 ZDV (0) 20 (0) Changed to D4T 14 d4t (0) 18 (0) No change 15 ZDV (0) 20 (0) Changed to D4T Peripheral neuropathy 16 ZDV (0) 11 (0) No change *Only 1 woman (subject 2) experienced.1 severe toxicity. ZDV regimen: ZDV, 3TC, and NVP; d4t regimen: d4t, 3TC, and NVP. Stevens-Johnson syndrome. 374 q 2007 Lippincott Williams & Wilkins

5 J Acquir Immune Defic Syndr Volume 44, Number 4, April 1, 2007 Antiretroviral Toxicity in Pregnancy approximately 1 month after initiating NVP, 3TC, and ZDV. She changed from ZDV to d4t and developed grade IV hepatotoxicity 1 month later. As a result of these toxicities, she stopped taking HAART. For the 12 women with severe toxicities who required a change in regimen, the incident toxicity subsided following the regimen change. There were no mortalities as a result of HAART toxicity. DISCUSSION In this study, 146 HIV-1 infected women with CD4 T-cell counts #350 cells/ml were treated with a NVP-containing HAART regimen during pregnancy and lactation in a government health center per national guidelines. We found that a greater proportion of women with higher CD4 cell counts had moderate to severe side effects as a result of their antiretroviral medications when compared with those women with CD4 counts,250 cells/ml. We also found that overall rates of hepatotoxicity were relatively high, with 11 (8%) of the 146 pregnant women on NVP-containing HAART developing grade $II hepatotoxicity and 4 (3%) developing severe (grade III IV) hepatotoxicity. This confirms the importance of careful clinical and laboratory monitoring when administering HAART during pregnancy and the need to consider alternative non NVP-containing regimens for pregnant women with CD4 counts $250 cells/ml. This study reports rates of NVP-associated toxicity that are high compared with those found among pregnant women in similar settings. 13 A Brazilian study evaluating NVP toxicity among 197 pregnant women who were taking NVP for.7 days reported only 1 case of Stevens-Johnson syndrome and no cases of grade III or IV hepatotoxicity. 13 The authors reported 11 (6%) cases of mild hepatotoxicity or skin toxicity overall, with only 7 participants discontinuing NVP. In our cohort, any toxicity (grade I IV) involving the skin or liver was observed in 39% of participants and 6% of study participants experienced grade IV toxicities requiring a change in regimen. One possible explanation for increased toxicity in our cohort may be higher rates of comorbidities such as malaria and viral hepatitis, the magnitude of which we were unable to assess in this study. In this African cohort, we also documented differences in NVP toxicity between women with lower (,250 cells/ml) versus higher ($250 cells/ml) CD4 counts. Although a study conducted in South Africa did not find this association for nonpregnant women, 14 studies conducted in North America and Brazil have reported a similar positive relation between baseline CD4 cell count and incidence of hepatotoxicity as well as an association between CD4 cell count and risk of skin toxicity. 8,10,13 Furthermore, in a notification from NVP manufacturer Boehringer Ingelheim after initiation of this study, it was reported that there was a ;12-fold increased risk of severe hepatotoxicity in women with a CD4 cell count.250 cells/ml, including some fatal events. 15 Our data support the need for caution when administering NVPcontaining regimens to women with higher CD4 cell counts, and future policy decisions regarding guidelines may take these data into consideration. Our study has several limitations. First, there was attrition bias as a result of loss to follow-up before the initiation of HAART. Clinical characteristics of women lost to follow-up were not available, making it is difficult to infer how this might have affected results. For example, if women who experienced toxicity were lost to follow-up, the study might have underestimated toxicity. Conversely, if women with the poorest health conditions are more likely to be followed and treated during the antenatal and postnatal periods, the study could have overestimated toxicity, because the chance of diagnosing toxicity would be higher for them than for other women. Second, limited laboratory capacity hindered our ability to identify other risk factors for toxicity, such as hepatitis B and C infection, and laboratory data (liver function and hemoglobin tests) were only measured up to ;6 months postpartum. Thus, we were unable to assess the long-term affects of HAART initiated in pregnancy. Few studies have examined HAART-associated toxicities in pregnant women in resource-limited settings. This study demonstrates that HAART can be effectively delivered to pregnant women in these settings. Currently, NVPcontaining antiretroviral regimens are the most affordable regimens available for HAART in resource-constrained areas. They may also be quite toxic, however, particularly among women with higher CD4 cell counts, making it important for programs to review guidelines regarding NVP-containing regimens and to provide monitoring for all pregnant women taking HAART. REFERENCES 1. European Collaborative Study. HIV-infected pregnant women and vertical transmission in Europe since AIDS. 2001;15: Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1 infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr. 2002;29: Wade NA, Zielinski MA, Butsashvili M, et al. Decline in perinatal transmission in New York State ( ). J Acquir Immune Defic Syndr. 2004;36: Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudinezidovudine combination therapy for prevention of maternal-infant transmission of HIV-1. JAMA. 2001;285: World Health Organization. Treating 3 Million by 2005: Making It Happen: the WHO Strategy: the WHO and UNAIDS Global Initiative to Provide Antiretroviral Therapy to 3 Million People With HIV/AIDS in Developing Countries by the End of World Health Organization; World Health Organization. Antiretroviral Drugs and the Prevention of Mother-to-Child Transmission of HIV Infection in Resource-Limited Settings: Recommendations for a Public Health Approach (2005 Revision). Geneva, Switzerland: WHO; Available at: World Health Organization. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Guidelines on Care, Treatment and Support for Women Living With HIV/AIDS and TheirChildren in Resource-Constrained Settings. World Health Organization; van Leth F, Andrews S, Grinsztejn B, et al. The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine and efavirenz-based first-line HAART. AIDS. 2005;19: Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000;356: Hitti J, Frenkel LM, Stek AM, et al. Maternal toxicity with continuous nevirapine in pregnancy. J Acquir Immune Defic Syndr. 2004;36: Timmermans S, Tempelman C, Godfried MH, et al. Nelfinavir and nevirapine side effects during pregnancy. AIDS. 2005;19: q 2007 Lippincott Williams & Wilkins 375

6 Jamisse et al J Acquir Immune Defic Syndr Volume 44, Number 4, April 1, República de Mocxambique. Programa Nacional de Controle DTS/SIDA. Guia para o tratamento das infeccxões oportunistas no adulto infectado por HIV e Profilaxia das infeccxões oportunistas. Maputo, Mozambique: Ministry of Health; Joao EC, Calvet GA, Menezes JA, et al. Nevirapine toxicity in a cohort of HIV-1-infected pregnant women. Am J Obstet Gynecol. 2006;194: Sanne I, Mommeja-Marin H, Hinkle J, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis. 2005;191: Shepard KV. Clarification of risk factors for severe, life-threatening and fatal hepatic toxicity with VIRAMUNE (nevirapine). Available at: pdf. 376 q 2007 Lippincott Williams & Wilkins