Appendix B
Comparisons to Other Perinatal HIV Prevention Studies Using NVP and ZDV

INTRODUCTION

This review compares primary and secondary outcomes from the HIVNET 012 trial with results from similar study arms in other trials. Specifically this review describes the range and weighted mean average of the effects of the simplified maternal-infant nevirapine (NVP)- and zidovudine (ZDV)-dosing regimens employed in the HIVNET 012 trial on the risk of mother-to-child transmission of HIV and on the occurrence of serious adverse events and secondarily compares these outcomes with those of the two treatment arms of the HIVNET 012 trial.

METHODS

Criteria for Considering Studies for This Review

Types of Studies

This review was limited to randomized controlled trials.

Types of Participants

Infants born to HIV-infected mothers.



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Review of the HIVNET 012 Perinatal HIV Prevention Study Appendix B Comparisons to Other Perinatal HIV Prevention Studies Using NVP and ZDV INTRODUCTION This review compares primary and secondary outcomes from the HIVNET 012 trial with results from similar study arms in other trials. Specifically this review describes the range and weighted mean average of the effects of the simplified maternal-infant nevirapine (NVP)- and zidovudine (ZDV)-dosing regimens employed in the HIVNET 012 trial on the risk of mother-to-child transmission of HIV and on the occurrence of serious adverse events and secondarily compares these outcomes with those of the two treatment arms of the HIVNET 012 trial. METHODS Criteria for Considering Studies for This Review Types of Studies This review was limited to randomized controlled trials. Types of Participants Infants born to HIV-infected mothers.

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Review of the HIVNET 012 Perinatal HIV Prevention Study Types of Interventions Nevirapine or zidovudine administered both in the intrapartum period, i.e., labor, to HIV-infected mothers and/or in the immediate postpartum period to exposed infants. In HIVNET 012 the NVP regimen was 200 milligrams (mg) of NVP orally to the mother at onset of labor plus 2 mg per kilogram (kg) of body weight of NVP orally to the infant at 72 hours of age or at discharge from hospital, whichever occurred first. The maternal dose could be repeated if vomited within 30 minutes. It could also be redosed if labor failed to progress and there were more than 48 hours until next onset of labor. Infants born outside the study hospital could receive a dose up to 7 days postpartum. The ZDV regimen included two 300-mg tablets at the start of labor followed by one 300-mg tablet every 3 hours during labor plus 4 mg per kg of body weight orally twice daily for 7 days after birth. Interventions that included the treatment of mothers or infants with other antiretroviral drugs or with combinations of NVP and ZDV were excluded. Types of Outcome Measures The primary outcome measure was the proportion of HIV-exposed infants in each arm who were infected during the first 6–8 weeks of age. This includes infants infected in the antepartum, intrapartum, and early postpartum periods. The secondary outcome measure was the proportion of infants infected in the intrapartum and early postpartum periods, excluding the antepartum period. Intrapartum and early postpartum transmission, if not specifically described, was calculated for each study by subtracting the number of HIV-infected infants at 1–3 days of age from the total number of infants with HIV infection at 6–8 weeks of age. We used the same denominator as the number of infants uninfected at the end of 3 days of age unless otherwise specified (that is, we made no allowance for infants lost to follow-up from 3 days to 6–8 weeks of age unless specified in the report). Other secondary outcome measures were the proportion of infants infected in the antepartum period as measured by the presence of a positive HIV DNA test at 1–3 days of age and the proportion of infants who developed Grades 3 or 4 adverse events during the trial (serious adverse effects). Identification of Studies Search We used the Cochrane Collaborative Review Group on HIV Infection and AIDS’ search strategy for identifying randomized controlled trials and included additional search terms for NVP or ZDV and prevention of

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Review of the HIVNET 012 Perinatal HIV Prevention Study mother-to-child transmission. Searched databases included MEDLINE, AIDSLINE, the Cochrane Controlled Trials Register and EMBASE. Abstracts from the XIV International AIDS Conference (Bangkok, 2004) were hand searched for trials. We supplemented this by searching bibliographies of identified studies, relevant editorials, and review articles. There were no language restrictions. We examined studies initially identified by database or hand searches for eligibility. We included data from studies that had arms that administered NVP or ZDV but not other antiretrovirals to HIV-infected mothers and HIV-exposed infants. Data Abstraction We abstracted data from eligible studies including the country where the trial was conducted, study population, inclusion and exclusion criteria, intervention, timing of outcomes, HIV-related outcomes for infants (HIV infection and HIV-1-free survival), adverse events among mothers and infants, and proportion of infants breast fed. If authors reported data in more than one study, we abstracted data from the most recent article. Statistical Methods We recorded the ranges of the outcome variables and the weighted mean average effects of the included trials (without HIVNET 012 results). We compared these primary and secondary outcomes of the included studies with those of the HIVNET 012 trial1 (1-5). We did not attempt to model interstudy variation, for instance using fixed effects or random effects models. RESULTS Nevirapine Description of Included Studies We identified five trials in addition to HIVNET 012 (6-12) that had NVP-treatment arms (Table B.1). Kiarie and colleagues (6) randomized HIV-infected Kenyan women to either the HIVNET 012 intervention or the Thai-Centers for Disease Con- 1   Results from the HIVNET 012 study were reported in five articles. For purposes of this review we abstracted data from Jackson (4).

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE B.1 Description and Outcomes of Included Studies (NVP arms only) Author, Study, and Reference Study Population Randomized Study Arms Infants Infected Antepartum (%) Kiarie (2003) [6] HIV-infected pregnant women in Kenya NVP/NVP v. Thai-CDC   Moodley (2003) SAINT [7, 8] HIV-infected pregnant women in South Africa NVP/NVP v. ZDV+3TC 45/643 (7%) Taha (2003) NVAZ [9, 10] Infants born to HIV-infected, untreated mothers in Malawi 98/468 (20.9%) NVP v. NVP+ZDV 56/551** (10.2%) 31/554 (5.6%) Taha (2004) [11] Infants of HIV-infected, NVP-treated mothers in Malawi NVP v. NVP+ZDV 36/445 (8.1%) McIntyre (2004) Trial 1413 [12] Infants of HIV-infected, NVP-treated mothers in South Africa NVP v. ZDV+3TC 4/68 (5.9%) (both arms) Non-HIVNET 012 trials combined     141/1707 (8.3%) Non-HIVNET 012 trials combined excluding NVAZ [9]a     86/1156 (7.4%) Jackson (2003) HIVNET 012 [1-5] HIV-infected pregnant women in Uganda NVP/NVP v. ZDV v. placebo 25/308 (8.1%) NOTES: NVP (nevirapine), ZDV (zidovudine), 3TC (lamivudine); *includes antepartum; **as reported. trol and Prevention (CDC) regimen (ZDV twice daily from 36 weeks gestation and 3-hourly during labor). The primary outcome of this trial was compliance with antiretroviral regimens. However, data were also reported on rates of transmission; 9% of mothers on the Thai-CDC regimen had transmitted HIV to their infants by the first 6 weeks of life (antepartum, intrapartum, and early postpartum transmission combined) compared to 22% of mothers on the HIVNET 012 regimen. The primary finding of this

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Review of the HIVNET 012 Perinatal HIV Prevention Study Infants Infected Intrapartum and Early Postpartum (%) Total Infant HIV Infections By 6–8 Weeks (%) Infant Serious Adverse Events (%)   12/55 (22%) — 28/491 (5.7%) 68/496 (13.7%) 60/663 (9.1%) 51/421 (12.1%)** — — 23/353 (6.5%) 59/389 (15.2%) 22/448 (4.9%) 1/18 (5.6%) — — 103/1283 (8.0%) 242/1488 (16.7%) 113/1665 (6.8%) 52/862 (6.0%) 144/980 (14.7%) 82/1111 (7.4%) 11/283 (3.9%) 36/308 (11.7%) 29/320 (9.1%) aNVAZ study excluded because of no NVP treatment in mothers. study was that 41% of patients complied with the Thai-CDC ZDV regimen and 87% with the HIVNET 012 regimen (p<0.001). Moodley and colleagues (7, 8) reported on the South African Intrapartum Nevirapine Trial (SAINT), an open-label trial that compared two doses of NVP to the mother at onset of labor and 24–48 hours postpartum plus one dose to the baby at 24–48 hours to a multiple dose intrapartum and 7 days postpartum regimen of zidovudine and lamivudine (3TC), similar to

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Review of the HIVNET 012 Perinatal HIV Prevention Study the regimen that had been evaluated in the Promoting Evaluation, Teaching, and Research on AIDS Project (PETRA) study. The primary outcome of this study was intrapartum and early postpartum transmission. Excluding antepartum transmission, new infections were detected in 5.7% of infants in the NVP group and 3.6% of infants in the zidovudine-lamivudine group at 8 weeks of age. Taha and colleagues (9, 10) conducted the NVAZ trial in Malawi and compared single-dose NVP alone to twice-daily zidovudine for 1 week plus single-dose NVP among HIV-exposed infants. In this trial mothers presented late in labor, were untreated at the time of delivery, and were diagnosed in the postpartum period, and thus there was no maternal dose of NVP. The primary outcome was HIV infection at 6–8 weeks of age. At 6–8 weeks of age among babies who were HIV-uninfected at birth, 7.7% who had received NVP plus zidovudine were infected compared to 12.1% of those who had received NVP alone (p=0.03). Taha and colleagues (9, 11) also conducted a second trial in Malawi that randomized infants of HIV-infected, NVP-treated mothers to receive NVP or NVP plus zidovudine, the same regimens tested in the NVAZ trial. The primary outcome was postpartum HIV transmission. Among infants uninfected at birth, transmission was 6.5% in those who received NVP alone and 6.9% among those who had received NVP and zidovudine (p=0.88). In a separate publication, spanning both the NVAZ trial and the second trial conducted in NVP-treated mothers, Taha and colleagues reviewed hepatic and hematologic toxicity data (10), comparing the four arms of the two trials plus an unexposed and untreated control group. At 6 weeks of age geometric mean serum alanine aminotransferase levels were significantly higher among the treated groups (16.2–19.1 U/L) than in controls (11.5 U/L). Similarly hematologic parameters (hemoglobin, hematocrit, granulocytes, and platelets) were significantly lower among the treated groups than controls at 6 weeks of age, consistent with Grade 1 (mild) toxicity. McIntyre and colleagues (12) reported preliminary data from Trial 1413 in South Africa that compared standard maternal-infant NVP with NVP plus two regimens of a fixed-dose zidovudine-lamivudine combination given to infants for 4 or 7 days. The primary endpoint of this study is antiretroviral resistance, and this abstract reported 50% resistance to non-nucleoside reverse transcriptase inhibitors at 2 and 6 weeks in infants in the NVP-alone arm compared to 5% in the NVP plus 4-day zidovudine-lamivudine regimen and 13% in the 7-day regimen. Data on risk of transmission were also reported. Four of 68 infants had intrauterine transmission; one of 18 infants in the NVP-alone arm was infected in the intrapartum or early postpartum periods.

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Review of the HIVNET 012 Perinatal HIV Prevention Study Outcomes The proportion of infants in the NVP arm infected with HIV in HIVNET 012 was 8.1% at birth, 11.7% at 6–8 weeks, 13.3% at 14–16 weeks, 14.9% at 12 months, and 15.3% at 18 months of age (4). Antepartum transmission. Four of the other trials (8, 10, 11, 12) reported the proportion of infants infected immediately following birth. Overall, 141 (8.3%, range 5.9–10.2%) of the 1,707 infants in these studies were infected in the antepartum period, and this was consistent with the 8.1% reported by HIVNET 012. Antepartum, intrapartum, and early postpartum transmission. Four of the other trials (6, 7, 8, 9, 11) reported the total proportion of infants infected at approximately 6 weeks of age. Overall, 242 (16.7%, range 13.7–22%) of the 1,488 infants in these studies were infected by approximately 6 weeks of age, while in HIVNET 012 11.7% were infected. Intrapartum and early postpartum transmission. In HIVNET 012 the proportion of infants uninfected at birth that became infected during the intrapartum plus early postpartum period as measured at 6–8 weeks of age was 3.9%. Four other studies (8, 9, 11, 12) contributed data on this outcome. Overall in these four studies, 103 (8.0%, range 5.6–12.1%) of 1,283 initially uninfected infants were infected by 6–8 weeks of age. This was higher than the rate of 3.9% observed in HIVNET 012. However, excluding the NVAZ trial in which HIV-infected mothers did not receive a dose of NVP, which presumably would have contributed to a decrease in intrapartum transmission, 52 (6.0%, range 5.6%–6.5%) of 862 infants were infected in the three remaining studies during this period. This proportion was not significantly different from the proportion observed in HIVNET 012 (Odds Ratio [OR], 0.61, 95% confidence interval, 0.32–1.18). Serious adverse events. HIVNET 012 and three other studies (7, 9, 10, 11) reported detailed information on serious adverse events among infants receiving NVP. In HIVNET 012, 29 (9.1%) of 320 infants had experienced Grades 3 or 4 events by 6–8 weeks of age. In the other three studies, overall 113 (6.8%, range 4.9–9.1%) of 1,665 had experienced Grades 3 or 4 events by this age. There was no difference between the rates of these adverse events between HIVNET 012 and other studies combined (OR, 1.37, 95% confidence interval, 0.89–2.10). Removal of the NVAZ trial made no difference.

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Review of the HIVNET 012 Perinatal HIV Prevention Study Description of Excluded Studies Three randomized controlled trials were excluded because they either combined NVP with other antiretrovirals (13-18) or included multiple doses of NVP postnatally (19) (see Table B.2). Zidovudine Description of Included Studies We identified five trials that had ZDV-treatment arms similar, but not identical, to HIVNET 012. In HIVNET 012 there was no antepartum treatment with ZDV; 600 mg was given at the onset of labor and 300 mg every 3 hours during labor. The neonatal dose was 4 mg/kg twice daily for 7 days. There were no other studies that we could identify that used this exact dosing regimen. Dabis and colleagues (20) randomized 431 HIV-infected pregnant women in Côte d’Ivoire and Burkina Faso to a regimen of 300 mg orally twice daily beginning at enrollment, 600 mg ZDV orally at onset of labor, and 300 mg orally twice daily for 7 days after delivery. There was no treatment given to the newborn. The Kaplan-Meier probability of HIV infection in the infant at 6 months was 18.0% in the ZDV group and 27.5% in the placebo group (p=0.027). Kiarie and colleagues (6) randomized HIV-infected Kenyan women to either the HIVNET 012 intervention or the Thai-CDC regimen (ZDV twice daily from 36 weeks gestation and every 3 hours during labor). The primary outcome of this trial was compliance with antiretroviral regimens. However, data were also reported on rates of transmission; 9% of mothers on the Thai-CDC regimen had transmitted HIV to their infants by the first 6 weeks of life (antepartum, intrapartum, and early postpartum transmission combined), compared to 22% of mothers on the HIVNET 012 regimen. The primary finding of this study was that 41% of patients complied with the Thai-CDC ZDV regimen and 87% with the HIVNET 012 regimen (p<0.001). Lallemant and colleagues (21) studied 1,437 HIV-infected Thai women and randomized them into four ZDV-treatment arms. The first arm began 300 mg of ZDV orally twice daily at 28 weeks gestation with 6 weeks of ZDV, 2 mg/kg every 6 hours, in the infant (long-long); this was equivalent to the Pediatric AIDS Clinical Trials Group (PACTG) 076 trial regimen. The second arm started treatment at 35 weeks gestation with 3 days of treatment in the infant (short-short). The other two arms’ regimens were the long course in the mother and the short course in the infant (long-short) and the short course in the mother and long course in the infant (short-

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE B.2 Excluded Studies (NVP arms) Author, Study, and Reference Study Population Randomized Study Arms Reason for Exclusion Infant Serious Adverse Events (%) Dorenbaum (2002) [13-16] HIV-infected pregnant women receiving standard antiretroviral therapy in U.S., Europe, Brazil, Bahamas Maternal NVP/infant NVP v. placebo/placebo Combination antiretroviral regimens 237/714 (33%) Lallemant (2004) PHPT [17, 18] HIV-infected pregnant women receiving ZDV in Thailand; infants received 1 week of ZDV and were formula fed Maternal NVP/infant NVP v. NVP/placebo v. placebo/placebo Combination antiretroviral regimens Not specifically reported (no significant difference among groups) Shetty (2003) HIVNET-023 [19] Breast-feeding infants of HIV-infected pregnant women in South Africa and Zimbabwe NVP daily v. NVP twice weekly v. NVP weekly for 24 weeks Multiple NVP doses to infant Not specifically reported (no serious adverse events related to study drug) NOTES: NVP (nevirapine), ZDV (zidovudine).

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE B.3 Description and Outcomes of Included Studies (ZDV arms only) Author, Study and Reference Study Population Randomized Study Arms Dabis (1999) [20] HIV-infected pregnant women in Côte d’Ivoire and Burkina Faso Ante-, intra-, and postpartum ZDV v. placebo Kiarie (2003) [6] HIV-infected pregnant women ≤35 weeks gestation in Nairobi ZDV v. antepartum and intrapartum NVP Lallemant (2000) [21] HIV-infected pregnant women in Thailand 4 ante-, intra-, and postpartum ZDV regimens: long-long, short-short, long-short, short-long Shaffer (1999) [22] HIV-infected pregnant women in Thailand Ante- and intrapartum ZDV vs. placebo Wiktor (1999) [23] HIV-infected pregnant women in Côte d’Ivoire Ante- and intrapartum ZDV vs. placebo Non-HIVNET 012 trials combined     Non-HIVNET 012 trials combined excluding [22]     Jackson (2003) HIVNET 012 [1-5] HIV-infected pregnant women in Uganda NVP/NVP v. ZDV v. placebo NOTES: NVP (nevirapine), ZDV (zidovudine). long). All mothers received of 300 mg zidovudine orally (or intravenously if not tolerated orally) at the start of labor and every 3 hours. All infants were formula fed. At the first interim analysis, the short-short arm was suspended, and the trial was redesigned as an equivalency trial to compare the long-long regimen with the two remaining arms. Transmission rates were 6.5% for the long-long regimen, 4.7% for the long-short regimen, and 8.6% for the short-long regimen. However, higher rates of antepartum transmission were observed with the short-long regimen. Transmission rates in the short-short arm, the regimen closest to the HIVNET 012 ZDV arm, were estimated to be 10.5% at 6 months by Kaplan-Meier analysis.

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Review of the HIVNET 012 Perinatal HIV Prevention Study Infants Infected Antepartum (%) Infants Infected Intrapartum and Early Postpartum (%) Total at 6–8 Weeks 5/182 (2.6%) 23/177 (13%) 28/155 (18.1%) — — 5/55 (9%) 24/229 (10.5%) at 6 months in short-short arm — — 9/188 (4.8%) 9/173 (5.2%) 18/188 (9.6%) 6/123 (4.9%) 9/117 (7.7%) 15/122 (12.3%) 20/503 (4.0%) 41/482 (8.5%) 66/520 (12.7%) — 32/294 (10.9%) 48/332 (14.5%) 31/302 (10.3%) 28/271 (10.3%) 59/302 (19.5%) Shaffer and colleagues (22) randomized 397 Thai women to placebo or 300 mg of zidovudine twice daily from 36 weeks gestation and every 3 hours during labor. Infants were not treated and were not breastfed. Estimated transmission rates at 6 months were 9.4% in the zidovudine group and 18.9% in the placebo group (p=0.006). Wiktor and colleagues (23) studied a regimen identical to the one used by Shaffer and colleagues but in a breast-feeding population in Côte d’Ivoire. Estimated transmission rates at 3 months were 15.7% in the zidovudine group and 24.9% in the placebo group (p=0.07).

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Review of the HIVNET 012 Perinatal HIV Prevention Study Outcomes The proportion of infants in the zidovudine arm infected with HIV in HIVNET 012 was 10.3% at birth, 19.5% at 6–8 weeks, 21.5% at 14–16 weeks, 23.2% at 12 months, and 24.8% at 18 months of age (4). Antepartum transmission. All identified trials treated mothers in the antepartum period starting at approximately 36 weeks, and there is no basis for comparing the HIVNET 012 regimen, which started treatment at the onset of labor. As expected, the antepartum transmission rate in HIVNET 012 was 10.3%, substantially higher than the 4.0% observed in the three trials that reported HIV infection rates at days 1–3 (20, 22, 23). Antepartum, intrapartum, and early postpartum transmission. Four trials reported total transmission rates at approximately 6 weeks. Overall, 66 (12.7%, range 9–18.1%) of 520 infants were infected at 6–8 weeks of age. This compares with 59/302 (19.5%) of infants in the HIVNET 012 ZDV. Because all these trials included antepartum treatment of the mother, which presumably results in lower risk of transmission in comparison to mothers treated only in the intrapartum period as in HIVNET 012, we also calculated the proportion of infants uninfected at birth who developed HIV infection as the result of exposure during the intrapartum and early postpartum periods. Intrapartum and early postpartum transmission. Three trials (20, 22, 23) also reported rates of transmission during the intrapartum and early postpartum periods. One of these trials (22) was conducted in a non-breastfeeding population in Thailand and may not be directly comparable. Also, one African trial (23) reported data at 4 weeks, rather than the 6–8 weeks in HIVNET 012 and the other two trials. Nonetheless, the rates reported in these three trials averaged 8.5% and ranged from 5.2–13%. Excluding the study conducted in Thailand, the two remaining trials ranged from 7.7–13% and averaged 10.9%. The comparable proportion of uninfected infants who were infected by 6–8 weeks in the HIVNET 012 trials was 10.3%. Description of Excluded Studies We excluded three studies because the duration and intensity of their antepartum and postpartum zidovudine treatment regimens were substantially dissimilar to HIVNET 012 (18, 24, 25) and one study (11) because it did not contain a ZDV-only arm (Table B.4).

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Review of the HIVNET 012 Perinatal HIV Prevention Study TABLE B.4 Excluded Studies (ZDV-only arms) Author, Study and Reference Study Population Randomized Study Arms Reason for Exclusion Bordeguez (2003) [24] PACTG 288—HIV-infected pregnant women in U.S. and France 14–34 weeks Ante-, intra-, and postpartum ZDV vs. placebo Follow-on study of Connor [25], infant outcomes not reported Connor (1994) [25] PACTG 076—HIV-infected pregnant women in U.S. and France at 14–34 weeks Ante-, intra-, and postpartum ZDV vs. placebo Ante- and postpartum ZDV regimens not similar to HIVNET 012 Lallemant [18,19] Pregnant HIV-infected women treated with ZDV beginning at 28 weeks Three arms: mother receives NVP and infant receives placebo, both get NVP, both get placebo. All infants treated with ZDV for 7 days. Antepartum ZDV regimen not similar to HIVNET 012 Taha (2004) [11] Malawi HIV-infected pregnant women receiving NVP NVP plus ZDV vs. NVP plus placebo No ZDV-only arm NOTES: NVP (nevirapine), ZDV (zidovudine). DISCUSSION Five randomized controlled trials included single-dose NVP-only arms for prevention of mother-to-child transmission of HIV. The proportions of infants infected in the antepartum period were similar between HIVNET 012 and the other studies. The review also showed that Grades 3 and 4 adverse events among infants were similar between HIVNET 012 and the other studies. Rates of transmission in the intrapartum and immediate postpartum periods were lower in HIVNET 012 (3.9%) compared to the other five studies that reported this variable (8.0%). However, after excluding the NVAZ study, in which mothers were not treated with NVP, this proportion

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Review of the HIVNET 012 Perinatal HIV Prevention Study was lower (6.0%) and thus more similar to the HIVNET 012 results. The NVAZ study was a Malawi study that randomized infants of women who presented in late stages of labor with unknown HIV status and did not receive NVP. The newborns were randomized to receive one dose of NVP or one dose of NVP plus a week of ZDV. The investigators subsequently analyzed the subset of infants born to mothers who were found to be infected with HIV. Since the mothers did not receive NVP, the infants were likely less protected against intrapartum transmission than those whose mothers did receive NVP. Hence, the intrapartum plus early postpartum transmission rates from this study are not directly comparable to those of HIVNET 012 or the other four studies. The ZDV-only arm of the HIVNET 012 trial was less directly comparable to other randomized controlled trials for prevention of mother-to-child transmission (MTCT) that included ZDV. Of the five trials we analyzed, all had employed antepartum treatment with ZDV, which was not part of the HIVNET 012 ZDV arm. Previous studies have suggested that the duration of antenatal treatment with ZDV is a strong predictor of prevention of antepartum transmission (22). However, when excluding transmission during the antepartum period (as measured by infant infection at 1–3 days of age), the rate of intrapartum and early postpartum transmission found in the two studies conducted in breastfeeding populations (10.5%) was similar to that found in HIVNET 012 (10.3%). These findings suggest that the findings in both arms of the HIVNET 012 trial are consistent with other studies that have used similar interventions, although over much shorter time periods. Other experimental trials that combined maternal and neonatal NVP with either ongoing highly active antiretroviral therapy (PACTG 316) (13-16) and ZDV during the third trimester (Perinatal HIV Prevention Trial [PHPT]) (17-18) showed similar or higher rates of serious adverse events. In PACTG 316 there was one Grade 3 rash-toxicity, 235 Grades 3 and 4 non-rash-toxicity, and one hepatic-toxicity (elevated liver transaminases) events from among 714 infants who received NVP (33% overall); this was no different than among infants who received placebo (14). In PHPT there were no significant differences among treatment groups in terms of rashes, elevated alanine aminotransferase levels, presence of hyperbilirubinemia, and rates of serious adverse reactions (18). Additionally HIVNET 023 (19), a trial of three separate regimens of postpartum NVP (daily, twice weekly, and weekly for 24 weeks) in infants of HIV-infected breast-feeding mothers found no severe skin, hepatic, or renal toxicity related to NVP; neutropenia occurred in 8 of 36 infants monitored at the Zimbabwe site. Anemia and thrombocytopenia also occurred in 2 infants each (total hematologic abnormalities 12/36 [33%]). None of the enrolled infants had Grades 3 or 4 elevations in serum alanine transferase levels. Observational studies have also suggested similar rates of transmission

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Review of the HIVNET 012 Perinatal HIV Prevention Study and adverse events when the HIVNET 012 NVP regimen has been employed. For example, Stringer and colleagues have followed two observational cohort studies of HIV-exposed infants who received single-dose NVP and whose mothers received intrapartum NVP in Zambia (26-27). They found transmission rates of 11.7% at 4–6 weeks (26) and 11.2% at 6–8 weeks of age (27). Other observational studies have been published, which examined the effectiveness of NVP in practice in Kenya (28), South Africa (29), and Cameroon (30). The studies from Kenya and South Africa found higher rates of transmission (13% at 6 weeks, 18.1% at 14 weeks, respectively), while the study from Cameroon found a slightly lower transmission rate of 10.6% at 6–8 weeks. No maternal or infant complications or adverse effects were reported from Cameroon (30). In conclusion, the findings from both the NVP and ZDV arms from HIVNET 012 appear to be consistent with findings on HIV transmission from other randomized controlled trials that tested similar treatment regimens. Additionally the observed rates of serious adverse events were similar to those observed in randomized controlled trials that tested similar NVP regimens, randomized controlled trials that used NVP plus other antiretrovirals, a randomized postnatal prophylaxis trial (HIVNET 023), and observational studies. REFERENCES 1. Guay LA, Musoke P, Fleming T, et al. 1999. Intrapartum and neonatal single-dose NVP compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354:795-802. 2. Deseyve M, Duefield C, Musisi M, et al. 2000. The one year safety and efficacy data of the HIVNET 012 trial. XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000 [Abstract LbOr1]. 3. Eshleman SH, Mracna M, Guay LA, et al. 2001. Selection and fading of resistance mutations in women and infants receiving NVP to prevent HIV-1 vertical transmission (HIVNET 012). AIDS 15:1951-1957. 4. Jackson JB, Musoke P, Fleming et al. 2003. Intrapartum and neonatal single-dose NVP compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 362:859-68. 5. Jackson JB, Musoke P, Fleming T, King S. 2004. Short course NVP was better than zidovudine for reducing the risk of mother to child transmission of HIV-1 infection. Evidence-Based Medicine 9:53. 6. Kiarie JN, Kreiss JK, Richardson BA, John-Stewart GC. 2003. Compliance with antiretroviral regimens to prevent perinatal HIV-1 transmission in Kenya. AIDS 17: 65-71. 7. Moodley D, on behalf of the SAINT Investigators Team. 2000. The SAINT trial: Nevirapine (NVP) versus zidovudine (ZDV) + lamivudine (3TC) in prevention of peripartum HIV transmission. XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000 [Abstract LbOr2].

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