Epidemiology and Social
Timing of maternal and neonatal dosing of nevirapine and the risk of mother-to-child transmission of HIV-1: HIVNET 024*
Chi, Benjamin Ha,b; Wang, Leic; Read, Jennifer Sd; Sheriff, Muhsine; Fiscus, Susanf; Brown, Elizabeth Rc,g; Taha, Taha Eh; Valentine, Meganj; Goldenberg, Roberta,b
From the aUniversity of Alabama at Birmingham, Department of Obstetrics & Gynecology, Birmingham, Alabama, USA
bCentre for Infectious Disease Research in Zambia, Lusaka, Zambia
cStatistical Center for HIV/AIDS Research and Prevention (SCHARP), Seattle, Washington
dNational Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
eMUCHS–Harvard Research Collaboration, Dar-es-Salaam, Tanzania
fUniversity of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina
gUniversity of Washington, Department of Biostatistics, Seattle, Washington
hJohns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland
jFamily Health International, Durham, North Carolina, USA.
Received 8 June, 2005
Revised 9 August, 2005
Accepted 18 August, 2005
* See Appendix.
Correspondence to Dr. Benjamin Chi, Box 34681, 5977 Benakale Road, Lusaka, Zambia. E-mail: firstname.lastname@example.org
Objective: Despite a growing emphasis worldwide on complex and potent antiretroviral drug regimens for the prevention of mother-to-child transmission of HIV-1 (MTCT), two-dose nevirapine (NVP) prophylaxis remains an important choice in many settings. We analyzed data from a multicenter clinical trial to determine whether timing of maternal or infant NVP was associated with MTCT between delivery and 6 weeks of age (intrapartum/early postnatal transmission; I/EP).
Methods: HIVNET 024 was a placebo-controlled, double-blind trial of empiric antibiotics to reduce chorioamnionitis-associated MTCT. This secondary analysis used data collected in the original randomized trial. Enrolled women were instructed to self-administer NVP at labor onset; infants were to receive a dose within 72 h of birth.
Results: Data regarding 1491 mother–infant pairs were analyzed. The overall I/EP HIV-1 transmission rate was 8.1% at 6 weeks. Almost all women (93%) ingested NVP within 24 h of delivery; 90% of infants were given NVP within 48 h after delivery. Variations in mother or infant dose timing did not influence transmission rates, even when the combined pattern of both was taken into account through multivariate analysis. In the subset of women ingesting NVP ≤ 2 h before delivery, early NVP administration to the infant (< 4 h after birth) was not associated with lower MTCT risk when compared with later administration (≥ 4 h).
Conclusion: Variations in the timing of maternal and infant NVP doses (within reasonable proximity to delivery) do not appear to affect the risk of MTCT.
The HIVNET 012 trial demonstrated that a single dose of nevirapine (NVP) given to an HIV-1-infected pregnant woman at the onset of labor, followed by a single dose to her infant within 72 hours of birth, significantly reduced mother-to-child transmission of HIV-1 (MTCT) by 41% at 18 months in a breast-feeding population . Other clinical trials have demonstrated the benefit of this simple but potent regimen [2–5]; as a result, it has become a cornerstone of many large-scale programs for the prevention of MTCT, especially in resource-poor settings such as sub-Saharan Africa [6–9]. Despite the growing emphasis on more complex and potent antiretroviral drug regimens to prevent perinatal transmission of HIV-1, the two-dose NVP prophylactic regimen remains an important intervention in many settings [10,11].
Although this NVP regimen is easily administered, there can be wide variability in the timing of the drug doses in relation to delivery. Studies have shown that a maternal NVP dose ingested within 2 h of delivery can result in decreased cord blood concentrations of the drug  and that this may in turn lead to higher risks for MTCT . Interestingly, timing of the infant dose in relation to MTCT has not been investigated, despite the high degree of variability that is possible with this dose – up to 72 h according to the HIVNET 012 regimen.
We analyzed maternal and infant NVP timing and the risk of MTCT among HIV-1-infected women and their infants enrolled in HIVNET 024, one of the first large-scale clinical trials since HIVNET 012 to incorporate the two-dose NVP prophylactic regimen. We hypothesized that, among HIV-1-infected pregnant women who ingested NVP within 2 h of delivery, earlier administration of infant NVP (< 4 h after birth) would be associated with decreased risk of MTCT in comparison with later administration (≥ 4 h after birth).
HIVNET 024 was a placebo-controlled, double-blind, phase III trial of antepartum and peripartum antibiotics to reduce chorioamnionitis-associated MTCT. The study methods have been described elsewhere . Data collected in that original randomized trial was used in this observational analysis.
Briefly, the study was conducted in four sites in sub-Saharan Africa: Lusaka, Zambia; Blantyre, Malawi; Lilongwe, Malawi; and Dar Es Salaam, Tanzania. Women were enrolled between 20 and 24 weeks and randomized to either receive the antibiotic intervention or placebo. Those assigned to the intervention arm received two courses of empiric antibiotics. The 7-day course of metronidazole and erythromycin given at 20–24 weeks targeted organisms commonly associated with both bacterial vaginosis and chronic, subclinical chorioamnionitis (e.g. Ureaplasma, Mycoplasma, Gardnerella). A course of metronidazole and ampicillin also was initiated in labor (at 4-h intervals) as prophylaxis against chorioamnionitis due to group B streptococci, E. coli, Bacteriodes and anaerobes.
At approximately 28 weeks gestation, all HIV-1-infected women were given NVP 200 mg for self-administration at the onset of labor. Women were followed through the remainder of their pregnancy, through delivery, and 1 year postpartum. Infants born to HIV-1-infected mothers were given a 2 mg/kg dose of NVP syrup within the first 72 h of life, and were followed for 1 year after birth. Timing of delivery was precise to the hour and minute. Timing of self-administered maternal NVP was based on participant report. For pregnant women ingesting NVP after arrival at the study site, exact time of NVP ingestion was recorded following direct observation. Infants were given NVP syrup prior to discharge; timing was recorded following administration.
Infant blood samples were collected as dried blood spots via heelstick at birth, at 6 weeks, and at subsequent time points during the first year of life. Infant HIV-1 infection was diagnosed by RNA polymerase chain reaction (PCR) from whole blood on filter paper. Organon-Teknika NucliSens (Organon-Teknika, Durham, North Carolina, USA) was used for the Malawi and Zambia sites; Roche Amplicor ver 1.5 (Roche Diagnostics, Branchburg, New Jersey, USA) was used for samples from the Tanzania sites. All tests were performed at a reference laboratory (University of North Carolina, Chapel Hill, NC, USA). Transmission was assumed to have occurred in utero if the birth RNA PCR result was positive. If the birth specimen RNA PCR result was negative, but the week 6 was positive, the infection was classified as having occurred in the intrapartum/early postnatal period . For the purposes of this analysis we did not require a confirmatory HIV-1 PCR test to categorize an infant as HIV-1-infected.
Because the two-dose NVP regimen is only initiated after labor has commenced, it would not be expected to prevent in utero transmission. As such, this analysis was restricted to that subset of infants at risk for intrapartum/early postnatal infection. In order to accomplish this, we limited our study to mother–infant pairs meeting the following characteristics: (1) the mother was HIV-1-infected; (2) the infant was born alive; (3) the infant's HIV-1 infection status was ultimately determined; (4) the infant's HIV-1 diagnostic test at birth was negative; and (5) an HIV-1 diagnostic assay was obtained at the 6-week visit. If a participant gave birth to twins, only the first-born was included.
To compare various maternal, delivery, and infant characteristics among members of our study population, we analyzed categorical variables using either Pearson's chi-squared test or Fisher's exact test. Two-tailed Student's t-tests were used primarily for normally distributed continuous variables, and the median test was employed in scenarios in which the distribution of the variable was not believed to be normal. When the distribution of a continuous variable was skewed, log10 transformation was applied. A P-value of 0.05 or less was considered significant.
To determine the pattern of MTCT according to both maternal and infant NVP dose timing, we stratified the population into pre-determined categories. Administration of the maternal NVP dose was described as ‘optimal’ when ingested between 2 and 48 h prior to delivery or ‘suboptimal’ when ingested less than 2 h prior to delivery. The interval between birth and infant dose administration was classified in three categories: less than 4 h, 4 to 24 h, and 24 to 72 h. Women ingesting NVP between 2 and 48 h prior to delivery, whose infants received NVP between 24 and 72 h after birth, represented the reference group (based on the rationale that infants in this group would have NVP in their circulation for the longest period of time). Multivariate logistic regression analyses were performed with covariates significant at a P ≤ 0.10 level in bivariate analysis comparing transmitters and non-transmitters. All data analysis was performed using SAS version 9.1 (SAS Institute, Cary, North Carolina, USA).
Enrollment began at the clinical sites in July 2001. In February 2003, enrollment was stopped when, on interim analysis by the Data Safety and Monitoring Board, it was determined that the results were sufficiently unfavorable to rule out the primary hypothesis, that the study intervention would provide a meaningful reduction in MTCT. However, regardless of whether they delivered before or after the enrollment discontinuation date of 5 March 2003, all HIV-1-infected women were provided NVP for infant prophylaxis. As such, we did not exclude any participants based on delivery date.
Of the HIV-1 infected women enrolled in HIVNET 024, 2127 participants gave birth to a total of 2078 liveborn infants. Of these infants, 2052 were either singleton or first-born twins. Of these 2052 infants, HIV-1 infection status was ultimately determined for 2050. Of these 2050, 142 had missing HIV PCR tests at birth. Another 153 tested HIV-1-positive at birth and thus were presumed to be infected in utero. Of the remaining 1755 infants who tested negative for HIV-1 at birth, 1491 underwent HIV-1 diagnostic testing at the 6-week visit. These 1491 infants and their mothers were included in this analysis (Fig. 1).
We compared these 1491 mother–infant pairs with the 316 participants who were excluded from the analysis due to missing or inconsistent HIV-1 diagnostic test results. Differences were noted between the two groups. Women included in the analysis were more likely to be older (P < 0.0001), more likely to have higher gravidity (P < 0.0001) and higher parity (P = 0.0003), and more likely to deliver infants with a higher birthweight (P = 0.0001). No differences were noted in terms of CD4 cell count at enrollment or at 36 weeks, viral load at enrollment, preterm birth, duration of labor, or duration of ruptured membranes (Table 1). Left out of this comparison were infants who had: (1) a positive HIV PCR test at birth (n = 153); or (2) died before the week 6 visit (n = 92). We reasoned that these participants were likely to be inherently different from the other 1807 mother–child pairs in terms of maternal and infant disease status.
Predictors for infant HIV-1 infection at 6 weeks
The overall rate of intrapartum/early postnatal MTCT was 8.1% (121 of 1491). Women with CD4 cell counts < 200 cells/μl [relative risk (RR), 2.64; 95% confidence interval (CI), 1.85–3.78], plasma HIV-1 concentration > 100 000 copies/ml (RR, 3.16; 95% CI, 2.21–4.51), or ruptured membranes for more than 4 h before delivery (RR, 1.48; 95% CI, 1.01–2.18) were more likely to transmit HIV-1 to their infants. Similarly, infants born preterm (< 37 completed weeks of gestation; RR, 1.51; 95% CI, 1.04–2.21) or low birth weight (< 2500 g; RR, 1.68; 95% CI, 1.05–2.70) were more likely to become HIV-1-infected within the first 6 weeks of life. Rates of MTCT did not vary according to clinic site (P = 1.00).
Maternal dose timing and MTCT
Distribution of maternal dose timing is shown in Table 2. Of the 1460 women with NVP timing information available, 224 (15%) ingested their dose < 2 h prior to delivery; 1130 (77%) between 2 and 24 h; 87 (6%) between 24 and 48 h, and 19 (1%) over 48 h. Within these categories, no statistically significant differences in HIV-1 transmission rates were observed (P value for trend = 0.27). Although the transmission rate was higher in the few women who ingested NVP more than 48 h before delivery (10.5%) when compared with those ingesting NVP less than 48 h prior to delivery (7.9%), this difference was not statistically significant (P = 0.68). HIV-1 transmission according to more discrete time intervals is depicted in Fig. 2a.
Infant dose timing and MTCT
The distribution of infant dose timing also is shown in Table 2. Of the 1480 infants with NVP timing information available, 269 (18%) ingested their dose < 4 h from delivery; 644 (44%) between 4 and 24 h; 530 (36%) between 24 and 72 h, and 37 (3%) over 72 h. Within these categories, no statistically significant differences were observed in the HIV-1 transmission rates (P value for trend = 0.81). The 37 infants who ingested NVP more than 72 h after delivery did not have a significantly greater HIV-1 transmission rate when compared with others (8.1 versus 8.0%; P = 1.00). More detailed information regarding HIV-1 transmission rates according to infant NVP timing is presented in Fig. 2b.
The population of women ingesting NVP < 2 h before delivery was then considered separately (n = 224). Of infants born to these women, 63 were given NVP syrup within 4 h of birth. Two (3.2%) became HIV-1-infected. In contrast, 155 infants were given NVP syrup between 4 and 72 hours after birth, 12 (7.7%) of whom tested positive at 6 weeks of life. This difference was not statistically significant (P = 0.36).
Multivariate analysis of maternal and infant dose timing
We stratified the study population according to maternal and infant NVP dosing as described in the methods section. The unadjusted and adjusted odds ratios are shown in Table 3. Due to their association with MTCT in this analysis, we controlled for maternal CD4 cell count at enrollment, maternal plasma HIV-1 concentration at enrollment, preterm birth, and duration of ruptured membranes. There was no statistically significant difference in MTCT observed among the different strata according to infant timing. The trend seen in the ‘optimal’ maternal dose group – an increase in HIV-1 transmission risk the closer the infant dose was given to delivery – was not statistically significant (P value for trend = 0.84).
Although drug resistance associated with the two-dose NVP prophylaxis regimen is a matter of concern [15–17], this regimen remains an important choice for the prevention of MTCT in many locations [10,18]. These analyses were performed in hopes of optimizing NVP use in areas with resource-constrained, infrastructure-poor healthcare. Our results suggest MTCT is not affected by the timing of either the maternal or infant dose, as long as they are in reasonable proximity to the time of delivery (defined by this study as within 48 h of delivery for the maternal NVP and within 72 h after birth for the infant dose). Although high maternal HIV-1 viral load and low maternal CD4 cell count were associated with increased risk for intrapartum/early postnatal MTCT, on multivariate analysis these factors did not appear to influence infant HIV-1 infection in relation to NVP dose timing.
We believe these results are due in large part to the rapid absorption of NVP into the maternal circulation, the rapid transport of NVP across the placenta, and the relatively long half-life of the drug [19–21]. Phase I/II trials in Uganda demonstrated that ingestion of one dose of NVP during labor results in rapid drug delivery to the infant via the placenta. Infant NVP levels at delivery (after a median time of 3.8 h since maternal ingestion) showed an average serum level of more than 150 times the in-vitro 50% inhibitory concentration (IC50) of the drug . However, cord blood NVP levels are more likely to be ‘sub-therapeutic’ (i.e. under 100 ng/ml) if maternal NVP is ingested within 2 h of delivery . In this scenario, it has been recommended  that one infant NVP dose be administered immediately after birth (in order to boost the infant's circulating drug concentration), followed by a second dose 48 to 72 h later.
Our analyses suggest such repeat dosing may not be needed. Even in the subset of mothers receiving NVP within 2 h of delivery, we did not observe that early infant dosing (< 4 h after) was associated with a lowered risk of MTCT. There could be a number of explanations for these findings. First, it is possible that the serum level of 100 ng/ml targeted in pharmacokinetic studies may not represent a true therapeutic threshold. Even in the phase I/II trials for NVP, this level was not chosen because of clinical evidence, but because it was 10 times greater than the IC50 of NVP. It is plausible that NVP may offer some protective effect even when cord blood concentrations are far below this suggested cut-off. In their analysis of maternal dose timing, Stringer et al found that although maternal NVP ingestion within 1 h of delivery did result in a higher proportion of ‘sub-therapeutic’ cord blood levels, there was no apparent threshold for increased MTCT. That study however was not adequately powered to definitively answer this question .
Study-related factors also could have contributed to our findings. Despite the large sample size, the primary limitation of this analysis is its observational nature. Study participants were not randomized to different infant dose timing schedules, and this may have led to identifiable and unidentifiable confounding. In addition, the study is not sufficiently powered to definitively answer the study question. To address for these issues through the study design (e.g. randomization), however, would present numerous ethical, practical, and logistical problems.
In summary, we found that early infant NVP administration is not associated with a statistically significant decrease in the risk of MTCT, even when the analysis is restricted to infants born to mothers who ingested NVP within 2 h of delivery. This finding suggests that the repeat dosing of infants previously recommended by Mirochnick and others  may not be necessary. In settings where health care is sporadic or where large proportions of women deliver at home, delaying infant NVP administration for up to 72 h does not appear to increase the risk of MTCT, provided that the maternal dose was taken within reasonable proximity (less than 48 h) of delivery. Even though the difference was not statistically significant, the higher risk of MTCT among women taking NVP more than 48 h before delivery suggests that further research may needed in this area. These findings are important for all antiretroviral drug regimens that incorporate the HIVNET 012 NVP dosing, including combinations with antenatal, intrapartum, and neonatal zidovudine [23,24].
The conclusions and opinions expressed in this paper are those of the authors and do not necessarily reflect those of the funding agencies and participating institutions.
Sponsorship: This work was supported by the HIV Network for Prevention Trials (HIVNET) and sponsored by the US National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, through contract N01-AI-35173 with Family Health International; contract N01-AI-45200 with Fred Hutchinson Cancer Research Center; and subcontract N01-AI-35173-117/412 with Johns Hopkins University. In addition, this work was supported by the HIV Prevention Trials Network (HPTN) and sponsored by the National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute on Drug Abuse, National Institute of Mental Health, and Office of AIDS Research, of the National Institutes of Health, US Department of Health and Human Services, Harvard University (U01-AI-480006), Johns Hopkins University (U01-AI-48005), and the University of Alabama at Birmingham (U01-AI-47972). Nevirapine (Viramune) for the study was provided by Boehringer Ingelheim Pharmaceuticals, Inc.
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HIVNET 024 Team
Protocol Co-Chairs: Taha E. Taha, MD, PhD (Johns Hopkins University Bloomberg School of Public Health); Robert Goldenberg, MD (University of Alabama at Birmingham).
In-Country Co-Chairs/Investigators of Record: Newton Kumwenda, PhD, George Kafulafula, MBBS, FCOG (Blantyre, Malawi); Francis Martinson, MD, PhD (Lilongwe, Malawi); Gernard Msamanga, MD, ScD (Dare es Salaam, Tanzania); Moses Sinkala, MD, MPH, Jeffrey Stringer, MD (Lusaka, Zambia).
US Co-Chairs: Irving Hoffman, PA, MPH (University of North Carolina, Chapel Hill); Wafaie Fawzi, MD, DrPH (Harvard School of Public Health).
In-Country Investigators, Consultants and Key Site Personnel: Robin Broadhead, MBBS, FRCP, George Liomba, MBBS, FRCPath, Johnstone Kumwenda, MBChB, MRCP, Tsedal Mebrahtu, ScM, Pauline Katunda, MHS, Maysoon Dahab, MHS (Blantyre, Malawi); Peter Kazembe, MBChB, David Chilongozi CO, MPH, Charles Chasela CO, MPH, George Joaki, MD, Willard Dzinyemba, Sam Kamanga (Lilongwe, Malawi); Elgius Lyamuya, MD, PhD, Charles Kilewo, MD, MMed, Karim Manji, MD, MMed, Sylvia Kaaya, MD, MS, Said Aboud, MD, MMed, Muhsin Sheriff MD, MPH, Elmar Saathoff, PhD, Priya Satow, MPH, Illuminata Ballonzi, SRN, Gretchen Antelman, ScD, Edgar Basheka, BPharm (Dar es Salaam, Tanzania); Victor Mudenda, MD, Christine Kaseba, MD, Maureen Njobvu, MD, Makungu Kabaso, MD, Muzala Kapina, MD, Anthony Yeta, MD, Seraphine Kaminsa, MD, MPH, Constantine Malama, MD, Dara Potter, MBA, Maclean Ukwimi, RN, Alison Taylor, BSc, Patrick Chipaila, MSc, Bernice Mwale, BPharm (Lusaka, Zambia).
US Investigators, Consultants and Key Site Personnel: Priya Joshi, BS, Ada Cachafeiro, BS, Shermalyn Greene, PhD, Marker Turner, BS, Melissa Kerkau, BS, Paul Alabanza, BS, Amy James, BS, Som Siharath, BS, Tiffany Tribull, MS (UNC-CH); Saidi Kapiga, MD, ScD, George Seage, PhD (HSPH); Sten Vermund, MD, PhD, William Andrews, PhD, MD, Deedee Lyon, BS, MT(ASCP) (UAB).
NIAID Medical Officer: Samuel Adeniyi-Jones, MD;
NICHD Medical Officer: Jennifer S. Read, MD, MS, MPH, DTM&H.
Protocol Pharmacologist: Scharla Estep, RPh, MS.
Protocol Statisticians: Elizabeth R. Brown, ScD, Thomas R. Fleming, PhD, Anthony Mwatha, MS, Lei Wang, PhD, Deborah Donnell, PhD, Ying Q. Chen, PhD.
Protocol Virologist: Susan Fiscus, PhD.
Protocol Operations Coordinator: Lynda Emel, PhD.
Data Coordinators: Debra J. Lands, Ed.M, Ceceilia J. Dominique.
Systems Analyst Programmers: Alice H. Fisher, BA, Martha Doyle.
Protocol Specialist: Megan Valentine, PA-C, MS.
prevention of mother-to-child transmission of HIV-1; mother-to-child transmission; sub-Saharan Africa; nevirapine; HIVNET 024; dose timing
© 2005 Lippincott Williams & Wilkins, Inc.
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