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).
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.
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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.