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Introduction: In recent years, the expansion of HIV treatment eligibility has resulted in an increase in people with antiretroviral therapy (ART) experience prior to pregnancy but little is known about postpartum engagement in care in this population. We examined differences in disengagement from HIV care after delivery by maternal ART history before conception., Methods: We analysed data from people living with HIV (aged 15-49) in Khayelitsha, South Africa, with ≥1 live birth between April 2013 and March 2019. We described trends over time in ART history prior to estimated conception, classifying ART history groups as: (A) on ART with no disengagement (>270 days with no evidence of HIV care); (B) returned before pregnancy following disengagement; (C) restarted ART in pregnancy after disengagement; and (D) ART new start in pregnancy. We used Kaplan-Meier curves and proportional-hazards models (adjusted for maternal age, number of pregnancy records and year of delivery) to examine the time to disengagement from delivery to 2 years postpartum., Results: Among 7309 pregnancies (in 6680 individuals), the proportion on ART (A) increased from 19% in 2013 to 41% in 2019. The proportions of those who returned (B) and restarted (C) increased from 2% to 13% and from 2% to 10%, respectively. There was a corresponding decline in the proportion of new starts (D) from 77% in 2013 to 36% in 2019. In the first recorded pregnancy per person in the study period, 26% (95% CI 25-27%) had disengaged from care by 1 year and 34% (95% CI 33-36%) by 2 years postpartum. Individuals who returned (B: aHR 2.10, 95% CI 1.70-2.60), restarted (C: aHR 3.32, 95% CI 2.70-4.09) and newly started ART (D: aHR 2.41, 95% CI 2.12-2.74) had increased hazards of postpartum disengagement compared to those on ART (A)., Conclusions: There is a growing population of people with ART experience prior to conception and postpartum disengagement varies substantially by ART history. Antenatal care presents an important opportunity to understand prior ART experiences and an entry into interventions for strengthened engagement in HIV care., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Antiretroviral therapy (ART) is associated with high rates of adverse birth outcomes, including preterm birth and low birthweight. Studies suggest that progesterone and prolactin may play important intermediary roles., Methods: We analyzed data from the Antenatal Component of the PROMISE trial, a multi-center study of pregnant women taking antiretroviral regimens (lopinavir/ritonavir-containing ART or zidovudine alone) to prevent mother-to-child HIV transmission. In a nested case-control study, we compared data from women who gave birth to preterm (<37 weeks gestation) and/or low birthweight (<2500 g) infants to matched individuals who did not. We measured serum progesterone and prolactin at 24-34 weeks gestation. We used conditional logistic regression to describe relationships between hormone levels, birth outcomes, and antiretroviral regimens., Results: 299 women and their newborns were included (146 cases, 153 controls). When compared to women receiving zidovudine alone, those on ART had higher odds of progesterone levels under the 10th percentile (adjusted odds ratio [AOR]:2.34, 95%CI:1.41-3.89) and 25th percentile (AOR:2.07, 95%CI:1.46-2.94). However, higher levels of progesterone-rather than lower levels-were associated with our composite case outcome at the 10th percentile (AOR:1.88, 95%CI:0.77-4.59) and 25th percentile (AOR:1.96, 95%CI:1.06-3.61). Associations were not observed between prolactin, antiretroviral regimen, and birth outcomes., Conclusion: We observed lower progesterone levels among women allocated to ART regimens; however, higher progesterone levels were associated with preterm birth and/or low birthweight. While features of the study design may have contributed to these findings, they nevertheless highlight the potentially complex mechanisms underpinning adverse birth outcomes and HIV., Competing Interests: The study products in the PROMISE trial were provided free of charge by Abbott, Gilead Sciences, Boehringer Ingelheim, and GlaxoSmithKline. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Chi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: NER is supported, in part, through the National Institutes of Health (NIH) through grants R21MH125705 and R01 MH124526. BHC is supported by NIH grants K24 AI120796 and R01 AI131060. We declare no competing interests.

Efforts to prevent mother-to-child transmission of human immunodeficiency virus (HIV) have led to dramatic reductions in pediatric HIV worldwide. New advances in HIV treatment and prevention, focused on pregnant and breastfeeding women living with HIV, have improved maternal health while decreasing vertical and horizontal HIV transmission. In this article, we describe how such interventions-including antiretroviral therapy and HIV pre-exposure prophylaxis-can be incorporated into antepartum and postpartum care in global settings., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Pregnant women are routinely excluded from clinical trials, leading to the absence or delay in even the most basic pharmacokinetic (PK) information needed for dosing in pregnancy. When available, pregnancy PK studies use a small sample size, resulting in limited safety information. We discuss key study design elements that may enhance the timely availability of pregnancy data, including the role and timing of randomized controlled trials (RCTs) to evaluate pregnancy safety; efficacy and safety outcome measures; stand-alone protocols, platform trials, single arm studies, sample size and the effect that follow-up time during gestation has on analysis interpretations; and observational studies., Discussion: Pregnancy PK should be studied during drug development, after dosing in non-pregnant persons is established (unless non-clinical or other data raise pregnancy concerns). RCTs should evaluate the safety during pregnancy of priority new HIV agents that are likely to be used by large numbers of females of childbearing age. Key endpoints for pregnancy safety studies include birth outcomes (prematurity, small for gestational age and stillbirth) and neonatal death, with traditional adverse events and infant growth also measured (congenital anomalies are best studied through surveillance). We recommend that viral efficacy be studied as a secondary endpoint of pregnancy RCTs, once PK studies confirm adequate drug exposure in pregnancy. RCTs typically use a stand-alone protocol for new agents. In contrast, master protocols using a platform design can add agents over time, possibly speeding safety data ascertainment. To speed accrual, stand-alone pregnancy trial protocols can include pre-specified starting rules based upon adequate PK levels in pregnancy; and seamless master protocols or platform trials can include a pregnancy PK and safety component. When RCTs are unethical or cost-prohibitive, observational studies should be conducted, preferably using target trial emulation to avoid bias., Conclusions: Pregnancy PK needs to be obtained earlier in drug evaluation. Timely RCTs are needed to understand safety in pregnancy for high-priority new HIV agents. RCTs that enrol pregnant women should focus on outcomes unique to pregnancy, and observational studies should focus on questions that RCTs are not equipped to answer., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

There is increasing focus in HIV prevention and treatment on couples-based approaches. No systematic review has synthesized prospective behavioral couples-based HIV trials targeting prevention of mother-to-child transmission (PMTCT) outcomes in low- and middle-income countries (LMICs). We systematically reviewed published abstracts and articles reporting prospective comparative evaluations of behavioral couples-based HIV interventions delivered during pregnancy to both members of a self-identified heterosexual couple in LMICs following PRISMA. Citations, abstracts, and full texts were double screened for eligibility. References meeting eligibility criteria underwent double data abstraction, quality appraisal, and qualitative synthesis. We identified 295 unique publications. Of these, 5 randomized trials were deemed eligible and synthesized. Studies were conducted in 3 different African countries using three overarching intervention approaches: home-based; group workshops; and faith-based. Studies included various PMTCT outcome measures. We found evidence that behavioral couples-based approaches around the time of pregnancy can positively affect HIV testing among pregnant women and their male partners, infant HIV prophylaxis use, and HIV-free infant survival. The effects on other PMTCT outcomes were not well supported. There was a low to moderate risk of bias among the included studies. Few couples-based PMTCT interventions have been tested in LMICs. Of the interventions we located, workshops/group education and home-based couple counseling and testing were most commonly used to promote PMTCT. Research is needed on the role of relationship dynamics within such interventions and whether couples-based approaches during pregnancy can extend to health outcomes across the PMTCT continuum of care., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In sub-Saharan Africa, 3 community-facility linkage (CFL) models-Expert Clients, Community Health Workers (CHWs), and Mentor Mothers-have been widely implemented to support pregnant and breastfeeding women (PBFW) living with HIV and their infants to access and sustain care for prevention of mother-to-child transmission of HIV (PMTCT), yet their comparative impact under real-world conditions is poorly understood., Methods and Findings: We sought to estimate the effects of CFL models on a primary outcome of maternal loss to follow-up (LTFU), and secondary outcomes of maternal longitudinal viral suppression and infant "poor outcome" (encompassing documented HIV-positive test result, LTFU, or death), in Malawi's PMTCT/ART program. We sampled 30 of 42 high-volume health facilities ("sites") in 5 Malawi districts for study inclusion. At each site, we reviewed medical records for all newly HIV-diagnosed PBFW entering the PMTCT program between July 1, 2016 and June 30, 2017, and, for pregnancies resulting in live births, their HIV-exposed infants, yielding 2,589 potentially eligible mother-infant pairs. Of these, 2,049 (79.1%) had an available HIV treatment record and formed the study cohort. A randomly selected subset of 817 (40.0%) cohort members underwent a field survey, consisting of a questionnaire and HIV biomarker assessment. Survey responses and biomarker results were used to impute CFL model exposure, maternal viral load, and early infant diagnosis (EID) outcomes for those missing these measures to enrich data in the larger cohort. We applied sampling weights in all statistical analyses to account for the differing proportions of facilities sampled by district. Of the 2,049 mother-infant pairs analyzed, 62.2% enrolled in PMTCT at a primary health center, at which time 43.7% of PBFW were ≤24 years old, and 778 (38.0%) received the Expert Client model, 640 (31.2%) the CHW model, 345 (16.8%) the Mentor Mother model, 192 (9.4%) ≥2 models, and 94 (4.6%) no model. Maternal LTFU varied by model, with LTFU being more likely among Mentor Mother model recipients (adjusted hazard ratio [aHR]: 1.45; 95% confidence interval [CI]: 1.14, 1.84; p = 0.003) than Expert Client recipients. Over 2 years from HIV diagnosis, PBFW supported by CHWs spent 14.3% (95% CI: 2.6%, 26.1%; p = 0.02) more days in an optimal state of antiretroviral therapy (ART) retention with viral suppression than women supported by Expert Clients. Infants receiving the Mentor Mother model (aHR: 1.24, 95% CI: 1.01, 1.52; p = 0.04) and ≥2 models (aHR: 1.44, 95% CI: 1.20, 1.74; p < 0.001) were more likely to undergo EID testing by age 6 months than infants supported by Expert Clients. Infants receiving the CHW and Mentor Mother models were 1.15 (95% CI: 0.80, 1.67; p = 0.44) and 0.84 (95% CI: 0.50, 1.42; p = 0.51) times as likely, respectively, to experience a poor outcome by 1 year than those supported by Expert Clients, but not significantly so. Study limitations include possible residual confounding, which may lead to inaccurate conclusions about the impacts of CFL models, uncertain generalizability of findings to other settings, and missing infant medical record data that limited the precision of infant outcome measurement., Conclusions: In this descriptive study, we observed widespread reach of CFL models in Malawi, with favorable maternal outcomes in the CHW model and greater infant EID testing uptake in the Mentor Mother model. Our findings point to important differences in maternal and infant HIV outcomes by CFL model along the PMTCT continuum and suggest future opportunities to identify key features of CFL models driving these outcome differences., Competing Interests: The authors have declared that no competing interests exist.

To eliminate mother-to-child transmission of HIV (EMTCT), scalable strategies to enhance antiretroviral adherence for both antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are needed as part of integrated HIV and maternal-child health services. We developed Tonse Pamodzi ("all of us together"), an adaptable intervention integrating biomedical and behavioral components to support HIV treatment and prevention. We describe our intervention development process, which comprised formative qualitative research, a review of the literature, and technical input from stakeholders representing the community, health systems, and policymakers. The resulting intervention, described herein, integrates patient-centered counseling and engagement of a patient-selected adherence supporter for pregnant and breastfeeding women initiating ART or PrEP. Patients receiving the intervention engage in Integrated Next Step Counseling (iNSC) sessions delivered by trained counselors to build and maintain adherence skills. Each patient also has the option of selecting an adherence supporter (partner, family member, or friend) who may participate in iNSC sessions and provide adherence support outside of these sessions. This flexible intervention is adaptable not only to ART or PrEP use, but also to the needs and preferences of each woman and the clinical context. If shown to be acceptable and feasible, the Tonse Pamodzi intervention may be an important tool in continuing efforts for EMTCT., Competing Interests: LMH reports grant support from Gilead Sciences. KRA reports consulting for Gilead Sciences in two expert advisory meetings (December 2020 and June 2021). This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors otherwise have declared that no competing interests exist.

Introduction: Findings from biomedical, behavioural and implementation studies provide a rich foundation to guide programmatic efforts for the prevention of mother-to-child HIV transmission (PMTCT)., Methods: We summarized the current evidence base to support policy makers, programme managers, funding agencies and other stakeholders in designing and optimizing PMTCT programmes. We searched the scientific literature for PMTCT interventions in the era of universal antiretroviral therapy for pregnant and breastfeeding women (i.e. 2013 onward). Where evidence was sparse, relevant studies from the general HIV treatment literature or from prior eras of PMTCT programme implementation were also considered. Studies were organized into six categories: HIV prevention services for women, timely access to HIV testing, timely access to ART, programme retention and adherence support, timely engagement in antenatal care and services for infants at highest risk of HIV acquisition. These were mapped to specific missed opportunities identified by the UNAIDS Spectrum model and embedded in UNICEF operational guidance to optimize PMTCT services., Results and Discussion: From May to November 2019, we identified numerous promising, evidence-based strategies that, properly tailored and adopted, could contribute to population reductions in vertical HIV transmission. These spanned the HIV and maternal and child health literature, emphasizing the importance of continued alignment and integration of services. We observed overlap between several intervention domains, suggesting potential for synergies and increased downstream impact. Common themes included integration of facility-based healthcare; decentralization of health services from facilities to communities; and engagement of partners, peers and lay workers for social support. Approaches to ensure early HIV diagnosis and treatment prior to pregnancy would strengthen care across the maternal lifespan and should be promoted in the context of PMTCT., Conclusions: A wide range of effective strategies exist to improve PMTCT access, uptake and retention. Programmes should carefully consider, prioritize and plan those that are most appropriate for the local setting and best address existing gaps in PMTCT health services., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Objectives: A previous meta-analysis reported high HIV incidence among pregnant and breast-feeding women in sub-Saharan Africa (SSA), but limited evidence of elevated risk of HIV acquisition during pregnancy or breast-feeding when compared with nonpregnant periods. The rapidly evolving HIV prevention and treatment landscape since publication of this review may have important implications for maternal HIV incidence., Design: Systematic review and meta-analysis., Methods: We searched four databases and abstracts from relevant conferences through 1 December 2018, for literature on maternal HIV incidence in SSA. We used random-effects meta-analysis to summarize incidence rates and ratios, and to estimate 95% prediction intervals. We evaluated potential sources of heterogeneity with random-effects meta-regression., Results: Thirty-seven publications contributed 100 758 person-years of follow-up. The estimated average HIV incidence rate among pregnant and breast-feeding women was 3.6 per 100 person-years (95% prediction interval: 1.2--11.1), while the estimated average associations between pregnancy and risk of HIV acquisition, and breast-feeding and risk of HIV acquisition, were close to the null. Wide 95% prediction intervals around summary estimates highlighted the variability of HIV incidence across populations of pregnant and breast-feeding women in SSA. Average HIV incidence appeared associated with age, partner HIV status, and calendar time. Average incidence was highest among studies conducted pre-2010 (4.1/100 person-years, 95% prediction interval: 1.1--12.2) and lowest among studies conducted post-2014 (2.1/100 person-years, 95% prediction interval: 0.7--6.5)., Conclusion: Substantial HIV incidence among pregnant and breast-feeding women in SSA, even in the current era of combination HIV prevention and treatment, underscores the need for prevention tailored to high-risk pregnant and breast-feeding women.

Introduction: HIV incidence is high during pregnancy and breastfeeding with HIV acquisition risk more than doubling during pregnancy and the postpartum period compared to when women are not pregnant. The World Health Organization recommends offering pre-exposure prophylaxis (PrEP) to pregnant and postpartum women at substantial risk of HIV infection. However, maternal PrEP national guidelines differ and most countries with high maternal HIV incidence are not offering PrEP. We conducted a systematic review of recent research on PrEP safety in pregnancy to inform national policy and rollout., Methods: We used a standard Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) approach to conduct a systematic review by searching for completed, ongoing, or planned PrEP in pregnancy projects or studies from clinicaltrials.gov, PubMed and NIH RePORTER from 2014 to March 2019. We performed a systematic review of studies that assess tenofovir disoproxil fumarate (TDF)-based oral PrEP safety in pregnant and breastfeeding HIV-uninfected women., Results and Discussion: We identified 14 completed (n = 5) and ongoing/planned (n = 9) studies that evaluate maternal and/or infant outcomes following PrEP exposure during pregnancy or breastfeeding. None of the completed studies found differences in pregnancy or perinatal outcomes associated with PrEP exposure. Nine ongoing studies, to be completed by 2022, will provide data on >6200 additional PrEP-exposed pregnancies and assess perinatal, infant growth and bone health outcomes, expanding by sixfold the data on PrEP safety in pregnancy. Research gaps include limited data on (1) accurately measured PrEP exposure within maternal and infant populations including drug levels needed for maternal protection; (2) uncommon perinatal outcomes (e.g. congenital anomalies); (3) infant outcomes such as bone growth beyond one year following PrEP exposure; (4) outcomes in HIV-uninfected women who use PrEP during pregnancy and/or lactation., Conclusions: Expanding delivery of PrEP is an essential strategy to reduce HIV incidence in pregnancy and breastfeeding women. Early safety studies of PrEP among pregnant women without HIV infection are reassuring and ongoing/planned studies will contribute extensive new data to bolster the safety profile of PrEP use in pregnancy. However, addressing research gaps is essential to expanding PrEP delivery for women in the context of pregnancy., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Objective: To evaluate the association between HIV antiretroviral therapy (ART) and preterm birth (PTB), when defined by gold standard antenatal ultrasound versus newborn exam., Design: A secondary analysis of the PROMISE 1077BF/1077FF randomized controlled trial, which compared antiretroviral strategies to reduce perinatal HIV transmission and improve maternal health. The trial used newborn exam (i.e. New Ballard Score, NBS) to assess gestational age. This analysis included liveborn singleton pregnancies with both newborn exam and ultrasound data. The primary exposure was the trial's antiretroviral strategies: zidovudine with intrapartum nevirapine ('ZDV alone'); zidovudine/lamivudine/lopinavir-ritonavir ('ZDV-based ART'); or tenofovir/emtricitabine/lopinavir-ritonavir ('TDF-based ART'). The primary outcome was PTB less than 37 and less than 34 weeks based on the gold standard of ultrasound dating. We evaluated the association between antiretroviral strategy and PTB. We fit multivariable logistic regression models, adjusting for maternal characteristics, obstetric history, and HIV disease severity., Results: Among 720 assessed pregnant women, PTB less than 37 weeks was 15.4% by NBS and 18.3% by ultrasound. The NBS was specific but not sensitive for PTB less than 37 weeks (92.0% and 48.5%). Women receiving ZDV-based and TDF-based ART had significantly higher odds of PTB less than 37 by ultrasound compared with ZDV alone (adjusted odds ratios: 1.68; 95% confidence interval 1.10-2.57, and 2.71; 95% confidence interval 1.39-5.29), as well as for PTB less than 34 weeks. These results held for ultrasounds performed less than 24 weeks, and were generally consistent with prior analyses from the PROMISE trial using the NBS., Conclusion: Women starting HIV ART in pregnancy remained at higher risk of PTB when determined by ultrasound, consistent with prior data using newborn exam. However, newborn exam misclassified cases of PTB compared with gold standard ultrasound.

High HIV incidence rates have been observed among pregnant and breastfeeding women in sub-Saharan Africa. Oral pre-exposure prophylaxis (PrEP) can effectively reduce HIV acquisition in women during these periods; however, understanding of its acceptability and feasibility in antenatal and postpartum populations remains limited. To address this gap, we conducted in-depth interviews with 90 study participants in Malawi and Zambia: 39 HIV-negative pregnant/breastfeeding women, 14 male partners, 19 healthcare workers, and 18 policymakers. Inductive and deductive approaches were used to identify themes related to PrEP. As a public health intervention, PrEP was not well-known among patients and healthcare workers; however, when it was described to participants, most expressed positive views. Concerns about safety and adherence were raised, highlighting two critical areas for community outreach. The feasibility of introducing PrEP into antenatal services was also a concern, especially if introduced within already strained health systems. Support for PrEP varied among policymakers in Malawi and Zambia, reflecting the ongoing policy discussions in their respective countries. Implementing PrEP during the pregnancy and breastfeeding periods will require addressing barriers at the individual, facility, and policy levels. Multi- level approaches should be considered in the design of new PrEP programs for antenatal and postpartum populations., Competing Interests: The authors have declared that no competing interests exist.

Background: In the multicountry PROMISE 1077BF/1077FF trial, the risk of low birth weight (LBW; <2500 g) and preterm delivery (PTD; <37 weeks) was significantly higher among women initiating a protease inhibitor-based antiretroviral treatment (ART) regimen than those receiving ZDV alone. Among those assigned to a protease inhibitor regimen, tenofovir/emtricitabine was associated with the more severe outcomes of very LBW (<1500 g) and very PTD (<34 weeks) compared with zidovudine/lamivudine., Methods: We used multivariate logistic regression to further explore these treatment findings, taking into account demographic baseline clinical and postentry obstetrical factors. We evaluated individual adverse outcomes and composites that included stillbirth and early loss/spontaneous abortion., Results: Among 3333 women delivering at least 1 live infant, median maternal age at enrollment was 26 years; 661 (20%) were primiparous, and 110 (3.3%) reported at least 1 previous PTD. Seventeen percent of newborns were LBW, 1% were very LBW, 17% had PTD, and 3% had very PTD. Treatment allocation remained strongly associated with multiple adverse outcomes after controlling for other risk factors with both ART regimens exhibiting increased risk relative to ZDV alone. Other risk factors remaining significant in at least one of the multivariate models included the following: country, gestational age at entry, maternal age, maternal body mass index, previous PTD, history of alcohol use, baseline HIV viral titer, multiple gestation, and several obstetric risk factors., Conclusions: ART effects on adverse pregnancy outcomes reported in the randomized PROMISE trial remained strongly significant even after controlling for demographic, baseline clinical, and obstetrical risk factors, which were also associated with these outcomes.

Background: Lifelong antiretroviral therapy (ART) is now recommended for all human immunodeficiency virus (HIV)-infected pregnant and breastfeeding women; however, few have described overall infant outcomes in this new era for the prevention of mother-to-child HIV transmission (PMTCT)., Methods: As part of an assessment of PMTCT program impact, we enrolled a prospective cohort study in 4 predominantly rural districts in Zambia. HIV-infected mothers and their newborns (≤30 days old) were recruited and followed at 6 weeks, 6 months and 12 months postpartum; infant specimens were tested via HIV DNA polymerase chain reaction. In Kaplan-Meier analyses, we estimated overall infant HIV-free survival and then stratified by district, community and maternal ART use. We investigated the relationship between community-level 12-month, self-reported maternal ART use and infant HIV-free survival via linear regression., Results: From June 2014 to November 2015, we enrolled 827 mother-infant pairs in 33 communities. At 12 months, small proportions of infants had died (2.8%), were HIV-infected (3.0%) or were lost to follow-up (4.3%). Overall, infant HIV-free survival was 99.0% [95% confidence interval (CI): 98.0%-99.5%] at 6 weeks, 97.5% (95% CI: 96.1%-98.4%) at 6 months and 96.3% (95% CI: 94.8%-97.4%) at 12 months. Women reporting ART use at enrollment had higher infant HIV-free survival than those who did not (97.4% vs. 89.0%, P = 0.01). Differences were noted at the district and site levels (P = 0.01). In community-level analysis, no relationship was observed between 12-month infant HIV-free survival and self-reported maternal ART use (P = 0.65)., Conclusion: Although encouraging, these findings highlight the need for rigorous monitoring and evaluation of PMTCT services at the population level.

Background: Investigations of the association of combination antiretroviral therapy (ART) with pregnancy outcomes often rely on routinely collected clinical data, which are prone to missing data and measurement error. Measurement error in gestational age may bias the relation between combination ART and gestational age-based outcomes., Methods: We demonstrate the use of multiple overimputation to address missing data and measurement error in gestational age. Using routinely collected clinical data from public health facilities in Lusaka, Zambia, we multiply imputed missing data and multiply overimputed observed values of gestational age. Poisson models with robust variance estimators were used to estimate risk ratios (RRs) for the associations of duration of combination ART with small for gestational age (SGA) and preterm birth. We compared results from a complete-case analysis, using multiple imputation to address missing data only and using multiple overimputation to address missing data and measurement error., Results: In the complete-case analysis, there was no evidence of an association between duration of combination ART and SGA or preterm birth. When we performed multiple overimputation, RRs for SGA moved past the null, but remained imprecise. For preterm birth, RRs for 9-32 weeks of combination ART moved away from the null as the variance due to measurement error increased., Conclusion: When we used multiple overimputation to account for measurement error and missing data, we observed an increased risk of preterm birth with longer duration of combination ART. Future analyses examining associations between combination ART and pregnancy outcomes should consider using multiple overimputation to address measurement error in gestational age.

Objective: To investigate the association between HIV, antiretroviral therapy (ART), and pregnancy-associated hypertension (PAH) in an HIV-endemic setting., Methods: A retrospective cohort study was undertaken of pregnant women for whom information was recorded between February 2006 and December 2012 in the Zambia Electronic Perinatal Record System, which captures data from 25 facilities in Lusaka, Zambia. PAH was defined as eclampsia, pre-eclampsia, hypertension, or elevated blood pressure (>140/80mm Hg) during delivery admission. Logistic regression estimated the odds of PAH among women by HIV serostatus, and by most recent CD4 T lymphocyte count and ART status among women with HIV infection., Results: Among 249 771 women included in the analysis, 5354 (2.1%) had PAH. Compared with women without HIV infection, women with HIV infection not receiving ART had lower odds of PAH (adjusted odds ratio [AOR] 0.86, 95% confidence interval 0.78-0.95), whereas those with HIV infection who had initiated ART had higher odds of PAH (AOR 1.15, 95% CI 1.01-1.32). No association was found between PAH and timing of ART initiation or CD4 lymphocyte count., Conclusion: In a large African urban cohort, women with untreated HIV infection had the lowest odds of PAH. Treatment with ART could increase PAH risk beyond that of women without HIV infection and those with untreated infection., (Published by Elsevier Ireland Ltd.)

Objective: Although tremendous gains have been made to reduce mother-to-child HIV transmission (MTCT) globally, evidence-based practice implementation remains inconsistent in sub-Saharan Africa. We sought to identify the key domains for effective prevention of MTCT (PMTCT) implementation, using a participatory mixed-methods approach., Methods: Participants were members of the NIH-PEPFAR PMTCT Implementation Science Alliance (ISA), a platform of researchers, public-health practitioners, policymakers, and donors supported through NIH/PEPFAR. We used concept mapping to identify priority areas for PMTCT implementation science. Participants responded to the focus question: "In your experience, what factors have facilitated or hindered implementation of PMTCT interventions?" Responses were consolidated into discrete statements, grouped together based on similarity, and rated for importance, changeability, and extent to which ISA participation enhanced the capacity to influence/change the factor., Results: Using multidimensional scaling and cluster analysis, we identified 12 key domains of PMTCT implementation. Two domains (Governmental Commitment and Data Measurement & Collection) were consistently ranked at or near the top for overall importance, perceived changeability, and enhanced ability to address through ISA participation., Discussion: Through a stakeholder-based, participatory approach, we identified key domains for that should be considered for future PMTCT implementation research in sub-Saharan Africa.

Introduction: Antiretroviral pre-exposure prophylaxis (PrEP) for the prevention of HIV acquisition is cost-effective when delivered to those at substantial risk. Despite a high incidence of HIV infection among pregnant and breastfeeding women in sub-Saharan Africa (SSA), a theoretical increased risk of preterm birth on PrEP could outweigh the HIV prevention benefit., Methods: We developed a decision analytic model to evaluate a strategy of daily oral PrEP during pregnancy and breastfeeding in SSA. We approached the analysis from a health care system perspective across a lifetime time horizon. Model inputs were derived from existing literature and local sources. The incremental cost-effectiveness ratio (ICER) of PrEP versus no PrEP was calculated in 2015 U.S. dollars per disability-adjusted life year (DALY) averted. We evaluated the effect of uncertainty in baseline estimates through one-way and probabilistic sensitivity analyses., Results: PrEP administered to pregnant and breastfeeding women in SSA was cost-effective. In a base case of 10,000 women, the administration of PrEP averted 381 HIV infections but resulted in 779 more preterm births. PrEP was more costly per person ($450 versus $117), but resulted in fewer disability-adjusted life years (DALYs) (3.15 versus 3.49). The incremental cost-effectiveness ratio of $965/DALY averted was below the recommended regional threshold for cost-effectiveness of $6462/DALY. Probabilistic sensitivity analyses demonstrated robustness of the model., Conclusions: Providing PrEP to pregnant and breastfeeding women in SSA is likely cost-effective, although more data are needed about adherence and safety. For populations at high risk of HIV acquisition, PrEP may be considered as part of a broader combination HIV prevention strategy., Competing Interests: BHC received grant funding from the Gilead Foundation to support global health research training. The remaining authors have no conflicts of interest to disclose.

Objective: To estimate the association between duration of combination antiretroviral therapy (cART) during pregnancy and low infant birthweight (LBW), among women ≥37 weeks of gestation., Design: We conducted a retrospective cohort study of HIV-infected women who met eligibility criteria based on CD4 count ≤350 but had not started cART at entry into antenatal care. Our cohort was restricted to births that occurred ≥37 weeks of gestation., Methods: We used Poisson models with robust variance estimators to estimate risk ratios (RRs) and 95% confidence intervals (CIs)., Results: Of 50,765 HIV-infected women with antenatal visits between January 2009 and September 2013, 4474 women met the inclusion criteria. LBW occurred in 302 pregnancies (7%). Nearly two-thirds of women (62%) eligible to initiate cART never started treatment. Overall, 14% were on cART for ≤8 weeks, 22% for 9-20 weeks, and 2% for 21-36 weeks. There was no evidence of an increased risk of LBW for women receiving cART for ≤8 weeks (RR = 1.22; 95% CI: 0.77 to 1.91), 9-20 weeks (RR = 1.23; 95% CI: 0.82 to 1.83), or 21-36 weeks (RR = 0.87; 95% CI: 0.22 to 3.46), compared with women who never initiated treatment. These findings were consistent across several sensitivity analyses., Conclusions: Longer duration of cART was not associated with poor fetal growth among term pregnancies in our cohort. However, the relationship between cART and adverse pregnancy outcomes remains complicated. Continued work is required to investigate causality. An understanding cART's impact on adverse pregnancy outcomes is essential as cART becomes the cornerstone of preventing mother-to-child transmission programs globally.

Background: In rural settings, HIV-infected pregnant women often live significant distances from facilities that provide prevention of mother-to-child transmission (PMTCT) services., Methods: We offered universal maternal combination antiretroviral regimens in 4 pilot sites in rural Zambia. To evaluate the impact of services, we conducted a household survey in communities surrounding each facility. We collected information about HIV status and antenatal service utilization from women who delivered in the past 2 years. Using household Global Positioning System coordinates collected in the survey, we measured Euclidean (i.e., straight line) distance between individual households and clinics. Multivariable logistic regression and predicted probabilities were used to determine associations between distance and uptake of PMTCT regimens., Results: From March to December 2011, 390 HIV-infected mothers were surveyed across four communities. Of these, 254 (65%) had household geographical coordinates documented. One hundred sixty-eight women reported use of a PMTCT regimen during pregnancy including 102 who initiated a combination antiretroviral regimen. The probability of PMTCT regimen initiation was the highest within 1.9 km of the facility and gradually declined. Overall, 103 of 145 (71%) who lived within 1.9 km of the facility initiated PMTCT versus 65 of 109 (60%) who lived farther away. For every kilometer increase, the association with PMTCT regimen uptake (adjusted odds ratio: 0.90, 95% confidence interval: 0.82 to 0.99) and combination antiretroviral regimen uptake (adjusted odds ratio: 0.88, 95% confidence interval: 0.80 to 0.97) decreased., Conclusions: In this rural African setting, uptake of PMTCT regimens was influenced by distance to health facility. Program models that further decentralize care into remote communities are urgently needed.

Background: Programs to prevent mother-to-child HIV transmission are plagued by loss to follow-up (LTFU) of HIV-exposed infants. We assessed if providing combination antiretroviral therapy (cART) to HIV-infected mothers was associated with reduced LTFU of their HIV-exposed infants in Kinshasa, DR Congo., Methods: We constructed a cohort of mother-infant pairs using routinely collected clinical data. Maternal cART eligibility was based on national guidelines in effect at the time. Infants were considered LTFU after 3 failed tracking attempts after a missed visit or if more than 6 months passed since they were last seen in clinic. Statistical methods accounted for competing risks (eg, death)., Results: A total of 1318 infants enrolled at a median age of 2.6 weeks (interquartile range: 2.1-6.9), at which point 24% of mothers were receiving cART. Overall, 5% of infants never returned to care after enrollment and 18% were LTFU by 18 months. The 18-month cumulative incidence of LTFU was 8% among infants whose mothers initiated cART by infant enrollment and 20% among infants whose mothers were not yet on cART. Adjusted for baseline factors, infants whose mothers were not on cART were over twice as likely to be LTFU, with a subdistribution hazard ratio of 2.75 (95% confidence limit: 1.81 to 4.16). The association remained strong regardless of maternal CD4 count at infant enrollment., Conclusions: Increasing access to cART for pregnant women could improve retention of HIV-exposed infants, thereby increasing the clinical and population-level impacts of prevention of mother-to-child HIV transmission interventions and access to early cART for HIV-infected infants.

Objective: To evaluate if a pilot programme to prevent mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV) was associated with changes in early childhood survival at the population level in rural Zambia., Methods: Combination antiretroviral regimens were offered to pregnant and breastfeeding, HIV-infected women, irrespective of immunological status, at four rural health facilities. Twenty-four-month HIV-free survival among children born to HIV-infected mothers was determined before and after PMTCT programme implementation using community surveys. Households were randomly selected and women who had given birth in the previous 24 months were asked to participate. Mothers were tested for HIV antibodies and children born to HIV-infected mothers were tested for viral deoxyribonucleic acid. Multivariable models were used to determine factors associated with child HIV infection or death., Findings: In the first survey (2008-2009), 335 of 1778 women (18.8%) tested positive for HIV. In the second (2011), 390 of 2386 (16.3%) tested positive. The 24-month HIV-free survival in HIV-exposed children was 0.66 (95% confidence interval, CI: 0.63-0.76) in the first survey and 0.89 (95% CI: 0.83-0.94) in the second. Combination antiretroviral regimen use was associated with a lower risk of HIV infection or death in children (adjusted hazard ratio: 0.33, 95% CI: 0.15-0.73). Maternal knowledge of HIV status, use of HIV tests and use of combination regimens during pregnancy increased between the surveys., Conclusion: The PMTCT programme was associated with an increased HIV-free survival in children born to HIV-infected mothers. Maternal utilization of HIV testing and treatment in the community also increased.

Considerable advances have been made in the effort to prevent mother-to-child HIV transmission (PMTCT) in sub-Saharan Africa. Clinical trials have demonstrated the efficacy of antiretroviral regimens to interrupt HIV transmission through the antenatal, intrapartum, and postnatal periods. Scientific discoveries have been rapidly translated into health policy, bolstered by substantial investment in health infrastructure capable of delivering increasingly complex services. A new scientific agenda is also emerging, one that is focused on the challenges of effective and sustainable program implementation. Finally, global campaigns to "virtually eliminate" pediatric HIV and dramatically reduce HIV-related maternal mortality have mobilized new resources and renewed political will. Each of these developments marks a major step in regional PMTCT efforts; their convergence signals a time of rapid progress in the field, characterized by an increased interdependency between clinical research, program implementation, and policy. In this review, we take stock of recent advances across each of these areas, highlighting the challenges--and opportunities--of improving health services for HIV-infected mothers and their children across the region.

Objective: To evaluate the effectiveness of maternal combination antiretroviral prophylaxis for prevention of mother-to-child transmission of HIV (PMTCT) in a program setting., Design: Prospective cohort study., Setting: Nine primary care clinics in rural Zambia., Participants: Two hundred and eighty-four HIV-infected pregnant women at at least 28 weeks gestation initiating PMTCT services between April 2009 and January 2011 and their newborn infants., Intervention: In four 'intervention' sites, PMTCT comprised universal combination antiretroviral prophylaxis (i.e. irrespective of CD4 cell count) from pregnancy until the cessation of breastfeeding. In five 'control' sites, women received antenatal zidovudine and peripartum nevirapine, the standard of care at the time. Prophylaxis during breastfeeding was not available in control sites., Main Outcome Measure: Cumulative infant HIV infection and death at 12 months postpartum., Results: At 12 month postpartum, one of 104 (1.0%) infants born to mothers at the intervention sites were HIV-infected, compared with 14 of 116 (12.1%) receiving care in the control sites [relative risk (RR): 12.6, 95% CI: 2.2-73.1; P = 0.005]. When we considered the composite outcome of HIV infection or death, similar trends were observed in the overall study population (RR: 3.4, 95% CI: 1.6-7.6; P = 0.002) and in a sub-analysis of women with CD4 cell count more than 350 cells/μl (RR: 3.2; 95% CI: 1.1-9.6; P = 0.04)., Conclusion: When compared with PMTCT services based on antenatal zidovudine and peripartum nevirapine, the provision of maternal combination prophylaxis imparted measurable health benefits to HIV-exposed infants. Implementation research is needed to further tailor and optimize these strategies for similar field settings.

Objectives: To determine the impact of time between initiating highly active antiretroviral therapy (HAART) and delivery-duration of antenatal HAART-on perinatal HIV infection., Design: We conducted a retrospective cohort analysis of pregnant HIV-infected women in Lusaka, Zambia. Women in our cohort were receiving HAART and had an infant HIV polymerase chain reaction test between 3 and 12 weeks of life., Methods: We examined factors associated with infant HIV infection and performed a locally weighted regression analysis to examine the effect of duration of antenatal HAART on perinatal HIV infection., Results: : From January 2007 to March 2010, 1813 HIV-infected pregnant women met inclusion criteria. Mean gestational age at first antenatal visit was 21 weeks (SD ± 6), median CD4+ cell count was 231 cells per microliter (interquartile range: 164-329), and median duration of antenatal HAART was 13 weeks (interquartile range 8-19). Fifty-nine (3.3%) infants were HIV infected. Duration of antenatal HAART was the most important predictor of perinatal HIV transmission. Compared with women initiating HAART at least 13 weeks before delivery, women on HAART for ≤4 weeks had a 5.5-fold increased odds of HIV transmission (95% confidence interval: 2.6 to 11.7). Locally weighted regression analysis suggested limited additional prophylactic benefit beyond 13 weeks on antenatal HAART., Conclusions: Low rates of mother-to-child HIV transmission can be achieved within programmatic settings in Africa. Maximal effectiveness of prevention of mother-to-child transmission programs is achieved by initiating HAART at least 13 weeks before delivery.

Background: In resource-limited settings, CD4 testing is a barrier to antiretroviral therapy initiation in pregnancy., Methods: We used logistic regression to identify predictors of CD4 cell count ≤ 350 cells/uL in 20,233 pregnant women., Results: The best-performing model included any 3 of: age ≥ 28 years old, hemoglobin ≤ 9.8 g/dL, gestational age ≤ 30 weeks, weight ≤ 64 kg, history of tuberculosis or previous death of an infant prior to one year old. Sensitivity was 45.7% (95% CI: 44.5-47.0), specificity 70.7% (95% CI: 69.6-71.8), and misclassification rate 41.4% (95% CI: 40.5-42.2)., Conclusion: CD4 triage remains a critical element of maternal HIV care and PMTCT.

Context: Few studies have objectively evaluated the coverage of services to prevent transmission of human immunodeficiency virus (HIV) from mother to child., Objective: To measure the coverage of services to prevent mother-to-child HIV transmission in 4 African countries., Design, Setting, and Patients: Cross-sectional surveillance study of mother-infant pairs using umbilical cord blood samples collected between June 10, 2007, and October 30, 2008, from 43 randomly selected facilities (grouped as 25 service clusters) providing delivery services in Cameroon, Côte d'Ivoire, South Africa, and Zambia. All sites used at least single-dose nevirapine to prevent mother-to-child HIV transmission and some sites used additional prophylaxis drugs., Main Outcome Measure: Population nevirapine coverage, defined as the proportion of HIV-exposed infants in the sample with both maternal nevirapine ingestion (confirmed by cord blood chromatography) and infant nevirapine ingestion (confirmed by direct observation)., Results: A total of 27,893 cord blood specimens were tested, of which 3324 were HIV seropositive (12%). Complete data for cord blood nevirapine results were available on 3196 HIV-seropositive mother-infant pairs. Nevirapine coverage varied significantly by site (range: 0%-82%). Adjusted for country, the overall coverage estimate was 51% (95% confidence interval [CI], 49%-53%). In multivariable analysis, failed coverage of nevirapine-based services was significantly associated with maternal age younger than 20 years (adjusted odds ratio [AOR], 1.44; 95% CI, 1.18-1.76) and maternal age between 20 and 25 years (AOR, 1.28; 95% CI, 1.07-1.54) vs maternal age of older than 30 years; 1 or fewer antenatal care visits (AOR, 2.91; 95% CI, 2.40-3.54), 2 or 3 antenatal care visits (AOR, 1.93; 95% CI, 1.60-2.33), and 4 or 5 antenatal care visits (AOR, 1.56; 95% CI, 1.34-1.80) vs 6 or more antenatal care visits; vaginal delivery (AOR, 1.22; 95% CI, 1.03-1.44) vs cesarean delivery; and infant birth weight of less than 2500 g (AOR, 1.34; 95% CI, 1.11-1.62) vs birth weight of 3500 g or greater., Conclusion: In this random sampling of sites with services to prevent mother-to-child HIV transmission, only 51% of HIV-exposed infants received the minimal regimen of single-dose nevirapine.

Objective: Prior exposure to intrapartum/neonatal nevirapine (NVP) is associated with compromised virologic treatment outcomes once non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) is initiated. We examined the longer-term clinical outcomes in a programmatic setting., Methods: We compared post-12 month mortality and clinical treatment failure (defined by WHO clinical and immunologic criteria) among women with and without prior NVP exposure in Lusaka, Zambia., Results: Between April 2004 and July 2006, 6740 women initiated an NNRTI-containing regimen. At 12 months, 5172 (78%) remained active and were included in this analysis. Of these, 596 (12%) reported prior NVP exposure, whose time from exposure to ART initiation was: <6 months for 11%, 6-12 months for 13%, >12 months for 37%, unknown for 39%. Overall, women with prior NVP exposure trended towards increased survival (adjusted hazard ratio [AHR]: 0.53; 95% confidence interval [CI]: 0.27-1.06, P = 0.07) and towards increased hazard of clinical treatment failure (AHR: 1.18; 95% CI: 0.95-1.47, P = 0.14), particularly those with exposure for <6 months (AHR: 1.52; 95% CI: 0.94-2.45, P = 0.09)., Conclusions: Prior NVP exposure appeared to increase risk for clinical treatment failure after 12 months of follow-up, but this finding did not reach statistical significance. With growing evidence linking recent NVP exposure to virologic failure, optimized monitoring algorithms should be considered for women with starting NNRTI-based ART. The association between prior NVP exposure and improved survival has not been previously shown and may be a result of residual confounding around health-seeking behaviours.

Objectives: To determine the optimal time for a second HIV-1 nucleic acid amplification assay to detect late postnatal transmission of HIV-1 (first negative test at 4-8 weeks of age) in resource-limited settings., Design: A longitudinal analysis of data from HIV Prevention Trial Network trial 024., Methods: Children born to HIV-1-infected mothers enrolled in the HIV Prevention Trial Network trial 024 were tested for HIV-1 infection at six intervals within the first year of life. Mothers and infants received nevirapine prophylaxis. We estimated the probability of being alive and having a positive test in each interval after 4-8 weeks and at 30 days after weaning, conditional on having acquired HIV during the late postnatal period. The interval with the highest probability was taken to be the optimal visit interval., Results: A total of 1609 infants from HIV Prevention Trial Network trial 024 had at least one HIV-1 diagnostic test and were included in the analysis. We found that testing at 1 month after weaning or 12 months of age (whichever comes first) identified 81% of those infected during the late postnatal period (after 4-8 weeks) through breastfeeding. In total, 93% (95% confidence interval 89, 98) of all infected infants would be detected if tests were performed at these two time points., Conclusion: In resource-limited settings, HIV-1 PCR testing at 4-8 weeks followed by a second test at 1 month after weaning or at 1 year of age (whichever comes first), led to the identification of the vast majority of HIV-1-infected infants.

Objective: HIV prevention has been ongoing in Lusaka for many years. Recent reports suggest a possible decline in HIV sero-incidence in Zambia and some neighbouring countries. This study aimed to examine trends in HIV seroprevalence among pregnant and parturient women between 2002 and 2006., Methods: We analysed HIV seroprevalence trends from two Lusaka sources: (i) antenatal data from a city-wide programme to prevent mother-to-child HIV transmission, and (ii) delivery data from two anonymous unlinked cord-blood surveillances performed in 2003 and again in 2005-2006, where specimens from > 97% of public-sector births in each period were obtained and analysed., Findings: Between July 2002 and December 2006, the Lusaka district tested 243 302 antenatal women for HIV; 54 853 (22.5%) were HIV infected. Over this period, the HIV seroprevalence among antenatal attendees who were tested declined steadily from 24.5% in the third quarter of 2002 to 21.4% in the last quarter of 2006 (P < 0.001). The cord-blood surveillances were conducted between June and August 2003 and again between October 2005 and January 2006. Overall HIV seroprevalence declined from 25.7% in 2003 to 21.8% in 2005-2006 (P = 0.001). Among women < or =17 years of age, seroprevalence declined from 12.1% to 7.7% (P = 0.015)., Conclusion: HIV seroprevalence appears to be declining among antenatal and parturient women in Lusaka. The decline is most dramatic among women < or = 17 years of age, suggesting a reduction in sero-incidence in this important age group.

Objective: To determine the impact of adjuvant single-dose peripartum tenofovir/emtricitabine (TDF/FTC) on intrapartum/early postpartum HIV transmission., Methods: In the setting of routine short-course zidovudine (ZDV) and peripartum nevirapine (NVP) for perinatal HIV prevention, participants were randomized to single-dose TDF (300 mg)/FTC (200 mg) or to no intervention in labor. Six-week infant HIV infection was compared according to actual-use drug regimens., Results: Of 397 women randomized, 355 (89%) had infants who were alive and active at 6 weeks postpartum. Of these, 18 (5.1%) were infected in utero and 6 (1.8%) were infected intrapartum/early postpartum. Among the 243 who used ZDV and NVP, intrapartum/early postpartum transmission was not reduced among infants whose mothers received TDF/FTC compared with those who did not (2 of 123 [1.6%] vs. 3 of 109 [2.8%]; P = 0.67). Among the 49 infants whose mothers did not receive antenatal ZDV but who had confirmed NVP ingestion, transmission similarly did not differ (0 of 19 [0%] vs. 1 of 26 [3.4%]). TDF/FTC was not significantly associated with reduced overall transmission (odds ratio [OR] = 0.7, 95% confidence interval [CI]: 0.3 to 1.6), even when other antiretroviral drugs were considered (adjusted OR = 0.8, 95% CI: 0.3 to 1.8)., Conclusions: Adjuvant peripartum single-dose TDF/FTC did not reduce perinatal transmission. Whether a higher dose might be effective remains unknown but should be studied in settings in which NVP is used without antenatal ZDV.

Ambitious goals for paediatric AIDS control have been set by various international bodies, including a 50% reduction in new paediatric infections by 2010. While these goals are clearly appropriate in their scope, the lack of clarity and consensus around how to monitor the effectiveness of programmes to prevent mother-to-child HIV transmission (PMTCT) makes it difficult for policy-makers to mount a coordinated response. In this paper, we develop the case for using population HIV-free child survival as a gold standard metric to measure the effectiveness of PMTCT programmes, and go on to consider multiple study designs and source populations. Finally, we propose a novel community survey-based approach that could be implemented widely throughout the developing world with minor modifications to ongoing Demographic and Health Surveys.

Objective: To describe the incidence and predictors of stillbirth in a predominantly human immunodeficiency virus (HIV)-infected African cohort., Methods: Human Immunodeficiency Virus (HIV) Prevention Trials Network (HPTN) 024 was a randomized controlled trial of empiric antibiotics to reduce chorioamnionitis-related perinatal HIV transmission. A proportion of HIV-uninfected individuals were enrolled to reduce community-based stigma surrounding the trial. For this analysis, only women who gave birth to singleton infants were included., Results: Of 2,659 women enrolled, 2,434 (92%) mother- child pairs met inclusion criteria. Of these, 2,099 (86%) infants were born to HIV-infected women, and 335 (14%) were born to HIV-uninfected women. The overall stillbirth rate was 32.9 per 1,000 deliveries (95% confidence interval [CI] 26.1-40.7). In univariable analyses, predictors for stillbirth included previous stillbirth (odds ratio [OR] 2.3, 95% CI 1.2-4.3), antenatal hemorrhage (OR 14.4, 95% CI 4.3-47.9), clinical chorioamnionitis (OR 20.9, 95% CI 5.1-86.2), and marked polymorphonuclear infiltration on placental histology (OR 2.9, 95% CI 1.7-5.2). When compared with pregnancies longer than 37 weeks, those at 34-37 weeks (OR 1.7, 95% CI 0.8-3.4) and those at less than 34 weeks (OR 22.8, 95% CI 13.6-38.2) appeared more likely to result in stillborn delivery. Human immunodeficiency virus infection was not associated with a greater risk for stillbirth in either univariable (OR 1.5, 95% CI 0.7-3.0) or multivariable (adjusted OR 1.11, 95% CI 0.38-3.26) analysis. Among HIV-infected women, however, decreasing CD4 cell count was inversely related to stillbirth risk (P=.009)., Conclusion: In this large cohort, HIV infection was not associated with increased stillbirth risk. Further work is needed to elucidate the relationship between chorioamnionitis and stillbirth in African populations., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00021671, Level of Evidence: II.

Objectives: To determine the influence of body mass index (BMI) on pregnancy outcomes of HIV-infected and HIV-uninfected Zambian women and to assess the possible role of BMI on mother-to-child transmission rate of HIV., Methods: We analysed data from a clinical trial on nevirapine administration for the prevention of mother-to-child transmission of HIV in Lusaka, Zambia. Demographic characteristics, medical information and pregnancy outcomes were used in this secondary analysis., Results: A total of 1211 women were included in this analysis and 36% were HIV-infected. Among HIV-infected women, maternal parity and prior stillbirths increased with increasing BMI in univariate analysis. Mean birth weight rose as well at 28.3 g [95% confidence interval (CI)=14.0-42.6] of infant weight per BMI unit. Transmission of HIV from mother to child appeared inversely related to BMI when compared according to BMI quartile (P for trend=0.07). In the HIV-uninfected group, infant birth weight increased with increasing BMI, at 32.7 g (95% CI=23.5-41.9) of infant weight per BMI unit., Conclusion: Birth weight increased alongside BMI in both HIV-infected and HIV-uninfected women. There is a suggestion that women with lower BMI have a greater risk of perinatal HIV transmission, even after adjustments for HIV viral load and CD4 count.

Objective: We studied the prevalence of and predictors for traditional medicine use among pregnant women seeking care in the Lusaka, Zambia public health system., Subjects: We surveyed 1128 pregnant women enrolled in a clinical trial of perinatal human immunodeficiency virus (HIV) prevention strategies at two district delivery centers., Outcome Measures: Postpartum questionnaires were administered to determine demographic characteristics, behavioral characteristics, HIV knowledge, and prior use of traditional medicines., Results: Of the 1128 women enrolled, 335 (30%) reported visiting a traditional healer in the past; 237 (21%) reported using a traditional healer during the current pregnancy. Overall, 54% believed that admitting to a visit to a traditional healer would result in worse medical care. When women who had used traditional medicines were compared to those who had not, no demographic differences were noted. However, women who reported use of traditional medicine were more likely to drink alcohol during pregnancy, have >or=2 sex partners, engage in "dry sex," initiate sex with their partner, report a previously treated sexually transmitted disease, and use contraception (all p < 0.01). HIV-infected women who reported using traditional healers were also less likely to adhere to a proven medical regimen to reduce HIV transmission to their infant (25% versus 50%, p = 0.048)., Conclusions: Use of traditional medicine during pregnancy is common, stigmatized, and may be associated with nonadherence to antiretroviral regimens. Health care providers must open lines of communication with traditional healers and with pregnant women themselves to maximize program success.

Purpose: Although cord blood surveillance can measure the effectiveness of nevirapine (NVP)-based programs for the prevention of mother-to-child HIV transmission (PMTCT), it requires the ability to detect nevirapine in plasma. At present, the only validated method is high-performance liquid chromatography (HPLC), a technique poorly suited for most resource-constrained settings., Method: We evaluated the field performance for a simple and inexpensive thin-layer chromatography (TLC) assay for NVP detection. We developed a conditional probability model to compare 2 testing algorithms: HPLC alone, and TLC screening followed by HPLC confirmation of negative results., Results: When compared to HPLC, sensitivity of TLC was 0.67 (95% confidence interval [CI] 0.49-0.84) and specificity was 0.84 (95% CI 0.69-0.95). In this sample - where overall NVP coverage was 49% - positive predictive value was 0.80 and negative predictive value was 0.72. At baseline with population NVP coverage of 33%, cost per specimen was lower in the TLC-HPLC testing algorithm (40 dollars vs. 50 dollars), and the proportion of false results was acceptable (11%). As population NVP coverage increased, cost-efficiency improved and error rate dropped substantially., Conclusion: TLC is reasonably sensitive and specific for NVP detection. A 2-step testing algorithm incorporating TLC and HPLC provides cost-efficiency at little expense to test performance.

Despite the availability of antiretroviral prophylaxis, roughly one-fifth of public-sector antenatal patients decline HIV testing in Lusaka, Zambia. We administered a survey to determine individual-level predictors of HIV testing. Of 1064 antenatal attendees approached after pretest counseling, 1060 (>99%) participated. Of these, 686 (65%) agreed to HIV testing. On bivariate analysis controlling for clinic of attendance, women younger than 20 years old (adjusted RR [ARR] = 1.14), unmarried (ARR = 1.14), pregnant for the first time (ARR = 1.14), with lower educational attainment (ARR = 1.15), and with lower income (ARR = 1.14) were all more likely to undergo testing. When HIV risk was considered, women with low self-perceived risk were most likely to undergo HIV testing. As risk perception increased, likelihood for testing decreased (P for trend < 0.001). Although not statistically predictive, we identified prevalent community beliefs that may act as barriers to testing. Because individual-level characteristics were only weakly predictive of HIV testing, future work should concentrate on community-level factors.

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 or= 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.

Background: Rapid scale-up of antiretroviral therapy (ART) is a worldwide priority, and ambitious targets for numbers on ART have been set. Antenatal clinics (ANCs) and tuberculosis (TB) clinics have been targeted as entry points into HIV care., Methods: We developed a conditional probability model to evaluate the effects of ANC and TB clinic populations on ART program enrollment., Results: To start 1 individual on ART, 3 TB patients have to be screened at a crude program cost of 36 US dollars per patient initiated on therapy. By contrast, 48 ANC patients have to be screened at a cost of US 214 US dollars per patient on therapy. In an incremental analysis in which ANC HIV testing was borne by a program to prevent mother-to-child transmission, recruitment efficiency increased (8 screened per patient starting ART) and cost decreased (114 US dollars per patient on therapy). Absolute numbers starting ART, however, remained fixed. If all 60,000 ANC patients seen yearly in the Lusaka District were screened, 1247 would start ART. Approaching the district's 35,000 annual TB patients would generate 11,947 patients on ART., Conclusion: In areas with high HIV prevalence, targeting chronically ill populations for HIV treatment may have significant short-term benefits in cost savings and recruitment efficiency.

Mother-to-child transmission of HIV (MTCT) is a major contributor to Zambia's HIV burden. Based on our experience in Zambia, we felt that provider perceptions, knowledge base, and practice patterns toward HIV-positive mothers may pose as significant obstacles to preventing MTCT. Two hundred and twenty-five health care providers throughout Zambia were surveyed in 2002. Providers reported widespread stigma associated with HIV. Physicians (OR = 1.9), providers with research affiliations (OR = 2.3), and those located in Lusaka (OR = 9.0) were more likely to offer HIV testing. Only 30% routinely prescribed antiretroviral treatment (ART) to reduce MTCT. Practitioners from district facilities, those from Lusaka, and those employed at research facilities were more likely to prescribe ART routinely (OR = 2.8, 10.1 and 3.4 respectively). Among those never prescribing ART, most cited a lack of availability (83%). Our results highlight the need for further provider education, critical appraisal of the current system for HIV testing, and widespread distribution of ART.