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Background: Antiretroviral therapy (ART) use during pregnancy is essential to prevent vertical transmission of HIV, but it may also increase the risk of adverse birth outcomes. This study investigated the impact of both maternal HIV infection and the timing of ART initiation on birth outcomes in women living with HIV in South Africa., Methods: This secondary data analysis examined the dataset from an earlier cohort study involving 1709 pregnant women living with HIV who delivered their babies at three major maternity centres in the Eastern Cape province of South Africa between September 2015 and May 2018. The associations between adverse birth outcomes (stillbirth, preterm birth, very preterm birth, and low birth weight) and the timing of maternal ART initiation, peripartum CD4 count, and HIV viral load were examined using logistic regression analysis., Results: The observed rates of stillbirth, preterm birth, very preterm birth, and low birth weight were 1.4%, 33.5%, 5.4% and 18.0%, respectively. In the multivariable analysis, low birth weight was associated with ART initiated during the second trimester (adjusted odds ratio [aOR] 1.38; 95% confidence interval [CI], 1.03-1.85), low-level viraemia (21-999 copies/ml) (aOR, 1.62; 95% CI, 1.17-2.22), and high-level viraemia (≥1000 copies/ml) (aOR, 1.66; 95% CI, 1.66-2.38) during the peripartum period. Preterm birth was associated with low-level viraemia (aOR, 1.44; 95% CI, 1.16-1.79) and a CD4 count of less than 200 cells/mm3 (aOR, 1.35; 95% CI, 1.01-1.82). Very preterm birth was associated with detectable maternal viraemia., Conclusion: Adverse birth outcomes are common among pregnant women living with HIV, especially those with unsuppressed viraemia. Clinicians and programme managers should prioritise timeous ART initiation and virological suppression in all pregnant women living with HIV., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Siqithi 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.)

Background: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs., Methods: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure., Results: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028)., Conclusions: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

SARS-CoV-2 cell-mediated immunity remains understudied during pregnancy in unvaccinated Black African women living with HIV (WLWH) from low- and middle-income countries. We investigated SARS-CoV-2-specific T-cell responses 1 month following infection in 24 HIV-uninfected women and 15 WLWH at any stage during pregnancy or postpartum. The full-length spike (FLS) glycoprotein and nucleocapsid (N) protein of wild-type (WT) SARS-CoV-2, as well as mutated spike protein regions found in the Omicron variant (B.1.1.529) were targeted by flow cytometry. WT-specific CD4 + and CD8 + T cells elicited similar FLS- and N-specific responses in HIV-uninfected women and WLWH. SARS-CoV-2-specific T-lymphocytes were predominantly TNF-α monofunctional in pregnant and postpartum women living with and without HIV, with fever cells producing either IFN-γ or IL-2. Furthermore, T-cell responses were unaffected by Omicron-specific spike mutations as similar responses between Omicron and the ancestral virus were detected for CD4 + and CD8 + T cells. Our results collectively demonstrate comparable T-cell responses between WLWH on antiretroviral therapy and HIV-uninfected pregnant and postpartum women who were naïve to Covid-19 vaccination. Additionally, we show that T cells from women infected with the ancestral virus, Beta variant (B.1.351), or Delta variant (B.1.617.2) can cross-recognize Omicron, suggesting an overall preservation of T-cell immunity., (© 2024. The Author(s).)

Introduction: Dolutegravir (DTG)-based antiretroviral therapy is the World Health Organization's preferred first-line regimen for all persons with HIV, including pregnant women. While DTG has been implicated as an obesogen associated with greater weight gain compared to other antiretrovirals, there is a paucity of data in pregnant women and their children. The Obesogenic oRigins of maternal and Child metabolic health Involving Dolutegravir (ORCHID) study is investigating associations between DTG, weight gain, and metabolic outcomes in the context of HIV., Materials & Methods: ORCHID is a prospective observational study taking place in Cape Town, South Africa (NCT04991402). A total of 1920 pregnant women with and without HIV infection are being followed from ≤18 weeks gestational age to 24 months postpartum with their children. Participants attend eleven study visits: 3 antenatal, delivery, and 7 postnatal visits. Several embedded sub-studies address specific scientific aims. Primary outcome measurements in mothers include anthropometry, blood pressure, body composition, dysglycemia, insulin resistance (IR), and dyslipidemia. Other maternal measures include demographics, resting energy expenditure, viral load, physical activity, dietary intake, hepatic steatosis, and repository specimens. Sub-study measurements include markers of adipose inflammation, gut integrity, and satiety/hunger, subcutaneous adipose tissue morphology and mitochondrial function, and metabolomics. Primary outcome measurements in children include anthropometry, adipose tissue mass, dysglycemia, IR, and dyslipidemia. Other variables include fetal growth, birth outcomes, medical/breastfeeding history, caloric intake, neurodevelopment, and repository specimens. Sub-study measurements include metabolites/lipid subspecies in umbilical cord blood, as well as breast milk composition and DTG exposure., Discussion: ORCHID will play a pivotal role in defining obesogenic mechanisms and clinical consequences of DTG use in pregnancy in women with HIV and their children. It will provide insights into metabolic disease risk reduction in the context of HIV/DTG, identify intervention targets, and inform public health approaches to diminish chronic metabolic co-morbidities for women and children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Abrams 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.)

Objective: To investigate the role of early antiretroviral therapy (ART) on growth trajectories of infants with human immunodeficiency virus (IHIV) in the first year of life., Study Design: As part of a clinical trial of early ART in Johannesburg, South Africa (2015-2018), 116 IHIV diagnosed within 48 hours of birth were started on ART as soon as possible, and 80 uninfected infants born to mothers living with HIV (IHEU) were enrolled. Both groups were followed prospectively from birth through 48 weeks and growth parameters collected. The groups were compared and risk factors for poor growth investigated, in the full cohort and among IHIV separately., Results: IHIV had lower mean weight-for-age Z-scores (WAZ) than IHEU at 4 and 8 weeks (-1.17 [SE:0.14] vs -0.72 [0.14], P = .035 and -1.23 [0.15] vs -0.67 [0.14], P = .012). Although there was some closing of the gap over time, means remained lower in IHIV through 48 weeks. In length-for-age Z-scores (LAZ), differences widened over time and IHIV had lower Z-scores by 48 weeks (-1.41 [0.15] vs -0.80 [0.18], P = .011). Deficits in WAZ and LAZ in IHIV vs IHEU were most marked among girls. IHIV with pre-ART viral load ≥1000 copies/ml had significantly lower weight-for-length and mid-upper arm circumference Z-scores across all time points through 48 weeks., Conclusions: IHIV on early ART had deficits in WAZ over the first 8 weeks of life and lower LAZ at 48 weeks than IHEU. Among IHIV, higher pre-ART viral load was associated with worse anthropometric indicators through 48 weeks., Competing Interests: Declaration of Competing Interest Funding: The Latency and Early Neonatal Provision of Antiretroviral Drugs (LEOPARD) study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institute of Allergy and Infectious Disease, National Institutes of Health (U01HD080441), the South African National HIV Programme, and South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (84177)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To describe the prevalence of unintended pregnancy and its association with HIV status among pregnant women in South Africa. A cross-sectional survey was conducted between October and mid-November 2019 among pregnant women aged 15-49 years in 1589 selected public antenatal care facilities. Pregnancy intention was assessed using two questions from the London Measure of Unplanned Pregnancy. Survey logistic regression examined factors associated with unintended pregnancy. Among 34,946 participants, 51.6% had an unintended pregnancy. On multivariable analysis, the odds of unintended pregnancy was higher among women who knew their HIV-positive status before pregnancy but initiated treatment after the first antenatal visit (adjusted odds ratio [aOR], 1.5 [95% confidence interval (CI):1.2-1.8]), women who initiated treatment before pregnancy (aOR, 1.3 [95% CI:1.2-1.3]), and women with a new HIV diagnosis during pregnancy (aOR, 1.2 [95% CI:1.1-1.3]) compared to HIV-negative women. Women who were single, in a non-cohabiting or a cohabiting relationship, and young women (15-24 years) had significantly higher risk of unintended pregnancy compared to married women and women aged 30-49 years, respectively. A comprehensive approach, including regular assessment of HIV clients' pregnancy intention, and adolescent and youth-friendly reproductive health services could help prevent unintended pregnancy., (© 2021. The Author(s).)

Background: The impact of SARS-CoV-2 infection in pregnant women living with HIV (PLHIV) has not been described previously., Objectives: To describe the clinical presentation and outcomes of a cohort of women with high-risk pregnancies with confirmed COVID-19 to determine whether risk factors for disease severity and adverse outcomes of COVID-19 differed in pregnant women without HIV compared with PLHIV., Methods: We prospectively enrolled pregnant women with COVID-19 attending the high-risk obstetric service at Tygerberg Hospital, Cape Town, South Africa, from 1 May to 31 July 2020, with follow-up until 31 October 2020. Women were considered high risk if they required specialist care for maternal, neonatal and/or anaesthetic conditions. Common maternal or obstetric conditions included hypertensive disorders, morbid obesity (body mass index (BMI) ≥40 kg/m2) and diabetes. Information on demographics, clinical features, and maternal and neonatal outcomes was collected and compared for PLHIV v. pregnant women without HIV., Results: One hundred women (72 without HIV and 28 PLHIV) with high-risk pregnancies had laboratory-confirmed COVID-19. Among the 28 PLHIV, the median (interquartile range) CD4 count was 441 (317 - 603) cells/µL, and 19/26 (73%) were virologically suppressed. COVID-19 was diagnosed predominantly in the third trimester (81%). Obesity (BMI ≥30 in n=61/81; 75%) and hypertensive disorders were frequent comorbidities. Of the 100 women, 40% developed severe or critical COVID-19, 15% required intensive care unit admission and 6% needed invasive ventilation. Eight women died, 1 from advanced HIV disease complicated by bacteraemia and urosepsis. The crude maternal mortality rate was substantially higher in women with COVID-19 compared with all other deliveries at our institution during this period (8/91 (9%) v. 7/4 058 (0.2%); p<0.001). Neonatal outcomes were favourable. No significant differences in COVID-19 risk factors, disease severity, and maternal/neonatal outcome were noted for PLHIV v. those without HIV., Conclusions: In this cohort of high-risk pregnant women, the impact of COVID-19 was severe, significantly increasing maternal mortality risk compared with baseline rates. Virally suppressed HIV infection was not associated with worse COVID-19 outcomes in pregnancy.

Background: The risk of cardiovascular diseases (CVDs) is becoming more prevalent in pregnant women though not much data is available for pregnant women with human immunodeficiency virus (HIV). Foetoplacental vascular endothelial dysfunction is thought to be at the origin of chronic diseases such as diabetes and obesity later on in life. Because HIV and anti-retroviral treatment (ARTs) are associated with endothelial dysfunction, children exposed in utero to these conditions may be at greater risk of developing CVDs. Despite the high prevalence of HIV in pregnant South African women, little is known about the effects of ART on the cardiovascular health of the mother and offspring. Hence, the proposed study intends to investigate how HIV/ARTs may affect the cardiovascular health of the mother and offspring at different time points during the pregnancy and up to 2 years after birth., Methods: A longitudinal case-control study in HIV positive pregnant women on ART and HIV negative pregnant women will be conducted. All pregnant women will be assessed for cardio-metabolic risk factors and markers (lipids, anthropometric and glycaemic indies, oxidative stress), hemodynamic status (blood pressure parameters) and vascular function (arterial compliance, retinal microvasculature, uterine artery mean pulsatility index). Child health will be monitored in utero and postnatally via routine foetal health screening, placental integrity, anthropometry, blood pressure parameters, markers of oxidative stress and endothelial function in cord blood and cardiovascular epigenetic markers in urine., Discussion: There is a paucity of studies in South Africa and sub-Sahara Africa as a whole that utilised a longitudinal study model to assess the effects of ARTs on vascular endothelial changes in pregnant women living with HIV and the cardiometabolic health of their offspring. This study will therefore help to monitor changes in cardiometabolic risk during pregnancy and in children exposed in utero to HIV-infection and ART use. Findings from this study will provide useful information for developing guidelines on the use of ARTs in pregnancy and management of cardiometabolic health of the offspring of HIV positive mothers.

In South Africa, pre-eclampsia (PE) and human immunodeficiency virus (HIV) infection are major causes of pregnancy-related deaths. This study aimed to measure serum levels of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS), soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng) and placental growth factor (PlGF) in HIV-infected highly active antiretroviral therapy (HAART)-treated and HIV-uninfected PE and normotensive women to ascertain if HIV/HAART alters their concentrations. Mean sFlt-1 levels were significantly up-regulated in the PE (HIV-uninfected 4.39 ± 1.29; HIV-infected 5.10 ± 1.10 ng/ml) compared to normotensive women (HIV-uninfected 2.59 ± 0.83; HIV-infected 2.20 ± 0.85 ng/ml). Mean PlGF levels were significantly lower in HIV-uninfected PE vs. HIV-infected normotensive women (29.69 ± 4.47 pg/ml vs. 32.86 ± 6.46 pg/ml; p  = .002). In conclusion, PE women with HIV exhibited significantly low serum PlGF, ET-1 and eNOS levels. Infection with HIV may have further increased the sFlt-1 levels.IMPACT STATEMENT What is already known on this subject? In PE, the numerous identified local and circulating bioactive factors differed in concentrations when compared to normal pregnancy. What do the results of this study add? PE women with HIV exhibited significantly low serum PlGF, ET-1 and eNOS levels as well as increased levels of sFlt-1. What are the implications of these findings for clinical practice and/or further research? Understanding the link between PE, HIV and HAART during pregnancy will improve prognosis, management and treatment strategies for women clinically.

Background: Pregnant and breastfeeding women living with HIV (WLHIV) are a target population for elimination of mother-to-child transmission of HIV (eMTCT). However, there are limited data on maternal virological responses during pregnancy and the postpartum period in South Africa (SA)., Objectives: To review compliance of viral load (VL) testing with national guidelines and suppression rates during pregnancy and up to 9  months postpartum among WLHIV delivering in four tertiary hospitals in Gauteng Province, SA., Methods: All women who had a point-of-care HIV VL test using Xpert HIV-1 VL (Cepheid, USA) at delivery in four tertiary obstetric units in Gauteng between June 2018 and February 2020 were included. HIV VL tests of eligible women performed up to 9 months before and after delivery were extracted from the National Health Laboratory Service's Corporate Data Warehouse. Proportions of women delivering who had antenatal and postpartum VL tests performed and their suppression rates were determined and expressed as percentages., Results: Of 4 989 eligible WLHIV (median age 31.1 years), 917 (18.4%) had a VL performed during the antenatal period; of these, 335 (36.5%) had a VL ≥50 copies/mL and 165 (18.0%) a VL ≥1 000 copies/mL. At delivery, 1 911 women (38.3%) had a VL ≥50 copies/mL and 1 028 (20.6%) a VL ≥1 000 copies/mL. Among 627 women (12.6%) with a VL test postpartum, 234 (37.3%) had a VL ≥50 copies/mL and 93 (14.8%) a VL ≥1 000 copies/mL. Overall, having a VL test performed during the antenatal period was associated with viral suppression at delivery and receiving a VL test postpartum (p<0.001). Women with a VL ≥50 copies/mL at delivery were more likely to be younger and to remain virally unsuppressed postpartum (p<0.001) compared with women with a VL <50 copies/mL., Conclusions: Fewer than 5% of WLHIV with a VL at the time of delivery received VL monitoring during the antenatal and postpartum periods in accordance with national guidelines. More than 80% of WLHIV delivering had no evidence of VL monitoring during the antenatal period, and they were more likely than women who received monitoring during the antenatal period to be virally unsuppressed at delivery and to receive no VL monitoring postpartum. Women with a high VL at delivery were likely to remain virally unsuppressed postpartum. These results emphasise the need for closer monitoring of and rapid reaction to high maternal VLs during pregnancy, at delivery and postpartum for attainment of eMTCT.

Background: To effectively reduce vertical HIV transmission requires a reduction of HIV prevalence and incidence among pregnant women and a full understanding of its epidemiology. The study aimed to determine the prevalence of HIV among women attending antenatal care and further determine spousal support during antenatal care attendance in rural areas in Eastern Cape province, South Africa., Methods: A Cross-sectional study of women attending antenatal care in four Primary Care facilities was conducted using an interviewer-administered questionnaire which collected information on socio-demographic characteristics and medical history. Binomial logistic regression analyses were used to determine factors associated with HIV and to estimate the prevalence ratio (PR). The 95% confidence interval (95%CI) is used for precision of estimates; p≤0.05 for statistical significance., Results: A total of 343 participants were included in the final analysis. The antenatal HIV prevalence was 38.2% (95%CI: 33.2-43.9). For 75% of the women, the HIV diagnosis was made 141 days before the date of the interview (median=77 days, interquartile range=42-141 days). Participants between the age of 30 to 39 years were 50% more likely to be HIV positive compared to those who were between the age of 20 to 29, these differences were statistically significant (PR=1.5; p-value=0.001). Furthermore, self-employed women were 30% less likely to be HIV positive when compared to unemployed participants, this was also statistically significant (PR=0.7; p-value< 0.0001)., Conclusion: Despite a 100% antenatal HIV testing rate, the antenatal HIV prevalence remains high in this population, coupled with no spousal attendance in antenatal care. It is important to move beyond awareness about the HIV status to actionable strategies of reducing the HIV incident cases. It is therefore important to remain vigilant and monitor mother-to-child transmission that could be associated with this increased prevalence.

Background: In 2018, 4% of all people living with HIV globally were adolescents aged 10 - 19 years. It is reported that adolescents on antiretroviral therapy (ART) are at increased risk of poor viral load suppression (VLS) compared with children and adults., Objectives: To determine the 24-month prevalence of VLS among adolescents initiated on ART in 2013 in public health facilities in the Metro District Health Services of Western Cape Province, South Africa., Methods: A retrospective cohort analysis was done on 220 adolescents initiated on ART in 2013; they were followed up for 24 months. Data were extracted from the provincial Tier.Net electronic database and patients' clinical records, and captured in Excel. SPSS statistical software was used for descriptive and inferential analysis; bivariate analysis was used to determine significance and strength of associations between VLS and various sociodemographic and clinical characteristics at 4, 12 and 24 months (with significance set at p&lt;0.05)., Results: VLS declined over the study period, with rates of 59.5%, 40.0% and 25.0% at 4, 12 and 24 months post initiation on treatment, respectively. In bivariate analysis, VLS was significantly associated with younger age (10 - 14 years) at month 12 (crude risk ratio (RR) 1.83 (95% confidence interval (CI) 1.35 - 2.49)) and month 24 (RR 3.38 (95% CI 2.24 - 5.10)) after initiation on ART. Male adolescents were significantly more likely to achieve VLS than females (month 4: RR 1.49 (95% CI 1.22 - 1.81); month 12: RR 1.50 (95% CI 1.07 - 2.12); and month 24: RR 2.33 (95% CI 1.50 - 3.62)). Pregnant adolescents were significantly less likely to attain VLS (month 4: RR 0.69 (95% CI 0.53 - 0.89); month 12: RR 0.64 (95% CI 0.44 - 0.94); and month 24: RR 0.24 (95% CI 0.11 - 0.50)) compared with those who were not pregnant. However, of those adolescents who were retained in care, VLS was higher at months 4, 12 and 24, with rates of 86.8%, 79.3% and 68.8%, respectively., Conclusions: Targeted interventions are required to improve retention in care and VLS among adolescents on ART, with specific focus on older (15 - 19-year-olds) and pregnant adolescents.

Background: The correct antiretroviral (ARV) management of HIV-positive pregnant women can be complex, with many variables to consider. uMgungundlovu District Management in KwaZulu-Natal (KZN) Province, South Africa, suspected that the taking and retrieval of blood tests relating to ARV management in pregnancy could be improved. An antenatal ARV tracking form was therefore designed: a dedicated page on which to write all the ARV-related blood results and remind clinicians to take the correct bloods at the appropriate time. The form was photocopied and distributed to all antenatal clinics throughout uMgungundlovu District., Objectives: To audit uptake of use of the tracking form by antenatal clinicians, and to audit quality of care - did using the tracking form prompt the correct bloods to be taken and retrieved at the right time, and with correct antiretroviral management and outcome?, Methods: Data were collected by retrospective chart review of maternity case records of women who delivered at Northdale District Hospital, uMgungundlovu District, KZN. We determined compliance with use of the tracking form in the maternity case records of all HIV-positive women delivering at the hospital, and assessed quality of care by scoring 100 records of women with a tracking form in comparison with 100 records of women without one., Results: District-wide uptake of use of the tracking form in maternity case records was 95%. Quality of care showed a statistically significant improvement in women with a tracking form present in their maternity case record: nearly 80% of those with a form were correctly managed at the booking visit, v. &lt;20% of those without one (79% v. 19%; p&lt;0.001). The differences in quality of care persisted at 3 and 6 months after booking. In terms of outcome, HIV viral load was suppressed at the time of delivery in 86% of women with a tracking form v. 65% of those without, and 5% of women with a tracking form had an unknown viral load v. 21% of those without., Conclusions: Uptake of use of the tracking form increased markedly after implementation. Use of the form significantly improved the taking and retrieval of blood tests and the management of ARVs. The form has since been printed as part of the new maternity case records in KZN.

Preterm birth is the leading cause of neonatal and child mortality worldwide. Globally, 1.4 million pregnant women are estimated to be living with HIV/AIDS, the majority of whom live in sub-Saharan Africa. Maternal HIV infection and antiretroviral treatment (ART) have been associated with increased rates of preterm birth, but the underlying mechanisms remain unknown. Acute HIV infection is associated with a rapid depletion of all three subsets of innate lymphoid cells (ILCs), ILC1s, ILC2s and ILC3s, which is not reversed by ART. ILCs have been found at the maternal-fetal interface and we therefore investigated the potential association between maternal HIV infection, peripheral ILC frequencies and preterm birth. In our study of pregnant South African women with accurately dated pregnancies, we show that maternal HIV infection is associated with reduced levels of all three ILC subsets. Preterm birth was also associated with lower levels of all three ILC subsets in early pregnancy. ILC frequencies were lowest in HIV positive women who experienced preterm birth. Moreover, ILC levels were reduced in pregnancies resulting in spontaneous onset of preterm labour and in extreme preterm birth (< 28 weeks gestation). Our findings suggest that reduced ILC frequencies may be a link between maternal HIV infection and preterm birth. In addition, ILC frequencies in early pregnancy may serve as predictive biomarkers for women who are at risk of delivering preterm.

Successful vertical HIV transmission prevention programmes (VTP) have resulted in an expanding population of HIV-exposed uninfected (HEU) infants whose growth, health and neurodevelopmental outcomes could have consequences for future resource allocation. We compared neurodevelopmental and behavioural outcomes in a prospective cohort of 2-3 year old HEU and HIV-unexposed uninfected (HU) children.Women living with and without HIV and their infants were enrolled within three days of birth from a low-risk midwife obstetric unit in Cape Town, South Africa during 2012 and 2013, under WHO Option A VTP guidelines. HIV-uninfected children aged 30-42 months were assessed using the Bayley scales of Infant Development-Third edition (BSID) and Strengths and Difficulties questionnaire (SDQ).Thirty-two HEU and 27 HU children (mean birth weight 3048g vs 3096g) were assessed. HEU children performed as well as HU children on BSID cognitive, language and motor domains. Mean scores fell within the low average range. Mothers of HEU children reported fewer conduct problems but stunting was associated with increased total difficulties on the SDQ.HEU and HU children's performance on the BSID was similar. In this low-risk cohort, HIV exposure did not confer additional risk. Stunting was associated with increased behavioural problems irrespective of HIV exposure.

Objective: To describe viral load levels among pregnant women and factors associated with failure to achieve viral suppression (viral load ≤50 copies/ml) during pregnancy., Design: Between 1 October and 15 November 2017, a cross-sectional survey was conducted among 15-49-year-old pregnant women attending antenatal care (ANC) at 1595 nationally representative public facilities., Methods: Blood specimens were taken from each pregnant woman and tested for HIV. Viral load testing was done on all HIV-positive specimens. Demographic and clinical data were extracted from medical records or self-reported. Survey logistic regression examined factors associated with failure to achieve viral suppression., Result: Of 10 052 HIV-positive participants with viral load data, 56.2% were virally suppressed. Participants initiating antiretroviral therapy (ART) prior to pregnancy had higher viral suppression (71.0%) by their third trimester compared with participants initiating ART during pregnancy (59.3%). Booking for ANC during the third trimester vs. earlier: [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI):1.4-2.3], low frequency of ANC visits (AOR for 2 ANC visits vs. ≥4 ANC visits: 2.0, 95% CI:1.7-2.4), delayed initiation of ART (AOR for ART initiated at the second trimester vs. before pregnancy:2.2, 95% CI:1.8-2.7), and younger age (AOR for 15-24 vs. 35-49 years: 1.4, 95% CI:1.2-1.8) were associated with failure to achieve viral suppression during the third trimester., Conclusion: Failure to achieve viral suppression was primarily associated with late ANC booking and late initiation of ART. Efforts to improve early ANC booking and early ART initiation in the general population would help improve viral suppression rates among pregnant women. In addition, the study found, despite initiating ART prior to pregnancy, more than one quarter of participants did not achieve viral suppression in their third trimester. This highlights the need to closely monitor viral load and strengthen counselling and support services for ART adherence.

Introduction: Knowledge of HIV status in South Africa (SA) is reported to be 90% among people living with HIV. National level estimates could mask population-specific levels, which are critical to monitor program coverage and potential impact. Using data from the 2017 national antenatal sentinel survey, we assessed knowledge of HIV-positive status, initiation of antiretroviral therapy (ART), and socio-demographic characteristics associated with knowledge of HIV-positive status prior to the current pregnancy among women attending antenatal care., Methods: Between 1 October and 15 November 2017, a nationally representative sample of 32,716 pregnant women were enrolled from 1,595 public health facilities selected from all districts of SA. Data on age, gravidity, knowledge of HIV-positive status and ART initiation prior to pregnancy were extracted from medical records. A blood sample was collected from each woman regardless of prior knowledge of HIV status or ART history, and tested for HIV in the laboratory. All HIV-positive pregnant women enrolled in the survey were eligible for inclusion in the analysis. Multivariable survey logistic regression was used to examine factors associated with knowledge of HIV-positive status prior to the current pregnancy., Results: Of 10,065 eligible HIV-positive women, 60.8% (95% confidence interval (CI):59.9%-61.7%) knew their HIV status prior to the current pregnancy, of whom 91.1% (95% CI: 90.4%-91.7%) initiated ART prior to the current pregnancy. Knowledge of HIV-positive status was lower among adolescent girls and young women (15-24 years) (38.9%) and primigravid women (40.5%) compared with older women (35-49 years) (75.5%) and multigravid women (64.7%). In a multivariable analysis, significant effect modification was found between gravidity and age (P value = 0.047). Being in the age group 15-24 years compared to the age group 35-49 years decreased the odds of knowing HIV-positive status by 80% (adjusted odds ratio (AOR): 0.2, 95% CI:0.1-0.4) among primigravid women and by 60%(AOR: 0.4, 95% CI:0.3-0.4) among multigravid women., Conclusion: Knowledge of HIV-positive status prior to the current pregnancy fell short of the target of 90% among pregnant women living with HIV. This was especially low among adolescent girls and young women, highlighting the gap in youth friendly reproductive health and HIV testing services., Competing Interests: The authors have declared that no competing interests exist.

Paediatric antiretroviral programmes have been implemented globally for more than a decade, yet information on long-term treatment outcomes in perinatally HIV-infected adolescents is limited. Published literature on long-term treatment outcomes was reviewed, including virologic, immunologic and growth outcomes, as well as drug resistance and factors associated with drug resistance. Outcomes were compared between high-income countries and low- and middle-income countries (LMIC), with additional focus on South Africa, the country with the biggest HIV epidemic in the world and the largest treatment programme. Treatment outcomes varied but viral suppression results globally were generally concerning. No studies from LMIC have reported on outcomes after >10 years follow-up, demonstrating that further studies are needed.

Background : Despite the availability of prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) services, many factors and reasons prevent mothers from accessing these services. HIV prevalence is still high among South African women of reproductive age and mother-to-child-transmission (MTCT) is a concern. This study ascertained the perspectives of healthcare workers regarding availability and accessibility of the PMTCT programme. Objective : To explore and describe the perspectives of healthcare workers regarding availability and accessibility of the PMTCT programme. Method : Qualitative research with exploratory-descriptive design was utilised. Data were collected from 21 healthcare workers using three focus-group discussions. The participants were selected based on rendering the PMTCT programme services for more than two years. Moreover, the participants had undergone training, formal education and continuous support on the PMTCT programme. Three large clinics were selected as the main clusters of the sub-district. Tesch's method was used to analyse the qualitative data. Results : Healthcare workers indicated ineffective utilisation of the PMTCT programme services by HIV-positive pregnant women. Most women had challenges with child feeding owing to limited knowledge. Another challenge indicated by healthcare workers was lack of resources. It is important that recommendations be implemented to assist with availability and accessibility of the PMTCT programme. Conclusion : Availability and accessibility of PMTCT programme services are still problematic. The study has the potential to inform development of strategies that may facilitate access to care for PMTCT programme clients.

Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe disease with fatalities. Awareness of potential sources of infection is important to reduce risk to healthcare workers and contacts. We detected CCHFV RNA in formalin-fixed, paraffin-embedded tissues from a spontaneous abortion that were submitted for histology 9 weeks after a suspected CCHFV infection in the mother.

Introduction: There is a risk of mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding. The aim of this study was to assess vertical transmission of HIV among pregnant women who initially had false-negative rapid HIV tests in South African antenatal care (ANC) clinics., Methods: Pregnant participants were enrolled in a diagnostic study that used nucleic acid amplification testing (NAAT) to screen for early HIV infection among individuals who tested negative on rapid HIV tests used at the point-of-care (POC) facilities. Participants were enrolled from four ANC clinics in the Tshwane district of South Africa. All NAAT-positive participants were recalled to the clinics for further management. Vertical transmission was assessed among exposed infants whose HIV polymerase chain reaction (PCR) results were available., Results: This study enrolled 8208 pregnant participants who tested negative on rapid HIV tests between 2013 and 2016. Their median age was 26 years (interquartile range [IQR]: 23-30). NAAT detected HIV infections in 0.6% (n = 49; 95% confidence interval {CI}: 0.5-0.8) of all study participants. The distribution of these infections among the four clinics ranged from 0.3%- 1.1%, but this was not statistically significant (p = 0.07). Forty-seven participants (95.9%) were successfully recalled and referred for antiretroviral treatment initiation as part of prevention of MTCT (PMTCT). Most women with newly diagnosed HIV infection presented for the first ANC visit in the second (61.9%, n = 26) and third (31.0%, n = 13) trimesters. HIV PCR results were available for thirty-two infants, three of whom tested positive (9.4%; 95% CI: 1.98-25.02)., Conclusions: This study showed that supplemental HIV testing for pregnant women led to earlier linkage to the PMTCT programme. Inaccurate diagnosis of HIV infection at ANC clinics is likely to undermine the efforts of eliminating MTCT particularly in HIV-endemic settings., Competing Interests: Toga Laboratories provided support in the form of salaries for DJM. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: The coverage of prevention of mother-to-child transmission (PMTCT) services in South Africa is variable. Identifying gaps in the implementation of these services is necessary to isolate steps needed to further reduce paediatric infections and eliminate transmission., Setting: Two primary care clinics in Paarl, South Africa., Participants: 1225 pregnant women; inclusion criteria were 18 years or older, clinic attendance and remaining in area for at least 1 year., Methods: Data were collected through the Drakenstein Child Health Study, a population-based birth cohort in a periurban area of the Western Cape, South Africa. A combination of clinic records, hospital records, national database searches and maternal self-report were collected during the study., Results: Of the 1225 mothers enrolled in the cohort between 2012 and 2015, 260 (21%) were confirmed HIV infected antenatally and 1 mother tested positive in the postnatal period. Of those with documentation (n=250/260, 96%), the majority (99%) received antiretroviral prophylaxis or therapy (ART) before labour; however, there was a high rate of defaulting from ART noted during pregnancy (20%). All HIV-exposed infants with data received antiretroviral prophylaxis, 35% were exclusively breast fed until 6 weeks and 16% for 6 months. There were two cases of infant HIV infection (0.8%) who were initiated on ART but had complicated histories., Conclusion: Despite the low transmission rate in this cohort, reaching elimination will require further work, and this study illustrates several areas to improve implementation of PMTCT services and reduce paediatric infections including retesting at-risk HIV-negative mothers through the duration of breast feeding, infant HIV testing at any admission in addition to routine testing and improved counselling to prevent defaulting from treatment. Better data surveillance systems are essential for determining the implementation of PMTCT guidelines., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: There is a paucity of data on the burden of congenital cytomegalovirus (cCMV) infections in low- and middle-income countries, including their association with maternal human immunodeficiency virus (HIV) infections. We investigated the prevalence of cCMV in a patient population with a high rate of HIV and antiretroviral therapy (ART) use during pregnancy in Soweto, Johannesburg., Methods: Saliva from neonates were screened for cytomegalovirus (CMV) infection by polymerase chain reaction (PCR) at birth. Additional saliva and urine samples were tested within 3 weeks of birth to confirm positive saliva results. HIV PCR testing was done on the whole blood of HIV-exposed neonates. Maternal and neonatal data were extracted from clinical records., Results: Of 2685 neonates screened for cCMV, 828 (31%) were born to HIV-infected women, 95% of whom (790/828) were on ART at delivery. The overall prevalence of cCMV was 2.5% (95% confidence interval [CI] 1.9-3.2), with significantly higher cCMV prevalence in HIV-exposed neonates (5.2%, 95% CI 3.8-6.9) than HIV-unexposed neonates (1.4%, 95% CI 0.9-2.0). The risk of in utero HIV infection was 20-fold greater (odds ratio 20.1, 95% CI 6.09-66.46) in HIV-exposed, cCMV-infected neonates, and this increased risk was not associated with the maternal CD4+ T-cell count or the maternal duration of ART., Conclusions: The prevalence of cCMV in our setting is substantially higher than the global estimate of 0.64%, partly due to the increased susceptibility for cCMV in HIV-exposed neonates. The significantly increased risk of in utero HIV infection in neonates with cCMV indicates that CMV coinfection plays a major role in the residual burden of in utero HIV transmission, even in the era of ART., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose: A key global health challenge is the persistence of new pediatric HIV infections due to mother-to-child transmission (MCTC), particularly in sub-Saharan Africa. The purpose of this study was to identify the key strategies that some sub-Saharan African countries have used to successfully reduce new pediatric HIV infections., Methods: A qualitative study utilizing semistructured interviews with key stakeholders in 6 sub-Saharan African countries (Burundi, Malawi, Mozambique, South Africa, Swaziland, and Uganda) was conducted from September 2017 to September 2018. These stakeholders were situated in the National Department of Health or in international health-funding bodies relating to the provision of the HIV/AIDS implementation program in these countries. The countries were selected based on considerable success achieved with HIV treatment in pregnant women. Audio-recorded interviews were transcribed verbatim and thematic analysis was undertaken., Findings: In all, 6 interviews were conducted, and the mean time of the interviews was 62 min. There were similar numbers of men and women, and most were in the 35- to 45-year age group. Five in six were either a medical doctor or held a doctorate degree. Four in six had >10 years of experience working in the prevention of HIV (PMTCT). Four key strategies that contributed to significant reductions in pediatric HIV infection in the respective countries were identified: (1) committed political leadership; (2) support structures within the community; (3) innovation in service delivery; and (4) robust monitoring and evaluation systems. Stakeholders spoke about how their governments played a leading role in engagement with communities, and in the dissemination of services. Innovative service delivery comprising task-shifting initiatives and the integration of maternal, newborn, and child health and HIV PMCTC services played an important role in reducing the burdens experienced by women and health care workers, leading to improved health outcomes. Peer support also helped mothers to adhere to their treatment during and after pregnancy. The capacity of national programs to monitor and evaluate the PMTCT services and the importance of regular viral-load monitoring were highlighted by the stakeholders., Implications: These strategies can be reviewed for possible implementation by other sub-Saharan African countries as possible means of reducing new pediatric HIV infections., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Recruitment and retention present major challenges to longitudinal research in maternal and child health, yet there are few insights into optimal strategies that can be employed in low-resource settings. Following prior participation in a longitudinal study following women living with HIV through pregnancy and breastfeeding in Cape Town, women were re-contacted at least 18 months after the last study contact and were invited to attend an additional follow-up visit. We describe lessons learnt and offer recommendations for a multiphase recruitment approach., Results: Using telephone calls, home visits, clinic tracing and Facebook/WhatsApp messages, we located 387 of the 463 eligible women and successfully enrolled 353 (91% of those contacted). Phone calls were the most successful strategy, yielding 67% of enrolments. Over half of the women had changed their contact information since participation in the previous study. We recommend that researchers collect multiple contact details and use several recruitment strategies in parallel from the start of a study. Participants in longitudinal studies may require frequent contact to update contact information, particularly in settings where mobility is common.

Background: Safer conception strategies empower individuals trying to conceive to minimise HIV transmission risk to partners and potential children; however, effectiveness data are scarce. We aimed to assess adoption of safer conception methods and HIV and pregnancy outcomes from Sakh'umndeni, a novel safer conception service in South Africa., Methods: In this prospective cohort study, the Sakh'umndeni clinical cohort at Witkoppen Cinic in Johannesburg (South Africa) enrolled adults aged at least 18 years who were trying to conceive and in relationships with an HIV-positive partner. Couples who were pregnant at enrolment or had been previously diagnosed as infertile were excluded. Participants received safer conception care by a nurse, including antiretroviral therapy (ART) for HIV-positive partners, pre-exposure prophylaxis (PrEP) for HIV-negative partners, counselling around timed condomless sex, or syringes for self-insemination. Primary outcomes were pregnancy incidence and HIV transmission to partners and infants. We estimated time to first pregnancy using Kaplan-Meier curves; pregnancy and HIV incidence were estimated as events per person-years of risk., Findings: Between July 16, 2013, and April 5, 2017, 526 individuals (334 women and 192 men) from 334 partnerships enrolled. 162 (48%) of 334 couples were serodifferent, 149 (45%) were HIV-positive seroconcordant, and 23 (7%) were an HIV-positive woman and an unknown status male partner. At enrolment, 176 (61%) of 287 HIV-positive women and 60 (46%) of 131 HIV-positive men were virally suppressed (<50 copies per mL). Among the safer conception strategies, ART was initiated by 73 (91%) of 80 HIV-positive participants not on ART and PrEP was initiated by 28 (28%) of 101 HIV-negative participants. 2719 follow-up visits were completed, and 99 pregnancies were observed in 89 women. Pregnancy incidence was 41·2 per 100 person-years (95% CI 33·4-50·7); 25 (28%) of 89 pregnancies with a known outcome were miscarried or terminated because of risk to the mother. Pregnancy incidence was 79·0 per 100 person-years (95% CI 49·8-125·4) among HIV-negative women and 36·7 per 100 person-years (29·1-46·3) among HIV-positive women. At the time of pregnancy, viral suppression among women was high (68 [87%] of 78 women had viral loads of <50 copies per mL and 77 [99%] had viral loads of <1000 copies per mL). No horizontal or vertical HIV transmission events were observed., Interpretation: Safer conception strategies empowered couples to safely conceive. Pregnancy incidence among service users was high. Integration of safer conception counselling could promote HIV prevention and linkage to care., Funding: US Agency for International Development; UJMT Consortium/Fogarty International Center, US National Institutes of Health (NIH); and Johns Hopkins University Center for AIDS Research (NIH)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the need to optimize strategies for prevention, diagnosis and treatment of hepatitis B virus (HBV) infection. An important priority for Africa is to have affordable, accessible and sustainable prevention of mother to child transmission (PMTCT) programmes, delivering screening and treatment for antenatal women and implementing timely administration of HBV vaccine for their babies., Methods: We developed a decision-analytic model simulating 10,000 singleton pregnancies to assess the cost-effectiveness of three possible strategies for deployment of tenofovir in pregnancy, in combination with routine infant vaccination: S1: no screening nor antiviral therapy; S2: screening and antiviral prophylaxis for all women who test HBsAg-positive; S3: screening for HBsAg, followed by HBeAg testing and antiviral prophylaxis for women who are HBsAg-positive and HBeAg-positive. Our outcome was cost per infant HBV infection avoided and the analysis followed a healthcare perspective., Results: Based on 10,000 pregnancies, S1 predicts 45 infants would be HBV-infected at six months of age, compared to 21 and 28 infants in S2 and S3, respectively. Relative to S1, S2 had an incremental cost of $3940 per infection avoided. S3 led to more infections and higher costs., Conclusion: Given the long-term health burden for individuals and economic burden for society associated with chronic HBV infection, screening pregnant women and providing tenofovir for all who test HBsAg+ may be a cost-effective strategy for South Africa and other low/middle income settings.

Background: Congenital rubella syndrome (CRS) includes disorders associated with intrauterine rubella infection. Incidence of CRS is higher in countries with no rubella-containing vaccines (RCV) in their immunization schedules. In the World Health Organization African region, RCVs are being introduced as part of the 2012-2020 global measles and rubella strategic plan. This study aimed to describe the epidemiology of confirmed CRS in South Africa prior to introduction of RCVs in the immunization schedule., Methods: This was a descriptive study with 28 sentinel sites reporting laboratory-confirmed CRS cases in all 9 provinces of South Africa. In the retrospective phase (2010 to 2014), CRS cases were retrieved from medical records, and in the prospective phase (2015 to 2017) clinicians at study sites reported CRS cases monthly., Results: There were 42 confirmed CRS cases in the retrospective phase and 53 confirmed CRS cases in the prospective phase. Most frequently reported birth defects were congenital heart disease and cataracts. The median age of mothers of CRS cases was 21 years in the retrospective phase (range: 11 to 38 years) and 22 years in the prospective phase (range: 15 to 38 years)., Conclusion: Baseline data on laboratory-confirmed CRS will enable planning and monitoring of RCV implementation in the South African Expanded Programme on Immunization program. Ninety-eight percent of mothers of infants with CRS were young women 14-30 years old, indicating a potential immunity gap in this age group for consideration during introduction of RCV., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Postnatal care (PNC) provides the opportunity for protecting the lives of women infected with human immune deficiency virus (HIV) and their babies. The prevention of mother-to-child transmission of HIV (PMTCT) guidelines provide a framework for implementation of PNC. There has been no empirical evidence on how the nurses at the clinic level implement these guidelines. In addition, there are reports that PNC has been neglected in South Africa., Aim: The study aimed to explore the implementation of PNC for HIV-positive women, by explicating nurses' views regarding their practices., Setting: The study was conducted in 2015 at three clinics at Mangaung Metro Municipality in the Free State., Methods: A qualitative, evaluative case study was conducted to provide a detailed account of the implementation of PNC, using 2015 PMTCT guidelines as a framework for evaluation. Eighteen key informants participated in three focus groups. Data were reviewed through direct thematic analysis., Results: Four themes emerged from data analysis, namely, guidelines as an empowering tool, implementation of HIV guidelines, perceived successes and challenges of postnatal HIV care, and measures to strengthen postnatal HIV care services. The study found that nurses interpreted and used guidelines to direct their practice. However, there were challenges and some successes., Conclusion: It was concluded that nurses had a good understanding of the guidelines provided for their practices and implemented them with various levels of success. Effective management of HIV-infected women during the postnatal period requires well-designed multidisciplinary collaborations, adequate resources, continuous professional development programmes, a high level of competence and confidence.

Objective: Unintended pregnancies are common among women living with HIV, but there are no data on their long-term impact on treatment outcomes. In a cohort of women initiating antiretroviral therapy (ART) during pregnancy, we examined the association between the intendedness of the current pregnancy, measured antenatally, and elevated viral load up to 5 years postpartum., Design: Prospective study with enrolment at entry into antenatal care and follow-up at study visits separate from routine care., Methods: At enrolment women completed the London Measure of Unplanned Pregnancy. Mixed effects models examined the impact of the intendedness of the pregnancy (planned versus each of unplanned or ambivalent, respectively) on viral load 50 or more copies/ml across postpartum study visits., Results: Overall, 459 women were followed for a median of 43 months postpartum, contributing 2535 viral load measures (median per woman: 6). Ambivalent and unplanned pregnancy were commonly reported (20 and 60%, respectively), and the proportion of women with elevated viral load increased over time (16% at 6 weeks to 43% by 36-60 months postpartum). Compared with those reporting a planned pregnancy, elevated viral load was more common among women reporting an unplanned pregnancy (odds ratio: 2.87; 95% confidence interval: 1.46-5.64), with a trend towards a higher odds among those reporting ambivalence (odds ratio: 2.19; 95% confidence interval: 0.97-4.82); associations persisted after adjustment for a wide range of demographic, clinical and psychosocial factors., Conclusion: These novel data suggest that unplanned pregnancy may be a prevalent and persistent predictor of poor ART outcomes among women initiating ART during pregnancy.

Background: Elevated HIV viral load (VL) in pregnancy has been linked to increased risk of mortality, immunologic abnormalities, infectious morbidity and restricted growth among HIV-exposed uninfected (HEU) children, but little is known about effects on child development., Methods: HIV-infected women initiating lifelong antiretroviral therapy (ART; tenofovir + emtricitabine + efavirenz) antenatally were followed from first antenatal visit through delivery and with their breastfed infants postpartum. Cognitive, motor and expressive language development (Bayley Scales of Infant and Toddler Development-Third Edition; delay defined as score <85) were assessed on a subset of HEU infants. HIV VL was measured at ART initiation, in third trimester and around delivery. Cumulative viremia in pregnancy was expressed as log10 VL copies × year/mL [viremia copy-years (VCY)]. Relationships between VCY and development were examined after adjusting for socioeconomic, behavioral and psychosocial confounders., Results: Women (median pre-ART log10 VL 4.1, CD4 349 cells/mm) commonly reported adverse social circumstances (44% informal housing, 63% unemployed, 29% risky drinking). Among 214 infants (median age, 13 months; 53% male; 13% born <37 weeks' gestation), viremia predicted lower motor and expressive language, but not cognitive, scores in crude and adjusted analysis [per log10 VCY increase, αβ (95% confidence interval [CI]): motor, -2.94 (-5.77 to -0.11); language, -3.71 (-6.73 to -0.69) and cognitive -2.19 (-5.02 to 0.65)]. Increasing VCY also predicted higher relative odds of motor delay [adjusted odds ratio (aOR): 3.32; 95% CI: 1.36-8.14) and expressive language delay (aOR: 2.79; 95% CI: 1.57-4.94), but not cognitive delay (aOR: 1.68; 95% CI: 0.84-3.34)., Conclusions: Cumulative maternal HIV viremia in pregnancy may have adverse implications for HEU child development.

The World Health Organization guidelines for treating pregnant HIV-positive women and preventing HIV transmission to infants now recommend lifelong antiretroviral treatment for pregnant and breastfeeding women. We applied quality improvement (QI) methods to support governments and facility staff to address service gaps in 5 countries under the Partnership for HIV-Free Survival (PHFS). We used 3 key strategies: break the complex problem of improving HIV-free survival into more easily implementable phases, support a national management team to oversee the project, and support facility-level staff to learn and apply QI methods to reducing mother-to-child transmission. The key results in each country were increases in data completeness and accuracy, increases in retention in care of mother-baby pairs (MBPs), increase in coverage of MBPs with appropriate services, and reduction in vertical transmission of HIV. The PHFS experience offers a model that other multicountry networks can adopt to improve service delivery and quality of care.

For women enrolled in prevention of mother-to-child transmission (PMTCT) programs, non-disclosure of their HIV status can be a significant barrier to sustained HIV care engagement. To explore decision-making surrounding HIV disclosure among HIV-infected pregnant women, we conducted repeated in-depth interviews during pregnancy and postpartum with 20 women recruited from a PMTCT clinic in Cape Town, South Africa. Three domains were examined using thematic analysis: (1) disclosure experiences, (2) challenges associated with partner disclosure, and (3) implications of nondisclosure. All women had disclosed to someone by the time of the baby's birth, typically limiting their disclosure to trusted individuals. Only half of participants disclosed to the father of the child. Nondisclosure, particularly to partners, was a significant source of worry and stress. Women used pregnancy as an explanation for using medication and attending frequent clinic appointments, and recognized impending challenges in the postpartum period when this excuse would no longer apply. Results suggest that PMTCT programs have a key role to play in helping individuals to make decisions about HIV disclosure, and assisting patients to navigate the disclosure process, especially with partners.

We investigated whether mortality risk increases with the number of full-term pregnancies in HIV-infected women. Our study is based on data from the ACDIS cohort, collected in rural KwaZulu-Natal, South Africa. Mortality risk for different number of pregnancies in HIV-infected women was analyzed using Cox proportional hazards model. The risk of TB or AIDS mortality in HIV-uninfected women did not change with the number of full-term pregnancies, while the corresponding risk increased markedly in HIV-infected women. The risk of TB or AIDS mortality increased 1.48-fold (95% CI 1.25-1.75), 1.76-fold (95% CI 1.45-2.13), and 1.59-fold (95% CI 1.31-1.94) for one, two, and three or more full-term pregnancies compared to none, respectively. Finally, women who are young (age < 26) have greater risk of TB or AIDS mortality compared to women who are old (age ≥ 26), and women residing in rural areas have greater risk compared to women who reside in non-rural areas.

Background: Sexual behaviors in human immunodeficiency virus (HIV)-infected pregnant women in South Africa are not well understood., Methods: Human immunodeficiency virus-infected pregnant women were recruited into a prospective cohort at first antenatal care visit. Sociodemographic information and self-collected vulvovaginal swab samples were collected from participants. Vulvovaginal swab samples were tested for Chlamydia trachomatis, Neisseria gonorrhoea, and Trichomonas vaginalis using GeneXpert. We investigated sexual behaviors, alcohol use, factors associated with condomless sex during pregnancy, and prevalent sexually transmitted infection (STI) among our cohort. We report descriptive, univariate and multivariable logistic regression results of sexual behaviors and alcohol use, factors associated with condomless sex at last sex, and having any STI during pregnancy adjusting for a priori confounders., Results: We recruited and enrolled 430 HIV-infected pregnant women. Median age was 30 years; median gestational age was 20 weeks. Eighty-nine percent of women reported sex during pregnancy. At last sex, 68% reported condomless sex; 18% reported having more than 1 sex partner in the past 12 months. Adjusting for age, income and relationship status, condom use at last sex was associated with prior knowledge of HIV status (adjusted odds ratio [aOR], 2.46; 95% confidence interval [CI], 1.54-3.92) and being in a concordant HIV-positive (aOR, 3.17; 95% CI, 1.84-5.50), or serodiscordant relationship (aOR, 6.50; 95% CI, 3.59-11.80). The prevalence of any STI was 41% (95% CI, 36%-45%). Adjusting for mothers' age and employment, odds of having an STI increased if the woman reported alcohol use during pregnancy (aOR, 1.96; 95% CI, 1.06-3.64) or if the father of the child was a non-cohabiting or casual partner (aOR, 1.42; 95% CI, 0.97-2.03)., Conclusions: Almost all HIV-infected pregnant women were sexually active during pregnancy and most women reported condomless sex at last sex. Condom use was associated with knowledge of serostatus and/or partner's serostatus before first antenatal care visit. Factors associated with having STIs included: alcohol use during pregnancy and father of child being a non-cohabiting partner.

This study examines the associations between maternal Traditional dietary pattern adherence and HIV/treatment with neonatal size and adiposity in urban, black South Africans, as well as how specific maternal factors - that is BMI and gestational weight gain (GWG) - may influence these associations. Multiple linear regression models were used to examine associations among maternal Traditional diet pattern adherence (pattern score), HIV/treatment status (three groups: HIV negative, HIV positive (antenatal antiretroviral treatment (ART) initiation), HIV positive (pre-pregnancy ART initiation)), BMI and GWG (kg/week), and newborn (1) weight:length ratio (WLR, kg/m) in 393 mother-neonate pairs, and (2) Peapod estimated fat mass index (FMI, kg/m3) in a 171-pair subsample. In fully adjusted models, maternal obesity and GWG were associated with 0·25 kg/m (P=0·008) and 0·48 kg/m (P=0·002) higher newborn WLR, whereas Traditional diet pattern score was associated with lower newborn WLR (-0·04 kg/m per +1 sd; P=0·033). In addition, Traditional diet pattern score was associated with 0·13 kg/m3 (P=0·027) and 0·32 kg/m3 (P=0·005) lower FMI in the total sample and in newborns of normal-weight women, respectively. HIV-positive (pre-pregnancy ART) v. HIV-negative (ref) status was associated with 1·11 kg/m3 (P=0·002) higher newborn FMI. Promotion of a Traditional dietary pattern, alongside a healthy maternal pre-conception weight, in South African women may reduce newborn adiposity and metabolic risk profiles. In HIV-positive women, targeted monitoring and management strategies are necessary to limit treatment-associated effects on in utero fat deposition.

This study aimed to assess the maternal anthropometric parameters of human immunodeficiency virus (HIV)-infected and HIV-uninfected mothers as well as to assess the neonatal anthropometric parameters of premature infants in relation to maternal anthropometric parameters (weight, height and mid-upper-arm circumference), HIV status and anti-retroviral therapy (ART) regimen. Study participants included HIV-infected and HIV-uninfected mothers who gave birth to premature infants. All HIV-infected mothers received ART. The incidence of intra-uterine growth restriction (IUGR) among premature infants was high. Maternal anthropometric parameters, HIV status and ART exposure showed no association with IUGR in this study. Sufficient maternal ART exposure may positively influence head circumference at birth, which might determine the neurodevelopmental outcome of these infants.

Effective prevention of mother-to-child transmission benefits from early presentation to antenatal care (ANC). It is, however, unclear whether a previous HIV diagnosis results in earlier initiation of ANC. We estimated the probability of early ANC initiation among women with a previous HIV-positive diagnosis compared to those who first tested for HIV during ANC and explored determinants of early ANC among HIV-positive women. We conducted an analysis of a cross-sectional survey among 411 HIV-positive adult (>18 years) women who gave birth at midwife obstetrics units in Gauteng between October 2016 and May 2017. Predictors of early ANC (defined as initiating ANC before or at 14 weeks of gestation) were assessed by multivariate log-binomial regression model. Overall, 51% (210) were diagnosed during pregnancy with 89% (188) initiating antiretroviral therapy on the same day of diagnosis. There was no meaningful difference in the timing of ANC initiation between women with previous HIV diagnosis [adjusted risk ratio (aRR) = 1.2; 95% confidence interval (95% CI): 0.9-1.7] compared with those diagnosed during pregnancy. Early ANC was predicted by planned pregnancy [aRR = 1.3; 95% CI: 1.1-1.7], parity (>2 children) [aRR = 0.6; 95% CI: 0.2-0.9] compared to not having a child, and tuberculosis diagnosis [aRR = 2.9; 95% CI: 1.4-6.1]. Our results suggest the need for a targeted intervention among HIV-positive women by improving the quality, content and outreach of ANC services to enhance early ANC uptake, and minimize mother-to-child transmission risk.

Background: Limited data exist on the burden of respiratory syncytial virus (RSV) illness among pregnant women, to determine their potential benefit from RSV vaccination. We evaluated the incidence of RSV illness from midpregnancy until 24 weeks postpartum in human immunodeficiency virus (HIV)-uninfected and HIV-infected women and their infants., Methods: Mother-infant dyads were enrolled in maternal influenza vaccine efficacy trials. These included 1060 and 1056 HIV-uninfected pregnant women in 2011 and 2012, respectively, 194 HIV-infected pregnant women in 2011, and their infants. Upper respiratory tract samples obtained at illness visits were tested for RSV., Results: The incidence (per 1000 person-months) of RSV illness (n = 43 overall) among HIV-uninfected women was lower in 2011 (1.2; 95% confidence interval [CI], .6-2.2) than in 2012 (4.0; 95% CI, 2.8-5.6). The incidence of RSV illness (n = 5) in HIV-infected women was 3.4 (95% CI, 1.4-8.1). Maternal RSV infection was associated with respiratory symptoms including cough (72.1%), rhinorrhea (39.5%), sore throat (37.2%), and headache (42%), but fever was absent. RSV infection during pregnancy was not associated with adverse pregnancy outcomes. Postpartum, RSV infection in mothers (n = 27) was associated with concurrent infection among 51.9% of their infants and, conversely, 29.8% of mothers investigated within 7 days of their infants having an RSV illness also tested positive for RSV., Conclusions: RSV infection is associated with respiratory illness during pregnancy and postpartum. Vaccination of pregnant women against RSV could benefit the mother, albeit primarily against nonfebrile illness, and her infant., Clinical Trial Registration: NCT01306669 and NCT01306682.

Background: To evaluate the effect of antenatal influenza vaccination on all-cause severe infant pneumonia, we performed pooled analysis of 3 randomized controlled trials conducted in Nepal, Mali and South Africa., Methods: The trials were coordinated from the planning phase. The follow-up period was 0-6 months postpartum in Nepal and Mali and 0-24 weeks in South Africa. Pregnant women with gestational age 17-34 weeks in Nepal, ≥28 weeks in Mali and 20-36 weeks in South Africa were enrolled. Trivalent inactivated influenza vaccine (IIV) was compared with either saline placebo (Nepal and South Africa) or quadrivalent meningococcal conjugate vaccine (Mali). In South Africa, cases were hospitalized and were therefore considered to have severe pneumonia. In Nepal and Mali, severe infant pneumonia diagnosis was based on the WHO Integrated Management of Childhood Illness definition., Results: A total of 10,002 mothers and 9801 live-born eligible infants were included in the present analysis. There was a 31% lower incidence rate of severe pneumonia in the IIV group compared with the control group in Nepal [incidence rate ratio (IRR): 0.69; 95% CI: 0.50-0.94; ]. In South Africa, there was a 43% lower incidence rate of severe pneumonia in the IIV group versus the control group (IRR: 0.57; 95% CI: 0.33-1.0). There was no difference in incidence rates between the IIV group and the control group in Mali. Overall, incidence rate of severe pneumonia was 20% lower in the IIV group compared with the control group (IRR: 0.80; 95% CI: 0.66-0.99; P = 0.04). Protection was highest in the high influenza circulation period (IRR: 0.44; 95% CI: 0.23-0.84)., Conclusions: Maternal influenza immunization may reduce severe pneumonia episodes among infants-particularly those too young to be completely vaccinated against Streptococcus pneumoniae and influenza.

Background: Trichomonas vaginalis is a sexually transmitted infection associated with increased transmission of HIV and significant adverse birth outcomes; culture and polymerase chain reaction (PCR) are commonly used in diagnosis., Methods: Consenting HIV-infected pregnant women were recruited from clinics in South Africa and screened for T. vaginalis using PCR. Polymerase chain reaction-positive women provided an additional sample for culture. We compared T. vaginalis detection between PCR and culture, and investigated how PCR cycle threshold (Ct) values differ among culture results., Results: A total of 359 women were enrolled and 76 (20%) tested T. vaginalis PCR positive. Cultures were obtained from 61 of the PCR-positive women, and 38 (62%) were culture positive. The median baseline Ct of the PCR-positive/culture-positive group was 22.6 versus 38.0 among those who were PCR positive/culture negative (P < 0.001). Culture-positive cases had lower Ct values (higher DNA load); a Ct value less than 30 predicted positivity with a sensitivity of 97% and a specificity of 96%., Conclusions: Culture was positive in roughly half of PCR-positive cases. The culture-negative cases had significantly higher Ct values, indicating a lower concentration of T. vaginalis DNA. A Ct value of 30 provides a reliable threshold for predicting culture positivity. The clinical significance of culture-negative infections detected by PCR is still unclear.

Background: Context-specific factors influence adherence to antiretroviral therapy (ART) among pregnant women living with HIV. Gaps exist in the understanding of the reasons for the variable outcomes of the prevention of mother-to-child transmission (PMTCT) programme at the health facility level in South Africa. This study examined adherence levels and reasons for non-adherence during pregnancy in a cohort of parturient women enrolled in the PMTCT programme in the Eastern Cape, South Africa., Methods: This was a mixed-methods study involving 1709 parturient women in the Eastern Cape, South Africa. We conducted a multi-centre retrospective analysis of the mother-infant pair in the PMTCT electronic database in 2016. Semi-structured interviews of purposively selected parturient women with self-reported poor adherence (n = 177) were conducted to gain understanding of the main barriers to adherence. Binary logistic regression was used to determine the independent predictors of ART non-adherence., Results: A high proportion (69.0%) of women reported perfect adherence. In the logistic regression analysis, after adjusting for confounding factors, marital status, cigarette smoking, alcohol use and non-disclosure to a family member were the independent predictors of non-adherence. Analysis of the qualitative data revealed that drug-related side-effects, being away from home, forgetfulness, non-disclosure, stigma and work-related demand were among the main reasons for non-adherence to ART., Conclusions: Non-adherence to the antiretroviral therapy among pregnant women in this setting is associated with lifestyle behaviours, HIV-related stigma and ART side-effects. In order to eliminate mother-to-child transmission of HIV, clinicians need to screen for these factors at every antenatal clinic visit.

Background: Before the wide availability of antiretroviral therapy (ART), tuberculosis and human immunodeficiency virus (HIV) disease among pregnant women resulted in poor maternal and neonatal outcomes, including high rates of mother-to-child transmission of both HIV and tuberculosis. We aimed to describe the impact of tuberculosis among HIV-infected mothers on obstetric and infant outcomes in a population with access to ART., Methods: In this prospective cohort study, we followed up HIV-infected pregnant women with or without tuberculosis disease from January 2011 through January 2014 in Soweto, South Africa. Two controls were enrolled for each case patient, matched by enrollment time, maternal age, gestational age, and planned delivery clinic and followed up for 12 months after delivery., Results: We recruited 80 case patients and 155 controls, resulting in 224 live-born infants. Infants of mothers with HIV infection and tuberculosis disease had a higher risk of low birth weight (20.8% vs 10.7%; P = .04), prolonged hospitalization at birth (51% vs 16%; P < .001), infant death (68 vs 7 deaths per 1000 births; P < .001), and tuberculosis disease (12% vs 0%; P < .001) despite appropriate maternal therapy and infant tuberculosis preventive therapy. HIV transmission was higher among these infants (4.1% vs 1.3%; P = .20), though this difference was not statistically significant. Obstetric outcomes in coinfected women were also poorer with higher risks of maternal hospitalization (25% vs 11%; P = .005) and preeclampsia (5.5% vs 0.7%; P = .03)., Conclusions: Tuberculosis in HIV coinfected pregnant women remains a significant threat to the health of both mothers and infants. Improving tuberculosis prevention and early diagnosis among pregnant women is critical., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Despite substantial progress in the delivery of HIV prevention programs, some communities continue to experience high rates of HIV infection. We report on temporal trends in HIV prevalence in pregnant women in a community in rural KwaZulu-Natal in South Africa., Methods: Annual, anonymous cross-sectional HIV sero-prevalence surveys were conducted between 2001 and 2013 among first visit prenatal clinic attendees. The time periods 2001 to 2003 were defined as pre-antiretroviral therapy (ART), 2004 to 2008 as early ART, and 2009 to 2013 as contemporary ART roll-out, to correspond with the substantial scale-up of ART program., Results: Overall, HIV prevalence rose from 35.3% [95% confidence interval (CI): 32.3 to 38.3] pre-ART (2001-2003) to 39.0% (95% CI: 36.8 to 41.1) in the early ART (2004-2008) to 39.3% (95% CI: 37.2 to 41.4) in the contemporary ART (2009-2013) roll-out periods. In teenage women (<20 years), HIV prevalence declined from 22.5% (95% CI: 17.5 to 27.5) to 20.7% (95% CI: 17.5 to 23.8) and to 17.2% (95% CI: 14.3 to 20.2) over the similar ART roll-out periods (P = 0.046). Prevalence increased significantly in women 30 years and older (P < 0.001) over the same time period largely because of survival after ART scale up. Teenage girls with male partners of age 20-24 and ≥ 25 years had a 1.7-fold (95% CI: 1.3-2.4; P = 0.001) and 3-fold (95% CI: 2.1 to 4.3; P < 0.001) higher HIV prevalence respectively., Conclusions: Notwithstanding the encouraging decline in teenagers, the ongoing high HIV prevalence in pregnant women in this rural community, despite prevention and treatment programs, is deeply concerning. Targeted interventions for teenagers, especially for those in age-disparate relationships, are needed to impact this HIV epidemic trajectory., Competing Interests: The authors declare no conflicts of interest.

Although the rates of vertical transmission of HIV in the developing world have improved to around 3% in countries like South Africa, resistance to antiretrovirals (ARV) used in Prevention of Mother-to-Child transmission (pMTCT) strategies may thwart such outcomes and affect the efficacy of future ARV regimens in mothers and children. This study conducted in Durban, South Africa, between 2010 and 2013 found a high rate of nevirapine (NVP) resistance among women receiving Zidovudine (AZT) from 14 weeks gestation, single dose nevirapine (sd NVP) at the onset of labor and a single dose of coformulated Tenofovir/Emtricitabine (TDF/FTC) postpartum. Using Sanger sequencing, high and intermediate levels of nevirapine (NVP) resistance were detected in 15/44 (34%) and in 1/44 (2%) of women tested, respectively. Most subjects selected the K103N mutation (22% (10/45) of all patients and 66% (10/15) of those with high-level NVP resistance). Such rate of NVP resistance is comparable to studies where only sd NVP was used. In conclusion, a post-partum single-dose TDF/FTC tail does not prevent the selection of NNRTI resistance in women receiving pre-partum ZDV and intrapartum sd NVP to prevent mother-to-child HIV-1 transmission., (© 2015 Wiley Periodicals, Inc.)

Involving male partners of pregnant women accessing PMTCT programs has the potential to improve health outcomes for women and children. This study explored community members' (men and women) and healthcare workers' perceptions of male involvement in the prevention of mother-to-child transmission of HIV in Khayelitsha, South Africa. Two focus group discussions were held with 25 men of unknown HIV status and one focus group discussion held with 12 HIV-positive women in the community. In depth interviews were conducted with four HIV-positive couples and five service providers purposely sampled from the community and a health facility, respectively. Both men and women interviewed in this study were receptive towards male involvement in PMTCT. However, men were reluctant to engage with health services due to stigma and negative attitudes from nurses. This study also found HIV testing, disclosure and direct health worker engagement with men increases male involvement in PMTCT. Using men in the media and community to reach out to fellow men with prevention messages tailored to suit specific audiences may reduce perceptions of antenatal care as being a woman`s domain.

Reasons for Performing Study: Equine herpesvirus 1 (EHV-1) is one of the most common causes of infectious abortion in mares. Analysing the demography of outbreaks and detailing subsequent reproductive performance of affected mares will assist in the management of future (threatened) epizootics., Objectives: To examine the epidemiology and reproductive outcomes of 2 EHV-1 abortion epizootics with very different patterns of morbidity., Study Design: Epidemiological and reproductive data were analysed retrospectively following abortion epizootics associated with EHV-1, but initiated via different routes, among unvaccinated mares on 2 Thoroughbred farms in South Africa., Methods: Aborting mares were assigned to either the EHV-1 abortion cohort via positive immunostaining (Farms 1 and 2) or quantitative PCR (Farm 2) on tissue samples, or to the non-EHV abortion cohort., Results: During their respective epizootics, EHV-1 abortions affected 9/30 (30.0%) and 18/316 (5.7%) of the pregnant mares on Farms 1 and 2, respectively; there were also 25 (7.9%) non-EHV abortions on Farm 2. Epizootic differences included: durations (Farm 1 = 135 days; Farm 2 = 34 days), intervals between first and subsequent abortions (Farm 1 = 39 days; Farm 2 = 2 days) and intervals to confirmation of EHV-1 (Farm 1 = 40 days; Farm 2 = 2 days). The median (range) age of EHV-1 abortion mares (8.0; 5-18 years) in both epizootics was similar but significantly younger (P = 0.004) than the 25 non-EHV-1 abortion mares (11.0; 4-24 years) on Farm 2. Gestation stage (median; range) of EHV-1 (291.5; 277-313) and non-EHV-1 (211.9; 61-339 days) abortions were significantly different (P = 0.001). The post abortion complications and subsequent reproductive outcomes had no significant association with EHV-1 abortion., Conclusions: The marked difference in morbidity between the 2 epizootics may be associated with routes of introduction or intervention strategy dictated by availability of molecular diagnostic techniques. Unexpectedly, EHV-1 was not more commonly associated with post abortion complications., (© 2014 EVJ Ltd.)

Background: Pregnancy and tuberculosis treatment or prophylaxis can affect efavirenz pharmacokinetics, maternal human immunodeficiency virus type 1 (HIV-1) treatment outcomes, and mother-to-child transmission (MTCT) risk., Methods: We evaluated a prospective cohort of pregnant, HIV-infected women with and without tuberculosis in Soweto, South Africa. Pharmacokinetic sampling was performed at gestation week 37 and during the postpartum period. Efavirenz trough concentrations (Cmin) were predicted using population pharmacokinetic models. HIV-viral load was measured at delivery for mothers and at 6 weeks of age for infants., Results: Ninety-seven women participated; 44 had tuberculosis. Median efavirenz Cmin during pregnancy was 1.35 µg/mL (interquartile range [IQR], 0.90-2.07 µg/mL; 27% had an efavirenz Cmin of < 1 µg/mL), compared with a median postpartum value of 2.00 µg/mL (IQR, 1.40-3.59 µg/mL; 13% had an efavirenz Cmin of < 1 µg/mL). A total of 72% of pregnant women with extensive CYP2B6 genotypes had an efavirenz Cmin of <1 µg/mL. Rifampin did not reduce the efavirenz Cmin. Isoniazid (for prophylaxis or treatment), though, reduced the rate of efavirenz clearance. At delivery, median durations of ART were 13 weeks (IQR, 9-18 weeks) and 21 weeks (IQR, 13-64 weeks) for women with and those without tuberculosis, respectively; 55% and 83%, respectively, had a viral load of <20 copies/mL (P = .021). There was 1 case of MTCT., Conclusions: Pregnancy increased the risk of low efavirenz concentrations, but MTCT was rare. A detectable HIV-viral load at delivery was more common among pregnant women with tuberculosis, in whom ART was generally initiated later., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)