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Background: Few data are available on COVID-19 outcomes among pregnant women in sub-Saharan Africa (SSA), where high-risk comorbidities are prevalent. We investigated the impact of pregnancy on SARS-CoV-2 infection and of SARS-CoV-2 infection on pregnancy to generate evidence for health policy and clinical practice., Methods: We conducted a 6-country retrospective cohort study among hospitalized women of childbearing age between 1 March 2020 and 31 March 2021. Exposures were (1) pregnancy and (2) a positive SARS-CoV-2 RT-PCR test. The primary outcome for both analyses was intensive care unit (ICU) admission. Secondary outcomes included supplemental oxygen requirement, mechanical ventilation, adverse birth outcomes, and in-hospital mortality. We used log-binomial regression to estimate the effect between pregnancy and SARS-CoV-2 infection. Factors associated with mortality were evaluated using competing-risk proportional subdistribution hazards models., Results: Our analyses included 1315 hospitalized women: 510 pregnant women with SARS-CoV-2, 403 nonpregnant women with SARS-CoV-2, and 402 pregnant women without SARS-CoV-2 infection. Among women with SARS-CoV-2 infection, pregnancy was associated with increased risk for ICU admission (adjusted risk ratio [aRR]: 2.38; 95% CI: 1.42-4.01), oxygen supplementation (aRR: 1.86; 95% CI: 1.44-2.42), and hazard of in-hospital death (adjusted sub-hazard ratio [aSHR]: 2.00; 95% CI: 1.08-3.70). Among pregnant women, SARS-CoV-2 infection increased the risk of ICU admission (aRR: 2.0; 95% CI: 1.20-3.35), oxygen supplementation (aRR: 1.57; 95% CI: 1.17-2.11), and hazard of in-hospital death (aSHR: 5.03; 95% CI: 1.79-14.13)., Conclusions: Among hospitalized women in SSA, both SARS-CoV-2 infection and pregnancy independently increased risks of ICU admission, oxygen supplementation, and death. These data support international recommendations to prioritize COVID-19 vaccination among pregnant women., Competing Interests: Potential conflicts of interest. J. B. N. is an infectious disease internist and epidemiologist and Principal Investigator (PI) of NIH/FIC grant numbers 1R25TW011217-01, 1R21TW011706-01, and 1D43TW010937-01A1; and payment to University of Pittsburgh. N. A. S.-A. is a clinician-scientist in Pediatric Infectious Diseases and implementation research; she is supported by the NIH National Institute of Child Health and Human Development (NICHD) grant number R01HD089866; by an NIH/FIC award through the Adolescent HIV Prevention and Treatment Implementation Science Alliance (AHISA) for the Central and West Africa Implementation Science Alliance (CAWISA) (payment to institution); and by NIH/FIC grant number 1D43TW012280-01. F. S., N. K. S., and A. P. are supported as PIs by NIH/FIC grant number 1R25TW011217-01. A. Z. is PIs of the Pan-African Network on Emerging and Re-Emerging Infections (PANDORA-ID-NET; https://www.pandora-id.net) funded by the European Developing Countries Clinical Trial Partnership (EDCTP) and the European Union Horizon 2020 Framework Program for Research and Innovation, paid to institution (University College London, London, UK). R. N. M. reports grants or contracts unrelated to this work, and payment to their institution: NIH/FIC1D43TW010547-01—The African Center for Biostatistical Excellence (ACBE). P. J. R. reports the following grants or contracts unrelated to this work and paid to their institution: 5R01AI075045-12, 5R01AI139179-04, and 5R01AI117001-07. E. R. S. reports a Bill and Melinda Gates Foundation grant for a prospective meta-analysis of COVID-19 in pregnancy, unrelated to this work, and payment to George Washington University. A. B. reports grants or contracts unrelated to this work—NIH: IMPAACT Vice-chair Funding for P1106; and UNITAID: Benefit KIDS funding for PETITE Study. P. A. reports grants or contracts unrelated to this work and paid to the University of Ibadan, Nigeria: NIH/FIC R25 grant number 1R25TW011217-01 to AFREhealth. J. W. N. reports grants paid to the University of Pittsburgh from the NIH to the Pitt-Ohio State Clinical Trials Unit (UM1 AI068636), the University of Pittsburgh Virology Support Laboratory (UM1 AI106701), the I4C Martin Delaney Collaboratory for an HIV Cure (UM1 AI126603), the REACH Martin Delaney Collaboratory for HIV Cure (UM1 AI164565), and from the National Cancer Institute through Leidos contract numbers HHSN261200800001E and 75N91019D00024 USAID; Gilead Sciences, Inc; and Janssen Pharmaceuticals. J. W. N. also reports consulting fees from Gilead Sciences, Inc (Scientific Advisory Board), Accelevir Diagnostics (Consulting Agreement), and Merck (Consulting Agreement); shares from Abound Bio, Inc, share options from Co-Crystal Pharma, Inc, and share options from Infectious Diseases Connect; a consulting agreement with Xi’an Yufan Biotechnologies; and employment with the University of Pittsburgh. M. S. reports grants or contracts unrelated to this work and paid to their institution (MGH-Boston, MA, USA): NIH/NIA R01AG059504-03 and NIH/NHLBI R01 HL141053-04. A.-P. K. reports research support unrelate to this work paid to their institution (South African Medical Research Council): NIH/FIC 1R21TW011706-01-Dolutegravir, Weight Gain and Metabolic Outcomes in South Africa. L. M. reports consulting fees from the World Health Organization on COVID in pregnancy and mother to child SARS-CoV-2 transmission (this contract is now completed); and payment from Virology Education for a talk on SARS-CoV-2 in pregnancy and possibility of mother-to-child SARS-CoV-2 transmission for continuing education sponsored by Virology Education. M. Y. is PI of the NIH/National Institute of Allergy and Infectious Diseases (NIH/NIAID) grant number 5U01AI096299-13 of the Central Africa-International epidemiology to Evaluate AIDS (CA-IeDEA). M. Y. also reports grants or contracts unrelated to this work and paid to their institution: NIH grant numbers 5U01AI096299 (NIAID), R01HD087993 (NICHD), U54CA254568 (National Cancer Institute), and R01HD105526 (NICHD). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Objective: STIs remain a global public health problem with a high burden among pregnant women. STIs in pregnant women may lead to various adverse pregnancy outcomes. In most sub-Saharan African countries, syndromic management is used for screening and treatment of STIs. We aimed to update and summarise pooled prevalence of curable STIs and bacterial vaginosis (BV) among pregnant women in sub-Saharan Africa., Methods: Electronic databases and reference lists of relevant published and unpublished studies were searched from March 2015 to October 2020. Studies were included if they estimated prevalence of Chlamydia trachomatis (CT), Trichomonas vaginalis (TV), Neisseria gonorrhoeae (NG), Treponema pallidum (syphilis), Mycoplasma genitalium (MG) and BV among pregnant women in sub-Saharan Africa. Meta-analyses were performed with observed prevalences corrected for diagnostic errors to estimate the pooled prevalence of diagnosed infections by region., Results: A total of 48 studies met the inclusion criteria, providing 85-point prevalence estimates for curable STIs and BV. Pooled prevalence estimates (with 95% CI and number of women tested) were as follows: MG: 13.5% (4.0-27.2, n=1076); CT: 10.8% (6.9-15.5, n=6700); TV: 13.8% (10.0-18.0, n=9264); NG: 3.3% (2.1-4.7, n=6019); syphilis: 2.9% (2.0-4.0, n=95 308) and BV: 36.6% (27.1-46.6, n=5042). By region, BV was the most prevalent and ranged from 28.5% (24.5-32.8, n=1030) in Eastern Africa to 52.4% (33.5-70.9, n=2305) in Southern Africa; NG had the lowest prevalence, ranging from 1.4% (95% CI 0.1 to 3.1, n=367) in Central Africa to 4.4% (95% CI 2.6 to 6.4, n=4042) in Southern Africa., Conclusion: The prevalence of curable STIs and BV in sub-Saharan Africa is substantial in pregnant women but most prevalent in Southern Africa where HIV prevalence is highest. It is crucial to integrate screening of curable STIs into antenatal care programmes that have previously focused on diagnosis and treatment of syphilis and HIV., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Pregnant and postpartum women (PPW) in sub-Saharan Africa are at disproportionately high risk of HIV infection compared to non-pregnant women. When used consistently, pre-exposure prophylaxis (PrEP) can prevent HIV acquisition and transmission to the foetus or infant during these critical periods. Recent studies have demonstrated associations between mental health challenges (e.g. depression and traumatic stress associated with intimate partner violence) and decreased PrEP adherence and persistence, particularly among adolescents, younger women and women in the postpartum period. However, mental health is not currently a major focus of PrEP implementation research and programme planning for PPW., Discussion: PrEP implementation programmes for PPW need to assess and address mental health barriers to consistent PrEP use to ensure effectiveness and sustainability in routine care. We highlight three key research priorities that will support PrEP adherence and persistence: (1) include mental health screening tools in PrEP implementation research with PPW, both to assess the feasibility of integrating these tools into routine antenatal and postpartum care and to ensure that limited resources are directed towards women whose symptoms may interfere most with PrEP use; (2) identify cross-cutting, transdiagnostic psychological mechanisms that affect consistent PrEP use during these periods and can realistically be targeted with intervention in resource-limited settings; and (3) develop/adapt and test interventions that target those underlying mechanisms, leveraging strategies from existing interventions that have successfully mitigated mental health barriers to antiretroviral therapy use among people with HIV., Conclusions: For PPW, implementation of PrEP should be guided by a robust understanding of the unique psychological difficulties that may act as barriers to uptake, adherence and persistence (i.e. sustained adherence over time). We strongly encourage PrEP implementation research in PPW to incorporate validated mental health screening tools and ultimately treatment in routine antenatal and postnatal care, and we stress the potential public health benefits of identifying women who face mental health barriers to PrEP use., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: Uptake of early infant HIV diagnosis (EID) varies widely across sub-Saharan African settings. We evaluated the potential clinical impact and cost-effectiveness of universal maternal HIV screening at infant immunization visits, with referral to EID and maternal antiretroviral therapy (ART) initiation., Methods: Using the CEPAC-Pediatric model, we compared two strategies for infants born in 2017 in Côte d'Ivoire (CI), South Africa (SA), and Zimbabwe: (1) existing EID programmes offering six-week nucleic acid testing (NAT) for infants with known HIV exposure (EID), and (2) EID plus universal maternal HIV screening at six-week infant immunization visits, leading to referral for infant NAT and maternal ART initiation (screen-and-test). Model inputs included published Ivoirian/South African/Zimbabwean data: maternal HIV prevalence (4.8/30.8/16.1%), current uptake of EID (40/95/65%) and six-week immunization attendance (99/74/94%). Referral rates for infant NAT and maternal ART initiation after screen-and-test were 80%. Costs included NAT ($24/infant), maternal screening ($10/mother-infant pair), ART ($5 to 31/month) and HIV care ($15 to 190/month). Model outcomes included mother-to-child transmission of HIV (MTCT) among HIV-exposed infants, and life expectancy (LE) and mean lifetime per-person costs for children with HIV (CWH) and all children born in 2017. We calculated incremental cost-effectiveness ratios (ICERs) using discounted (3%/year) lifetime costs and LE for all children. We considered two cost-effectiveness thresholds in each country: (1) the per-capita GDP ($1720/6380/2150) per year-of-life saved (YLS), and (2) the CEPAC-generated ICER of offering 2 versus 1 lifetime ART regimens (e.g. offering second-line ART; $520/500/580/YLS)., Results: With EID, projected six-week MTCT was 9.3% (CI), 4.2% (SA) and 5.2% (Zimbabwe). Screen-and-test decreased total MTCT by 0.2% to 0.5%, improved LE by 2.0 to 3.5 years for CWH and 0.03 to 0.07 years for all children, and increased discounted costs by $17 to 22/child (all children). The ICER of screen-and-test compared to EID was $1340/YLS (CI), $650/YLS (SA) and $670/YLS (Zimbabwe), below the per-capita GDP but above the ICER of 2 versus 1 lifetime ART regimens in all countries., Conclusions: Universal maternal HIV screening at immunization visits with referral to EID and maternal ART initiation may reduce MTCT, improve paediatric LE, and be of comparable value to current HIV-related interventions in high maternal HIV prevalence settings like SA and Zimbabwe., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Young women in sub-Saharan Africa are disproportionally affected by HIV infection and unintended pregnancies. However, hormonal contraceptive (HC) use may influence HIV risk through changes in genital tract microbiota and inflammatory cytokines. To investigate this, 130 HIV negative adolescent females aged 15-19 years were enrolled into a substudy of UChoose, an open-label randomized crossover study (NCT02404038), comparing acceptability and contraceptive product preference as a proxy for HIV prevention delivery methods. Participants were randomized to injectable norethisterone enanthate (Net-En), combined oral contraceptives (COC) or etonorgesterol/ethinyl estradiol combined contraceptive vaginal ring (CCVR) for 16 weeks, then crossed over to another HC for 16 weeks. Cervicovaginal samples were collected at baseline, crossover and exit for characterization of the microbiota and measurement of cytokine levels; primary endpoints were cervical T cell activation, vaginal microbial diversity and cytokine concentrations. Adolescents randomized to COCs had lower vaginal microbial diversity and relative abundance of HIV risk-associated taxa compared to Net-En or CCVR. Cervicovaginal inflammatory cytokine concentrations were significantly higher in adolescents randomized to CCVR compared to COC and Net-En. This suggests that COC use may induce an optimal vaginal ecosystem by decreasing bacterial diversity and inflammatory taxa, while CCVR use is associated with genital inflammation.

Background: Adolescents in sub-Saharan Africa are at risk for human immunodeficiency virus (HIV) infection and unintended pregnancies. Observational studies suggest that injectable hormonal contraceptives (HCs) increase the HIV risk, although their effects on genital inflammation, particularly HIV-susceptible T-helper 17 (Th17) cells, are unknown. In a randomized crossover study, the effect of injectable norethisterone oenanthate (NET-EN), combined contraceptive vaginal rings (CCVR; NuvaRing), and combined oral contraceptive pills (COCPs) on cervical Th17 cells and cytokines were compared., Methods: Adolescents (n = 130; 15-19 years) were randomly assigned 1:1:1 to NET-EN, CCVR, or COCPs for 16 weeks, then subsequently crossed over to another HC for 16 weeks. Estrogen, follicular stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured. Chemokine receptor 5 (CCR5), human leukocyte antigen (HLA) DR isotope, and cluster of differentiation 38 (CD38) expression by cervical cytobrush-derived CD4+ T cells was assessed by fluorescence-activated cell sorting. Th17 cells were defined as CCR6+ and CCR10-. Cervicovaginal Th17-related cytokines were measured by Luminex., Results: CCVR use for the first 16 weeks was associated with reduced Th17 frequencies and lower FSH and LH concentrations, as compared to NET-EN and COCPs, with FSH concentrations and Th17 frequencies correlating significantly. However, Th17-related cytokine concentrations (interleukin [IL]-21, IL-1β, tumor necrosis factor-α, interferon-γ) and CCR5, HLA-DR, CD38, and Th17 frequencies were significantly higher in CCVR than NET-EN and COCP. At crossover, CCVR users changing to COCPs or NET-EN did not resolve activation or cytokines, although switching from COCP to CCVRs increased cytokine concentrations., Conclusions: CCVR use altered endogenous hormone levels and associated cervical Th17 cell frequencies to a greater extent than use of NET-EN or COCPs, although Th17 cells were more activated and Th17-related cytokine concentrations were elevated. While CCVRs may impact the HIV risk by regulating Th17 numbers, increased activation and inflammation may balance any risk gains., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Globally, 1·7 million children are living with HIV, of which 90% are in sub-Saharan Africa. The remarkable scale-up of combination antiretroviral therapy has resulted in increasing numbers of children with HIV surviving to adolescence. Unfortunately, in sub-Saharan Africa, HIV diagnosis is often delayed with children starting antiretroviral therapy late in childhood. There have been increasing reports from low-income settings of children with HIV who have multisystem chronic comorbidities despite antiretroviral therapy. Many of these chronic conditions show clinical phenotypes distinct from those in adults with HIV, and result in disability and reduced quality of life. In this Review, we discuss the spectrum and pathogenesis of comorbidities in children with HIV in sub-Saharan Africa. Prompt diagnosis and treatment of perinatally acquired HIV infection is a priority. Additionally, there is a need for increased awareness of the burden of chronic comorbidities. Diagnostic and therapeutic strategies need to be collectively developed if children with HIV are to achieve their full potential., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Intensified viral load monitoring for pregnant and breastfeeding women has been proposed to help address concerns around antiretroviral therapy (ART) adherence, viraemia and transmission risk, but there have been no systematic evaluations of existing policies., Methods: We used an individual Monte Carlo simulation to describe longitudinal ART adherence and viral load from conception until 2 years' postpartum. We applied national and international guidelines for viral load monitoring to the simulated data. We compared guidelines on the percentage of women receiving viral load monitoring and the percentage of women monitored at the time of elevated viral load., Results: Coverage of viral load monitoring in pregnancy and breastfeeding varied markedly, with between 14% and 100% of women monitored antenatally and 38-98% monitored during breastfeeding. Specific recommendations for testing at either a fixed gestation or a short, fixed period after ART initiation achieved more than 95% testing in pregnancy but this was much lower (14-83%) among guidelines with no special stipulations. By the end of breastfeeding, only a small proportion of simulated episodes of elevated viral load more than 1000 copies/ml were successfully detected by monitoring (range, 20-50%)., Discussion: Although further research is needed to understand optimal viral load frequency and timing in this population, these results suggest that current policies yield suboptimal detection of elevated viral load in pregnant and breastfeeding women.

Background: Little is known about renal pathology among perinatally HIV-infected children and adolescents in Africa. We assessed the prevalence of risk factors for chronic kidney disease in South African children and adolescents with perinatally acquired HIV-1 (HIV+) on antiretroviral therapy (ART) and HIV-negative children and adolescents., Methods: HIV+ youth aged 9-14 years, on ART for > 6 months and age-matched HIV-negative children and adolescents were eligible for assessment of proteinuria and microalbuminuria using urine dipstick and Vantage analyser method. Blood pressure, estimated glomerular filtration rate, HIV-related variables and metabolic co-morbidities were assessed at enrolment., Results: Among 620 children and adolescents, 511 were HIV+. The median age was 12.0 years and 50% were female. In HIV+ children and adolescents, 425 (83.2%) had a CD4 count > 500 cells/mm 3 and 391 (76.7%) had an undetectable viral load. The median duration of ART was 7.6 years (IQR 4.6-9.3) with 7 adolescents receiving Tenofovir. The prevalence of any proteinuria, microalbuminuria and hypertension was 6.6%, 8.5% and 13.9%, respectively, with no difference between HIV+ and negative children and adolescents. All participants had a normal glomerular filtration rate. There was no association between metabolic co-morbidities and microalbuminuria., Conclusions: Proteinuria and microalbuminuria appear to be uncommon in this population. Follow up of those with microalbuminuria may inform long-term outcomes and management of this growing population of HIV+ youth.

Background: Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC., Methods and Findings: Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15-49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24-1.83) for DMPA use, 1.24 (95% CI 0.84-1.82) for NET-EN use, and 1.03 (95% CI 0.88-1.20) for COC use. Between-study heterogeneity was mild (I(2) < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23-1.67) and NET-EN use (aHR 1.32, 95% CI 1.08-1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99-1.50; for NET-EN use 0.67, 95% CI 0.47-0.96; and for COC use 0.91, 95% CI 0.73-1.41) compared to those at higher risk of bias (p(interaction) = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC-HIV relationship., Conclusions: This IPD meta-analysis found no evidence that COC or NET-EN use increases women's risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.

Background: Although there is widespread interest in understanding how models of care for delivering antiretroviral therapy (ART) may influence patient outcomes, family-focused approaches have received little attention. In particular, there have been few investigations of whether the co-enrollment of HIV-infected family members may improve adult ART outcomes over time., Methods: We examined the association between co-enrollment of HIV-infected family members into care and outcomes of women initiating ART in 12 HIV care and treatment programs across sub-Saharan Africa. Using data from the mother-to-child transmission-(MTCT) Plus Initiative, women starting ART were categorized according to the co-enrollment of an HIV-infected partner and/or HIV-infected child within the same program. Mortality and loss to follow-up were assessed for up to 5 years after women's ART initiation., Results: Of the 2877 women initiating ART included in the analysis, 31% (n = 880) had at least 1 HIV-infected family member enrolled into care at the same program, including 24% (n = 689) who had an HIV-infected male partner, and 10% (n = 295) who had an HIV-infected child co-enrolled. There was no significant difference in the risk of death of women by family co-enrollment status (P = 0.286). However, the risk of loss to follow-up was greatest among women who did not have an HIV-infected family member co-enrolled (19% after 36 months on ART) compared with women who had an HIV-infected family member co-enrolled (3%-8% after 36 months on ART) (P < 0.001). These associations persisted after adjustment for demographic and clinical covariates and were consistent across countries and care programs., Discussion: These data provide novel evidence for the association between adult outcomes on ART and co-enrollment of HIV-infected family members into care at the same program. Interventions that build on women's family contexts warrant further consideration in both research and policies to promote retention in ART services across sub-Saharan Africa.

Objective: In sub-Saharan Africa, HIV-exposed uninfected (HEU) infants have higher morbidity and mortality than HIV-unexposed infants. To evaluate whether immune dysfunction contributes to this vulnerability of HEU infants, we conducted a longitudinal, observational cohort study to assess T-cell immune responses to infant vaccines (Mycobacterium bovis BCG and acellular pertussis) and staphylococcal enterotoxin B (SEB). In total, 46 HEU and 46 HIV-unexposed infants were recruited from Khayelitsha, Cape Town., Methods: Vaccine-specific T-cell proliferation (Ki67 expression) and intracellular expression of four cytokines [interferon-γ, interleukin (IL)-2, IL-13 and IL-17] were measured after whole blood stimulation with antigens at 6 and 14 weeks of age., Results: HEU infants demonstrated elevated BCG-specific CD4 and CD8 T-cell proliferative responses at 14 weeks (P  = 0.041 and 0.002, respectively). These responses were significantly increased even after adjusting for birth weight, feeding mode and gestational age. Similar to BCG, increased CD4 and CD8 T-cell proliferation was evident in response to SEB stimulation (P  = 0.004 and 0.002, respectively), although pertussis-specific T cells proliferated comparably between the two groups. Within HEU infants, maternal CD4 cell count and length of antenatal antiretroviral exposure had no effect on T-cell proliferation to BCG or SEB. HIV exposure significantly diminished measurable cytokine polyfunctionality in response to BCG, Bordetella pertussis and SEB stimulation., Conclusion: These data show for the first time, when adjusting for confounders, that exposure to HIV in utero is associated with significant alterations to CD4 and CD8T-cell immune responses in infants to vaccines and nonspecific antigens.

Background: Identifying modifiable factors that increase women's vulnerability to HIV is a critical step in developing effective female-initiated prevention interventions. The primary objective of this study was to pool individual participant data from prospective longitudinal studies to investigate the association between intravaginal practices and acquisition of HIV infection among women in sub-Saharan Africa. Secondary objectives were to investigate associations between intravaginal practices and disrupted vaginal flora; and between disrupted vaginal flora and HIV acquisition., Methods and Findings: We conducted a meta-analysis of individual participant data from 13 prospective cohort studies involving 14,874 women, of whom 791 acquired HIV infection during 21,218 woman years of follow-up. Data were pooled using random-effects meta-analysis. The level of between-study heterogeneity was low in all analyses (I(2) values 0.0%-16.1%). Intravaginal use of cloth or paper (pooled adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.18-1.83), insertion of products to dry or tighten the vagina (aHR 1.31, 95% CI 1.00-1.71), and intravaginal cleaning with soap (aHR 1.24, 95% CI 1.01-1.53) remained associated with HIV acquisition after controlling for age, marital status, and number of sex partners in the past 3 months. Intravaginal cleaning with soap was also associated with the development of intermediate vaginal flora and bacterial vaginosis in women with normal vaginal flora at baseline (pooled adjusted odds ratio [OR] 1.24, 95% CI 1.04-1.47). Use of cloth or paper was not associated with the development of disrupted vaginal flora. Intermediate vaginal flora and bacterial vaginosis were each associated with HIV acquisition in multivariable models when measured at baseline (aHR 1.54 and 1.69, p<0.001) or at the visit before the estimated date of HIV infection (aHR 1.41 and 1.53, p<0.001), respectively., Conclusions: This study provides evidence to suggest that some intravaginal practices increase the risk of HIV acquisition but a direct causal pathway linking intravaginal cleaning with soap, disruption of vaginal flora, and HIV acquisition has not yet been demonstrated. More consistency in the definition and measurement of specific intravaginal practices is warranted so that the effects of specific intravaginal practices and products can be further elucidated. Please see later in the article for the Editors' Summary.

Background: Prognostic models have been developed for patients infected with HIV-1 who start combination antiretroviral therapy (ART) in high-income countries, but not for patients in sub-Saharan Africa. We developed two prognostic models to estimate the probability of death in patients starting ART in sub-Saharan Africa., Methods: We analysed data for adult patients who started ART in four scale-up programmes in Côte d'Ivoire, South Africa, and Malawi from 2004 to 2007. Patients lost to follow-up in the first year were excluded. We used Weibull survival models to construct two prognostic models: one with CD4 cell count, clinical stage, bodyweight, age, and sex (CD4 count model); and one that replaced CD4 cell count with total lymphocyte count and severity of anaemia (total lymphocyte and haemoglobin model), because CD4 cell count is not routinely measured in many African ART programmes. Death from all causes in the first year of ART was the primary outcome., Findings: 912 (8.2%) of 11 153 patients died in the first year of ART. 822 patients were lost to follow-up and not included in the main analysis; 10 331 patients were analysed. Mortality was strongly associated with high baseline CD4 cell count (>/=200 cells per muL vs <25; adjusted hazard ratio 0.21, 95% CI 0.17-0.27), WHO clinical stage (stages III-IV vs I-II; 3.45, 2.43-4.90), bodyweight (>/=60 kg vs <45 kg; 0.23, 0.18-0.30), and anaemia status (none vs severe: 0.27, 0.20-0.36). Other independent risk factors for mortality were low total lymphocyte count, advanced age, and male sex. Probability of death at 1 year ranged from 0.9% (95% CI 0.6-1.4) to 52.5% (43.8-61.7) with the CD4 model, and from 0.9% (0.5-1.4) to 59.6% (48.2-71.4) with the total lymphocyte and haemoglobin model. Both models accurately predict early mortality in patients starting ART in sub-Saharan Africa compared with observed data., Interpretation: Prognostic models should be used to counsel patients, plan health services, and predict outcomes for patients with HIV-1 infection in sub-Saharan Africa., Funding: US National Institute of Allergy And Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and National Cancer Institute., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective(s): Few data are available from resource-limited countries on long-term outcomes of HIV-infected women who initiate antiretroviral therapy (ART) during pregnancy., Design: Analysis of data from adult patients enrolled in the MTCT-Plus Initiative who initiated ART between 2003 and 2006 in seven countries in Sub-Saharan Africa and Thailand., Methods: Mean population changes were assessed and multivariable mixed linear regression modeling was used to examine covariate effects on differences in absolute CD4 cell count responses. Kaplan-Meier methods were used to examine program retention combining survival and losses to follow-up., Results: Of 2229 individuals initiating ART, 1688 were women, of which 605 were pregnant (median gestational age 7 months), 1083 were not pregnant, and 541 were men. The average CD4 response by 30 months on ART was 451 cells/microl among women who were pregnant at ART initiation as compared with 435 cells/microl among nonpregnant women (P = 0.53) and 349 cells/microl among men (P < 0.001). In multivariable analysis, lower CD4 cell increase was independently associated with male sex, older age, and lower CD4 cell count at initiation. After 30 months on ART retention was 0.85 with no retention differences between pregnant women, nonpregnant women, and men., Conclusion: HIV-infected women in resource-limited countries who start ART during pregnancy have similar or better long-term CD4 cell count responses as compared with other adults. These data support efforts to provide pregnant HIV-infected women with access to ART in resource-limited countries.

Background: With the rapid expansion of antiretroviral therapy (ART) services in sub-Saharan Africa there is growing recognition of the importance of fertility and childbearing among HIV-infected women. However there are few data on whether ART initiation influences pregnancy rates., Methods and Findings: We analyzed data from the Mother-to-Child Transmission-Plus (MTCT-Plus) Initiative, a multicountry HIV care and treatment program for women, children, and families. From 11 programs in seven African countries, women were enrolled into care regardless of HIV disease stage and followed at regular intervals; ART was initiated according to national guidelines on the basis of immunological and/or clinical criteria. Standardized forms were used to collect sociodemographic and clinical data, including incident pregnancies. Overall 589 incident pregnancies were observed among the 4,531 women included in this analysis (pregnancy incidence, 7.8/100 person-years [PY]). The rate of new pregnancies was significantly higher among women receiving ART (9.0/100 PY) compared to women not on ART (6.5/100 PY) (adjusted hazard ratio, 1.74; 95% confidence interval, 1.19-2.54). Other factors independently associated with increased risk of incident pregnancy included younger age, lower educational attainment, being married or cohabiting, having a male partner enrolled into the program, failure to use nonbarrier contraception, and higher CD4 cell counts., Conclusions: ART use is associated with significantly higher pregnancy rates among HIV-infected women in sub-Saharan Africa. While the possible behavioral or biomedical mechanisms that may underlie this association require further investigation, these data highlight the importance of pregnancy planning and management as a critical but neglected component of HIV care and treatment services. Please see later in the article for the Editors' Summary.

Objectives: To describe temporal trends in baseline clinical characteristics, initial treatment regimens and monitoring of patients starting antiretroviral therapy (ART) in resource-limited settings., Methods: We analysed data from 17 ART programmes in 12 countries in sub-Saharan Africa, South America and Asia. Patients aged 16 years or older with documented date of start of highly active ART (HAART) were included. Data were analysed by calculating medians, interquartile ranges (IQR) and percentages by regions and time periods. Not all centres provided data for 2006 and 2005 and 2006 were therefore combined., Results: A total of 36,715 patients who started ART 1996-2006 were included in the analysis. Patient numbers increased substantially in sub-Saharan Africa and Asia, and the number of initial regimens declined, to four and five, respectively, in 2005-2006. In South America 20 regimes were used in 2005-2006. A combination of 3TC/D4T/NVP was used for 56% of African patients and 42% of Asian patients; AZT/3TC/EFV was used in 33% of patients in South America. The median baseline CD4 count increased in recent years, to 122 cells/microl (IQR 53-194) in 2005-2006 in Africa, 134 cells/microl (IQR 72-191) in Asia, and 197 cells/microl (IQR 61-277) in South America, but 77%, 78% and 51%, respectively, started with <200 cells/microl in 2005-2006. In all regions baseline CD4 cell counts were higher in women than men: differences were 22cells/microl in Africa, 65 cells/microl in Asia and 10 cells/microl in South America. In 2005-2006 a viral load at 6 months was available in 21% of patients Africa, 8% of Asian patients and 73% of patients in South America. Corresponding figures for 6-month CD4 cell counts were 74%, 77% and 81%., Conclusions: The public health approach to providing ART proposed by the World Health Organization has been implemented in sub-Saharan Africa and Asia. Although CD4 cell counts at the start of ART have increased in recent years, most patients continue to start with counts well below the recommended threshold. Particular attention should be paid to more timely initiation of ART in HIV-infected men.

While the ability to lead a healthy sexual life and to choose whether and when to have children are well-established features of reproductive health and human rights, issues surrounding sexual activity and childbearing among HIV-infected women and men have received little attention in sub-Saharan Africa. We conducted a semi-structured, cross-sectional survey at 26 primary health care clinics in South Africa to investigate community attitudes towards sexual activity and reproduction by HIV-infected individuals. Of the 843 women interviewed, slightly less than half (43%, n = 361) thought that people living with HIV/AIDS should remain sexually active if they choose, while 13% (n = 113) said they thought that people living with HIV/AIDS should have children if they wished to do so. In multivariate analysis, negative attitudes towards both sexuality and childbearing were persistently associated with not knowing someone infected with HIV (p = 0.001 and 0.043, respectively). These findings suggest that the sexual and reproductive health rights of HIV-infected women and men may be an important target as part of efforts to reduce HIV/AIDS-related stigma. Health policies and services are required to reinforce the reproductive rights of HIV-infected individuals in South Africa and other countries in sub-Saharan Africa where HIV is most prevalent.

Objectives: To determine burden and risk factors for tuberculosis (TB) in an antiretroviral treatment (ART) programme and its impact on ART outcomes., Design: Prospective cohort study., Methods: Prevalent TB was assessed at baseline and incident TB was ascertained prospectively over 3 years among 944 patients accessing a community-based ART programme in South Africa., Results: At enrollment, median CD4 cell count was 96 cells/microl and 52% of patients had a previous history of TB. Prevalent TB (current antituberculosis treatment or active TB) was present in 25% and was strongly associated with advanced immunodeficiency. During 782 person-years of ART, 81 cases of TB were diagnosed. The incidence was 22.1/100 person-years during the first 3 months of ART and decreased to an average of 4.5/100 person-years during the second and third years. In multivariate analysis, risk of incident TB during follow-up was only associated with the current absolute CD4 cell count at that time point; an increase of 100 cells/mul was associated with a 25% lower risk (P = 0.007). Although prevalent and incident TB were associated with greater than two-fold increased mortality risk, they did not compromise immunological and virological outcomes among survivors at 48 weeks., Conclusions: Late initiation of ART was associated with a major burden of TB in this ART programme. TB reduced survival but did not impair immunovirological outcomes. Reductions in TB incidence during ART were dependent on CD4 cell count; however, after 3 years of treatment, rates were still 5- to 10-fold higher than among non-HIV-infected people. Earlier initiation of ART may reduce this burden of TB.

Background: Patients accessing antiretroviral treatment (ART) programmes in sub-Saharan Africa frequently have very advanced immunodeficiency. Previous data suggest that such patients may have diminished capacity for CD4 cell count recovery., Methods: Rates of CD4 cell increase were determined over 48 weeks among ART-naïve individuals (n = 596) commencing ART in a South African community-based ART programme., Results: The CD4 cell count increased from a median of 97 cells/microl at baseline to 261 cells/microl at 48 weeks and the proportion of patients with a CD4 cell count < 100 cells/microl decreased from 51% at baseline to just 4% at 48 weeks. A rapid first phase of recovery (0-16 weeks, median rate = 25.5 cells/microl/month) was followed by a slower second phase (16-48 weeks, median rate = 7.7 cells/microl/month). Compared to patients with higher baseline counts, multivariate analysis showed that those with baseline CD4 counts < 50 cells/microl had similar rates of phase 1 CD4 cell recovery (P = 0.42), greater rates of phase 2 recovery (P = 0.007) and a lower risk of immunological non-response (P = 0.016). Among those that achieved a CD4 cell count > 500 cells/microl at 48 weeks, 19% had baseline CD4 cell counts < 50 cells/microl. However, the proportion of these patients that attained a CD4 count 200 cells/microl at 48 weeks was lower than those with higher baseline CD4 cell counts., Conclusion: Patients in this cohort with baseline CD4 cell counts < 50 cells/microl have equivalent or greater capacity for immunological recovery during 48 weeks of ART compared to those with higher baseline CD4 cell counts. However, their CD4 counts remain < 200 cells/microl for a longer period, potentially increasing their risk of morbidity and mortality in the first year of ART.

Background: A number of countries in sub-Saharan Africa are preparing for HIV vaccine efficacy trials. Social and behavioural factors related to HIV transmission require examination in each setting where these trials are considered. As part of this, several countries have also recently begun preparatory research investigating relevant social and behavioural issues. There is a need for a review of the literature to help focus such research efforts in Sub-Saharan Africa., Objectives: To examine key social and behavioural issues that may impact on the conduct of HIV vaccine efficacy trials in sub-Saharan Africa., Design: Literature review, Methods: Major databases (PubMed, PsychInfo, EBSCOhost, and AIDSline) were searched for literature that discussed social and behavioural issues related to HIV vaccine trials. Three areas are highlighted as being particularly significant for HIV vaccine research: (1) willingness to participate in future HIV vaccine efficacy trials, (2) retention of participants in studies, and (3) sexual risk reporting during trials. For each of these topics, major findings from both developed and developing countries are described and avenues for further research are discussed., Results: There are few data from Sub-Saharan Africa regarding willingness to participate in HIV vaccine trials. Data on participant retention rates varies widely, and maintaining large cohorts of individuals within Phase III trials presents an important challenge. In addition, the possible impact of trial participation on sexual disinhibition, and response bias on sexual risk-reporting remain as issues for HIV vaccine trials in African contexts., Conclusion: Social and behavioural research forms an important part of preparations for HIV vaccine efficacy trials, and there is a clear need for more research of this type in Sub-Saharan Africa. Innovative approaches are required to address issues such as willingness to participate in vaccine research, participant retention during efficacy trials, and the accurate reporting by participants of sexual risk behaviours.

Despite important advances in expanding access to antiretroviral therapy in the countries most heavily affected by HIV/AIDS, there has been little consideration of the connections between HIV prevention, care and treatment programmes and reproductive health services. In this paper, we explore the integration of reproductive health services into HIV care and treatment programmes. We review the design and progress of the MTCT-Plus Initiative, which provides HIV care and treatment services to HIV positive women as well as their HIV positive children and partners. By emphasising the long-term follow-up of families and the provision of comprehensive care across the spectrum of HIV disease, MTCT-Plus highlights the potential synergies in linking reproductive health services to HIV care and treatment programmes. While HIV care and treatment programmes in resource-limited settings may not be able to integrate all reproductive health services into a single service delivery model, there is a clear need to include basic reproductive health services, such as access to appropriate contraception and counselling and management of unplanned pregnancies. The integration of these services would be facilitated by greater insight into the reproductive choices of HIV positive women and men, and into how health care providers influence access to reproductive health services of people with HIV and AIDS.