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Objective To determine the population-based incidence of disseminated bacille Calmette-Guerin (BCG) disease in HIV-infected infants (aged [less than or equal to] 1 year) in a setting with a high burden of tuberculosis and HIV infection coupled with a well-functioning programme for the prevention of HIV infection in infants. Methods The numerator, or number of new cases of disseminated BCG disease, was derived from multicentre surveillance data collected prospectively on infants with a confirmed HIV infection during 2004-2006. The denominator, or total number of HIV-infected infants who were BCG-vaccinated, was derived from population-based estimates of the number of live infants and from reported maternal HIV infection prevalence, vertical HIV transmission rates and BCG vaccination rates. Findings The estimated incidences of disseminated BCG disease per 1 00 000 BCG-vaccinated, HIV-infected infants were as follows: 778 (95% confidence interval, CI: 361-1319) in 2004 (vertical HIV transmission rate: 10.4%); 1300 (95% CI: 587-2290) in 2005 (transmission rate; 6.1%); and 1013 (95% CI: 377-1895) in 2006 (transmission rate: 5.4%). The pooled incidence over the study period was 992 (95% CI: 567-1495) per 1 00 000. Conclusion Multicentre surveillance data showed that the risk of disseminated BCG disease in HIV-infected infants is considerably higher than previously estimated, although likely to be under-estimated. There is an urgent need for data on the risk-benefit ratio of BCG vaccination in HIV-infected infants to inform decision-making in settings where HIV infection and tuberculosis burdens are high. Safe and effective tuberculosis prevention strategies are needed for HIV-infected infants. Objectif Determiner l'incidence en population de l'infection disseminee par le bacille de Calmette-Guerin (BCG) chez les nourrissons infectes par le VIH (age [menor que o igual a] 1 an) dans une situation caracterisee par une forte charge de tuberculose et d'infections a VIH, mais aussi par un bon fonctionnement du programme de prevention de l'infection par le VIH chez les nourrissons. Methodes Le numerateur, ou nombre de nouveaux cas d'infection disseminee par le BCG, a ete determine a partir des donnees de surveillance multicentrique, collectees prospectivement au sujet des nourrissons presentant une infection a VIH confirmee au cours de la periode 2004-2006. Le denominateur, ou nombre total de nourrissons infectes par le VIH et vaccines par le BCG, a ete obtenu a partir d'estimations en population du nombre de nourrissons vivants et a partir de la prevalence rapportee des infections a VIH maternelles, des taux de transmission verticale du VIH et des taux de vaccination par le BCG. Resultats L'incidence de l'infection disseminee par le BCG pour 100 000 nourrissons vaccines par le BCG a ete estimee a: 778 cas (intervalle de confiance a 95 %, IC : 361-1319) en 2004 (taux de transmission verticale du VIH : 10,4 %) ; 1300 cas (IC a 95 % : 587-2290) en 2005 (taux de transmission : 6,1%) ; et 1013 cas (IC a 95 % : 377-1895) en 2006 (taux de transmission : 5,4 %). L'incidence globale sur l'ensemble de la periode etudiee etait de 992 (IC a 95 % : 567-1495) pour 100 000. Conclusion Les donnees de surveillance multicentrique ont montre que le risque d'infection disseminee par le BCG chez les nourrissons infectes par le VIH etait considerablement plus eleve qu'on ne l'avait estime auparavant, bien que probablement encore sous-estime. On a besoin d'urgence de donnees sur le rapport risque/benefice de la vaccination par le BCG chez les nourrissons infectes par le VIH pour etayer la prise de decisions dans des contextes ou les charges d'infection a VIH et de tuberculose sont importantes. Des strategies sures et efficaces de prevention de la tuberculose sont necessaires pour les nourrissons infectes par le VIH. Objetivo Determinar la incidencia poblacional de la infeccion diseminada por el bacilo de Calmette-Guerin (BCG) en lactantes (ninos [menor que o igual a] 1 anos) en un entorno de alta carga de tuberculosis e infeccion por VIH y de aplicacion satisfactoria de un programa de prevencion de la infeccion por VIH en los lactantes. Metodos El numerador, o numero de nuevos casos de infeccion diseminada por BCG, se calculo a partir de datos de vigilancia multicentricos reunidos prospectivamente sobre lactantes con infeccion confirmada por VIH durante 2004-2006. El denominador, o numero total de lactantes infectados por el VIH y vacunados con la BCG, se calculo a partir de estimaciones poblacionales del numero de lactantes vivos y de la prevalencia de infeccion materna por VIH, de las rasas de transmision vertical del VIH y de las tasas de vacunacion con BCG. Resultados Las incidencias estimadas de infeccion diseminada por BCG por 100 000 lactantes infectados por el VIH y vacunados con BCG fueron las siguientes: 778 (intervalo de confianza del 95%, IC95%: 361-1319) en 2004 (transmision vertical del VIH: 10,4%); 1300 (IC95%: 587-2290) en 2005 (tasa de transmision: 6,1%); y 1013 (IC95%: 377-1895) en 2006 (tasa de transmision: 5,4%). La incidencia combinada a lo largo del periodo estudiado fue de 992 (IC95%: 567-1495) por 100 000. Conclusion Los datos de la vigilancia multicentrica revelaron que el riesgo de infeccion diseminada por BCG en los lactantes infectados por el VIH era considerablemente superior al estimado anteriormente. Urge disponer de datos sobre la relacion riesgobeneficio de la vacunacion con BCG en los lactantes infectados por el VIH a fin de fundamentar la adopcion de decisiones en los entornos con alta carga de infeccion por VIH y de tuberculosis. Es preciso formular estrategias seguras y eficaces de prevencion de la tuberculosis para los lactantes infectados por el VIH., Introduction Vaccination with bacille Calmette-Guerin (BCG), alive attenuated strain of Mycobacterium bovis, is almost universally given in sub-Saharan African countries where the brunt of the global burden of paediatric infection [...]

Abstract Background Very few data are available on treatment outcomes of adolescents living with HIV infection (whether perinatally acquired or sexually acquired) in sub-Saharan Africa. The present study therefore compared the treatment outcomes in adolescents with those of young adults at a public sector community-based ART programme in Cape Town, South Africa. Methods Treatment outcomes of adolescents (9-19 years) were compared with those of young adults (20-28 years), enrolled in a prospective cohort between September 2002 and June 2009. Kaplan-Meier estimates and Cox proportional hazard models were used to assess outcomes and determine associations with age, while adjusting for potential confounders. The treatment outcomes were mortality, loss to follow-up (LTFU), immunological response, virological suppression and virological failure. Results 883 patients, including 65 adolescents (47 perinatally infected and 17 sexually infected) and 818 young adults, received ART. There was no difference in median baseline CD4 cell count between adolescents and young adults (133.5 vs 116 cells/μL; p = 0.31). Overall mortality rates in adolescents and young adults were 1.2 (0.3-4.8) and 3.1 (2.4-3.9) deaths per 100 person-years, respectively. Adolescents had lower rates of virological suppression (< 400 copies/mL) at 48 weeks (27.3% vs 63.1%; p < 0.001). Despite this, however, the median change in CD4 count from baseline at 48 weeks of ART was significantly greater for adolescents than young adults (373 vs 187 cells/μL; p = 0.0001). Treatment failure rates were 8.2 (4.6-14.4) and 5.0 (4.1-6.1) per 100 person-years in the two groups. In multivariate analyses, there was no significant difference in LTFU and mortality between age groups but increased risk in virological failure [AHR 2.06 (95% CI 1.11-3.81; p = 0.002)] in adolescents. Conclusions Despite lower virological suppression rates and higher rates of virological failure, immunological responses were nevertheless greater in adolescents than young adults whereas rates of mortality and LTFU were similar. Further studies to determine the reasons for poorer virological outcomes are needed.

Abstract Background As HIV-infected infants have high mortality, the World Health Organization now recommends initiating antiretroviral therapy as early as possible in the first year of life. However, in many settings, laboratory diagnosis of HIV in infants is not readily available. We aimed to develop a clinical algorithm for HIV presumptive diagnosis in infants < 10 weeks old using screening data from the Children with HIV Early Antiretroviral therapy (CHER) study in South Africa. HIV-infected and HIV-uninfected exposed infants < 10 weeks of age were identified through Vertical Transmission Prevention programs. Clinical and laboratory data were systematically recorded, groups were compared using Kruskal-Wallis, analysis of variance (ANOVA), and Fisher's exact tests. Receiver Operating Characteristic (ROC) curves were compiled using combinations of clinical findings. Results 417 HIV-infected and 125 HIV-exposed, uninfected infants, median age 46 days (IQR 38-55), were included. The median CD4 percentage in HIV-infected infants was 34 (IQR 28-41)%. HIV-infected infants had lower weight-for-age, more lymphadenopathy, oral thrush, and hepatomegaly than exposed uninfected infants (Adjusted Odds Ratio 0.51, 8.8, 5.6 and 23.5 respectively; p < 0.001 for all). Sensitivity of individual signs was low (< 20%) but specificity high (98-100%). If any one of oral thrush, hepatomegaly, splenomegaly, lymphadenopathy, diaper dermatitis, weight < 50th centile are present, sensitivity for HIV infection amongst HIV-exposed infants was 86%. These algorithms performed similarly when used to predict severe immune suppression. Conclusions A combination of physical findings is helpful in identifying infants most likely to be HIV-infected. This may inform management algorithms and provide guidance for focused laboratory testing in some settings, and should be further validated in these settings and elsewhere.

Abstract Background Mortality among HIV-infected children in developing countries remains high after serious bacterial infections despite the use of antibiotics. Intravenous immunoglobulin (IVIG) has been used as an adjuvant therapy to treat these infections, but little data exists regarding its efficacy, and previous studies have focused on IVIG as a prophylactic agent. We examined the impact of IVIG as an adjuvant therapy in reducing mortality and length of hospital stay in HIV-infected children with serious bacterial infections. Methods This retrospective study focused on pediatric admissions at a large urban hospital between 2002 and 2006. Children between the ages of one month and nine years of age with laboratory confirmed HIV-status, serious bacterial infection, no prior exposure to IVIG, and a hospital length of stay of 5 days or more, were eligible for inclusion. Results A total of 140 children (median age 1.2 years) met inclusion criteria; lower respiratory tract infection was diagnosed in 94 (67%) of the children, while 74 (53%) had bacterial sepsis. Fifty-four (39%) children were receiving antiretroviral therapy and 39 (28%) were receiving tuberculosis treatment. Overall 73 (52%) were treated with IVIG, with the majority (74%) of children receiving a single dose. Thirteen (9%) died during their hospital admission. In crude analysis IVIG was significantly associated with increased mortality was (Odds Ratio (OR): 5.8; 95% Confidence Interval (CI): 1.2–27.1) and this association was weakened by adjustment for other predictors of mortality (OR 4.3, 95% CI 0.7–27.9, p = 0.123). IVIG use was also associated with longer hospital stays. Conclusion Administration of one to three doses of IVIG during the acute phase of illness does not appear to reduce mortality or the length of hospital stays in HIV-infected children with serious bacterial infections. However, the retrospective nature of this study makes confounding by indication difficult to control and further studies regarding the timing, dosing, and method of administration are required. Nonetheless the routine use of IVIG in resource-limited settings should be carefully considered given its high cost.

We previously showed a link between maternal vascular malperfusion and pre-term birth (PTB) in pregnant people living with HIV (PPLH) initiating antiretroviral treatment (ART) before pregnancy, indicating poor placental vascularisation. After measuring antenatal plasma angiogenic factors to seek mechanistic insights, low levels of plasma Factor XIIIA1 (FXIIIA1) and vascular-endothelial-growth-factor (VEGF) was significantly associated with PTB at the time closest to delivery (median 34 weeks) in PPLH initiating ART before pregnancy. Knowing that FXIIIA1 is crucial for haemostasis, angiogenesis, implantation and pregnancy maintenance and that expression is found on placental macrophages (Hofbauer cells), we examined placentae at delivery from matching participants who either initiating ART before pregnancy or during gestation. Highest FXIIIA1 expression was on Hofbauer cells but was significantly lower in PTB regardless of HIV infection, but was significantly lower in PPLH in PTB from women who initiated ART before pregnancy. To test the hypothesis that antiretroviral drugs may disrupt vascularisation in the placenta, we used a human umbilical vein endothelial cell (HUVEC) matrigel angiogenesis assay. We identified that addition of pre-treated FXIIIA1-expressing MCSF-and IL-10-induced placenta-like macrophages with physiological concentrations of tenofovir, 3TC, and efavirenz resulted in significantly inhibited angiogenesis; akin to the inhibition observed with titratable concentrations of ZED1301, an inhibitor of FXIIIA1. Overall, an efavirenz-containing ART combination inhibits vasculogenesis without causing toxicity and likely does so through inhibition of a FXIIIA1-mediated-placental macrophage pathway.

Some studies have reported increased infectious morbidity and all-cause mortality risk among infants HIV-exposed uninfected compared with infants HIV-unexposed uninfected. In a retrospective analysis of infants enrolled in the Botswana-based Tshilo Dikotla study, we found no difference in the prevalence of infectious hospitalizations or deaths from any cause in the first year of life by perinatal HIV exposure., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Infants who are HIV exposed but uninfected (iHEU) have higher risk of viral infections compared to infants who are HIV unexposed (iHUU). We explored the effect of intrauterine HIV exposure on the infant antibody repertoire by quantifying plasma immunoglobulin (Ig) G against 206 eukaryote-infecting viruses using phage immunoprecipitation sequencing (PhiPSeq) in iHEU and iHUU at birth and 36 weeks of life. Maternal HIV infection altered the infant IgG repertoire against eukaryote-infecting viruses at birth, resulting in significantly lower antibody breadth and diversity among iHEU compared to iHUU. Neonatal anti-viral IgG repertoire was dominated by antibodies against viruses belonging to the Herpesviridae family, although, by 36 weeks, this had shifted toward antibodies against enteroviruses, likely due to waning of maternal-derived antibodies and polio vaccine-induced antibody responses as expected. The observed reduced anti-viral IgG repertoire breadth and diversity acquired at birth in iHEU might contribute to the increased rates of viral infections among iHEU during early life., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Pregnant women in sub-Saharan Africa have high rates of maternal morbidity. There is interest in the impact of the vaginal microbiome on maternal health, including HIV and sexually transmitted infection (STI) acquisition. We characterized the vaginal microbiota of South African women ≥ 18 years with and without HIV in a longitudinal cohort over two visits during pregnancy and one visit postpartum. At each visit, we obtained HIV testing and self-collected vaginal swabs for point-of-care testing for STIs and microbiota sequencing. We categorized microbial communities and evaluated changes over pregnancy and associations with HIV status and STI diagnosis. Across 242 women (mean age 29, 44% living with HIV, 33% diagnosed with STIs), we identified four main community state types (CSTs): two lactobacillus-dominant CSTs (dominated by Lactobacillus crispatus and Lactobacillus iners respectively) and two diverse, non-lactobacillus-dominant CSTs (one dominated by Gardnerella vaginalis and one by diverse facultative anaerobes). From the first antenatal visit to the third trimester (24-36 weeks gestation), 60% of women in the Gardnerella-dominant CST shifted to lactobacillus-dominant CSTs. From the third trimester to postpartum (mean 17 days post-delivery), 80% of women in lactobacillus-dominant CSTs shifted to non-lactobacillus-dominant CSTs with a large proportion in the facultative anaerobe-dominant CST. Microbial composition differed by STI diagnosis (PERMANOVA R 2 = 0.002, p = 0.004), and women diagnosed with an STI were more likely to be categorized as L. iners-dominant or Gardnerella-dominant CSTs. Overall, we found a shift toward lactobacillus dominance during pregnancy and the emergence of a distinct, highly diverse anaerobe-dominant microbiota profile in the postpartum period., (© 2023. The Author(s).)

Purpose of Review: The long-acting reversible intramuscularly-injected contraceptive depot medroxyprogesterone acetate (DMPA-IM) is widely used by cisgender women in Africa. Although DMPA-IM provides reliable contraception, potential effects on the female genital tract (FGT) mucosa have raised concern, including risk of HIV infection. This review summarises and compares evidence from observational cohort studies and the randomised Evidence for Contraceptive Options in HIV Outcomes (ECHO) Trial., Recent Findings: Although previous observational studies found women using DMPA-IM had higher abundance of bacterial vaginosis (BV)-associated bacteria, increased inflammation, increased cervicovaginal HIV target cell density, and epithelial barrier damage, sub-studies of the ECHO Trial found no adverse changes in vaginal microbiome, inflammation, proteome, transcriptome, and risk of viral and bacterial STIs, other than an increase in Th17-like cells. Randomised data suggest that DMPA-IM use does not adversely change mucosal endpoints associated with acquisition of infections. These findings support the safe use of DMPA-IM in women at high risk of acquiring STIs, including HIV., (© 2023. The Author(s).)

Background: Persons with HIV (PWH) on antiretroviral therapy (ART) have persistent immune activation associated with increased risk for non-AIDS related diseases. Latent tuberculosis infection (LTBI), endemic in Africa, may contribute to this immune dysregulation. We evaluated the impact of HIV and TB co-infection on plasma pro- and anti-inflammatory cytokines among Kenyan adults., Methods: We compared data from 221 PWH on long-term ART and 177 HIV-negative adults examining biomarkers of pro-[sCD14, interleukin (IL)-2, IL-6, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-12p70, IL-17A] and anti(IL-4, IL-5, IL-13) inflammatory cytokines, by HIV/LTBI status (HIV+LTBI+, HIV+LTBI-, HIV-LTBI+, HIV-LTBI-). LTBI was diagnosed based on a positive QuantiFERON TB Gold-Plus test in the absence of active TB symptoms. Linear regression was used to evaluate the associations of HIV, LTBI, and HIV/LTBI status with biomarkers adjusting for clinical factors including HIV-specific factors., Results: Half of the participants were women and 52% had LTBI. HIV was independently associated with higher sCD14, IL-15, IL-6, IL-4, IL-5. LTBI was independently associated with higher TNF-α, IL-12p70, IL-17A, IL-4, IL-13 in adjusted models ( P  < 0.05). LTBI status was associated with higher IL-4 and IL-12p70 only among PWH, but not HIV-negative participants ( P  < 0.05 for interactions). In multivariate analysis, only HIV+LTBI+ demonstrated elevated levels of TNF-α, IL-6, IL-12p70, IL-15, IL-17A, IL4, IL-5, IL-13 in comparison to the HIV-LTBI- ( P  < 0.05 for all). The effect of LTBI on cytokines among PWH was independent of CD4 + T-cell count and ART duration., Conclusions: Despite viral suppression, persons with HIV and LTBI exhibit abnormal cytokine production accompanied by high concentrations of pro- and anti-inflammatory cytokines., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

The Evidence for Contraceptive Options and HIV Outcomes (ECHO) trial found no substantial difference in HIV acquisition risk between women randomised to injectable intramuscular depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (Cu-IUD) or the levonorgestrel (LNG) implant. We evaluated post-randomization sexual behavior using an objective marker of condomless vaginal sex in a subset of participants. We conducted a sub-study among 458 ECHO participants at three sites (Cape Town, Johannesburg, Kisumu) to evaluate the frequency of condomless vaginal sex, measured by prostate specific antigen (PSA) detection in vaginal swabs, collected at the month 6 and final visit and the concordance of self-reported condomless vaginal sex with PSA detection, by randomized arm. We compared PSA detection frequency and concordance of PSA and self-reported condomless vaginal sex, by randomized group using Cochran-Mantel-Haenszel tests and adjusted generalized logistic growth curve models. PSA was detected less frequently in the DMPA-IM (16%), compared to the Cu-IUD (21%) and LNG implant (24%) groups, although results were not statistically significant in the unadjusted model when accounting for pre-specified multiple-testing criteria. There were significant differences in PSA detection between the DMPA-IM and LNG-implant groups (odds ratio 0.61 (95% CI 0.40, 0.94) in the adjusted model. There was moderate discordance between self-reported condomless vaginal sex and detection of PSA that was similar across randomized groups. These data suggest that women randomized to Cu-IUD and LNG implant may have had condomless sex more frequently than women randomized to DMPA-IM. The discordance between detectable PSA and self-reported sexual behaviour has important implications for design of future HIV prevention studies., (© 2022. The Author(s).)

Background: Cervicovaginal CD4+ T cells are preferential targets for human immunodeficiency virus (HIV) infection and have consequently been used as a proxy measure for HIV susceptibility. The ECHO randomized trial offered a unique opportunity to consider the association between contraceptives and Th17-like cells within a trial designed to evaluate HIV risk. In a mucosal substudy of the ECHO trial, we compared the impact of initiating intramuscular depot medroxyprogesterone acetate (DMPA-IM), copper-IUD, and the levonorgestrel (LNG) implant on cervical T cells., Methods: Cervical cytobrushes from 58 women enrolled in the ECHO trial were collected at baseline and 1 month after contraceptive initiation. We phenotyped cervical T cells using multiparameter flow cytometry, characterized the vaginal microbiome using 16s sequencing, and determined proteomic signatures associated with Th17-like cells using mass spectrometry., Results: Unlike the LNG implant or copper-IUD, DMPA-IM was associated with higher frequencies of cervical Th17-like cells within 1 month of initiation (P = .012), including a highly susceptible, activated population co-expressing CD38, CCR5, and α4β7 (P = .003). After 1 month, women using DMPA-IM also had more Th17-like cells than women using the Cu-IUD (P = .0002) or LNG implant (P = .04). Importantly, in women using DMPA-IM, proteomic signatures signifying enhanced mucosal barrier function were associated with the increased abundance of Th17-like cells. We also found that a non-Lactobacillus-dominant microbiome at baseline was associated with more Th17-like cells post-DMPA-IM (P = .03), although this did not influence barrier function., Conclusions: Our data suggest that DMPA-IM-driven accumulation of HIV-susceptible Th17-like cells might be counteracted by their role in maintaining mucosal barrier integrity., Clinical Trials Registration: NCT02550067., Competing Interests: Potential conflicts of interest. J.-A. S. P. reports the following grants or contracts all paid to the author’s institution and unrelated to this work: Bill and Melinda Gates Foundation (BMGF) Vaginal Microbiome Research Consortium (VMRC) Planning Grant (Principal Investigator [PI]: Dr Jo-Ann Passmore. Co-PI: Dr Leila Mansoor; Co-Investigators: Nigel Garrett, Cheryl Baxter, Sinaye Ngcapu, Lenine Liebenberg, Aida Sivro, Brian Kullin, Anna Happel. US $512 088 for 12 months); European and Developing Countries Clinical Trials Partnership (EDCTP) RIA2020I (3297) for project entitled “GIFT for HIV Prevention” (Passmore, Co-PI: Masson (Burnett Institute, Australia); Co-Investigators: Suzanna Francis and Katharina Kranzer (The London School of Hygiene & Tropical Medicine, UK), Janneke van der Wijgert (University Medical Center, Netherlands), Tania Crucitti (Institute Pasteur Madegascar, Madagascar), David Anderson (Burnet Institute, Australia), Ayako Honda (Sophia University, Japan), Chido Dziva-Chikwari (The Organization for Public Health Interventions and Development, Zimbabwe), Katherine Gill (Desmond Tutu Health Foundation, South Africa) (Euro 3 508 462 for 36 months); BMGF Calestous Juma Scientific Leadership Award for project entitled “VMRC4Africa” (PI: Passmore. US $1 million over 5 years); and Medical Research Council Strategic Health Innovation Partnerships (South Africa), Genital inflammation test for females (GIFT) (PIs: Dr Jo-Ann Passmore and Dr Lindi Masson, ZAR 5 million per year for 4 years). J.-A. S. P. also reports a patent granted in 2022 with no payment made (Method for diagnosing an inflammatory condition in the female genital tract; PCT/IB2014/065740; EP3063542B1); and unpaid participation on a Data Safety Monitoring Board (DSMB) or Advisory Board for a phase 2 placebo-controlled randomized trial of LACTIN-V (Lactobacillus crispatus CTV-05) among women at high risk of HIV acquisition in Durban, South Africa (Chair DSMB; Cohen et al National Institute of Child Health and Human Development [NICHD] grant 1R01HD098978). R. H. reports grants or contracts unrelated to this work and paid to the author’s institution from the NICHD. H. J. reports support for attending meetings and/or travel from World Vaccine Congress. S. E. B. reports grants or contracts unrelated to this work from the National Institutes of Health (NIH R01 HD089831): Effects of Hormonal Contraceptives on Genital Immunity and HIV Susceptibility. B. P. B. reports support for attending meetings and/or travel (NIH R01HD089831). J. M. H. reports grants to institution unrelated to this work from the NIH, USAID, and BMGF; and employment (with stocks and stock options) with Gilead Sciences. 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 Infectious Diseases Society of America.)

There is limited data on the role of asymptomatic STIs (aSTIs) on the risk of human immunodeficiency virus (HIV) acquisition in the male genital tract (MGT). The impact of foreskin removal on lowering HIV acquisition is well described, but molecular events leading to HIV acquisition are unclear. Here, in this pilot study, we show that asymptomatic urethral infection with Chlamydia trachomatis (CT) significantly impacts the foreskin proteome composition. We developed and optimized a shotgun liquid chromatography coupled tandem mass spectrometry (MS)-based proteomics approach and utilized this on foreskins collected at medical male circumcision (MMC) from 16 aSTI + men and 10 age-matched STI- controls. We used a novel bioinformatic metaproteomic pipeline to detect differentially expressed (DE) proteins. Gene enrichment ontology analysis revealed proteins associated with inflammatory and immune activation function in both inner and outer foreskin from men with an aSTI. Neutrophil activation/degranulation and viral-evasion proteins were significantly enriched in foreskins from men with aSTI, whereas homotypic cell-cell adhesion proteins were enriched in foreskin tissue from men without an aSTI. Collectively, our data show that asymptomatic urethral sexually transmitted infections result in profound alterations in epithelial tissue that are associated with depletion of barrier integrity and immune activation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chigorimbo-Murefu, Potgieter, Dzanibe, Gabazana, Buri, Chawla, Nleya, Olivier, Harryparsad, Calder, Garnett, Maziya, Lewis, Jaspan, Wilson, Passmore, Mulder, Blackburn, Bekker and Gray.)

Introduction: South Africa's evolving burden of disease is challenging due to a persistent infectious disease, burgeoning obesity, most notably among women and rising rates of non-communicable diseases (NCDs). With two thirds of women presenting at their first antenatal visit either overweight or obese in urban South Africa (SA), the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and NCDs., Methods and Analysis: Bukhali is the first individual randomised controlled trial in Africa to test the efficacy of a complex continuum of care intervention and forms part of the Healthy Life Trajectories Initiative (HeLTI) consortium implementing harmonised trials in Canada, China, India and SA. Starting preconception and continuing through pregnancy, infancy and childhood, the intervention is designed to improve nutrition, physical and mental health and health behaviours of South African women to offset obesity-risk (adiposity) in their offspring. Women aged 18-28 years (n=6800) will be recruited from Soweto, an urban-poor area of Johannesburg. The primary outcome is dual-energy X-ray absorptiometry derived fat mass index (fat mass divided by height 2 ) in the offspring at age 5 years. Community health workers will deliver the intervention randomly to half the cohort by providing health literacy material, dispensing a multimicronutrient supplement, providing health services and feedback, and facilitating behaviour change support sessions to optimise: (1) nutrition, (2) physical and mental health and (3) lay the foundations for healthier pregnancies and early child development., Ethics and Dissemination: Ethical approval has been obtained from the Human Ethics Research Committee University of the Witwatersrand, Johannesburg, South Africa (M1811111), the University of Toronto, Canada (19-0066-E) and the WHO Ethics Committee (ERC.0003328). Data and biological sample sharing policies are consistent with the governance policy of the HeLTI Consortium (https://helti.org) and South African government legislation (POPIA). The recruitment and research team will obtain informed consent., Trial Registration: This trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871)., Protocol Version: 20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The interaction between gut bacterial and viral microbiota is thought to be important in human health. While fluctuations in female genital tract (FGT) bacterial microbiota similarly determine sexual health, little is known about the presence, persistence, and function of vaginal bacteriophages. We conducted shotgun metagenome sequencing of cervicovaginal samples from South African adolescents collected longitudinally, who received no antibiotics. We annotated viral reads and circular bacteriophages, identified CRISPR loci and putative prophages, and assessed their diversity, persistence, and associations with bacterial microbiota composition. Siphoviridae was the most prevalent bacteriophage family, followed by Myoviridae , Podoviridae , Herelleviridae , and Inoviridae . Full-length siphoviruses targeting bacterial vaginosis (BV)-associated bacteria were identified, suggesting their presence in vivo. CRISPR loci and prophage-like elements were common, and genomic analysis suggested higher diversity among Gardnerella than Lactobacillus prophages. We found that some prophages were highly persistent within participants, and identical prophages were present in cervicovaginal secretions of multiple participants, suggesting that prophages, and thus bacterial strains, are shared between adolescents. The number of CRISPR loci and prophages were associated with vaginal microbiota stability and absence of BV. Our analysis suggests that (pro)phages are common in the FGT and vaginal bacteria and (pro)phages may interact.

The role of Myeloid-Derived Suppressor Cells (MDSC) in infant immune ontogeny is unknown. Here, we evaluated MDSC frequency and relationship with infant vaccine responses throughout the first year of life in a prospective cohort study. Ninety-one South African infant-mother pairs were enrolled at delivery, and blood samples were collected at 0, 6, 10, and 14 weeks, 6 months, 9 months, and 1 year. MDSC frequencies were quantified, and immune responses to the childhood vaccines Bacillus Calmette-Guérin (BCG), hepatitis B (HepB), and combination diphtheria, tetanus, and pertussis (dTaP) were measured by Ag-specific CD4 + T cell proliferation and interferon gamma (IFN-γ) production. Vaccine-specific Ab responses to HepB, dTaP, and Haemophilus influenzae type b (Hib) were quantified via Enzyme-Linked Immunosorbent assay (ELISA). MDSC frequency in mother-infant pairs was strongly correlated; the frequency of MDSC decreased in both mothers and infants during the months after delivery/birth; and by 1 year, infant MDSC frequencies rebounded to birth levels. Higher MDSC frequency at vaccination was associated with a lack of subsequent IFN-γ release in response to vaccine Ags, with the exception of BCG. With the exception of a weak, positive correlation between MDSC frequency at 6 weeks (time of initial vaccination) and peak Hepatitis B surface antigen Ab titer, Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSC) was not correlated with T cell proliferation or Ab responses in this study. The potential for MDSC-mediated suppression of vaccine Ag-specific IFN-γ responses should be explored further, and considered when evaluating candidate infant vaccines., (©2021 Society for Leukocyte Biology.)

Although rates of human immunodeficiency virus (HIV) have declined globally over the past 10 years, United Nations Programme on HIV/AIDS estimates 1.7 million new infections occurred in 2019, with cisgender women (cis women) and girls accounting for 48%. Acquired immune deficiency syndrome-related illnesses are the leading global cause of mortality in cis women aged 15 to 49, and in many sub-Saharan Africa countries, young women face substantially higher HIV risk than their male counterparts. Drivers of this increased risk include sexual and reproductive health characteristics unique to cis women. This review discusses the role of sexually transmitted infections, contraception and pregnancy in HIV risk, and biomedical HIV prevention technologies available and in development., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Young women in Southern Africa have extremely high HIV incidence rates necessitating the availability of female-controlled prevention methods. Understanding adolescent preference for seeking contraception would improve our understanding of acceptability, feasibility and adherence to similar modes of delivery for HIV prevention., Methods: UChoose was an open-label randomized crossover study over 32 weeks which aimed to evaluate the acceptability and preference for contraceptive options in healthy, HIV-uninfected, female adolescents aged 15 to 19 years, as a proxy for similar HIV prevention methods. Participants were assigned to a contraceptive method for a period of 16 weeks in the form of a bi-monthly injectable contraceptive, monthly vaginal Nuvaring ® or daily combined oral contraceptive (COC) and then asked to state their preference. At 16 weeks, participants crossed over to another contraceptive method, to ensure that all participants tried the Nuvaring ® (least familiar modality) and additionally, either the injection or COC. Primary outcomes were contraceptive acceptability and preference. At the end of the 32 weeks they were also asked to imagine their preference for an HIV prevention modality. Secondary endpoints included changes in sexual behaviour, contraceptive adherence and preference for biomedical and behavioural HIV prevention methods., Results: Of the 180 participants screened, 130 were enrolled and randomized to the Nuvaring ® (n = 45), injection (n = 45) or COC (n = 40). Significantly more Nuvaring ® users (24/116; 20.7%) requested to change to another contraceptive option compared to injection (1/73; 1.4% p = 0.0002) and COC users (4/49; 8% p = 0.074). Of those that remained on the Nuvaring ® , adherence was significantly higher than to COC (p < 0.0001). Significantly more injection users (77/80; 96.3%) thought this delivery mode was convenient to use compared to Nuvaring ® (74/89; 83.1%; p = 0.0409) or COC (38/50; 76.0%; p = 0.0034). Overall, the preferred contraceptive choice was injection, followed by the ring and lastly the pill., Conclusions: Adherence to daily COC was difficult for adolescents in this cohort and the least favoured potential HIV prevention option. While some preferred vaginal ring use, these data suggest that long-acting injectables would be the preferred prevention method for adolescent girls and young women. This study highlights the need for additional options for HIV prevention in youth., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Besides bacteria, fungi, protists and archaea, the vaginal ecosystem also contains a range of prokaryote- and eukaryote-infecting viruses, which are collectively referred to as the "virome". Despite its well-described role in the gut and other environmental niches, the vaginal virome remains understudied. With a focus on sexual and reproductive health, we summarize the currently known components of the vaginal virome, its relationship with other constituents of the vaginal microbiota and its association with adverse health outcomes. While a range of eukaryote-infecting viruses has been described to be present in the female genital tract (FGT), few prokaryote-infecting viruses have been described. Literature suggests that various vaginal viruses interact with vaginal bacterial microbiota and host immunity and that any imbalance thereof may contribute to the risk of adverse reproductive health outcomes, including infertility and adverse birth outcomes. Current limitations of vaginal virome research include experimental and analytical constraints. Considering the vaginal virome may represent the missing link in our understanding of the relationship between FGT bacteria, mucosal immunity, and adverse sexual and reproductive health outcomes, future studies evaluating the vaginal microbiome and its population dynamics holistically will be important for understanding the role of the vaginal virome in balancing health and disease.

Female genital tract (FGT) inflammation increases HIV infection susceptibility. Non-optimal cervicovaginal microbiota, characterized by depletion of Lactobacillus species and increased bacterial diversity, is associated with increased FGT cytokine production. Lactobacillus species may protect against HIV partly by reducing FGT inflammation. We isolated 80 lactobacilli from South African women with non-optimal (Nugent 4-10; n = 18) and optimal microbiota (Nugent 0-3; n = 14). Cytokine production by vaginal epithelial cells in response to lactobacilli in the presence and absence of Gardnerella vaginalis was measured using Luminex. Adhesion to vaginal epithelial cells, pH, D/L-lactate production and lactate dehydrogenase relative abundance were assessed. Lactobacilli from women with non-optimal produced less lactic acid and induced greater inflammatory cytokine production than those from women with optimal microbiota, with IL-6, IL-8, IL-1α, IL-1β and MIP-1α/β production significantly elevated. Overall, lactobacilli suppressed IL-6 (adjusted p < 0.001) and IL-8 (adjusted p = 0.0170) responses to G. vaginalis. Cytokine responses to the lactobacilli were inversely associated with lactobacilli adhesion to epithelial cells and D-lactate dehydrogenase relative abundance. Thus, while cervicovaginal lactobacilli reduced the production of the majority of inflammatory cytokines in response to G. vaginalis, isolates from women with non-optimal microbiota were more inflammatory and produced less lactic acid than isolates from women with optimal microbiota.

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (T H 2) impaired IL-4Rα -/- offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived T H 2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes.

Bacterial vaginosis (BV) causes genital inflammation and increased HIV acquisition risk. The standard-of-care for BV, antibiotic therapy, is associated with high recurrence rates. Probiotics may improve treatment outcomes, although substantial heterogeneity in efficacy has been observed during clinical trials. To evaluate the potential to improve existing probiotics, we compared the inflammatory and antimicrobial (adhesion, H 2 O 2 , D-lactate and L-lactate production) characteristics of 23 vaginal Lactobacillus isolates from South African women, commercial vaginal probiotics (L. casei rhamnosus, L. acidophilus) and 4 reference strains. All lactobacilli induced inflammatory cytokine production by genital epithelial cells and produced D-lactate. Of six isolates assessed, five suppressed inflammatory responses to Gardnerella vaginalis. Although the L. acidophilus probiotic was the most adherent, many clinical isolates produced greater amounts of H 2 O 2 , D-lactate and L-lactate than the probiotics. The most L-lactate and H 2 O 2 were produced by L. jensenii (adjusted p = 0.0091) and L. mucosae (adjusted p = 0.0308) species, respectively. According to the characteristics evaluated, the top 10 isolates included 4 L. jensenii, 2 L. crispatus, 1 L. mucosae, 1 L. vaginalis and the L. acidophilus probiotic. There is potential to develop an improved vaginal probiotic using clinical Lactobacillus isolates. Inflammatory profiles are critical to evaluate as some isolates induced substantial cytokine production.

Objectives: Vaginal dysbiosis and STIs are important drivers of the HIV epidemic and reproductive complications. These conditions remain prevalent, partly because most cases are asymptomatic. We have shown that inflammatory cytokines interleukin (IL)-1α, IL-1β and interferon-γ-induced protein (IP)-10 are biomarkers for detecting asymptomatic STIs and vaginal dysbiosis (bacterial vaginosis (BV) or intermediate microbiota). This study aimed to validate the performance of these biomarkers in African women recruited regardless of symptoms., Methods: IL-1α, IL-1β and IP-10 were measured in menstrual cup secretions, endocervical, lateral vaginal wall and vulvovaginal swabs from 550 women from Pretoria, Soweto and Cape Town, South Africa and Bondo, Kenya using Luminex and ELISA. STIs were assessed by PCR, BV by Nugent scoring and vaginal microbiota by 16S rRNA sequencing., Results: Across four study populations and four types of genital specimens, the performance of IL-1α, IL-1β and IP-10 for identification of women with STIs, BV or intermediate microbiota was consistent. Of the genital samples assessed, biomarkers measured in lateral vaginal wall swabs performed best, correctly classifying 76%(95% CI 70% to 81%) of women according to STI, BV or intermediate microbiota status (sensitivity 77%, specificity 71%) and were more accurate than clinical symptoms (sensitivity 41%, specificity 57%) (p=0.0003). Women incorrectly classified as STI/BV positive using the biomarkers had more abundant dysbiosis-associated bacteria, including Prevotella bivia and Gardnerella sp, detected by 16S rRNA sequencing, but not Nugent scoring. Including vaginal pH with the cytokine biomarkers improved the accuracy of the test (82% (95% CI 75% to 88%) correctly classified), although pH alone had poor specificity (61%)., Conclusions: An inexpensive, point-of-care screening test including IL-1α, IL-1β and IP-10 (and potentially pH) could be used in resource-limited settings to identify women with asymptomatic STIs and dysbiosis. These women could then be referred for aetiological testing, followed by specific treatment., Competing Interests: Competing interests: JASP and LM, together with the University of Cape Town, have submitted a Patent application for IP-10 and IL-1α/β use for diagnosing an inflammatory condition in the female genital tract likely caused by an STI or BV., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The objectives of the study were to investigate prevalence of cervical human papillomavirus (HPV) genotypes to inform HPV vaccination strategy in South Africa and to study factors associated with HPV prevalence. Sexually active, HIV-negative women, aged 16-22 years recruited from Soweto (n = 143) and Cape Town (n = 148) were tested for cervical HPV and other genital infections. Overall HPV prevalence was 66.7% (194/291) in young women. Cape Town women were more likely to have multiple HPV infections than the Soweto women (48.0%, 71/148 versus 35.0%, 50/143 respectively, p = 0.033) and probable HR-HPV types (34.5%, 51/148 versus 21.7%, 31/143 respectively, p = 0.022). The most frequently detected HPV types were HPV-16 (11.7%), HPV-58 (10.3%), HPV-51 (8.9%), HPV-66 (8.6%), HPV-18 and HPV-81 (7.6% each). HPV types targeted by the bivalent HPV vaccine (HPV-16/18) were detected in 18.6% (54/291) of women, while those in the quadrivalent vaccine (HPV-6/11/16/18) were detected in 24.7% (72/291) of women; and those in the nonavalent vaccine (HPV-6/11/16/18/31/33/45/52/58) were detected in 38.5% (112/291) of women. In a multivariable analysis, bacterial vaginosis remained significantly associated with HPV infection (OR: 4.0, 95% CI: 1.4-12.6). Women were more likely to be HPV positive if they had received treatment for STI during the past 6-months (OR: 3.4, 95% CI: 1.1-12.4) or if they had ever been pregnant (OR: 2.3, 95% CI: 1.1-5.5). Compared to women who reported only one sexual partner, those with increased number of lifetime sex partners were more likely to have HPV (4-10 partners: OR: 2.9, 95% CI: 1.1-8.0). The high prevalence of HPV types targeted by the nonavalent HPV vaccine encourages the introduction of this vaccine and catch-up HPV vaccination campaigns in South Africa. The high burden of BV and concurrent STIs also highlights the need to improve the prevention and appropriate management of sexually-acquired and other genital tract infections in South African youth.

Over 4 million infants die each year from infections, many of which are vaccine-preventable. Young infants respond relatively poorly to many infections and vaccines, but the basis of reduced immunity in infants is ill defined. We sought to investigate whether myeloid-derived suppressor cells (MDSC) represent one potential impediment to protective immunity in early life, which may help inform strategies for effective vaccination prior to pathogen exposure. We enrolled healthy neonates and children in the first 2 years of life along with healthy adult controls to examine the frequency and function of MDSC, a cell population able to potently suppress T cell responses. We found that MDSC, which are rarely seen in healthy adults, are present in high numbers in neonates and their frequency rapidly decreases during the first months of life. We determined that these neonatal MDSC are of granulocytic origin (G-MDSC), and suppress both CD4+ and CD8+ T cell proliferative responses in a contact-dependent manner and gamma interferon production. Understanding the role G-MDSC play in infant immunity could improve vaccine responsiveness in newborns and reduce mortality due to early-life infections.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of granulocytic or monocytic cells that suppress innate as well as adaptive immune responses. In healthy adults, immature myeloid cells differentiate into macrophages, dendritic cells, and granulocytes in the bone marrow and MDSC are rarely detected in peripheral blood. However, in certain pathologies, in particular malignancies and chronic infection, differentiation of these cells is altered resulting in accumulation of circulating suppressive myeloid cells. MDSC express suppressive factors such as arginase-1, reactive oxygen species, and inducible nitric oxide synthase, which have the ability to inhibit T cell proliferation and cytoxicity, induce the expansion of regulatory T cells, and block natural killer cell activation. It is increasingly recognized that MDSC alter the immune response to several cancers, and perhaps chronic viral infections, in clinically important ways. In this review, we outline the potential contribution of MDSC to the generation of feto-maternal tolerance and to the ineffective immune responses to many infections and vaccines observed in early post-natal life. Granulocytic MDSC are present in large numbers in pregnant women and in cord blood, and wane rapidly during infancy. Furthermore, cord blood MDSC suppress in vitro T cell and NK responses, suggesting that they may play a significant role in human immune ontogeny. However, there are currently no data that demonstrate in vivo effects of MDSC on feto-maternal tolerance or immune ontogeny. Studies are ongoing to evaluate the functional importance of MDSC, including their effects on control of infection and response to vaccination in infancy. Importantly, several pharmacologic interventions have the potential to reverse MDSC function. Understanding the role of MDSC in infant ontogeny and their mechanisms of action could lead to interventions that reduce mortality due to early-life infections.

Background: The epidemiology and impact of multiple concurrent Human papillomavirus (HPV) infections on the natural history of cervical disease is uncertain, but could have significant implications for cervical cancer prevention and HPV vaccination strategies., Methods: A cross-sectional prevalence study was conducted to determine the overall prevalence of HPV and the rate of multiple concurrent HPV infections, in a cohort of sexually active HIV-uninfected South African adolescents. HPV genotyping was performed using the polymerase chain reaction., Results: Overall prevalence of HPV was 64.1%. Multiple concurrent HPV infections were found in 43.6% of participants and 68% of HPV-infected participants. Non-vaccine high-risk HPV (HR-HPV) genotypes were found much more often than vaccine types (HPV16 and HPV18)., Conclusions: Our cohort of young South African females was found to have a high overall prevalence of HPV and multiple concurrent HPV infections. Most HR-HPV infections found were genotypes other than HPV16 or HPV18.

With the increasing availability of highly active antiretroviral therapy, vertically infected children have a better chance of surviving into adolescence and adulthood. Additionally, sexual transmission of human immunodeficiency virus (HIV) remains a problem, and incidence and prevalence among youth remain high. Therefore, HIV-infected adolescents are becoming a more prominent sub-group in the HIV/AIDS epidemic. Experience from the developed world indicates that providing effective care and treatment for adolescents poses unique challenges. This study aimed to identify the experiences and needs of adolescents growing up in care or on treatment for HIV in Cape Town, South Africa. Four focus groups interviews were conducted with a total of 26 young people attending an adolescent infectious diseases clinic at a tertiary hospital. Questions explored participant's perceptions on their present and future lives, and their self-identified needs. Focus groups revealed that adolescents viewed their illness negatively, but that social issues such as violence and poverty were also concerns. Despite these stressors, most respondents remained positive about the present and future, and wanted support for achieving their goals. As increasing numbers of HIV-infected children enter adolescence, healthcare providers and communities must find ways to support these young people to transition into adulthood.

Sixty-six children who were receiving antiretroviral treatment were assessed for treatment adherence and virological outcome to compare boosted protease inhibitor-based regimens with nonnucleoside reverse-transcriptase inhibitor-based regimens. Children who were receiving protease inhibitor-based regimens demonstrated higher rates of virological suppression, even with poor treatment adherence (<80%). In children, boosted protease inhibitors seem to be more forgiving of poor adherence than do nonnucleoside reverse-transcriptase inhibitors.

Adolescents worldwide are at high risk for HIV, which makes them essential candidates for HIV vaccine trials. However, enrollment of adolescents into such trials has implications for trial sites. Adolescents are considered vulnerable subjects and require proxy consent in addition to their assent, which brings issues of confidentiality and access into play. HIV vaccine trial sites often do not have experience recruiting and retaining adolescents, and creating youth-friendly environments that are comfortable for guardians. This includes development of education materials that target both youth and their parents. Because these trials are of minimal individual benefit, sites will likely need to provide service in the form of health care and supportive structures to adolescents. Finally, a number of trial design options exist, and researchers will need to balance the risks and benefits of each, as for all issues surrounding the involvement of adolescents in HIV vaccine trials.