Search

Background: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV., Methods: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms., Discussion: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV., Protocol Version: Version 4.0 dated 15 March 2024., Trial Registration: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058., (© 2024. The Author(s).)

South Africa is faced with a high HIV and STI prevalence and incidence, respectively, with pockets of high burden areas driving these diseases. Localised monitoring of the HIV epidemic and STI endemic would enable more effective targeted prevention strategies. We assessed spatial variations in curable STI incidence among a cohort of women enrolled in HIV prevention clinical trials between 2002 and 2012. STI incidence rates from 7557 South African women enrolled in five HIV prevention trials were geo-mapped using participant household GPS coordinates. Age and period standardised incidence rates were calculated for 43 recruitment areas and Bayesian conditional autoregressive areal spatial regression (CAR) was used to identify significant patterns and spatial patterns of STI infections in recruitment communities. Overall age and period standardised STI incidence rate were estimated as 15 per 100 PY and ranged from 6 to 24 per 100 PY. We identified five significant STI high risk areas with higher-than-expected incidence of STIs located centrally (three-locations) and southern neighbouring areas of Durban (two-locations). Younger age (<25), not married/cohabitating, parity <3 and poor education were all significant correlates of high STI communities. Findings demonstrate sustained STI incidence rates across the greater Durban area. The role of STI incidence in HIV acquisition in high HIV endemic areas need to be revisited as current highly effective PrEP interventions do not protect from STI acquisition. In these settings there is an urgent need for integrative HIV and STI prevention and treatment services.

Background: Elimination of vertical HIV Transmission (VHT) and maternal deaths are global health priorities. Male involvement is one of the most important factors that influences women's decisions, including the uptake of Prevention of vertical HIV transmission (P-VHT). We sought to understand not knowing a male partner's HIV status (MPHIVs) amongst women using services to prevent vertical HIV transmission in six South African districts with high antenatal HIV burden., Methods: A mixed-methods cross-sectional study was conducted in six South African districts, and data collected through face-to-face interviews with women and focus group discussions (FGDs) with women or male partners. The quantitative data were analyzed using STATA SE-17.0 and an inductive approach was used for qualitative data analysis., Results: Overall, 28.7% of women were unaware of their MPHIVs, while 25.3% and 46.0% knew the MPHIVs was positive or negative, respectively. In multivariable logistic regression, single marital status and unplanned pregnancy increased the odds of not knowing a MPHIVs while a woman's disclosure of her HIV status to the male partner reduced the odds. FDGs highlighted complexities around MPHIVs disclosure, e.g., reluctance to test for HIV and potential interventions including healthcare worker (HCW) assisted HIV disclosure., Conclusion: User-informed interventions to address MPHIVs non-disclosure amongst women of child-bearing age, particularly those at risk of unstable sexual partners and unplanned pregnancies, should be strengthened., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Hospital settings are at increased risk of spreading Coronavirus Disease 2019 (COVID-19) infections, hence non-pharmaceutical prevention interventions (NPPIs) and prioritized vaccination of healthcare workers and resident patients are critical. The status of COVID-19 hospital acquired infections (HAIs) in low-income settings is unclear. We aimed to identify and summarize the existing evidence on COVID-19 HAIs amongst patients, prior to the rollout of vaccines in countries worldwide., Methods: We conducted a scoping review of English peer-reviewed literature in PubMed, Web of Science and Scopus using a combination of selected search terms. Full texts articles presenting results on COVID-19 HAIs in hospitalised patients before the rollout of vaccines in countries worldwide were eligible. Data extracted from eligible articles included estimates of COVID-19 HAIs, country, and type of hospital setting, and was summarized narratively. Quality assessment of included articles was not possible., Results: Literature searches generated a total of 5920 articles, and 45 were eligible for analysis. Eligible articles were from Europe, North America, Asia, and Brazil and none were from low-income countries. The proportion of COVID-19 HAIs ranged from 0% when strict NPPIs were applied, to 65% otherwise. The estimates of COVID-19 HAIs did not differ by country but were lower in studies conducted after implementation of NPPIs and in specialized hospital settings for operative surgery. Studies conducted before the implementation of NPPIs or in long-term care and psychiatric wards often reported high estimates of HAI. Although there was no clear trend in general wards, those situated in academic hospitals managed to reduce HAI rates under strict NPPI protocols. Operative surgery settings, unlike psychiatric settings, effectively prevented COVID-19 HAI using tailored NPPIs., Conclusion: The available evidence shows a high risk of COVID-19 HAIs, the feasibility of preventing HAIs in different healthcare settings and the importance of appropriately tailored NPPIs. There were no data from low-income settings, therefore, it is unclear whether the reported NPPI approaches could be equally effective elsewhere. We recommend routine monitoring of COVID-19 HAIs in countries with low vaccination coverage, to identify and close gaps in NPPIs and understand gains made from vaccinating healthcare workers and hospitalized patients., (© 2022. The Author(s).)

Objective: Despite all efforts, high pregnancy rates are often reported in HIV biomedical intervention trials conducted in African countries. We therefore aimed to develop a pregnancy risk scoring algorithm for targeted recruitment and screening strategies among a cohort of women in South Africa., Methods: The study population was ~ 10,000 women who enrolled in one of the six biomedical intervention trials conducted in KwaZulu Natal, South Africa. Cox regression models were used to create a pregnancy risk scoring algorithm which was internally validated using standard statistical measures., Results: Five factors were identified as significant predictors of pregnancy incidence:<25 years old, not using injectable contraceptives, parity (<3), being single/not cohabiting and having ≥ 2 sexual partners in the past three months. Women with total scores of 21-24, 25-35 and 36+ were classified as being at "moderate", "high", "severe" risk of pregnancy. Sensitivity of the development and validation models were reasonably high (sensitivity 76% and 74% respectively)., Conclusion: Our risk scoring algorithm can identify and alert researchers to women who need additional non-routine pregnancy assessment and counselling, with statistically acceptable accuracy and robustness., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In addition to being the epicentre of the HIV epidemic, South Africa also has the highest burden of sexually transmitted infections (STIs) in the world. Therefore, understanding the most influential risk factors of STIs is a research priority. Using the data from 9948 women who resided in KwaZulu Natal, South Africa, we estimated the population attributable risk to quantify the combined impacts of the most influential factors on STI diagnosis. Overall STI prevalence was 20%, and STI incidence was 15 per 100 person-years. Four factors: age at sexual debut, single/not cohabiting, two or more sex partners and parity <3 were identified as the most influential risk factors for STI prevalence and incidence rates. However, these factors collectively associated with only 51% and 53% of the excess STI prevalence and incidence rates, respectively. These relatively modest impacts provide empirical evidence for the significant impacts of unmeasured factors on STIs. Culturally and socially appropriate prevention programs may be more effective to target those at highest risk of STIs.

South Africa has the highest burden of human immunodeficiency virus (HIV) infections in the world. There is also growing evidence that an individual's risk of contracting HIV is increased by the presence of other sexually transmitted infections (STIs). The primary objective of this study was to examine the association between the prevalence of STIs in a cohort of South African women who enrolled in HIV prevention trials (2002-2012). The current study linked the individual factors with the community-level characteristics using geo-referencing. These multi-level data were analyzed in generalized additive mixed models settings. In the multivariate logistic regression model, younger age (odds ratio [OR] 4.30, 95% CI 3.20, 5.77 and OR 2.72, 95% CI 2.02, 3.66 for age < 25 and 25-29, respectively); being single/not cohabiting (OR 4.57, 95% CI 3.18, 6.53), two + sex partners (OR 1.46, 95% CI 1.18,1.80); parity < 2 (OR 2.04, 95% CI 1.53, 2.72), parity = 2 (OR 1.85, 95% CI 1.37, 2.48), and using injectables (contraceptive) (OR 1.53, 95% CI 1.13, 2.06) were all significantly associated with increased prevalence of STIs. Women who resided in the communities with high proportions of female headed-households were also significantly at higher risk for STIs (OR 1.20, p = .0025). Because these factors may reflect characteristics of the larger groups who share similar cultural norms and social environments, they can provide considerable insight into the spread of STIs. Prevention strategies based on individual and community-level drivers of STIs are likely to be the most effective means of targeting and reaching those at greatest risk of infection. This strategy has the potential to play a significant role in the epidemic's trajectory.

South Africa has the highest burden of human immunodeficiency virus (HIV) infections in the world with significant geographical variations. We identified the predictors of HIV infections and their sub-geographical-level contributions to the epidemic using a decade long data (2002-2012) from 6484 South African women. Generalized additive models were used to uncover the most significant features of these estimates across the region. In the overall analysis, younger age, not married or cohabiting with a partner, partner has another partner(s) and null/prim parity, using injectable contraceptives and presence of other sexually transmitted infections (STIs) were identified as independent predictors of HIV seroconversions. Overall, the top three highest contributors to infections were women's marital status (PAR% = 73%, 95% CI: 68%, 77%), parity (PAR% = 47%, 95% CI: 42%, 53%) and partnership factors (PAR% = 37%, 95% CI: 30%, 44%). However, their contributions varied remarkably at sub-geographical level. This was mainly due to the substantial localized variations in their prevalence and hazard ratios across the region. Our results will guide policy makers to develop tailored prevention strategies in order to allocate scarce resources by targeting the most significant contributors of HIV infection at sub-geographical level.

Background: Women enrolled in human immunodeficiency virus (HIV) prevention efficacy trials receive counseling on prevention of HIV, sexually transmitted infections (STIs), and pregnancy during every visit. Incident pregnancy has an impact on efficacy outcomes. Incidence rates of pregnancy and HIV/STIs among women who became pregnant and associated risk factors were assessed., Methods: Data from 9165 women participating in HIV prevention trials in KwaZulu-Natal, South Africa from 2002-2012 were combined. Demographic and behavioral predictors of incidence pregnancy and incidence HIV and STIs were determined using Cox regression models., Results: Overall pregnancy incidence was 9.6 per 100 person-year (py) (95% confidence interval [Cl], 9.1-10.3). Human immunodeficiency virus incidence among pregnant women was 5.93 per 100 py (95% Cl, 4.73-7.44). Incidence of STIs among pregnant women for Chlamydia trachomatis, Trichomonas vaginalis, Neisseria gonorrhoeae, and Treponema pallidum (syphilis) were 10.87, 7.42, 3.92, and 1.43 per 100 py, respectively. In the adjusted analyses, we observed overlapping risk factors for HIV acquisition during pregnancy, ie, young age, not married/not cohabitating, and low parity. The risk of pregnancy and HIV acquisition is more than 3 times higher among young women (<20 years of age)., Conclusions: We identified overlapping risk factors for pregnancy and HIV incidence, suggesting an urgent need for appropriate, targeted, individual-centred counseling for women participating in HIV prevention trials.

Lineage tracing studies have revealed that transcription factors play a cardinal role in pancreatic development, differentiation and function. Three transitions define pancreatic organogenesis, differentiation and maturation. In the primary transition, when pancreatic organogenesis is initiated, there is active proliferation of pancreatic progenitor cells. During the secondary transition, defined by differentiation, there is growth, branching, differentiation and pancreatic cell lineage allocation. The tertiary transition is characterized by differentiated pancreatic cells that undergo further remodeling, including apoptosis, replication and neogenesis thereby establishing a mature organ. Transcription factors function at multiple levels and may regulate one another and auto-regulate. The interaction between extrinsic signals from non-pancreatic tissues and intrinsic transcription factors form a complex gene regulatory network ultimately culminating in the different cell lineages and tissue types in the developing pancreas. Mutations in these transcription factors clinically manifest as subtypes of diabetes mellitus. Current treatment for diabetes is not curative and thus, developmental biologists and stem cell researchers are utilizing knowledge of normal pancreatic development to explore novel therapeutic alternatives. This review summarizes current knowledge of transcription factors involved in pancreatic development and β-cell differentiation in rodents.