Correcting mortality estimates among children and youth on antiretroviral therapy in southern Africa: A comparative analysis between a multi-country tracing study and linkage to a health information exchange.

OBJECTIVES: The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for children, adolescents and young adults with HIV for unascertained outcomes in those loss to follow-up (LTFU) based on tracing and linkage data separately using data from the International epidemiology Databases to Evaluate AIDS in Southern Africa. METHODS: We included data from two different populations of children, adolescents and young adults with HIV; (1) clinical data from children, adolescents and young adults with HIV aged ≤24 years from Lesotho, Malawi, Mozambique, Zambia and Zimbabwe; (2) clinical data from children, adolescents and young adults with HIV aged ≤14 years from the Western Cape (WC) in South Africa. Outcomes of patients lost to follow-up were available from (1) a tracing study and (2) linkage to a health information exchange. For both populations, we compared six methods for correcting mortality estimates for all children, adolescents and young adults with HIV. RESULTS: We found substantial variations of mortality estimates among children, adolescents and young adults with HIV reported as lost to follow-up versus those retained in care. Ascertained mortality was higher among lost and traceable children, adolescents and young adults with HIV and lower among lost and linkable than those retained in care (mortality: 13.4% [traced] vs. 12.6% [retained-other Southern Africa countries]; 3.4% [linked] vs. 9.4% [retained-WC]). A high proportion of lost to follow-up children, adolescents and young adults with HIV had self-transferred (21.0% and 47.0%) in the traced and linked samples, respectively. The uncorrected method of non-informative censoring yielded the lowest mortality estimates among all methods for both tracing (6.0%) and linkage (4.0%) approaches at 2 years from ART start. Among corrected methods using ascertained data, multiple imputation, incorporating ascertained data (MI(asc.)) and inverse probability weighting with logistic weights were most robust for the tracing approach. In contrast, for the linkage approach, MI(asc.) was the most robust. CONCLUSIONS: Our findings emphasise that lost to follow-up is non-ignorable and both tracing and linkage improved outcome ascertainment: tracing identified substantial mortality in those reported as lost to follow-up, whereas linkage did not identify out-of-facility deaths, but showed that a large proportion of those reported as lost to follow-up were self-transfers.

A prospective randomised controlled trial investigating household SARS-CoV-2 transmission in a densely populated community in Cape Town, South Africa - the transmission of COVID-19 in crowded environments (TRACE) study.

BACKGROUND: South Africa's first SARS-CoV-2 case was identified 5th March 2020 and national lockdown followed March 26th. Households are an important location for secondary SARS-CoV-2 infection. Physical distancing and sanitation - infection mitigation recommended by the World Health Organization (WHO) at the time - are difficult to implement in limited-resource settings because of overcrowded living conditions. METHODS: This study (ClinicalTrials.gov NCT05119348) was conducted from August 2020 to September 2021 in two densely populated, low socioeconomic Cape Town community sub-districts. New COVID-19 index cases (ICs) identified at public clinics were randomised to an infection mitigation intervention (STOPCOV) delivered by lay community health workers (CHWs) or standard of care group. STOPCOV mitigation measures included one initial household assessment conducted by a CHW in which face masks, sanitiser, bleach and written information on managing and preventing spread were provided. This was followed by regular telephonic follow-up from CHWs. SARS-CoV-2 PCR and IgM/IgG serology was performed at baseline, weeks 1, 2, 3 and 4 of follow-up. RESULTS: The study randomised 81 ICs with 245 HHCs. At baseline, no HHCs in the control and 7 (5%) in the intervention group had prevalent SARS-CoV-2. The secondary infection rate (SIR) based on SARS-CoV-2 PCR testing was 1.9% (n = 2) in control and 2.9% (n = 4) in intervention HHCs (p = 0.598). At baseline, SARS-CoV-2 antibodies were present in 15% (16/108) of control and 38% (52/137) of intervention participants. At study end incidence was 8.3% (9/108) and 8.03% (11/137) in the intervention and control groups respectively. Antibodies were present in 23% (25/108) of control HHCs over the course of the study vs. 46% (63/137) in the intervention arm. CHWs made twelve clinic and 47 food parcel referrals for individuals in intervention households in need. DISCUSSION: Participants had significant exposure to SARS-CoV-2 infections prior to the study. In this setting, household transmission mitigation was ineffective. However, CHWs may have facilitated other important healthcare and social referrals.

Analysis of patient flow and barriers to timely discharge from general medical wards at a tertiary academic hospital in Cape Town, South Africa.

BACKGROUND: Movement of patients through a health establishment is a complex activity reliant upon multi-actor co-ordination across departments. The challenge of enhancing service delivery to meet the needs of a growing and aging population, whilst minimizing expense, is a global concern. There is an urgent need to understand and quantify systemic gaps in the efficient delivery of healthcare services. Stagnation of patient flow has negative impacts on both staff and patients by increasing risks of adverse outcomes, staff frustration and job dissatisfaction. An inefficient discharge process can be a significant barrier to timely patient movement. METHODS: A retrospective cohort study was conducted at a tertiary, academic hospital in the Western Cape, South Africa to assess the journey of medical patients from admission to discharge across the five different medical teams (firms) within the general medicine department. Consecutive sampling was used to capture all eligible adult medical in-patients admitted from the emergency department (ED) to general medicine from the 11th - 20th April 2023 and discharged up until the 30th of April 2023. We reviewed the patient notes (folders) of these individuals using a data-extraction tool to ascertain reasons for admission and barriers to timely discharge. RESULTS: Among 86 patient folders reviewed, cumulatively accounting for 596 in-patient days, a difference in the median length of in-patient stay between medical firms (p = 0.042) was noted. The shortest length of stay corresponded to firms with the greatest proportion of daily senior staff oversight (defined as documented patient reviews by a registrar, medical officer and/or consultant independently or in addition to reviews done for the day by interns and/or students). While 52% of patients vacated their beds between 14:00 and 17:00, 66% of patients were admitted after 20:00. Reasons for prolonged admission were variable, and attributable to a range of different disciplines across the multidisciplinary team. CONCLUSION: Whilst this study did not evaluate the appropriateness of chosen medical management but rather systemic drivers affecting patient movement and barriers to timely discharge, the delays in discharge were noted to be multi-factorial including facets across the efficient delivery of medical care, availability of resources and the internal operational frameworks for the institution. Understanding the need to optimize internal process efficiencies with regards to prompt acquisition of investigations, improvement of senior staff oversight and the creation of a standardized discharge process, could enhance efficient patient movement.

Factors associated with vertical transmission of HIV in the Western Cape, South Africa: a retrospective cohort analysis.

INTRODUCTION: Monitoring mother-infant pairs with HIV exposure is needed to assess the effectiveness of vertical transmission (VT) prevention programmes and progress towards VT elimination. METHODS: We used routinely collected data on infants with HIV exposure, born May 2018-April 2021 in the Western Cape, South Africa, with follow-up through mid-2022. We assessed the proportion of infants diagnosed with HIV at birth (≤7 days), 10 weeks (>1 to 14 weeks) and >14 weeks as proxies for intrauterine, intrapartum/early breastfeeding and late breastfeeding transmission, respectively. We used mixed-effects Poisson regression to assess factors associated with VT in mothers known with HIV by delivery. RESULTS: We included 50,461 infants born to mothers known with HIV by delivery. HIV was diagnosed in 894 (1.8%) infants. Among mothers, 51% started antiretroviral treatment (ART) before and 27% during pregnancy; 17% restarted during pregnancy after ≥6 months interruption; and 6% had no recorded ART during pregnancy. Most pregnancy ART regimens included non-nucleoside reverse transcriptase inhibitors (83%). Of mothers with available results (90% with viral load [VL]; 70% with CD4), VL nearest delivery was <100 copies/ml in 78% and CD4 count ≥350 cells/µl in 62%. HIV-PCR results were available for 86%, 67% and 48% of eligible infants at birth, 10 weeks and >14 weeks. Among these infants, 0.9%, 0.4% and 1.5% were diagnosed positive at birth, 10 weeks and >14 weeks, respectively. Among infants diagnosed with HIV, 43%, 16% and 41% were diagnosed at these respective time periods. Among mothers with VL<100, 100-999, 1000-99,000 and ≥100,000 copies/ml nearest delivery, infant HIV diagnosis incidence was 0.4%, 2.3%, 6.6% and 18.4%, respectively. Increased VT was strongly associated with recent elevated maternal VL with a seven-fold increased rate with even modestly elevated VL (100-999 vs. <100 copies/ml). VT was also associated with unknown/low maternal CD4, maternal age <20 years, no antenatal ART, later maternal ART start/restart in pregnancy and ART gaps. CONCLUSIONS: Despite high maternal ART coverage and routine postnatal prophylaxis, ongoing VT remains a concern. Timing of infant HIV diagnoses suggests intrapartum and/or breastfeeding transmission in nearly 60%. Interventions to ensure retention on ART and sustained maternal viral suppression are needed to reduce VT.

The effect of care interruptions on mortality in adults resuming antiretroviral therapy.

OBJECTIVE: To estimate the relative rate of all-cause mortality amongst those on antiretroviral treatment (ART) with a history of interruptions compared with those with no previous interruptions in care. DESIGN: Retrospective cohort study. METHODS: We used data from four South African cohorts participating in the International epidemiology Databases to Evaluate AIDS Southern Africa collaboration. We included adults who started ART between 2004 and 2019. We defined a care interruption as a gap in contact longer than 180 days. Observation time prior to interruption was allocated to a 'no interruption' group. Observation time after interruption was allocated to one of two groups based on whether the first interruption started before 6 months of ART ('early interruption') or later ('late interruption'). We used Cox regression to estimate hazard ratios. RESULTS: Sixty-three thousand six hundred and ninety-two participants contributed 162 916 person-years of observation. There were 3469 deaths. Most participants were female individuals (67.4%) and the median age at ART initiation was 33.3 years (interquartile range: 27.5-40.7). Seventeen thousand and eleven (26.7%) participants experienced care interruptions. Those resuming ART experienced increased mortality compared with those with no interruptions: early interrupters had a hazard ratio of 4.37 (95% confidence interval (CI) 3.87-4.95) and late interrupters had a hazard ratio of 2.74 (95% CI 2.39-3.15). In sensitivity analyses, effect sizes were found to be proportional to the length of time used to define interruptions. CONCLUSION: Our findings highlight the need to improve retention in care, regardless of treatment duration. Programmes to encourage return to care also need to be strengthened.

Changes Over Time in the Proportion of Advanced HIV Disease in Two High HIV Prevalence Settings in Ndhiwa (Kenya) and Eshowe (South Africa).

BACKGROUND: The burden of advanced HIV disease remains a significant concern in sub-Saharan Africa. In 2015, the World Health Organization released recommendations to treat all people living with HIV (PLHIV) regardless of CD4 ("treat all") and in 2017 guidelines for managing advanced HIV disease. We assessed changes over time in the proportion of PLHIV with advanced HIV and their care cascade in two community settings in sub-Saharan Africa. METHODS: Cross-sectional population-based surveys were conducted in Ndhiwa (Kenya) in 2012 and 2018 and in Eshowe (South Africa) in 2013 and 2018. We recruited individuals aged 15-59 years. Consenting participants were interviewed and tested for HIV at home. All participants with HIV had CD4 count measured. Advanced HIV was defined as CD4 < 200 cells/µL. RESULTS: Overall, 6076 and 6001 individuals were included in 2012 and 2018 (Ndhiwa) and 5646 and 3270 individuals in 2013 and 2018 (Eshowe), respectively. In Ndhiwa, the proportion of PLHIV with advanced HIV decreased from 2012 (159/1376 (11.8%; 95% CI: 9.8-14.2)) to 2018 (53/1000 (5.0%; 3.8-6.6)). The proportion of individuals with advanced HIV on antiretroviral therapy (ART) was 9.1% (6.9-11.8) in 2012 and 4.2% (3.0-5.8) in 2018. In Eshowe, the proportion with advanced HIV was 130/1400 (9.8%; 8.0-11.9) in 2013 and 38/834 (4.5%; 3.3-6.1) in 2018. The proportion with advanced HIV among those on ART was 6.9% (5.5-8.8) in 2013 and 2.8% (1.8-4.3) in 2018. There was a significant increase in coverage for all steps of the care cascade among people with advanced HIV between the two Ndhiwa surveys, with all the changes occurring among men and not women. No significant changes were observed in Eshowe between the surveys overall and by sex. CONCLUSION: The proportion with advanced HIV disease decreased between the first and second surveys where all guidelines have been implemented between the two HIV surveys.

Distribution of advanced HIV disease between two time periods in Ndhiwa (Kenya) and Eshowe (South Africa)We examined changes over time in the proportion of people living with HIV (PLHIV) with advanced HIV and their care cascade in two community settings in sub-Saharan Africa: Ndhiwa (Kenya) and Eshowe (South Africa). In 2012 and 2018, a total of 6,076 and 6,001 individuals were included in Ndhiwa, and 5,646 and 3,270 individuals were included in Eshowe in 2013 and 2018, respectively. In Ndhiwa, the proportion of PLHIV with advanced HIV decreased from 11.8% in 2012 to 5.0% in 2018. The proportion of individuals with advanced HIV on antiretroviral therapy (ART) decreased from 9.1% in 2012 to 4.2% in 2018. In Eshowe, the proportion PLHIV with advanced HIV decreased from 9.8% in 2013 to 4.5% in 2018. Among those on ART, the proportion of PLHIV with advanced HIV decreased from 6.9% in 2013 to 2.8% in 2018. The results also showed a significant increase in coverage for all steps of the care cascade among people with advanced HIV in Ndhiwa in 2018 compared to 2012, with these changes observed only among men and not women. No significant changes were observed in Eshowe between the surveys, both overall and when comparing by sex.

Self-transfers, Hospital Admissions and Mortality Among Children and Adolescents Lost to Follow-up From Antiretroviral Therapy Programs in the Western Cape, South Africa Between 2004 and 2019: Linkage to Provincial Records.

BACKGROUND: Pediatric programs face a high rate of loss to follow-up (LTFU) among children and adolescents living with HIV (CAHIV). We assessed true outcomes and predictors of these among CAHIV who were LTFU using linkage to the Western Cape Provincial Health Data Centre at Western Cape sites of the International epidemiology Databases to Evaluate AIDS-Southern Africa collaboration. METHODS: We examined factors associated with self-transfer, hospital admission and mortality using competing risks regression in a retrospective cohort of CAHIV initiating antiretroviral therapy <15 years old between 2004 and 2019 and deemed LTFU (no recorded visit at the original facility for ≥180 days from the last visit date before database closure and not known to have officially transferred out or deceased). RESULTS: Of the 1720 CAHIV deemed LTFU, 802 (46.6%) had self-transferred and were receiving care elsewhere within the Western Cape, 463 (26.9%) had been hospitalized and 45 (2.6%) CAHIV had died. The overall rates of self-transfer, hospitalization, mortality and LTFU were 9.4 [95% confidence interval (CI): 8.8-10.1], 5.4 (95% CI: 5.0-6.0), 0.5 (95% CI: 0.4-0.7) and 4.8 (95% CI: 4.4-5.3) per 100 person-years respectively. Increasing duration on antiretroviral therapy before LTFU was associated with self-transfers while male sex, older age at last visit (≥10 years vs. younger) were associated with hospital admission and immune suppression at last visit was associated with 5 times higher mortality. CONCLUSIONS: Nearly half of CAHIV classified as LTFU had self-transferred to another health facility, a quarter had been hospitalized and a small proportion had died.

Creating a data collection and management platform to support measurement of adolescent HIV care transition processes within low- and middle-income countries: The GRADUATE project.

Few national programs and research cohorts within low- and middle-income countries (LMICs) document transition-related processes and outcomes for adolescents and young adults living with HIV (AYLH) transitioning to adulthood. Between 2017-2020, The Global fRAmework of Data collection Used for Adolescent HIV Transition Evaluation (GRADUATE) project convened a collaborative advisory group to identify key variables and definitions capturing the process, predictors, and outcomes across the transition period. In total, 114 variables identified as essential to measuring AYLH transition-related data were identified and formatted into a GRADUATE Data Exchange Standard (DES), which was added to and harmonized with the existing International epidemiology Databases to Evaluate AIDS (IeDEA) DES. In 2019, the GRADUATE DES was pilot tested at four IeDEA facilities in Malawi, South Africa, and Thailand through a cross-sectional study. Upon comparing the variables to routine medical records, available data were too limited to adequately capture transition-related processes and outcomes. However, additional data collection using GRADUATE tools was feasible and improved completeness. Of the 100 (52% female) AYLH included in the pilot study, 71% had transitioned/transferred to adult care, with 42% transitioning from an adolescent-specific model of care within an integrated family clinic to having their clinic visits scheduled on a different day of the week while 58% transferred from a pediatric facility to one offering adult HIV care. While almost all (94%) had a transition-related discussion with their healthcare providers prior to the transition, we found that 69% (95% CI 49-85%) were somewhat or very satisfied/comfortable with the post-transfer clinic and the staff. Utilization of the GRADUATE DES better characterized AYLH transitioning to adulthood across LMICs, and optimally measured transition preparation activities and outcomes. Utilization of the GRADUATE DES in other settings could facilitate comparisons and identify gaps in the care of transitioning adolescents that need to be addressed.

ART history prior to conception: trends and association with postpartum disengagement from HIV care in Khayelitsha, South Africa (2013-2019): a retrospective cohort study.

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

Pharmacovigilance in Pregnancy Studies, Exposures and Outcomes Ascertainment, and Findings from Low- and Middle-Income Countries: A Scoping Review.

INTRODUCTION: Pharmacovigilance (PV), or the ongoing safety monitoring after a medication has been licensed, plays a crucial role in pregnancy, as clinical trials often exclude pregnant people. It is important to understand how pregnancy PV projects operate in low- and middle-income countries (LMICs), where there is a disproportionate lack of PV data yet a high burden of adverse pregnancy outcomes. We conducted a scoping review to assess how exposures and outcomes were measured in recently published pregnancy PV projects in LMICs. METHODS: We utilized a search string, secondary review, and team knowledge to review publications focusing on therapeutic or vaccine exposures among pregnant people in LMICs. We screened abstracts for relevance before conducting a full text review, and documented measurements of exposures and outcomes (categorized as maternal, birth, or neonatal/infant) among other factors, including study topic, setting, and design, comparator groups, and funding sources. RESULTS: We identified 31 PV publications spanning at least 24 LMICs, all focusing on therapeutics or vaccines for infectious diseases, including HIV (n = 17), tuberculosis (TB; n = 9), malaria (n = 7), pertussis, tetanus, and diphtheria (n = 1), and influenza (n = 3). As for outcomes, n = 15, n = 31, and n = 20 of the publications covered maternal, birth, and neonatal/infant outcomes, respectively. Among HIV-specific publications, the primary exposure-outcome relationship of focus was exposure to maternal antiretroviral therapy and adverse outcomes. For TB-specific publications, the main exposures of interest were second-line drug-resistant TB and isoniazid-based prevention therapeutics for pregnant people living with HIV. For malaria-specific publications, the primary exposure-outcome relationship of interest was antimalarial medication exposure during pregnancy and adverse outcomes. Among vaccine-focused publications, the exposure was assessed during a specific time during pregnancy, with an overall interest in vaccine safety and/or efficacy. The study settings were frequently from Africa, designs varied from cohort or cross-sectional studies to clinical trials, and funding sources were largely from high-income countries. CONCLUSION: The published pregnancy PV projects were largely centered in Africa and concerned with infectious diseases. This may reflect the disease burden in LMICs but also funding priorities from high-income countries. As the prevalence of non-communicable diseases increases in LMICs, PV projects will have to broaden their scope. Birth and neonatal/infant outcomes were most reported, with fewer reporting on maternal outcomes and none on longer-term child outcomes; additionally, heterogeneity existed in definitions and ascertainment of specific measures. Notably, almost all projects covered a single therapeutic exposure, missing an opportunity to leverage their projects to cover additional exposures, add scientific rigor, create uniformity across health services, and bolster existing health systems. For many publications, the timing of exposure, specifically by trimester, was crucial to maternal and neonatal safety. While currently published pregnancy PV literature offer insights into the PV landscape in LMICs, further work is needed to standardize definitions and measurements, integrate PV projects across health services, and establish longer-term monitoring.

Population-based prevalence of congenital defects in a routine sentinel site-based surveillance system in the Western Cape, South Africa.

BACKGROUND: Lack of data on the burden and scope of congenital disorders (CDs) in South Africa undermines resource allocation and limits the ability to detect signals from potentially teratogenic pregnancy exposures. METHODS: We used routine electronic data in the Western Cape Pregnancy Exposure Registry (PER) to determine the overall and individual prevalence of CD identified on neonatal surface examination at birth in the Western Cape, South Africa, 2016-2022. CD was confirmed by record review. The contribution of late (≤24 months) and antenatal diagnoses was assessed. We compared demographic and obstetric characteristics between women with/without pregnancies affected by CD. RESULTS: Women with a viable pregnancy (>22 weeks gestation; birth weight ≥ 500 g) (n = 32,494) were included. Of 1106 potential CD identified, 56.1% were confirmed on folder review. When internal and minor CD were excluded the prevalence of major CD identified on surface examination at birth was 7.2/1000 births. When missed/late diagnoses on examination (16.8%) and ultrasound (6.8%) were included, the prevalence was 9.2/1000 births: 8.9/1000 livebirths and 21.5/1000 stillbirths. The PER did not detect 21.5% of major CD visible at birth. Older maternal age and diabetes mellitus were associated with an increased prevalence of CD. Women living with/without HIV (or the timing of antiretroviral therapy, before/after conception), hypertension or obesity did not significantly affect prevalence of CD. CONCLUSIONS: A surveillance system based on routine data successfully determined the prevalence of major CD identified on surface examination at birth at rates slightly higher than in equivalent studies. Overall rates, modeled at ~2%, are likely underestimated. Strengthening routine neonatal examination and clinical record-keeping could improve CD ascertainment.

Maternal and birth outcomes in pregnant people with and without HIV in the Western Cape, South Africa.

INTRODUCTION: We evaluated associations of HIV and antiretroviral therapy (ART) with birth and maternal outcomes at a province-wide-level in the Western Cape, South Africa, in a recent cohort before dolutegravir-based first-line ART implementation. METHODS: This retrospective cohort study included pregnant people delivering in 2018-2019 with data in the Western Cape Provincial Health Data Centre which integrates individual-level data on all public sector patients from multiple electronic platforms using unique identifiers. Adverse birth outcomes (stillbirth, low birth weight (LBW), very LBW (VLBW)) and maternal outcomes (early and late pregnancy-related deaths, early and late hospitalizations) were compared by HIV/ART status and adjusted prevalence ratios (aPRs) calculated using log-binomial regression. RESULTS: Overall 171,960 pregnant people and their singleton newborns were included, 19% (N = 32 015) identified with HIV. Amongst pregnant people with HIV (PPHIV), 60% (N = 19 157) were on ART preconception, 29% (N = 9276) initiated ART during pregnancy and 11% (N = 3582) had no ART. Adjusted for maternal age, multiparity, hypertensive disorders and residential district, stillbirths were higher only for PPHIV not on ART [aPR 1.31 (95%CI 1.04-1.66)] compared to those without HIV. However, LBW and VLBW were higher among all PPHIV, with aPRs of 1.11-1.22 for LBW and 1.14-1.54 for VLBW. Pregnancy-initiated ART was associated with early pregnancy-related death (aPR 3.21; 95%CI 1.55-6.65), and HIV with or without ART was associated with late pregnancy-related death (aPRs 7.89-9.01). CONCLUSIONS: Even in the universal ART era, PPHIV experienced higher rates of LBW and VLBW newborns, and higher late pregnancy-related death regardless of ART status than pregnant people without HIV.

HIV Drug Resistance in Newly Diagnosed Young Children in the Western Cape, South Africa.

BACKGROUND: Pretreatment of HIV drug resistance among children living with HIV (CLHIV) can compromise antiretroviral therapy (ART) effectiveness. Resistance may be transmitted directly from mothers or acquired following exposure to antiretrovirals consumed through breastfeeding or administered as prophylaxis. METHODS: We performed resistance testing in children aged <3 years, newly diagnosed with HIV in Western Cape, South Africa (2021-2022), who either (1) acquired HIV via possible breastfeeding transmission from mothers who received ART (any regimen) during pregnancy/postpartum and/or (2) were exposed to protease inhibitors or integrase strand transfer inhibitors (INSTIs) in utero. Possible breastfeeding transmission was defined as testing HIV-polymerase chain reaction positive at age >28 days, after previously testing negative. We used surveillance drug-resistance mutation lists to define mutations. RESULTS: We included 135 CLHIV. Most mothers started ART prepregnancy (73%). Overall, 57% (77/135) of children had resistance mutations detected. Nonnucleoside reverse transcriptase inhibitor-associated, nucleoside reverse transcriptase inhibitor-associated, protease inhibitor-associated and INSTI-associated mutations were found in 55% (74/135), 10% (13/135), <1% (1/135) and <1% (1/122) of children tested, respectively. One child with breastfeeding transmission had high-level INSTI resistance detected at HIV diagnosis, aged 18 months (E138K and G118R mutations). CONCLUSIONS: Although not clinically relevant, nonnucleoside reverse transcriptase inhibitor-associated mutations were common. Dolutegravir is currently the preferred first-line treatment for adults and CLHIV age ≥4 weeks, and although very low INSTI resistance levels have been observed in adults, limited data exist on genotyping the integrase region in children. Pretreatment INSTI resistance in children is likely to be unusual, but future surveillance, including longitudinal studies with paired mother-child resistance testing, is needed.

The Retrospective Implementation of Standardized In Utero HIV Exposure Definitions Using Routinely Collected Public Sector Data Across the Western Cape Province, South Africa.

Using the Data Evaluation and Preparation for HIV-Exposed Uninfected Child Cohorts project's standardized child HIV exposure definitions, 64%, 64% and 90% of children exposed to HIV in utero could be classified as HIV-uninfected with moderate or high certainty at the ages of 1 and 3 years and at the time of first infectious disease hospitalization, respectively. These definitions can be applied retrospectively to routine datasets with linked mother-child data.

COVID-19 Vaccine Uptake and Effectiveness by Time since Vaccination in the Western Cape Province, South Africa: An Observational Cohort Study during 2020-2022.

There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced widespread SARS-CoV-2 infection before vaccine availability. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa, in an observational cohort study of >2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalization and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies, and healthcare utilization. We found that by the end of 2022, 41% of surviving adults had completed vaccination and 8% had received a booster dose. Recent vaccination was associated with notable reductions in severe COVID-19 during periods dominated by Delta, and Omicron BA.1/2 and BA.4/5 (sub)lineages. During the latest Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57-94 and 49-95, respectively). However, distinct reductions of effectiveness occurred at longer times post completing or boosting vaccination. Results highlight the importance of continued emphasis on COVID-19 vaccination and boosting for those at high risk of severe COVID-19, even in settings with widespread infection-induced immunity.

COVID-19 vaccine uptake and effectiveness by time since vaccination in the Western Cape province, South Africa: An observational cohort study during 2020-2022.

Background: There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced high levels of SARS-CoV-2 infection in a mostly vaccine-naïve population, and has limited vaccine coverage and competing health service priorities. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa. Methods: We performed an observational cohort study of >2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalisation and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies and healthcare utilisation. Results: By end 2022, only 41% of surviving adults had completed vaccination and 8% a booster dose, despite several waves of severe COVID-19. Recent vaccination was associated with notable reductions in severe COVID-19 during distinct analysis periods dominated by Delta, Omicron BA.1/2 and BA.4/5 (sub)lineages: within 6 months of completing vaccination or boosting, vaccine effectiveness was 46-92% for death (range across periods), 45-92% for admission with severe disease or death, and 25-90% for any admission or death. During the Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57-94 and 49-95, respectively). However, there were distinct reductions of VE at larger times post completing or boosting vaccination. Conclusions: Continued emphasis on regular COVID-19 vaccination including boosting is important for those at high risk of severe COVID-19 even in settings with widespread infection-induced immunity.

SARS-CoV-2 seroepidemiology in Cape Town, South Africa, and implications for future outbreaks in low-income communities.

In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can help describe and characterise the extent of the pandemic, as well as elucidate protection conferred by prior exposure. We conducted repeated cross-sectional serosurveys (July 2020 -November 2021) using residual samples from patients from Cape Town, South Africa, sent for routine laboratory studies for non-COVID-19 conditions. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses. Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.19% (95% confidence interval [CI] 37.23-41.19) in July 2020 to 67.8% (95%CI 66.31-69.25) in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10% of seropositive individuals had a recorded positive SARS-CoV-2 test. Using COVID-19 hospital admission and death data at the Provincial Health Data Centre, antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95%CI 0.05-0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95%CI 0.01-0.35). The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19 disease. In low-income communities, where diagnostic testing capacity is often limited, surveillance systems dependent on them will underestimate the true extent of an outbreak. Rapidly conducted seroprevalence studies can play an important role in addressing this.

Authorship inequalities in global health research: the IeDEA Southern Africa collaboration.

BACKGROUND: The International epidemiology Databases to Evaluate AIDS conducts research in several regions, including in Southern Africa. We assessed authorship inequalities for the Southern African region, which is led by South African and Swiss investigators. METHODS: We analysed authorships of publications from 2007 to 2020 by gender, country income group, time and citation impact. We used 2020 World Bank categories to define income groups and the relative citation ratio (RCR) to assess citation impact. Authorship parasitism was defined as articles without authors from the countries where the study was conducted. A regression model examined the probability of different authorship positions. RESULTS: We included 313 articles. Of the 1064 contributing authors, 547 (51.4%) were women, and 223 (21.0%) were from 32 low-income/lower middle-income countries (LLMICs), 269 (25.3%) were from 13 upper middle-income countries and 572 (53.8%) were from 25 high-income countries (HICs). Most articles (150/157, 95.5%) reporting data from Southern Africa included authors from all participating countries. Women were more likely to be the first author than men (OR 1.74; 95% CI 1.06 to 2.83) but less likely to be last authors (OR 0.63; 95% CI 0.40 to 0.99). Compared with HIC, LLMIC authors were less likely to publish as first (OR 0.21; 95% CI 0.11 to 0.41) or last author (OR 0.20; 95% CI 0.09 to 0.42). The proportion of women and LLMIC first and last authors increased over time. The RCR tended to be higher, indicating greater impact, if first or last authors were from HIC (p=0.06). CONCLUSIONS: This analysis of a global health collaboration co-led by South African and Swiss investigators showed little evidence of authorship parasitism. There were stark inequalities in authorship position, with women occupying more first and men more last author positions and researchers from LLMIC being 'stuck in the middle' on the byline. Global health research collaborations should monitor, analyse and address authorship inequalities.

Changing character and waning impact of COVID-19 at a tertiary centre in Cape Town, South Africa.

Background: The emergence of genetic variants of SARS-CoV-2 was associated with changing epidemiological characteristics throughout coronavirus disease 2019 (COVID-19) pandemic in population-based studies. Individual-level data on the clinical characteristics of infection with different SARS-CoV-2 variants in African countries is less well documented. Objectives: To describe the evolving clinical differences observed with the various SARS-CoV-2 variants of concern and compare the Omicron-driven wave in infections to the previous Delta-driven wave. Method: We performed a retrospective observational cohort study among patients admitted to a South African referral hospital with COVID-19 pneumonia. Patients were stratified by epidemiological wave period, and in a subset, the variants associated with each wave were confirmed by genomic sequencing. Outcomes were analysed by Cox proportional hazard models. Results: We included 1689 patients were included, representing infection waves driven predominantly by ancestral, Beta, Delta and Omicron BA1/BA2 & BA4/BA5 variants. Crude 28-day mortality was 25.8% (34/133) in the Omicron wave period versus 37.1% (138/374) in the Delta wave period (hazard ratio [HR] 0.68 [95% CI 0.47-1.00] p = 0.049); this effect persisted after adjustment for age, gender, HIV status and presence of cardiovascular disease (adjusted HR [aHR] 0.43 [95% CI 0.28-0.67] p < 0.001). Hospital-wide SARS-CoV-2 admissions and deaths were highest during the Delta wave period, with a decoupling of SARS-CoV-2 deaths and overall deaths thereafter. Conclusion: There was lower in-hospital mortality during Omicron-driven waves compared with the prior Delta wave, despite patients admitted during the Omicron wave being at higher risk. Contribution: This study summarises clinical characteristics associated with SARS-CoV-2 variants during the COVID-19 pandemic at a South African tertiary hospital, demonstrating a waning impact of COVID-19 on healthcare services over time despite epidemic waves driven by new variants. Findings suggest the absence of increasing virulence from later variants and protection from population and individual-level immunity.