Characterisation and application of tests for recent infection for HIV incidence surveillance

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy. 21 October, 2014.Three decades ago, the discovery of the Human Immunodeficiency Virus (HIV) was announced. The subsequent HIV pandemic has continued to devastate the global community, and many countries have set ambitious HIV reduction targets over the years. Reliable methods for measuring incidence, the rate of new infections, are essential for monitoring the virus, allocating resources, and assessing interventions. The estimation of incidence from single cross-sectional surveys using tests that distinguish between ‘recent’ and ‘non-recent’ infection has therefore attracted much interest. The approach provides a promising alternative to traditional estimation methods which often require more complex survey designs, rely on poorly known inputs, and are prone to bias. More specifically, the prevalence of HIV and ‘recent’ HIV infection, as measured in a survey, are used together with relevant test properties to infer incidence. However, there has been a lack of methodological consensus in the field, caused by limited applicability of proposed estimators, inconsistent test characterisation (or estimation of test properties) and uncertain test performance. This work aims to address these key obstacles. A general theoretical framework for incidence estimation is developed, relaxing unrealistic assumptions used in earlier estimators. Completely general definitions of the required test properties emerge from the analysis. The characterisation of tests is then explored: a new approach, that utilises specimens from subjects observed only once after infection, is demonstrated; and currently-used approaches, that require that subjects are followed-up over time after infection, are systematically benchmarked. The first independent and consistent characterisation of multiple candidate tests is presented, and was performed on behalf of the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA), which was established to provide guidance and foster consensus in the field. Finally, the precision of the incidence estimator is presented as an appropriate metric for evaluating, optimising and comparing tests, and the framework serves to counter existing misconceptions about test performance. The contributions together provide sound theoretical and methodological foundations for the application, characterisation and optimisation of recent infection tests for HIV incidence surveillance, allowing the focus to now shift towards practical application

Sexual violence against children in South Africa: A nationally representative cross-sectional study of prevalence and correlates

Background We could identify no nationally representative South African studies of sexual violence against children. Methods A multistage sampling frame, stratified by province, urban/rural and race group, selected households. Within households, children aged 15-17 years were interviewed after obtaining parental consent. The final sample was 5,631 (94.6% participation rate). Findings 9.99% (95%CI 8.65-11.47) of boys and 14.61% (95%CI 12.83-16.56) of girls reported some lifetime sexual victimisation. Physical abuse, emotional abuse, neglect, family violence, and other victimisations, were all strongly associated with sexual victimisation. The following were associated with greater risk of sexual abuse (adjusted OR); school enrolment (OR 2.12; 95%CI 1.29-3.48); urban dwelling (OR 0.59; 95%CI 0.43-0.80); having a flush toilet (OR 1.43; 95%CI 1.04-1.96); having a substance-misusing parent ( OR 2.37; 95%CI 1.67-3.36); being disabled (OR 1.42; 95%CI 1.10-1.82); female but not male caregivers’ poorer knowledge of the child’s whereabouts, friends and activities (OR 1.07; 95%CI 0.75-1.53) and poorer quality of the relationship with the child (OR 1.20; 95%CI 0.55-2.60). Respondents’ own substance misuse (OR 4.72; 95%CI 3.73-5.98) and high-risk sexual behaviour (OR 3.71; 95%CI 2.99-4.61) were the behaviours most frequently associated with sexual abuse, with mental health conditions far less prevalent but nonetheless strongly associated with sexual victimisation (PTSD OR 2.81, 95%CI 1.65-4.78; depression OR 3.43, 95% CI 2.26-5.19; anxiety OR 2.48, 95%CI 1.61-3.81). Interpretation Sexual violence is widespread among both girls and boys, and is associated with serious health problems. Associated factors require multi-sectoral responses to prevent sexual violence or mitigate consequences

Covid-19 among adults living with HIV: Correlates of mortality among public sector healthcare users in Western Cape, South Africa

Introduction: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower-income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. Methods: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID-19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Results: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17,831 first-diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults

COVID-19 among adults living with HIV:correlates of mortality among public sector healthcare users in Western Cape, South Africa

Abstract Introduction While a large proportion of people with HIV (PWH) have experienced SARS‐CoV‐2 infections, there is uncertainty about the role of HIV disease severity on COVID‐19 outcomes, especially in lower‐income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. Methods We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS‐CoV‐2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID‐19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Results Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17,831 first‐diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. Conclusions Mortality was strongly associated with suboptimal HIV control, and the prevalence of these risk factors increased in later COVID‐19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimized

High unreported mortality in children and youth (<25 years) living with HIV who were lost to care from antiretroviral therapy programs in Southern Africa: results from a multi-country tracing study.

BACKGROUND Antiretroviral therapy (ART) program mortality maybe underestimated if deceased patients are misclassified as lost. METHODS We used two-stage inverse probability weighting to account for probability of being: sampled for tracing and found by the tracer. RESULTS Among 680 children and youth aged <25 years on ART who were lost and traced in Southern Africa between October 2017-November 2019, estimated mortality was high at 9.1% (62/680). After adjusting for measured covariates and within-site clustering, mortality remained lower for young adults aged 20-24 years compared to infants aged <2years (adjusted Hazard ratio (aHR): 0.40 (95% confidence interval (CI): 0.31, 0.51)). CONCLUSIONS Our study confirms high unreported mortality in children and youth who are lost and the need for tracing to assess vital status among those who are lost to accurately report on program mortality

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study) : results from a single-arm, open-label, phase 3B, implementation study

DATA SHARING : Individual participant data will not be made available. Study protocol, statistical analysis plan, and analytical code will be available from the time of publication in response to any reasonable request to the corresponding author.BACKGROUND : We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS : In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 x 10¹⁰ viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS : Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0–51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75–89) to prevent COVID-19-related deaths, 75% (69–82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62–71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42–76] and during delta wave was 67% [62–71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57–100] and during delta wave was 82% [74–89]). INTERPRETATION : The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally.National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.http;//thelancet.comam2023Paediatrics and Child HealthSchool of Health Systems and Public Health (SHSPH

Risk factors for Coronavirus disease 2019 (Covid-19) death in a population cohort study from the Western Cape province, South Africa

Risk factors for coronavirus disease 2019 (COVID-19) death in sub-Saharan Africa and the effects of human immunodeficiency virus (HIV) and tuberculosis on COVID-19 outcomes are unknown. We conducted a population cohort study using linked data from adults attending public-sector health facilities in the Western Cape, South Africa. We used Cox proportional hazards models, adjusted for age, sex, location, and comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death from 1 March to 9 June 2020 among (1) public-sector “active patients” (≥1 visit in the 3 years before March 2020); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We calculated the standardized mortality ratio (SMR) for COVID-19, comparing adults living with and without HIV using modeled population estimates.Among 3 460 932 patients (16% living with HIV), 22 308 were diagnosed with COVID-19, of whom 625 died. COVID19 death was associated with male sex, increasing age, diabetes, hypertension, and chronic kidney disease. HIV was associated with COVID-19 mortality (adjusted hazard ratio [aHR], 2.14; 95% confidence interval [CI], 1.70–2.70), with similar risks across strata of viral loads and immunosuppression. Current and previous diagnoses of tuberculosis were associated with COVID-19 death (aHR, 2.70 [95% CI, 1.81–4.04] and 1.51 [95% CI, 1.18–1.93], respectively). The SMR for COVID-19 death associated with HIV was 2.39 (95% CI, 1.96–2.86); population attributable fraction 8.5% (95% CI, 6.1–11.1)

Age-disparate relationships and implications for STI transmission among young adults in Cape Town, South Africa

Objectives: To estimate the prevalence of age-disparate (AD) relationships among young black and coloured adults in Cape Town (South Africa) and determine socio-demographic predictors and individual and relationship characteristics of women in these relationships. Methods: A secondary analysis of the Cape Area Panel Study (N = 1960) data was conducted. Descriptive statistics were used to quantify the age-mixing pattern and logistic regression was used to identify significant socio-demographic and behavioural correlates of AD relationships. Results: Prevalence of AD relationships was high in both black (36%) and coloured (28%) women. The average age difference between male respondents and their partners increased with age. Young, black women who spent fewer nights under the same roof in one week, had a deceased parent, and were not currently attending classes were more likely to be in an AD relationship. Reports of sexually-transmitted infection (STI) symptoms in the last month and unprotected sex were more common among women in AD relationships. Conclusions: AD relationships are common among young women in Cape Town. Home and family stability is preventative of young women engaging in AD relationships. Therefore, holistic, societal interventions may reduce AD relationships, which are a risk factor for STIs