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

Parental misperceptions of ingroup norms for child discipline

This work is based on research supported in part by the National Research Foundation of South Africa (grants numbered IFR2011033100037 and IFR170206222035) and the Economic and Social Research Council (ES/N01068X/1).The influence of perceived social norms on behaviour has been studied in a variety of domains. However, little research has examined their application to child discipline. This study explored social norms perceptions and their associations with parental discipline in greater Cape Town, South Africa. A cross‐sectional study of 195 mothers (using convenience sampling) from two Early Childhood Development centres examined self‐reported violent and non‐violent parenting behaviour, and perceived descriptive (usual behaviour in a group) and injunctive (appraisal of such behaviour) group norms. Parents overestimated the prevalence of violent parenting. Perceived descriptive norms of violent parenting were associated with self‐reported violent parenting behaviour; and perceived descriptive norms of non‐violent parenting were associated with self‐reported non‐violent parenting behaviour. Estimation of support for violent and for non‐violent parenting differed by centre, as did the relationship between perceived injunctive norms of non‐violent parenting and self‐reported non‐violent parenting behaviour. We also found significant effects of social identification, parent educational attainment and parent‐reported child misbehaviour. Parents' perceptions of group norms of parental discipline may be mistaken yet influence their own behaviour, providing the potential basis for violence prevention interventions.Publisher PDFPeer reviewe

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

Primary cutaneous malignancies in the Northern Cape Province of South Africa: A retrospective histopathological review

Background. Excessive sun exposure and a high prevalence of HIV increase skin cancer risk in South Africa (SA).Objective. To describe the nature and extent of skin cancers presenting in the public and private health sectors of the Northern Cape Province of SA.Methods. A retrospective analysis of histologically confirmed new primary cutaneous malignancies from 1 January 2008 to 31 December 2012 was conducted using public and private health sector databases. Types, quantity and distribution of common invasive malignancies by population group, age, gender, anatomical site and health sector were explored. One-year cumulative incidence was calculated and logistic regression models were used to analyse incidence and melanoma thickness trends.Results. A total of 4 270 biopsies (13 cutaneous malignancies) were identified. The commonest was squamous cell carcinoma (SCC), followed by basal cell carcinoma, Kaposi’s sarcoma (KS), cutaneous malignant melanoma (CMM) and basosquamous carcinoma, in descending order. The odds of a white male developing SCC increased by 8% each year (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 - 1.15; p=0.022), while the odds of a black male developing SCC and KS decreased by 9% (OR 0.91, 95% CI 0.84 - 0.99; p=0.033) and 18% (OR 0.82, 95% CI 0.70 - 0.97; p=0.022), respectively, each year. SCC and CMM were diagnosed at more advanced stages in the public than in the private healthcare sector. CMM is being detected earlier, as indicated by low-stage depth increasing by 72% annually (OR 1.72, 95% CI 1.04 - 3.01; p=0.042).Conclusions. Results suggest that reported skin cancer patterns are changing. There is a need for further research and equitable appropriation of financial resources and effort towards developing primary skin cancer prevention initiatives in SA

Cross-Sectional HIV Incidence Surveillance: A Benchmarking of Approaches for Estimating the 'Mean Duration of Recent Infection'.

The application of biomarkers for 'recent' infection in cross-sectional HIV incidence surveillance requires the estimation of critical biomarker characteristics. Various approaches have been employed for using longitudinal data to estimate the Mean Duration of Recent Infection (MDRI) - the average time in the 'recent' state. In this systematic benchmarking of MDRI estimation approaches, a simulation platform was used to measure accuracy and precision of over twenty approaches, in thirty scenarios capturing various study designs, subject behaviors and test dynamics that may be encountered in practice. Results highlight that assuming a single continuous sojourn in the 'recent' state can produce substantial bias. Simple interpolation provides useful MDRI estimates provided subjects are tested at regular intervals. Regression performs the best - while 'random effects' describe the subject-clustering in the data, regression models without random effects proved easy to implement, stable, and of similar accuracy in scenarios considered; robustness to parametric assumptions was improved by regressing 'recent'/'non-recent' classifications rather than continuous biomarker readings. All approaches were vulnerable to incorrect assumptions about subjects' (unobserved) infection times. Results provided show the relationships between MDRI estimation performance and the number of subjects, inter-visit intervals, missed visits, loss to follow-up, and aspects of biomarker signal and noise.MRC Funding: MC_UP_1302/3’ and U10526056

Long‐term usage patterns and clinical outcomes in a community‐based differentiated antiretroviral therapy delivery programme in South Africa

Introduction: There is little data on long-term implementation and outcomes for people living with HIV (PLHIV) in differentiated antiretroviral therapy (ART) delivery programmes. We aimed to analyse usage patterns of and associated treatment outcomes in a community ART programme, within the Centralized Chronic Medicines Dispensing and Distribution programme, in South Africa over 3.5 years. Methods: We performed a retrospective cohort study among PLHIV on first-line ART who were eligible for community ART delivery between October 2016 and March 2019, from 56 urban clinics in KwaZulu-Natal, South Africa. Follow-up ended in March 2020. We measured referral rates and, among those referred, we characterized patterns of community ART usage using group-based trajectory modelling following referral. We used survival analysis to measure the association between community ART usage and loss-to-care (no visit for ≥365 days) and logistic regression to measure the association between community ART usage and viraemia (≥50 copies/ml). Results: Among the 80,801 patients eligible for community ART, the median age was 36 years, 69.8% were female and the median (interquartile range [IQR]) follow-up time was 22 (13–31) months. In total, 49,961 (61.8%) were referred after a median of 6 (IQR 2–13) months from first eligibility. After referral, time spent in community ART varied; 42% remained consistently in community ART, 15% returned to consistent clinic-based care and the remaining 43% oscillated between community ART and clinic-based care. Following referral, the incidence of loss-to-care was 3.93 (95% confidence interval [CI]: 3.71–4.15) per 100 person-years during periods of community ART usage compared to 5.75 (95% CI: 5.28–6.25) during clinic-based care. In multivariable models, community ART usage was associated with a 36% reduction in the hazards of loss-to-care (adjusted hazard ratio: 0.64 [95% CI: 0.57–0.72]). The proportion of patients who became viraemic after first community ART referral was 5.2% and a 10% increase in time in community ART was associated with a 3% reduction in odds of viraemia (adjusted odds ratio: 0.97 [95% CI: 0.95–0.99]). Conclusions: Community ART usage patterns vary considerably, while clinical outcomes were good. Promoting consistent community ART usage may reduce clinic burden and the likelihood of patients being lost to care, while sustaining viral suppression