The cyclical cascade of HIV care: Temporal care engagement trends within a population-wide cohort.

BACKGROUND: The traditional HIV treatment cascade aims to visualise the journey of each person living with HIV from diagnosis, through initiation on antiretroviral therapy (ART) to treatment success, represented by virological suppression. This representation has been a pivotal tool in highlighting and quantifying sequential gaps along the care continuum. There is longstanding recognition, however, that this may oversimplify the complexity of real-world engagement with HIV services in settings with mature high-burden HIV epidemics. A complementary "cyclical" cascade has been proposed to represent the processes of disengagement at different points on the care continuum, with multiple pathways to re-engagement, although the feasibility of implementing this at scale has been uncertain. This study aimed to populate, refine, and explore the utility of a cyclical representation of the HIV cascade, using routine data from a high-burden HIV setting. METHODS AND FINDINGS: This observational cohort study leveraged person-level data on all people living with HIV in the Western Cape (WC), South Africa, who accessed public health services in the 2 years prior to 31 December 2023. Programme data from disease registers were complemented by data from pharmacy and laboratory systems. At study closure, 494 370 people were included, constituting 93% of those of those estimated to be living with HIV in the province, of whom 355 104 were on ART. Substantial disengagement from HIV care was evident at every point on the cascade. Early treatment emerged as a period of higher risk of disengagement, but it did not account for the majority of disengagement. Almost all those currently disengaged had prior experience of treatment. While re-engagement was also common, overall treatment coverage had increased slowly over 5 years. The transition to dolutegravir-based regimens was dramatic with good virological outcomes for those in care, notwithstanding a clearly discernible impact of the Coronavirus Disease 2019 (COVID-19) pandemic on viral load (VL) testing. People currently engaged and disengaged in care are similar with respect to age and gender. Those who died or disengaged recently were previously distributed across a range of cascade statuses, and a substantial proportion of those newly initiating and re-initiating treatment were no longer on treatment 6 months later. The main limitation of this study was incomplete evidence of HIV testing, linkage to HIV-specific services, and out-of-facility mortality. CONCLUSIONS: Using routine data, it was possible to populate and automate a cyclical cascade of HIV care that continuously captured the nonlinear care journeys of individuals living with HIV. In this generalised mature HIV epidemic, most people are treatment experienced. Disengagement is common and occurs at various points along the cascade, making it challenging to identify high-impact intervention opportunities. While historical HIV cascades remain valuable for target setting and service monitoring, they can be complemented with insights from more detailed cyclical cascades.

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.

Early assessment of the clinical severity of the SARS-CoV-2 omicron variant in South Africa: a data linkage study.

BACKGROUND: The SARS-CoV-2 omicron variant of concern was identified in South Africa in November, 2021, and was associated with an increase in COVID-19 cases. We aimed to assess the clinical severity of infections with the omicron variant using S gene target failure (SGTF) on the Thermo Fisher Scientific TaqPath COVID-19 PCR test as a proxy. METHODS: We did data linkages for national, South African COVID-19 case data, SARS-CoV-2 laboratory test data, SARS-CoV-2 genome data, and COVID-19 hospital admissions data. For individuals diagnosed with COVID-19 via TaqPath PCR tests, infections were designated as either SGTF or non-SGTF. The delta variant was identified by genome sequencing. Using multivariable logistic regression models, we assessed disease severity and hospitalisations by comparing individuals with SGTF versus non-SGTF infections diagnosed between Oct 1 and Nov 30, 2021, and we further assessed disease severity by comparing SGTF-infected individuals diagnosed between Oct 1 and Nov 30, 2021, with delta variant-infected individuals diagnosed between April 1 and Nov 9, 2021. FINDINGS: From Oct 1 (week 39), 2021, to Dec 6 (week 49), 2021, 161 328 cases of COVID-19 were reported in South Africa. 38 282 people were diagnosed via TaqPath PCR tests and 29 721 SGTF infections and 1412 non-SGTF infections were identified. The proportion of SGTF infections increased from two (3·2%) of 63 in week 39 to 21 978 (97·9%) of 22 455 in week 48. After controlling for factors associated with hospitalisation, individuals with SGTF infections had significantly lower odds of admission than did those with non-SGTF infections (256 [2·4%] of 10 547 vs 121 [12·8%] of 948; adjusted odds ratio [aOR] 0·2, 95% CI 0·1-0·3). After controlling for factors associated with disease severity, the odds of severe disease were similar between hospitalised individuals with SGTF versus non-SGTF infections (42 [21%] of 204 vs 45 [40%] of 113; aOR 0·7, 95% CI 0·3-1·4). Compared with individuals with earlier delta variant infections, SGTF-infected individuals had a significantly lower odds of severe disease (496 [62·5%] of 793 vs 57 [23·4%] of 244; aOR 0·3, 95% CI 0·2-0·5), after controlling for factors associated with disease severity. INTERPRETATION: Our early analyses suggest a significantly reduced odds of hospitalisation among individuals with SGTF versus non-SGTF infections diagnosed during the same time period. SGTF-infected individuals had a significantly reduced odds of severe disease compared with individuals infected earlier with the delta variant. Some of this reduced severity is probably a result of previous immunity. FUNDING: The South African Medical Research Council, the South African National Department of Health, US Centers for Disease Control and Prevention, the African Society of Laboratory Medicine, Africa Centers for Disease Control and Prevention, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the Fleming Fund.

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.

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 × 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. FUNDING: 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.

Attrition from Care Among Men Initiating ART in Male-Only Clinics Compared with Men in General Primary Healthcare Clinics in Khayelitsha, South Africa: A Matched Propensity Score Analysis.

Men have higher rates of attrition from antiretroviral therapy (ART) programs than women. In Khayelitsha, a high HIV prevalence area in South Africa, two public sector primary healthcare clinics offer services, including HIV testing and treatment, exclusively to men. We compared attrition from ART care among men initiating ART at these clinics with male attrition in six general primary healthcare clinics in Khayelitsha. We described baseline characteristics of patients initiating ART at the male and general clinics from 1 January 2014 to 31 March 2018. We used exposure propensity scores (generated based on baseline health and age) to match male clinic patients 1:1 to males at other clinics. The association between attrition (death or loss to follow-up, defined as no visits for nine months) and clinic type was estimated using Cox proportional hazards regression. Follow-up time began at ART initiation and ended at attrition, clinic transfer, or dataset closure. Before matching, patients from male clinics (n = 784) were younger than males from general clinics (n = 2726), median age: 31.2 vs 35.5 years. Those initiating at male clinics had higher median CD4 counts at ART initiation [Male Clinic 1: 329 (IQR 210-431), Male Clinic 2: 364 (IQR 260-536), general clinics 258 (IQR 145-398), cells/mm3]. In the matched analysis (1451 person-years, 1568 patients) patients initiating ART at male clinics had lower attrition (HR 0.71; 95% CI 0.60-0.85). In separate analyses for each of the two male clinics, only the more established male clinic showed a protective effect. Male-only clinics reached younger, healthier men, and had lower ART attrition than general services. These findings support clinic-specific adaptations to create more male-friendly environments.

Maternal weight trajectories and associations with infant growth in South African women.

BACKGROUND: Despite the close relationship between pre-pregnancy body mass index (BMI), gestational weight gain (GWG) and postpartum weight (PPW), these factors are often studied separately. There are no data characterising longitudinal weight trajectories among pregnant and postpartum women in urban African populations. We examined maternal weight trajectories from pregnancy through to 12 months postpartum, factors associated with higher weight trajectory class membership and associations of weight trajectories with infant growth at 12 months. METHODS: Data from 989 women were examined for weight trajectories from first antenatal care visit in pregnancy to 12 months postpartum using latent-class growth models. Baseline factors associated with class membership were assessed using multinomial logistic regression. Of the enrolled women, 613 of their infants were assessed for growth at 12 months. Anthropometry measurements for mothers and infants were conducted by a trained study nurse. Associations between maternal weight trajectory class and infant weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ) at 12 months of age were analysed using linear regression. RESULTS: Four distinct classes of maternal weight trajectories were identified. The classes included consistent low (29%), consistent medium (37%), medium-high (24%) and consistent high (10%) trajectories. Similar to trends observed with medium-high trajectory, baseline factors positively associated with consistent high class membership included age (OR 1.05, 95% CI 1.01-1.09), pre-pregnancy BMI (OR 2.24, 95% CI 1.97-2.56), stage 1 hypertension (OR 3.28, 95% CI 1.68-6.41), haemoglobin levels (OR 1.39, 95% CI 1.11-1.74) and parity (OR 1.39, 95% CI 1.15-1.67); living with HIV (OR 0.47, 95% CI 0.30-0.74) was inversely associated. In adjusted analyses, compared to consistent medium weight trajectory, consistent low weight trajectory (mean difference -0.41, 95% CI -0.71;-0.12) was associated with decreased, and consistent high weight trajectory (mean difference 1.21, 95% CI 0.59-1.83) with increased infant WAZ at 12 months of age. CONCLUSION: Identification of unique longitudinal weight trajectory groupings might inform comprehensive efforts targeted at improving healthy maternal weight and infant outcomes.

Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa.

OBJECTIVES: The objective was to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, assess the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection and determine whether protection against severe disease conferred by prior infection and/or vaccination was maintained. METHODS: In this cohort study, we included public sector patients aged ≥20 years with a laboratory-confirmed COVID-19 diagnosis between 14 November and 11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalisation or death and any hospitalisation or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. RESULTS: We included 5144 patients from wave four and 11,609 from prior waves. The risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted hazard ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR: 0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). CONCLUSIONS: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for a modest reduction in risk of severe hospitalisation or death compared to the Delta-driven wave.

Determining antenatal medicine exposures in South African women: a comparison of three methods of ascertainment.

BACKGROUND: In the absence of clinical trials, data on the safety of medicine exposures in pregnancy are dependent on observational studies conducted after the agent has been licensed for use. This requires an accurate history of antenatal medicine use to determine potential risks. Medication use is commonly determined by self-report, clinician records, and electronic pharmacy data; different data sources may be more informative for different types of medication and resources may differ by setting. We compared three methods to determine antenatal medicine use (self-report, clinician records and electronic pharmacy dispensing records [EDR]) in women attending antenatal care at a primary care facility in Cape Town, South Africa in a setting with high HIV prevalence. METHODS: Structured, interview-administered questionnaires recorded self-reported medicine use. Data were collected from clinician records and EDR on the same participants. We determined agreement between these data sources using Cohen's kappa and, lacking a gold standard, used Latent Class Analysis to estimate sensitivity, specificity and positive predictive value (PPV) for each data source. RESULTS: Between 55% and 89% of 967 women had any medicine use documented depending on the data source (median number of medicines/participant = 5 [IQR 3-6]). Agreement between the datasets was poor regardless of class except for antiretroviral therapy (ART; kappa 0.6-0.71). Overall, agreement was better between the EDR and self-report than with either dataset and the clinician records. Sensitivity and PPV were higher for self-report and the EDR and were similar for the two. Self-report was the best source for over-the-counter, traditional and complementary medicines; clinician records for vaccines and supplements; and EDR for chronic medicines. CONCLUSIONS: Medicine use in pregnancy was common and no single data source included all the medicines used. ART was the most consistently reported across all three datasets but otherwise agreement between them was poor and dependent on class. Using a single data collection method will under-estimate medicine use in pregnancy and the choice of data source should be guided by the class of the agents being investigated.

Growth patterns of infants with in- utero HIV and ARV exposure in Cape Town, South Africa and Lusaka, Zambia.

BACKGROUND: Infants born HIV-exposed yet remain uninfected (HEU) are at increased risk of poorer growth and health compared to infants born HIV-unexposed (HU). Whether maternal antiretroviral treatment (ART) in pregnancy ameliorates this risk of poorer growth is not well understood. Furthermore, whether risks are similar across high burden HIV settings has not been extensively explored. METHODS: We harmonized data from two prospective observational studies conducted in Cape Town, South Africa, and Lusaka, Zambia, to compare weight-for-age (WAZ), length-for-age (LAZ) and weight-for-length (WLZ) Z-scores between infants who were HEU and HU, converting infant anthropometric measures using World Health Organisation Growth Standards adjusted for age and sex. Linear mixed effects models were fit to identify risk factors for differences in anthropometrics at 6-10 weeks and 6 months by infant HIV exposures status and by timing of exposure to maternal ART, either from conception or later in gestation. RESULTS: Overall 773 mother-infant pairs were included across two countries: women living with HIV (WLHIV), 51% (n = 395) with 65% on ART at conception and 35% initiating treatment in pregnancy. In linear mixed effects models, WAZ and WLZ at 6-10 weeks were lower among infants who were HEU vs HU [ß = - 0.29 (95% CI: - 0.46, - 0.12) and [ß = - 0.42 (95% CI: - 0.68, - 0.16)] respectively after adjusting for maternal characteristics and infant feeding with a random intercept for country. At 6 months, LAZ was lower [ß = - 0.28 CI: - 0.50, - 0.06)] among infants who were HEU, adjusting for the same variables, with no differences in WAZ and WLZ. Within cohort evaluations identified different results with higher LAZ among infants who were HEU from Zambia at 6-10 weeks, [ß = + 0.34 CI: + 0.01, + 0.68)] and lower LAZ among infants who were HEU from South Africa [ß = - 0.30 CI: - 0.59, - 0.01)] at 6 months, without other anthropometric differences at either site. CONCLUSION: Infant growth trajectories differed by country, highlighting the importance of studying contextual influences on outcomes of infants who were HEU.

Evaluation of a public COVID-19 dashboard in the Western Cape, South Africa: a tool for communication, trust, and transparency.

BACKGROUND: Public health dashboards have been used in the past to communicate and guide local responses to outbreaks, epidemics, and a host of various health conditions. During the first year of the COVID-19 pandemic, dashboards proliferated but the availability and quality differed across the world. This study aimed to evaluate the quality, access, and end-user experience of one such dashboard in the Western Cape province, South Africa. METHODS: We analysed retrospective aggregate data on viewership over time for the first year since launch of the dashboard (30 April 2020 - 29 April 2021) and conducted a cross-sectional survey targeting adult users of the dashboard at one year post the initial launch. The self-administered, anonymous questionnaire with a total of 13 questions was made available via an online digital survey tool for a 2-week period (6 May 2021 - 21 May 2021). RESULTS: After significant communication by senior provincial political leaders, adequate media coverage and two waves of COVID-19 the Western Cape public COVID-19 dashboard attracted a total of 2,248,456 views during its first year. The majority of these views came from Africa/South Africa with higher median daily views during COVID-19 wave periods. A total of 794 participants responded to the survey questionnaire. Reported devices used to access the dashboard differed statistically between occupational status groups with students tending toward using mobile devices whilst employed and retired participants tending toward using desktop computers/laptops. Frequency of use increases with increasing age with 65.1% of those > 70 years old viewing it daily. Overall, 76.4% of respondents reported that the dashboard influenced their personal planning and behaviour. High Likert score ratings were given for clarity, ease of use and overall end-user experience, with no differences seen across the various age groups surveyed. CONCLUSION: The study demonstrated that both the availability of data and an understanding of end-user need is critical when developing and delivering public health tools that may ultimately garner public trust and influence individual behaviour.

High Rates of Recurrent Tuberculosis Disease: A Population-level Cohort Study.

BACKGROUND: Retreatment tuberculosis (TB) disease is common in high-prevalence settings. The risk of repeated episodes of recurrent TB is unknown. We calculated the rate of recurrent TB per subsequent episode by matching individual treatment episodes over a period of 13 years. METHODS: All recorded TB episodes in Cape Town between 2003 and 2016 were matched by probabilistic linkage of personal identifiers. Among individuals with a first episode notified in Cape Town and who completed their prior treatment successfully we estimated the recurrence rate stratified by subsequent episode and HIV status. We adjusted person-time to background mortality by age, sex, and HIV status. RESULTS: A total of 292 915 TB episodes among 263 848 individuals were included. The rate of recurrent TB was 16.4 per 1000 person-years (95% CI, 16.2-16.6), and increased per subsequent episode (8.4-fold increase, from 14.6 to 122.7 per 1000 from episode 2 to 6, respectively). These increases were similar stratified by HIV status. Rates among HIV positives were higher than among HIV negatives for episodes 2 and 3 (2- and 1.5-fold higher, respectively), and the same thereafter. CONCLUSIONS: TB recurrence rates were high and increased per subsequent episode, independent of HIV status. This suggests that HIV infection is insufficient to explain the high burden of recurrence; it is more likely due to a high annual risk of infection combined with an increased risk of infection or progression to disease associated with a previous TB episode. The very high recurrence rates would justify increased TB surveillance of patients with >1 episode.

The revolving door of HIV care: Revising the service delivery cascade to achieve the UNAIDS 95-95-95 goals.

Peter Ehrenkranz and co-authors present a cyclical cascade of care for people with HIV infection, aiming to facilitate assessment of outcomes.

The Impact of Same-Day Antiretroviral Therapy Initiation Under the World Health Organization Treat-All Policy.

Rapid initiation of antiretroviral therapy (ART) is recommended for people living with human immunodeficiency virus (HIV), with the option to start treatment on the day of diagnosis (same-day ART). However, the effect of same-day ART remains unknown in realistic public sector settings. We established a cohort of ≥16-year-old patients who initiated first-line ART under a treat-all policy in Nhlangano (Eswatini) during 2014-2016, either on the day of HIV care enrollment (same-day ART) or 1-14 days thereafter (early ART). Directed acyclic graphs, flexible parametric survival analysis, and targeted maximum likelihood estimation (TMLE) were used to estimate the effect of same-day-ART initiation on a composite unfavorable treatment outcome (loss to follow-up, death, viral failure, treatment switch). Of 1,328 patients, 839 (63.2%) initiated same-day ART. The adjusted hazard ratio of the unfavorable outcome was higher, 1.48 (95% confidence interval: 1.16, 1.89), for same-day ART compared with early ART. TMLE suggested that after 1 year, 28.9% of patients would experience the unfavorable outcome under same-day ART compared with 21.2% under early ART (difference: 7.7%; 1.3%-14.1%). This estimate was driven by loss to follow-up and varied over time, with a higher hazard during the first year after HIV care enrollment and a similar hazard thereafter. We found an increased risk with same-day ART. A limitation was that possible silent transfers that were not captured.

Changing contextual factors from baseline to 9-months post-HIV diagnosis predict 5-year mortality in Durban, South Africa.

Changes in an individual's contextual factors following HIV diagnosis may influence long-term outcomes. We evaluated how changes to contextual factors between HIV diagnosis and 9-month follow-up predict 5-year mortality among HIV-infected individuals in Durban, South Africa enrolled in the Sizanani Trial (NCT01188941). We used random survival forests to identify 9-month variables and changes from baseline predictive of time to mortality. We incorporated these into a Cox proportional hazards model including age, sex, and starting ART by 9 months a priori, 9-month social support and competing needs, and changes in mental health between baseline and 9 months. Among 1,154 participants with South African ID numbers, 900 (78%) had baseline and 9-month data available of whom 109 (12%) died after 9-month follow-up. Those who reported less social support at 9 months had a 16% higher risk of mortality. Participants who went without basic needs or healthcare at 9 months had a 2.6 times higher hazard of death compared to participants who did not. Low social support and competing needs at 9-month follow-up substantially increase long-term mortality risk. Reassessing contextual factors during follow-up and targeting interventions to increase social support and affordability of care may reduce long-term mortality for HIV-infected individuals in South Africa.

Optimised electronic patient records to improve clinical monitoring of HIV-positive patients in rural South Africa (MONART trial): study protocol for a cluster-randomised trial.

BACKGROUND: There is poor viral load monitoring (VLM) and inadequate management of virological failure in HIV-positive individuals on antiretroviral therapy in rural KwaZulu-Natal, South Africa. This could be contributing to increasing HIV drug resistance in the setting. This study aims to investigate the clinical and process impediments in VLM within the health system and to evaluate a quality improvement package (QIP) to address the identified gaps. The QIP comprises (i) a designated viral load champion responsible for administrative management and triaging of viral load results (ii) technological enhancement of the routine clinic-based Three Interlinked Electronic Register (TIER.Net) to facilitate daily automatic import of viral load results from the National Health Service Laboratory to TIER.Net (iii) development of a dashboard system to support VLM. METHODS/DESIGN: The study will evaluate the effectiveness of the QIP compared to current care for improving VLM and virological suppression using an effectiveness implementation hybrid type 3 design. This will use a cluster-randomised design with the primary healthcare clinics as the unit of randomisation with ten clinics randomised in a 1:1 ratio to either the intervention or control arm. We will enrol 150 HIV-positive individuals who had been on ART for ≥ 12 months from each of the ten clinics (750 in 5 intervention clinics vs. 750 in 5 control clinics) and follow them up for a period of 12 months. The primary outcome is the proportion of all patients who have a viral load (VL) measurement and are virally suppressed (composite outcome) after 12 months of follow up. Secondary outcomes during follow up include proportion of all patients with at least one documented VL in TIER.Net, proportion with VL ≥ 50 copies/mL, proportion with VL ≥ 1000 copies/mL (virological failure) and subsequent switch to second-line ART. DISCUSSION: We aim to provide evidence that a staff-centred quality improvement package, designated viral load monitoring champion, and augmentation of TIER.Net with a dashboard system will improve viral load monitoring and lead to improved virological suppression. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov on 8 Oct 2021. Identifier: NCT05071573; https://clinicaltrials.gov/ct2/show/NCT05071573?term=NCT05071573&draw=2&rank=1.

Lower birth weight-for-age and length-for-age z-scores in infants with in-utero HIV and ART exposure: a prospective study in Cape Town, South Africa.

BACKGROUND: Successful scale-up of antiretroviral therapy (ART) during pregnancy has minimized infant HIV acquisition, and over 1 million infants are born HIV-exposed but uninfected (HEU), with an increasing proportion also exposed in utero to maternal ART. While benefits of ART in pregnancy outweigh risks, some studies have reported associations between in utero ART exposure and impaired fetal growth, highlighting the need to identify the safest ART regimens for use in pregnancy. METHODS: We compared birth anthropometrics of infants who were HEU with those HIV-unexposed (HU) in Cape Town, South Africa. Pregnant women had gestational age assessed by ultrasound at enrolment. Women living with HIV were on ART (predominately tenofovir-emtricitabine-efavirenz) either prior to conception or initiated during pregnancy. Birth weights and lengths were converted to weight-for-age (WAZ) and length-for-age (LAZ) z-scores using Intergrowth-21st software. Linear regression was used to compare mean z-scores adjusting for maternal and pregnancy characteristics. RESULTS: Among 888 infants, 49% (n = 431) were HEU and 51% (n = 457) HU. Of 431 HEU infants, 62% (n = 268) were exposed to HIV and antiretrovirals (ARVs) from conception and 38% (n = 163) were exposed to ARVs during gestation but after conception (median fetal ARV exposure of 21 weeks [IQR; 17-26]). In univariable analysis, infants who were HEU had lower mean WAZ compared with HU [ß = - 0.15 (95% Confidence Interval (CI): - 0.28, - 0.020)]. After adjustment for maternal age, gravidity, alcohol use, marital and employment status the effect remained [adjusted ß - 0.14 (95%CI: - 0.28, - 0.01]. Similar differences were noted for mean LAZ in univariable [ß - 0.20 (95%CI: - 0.42, - 0.01] but not multivariable analyses [adjusted ß - 0.18 (95%CI: - 0.41, + 0.04] after adjusting for the same variables. Mean WAZ and LAZ did not vary by in utero ARV exposure duration among infants who were HEU. CONCLUSION: In a cohort with high prevalence of ART exposure in pregnancy, infants who were HEU had lower birth WAZ compared with those HU. Studies designed to identify the mechanisms and clinical significance of these disparities, and to establish the safest ART for use in pregnancy are urgently needed.

Association between food intake and obesity in pregnant women living with and without HIV in Cape Town, South Africa: a prospective cohort study.

BACKGROUND: Although global nutrition/dietary transition resulting from industrialisation and urbanisation has been identified as a major contributor to widespread trends of obesity, there is limited data in pregnant women, including those living with HIV in South Africa. We examined food-based dietary intake in pregnant women with and without HIV at first antenatal care (ANC) visit, and associations with maternal overweight/obesity and gestational weight gain (GWG). METHODS: In an urban South African community, consecutive women living with (n = 479) and without (n = 510) HIV were enrolled and prospectively followed to delivery. Interviewer-administered non-quantitative food frequency questionnaire was used to assess dietary intake (starch, protein, dairy, fruits, vegetables, legumes, oils/fats) at enrolment. Associations with maternal body mass index (BMI) and GWG were examined using logistic regression models. RESULTS: Among women (median age 29 years, IQR 25-34), the prevalence of obesity (BMI ≥ 30 kg/m2) at first ANC was 43% and that of excessive GWG (per IOM guidelines) was 37% overall; HIV prevalence was 48%. In women without HIV, consumption of potato (any preparation) (aOR 1.98, 95% CI 1.02-3.84) and pumpkin/butternut (aOR 2.13, 95% CI 1.29-3.49) for 1-3 days a week increased the odds of overweight/obesity compared to not consuming any; milk in tea/coffee (aOR 6.04, 95% CI 1.37-26.50) increased the odds of excessive GWG. Consumption of eggs (any) (aOR 0.52, 95% CI 0.32-0.86) for 1-3 days a week reduced the odds of overweight/obesity while peanut and nuts consumption for 4-7 days a week reduced the odds (aOR 0.34, 95% CI 0.14-0.80) of excessive GWG. In women with HIV, consumption of milk/yoghurt/maas to drink/on cereals (aOR 0.35, 95% CI 0.18-0.68), tomato (raw/cooked) (aOR 0.50, 95% CI 0.30-0.84), green beans (aOR 0.41, 95% CI 0.20-0.86), mixed vegetables (aOR 0.49, 95% CI 0.29-0.84) and legumes e.g. baked beans, lentils (aOR 0.50, 95% CI 0.28-0.86) for 4-7 days a week reduced the odds of overweight/obesity; tomato (raw/cooked) (aOR 0.48, 95% CI 0.24-0.96) and mixed vegetables (aOR 0.38, 95% CI 0.18-0.78) also reduced the odds of excessive GWG. CONCLUSIONS: Diet modification may promote healthy weight in pregnant women living with and without HIV.

Effect of HIV Infection and Antiretroviral Treatment on Pregnancy Rates in the Western Cape Province of South Africa.

BACKGROUND: Previous studies suggest that untreated human immunodeficiency virus (HIV) infection is associated with a reduced incidence of pregnancy, but studies of the effect of antiretroviral treatment (ART) on pregnancy incidence have been inconsistent. METHODS: Routine data from health services in the Western Cape province of South Africa were linked to identify pregnancies during 2007-2017 and maternal HIV records. The time from the first (index) pregnancy outcome date to the next pregnancy was modeled using Cox proportional hazards models. RESULTS: During 2007-2017, 1 042 647 pregnancies were recorded. In all age groups, pregnancy incidence rates were highest in women who had started ART, lower in HIV-negative women, and lowest in ART-naive HIV-positive women. In multivariable analysis, after controlling for the most recent CD4+ T-cell count, pregnancy incidence rates in HIV-positive women receiving ART were higher than those in untreated HIV-positive women (adjusted hazard ratio, 1.63; 95% confidence interval, 1.59-1.67) and those in HIV-negative women. CONCLUSION: Among women who have recently been pregnant, receipt of ART is associated with high rates of second pregnancy. Better integration of family planning into HIV care services is needed.

Safety and Effectiveness of Isoniazid Preventive Therapy in Pregnant Women Living with Human Immunodeficiency Virus on Antiretroviral Therapy: An Observational Study Using Linked Population Data.

BACKGROUND: Isoniazid preventive therapy (IPT) is widely used to protect against tuberculosis (TB) in people living with human immunodeficiency virus (HIV). Data on the safety and efficacy of IPT in pregnant women living with HIV (PWLHIV) are mixed. We used an individual-level, population-wide health database to examine associations between antenatal IPT exposure and adverse pregnancy outcomes, maternal TB, all-cause mortality, and liver injury during pregnancy through 12 months postpartum. METHODS: We used linked routine electronic health data generated in the public sector of the Western Cape, South Africa, to define a cohort of PWLHIV on antiretroviral therapy. Pregnancy outcomes were assessed using logistic regression; for maternal outcomes we applied a proportional hazards model with time-updated IPT exposure. RESULTS: Of 43 971 PWLHIV, 16.6% received IPT. Women who received IPT were less likely to experience poor pregnancy outcomes (adjusted odds ratio [aOR], 0.83 [95% confidence interval {CI}, .78-.87]); this association strengthened with IPT started after the first trimester compared with none (aOR, 0.71 [95% CI, .65-.79]) or with first-trimester exposure (aOR, 0.64 [95% CI, .55-.75]). IPT reduced the risk of TB by approximately 30% (aHR, 0.71 [95% CI, .63-.81]; absolute risk difference, 1518/100 000 women). The effect was modified by CD4 cell count with protection conferred if CD4 count was ≤350 cells/µL (aHR, 0.51 [95% CI, .41-.63]) vs 0.93 [95% CI, .76-1.13] for CD4 count >350 cells/µL). CONCLUSIONS: This analysis of programmatic data is reassuring regarding the safety of antenatal IPT, with the greatest benefits against TB disease observed in women with CD4 count ≤350 cells/µL.

The Impact of Delayed Switch to Second-Line Antiretroviral Therapy on Mortality, Depending on Definition of Failure Time and CD4 Count at Failure.

Little is known about the functional relationship of delaying second-line treatment initiation for human immunodeficiency virus-positive patients and mortality, given a patient's immune status. We included 7,255 patients starting antiretroviral therapy during 2004-2017, from 9 South African cohorts, with virological failure and complete baseline data. We estimated the impact of switch time on the hazard of death using inverse probability of treatment weighting of marginal structural models. The nonlinear relationship between month of switch and the 5-year survival probability, stratified by CD4 count at failure, was estimated with targeted maximum likelihood estimation. We adjusted for measured time-varying confounding by CD4 count, viral load, and visit frequency. Five-year mortality was estimated to be 10.5% (95% CI: 2.2, 18.8) for immediate switch and to be 26.6% (95% CI: 20.9, 32.3) for no switch (51.1% if CD4 count was <100 cells/mm3). The hazard of death was estimated to be 0.37 (95% CI: 0.30, 0.46) times lower if everyone had been switched immediately compared with never. The shorter the delay in switching, the lower the hazard of death-delaying 30-59 days reduced the hazard by 0.53 (95% CI: 0.43, 0.65) times and 60-119 days by 0.58 (95% CI: 0.49, 0.69) times, compared with no switch. Early treatment switch is particularly important for patients with low CD4 counts at failure.