Taking connected mobile-health diagnostics of infectious diseases to the field.

Mobile health, or 'mHealth', is the application of mobile devices, their components and related technologies to healthcare. It is already improving patients' access to treatment and advice. Now, in combination with internet-connected diagnostic devices, it offers novel ways to diagnose, track and control infectious diseases and to improve the efficiency of the health system. Here we examine the promise of these technologies and discuss the challenges in realizing their potential to increase patients' access to testing, aid in their treatment and improve the capability of public health authorities to monitor outbreaks, implement response strategies and assess the impact of interventions across the world.

Pregnancy-related mortality up to 1 year postpartum in sub-Saharan Africa: an analysis of verbal autopsy data from six countries.

OBJECTIVE: To compare the causes of death for women who died during pregnancy and within the first 42 days postpartum with those of women who died between >42 days and within 1 year postpartum. DESIGN: Open population cohort (Health and Demographic Surveillance Systems). SETTING: Ten Health and Demographic Surveillance Systems (HDSS) in The Gambia, Kenya, Malawi, Tanzania, Ethiopia and South Africa. POPULATION: 2114 deaths which occurred within 1 year of the end of pregnancy where a verbal autopsy interview was conducted from 2000 to 2019. METHODS: InterVA5 and InSilicoVA verbal autopsy algorithms were used to attribute the most likely underlying cause of death, which were grouped according to adapted International Classification of Diseases-Maternal Mortality categories. Multinomial regression was used to compare differences in causes of deaths within 42 days versus 43-365 days postpartum adjusting for HDSS and time period (2000-2009 and 2010-2019). MAIN OUTCOME MEASURES: Cause of death and the verbal autopsy Circumstances of Mortality Categories (COMCATs). RESULTS: Of 2114 deaths, 1212 deaths occurred within 42 days postpartum and 902 between 43 and 365 days postpartum. Compared with deaths within 42 days, deaths from HIV and TB, other infectious diseases, and non-communicable diseases constituted a significantly larger proportion of late pregnancy-related deaths beyond 42 days postpartum, and health system failures were important in the circumstances of those deaths. The contribution of HIV and TB to deaths beyond 42 days postpartum was greatest in Southern Africa. The causes of pregnancy-related mortality within and beyond 42 days postpartum did not change significantly between 2000-2009 and 2010-2019. CONCLUSIONS: Cause of death data from the extended postpartum period are critical to inform prevention. The dominance of HIV and TB, other infectious and non-communicable diseases to (late) pregnancy-related mortality highlights the need for better integration of non-obstetric care with ante-, intra- and postpartum care in high-burden settings.

Large age shifts in HIV-1 incidence patterns in KwaZulu-Natal, South Africa.

Recent declines in adult HIV-1 incidence have followed the large-scale expansion of antiretroviral therapy and primary HIV prevention across high-burden communities of sub-Saharan Africa. Mathematical modeling suggests that HIV risk will decline disproportionately in younger adult age-groups as interventions scale, concentrating new HIV infections in those >age 25 over time. Yet, no empirical data exist to support these projections. We conducted a population-based cohort study over a 16-y period (2004 to 2019), spanning the early scale-up of antiretroviral therapy and voluntary medical male circumcision, to estimate changes in the age distribution of HIV incidence in a hyperepidemic region of KwaZulu-Natal, South Africa, where adult HIV incidence has recently declined. Median age of HIV seroconversion increased by 5.5 y in men and 3.0 y in women, and the age of peak HIV incidence increased by 5.0 y in men and 2.0 y in women. Incidence declined disproportionately among young men (64% in men 15 to 19, 68% in men 20 to 24, and 46% in men 25 to 29) and young women (44% in women 15 to 19, 24% in women 20 to 24) comparing periods pre- versus post-universal test and treat. Incidence was stable (<20% change) in women aged 30 to 39 and men aged 30 to 34. Age shifts in incidence occurred after 2012 and were observed earlier in men than in women. These results provide direct epidemiological evidence of the changing demographics of HIV risk in sub-Saharan Africa in the era of large-scale treatment and prevention. More attention is needed to address lagging incidence decline among older individuals.

Predicting the Risk of Human Immunodeficiency Virus Type 1 (HIV-1) Acquisition in Rural South Africa Using Geospatial Data.

BACKGROUND: Accurate human immunodeficiency virus (HIV) risk assessment can guide optimal HIV prevention. We evaluated the performance of risk prediction models incorporating geospatial measures. METHODS: We developed and validated HIV risk prediction models in a population-based cohort in South Africa. Individual-level covariates included demographic and sexual behavior measures, and geospatial covariates included community HIV prevalence and viral load estimates. We trained models on 2012-2015 data using LASSO Cox models and validated predictions in 2016-2019 data. We compared full models to simpler models restricted to only individual-level covariates or only age and geospatial covariates. We compared the spatial distribution of predicted risk to that of high incidence areas (≥ 3/100 person-years). RESULTS: Our analysis included 19 556 individuals contributing 44 871 person-years and 1308 seroconversions. Incidence among the highest predicted risk quintile using the full model was 6.6/100 person-years (women) and 2.8/100 person-years (men). Models using only age group and geospatial covariates had similar performance (women: AUROC = 0.65, men: AUROC = 0.71) to the full models (women: AUROC = 0.68, men: AUROC = 0.72). Geospatial models more accurately identified high incidence regions than individual-level models; 20% of the study area with the highest predicted risk accounted for 60% of the high incidence areas when using geospatial models but only 13% using models with only individual-level covariates. CONCLUSIONS: Geospatial models with no individual measures other than age group predicted HIV risk nearly as well as models that included detailed behavioral data. Geospatial models may help guide HIV prevention efforts to individuals and geographic areas at highest risk.

Early HIV treatment and survival over six years of observation in the ANRS 12249 Treatment as Prevention Trial.

OBJECTIVES: Population-based universal test and treat (UTT) trials have shown an impact on population-level virological suppression. We followed the ANRS 12249 TasP trial population for 6 years to determine whether the intervention had longer-term survival benefits. METHODS: The TasP trial was a cluster-randomized trial in South Africa from 2012 to 2016. All households were offered 6-monthly home-based HIV testing. Immediate antiretroviral therapy (ART) was offered through trial clinics to all people living with HIV (PLHIV) in intervention clusters and according to national guidelines in control clusters. After the trial, individuals attending the trial clinics were transferred to the public ART programme. Deaths were ascertained through annual demographic surveillance. Random-effects Poisson regression was used to estimate the effect of trial arm on mortality among (i) all PLHIV; (ii) PLHIV aware of their status and not on ART at trial entry; and (iii) PHLIV who started ART during the trial. RESULTS: Mortality rates among PLHIV were 9.3/1000 and 10.4/1000 person-years in the control and intervention arms, respectively. There was no evidence that the intervention decreased mortality among all PLHIV [adjusted rate ratio (aRR) = 1.10, 95% confidence interval (CI) = 0.85-1.43, p = 0.46] or among PLHIV who were aware of their status but not on ART. Among individuals who initiated ART, the intervention decreased mortality during the trial (aRR = 0.49, 95% CI = 0.28-0.85, p = 0.01), but not after the trial ended. CONCLUSIONS: The 'treat all' strategy reduced mortality among individuals who started ART but not among all PLHIV. To achieve maximum benefit of immediate ART, barriers to ART uptake and retention in care need to be addressed.

Impact of the Covid-19 epidemic and related social distancing regulations on social contact and SARS-CoV-2 transmission potential in rural South Africa: analysis of repeated cross-sectional surveys.

BACKGROUND: South Africa implemented rapid and strict physical distancing regulations to minimize SARS-CoV-2 epidemic spread. Evidence on the impact of such measures on interpersonal contact in rural and lower-income settings is limited. METHODS: We compared population-representative social contact surveys conducted in the same rural KwaZulu-Natal location once in 2019 and twice in mid-2020. Respondents reported characteristics of physical and conversational ('close interaction') contacts over 24 hours. We built age-mixing matrices and estimated the proportional change in the SARS-CoV-2 reproduction number (R0). Respondents also reported counts of others present at locations visited and transport used, from which we evaluated change in potential exposure to airborne infection due to shared indoor space ('shared air'). RESULTS: Respondents in March-December 2019 (n = 1704) reported a mean of 7.4 close interaction contacts and 196 shared air person-hours beyond their homes. Respondents in June-July 2020 (n = 216), as the epidemic peaked locally, reported 4.1 close interaction contacts and 21 shared air person-hours outside their home, with significant declines in others' homes and public spaces. Adults aged over 50 had fewer close contacts with others over 50, but little change in contact with 15-29 year olds, reflecting ongoing contact within multigenerational households. We estimate potential R0 fell by 42% (95% plausible range 14-59%) between 2019 and June-July 2020. CONCLUSIONS: Extra-household social contact fell substantially following imposition of Covid-19 distancing regulations in rural South Africa. Ongoing contact within intergenerational households highlighted a potential limitation of social distancing measures in protecting older adults.

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.

The impact of continuous quality improvement on coverage of antenatal HIV care tests in rural South Africa: Results of a stepped-wedge cluster-randomised controlled implementation trial.

BACKGROUND: Evidence for the effectiveness of continuous quality improvement (CQI) in resource-poor settings is very limited. We aimed to establish the effects of CQI on quality of antenatal HIV care in primary care clinics in rural South Africa. METHODS AND FINDINGS: We conducted a stepped-wedge cluster-randomised controlled trial (RCT) comparing CQI to usual standard of antenatal care (ANC) in 7 nurse-led, public-sector primary care clinics-combined into 6 clusters-over 8 steps and 19 months. Clusters randomly switched from comparator to intervention on pre-specified dates until all had rolled over to the CQI intervention. Investigators and clusters were blinded to randomisation until 2 weeks prior to each step. The intervention was delivered by trained CQI mentors and included standard CQI tools (process maps, fishbone diagrams, run charts, Plan-Do-Study-Act [PDSA] cycles, and action learning sessions). CQI mentors worked with health workers, including nurses and HIV lay counsellors. The mentors used the standard CQI tools flexibly, tailored to local clinic needs. Health workers were the direct recipients of the intervention, whereas the ultimate beneficiaries were pregnant women attending ANC. Our 2 registered primary endpoints were viral load (VL) monitoring (which is critical for elimination of mother-to-child transmission of HIV [eMTCT] and the health of pregnant women living with HIV) and repeat HIV testing (which is necessary to identify and treat women who seroconvert during pregnancy). All pregnant women who attended their first antenatal visit at one of the 7 study clinics and were ≥18 years old at delivery were eligible for endpoint assessment. We performed intention-to-treat (ITT) analyses using modified Poisson generalised linear mixed effects models. We estimated effect sizes with time-step fixed effects and clinic random effects (Model 1). In separate models, we added a nested random clinic-time step interaction term (Model 2) or individual random effects (Model 3). Between 15 July 2015 and 30 January 2017, 2,160 participants with 13,212 ANC visits (intervention n = 6,877, control n = 6,335) were eligible for ITT analysis. No adverse events were reported. Median age at first booking was 25 years (interquartile range [IQR] 21 to 30), and median parity was 1 (IQR 0 to 2). HIV prevalence was 47% (95% CI 42% to 53%). In Model 1, CQI significantly increased VL monitoring (relative risk [RR] 1.38, 95% CI 1.21 to 1.57, p < 0.001) but did not improve repeat HIV testing (RR 1.00, 95% CI 0.88 to 1.13, p = 0.958). These results remained essentially the same in both Model 2 and Model 3. Limitations of our study include that we did not establish impact beyond the duration of the relatively short study period of 19 months, and that transition steps may have been too short to achieve the full potential impact of the CQI intervention. CONCLUSIONS: We found that CQI can be effective at increasing quality of primary care in rural Africa. Policy makers should consider CQI as a routine intervention to boost quality of primary care in rural African communities. Implementation research should accompany future CQI use to elucidate mechanisms of action and to identify factors supporting long-term success. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov under registration number NCT02626351.

Home deaths of children under 5 years in rural South Africa: a population-based longitudinal study.

OBJECTIVES: To determine the proportion of under-5 deaths that occurred at home in rural South Africa, whether care was sought prior to death, and determinants of home deaths amongst those who sought care. METHODS: Verbal autopsy data were used for all under-5 deaths, 2000-2015, in two health and demographic surveillance system sites. Trends in place of death and care-seeking were assessed. Associations between sociodemographic factors and home death despite seeking care were assessed by multivariate logistic regressions. RESULTS: There were 3760 under-5 deaths; 1954 (53%) at home and 1510 (41%) in health facilities. Eighty-four per cent of children who died at home accessed healthcare during their final illness. Amongst neonates for whom care was sought, those who were 8-27 days old were more likely to die at home than those who were 0-7 days old (OR = 5.56, 95%CI 2.69-11.55, P < 0.001). Factors associated with home death of infants and young children despite seeking care included low maternal education (OR = 1.71, 95%CI 1.31-2.24, P < 0.001), larger household size (OR = 1.56, 95%CI 1.17-2.06, P = 0.002), traditional medicine use (OR = 2.33, 95%CI 1.75-3.12, P < 0.001) and Mozambican descent (OR = 1.47, 95%CI 1.06-2.03, P = 0.020). The proportion of HIV-related deaths that occurred at home fell from 60% in 2008-2011 to 39% in 2012-2015 ( χ2  = 13.86, P < 0.001). CONCLUSION: More than half of under-5 deaths in rural South Africa occurred at home although healthcare was sought for most children, highlighting that home deaths are not simply a function of poor care-seeking. Interventions should target high-risk sociodemographic groups.

OBJECTIFS: Déterminer la proportion de décès d'enfants de moins de 5 ans survenus à domicile dans les zones rurales d'Afrique du Sud, si des soins ont été recherchés avant le décès et les déterminants des décès à domicile chez ceux qui ont recherché des soins. MÉTHODES: Les données d'autopsie verbale ont été utilisées pour tous les décès d'enfants de moins de 5 ans entre 2000 et 2015, dans deux sites du système de surveillance démographique et de santé. Les tendances en matière de lieu de décès et de recherche de soins ont été évaluées. Les associations entre les facteurs sociodémographiques et le décès à domicile malgré les soins recherchés ont été évaluées par des régressions logistiques multivariées. RÉSULTATS: Il y a eu 3.760 décès de moins de 5 ans; 1.954 (53%) à domicile et 1.510 (41%) dans les établissements de santé. 84% des enfants décédés à domicile ont eu accès à des soins de santé au cours de leur dernière maladie. Parmi les nouveau-nés pour lesquels des soins ont été recherchés, ceux âgés de 8 à 27 jours étaient plus susceptibles de mourir à domicile que ceux âgés de 0 à 7 jours (OR = 5,56; IC95% 2,69-11,55; p <0,001). Les facteurs associés au décès des nourrissons et des jeunes enfants à domicile malgré la recherche de soins comprenaient un niveau d'éducation maternelle faible (OR = 1,71; IC95%: 1,31-2,24; p <0,001), une taille du ménage plus grande (OR = 1,56; IC95%: 1,17-2,06; p = 0,002), l'utilisation de la médecine traditionnelle (OR = 2,33; IC95%: 1,75-3,12; p <0,001) et l'origine mozambicaine (OR = 1,47; IC95%: 1,06-2,03; p = 0,020). La proportion de décès liés au VIH survenus à domicile est passée de 60% en 2008-2011 à 39% en 2012-2015 (Chi2 = 13,86; p <0,001). CONCLUSION: Plus de la moitié des décès des moins de 5 ans dans les zones rurales d'Afrique du Sud sont survenus à domicile bien que pour la plupart des enfants une recherche de soins de santé a été effectuée, soulignant que les décès à domicile ne sont pas simplement liés à un mauvais recours aux soins. Les interventions devraient cibler les groupes sociodémographiques à haut risque.

List randomization for eliciting HIV status and sexual behaviors in rural KwaZulu-Natal, South Africa: a randomized experiment using known true values for validation.

BACKGROUND: List randomization (LR), a survey method intended to mitigate biases related to sensitive true/false questions, has received recent attention from researchers. However, tests of its validity are limited, with no study comparing LR-elicited results with individually known truths. We conducted a test of LR for HIV-related responses in a high HIV prevalence setting in KwaZulu-Natal. By using researcher-known HIV serostatus and HIV test refusal data, we were able to assess how LR and direct questionnaires perform against individual known truth. METHODS: Participants were recruited from the participation list from the 2016 round of the Africa Health Research Institute demographic surveillance system, oversampling individuals who were HIV positive. Participants were randomized to two study arms. In Arm A, participants were presented five true/false statements, one of which was the sensitive item, the others non-sensitive. Participants were then asked how many of the five statements they believed were true. In Arm B, participants were asked about each statement individually. LR estimates used data from both arms, while direct estimates were generated from Arm B alone. We compared elicited responses to HIV testing and serostatus data collected through the demographic surveillance system. RESULTS: We enrolled 483 participants, 262 (54%) were randomly assigned to Arm A, and 221 (46%) to Arm B. LR estimated 56% (95% CI: 40 to 72%) of the population to be HIV-negative, compared to 47% (95% CI: 39 to 54%) using direct estimates; the population-estimate of the true value was 32% (95% CI: 28 to 36%). LR estimates yielded HIV test refusal percentages of 55% (95% CI: 37 to 73%) compared to 13% (95% CI: 8 to 17%) by direct estimation, and 15% (95% CI: 12 to 18%) based on observed past behavior. CONCLUSIONS: In this context, LR performed poorly when compared to known truth, and did not improve estimates over direct questioning methods when comparing with known truth. These results may reflect difficulties in implementation or comprehension of the LR approach, which is inherently complex. Adjustments to delivery procedures may improve LR's usefulness. Further investigation of the cognitive processes of participants in answering LR surveys is warranted.

The MONARCH intervention to enhance the quality of antenatal and postnatal primary health services in rural South Africa: protocol for a stepped-wedge cluster-randomised controlled trial.

BACKGROUND: Gaps in maternal and child health services can slow progress towards achieving the Sustainable Development Goals. The Management and Optimization of Nutrition, Antenatal, Reproductive, Child Health & HIV Care (MONARCH) study will evaluate a Continuous Quality Improvement (CQI) intervention targeted at improving antenatal and postnatal health service outcomes in rural South Africa where HIV prevalence among pregnant women is extremely high. Specifically, it will establish the effectiveness of CQI on viral load (VL) testing in pregnant women who are HIV-positive and repeat HIV testing in pregnant women who are HIV-negative. METHODS: This is a stepped-wedge cluster-randomised controlled trial (RCT) of 7 nurse-led primary healthcare clinics to establish the effect of CQI on selected routine antenatal and postnatal services. Each clinic was a cluster, with the exception of the two smallest clinics, which jointly formed one cluster. The intervention was applied at the cluster level, where staff received training on CQI methodology and additional mentoring as required. In the control exposure state, the clusters received the South African Department of Health standard of care. After a baseline data collection period of 2 months, the first cluster crossed over from control to intervention exposure state; subsequently, one additional cluster crossed over every 2 months. The six clusters were divided into 3 groups by patient volume (low, medium and high). We randomised the six clusters to the sequences of crossing over, such that both the first three and the last three sequences included one cluster with low, one with medium, and one with high patient volume. The primary outcome measures were (i) viral load testing among pregnant women who were HIV-positive, and (ii) repeat HIV testing among pregnant women who were HIV-negative. Consenting women ≥18 years attending antenatal and postnatal care during the data collection period completed outcome measures at delivery, and postpartum at three to 6 days, and 6 weeks. Data collection started on 15 July 2015. The total study duration, including pre- and post-exposure phases, was 19 months. Data will be analyzed by intention-to-treat based on first booked clinic of study participants. DISCUSSION: The results of the MONARCH trial will establish the effectiveness of CQI in improving antenatal and postnatal clinic processes in primary care in sub-Saharan Africa. More generally, the results will contribute to our knowledge on quality improvement interventions in resource-poor settings. TRIAL REGISTRATION: This trial was registered on 10 December 2015: www.clinicaltrials.gov, identifier NCT02626351 .

Mass HIV Treatment and Sex Disparities in Life Expectancy: Demographic Surveillance in Rural South Africa.

BACKGROUND: Women have better patient outcomes in HIV care and treatment than men in sub-Saharan Africa. We assessed--at the population level--whether and to what extent mass HIV treatment is associated with changes in sex disparities in adult life expectancy, a summary metric of survival capturing mortality across the full cascade of HIV care. We also determined sex-specific trends in HIV mortality and the distribution of HIV-related deaths in men and women prior to and at each stage of the clinical cascade. METHODS AND FINDINGS: Data were collected on all deaths occurring from 2001 to 2011 in a large population-based surveillance cohort (52,964 women and 45,688 men, ages 15 y and older) in rural KwaZulu-Natal, South Africa. Cause of death was ascertained by verbal autopsy (93% response rate). Demographic data were linked at the individual level to clinical records from the public sector HIV treatment and care program that serves the region. Annual rates of HIV-related mortality were assessed for men and women separately, and female-to-male rate ratios were estimated in exponential hazard models. Sex-specific trends in adult life expectancy and HIV-cause-deleted adult life expectancy were calculated. The proportions of HIV deaths that accrued to men and women at different stages in the HIV cascade of care were estimated annually. Following the beginning of HIV treatment scale-up in 2004, HIV mortality declined among both men and women. Female adult life expectancy increased from 51.3 y (95% CI 49.7, 52.8) in 2003 to 64.5 y (95% CI 62.7, 66.4) in 2011, a gain of 13.2 y. Male adult life expectancy increased from 46.9 y (95% CI 45.6, 48.2) in 2003 to 55.9 y (95% CI 54.3, 57.5) in 2011, a gain of 9.0 y. The gap between female and male adult life expectancy doubled, from 4.4 y in 2003 to 8.6 y in 2011, a difference of 4.3 y (95% CI 0.9, 7.6). For women, HIV mortality declined from 1.60 deaths per 100 person-years (95% CI 1.46, 1.75) in 2003 to 0.56 per 100 person-years (95% CI 0.48, 0.65) in 2011. For men, HIV-related mortality declined from 1.71 per 100 person-years (95% CI 1.55, 1.88) to 0.76 per 100 person-years (95% CI 0.67, 0.87) in the same period. The female-to-male rate ratio for HIV mortality declined from 0.93 (95% CI 0.82-1.07) in 2003 to 0.73 (95% CI 0.60-0.89) in 2011, a statistically significant decline (p = 0.046). In 2011, 57% and 41% of HIV-related deaths occurred among men and women, respectively, who had never sought care for HIV in spite of the widespread availability of free HIV treatment. The results presented here come from a poor rural setting in southern Africa with high HIV prevalence and high HIV treatment coverage; broader generalizability is unknown. Additionally, factors other than HIV treatment scale-up may have influenced population mortality trends. CONCLUSIONS: Mass HIV treatment has been accompanied by faster declines in HIV mortality among women than men and a growing female-male disparity in adult life expectancy at the population level. In 2011, over half of male HIV deaths occurred in men who had never sought clinical HIV care. Interventions to increase HIV testing and linkage to care among men are urgently needed.

Effect of HIV infection on pregnancy-related mortality in sub-Saharan Africa: secondary analyses of pooled community-based data from the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA).

BACKGROUND: Model-based estimates of the global proportions of maternal deaths that are in HIV-infected women range from 7% to 21%, and the effects of HIV on the risk of maternal death is highly uncertain. We used longitudinal data from the Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA) network to estimate the excess mortality associated with HIV during pregnancy and the post-partum period in sub-Saharan Africa. METHODS: The ALPHA network pooled data gathered between June, 1989 and April, 2012 in six community-based studies in eastern and southern Africa with HIV serological surveillance and verbal-autopsy reporting. Deaths occurring during pregnancy and up to 42 days post partum were defined as pregnancy related. Pregnant or post-partum person-years were calculated for HIV-infected and HIV-uninfected women, and HIV-infected to HIV-uninfected mortality rate ratios and HIV-attributable rates were compared between pregnant or post-partum women and women who were not pregnant or post partum. FINDINGS: 138,074 women aged 15-49 years contributed 636,213 person-years of observation. 49,568 women had 86,963 pregnancies. 6760 of these women died, 235 of them during pregnancy or the post-partum period. Mean prevalence of HIV infection across all person-years in the pooled data was 17.2% (95% CI 17.0-17.3), but 60 of 118 (50.8%) of the women of known HIV status who died during pregnancy or post partum were HIV infected. The mortality rate ratio of HIV-infected to HIV-uninfected women was 20.5 (18.9-22.4) in women who were not pregnant or post partum and 8.2 (5.7-11.8) in pregnant or post-partum women. Excess mortality attributable to HIV was 51.8 (47.8-53.8) per 1000 person-years in women who were not pregnant or post partum and 11.8 (8.4-15.3) per 1000 person-years in pregnant or post-partum women. INTERPRETATION: HIV-infected pregnant or post-partum women had around eight times higher mortality than did their HIV-uninfected counterparts. On the basis of this estimate, we predict that roughly 24% of deaths in pregnant or post-partum women are attributable to HIV in sub-Saharan Africa, suggesting that safe motherhood programmes should pay special attention to the needs of HIV-infected pregnant or post-partum women. FUNDING: Wellcome Trust, Health Metrics Network (WHO).

Mortality variability and differentials by age and causes of death in rural South Africa, 1994-2018.

INTRODUCTION: Understanding mortality variability by age and cause is critical to identifying intervention and prevention actions to support disadvantaged populations. We assessed mortality changes in two rural South African populations over 25 years covering pre-AIDS and peak AIDS epidemic and subsequent antiretroviral therapy (ART) availability. METHODS: Using population surveillance data from the Agincourt Health and Socio-Demographic Surveillance System (AHDSS; 1994-2018) and Africa Health Research Institute (AHRI; 2000-2018) for 5-year periods, we calculated life expectancy from birth to age 85, mortality age distributions and variation, and life-years lost (LYL) decomposed into four cause-of-death groups. RESULTS: The AIDS epidemic shifted the age-at-death distribution to younger ages and increased LYL. For AHDSS, between 1994-1998 and 1999-2003 LYL increased for females from 13.6 years (95% CI 12.7 to 14.4) to 22.1 (95% CI 21.2 to 23.0) and for males from 19.9 (95% CI 18.8 to 20.8) to 27.1 (95% CI 26.2 to 28.0). AHRI LYL in 2000-2003 was extremely high (females=40.7 years (95% CI 39.8 to 41.5), males=44.8 years (95% CI 44.1 to 45.5)). Subsequent widespread ART availability reduced LYL (2014-2018) for women (AHDSS=15.7 (95% CI 15.0 to 16.3); AHRI=22.4 (95% CI 21.7 to 23.1)) and men (AHDSS=21.2 (95% CI 20.5 to 22.0); AHRI=27.4 (95% CI 26.7 to 28.2)), primarily due to reduced HIV/AIDS/TB deaths in mid-life and other communicable disease deaths in children. External causes increased as a proportion of LYL for men (2014-2018: AHRI=25%, AHDSS=17%). The share of AHDSS LYL 2014-2018 due to non-communicable diseases exceeded pre-HIV levels: females=43%; males=40%. CONCLUSIONS: Our findings highlight shifting burdens in cause-specific LYL and persistent mortality differentials in two populations experiencing complex epidemiological transitions. Results show high contributions of child deaths to LYL at the height of the AIDS epidemic. Reductions in LYL were primarily driven by lowered HIV/AIDS/TB and other communicable disease mortality during the ART periods. LYL differentials persist despite widespread ART availability, highlighting the contributions of other communicable diseases in children, HIV/AIDS/TB and external causes in mid-life and non-communicable diseases in older ages.

HIV, multimorbidity, and health-related quality of life in rural KwaZulu-Natal, South Africa: A population-based study.

Health-related quality of life (HRQoL) assesses the perceived impact of health status across life domains. Although research has explored the relationship between specific conditions, including HIV, and HRQoL in low-resource settings, less attention has been paid to the association between multimorbidity and HRQoL. In a secondary analysis of cross-sectional data from the Vukuzazi ("Wake up and know ourselves" in isiZulu) study, which identified the prevalence and overlap of non-communicable and infectious diseases in the uMkhanyakunde district of KwaZulu-Natal, we (1) evaluated the impact of multimorbidity on HRQoL; (2) determined the relative associations among infectious diseases, non-communicable diseases (NCDs), and HRQoL; and (3) examined the effects of controlled versus non-controlled disease on HRQoL. HRQoL was measured using the EQ-5D-3L, which assesses overall perceived health, five specific domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), and three levels of problems (no problems, some problems, and extreme problems). Six diseases and disease states were included in this analysis: HIV, diabetes, stroke, heart attack, high blood pressure, and TB. After examining the degree to which number of conditions affects HRQoL, we estimated the effect of joint associations among combinations of diseases, each HRQoL domain, and overall health. Then, in one set of ridge regression models, we assessed the relative impact of HIV, diabetes, stroke, heart attack, high blood pressure, and tuberculosis on the HRQoL domains; in a second set of models, the contribution of treatment (controlled vs. uncontrolled disease) was added. A total of 14,008 individuals were included in this analysis. Having more conditions adversely affected perceived health (r = -0.060, p<0.001, 95% CI: -0.073 to -0.046) and all HRQoL domains. Infectious conditions were related to better perceived health (r = 0.051, p<0.001, 95% CI: 0.037 to 0.064) and better HRQoL, whereas non-communicable diseases (NCDs) were associated with worse perceived health (r = -0.124, p<0.001, -95% CI: 0.137 to -0.110) and lower HRQoL. Particular combinations of NCDs were detrimental to perceived health, whereas HIV, which was characterized by access to care and suppressed viral load in the large majority of those affected, was counterintuitively associated with better perceived health. With respect to disease control, unique combinations of uncontrolled NCDs were significantly related to worse perceived health, and controlled HIV was associated with better perceived health. The presence of controlled and uncontrolled NCDs was associated with poor perceived health and worse HRQoL, whereas the presence of controlled HIV was associated with improved HRQoL. HIV disease control may be critical for HRQoL among people with HIV, and incorporating NCD prevention and attention to multimorbidity into healthcare strategies may improve HRQoL.

Household structure, composition and child mortality in the unfolding antiretroviral therapy era in rural South Africa: comparative evidence from population surveillance, 2000-2015.

OBJECTIVES: The structure and composition of the household has important influences on child mortality. However, little is known about these factors in HIV-endemic areas and how associations may change with the introduction and widespread availability of antiretroviral treatment (ART). We use comparative, longitudinal data from two demographic surveillance sites in rural South Africa (2000-2015) on mortality of children younger than 5 years (n=101 105). DESIGN: We use multilevel discrete time event history analysis to estimate children's probability of dying by their matrilineal residential arrangements. We also test if associations have changed over time with ART availability. SETTING: Rural South Africa. PARTICIPANTS: Children younger than 5 years (n=101 105). RESULTS: 3603 children died between 2000 and 2015. Mortality risks differed by co-residence patterns along with different types of kin present in the household. Children in nuclear households with both parents had the lowest risk of dying compared with all other household types. Associations with kin and child mortality were moderated by parental status. Having older siblings lowered the probability of dying only for children in a household with both parents (relative risk ratio (RRR)=0.736, 95% CI (0.633 to 0.855)). Only in the later ART period was there evidence that older adult kin lowered the probability of dying for children in single parent households (RRR=0.753, 95% CI (0.664 to 0.853)). CONCLUSIONS: Our findings provide comparative evidence of how differential household profiles may place children at higher mortality risk. Formative research is needed to understand the role of other household kin in promoting child well-being, particularly in one-parent households that are increasingly prevalent.

Operational manager's knowledge and attitudes toward data and universal health coverage indicators in primary health clinics in Ugu, South Africa.

Universal health coverage (UHC) aims to ensure people have access to the health services they need. Sixteen tracer indicators were developed for implementation by countries to measure UHC in the health system. South Africa uses 15 of the proposed 16 indicators. Operational managers in the public health care sector collect data and report on these indicators at a primary health clinic level. This qualitative study explored the knowledge and attitudes of managers toward data and UHC service indicators in a sub-district in Ugu, KwaZulu-Natal, South Africa. Operational managers saw data collection as information gathering, measuring performance and driving action. They understood UHC indicators as 'health for all' linking them to National Department of Health Strategic plans and saw the value of indicators for health promotion. They found the lack of training, inadequate numeracy skills, requests for data from multiple spheres of government and the indicator targets that they had to reach as challenging and untenable. While operational managers made the link between data, measuring performance and action, the limited training, skills gaps and pressures from higher levels of government may impede their ability to use data for local level planning and decision making.

The Impact of Drought on HIV Care in Rural South Africa: An Interrupted Time Series Analysis.

This analysis investigates the relationship between drought and antiretroviral treatment (ART) adherence and retention in HIV care in the Hlabisa sub-district, KwaZulu-Natal, South Africa. Data on drought and ART adherence and retention were collated for the study period 2010-2019. Drought was quantified using the 3-month Standard Precipitation Evapotranspiration Index (SPEI) and Standard Precipitation Index (SPI) from station data. Adherence, proxied by the Medication Possession Ratio (MPR), and retention data were obtained from the public ART programme database. MPR and retention were calculated from individuals aged 15-59 years who initiated ART between January 2010 and December 2018 and visited clinic through February 2019. Between 01 January 2010 and 31 December 2018, 40,714 individuals started ART in the sub-district and made 1,022,760 ART visits. The SPI showed that 2014-2016 were dry years, with partial recovery after 2016 in the wet years. In the period from 2010 to 2012, mean 6-month MPR increased from 0.85 in July 2010 to a high of 0.92 in December 2012. MPR then decreased steadily through 2013 and 2014 to 0.78 by December 2014. The mean proportion retained in care 6 months after starting ART showed similar trends to MPR, increasing from 86.9% in July 2010 to 91.4% in December 2012. Retention then decreased through 2013, with evidence of a pronounced drop in January 2014 when the odds of retention decreased by 30% (OR = 0.70, CI = 0.53-0.92, P = 0.01) relative to the end of 2013. Adherence and retention in care decreased during the drought years.

COVID-19 vaccine uptake, confidence and hesitancy in rural KwaZulu-Natal, South Africa between April 2021 and April 2022: A continuous cross-sectional surveillance study.

High COVID-19 vaccine hesitancy in South Africa limits protection against future epidemic waves. We evaluated how vaccine hesitancy and its correlates evolved April 2021-April 2022 in a well-characterized rural KwaZulu-Natal setting. All residents aged >15 in the Africa Health Research Institute's surveillance area were invited to complete a home-based, in-person interview. We described vaccine uptake and hesitancy trends, then evaluated associations with pre-existing personal factors, dynamic environmental context, and cues to action using ordinal logistic regression. Among 10,011 respondents, vaccine uptake rose as age-cohorts became vaccine-eligible before levelling off three months post-eligibility; younger age-groups had slower uptake and plateaued faster. Lifetime receipt of any COVID-19 vaccine rose from 3.0% in April-July 2021 to 32.9% in January-April 2022. Among 7,445 unvaccinated respondents, 47.7% said they would definitely take a free vaccine today in the first quarter of the study time period, falling to 32.0% in the last. By March/April 2022 only 48.0% of respondents were vaccinated or said they would definitely would take a vaccine. Predictors of lower vaccine hesitancy included being male (adjusted odds ratio [aOR]: 0.70, 95% confidence interval [CI]: 0.65-0.76), living with vaccinated household members (aOR:0.65, 95%CI: 0.59-0.71) and knowing someone who had had COVID-19 (aOR: 0.69, 95%CI: 0.59-0.80). Mistrust in government predicted greater hesitancy (aOR: 1.47, 95%CI: 1.42-1.53). Despite several COVID-19 waves, vaccine hesitancy was common in rural South Africa, rising over time and closely tied to mistrust in government. However, interpersonal experiences countered hesitancy and may be entry-points for interventions.

Implementation and effectiveness of a linkage to HIV care intervention in rural South Africa (ANRS 12249 TasP trial).

BACKGROUND: Timely linkage to care and ART initiation is critical to decrease the risks of HIV-related morbidity, mortality and HIV transmission, but is often challenging. We report on the implementation and effectiveness of a linkage-to-care intervention in rural KwaZulu-Natal, South Africa. METHODS: In the ANRS 12249 TasP trial on Universal Testing and Treatment (UTT) implemented between 2012-2016, resident individuals ≥16 years were offered home-based HIV testing every six months. Those ascertained to be HIV-positive were referred to trial clinics. Starting May 2013, a linkage-to-care intervention was implemented in both trial arms, consisting of tracking through phone calls and/or home visits to "re-refer" people who had not linked to care to trial clinics within three months of the first home-based referral. Fidelity in implementing the planned intervention was described using Kaplan-Meier estimation to compute conditional probabilities of being tracked and of being re-referred by the linkage-to-care team. Effect of the intervention on time to linkage-to-care was analysed using a Cox regression model censored for death, migration, and end of data follow-up. RESULTS: Among the 2,837 individuals (73.7% female) included in the analysis, 904 (32%) were tracked at least once, and 573 of them (63.4%) were re-referred. Probabilities of being re-referred was 17% within six months of first referral and 31% within twelve months. Compared to individuals not re-referred by the intervention, linkage-to-care was significantly higher among those with at least one re-referral through phone call (adjusted hazard ratio [aHR] = 1.82; 95% confidence interval [95% CI] = 1.47-2.25), and among those with re-referral through both phone call and home visit (aHR = 3.94; 95% CI = 2.07-7.48). CONCLUSIONS: Phone calls and home visits following HIV testing were challenging to implement, but appeared effective in improving linkage-to-care amongst those receiving the intervention. Such patient-centred strategies should be part of UTT programs to achieve the UNAIDS 95-95-95 targets.