Association between HIV and acquisition of rifamycin resistance with first-line TB treatment: a systematic review and meta-analysis.

BACKGROUND: Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR). METHODS: To assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment. RESULTS: Ten studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7%) PLHIV. Overall, 312 (0.32%) acquired rifamycin-resistance, among whom 115 (36.9%) were PLHIV. The weighted odds of ARR were 4.57 (95% CI, 2.01-10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment. CONCLUSION: The available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022327337.

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.

Linking mortuary data improves vital statistics on cause of death of children under five years in the Western Cape Province of South Africa.

OBJECTIVES: Reducing child mortality requires good information on its causes. Whilst South African vital registration data have improved, the quality of cause-of-death data remains inadequate. To improve this, data from death certificates were linked with information from forensic mortuaries in Western Cape Province. METHODS: A local mortality surveillance system was established in 2007 by the Western Cape Health Department to improve data quality. Cause-of-death data were captured from copies of death notification forms collected at Department of Home Affairs Offices. Using unique identifiers, additional forensic mortuary data were linked with mortality surveillance system records. Causes of death were coded to the ICD-10 classification. Causes of death in children under five were compared with those from vital registration data for 2011. RESULTS: Cause-of-death data were markedly improved with additional data from forensic mortuaries. The proportion of ill-defined causes was halved (25-12%), and leading cause rankings changed. Lower respiratory tract infections moved above prematurity to rank first, accounting for 20.8% of deaths and peaking in infants aged 1-3 months. Only 11% of deaths from lower respiratory tract infections occurred in hospital, resulting in 86% being certified in forensic mortuaries. Road traffic deaths increased from 1.1-3.1% (27-75) and homicides from 3 to 28. CONCLUSIONS: The quality and usefulness of cause-of-death information for children in the WC was enhanced by linking mortuary and vital registration data. Given the death profile, interventions are required to prevent and manage LRTI, diarrhoea and injuries and to reduce neonatal deaths.

Can verbal autopsies be used on a national scale? Key findings and lessons from South Africa's national cause-of-death validation study.

BACKGROUND: Verbal autopsy (VA), though imperfect, serves as a vital tool to determine cause-of-death, particularly for out-of-facility deaths, but challenges persist in integrating VA into Civil Registration and Vital Statistics systems. OBJECTIVE: To describe the challenges and successes of collecting a national sample of verbal autopsy interviews in South Africa to obtain the cause of death profile in 2017/18. METHODS: We recruited next of kin from 27 randomly selected sub-districts (10.5%) across South Africa between September 2017 and April 2018. Trained fieldworkers conducted face-to-face interviews using the WHO2016 VA instrument, with physicians certifying underlying causes of death. Feasibility was evaluated based on response rates, participation, and data quality. RESULTS: Of the total 36,976 deaths registered, only 26% were identified during recruitment, with a 55% overall response rate for VA interviews. Physician-reviewed VA data were deemed of good quality for assigning underlying causes of death in 83% of cases. By comparing cause-specific mortality fractions, physician-reviewed VA identified 22.3% HIV/AIDS and InterVA-5 identified 18.5%, aligning with burden of disease estimates, while Statistics South Africa reported 4.9% HIV/AIDS. CONCLUSIONS: The study demonstrated the feasibility of using VA on a national scale, but immense challenges in identifying and recruiting next of kin highlight the importance of formalising VAs within the country's death notification system.

• Main findings: Next of kin of 9 730 decedents were approached at the time of registration of death and 55% consented to be approached later and agreed to do a VA interview by a trained field-worker; 83% of physician-reviewed VA data were considered high-quality for determining underlying causes and 22.3% of all the deaths were due to HIV/AIDS, much higher than the proportion reported in the national statistical office.• Added knowledge: Implementing the VA on a national scale was achievable but significant challenges in recruiting next of kin, emphasising a need to formalise VAs within the country's death notification system.• Global health impact for policy and action: Accurate cause-of-death data are crucial for policymakers to make informed decisions about the country's health system and could be supported by using VAs, particularly for the deaths that occur outside health facilities.

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

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

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. CONCLUSIONS: Mortality was strongly associated with suboptimal HIV control, and the prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimized.

COVID-19 among adults living with HIV: Correlates of mortality in a general population in a resource-limited setting.

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 between mortality and 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 CD4 cell count, viral load, evidence of ART, time since first HIV evidence, and 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 (among those with ART evidence), and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis, chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. Conclusions: Mortality was strongly associated with suboptimal HIV control, and prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimised.

Epidemiology and outcomes of SARS-CoV-2 infection associated with anti-nucleocapsid seropositivity in Cape Town, South Africa.

Background: In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can characterise the scale and determinants of the pandemic, as well as elucidate protection conferred by prior exposure. Methods: We conducted repeated cross-sectional serosurveys (July 2020 - November 2021) using residual plasma from routine convenient blood samples from patients with non-COVID-19 conditions from Cape Town, South Africa. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses, to estimate variant disease severity. Findings: Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.2% in July 2020 to 67.8% in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10% of seropositive individuals had a recorded positive SARS-CoV-2 test. Antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95%CI 0.05-0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95%CI 0.01-0.35). Interpretation: The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19. Funding: Wellcome Trust, National Health Laboratory Service, the Division of Intramural Research, NIAID, NIH (ADR) and Western Cape Government Health.

Higher COVID-19 mortality in low-income communities in the City of Cape Town - a descriptive ecological study.

Background Cape Town, a South African city with high levels of economic inequality, has gone through two COVID-19 waves. There is evidence globally that low-income communities experience higher levels of morbidity and mortality during the pandemic. Methods Age-standardized COVID-19 mortality in the eight sub-districts of Cape Town was compared by economic indicators taken from the most recent Census (unemployment rate, monthly income). Results The overall Standardized Death Rate (SDR) for COVID-19 in Cape Town was 1 640 per million, but there was wide variation across the different sub-districts. A linear relationship was seen between sub-districts with high poverty and high COVID-19 SDRs. Conclusions Low-income communities in Cape Town experienced higher levels of COVID-19 mortality. As we continue to contend with COVID-19, these communities need to be prioritized for access to quality health care.

Local-level mortality surveillance in resource-limited settings: a case study of Cape Town highlights disparities in health.

OBJECTIVE: To identify the leading causes of mortality and premature mortality in Cape Town, South Africa, and its subdistricts, and to compare levels of mortality between subdistricts. METHODS: Cape Town mortality data for the period 2001-2006 were analysed by age, cause of death and sex. Cause-of-death codes were aggregated into three main cause groups: (i) pre-transitional causes (e.g. communicable diseases, maternal causes, perinatal conditions and nutritional deficiencies), (ii) noncommunicable diseases and (iii) injuries. Premature mortality was calculated in years of life lost (YLLs). Population estimates for the Cape Town Metro district were used to calculate age-specific rates per 100,000 population, which were then age-standardized and compared across subdistricts. FINDINGS: The pattern of mortality in Cape Town reflects the quadruple burden of disease observed in the national cause-of-death profile, with HIV/AIDS, other infectious diseases, injuries and noncommunicable diseases all accounting for a significant proportion of deaths. HIV/AIDS has replaced homicide as the leading cause of death. HIV/AIDS, homicide, tuberculosis and road traffic injuries accounted for 44% of all premature mortality. Khayelitsha, the poorest subdistrict, had the highest levels of mortality for all main cause groups. CONCLUSION: Local mortality surveillance highlights the differential needs of the population of Cape Town and provides a wealth of data to inform planning and implementation of targeted interventions. Multisectoral interventions will be required to reduce the burden of disease.

Self-enrolment antenatal health promotion data as an adjunct to maternal clinical information systems in the Western Cape Province of South Africa.

Information systems designed to support health promotion in pregnancy, such as the MomConnect programme, are potential sources of clinical information which can be used to identify pregnancies prospectively and early on. In this paper we demonstrate the feasibility and value of linking records collected through the MomConnect programme, to an emergent province-wide health information exchange in the Western Cape Province of South Africa, which already enumerates pregnancies from a range of other clinical data sources. MomConnect registrations were linked to pregnant women known to the public health services using the limited identifiers collected by MomConnect. Three-quarters of MomConnect registrations could be linked to existing pregnant women, decreasing over time as recording of the national identifier decreased. The MomConnect records were usually the first evidence of pregnancy in pregnancies which were subsequently confirmed by other sources. Those at lower risk of adverse pregnancy outcomes were more likely to register. In some cases, MomConnect was the only evidence of pregnancy for a patient. In addition, the MomConnect records provided gestational age information and new and more recently updated contact numbers to the existing contact registry. The pilot integration of the data in the Western Cape Province of South Africa demonstrates how a client-facing system can augment clinical information systems, especially in contexts where electronic medical records are not widely available.