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.

A health systems intervention to strengthen the integration of tuberculosis and COVID-19 detection: Outcomes of a quasi-experimental study in a high burden tuberculosis district in KwaZulu Natal, South Africa.

OBJECTIVES: The adverse effects of the COVID-19 pandemic on tuberculosis (TB) detection have been well documented. Despite shared symptoms, guidance for integrated screening for TBand COVID-19 are limited, and opportunities for health systems strengthening curtailed by lockdowns. We partnered with a high TB burden district in KwaZulu-Natal, South Africa, to co-develop an integrated approach to assessing COVID-19 and TB, delivered using online learning and quality improvement, and evaluated its performance on TB testing and detection. METHODS: We conducted a mixed methods study incorporating a quasi-experimental design and process evaluation in 10 intervention and 18 control clinics. Nurses in all 28 clinics were all provided access to a four-session online course to integrate TB and COVID-19 screening and testing, which was augmented with some webinar and in-person support at the 10 intervention clinics. We estimated the effects of exposure to this additional support using interrupted time series Poisson regression mixed models. Process evaluation data comprised interviews before and after the intervention. Thematic coding was employed to provide explanations for effects of the intervention. RESULTS: Clinic-level support at intervention clinics was associated with a markedly higher uptake (177 nurses from 10 intervention clinics vs. 19 from 18 control clinics). Lack of familiarity with online learning, and a preference for group learning hindered the transition from face-to-face to online learning. Even so, any exposure to training was initially associated with higher rates of GeneXpert testing (adjusted incidence ratio [IRR] 1.11, 95% confidence interval 1.07-1.15) and higher positive TB diagnosis (IRR 1.38, 1.11-1.71). CONCLUSIONS: These results add to the knowledge base regarding the effectiveness of interventions to strengthen TB case detection during the COVID-19 pandemic. The findings support the feasibility of a shift to online learning approaches in low-resource settings with appropriate support and suggest that even low-intensity interventions are capable of activating nurses to integrate existing disease control priorities during pandemic conditions.

Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial.

BACKGROUND: Real-world evaluation of the safety profile of vaccines after licensure is crucial to accurately characterise safety beyond clinical trials, support continued use, and thereby improve public confidence. The Sisonke study aimed to assess the safety and effectiveness of the Janssen Ad26.COV2.S vaccine among healthcare workers (HCWs) in South Africa. Here, we present the safety data. METHODS AND FINDINGS: In this open-label phase 3b implementation study among all eligible HCWs in South Africa registered in the national Electronic Vaccination Data System (EVDS), we monitored adverse events (AEs) at vaccination sites through self-reporting triggered by text messages after vaccination, healthcare provider reports, and active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from the day of first vaccination (17 February 2021) until 28 days after the final vaccination in the study (15 June 2021). COVID-19 breakthrough infections, hospitalisations, and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. Among 477,234 participants, 10,279 AEs were reported, of which 138 (1.3%) were serious AEs (SAEs) or AEs of special interest. Women reported more AEs than men (2.3% versus 1.6%). AE reports decreased with increasing age (3.2% for age 18-30 years, 2.1% for age 31-45 years, 1.8% for age 46-55 years, and 1.5% for age > 55 years). Participants with previous COVID-19 infection reported slightly more AEs (2.6% versus 2.1%). The most common reactogenicity events were headache (n = 4,923) and body aches (n = 4,483), followed by injection site pain (n = 2,767) and fever (n = 2,731), and most occurred within 48 hours of vaccination. Two cases of thrombosis with thrombocytopenia syndrome and 4 cases of Guillain-Barré Syndrome were reported post-vaccination. Most SAEs and AEs of special interest (n = 138) occurred at lower than the expected population rates. Vascular (n = 37; 39.1/100,000 person-years) and nervous system disorders (n = 31; 31.7/100,000 person-years), immune system disorders (n = 24; 24.3/100,000 person-years), and infections and infestations (n = 19; 20.1/100,000 person-years) were the most common reported SAE categories. A limitation of the study was the single-arm design, with limited routinely collected morbidity comparator data in the study setting. CONCLUSIONS: We observed similar patterns of AEs as in phase 3 trials. AEs were mostly expected reactogenicity signs and symptoms. Furthermore, most SAEs occurred below expected rates. The single-dose Ad26.COV2.S vaccine demonstrated an acceptable safety profile, supporting the continued use of this vaccine in this setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT04838795; Pan African Clinical Trials Registry PACTR202102855526180.

A geospatial analysis of two-hour surgical access to district hospitals in South Africa.

BACKGROUND: In a robust health care system, at least 80% of a country's population should be able to access a district hospital that provides surgical care within 2 hours. The objective was to identify the proportion of the population living within 2 hours of a district hospital with surgical capacity in South Africa. METHODS: All government hospitals in the country were identified. Surgical district hospitals were defined as district hospitals with a surgical provider, a functional operating theatre, and the provision of at least one caesarean section annually. The proportion of the population within two-hour access was estimated using service area methods. RESULTS: Ninety-eight percent of the population had two-hour access to any government hospital in South Africa. One hundred and thirty-eight of 240 (58%) district hospitals had surgical capacity and 86% of the population had two-hour access to these facilities. CONCLUSION: Improving equitable surgical access is urgently needed in sub-Saharan Africa. This study demonstrated that in South Africa, just over half of district hospitals had surgical capacity but more than 80% of the population had two-hour access to these facilities. Strengthening district hospital surgical capacity is an international mandate and needed to improve access.

Alcohol use and sexual risk behaviour among men and women in inner-city Johannesburg, South Africa.

BACKGROUND: Alcohol misuse is a key factor underlying the remarkable vulnerability to HIV infection among men and women in sub-Saharan Africa, especially within urban settings. Its effects, however, vary by type of drinking, population group and are modified by socio-cultural co-factors. METHODS: We interviewed a random sample of 1465 men living in single-sex hostels and 1008 women in adjacent informal settlements in inner-city, Johannesburg, South Africa. Being drunk in the past week was used as an indicator of heavy episodic drinking, and frequency of drinking and number of alcohol units/week used as measures of volume. Associations between dimensions of alcohol use (current drinking, volume of alcohol consumed and heavy episodic drinking patterns) and sexual behaviours were assessed using multivariate logistic regression. RESULTS: Most participants were internal migrants from KwaZulu Natal province. About half of men were current drinkers, as were 13% of women. Of current male drinkers, 18% drank daily and 23% were drunk in the past week (women: 14% and 29% respectively). Among men, associations between heavy episodic drinking and sexual behaviour were especially pronounced. Compared with non-drinkers, episodic ones were 2.6 fold more likely to have transactional sex (95%CI = 1.7-4.1) and 2.2 fold more likely to have a concurrent partner (95%CI = 1.5-3.2). Alcohol use in men, regardless of measure, was strongly associated with having used physical force to have sex. Overall effects of alcohol on sexual behaviour were larger in women than men, and associations were detected between all alcohol measures in women, and concurrency, transactional sex and having been forced to have sex. CONCLUSIONS: Alcohol use and sexual behaviours are strongly linked among male and female migrant populations in inner-city Johannesburg. More rigorous interventions at both local and macro level are needed to alleviate alcohol harms and mitigate the alcohol-HIV nexus, especially among already vulnerable groups. These should target the specific dimensions of alcohol use that are harmful, assist women who drink to do so more safely and address the linkages between alcohol and sexual violence.

Nevirapine versus ritonavir-boosted lopinavir for HIV-infected children.

BACKGROUND: Nevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established. METHODS: In a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24. RESULTS: A total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06). CONCLUSIONS: Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).

Pharmacokinetics and safety of rifabutin in young HIV-infected children receiving rifabutin and lopinavir/ritonavir.

OBJECTIVES: Co-treatment of HIV and TB in young children is complicated by limited treatment options and complex drug-drug interactions. Rifabutin is an alternative to rifampicin for adults receiving a ritonavir-boosted PI. We aimed to evaluate the short-term safety and pharmacokinetics of rifabutin when given with lopinavir/ritonavir in children. PATIENTS AND METHODS: We conducted an open-label study of rifabutin dosed at 5 mg/kg three times a week in HIV-infected children≤5 years of age receiving lopinavir/ritonavir. Intensive steady-state pharmacokinetic sampling was conducted after six doses. The Division of AIDS 2004, clarification 2009, table for grading severity of adverse events was used to classify drug toxicities. The study was registered with ClinicalTrials.gov, number NCT01259219. RESULTS: Six children completed the study prior to closure by institutional review boards. The median (range) AUC0-48 of rifabutin was 6.91 (3.52-8.67) µg ·â€Šh/mL, the median (range) Cmax of rifabutin was 0.39 (0.19-0.46) µg/mL, the median (range) AUC0-48 of 25-O-desacetyl rifabutin was 5.73 (2.85-9.13) µg ·â€Šh/mL and the median (range) Cmax of 25-O-desacetyl rifabutin was 0.17 (0.08-0.32) µg/mL. The neutrophil count declined in all children; two children experienced grade 4 neutropenia, which resolved rapidly without complications. There was strong correlation between AUC0-48 measures and neutrophil counts. CONCLUSIONS: Rifabutin dosed at 5 mg/kg three times per week resulted in lower AUC0-48, AUC0-24 and Cmax values for rifabutin and 25-O-desacetyl rifabutin compared with adults receiving 150 mg of rifabutin daily, the current recommended dose. We observed high rates of severe transient neutropenia, possibly due to immaturity of CYP3A4 in young children. It remains unclear whether a safe and effective rifabutin dose exists for treatment of TB in children receiving lopinavir/ritonavir.

COVID-19 Vaccine Uptake and Effectiveness by Time since Vaccination in the Western Cape Province, South Africa: An Observational Cohort Study during 2020-2022.

There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced widespread SARS-CoV-2 infection before vaccine availability. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa, in an observational cohort study of >2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalization and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies, and healthcare utilization. We found that by the end of 2022, 41% of surviving adults had completed vaccination and 8% had received a booster dose. Recent vaccination was associated with notable reductions in severe COVID-19 during periods dominated by Delta, and Omicron BA.1/2 and BA.4/5 (sub)lineages. During the latest Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57-94 and 49-95, respectively). However, distinct reductions of effectiveness occurred at longer times post completing or boosting vaccination. Results highlight the importance of continued emphasis on COVID-19 vaccination and boosting for those at high risk of severe COVID-19, even in settings with widespread infection-induced immunity.

COVID-19 vaccine uptake and effectiveness by time since vaccination in the Western Cape province, South Africa: An observational cohort study during 2020-2022.

Background: There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced high levels of SARS-CoV-2 infection in a mostly vaccine-naïve population, and has limited vaccine coverage and competing health service priorities. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa. Methods: We performed an observational cohort study of >2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalisation and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies and healthcare utilisation. Results: By end 2022, only 41% of surviving adults had completed vaccination and 8% a booster dose, despite several waves of severe COVID-19. Recent vaccination was associated with notable reductions in severe COVID-19 during distinct analysis periods dominated by Delta, Omicron BA.1/2 and BA.4/5 (sub)lineages: within 6 months of completing vaccination or boosting, vaccine effectiveness was 46-92% for death (range across periods), 45-92% for admission with severe disease or death, and 25-90% for any admission or death. During the Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57-94 and 49-95, respectively). However, there were distinct reductions of VE at larger times post completing or boosting vaccination. Conclusions: Continued emphasis on regular COVID-19 vaccination including boosting is important for those at high risk of severe COVID-19 even in settings with widespread infection-induced immunity.

When to start antiretroviral therapy in children aged 2-5 years: a collaborative causal modelling analysis of cohort studies from southern Africa.

BACKGROUND: There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2-5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2-5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4 percentage (CD4%) <25%. METHODS AND FINDINGS: ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping. The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm(3) (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1-6.5) (no ART) to 2.1% (95% CI: 1.3%-3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%-3.5%) and 2.2% (95% CI: 1.4%-3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data. CONCLUSIONS: The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm(3) or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values. Please see later in the article for the Editors' Summary.

Estimating the time-varying reproduction number for COVID-19 in South Africa during the first four waves using multiple measures of incidence for public and private sectors across four waves.

OBJECTIVES: The aim of this study was to quantify transmission trends in South Africa during the first four waves of the COVID-19 pandemic using estimates of the time-varying reproduction number (R) and to compare the robustness of R estimates based on three different data sources, and using data from public and private sector service providers. METHODS: R was estimated from March 2020 through April 2022, nationally and by province, based on time series of rt-PCR-confirmed cases, hospitalisations, and hospital-associated deaths, using a method that models daily incidence as a weighted sum of past incidence, as implemented in the R package EpiEstim. R was also estimated separately using public and private sector data. RESULTS: Nationally, the maximum case-based R following the introduction of lockdown measures was 1.55 (CI: 1.43-1.66), 1.56 (CI: 1.47-1.64), 1.46 (CI: 1.38-1.53) and 3.33 (CI: 2.84-3.97) during the first (Wuhan-Hu), second (Beta), third (Delta), and fourth (Omicron) waves, respectively. Estimates based on the three data sources (cases, hospitalisations, deaths) were generally similar during the first three waves, but higher during the fourth wave for case-based estimates. Public and private sector R estimates were generally similar except during the initial lockdowns and in case-based estimates during the fourth wave. CONCLUSION: Agreement between R estimates using different data sources during the first three waves suggests that data from any of these sources could be used in the early stages of a future pandemic. The high R estimates for Omicron relative to earlier waves are interesting given a high level of exposure pre-Omicron. The agreement between public and private sector R estimates highlights that clients of the public and private sectors did not experience two separate epidemics, except perhaps to a limited extent during the strictest lockdowns in the first wave.

The role of modelling and analytics in South African COVID-19 planning and budgeting.

BACKGROUND: The South African COVID-19 Modelling Consortium (SACMC) was established in late March 2020 to support planning and budgeting for COVID-19 related healthcare in South Africa. We developed several tools in response to the needs of decision makers in the different stages of the epidemic, allowing the South African government to plan several months ahead. METHODS: Our tools included epidemic projection models, several cost and budget impact models, and online dashboards to help government and the public visualise our projections, track case development and forecast hospital admissions. Information on new variants, including Delta and Omicron, were incorporated in real time to allow the shifting of scarce resources when necessary. RESULTS: Given the rapidly changing nature of the outbreak globally and in South Africa, the model projections were updated regularly. The updates reflected 1) the changing policy priorities over the course of the epidemic; 2) the availability of new data from South African data systems; and 3) the evolving response to COVID-19 in South Africa, such as changes in lockdown levels and ensuing mobility and contact rates, testing and contact tracing strategies and hospitalisation criteria. Insights into population behaviour required updates by incorporating notions of behavioural heterogeneity and behavioural responses to observed changes in mortality. We incorporated these aspects into developing scenarios for the third wave and developed additional methodology that allowed us to forecast required inpatient capacity. Finally, real-time analyses of the most important characteristics of the Omicron variant first identified in South Africa in November 2021 allowed us to advise policymakers early in the fourth wave that a relatively lower admission rate was likely. CONCLUSION: The SACMC's models, developed rapidly in an emergency setting and regularly updated with local data, supported national and provincial government to plan several months ahead, expand hospital capacity when needed, allocate budgets and procure additional resources where possible. Across four waves of COVID-19 cases, the SACMC continued to serve the planning needs of the government, tracking waves and supporting the national vaccine rollout.

Differential in-hospital mortality and intensive care treatment over time: Informing hospital pathways for modelling COVID-19 in South Africa.

There are limited published data within sub-Saharan Africa describing hospital pathways of COVID-19 patients hospitalized. These data are crucial for the parameterisation of epidemiological and cost models, and for planning purposes for the region. We evaluated COVID-19 hospital admissions from the South African national hospital surveillance system (DATCOV) during the first three COVID-19 waves between May 2020 and August 2021. We describe probabilities and admission into intensive care units (ICU), mechanical ventilation, death, and lengths of stay (LOS) in non-ICU and ICU care in public and private sectors. A log-binomial model was used to quantify mortality risk, ICU treatment and mechanical ventilation between time periods, adjusting for age, sex, comorbidity, health sector and province. There were 342,700 COVID-19-related hospital admissions during the study period. Risk of ICU admission was 16% lower during wave periods (adjusted risk ratio (aRR) 0.84 [0.82-0.86]) compared to between-wave periods. Mechanical ventilation was more likely during a wave overall (aRR 1.18 [1.13-1.23]), but patterns between waves were inconsistent, while mortality risk in non-ICU and ICU were 39% (aRR 1.39 [1.35-1.43]) and 31% (aRR 1.31 [1.27-1.36]) higher during a wave, compared to between-wave periods, respectively. If patients had had the same probability of death during waves vs between-wave periods, we estimated approximately 24% [19%-30%] of deaths (19,600 [15,200-24,000]) would not have occurred over the study period. LOS differed by age (older patients stayed longer), ward type (ICU stays were longer than non-ICU) and death/recovery outcome (time to death was shorter in non-ICU); however, LOS remained similar between time periods. Healthcare capacity constraints as inferred by wave period have a large impact on in-hospital mortality. It is crucial for modelling health systems strain and budgets to consider how input parameters related to hospitalisation change during and between waves, especially in settings with severely constrained resources.

Cross-municipality migration and spread of tuberculosis in South Africa.

Human migration facilitates the spread of infectious disease. However, little is known about the contribution of migration to the spread of tuberculosis in South Africa. We analyzed longitudinal data on all tuberculosis test results recorded by South Africa's National Health Laboratory Service (NHLS), January 2011-July 2017, alongside municipality-level migration flows estimated from the 2016 South African Community Survey. We first assessed migration patterns in people with laboratory-diagnosed tuberculosis and analyzed demographic predictors. We then quantified the impact of cross-municipality migration on tuberculosis incidence in municipality-level regression models. The NHLS database included 921,888 patients with multiple clinic visits with TB tests. Of these, 147,513 (16%) had tests in different municipalities. The median (IQR) distance travelled was 304 (163 to 536) km. Migration was most common at ages 20-39 years and rates were similar for men and women. In municipality-level regression models, each 1% increase in migration-adjusted tuberculosis prevalence was associated with a 0.47% (95% CI: 0.03% to 0.90%) increase in the incidence of drug-susceptible tuberculosis two years later, even after controlling for baseline prevalence. Similar results were found for rifampicin-resistant tuberculosis. Accounting for migration improved our ability to predict future incidence of tuberculosis.

The National COVID-19 Epi Model (NCEM): Estimating cases, admissions and deaths for the first wave of COVID-19 in South Africa.

In March 2020 the South African COVID-19 Modelling Consortium was formed to support government planning for COVID-19 cases and related healthcare. Models were developed jointly by local disease modelling groups to estimate cases, resource needs and deaths due to COVID-19. The National COVID-19 Epi Model (NCEM) while initially developed as a deterministic compartmental model of SARS-Cov-2 transmission in the nine provinces of South Africa, was adapted several times over the course of the first wave of infection in response to emerging local data and changing needs of government. By the end of the first wave, the NCEM had developed into a stochastic, spatially-explicit compartmental transmission model to estimate the total and reported incidence of COVID-19 across the 52 districts of South Africa. The model adopted a generalised Susceptible-Exposed-Infectious-Removed structure that accounted for the clinical profile of SARS-COV-2 (asymptomatic, mild, severe and critical cases) and avenues of treatment access (outpatient, and hospitalisation in non-ICU and ICU wards). Between end-March and early September 2020, the model was updated 11 times with four key releases to generate new sets of projections and scenario analyses to be shared with planners in the national and provincial Departments of Health, the National Treasury and other partners. Updates to model structure included finer spatial granularity, limited access to treatment, and the inclusion of behavioural heterogeneity in relation to the adoption of Public Health and Social Measures. These updates were made in response to local data and knowledge and the changing needs of the planners. The NCEM attempted to incorporate a high level of local data to contextualise the model appropriately to address South Africa's population and health system characteristics that played a vital role in producing and updating estimates of resource needs, demonstrating the importance of harnessing and developing local modelling capacity.

Integrating Molecular Diagnostics and GIS Mapping: A Multidisciplinary Approach to Understanding Tuberculosis Disease Dynamics in South Africa Using Xpert MTB/RIF.

An investigation was carried out to examine the use of national Xpert MTB/RIF data (2013-2017) and GIS technology for MTB/RIF surveillance in South Africa. The aim was to exhibit the potential of using molecular diagnostics for TB surveillance across the country. The variables analysed include Mycobacterium tuberculosis (Mtb) positivity, the mycobacterial proportion of rifampicin-resistant Mtb (RIF), and probe frequency. The summary statistics of these variables were generated and aggregated at the facility and municipal level. The spatial distribution patterns of the indicators across municipalities were determined using the Moran's I and Getis Ord (Gi) statistics. A case-control study was conducted to investigate factors associated with a high mycobacterial load. Logistic regression was used to analyse this study's results. There was striking spatial heterogeneity in the distribution of Mtb and RIF across South Africa. The median patient age, urban setting classification, and number of health care workers were found to be associated with the mycobacterial load. This study illustrates the potential of using data generated from molecular diagnostics in combination with GIS technology for Mtb surveillance in South Africa. Spatially targeted interventions can be implemented in areas where high-burden Mtb persists.