A cost-effectiveness analysis of South Africa's COVID-19 vaccination programme.

BACKGROUND: COVID-19 vaccines were rolled out in South Africa beginning in February 2021. In this study we retrospectively assessed the cost-effectiveness of the vaccination programme in its first two years of implementation. METHOD: We modelled the costs, expressed in 2021 US$, and health outcomes of the COVID-19 vaccination programme compared to a no vaccination programme scenario. The study was conducted from a public payer's perspective over two time-horizons - nine months (February to November 2021) and twenty-four months (February 2021 to January 2023). Health outcomes were estimated from a disease transmission model parameterised with data on COVID-19-related hospitalisations and deaths and were converted to disability adjusted life years (DALYs). Deterministic and probabilistic sensitivity analyses (DSA and PSA) were conducted to assess parameter uncertainty. RESULTS: Incremental cost-effectiveness ratio (ICER) was estimated at US$1600 per DALY averted during the first study time horizon. The corresponding ICER for the second study period was estimated at US$1300 per DALY averted. When 85% of all excess deaths during these periods were included in the analysis, ICERs in the first and second study periods were estimated at US$1070 and US$660 per DALY averted, respectively. In the PSA, almost 100% of simulations fell below the estimated opportunity cost-based cost-effectiveness threshold for South Africa (US$2300 DALYs averted). COVID-19 vaccination programme cost per dose had the greatest impact on the ICERs. CONCLUSION: Our findings suggest that South Africa's COVID-19 vaccination programme represented good value for money in the first two years of rollout.

Future HIV epidemic trajectories in South Africa and projected long-term consequences of reductions in general population HIV testing: a mathematical modelling study.

BACKGROUND: After successful intensive interventions to rapidly increase HIV awareness, coverage of antiretroviral therapy (ART), and viral suppression, HIV programmes in eastern and southern Africa are considering scaling back of some interventions, such as widespread general population HIV testing. We aimed to model whether scaling back of general population HIV testing in South Africa could result in a resurgence of the HIV epidemic or substantial slowing of declines in HIV incidence, resulting in increased long-term ART. METHODS: In this modelling study, we used the Thembisa 4.5 model (a deterministic compartmental model of HIV transmission in South Africa) to project the South African HIV epidemic to 2100 assuming the continuation of 2022 epidemiological conditions and HIV programme implementation. We assessed how implementing reductions in general population HIV testing services in 2025 (while maintaining antenatal, symptom-based, and risk-based testing modalities and other HIV prevention services at 2022 levels) would affect HIV incidence and prevalence among people aged 15-49 years, the year in which incidence would reach one per 1000 people aged 15-49 years (the threshold for virtual elimination of HIV), and associated costs, as well as numbers of additional new HIV infections and AIDS-related deaths. We also modelled the effects of delaying reductions in general population testing services by 5-year increments. Additionally, we modelled the potential effects of reductions in general population testing services in combination with increases or decreases in ART interruption rates (ie, the annual rate at which people who are on ART discontinue ART) and condom usage in 2025-35. FINDINGS: If general population HIV testing services and the HIV risk environment of 2022 were maintained, we projected that HIV incidence would steadily decline from 4·95 (95% CI 4·40-5·34) per 1000 population in 2025 to 0·14 (0·05-0·31) per 1000 in 2100, and that the so-called virtual elimination threshold of less than one new infection per 1000 population per year would be reached in 2055 (95% CI 2051-2060). Scaling back of general population HIV testing services by 25%, 50%, or 75% in 2025 delayed time to reaching the virtual elimination threshold by 5, 13, or 35 years, respectively, whereas complete cessation of general population testing would result in the threshold not being attained by 2100. Although the incidence of HIV continued to fall when general HIV testing services were reduced, our modelling suggested that, with reductions of between 25% and 100%, between 396 000 (95% CI 299 000-474 000) and 2·50 million (1·97 million-2·98 million) additional HIV infections and between 115 000 (94 000-135 000) and 795 000 (670 000-926 000) additional AIDS-related deaths would occur between 2025 and 2075, depending on the extent of reduction in testing. Delaying reductions in general population HIV testing services for 5-25 years mitigated some of these effects. HIV testing accounted for only 5% of total programmatic costs at baseline; reducing testing moderately reduced short-term total annual costs, but increased annual costs after 25 years. Increases in ART interruption and reductions in condom usage were projected to slow the decline in incidence and increase the coverage of general HIV testing services required to control transmission but did not cause rapid resurgence in HIV infections. INTERPRETATION: Our modelling suggests that scaling back of general population HIV testing would not result in a resurgence of HIV infections, but would delay attainment of incidence-reduction targets and result in long-term increases in HIV infections, AIDS-related deaths, and costs (via increased need for ART provision). HIV programmes need to balance short-term potential resource savings with long-term epidemic control objectives. FUNDING: Bill & Melinda Gates Foundation.

Costs of distributing HIV self-testing kits in Eswatini through community and workplace models.

BACKGROUND: This study evaluates the implementation and running costs of an HIV self-testing (HIVST) distribution program in Eswatini. HIVST kits were delivered through community-based and workplace models using primary and secondary distribution. Primary clients could self-test onsite or offsite. This study presents total running economic costs of kit distribution per model between April 2019 and March 2020, and estimates average cost per HIVST kit distributed, per client self-tested, per client self-tested reactive, per client confirmed positive, and per client initiating antiretroviral therapy (ART). METHODS: Distribution data and follow-up phone interviews were analysed to estimate implementation outcomes. Results were presented for each step of the care cascade using best-case and worst-case scenarios. A top-down incremental cost-analysis was conducted from the provider perspective using project expenditures. Sensitivity and scenario analyses explored effects of economic and epidemiological parameters on average costs. RESULTS: Nineteen thousand one hundred fifty-five HIVST kits were distributed to 13,031 individuals over a 12-month period, averaging 1.5 kits per recipient. 83% and 17% of kits were distributed via the community and workplace models, respectively. Clients reached via the workplace model were less likely to opt for onsite testing than clients in the community model (8% vs 29%). 6% of onsite workplace testers tested reactive compared to 2% of onsite community testers. Best-case scenario estimated 17,458 (91%) clients self-tested, 633 (4%) received reactive-test results, 606 (96%) linked to confirmatory testing, and 505 (83%) initiated ART. Personnel and HIVST kits represented 60% and 32% of total costs, respectively. Average costs were: per kit distributed US$17.23, per client tested US$18.91, per client with a reactive test US$521.54, per client confirmed positive US$550.83, and per client initiating ART US$708.60. Lower rates for testing, reactivity, and linkage to care in the worst-case scenario resulted in higher average costs along the treatment cascade. CONCLUSION: This study fills a significant evidence gap regarding costs of HIVST provision along the client care cascade in Eswatini. Workplace and community-based distribution of HIVST accompanied with effective linkage to care strategies can support countries to reach cascade objectives.

Substantial but spatially heterogeneous progress in male circumcision for HIV prevention in South Africa.

BACKGROUND: Voluntary medical male circumcision (VMMC) reduces the risk of male HIV acquisition by 60%. Programmes to provide VMMCs for HIV prevention have been introduced in sub-Saharan African countries with high HIV burden. Traditional circumcision is also a long-standing male coming-of-age ritual, but practices vary considerably across populations. Accurate estimates of circumcision coverage by age, type, and time at subnational levels are required for planning and delivering VMMCs to meet targets and evaluating their impacts on HIV incidence. METHODS: We developed a Bayesian competing risks time-to-event model to produce region-age-time-type specific probabilities and coverage of male circumcision with probabilistic uncertainty. The model jointly synthesises data from household surveys and health system data on the number of VMMCs conducted. We demonstrated the model using data from five household surveys and VMMC programme data to produce estimates of circumcision coverage for 52 districts in South Africa between 2008 and 2019. RESULTS: Nationally, in 2008, 24.1% (95% CI: 23.4-24.8%) of men aged 15-49 were traditionally circumcised and 19.4% (18.9-20.0%) were medically circumcised. Between 2010 and 2019, 4.25 million VMMCs were conducted. Circumcision coverage among men aged 15-49 increased to 64.0% (63.2-64.9%) and medical circumcision coverage to 42% (41.3-43.0%). Circumcision coverage varied widely across districts, ranging from 13.4 to 86.3%. The average age of traditional circumcision ranged between 13 and 19 years, depending on local cultural practices. CONCLUSION: South Africa has made substantial, but heterogeneous, progress towards increasing medical circumcision coverage. Detailed subnational information on coverage and practices can guide programmes to identify unmet need to achieve national and international targets.

Voluntary medical male circumcision reduces the risk of male HIV acquisition. Programmes to provide circumcisions for HIV prevention have been introduced in sub-Saharan African countries with high HIV burden. Estimates of circumcision coverage are needed for planning and delivering circumcisions to meet targets and evaluate their impacts on HIV incidence. We developed a model to integrate date from both household surveys and health systems on the number of circumcisions conducted, and applied it to understand how the practices and coverage of circumcision are changing in South Africa. National circumcision coverage increased considerably between 2008 and 2019, however, there remains a substantial subnational variation across districts and age groups. Further progress is needed to reach national and international targets.

The potential benefits of long-acting injectable cabotegravir in pregnant and breastfeeding women and their infants.

BACKGROUND: Pregnant and breastfeeding women (PBW) in sub-Saharan Africa have high HIV incidence rates and associated risk of vertical transmission to their infants. Oral preexposure prophylaxis (PrEP) and injectable PrEP (long-acting cabotegravir, or CAB-LA) can potentially reduce this HIV transmission, but population-level impacts are uncertain. METHODS: We extended a previously developed model of HIV and PrEP in South Africa to allow for variable PrEP duration and preference in PBW. We considered three potential scenarios for PrEP provision to PBW: oral PrEP only, CAB-LA only, and allowing oral/CAB-LA choice, with uptake and retention assumptions informed by South African data, each compared with a 'base' scenario without PrEP for PBW. RESULTS: Without PrEP for PBW, the model estimates 1.31 million new infections will occur between 2025 and 2035 in South African adults and children, including 100 000 in PBW, 16 800 in infants at/before birth, and 35 200 in children through breastmilk. In the oral PrEP-only scenario, these numbers would reduce by 1.2% (95% CI: 0.7-1.7%), 8.6% (4.8-12.9%), 4.0% (2.1-5.8%), and 5.3% (3.0-8.2%) respectively. In the CAB-LA-only scenario, the corresponding reductions would be 6.1% (2.9-9.6%), 41.2% (19.8-65.0%), 12.6% (6.0-19.4%), and 29.5% (13.9-46.8%), respectively, and in the oral/CAB-LA choice scenario, similar reductions would be achieved [5.6% (3.4-8.0%), 39% (23.4-55.9%), 12.4% (7.4-16.8%) and 27.6% (16.5-39.9%) respectively]. CONCLUSION: CAB-LA has the potential to be substantially more effective than oral PrEP in preventing HIV acquisition in PBW and vertical transmission, and can also modestly reduce HIV incidence at a population level.

Integration of point-of-care screening for type 2 diabetes mellitus and hypertension into the COVID-19 vaccine programme in Johannesburg, South Africa.

BACKGROUND: South Africa grapples with a substantial burden of non-communicable diseases (NCDs), particularly type 2 diabetes (diabetes) and hypertension. However, these conditions are often underdiagnosed and poorly managed, further exacerbated by the strained primary healthcare (PHC) system and the disruptive impact of the COVID-19 pandemic. Integrating NCD screening with large-scale healthcare initiatives, such as COVID-19 vaccination campaigns, offers a potential solution, especially in low- and middle-income countries (LMICs). We investigated the feasibility and effectiveness of this integration. METHODS: A prospective cohort study was conducted at four government health facilities in Johannesburg, South Africa. NCD screening was incorporated into the COVID-19 vaccination campaign. Participants underwent COVID-19 rapid tests, blood glucose checks, blood pressure assessments, and anthropometric measurements. Those with elevated blood glucose or blood pressure values received referrals for diagnostic confirmation at local PHC centers. RESULTS: Among 1,376 participants screened, the overall diabetes prevalence was 4.1%, combining previously diagnosed cases and newly identified elevated blood glucose levels. Similarly, the hypertension prevalence was 19.4%, comprising pre-existing diagnoses and newly detected elevated blood pressure cases. Notably, 46.1% of participants displayed waist circumferences indicative of metabolic syndrome, more prevalent among females. Impressively, 7.8% of all participants screened were potentially newly diagnosed with diabetes or hypertension. Approximately 50% of individuals with elevated blood glucose or blood pressure successfully linked to follow-up care within four weeks. CONCLUSION: Our study underscores the value of utilizing even brief healthcare interactions as opportunities for screening additional health conditions, thereby aiding the identification of previously undiagnosed cases. Integrating NCD screenings into routine healthcare visits holds promise, especially in resource-constrained settings. Nonetheless, concerted efforts to strengthen care linkage are crucial for holistic NCD management and control. These findings provide actionable insights for addressing the NCD challenge and improving healthcare delivery in LMICs.

A quantitative assessment of the consistency of projections from five mathematical models of the HIV epidemic in South Africa: a model comparison study.

BACKGROUND: Mathematical models are increasingly used to inform HIV policy and planning. Comparing estimates obtained using different mathematical models can test the robustness of estimates and highlight research gaps. As part of a larger project aiming to determine the optimal allocation of funding for HIV services, in this study we compare projections from five mathematical models of the HIV epidemic in South Africa: EMOD-HIV, Goals, HIV-Synthesis, Optima, and Thembisa. METHODS: The five modelling groups produced estimates of the total population, HIV incidence, HIV prevalence, proportion of people living with HIV who are diagnosed, ART coverage, proportion of those on ART who are virally suppressed, AIDS-related deaths, total deaths, and the proportion of adult males who are circumcised. Estimates were made under a "status quo" scenario for the period 1990 to 2040. For each output variable we assessed the consistency of model estimates by calculating the coefficient of variation and examining the trend over time. RESULTS: For most outputs there was significant inter-model variability between 1990 and 2005, when limited data was available for calibration, good consistency from 2005 to 2025, and increasing variability towards the end of the projection period. Estimates of HIV incidence, deaths in people living with HIV, and total deaths displayed the largest long-term variability, with standard deviations between 35 and 65% of the cross-model means. Despite this variability, all models predicted a gradual decline in HIV incidence in the long-term. Projections related to the UNAIDS 95-95-95 targets were more consistent, with the coefficients of variation below 0.1 for all groups except children. CONCLUSIONS: While models produced consistent estimates for several outputs, there are areas of variability that should be investigated. This is important if projections are to be used in subsequent cost-effectiveness studies.

The cost of adding rapid screening for diabetes, hypertension, and COVID-19 to COVID-19 vaccination queues in Johannesburg, South Africa.

Background: Non-communicable diseases (NCDs) are responsible for 51% of total mortality in South Africa, with a rising burden of hypertension (HTN) and diabetes mellitus (DM). Incorporating NCD and COVID-19 screening into mass activities such as COVID-19 vaccination programs could offer significant long-term benefits for early detection interventions. However, there is limited knowledge of the associated costs and resources required. We evaluated the cost of integrating NCD screening and COVID-19 antigen rapid diagnostic testing (Ag-RDT) into a COVID-19 vaccination program. Methods: We conducted a prospective cost analysis at three public sector primary healthcare clinics and one academic hospital in Johannesburg, South Africa, conducting vaccinations. Participants were assessed for eligibility and recruited during May-Dec 2022. Costs were estimated from the provider perspective using a bottom-up micro-costing approach and reported in 2022 USD. Results: Of the 1,376 enrolled participants, 240 opted in to undergo a COVID-19 Ag-RDT, and none tested positive for COVID-19. 138 (10.1%) had elevated blood pressure, with 96 (70%) having no prior HTN diagnosis. 22 (1.6%) were screen-positive for DM, with 12 (55%) having no prior diagnosis. The mean and median costs per person screened for NCDs were $2.53 (SD: 3.62) and $1.70 (IQR: $1.38-$2.49), respectively. The average provider cost per person found to have elevated blood glucose levels and blood pressure was $157.99 and $25.19, respectively. Finding a new case of DM and HTN was $289.65 and $36.21, respectively. For DM and DM + HTN screen-positive participants, diagnostic tests were the main cost driver, while staff costs were the main cost driver for - and HTN screen-positive and screen-negative participants. The mean and median cost per Ag-RDT was $6.13 (SD: 0.87) and $5.95 (IQR: $5.55-$6.25), with costs driven mainly by test kit costs. Conclusions: We show the cost of finding new cases of DM and HTN in a vaccine queue, which is an essential first step in understanding the feasibility and resource requirements for such initiatives. However, there is a need for comparative economic analyses that include linkage to care and retention data to fully understand this cost and determine whether opportunistic screening should be added to general mass health activities.

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.

What will it take for an injectable ARV to change the face of the HIV epidemic in high-prevalence countries? Considerations regarding drug costs and operations.

INTRODUCTION: The proven effectiveness of injectable cabotegravir (CAB-LA) is higher than that of any other HIV prevention intervention ever trialled or implemented, surpassing medical male circumcision, condoms and combination antiretroviral treatment. Based on our own analyses and experience with the South African oral pre-exposure prophylaxis (PrEP) programme, we review the supply and demand side factors that would need to be in place for a successful rollout of CAB-LA, and delineate lessons for the launch of other long-acting and extended delivery (LAED) antiretroviral drugs. DISCUSSION: On the supply side, CAB-LA will have to be offered at a price that makes the drug affordable and cost-effective to low- and middle-income countries, especially those with high HIV prevalence. An important factor in lowering prices is a guaranteed market volume, which in turn necessitates the involvement of large funders, such as PEPFAR and the Global Fund, and a fairly rapid scale-up of the drug. Such a scale-up would have to involve speedy regulatory approval and WHO pre-qualification, swift integration of CAB-LA into national guidelines and planning for large enough manufacturing capacity, including the enabling of local manufacture. On the demand side, existing demand for HIV prevention products has to be harnessed and additional demand created, which will be aided by designing CAB-LA programmes at the primary healthcare or community level, and involving non-traditional outlets, such as private pharmacies and doctors' practices. CONCLUSIONS: CAB-LA could be the game changer for HIV prevention that we have been hoping for, and serve as a useful pilot for other LAEDs. A successful rollout would involve building markets of a guaranteed size; lowering the drug's price to a level possibly below the cost of production, while also lowering the cost of production altogether; harnessing, creating and sustaining demand for the product over the long term, wherever possible, in national programmes rather than single demonstration sites; and establishing and maintaining manufacturing capacity and supply chains. For this, all parties have to work together-including originator and generic manufacturers, donor organizations and other large funders, and the governments of low- and middle-income countries, in particular those with high HIV prevalence.

Integration of point-of-care screening for type 2 diabetes mellitus and hypertension with COVID-19 rapid antigen screening in Johannesburg, South Africa.

AIMS: We sought to evaluate the yield and linkage-to-care for diabetes and hypertension screening alongside a study assessing the use of rapid antigen tests for COVID-19 in taxi ranks in Johannesburg, South Africa. METHODS: Participants were recruited from Germiston taxi rank. We recorded results of blood glucose (BG), blood pressure (BP), waist circumference, smoking status, height, and weight. Participants who had elevated BG (fasting ≥7.0; random ≥11.1mmol/L) and/or BP (diastolic ≥90 and systolic ≥140mmHg) were referred to their clinic and phoned to confirm linkage. RESULTS: 1169 participants were enrolled and screened for elevated BG and elevated BP. Combining participants with a previous diagnosis of diabetes (n = 23, 2.0%; 95% CI:1.3-2.9%) and those that had an elevated BG measurement (n = 60, 5.2%; 95% CI:4.1-6.6%) at study enrollment, we estimated an overall indicative prevalence of diabetes of 7.1% (95% CI:5.7-8.7%). When combining those with known hypertension at study enrollment (n = 124, 10.6%; 95% CI:8.9-12.5%) and those with elevated BP (n = 202; 17.3%; 95% CI:15.2-19.5%), we get an overall prevalence of hypertension of 27.9% (95% CI:25.4-30.1%). Only 30.0% of those with elevated BG and 16.3% of those with elevated BP linked-to-care. CONCLUSION: By opportunistically leveraging existing COVID-19 screening in South Africa to screen for diabetes and hypertension, 22% of participants received a potential new diagnosis. We had poor linkage-to-care following screening. Future research should evaluate options for improving linkage-to-care, and evaluate the large-scale feasibility of this simple screening tool.

Secondary distribution of HIV self-test kits by HIV index and antenatal care clients: implementation and costing results from the STAR Initiative in South Africa.

BACKGROUND: Partner-delivered HIV self-testing kits has previously been highlighted as a safe, acceptable and effective approach to reach men. However, less is known about its real-world implementation in reaching partners of people living with HIV. We evaluated programmatic implementation of partner-delivered self-testing through antenatal care (ANC) attendees and people newly diagnosed with HIV by assessing use, positivity, linkage and cost per kit distributed. METHODS: Between April 2018 and December 2019, antenatal care (ANC) clinic attendees and people or those newly diagnosed with HIV clients across twelve clinics in three cities in South Africa were given HIVST kits (OraQuick Rapid HIV-1/2 Antibody Test, OraSure Technologies) to distribute to their sexual partners. A follow-up telephonic survey was administered to all prior consenting clients who were successfully reached by telephone to assess primary outcomes. Incremental economic costs of the implementation were estimated from the provider's perspective. RESULTS: Fourteen thousand four hundred seventy-three HIVST kits were distributed - 10,319 (71%) to ANC clients for their male partner and 29% to people newly diagnosed with HIV for their partners. Of the 4,235 ANC clients successfully followed-up, 82.1% (3,475) reportedly offered HIVST kits to their male partner with 98.1% (3,409) accepting and 97.6% (3,328) using the kit. Among ANC partners self-testing, 159 (4.8%) reported reactive HIVST results, of which 127 (79.9%) received further testing; 116 (91.3%) were diagnosed with HIV and 114 (98.3%) initiated antiretroviral therapy (ART). Of the 1,649 people newly diagnosed with HIV successfully followed-up; 1,312 (79.6%) reportedly offered HIVST kits to their partners with 95.8% (1,257) of the partners accepting and 95.9% (1,206) reported that their partners used the kit. Among these index partners, 297 (24.6%) reported reactive HIVST results of which 261 (87.9%) received further testing; 260 (99.6%) were diagnosed with HIV and 258 (99.2%) initiated ART. The average cost per HIVST distributed in the three cities was US$7.90, US$11.98, and US$14.81, respectively. CONCLUSIONS: Partner-delivered HIVST in real world implementation was able to affordably reach many male partners of ANC attendees and index partners of people newly diagnosed with HIV in South Africa. Given recent COVID-19 related restrictions, partner-delivered HIVST provides an important strategy to maintain essential testing services.

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.

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.

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of $500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs $150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82% of setting-scenarios at the cost of $144 per year, in 52% at $264, and in 87% at $114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

Cost-effectiveness of voluntary medical male circumcision for HIV prevention across sub-Saharan Africa: results from five independent models.

BACKGROUND: Voluntary medical male circumcision (VMMC) has been a recommended HIV prevention strategy in sub-Saharan Africa since 2007, particularly in countries with high HIV prevalence. However, given the scale-up of antiretroviral therapy programmes, it is not clear whether VMMC still represents a cost-effective use of scarce HIV programme resources. METHODS: Using five existing well described HIV mathematical models, we compared continuation of VMMC for 5 years in men aged 15 years and older to no further VMMC in South Africa, Malawi, and Zimbabwe and across a range of setting scenarios in sub-Saharan Africa. Outputs were based on a 50-year time horizon, VMMC cost was assumed to be US$90, and a cost-effectiveness threshold of US$500 was used. FINDINGS: In South Africa and Malawi, the continuation of VMMC for 5 years resulted in cost savings and health benefits (infections and disability-adjusted life-years averted) according to all models. Of the two models modelling Zimbabwe, the continuation of VMMC for 5 years resulted in cost savings and health benefits by one model but was not as cost-effective according to the other model. Continuation of VMMC was cost-effective in 68% of setting scenarios across sub-Saharan Africa. VMMC was more likely to be cost-effective in modelled settings with higher HIV incidence; VMMC was cost-effective in 62% of settings with HIV incidence of less than 0·1 per 100 person-years in men aged 15-49 years, increasing to 95% with HIV incidence greater than 1·0 per 100 person-years. INTERPRETATION: VMMC remains a cost-effective, often cost-saving, prevention intervention in sub-Saharan Africa for at least the next 5 years. FUNDING: Bill & Melinda Gates Foundation for the HIV Modelling Consortium.

The costs of interventions for type 2 diabetes mellitus, hypertension and cardiovascular disease in South Africa - a systematic literature review.

BACKGROUND: In the context of a move to universal health coverage, three separate systematic reviews were conducted to summarise available evidence on the direct costs of interventions for type 2 diabetes mellitus, hypertension, and cardiovascular disease in South Africa. METHODS: PubMed® and Web of Science was searched for literature published between 01 and 1995 and 27 October 2022. Additionally, reference and citations lists of retrieved articles and experts were consulted. We also tracked reference lists of previous, related systematic reviews. Eligible publications were cost analyses of clinical interventions targeted at adults age 15 + reporting primary estimates of in- and out-of-hospital costs from a provider perspective. Costs were extracted and converted to 2021 US dollars, and article methodological and reporting quality was appraised using the 2013 CHEERS checklist. RESULTS: Of the 600, 1,172 and 1,466 identified publications for type 2 diabetes mellitus, hypertension, and cardiovascular disease, respectively, 10, 12, and 17 met full inclusion criteria. 60% of articles reported cardiovascular disease costs, 52% were of good reporting quality, and 10%, 50%, and 39% of type 2 diabetes mellitus, hypertension and cardiovascular disease papers reported private-sector costs only. Hypertension drug costs ranged from $2 to $85 per person-month, while type 2 diabetes mellitus drug costs ranged between $57 and $630 per person-year (ppy). Diabetes-related complication treatment costs ranged from $55 for retinopathy treatment to $25,193 ppy for haemodialysis, while cardiovascular disease treatment costs were between $160 and $37,491 ppy. Drugs and treatment of complications were major cost drivers for hypertension and type 2 diabetes mellitus, while hospitalisation drove cardiovascular disease costs. CONCLUSION: The intervention costs of type 2 diabetes mellitus, hypertension and cardiovascular disease care have received more attention recently, particularly diabetes-related complications and cardiovascular disease. However, 39% of identified cardiovascular disease treatment costs used a private sector perspective, leaving significant research gaps in the public sector and the cheaper to treat hypertension and type 2 diabetes mellitus. This review fills an information gap regarding the intervention costs of these diseases in South Africa.

Relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis in South Africa based on the HPTN 083 and HPTN 084 trials: a modelled economic evaluation and threshold analysis.

BACKGROUND: Long-acting injectable cabotegravir, a drug taken every 2 months, has been shown to be more effective at preventing HIV infection than daily oral tenofovir disoproxil fumarate and emtricitabine, but its cost-effectiveness in a high-prevalence setting is not known. We aimed to estimate the incremental cost-effectiveness of long-acting injectable cabotegravir compared with tenofovir disoproxil fumarate and emtricitabine in South Africa, using methods standard to government planning, and to determine the threshold price at which long-acting injectable cabotegravir is as cost-effective as tenofovir disoproxil fumarate and emtricitabine. METHODS: In this modelled economic evaluation and threshold analysis, we updated a deterministic model of the South African HIV epidemic with data from the HPTN 083 and HPTN 084 trials to evaluate the effect of tenofovir disoproxil fumarate and emtricitabine and long-acting injectable cabotegravir provision to heterosexual adolescents and young women and men aged 15-24 years, female sex workers, and men who have sex with men. We estimated the average intervention cost, in 2021 US$, using ingredients-based costing, and modelled the cost-effectiveness of two coverage scenarios (medium or high, assuming higher uptake of long-acting injectable cabotegravir than tenofovir disoproxil fumarate and emtricitabine throughout) and, for long-acting injectable cabotegravir, two duration subscenarios (minimum: same pre-exposure prophylaxis duration as for tenofovir disoproxil fumarate and emtricitabine; maximum: longer duration than tenofovir disoproxil fumarate and emtricitabine) over 2022-41. FINDINGS: Across long-acting injectable cabotegravir scenarios, 15-28% more new HIV infections were averted compared with the baseline scenario (current tenofovir disoproxil fumarate and emtricitabine roll-out). In scenarios with increased coverage with oral tenofovir disoproxil fumarate and emtricitabine, 4-8% more new HIV infections were averted compared with the baseline scenario. If long-acting injectable cabotegravir drug costs were equal to those of tenofovir disoproxil fumarate and emtricitabine for the same 2-month period, the incremental cost of long-acting injectable cabotegravir to the HIV programme was higher than that of tenofovir disoproxil fumarate and emtricitabine (5-10% vs 2-4%) due to higher assumed uptake of long-acting injectable cabotegravir. The cost per infection averted was $6053-6610 (tenofovir disoproxil fumarate and emtricitabine) and $4471-6785 (long-acting injectable cabotegravir). The cost per long-acting cabotegravir injection needed to be less than twice that of a 2-month supply of tenofovir disoproxil fumarate and emtricitabine to remain as cost-effective, with threshold prices ranging between $9·03 per injection (high coverage; maximum duration) and $14·47 per injection (medium coverage; minimum duration). INTERPRETATION: Long-acting injectable cabotegravir could potentially substantially change HIV prevention. However, for its implementation to be financially feasible across low-income and middle-income countries with high HIV incidence, long-acting injectable cabotegravir must be reasonably priced. FUNDING: United States Agency for International Development, The Bill & Melinda Gates Foundation.

Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical models.

BACKGROUND: In this so-called treat-all era, antiretroviral therapy (ART) interruptions contribute to an increasing proportion of HIV infections and deaths. Many strategies to improve retention on ART cost more than standard of care. In this study, we aimed to estimate the upper-bound costs at which such interventions should be adopted. METHODS: In this combined analysis, we compared the infections averted, disability-adjusted life-years (DALYs) averted, and upper-bound costs of interventions that improve ART retention in three HIV models with diverse structures, assumptions, and baseline settings: EMOD in South Africa, Optima in Malawi, and Synthesis in sub-Saharan African low-income and middle-income countries (LMICs). We modelled estimates over a 40-year time horizon, from a baseline of Jan 1, 2022, when interventions would be implemented, to Jan 1, 2062. We varied increment of ART retention (25%, 50%, 75%, and 100% retention), the extent to which interventions could be targeted towards individuals at risk of interrupting ART, and cost-effectiveness thresholds in each setting. FINDINGS: Despite simulating different settings and epidemic trends, all three models produced consistent estimates of health benefit (ie, DALYs averted) and transmission reduction per increment in retention. The range of estimates was 1·35-3·55 DALYs and 0·12-0·20 infections averted over the 40-year time horizon per additional person-year retained on ART. Upper-bound costs varied by setting and intervention effectiveness. Improving retention by 25% among all people receiving ART, regardless of risk of ART interruption, gave an upper-bound cost per person-year of US$2-6 in Optima (Malawi), $43-68 in Synthesis (LMICs in sub-Saharan Africa), and $28-180 in EMOD (South Africa). A maximally targeted and effective retention intervention had an upper-bound cost per person-year of US$93-223 in Optima (Malawi), $871-1389 in Synthesis (LMICs in sub-Saharan Africa), and $1013-6518 in EMOD (South Africa). INTERPRETATION: Upper-bound costs that could improve ART retention vary across sub-Saharan African settings and are likely to be similar to or higher than was estimated before the start of the treat-all era. Upper-bound costs could be increased by targeting interventions to those most at risk of interrupting ART. FUNDING: Bill & Melinda Gates Foundation.

Cost-effectiveness of easy-access, risk-informed oral pre-exposure prophylaxis in HIV epidemics in sub-Saharan Africa: a modelling study.

BACKGROUND: Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS: We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug $11, HIV test $4, and $14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3%, and a time horizon of 50 years. In sensitivity analyses, we considered a cost-effectiveness threshold of $100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS: In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION: Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING: US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation.