Modelling the health and economic impacts ofM72/AS01E vaccination and BCG-revaccination: Estimates for South Africa.

BACKGROUND: Tuberculosis remains a major public health problem in South Africa, with an estimated 300,000 cases and 55,000 deaths in 2021. New tuberculosis vaccines could play an important role in reducing this burden. Phase IIb trials have suggested efficacy of the M72/AS01E vaccine candidate and BCG-revaccination. The potential population impact of these vaccines is unknown. METHODS: We used an age-stratified transmission model of tuberculosis, calibrated to epidemiological data from South Africa, to estimate the potential health and economic impact of M72/AS01E vaccination and BCG-revaccination. We simulated M72/AS01E vaccination scenarios over the period 2030-2050 and BCG-revaccination scenarios over the period 2025-2050. We explored a range of product characteristics and delivery strategies. We calculated reductions in tuberculosis cases and deaths and costs and cost-effectiveness from health-system and societal perspectives. FINDINGS: M72/AS01E vaccination may have a larger impact than BCG-revaccination, averting approximately 80% more cases and deaths by 2050. Both vaccines were found to be cost-effective or cost saving (compared to no new vaccine) across a range of vaccine characteristics and delivery strategies from both the health system and societal perspective. The impact of M72/AS01E is dependent on the assumed efficacy of the vaccine in uninfected individuals. Extending BCG-revaccination to HIV-infected individuals on ART increased health impact by approximately 15%, but increased health system costs by approximately 70%. INTERPRETATION: Our results show that M72/AS01E vaccination or BCG-revaccination could be cost-effective in South Africa. However, there is considerable uncertainty in the estimated impact and costs due to uncertainty in vaccine characteristics and the choice of delivery strategy. FUNDING: This work was funded by the Bill & Melinda Gates Foundation (INV-001754). This work used the Cirrus UK National Tier-2 HPC Service at EPCC (https://www.cirrus.ac.uk) funded by the University of Edinburgh and EPSRC (EP/P020267/1).

COVID-19 vaccination implementation in 52 African countries: trajectory and implications for future pandemic preparedness.

INTRODUCTION: To end the COVID-19 pandemic, the WHO set a goal in 2021 to fully vaccinate 70% of the global population by mid-2022. We projected the COVID-19 vaccination trajectory in 52 African countries and compared the projected to the 'actual' or 'observed' coverage as of December 2022. We also estimated the required vaccination speed needed to have attained the WHO 70% coverage target by December 2022. METHODS: We obtained publicly available, country-reported daily COVID-19 vaccination data, covering the initial 9 months following the deployment of vaccines. We used a deterministic compartmental Susceptible-Exposed-Infectious-Recovered-type model and fit the model to the number of COVID-19 cases and vaccination coverage in each African country using a Markov chain Monte Carlo approach within a Bayesian framework. FINDINGS: Only nine of the 52 African countries (Tunisia, Cabo Verde, Lesotho, Mozambique, Rwanda, Seychelles, Morocco, Botswana and Mauritius) were on track to achieve full COVID-19 vaccination coverage rates ranging from 72% to 97% by the end of December 2022, based on their progress after 9 months of vaccine deployment. Of the 52 countries, 26 (50%) achieved 'actual' or 'observed' vaccination coverage rates within ±10 percentage points of their projected vaccination coverage. Among the countries projected to achieve <30% by December 2022, nine of them (Chad, Niger, Nigeria, South Sudan, Tanzania, Somalia, Zambia, Sierra Leone and Côte d'Ivoire) achieved a higher observed coverage than the projected coverage, ranging from 12.3 percentage points in South Sudan to 35.7 percentage points above the projected coverage in Tanzania. Among the 52 countries, 83% (43 out of 52) needed to at least double their vaccination trajectory after 9 months of deployment to reach the 70% target by December 2022. CONCLUSION: Our findings can guide countries in planning strategies for future global health emergencies and learning from each other, especially those that exceeded expectations and made significant progress towards the WHO's 2022 COVID-19 vaccination target despite projected poor coverage rates.

New tuberculosis vaccines in India: modelling the potential health and economic impacts of adolescent/adult vaccination with M72/AS01E and BCG-revaccination.

BACKGROUND: India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01E and BCG-revaccination have recently completed phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and economic impact of M72/AS01E and BCG-revaccination in India and investigated the impact of variation in vaccine characteristics and delivery strategies. METHODS: We developed an age-stratified compartmental tuberculosis transmission model for India calibrated to country-specific epidemiology. We projected baseline epidemiology to 2050 assuming no-new-vaccine introduction, and M72/AS01E and BCG-revaccination scenarios over 2025-2050 exploring uncertainty in product characteristics (vaccine efficacy, mechanism of effect, infection status required for vaccine efficacy, duration of protection) and implementation (achieved vaccine coverage and ages targeted). We estimated reductions in tuberculosis cases and deaths by each scenario compared to the no-new-vaccine baseline, as well as costs and cost-effectiveness from health-system and societal perspectives. RESULTS: M72/AS01E scenarios were predicted to avert 40% more tuberculosis cases and deaths by 2050 compared to BCG-revaccination scenarios. Cost-effectiveness ratios for M72/AS01E vaccines were around seven times higher than BCG-revaccination, but nearly all scenarios were cost-effective. The estimated average incremental cost was US$190 million for M72/AS01E and US$23 million for BCG-revaccination per year. Sources of uncertainty included whether M72/AS01E was efficacious in uninfected individuals at vaccination, and if BCG-revaccination could prevent disease. CONCLUSIONS: M72/AS01E and BCG-revaccination could be impactful and cost-effective in India. However, there is great uncertainty in impact, especially given the unknowns surrounding the mechanism of effect and infection status required for vaccine efficacy. Greater investment in vaccine development and delivery is needed to resolve these unknowns in vaccine product characteristics.

The potential impact of novel tuberculosis vaccines on health equity and financial protection in low-income and middle-income countries.

INTRODUCTION: One in two patients developing tuberculosis (TB) in low-income and middle-income countries (LMICs) faces catastrophic household costs. We assessed the potential financial risk protection from introducing novel TB vaccines, and how health and economic benefits would be distributed across income quintiles. METHODS: We modelled the impact of introducing TB vaccines meeting the World Health Organization preferred product characteristics in 105 LMICs. For each country, we assessed the distribution of health gains, patient costs and household financial vulnerability following introduction of an infant vaccine and separately for an adolescent/adult vaccine, compared with a 'no-new-vaccine' counterfactual. Patient-incurred direct and indirect costs of TB disease exceeding 20% of annual household income were defined as catastrophic. RESULTS: Over 2028-2050, the health gains resulting from vaccine introduction were greatest in lower income quintiles, with the poorest 2 quintiles in each country accounting for 56% of total LMIC TB cases averted. Over this period, the infant vaccine was estimated to avert US$5.9 (95% uncertainty interval: US$5.3-6.5) billion in patient-incurred total costs, and the adolescent/adult vaccine was estimated to avert US$38.9 (US$36.6-41.5) billion. Additionally, 3.7 (3.3-4.1) million fewer households were projected to face catastrophic costs with the infant vaccine and 22.9 (21.4-24.5) million with the adolescent/adult vaccine, with 66% of gains accruing in the poorest 2 income quintiles. CONCLUSION: Under a range of assumptions, introducing novel TB vaccines would reduce income-based inequalities in the health and household economic outcomes of TB in LMICs.

The potential impact of novel tuberculosis vaccine introduction on economic growth in low- and middle-income countries: A modeling study.

BACKGROUND: Most individuals developing tuberculosis (TB) are working age adults living in low- and middle-income countries (LMICs). The resulting disability and death impact economic productivity and burden health systems. New TB vaccine products may reduce this burden. In this study, we estimated the impact of introducing novel TB vaccines on gross domestic product (GDP) growth in 105 LMICs. METHODS AND FINDINGS: We adapted an existing macroeconomic model to simulate country-level GDP trends between 2020 and 2080, comparing scenarios for introduction of hypothetical infant and adolescent/adult vaccines to a no-new-vaccine counterfactual. We parameterized each scenario using estimates of TB-related mortality, morbidity, and healthcare spending from linked epidemiological and costing models. We assumed vaccines would be introduced between 2028 and 2047 and estimated incremental changes in GDP within each country from introduction to 2080, in 2020 US dollars. We tested the robustness of results to alternative analytic specifications. Both vaccine scenarios produced greater cumulative GDP in the modeled countries over the study period, equivalent to $1.6 (95% uncertainty interval: $0.8, 3.0) trillion for the adolescent/adult vaccine and $0.2 ($0.1, 0.4) trillion for the infant vaccine. These GDP gains were substantially lagged relative to the time of vaccine introduction, particularly for the infant vaccine. GDP gains resulting from vaccine introduction were concentrated in countries with higher current TB incidence and earlier vaccine introduction. Results were sensitive to secular trends in GDP growth but relatively robust to other analytic assumptions. Uncertain projections of GDP could alter these projections and affect the conclusions drawn by this analysis. CONCLUSIONS: Under a range of assumptions, introducing novel TB vaccines would increase economic growth in LMICs.

New tuberculosis vaccines in India: Modelling the potential health and economic impacts of adolescent/adult vaccination with M72/AS01 E and BCG-revaccination.

Background India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01E and BCG-revaccination have recently completed Phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and economic impact of M72/AS01E and BCG-revaccination in India and investigated the impact of variation in vaccine characteristics and delivery strategies. Methods We developed an age-stratified compartmental tuberculosis transmission model for India calibrated to country-specific epidemiology. We projected baseline epidemiology to 2050 assuming no-new-vaccine introduction, and M72/AS01E and BCG-revaccination scenarios over 2025-2050 exploring uncertainty in product characteristics (vaccine efficacy, mechanism of effect, infection status required for vaccine efficacy, duration of protection) and implementation (achieved vaccine coverage and ages targeted). We estimated reductions in tuberculosis cases and deaths by each scenario compared to no-new-vaccine introduction, as well as costs and cost-effectiveness from health-system and societal perspectives. Results M72/AS01E scenarios were predicted to avert 40% more tuberculosis cases and deaths by 2050 compared to BCG-revaccination scenarios. Cost-effectiveness ratios for M72/AS01E vaccines were around seven times higher than BCG-revaccination, but nearly all scenarios were cost-effective. The estimated average incremental cost was US$190 million for M72/AS01E and US$23 million for BCG-revaccination per year. Sources of uncertainty included whether M72/AS01E was efficacious in uninfected individuals at vaccination, and if BCG-revaccination could prevent disease. Conclusions M72/AS01E and BCG-revaccination could be impactful and cost-effective in India. However, there is great uncertainty in impact, especially given unknowns surrounding mechanism of effect and infection status required for vaccine efficacy. Greater investment in vaccine development and delivery is needed to resolve these unknowns in vaccine product characteristics.

The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling study.

BACKGROUND: Tuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks resulting from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low-income and middle-income countries (LMICs) in several delivery scenarios. METHODS: We calibrated a tuberculosis model to 105 LMICs (accounting for 93% of global incidence). Vaccine scenarios were implemented as the base-case (routine vaccination of those aged 9 years and one-off vaccination for those aged 10 years and older, with country-specific introduction between 2028 and 2047, and 5-year scale-up to target coverage); accelerated scale-up similar to the base-case, but with all countries introducing vaccines in 2025, with instant scale-up; and routine-only (similar to the base-case, but including routine vaccination only). Vaccines were assumed to protect against disease for 10 years, with 50% efficacy. FINDINGS: The base-case scenario would prevent 44·0 million (95% uncertainty range 37·2-51·6) tuberculosis cases and 5·0 million (4·6-5·4) tuberculosis deaths before 2050, compared with equivalent estimates of cases and deaths that would be predicted to occur before 2050 with no new vaccine introduction (the baseline scenario). The accelerated scale-up scenario would prevent 65·5 million (55·6-76·0) cases and 7·9 million (7·3-8·5) deaths before 2050, relative to baseline. The routine-only scenario would prevent 8·8 million (95% uncertainty range 7·6-10·1) cases and 1·1 million (0·9-1·2) deaths before 2050, relative to baseline. INTERPRETATION: Our results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction-at a pace similar to that seen for COVID-19 vaccines-would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up. FUNDING: WHO (2020/985800-0). TRANSLATIONS: For the French, Spanish, Italian and Dutch translations of the abstract see Supplementary Materials section.

Demonstrating multi-country calibration of a tuberculosis model using new history matching and emulation package - hmer.

Infectious disease models are widely used by epidemiologists to improve the understanding of transmission dynamics and disease natural history, and to predict the possible effects of interventions. As the complexity of such models increases, however, it becomes increasingly challenging to robustly calibrate them to empirical data. History matching with emulation is a calibration method that has been successfully applied to such models, but has not been widely used in epidemiology partly due to the lack of available software. To address this issue, we developed a new, user-friendly R package hmer to simply and efficiently perform history matching with emulation. In this paper, we demonstrate the first use of hmer for calibrating a complex deterministic model for the country-level implementation of tuberculosis vaccines to 115 low- and middle-income countries. The model was fit to 9-13 target measures, by varying 19-22 input parameters. Overall, 105 countries were successfully calibrated. Among the remaining countries, hmer visualisation tools, combined with derivative emulation methods, provided strong evidence that the models were misspecified and could not be calibrated to the target ranges. This work shows that hmer can be used to simply and rapidly calibrate a complex model to data from over 100 countries, making it a useful addition to the epidemiologist's calibration tool-kit.

Impact and cost-effectiveness of the national scale-up of HIV pre-exposure prophylaxis among female sex workers in South Africa: a modelling analysis.

INTRODUCTION: In 2016, South Africa (SA) initiated a national programme to scale-up pre-exposure prophylaxis (PrEP) among female sex workers (FSWs), with ∼20,000 PrEP initiations among FSWs (∼14% of FSW) by 2020. We evaluated the impact and cost-effectiveness of this programme, including future scale-up scenarios and the potential detrimental impact of the COVID-19 pandemic. METHODS: A compartmental HIV transmission model for SA was adapted to include PrEP. Using estimates on self-reported PrEP adherence from a national study of FSW (67.7%) and the Treatment and Prevention for FSWs (TAPS) PrEP demonstration study in SA (80.8%), we down-adjusted TAPS estimates for the proportion of FSWs with detectable drug levels (adjusted range: 38.0-70.4%). The model stratified FSW by low (undetectable drug; 0% efficacy) and high adherence (detectable drug; 79.9%; 95% CI: 67.2-87.6% efficacy). FSWs can transition between adherence levels, with lower loss-to-follow-up among highly adherent FSWs (aHR: 0.58; 95% CI: 0.40-0.85; TAPS data). The model was calibrated to monthly data on the national scale-up of PrEP among FSWs over 2016-2020, including reductions in PrEP initiations during 2020. The model projected the impact of the current programme (2016-2020) and the future impact (2021-2040) at current coverage or if initiation and/or retention are doubled. Using published cost data, we assessed the cost-effectiveness (healthcare provider perspective; 3% discount rate; time horizon 2016-2040) of the current PrEP provision. RESULTS: Calibrated to national data, model projections suggest that 2.1% of HIV-negative FSWs were currently on PrEP in 2020, with PrEP preventing 0.45% (95% credibility interval, 0.35-0.57%) of HIV infections among FSWs over 2016-2020 or 605 (444-840) infections overall. Reductions in PrEP initiations in 2020 possibly reduced infections averted by 18.57% (13.99-23.29). PrEP is cost-saving, with $1.42 (1.03-1.99) of ART costs saved per dollar spent on PrEP. Going forward, existing coverage of PrEP will avert 5,635 (3,572-9,036) infections by 2040. However, if PrEP initiation and retention doubles, then PrEP coverage increases to 9.9% (8.7-11.6%) and impact increases 4.3 times with 24,114 (15,308-38,107) infections averted by 2040. CONCLUSIONS: Our findings advocate for the expansion of PrEP to FSWs throughout SA to maximize its impact. This should include strategies to optimize retention and should target women in contact with FSW services.

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study.

BACKGROUND: Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies. METHODS AND FINDINGS: We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs. CONCLUSIONS: TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.

Assessing the Potential Impact of Disruptions Due to COVID-19 on HIV Among Key and Lower-Risk Populations in the Largest Cities of Cameroon and Benin.

BACKGROUND: The COVID-19 pandemic indirectly impacts HIV epidemiology in Central/West Africa. We estimated the potential impact of COVID-19-related disruptions to HIV prevention/treatment services and sexual partnerships on HIV incidence and HIV-related deaths among key populations including female sex workers (FSW), their clients, men who have sex with men, and overall. SETTING: Yaoundé (Cameroon) and Cotonou (Benin). METHODS: We used mathematical models of HIV calibrated to city population-specific and risk population-specific demographic/behavioral/epidemic data. We estimated the relative change in 1-year HIV incidence and HIV-related deaths for various disruption scenarios of HIV prevention/treatment services and decreased casual/commercial partnerships, compared with a scenario without COVID-19. RESULTS: A 50% reduction in condom use in all partnerships over 6 months would increase 1-year HIV incidence by 39%, 42%, 31%, and 23% among men who have sex with men, FSW, clients, and overall in Yaoundé, respectively, and 69%, 49%, and 23% among FSW, clients, and overall, respectively, in Cotonou. Combining a 6-month interruption of ART initiation and 50% reduction in HIV prevention/treatment use would increase HIV incidence by 50% and HIV-related deaths by 20%. This increase in HIV infections would be halved by a simultaneous 50% reduction in casual and commercial partnerships. CONCLUSIONS: Reductions in condom use after COVID-19 would increase infections among key populations disproportionately, particularly FSW in Cotonou, who need uninterrupted condom provision. Disruptions in HIV prevention/treatment services have the biggest impacts on HIV infections and deaths overall, only partially mitigated by equal reductions in casual/commercial sexual partnerships. Maintaining ART provision must be prioritized to minimize short-term excess HIV-related deaths.

Estimating the contribution of key populations towards HIV transmission in South Africa.

INTRODUCTION: In generalized epidemic settings, there is insufficient understanding of how the unmet HIV prevention and treatment needs of key populations (KPs), such as female sex workers (FSWs) and men who have sex with men (MSM), contribute to HIV transmission. In such settings, it is typically assumed that HIV transmission is driven by the general population. We estimated the contribution of commercial sex, sex between men, and other heterosexual partnerships to HIV transmission in South Africa (SA). METHODS: We developed the "Key-Pop Model"; a dynamic transmission model of HIV among FSWs, their clients, MSM, and the broader population in SA. The model was parameterized and calibrated using demographic, behavioural and epidemiological data from national household surveys and KP surveys. We estimated the contribution of commercial sex, sex between men and sex among heterosexual partnerships of different sub-groups to HIV transmission over 2010 to 2019. We also estimated the efficiency (HIV infections averted per person-year of intervention) and prevented fraction (% IA) over 10-years from scaling-up ART (to 81% coverage) in different sub-populations from 2020. RESULTS: Sex between FSWs and their paying clients, and between clients with their non-paying partners contributed 6.9% (95% credibility interval 4.5% to 9.3%) and 41.9% (35.1% to 53.2%) of new HIV infections in SA over 2010 to 2019 respectively. Sex between low-risk groups contributed 59.7% (47.6% to 68.5%), sex between men contributed 5.3% (2.3% to 14.1%) and sex between MSM and their female partners contributed 3.7% (1.6% to 9.8%). Going forward, the largest population-level impact on HIV transmission can be achieved from scaling up ART to clients of FSWs (% IA = 18.2% (14.0% to 24.4%) or low-risk individuals (% IA = 20.6% (14.7 to 27.5) over 2020 to 2030), with ART scale-up among KPs being most efficient. CONCLUSIONS: Clients of FSWs play a fundamental role in HIV transmission in SA. Addressing the HIV prevention and treatment needs of KPs in generalized HIV epidemics is central to a comprehensive HIV response.

Estimating the health impact of vaccination against ten pathogens in 98 low-income and middle-income countries from 2000 to 2030: a modelling study.

BACKGROUND: The past two decades have seen expansion of childhood vaccination programmes in low-income and middle-income countries (LMICs). We quantify the health impact of these programmes by estimating the deaths and disability-adjusted life-years (DALYs) averted by vaccination against ten pathogens in 98 LMICs between 2000 and 2030. METHODS: 16 independent research groups provided model-based disease burden estimates under a range of vaccination coverage scenarios for ten pathogens: hepatitis B virus, Haemophilus influenzae type B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, Streptococcus pneumoniae, rotavirus, rubella, and yellow fever. Using standardised demographic data and vaccine coverage, the impact of vaccination programmes was determined by comparing model estimates from a no-vaccination counterfactual scenario with those from a reported and projected vaccination scenario. We present deaths and DALYs averted between 2000 and 2030 by calendar year and by annual birth cohort. FINDINGS: We estimate that vaccination of the ten selected pathogens will have averted 69 million (95% credible interval 52-88) deaths between 2000 and 2030, of which 37 million (30-48) were averted between 2000 and 2019. From 2000 to 2019, this represents a 45% (36-58) reduction in deaths compared with the counterfactual scenario of no vaccination. Most of this impact is concentrated in a reduction in mortality among children younger than 5 years (57% reduction [52-66]), most notably from measles. Over the lifetime of birth cohorts born between 2000 and 2030, we predict that 120 million (93-150) deaths will be averted by vaccination, of which 58 million (39-76) are due to measles vaccination and 38 million (25-52) are due to hepatitis B vaccination. We estimate that increases in vaccine coverage and introductions of additional vaccines will result in a 72% (59-81) reduction in lifetime mortality in the 2019 birth cohort. INTERPRETATION: Increases in vaccine coverage and the introduction of new vaccines into LMICs have had a major impact in reducing mortality. These public health gains are predicted to increase in coming decades if progress in increasing coverage is sustained. FUNDING: Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation.

Quantifying the Evolving Contribution of HIV Interventions and Key Populations to the HIV Epidemic in Yaoundé, Cameroon.

BACKGROUND: Key populations (KP) including men who have sex with men (MSM), female sex workers (FSW), and their clients are disproportionately affected by HIV in Sub-Saharan Africa. We estimated the evolving impact of past interventions and contribution of unmet HIV prevention/treatment needs of key populations and lower-risk groups to HIV transmission. SETTING: Yaoundé, Cameroon. METHODS: We parametrized and fitted a deterministic HIV transmission model to Yaoundé-specific demographic, behavioral, HIV, and intervention coverage data in a Bayesian framework. We estimated the fraction of incident HIV infections averted by condoms and antiretroviral therapy (ART) and the fraction of all infections over 10-year periods directly and indirectly attributable to sex within and between each risk group. RESULTS: Condom use and ART together may have averted 43% (95% uncertainty interval: 31-54) of incident infections over 1980-2018 and 72% (66-79) over 2009-2018. Most onward transmissions over 2009-2018 stemmed from sex between lower-risk individuals [47% (32-61)], clients [37% (23-51)], and MSM [35% (20-54)] with all their partners. The contribution of commercial sex decreased from 25% (8-49) over 1989-1998 to 8% (3-22) over 2009-2018, due to higher intervention coverage among FSW. CONCLUSION: Condom use and recent ART scale-up mitigated the HIV epidemic in Yaoundé and changed the contribution of different partnerships to onward transmission over time. Findings highlight the importance of prioritizing HIV prevention and treatment for MSM and clients of FSW whose unmet needs now contribute most to onward transmission, while maintaining services that successfully reduced transmissions in the context of commercial sex.

Effects and cost of different strategies to eliminate hepatitis C virus transmission in Pakistan: a modelling analysis.

BACKGROUND: The WHO elimination strategy for hepatitis C virus advocates scaling up screening and treatment to reduce global hepatitis C incidence by 80% by 2030, but little is known about how this reduction could be achieved and the costs of doing so. We aimed to evaluate the effects and cost of different strategies to scale up screening and treatment of hepatitis C in Pakistan and determine what is required to meet WHO elimination targets for incidence. METHODS: We adapted a previous model of hepatitis C virus transmission, treatment, and disease progression for Pakistan, calibrating using available data to incorporate a detailed cascade of care for hepatitis C with cost data on diagnostics and hepatitis C treatment. We modelled the effect on various outcomes and costs of alternative scenarios for scaling up screening and hepatitis C treatment in 2018-30. We calibrated the model to country-level demographic data for 1960-2015 (including population growth) and to hepatitis C seroprevalence data from a national survey in 2007-08, surveys among people who inject drugs (PWID), and hepatitis C seroprevalence trends among blood donors. The cascade of care in our model begins with diagnosis of hepatitis C infection through antibody screening and RNA confirmation. Diagnosed individuals are then referred to care and started on treatment, which can result in a sustained virological response (effective cure). We report the median and 95% uncertainty interval (UI) from 1151 modelled runs. FINDINGS: One-time screening of 90% of the 2018 population by 2030, with 80% referral to treatment, was projected to lead to 13·8 million (95% UI 13·4-14·1) individuals being screened and 350 000 (315 000-385 000) treatments started annually, decreasing hepatitis C incidence by 26·5% (22·5-30·7) over 2018-30. Prioritised screening of high prevalence groups (PWID and adults aged ≥30 years) and rescreening (annually for PWID, otherwise every 10 years) are likely to increase the number screened and treated by 46·8% and decrease incidence by 50·8% (95% UI 46·1-55·0). Decreasing hepatitis C incidence by 80% is estimated to require a doubling of the primary screening rate, increasing referral to 90%, rescreening the general population every 5 years, and re-engaging those lost to follow-up every 5 years. This approach could cost US$8·1 billion, reducing to $3·9 billion with lowest costs for diagnostic tests and drugs, including health-care savings, and implementing a simplified treatment algorithm. INTERPRETATION: Pakistan will need to invest about 9·0% of its yearly health expenditure to enable sufficient scale up in screening and treatment to achieve the WHO hepatitis C elimination target of an 80% reduction in incidence by 2030. FUNDING: UNITAID.

Phylodynamic analysis of HIV-1 subtypes B, C and CRF 02_AG in Senegal.

Surveillance of HIV epidemics in key populations and in developing countries is often challenging due to sparse, incomplete, or low-quality data. Analysis of HIV sequence data can provide an alternative source of information about epidemic history, population structure, and transmission patterns. To understand HIV-1 dynamics and transmission patterns in Senegal, we carried out model-based phylodynamic analyses using the structured-coalescent approach using HIV-1 sequence data from three different subgroups: reproductive aged males and females from the adult Senegalese population and men who have sex with other men (MSM). We fitted these phylodynamic analyses to time-scaled phylogenetic trees individually for subtypes C and CRF 02_AG, and for the combined data for subtypes B, C and CRF 02_AG. In general, the combined analysis showed a decreasing proportion of effective number of infections among all reproductive aged adults relative to MSM. However, we observed a nearly time-invariant distribution for subtype CRF 02_AG and an increasing trend for subtype C on the proportion of effective number of infections. The population attributable fraction also differed between analyses: subtype CRF 02_AG showed little contribution from MSM, while for subtype C and combined analyses this contribution was much higher. Despite observed differences, results suggested that the combination of high assortativity among MSM and the unmet HIV prevention and treatment needs represent a significant component of the HIV epidemic in Senegal.

Estimating the contribution of key populations towards the spread of HIV in Dakar, Senegal.

INTRODUCTION: Key populations including female sex workers (FSW) and men who have sex with men (MSM) bear a disproportionate burden of HIV. However, the role of focusing prevention efforts on these groups for reducing a country's HIV epidemic is debated. We estimate the extent to which HIV transmission among FSW and MSM contributes to overall HIV transmission in Dakar, Senegal, using a dynamic assessment of the population attributable fraction (PAF). METHODS: A dynamic transmission model of HIV among FSW, their clients, MSM and the lower-risk adult population was parameterized and calibrated within a Bayesian framework using setting-specific demographic, behavioural, HIV epidemiological and antiretroviral treatment (ART) coverage data for 1985 to 2015. We used the model to estimate the 10-year PAF of commercial sex between FSW and their clients, and sex between men, to overall HIV transmission (defined as the percentage of new infections prevented when these modes of transmission are removed). In addition, we estimated the prevention benefits associated with historical increases in condom use and ART uptake, and impact of further increases in prevention and treatment. RESULTS: The model projections suggest that unprotected sex between men contributed to 42% (2.5 to 97.5th percentile range 24 to 59%) of transmissions between 1995 and 2005, increasing to 64% (37 to 79%) from 2015 to 2025. The 10-year PAF of commercial sex is smaller, diminishing from 21% (7 to 39%) in 1995 to 14% (5 to 35%) in 2015. Without ART, 49% (32 to 71%) more HIV infections would have occurred since 2000, when ART was initiated, whereas without condom use since 1985, 67% (27 to 179%) more HIV infections would have occurred, and the overall HIV prevalence would have been 60% (29 to 211%) greater than what it is now. Further large decreases in HIV incidence (68%) can be achieved by scaling up ART in MSM to 74% coverage and reducing their susceptibility to HIV by two-thirds through any prevention modality. CONCLUSIONS: Unprotected sex between men may be an important contributor to HIV transmission in Dakar, due to suboptimal coverage of evidence-informed interventions. Although existing interventions have effectively reduced HIV transmission among adults, it is crucial that further strategies address the unmet need among MSM.

Modelling the impact of a national scale-up of interventions on hepatitis C virus transmission among people who inject drugs in Scotland.

BACKGROUND AND AIMS: To reduce hepatitis C virus (HCV) transmission among people who inject drugs (PWID), Scottish Government-funded national strategies, launched in 2008, promoted scaling-up opioid substitution therapy (OST) and needle and syringe provision (NSP), with some increases in HCV treatment. We test whether observed decreases in HCV incidence post-2008 can be attributed to this intervention scale-up. DESIGN: A dynamic HCV transmission model among PWID incorporating intervention scale-up and observed decreases in behavioural risk, calibrated to Scottish HCV prevalence and incidence data for 2008/09. SETTING: Scotland, UK. PARTICIPANTS: PWID. MEASUREMENTS: Model projections from 2008 to 2015 were compared with data to test whether they were consistent with observed decreases in HCV incidence among PWID while incorporating the observed intervention scale-up, and to determine the impact of scaling-up interventions on incidence. FINDINGS: Without fitting to epidemiological data post-2008/09, the model incorporating observed intervention scale-up agreed with observed decreases in HCV incidence among PWID between 2008 and 2015, suggesting that HCV incidence decreased by 61.3% [95% credibility interval (CrI) = 45.1-75.3%] from 14.2/100 person-years (py) (9.0-20.7) to 5.5/100 py (2.9-9.2). On average, each model fit lay within 84% (10.1/12) of the confidence bounds for the 12 incidence data points against which the model was compared. We estimate that scale-up of interventions (OST + NSP + HCV treatment) and decreases in high-risk behaviour from 2008 to 2015 resulted in a 33.9% (23.8-44.6%) decrease in incidence, with the remainder [27.4% (17.6-37.0%)] explained by historical changes in OST + NSP coverage and risk pre-2008. Projections suggest that scaling-up of all interventions post-2008 averted 1492 (657-2646) infections over 7 years, with 1016 (308-1996), 404 (150-836) and 72 (27-137) due to scale-up of OST + NSP, decreases in high-risk behaviour and HCV treatment, respectively. CONCLUSIONS: Most of the decline in hepatitis C virus (HCV) incidence in Scotland between 2008 and 2015 appears to be attributable to intervention scale-up (opioid substitution therapy and needle and syringe provision) due to government strategies on HCV and drugs.

Curbing the hepatitis C virus epidemic in Pakistan: the impact of scaling up treatment and prevention for achieving elimination.

Background: The World Health Organization (WHO) has developed a global health strategy to eliminate viral hepatitis. We project the treatment and prevention requirements to achieve the WHO HCV elimination target of reducing HCV incidence by 80% and HCV-related mortality by 65% by 2030 in Pakistan, which has the second largest HCV burden worldwide. Methods: We developed an HCV transmission model for Pakistan, and calibrated it to epidemiological data from a national survey (2007), surveys among people who inject drugs (PWID), and blood donor data. Current treatment coverage data came from expert opinion and published reports. The model projected the HCV burden, including incidence, prevalence and deaths through 2030, and estimated the impact of varying prevention and direct-acting antiviral (DAA) treatment interventions necessary for achieving the WHO HCV elimination targets. Results: With no further treatment (currently ∼150 000 treated annually) during 2016-30, chronic HCV prevalence will increase from 3.9% to 5.1%, estimated annual incident infections will increase from 700 000 to 1 100 000, and 1 400 000 HCV-associated deaths will occur. To reach the WHO HCV elimination targets by 2030, 880 000 annual DAA treatments are required if prevention is not scaled up and no treatment prioritization occurs. By targeting treatment toward persons with cirrhosis (80% treated annually) and PWIDs (double the treatment rate of non-PWIDs), the required annual treatment number decreases to 750 000. If prevention activities also halve transmission risk, this treatment number reduces to 525 000 annually. Conclusions: Substantial HCV prevention and treatment interventions are required to reach the WHO HCV elimination targets in Pakistan, without which Pakistan's HCV burden will increase markedly.

Behavioural, not biological, factors drive the HCV epidemic among HIV-positive MSM: HCV and HIV modelling analysis including HCV treatment-as-prevention impact.

Background: Uncertainty surrounds why hepatitis C virus (HCV) is concentrated among HIV-positive men who have sex with men (MSM). We used mathematical modelling to explore reasons for these infection patterns, and implications for HCV treatment-as-prevention. Methods: Using a joint MSM HIV/HCV transmission model parameterized with UK behavioural data, we considered how biological (heightened HCV infectivity and reduced spontaneous clearance among HIV-positive MSM) and/or behavioural factors (preferential sexual mixing by HIV status and risk heterogeneity) could concentrate HCV infection in HIV-positive MSM as commonly observed (5-20 times the HCV prevalence in HIV-negative MSM; defined as the HCV ratio). We explored how HCV treatment-as-prevention impact varies under differing HCV ratios. Results: Biological factors produced low HCV ratios (< 3), not explaining the skewed epidemic. However, combining preferential mixing by HIV status with sexual risk behaviour heterogeneity produced high HCV ratios (> 10) that were highly sensitive to both factors. Irrespective of the HCV ratio or behavioural/biological factors, HCV treatment of HIV-diagnosed MSM markedly reduced the HCV prevalence among HIV-positive MSM, but less impact was achieved among all MSM for lower HCV ratios. Conclusions: Sexual behaviour patterns likely drive observed HCV infection patterns among HIV-positive MSM. Changes in these patterns could disseminate HCV amongst HIV-negative MSM, limiting the impact of targeting HCV treatment to HIV-diagnosed MSM.