Patient and health provider costs of integrated HIV, diabetes and hypertension ambulatory health services in low-income settings - an empirical socio-economic cohort study in Tanzania and Uganda.

BACKGROUND: Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed. METHODS: 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations. RESULTS: Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics' mean efficiency benchmark score was 0.86 (range 0.30-1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2-23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities. CONCLUSION: Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa's ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes.

Cryptococcal Meningitis Screening and Community-based Early Adherence Support in People With Advanced Human Immunodeficiency Virus Infection Starting Antiretroviral Therapy in Tanzania and Zambia: A Cost-effectiveness Analysis.

BACKGROUND: A randomized trial demonstrated that among people living with late-stage human immunodeficiency virus (HIV) infection initiating antiretroviral therapy, screening serum for cryptococcal antigen (CrAg) combined with adherence support reduced all-cause mortality by 28%, compared with standard clinic-based care. Here, we present the cost-effectiveness. METHODS: HIV-infected adults with CD4 count <200 cells/µL were randomized to either CrAg screening plus 4 weekly home visits to provide adherence support or to standard clinic-based care in Dar es Salaam and Lusaka. The primary economic outcome was health service care cost per life-year saved as the incremental cost-effectiveness ratio (ICER), based on 2017 US dollars. We used nonparametric bootstrapping to assess uncertainties and univariate deterministic sensitivity analysis to examine the impact of individual parameters on the ICER. RESULTS: Among the intervention and standard arms, 1001 and 998 participants, respectively, were enrolled. The annual mean cost per participant in the intervention arm was US$339 (95% confidence interval [CI], $331-$347), resulting in an incremental cost of the intervention of US$77 (95% CI, $66-$88). The incremental cost was similar when analysis was restricted to persons with CD4 count <100 cells/µL. The ICER for the intervention vs standard care, per life-year saved, was US$70 (95% CI, $43-$211) for all participants with CD4 count up to 200 cells/µL and US$91 (95% CI, $49-$443) among those with CD4 counts <100 cells /µL. Cost-effectveness was most sensitive to mortality estimates. CONCLUSIONS: Screening for cryptococcal antigen combined with a short period of adherence support, is cost-effective in resource-limited settings.

Addition of Flucytosine to Fluconazole for the Treatment of Cryptococcal Meningitis in Africa: A Multicountry Cost-effectiveness Analysis.

BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. METHODS: The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. RESULTS: The mean costs per patient were US $847 (95% confidence interval [CI] $776-927) for FLU+5FC, and US $628 (95% CI $557-709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9-41.7%) with FLU+5FC and 53.8% (95% CI 43.1-64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28-208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. CONCLUSIONS: The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus-infected persons in Africa.

Pneumococcal Disease: A Systematic Review of Health Utilities, Resource Use, Costs, and Economic Evaluations of Interventions.

BACKGROUND: Pneumococcal diseases cause substantial mortality, morbidity, and economic burden. Evidence on data inputs for economic evaluations of interventions targeting pneumococcal disease is critical. OBJECTIVES: To summarize evidence on resource use, costs, health utilities, and cost-effectiveness for pneumococcal disease and associated interventions to inform future economic analyses. METHODS: We searched MEDLINE, Embase, Web of Science, CINAHL, PsycINFO, EconLit, and Cochrane databases for peer-reviewed studies in English on pneumococcal disease that reported health utilities using direct or indirect valuation methods, resource use, costs, or cost-effectiveness of intervention programs, and summarized the evidence descriptively. RESULTS: We included 383 studies: 9 reporting health utilities, 131 resource use, 160 economic costs of pneumococcal disease, 95 both resource use and costs, and 178 economic evaluations of pneumococcal intervention programs. Health state utility values ranged from 0 to 1 for both meningitis and otitis media and from 0.3 to 0.7 for both pneumonia and sepsis. Hospitalization was shortest for otitis media (range: 0.1-5 days) and longest for sepsis/septicemia (6-48). The main categories of costs reported were drugs, hospitalization, and household or employer costs. Resource use was reported in hospital length of stay and number of contacts with general practitioners. Costs and resource use significantly varied among population ages, disease conditions, and settings. Current vaccination programs for both adults and children, antibiotic use and outreach programs to promote vaccination, early disease detection, and educational programs are cost-effective in most countries. CONCLUSION: This study has generated a comprehensive repository of health economic evidence on pneumococcal disease that can be used to inform future economic evaluations of pneumococcal disease intervention programs.

The impact of childhood pneumococcal vaccination on hospital admissions in England: a whole population observational study.

BACKGROUND: Pneumococcal infections are major causes of morbidity and mortality worldwide. We use routine hospital admissions data and time-series modelling analysis to estimate the impact of the seven and thirteen valent pneumococcal conjugate vaccines (PCV7 and PCV13) on hospital admissions due to pneumococcal disease in England. METHODS: Hospital admissions for pneumococcal meningitis, bacteraemia and pneumonia between January 1, 2003 and December 31, 2015 were identified from the national Hospital Episode Statistics database for all age groups in England. We model the impact of pneumococcal vaccination using interrupted time series analysis. Hospital admissions prior to vaccine introduction were extrapolated to predict the expected number of admissions in the absence of pneumococcal vaccines. Admissions avoided over time were estimated by comparing the fitted interrupted time series and the expected model for no vaccination in a Bayesian framework. RESULTS: Overall, there were 43,531 (95% credible interval (CrI): 36486-51,346) fewer hospital admissions due to bacteraemia, meningitis and pneumonia in England during the period from 2006 to 2015 than would have been expected if pneumococcal vaccines had not been implemented, with the majority of hospital admissions avoided due to pneumonia. Among young children reductions in meningitis were more common, while among adults reductions in pneumonia admissions were relatively more important, with no evidence for reduced bacteraemia and meningitis among older adults. We estimated that 981 (95% CrI: 391-2018), 749 (95% CrI: 295-1442) and 1464 (95% CrI: 793-2522) bacteraemia, meningitis and pneumonia related hospital admissions, respectively, were averted in children < 2 years of age. CONCLUSIONS: Substantial reductions in hospital admissions for bacteraemia, meningitis and pneumonia in England were estimated after the introduction of childhood vaccination, with indirect effects being responsible for most of the hospital admissions avoided.

Imputing the Direct and Indirect Effectiveness of Childhood Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease by Surveying Temporal Changes in Nasopharyngeal Pneumococcal Colonization.

The limited capability in most low- to middle-income countries to study the benefit of pneumococcal conjugate vaccine (PCV) in protecting against invasive pneumococcal disease (IPD) calls for alternate strategies to assess this. We used a mathematical model to predict the direct and indirect effectiveness of PCV by analyzing serotype-specific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005 to 2012 and colonization studies undertaken in human immunodeficiency virus (HIV)-uninfected and HIV-infected child-mother dyads from 2007 to 2009 (pre-PCV era), in 2010 (7-valent PCV era), and in 2012 (13-valent PCV era). We compared the model-predicted changes in IPD incidence with observed changes in IPD incidence, according to HIV status, in children aged 3 months-5 years and in women aged 18-45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCV-unvaccinated children and adults, but not among children under age 24 months. Surveillance of colonization prior to and following PCV use can be used to impute the indirect protection afforded by PCV in unvaccinated age groups, including those in high-HIV-prevalence settings.

Serotype-Specific Cell-Mediated Immunity Associated With Clearance of Homotypic Group B Streptococcus Rectovaginal Colonization in Pregnant Women.

We investigated the association between group B Streptococcus (GBS) serotype-specific capsular polysaccharide cellular immunity, measured with enzyme-linked immunospot (ELISPOT) interferon γ release assay at 20 weeks gestation in pregnant women, and its effect on rectovaginal serotype-specific GBS colonization up to 37 weeks gestation. Among women colonized by serotype III at enrollment, interferon γ ELISPOT positivity was more common in those in whom colonization was cleared (44.4%) than in those in whom colonization persisted (7.4%; P = .008), with a similar trend observed for serotype Ia. Presence of serotype-specific capsular polysaccharide cell-mediated immunity contributes to the clearance of GBS rectovaginal colonization.

Temporal Changes in Pneumococcal Colonization in HIV-infected and HIV-uninfected Mother-Child Pairs Following Transitioning From 7-valent to 13-valent Pneumococcal Conjugate Vaccine, Soweto, South Africa.

BACKGROUND: We investigated the impact of infant pneumococcal conjugate vaccine (PCV) immunization on pneumococcal colonization among human immunodeficiency virus (HIV)-infected and HIV-uninfected mother-child pairs. METHODS: Pneumococcal colonization was assessed in May 2010-February 2011 (period 1; 7-valent PCV era) and May 2012-April 2013 (period 2; 13-valent PCV era). Standard microbiological methods were used for pneumococcus isolation and serotyping. RESULTS: In children 0-12 years, PCV13-serotype colonization decreased from period 1 to period 2 among HIV-uninfected (adjusted odds ratio [OR], 0.32; 95% confidence interval [CI], .25-.40) and HIV-infected children (adjusted OR, 0.37; 95% CI, .28-.49), while there was an increase in nonvaccine serotype colonization. Decreases in PCV13-serotype colonization were observed in HIV-uninfected women (adjusted OR, 0.44; 95% CI, .23-.81), with a similar trend in HIV-infected women. HIV-infected compared to -uninfected women had higher prevalence of overall (20.5% vs 9.7% in period 1; 13.8% vs 9.7% in period 2) and PCV13-serotype colonization (8.7% vs 5.4% in period 1; 4.8% vs 2.0% in period 2), P < .04 for all observations. CONCLUSIONS: Targeted PCV vaccination of African infants in a setting with high HIV prevalence was associated with PCV13-serotype colonization reduction, including among unvaccinated HIV-infected women.

Dynamics of pneumococcal transmission in vaccine-naive children and their HIV-infected or HIV-uninfected mothers during the first 2 years of life.

Pneumococcal vaccine-naïve mother-child dyads in South Africa had nasopharyngeal swabs taken 9 times within the first 2 years of the children's lives between January 2007 and May 2009. To quantify the strength of the association of serotype-specific carriage in mother-child dyads, a stochastic transmission model was fitted to the data. Children were more susceptible to individual serotypes included in the 7-valent pneumococcal conjugate vaccine (PCV7) transmitted by their mothers than vice versa; however, children infected their mothers with these serotypes more frequently than mothers infected children. The child-to-mother steady-state forces of pneumococcal acquisition were between 0.36 and 3.29 (per 1,000 days) compared with 0.06-0.51 for mother-to-child transmission. Although children of mothers infected with human immunodeficiency virus were more often exposed to PCV7 serotypes by their mothers, their risk of acquisition remained low compared with the risk of child-to-mother transmission. Mothers acquired pneumococci at lower rates (per 1,000 days) from unmeasured exposure within families and in the wider community (range, 0.12-1.69 per 1,000 days) than did children (range, 1.10-5.21 per 1,000 days). Pneumococcal immunization of young children is expected to have an indirect effect of reducing PCV7 serotype maternal colonization and possibly disease even in settings such as ours, in which there is a high prevalence of human immunodeficiency virus-infected mothers.

Interrelationship of Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus colonization within and between pneumococcal-vaccine naïve mother-child dyads.

BACKGROUND: A high prevalence of bacterial nasopharyngeal co-infections has been reported in children, however, such data is limited in adults. We examined the interaction of Haemophilus influenzae, Staphylococcus aureus and Streptococcus pneumoniae pharyngeal colonization in mother-child dyads. METHODS: Pneumococcal-vaccine naïve children and their mothers had pharyngeal swabs undertaken at 1.6, 2.5, 3.5, 4.5, 7.4, 9.5, 12.5, 16.2 and 24.2 months of child's age. Swabs were cultured for S. pneumoniae, H. influenzae and S. aureus using standard microbiologic methods. Multivariate generalized estimating equation-models were used to explore the associations of the three bacteria within and between children and their mothers. RESULTS: In children, the observed probability of co-colonization was higher than expected. Well-defined associations in colonization between the bacteria were observed in children but not among mothers. In children, a synergistic association was observed between S. pneumoniae and H. influenzae (Adjusted odds ratio (AOR): 1.75, 95% CI: 1.32-2.32) and a negative association between S. pneumoniae and S. aureus (AOR: 0.51, 95% CI: 0.39-0.67) or H. influenzae and S. aureus (AOR: 0.24, 95% CI: 0.16-0.34) colonization. Additionally, all three bacteria had a higher likelihood of concurrent colonization. There was a strong association in colonization by the bacteria in children and their mothers, including increased likelihood of maternal colonization if the child was colonized by S. pneumoniae (AOR: 1.84, 95% CI: 1.28-2.63) and H. influenzae (AOR: 6.34, 95% CI: 2.24-18.0). CONCLUSIONS: The effects of immunization of children with pneumococcal-conjugate-vaccine in settings such as ours needs monitoring with regard to potential changes of pharyngeal bacterial ecology which could occur in vaccinated and -unvaccinated age-groups.

Clinical and economic impact of ferric carboxymaltose treatment for iron deficiency in patients stabilized following acute heart failure: a multinational study.

OBJECTIVE: To estimate clinical events and evaluate the financial implications of introducing ferric carboxymaltose (FCM) to treat iron deficiency (ID) at discharge in patients hospitalized for acute heart failure (AHF) with left ventricular ejection fraction (LVEF) <50% in the UK, Switzerland and Italy. METHODS: A decision analytic cost-offset model was developed to evaluate the costs associated with introducing FCM for all eligible patients in three countries compared to a world without FCM, over a five-year time horizon. Data from AFFIRM-AHF clinical trial were used to model clinical outcomes, using an established cohort state-transition Markov model. Country-specific prevalence estimates were derived using data from real-world studies to extrapolate number of events and consequent cost totals to the population at risk on a national scale. RESULTS: The cost-offset modeling demonstrated that FCM is projected to be a cost-saving intervention in all three country settings over a five-year time horizon. Savings were driven primarily by reduced hospitalizations and avoided cardiovascular deaths, with net cost savings of -£14,008,238, -CHF25,456,455 and -€105,295,146 incurred to the UK, Switzerland and Italy, respectively. LIMITATIONS: Although AFFIRM-AHF was a multinational trial, efficacy data per country was not sufficiently large to enable country-specific analysis, therefore overall clinical parameters have been assumed to apply to all countries. CONCLUSIONS: This study provides further evidence of the potential cost savings achievable by treating ID with FCM at discharge in patients hospitalized for AHF with LVEF <50%. The value of FCM treatment within the healthcare systems of the UK, Switzerland and Italy was demonstrated even within a limited time frame of one year, with consistent cost savings indicated over a longer term.

The Population-Wide Risk-Benefit Profile of Extending the Primary COVID-19 Vaccine Course Compared with an mRNA Booster Dose Program.

The vaccination program is reducing the burden of COVID-19. However, recently, COVID-19 infections have been increasing across Europe, providing evidence that vaccine efficacy is waning. Consequently, booster doses are required to restore immunity levels. However, the relative risk-benefit ratio of boosters, compared to pursuing a primary course in the unvaccinated population, remains uncertain. In this study, a susceptible-exposed-infectious-recovered (SEIR) transmission model of SARS-CoV-2 was used to investigate the impact of COVID-19 vaccine waning on disease burden, the benefit of a booster vaccine program compared to targeting the unvaccinated population, and the population-wide risk-benefit profile of vaccination. Our data demonstrates that the rate of vaccine efficacy waning has a significant impact on COVID-19 hospitalisations with the greatest effect in populations with lower vaccination coverage. There was greater benefit associated with a booster vaccination strategy compared to targeting the unvaccinated population, once >50% of the population had received their primary vaccination course. The population benefits of vaccination (reduced hospitalisations, long-COVID and deaths) outweighed the risks of myocarditis/pericarditis by an order of magnitude. Vaccination is important in ending the COVID-19 pandemic sooner, and the reduction in hospitalisations, death and long-COVID associated with vaccination significantly outweigh any risks. Despite these obvious benefits some people are vaccine reluctant, and as such remain unvaccinated. However, when most of a population have been vaccinated, a focus on a booster vaccine strategy for this group is likely to offer greater value, than targeting the proportion of the population who choose to remain unvaccinated.

Cost-Effectiveness of a Culturally Adapted Manual-Assisted Brief Psychological Intervention for Self-Harm in Pakistan: A Secondary Analysis of the Culturally Adapted Manual-Assisted Brief Psychological Randomized Controlled Trial.

OBJECTIVES: Self-harm is a serious public health problem. A culturally adapted manual-assisted problem-solving training (C-MAP) intervention improved and sustained a reduction in suicidal ideation, hopelessness, and depression compared with treatment as usual (TAU) alone. Here, we evaluate its cost-effectiveness. METHODS: Patients admitted after an episode of self-harm were randomized individually to either C-MAP plus TAU or TAU alone in Karachi. Improvement in health-related quality-adjusted life-years (QALYs) was measured using the EQ-5D with 3 levels instrument at baseline, 3 months, and 6 months after randomization. The primary economic outcome was health service cost per QALY gained as the incremental cost-effectiveness ratio, based on 2019 US$ and a 6-month time horizon. Nonparametric bootstrapping was used to assess uncertainties and sensitivity analysis to examine the impact of hospitalization costs. RESULTS: A total of 108 and 113 participants were enrolled among the intervention and standard arms, respectively. The intervention resulted in 0.04 (95% confidence interval [CI] 0.00-0.08) more QALYs 6 months after enrolment. The mean cost per participant in the intervention arm was $1001 (95% CI 968-1031), resulting in an incremental cost of the intervention of $640 (95% CI 595-679). The incremental cost-effectiveness ratio for the C-MAP intervention versus TAU was $16 254 (95% CI 7116-99 057) per QALY gained. The probability that C-MAP is cost-effective was between 66% and 83% for cost-effective thresholds between $20 000 and $30 000. Cost-effectiveness results remained robust to sensitivity analyses. CONCLUSIONS: C-MAP may be a valuable self-harm intervention. Further studies with longer follow-up and larger sample sizes are needed to draw reliable conclusions.

Youth Culturally adapted Manual Assisted Problem Solving Training (YCMAP) in Pakistani adolescent with a history of self-harm: protocol for multicentre clinical and cost-effectiveness randomised controlled trial.

INTRODUCTION: Suicide is a global health concern. Sociocultural factors have an impact on self-harm and suicide rates. In Pakistan, both self-harm and suicide are considered as criminal offence's and are condemned on both religious and social grounds. The proposed intervention 'Youth Culturally Adapted Manual Assisted Problem Solving Training (YCMAP)' is based on principles of problem-solving and cognitive-behavioural therapy. YCMAP is a brief, culturally relevant, scalable intervention that can be implemented in routine clinical practice if found to be effective. METHOD AND ANALYSIS: A multicentre rater blind randomised controlled trial to evaluate the clinical and cost-effectiveness of YCMAP including a sample of 652 participants, aged 12-18 years, presenting to general physicians/clinicians, emergency room after self harm or self referrals. We will test the effectiveness of 8-10 individual sessions of YCMAP delivered over 3 months compared with treatment as usual. Primary outcome measure is repetition of self-harm at 12 months. The seconday outcomes include reduction in suicidal ideation, hopelessness and distress and improvement in health related quality of life. Assessments will be completed at baseline, 3, 6, 9 and 12 months postrandomisation. The nested qualitative component will explore perceptions about management of self-harm and suicide prevention among adolescents and investigate participants' experiences with YCMAP. The study will be guided by the theory of change approach to ensure that the whole trial is centred around needs of the end beneficiaries as key stakeholders in the process. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committee of University of Manchester, the National Bioethics Committee in Pakistan. The findings of this study will be disseminated through community workshops, social media, conference presentations and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04131179.

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial.

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95% CI 1314-1424) in the AmBisome group and $1237 (1181-1293) in the control group. The incremental cost-effectiveness ratio was $128 (59-257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to $80 (15-275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to $121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. TRANSLATIONS: For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

Modelling the impact of acute infection dynamics on the accumulation of HIV-1 mutations.

Events over the past year have brought hope and have re-energized the interest in targeting pre-infection or early infection period with preventative or therapeutic interventions such as vaccines and pre-exposure prophylaxis (PrEP). In breakthrough infections, the incidence, long term prognosis and clinical significance of early infection events is not well understood but it is possible that these early events may be crucial in determining the subsequent course of disease. We use a branching process model in a deterministically varying environment to explore how the dynamics of early infection affects the accumulation of mutations which lay the seeds for long term evolution of drug resistance and immune system evasion. We relate this exploration to regimes of impact, on diversity, of tropical interventions strategies such as PrEP and vaccines. As a metric of diversity we compute the probability of existence of particular genomes which potentially arise. Using several model scenarios, we demonstrate various regimes of 'response' of evolution to 'intervention'. Transient effects of therapeutic interventions early in infection that impose a fitness cost on early viruses can significantly reduce the probability of diversity later during the chronic state of infection. This stands in contrast to the concern that early selective pressure may increase the probability of later existence of drug resistance mutations, for example. The branching process paradigm offers the ability to efficiently compute important indicators of viral diversity, in a framework with a modest number of simplifying assumptions, without simulating the full range of individual level scenarios. These models may be useful to illustrate the impact of vaccines and PrEP on viral evolution in the case of breakthrough infection. They also suggest that new measures of viral diversity which correlate to prognosis should be sought in trials for PrEP and vaccines.

Vaccinating Adolescents and Children Significantly Reduces COVID-19 Morbidity and Mortality across All Ages: A Population-Based Modeling Study Using the UK as an Example.

Debate persists around the risk-benefit balance of vaccinating adolescents and children against COVID-19. Central to this debate is quantifying the contribution of adolescents and children to the transmission of SARS-CoV-2, and the potential impact of vaccinating these age groups. In this study, we present a novel SEIR mathematical disease transmission model that quantifies the impact of different vaccination strategies on population-level SARS-CoV-2 infections and clinical outcomes. The model employs both age- and time-dependent social mixing patterns to capture the impact of changes in restrictions. The model was used to assess the impact of vaccinating adolescents and children on the natural history of the COVID-19 pandemic across all age groups, using the UK as an example. The base case model demonstrates significant increases in COVID-19 disease burden in the UK following a relaxation of restrictions, if vaccines are limited to those ≥18 years and vulnerable adolescents (≥12 years). Including adolescents and children in the vaccination program could reduce overall COVID-related mortality by 57%, and reduce cases of long COVID by 75%. This study demonstrates that vaccinating adolescents and children has the potential to play a vital role in reducing SARS-CoV-2 infections, and subsequent COVID-19 morbidity and mortality, across all ages. Our results have major global public health implications and provide valuable information to inform a potential pandemic exit strategy.

Cost-Effectiveness of a Culturally Adapted Manual-Assisted Brief Psychological Intervention for Self-Harm in Pakistan: A Secondary Analysis of the Culturally Adapted Manual-Assisted Problem-Solving Training Randomized Controlled Trial.

OBJECTIVES: Self-harm is a serious public health problem. A culturally adapted manual-assisted problem-solving training (C-MAP) intervention improved and sustained the reduction in suicidal ideation, hopelessness, and depression compared with treatment as usual (TAU) alone. Here, we evaluate its cost-effectiveness. METHODS: Patients admitted after an episode of self-harm were randomized individually to either C-MAP plus TAU or TAU alone in Karachi. Improvement in health-related quality-adjusted life years (QALYs) was measured using the Euro Qol-5D-3L instrument at baseline and at 3 months and 6 months after randomization. The primary economic outcome was health service cost per QALY gained as the incremental cost-effectiveness ratio, based on 2019 US dollars and a 6-month time horizon. Nonparametric bootstrapping was used to assess uncertainties, and sensitivity analysis to examine the impact of hospitalization costs. RESULTS: A total of 108 and 113 participants were enrolled among the intervention and standard arms, respectively. The intervention resulted in 0.04 more QALYs (95% confidence interval [CI] 0.00-0.08) 6 months after enrolment. The mean cost per participant in the intervention arm was US $1001 (95% CI 968-1031), resulting in an incremental cost of the intervention of US $640 (95% CI 595-679). The incremental cost-effectiveness ratio for the C-MAP intervention versus TAU was US $16 254 (95% CI 7116-99 057) per QALY gained. The probability that C-MAP is cost-effective was between 66% and 83% for cost-effective thresholds between US $20 000 and US $30 000. Cost-effectiveness results remained robust to sensitivity analyses. CONCLUSIONS: C-MAP may be a valuable self-harm intervention. Further studies with longer follow-up and larger sample sizes are needed to draw reliable conclusions.

Developing a Framework for Public Involvement in Mathematical and Economic Modelling: Bringing New Dynamism to Vaccination Policy Recommendations.

OBJECTIVES: The Mathematical and Economic Modelling for Vaccination and Immunisation Evaluation (MEMVIE) programme aimed to explore, capture and support the potential contribution of the public to mathematical and economic modelling, in order to identify the values that underpin public involvement (PI) in modelling and co-produce a framework that identifies the nature and type of PI in modelling and supports its implementation. METHODS: We established a PI Reference Group, who worked collaboratively with the academic contributors to create a deliberative knowledge space, which valued different forms of knowledge, expertise and evidence. Together, we explored the key steps of mathematical and economic methods in 21 meetings during 2015-2020. These deliberations generated rich discussion, through which we identified potential points of public contribution and the values that underpin PI in modelling. We iteratively developed a framework to guide future practice of PI in modelling. RESULTS: We present the MEMVIE Public Involvement Framework in two forms: a short form to summarise key elements, and a long form framework to provide a detailed description of each potential type of public contribution at each stage of the modelling process. At a macro level, the public can contribute to reviewing context, reviewing relevance, assessing data and justifying model choice, troubleshooting, and interpreting and reviewing outcomes and decision making. The underpinning values that drive involvement include the public contributing to the validity of the model, potentially enhancing its relevance, utility and transparency through diverse inputs, and enhancing the credibility, consistency and continuous development through scrutiny, in addition to contextualising the model within a wider societal view. DISCUSSION AND CONCLUSION: PI in modelling is in its infancy. The MEMVIE Framework is the first attempt to identify potential points of collaborative public contribution to modelling, but it requires further evaluation and refinement that we are undertaking in a subsequent study.

A Group Parenting Intervention for Depressed Fathers (LTP + Dads): A Feasibility Study from Pakistan.

BACKGROUND: Globally, paternal depression is a neglected and under-researched area. AIMS: To feasibility test Learning Through Play Plus Dads (LTP+ Dads), a group parenting psychoeducation program adapted for depressed Pakistani fathers of children under 3 years of age. METHODS: Fathers with depression were recruited in Karachi, Pakistan, for a pre-post feasibility study. Ten sessions of group LTP+ Dads were offered over three months. Clinical assessments were administered at baseline, three (end of intervention), and six (follow-up) months and included the Edinburgh Postnatal Depression Scale, 17-item Hamilton Depression Rating Scale, Brief Disability Questionnaire, Multidimensional Scale of Perceived Social Support, Euro-Qol-5 Dimensions, Rosenberg Self-esteem Scale, Parenting Stress Index, and Knowledge, Attitude and Practices questionnaire. RESULTS: Of the 78 fathers approached, 34 consented to screening and 18 were eligible to participate. Participants had a mean age of 33 years, with a mean of 3.61 children. Most were unemployed and were from low-income households with low education backgrounds. The intervention was feasible and acceptable based on a recruitment rate of 100% of eligible participants and a 100% attendance rate for five of the 10 sessions. Fathers showed, on average, a reduction in depressive symptoms, an increase in most areas of knowledge, and positive attitudes about child development. Perceived social support, self-esteem, and functioning scores also increased. CONCLUSIONS: A low-cost, culturally adapted group intervention was found to be feasible and acceptable. Changes in depression, parenting-related, and other outcomes are promising and inform a future larger trial. TRIAL REGISTRATION: The trial was registered on Clinicaltrials.gov on 9 December 2020 (identifier: NCT04660253).