Effective coverage and systems effectiveness for malaria case management in sub-saharan african countries

Scale-up of malaria preventive and control interventions over the last decade resulted in substantial declines in mortality and morbidity from the disease in sub-Saharan Africa and many other parts of the world. Sustaining these gains will depend on the health system performance. Treatment provides individual benefits by curing infection and preventing progression to severe disease as well as community-level benefits by reducing the infectious reservoir and averting emergence and spread of drug resistance. However many patients with malaria do not access care, providers do not comply with treatment guidelines, and hence, patients do not necessarily receive the correct regimen. Even when the correct regimen is administered some patients will not adhere and others will be treated with counterfeit or substandard medication leading to treatment failures and spread of drug resistance. We apply systems effectiveness concepts that explicitly consider implications of health system factors such as treatment seeking, provider compliance, adherence, and quality of medication to estimate treatment outcomes for malaria case management. We compile data for these indicators to derive estimates of effective coverage for 43 high-burden Sub-Saharan African countries. Parameters are populated from the Demographic and Health Surveys and other published sources. We assess the relative importance of these factors on the level of effective coverage and consider variation in these health systems indicators across countries. Our findings suggest that effective coverage for malaria case management ranges from 8% to 72% in the region. Different factors account for health system inefficiencies in different countries. Significant losses in effectiveness of treatment are estimated in all countries. The patterns of inter-country variation suggest that these are system failures that are amenable to change. Identifying the reasons for the poor health system performance and intervening to tac them become key priority areas for malaria control and elimination policies in the region

Cost-Effectiveness Analysis of Etranacogene Dezaparvovec Versus Extended Half-Life Prophylaxis for Moderate-to-Severe Haemophilia B in Germany

Background and Objective Haemophilia B is a rare genetic disease that is caused by a deficiency of coagulation factor IX (FIX) in the blood and leads to internal and external bleeding. Under the current standard of care, haemophilia is treated either prophylactically or on-demand via intravenous infusions of FIX. These treatment strategies impose a high burden on patients and health care systems as haemophilia B requires lifelong treatment, and FIX is costly. Etranacogene dezaparvovec (ED) is a gene therapy for haemophilia B that has been recently approved by the United States Food and Drug Administration and has received a recommendation for conditional marketing authorization by the European Medicines Agency. We aimed to examine the cost-effectiveness of ED versus extended half-life FIX (EHL-FIX) prophylaxis for moderate-to-severe haemophilia B from a German health care payer perspective. Methods A microsimulation model was implemented in R. The model used data from the ED phase 3 clinical trial publication and further secondary data sources to simulate and compare patients receiving ED or EHL-FIX prophylaxis over a lifetime horizon, with the potential for ED patients to switch treatment to EHL-FIX prophylaxis when the effectiveness of ED waned. Primary outcomes of this analysis included discounted total costs, discounted quality-adjusted life years (QALYs), incremental cost-effectiveness, and the incremental net monetary benefit. The annual discount rate for costs and effects was 3%. Uncertainty was examined via probabilistic analysis and additional univariate sensitivity analyses. Results Probabilistic analysis indicated that patients treated with ED instead of EHL-FIX prophylaxis gained 0.50 QALYs and experienced cost savings of EUR 1,179,829 at a price of EUR 1,500,000 per ED treatment. ED was the dominant treatment strategy. At a willingness to pay of EUR 50,000/QALY, the incremental net monetary benefit amounted to EUR 1,204,840. Discussion Depending on the price, ED can save costs and improve health outcomes of haemophilia patients compared with EHL-FIX prophylaxis, making it a potentially cost-effective alternative. These results are uncertain due to a lack of evidence regarding the long-term effectiveness of ED

State of inequality in malaria intervention coverage in sub-Saharan African countries

Scale-up of malaria interventions over the last decade have yielded a significant reduction in malaria transmission and disease burden in sub-Saharan Africa. We estimated economic gradients in the distribution of these efforts and of their impacts within and across endemic countries.; Using Demographic and Health Surveys we computed equity metrics to characterize the distribution of malaria interventions in 30 endemic countries proxying economic position with an asset-wealth index. Gradients were summarized in a concentration index, tabulated against level of coverage, and compared among interventions, across countries, and against respective trends over the period 2005-2015.; There remain broad differences in coverage of malaria interventions and their distribution by wealth within and across countries. In most, economic gradients are lacking or favor the poorest for vector control; malaria services delivered through the formal healthcare sector are much less equitable. Scale-up of interventions in many countries improved access across the wealth continuum; in some, these efforts consistently prioritized the poorest. Expansions in control programs generally narrowed coverage gaps between economic strata; gradients persist in countries where growth was slower in the poorest quintile or where baseline inequality was large. Despite progress, malaria is consistently concentrated in the poorest, with the degree of inequality in burden far surpassing that expected given gradients in the distribution of interventions.; Economic gradients in the distribution of interventions persist over time, limiting progress toward equity in malaria control. We found that, in countries with large baseline inequality in the distribution of interventions, even a small bias in expansion favoring the least poor yielded large gradients in intervention coverage while pro-poor growth failed to close the gap between the poorest and least poor. We demonstrated that dimensions of disadvantage compound for the poor; a lack of economic gradients in the distribution of malaria services does not translate to equity in coverage nor can it be interpreted to imply equity in distribution of risk or disease burden. Our analysis testifies to the progress made by countries in narrowing economic gradients in malaria interventions and highlights the scope for continued monitoring of programs with respect to equity

Incidence and admission rates for severe malaria and their impact on mortality in Africa

Appropriate treatment of life-threatening Plasmodium falciparum malaria requires in-patient care. Although the proportion of severe cases accessing in-patient care in endemic settings strongly affects overall case fatality rates and thus disease burden, this proportion is generally unknown. At present, estimates of malaria mortality are driven by prevalence or overall clinical incidence data, ignoring differences in case fatality resulting from variations in access. Consequently, the overall impact of preventive interventions on disease burden have not been validly compared with those of improvements in access to case management or its quality.; Using a simulation-based approach, severe malaria admission rates and the subsequent severe malaria disease and mortality rates for 41 malaria endemic countries of sub-Saharan Africa were estimated. Country differences in transmission and health care settings were captured by use of high spatial resolution data on demographics and falciparum malaria prevalence, as well as national level estimates of effective coverage of treatment for uncomplicated malaria. Reported and modelled estimates of cases, admissions and malaria deaths from the World Malaria Report, along with predicted burden from simulations, were combined to provide revised estimates of access to in-patient care and case fatality rates.; There is substantial variation between countries' in-patient admission rates and estimated levels of case fatality rates. It was found that for many African countries, most patients admitted for in-patient treatment would not meet strict criteria for severe disease and that for some countries only a small proportion of the total severe cases are admitted. Estimates are highly sensitive to the assumed community case fatality rates. Re-estimation of national level malaria mortality rates suggests that there is substantial burden attributable to inefficient in-patient access and treatment of severe disease.; The model-based methods proposed here offer a standardized approach to estimate the numbers of severe malaria cases and deaths based on national level reporting, allowing for coverage of both curative and preventive interventions. This makes possible direct comparisons of the potential benefits of scaling-up either category of interventions. The profound uncertainties around these estimates highlight the need for better data

Country specific predictions of the cost-effectiveness of malaria vaccine RTS,S/AS01 in endemic Africa

RTS,S/AS01 is a safe and moderately efficacious vaccine considered for implementation in endemic Africa. Model predictions of impact and cost-effectiveness of this new intervention could aid in country adoption decisions.; The impact of RTS,S was assessed in 43 countries using an ensemble of models of Plasmodium falciparum epidemiology. Informed by the 32months follow-up data from the phase 3 trial, vaccine effectiveness was evaluated at country levels of malaria parasite prevalence, coverage of control interventions and immunization. Benefits and costs of the program incremental to routine malaria control were evaluated for a four dose schedule: first dose administered at six months, second and third - before 9months, and fourth dose at 27months of age. Sensitivity analyses around vaccine properties, transmission, and economic inputs were conducted.; If implemented in all 43 countries the vaccine has the potential to avert 123 (117;129) million malaria episodes over the first 10years. Burden averted averages 18,413 (range of country median estimates 156-40,054) DALYs per 100,000 fully vaccinated children with much variation across settings primarily driven by differences in transmission intensity. At a price of $5 per dose program costs average$39.8 per fully vaccinated child with a median cost-effectiveness ratio of $188 (range$78-$22,448) per DALY averted; the ratio is lower by one third -$136 (range $116-$220) - in settings where parasite prevalence in children aged 2-10years is at or above 10%.; RTS,S/AS01has the potential to substantially reduce malaria burden in children across Africa. Conditional on assumptions on price, coverage, and vaccine properties, adding RTS,S to routine malaria control interventions would be highly cost-effective. Implementation decisions will need to further consider feasibility of scaling up existing control programs, and operational constraints in reaching children at risk with the schedule

Costing malaria interventions from pilots to elimination programmes

Malaria programmes in countries with low transmission levels require evidence to optimize deployment of current and new tools to reach elimination with limited resources. Recent pilots of elimination strategies in Ethiopia, Senegal, and Zambia produced evidence of their epidemiological impacts and costs. There is a need to generalize these findings to different epidemiological and health systems contexts.; Drawing on experience of implementing partners, operational documents and costing studies from these pilots, reference scenarios were defined for rapid reporting (RR), reactive case detection (RACD), mass drug administration (MDA), and in-door residual spraying (IRS). These generalized interventions from their trial implementation to one typical of programmatic delivery. In doing so, resource use due to interventions was isolated from research activities and was related to the pilot setting. Costing models developed around this reference implementation, standardized the scope of resources costed, the valuation of resource use, and the setting in which interventions were evaluated. Sensitivity analyses were used to inform generalizability of the estimates and model assumptions.; Populated with local prices and resource use from the pilots, the models yielded an average annual economic cost per capita of $0.18 for RR,$0.75 for RACD, $4.28 for MDA (two rounds), and$1.79 for IRS (one round, 50% households). Intervention design and resource use at service delivery were key drivers of variation in costs of RR, MDA, and RACD. Scale was the most important parameter for IRS. Overall price level was a minor contributor, except for MDA where drugs accounted for 70% of the cost. The analyses showed that at implementation scales comparable to health facility catchment area, systematic correlations between model inputs characterizing implementation and setting produce large gradients in costs.; Prospective costing models are powerful tools to explore resource and cost implications of policy alternatives. By formalizing translation of operational data into an estimate of intervention cost, these models provide the methodological infrastructure to strengthen capacity gap for economic evaluation in endemic countries. The value of this approach for decision-making is enhanced when primary cost data collection is designed to enable analysis of the efficiency of operational inputs in relation to features of the trial or the setting, thus facilitating transferability

Cost-effectiveness, burden of disease and budget impact of inclisiran : dynamic cohort modelling of a real-world population with cardiovascular disease

Objective: We aimed to estimate the cost-effectiveness, burden of disease and budget impact of inclisiran added to standard-of-care lipid-lowering therapy in the real-world secondary cardiovascular prevention population in Switzerland. Methods: An open-cohort Markov model captured event risks by sex, age and low-density lipoprotein cholesterol based on epidemiological and real-world data. Low-density lipoprotein cholesterol reduction with add-on inclisiran was based on trial results and translated to meta-analysis-based relative risks of cardiovascular events. Unit costs for 2018 were based on publicly available sources, adopting a Swiss healthcare system perspective. Price assumptions of Swiss francs (CHF) 500 and CHF 3,000 per dose of inclisiran were evaluated, combined with uptake assumptions for burden of disease and budget impact. The assessment of cost-effectiveness used a discount rate of 3% per year. We performed deterministic and probabilistic sensitivity analyses, and extensive scenario analyses. Results: Patients treated with inclisiran gained a 0.291 qualityadjusted life-year at an incremental cost per QALY gained of CHF 21,107/228,040 (life-long time horizon, discount rate 3%) under the lower/higher price. Inclisiran prevented 1025 cardiovascular deaths, 3425 acute coronary syndrome episodes, and 1961 strokes in 48,823 patients ever treated during 10 years; the 5-year budget impact was CHF 49.3/573.4 million under the lower/higher price. Estimates were sensitive to calibration targets and treatment eligibility; burden of disease/budget impact results also to uptake. Limitations included uncertainties about model assumptions and the size and characteristics of the population modelled. Conclusions: Inclisiran may be cost-effective at a willingness to pay of CHF 30,000 if priced at CHF 500; a threshold upwards of CHF 250,000 will be required if priced at CHF 3000. Inclisiran could enable important reductions in cardiovascular burden particularly under broader eligibility with a budget impact range from moderate to high depending on price

Cost-effectiveness of palbociclib in early breast cancer patients with a high risk of relapse: Results from the PENELOPE-B trial

BACKGROUND Patients with hormone receptor-positive, HER2-negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) are at a high risk of relapse. PENELOPE-B was a double-blind, placebo-controlled, phase III trial that investigated adding palbociclib (PAL) for thirteen 28-day cycles to adjuvant endocrine therapy (ET) in these patients. Clinical results showed no significant improvement in invasive disease-free survival with PAL. METHODS We performed a pre-planned cost-effectiveness analysis of PAL within PENELOPE-B from the perspective of the German statutory health insurance. Health-related quality of life scores, collected in the trial using the EQ-5D-3L instrument, were converted to utilities based on the German valuation algorithm. Resource use was valued using German price weights. Outcomes were discounted at 3% and modeled with mixed-level linear models to adjust for attrition, repeated measurements, and residual baseline imbalances. Subgroup analyses were performed for key prognostic risk factors. Scenario analyses addressed data limitations and evaluated the robustness of the estimated cost-effectiveness of PAL to methodological choices. RESULTS The effects of PAL on quality-adjusted life years (QALYs) were marginal during the active treatment phase, increasing thereafter to 0.088 (95% confidence interval: -0.001; 0.177) QALYs gained over the 4 years of follow-up. The incremental costs were dominated by PAL averaging EUR 33,000 per patient; costs were higher in the PAL arm but not significantly different after the second year. At an incremental cost-effectiveness ratio of EUR 380,000 per QALY gained, PAL was not cost-effective compared to the standard-of-care ET. Analyses restricted to Germany and other subgroups were consistent with the main results. Findings were robust in the scenarios evaluated. CONCLUSIONS One year of PAL added to ET is not cost-effective in women with residual invasive disease after NACT in Germany

Evaluating the sustainability, scalability, and replicability of an STH transmission interruption intervention: The DeWorm3 implementation science protocol.

Hybrid trials that include both clinical and implementation science outcomes are increasingly relevant for public health researchers that aim to rapidly translate study findings into evidence-based practice. The DeWorm3 Project is a series of hybrid trials testing the feasibility of interrupting the transmission of soil transmitted helminths (STH), while conducting implementation science research that contextualizes clinical research findings and provides guidance on opportunities to optimize delivery of STH interventions. The purpose of DeWorm3 implementation science studies is to ensure rapid and efficient translation of evidence into practice. DeWorm3 will use stakeholder mapping to identify individuals who influence or are influenced by school-based or community-wide mass drug administration (MDA) for STH and to evaluate network dynamics that may affect study outcomes and future policy development. Individual interviews and focus groups will generate the qualitative data needed to identify factors that shape, contextualize, and explain DeWorm3 trial outputs and outcomes. Structural readiness surveys will be used to evaluate the factors that drive health system readiness to implement novel interventions, such as community-wide MDA for STH, in order to target change management activities and identify opportunities for sustaining or scaling the intervention. Process mapping will be used to understand what aspects of the intervention are adaptable across heterogeneous implementation settings and to identify contextually-relevant modifiable bottlenecks that may be addressed to improve the intervention delivery process and to achieve intervention outputs. Lastly, intervention costs and incremental cost-effectiveness will be evaluated to compare the efficiency of community-wide MDA to standard-of-care targeted MDA both over the duration of the trial and over a longer elimination time horizon