Hayley Bennett

Estimating the Clinical and Economic Benefit Associated with Incremental Improvements in Sustained Virologic Response in Chronic Hepatitis C

Introduction Hepatitis C virus (HCV) infection is one of the principle causes of chronic liver disease. Successful treatment significantly decreases the risk of hepatic morbidity and mortality. Current standard of care achieves sustained virologic response (SVR) rates of 40–80%; however, the HCV therapy landscape is rapidly evolving. The objective of this study was to quantify the clinical and economic benefit associated with increasing levels of SVR. Methods A published Markov model (MONARCH) that simulates the natural history of hepatitis C over a lifetime horizon was used. Discounted and non-discounted life-years (LYs), quality-adjusted life-years (QALYs) and cost of complication management were estimated for various plausible SVR rates. To demonstrate the robustness of projections obtained, the model was validated to ten UK-specific HCV studies. Results QALY estimates ranged from 18.0 years for those treated successfully in fibrosis stage F0 to 7.5 years (discounted) for patients in fibrosis stage F4 who remain untreated. Predicted QALY gains per 10% improvement in SVR ranged from 0.23 (F0) to 0.64 (F4) and 0.58 (F0) to 1.35 (F4) in 40 year old patients (discounted and non-discounted results respectively). In those aged 40, projected discounted HCV-related costs are minimised with successful treatment in F0/F1 (at approximately £300), increasing to £49,300 in F4 patients who remain untreated. Validation of the model to published UK cost-effectiveness studies produce R2 goodness of fit statistics of 0.988, 0.978 and of 0.973 for total costs, QALYs and incremental cost effectiveness ratios, respectively. Conclusion Projecting the long-term clinical and economic consequences associated with chronic hepatitis C is a necessary requirement for the evaluation of new treatments. The principle analysis demonstrates the significant impact on expected costs, LYs and QALYs associated with increasing SVR. A validation analysis demonstrated the robustness of the results reported.

Assessing the Long-Term Impact of Treating Hepatitis C Virus (HCV)-Infected People Who Inject Drugs in the UK and the Relationship between Treatment Uptake and Efficacy on Future Infections.

Objective The prevalence of the hepatitis C virus (HCV) remains high amongst people who inject drugs (PWID) and accounts for the majority of newly acquired infections. This study aims to quantify the value of treatment amongst PWID with more efficacious treatments and at increased uptake rates, with respect to the avoidance of future infections and subsequent long-term complications of HCV. Methods A dynamic HCV transmission and disease progression model was developed, incorporating acute and chronic infection and their long-term complications (decompensated cirrhosis, cancer, liver transplant and mortality), with the potential for HCV transmission to other PWID prior to successful treatment. The model was populated with prevalence and therapy data from a UK setting. Scenarios of current standard of care (SoC) treatment efficacy and uptake were compared to anticipated sustained virologic response (SVR) rates of 90–100% and increased uptake over varied horizons. Results SoC led to modest reductions in prevalence; >5% after 200 years. New treatments achieving 90% SVR could reduce prevalence below 5% within 60 years at current uptake rates or within 5 years if all patients are treated. Amongst 4,240 PWID, chronic HCV infections avoided as a result of increasing treatment uptake over the period 2015–2027 ranged from 20–580 and 34–912 with SoC and 90% SVR rates respectively. The reduction in downstream HCV infections due to increasing treatment uptake resulted in an approximate discounted gain of 300 life-years (from avoiding reduced life expectancy from HCV infection) and a gain of 1,700 QALYs (from avoiding the disutility of HCV infection and related complications), with a projected £5.4 million cost saving. Conclusion While improved SVR profiles led to reductions in modelled prevalence, increased treatment uptake was the key driver of future infections avoided. Increased treatment among PWID with new more efficacious therapies could significantly change the future dynamics, cost and health burden of HCV-related disease.

The cost-effectiveness of daclatasvir-based regimens for the treatment of hepatitis C virus genotypes 1 and 4 in the UK.

Objective This study aimed to determine the cost-effectiveness of daclatasvir in combination with other medicinal products for the treatment of patients with hepatitis C virus genotypes 1 and 4 and advanced liver disease in the UK. Methods A published and validated Markov model designed to simulate the natural history of chronic hepatitis C was used to compare daclatasvir with relevant treatment options for patients with hepatitis C virus genotypes 1 and 4 and a METAVIR score of F3–F4. Patients were defined according to their treatment status; that is, naive, experienced or interferon ineligible/intolerant. Data inputs for the analysis were derived from published sources, UK-specific where possible. A lifetime horizon was used, with costs and benefits discounted at 3.5%. Results Daclatasvir-based regimens are estimated to be cost-effective versus no treatment and established standard-of-care regimens, including telaprevir in combination with pegylated interferon-&agr;+ribavirin (PR), boceprevir in combination with PR and PR alone (incremental cost-effectiveness ratio range: £3715–£15 408). The cost-effectiveness of daclatasvir-based regimens versus emerging regimens (sofosbuvir or simeprevir based) is less consistent, but was dominant or cost-effective (incremental cost-effectiveness ratio range: £1394–£28 393) in all except two scenarios. Conclusion Daclatasvir-based regimens are expected to be highly cost-effective for the majority patients with advanced disease versus relevant comparator regimens, including newer direct-acting antiviral regimens.

Estimating Cost-Effectiveness in Type 2 Diabetes: The Impact of Treatment Guidelines and Therapy Duration.

Objectives. Type 2 diabetes mellitus (T2DM) clinical guidelines focus on optimizing glucose control, with therapy escalation classically initiated within a “failure-based” regimen. Within many diabetes models, HbA1c therapy escalation thresholds play a pivotal role, controlling duration of therapy and, consequently, incremental costs and benefits. The objective of this study was to assess the relationship between therapy escalation threshold and time to therapy escalation on predicted cost-effectiveness of T2DM treatments. Methods. This study used the Cardiff Diabetes Model to illustrate the relationship between costs and health outcomes associated with first-, second-, and third-line therapy as a function of time on each. Data from routine clinical practice were used to contrast predicted costs and health outcomes associated with guideline therapy escalation thresholds compared with clinical practice. The impact of baseline HbA1c and therapy escalation thresholds on cost-effectiveness was investigated, comparing a sodium/glucose cotransporter 2 inhibitor v. sulfonylurea added to metformin monotherapy. Results. Lower thresholds are associated with a shorter time spent on monotherapy, ranging from 1.1 years (escalation at 6.5%) to 13 years (escalation at 9.0%) and an increase in total lifetime cost of therapy. Treatment-related disutility is minimized with higher thresholds because progression to insulin is delayed. Using metformin combined with either dapagliflozin or a sulfonylurea to illustrate lower baseline HbA1c and/or higher therapy escalation thresholds was associated with increased cost-effectiveness ratios, driven by a longer duration of therapy. Discussion. A marked difference in treatment cost-effectiveness was demonstrated when comparing routine clinical practice with guideline-advocated therapy escalation. This is important to both health care professionals and the wider health economic community with respect to understanding the true cost-effectiveness profile of any particular T2DM therapy option.

The economic burden of posttransplant events in renal transplant recipients in Europe.

Background This study aims to describe the healthcare resource utilization and costs of managing renal posttransplant patients over 3 years posttransplant in nine European countries and to stratify them by year 1 glomerular filtration rate (GFR). Methods A retrospective observational and database analysis of renal transplant patients and a physician questionnaire study were conducted to collect recipient and donor characteristics, posttransplant events, and healthcare resource utilization related to these posttransplant events. In each country, local published costs were applied to the resource use identified. The results were stratified by the patient GFR reading at a time point 1 year after renal transplant. Results The database study identified 3,181 patients who met the inclusion criteria, along with 2,818 transplants carried out in the centers surveyed by questionnaire. Total 3-year costs derived from the questionnaire analysis vary depending on local treatment practices, from a minimum of &OV0556;33,602 per patient in the Czech Republic to &OV0556;77,461 per patient in the Netherlands. Consistently across countries, estimated costs appear to decrease with improved graft functioning status (increased GFR) at 1 year. The average 3-year costs, discounting immunosuppresion therapy and certain posttransplant events, per patient with a GFR greater than or equal to 60 at 1 year are estimated to be around 35% lower than those with 15⩽GFR<30. Conclusion This study demonstrates that in Europe, worsening posttransplant renal function may contribute to substantive increases in resource use, with some variation across regions. Therefore, management strategies that promote renal function after transplantation have the potential to provide important resource savings.

Tackling the burden of the hepatitis C virus in the UK: characterizing and assessing the clinical and economic consequences

OBJECTIVES The hepatitis C virus (HCV) remains a significant public health issue. This study aimed to quantify the clinical and economic burden of chronic hepatitis C in the UK, stratified by disease severity, age and awareness of infection, with concurrent assessment of the impact of implementing a treatment prioritization approach. STUDY DESIGN AND METHODS A previously published back projection, natural history and cost-effectiveness HCV model was adapted to a UK setting to estimate the disease burden of chronic hepatitis C and end-stage liver disease (ESLD) between 1980 and 2035. A published meta-regression analysis informed disease progression, and UK-specific data informed other model inputs. RESULTS At 2015, prevalence of chronic hepatitis C is estimated to be 241,487 with 22.20%, 33.72%, 17.22%, 16.67% and 10.19% of patients in METAVIR stages F0, F1, F2, F3 and F4, respectively, but is estimated to fall to 193,999 by 2035. ESLD incidence is predicted to peak in 2031. Assuming all patients are diagnosed and treatment is prioritized in F3 and F4 using highly efficacious direct-acting antiviral (DAA) regimens, a 69.85% reduction in ESLD incidence is predicted between 2015 and 2035, and the cumulative discounted medical expenditure associated with the lifetime management of incident ESLD events is estimated to be £1,202,827,444. CONCLUSIONS The prevalence of chronic hepatitis C is expected to fall in coming decades; however, the ongoing financial burden is expected to be high due to an increase in ESLD incidence. This study highlights the significant costs of managing ESLD that are likely to be incurred without the employment of effective treatment approaches.

Hepatitis C disease transmission and treatment uptake: impact on the cost-effectiveness of new direct-acting antiviral therapies

BackgroundHepatitis C virus (HCV) treatment can reduce the incidence of future infections through removing opportunities for onward transmission. This benefit is not captured in conventional cost-effectiveness evaluations of treatment and is particularly relevant in patient groups with a high risk of transmission, such as those people who inject drugs (PWID), where the treatment rates have been historically low. This study aimed to quantify how reduced HCV transmission changes the cost-effectiveness of new direct-acting antiviral (DAA) regimens as a function of treatment uptake rates.MethodsAn established model of HCV disease transmission and progression was used to quantify the impact of treatment uptake (10–100%), within the PWID population, on the cost-effectiveness of a DAA regimen versus pre-DAA standard of care, conducted using daclatasvir plus sofosbuvir in the UK setting as an illustrative example.ResultsThe consequences of reduced disease transmission due to treatment were associated with additional net monetary benefit of £24,304–£90,559 per patient treated at £20,000/QALY, when 10–100% of eligible patients receive treatment with 100% efficacy. Dependent on patient genotype, the cost-effectiveness of HCV treatment using daclatasvir plus sofosbuvir improved by 36–79% versus conventional analysis, at 10–100% treatment uptake in the PWID population.ConclusionsThe estimated cost-effectiveness of HCV treatment was shown to improve as more patients are treated, suggesting that the value of DAA regimens to the NHS could be enhanced by improved treatment uptake rates among PWID. However, the challenge for the future will lie in achieving increased rates of treatment uptake, particularly in the PWID population.

Value of Sustained Virologic Response in Patients with Hepatitis C as a Function of Time to Progression of End-Stage Liver Disease.

BackgroundTargeted intervention in patients with hepatitis C virus (HCV) closest to end-stage liver disease (ESLD) progression may offer an approach to treatment prioritisation whilst delivering benefits for patients and the healthcare system. In contrast to previous HCV economic analyses, this study aimed to estimate the health economic value of sustained virologic response (SVR) stratified by the patient’s propensity to progress to ESLD.MethodsAn HCV natural history model was adapted to estimate the value of avoiding ESLD complications following SVR, assessed as cost offsets and quality-adjusted life year (QALY) gains, as a function of time to ESLD at treatment initiation. These outcomes were used to estimate the financial value of achieving SVR, defined as the maximum investment that could be allocated without exceeding a willingness-to-pay threshold of £20,000/QALY.ResultsRegardless of time to ESLD onset, achieving SVR was beneficial, resulting in cost offsets and QALY gains, due to avoidance of ESLD complications. The value of achieving SVR was greatest in patients closest to ESLD onset, resulting in increased cost offsets and QALY gains (up to £50,901 and 9.56 QALYs). In patients closest to ESLD onset, the financial value of achieving SVR was £242,051, compared with £127,116 in patients furthest from onset.ConclusionsStandard cost-effectiveness evaluations may underestimate the value of treatment in HCV patients closest to ESLD development. Targeted intervention would promote efficient allocation of limited healthcare resources and reconcile concerns surrounding the affordability of new direct-acting antivirals, by minimising the number-needed-to-treat to maximise health benefit, whilst minimising healthcare expenditure.

The Health Economic Value of Changes in Glycaemic Control, Weight and Rates of Hypoglycaemia in Type 1 Diabetes Mellitus

Aims Therapy-related consequences of treatment for type 1 diabetes mellitus (T1DM), such as weight gain and hypoglycaemia, act as a barrier to attaining optimal glycaemic control, indirectly influencing the incidence of vascular complications and associated morbidity and mortality. This study quantifies the individual and combined contribution of changes in hypoglycaemia frequency, weight and HbA1c to predicted quality-adjusted life-years (QALYs) within a T1DM population. Materials and methods We describe the Cardiff Type 1 Diabetes (CT1DM) Model, originally informed by the Diabetes Control and Complications Trial (DCCT) and updated with the Epidemiology of Diabetes Interventions and Complications (EDIC) study and Swedish National Diabetes Registry for microvascular and cardiovascular complications respectively. We report model validation results and the QALY impact of HbA1c, weight and hypoglycaemia changes. Results Validation results demonstrated coefficients of determination for clinical endpoints of R2 = 0.863 (internal R2 = 0.999; external R2 = 0.823), costs R2 = 0.980 and QALYs R2 = 0.951. Achieving and maintaining a 1% HbA1c reduction was estimated to provide 0.61 additional discounted QALYs. Weight changes of ±1kg, ±2kg or ±3kg led to discounted QALY changes of ±0.03, ±0.07 and ±0.10 respectively, while modifying hypoglycaemia frequency by -10%, -20% or -30% resulted in changes of -0.05, -0.11 and -0.17. The differences in discounted costs, life-years and QALYs associated with HbA1c 6% versus 10% were -£19,037, 2.49 and 2.35 respectively. Conclusions Using a model updated with contemporary epidemiological data, this study presents an outcome-focused perspective to assessing the health economic consequences of differing levels of glycaemic control in T1DM with and without weight and hypoglycaemia effects.

A clinician's guide to the cost and health benefits of hepatitis C cure assessed from the individual patient perspective.

Background and aims The hepatitis C virus (HCV) remains a considerable public health challenge. Novel direct-acting antiviral (DAA) regimens offer high cure rates and the promise of reduced HCV incidence and prevalence following the up-scaling of treatment. This has focused attention towards affordability. This study aimed to estimate the economic value of cure to evaluate the treatment costs justifiable from the patient perspective. Patients and methods A published, validated HCV model was utilized to contrast clinical and cost outcomes for patients aged 30–70 years, stratified by METAVIR F0–F4, for (i) no treatment and (ii) successful treatment [i.e. sustained virologic response (SVR)] ignoring the cost of treatment. Regression equations were fitted and used to determine the financial expenditure justifiable to achieve a cost-neutral or a cost-effective [£20 000 per quality-adjusted life-year (QALY)] cure. Model inputs were derived from UK literature; costs and utilities were discounted at 3.5% over a lifetime horizon. Results To achieve cost-neutrality, the maximum discounted expenditure justifiable for SVR was £3774–43 607 across ages and fibrosis stages. Spending between £19 745 (70 years, F0) and £188 420 (30 years, F4) on SVR is expected to be cost-effective at £20 000/QALY willingness-to-pay threshold. Conclusion Heterogeneity across HCV patients is considerable, which can obscure the relevance of conventional cohort-based economic models evaluated at the mean, particularly when considering the value of treatment at the individual patient level. By quantifying the full exposition of HCV cost-savings and health benefits realizable following HCV cure, this study provides insight into the economic value of successful treatment from the patient perspective.