Cost-effectiveness of maribavir versus conventional antiviral therapies for post-transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective.

This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.

Cost-effectiveness of Oral Regimens for Adolescents With Chronic Hepatitis C Virus Infection.

BACKGROUND: Novel oral regimes have been approved for treating hepatitis C virus (HCV) infection in adolescents due to their superior effectiveness and safety. However, its economic outcome is still unclear in this population. The current analysis investigates the cost-effectiveness of novel oral regimens compared with that of pegylated interferon α with ribavirin (PR) therapies in adolescents in the context of the United States and China. METHODS: A Markov model was developed to measure the economic and health outcomes of ledipasvir/sofosbuvir (LS) for genotypes 1 and 4, sofosbuvir/ribavirin (SR) for genotype 2, and ledipasvir/sofosbuvir/ribavirin (LSR) for genotype 3 HCV infection compared with the outcomes of PR treatment. Clinical costs and utility inputs were gathered from published sources. Lifetime discounted quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) were measured. The uncertainty was facilitated by 1-way and probabilistic sensitivity analyses. RESULTS: In the United States, the ICERs of LS strategy were $14,699 and $14,946/QALY for genotypes 1 and 4 HCV infection, respectively; the ICER of SR strategy for genotype 2 was $42,472/QALY; and the ICER of LSR for genotype 3 was $49,409/QALY in comparison with the PR strategy. In Chinese adolescents, LS for genotypes 1 and 4, SR for genotype 2, and LSR for genotype 3 were the dominant alternatives to the PR strategy. The results were robust to sensitivity analyses. CONCLUSIONS: Novel oral regimes for adolescents with HCV infection are likely to be cost-effective in the context of the United States and China.

A Cost-Effectiveness Analysis of Glecaprevir/Pibrentasvir Versus Existing Direct-Acting Antivirals to Treat Chronic Hepatitis C in Japan.

INTRODUCTION: The objective of the study was to evaluate the cost-effectiveness of glecaprevir/pibrentasvir versus other direct-acting antivirals (DAAs) for treating chronic hepatitis C virus (HCV) infections in Japan. METHODS: We developed a health state transition model to capture the natural history of HCV. A cost-effectiveness analysis of DAAs from the perspective of a public healthcare payer in Japan with a lifetime horizon over annual cycles was performed. Treatment attributes, baseline demographics, transition probabilities, health-state utilities, and costs data were extracted from publications. Costs and outcomes were discounted at 2% per annum. In the base case we focused on genotype 1 (GT1) treatment-naïve patients without cirrhosis. The scenario analysis examined a pan-genotype treatment in GT1-3 (i.e., portfolio), treatment-naïve, and treatment-experienced patients. The portfolio cost-effectiveness of DAAs was derived by calculating a weighted average of patient segments defined by treatment history, cirrhosis status, and genotype. RESULTS: The base case results indicated that glecaprevir/pibrentasvir was dominant (i.e., generating higher quality-adjusted life years [QALYs] and lower lifetime costs) compared to all other DAAs. The predicted lifetime risk of hepatocellular carcinoma was 3.66% for glecaprevir/pibrentasvir and sofosbuvir/ledipasvir, 4.99% for elbasvir/grazoprevir, and 5.27% for daclatasvir/asunaprevir/beclabuvir. In scenario analysis the glecaprevir/pibrentasvir (GLE/PIB) portfolio dominated the sofosbuvir (SOF)-based portfolio (namely sofosbuvir/ledipasvir in GT1-2 and sofosbuvir + ribavirin in GT3). The base case probabilistic sensitivity analysis (PSA) showed that glecaprevir/pibrentasvir was cost-effective in 93.4% of the simulations for a willingness-to-pay/QALY range of Japanese yen (JPY) 1.6-20 million. The PSA for the portfolio scenario indicated that the GLE/PIB portfolio was cost-effective in 100% of simulations until the willingness-to-pay/QALY reached JPY 5.2 million; this proportion decreased to 69.4% at a willingness-to-pay/QALY of JPY 20 million. Results were also robust in deterministic sensitivity analyses. CONCLUSION: In GT1 treatment-naïve non-cirrhotic patients GLE/PIB was a cost-effective strategy compared to other DAAs. When a pan-genotypic framework was used, the GLE/PIB portfolio dominated the SOF-based portfolio.

Cost-effectiveness of treating hepatitis C in Seychelles.

INTRODUCTION: approximately eighty million people around the world are living with hepatitis C, and 700,000 people die every year, due to hepatitis C related complications. In Seychelles, a total of 777 cases of hepatitis C were reported from 2002 to 2016, but up to mid of 2016, the cases were not being treated. Treatment with Harvoni, a combination of sofosbuvir and ledipasvir (SOF/LDV), is now being offered on the condition that the patient does not, or has stopped, injecting drugs. This paper is the first to establish the cost effectiveness of treating all cases of hepatitis C in Seychelles with Harvoni, as compared to no treatment. METHODS: data extracted from literature was used to populate an economic model to calculate cost-effectiveness from Seychelles' government perspective. The model structure was also informed by the systematic review and an accompanying grading of economic models using the Consolidated Health Economic Evaluation Reporting Standard (CHEERS) checklist. A Markov model was developed, employing a lifetime horizon and costs and benefits were analysed from a payer's perspective and combined into incremental cost effectiveness ratios (ICERs). RESULTS: the direct-acting antiviral (DAA), Harvoni, was found to be cost-saving in Seychelles hepatitis C virus (HCV) cohort, as compared to no treatment, with an ICER of € 753.65/QALY. The treatment was also cost-saving when stratified by gender, with the ICER of male and female being € 783.74/QALY and € 635.20/QALY, respectively. Moreover, the results obtained from acceptability curves showed that treating patients with Harvoni is the most cost-effective option, even for low thresholds. CONCLUSION: treating hepatitis C cases in Seychelles is cost-saving. It is worth developing a treatment programme to include all cases of hepatitis C, regardless of status of drug injection.

The cost implication of primary prevention in the HOPE 3 trial.

AIMS: The Heart Outcomes Prevention Evaluation-3 (HOPE-3) found that rosuvastatin alone or with candesartan and hydrochlorothiazide (HCT) (in a subgroup with hypertension) significantly lowered cardiovascular events compared with placebo in 12 705 individuals from 21 countries at intermediate risk and without cardiovascular disease. We assessed the costs implications of implementation in primary prevention in countries at different economic levels. METHODS AND RESULTS: Hospitalizations, procedures, study and non-study medications were documented. We applied country-specific costs to the healthcare resources consumed for each patient. We calculated the average cost per patient in US dollars for the duration of the study (5.6 years). Sensitivity analyses were also performed with cheapest equivalent substitutes. The combination of rosuvastatin with candesartan/HCT reduced total costs and was a cost-saving strategy in United States, Canada, Europe, and Australia. In contrast, the treatments were more expensive in developing countries even when cheapest equivalent substitutes were used. After adjustment for gross domestic product (GDP), the costs of cheapest equivalent substitutes in proportion to the health care costs were higher in developing countries in comparison to developed countries. CONCLUSION: Rosuvastatin and candesartan/HCT in primary prevention is a cost-saving approach in developed countries, but not in developing countries as both drugs and their cheapest equivalent substitutes are relatively more expensive despite adjustment by GDP. Reductions in costs of these drugs in developing countries are essential to make statins and blood pressure lowering drugs affordable and ensure their use. CLINICAL TRIAL REGISTRATION: HOPE-3 ClinicalTrials.gov number, NCT00468923.

Why upfront use of CDK inhibitors for the treatment of advanced breast cancer may be wasteful, and how we can increase their value.

Three Cyclin Dependent Kinase 4/6 (CDK) inhibitors have been approved by the United Stated Food and Drug Administration for front line treatment of advanced hormone receptor positive breast cancer based on improvements in progression free survival against endocrine monotherapy. Two clinical trials have so far reported results on overall survival but both are negative. CDK inhibitors are usually tolerated well but they do add to inconvenience and cost - for example, grade III-IV neutropenia occur at a frequency of over 60% requiring frequent blood work at least during the initial months of treatment. These drugs cost over $ 13,500 for a 4-week cycle in the United States, and are responsible for billions of dollars annually in drug cost alone. Importantly, many women with metastatic breast cancer do well for a long time with endocrine therapy alone and CDK inhibitors do not have a predictive marker. Selective use of these agents in later lines may improve substantially the convenience and cost without compromise in overall outcome. However, with results demonstrating impressive improvements in PFS published in major medical journals coupled with patients' natural desire for "best available" options, the trend among oncologists is to prescribe these drugs as the default front-line treatment. In this commentary I caution readers against over interpretation of results from the CDK inhibitor trials, describe adverse consequences of routine front-line use, and explain why selective use in later line may yield a higher value.

The impact of generics and generic reference pricing on candesartan and rosuvastatin utilisation, price and expenditure in South Africa.

Background In the South African private sector context, generically similar products are grouped together and the reimbursement rate is set at the average price of the generically equivalent products. Very little evidence exists in low and middle-income countries with regards to the impact of this policy over time. Objectives To determine the impact of the introduction of generics and generic reference pricing on candesartan and rosuvastatin in the South African private health care sector in terms of medicine utilisation, medicine price and medicine expenditure. Setting South African private health sector. Method Medicine claims for candesartan and rosuvastatin was obtained from a Pharmacy Benefit Manager in South Africa. The claims covered a 48-month period from January 2012 to December 2015 and provided a pre- and post-reference price period for analysis. Medicine utilisation was measured as the number of Defined Daily Doses dispensed per 100,000 beneficiaries. Medicine price and expenditure was calculated as the average per Defined Daily Dose. Main outcome measure Medicine utilisation, price and expenditure. Results Candesartan experienced an average 7.0% year-on-year decline in utilisation and rosuvastatin a 5.0% increase. Medicine expenditure reduced by an additional 34.6% and 20.9% for candesartan and rosuvastatin respectively. The total savings was 54.8% for candesartan and 31.9% for rosuvastatin. Conclusion The introduction of generics and generic reference pricing did not have an impact on medicine utilisation, but reduced the price and expenditure of both candesartan and rosuvastatin.

Cost-effectiveness analysis of Daclatasvir/Sofosbuvir for the treatment of the HCV patients failed after the first line with second generation of DAAs in Italy.

BACKGROUND: Daclatasvir (DCV) combinated with Sofosbuvir (SOF) has shown good efficacy and safety profile for HCV patients. The aim was to evaluate the cost-effectiveness of DCV/SOF regimen versus HCV alternative treatments for patients who failed to achieve the SVR12 after a first DAA treatment from Italian perspective (PITER cohort). METHODS: A Markov model of HCV chronically infected patients was used to develop two scenarios: 1) DCV+ SOF versus Ledipasvir (LDV)+ SOF in Genotype (Gt)1 and Gt4; 2) DCV+ SOF versus no retreatment option in Gt1, Gt3, and Gt4. The percentage of patients who failed the first line with SOF/Simeprevir/Ribavirin (RBV) or SOF/RBV and were retreated or not according to evidences from PITER cohort, were used to populate the model. HCV resources consumption and SVR rates were quantified using PITER data. Transition probabilities and utility rates were derived from the literature. The outcomes were expressed in terms of Quality adjusted life years (QALYs). Probabilistic sensitivity analysis (PSA) was performed considering a cost-effectiveness threshold of € 30,000/QALY. RESULTS: In the base-case analysis, DCV+ SOF represents a cost-effectiveness therapy with ICERs lower than the threshold. The PSA showed robust results, ICERs remain below the threshold in 94% and 99% simulations in Scenario 1 and 2, respectively.

Glecaprevir/pibrentasvir expands reach while reducing cost and duration of hepatitis C virus therapy.

Hepatitis C virus (HCV) treatments have dramatically progressed from poorly tolerated, moderately successful interferon-based therapies to highly effective all-oral interferon-free regimens. While sustained virologic responses have significantly improved with fixed-dose combinations (FDC) of these direct-acting antivirals (DAA), cost remains high and certain populations of patients remain difficult to treat. Glecaprevir (GLE, an NS3/4A protease inhibitor) and pibrentasvir (PIB, NS5A inhibitor) were recently approved as a FDC therapy for HCV, and have expanded reach, reduced cost, and in certain populations, reduced HCV treatment duration. GLE/PIB is effective across all genotypes, and has been shown to be effective in HIV-infected patients, patients with chronic kidney disease, and Child-Pugh A-compensated cirrhosis. GLE/PIB is also effective for a shortened duration of 8 weeks in treatment-naive non-cirrhotic patients.

Take a Bow, Pharma, for the Hepatitis C Drugs.

The direct-acting virals revolutionized the treatment of hepatitis C. They also ushered turbocharged pricing. At least patients-and society-got a major health benefit in return.

Fixed-dose vs free-dose combinations for the management of hypertension-An analysis of 81 958 patients.

Fixed-dose combinations (FDC) have been developed to reduce the pill burden for hypertensive patients. Data on fixed-dose or free-dose (freeDC) ramipril/amlodipine (R/A) or candesartan/amlodipine (C/A) combination treatment initiation were assessed. 71 463 patients were prescribed R/A and 10 495 C/A. For both R/A and C/A, FDC patients were younger (both P < .001) and less comorbid. Prior MI (OR: 0.61 and 0.60), prior stroke (OR: 0.68 and 0.70) and CHD (OR: 0.68 and 0.64) were negatively associated with FDC use, whereas hyperlipidemia was positively associated (OR: 1.26 and 1.19). Use of antihypertensive comedication (OR: 0.78; OR: 0.55) and treatment discontinuation within 12 months (HR: 0.65 and 0.82) were less likely in FDC patients, who also showed superior adherence (mean MPR; both P < .001). Cost of the combination was higher for FDCs (both P < .001). FDCs improve persistence and adherence, although they are more commonly prescribed in patients with less cardiovascular disease.

Modeling the fiscal costs and benefits of alternative treatment strategies in the United Kingdom for chronic hepatitis C.

BACKGROUND: Hepatitis C (HCV) infection causes substantial direct health costs, but also impacts broader societal and governmental costs, such as tax revenue and social protection benefits. This study investigated the broader fiscal costs and benefits of curative interventions for chronic Hepatitis C (CHC) that allow individuals to avoid long-term HCV attributed health conditions. METHODS: A prospective cohort model, assessing the long-term fiscal consequences of policy decisions, was developed for HCV infected individuals, following the generational accounting analytic framework that combines age-specific lifetime gross taxes paid and governmental transfers received (i.e. healthcare and social support costs). The analysis assessed the burden of a theoretical cohort of untreated HCV infected patients with the alternative of treating these patients with a highly efficacious curative intervention (ledipasvir/sofosbuvir [LDV/SOF]). It also compared treating patients at all fibrosis stages (Stages F0-F4) compared to late treatment (Stage F4). RESULTS: Based on projected lifetime work activity and taxes paid, the treated cohort paid an additional £5,900 per patient compared to the untreated cohort. Lifetime government disability costs of £97,555 and £125,359 per patient for treated cohort vs no treatment cohort were estimated, respectively. Lifetime direct healthcare costs in the treated cohort were £32,235, compared to non-treated cohort of £26,424, with an incremental healthcare costs increase of £5,901 per patient. The benefit cost ratio (BCR) of total government benefits and savings relative to government treatment costs (including LDV/SOF) ranged from 1.8-5.6. Treating patients early resulted in 77% less disability costs, 43% lower healthcare costs, and 33% higher tax revenue. CONCLUSION: The ability to cure Hepatitis C offers considerable fiscal benefits beyond direct medical costs and savings attributed to reduced disability costs, public allowances, and improved tax revenue. Changes in parameters, such as productivity, wage growth, and tax rates, can influence the conclusions described here.

Cost-Effectiveness Analysis of New HCV Treatments in Egyptian Cirrhotic and Non-Cirrhotic Patients: A Societal Perspective.

OBJECTIVES: To evaluate the cost-effectiveness of sofosbuvir (SOF) + ribavirin (RBV), SOF + daclatasvir (DCV), and SOF + ledipasvir (LDV) + RBV compared with SOF + pegylated interferon alfa (pegIFN) + RBV in the treatment of patients infected with hepatitis C virus in Egypt. METHODS: Two Markov models were developed on the basis of the Egyptian clinical data and practice and were derived from published sources. The clinical parameters were derived from two sources: the Egypt multicenter national treatment program and previously published randomized clinical trials. The utility of the health states was derived using the available published data. Direct medical costs were obtained from the National Liver Institute database. RESULTS: In noncirrhotic patients, incremental cost-effectiveness ratios of US $2330 per quality-adjusted life-year (QALY) gained for the SOF + LDV + RBV, -US $9043/QALY for the SOF + DCV, and -US $1332/QALY for the SOF + RBV regimens were yielded. In cirrhotic patients, incremental cost-effectiveness ratios of -US $4170/QALY gained for the SOF + LDV + RBV, -US $9515/QALY for the SOF + DCV, and -US $2289/QALY for the SOF + RBV regimens were yielded. The SOF + DCV regimen was the most cost-saving option for cirrhotic and noncirrhotic patients. Deterministic sensitivity analyses remain robust. CONCLUSIONS: The present study concludes that the SOF + DCV regimen among other currently available regimens is the most cost-saving option that yields the most favorable future health economic outcomes compared with the SOF + pegIFN + RBV regimen across a broad spectrum of patients, including those with cirrhosis.

Impact of the Commercialization of Three Generic Angiotensin II Receptor Blockers on Adverse Events in Quebec, Canada: A Population-Based Time Series Analysis.

BACKGROUND: Once the patent of a brand-name drug expires, generic drugs are commercialized, and substitution from brand-name to generics may occur. Generic drug equivalence is evaluated through comparative bioavailability studies. Few studies have assessed outcomes after generic drug commercialization at a population level. We evaluated the impact of 3 generic angiotensin II receptor blockers commercialization on adverse events: hospitalizations or emergency room consultations. METHODS AND RESULTS: This is an interrupted time series analysis using the Quebec Integrated Chronic Disease Surveillance System. Rates of adverse events for losartan, valsartan, and candesartan users (N=136 177) aged ≥66 years were calculated monthly, 24 months before and 12 months after generics commercialization. Periods before and after generics commercialization were compared by negative binomial segmented regression models. Sensitivity analyses were also conducted. For all users, there was a monthly mean rate of 100 adverse events for 1000 angiotensin II receptor blocker users before and after generic commercialization. Among generic users of losartan, valsartan, and candesartan, there was an increase in rates of adverse events of 8.0% (difference of proportions versus brand-name, 7.5% [95% confidence interval, -0.9% to 15.9%]; P=0.0643), 11.7% (difference of proportions, 17.1% [95% confidence interval, 9.9%-24.3%]; P<0.0001), and 14.0% (difference of proportions, 16.6% [95% confidence interval, 7.9%-25.3%]; P<0.0001), respectively, the month of generic commercialization. The monthly trend of adverse events was affected for generic versus brand-name losartan users only (difference of proportions, 2.0% [0.7%-3.4%]; P=0.0033) ≤1 year after generics commercialization. Similar results were found in sensitivity analyses. CONCLUSIONS: Among generic users, immediate or delayed differences in adverse events rates were observed right after generic commercialization for 3 antihypertensive drugs. Rates of adverse events remained higher for generic users. Increases were more pronounced for generic candesartan, which is the studied product with the largest difference in comparative bioavailability. Risk and survival analysis studies controlling for several potential confounding factors are required to better characterize generic substitution.

Assessing the Budget Impact and Economic Outcomes of the Introduction of Daclatasvir + Asunaprevir and Sofosbuvir/Ledipasvir for the Treatment of Chronic Hepatitis C Virus Infection in Japan.

BACKGROUND: The advent of highly efficacious, well-tolerated, all-oral direct-acting antiviral regimens has revolutionized the standard of care for patients chronically infected with hepatitis C virus. As efficacy and safety rates converge, prescribers and payers need to consider value for money. OBJECTIVES: To evaluate the health economic value of daclatasvir + asunaprevir versus sofosbuvir/ledipasvir via a cost-effectiveness analysis, and determine the optimal treatment considering both costs and health outcomes in Japan. METHODS: A previously published Markov model was used to estimate the cost-effectiveness of daclatasvir + asunaprevir compared with sofosbuvir/ledipasvir on the basis of a matching-adjusted indirect comparison of pivotal trials and modeling inputs specific to the Japanese setting. A de novo budget impact model was developed and used to predict the cost implications of differing treatment sequences. RESULTS: Cost-effectiveness results demonstrated minimal difference in terms of benefit (0.037 fewer QALYs and 0.014 fewer life-years with daclatasvir + asunaprevir); nevertheless, a significant difference in cost was predicted (estimated ¥2,299,700 [US $21,695] reduction with daclatasvir + asunaprevir). The budget impact analysis estimated that treatment with daclatasvir + asunaprevir is expected to be less expensive than treatment with sofosbuvir/ledipasvir (as the proportion of patients initially treated with sofosbuvir/ledipasvir increased from 0% to 100%, total costs increased from ¥206 to ¥403 billion [US $1.94 billion to US $3.80 billion]). CONCLUSIONS: On the basis of results from an established cost-effectiveness model and a conventional budget impact analysis, treatment with daclatasvir + asunaprevir is expected to be cost-saving compared with treatment with sofosbuvir/ledipasvir in Japan with similar health outcomes, regardless of treatment sequence.

Exploring the Case for Eminent Domain of Hepatitis C Virus Treatment Patents.

Hepatitis C virus (HCV) is a silent epidemic affecting millions of patients and represents the leading indication for liver transplantation in the United States and worldwide. New direct-acting antiviral agents offer the potential to cure patients infected with HCV but it comes at a staggering cost. Given the recent attention to these high-priced HCV therapies and the impact treating individuals with HCV is having on drug expenditures in the United States, there may be a need to revisit drug patent laws and the options the federal government has to ensure patient access to care.