Imaging structurally dynamic ribosomes with cryogenic electron microscopy.

Throughout the history of electron microscopy, ribosomes have served as an ideal subject for imaging and technological development, which in turn has driven our understanding of ribosomal biology. Here, we provide a historical perspective at the intersection of electron microscopy technology development and ribosome biology and reflect on how this technique has shed light on each stage of the life cycle of this dynamic macromolecular machine. With an emphasis on prokaryotic systems, we specifically describe how pairing cryo-EM with clever experimental design, time-resolved techniques, and next-generation heterogeneous structural analysis has afforded insights into the modular nature of assembly, the roles of the many transient biogenesis and translation co-factors, and the subtle variations in structure and function between strains and species. The work concludes with a prospective outlook on the field, highlighting the pivotal role cryogenic electron tomography is playing in adding cellular context to our understanding of ribosomal life cycles, and noting how this exciting technology promises to bridge the gap between cellular and structural biology.

Estimating the cost-effectiveness of daclatasvir + sofosbuvir versus sofosbuvir + ribavirin for patients with genotype 3 hepatitis C virus.

BACKGROUND: As treatments for chronic hepatitis C are moving away from interferon-containing regimens, the most appropriate allocation of resources to higher cost, interferon-free, direct-acting antiviral (DAA) regimens needs to be assessed. Hepatitis C virus (HCV) genotype 3 is associated with faster disease progression and has fewer treatment options, historically, than other HCV genotypes. This analysis aims to estimate the comparative cost-effectiveness of two recently licenced interferon-free regimens for the treatment of HCV genotype 3. METHODS: Utilising a published Markov model and results of a matching-adjusted indirect comparison of recently published clinical trial data (ALLY-3 and VALENCE, respectively), 12 weeks of treatment with daclatasvir + sofosbuvir (DCV + SOF) was compared to 24 weeks of treatment with sofosbuvir + ribavirin (SOF + RBV). UK-specific model inputs were used to inform a cost-utility analysis of these regimens. RESULTS: In the base case analysis, DCV + SOF was found to be dominant over SOF + RBV in treatment-naïve patients, patients that had previously been treated, and patients that are intolerant to, or ineligible for, interferon-containing regimens. Given the low rates of treatment currently observed in the UK, DCV + SOF was also compared to no treatment in the interferon-ineligible/intolerant patients, and may be considered cost-effective with an incremental cost-effectiveness ratio of £8817. CONCLUSIONS: When compared to 24 weeks of SOF + RBV, 12 weeks of treatment with DCV + SOF results in improved quality of life and reduced total costs, and therefore is likely to represent significant clinical and economic value as a treatment option for genotype 3 HCV infection.

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.

Estimating the Cost-Effectiveness of One-Time Screening and Treatment for Hepatitis C in Korea.

BACKGROUND AND AIMS: This study aims to investigate the cost-effectiveness of a one-time hepatitis C virus (HCV) screening and treatment program in South Korea where hepatitis B virus (HBV) prevails, in people aged 40-70, compared to current practice (no screening). METHODS: A published Markov model was used in conjunction with a screening and treatment decision tree to model patient cohorts, aged 40-49, 50-59 and 60-69 years, distributed across chronic hepatitis C (CHC) and compensated cirrhosis (CC) health states (82.5% and 17.5%, respectively). Based on a published seroepidemiology study, HCV prevalence was estimated at 0.60%, 0.80% and 1.53%, respectively. An estimated 71.7% of the population was screened. Post-diagnosis, 39.4% of patients were treated with a newly available all-oral direct-acting antiviral (DAA) regimen over 5 years. Published rates of sustained virologic response, disease management costs, transition rates and utilities were utilised. RESULTS: Screening resulted in the identification of 43,635 previously undiagnosed patients across all cohorts. One-time HCV screening and treatment was estimated to be cost-effective across all cohorts; predicted incremental cost-effectiveness ratios ranged from $5,714 to $8,889 per quality-adjusted life year gained. Incremental costs associated with screening, treatment and disease management ranged from $156.47 to $181.85 million USD; lifetime costs-offsets associated with the avoidance of end stage liver disease complications ranged from $51.47 to $57.48 million USD. CONCLUSIONS: One-time HCV screening and treatment in South Korean people aged 40-70 is likely to be highly cost-effective compared to the current practice of no screening.

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

BACKGROUND: Targeted 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. METHODS: An 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. RESULTS: Regardless 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. CONCLUSIONS: Standard 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.

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

BACKGROUND: Hepatitis 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. METHODS: An 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. RESULTS: The 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. CONCLUSIONS: The 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.

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.

Estimating the cost-effectiveness of daclatasvir plus asunaprevir in difficult to treat Japanese patients chronically infected with hepatitis C genotype 1b.

AIM: Standard of care for chronic hepatitis C in Japan is currently a pegylated interferon (IFN)-α + ribavirin (PR)-based regimen, notably associated with efficacy and tolerability issues. The advent of novel direct-acting antivirals (DAA) has provided more efficacious and better tolerated treatments. This study investigated the cost-effectiveness of the daclatasvir + asunaprevir (DCV + ASV) DAA regimen in patients infected with hepatitis C virus (HCV) genotype 1b who had previously not responded to or were ineligible for IFN-containing regimens. METHODS: A cost-utility analysis using an established Markov model compared DCV + ASV with simeprevir + PR (SMV + PR), telaprevir + PR (TVR + PR) and no treatment using Japanese-specific model inputs, with costs and utility values discounted at 2%. A cohort of patients was simulated until death and predicted quality-adjusted life-years (QALY) and costs were estimated. A subgroup analysis of patients with no DCV resistance was conducted. RESULTS: In all scenarios, DCV + ASV was predicted to be dominant over the comparator; namely, DCV + ASV was associated with increased QALY gains and decreased cost. In patients treated during the chronic hepatitis C stage, cost reductions were ¥1 057 288-2 619 206, and in patients treated during the compensated cirrhosis (CC) stage, reductions were ¥1 032 224-2 531 930. QALY gains were 0.749-2.609 and 0.874-3.043, respectively. Results improved when considering the subgroup of patients without DCV resistance. CONCLUSION: Cost-effectiveness conclusions are similar for patients treated in the chronic hepatitis C and CC disease stages, with DCV + ASV expected to be cost-saving versus standard of care in Japan for patients with HCV genotype 1b patients who have failed prior therapy or are IFN-ineligible/intolerant.

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-α+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 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.

Estimating the Long-Term Clinical and Economic Outcomes of Daclatasvir Plus Asunaprevir in Difficult-to-Treat Japanese Patients Chronically Infected with Hepatitis C Genotype 1b.

OBJECTIVES: Japan has one of the highest endemic rates of hepatitis C virus (HCV) infection. Treatments in Japan are currently limited to interferon-alfa-based regimens, which are associated with tolerability and efficacy issues. A novel regimen combining two oral HCV therapies, daclatasvir and asunaprevir (DCV + ASV), has shown favorable results in Japanese patients with chronic genotype 1b HCV infection. Comparisons of clinical and economic outcomes associated with DCV + ASV treatment and current standards of care were investigated. METHODS: The MOdelling the NAtural histoRy and Cost-effectiveness of Hepatitis cost-effectiveness model projected outcomes in 1000 patients aged 70 years with either chronic hepatitis C or compensated cirrhosis over a lifetime simulation. Japanese-specific disease transition rates were used, and discounting was applied annually at a rate of 2%. Efficacy data for DCV + ASV and telaprevir triple therapy (telaprevir + pegylated interferon-alfa + ribavirin [TVR + pegIFN-α/RBV]) were obtained from a Japanese subgroup analysis found within a global meta-analysis: sustained virological response rates of 74%, 85%, and 87% were reported for null responders (NRs), partial responders (PRs), and interferon-alfa-ineligible/intolerant patients, respectively, treated with DCV + ASV, and rates of 42% and 59% were reported for NRs and PRs, respectively, treated with TVR + pegIFN-α/RBV. RESULTS: Initiating DCV + ASV treatment in patients in the chronic hepatitis C disease stage resulted in quality-adjusted life-year gains of 0.96 and 0.77 over TVR + pegIFN-α/RBV for NRs and PRs, respectively, and a gain of 2.61 in interferon-alfa-ineligible/intolerant patients over no treatment. Similarly, quality-adjusted life-year gains of 1.11, 0.90, and 3.05 were observed when initiating treatment in patients in the compensated cirrhosis stage. Cumulative lifetime events of decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality were reduced by up to 66, 115, and 128, respectively, with DCV + ASV treatment. CONCLUSIONS: There is a lack of successful therapies for patients with HCV who have previously failed to achieve sustained virological response or are ineligible for interferon-alfa-based therapies. Results demonstrate that the provision of an alternative, interferon-alfa-free regimen, such as DCV + ASV, offers significant value in terms of avoiding life-threatening liver complications and increasing patients' quality of life.