Impact of Stigma on People Living with Chronic Hepatitis B.

BACKGROUND: People with chronic infectious diseases such as hepatitis B can face stigma, which can influence everyday life as well as willingness to engage with medical professionals or disclose disease status. A systematic literature review was performed to characterize the level and type of stigma experienced by people infected with hepatitis B virus (HBV) as well as to identify instruments used to measure it. METHODS: A literature review was performed using the PubMed, Embase and Cochrane Library databases to identify studies describing HBV-related stigma. For inclusion, articles were required to be published in full-text form, in English and report quantitative or qualitative data on HBV-related stigma that could be extracted. RESULTS: A total of 23 (17 quantitative and 6 qualitative) articles examined HBV-related stigma. The scope of the review was global but nearly all identified studies were conducted in countries in the WHO Southeast Asia or Western Pacific regions or within immigrant communities in North America. Several quantitative studies utilized tools specifically designed to assess aspects of stigma. Qualitative studies were primarily conducted via patient interviews. Internalized and social stigma were common among people living with chronic HBV . Some people also perceived structural/institutional stigma, with up to 20% believing that they may be denied healthcare and up to 30% stating they may experience workplace discrimination due to HBV. CONCLUSION: HBV-related stigma is common, particularly in some countries in Southeast Asia and the Western Pacific region and among Asian immigrant communities, but is poorly characterized in non-Asian populations. Initiatives are needed to document and combat stigma (particularly in settings/jurisdictions where it is poorly described) as well as its clinical and socioeconomic consequences.

Cost-effectiveness analysis of simeprevir in combination with peginterferon and ribavirin for treatment-naïve chronic hepatitis C genotype 1 patients in Japan.

AIM: Simeprevir (SMV), a protease inhibitor, recently became available for the treatment of chronic hepatitis C (HCV) genotype 1 patients in Japan. The introduction of triple therapy using SMV in combination with peginterferon and ribavirin (PR) significantly improves the cure rate. The aim was to assess the cost-effectiveness of SMV with PR (SMV/PR) compared to telaprevir with PR (TVR/PR), PR alone, or no treatment in treatment-naïve patients in Japan. METHODS: A Markov model was developed to reflect the natural disease progression of HCV and to estimate the average life years and lifetime healthcare costs per patient. Sustained virologic response rates were obtained from a network meta-analysis including randomized clinical trials conducted in Japan. Patient baseline characteristics, HCV progression rates, mortality, medical resource utilization, and unit costs were obtained from Japanese sources. Outcomes were reported as incremental cost-effectiveness ratios as well as incremental cost and life years. Various sensitivity analyses were conducted to assess the uncertainty around model outcomes. RESULTS: SMV/PR was estimated to be a cost-effective treatment option as more life years were gained by 0.235 and 0.873 years at a reduced cost by ¥263,037 and ¥776,900 compared to TVR/PR and PR alone, respectively. The results were robust to sensitivity analyses, in particular in the comparison of SMV/PR with PR alone. The multivariate probabilistic sensitivity analyses showed that the probability of SMV/PR being cost-effective was relatively constant at ∼87% at any willingness to pay. CONCLUSIONS: SMV/PR is estimated to be the most cost-effective treatment strategy for treatment-naïve HCV genotype 1 patients in Japan.

Relative efficacy and safety of simeprevir and telaprevir in treatment-naïve hepatitis C-infected patients in a Japanese population: A Bayesian network meta-analysis.

AIM: Simeprevir (SMV) is an oral, once-daily protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In phase II/III randomized controlled trials (RCT) conducted in Japan, SMV, in combination with peginterferon-α and ribavirin (PEG IFN/RBV), demonstrated potent efficacy in HCV genotype 1-infected patients relative to PEG IFN/RBV and was generally well tolerated. Telaprevir (TVR) in combination with PEG IFN/RBV is licensed for the treatment of HCV in Japan. In the absence of head-to-head comparisons of TVR and SMV in a Japanese population, we undertook a network meta-analysis (NMA) to examine the relative efficacy and safety of SMV and TVR in combination with PEG IFN/RBV. METHODS: A systematic review identified SMV and TVR RCT in Japanese treatment-naïve patients. Bayesian NMA was performed assuming fixed study effects. RESULTS: Three studies met our inclusion criteria: two SMV and one TVR. SMV showed a higher mean odds ratio (OR) of achieving SVR versus TVR (OR, 1.68 (95% credible interval 0.66-4.26)). SMV showed a lower mean OR of discontinuation: overall, 0.35 (0.12-1.00); and due to AE, 0.87 (0.23-3.34) versus TVR. SMV showed a lower mean OR of experiencing anemia 0.20 (0.07-0.56) and rash 0.41 (0.17-0.99) but a higher mean OR of experiencing pruritus 1.26 (0.46-3.47) versus TVR. CONCLUSION: In this indirect treatment comparison, SMV, in combination with PEG IFN/RBV, showed a favorable risk-benefit profile compared with TVR with PEG IFN/RBV in Japanese treatment-naïve HCV patients.

Predicting the impact of adverse events and treatment duration on medical resource utilization-related costs in hepatitis C genotype 1 treatment-naïve patients receiving antiviral therapy.

OBJECTIVES: Studies on medical resource utilization (MRU) and related costs are important for evaluating the potential patient management and cost-effectiveness implications of antiviral treatments for hepatitis C virus (HCV) infection. The objectives of this study were (i) to compare the MRU and related costs for two treatment approaches; (ii) to identify the main drivers of resource use and costs; and (iii) to assess the effects of various treatment regimen attributes on MRU-related costs in a UK clinical setting. METHODS: The analysis used data collected alongside the simeprevir (SMV) phase III trials for treatment-naïve genotype 1 HCV-infected patients; these data covered outpatient consultations with specialists, emergency room visits and hospital admissions. Logistic regressions were constructed to estimate the predictors of resource utilization, and a two-part multivariable analysis model was used to determine the total costs of treatment in the UK. RESULTS: Data on 731 patients receiving SMV plus pegylated interferon and ribavirin (SMV/PegIFN/R) or PegIFN/R were included in the analysis. While MRU was similar between the SMV and PegIFN/R groups, MRU-related costs were significantly lower in the SMV group than in the PegIFN/R group (P < 0.05). High body mass index (P < 0.05), severe fibrosis (P < 0.05), shortened treatment duration to 24 weeks (P < 0.05), and anaemia and rash during treatment (P < 0.001) were identified as predictors of hospitalization and outpatient visits and as drivers of total costs. Univariate sensitivity analyses suggested that shortened treatment duration and lower occurrence of rash lead to large cost savings. CONCLUSION: This study identified both baseline and on-treatment antiviral therapy characteristics as drivers of MRU-related costs for HCV patients following antiviral therapy. The shortened treatment duration and reduction in rash due to treatment with SMV triple therapy lead to substantial non-drug cost savings, compared with PegIFN/R treatment. This suggests that there are potential patient management and cost-effectiveness implications associated with the choice of specific antiviral treatments.

Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits.

BACKGROUND: The goal of chronic hepatitis C treatment is to remove the virus to avoid progression of HCV-related disease. Sustained virologic response (SVR) is the most widely used efficacy endpoint in clinical studies of hepatitis C, and represents the eradication of HCV from the body. The aim of the current review was to examine the long-term clinical, economic and quality of life benefits associated with achieving SVR. METHODS: A systematic literature review was performed using the PubMed, EMBASE and Cochrane library databases to identify articles examining the clinical, economic and quality of life benefits associated with SVR, published in English language from 2002-2013. For inclusion studies were required to enroll ≥100 patients and to report clinical endpoints including hepatocellular carcinoma, overall- or liver-related mortality, or progression of disease/complications (e.g. portal hypertension, esophageal varices). Review of economic studies on cost/cost-effectiveness of achieving SVR were focused on studies assessing boceprevir/telaprevir plus pegIFN and ribavirin as this represents the current standard of care in several jurisdictions worldwide. Quality of life evidence was required to use validated quality of life instruments and provide a quantitative analysis of the impact of SVR versus no treatment or treatment failure. RESULTS: SVR is durable with late relapse rates over 4-5 year periods being in the range of 1-2%. Patients who achieve SVR frequently demonstrate some regression of fibrosis/cirrhosis and have a substantially reduced risk for hepatocellular carcinoma (relative risk [RR] 0.1-0.25), liver-related mortality (RR 0.03-0.2) and overall mortality (RR 0.1-0.3) in comparison with no treatment or treatment failure. In the 5 years post-treatment, medical costs for patients achieving SVR are 13-fold lower than patients not achieving SVR. Patients who achieve SVR also have health state utility values that are 0.05 to 0.31 higher than non-responders to treatment. CONCLUSIONS: SVR represents the fundamental goal of antiviral treatment for patients infected with chronic HCV, so as to reduce risk of liver disease progression. Achievement of SVR has implications beyond those of clearing viral infection; it is associated with improved long-term clinical outcomes, economic benefits and improved health-related quality of life.

Fatigue during treatment for hepatitis C virus: results of self-reported fatigue severity in two Phase IIb studies of simeprevir treatment in patients with hepatitis C virus genotype 1 infection.

BACKGROUND: Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330]. METHODS: Treatment-naïve patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to simeprevir plus PR (simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72. RESULTS: During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study. CONCLUSIONS: Combination of simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone.

Validation of the Fatigue Severity Scale in chronic hepatitis C.

BACKGROUND: Fatigue is a common symptom of chronic hepatitis C virus (cHCV) infection and a common side effect of interferon-based treatment for cHCV. This study provides confirmatory evidence of the reliability and validity of the Fatigue Severity Scale (FSS) to document fatigue in cHCV research and identifies values that indicate clinically important differences in FSS to aid in interpreting fatigue in cHCV clinical trials. METHODS: The study used data from two double-blind, randomized, placebo-controlled, Phase IIb trials evaluating the efficacy and safety of simeprevir plus peginterferon-α/ribavirin in treatment-naïve (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) with cHCV infection. Patients completed the FSS and EuroQoL 5 dimension questionnaire (EQ-5D) at baseline and at regular intervals throughout both trials. Reliability was assessed using Cronbach's coefficient α at Week 24 (internal consistency reliability) and intraclass correlation (ICC) between FSS at Weeks 12 and 24 in stable patients (<0.5 g/dL hemoglobin [Hb] change between Weeks 12/24). Correlation with the EQ-5D visual analog scale (VAS) and "Usual Activity" domain score was used to assess concurrent validity. Clinical validity was evaluated using a case-control method to link spontaneously reported fatigue and anemia adverse events (AEs) during the study to FSS scores. RESULTS: FSS total scores demonstrated good reliability (Cronbach's α: 0.95, 0.96; ICC: 0.74, 0.86 for PILLAR and ASPIRE, respectively) and concurrent validity (correlation with EQ-5D VAS: -0.63, -0.66) with a monotonic relationship between the EQ-5D "Usual Activities" item response and FSS. Clinical validity was confirmed by a significant difference between cases and controls for fatigue AEs (p < 0.05); however, anemia defined by AE or Hb abnormalities was only weakly related to FSS score. Analyses indicate that a change of 0.33-0.82 in mean FSS scores represents a meaningful improvement in fatigue, and a one-point change is a conservative indicator of an important change in individual FSS scores. CONCLUSION: A difference of ≥0.7 in mean FSS scores can be considered a clinically important difference within groups over time or between groups. A one-point change or less in individual FSS scores indicates a clinically relevant change in fatigue.

Decision making by NICE: examining the influences of evidence, process and context.

The National Institute for Health and Clinical Excellence (NICE) provides guidance to the National Health Service (NHS) in England and Wales on funding and use of new technologies. This study examined the impact of evidence, process and context factors on NICE decisions in 2004-2009. A data set of NICE decisions pertaining to pharmaceutical technologies was created, including 32 variables extracted from published information. A three-category outcome variable was used, defined as the decision to 'recommend', 'restrict' or 'not recommend' a technology. With multinomial logistic regression, the relative contribution of explanatory variables on NICE decisions was assessed. A total of 65 technology appraisals (118 technologies) were analysed. Of the technologies, 27% were recommended, 58% were restricted and 14% were not recommended by NICE for NHS funding. The multinomial model showed significant associations (p ⩽ 0.10) between NICE outcome and four variables: (i) demonstration of statistical superiority of the primary endpoint in clinical trials by the appraised technology; (ii) the incremental cost-effectiveness ratio (ICER); (iii) the number of pharmaceuticals appraised within the same appraisal; and (iv) the appraisal year. Results confirm the value of a comprehensive and multivariate approach to understanding NICE decision making. New factors affecting NICE decision making were identified, including the effect of clinical superiority, and the effect of process and socio-economic factors.

Public funding of pharmaceuticals in The Netherlands: investigating the effect of evidence, process and context on CVZ decision-making.

The College Voor Zorgverzekeringen (CVZ) provides guidance to the Dutch healthcare system on funding and use of new pharmaceutical technologies. This study examined the impact of evidence, process and context factors on CVZ decisions in 2004-2009. A data set of CVZ decisions pertaining to pharmaceutical technologies was created, including 29 variables extracted from published information. A three-category outcome variable was used, defined as the decision to 'recommend', 'restrict' or 'not recommend' a technology. Technologies included in list 1A/1B or on the expensive drug list were considered recommended; those included in list 2 or for which patient co-payment is required were considered restricted; technologies not included on any reimbursement list were classified as 'not recommended'. Using multinomial logistic regression, the relative contribution of explanatory variables on CVZ decisions was assessed. In all, 244 technology appraisals (256 technologies) were analysed, with 51%, of technologies recommended, 33% restricted and 16% not recommended by CVZ for funding. The multinomial model showed significant associations (p ≤ 0.10) between CVZ outcome and several variables, including: (1) use of an active comparator and demonstration of statistical superiority of the primary endpoint in clinical trials, (2) pharmaceutical budget impact associated with introduction of the technology, (3) therapeutic indication and (4) prevalence of the target population. Results confirm the value of a comprehensive and multivariate approach to understanding CVZ decision-making.