A Comparison of the EQ-5D-3L and EQ-5D-5L.

INTRODUCTION: The EQ-5D-3L (3L) and EQ-5D-5L (5L) are both frequently used measures of health status. Previous studies have found the EQ-5D-5L to have superior measurement properties but no study has compared the two measures in a large general population survey using matched respondents. METHODS: Using data from the GP Patient Survey, coarsened exact matching was used to match individuals completing the 3L in 2011 with those completing the 5L in 2012. Measurement properties were assessed for a general population and multimorbid population (chronic conditions ≥ 2), with ceiling effects, informativity and distribution of response compared. Changes in the direction of response, as well as the impact on utility distributions, were quantified. RESULTS: Matching resulted in a cohort of 1,023,218 respondents (2011: 511,609; 2012: 511,609) for analysis. Ceiling effects for the 5L were lower than the 3L (43.8% vs. 54.4%). The 5L had improved informativity and broader spread of responses than the 3L (5L top 50 profiles: 77.4% vs. 3L: 98.8%). Overall, there was an upwards shift in utility values for the 5L versus the 3L as respondents using the 5L reported ill health more frequently but with less severity. Measurement improvements and effects on utility values were more pronounced for the multimorbid population. CONCLUSION: The 5L had superior measurement properties than the 3L and should be preferred in general population surveys and for use in individuals with multimorbidity. At increasing levels of morbidity, the 5L is currently associated with higher utility values than the 3L.

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1.

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients. METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome. RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria. CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Antifibrotic therapies: will we ever get there?

Progressive hepatic fibrosis is the final common pathway for most chronic liver injuries, leading to cirrhosis with risk of liver failure and hepatocellular carcinoma. It is now recognized that fibrosis is a dynamic process, and may be reversible prior to the establishment of advanced architectural changes to the liver. The most effective antifibrotic strategy is to cure the underlying disease process before advanced fibrosis has developed. Unfortunately, this is often not possible, and specific antifibrotic therapies are needed. Advances in the understanding of the pathogenesis of liver fibrosis have identified several potential novel therapeutic targets, but unfortunately clinical development has been disappointing. One major limitation has been the often prolonged natural history of fibrosis compared to experimental models, and difficulties in accurate noninvasive fibrosis assessment, thus making clinical trial design difficult. In this review, we highlight the most promising current antifibrotic strategies.