Host- rather than virus-related factors reduce health-related quality of life in hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is associated with decreased health-related quality of life (HRQOL). Although HCV has been suggested to directly impair neuropsychiatric functions, other factors may also play a role. PATIENTS AND METHODS: In this cross-sectional study, we assessed the impact of various host-, disease- and virus-related factors on HRQOL in a large, unselected population of anti-HCV-positive subjects. All individuals (n = 1736) enrolled in the Swiss Hepatitis C Cohort Study (SCCS) were asked to complete the Short Form 36 (SF-36) and the Hospital Anxiety Depression Scale (HADS). RESULTS: 833 patients (48%) returned the questionnaires. Survey participants had significantly worse scores in both assessment instruments when compared to a general population. By multivariable analysis, reduced HRQOL (mental and physical summary scores of SF-36) was independently associated with income. In addition, a low physical summary score was associated with age and diabetes, whereas a low mental summary score was associated with intravenous drug use. HADS anxiety and depression scores were independently associated with income and intravenous drug use. In addition, HADS depression score was associated with diabetes. None of the SF-36 or HADS scores correlated with either the presence or the level of serum HCV RNA. In particular, SF-36 and HADS scores were comparable in 555 HCV RNA-positive and 262 HCV RNA-negative individuals. CONCLUSIONS: Anti-HCV-positive subjects have decreased HRQOL compared to controls. The magnitude of this decrease was clinically important for the SF-36 vitality score. Host and environmental, rather than viral factors, seem to impact on HRQOL level.

Impact of soluble CD26 on treatment outcome and hepatitis C virus-specific T cells in chronic hepatitis C virus genotype 1 infection.

BACKGROUND: Interferon and ribavirin therapy for chronic hepatitis C virus (HCV) infection yields sustained virological response (SVR) rates of 50-80%. Several factors such as non-1 genotype, beneficial IL28B genetic variants, low baseline IP-10, and the functionality of HCV-specific T cells predict SVR. With the pending introduction of new therapies for HCV entailing very rapid clearance of plasma HCV RNA, the importance of baseline biomarkers likely will increase in order to tailor therapy. CD26 (DPPIV) truncates the chemokine IP-10 into a shorter antagonistic form, and this truncation of IP-10 has been suggested to influence treatment outcome in patients with chronic HCV infection patients. In addition, previous reports have shown CD26 to be a co-stimulator for T cells. The aim of the present study was to assess the utility of CD26 as a biomarker for treatment outcome in chronic hepatitis C and to define its association with HCV-specific T cells. METHODS: Baseline plasma from 153 genotype 1 and 58 genotype 2/3 infected patients enrolled in an international multicenter phase III trial (DITTO-HCV) and 36 genotype 1 infected patients participating in a Swedish trial (TTG1) were evaluated regarding baseline soluble CD26 (sCD26) and the functionality of HCV-specific CD8(+) T cells. RESULTS: Genotype 1 infected patients achieving SVR in the DITTO (P = 0.002) and the TTG1 (P = 0.02) studies had lower pretreatment sCD26 concentrations compared with non-SVR patients. Sixty-five percent of patients with sCD26 concentrations below 600 ng/mL achieved SVR compared with 39% of the patients with sCD26 exceeding 600 ng/mL (P = 0.01). Patients with sCD26 concentrations below 600 ng/mL had significantly higher frequencies of HCV-specific CD8(+) T cells (P = 0.02). CONCLUSIONS: Low baseline systemic concentrations of sCD26 predict favorable treatment outcome in chronic HCV infection and may be associated with higher blood counts of HCV-specific CD8(+) T cells.

Genetic association analyses reveal a role for vitamin D insufficiency in hepatitis C virus-associated hepatocellular carcinoma development

Background: V itamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. Methods: Associations between t he r isk o f HCV-related HCC development and CYP2R1 , GC, and DHCR7 genotypes, which are genetic determinants of reduced 25-OH-vitamin D3 (25[OH]D3) serum levels, were determined. Results: A t otal of 5604 HCV-infected patients, 1279 with a nd 4325 without progression to HCC, w ere identified. The well-known association between 25(OH)D3 s erum levels and variations in CYP2R1 ( rs1993116, rs10741657), GC ( rs2282679), a nd DHCR7 ( rs7944926, rs12785878) g enotypes was also apparent in patients w ith chronic hepatitis C. The same genotypes of t hese single nucleotide polymorphisms (SNPs), w hich are associated with reduced 25(OH)D3 s erum levels, were significantly associated with HCV-associated HCC (P=0.07 [OR=1.13] for CYP2R1 , P=0.007 [OR=1.56] for GC, P=0.003 [OR=1.42] for DHCR7; ORs for risk genotypes). In contrast, no association between t hese genetic variations and the o utcome of antiviral therapy with pegylated interferon-α and ribavirin ( P>0.2 for e ach SNP) or liver fibrosis progression rate (P>0.2 for each SNP) was observed, s uggesting a specific influence o f the genetic d eterminants of 25(OH)D3 s erum levels o n hepatocarcinogenesis. Conclusions: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related HCC development. Controlled clinical trials to assess the benefit of vitamin D supplementation in HCVinfected patients with advanced liver fibrosis or cirrhosis are warranted.

Role of seipin in lipid droplet morphology and hepatitis C virus life cycle.

Infectious hepatitis C virus (HCV) particle assembly starts at the surface of lipid droplets, cytoplasmic organelles responsible for neutral fat storage. We analysed the relationship between HCV and seipin, a protein involved in lipid droplet maturation. Although seipin overexpression did not affect the total mean volume occupied by lipid droplets nor the total triglyceride and cholesterol ester levels per cell, it caused an increase in the mean diameter of lipid droplets by 60 %, while decreasing their total number per cell. The latter two effects combined resulted in a 34 % reduction of the total outer surface area of lipid droplets per cell, with a proportional decrease in infectious viral particle production, probably due to a defect in particle assembly. These results suggest that the available outer surface of lipid droplets is a critical factor for HCV release, independent of the neutral lipid content of the cell.

Impact of common risk factors of fibrosis progression in chronic hepatitis C.

OBJECTIVE: The natural course of chronic hepatitis C varies widely. To improve the profiling of patients at risk of developing advanced liver disease, we assessed the relative contribution of factors for liver fibrosis progression in hepatitis C. DESIGN: We analysed 1461 patients with chronic hepatitis C with an estimated date of infection and at least one liver biopsy. Risk factors for accelerated fibrosis progression rate (FPR), defined as ≥0.13 Metavir fibrosis units per year, were identified by logistic regression. Examined factors included age at infection, sex, route of infection, HCV genotype, body mass index (BMI), significant alcohol drinking (≥20 g/day for ≥5 years), HIV coinfection and diabetes. In a subgroup of 575 patients, we assessed the impact of single nucleotide polymorphisms previously associated with fibrosis progression in genome-wide association studies. Results were expressed as attributable fraction (AF) of risk for accelerated FPR. RESULTS: Age at infection (AF 28.7%), sex (AF 8.2%), route of infection (AF 16.5%) and HCV genotype (AF 7.9%) contributed to accelerated FPR in the Swiss Hepatitis C Cohort Study, whereas significant alcohol drinking, anti-HIV, diabetes and BMI did not. In genotyped patients, variants at rs9380516 (TULP1), rs738409 (PNPLA3), rs4374383 (MERTK) (AF 19.2%) and rs910049 (major histocompatibility complex region) significantly added to the risk of accelerated FPR. Results were replicated in three additional independent cohorts, and a meta-analysis confirmed the role of age at infection, sex, route of infection, HCV genotype, rs738409, rs4374383 and rs910049 in accelerating FPR. CONCLUSIONS: Most factors accelerating liver fibrosis progression in chronic hepatitis C are unmodifiable.