Role of Non-hepatic Medical Comorbidity and Functional Limitations in Predicting Mortality in Patients with HCV.

BACKGROUND: Medical comorbidities and functional status limitations are determinants of mortality in many chronic diseases. The extent to which survival in the rapidly aging cohort of patients with HCV is affected by these competing causes of mortality remains unclear. AIM: We sought to determine the effect of medical/functional comorbidities on survival after adjusting for liver disease severity in a cohort of patients with HCV infection. METHODS: We prospectively recruited consecutive patients from an HCV clinic 2009-2014. We calculated an index of survival (Schonberg Index, SI) based on age, gender, medical comorbidities, and functional status variables. We defined cirrhosis with the FibroSure test (F3/4-F4). We used multivariable Cox modeling to assess association between functional/survival measure and survival after adjustment for severity of liver disease. RESULTS: The cohort consisted of 1052 HCV patients. The average age was 56.8 years; 36 % had cirrhosis. The mean SI was 8.2 (SD = 2.7). During a mean follow-up of 5610 person-years, 102 (9.7 %) patients died. In unadjusted analysis, higher baseline SI predicted mortality (HR 1.17; 95 % CI 1.09-1.25). SI similarly predicted mortality in cirrhotic patients (HR 1.23, 95 % CI 1.13-1.34) and non-cirrhotic patients (HR 1.21, 95 % CI 1.08-1.36). This did not change after adjusting for age, drug use, or coronary artery disease. DISCUSSION: Comorbidities and functional limitations predict higher mortality in patients with HCV; this relationship is independent of cirrhosis. Use of general prognostic indices may help identify HCV patients at high risk for mortality, which could further guide clinical care in a manner not achievable with assessment of liver disease alone.

Coffee and Caffeine Are Associated With Decreased Risk of Advanced Hepatic Fibrosis Among Patients With Hepatitis C.

BACKGROUND & AIMS: Coffee or caffeine has been proposed to protect against hepatic fibrosis, but few data are available on their effects in patients with chronic hepatitis C virus (HCV) infection. METHODS: We conducted a cross-sectional study of veterans with chronic HCV infection to evaluate the association between daily intake of caffeinated and decaffeinated coffee, tea, and soda, and level of hepatic fibrosis, based on the FibroSURE test (BioPredictive, Paris, France) (F0-F3, mild [controls] vs. F3/F4-F4, advanced). Models were adjusted for multiple potential confounders including age, alcohol abuse, and obesity. RESULTS: Among 910 patients with chronic HCV infection, 98% were male and 38% had advanced hepatic fibrosis. Daily intake of caffeinated coffee was higher among controls than patients with advanced fibrosis (1.37 vs. 1.05 cups/d; P = .038). In contrast, daily intake of caffeinated tea (0.61 vs. 0.56 cups/d; P = .651) or soda (1.14 vs. 0.95 cans/d; P = .106) did not differ between the groups. A higher percentage of controls (66.0%) than patients with advanced fibrosis (57.9%) consumed 100 mg or more of caffeine daily from all sources (P = .014); controls also received a larger proportion of their caffeine from coffee (50.2% vs. 43.0%; P = .035). Hepatoprotective effects of an average daily intake of 100 mg or more of caffeine (adjusted odds ratio, 0.71; 95% confidence interval, 0.53-0.95; P = .020) and 1 cup or more of caffeinated tea by non-coffee drinkers (adjusted odds ratio, 0.56; 95% confidence interval, 0.34-0.94; P = .028) persisted after adjustment for confounders, including insulin resistance. CONCLUSIONS: A modest daily caffeine intake (as little as 100 mg) may protect against advanced hepatic fibrosis in men with chronic HCV infection. Additional research is needed to confirm these findings in women and in people with other chronic liver diseases.

Genetic Variants in Interleukin-28B Are Associated with Diabetes and Diabetes-Related Complications in Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: Few studies have shown that host interleukin-28B (IL28B) genetic polymorphisms are associated with insulin resistance in patients with chronic hepatitis C virus (HCV) infection. However, the clinical relevance of this relationship is unclear. AIMS: We examined the association between IL28B genotype for rs12980275 and risk of type 2 diabetes and diabetes-related complications. METHODS: We used a cross-sectional study of prospectively recruited male veterans with chronic HCV. We employed logistic regression analysis and adjusted for patients' age, race, body mass index, and hepatic fibrosis. RESULTS: A total of 528 participants were recruited (mean age 59.1 years; 38.5 % African-American; 40.3 % advanced fibrosis). Of these, 36.1 % were homozygous for favorable AA allele for rs12980275, 49.0 % were heterozygous (AG), and 14.0 % were homozygous for the unfavorable allele (GG). Prevalence of diabetes was significantly lower in patients with both favorable alleles (AA) than that with at least one unfavorable IL28B G allele (21.1 vs. 30.2 %, p = 0.02). Similarly, patients who were homozygous for the favorable alleles had lower prevalence of diabetes-related complications than patients with any unfavorable IL28B allele (5.7 vs. 12.2 %, p = 0.01). This association did not change after adjusting for sociodemographic characteristics, body mass index, and stage of hepatic fibrosis (adjusted ORdiabetes 0.56, 95 % CI 0.35-0.89; ORdiabetes-related complications 0.47, 95 % CI 0.23-0.96). CONCLUSIONS: Patients who have favorable AA IL28B alleles have a lower prevalence of diabetes and related complications compared with patients with unfavorable IL28B rs12980275 genotype. IL28B genotype information may be used to counsel HCV patients regarding their individualized risk of diabetes and diabetes-related complications.

Sex hormone pathway gene polymorphisms are associated with risk of advanced hepatitis C-related liver disease in males.

BACKGROUND: Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear. GOAL: To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males. METHODS: We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction. RESULTS: Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation. CONCLUSIONS: The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.

Many patients with interleukin 28B genotypes associated with response to therapy are ineligible for treatment because of comorbidities.

BACKGROUND & AIMS: Interleukin (IL)-28B (interferon-λ 3) genotype is the strongest predictor of response of patients with hepatitis C virus (HCV) infection to antiviral therapy. However, patients with HCV infection often have physical or mental comorbidities that contraindicate or complicate treatment, regardless of their genotype. The potential role of IL28B genotype within the context of patients' clinical and social environment is therefore unclear. METHODS: We characterized the IL28B genotype (for rs12980275 and rs8099917) in 308 patients (mean age, 56 y; 25% African American; 38% with advanced-stage fibrosis) with genotype 1 HCV infection seen at the Michael E. DeBakey Veterans Administration Medical Center in Houston, Texas, from May 1, 2009, through April 1, 2012. We evaluated their eligibility for antiviral treatment based on clinical and social factors such as physical or mental health comorbidity, ongoing alcohol or drug use, and noncompliance with treatment evaluation. RESULTS: Of the 308 subjects, 40% were homozygous for rs12980275 (associated with response to therapy), 46% were heterozygous, and 15% were homozygous for alleles associated with reduced response to therapy. Overall, 36% of patients were considered to be ineligible for treatment; of these, 40% had the rs12980275 genotype. More than half of the patients with rs12980275 who were ineligible for treatment were excluded because of mental health comorbidities; one-third of these patients had advanced fibrosis. The reason(s) for treatment exclusion resolved in only 8% of patients during a mean 1.5 years of follow-up evaluation. CONCLUSIONS: In a well-characterized cohort of patients with HCV, a large proportion (40%) with IL28B polymorphisms associated with response to therapy is ineligible for treatment because of contraindications. One potential role of IL28B genotype analysis could be to identify patients who, although not currently eligible for antiviral treatment, could become so by modifying fixable exclusions to treatment.

Dietary fructose intake and severity of liver disease in hepatitis C virus-infected patients.

BACKGROUND AND GOALS: Dietary fructose intake in the United States has been increasing, and fructose intake has been associated with the metabolic syndrome and hepatic steatosis. This study aimed to determine whether dietary fructose intake is associated with advanced hepatic fibrosis and inflammation in an hepatitis C virus (HCV)-infected male population. STUDY: We conducted a cross-sectional study of HCV-infected male veterans. The main exposure variable was daily dietary fructose calculated from the National Cancer Institute Diet History Questionnaire and the main outcome variables were FibroSURE-ActiTest determined hepatic fibrosis (F0-F3=mild vs. F3/F4-F4=advanced) and inflammation (A0-A2=mild vs. A2/A3-A3=advanced). We examined this association in logistic regression adjusting for demographic, clinical, and other dietary variables. RESULTS: Among 313 HCV* males, 103 (33%) had advanced fibrosis and 89 (28%) had advanced inflammation. Median daily fructose intake was 46.8 g (interquartile range, 30.4 to 81.0). Dietary fructose intake across quartiles among males with advanced versus mild fibrosis was 21.4% versus 25.2%, 32.0% versus 24.8%, 24.3% versus 25.2%, and 22.3% versus 24.8%, respectively, and among males with advanced versus mild inflammation was 20.2% versus 25.5%, 41.6% versus 21.4%, 22.5% versus 25.9%, and 15.7% versus 27.2%, respectively. In multivariate analysis, there were no significant associations between daily fructose intake and advanced fibrosis. There was a significant association only between the second quartile of daily fructose intake (30 to 48 g) and advanced inflammation. CONCLUSIONS: There were no significant associations between dietary fructose intake and hepatic fibrosis risk, as assessed by FibroSURE, in HCV-infected males. Additional research is needed to clarify the potential role of fructose intake and HCV-related hepatic inflammation.

WNT signaling pathway gene polymorphisms and risk of hepatic fibrosis and inflammation in HCV-infected patients.

BACKGROUND: Chronic hepatitis C infection is the leading cause of hepatocellular carcinoma (HCC), a highly lethal malignancy with rapidly increasing prevalence in the United States. Little is known about genetic variations and HCC risk. This study aimed to determine if genetic variation in Wnt signaling pathway genes are associated with advanced hepatic fibrosis and inflammation risk in a hepatitis C virus (HCV) infected population. METHODS: We performed a genetic association cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 58 candidate genes and risk of FibroSURE-Acti Test determined advanced fibrosis (F3/F4-F4 advanced cases vs. F0-F3 mild controls) and inflammation (A2/A3-A3 advanced cases vs. A0-A2 mild controls). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) employing multivariate logistic regression. Haplotypes were inferred by the HAPLO.STAT program, interactions were evaluated using multifactor dimensionality reduction (MDR) analysis. RESULTS: Among 425 chronically HCV-infected male veterans, 155 (37%) had advanced fibrosis and 180 (42%) had advanced inflammation. Of 3016 SNPs evaluated, eight were significantly associated with fibrosis risk (e.g., SFRP2 rs11937424: OR = 2.19, 95% CI 1.48-3.23, P = 0.00004), and seven were significantly associated with inflammation risk (e.g., SFRP1 rs16890282: OR = 2.15, 95% CI 1.39-3.16, P = 0.0004). MDR analysis identified overweight/obese, SOST rs1405952, SFRP2 rs11937424, and FZD4 rs11234870 as the best interaction model for predicting risk of fibrosis; whereas race/ethnicity, FZD1 rs1346665, and TBX3 rs1520177 as the best interaction model for predicting risk of inflammation. CONCLUSIONS: Polymorphisms in several genes involved in the Wnt signaling pathway were associated with hepatic fibrosis or inflammation risk in HCV-infected males. Additional studies in other multi-ethnic HCV cohorts are needed to validate our findings in males and to assess if similar associations exist in chronically HCV-infected females.

Racial differences in the association between adiposity measures and the risk of hepatitis C-related liver disease.

BACKGROUND: African Americans have lower reported likelihood of hepatitis C virus-related cirrhosis than whites. It is unknown whether relative differences in the distribution of adipose tissue, lean mass, and other anthropometric measurements may explain these observed interethnic differences in disease risk. AIM: : To evaluate the association between anthropometric measurements and advanced liver disease in a cross-sectional study of African American and white male veterans. METHODS: We used the validated FibroSURE-ActiTest to assess hepatic pathology, and direct segmental multichannel bioelectric impedance analysis for anthropometric measurements. Race-stratified logistic regression was employed to evaluate risk of high fibrosis progression rate (FPR) and advanced inflammation (A2 to A3). RESULTS: Among 330 eligible males (59% African American), there were 43 white and 57 African American males with high FPR, and 70 African American and 59 white with advanced inflammation. Percentage body fat (%BF) was a stronger predictor of high FPR risk than was a high body mass index in African Americans [odds ratio (OR)(adj)=2.08; 95% confidence interval (CI),0.83-5.23 for highest %BF vs. lowest tertile and OR(adj)=1.50; 95% CI,0.60-3.75 for obese vs. normal body mass index, respectively], but not in whites. Highest lean leg mass was associated with a nonsignificant increased risk of both high FPR and advanced inflammation in African Americans (OR(highFPRadj)=1.73; 95% CI, 0.73-4.10; OR(AdvancedinflammationAdj)=1.65; 95% CI, 0.76-3.56) versus a decreased risk of both in whites (OR(highFPRadj)=0.62; 95% CI, 0.21-1.79; OR(AdvancedinflammationAdj)=0.58; 95% CI, 0.22-1.48). CONCLUSIONS: Interethnic differences in nontraditional anthropometric measurements like %BF suggests their potential role in understanding interethnic differences in hepatitis C virus-related liver disease risk in males.

Finasteride and methadone use and risk of advanced hepatitis C related liver disease.

AIM: We evaluated the association between two medications that alter bioavailable androgen levels, finasteride and methadone, and risk of advanced HCV-related liver disease. BACKGROUND: Males have strikingly greater cirrhosis risk across disease etiologies, including hepatitis C virus (HCV) infection. METHODS: In a cross-sectional study in HCV+ male veterans, we determined medication use by up to 15-year medical record review, and hepatic pathology by the FibroSURE-ActiTest (F3/F4-F4, advanced vs. F0-F3, mild fibrosis; and A2/A3-A3, advanced vs. A0-A2, mild inflammation). We performed race-adjusted and race-stratified multivariate analyses. RESULTS: Among 571 HCV+ males, 43 % were White and 57 % African-American. There were non-significant decreased risks with finasteride use (OR(adj advanced fibrosis) = 0.75, 95 % CI 0.39-1.45 and OR(adj advanced inflammation) = 0.74, 95 % CI 0.41-1.43). For methadone, there was a non-significant 41 % increased advanced fibrosis risk in Whites and 51 % reduced risk in AA. White male methadone-users had 2.1-fold excess advanced inflammation risk (p = 0.15). CONCLUSIONS: Our preliminary study results suggest finasteride use is not significantly associated with a decreased risk of advanced hepatic fibrosis or inflammation in HCV+ males. The ethnically-divergent results for methadone associated fibrosis risk and finding of potentially increased inflammation risk in White males suggests the need for additional research.

Higher serum testosterone is associated with increased risk of advanced hepatitis C-related liver disease in males.

UNLABELLED: Males have strikingly increased risk of advanced liver disease. However, the association between testosterone and risk of hepatitis C virus (HCV)-related advanced liver disease is unknown. We performed a cross-sectional study in male veterans with chronic HCV. Blood samples were obtained to measure total serum testosterone and perform the FibroSURE-ActiTest. Other risk-factor data were obtained through systematic questionnaires (e.g., alcohol), physical measurements (e.g., body mass index), and serological tests (e.g., viral load). The association between total testosterone and risk of advanced hepatic fibrosis (F3 and F3/F4) and inflammatory activity (A3 and A2/3) measured by the FibroSURE-ActiTest was evaluated with logistic regression. A total of 308 eligible study participants were prospectively recruited (mean age: 57; 52% African-American). There were 105 cases with advanced fibrosis and 203 mild fibrosis controls as well as 88 cases with advanced inflammatory activity and 220 mild activity controls. Mean total serum testosterone was significantly higher in advanced fibrosis cases as well as advanced inflammatory activity cases, compared to mild disease controls (6.0 versus 5.3 ng/mL and 5.9 versus 5.4 ng/mL, respectively). We observed a significant 25% increase in advanced fibrosis risk and 15% increase in advanced inflammatory activity risk for each 1-ng/mL increase in total serum testosterone. Total testosterone in the upper tertile was associated with an even greater excess risk of advanced fibrosis than advanced inflammatory activity (odds ratio [OR](adjusted advanced fibrosis) = 3.74; 95% CI: 1.86-6.54 versus OR(adjusted advanced inflammatory activity) = 2.23; 95% CI: 1.07-4.93, respectively). CONCLUSIONS: Total serum testosterone is associated with an increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV-infected men. Testosterone may be important in the pathogenesis of HCV-related advanced liver disease in males.