Vitamin D deficiency and vitamin D therapy in chronic hepatitis C.

BACKGROUND: Vitamin D has immunomodulatory properties, exerts an anti-hepatitis C virus (HCV) effect in vitro and improves response to interferon-based therapy in patients with chronic hepatitis C (CHC). Low serum levels of 25(OH) vitamin D [25(OH)D] are frequently found in CHC patients and seem to be related to more advanced stages of liver fibrosis. The study aims to establish the incidence of vitamin D deficiency in Spanish patients with CHC, its possible relation with features of liver damage and with the IL28B gene polymorphism, and the immediate effect of vitamin D therapy on CHC-related analytical variables. MATERIALS AND METHODS: Baseline serum 25(OH)D levels were measured in 108 consecutive CHC patients (60 men, age 54.3 ± 10.5 yrs). Results of transient elastography and of IL28B rs12979860C/T genotype were available in 89 and 95 patients, respectively. Forty one patients with insufficient levels of 25(OH)D received vitamin D supplements and were re-evaluated thereafter. RESULTS: Deficiency of vitamin D (< 20 µg/dL) and suboptimal levels (20-30 µg/mL) were detected in 36.1% and 40.9% of patients, respectively. No relationships were found between 25(OH)D levels and biochemical liver tests, fibrosis stage and IL28B genotype. Vitamin D therapy normalized 25(OH)D levels in all treated patients, but did not modify significantly HCV-RNA serum levels or biochemical tests. CONCLUSIONS: Vitamin D deficiency is common in Spanish patients with CHC but it is related neither to biochemical and virological variables nor with the fibrosis stage and IL28B polymorphism. Vitamin D therapy has no immediate effect on HCV-RNA serum levels.

Polymorphism of the TLR4 gene reduces the risk of hepatitis C virus-induced hepatocellular carcinoma.

OBJECTIVE: Toll-like receptor 4 (TLR4) signalling participates in the innate immune response against hepatitis C virus (HCV) infection. TLR4 gene polymorphisms may influence the risk of HCV-induced hepatocellular carcinoma (HCC). This is a single-centre-based study designed to analyse the distribution of several TLR4 gene single nucleotide polymorphisms in healthy controls and in patients chronically infected with HCV, with and without HCC. METHODS: We have determined three single nucleotide polymorphisms (rs2149356, rs4986791 and rs5030719) at the TLR4 gene in 155 patients with HCV-related HCC, 153 patients with chronic hepatitis C and 390 healthy controls. All were white and most were Spaniards. RESULTS: (1) rs5030719 was monomorphic and was not further analysed; (2) the rs2149356 T allele carrier state was significantly less frequent in patients with HCC than in healthy controls (OR 0.421, 95% CI 0.285-0.625) and in patients with chronic hepatitis C (OR 0.426, 95% CI 0.236-0.767); (3) the proportion of rs2149356 T allele carriers progressively diminished with increasing clinical stage of HCC; (4) no significant differences were observed for the rs4986791 T allele. CONCLUSION: The TLR4 rs2148356 T allele is associated with a reduced risk of HCC and could slow down its clinical progression in HCV-induced chronic liver disease.

Predicting response to therapy in chronic hepatitis C: an approach combining interleukin-28B gene polymorphisms and clinical data.

BACKGROUND AND AIM: Polymorphisms at the interleukin-28B (IL28B) gene predict therapeutic response in chronic hepatitis C virus genotype 1 (CHC-1) infection. The aim of the present study was to establish whether a unique single-nucleotide polymorphism (SNP) represents the whole predictive value of the IL28B haplotype for sustained viral response (SVR) and primary non-response (PNR). METHODS: SNP rs12979860 and rs8099917 were determined by TaqMan assays in 110 CHC-1 Caucasian patients treated with pegylated interferon plus ribavirin. RESULTS: There were 51 SVR, 43 PNR, and 16 relapses. Baseline predictors of SVR were rs12979860CC genotype (P = 0.008), viral load < 400.000 IU/mL (P < 0.010), age (P = 0.013), γ-glutamyl transferase (P = 0.022), alkaline phosphatase (P = 0.008), and cholesterol (P = 0.048). The area under the receiver-operating curve (AUROC) of the model, including these variables, was 0.841 (95% confidence interval [CI] = 0.767-0.916). The same figures for PNR were rs12979860 T-allele carrier state (P = 0.00008), viral load ≥ 400.000 IU/mL (P = 0.007), aspartate aminotransferase/alanine aminotransferase (P = 0.048), and serum cholesterol (P = 0.064), (AUROC = 0.869, 95% CI = 0.792-0.945). After excluding rs12979860CT SNP from multivariate analyses, the rs8099917 genotype alone did not predict SVR (P = 0.185), but strongly predicted PNR (P = 0.003). The significance of haplotypes combining both SNP as predictors of SVR and PNR was higher than those of each separate SNP. CONCLUSIONS: The rs12979860 SNP strongly predicts therapeutic response in CHC-1 patients, and if associated with easy-to-obtain baseline criteria, provides a useful tool for the selection of candidates for antiviral therapy. IL28B haplotypes might improve the clinical usefulness of individual SNP.

Non-invasive evaluation of the fibrosis stage in chronic hepatitis C: a comparative analysis of nine scoring methods.

OBJECTIVE: Liver biopsy is an invasive procedure and new surrogate markers to assess fibrosis are needed. We performed a comparative external evaluation of nine non-invasive scores of liver fibrosis and tried to identify other potential biochemical markers of low-stage liver fibrosis in chronic hepatitis C (CHC). MATERIAL AND METHODS: We included 429 previously untreated consecutive patients from a single centre who underwent a liver biopsy between January 1999 and April 2009. Biopsies were evaluated for the stage of fibrosis according to the METAVIR scoring method. RESULTS: None of the evaluated scores were adequate to disclose null-low fibrosis due to a lack of specificity at the proposed cut-offs and the poor sensitivity of lower cut-offs. Serum ferritin and cholesterol values were found to be independently related to the fibrosis stage and their inclusion in the best performing scores at lower cut-off values (the APRI and King's scores) improved the sensitivity for null-low fibrosis by 8% with a specificity >or= 93%. CONCLUSIONS: Approximately 30% of patients with null-low fibrosis may be accurately identified by supplementing current scores with new independent variables (serum ferritin and cholesterol), thus obviating the need for a liver biopsy.

HIV Coinfection Predicts Failure of Ledipasvir/Sofosbuvir in Treatment-Naïve Noncirrhotic Patients With HCV Genotype 1.

BACKGROUND: The efficacy of licensed direct-acting antiviral (DAA) regimens is assumed to be the same for hepatitis C virus (HCV)-monoinfected patients (HCV-Mono) and HIV/HCV-coinfected patients (HCV-Co). However, the high sustained viral response (SVR) rates of DAA regimens and the small number of HIV-infected patients included in registration trials have made it difficult to identify predictors of treatment failure, including the presence of HIV. METHODS: We compared treatment outcomes for ledipasvir/sofosbuvir (LDV/SOF) against HCV G1 in treatment-naïve HCV-Mono and HCV-Co without cirrhosis in a prospective registry of individuals receiving DAAs for HCV. RESULTS: Up to September 2017, a total of 17 269 patients were registered, and 1358 patients (1055 HCV-Mono/303 HCV-Co) met the inclusion criteria. Significant differences between HCV-Mono and HCV-Co were observed for age, gender, and G1 subtype distribution. Among HCV-Co, 99.0% were receiving antiretroviral therapy. SVR rates for LDV/SOF at 8 weeks did not differ significantly between HCV-Mono and HCV-Co (96.9% vs 94.0%; P = .199). However, the SVR rate for LDV/SOF at 12 weeks was significantly higher for HCV-Mono than HCV-Co (97.2% vs 91.8%; P = .001). A multivariable logistic regression model including age, sex, liver stiffness, G1 subtype, HCV-RNA, HIV, and treatment duration showed the factors associated with treatment failure to be male sex (adjusted odds ratio [aOR], 2.49; 95% confidence interval [CI], 1.27-4.91; P = .008) and HIV infection (aOR, 2.23; 95% CI, 1.13-4.38; P = .020). CONCLUSIONS: The results of this large prospective study analyzing outcomes for LDV/SOF against HCV G1 in treatment-naïve noncirrhotic patients suggest that HIV infection is a predictor of treatment failure in patients with chronic hepatitis C.

[Utility of liver biopsy in the etiologic diagnosis of biochemical liver abnormalities of unknown cause]. / Utilidad de la biopsia hepática en el diagnóstico etiológico de las alteraciones de la analítica hepática de causa incierta.

INTRODUCTION: To establish the diagnostic usefulness of liver biopsy (LB) and its influence on the therapeutic approach in patients with persistent abnormal liver tests of unknown cause. METHODS: The 1135 LB performed between January 1999 and January 2007 were retrospectively evaluated. Patients with a strongly suspected diagnosis were excluded. One hundred and twelve patients with chronic elevation of aminotransferases (103 patients), gamma-glutamyltransferase (GGT) (7 patients) and ferritin (2 patients) were included in the analysis. RESULTS: The most common diagnoses were normal liver (35 patients, group 1), minimal changes (15 patients, group 2), bland steatosis (23 patients, group 3), non-alcoholic steatohepatitis (NASH) (17 patients, group 4), and chronic hepatitis (eight patients, group 5). Three patients had tuberculosis of the liver and the remaining 11 had other diagnoses. Ferritinemia was the only parameter significantly lower in group 1 than in groups 2 (p = 0.038), 3 (p = 0.023), and 4 (p < 0.001). Transaminase levels lacked discriminatory value except in chronic hepatitis (p = 0.008). Alkaline phosphatase levels (p = 0.003) were lower in group 4 than in group 1. Triglyceride levels were higher in group 3 (p = 0.009) and group 4 (p = 0.008) than in group 1. Ultrasonography detected steatosis in 28 of the 40 patients with fatty liver (specificity = 0.94; sensitivity = 0.70). CONCLUSIONS: LB modified the therapeutic approach only in the three patients with hepatic tuberculosis. LB confirmed ultrasonographic findings of steatosis and differentiated bland steatosis from NASH, but did not influence the therapeutic approach. Most patients with normal findings on ultrasonography had normal or near-normal biopsies. The indication for LB should be individualized.

"12 weeks' stopping rule" in the treatment of genotype 1 chronic hepatitis C: two prognostic categories under the same label?

OBJECTIVE: The current guidelines recommend maintenance of combined therapy for hepatitis C virus (HCV) genotype-1 chronic hepatitis when HCV-RNA is undetectable or < or = 2 log10 of baseline after 12 weeks of therapy. The aim of this study was to investigate whether the probability of obtaining sustained viral (SVR) response is similar when HCV-RNA is undetectable or is present at < or = 2 log10 level after 12 weeks of therapy. MATERIAL AND METHODS: Retrospective analysis was carried out in 208 HCV genotype-1 chronic hepatitis patients treated with pegylated interferon and ribavirin with available data on HCV viral load after 12 weeks of therapy and definite data on the results of therapy. RESULTS: Seventy-six (68.5%) out of 111 patients with undetectable HCV-RNA and 4 (11.8%) out of 34 patients with HCV-RNA < or = 2 log10 from baseline at week 12 reached SVR (odds ratio 16.29, 95% CI 5.08-67.12; p < 0.001). Sixty-three patients did not meet any of these criteria and therapy was discontinued. CONCLUSIONS: The "12-week stopping rule" includes two different categories of responders considered candidates for maintained therapy, but the probability of obtaining SVR is very low in patients with HCV-RNA that is still detectable at this time of treatment. We suggest that, in these partial responders, the prolongation of therapy should be decided on an individual basis.