Short versus standard treatment with pegylated interferon alfa-2A plus ribavirin in patients with hepatitis C virus genotype 2 or 3: the cleo trial

<p>Abstract</p> <p>Background</p> <p>In patients with chronic hepatitis C virus (HCV) genotype 2 or 3, 24 weeks' treatment with pegylated interferon alfa (PEG-IFN-alpha) and ribavirin induces a sustained virological response (SVR) in almost 80% of cases. Evidence suggests that a similar response rate may be obtained with shorter treatment periods, especially in patients with a rapid virological response (RVR). The aim of this study was to compare the efficacy of 12 or 24 weeks of treatment in patients with chronic HCV genotype 2 or 3 and to identify patients suitable for 12 weeks treatment.</p> <p>Methods</p> <p>Two hundred and ten patients received PEG-IFN-alpha-2a (180 ug/week) and ribavirin (800-1200 mg/day) for 4 weeks. Patients with a RVR (HCV RNA not detectable) were randomized (1:1) to either 12 (group A1) or 24 (group A2) weeks of combination therapy. Patients without a RVR continued with 24-weeks' combination therapy (group B). HCV RNA was monitored at weeks 4, 8, 12, and 24, and at week 24 post-treatment.</p> <p>Results</p> <p>At study end, end of treatment response (ETR) was observed in 62 (86%) patients of group A1 and in 55 (77%) patients of group A2 (p < 0.05) Relapse rate was 3% each in groups A1 and A2, and 6% in group B. Among patients with a HCVRNA test 24 weeks after the end of treatment, SVR was observed in 60 (83%) of group A1 patients and in 53 (75%) of group A2 patients. Rapid virological response, low baseline HCV RNA levels, elevated alanine aminotransferase levels and low fibrosis score, were the strongest covariates associated with SVR, independent of HCV genotype. No baseline characteristic was associated with relapse.</p> <p>Conclusion</p> <p>In HCV patients with genotype 2 or 3, 12-week combination therapy is as efficacious as 24-week therapy and several independent covariates were predictive of SVR.</p> <p>Trial registration</p> <p>Trial number ISRCTN29259563</p

Long term nucleotide and nucleoside analogs treatment in chronic hepatitis B HBeAg negative genotype D patients and risk for hepatocellular carcinoma

Background and rationale of the study. Effect of Long-term nucleoside/nucleotide (NUC) on hepatocellular carcinoma (HCC) incidence in a population of HBeAg-negative genotype D patients has not been adequately studied in real-life cohorts. Our aim was to evaluate the impact of liver fibrosis and other variables on HCC incidence in this population of patients. Of 745 patients with chronic hepatitis B (CHB), 306 HBeAg-negative genotype D were selected and included in this study. All patients received treatment with NUC for at least 18 months. Patients with CHB or compensated cirrhosis were included. Patients with HCC diagnosed before or during the first 18 months of NUC therapy were excluded. Results. HCC was diagnosed in 2 CHB patients (1.0%) and 23 cirrhosis patients (20%) (OR = 24.41, 95% CI 5.40 < OR < 153.2; p < 0.0001). Multivariate analysis revealed that HCC risk was independently associated with age ≥ 60 years (OR = 6.45, 95% CI 1.22 to 34.0; p = 0.02) and liver cirrhosis (OR = 12.1, 95% CI 1.39 to 106.2; p = 0.02), but not with virological response (VR), and previous resistance to NUC, or rescue therapy. Multivariate analysis in cirrhosis patients revealed that only age ≥ 60 years was an independent risk factor associated with HCC (p = 0.003). Conclusions. Liver cirrhosis and age ≥ 60 years are the stronger risk factors for HCC in genotype D HBeAgnegative patients. Previous resistance to NUC in patients that achieved a VR after rescue therapy was not a predictive factor regarding HCC. VR does not appear to significantly reduce the overall incidence of HCC when a patient has already progressed to liver cirrhosis

DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

Background: A minority of patients fails to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens . Methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018 . The geno2pheno system and Sorbo MC et al. Drug Resistance Updates 2018 were used to infer HCV- genotype/subtype and predict drug resistance . The changes in prevalence of RASs over time were evaluated by chi-square test for trend, predictors of RASs at failure were analysed by logistic regression . Results: We included 386 HCV infected patients: 75% males, median age was 56 years (IQR 52-61), metavir fibrosis stage F4 in 76%; 106 (28%) were treatment- experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAAs. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype was 1b in 122 pts (32%), 3 in 109 (28%), 1a in 97 (25%), 4 in 37 (10%), 2 in 21 (5%). DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%) . The NS5A fasta-sequence was available for all patients, NS5B for 361 (94%), NS3 for 365 (95%) . According to the DAA failed the prevalence of any RASs was 90%, namely 80/135 (59%) in NS3, 313/359 (87%) in NS5A, 114/286 (40%) in NS5B . The prevalence of any RASs significantly declined from 2015 to 2018 (93% vs 70%, p=0.004): NS5A RASs from 90% to 72% (p=0 .29), NS3 RASs from 74% to 18% (p&lt;0 .001), while NS5B RASs remained stable . Independent predictors of any RASs included advanced fibrosis (AOR 6.1, CI 95% 1.8-20.3, p=0 .004) and genotype (G2 vs G1a AOR 0 .03, CI 95% 0 .002- 0 .31, p=0 .004; G3 vs G1a AOR 0 .08, CI 95% 0 .01-0 .62, p=0 .02; G4 vs G1a AOR 0 .05, CI 95% 0 .006-0 .46, p=0 .008), after adjusting for age, previous HCV treatment and year of genotype . Notably, full activity was predicted for GLE/PIB in 75% of cases and for at least two components of VEL/SOF/VOX in 53% of cases, no case with full-resistance to either regimen was found . Conclusion: Despite decreasing prevalence over the years, RASs remain common at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. The identification of RASs after failure could play a crucial role in optimizing retreatment strategies

Sarcopenia predicts reduced survival in patients with hepatocellular carcinoma at first diagnosis.

Abstract: Background. Sarcopenia is a complication and independent risk factor for mortality in patients with liver cirrhosis. Aim. To assess the prevalence and influence of sarcopenia on overall survival in a cohort of cirrhotic patients with hepatocellular carcinoma managed in a tertiary center. Material and methods. Abdominal computed tomography of 92 consecutive hepatocellular carcinoma cirrhotic patients, enrolled and followed from 2004 to 2014, were retrospectively studied with a software analyzing the cross-sectional areas of muscles at third lumbar vertebra level. Data was normalized for height, skeletal muscle index (SMI) calculated and presence of Sarcopenia measured. Sarcopenia was defined by SMI ≤ 41 cm2/m2 for women and ≤ 53 cm2/m2 for men with body mass index (BMI) ≥ 25, and ≤ 43 cm2/m2 for men and women with BMI < 25, respectively. Results. Median age at diagnosis was 71.9 years (30.7-86.4) and BMI 24.7 (17.5-36.7), comparable in women 23.1, (17.5-36.7) and men 24.7 (18.4-36.7). A class of CHILD score and BCLC A prevailed (55.4% and 41.3%, respectively); metastatic disease was found in 12% of cases. Sarcopenia was present in 40.2% of cases, mostly in females (62.9%; p = 0.005). Mean overall survival was reduced in sarcopenic patients, 66 (95% CI 47 to 84) vs. 123 (95% CI 98 to 150) weeks (p = 0.001). At multivariate analysis, sarcopenia was a predictor of reduced overall survival, independent of age (p = 0.0027). Conclusions. This retrospective study shows high prevalence of sarcopenia among cirrhotic patients with hepatocellular carcinoma. Presence of sarcopenia was identified as independent predictor of reduced overall survival. As easily measurable by CT, sarcopenia should be determined for prognostic purposes in this patient population

Cholestatic hepatitis C after chemotherapy containing rituximab in diffuse large B cell lymphoma

Rituximab is a chimeric anti-CD20 monoclonal antibody that is a widely used for the treatment of B cells non-Hodgkin lymphoma. The use of chemotherapy regimens containing rituximab in HCV-positive patients with non-Hodgkin lymphoma has been associated with liver dysfunction, but no cases of cholestatic hepatitis C were described. To our knowledge, this is the first case of cholestatic hepatitis C in an HCV-positive patient with diffuse large B-cell lymphoma describes in the literature. We discuss the pathogenetic mechanisms underlying this severe form of hepatitis and describe its evolution after antiviral treatment

Combining Genetic Variants to Improve Risk Prediction for NAFLD and Its Progression to Cirrhosis: A Proof of Concept Study

Background & Aims. Identifying NAFLD patients at risk of progression is crucial to orient medical care and resources. We aimed to verify if the effects determined by different single nucleotide polymorphisms (SNPs) could add up to multiply the risk of NAFLD and NASH-cirrhosis. Methods. Three study populations, that is, patients diagnosed with NASH-cirrhosis or with noncirrhotic NAFLD and healthy controls, were enrolled. PNPLA3 rs738409, TM6SF2 rs58542926, KLF6 rs3750861, SOD2 rs4880, and LPIN1 rs13412852 were genotyped. Results. One hundred and seven NASH-cirrhotics, 93 noncirrhotic NAFLD, and 90 controls were enrolled. At least one difference in allele frequency between groups was significant, or nearly significant, for the PNPLA3, TM6SF2, and KLF6 variants (p<0.001, p<0.05, and p=0.06, resp.), and a risk score based on these SNPs was generated. No differences were observed for SOD2 and LPIN1 SNPs. When compared to a score of 0, a score of 1-2 quadrupled, and a score of 3-4 increased 20-fold the risk of noncirrhotic NAFLD; a score of 3-4 quadrupled the risk of NASH-cirrhosis. Conclusions. The effects determined by disease-associated variants at different loci can add up to multiply the risk of NAFLD and NASH-cirrhosis. Combining different disease-associated variants may represent the way for genetics to keep strength in NAFLD diagnostics

HCV genotype 1a shows a better virological response to antiviral therapy than HCV genotype 1b

Background: The impact of viral subtype on the rate of sustained virological response (SVR) to antiviral therapy in patients chronically infected with hepatitis C genotype 1 subtype 1a and 1b has not been extensively investigated. The aim of this study is to determine whether the HCV genotype 1 subtypes 1a and 1b respond differently to treatment with PEGylated interferon (PEG-IFN) plus ribavirin. Methods: For 48 weeks, 388 "naive" genotype 1 patients were treated weekly with PEG-IFN a-2a or PEG-INF a-2b combined with daily ribavirin (1000-1200 mg/day). The numbers of patients in whom HCV-RNA was undetectable were compared after 4 (rapid virological response, RVR), 12 (early virological response, EVR), and 48 (end treatment virological response, ETR) weeks of treatment as well as 24 weeks after the last treatment (sustained virological response, SVR). Results: The rate of SVR was higher in subtype 1a patients than subtype 1b patients (55% vs. 43%; p < 0.02). Multiple logistic regression analysis showed that infection with genotype 1a (odds ratio(OR) : 1.8; 95% confidence interval (CI): 1.4 to 4.1), age < 50 years (OR: 7.0; 95% CI 1.1 to 21.2), alanine aminotransferase level (ALT)<100 IU/ml (OR:2.1; 95% CI: 1.3 to3.5), HCV-RNA < 5.6 log(10) IU/ml (OR: 3.2; 95% CI: 2.7 to 6.9) and fibrosis score < S3 (OR: 3.8; 95% CI: 3.2 to 7.4), were all independent predictors of SVR. Conclusion: Dual antiviral therapy is more effective against HCV subtype 1a than against subtype 1b and this difference is independent of other factors that may favour viral clearance