Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin

Randomised trial of two different daily doses of interferon-α versus classical therapy in treatment-naïve patients with chronic hepatitis C

Objective: To evaluate the efficacy and tolerability of two different daily doses of interferon-α (lymphoblastoid-IFNα-N1, Wellferon®) [IFNα] for 2 months, followed by the same dose on alternate days for up to 1 year, versus administration on alternate days for 1 year. Patients and methods: A non-blind, randomised study of outpatients with chronic hepatitis C at five centres in Sicily, Italy. Ninety-seven consecutive treatment-naïve patients [72 patients with hepatitis C virus (HCV) genotype 1b infection] with histological chronic hepatitis C were included in the study and randomised to receive IFNα subcutaneously: 5 million international units (MIU) daily for 2 months, followed by the same dose on alternate days for up to 1 year (n = 33, group A); 3 MIU for 2 months, followed by the same dose on alternate days for up to 1 year (32, group B); 5 MIU on alternate days for 12 months (32, group C). Adverse effects were monitored through interviews and by clinical and biochemical check-ups at 1-month intervals. Results: There were no significant differences between the three groups with regard to age, gender, HCV genotype distribution, or severity of histological findings. Seven patients dropped out of the study because of severe adverse effects: three from group A, two from group B, and three from group C. Approximately 30% of the 97 patients, equally distributed between the three groups, had a 'flu-like syndrome of mild-to-moderate intensity. Dosage reduction of IFNα from 5 MIU to 3 MIU daily was necessary in two patients in group A during the first month of treatment. Overall, 88 patients completed treatment as scheduled. After the induction phase, HCV was eradicated from the bloodstream in 27 patients (81.8%) from group A versus 15 (46.9%) from group B (p < 0.001) and 15 (46.9%) from group C (p < 0.001). The switch to maintenance dosages caused some infection breakthroughs, with the result that at the end of treatment 16 patients in group A, 12 in group B and 14 in group C had undetectable serum levels of HCV-RNA. After treatment discontinuation, however, five patients in group A, four in group B and six in group C became HCV-RNA positive. Thus, at the end of follow-up, 11 patients in group A, eight in group B and eight in group C had a sustained virological response. Conclusion: The present study shows that induction therapy with 5 MIU of IFNα administered daily for 2 months is well tolerated and that the percentage of patients with viral eradication at the end of this phase is higher than the percentage obtained with traditional therapy. Unfortunately, this good initial response decreases as treatment continues with conventional therapy, thus nullifying the benefits of the induction phase

Decreasing role of HCV and HBV infections as aetiological factors of hepatocellular carcinoma in Italy

BACKGROUND:The epidemiology of hepatocellular carcinoma (HCC) is characterized by a dynamical temporal trend of well-established and emerging risk factors. METHODS:We evaluated the temporal trend of aetiological factors of HCC over the last two decades in Italy. HCC cases were recruited from two previously published national studies in 1996 and in 2008 and HCC cases were also enlisted from two national surveys in 2001 and in 2014 enrolling consecutive subjects with chronic liver disease (CLD) referring to more than 80 liver units scattered all over the country for a 6-month period. RESULTS:Out of the 9997 subjects with CLD recruited in 2001 and the 2408 recruited in 2014, 3.3% and 5.7% (P < 0.001), respectively, had HCC. The temporal trend of HBsAg -/HCV + HCC cases significantly linearly decreased from 71.1% in 1996 to 57.2% in 2014 (P < 0.001). Conversely, that of virus-negative cases significantly linearly increased from 12.1% to 28.3% (P < 0.001). The proportion of HBV-related HCC cases showed a steady low rate, reflecting the reduced endemicity of the infection in Italy. The proportion of HCC with compensated cirrhosis (i.e., Child-Pugh A) linearly increased over time from 55.6% in 1996 to 76.0% in 2014 (P < 0.001) reflecting the growing effectiveness of semi-annual ultrasound surveillance for early detection of HCC. CONCLUSION:In conclusion, with decreasing viral aetiology, an overall decrease in the incidence of HCC might be expected in the future. The proportion of metabolic diseases is conversely increasing being considered as an aetiology. The growing prevalence of metabolic disorders in the general population may further increase

Decreasing role of HCV and HBV infections as aetiological factors of hepatocellular carcinoma in Italy

BACKGROUND:The epidemiology of hepatocellular carcinoma (HCC) is characterized by a dynamical temporal trend of well-established and emerging risk factors. METHODS:We evaluated the temporal trend of aetiological factors of HCC over the last two decades in Italy. HCC cases were recruited from two previously published national studies in 1996 and in 2008 and HCC cases were also enlisted from two national surveys in 2001 and in 2014 enrolling consecutive subjects with chronic liver disease (CLD) referring to more than 80 liver units scattered all over the country for a 6-month period. RESULTS:Out of the 9997 subjects with CLD recruited in 2001 and the 2408 recruited in 2014, 3.3% and 5.7% (P < 0.001), respectively, had HCC. The temporal trend of HBsAg -/HCV + HCC cases significantly linearly decreased from 71.1% in 1996 to 57.2% in 2014 (P < 0.001). Conversely, that of virus-negative cases significantly linearly increased from 12.1% to 28.3% (P < 0.001). The proportion of HBV-related HCC cases showed a steady low rate, reflecting the reduced endemicity of the infection in Italy. The proportion of HCC with compensated cirrhosis (i.e., Child-Pugh A) linearly increased over time from 55.6% in 1996 to 76.0% in 2014 (P < 0.001) reflecting the growing effectiveness of semi-annual ultrasound surveillance for early detection of HCC. CONCLUSION:In conclusion, with decreasing viral aetiology, an overall decrease in the incidence of HCC might be expected in the future. The proportion of metabolic diseases is conversely increasing being considered as an aetiology. The growing prevalence of metabolic disorders in the general population may further increase

Migratory flow and hepatitis delta infection in Italy: A new challenge at the beginning of the third millennium

In Italy, HDV infection endemicity has greatly decreased overtime. Migratory flow may change this scenario as migrants often come from high HDV endemicity areas. Here, we studied characteristics of HDV infection in Italy, particularly addressed to the birth area of subjects. Chronic HBsAg carriers consecutively referring to 9 units in Italy prospectively enrolled for a six-month period in 2019 were tested for anti-HDV by ELISA. Multiple logistic regression analysis was performed to identify anti-HDV positivity independent predictors. A total of 894 HBsAg-positive subjects were enrolled. Of them, 786 (87.9%) were tested for anti-HDV. Anti-HDV overall prevalence was 9.9% (6.4% in Italian natives and 26.4% in non-natives; P&nbsp;&lt;&nbsp;.001). HDV-RNA was checked in 63 (80.8%) of the 78 anti-HDV+ subjects, and 49 (77.8%) tested positive. Compared to non-natives, Italians were more likely males (male/female 1.6 vs 0.6; P&nbsp;&lt;&nbsp;.05) and older (median age 57&nbsp;years vs 46&nbsp;years; P&nbsp;&lt;&nbsp;.05). Multivariate analysis showed that non-natives (OR&nbsp;=&nbsp;6.02; CI 95%&nbsp;=&nbsp;3.06-11.84) and cirrhosis (OR 9.6; CI 95%&nbsp;=&nbsp;5.39-17.30) were independently associated with anti-HDV positivity. A remarkable changing pattern in some characteristics of anti-HDV-positive subjects was observed over 1987-2019: a decreasing male/female ratio, an increasing mean age and proportion of cirrhotic subjects. Anti-HDV prevalence decreased from 7.4% to 6.4% among Italians, increasing from 12.2% to 26.4% among non-natives during 2001-2019. Hence, HDV infection in Italians is further decreasing and mostly affects old people and subjects with advanced disease reflecting a survival effect. Conversely, non-natives are sixfold more likely anti-HDV-positive with an increasing trend. Migratory flow may be a new challenge for HDV infection at the beginning of the third millennium

Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity

Background & Aims Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m2. We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. Methods We performed a retrospective cohort study of 669 consecutive patients with biopsy-proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima-media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m2, and obese was defined as a BMI of 30 kg/m2or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, 102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single-nucleotide polymorphisms. Variables in men and women were analyzed using chi-squared analysis and the MannâWhitney or KruskalâWallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features. Results Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 ± 13 y) had hypertension (P =.001), diabetes (P =.0001), and metabolic syndrome (P =.0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean age, 49 ± 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P =.0001), fibrosis of F2 or higher (17% vs 42%; P =.0001), or carotid plaques (27% vs 39%; P =.03). Patients with lean NAFLD had significantly thinner carotid intima-media (0.74 ± 0.1 mm) than obese or overweight patients with NAFLD (0.84 ± 0.3 mm; P =.0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P =.001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2â106; P =.03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4â4.2; P =.6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher. Conclusions In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms

Gender differences in chronic liver diseases in two cohorts of 2001 and 2014 in Italy

Gender differences in chronic liver disease (CLD) have been partially investigated. To extend the present knowledge, we evaluated 12,263 patients with CLD enrolled in two national surveys (9997 in 2001 and 2557 in 2014)

Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription

Declining prevalence and increasing awareness of HCV infection in Italy: A population-based survey in five metropolitan areas

BACKGROUND: Data on the prevalence of hepatitis C virus (HCV) infection in Italy are outdated and usually derived from studying residents in small towns. METHODS: To assess prevalence of and risk factors for HCV infection among Italian residents in 5 metropolitan areas, subjects ≥20 years of age were randomly selected from the list of the general practitioners' registers in 2015. Anti-HCV was tested by a salivary test; HCV-RNA, HCV genotypes, and ALT were determined in positive individuals. Logistic regression analysis evaluated independent risk factors for HCV. RESULTS: Of the 4907 enrolled subjects, 112 (2.3%) tested anti-HCV positive. The prevalence of HCV increased with age, from 0.2% in subjects born after the year 1984, to 4.2% in those born before the year 1935 (P  70 years, low education level, past use of glass syringes, blood transfusion, intravenous drug use, and cohabitation with an anti-HCV positive subject predicted the HCV positivity. INTERPRETATION: In metropolitan areas in Italy, HCV is prevalent in elderly, reflecting a cohort effect determined by modalities of viral transmission no longer operative. The impact of the infection will further diminish in the years to come due to the natural depletion of the reservoir of the virus. This age pattern and the high proportion of subjects aware of their status do not warrant a policy of screening. Copyright © 2018. Published by Elsevier B.V