Development and Validation of a Scoring System to Predict Response to Obeticholic Acid in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. METHODS: We used data from the Italian RECAPITULATE (N = 441) and the IBER-PBC (N = 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS) or also after 6 months of treatment (ORS+). Multivariable Cox regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (alkaline phosphatase [ALP]/upper limit of normal [ULN]<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or Normal range criteria (NR: normal ALP, alanine aminotransferase [ALT], and bilirubin) up to 24 months. RESULTS: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN, and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were 0.75, 0.78, and 0.72 for POISE, ALP/ULN<1.67, and NR response, which raised to 0.83, 0.88, and 0.81 with ORS+, respectively. The respective performances in validation were 0.70, 0.72, and 0.71 for ORS and 0.80, 0.84, and 0.78 for ORS+. Results were consistent across groups with mild/severe disease. CONCLUSIONS: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC.

Safety and efficacy of venous thromboembolism prophylaxis in patients with cirrhosis: A systematic review and meta-analysis.

BACKGROUND & AIMS: Patients with cirrhosis are considered in a haemostatic balance, though weaker than in normal subjects. In these patients, however, the use of pharmacological prophylaxis for venous thromboembolism (VTE) remains controversial. Therefore, in this study, we aimed to assess the safety and efficacy of VTE prophylaxis in patients with cirrhosis. METHODS: We conducted a systematic review of studies reporting the occurrence of bleeding and VTE events in patients with cirrhosis, and controls, undergoing VTE prophylaxis. Meta-regression analysis was conducted to further explore the determinants of heterogeneity in the study of the occurrence of either bleeding or VTE events. RESULTS: In a total of 10 studies, including 5712 patients, of which 2330 undergoing VTE prophylaxis, bleeding (n = 5513) and VTE events occurred in 8.2% and 2.8% patients respectively. A total of 2963 and 3162 patients were included from low-risk of bias studies in bleeding and VTE analysis respectively: while administration of VTE prophylaxis did not seem to reduce VTE (OR = 1.07, CI 0.39-2.96, p = .89), importantly prophylaxis was not associated with increased bleeding risk (OR = 0.56, CI 0.20-1.59, p = .27). Meta-regression analysis showed that no parameter significantly influenced the heterogeneity of data regarding bleeding or VTE events. CONCLUSIONS: In patients with cirrhosis, current evidence is insufficient to advise for or against the use of VTE prophylaxis, mainly due to lack of quality and homogeneity of available data. However, its use does not appear to be associated with a significant bleeding risk. Adequately designed studies are required to provide a measure of its overall utility.

Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach.

BACKGROUND AND AIMS: Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Noninvasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis (AF) at disease presentation in PBC. APPROACH AND RESULTS: We collected data from 167 consecutive treatment-naïve PBC patients who underwent liver biopsy (LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to the Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for AF (Ludwig stage ≥III). Effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. The derivation cohort consisted of 126 patients with valid LSM and LB; VCTE identified patients with AF with an AUROC of 0.89. LSM cutoffs ≤6.5 and >11.0 kPa enabled to exclude and confirm, respectively, AF (negative predictive value [NPV] = 0.94; positive predictive value [PPV] = 0.89; error rate = 5.6%). These values were externally validated in an independent cohort of 91 PBC patients (NPV = 0.93; PPV = 0.89; error rate = 8.6%). Multivariable analysis found that the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. CONCLUSIONS: In a multicenter study of treatment-naïve PBC patients, we identified two cutoffs (LSM ≤6.5 and >11.0 kPa) able to discriminate at diagnosis the absence or presence, respectively, of AF in PBC patients, with external validation. In patients with LSM between these two cutoffs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid.

BACKGROUND & AIMS: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. METHODS: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. CONCLUSIONS: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir.

BACKGROUND AND AIMS: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. METHODS: A total of 103 TDF-treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD ) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter. RESULTS: During 46 (4-115) months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFRMDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P = 0.018). CONCLUSIONS: Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment.

Safety and Efficacy of Atezolizumab/Bevacizumab in Patients with Hepatocellular Carcinoma and Impaired Liver Function: A Systematic Review and Meta-Analysis.

Background: Safety and outcome of atezolizumab/bevacizumab in Child-Pugh B patients with hepatocellular carcinoma (HCC) have not been completely characterized. Objectives: In this study, we aimed at addressing safety and efficacy of atezolizumab/bevacizumab in Child-Pugh B patients by reviewing the available data and analyzing them by meta-analysis. Methods: We compared the safety and efficacy of atezolizumab/becavizumab treatment in patients with unresectable HCC and various degrees of liver dysfunction. A total of 8 retrospective, non-randomized, cohort studies were included in this meta-analysis, for a total of 1,071 Child-Pugh A and 225 Child-Pugh B patients. The albumin-bilirubin (ALBI) grade was also used to assess liver function, when available. Results: Grade ≥3 adverse events were observed in 11.8% of Child-Pugh class A and 26.8% class B patients (p = 0.0001), with an odds ratio (OR) of 0.43 (confidence interval [CI] 0.21-0.90; p = 0.02). Progression-free survival (PFS) at both 6 months (4.90 ± 2.08 vs. 4.75 ± 2.08 months; p = 0.0004) and 12 months (8.83 ± 2.32 vs. 7.26 ± 2.33 months; p = 0.002) was lower in Child-Pugh class B patients. A trend toward a higher objective response rate (ORR) was observed in Child-Pugh class A patients (219/856, 25.6%) as compared to Child-Pugh class B patients (25/138, 18.1%; p = 0.070), while the probability of obtaining an ORR was significantly greater in Child-Pugh A patients (OR 1.79, CI 1.12-2.86; p = 0.02). Median overall survival (OS) was 16.8 ± 2.0 and 6.8 ± 3.2 months in Child-Pugh A and B patients, respectively (mean difference 9.06 months, CI 7.01-11.1, p < 0.0001). Lastly, OS was longer in patients with ALBI grades 1-2 than in those with grade 3 (8.3 ± 11.4 vs. 3.3 ± 5.0 months, p = 0.0008). Conclusions: Oncological efficacy of atezolizumab/bevacizumab is moderate in Child-Pugh class B patients, and the shorter PFS and OS associated with the greater likelihood of experiencing treatment-related adverse events observed in these patients suggest great caution and individualization of treatment, possibly with the support of the ALBI grade.

Excellent outcome in patients with primary biliary cholangitis in Northwest Italy followed up for up to 30†years.

OBJECTIVE: Primary biliary cholangitis (PBC) is a rare chronic autoimmune cholangiopathy, characterized by a variable course and response to treatment. We aimed to describe long-term outcomes of PBC patients referred to three academic centres in Northwest Italy. METHODS: This is an ambispective cohort study of PBC patients (retrospective component: diagnosis before 1 January 2019; prospective component: thereafter), including 302 patients: 101 (33%) followed up in Novara, 86 (28%) in Turin, 115 (38%) in Genoa. Clinical features at diagnosis, biochemical response to therapy and survival were analyzed. RESULTS: Among the 302 patients (88% women, median age 55 years, median follow-up 75 months), alkaline phosphatase (ALP) levels significantly decreased during treatment with ursodeoxycholic acid (UDCA, P < 0.0001) and obeticholic acid (P < 0.0001). At multivariate analysis, ALP at diagnosis was predictive of 1-year biochemical response to UDCA [odds ratio 3.57, 95% confidence interval (CI) 1.4-9, P < 0.001]. Estimated median survival free of liver transplantation and hepatic complications was 30 years (95% CI 19-41). Bilirubin level at diagnosis was the only independent risk factor for the combined outcome of death, transplantation or hepatic decompensation (hazard ratio, 1.65, 95% CI 1.66-2.56, P = 0.02). Patients presenting with total bilirubin at diagnosis ≥0.6 times the upper normal limit (ULN) had a significantly lower 10-year survival compared to those with bilirubin <0.6 times ULN (63% vs. 97%, P < 0.0001). CONCLUSION: In PBC, both short-term response to UDCA and long-term survival can be predicted by simple conventional biomarkers of disease severity, obtained at diagnosis.

Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study.

Introduction: Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE. Methods: We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT). Results: During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01-1.06), HE (HR 1.67, 95% CI 1.08-2.56), ascites (HR 2.56, 95% CI 1.55-4.23), and sodium levels (HR 0.94, 95% CI 0.90-0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39-18.49) and BMI (HR 0.86, 95% CI 0.75-0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission. Conclusion: In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.

Effect of contrast-enhanced ultrasound (CEUS) on liver stiffness measurements obtained by transient and shear-wave elastography.

BACKGROUND: Since liver fibrosis is one of the most accurate predictors of prognosis in hepatopatic patients, its accurate assessment and staging is a major public health issue. Transient elastography (TE) (Fibroscan, Echosens, Paris, France) and shear wave elastography (SWE) represent the gold standard techniques among non-invasive methods to assess liver fibrosis. Contrast-enhanced ultrasound (CEUS) is increasingly used to diagnose the nature of liver lesions and is often performed together with TE and SWE. In this study we evaluated the effect of CEUS on liver stiffness measurements obtained by TE and SWE. METHODS: A retrospective analysis of ultrasound (US) exams performed by an expert operator was carried out. TE and SWE were performed 30 seconds before and after the execution of CEUS. Statistical analysis was carried out using the statistical software R. Kolmogorov-Smirnov analysis was performed to test the normality of continuous variables. The pre- and post-CEUS liver stiffness values were compared using the Wilcoxon's Test. RESULTS: Ninety-six patients were enrolled. While the measurements were comparable when performed with TE, those obtained by SWE decreased by 6% after administration of the contrast agent (P=0.0005). Fibrosis stage deviated between pre- and post-CEUS in 16 (17%) patients with Fibroscan and 22 (23%) patients with SWE. Among the latter, in 9 cases (10%) a deviation from absent-low (F0-F2) to high-fibrosis (F3, F4), or vice versa, occurred. CONCLUSIONS: Our study, the first to assess the effects of CEUS on US elastography, shows that the contrast agent (Sonovue, Bracco Suisse SA, Cadempino, Switzerland) does not significantly affect liver stiffness measurements obtained by TE, whereas the accuracy decreases when performed by SWE.

Primary biliary cholangitis: perception and expectation of illness.

An important tool to explore personal experience of symptoms, treatment and clinical outcome is stratification of illness perception in patients affected by PBC. AIM: To assess the perception of illness in a cohort of Italian patients with PBC. METHODS: Between June and December 2019, a specific questionnaire was administered to a pool of 210 patients from 7 tertiary Italian centers, in order to identify and assess the patient's past history, symptoms and their impact on the quality of life, follow-up, treatment and perceived satisfaction of patients toward the provided care. RESULTS: Fatigue, pruritus, and abdominal discomfort and sicca syndrome were present in 50.4%, 45%, 30.4% and 28.5% of patients, fatigue having the most impacting the daily-life. After a consultation with a specialist, the diagnosis of PBC was met within 18 months for 143 patients. Patients were mostly concerned about possible health problems that occur and in 25% of cases, symptoms had a negative impact on their life. Eighty percent of patients said they were satisfied with efficacy and tolerability of treatment, while 26% requested an improvement in the relationship with the specialist. CONCLUSIONS: The results highlight the importance of both promoting timely referral to the specialist and facilitating communication between healthcare professionals and patients.

Characteristics and survival of patients with primary biliary cholangitis and hepatocellular carcinoma.

BACKGROUND: Comprehensive and contemporary data pertaining large populations of patients with Primary Biliary Cholangitis (PBC) and hepatocellular carcinoma (HCC) are missing. AIM: To describe main characteristics and outcome of PBC patients with HCC diagnosed in the new millennium. METHODS: Analysing the Italian Liver Cancer registry we identified 80 PBC patients with HCC diagnosed after the year 2000, and described their clinical characteristics, access to treatment and survival. RESULTS: Median age of patients was 71 years and 50.0% were males. Cirrhosis was present in 86.3% of patients, being well-compensated in 58.0%. Median HCC diameter was smaller in patients under surveillance (2.6 vs 4.0 cm, P = 0.007). Curative treatment, feasible in 50.0% of patients, was associated with improved survival compared to palliative and supportive care (42 vs 33 vs 6 months, P<0.0001). Surveillance was associated with a non-significant improved survival (36 vs 23 months), likely due to similar rate of curative treatment in patients under (51.4%) and outside surveillance (42.6%). CONCLUSIONS: PBC patients with HCC are often elderly males with well-preserved liver function. Feasibility of curative treatment is high and associated with improved prognosis. Description of these patients may help focus surveillance to identify earlier tumours, increase their curability, and improve prognosis.

Hepatic Elastometry and Glissonian Line in the Assessment of Liver Fibrosis.

The aim of this study was to identify a method for staging hepatic fibrosis using a non-invasive, rapid and inexpensive technique based on ultrasound morphologic hepatic features. A total of 215 patients with different liver diseases underwent B-mode (2-D brightness mode) ultrasonography, vibration-controlled transient elastography, 2-D shear wave elastography and measurement of the controlled attenuation parameter with transient elastography. B-Mode images of the anterior margin of the left lobe were obtained and processed with automatic Genoa Line Quantification (GLQ) software based on a neural network for staging liver fibrosis. The accuracy of GLQ was 90.6% during model training and 78.9% in 38 different patients with concordant elastometric measures. Receiver operating characteristic curve analysis of GLQ performance using vibration-controlled transient elastography as a reference yielded areas under the curves of 0.851 for F ≥ F1, 0.793 for F ≥ F2, 0.784 for F ≥ F3 and 0.789 for F ≥ F4. GLQ has the potential to be a rapid, easy-to-perform and tolerable method in the staging of liver fibrosis.

Effect of a common missense variant in LIPA gene on fatty liver disease and lipid phenotype: New perspectives from a single-center observational study.

Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive disease characterized by hypoalphalipoproteinemia, mixed hyperlipemia, and fatty liver (FL) due to mutations in LIPAse A, lysosomal acid type (LIPA) gene. The rs1051338 single-nucleotide polymorphism (SNP) in LIPA gene, in vitro, could adversely affect the LAL activity (LAL-A). Nonalcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome, and the diagnosis requires the exclusion of excess of alcohol intake and other causes of hepatic disease. The aim of the study was to evaluate the impact of rs1051338 rare allele on lipid phenotype, severity of FL, and LAL-A in patients suffering from dyslipidemia associated with NAFLD. We selected 74 subjects with hypoalphalipoproteinemia or mixed hyperlipemia and evaluated transaminases, liver assessment with controlled attenuation parameter (CAP), LAL-A, rs1051338 SNP genotype. The presence of rare allele caused higher levels of triglycerides and hepatic transaminase and lower levels of high-density lipoprotein cholesterol (HDL-C). Multivariate analysis highlighted independent association between rare allele and FL severity in subjects with NAFLD. The rs1051338 SNP may modulate FL severity and atherogenic dyslipidemia in patients suffering from NAFLD.

Concomitant therapy with direct-acting antivirals and chemoimmunotherapy in HCV-associated diffuse large B-cell lymphoma.

INTRODUCTION: The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin's Lymphomas (NHL) is well established. Antiviral therapy (AVT) is the first-line treatment for HCV-related indolent NHL whereas diffuse large B-cell lymphoma (DLBCL) requires immediate start of chemoimmunotherapy (CIT), usually deferring AVT. However, an early HCV elimination may reduce the risk of CIT-induced liver toxicity and consequent CIT interruption or withdrawal. To date few data are available on safety and efficacy of concomitant administration of direct-acting antivirals (DAA) and CIT in HCV-associated DLBCL. METHODS: 7 consecutive patients (5 males, median age 65 years) with HCV infection (four genotype 2a/2c, two genotype 1b, one genotype 4; one patient with compensated cirrhosis) and DLBCL received different DAA regimens concurrently with CIT. RESULTS: All patients completed the scheduled AVT and CIT with neither interruption nor withdrawal of the latter. One case of neutropenia was observed during concomitant therapy, no liver toxicity occurred. All patients achieved sustained virological response and complete DLBCL response (median follow-up of 12 months). CONCLUSIONS: Concomitant administration of DAA and CIT for HCV-associated DLBCL is safe and may prevent CIT-induced liver toxicity. Large, prospective studies are needed to confirm these preliminary data and to assess prognostic implications.

Lamivudine prophylaxis prevents hepatitis B virus reactivation in anti-HBc positive patients under rituximab for non-Hodgkin lymphoma.

BACKGOUND: A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation. AIMS: We wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication. METHODS: Eighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV. RESULTS: During 39 (2-108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression. CONCLUSION: LMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT.

HOMA, BMI, and Serum Leptin Levels Variations during Antiviral Treatment Suggest Virus-Related Insulin Resistance in Noncirrhotic, Nonobese, and Nondiabetic Chronic Hepatitis C Genotype 1 Patients.

Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.