Luchino Chessa

Early changes in hepatitis C viral quasispecies during interferon therapy predict the therapeutic outcome

Despite recent treatment advances, the majority of patients with chronic hepatitis C fail to respond to antiviral therapy. Although the genetic basis for this resistance is unknown, accumulated evidence suggests that changes in the heterogeneous viral population (quasispecies) may be an important determinant of viral persistence and response to therapy. Sequences within hepatitis C virus (HCV) envelope 1 and envelope 2 genes, inclusive of the hypervariable region 1, were analyzed in parallel with the level of viral replication in serial serum samples obtained from 23 patients who exhibited different patterns of response to therapy and from untreated controls. Our study provides evidence that although the viral diversity before treatment does not predict the response to treatment, the early emergence and dominance of a single viral variant distinguishes patients who will have a sustained therapeutic response from those who subsequently will experience a breakthrough or relapse. A dramatic reduction in genetic diversity leading to an increasingly homogeneous viral population was a consistent feature associated with viral clearance in sustained responders and was independent of HCV genotype. The persistence of variants present before treatment in patients who fail to respond or who experience a breakthrough during therapy strongly suggests the preexistence of viral strains with inherent resistance to IFN. Thus, the study of the evolution of the HCV quasispecies provides prognostic information as early as the first 2 weeks after starting therapy and opens perspectives for elucidating the mechanisms of treatment failure in chronic hepatitis C.

Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy

BackgroundMood and anxiety symptoms in chronic hepatitis C (CHC) may be related to the patient awareness of the diagnosis and prognosis, to side effects induced by interferon (IFN)-alpha treatment, as well as to substance abuse. However, the observation of metabolic alterations in patients with CHC has led to hypothesize a direct effect of hepatitis C virus (HCV) on brain function. This study was aimed at elucidating whether CHC is associated with specific anxiety or mood disorders independently of confounding factors.MethodsPatient cohort: consecutive patients, 135 with CHC and 76 with chronic hepatitis B (CHB). Exclusion criteria: previous treatment with IFN-alpha, co-infection with HCV and hepatitis B virus, infection with human immunodeficiency virus, drug or alcohol abuse, or malignancies. Controls: subjects without evidence of hepatitis randomly extracted from the database of a previous epidemiological study; they were divided into two groups of 540 (332 males) and 304 (220 males) as controls for patients with CHC and CHB, respectively. The psychiatric diagnosis was formulated by means of the Composite International Diagnostic Interview Simplified carried out by a physician according to DSM-IV criteria.ResultsA higher lifetime prevalence of major depressive disorder (MDD) was observed among CHC compared to CHB or controls. The risk of MDD was not statistically different between CHB and controls. Both the CHC and CHB groups showed a significantly higher frequency of panic disorder when compared to controls. No statistical differences were observed in the prevalence of general anxiety disorder and social phobia when CHC or CHB were compared to controls.ConclusionThe present study provides the first evidence of an association between CHC and MDD, diagnosed on the basis of well-defined international criteria. This association is independent of treatment with IFN-alpha and is not influenced by substance or alcohol abuse. By contrast, anxiety disorders do not appear to be specifically associated with CHC.

Treatment of chronic hepatitis D.

Summary.  Despite recent advances in the treatment of chronic viral hepatitis, therapy of chronic hepatitis D is not yet satisfactory. The only option currently available is interferon‐α (IFN), whose efficacy is related to the dose and duration of treatment. However, the rate of sustained hepatitis D virus (HDV) clearance after a 1‐year course with high doses of standard IFN is low. Better results have recently been reported with pegylated IFN both in IFN‐naïve and in previous nonresponders to standard IFN, suggesting the use of pegylated IFN as a first‐line therapy in chronic hepatitis D. Nucleoside analogues that inhibit hepatitis B virus (HBV) are ineffective against HDV and combination therapy with lamivudine or ribavirin has not shown significant advantages over monotherapy with either standard or pegylated IFN. Because the ultimate goal of treatment is eradication of both HDV and HBV, in responders IFN therapy should be continued as long as possible until the loss of hepatitis B surface antigen, adjusting the dose to patient tolerance. However, because side‐effects are common, continuous monitoring is mandatory. Although the first results obtained with pegylated IFN have been encouraging, the rate of sustained virological response is still low and the rate of relapse high, emphasizing the need for developing novel classes of antivirals specifically interfering with the life cycle of this unique virus.

Association of chronic hepatitis C with recurrent brief depression

BACKGROUND Depressive syndromes, including recurrent brief depression (RBD), have frequently been observed in association with chronic diseases characterized by immune activation, such as autoimmune thyroiditis or celiac disease. However, the association of RBD with chronic hepatitis C (CHC), a disease with an increased incidence of major depressive disorders, is unknown. METHODS CASES 135 (83 males, 52 females) consecutive treatment-naïve patients with CHC. EXCLUSION CRITERIA previous treatment with IFN-alpha, co-infection with hepatitis C virus (HCV) and hepatitis B virus, infection with human immunodeficiency virus (HIV), drug or alcohol abuse, or malignancy. CONTROLS 540 (332 males, 208 females) subjects without evidence of hepatitis, randomly extracted from the database of a previous epidemiological study. The psychiatric diagnosis was based on the Composite International Diagnostic Interview Simplified (CIDI-S), containing a specific section on RBD. RESULTS A significantly higher rate of RBD was observed among both male and female patients with CHC (n=21, 15.5%) as compared to controls (n=34, 6.3%) (OR=2.6, CI 95% from 1.37 to 4.93). CONCLUSION The present study provides the first evidence of an association between CHC and RBD, independent of treatment with IFN-alpha and not influenced by substance or alcohol abuse. The results are similar to those found in other conditions with immune activation. RBD may be another expression of mood disorders in such conditions.

Incidence of DAA failure and the clinical impact of retreatment in real-life patients treated in the advanced stage of liver disease: Interim evaluations from the PITER network

Background Few data are available on the virological and clinical outcomes of advanced liver disease patients retreated after first-line DAA failure. Aim To evaluate DAA failure incidence and the retreatment clinical impact in patients treated in the advanced liver disease stage. Methods Data on HCV genotype, liver disease severity, and first and second line DAA regimens were prospectively collected in consecutive patients who reached the 12-week post-treatment and retreatment evaluations from January 2015 to December 2016 in 23 of the PITER network centers. Results Among 3,830 patients with advanced fibrosis (F3) or cirrhosis, 139 (3.6%) failed to achieve SVR. Genotype 3, bilirubin levels >1.5mg/dl, platelet count <120,000/mm3 and the sofosbuvir+ribavirin regimen were independent predictors of failure by logistic regression analysis. The failure rate was 7.6% for patients treated with regimens that are no longer recommended or considered suboptimal (sofosbuvir+ribavirin or simeprevir+sofosbuvir±ribavirin), whereas 1.4% for regimens containing sofosbuvir combined with daclatasvir or ledipasvir or other DAAs. Of the patients who failed to achieve SVR, 72 (51.8%) were retreated with a second DAA regimen, specifically 38 (52.7%) with sofosbuvir+daclatasvir, 27 (37.5%) with sofosbuvir+ledipasvir, and 7 (9.7%) with other DAAs ±ribavirin. Among these, 69 (96%) patients achieved SVR12 and 3 (4%) failed. During a median time of 6 months (range: 5–14 months) between failure and the second DAA therapy, the Child-Pugh class worsened in 12 (16.7%) patients: from A to B in 10 patients (19.6%) and from B to C in 2 patients (10.5%), whereas it did not change in the remaining 60 patients. Following the retreatment SVR12 (median time of 6 months; range: 3–12 months), the Child-Pugh class improved in 17 (23.6%) patients: from B to A in 14 (19.4%) patients, from C to A in 1 patient (1.4%) and from C to B in 2 (2.9%) patients; it remained unchanged in 53 patients (73.6%) and worsened in 2 (2.8%) patients. Of patients who were retreated, 3 (4%) had undergone OLT before retreatment (all reached SVR12 following retreatment) and 2 (2.8%) underwent OLT after having achieved retreatment SVR12. Two (70%) of the 3 patients who failed to achieve SVR12 after retreatment, and 2 (2.8%) of the 69 patients who achieved retreatment SVR12 died from liver failure (Child-Pugh class deteriorated from B to C) or HCC complications. Conclusions Failure rate following the first DAA regimen in patients with advanced disease is similar to or lower than that reported in clinical trials, although the majority of patients were treated with suboptimal regimens. Interim findings showed that worsening of liver function after failure, in terms of Child Pugh class deterioration, was improved by successful retreatment in about one third of retreated patients within a short follow-up period; however, in some advanced liver disease patients, clinical outcomes (Child Pugh class, HCC development, liver failure and death) were independent of viral eradication.

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis

Background Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses. Methods and Findings KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups. Conclusions The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.

Modelling cost-effectiveness and health gains of a "universal" vs. "prioritized" HCV treatment policy in a real-life cohort

We evaluated the cost‐effectiveness of two alternative direct‐acting antiviral (DAA) treatment policies in a real‐life cohort of hepatitis C virus–infected patients: policy 1, “universal,” treat all patients, regardless of fibrosis stage; policy 2, treat only “prioritized” patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virus–infected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policies’ cost‐effectiveness. The patients’ age and fibrosis stage, assumed DAA treatment cost of €15,000/patient, and the Italian liver disease costs were used to evaluate quality‐adjusted life‐years (QALY) and incremental cost‐effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country‐specific health states costs and mean treatment cost of €30,000. For the Italian base‐case analysis, the cost‐effective ICER obtained using policy 1 was €8,775/QALY. ICERs remained cost‐effective in 94%‐97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was €19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0‐F3 post–sustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost‐saving for the base price (€15,000) discounts of at least 75% applied in patients with F0‐F2 fibrosis.

Modeling cost-effectiveness and health gains of a “universal” versus “prioritized” hepatitis C virus treatment policy in a real-life cohort

We evaluated the cost‐effectiveness of two alternative direct‐acting antiviral (DAA) treatment policies in a real‐life cohort of hepatitis C virus–infected patients: policy 1, “universal,” treat all patients, regardless of fibrosis stage; policy 2, treat only “prioritized” patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virus–infected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policies’ cost‐effectiveness. The patients’ age and fibrosis stage, assumed DAA treatment cost of €15,000/patient, and the Italian liver disease costs were used to evaluate quality‐adjusted life‐years (QALY) and incremental cost‐effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country‐specific health states costs and mean treatment cost of €30,000. For the Italian base‐case analysis, the cost‐effective ICER obtained using policy 1 was €8,775/QALY. ICERs remained cost‐effective in 94%‐97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was €19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0‐F3 post–sustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost‐saving for the base price (€15,000) discounts of at least 75% applied in patients with F0‐F2 fibrosis.

Absence of activating killer immunoglobulin-like receptor genes combined with hepatitis C viral genotype is predictive of hepatocellular carcinoma

Killer immunoglobulin-like receptors and their human leukocyte antigen class I ligands have a critical role in natural killer cell response to viral pathogens and tumors. To investigate whether killer immunoglobulin-like receptor genes could influence the chronic course of hepatitis C virus infection and/or progression to hepatocellular carcinoma we retrospectively analyzed a cohort of 228 patients transplanted for hepatitis C virus-induced cirrhotic end stage liver disease, combined or not with hepatocellular carcinoma. We found that patients completely lacking activating killer immunoglobulin-like receptor genes had a high risk of developing hepatocellular carcinoma. Hepatitis C viral genotype and viral load are other risk factors that can influence the course of chronic hepatitis C virus infection. In our study, the risk conferred by hepatitis C viral genotypes was enhanced in patients lacking activating killer immunoglobulin-like receptors. These results point to an important role for activating killer immunoglobulin-like receptors in the control of hepatitis C virus infection and progression to hepatocellular carcinoma. In clinical practice, assessment of killer immunoglobulin-like receptor and hepatitis C viral genotype combinations should allow for more accurate monitoring of patients with chronic hepatitis C virus infection.

HCV–Related Mixed Cryoglobulinemia: Data from Piter, a Nationwide Italian HCV Cohort Study

L.Valenti12, V. Borroni12, S.Pelusi12, D.Ieluzzi13, G.Nardone3, D.Angrisani3, G.Foti 14, S.Pellicano14, A.Ciancio15, G.Taliani16, E.Biliotti16, S.Madonia17, B.Stagno17, A.Alberti6, S.Piovesan6, M.Gonzo6, M.Massari18, F.Rosina19, G.Mazzella7, A.Di Leo20, M.Rendina20, A.Iannone20, A.Contaldo20, C.Ferrari21, E.Negri21, A.Orlandini21, M.Monti22, T.A.Santantonio23, L.Chessa24, E.M.Erne25, E.Castelli25, C.Coppola26, M.Andreoni27, F.Baldelli28, F.Di Candilo28, M.Mondelli29, P.Blanc30, A.Gasbarrini31, G.Verucchi7, V.Donati7, M.Colombo12, M.Borghi12, A.Craxì32, S.Petta32, E.Villa33, O.Patti33, F.P.Russo6, M.Strazzabosco34, S.Vella1, A.L.Zignego22