E. Degasperi

Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), which is a condition known to influence the progression of liver fibrosis and the response to pegylated interferon (PEG‐IFN)/ribavirin (RBV) therapy. We aimed to assess whether a sustained virological response (SVR) after antiviral therapy prevents the development of IR in the long term. Members of the Milan Safety Tolerability study cohort, who received PEG‐IFNα2a/RBV or PEG‐IFNα2b/RBV, underwent a homeostasis model assessment (HOMA) at the baseline and 24 months after treatment completion. For all patients (n = 431), a liver biopsy sample was scored for grading, staging (Ishak), and steatosis. At the baseline, IR (HOMA value > 2) was detected in 48 patients (12%), and it was associated with body weight (P = 0.03), an HCV load < 0.6 × 106 IU/L (P = 0.006), fibrosis staging ≥ 4 (P = 0.01), and moderate to severe steatosis (P = 0.03). IR did not influence the rates of end‐of‐treatment response (75% versus 69%, P = 0.4), SVR (63% versus 60%, P = 0.8), or relapse (19% versus 24%, P = 0.5). After treatment, IR developed in 49 of the 384 nondiabetic patients (14%). Although the mean baseline and posttreatment HOMA values were similar in SVR patients (1.11 ± 0.8 versus 1.18 ± 1.1, P = 0.25), patients experiencing treatment failure showed a significant increase in the mean HOMA value at the follow‐up visit (1.20 ± 0.85 versus 1.49 ± 1.3, P = 0.007), and there was an increased rate of de novo IR in non‐SVR patients versus SVR patients (17% versus 7%, P = 0.007). According to a logistic regression analysis, treatment failure (odds ratio = 2.81, 95% confidence interval = 1.39‐5.67, P = 0.004) and a 10% body mass index increase (odds ratio = 6.42, 95% confidence interval = 1.69‐24.3, P = 0.006) were significantly associated with the development of de novo IR. Conclusion: In nondiabetic patients with chronic HCV, the achievement of SVR with PEG‐IFN and RBV prevents the development of de novo IR. (HEPATOLOGY 2012;56:1681–1687)

Sofosbuvir for the treatment of chronic hepatitis C: between current evidence and future perspectives

In recent years, clinical research in the field of new treatments for chronic hepatitis C (HCV) has been devoted to developing regimens based on direct-acting antivirals (DAAs), with the goal of increasing treatment efficacy and improving tolerability and safety. This can be achieved by Peginterferon (PegIFN)-free anti-HCV regimens, as PegIFN is responsible for many side effects and limits treatment access due to contraindications in some patient categories. Sofosbuvir (SOF) is the first compound to enter the market with IFN-free combination regimens; it belongs to the nucleotide inhibitors of viral polymerase NS5B and acts as a chain terminator during the HCV replication process, exhibiting pan-genotypic antiviral activity with a high barrier to resistance. Clinical trials in HCV genotype 2/3 patients have demonstrated optimal efficacy in HCV-2, where the combination SOF/ribavirin (Rbv) for 12 weeks resulted in >90% sustained virological response (SVR) rates, while HCV-3 patients with advanced liver fibrosis and previous failure to PegIFN plus Rbv therapy still require individualized and optimized treatment strategies. Historically difficult-to-treat genotypes HCV-1, −4–6 can benefit from reduced duration of PegIFN plus SOF and Rbv, while IFN-free regimens in these patients will be based on SOF in combination with other DAA classes. Due to an optimal tolerability and safety profile with no significant drug-to-drug interactions, SOF is currently undergoing clinical trials in the setting of pre- and post-liver transplantation and HIV-coinfected patients, with the objective to address the until now unmet need for safe and efficient treatment in these populations. This article provides an overview of SOF features and the main clinical trials, discussing key results and potential future developments.

Hyporesponsiveness to PegIFNα2B plus ribavirin in patients with hepatitis C-related advanced fibrosis

BACKGROUND & AIMS The success of pegylated-interferon (PegIFN)/ribavirin (Rbv) therapy of chronic hepatitis C is compromised by liver fibrosis. Whether fibrosis equally affects the two PegIFNα-based therapies is unknown. To assess the response to the two PegIFN regimens in patients with different degree of liver fibrosis. METHODS A sub-analysis of the MIST study: 431 consecutive naïve patients randomly assigned, based on HCV genotype, to receive either (A) PegIFNα2a 180 μg/wk plus daily Rbv 800-1200 mg or (B) PegIFNα2b 1.5 μg/kg/week plus daily Rbv 800-1200 mg, were stratified according to Ishak staging (S) into mild (S0-S2) or moderate (S3, S4) fibrosis and cirrhosis (S5, S6). RESULTS In A the sustained virological response (SVR) rates were not significantly influenced by fibrosis stage (71% in S0-S2, 66% in S3, S4, 53% in S5, S6, p=0.12), compared to B where the SVR rates differed according to fibrosis stage (65%, 46%, and 38%, p=0.004, respectively). This was even more so in HCV-1/4 patients treated with PegIFNα2b where the SVR rates were twice as many in S0-S2 vs. S≥3 (44% vs. 22%, p=0.02), while in A the SVR rates were similar between the two fibrosis subgroups (S0-S2: 47% vs. S≥3: 48%, p=0.8). By logistic regression analysis genotype 1/4 and lack of rapid virological response were independent predictors of treatment failure in both treatment groups, while S≥3 fibrosis was associated to PegIFNα2b treatment failure, only (OR 2.83, 95% CI 1.4-5.68, p=0.004). CONCLUSIONS Liver fibrosis was an independent moderator of treatment outcome in patients receiving PegIFNα2b, not in those receiving PegIFNα2a.

Limited utility of ITPA deficiency to predict early anemia in HCV patients with advanced fibrosis receiving Telaprevir.

Background Severe anemia is a common side effect of Pegylated Interferon + Ribavirin (PR) and Telaprevir (TVR) in hepatitis C virus (HCV) genotype 1 patients with advanced fibrosis or cirrhosis (F3–F4). Inosine triphosphatase (ITPA) genetic variants are associated with RBV- induced anemia and dose reduction. Aim To test the association of ITPA polymorphisms rs1127354 and rs7270101 with hemoglobin (Hb) decline, need for RBV dose reduction (RBV DR), erythropoietin (EPO) support and blood transfusions during the first 12 weeks of TVR triple therapy. Materials and Methods 69 consecutive HCV-1 patients (mean age 57 years) with F3-F4 who received PR and TVR were genotyped for ITPA polymorphisms rs1127354 and rs7270101. Estimated ITPA deficiency was graded on severity (0–3, no deficiency/mild/moderate/severe). Results ITPA deficiency was absent in 48 patients (70%), mild in 12 (17%) and moderate in 9 patients (13%). Mean week 4 Hb decline was higher in non ITPA deficient patients (3,85 g/dL) than in mildly or moderately ITPA deficient patients (3,07 g/dL and 1,67 g/dL, p<0.0001). Grade 3–4 anemia developed in 81% non ITPA deficient patients versus 67% mild deficient and 55% moderate deficient patients (p = ns). Grade of ITPA deficiency was not associated with RbvDR (no deficiency: 60%, mild: 58%, moderate: 67%; p = ns), EPO use (no deficiency: 65%, mild: 58%, moderate:56%; p = ns) or need for blood transfusion (no deficiency: 27%, mild: 17%, moderate: 33%; p = ns). Conclusions In patients with F3–F4 chronic hepatitis C receiving TVR based therapy, ITPA genotype does not impact on the management of early anemia.

Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease

Hepatocellular carcinoma is the fifth most common cancer and the second leading cause of cancer-related death worldwide. Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis have been identified as emergent risk factors for this primary liver cancer. Incidence of NAFLD is increasing as a consequence of the epidemic spread of metabolic syndrome, which can result in progressive liver disease, leading to cirrhosis and its complications. Most data about the prevalence and incidence of hepatocellular carcinoma in patients with NAFLD are from a few population and cohort studies; its incidence is increasing and it is likely to become a leading indication for liver transplantation, especially in industrialised countries. In patients with NAFLD, hepatocellular carcinoma can arise in the context of non-cirrhotic liver, suggesting a specific carcinogenic pathway. Pathology studies have also described steatohepatitic hepatocellular carcinoma as a specific histological variant. NAFLD is underdiagnosed as causative liver disease, and patients are often diagnosed with hepatocellular carcinoma in the advanced stage because of the absence of efficient surveillance policies in this patient population. Management of hepatocellular carcinoma in patients with NAFLD is also complicated by comorbidities, mainly cardiac disease and diabetes, which negatively affect eligibility for radical treatments, including hepatic resection and, especially, liver transplantation. Finally, the effect of hepatocellular carcinoma treatments on postoperative morbidity, mortality, and disease-free survival remains to be precisely defined.

PegIFN-α2a for the treatment of chronic hepatitis B and C: a 10-year history

Chronic HBV and HCV are progressive diseases leading to cirrhosis and liver transplantation. Persistent viral eradication or suppression can positively affect the natural course of the infection, by preventing disease progression. Since its introduction more than 30 years ago, IFN-α has represented the foundation of HBV and, lately, anti-HCV treatment. Pegylation of the IFN-α molecule (PegIFN-α2a) has provided improvements in both efficacy and administration schedule, thus becoming part of the standard-of-care regimen for HCV and HBV therapy in the last 10 years. Currently, treatment of finite duration with PegIFN-α2a may achieve a sustained virological response off-treatment and HBsAg seroconversion. PegIFN-α2a will most likely remain the backbone of HCV treatment for the next few years, despite the availability of direct-acting antivirals that are expected to improve cure rates. However, many efforts are concentrated on developing new compounds, with the goal of administrating all oral regimens and eliminating PegIFN from anti-HCV treatment.

Serological Tests Do Not Predict Residual Fibrosis in Hepatitis C Cirrhotics with a Sustained Virological Response to Interferon

Background and Aim Liver biopsy (LB) has lost popularity to stage liver fibrosis in the era of highly effective anti-hepatitis C virus (HCV) therapy, yet diagnosis of persistent cirrhosis may have important implications following HCV eradication. As performance of serological non-invasive tests (NITs) to predict residual fibrosis in non-viremic HCV patients is unknown, we investigated accuracy of NITs to predict residual fibrosis in cirrhotics after a sustained virological response (SVR) to interferon (IFN). Methods Thirty-eight patients with a pre-treatment histological diagnosis of cirrhosis and a 48–104 months post-SVR LB were tested with APRI, CDS, FIB-4, FibroQ, Forns Score, GUCI Index, King Score, Lok Index, PLF, ELF. In 23 (61%) patients, cirrhosis had histologically regressed. Results All NITs values declined after SVR without any significant difference between regressors and non-regressors (AUROC 0.52–0.75). Using viremic cut-offs, PPV ranged from 34% to 100%, with lower NPV (63% - 68%). NITs performance did not improve using derived cut-offs (PPV: 40% - 80%; NPV: 66% - 100%). PLF, which combines several NITs with transient elastography, had the best diagnostic performance (AUROC 0.75, Sn 61%, Sp 90%, PPV 80%, NPV 78%). After treatment, none of the NITs resulted significantly associated with any of the histological features (activity grade, fibrosis stage, area of fibrosis). Conclusions The diagnostic estimates obtained using both viremic and derived cut-off values of NITs were suboptimal, indicating that none of these tests helps predicting residual fibrosis and that LB remains the gold standard for this purpose.

From current status to optimization of HCV treatment: Recommendations from an expert panel

Chronic hepatitis C virus (HCV) infection is a major public health problem at a global level, causing an enormous burden of hepatic and extra-hepatic morbidity and mortality. Treatment of chronic HCV (CHC) has been revolutionized in the last few years by the introduction of highly effective and well tolerated direct acting antiviral agents (DAAs) able to achieve >90% rates of sustained virological response (SVR) in many groups of patients, including those previously excluded from interferon-based regimens. For such reason interferon-free regimens are now the treatments of choice for all patients. Successful anti-HCV treatment can stop liver disease progression and can solve the HCV-related extra hepatic manifestations, eventually reducing both liver-related and overall mortality. Together with the rapidly accumulating data about the evolution of treatment landscape, different guidelines from national and international Liver Scientific Societies have been published until today. However, these recommendations may not be applied worldwide as, due to high treatment costs, most of them identify as priority groups only patients with advanced liver disease. Moreover some types of patients pose clinical management problems for which even the guidelines do not always provide useful answers. With the aim of treatment optimization by filling some of the gaps of the current guidelines and addressing the remaining unmet needs in practice, a group of Italian experts, experienced on treatment of HCV infection, met in Stresa in February 2016. The summary of all the considerations arising from this two-day meeting and the final statements are reported in this position paper.

Treatment of Extrahepatic Manifestations of Hepatitis C Virus

Chronic infection with hepatitis C virus (HCV) is a multifaceted disease characterized by many extrahepatic manifestations (EHMs) that affect outcome and quality of life. HCV eradication by antiviral treatment has been proved beneficial in preventing the development of EHMs and is also able to improve many HCV-related severe disorders and neurocognitive outcomes and quality of life. Until recently, antiviral therapy of EHMs was limited to the presence of interferon-based treatment, and was contraindicated in many patients because of hematologic toxicity or risk of exacerbating immune-mediated disorders. The availability of interferon-free regimens solves this issue allowing for enhanced safety and efficacy to provide universal treatment of HCV-related EHMs.

Daclatasvir for the treatment of chronic hepatitis C

Introduction: Following more than 20 years of Interferon (IFN)-based treatment for hepatitis C virus (HCV), the understanding of viral life cycle led to the development of new antiviral drugs directly targeting HCV replication steps. Daclatasvir (DCV) is a potent inhibitor of non-structural NS5A HCV protein with pangenotypic activity and low-moderate barrier to resistance suitable for IFN-free combination with other direct acting antivirals (DAAs). Areas covered: The present review summarizes DCV key pharmacokinetic features and results from Phase II and III trials, discussing also NS5A resistance. Main literature articles have been identified through Pubmed and Medline search; moreover, abstracts from recent international meetings on liver disease have been scrutinized. Expert opinion: DCV in combination with other DAAs has provided IFN-free regimens with increased efficacy and tolerability. However, suboptimal barrier to resistance and the rapid development of new second-generation NS5A inhibitors will probably make DCV a relatively short-lived drug.