Introducing treat-to-target strategies of autoimmune extrahepatic manifestations of chronic hepatitis C virus infection

Introduction: The hepatitis C virus (HCV) is recognized as one of the hepatic viruses most often associated with extrahepatic manifestations (EHMs). It is currently accepted that cryoglobulinemic vasculitis (CV) is the key autoimmune extrahepatic disease associated with HCV infection. Therapeutic approaches have mainly been based on the use of old antiviral interferon (IFN)-based regimens and immunosuppressive therapies, often with an inadequate balance between therapeutic benefits and excess side effects.

Areas covered: Therapeutic management of HCV patients with EHMs, including both non-autoimmune (cardiovascular, hematological, general features) and autoimmune complications (organ-specific and systemic autoimmune diseases). Therapies included antiviral (IFN, ribavirin, direct-acting antivirals – DAAs-) and non-antiviral (immunosuppressive agents, rituximab, plasma exchanges) options. The review analyses the current evidence for proposing a treat-to-target (T2T) approach for HCV-related autoimmune EHMs based on an organ-by-organ strategy.

Expert commentary: Eradication of HCV must be considered the key T2T in the therapeutic approach to HCV-related EHMs, as there has been a disruptive change due to the appearance of direct-acting antivirals (DAAs) as game-changers in HCV therapy, with an efficacy reaching nearly 100%. In this scenario, the central role played until now by IFN and ribavirin is not currently supported and they will not be used in the future.     

Grazoprevir + elbasvir for the treatment of hepatitis C virus infection

Introduction: Hepatitis C virus (HCV)-related liver disease is a cause of significant morbidity and mortality worldwide. Currently, direct-acting antiviral drugs (DAAs) are associated with an increased sustained virologic response (SVR) and are the gold standard for treating HCV infection.

Areas covered: The new combination of grazoprevir, an inhibitor of HCV NS3/4A, and elbasvir, an inhibitor of HCV NS5A, once daily will be available for the treatment of HCV infection. This combination therapy has a high efficacy in HCV genotype 1 and 4 infections, inducing a SVR up to 95%, even in difficult to treat patients such as cirrhotic, HIV co-infected, or dialysis-dependent patients, and patients with stage 4–5 chronic kidney disease or those who failed previous therapy. The safety of grazoprevir combined with elbasvir is very good and without significant adverse effects in phase 2 or 3 studies. For patients who failed prior DAA therapy, in vitro and in vivo studies showed that the grazoprevir and elbasvir combination is fully active against resistance to NS3/4A protease inhibitors. Resistance to NS5B inhibitors is least susceptible to grazoprevir or elbasvir.

Expert opinion: This new combination of gazoprevir with elbasvir offers an opportunity to cure HCV infection with short interferon-free therapy, even in difficult to treat patients.     

Current drug discovery strategies for treatment of hepatitis C virus infection

Objectives Hepatitis C virus (HCV) infection represents a major worldwide‐health problem. The current standard of care is combination therapy with pegylated interferon and ribavirin, which achieves a successful response in only approximately 40% of genotype I patients. Key findings The biology of HCV infection has been under intensive research and important progress has been made in understanding the replication cycle of the virus. Several therapeutic targets have been under investigation, such as NS3 protease, NS4A replicase and NS5B polymerase. New potential targets, such as NS2 protease, as well as CD‐81 and claudin‐1 entry co‐receptors, have also been identified. Summary Clinical evaluations of drug candidates targeting NS3 protease, NS4A cofactor, and NS5B polymerase have demonstrated the potential of developing small molecules that interfere with the replication of the virus. Additional issues, including genotype coverage, resistant mutations, and combination therapy represent major challenges for future drug discovery efforts.     

Epidemiological,demographic and clinical data on chronic viral hepatitis C in Tuscany

Background: Recent introduction of direct antiviral agents (DAAs) has completely changed the scenario regarding hepatitis C virus (HCV) treatment. Certain countries’ economic health programs prioritize DAAs according to specific clinical features of HCV-infected patients. The aim of this study was to define epidemiological, demographic and clinical characteristics of HCV-infected patients in the Tuscany region of central Italy.

Methods: We enrolled HCV patients with chronic viral hepatitis who were referred to the outpatient services of 16 hospitals in Tuscany from 1 January 2015 to 31 December 2015. Case report forms contained patient information including main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations (liver biopsy or transient elastometry, liver ultrasound), eligibility for DAAs, and liver transplantation or therapy already in progress.

Results: Of all patients considered, 2919 HCV patients were enrolled (mean age: 57.44?±?15.15; 54% males, 46% females). All routes of transmission were well represented (intravenous drug use in 20.7%; nosocomial/dental care in 20.6%; and coagulation factors/blood transfusions in 13.3%). Diabetes was the highest represented comorbidity (20.8%), followed by metabolic syndrome (15.5%) and ischemic heart disease (6.2%). The most prevalent HCV genotypes were 1b (47.4%) and 2 (16.5%). In the whole cohort of patients, 32.8% were cirrhotic (40 patients were listed for liver transplantation). Signs of portal hypertension were present mostly in the group older than 45 years (92.3%). Extrahepatic HCV-related diseases were present in 13.3% of cases (cryoglobulinemic syndrome in 58.3% and B-cell non-Hodgkin’s lymphoma in 10.5%).

Conclusions: Our study provides evidence of a high prevalence of epidemiological changes in HCV infection with a major prevalence of advanced liver disease, such as portal hypertension, in this elderly cohort of patients.     

Novel protease and polymerase inhibitors for the treatment of hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection remains a global health concern with nearly 200 million carriers worldwide. Present treatment consists of the use of pegylated interferon plus the purine analogue ribavirin. Serious side effects and the fact that an overall 40 – 50% of patients do not accomplish sustained virological response with the present treatment warrant the need for novel anti-HCV therapies. The HCV serine protease and the RNA-dependent RNA polymerase have shown to be excellent targets for selective antiviral therapy. Early clinical studies have resulted in encouraging results. However, and not unexpectedly, preclinical evidence suggests that the virus may become rapidly resistant to such inhibitors. Therefore, combination therapy of drugs with different mode of action and resistance profiles may be required. This review focuses on the present status of these two families of HCV inhibitors that are in development.     

Evolution and emergence of a new era of antiviral treatment for chronic hepatitis C infection

Chronic hepatitis C virus (HCV) infection is a major public health burden associated with significant morbidity and mortality. The approval of telaprevir and boceprevir for use with interferon and ribavirin in chronic HCV infection significantly increased viral eradication but has been accompanied by increased adverse events and therefore inferior clinical tolerance. Newer classes of antiviral agents, such as directly acting antiviral and host-targeting agents, offer a combination of drugs without the need for interferon and can achieve better response rates with a shorter duration of treatment. This offers an exciting prospect in the new era of antiviral treatment for HCV infection.     

丙型和乙型肝炎合并感染患者的抗病毒治疗分析

目的：探讨HBV／HCV合并感染患者的临床特征以及对聚乙二醇干扰素α-2a（ PEGIFNα-2a）联合利巴韦林的抗病毒疗效。方法选取收治的HBV／HCV合并感染患者45例（ A组）,单纯HBV感染患者49例（ B组）,单纯HCV感染患者38例（ C组）,比较病毒感染和抗病毒疗效。结果 A组与B组HBeAg阳性率、HBV DNA阳性率、HBV DNA平均值以及HBV DNA量的患者分布差异有统计学意义（ P ＜0貂．05）;A组与C组HCV RNA平均值差异无统计学意义（ P ＞0．05）,HCV RNA量的患者分布差异有统计学意义（ P ＜0．05）;A组与C组基因型分布、HCV RNA和ALT差异无统计学意义（ P ＞0．05）,PLT、WBC、PTA和Alb差异具有统计学意义（ P ＜0．05）;Ⅰ基因型中,A组与C组pEVR、ETVR以及复发率差异有统计学意义（ P ＜0．05）,RVR、cEVR以及SVR差异无统计学意义（ P ＞0．05）;非Ⅰ基因型中,RVR、cEVR、pEVR、ETVR、SVR以及复发率差异均无统计学意义（ P ＞0．05）;A组与C组不良反应例数以及WBC和PLT减少例数差异有统计学意义（ P ＜0．05）,溶血以及甲状腺功能减退差异无统计学意义（ P ＞0．05）;未获得SVR患者和获得SVR患者阳转率差异具有统计学意义（ P ＜0．05）。结论丙型和乙型肝炎合并感染患者以HCV为优势病毒株为主,HBV复制受抑制。合并感染Ⅰ基因型患者复发率、部分早期病毒学应答和治疗结束时病毒学应答高于单纯HCV感染患者,持续病毒学应答相似,但合并感染对非基因Ⅰ型病毒学应答率无影响。     

An evaluation of the cyclophilin inhibitor Debio 025 and its potential as a treatment for chronic hepatitis C

Debio 025 is a cyclophilin (Cyp) inhibitor without calcineurin-binding properties. The drug inhibits viral replication of genotype 1b and 2a replicons in nanomolar concentrations and shows an additive to synergistic antiviral effect with interferon, ribavirin, and specifically targeted antiviral therapy for hepatitis C (STAT-C) drugs. There is no cross-resistance with protease and polymerase inhibitors. In humans, Debio 025 has shown activity against genotypes 1, 2, 3, and 4, and displays an additive antiviral effect with pegylated interferon (peg-IFN)α2a in genotype 1 and 4 patients. The most prominent side effect is reversible hyperbilirubinaemia caused by inhibition of biliary transporters. Debio 025 is a potent anti-HCV drug, with a novel mechanism of action and an efficacy profile that makes it an attractive candidate for combination with current and future HCV treatments.     

Novel tripeptide inhibitors of hepatitis C virus NS3 serine protease

Available therapies for hepatitis C viral infection, a disease with a growing impact worldwide, have limited success and serious side effects. Among different possibilities to control the infection, the NS3 serine protease inhibitors constitute a promising alternative, based on a similar approach proved successful in the case of HIV antiviral agents. However, the structural particularities of this viral serine protease make the design of small molecule inhibitors a difficult task. In contrast, the peptidic and peptidomimetic approach gave better results, allowing submicromolar levels of inhibition. In this patent, Bristol-Myers Squibb presents new tripeptide inhibitors with improved potency against NS3 protease and a very good selectivity against related serine proteases. The disclosed compounds also exhibited a good inhibitory profile against different viral strain proteases, giving good hopes to the use of NS3 protease inhibitors as a cure to treat hepatitis C viral infections.     

Paritaprevir/ritonavir/ombitasvir and dasabuvir for the treatment of chronic hepatitis C virus infection

Introduction: The use of direct-acting antiviral (DAA) agents against chronic hepatitis C virus (HCV) infections can result in the successful treatment of nearly all patients. Effective antiviral treatments can prevent the progression to cirrhosis and hepatocellular malignancy, and decrease liver-related morbidity and mortality.

Areas covered: Paritaprevir–ritonavir–ombitasvir and dasabuvir (PrOD), with or without ribavirin, is an all-oral regimen approved for the treatment of HCV genotype 1 infections, including patients with compensated cirrhosis. Phase 2 and 3 clinical trials demonstrated the safety and efficacy of this regimen in HCV genotype 1-infected patients who are treatment-naïve and those who have failed peginterferon/ribavirin therapy. Additional studies evaluated the use of PrOD with or without ribavirin among special populations, including patients co-infected with human immunodeficiency virus-1 and HCV, liver transplant recipients with HCV recurrence, and patients with severe renal impairment. Additionally, the combination of paritaprevir-ritonavir-ombitasvir plus ribavirin is found to be highly efficacious, and is now approved in the US, for the treatment of HCV genotype 4 infections.

Expert opinion: The availability and use of interferon-free DAA combination regimens has resulted in a major paradigm shift in the treatment of HCV. PrOD, with or without ribavirin, is an effective, safe and tolerable treatment option.     

Developing therapies to treat hepatitis C infection in post-liver transplant recipients

Introduction: Currently, hepatitis C virus (HCV) infection remains the most common indication for liver transplant in the United States (US) with almost universal HCV recurrence in the post-liver transplant setting. Previous interferon (IFN)-related efficacy and tolerability concerns about worsening liver function have limited treatment options for many patients with HCV-associated decompensated liver disease and post-liver transplant recipients. However, the last decade has seen a seen a radical shift in the management of HCV with multiple direct-acting antiviral (DAA) treatments that provide more effective, all-oral, IFN-free alternatives.

Areas covered: This review will serve to highlight the various pharmacotherapies available to clinicians for patients with HCV recurrence post-liver transplant. A brief history of prior regimens is provided with evidence for newer treatments presented. Also detailed are updated guidelines from societal organizations. Finally, timing of HCV treatment is discussed as the decision to treat patients in a pre or post-liver transplant setting remains challenging.

Expert opinion: While there are many potential available therapies for HCV recurrence in the post-liver transplant setting, daclatasvir/sofosbuvir and ledipasvir/sofosbuvir have been the most extensively studied. Newer, pangenotypic generation drugs require more evidence before routine utilization in post-liver transplant recipients.     

NS5A inhibitor,daclatasvir, for the treatment of chronic hepatitis C virus infection

Gonadal and adrenal steroidal hormones and their related neuropeptides affect seizures. Seizures, in their turn, may affect the functioning of these endocrine systems. Both these sets of effects may be clinically important and open to therapeutic manipulation. Recent advances in understanding the effects of these hormones and their metabolites on neuronal excitability have opened the way for a number of new, hormonally-based therapeutic approaches to seizure management. Some of these have reached various stages of clinical trials, while others are still in the preclinical stages of testing. Similarly, treatment of some of the hormonal consequences of seizures has recently been explored and will be discussed.     

Emerging biological agents for hepatitis C

Introduction: New direct-acting antiviral agents have changed the landscape of treatment of chronic HCV infection. Despite current treatments are well tolerated with a high rate of sustained virological response (SVR), some medical needs remain. Nowadays there are a large number of approved medications for the treatment of HCV infection; nevertheless, new studies are conducted to find new agents and new combinations.

Areas covered: A literature research of new antiviral compounds indicated for the treatment of HCV infection was achieved by an online search of medication undergoing development on Pubmed and clinicalTrials.gov clinical trials registry. We considered phase I/II studies and some randomized Phase III trials.

Expert opinion: More knowledge about impact of HCV eradication on disease progression and more confidence regarding drug-drug interaction are needed. Furthermore, each treatment should be individualized targeting the patients needs with the aim not only to obtain viral suppression but also to stop progression of liver disease and HCV related conditions, and to improve patient health status.     

Therapeutic vaccination against chronic hepatitis C virus infection

Approximately 170 million people worldwide are chronic carriers of Hepatitis C virus (HCV). To date, there is no prophylactic vaccine available against HCV. The standard-of-care therapy for HCV infection involves a combination of pegylated interferon-α and ribavirin. This therapy, which is commonly associated with side effects, has a curative rate varying from 43% (HCV genotype 1) to 80% (HCV genotype 2). In 2011, two direct-acting antiviral agents, telaprevir and boceprevir, were approved by the US Food and drug Administration and are now being used in combination with standard-of-care therapy in selected patients infected with HCV genotype 1. Although both drugs are promising, resulting in a shortening of therapy, these drugs also induce additional side effects and have reduced efficacy in patients who did not respond to standard-of-care previously. An alternative approach would be to treat HCV by stimulating the immune system with a therapeutic vaccine ideally aimed at (i) the eradication of HCV-infected cells and (ii) neutralization of infectious HCV particles. The challenge is to develop therapeutic vaccination strategies that are either at least as effective as antiviral drugs but with lower side effects, or vaccines that, when combined with antiviral drugs, can circumvent long-term use of these drugs thereby reducing their side effects. In this review, we summarize and discuss recent preclinical developments in the area of therapeutic vaccination against chronic HCV infection. Although neutralizing antibodies have been described to exert protective immunity, clinical studies on the induction of neutralizing antibodies in therapeutic settings are limited. Therefore, we will primarily discuss therapeutic vaccines which aim to induce effective cellular immune response against HCV.     

The effect of direct acting antiviral agents on vascular endothelial function in Egyptian patients with chronic hepatitis C virus infection

Chronic hepatitis C virus (HCV) infection is correlated with cerebrovascular and cardiovascular disease (CVD). This study aimed to assess the effect of treatment with DAAs on vascular endothelial function in cirrhotic and non-cirrhotic HCV infected patients without any CVD risk factors. Fifty chronic HCV genotype 4 infected patients, without cardiovascular risks who have been listed to receive sofosbuvir/daclatasvir with ribavirin combination as triple therapy for 3 months were prospectively recruited. Endothelial dysfunction markers as soluble vascular cell adhesion molecule-1 (sVCAM-1) and Von willebrand factor (vWf) and inflammation marker (IL6) were estimated at baseline and 3 months post the end of therapy (SVR). All patients achieved SVR. VCAM1 level was significantly improved after HCV clearance with DAA in cirrhotic HCV patients (P = 0.002) compared to patients with mild liver fibrosis (P = 0.006). Levels of vWF also decreased significantly in cirrhosis and non-cirrhosis groups after SVR (P < 0.001 and P = 0.011, respectively). Systemic inflammatory marker (IL6) showed significant decrease in cirrhotic patients (P = 0.001). While, IL6 level did not change significantly in non-cirrhotic group (P = 0.061). Also at SVR, noninvasive liver fibrosis indices have been reduced significantly in the two groups (P < 0.001). HCV clearance by new DAA treatment improves the vascular endothelial dysfunction in Egyptian HCV infected patients with different levels of liver fibrosis and with no risk factors for endothelial dysfunction or CVD.     

血友病A患者丙肝感染现状的调查

目的了解血友病A患者血液传播性丙型肝炎病毒（HCV）的感染现状。方法对经本院确诊的56例血友病A患者进行了ALT、抗-HCV检测,并与2004年本院输血、手术前检测结果（对照组）共8429例做对比分析。结果56例血友病A患者的ALT、抗-HCV阳性率分别为19．64％、35．71％,对照组ALT、抗-HCV阳性率分别为3．44％、0．61％,血友病A患者的ALT、抗-HCV阳性率均显著高于对照组（P值均〈0．0005）。结论血友病A患者是HCV感染的高危人群,且HCV感染是血友病A患者肝功能受损的主要因素,1995年以后诊断的血友病A患者丙肝的发生率显著下降。     

Progress towards improving antiviral therapy for hepatitis C with hepatitis C virus polymerase inhibitors. Part I: Nucleoside analogues

Background: With an increasing worldwide burden of liver failure and liver cancer from chronic hepatitis C virus (HCV) infection, discovery and development efforts for new antiviral medicines for HCV are expanding rapidly. Two HCV protease inhibitors (PIs), telaprevir (VX950) and boceprevir (SCH503034), are now furthest along in clinical development, with Phase II data suggesting a potential treatment advance with triple combination regimens comprising a protease inhibitor, pegylated interferon and ribavirin. However, the current data suggest that such regimens will fail to produce sustained virologic responses in ≥ 30 – 40% of patients, and tolerance of interferon/ribavirin treatment regimens is often problematic; hence, there is a need for continued development of new anti-HCV agents to further optimize treatment efficacy and safety. The HCV polymerase (HCV Pol) is an attractive target for antiviral therapy because the gene sequences encoding HCV Pol are relatively conserved across the six main HCV genotypes and the emergence of viral resistance is expected to be relatively slow for pharmaceutical agents, such as nucleoside analogues, that are targeted to the active (catalytic) site of HCV Pol. Methods: This review (Part I) of HCV Pol inhibitors focuses on the scientific rationale and recent development progress for nucleoside-type HCV Pol inhibitors; a subsequent review (Part II) will assess progress with non-nucleosidic HCV Pol inhibitors. Results/conclusions: Early clinical data for several nucleosides targeted to HCV Pol indicate marked antiviral effects and a likelihood of relatively slow HCV resistance, consistent with the profile of nucleosidic inhibitors of HIV and hepatitis B virus infection and supporting potentially important roles for nucleoside agents in optimizing combination therapies for HCV infection. Optimally effective future anti-HCV therapies are likely to be based on multi-class treatment regimens combining polymerase and PIs, together with pegylated interferon and ribavirin or pharmaceutical agents from other mechanistic classes.     

Advances in hepatitis C virus vaccines,part two: advances in hepatitis C virus vaccine formulations and modalities

Introduction: Developing a vaccine against HCV is an important medical and global priority. Unavailability and potential dangers associated with using attenuated HCV viral particles for vaccine preparation have resulted in the use of HCV genes and proteins formulated in novel vaccine modalities.

Areas covered: In part one of this review, advances in basic knowledge for HCV vaccine design were provided. Herein, a detailed and correlated patents (searched by Espacenet) and literatures (searched by Pubmed) review on HCV vaccine formulations and modalities is provided, including: subunit, DNA, epitopic-peptide/polytopic, live vector- and whole yeast-based vaccines. Less-touched areas in vaccine studies such as mucosal, plant-based, and chimeric HBV/HCV vaccines are also discussed. Furthermore, results of preclinical/clinical studies on selected HCV vaccines as well as pros and cons of different strategies are reviewed. Finally, potential strategies for creation and/or improvement of HCV vaccine formulations are discussed.

Expert opinion: Promising outcomes of a few HCV vaccine modalities in phase I/II clinical trials predict the accessibility of at least partially effective vaccines to inhibit or treat the chronic state of HCV infection (specially in combination with standard antiviral therapy). ChronVac-C (plasmid DNA), TG4040 (MVA-based), and GI-5005 (whole yeast-based) might be the most obvious HCV vaccine candidates to be approved in the near future.