Regimens For Treatment Of Chronic Hepatitis Research Articles

Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrioR) of Chronically HBV Infected Patients.

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 μg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent.

Novel non-HAP class A HBV capsid assembly modulators have distinct in vitro and in vivo profiles.

Chronic hepatitis B is the most important cause of liver cancer worldwide and affects more than 290 million people. Current treatments are mostly suppressive and rarely lead to a cure. Therefore, there is a need for novel and curative drugs that target the host or the causative agent, hepatitis B virus itself. Capsid assembly modulators are an interesting class of antiviral molecules that may one day become part of curative treatment regimens for chronic hepatitis B. Here we explore the characteristics of a particularly interesting subclass of capsid assembly modulators. These so-called non-HAP CAM-As have intriguing properties in cell culture but also clear virus-infected cells from the mouse liver in a gradual and sustained way. We believe they represent a considerable improvement over previously reported molecules and may one day be part of curative treatment combinations for chronic hepatitis B.

Noncompliance with Therapeutic Guidelines for Chronic Hepatitis B Patients in Minas Gerais, Brazil.

Standardized treatment regimens for chronic hepatitis B (CHB) are crucial in suppressing viral replication, disease progression and the development of complications. However, information on routine compliance with such therapeutic recommendations in medical practice is rare. Aim: To evaluate the application of Brazilian therapeutic guidelines for CHB within the scope of the Unified Health System in Minas Gerais state. Four key recommendations from the national guidelines were compared with data from treated patients: (i) eligibility to start treatment; (ii) type of treatment applied; (iii) rescue antiviral therapy; and (iv) monitoring of virological response. Most physicians (69.8%) declared to adopt these guidelines, while 10 of them were unaware. However, according to the criteria established by the guidelines, only 39.5% of treated patients should have been considered "truly" eligible to start treatment and only 67.6% of these underwent the recommended pharmacological treatment. The virological response was laboratory monitored in just over a third of patients. Rescue therapy was adequately supplanted in 41.2% of patients previously treated with lamivudine. There was low compliance with national guidelines by public service physicians in Brazil, highlighting the need to raise awareness of the importance of its adherence to expand the control of CHB. Thus, increasing the adherence of health professionals to this tool is a current challenge for health institutions and managers.

Inflammation and Liver Cell Death in Patients with Hepatitis C Viral Infection.

Hepatitis C virus (HCV)-induced liver disease contributes to chronic hepatitis. The immune factors identified in HCV include changes in the innate and adaptive immune system. The inflammatory mediators, known as “inflammasome”, are a consequence of the metabolic products of cells and commensal or pathogenic bacteria and viruses. The only effective strategy to prevent disease progression is eradication of the viral infection. Immune cells play a pivotal role during liver inflammation, triggering fibrogenesis. The present paper discusses the potential role of markers in cell death and the inflammatory cascade leading to the severity of liver damage. We aim to present the clinical parameters and laboratory data in a cohort of 88 HCV-infected non-cirrhotic and 25 HCV cirrhotic patients, to determine the characteristic light microscopic (LM) and transmission electron microscopic (TEM) changes in their liver biopsies and to present the link between the severity of liver damage and the serum levels of cytokines and caspases. A matched HCV non-infected cohort was used for the comparison of serum inflammatory markers. We compared the inflammation in HCV individuals with a control group of 280 healthy individuals. We correlated the changes in inflammatory markers in different stages of the disease and the histology. We concluded that the serum levels of cytokine, chemokine, and cleaved caspase markers reveal the inflammatory status in HCV. Based upon the information provided by the changes in biomarkers the clinician can monitor the severity of HCV-induced liver damage. New oral well-tolerated treatment regimens for chronic hepatitis C patients can achieve cure rates of over 90%. Therefore, using the noninvasive biomarkers to monitor the evolution of the liver damage is an effective personalized medicine procedure to establish the severity of liver injury and its repair.

A Focused Review on Recent Advances in the Diagnosis and Treatment of Viral Hepatitis

The global burden of viral hepatitis remains substantial despite advances in antiviral therapy and effective vaccines. There are five hepatitis viruses (hepatitis A, B, C, D, and E). Mortality related to hepatitis B virus and hepatitis C virus infections is among the top four global infectious diseases, together with human immunodeficiency virus infection, malaria, and tuberculosis. Of those deaths, approximately 47% are attributable to hepatitis B virus, 48% to hepatitis C virus and the remainder to hepatitis A virus and hepatitis E virus. Ending hepatitis epidemics as a major public health threat is feasible with the tools and approaches currently available. Effective vaccines are available for preventing viral hepatitis A, B and E infections. New oral, well-tolerated treatment regimens for chronic hepatitis C patients can achieve cure rates of over 90%. Effective treatment is also available for people with chronic hepatitis B virus infection; although for most people such treatment needs to be long-term, and recent advanced aim at a “functional cure” of hepatitis B. In this review article, we discuss the most recent advances of the diagnosis and treatment of viral hepatitis.

PIN26 Choice of Recommended Treatment Options for Patients with Hepatitis C Genotype 1 in Moscow, Russian Federation

The possibilities of modern therapy for chronic hepatitis C include a large number of options that have marked differences in both effectiveness and cost. The aim of this study was to select optimal treatment regimens for chronic hepatitis C virus (HCV) genotype 1 for reimbursement in Moscow in 2020 based on their comparative efficacy and costs per course. Treatment regimens were ranked based on their comparative efficacy and costs per course. Comparative efficacy was evaluated based on published network meta-analyses, as well as our own indirect comparisons. Prices for drugs were provided by the Moscow Healthcare Department. When determining the target sub-groups of patients, the virus genotype, the presence or absence of treatment experience and liver cirrhosis were taken into account. List of comparators included pangenotypic and non-pangenotypic regimens, with the exception of regimens containing peginterferons. Based on the results of the analysis, several recommended schemes were selected for each of the target groups. Multilple regimens were recommended due to the fact that the cost of the course of treatment and the efficacy of all top regimens were comparable. In genotype 1a patients independent of subgroups top-3 regimens were: daclatasvir+sofosbuvir±ribavirin (€ 5938 per course), grasoprevir+elbasvir (€ 5964) and velpatasvir+sofosbuvir (€ 6223). The 4th and 5th positions in treatment-naïve and experienced patients without cirrhosis was dasabuvir+ombitasvir+paritaprevir+ritonavir+ribavirin (€ 6237) and glecaprevir+pibrentasvir (€ 6333). The 4th regimen for treatment-naïve cirrhotic patients was glecaprevir+pibrentasvir (€ 6333). In genotype 1b patients independent of subgroups top-4 regimens were: daclatasvir+sofosbuvir±ribavirin (€ 5938), grasoprevir+elbasvir (€ 5964), dasabuvir+ombitasvir+paritaprevir+ritonavir (€ 6219) and velpatasvir+sofosbuvir (€6223). The 5th regimen for all target groups, except treatment-experienced cirrhotic patients was glecaprevir+pibrentasvir (€ 6333). As a result of a transparent and scientific-based analysis were selected treatment regimens for patients with chronic HCV genotype 1 recommended for reimbursement in Moscow in 2020.

Real-life results of sofosbuvir based therapy for patients with hepatitis C

Purpose of the study. The sofosbuvir (SOF) based regimes for the treatment of patients infected with hepatitis C virus (HCV) has improved rates of sustained virological response (SVR) considerably in recent trials. There is only limited data concerning the efficacy and safety in a real-life cohort. We analyzed the treatment outcome of SOF based regimes for chronic hepatitis C patients in a real life setting.&#x0D; Materials and methods. This retrospective study analyzed 205 patients with chronic HCV infection. The following treatments were given according national guidelines: SOF + pegylated interferon alpha-2b + ribavirin for 12 weeks; SOF + ribavirin for 12–24 weeks.&#x0D; Results. Among 3 patients withgenotype 1a HCV the SVR12 rate was 100%, among 100 patients with genotype 1bHCV the SVR12 rate was 92%, among 11 patients with genotype 2 HCV the SVR12 rate was 90.9% and among 91 patients with genotype 3a HCV the SVR 12 rate was 96,7%. Treatment was safe, most of the side effects and laboratory abnormalities (anemia, neutropenia) found during this study were associated with pegylated interferon or ribavirin.&#x0D; Conclusion. In real life setting treatment regimens for chronic hepatitis C patients with SOF based regimens are highly effective and safe, including patients with cirrhosis and treatment experienced patients

Daclatasvir: A Review of Preclinical and Clinical Pharmacokinetics.

Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2h and an elimination half-life of~10 to 14h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection.

Real-world effectiveness of sofosbuvir-based treatment regimens for chronic hepatitis C genotype 3 infection: Results from the multicenter German hepatitis C cohort (GECCO-03).

There are limited data regarding the real world effectiveness of direct acting antivirals (DAA) for the therapy of chronic genotype 3 hepatitis C virus (HCV) infection. All HCV genotype 3 infected patients from the German hepatitis C cohort (GECCO), which is a prospective database of nine German hepatitis C treatment centers, were included in the study. Three hundred forty-two chronically infected HCV genotype 3 patients were analyzed (253 males [74.0%], mean age 47.3 years, 127 cirrhotic patients [37.1%] mostly with Child A cirrhosis, 113 treatment experienced patients [37.1%], 38 HCV/HIV co-infected patients [11.1%]). SVR12 rates in the "intention-to-treat" analysis were as follows: sofosbuvir/ribavirin 69.4% (75/108), sofosbuvir/peginterferon/ribavirin 80.6% (58/72), sofosbuvir/daclatasvir ± ribavirin for 12 weeks 88.3% (53/63), sofosbuvir/daclatasvir ± ribavirin for 24 weeks 79.3% (23/29), sofosbuvir/ledipasvir ± ribavirin for 12 weeks 71.4% (10/14), and sofosbuvir/ledipasvir ± ribavirin for 24 weeks 86.7% (26/30). Forty patients were lost to follow-up, 23 patients had a relapse, 4 patients stopped treatment prematurely and 1 patient died. Female sex (P = 0.038) and treatment with two different DAAs (P = 0.05) were predictors for SVR12 in the multivariate analysis. In conclusion, sofosbuvir/daclatasvir ± ribavirin for 12 weeks and sofosbuvir/ledipasvir ± ribavirin for 24 weeks are effective for the treatment of HCV genotype 3 infected patients including cirrhotic, treatment-experienced or HIV/HCV co-infected patients.

Economic study of the value of expanding HCV treatment capacity in Germany

BackgroundToday's highly efficacious, low-toxicity interferon-free treatment regimens for chronic hepatitis C virus (HCV) can cure most patients with HCV in 12–24 weeks. The aim of this study was to understand...

Normalization of Alanine Aminotransferase Levels at the End of Treatment with Direct-Acting Antiviral Therapy for Chronic Hepatitis C Infection Is Associated with Sustained Virological Response

Introduction: All oral treatment regimens for chronic Hepatitis C (HCV) infection offer high rates of sustained virological response(SVR) but there are no guidelines for on-treatment monitoring to predict SVR. The purpose of this study was to determine if alanine aminotransferase (ALT) levels during the treatment with direct acting antiviral therapy (DAA) predict response to treatment and if normalization of ALT at the end of treatment (EOT) predicts SVR. Methods: Charts of the patients treated with DAA's between February 2014 and September 2014 were reviewed. Patients with HCV genotype 1, 2 and 3 were included. Treatment regimens included sofosbuvir plus simeprevir or sofosbuvir plus weight based ribavirin for duration of 12 to 24 weeks. Age, gender, BMI, genotype (GT), +/- cirrhosis and prior treatment status were recorded. ALT levels were recorded pretreatment, at weeks 2, 4, 8, 12, 16, 24 or EOT and at 3 months' post treatment. HCV RNA levels were recorded pretreatment, week 4, EOT and at 3 months' post treatment. Normalization of ALT was defined as levels.Table 1: Association of End of Treatment Normalized ALT levels and HCV RNA levels at 3 months post treatmentTable 2: Association of End of Treatment Normalized ALT levels and HCV RNA levels at 3 months post treatment in patients with cirrhosisResults: 67 patients were treated with DAAs during the study period. 3 patients were excluded. 39 had HCV GT1 and 25 had HCV GT2 or 3 infection.Twenty-eight were cirrhotic. Normalization of ALT at week 4 did not predict the HCV suppression at the end of treatment (p=0.4). Overall, patients with normalized ALT level at the end of treatment had a 6-fold increase in the rates of SVR12 (p < 0.02). With each unit increase in the ALT at the end of treatment, patients were 14% less likely to achieve SVR12 (p=0.0009). Among patients with cirrhosis, normalized ALT level at the end of treatment was associated with 25-fold increase in the rates of SVR12 (p=0.04). With each unit increase in ALT, cirrhotic patients were 18% less likely to achieve SVR12 (p=0.009). In patients without cirrhosis ALT levels at the end of treatment did not predict SVR12. Conclusion: The ALT level at the end of treatment with DAA can help predict the SVR12, particularly in patients with cirrhosis. Increase in the ALT levels while on treatment or at the end of treatment should alert the physician of possible treatment failure.

PHARMACOECONOMIC ASSESSMENT OF USING INTERFERON-FREE REGIMENS FOR CHRONIC HEPATITIS C AFTER LIVER TRANSPLANTATION

This article contains analysis of current combination treatment regimens for chronic hepatitis C after liver transplantation. Antiviral therapy with long-acting interferons and ribavirin is of low efficiency and high costs. The clinical and economic benefits of interferon-free treatment regimen for patients infected with genotype 1 HCV using dasabuvir, paritaprevir boosted with ritonavir, ombitasvir (Viekira Pak) and ribavirin have been shown. Registration and introduction into clinical practice of new direct-acting antiviral drugs will significantly expand the arsenal of tools for the treatment of recurrent HCV infections, in particular in patients infected with hepatitis C virus genotypes 2 and 3.

Access of hepatitis C patients to interferon-free treatment regimens in Austria: a single center experience

Introduction: Until the end of July 2015 reimbursement of interferon-free treatment regimens for chronic hepatitis C was limited to patients with advanced liver fibrosis (F3 and F4) and to patients with severe extrahepatic manifestations. Since August 2015 treatment coverage was extended to include F2. In order to qualify for reimbursement liver disease has to be staged by Fibroscan®, biopsy or clinical findings. Furthermore, treatment can only be performed at selected specialized hospitals. The aim of this analysis was to assess the percentage of patients eligible for interferon-free regimens and the impact of extending insurance coverage to F2.

Evaluation of serum aminotransaminases and bilirubin in different treatment regimens for chronic hepatitis C virus

Hepatitis C virus (HCV) affects more than 180 million people worldwide and it is the leading cause of chronic liver disease .The aim of this study is to detect liver enzymes and bilirubin levels before and after different anti viral therapies in Egyptian chronic hepatitis C infected patients. One hundred and fifty patients with chronic HCV infection who have anti HCV antibodies detected by ELISA were selected to undergo Real-Time polymerase chain reaction (RT-PCR) ; of them 30 blood samples were positive for HCV antibodies and negative for HCV RNA (control group I) and 120 blood samples were positive for HCV antibodies and positive for HCV RNA (diseased group II) which is subdivided into four groups according to the received treatment; interferon and ribavirin (group IIa), interferon, sofosbuvir and ribavirin (group IIb), sofosbuvir and ribavirin (group IIc) and herbal therapy (group IId). Results revealed; after treatment there was a statistical significant reduction in the mean values of ALT in group IIa, group IIb and group IIc (mean: 38.00, 45.5 and 36.00 U/L respectively; P 0.05). AST levels showed a non significant increase after treatment in group IIa (mean: 43.7 U/L; P>0.05), a non significant decrease in group IIb and group IId (mean: 40.03 and 39.80 U/L respectively; P>0.05) and an extremely significant decrease after treatment in group IIc (mean: 28.30 U/L; P 0.05), a non significant increase after treatment in group IIb (mean: 0.811 mg/dL; P>0.05) and an extremely significant increase in group IIc (mean: 1.05 mg/dL; P 0.05). In conclusion, Serum ALT is a normal value after all treatment regimens included in our study; serum AST is slightly elevated in combination therapy of pegylated interferon plus ribavirin while serum bilirubin is highly elevated in case of sofosbuvir dual therapy than sofosbuvir trible therapy.

Evaluation of serum iron and ferritin in different treatment regimens for chronic hepatitis C virus

This work aims to develop a biochemical study on the effect of both interferon containing treatment regimens and interferon free regimens on serum iron and serum ferritin in patients with chronic hepatitis C and to evaluate the role of iron in the severity and course of disease. Blood samples from one hundred fifty patients aged from 25 to 57 years old were withdrawn; of them 30 blood samples were positive for HCV antibodies and negative for HCV RNA (control group I) and 120 blood samples were positive for HCV antibodies and positive for HCV RNA (diseased group II) which is subdivided into four groups according to the received treatment; interferon and ribavirin (group IIa), interferon, sofosbuvir and ribavirin (group IIb), sofosbuvir and ribavirin (group IIc) and herbal therapy (group IId). After treatment there was an extremely significant decrease in iron levels (94 ± 16.96 µg/dL) in group IIa, , while there was an extremely significant increase in iron levels after treatment in group IIb and group IIc (160.4 ± 37.53 µg/dL and 183.7 ± 37.36 µg/dL), respectively. Group IId showed a non significant decrease in iron levels after treatment (150.5 ± 21.35 µg/dL). For ferritin levels, group IIa, group IIb and group IIc showed significant increase in serum ferritin levels after treatment (157.6 ± 13.44, 99.5 ±14.99, and 96.63 ± 15.22 ng/mL), respectively. On the other hand, group IId showed a non significant increase in ferritin levels after treatment (90.93 ± 6.883 ng/mL). It can be concluded that serum ferritin increases in HCV patients treated with combined pegylated interferon--alfa (PEG-IFN)-ribavirin than the other treatment regimens. In addition, Serum iron decreases in HCV patients treated with combined PEG-IFN-

Adherence during antiviral treatment regimens for chronic hepatitis C: a qualitative study of patient-reported facilitators and barriers.

To understand patients' perceptions of factors which facilitate and hinder adherence to inform adherence-enhancing interventions. Adherence to antiviral therapy for hepatitis C viral infection is critical to achieving a sustained virological response. However, persistence with and adherence to antiviral regimens can pose challenges for patients that interfere with sustained virological response. A qualitative analysis of 21 semistructured patient interviews using open-ended questions and specific follow-up probes was conducted. Interviews were audio-recorded, transcribed, and content-analyzed iteratively to determine frequent and salient themes. Three broad themes emerged: (1) missing doses and dose-timing errors; (2) facilitators of adherence; and (3) barriers to adherence. Open-ended questioning revealed few dose-timing deviations, but more specific probes uncovered several more occurrences of delays in dosing. Facilitators of adherence fell into 2 broad categories: (a) patient knowledge and motivation; and (b) practical behavioral strategies and routines. Facilitators were noted post hoc to be consistent with the Information-Motivation-Behavioral Skills Model of Adherence. Barriers to adherence involved changes in daily routine, being preoccupied with family or work responsibilities, and sleeping through dosing times. A few patients reported skipping doses due to side effects. Patients with previous hepatitis C virus treatment experience may have fewer dose-timing errors. Finally, a high level of anxiety among some patients was discovered regarding dosing errors. Emotional and informational support from clinical and research staff was key to assuaging patient fears. This qualitative study improves our understanding of patients' perspectives regarding adhering to hepatitis C treatment and can lead to the development of adherence-enhancing interventions.

P0831 : Safety and efficacy of Sofosbuvir-based treatment regimens for chronic hepatitis C virus infection: A “Real-Life”, single-center experience in 117 patients

polymorphism in NS3 or NS5A, while two patients with the polymorphism experienced viral breakthrough. Except for the two patients, patients with NS5A Y93H/N or L31M showed similar viral response until 4 weeks of the therapy. The frequently reported adverse events were mild headache, fever, or elevations of ALT, g-GTP or ALP and one patient stopped the therapy because of the onset of brain infarction. There were no further serious adverse events during early course of the treatment. Conclusions: The response of HCV-RNA was favorable enough during the DCV+ASV therapy, even for women, aged patients, patients with liver cirrhosis or patients with intractable IL-28B polymorphism. However, resistance-associated polymorphism of HCV could affect treatment response, and further examination for absolute quantity of the resistance-associated polymorphism is desired to evaluate the effectiveness for the DCV+ASV treatment.

Adherence During Antiviral Treatment Regimens for Chronic Hepatitis C: A Qualitative Study of Patient-reported Facilitators and Barriers

Adherence During Antiviral Treatment Regimens for Chronic Hepatitis C: A Qualitative Study of Patient-reported Facilitators and Barriers

Sofosbuvir Has Come Out of the Magic Box

After the introduction of hepatitis B (HBV) vaccination, which leaded to a dramatically decrease of HBV prevalence in the communities (1), it is predicted that hepatitis C virus (HCV) will emerge as the most common chronic viral liver disease in the next decades (2, 3). The global prevalence of HCV is at least 3% with over 170 million infected cases (4). The treatment regimens for chronic hepatitis C (CHC) have progressed within the past decade. The current standard of care in our country consisting of pegylated interferon alpha (PegIFNα) and ribavirin (RBV), has significantly improved the sustained virological response (SVR) rates from 50% up to 80% in patients infected with different HCV genotypes (5, 6). Iranian patients respond well to antiviral therapies which may be related to more favorable distribution of IL28B SNP polymorphism (7). After the introduction of Boceprevir and Teleprevir as the standard therapy for HCV genotype 1 infections, the hope for eradication of infection grows significantly, but the costs imposed by the drug side effects were not satisfactory for both patients and scientists (8). Availability of these agents, protease inhibitors (PIs), which have been added to the current standard of care (SOC), has offered a new treatment option for patients infected with HCV, who are infected with GT1, and have not responded or relapsed to the previous therapies. It is reported that by adding these agents to the standard of care of patients who were infected with HCV genotype 1, non-responders or relapsers to the previous therapies, the response rate had increased. The therapy failure in patients infected with different HCV genotypes in Iran, depends on the liver fibrosis status, age and comorbidity (8). Chronic HCV infection and its treatment are significant health care economic burdens that should be reviewed according the rate of responses and should attract the attention of health policy makers and academics in many countries (9). The costs of PIs -based triple therapy for hepatitis C and adverse managements are very high per sustained viral response, which means that it is not cost effective to use these drugs in our practice at the present time.

Identification of Alpha Interferon-Induced Envelope Mutations of Hepatitis C Virus In Vitro Associated with Increased Viral Fitness and Interferon Resistance

Alpha interferon (IFN-α) is an essential component of innate antiviral immunity and of treatment regimens for chronic hepatitis C virus (HCV) infection. Resistance to IFN might be important for HCV persistence and failure of IFN-based therapies. Evidence for HCV genetic correlates of IFN resistance is limited. Experimental studies were hampered by lack of HCV culture systems. Using genotype (strain) 1a(H77) and 3a(S52) Core-NS2 JFH1-based recombinants, we aimed at identifying viral correlates of IFN-α resistance in vitro. Long-term culture with IFN-α2b in Huh7.5 cells resulted in viral spread with acquisition of putative escape mutations in HCV structural and nonstructural proteins. Reverse genetic studies showed that primarily amino acid changes I348T in 1a(H77) E1 and F345V/V414A in 3a(S52) E1/E2 increased viral fitness. Single-cycle assays revealed that I348T and F345V/V414A enhanced viral entry and release, respectively. In assays allowing viral spread, these mutations conferred a level of IFN-α resistance exceeding the observed fitness effect. The identified mutations acted in a subtype-specific manner but were not found in genotype 1a and 3a patients, who failed IFN-α therapy. Studies with HCV recombinants with different degrees of culture adaptation confirmed the correlation between viral fitness and IFN-α resistance. In conclusion, in vitro escape experiments led to identification of HCV envelope mutations resulting in increased viral fitness and conferring IFN-α resistance. While we established a close link between viral fitness and IFN-α resistance, identified mutations acted via different mechanisms and appeared to be relatively specific to the infecting virus, possibly explaining difficulties in identifying signature mutations for IFN resistance.