Sustained Virological Response In Genotype Research Articles

Direct-Acting Antivirals in the Treatment of Hepatitis C Virus (HCV)/Human Immunodeficiency Virus (HIV) Co-infected Patients: Real-Life Experience From Nepal.

BackgroundDirect-acting antivirals (DAA) have revolutionized the treatment of chronic hepatitis C patients. However, the real-life data regarding its use in a human immunodeficiency virus (HIV) co-infection from a developing country is lacking. We aimed to see the efficacy of DAA in hepatitis C virus (HCV)/HIV co-infected populations.MethodsIn this prospective, observational, intention-to-treat study from Nepal, treatment-naïve patients undergoing treatment for chronic HCV in HIV co-infected individuals with DAA were studied. Patients on nevirapine were switched to efavirenz or atazanavir. Patients received sofosbuvir/ledipasvir or sofosbuvir/daclatasvir with or without ribavirine. Sustained virological response (SVR) at week 12, adverse events, and treatment compliance were evaluated. Treatment efficacy was compared between cirrhotic and non-cirrhotic patients.ResultsOf 218 patients presenting with an anti-HCV report, 181 (83%) had detectable HCV RNA. Eighty-five (85; 47%) patients were having ART at presentation. Three patients could not complete treatment due to gall stone pancreatitis and 82 completed treatment. Twenty-nine (29; 35%) were cirrhotic at presentation. Fifty-one (51; 62%) patients were genotype 3, 27 (33%) were genotype 1, three (4%) were mixed 1a/3, and one (1%) was 6. Seventy-four (74; 90%) had SVR12. Non-cirrhotics had 96% SVR compared to 79% in cirrhotics. SVR in genotype 3 was 88% while it was 93% in genotype 1.ConclusionsReal-life experience showed that the DAAs are equally effective in HCV HIV co-infected patients. In non-cirrhotic patients, the result is comparable to mono-infected patients. Genotype 3 co-infected are also difficult-to-treat patients. DAA treatment is well-tolerated in HCV/HIV co-infected patients, and there was no dropout during treatment.

Ruptured hepatocellular carcinoma in a patient with chronic hepatitis C and a sustained viral response

Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease in the world (1). The goal of chronic hepatitis C therapy is to prevent cirrhosis of the liver and hepatocellular carcinoma (HCC) by achieving a sustained virologic response (SVR). It has been reported that telaprevir-based triple therapy enabled 60%–70% SVR in genotype 1 (G1) patients (2,3). The 74-year-old male patient was diagnosed with chronic hepatitis C 6 years ago, and peginterferon (P) + ribavirin (R) therapy was initiated. As HCV-RNA positivity continued in the 24th week of treatment, the patient was considered unresponsive, and his treatment was concluded. With the introduction of telaprevir into the therapy approximately one year later, the G1b patient was started on a triple therapy (telaprevir, PR) for 12 weeks followed by a 36-week course of double therapy (PR); thereby, his treatment was completed in a total of 48 weeks. The patient, who now had SVR, has been followed up in the 4 years since the completion of his therapy by carrying out tests on his HCV-RNA and alpha-fetoprotein (AFP) levels, alongside abdominal ultrasonography (ABD USG) performed every 6 months. The patient, who presented to the emergency department with a complaint of severe abdominal pain reflecting on his right shoulder about 4 months after his latest follow-up, had a heterogeneous solid mass about 6 cm in size in his eighth liver segment alongside free fluid in the perihepatic and pelvic areas, as revealed by ABD USG. The results of testing showed that the patient had a high AFP level of 36 ng/mL (0–8.1). The results of all abdominal computed tomography scans carried out in view of these findings showed that the patient’s liver was of a normal size with no pronounced undulation of the contours. A heterogeneous solid mass lesion about 67 × 73 × 68 mm in size growing toward the subdiaphragmatic space in liver segment 8 was observed to reveal a hyperdense, possibly arterial contrasting image; the presence of high-density fluid around the mass in the subdiaphragmatic space was also visualized. Consequently, the rapidly contrasting arterial mass on the hepatic dome was diagnosed as HCC (?), hepatic adenoma (?), and a ruptured mass, and it was recommended that the patient undergo dynamic magnetic resonance (MR). A T1A hypointense, T2A mildly hyperintense heterogeneous solid mass, 63 × 70 mm in size with fine borders and irregular contours, was visualized on the dome level of the eighth segment of the right lobe (Figure 1). As a result, the patient was diagnosed with spontaneous rupture of the mass because of his high AFP levels, the presence of a solid mass concordant with HCC, contour irregularity neighboring the superior, and signs of hemoperitoneum observed in the perihepatic area. The patient was taken into surgery and died in the perioperative period. The risk of HCC development in patients with SVR through direct-acting antiviral (DAA) has proven to be a controversial issue (4,5). Patients with SVR through DAA administration should be followed up every 6 months with regards to ABD USG results and AFP levels.

Effect of vitamin D supplementation on sustained virological response in genotype 1/4 chronic hepatitis C treatment-naïve patients from India.

Background & objectives:The effect of vitamin D supplementation on response to antiviral therapy in hepatitis C virus (HCV) genotype 1 and 4 infection still remains unclear, with studies yielding inconsistent results. The aim of the present study was to assess the effect of vitamin D supplementation on treatment outcome in patients with genotype 1/4 chronic hepatitis C (CHC) infection.Methods:Sixty consecutive, treatment-naïve, genotype 1 and 4 chronic HCV patients were included in the study. The patients were randomized into two groups: Vitamin D supplemented group received pegylated (PEG)-interferon α-2a 180 μg per week plus ribavirin (RBV) (1000-1200 mg/d) together with vitamin D3 (2000 IU/d) and control group received identical therapy without vitamin D (32 patients).Results:There were no significant differences between the two groups in terms of age, sex, body mass index and baseline laboratory values. Lower vitamin D levels were associated with higher grades of fibrosis in liver histology (vitamin D >20 ng/ml - 70% vs vitamin D <20 ng/ml - 37%, P<0.05). Vitamin D supplemented group had similar rapid viral response (40 vs 28%, P=0.36), complete early viral response (53.2 vs 40%, P=0.34), end of treatment response (64 vs 46%, P=0.17) and sustained virological response (SVR) (60 vs 44%, P=0.19) as compared to control group. Interleukin 28B polymorphism [odds ratio (OR)-15.37, 95% confidence interval (CI)-2.32-101.76, P=0.04] and baseline serum vitamin D levels (OR-6.36, 95% CI-1.36-29.61 P=0.02) were independent predictors of SVR in genotype 1/4 CHC. Vitamin D supplementation was not found to be predictor of response in genotype 1/4 CHC on multivariate analysis (OR-2.79, 95% CI- 0.63-12.34, P=0.74).Interpretation & conclusions:The present study showed that addition of vitamin D to PEG/RBV combination therapy in treatment-naïve patients who were infected with HCV genotype 1/4 had no effect on the rates of rapid, early and sustained viral responses.

Efficacy and safety of daclatasvir-based antiviral therapy in hepatitis C virus recurrence after liver transplantation. Role of cirrhosis and genotype 3. A multicenter cohort study.

Direct-acting antiviral agents (DAA) combining daclatasvir (DCV) have reported good outcomes in the recurrence of hepatitis C virus (HCV) infection after liver transplant (LT). However, its effect on the severe recurrence and the risk of death remains controversial. We evaluated the efficacy, predictors of survival, and safety of DAC-based regimens in a large real-world cohort. A total of 331 patients received DCV-based therapy. Duration of therapy and ribavirin use were at the investigator's discretion. The primary end point was sustained virological response (SVR) at week 12. A multivariate analysis of predictive factors of mortality was performed. Intention-to-treat (ITT) and per-protocol SVR were 93.05% and 96.9%. ITT-SVR was lower in cirrhosis (n=163) (96.4% vs. 89.6% P=0.017); the SVR in genotype 3 (n=91) was similar, even in advanced fibrosis (96.7% vs. 88%, P=0.2). Ten patients (3%) experienced virological failure. Therapy was stopped in 18 patients (5.44%), and ten died during treatment. A total of 22 patients (6.6%) died. Albumin (HR=0.376; 95% CI 0.155-0.910) and baseline MELD (HR=1.137; 95% CI: 1.061-1.218) were predictors of death. DCV-based DAA treatment is efficacious and safe in patients with HCV infection after LT. Baseline MELD score and serum albumin are predictors of survival irrespective of viral response.

Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study.

Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. A multicenter, retrospective observational study. The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). Our findings showed that the rate of SVR to dual therapy was higher in treatment-naïve Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients.

Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

BackgroundRibavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR).MethodsWe included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT).ResultsSVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype.ConclusionIn HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.

Boceprevir and telaprevir-based regimens for the treatment of hepatitis C virus in HIV/HCV coinfected patients.

Hepatitis C virus (HCV) treatment in patients coinfected with HIV has historically been limited by poor efficacy and medication toxicities. Direct-acting antivirals (e.g. boceprevir and telaprevir) improve treatment results in clinical trials, but little is known about the outcomes in community-based coinfected populations. This project aimed to describe the real-world effectiveness of boceprevir-based or telaprevir-based therapies in HIV/HCV coinfected patients. We identified HIV/HCV coinfected patients of all genotypes in the Veterans Affairs healthcare system who initiated pegylated interferon and ribavirin with or without boceprevir or telaprevir from June 2011 to November 2012 (n = 134). Sustained virologic response (SVR) was higher in genotype 1 patients receiving boceprevir or telaprevir [n = 62, SVR = 50.0%, 95% confidence interval (CI) 37-63] versus pegylated interferon/ribavirin alone (n = 48, SVR = 33.3%, 95% CI 20-47). Patients with genotypes 2/3 treated with pegylated interferon/ribavirin (n = 24) achieved an SVR of 41.7% (95% CI 20-63). Only a few patients (15-25%) of each genotype completed more than 44 of 48 projected weeks. Treatment with boceprevir or telaprevir was the only characteristic independently associated with SVR in genotype 1 (adjusted odds ratio 2.2, 95% CI 1.1-4.7). Addition of boceprevir or telaprevir to pegylated interferon/ribavirin improves treatment response in genotype 1 HIV/HCV coinfected patients. Treatment response is similar to reports from HCV monoinfected Veterans Affairs patients but lower than those reported in clinical trials. Early treatment discontinuation was common.

Role of Interleukin-10, Interleukin-12 in the Response Prediction during Combined PEG Interferon-alpha 2a and Ribavirin Therapy in Patients with Chronic Hepatitis C

Background: Egypt has the highest prevalence of adult HCV infection in the world, averaging 15%-25% in rural communities. Sustained virological response in genotype 4 Egyptian patients treated with PEG-IFN alfa-2a and ribavirin was estimated around 60%. It is of major interest for both patient care and economic approach to predict failure of response. Several factors have been shown to influence response to antiviral treatment. Cytokines play an important role in the pathogenesis, progression and treatment outcome of HCV infection. Aim: The current study was designated to assess serum interleukin-10 and interleukin-12 levels in CHC genotype 4 patients and investigate their benefit as predictors of antiviral response. Methods: This study was conducted on a total number of 70 participants admitted to Hepatology and Gastroenterology Department in NHTMRI (National Hepatology & Tropical Medicine Research Institute). The participants of this study were divided into two groups as following; Group I: 20 healthy subjects (as controls), while the cases in Group II: 50 patients with chronic hepatitis C (CHC) genotype 4. Results: Our results showed that IL-12 and IL-10 levels were higher in patients with HCV infection than in control participants and were significantly higher in the group of the sustained responders, compared with non-responders. Serum IL-10 level showed a sensitivity and specificity of 76.7% and 73.3% respectively while serum IL-12 level showed sensitivity and specificity of 90% and 75% respectively. Conclusion: These results demonstrate the beneficial role ofIL-10, IL-12 in achieving an SVR during IFN-alpha and ribavirin therapy

Predictive Value of Interferon-Lambda Gene Polymorphisms for Treatment Response in Chronic Hepatitis C

Background IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.MethodsOptimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.ResultsFrequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20–35% vs. 46–47%) this was also true for ss469415590 TT/TT (20–35% vs. 45–47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71–96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.Conclusion IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%.

Impact of host IL28B rs12979860, rs8099917 in interferon responsiveness and advanced liver disease in chronic genotype 3 hepatitis C patients.

Background and AimsGenetic polymorphisms near interleukin 28B gene are associated with spontaneous and treatment induced clearance of hepatitis C virus (HCV). Our objective was to evaluate the impact of interleukin 28B single nucleotide polymorphism (rs12979860, rs8099917) variability in HCV genotype 3 infected populations.Methods400 hepatitis C seroreactive patients from different population groups in Eastern and North Eastern part of India were assessed for host and viral genotypic analysis. 83 HCV genotype 3 infected patients were administered pegylated interferon- ribavirin therapy. Viral genotyping was performed using nested reverse transcriptase-PCR followed by direct sequencing methods. Host interleukin 28B genotyping was performed using real-time PCR based single nucleotide polymorphism analysis.ResultsOut of 400 hepatitis C seroreactive individuals, 73.25% were found to be RNA positive. HCV genotype 3 (65.87%) was found to be the major circulating strain in this region followed by genotype 1 (32.08%). rs12979860 CC genotype was significantly associated with sustained virological response in HCV genotype 3 infected population. In patients achieving rapid virological response, favourable CC/TT allele at rs12979860, rs8099917 was found to be predominant at both the alleles at 77%, 73.2% respectively; whereas in case of patients with relapsed HCV infection CT, TG alleles were found to be predominant. Additionally, CC genotypes at rs12979860 were found to be associated with sustained virological response in patients with high viral load (OR = 6.75, 0.05<p). HCV unfavourable rs12979860 TT, rs8099917 GG alleles were present in 34%, 27.6% patients with relapsed HCV infection respectively. Also unfavourable CT, TG genotypes were found to be predominant in patients with advanced stages of liver disease.ConclusionCC, TT the two favourable markers at SNPs rs12979860 and rs8099917 are strongly associated with sustained virological response in genotype 3 infected populations. This information will aid clinicians to effectively design response based treatment regimen.

Aminoadamantanes for chronic hepatitis C.

Aminoadamantanes for chronic hepatitis C.

Neutrophil-to-lymphocyte ratio as a predictor of response to peginterferon plus ribavirin therapy for chronic hepatitis C.

We aimed to determine whether neutrophil-to-lymphocyte ratio (NLR) could be a predictor of antiviral response in chronic hepatitis C patients. A total of 602 consecutive patients (genotype 1, n = 263; genotype 2, n = 297; others/unknown, n = 42) receiving response-guided therapy with peginterferon plus ribavirin were recruited. NLR was related to clinical and virological features and to treatment outcome. Rapid virological response (RVR) and sustained virological response (SVR) were achieved in 436 (73%) and 458 (76%) of the patients, respectively. Higher NLR (≥1.42) was found to be associated with higher prevalence of DM (P = 0.039) and higher hepatitis C viral load (P = 0.002) and white cell count (P < 0.001). NLR was significantly lower in patients with RVR and SVR compared to those without (P = 0.032 and 0.034, resp.). However, NLR was not an independent factor by multivariate analysis. In the subgroup analysis, higher NLR (≥1.42) (odds ratio, 0.494, P = 0.038) was an independent poor predictor of SVR in genotype 2 patients but was not in genotype 1 patients. In conclusion, NLR is a simple and easily accessible marker to predict response to peginterferon plus ribavirin therapy for chronic hepatitis C genotype 2.

Predictive value of FIB-4 and APRI versus METAVIR on sustained virologic response in genotype 1 hepatitis C patients.

Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications. Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients. CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores (N=1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50IU/mL] by week 4 of treatment (rapid virologic response) and 24weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR (p<0.1×10(-30)) was stronger than that between METAVIR (p=3.86×10(-13)) or APRI (p=5.48×10(-6)) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio. The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40KD)/ribavirin.

Impact of Added Fluvastatin to Standard-of-Care Treatment on Sustained Virological Response in Naïve Chronic Hepatitis C Patients Infected with Genotypes 1 and 3

Objectives: The combination of pegylated interferon-α and ribavirin is a standard-of-care (SOC) treatment for chronic hepatitis C (CHC), and it achieves a sustained virological response (SVR) in 41-52% of genotype 1 and in 73-79% of genotype 3 patients. In a few clinical trials, the combination of fluvastatin and SOC increased the SVR in genotype 1 patients. Methods: This prospective study enrolled 179 naïve CHC patients. In the fluvastatin group patients received the combination of SOC and fluvastatin 80 mg daily; historical controls matching the study group in genotype, age and gender were treated with the SOC treatment only. Results: On-treatment viral responses as well as the SVR did not differ significantly between the two groups, except for the genotype 1 patients with a high viral load presenting a significantly higher SVR rate in the fluvastatin group (75%) compared to the control group (41%; p = 0.024). Multivariate logistic regression identified hepatitis C virus (HCV) genotype 3 infection (p < 0.001), age ≤40 years (p < 0.001), liver steatosis <5% (p < 0.01) and low viral load (p < 0.001) as independent predictors of an SVR. Conclusion: A combination of fluvastatin and SOC significantly improved the SVR in naïve CHC patients infected with HCV genotype 1 and high viral load, but it did not improve the SVR in patients infected with HCV genotype 3.

Found in Translation.

Since the identification of the hepatitis C virus (HCV) and subsequent cloning of its genome in 1989, only relatively modest progress had been made in the treatment of its chronic infection until recently. Interferon-alfa was approved in 1991 for the treatment of HCV infection, and provided a sustained virological response (SVR) of 9% for genotype 1, and 20–30% for genotypes 2 and 3. With the addition of ribavirin in 1998, the SVR of interferon-ribavirin combination therapy increased to 29% for genotype 1, and 62% for genotypes 2 and 3. The development of long-acting pegylated (PEG)-interferons plus ribavirin in 2001–2002 increased SVR incrementally to 41% for genotype 1, and 82% for genotypes 2 and 3. After this advance, the situation remained static for almost 10 years without significant breakthroughs, until the advent of the protease inhibitors telaprevir and boceprevir in 2011. These agents represent the vanguard of a new class of HCV drugs, the direct-acting antiviral agents, and a new era in the treatment of HCV. With the triple therapy regimen of PEG-interferon, ribavirin, and either telaprevir or boceprevir, the SVR for genotype 1 HCV ranges from 70 to 80%. Now, for the first time, persons infected with genotype 1 HCV can expect a higher than 50% chance of achieving an SVR to antiviral therapy. The development of current protease inhibitors exemplifies translational research at its best. Fundamental structural crystallographic data on HCV proteases led to an understanding of the dimensions and chemical environment of the catalytic area. Based on these details, molecules were synthesized with peptide-like backbones containing several non-natural side chains arranged to optimally interact with catalytic domains of the HCV protease. Binding assays permitted screening of molecules capable of tight interactions with the protease. This, coupled with advances in the development of cell culture systems, allowed identification of agents that effectively inhibited HCV replication. Use of model human serine proteases permitted large-scale screening, and exclusion of molecules with the potential for causing side effects through the unintended interactions with host serine proteases. Development of these agents represents the translation of research on molecules at the bench to highly effective drugs at the bedside, and US FDA approval has made these new powerful agents available to the public as the first true “designer” drugs for the treatment of hepatitis C. Perhaps even more exciting than these advances in the understanding of the virus, and development of hepatitis therapeutics is evidence that research activity is continuing at a feverish pace, in both academic and commercial laboratories, with large financial commitments. Breakthroughs are continuing to be made on many fronts contributing to anti-HCV drug development. Having achieved this first quantum leap forward, the main goal of future research will be to develop new agents that will have fewer side effects, especially those attributed to interferon-like immune modulators, and broader specificity in terms of HCV genotypes, decreased drug-drug interactions, and especially decreased likelihood of the development of drug resistance. The objective of the Journal of Clinical and Translational Hepatology is to identify and publish articles that represent similar translations of fundamental research to contributions of direct practical value. Therefore, we believe that it is entirely fitting that we devote the theme of the inaugural issue of the Journal of Clinical and Translational Hepatology to drug development in hepatology. In the coming months, we intend to apply the same approach to the selection of articles of translational importance to other areas of hepatology. In particular, the increased understanding of the mechanisms of development of autoimmune liver and biliary diseases, and powerful agents for their treatment will be addressed. Infectious and inflammatory, as well as nutritional and neoplastic conditions of the liver will be areas of thematic emphasis for future issues. These are exciting times for clinicians and investigators who are interested in the liver and its diseases. We are thrilled to share the excitement by bringing to your attention the latest advances in translational research in hepatology through the pages of this new journal! Farmington, CT June 2013

Impact of the peginterferon‐α 2a and ribavirin plasma levels on viral kinetics and sustained virological response in genotype 1 HCV/HIV‐co‐infected patients with the unfavourable non‐CC IL28B genotypes

Studies on the association between the peginterferon-α and ribavirin levels and sustained virological response (SVR) have shown yielded conflicting results, but most of them were performed before the influence of IL28B polymorphisms was known. Our aim was to assess the effects of peginterferon-α 2a and ribavirin plasma levels on viral kinetics and SVR in hepatitis C virus genotype 1 HCV-1/HIV-co-infected patients according to IL28B genotype. This was a cohort study of HCV-1/HIV-co-infected patients who were HCV-treatment naïve and for whom the efficacy of peginterferon-α 2a plus ribavirin was evaluated by per-protocol analysis. The peginterferon-α 2a and ribavirin levels were measured by ELISA and HPLC-UV, respectively. The relationships among host and viral factors, the trough drugs levels and virological responses were analysed by multivariate regression analyses. A total of 131 Caucasian patients were included (cirrhosis:38.9%). Overall, SVR rate was 39.6%. In patients with CC IL28B genotype, SVR was related neither to peginterferon-α 2a nor to ribavirin plasma levels, while higher levels of both drugs were the only variables independently associated with SVR in individuals with CT/TT IL28B genotypes (OR, 5.02; CI95 , 1.45-17.1; P=0.001 and 4.0; CI95 , 1.08-14.7; P=0.038, respectively). Moreover, faster viral declines were observed in CT/TT patients when pegIFN-α 2a and ribavirin plasma levels were greater than 3400pg/mL and 1.6μg/mL, respectively. In contrast to the results for CC patients, the results in patients carrying the unfavourable CT/TT IL28B genotypes showed that plasma levels of both drugs have significant effects on viral kinetics and SVR.

A multicenter survey of re‐treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan

This study aimed to clarify the factors associated the efficacy of re-treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment. One hundred and forty-three patients who had previously shown relapse (n = 79), non-response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re-treated with PEG IFN plus ribavirin. Twenty-five patients with intolerance to previous treatment completed re-treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re-treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re-treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin-28B major genotype responded significantly better and earlier to re-treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re-treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05). Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re-treatment for HCV genotype 1 patients. Re-treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re-treatment.

Impact of genetic SLC28 transporter and ITPA variants on ribavirin serum level, hemoglobin drop and therapeutic response in patients with HCV infection

In the last decade, pegylated interferon-α (PegIFN-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed at studying genetic determinants of RBV kinetics, efficacy and treatment-associated anemia. We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726, and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101, and followed for treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients, RBV serum levels were additionally measured during treatment. Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ≥3 g/dl during treatment, in genotype (relative risk (RR)=2.1, 95% CI 1.3-3.5) as well as allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as allelic analyses (RR=2.0, 95% CI 1.1-3.4). The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response, may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.

Rapid, early and sustained virological responses in a cohort of Irish patients treated with pegylated interferon and ribavirin for chronic hepatitis C virus infection

The response to the treatment with pegylated interferon (PEG IFN)-α combined with ribavirin in chronic hepatitis C virus (HCV) infection varies with some patients having a rapid or early response which is not sustained. To investigate the rates of rapid virological response (RVR), early virological response (EVR) and sustained virological response (SVR) in an Irish cohort of HCV infected patients receiving IFN-α/ribavirin. Rates of RVR, EVR and SVR were examined in 123 patients undergoing standard treatment for chronic HCV infection between 2001 and 2007 at a Dublin Teaching Hospital. The rates of RVR, EVR and SVR in genotype 1 patients were 48, 68 and 50%, while in genotype 2/3 patients they were 87, 93 and 87%, respectively. The positive predictive values (PPV) of RVR for SVR in genotype 1 and genotype 2/3 patients were 90 and 92.4%, respectively. The rates of response to PEG IFN-α/ribavirin in Irish patients are consistent with other international reports. We support the regular monitoring of rapid and early virological response as a standard of care in treating chronic hepatitis C patients.

Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin Increased Sustained Virologic Response in Genotype 1 Chronic HCV and Allowed for Shorter Treatment Duration in Treatment-naïve and Prior Relapser Patients: 2011 ACG Presidential Poster

Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin Increased Sustained Virologic Response in Genotype 1 Chronic HCV and Allowed for Shorter Treatment Duration in Treatment-naïve and Prior Relapser Patients: 2011 ACG Presidential Poster