IFN-free Regimens Research Articles

Does a detectable HCV RNA at the end of DAA therapy herald treatment failure?

Background & aimsThe study aimed to assess the phenomenon of achieving sustained virologic response (SVR) in patients with detectable ribonucleic acid (RNA) of hepatitis C virus (HCV) at the end of treatment (ET) with direct-acting antivirals (DAA), find how this is affected by the type of regimen, and how patients experiencing this differed from non-responders with detectable HCV RNA at the ET. MethodsThe study included all consecutive patients with detectable HCV RNA at the ET selected from the EpiTer-2 database, a retrospective national multicentre project evaluating antiviral treatment in HCV-infected patients in 2015–2023. ResultsOf the 16106 patients treated with IFN-free regimens with available HCV RNA assessment at the ET and at follow-up 12 weeks after treatment completion (FU), 1253 (7.8%) had detectable HCV RNA at the ET, and 1120 of them (89%) finally achieved SVR. This phenomenon was significantly more frequent in pangenotypic regimens, 10.3% vs. 4.7% in genotype-specific options (p < 0.001), and the highest proportion was documented for glecaprevir/pibrentasvir (13.7%), and velpatasvir/sofosbuvir ± ribavirin (6.9%). Patients ET + FU- treated with these two pangenotypic regimens (n = 668) had less advanced liver disease, were less frequently infected with genotype (GT) 3, and were significantly more likely to be treatment-naïve than 61 non-responders. ConclusionsWe documented 7.8% rate of patients with detectable HCV RNA at the ET, of whom 89% subsequently achieved SVR, significantly more frequently in the population treated with pangenotypic regimens. Less severe liver disease, more often GT3 infection, and a higher percentage of treatment-naive patients distinguished this group from non-responders.

Impact of Interferon-Free Direct-Acting Antivirals on the Incidence of Extrahepatic Malignancies in Patients with Chronic Hepatitis C.

The incidence of extrahepatic malignancies (EHMs) after hepatitis C virus (HCV) eradication by interferon (IFN)-based and IFN-free direct-acting antivirals (DAAs) treatment remains unclear. The aim was to evaluate the cumulative incidence of EHMs diagnosed for the first time after the antiviral treatments. We analyzed a total 527 patients with chronic HCV infection and without prior history of any malignancies who achieved sustained virological response by antiviral treatments, including IFN-based (n = 242) or IFN-free DAAs (n = 285). The baseline predictors for EHM occurrence were analyzed using Cox regression analysis. Thirty-two patients were diagnosed with EHMs, 14 in IFN-based and 18 in IFN-free DAAs, respectively. The total duration of follow-up was 1,796 person-years in IFN-based and 823 person-years in IFN-free DAAs. The incidence of EHMs in IFN-based and IFN-free DAAs was 7.8 and 21.9 per 1,000 person-years, respectively. The cumulative incidence of EHMs was significantly higher in IFN-free DAAs than IFN-based (p = 0.002). IFN-free DAAs was a single independent predictor for incidence of EHMs (p = 0.012). As for gender, the incidence of EHMs was significantly higher in IFN-free DAAs only in the female cohort (p = 0.002). After propensity score matching, IFN-free DAAs was a single independent predictor for incidence of EHMs in the female patients (p = 0.045). The incidence of EHMs after HCV eradication is higher in IFN-free DAAs than IFN-based regimens, especially in female patients. We should carefully follow-up not only HCC but also EHMs after IFN-free DAAs regimens.

Assessment of carotid atherosclerosis in Egyptian chronic hepatitis C patients after treatment by direct-acting antiviral drugs

BackgroundRecent studies suggested association between hepatitis C virus (HCV) infection and cardiovascular disorders, including carotid atherosclerosis with evidence of an effect of HCV clearance on carotid atherosclerosis.ObjectivesWe aimed to evaluate the impact of direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection on carotid atherosclerosis.Subjects and methodsThis is a prospective cohort study that was carried out in Internal Medicine and Hepatology Department, and outpatient clinics of the Ain Shams University hospitals included 80 Egyptian patients with chronic HCV infection who started treatment in the form of IFN-free DAA-based regimen and completed the course of treatment and 6-month follow-up period. All patients were subjected to detailed history taking, full physical examination, full laboratory investigations, radiological assessment by abdominal ultrasonography, and high-resolution B-mode ultrasonography of both the common carotid arteries.ResultsThe mean age of cases was 58.13 ± 7.56 years, 49 (61.25%) males and 31 (38.75%) females. IMT was significantly decreased after treatment 1.24 versus 1.57 mm p < 0.001. The number of patients with IMT ≥ 1 mm was significantly decreased after 6 months 45 (56.3%) versus 57 (71.3%). There was significant positive correlation between baseline carotid IMT and age, BMI, bilirubin, INR, CTP score, carotid plaques, and total cholesterol. Meanwhile, there was significant negative correlation between baseline carotid IMT and hemoglobin, platelets, albumin, and HDL. In patients who achieved SVR, total cholesterol, triglycerides, LDL, and HDL were significantly increased after treatment. IMT was significantly lower in SVR group compared to non-SVR group (p = 0.016).ConclusionHepatitis C virus eradication by DAAs improves carotid atherosclerosis by decreasing carotid intima-media thickening.

Evolution of HCV associated porphyria cutanea tarda after HCV sustained virologic response by direct acting antivirals

ObjectivesPorphyria cutanea tarda (PCT) is common and usually associated with HCV chronic infection and HFE polymorphisms. Since DAA IFN-free regimens availability, SVR for HCV is nearly a constant and we wonder whether HCV SVR determine PCT evolution. MethodsRetrospective observational study including patients with HCV associated PCT from the Gastroenterology and Infectious Diseases Departments at our Hospital, treated with DAA (Apr/2015–Apr/2017). Clinical variables of PCT were collected at PCT diagnosis, after PCT treatment, before DAA use and after SVR achievement. UROD activity and C282Y/H63D polymorphisms were registered. SPSS 22.0. Results13 HCV-PCT patients included: median age 52.5 years; 4 females; 8 HCV/HIV co-infected (all on undetectable viral load). Classical PCT factors: 12 smoked, 9 alcohol abuse, 6 former IDU. 10 type I PCT and 1 type II PCT. HFE polymorphism: 2 cases with C282Y/H63D; H63D polymorphism in 8. PCT manifestations resolved with PCT treatment in 4 patients, almost completely in 7 patients, 1 patient referred stabilization and one worsened. After DAA treatment all the residual lesions resolved, what always led to specific treatment interruption. ConclusionsOur series of cases of HCV-associated PCT shows that SVR after DAA treatment leads to PCT resolution. Porphyrin levels are not needed after ending PCT specific treatment interruption when there are no residual skin lesions in HCV-associated PCT.

Diagnosis and monitoring of hepatitis C virus infection using the cobas® HCV test for use on the cobas® 4800 system.

• Accurate HCV RNA measurements is important for clinical decision-making • SVR, the endpoint of HCV therapy, is defined by undetectable HCV RNA 12 or 24 weeks after the end of therapy • The cobas® HCV Test is sensitive, precise and reproducible • The cobas HCV Test accurately quantifies HCV RNA in patients receiving IFN-free DAA regimens • Overall percentage agreement of SVR for cobas HCV test and Abbott RealTime HCV was 100%

Change in hepatitis C virus positivity among needle-stick injury source patients: a 10-year experience in a Japanese tertiary hospital

BackgroundAs a blood-borne pathogen, hepatitis C virus (HCV) has long been a major threat associated with needle-stick injuries (NSIs) mainly because no vaccine is available for HCV. Following an NSI, we usually test the source patient for HCV antibody (HCV-Ab). Since HCV-Ab positivity does not necessarily indicate current infection, HCV RNA is further examined in patients positive for HCV-Ab. Direct-acting antivirals (DAAs) have enabled us to treat most HCV-infected patients; therefore, we speculate that the rate of HCV RNA positivity among HCV-Ab-positive patients decreased after the emergence of DAAs. This cross-sectional study was performed to investigate the change in the actual HCV RNA positivity rate in source patients before and after the interferon (IFN)-free DAA era.MethodsThis was a cross-sectional study of NSI source patients at a tertiary academic hospital in Japan from 2009 to 2019. IFN-free DAA regimens were first introduced in Japan in 2014. Accordingly, we compared HCV status of NSI source patients that occurred between 2009 and 2014 (the era before IFN-free DAAs) with those that occurred between 2015 and 2019 (the era of IFN-free DAAs) in a tertiary care hospital in Japan.ResultsIn total, 1435 NSIs occurred, and 150 HCV-Ab-positive patients were analyzed. The proportion of HCV RNA-positive patients significantly changed from 2009 through 2019 (p = 0.005, Cochran–Armitage test). Between 2009 and 2014, 102 source patients were HCV-Ab-positive, 78 of whom were also positive for HCV RNA (76.5%; 95%CI, 67.4–83.6%). Between 2015 and 2019, 48 patients were HCV-Ab-positive, 23 of whom were also positive for HCV RNA (47.9%; 95%CI, 34.5–61.7%; p = 0.0007 compared with 2009–2014). In the era of IFN-free DAAs, 9 of 23 HCV RNA-negative patients (39.1%) and 2 of 22 HCV RNA-positive patients (9.1%) were treated with an IFN-free combination of DAAs (p = 0.0351). Regarding the departments where NSIs occurred, HCV RNA-negative patients were predominant in departments not related to liver diseases in the era of IFN-free DAAs (p = 0.0078, compared with 2009–2014).ConclusionsActual HCV RNA positivity in source patients of NSIs decreased after the emergence of IFN-free DAAs. IFN-free DAAs might have contributed to this reduction, and HCV RNA-negative patients were predominant in departments not related to liver diseases in the era of IFN-free DAAs.

Genotype 3-hepatitis C virus' last line of defense.

Chronic infection with hepatitis C virus (HCV) is one of the leading causes of liver disease globally, affecting approximately 71 million people. The majority of them are infected with genotype (GT) 1 but infections with GT3 are second in frequency. For many years, GT3 was considered to be less pathogenic compared to other GTs in the HCV family due to its favorable response to interferon (IFN)-based regimen. However, the growing evidence of a higher rate of steatosis, more rapid progression of liver fibrosis, and lower efficacy of antiviral treatment compared to infection with other HCV GTs has changed this conviction. This review presents the specifics of the course of GT3 infection and the development of therapeutic options for GT3-infected patients in the era of direct-acting antivirals (DAA). The way from a standard of care therapy with pegylated IFN-alpha (pegIFNα) and ribavirin (RBV) through a triple combination of pegIFNα + RBV and DAA to the highly potent IFN-free pangenotypic DAA regimens is discussed along with some treatment options which appeared to be dead ends. Although the implementation of highly effective pangenotypic regimens is the most recent stage of revolution in the treatment of GT3 infection, there is still room for improvement, especially in patients with liver cirrhosis and those who fail to respond to DAA therapies, particularly those containing inhibitors of HCV nonstructural protein 5A.

Противовирусная терапия хронического гепатита С: многолетний опыт реальной клинической практики

Direct-acting antivirals (DAAs) have significantly changed the treatment of chronic hepatitis C (CHC) and the prognosis for patients since their introduction into clinical practice in 2014–2015. Objective. Study of the evolution and efficacy of antiviral therapy (AVT) for CHC based on the results of providing medical care to patients in Moscow in 2002–2020. Patients and methods. The study was conducted in the Center for the Treatment of Chronic Viral Hepatitis “Infectious Clinical Hospital No 1 of the Moscow City Health Department”. For quantitative variables, the mean and standard deviation were used, while for categorical variables, frequency and proportion were counted (%). Results. 69,745 patients were diagnosed with CHC among all the patients who were examined in the Center. The pooled SVR rate of various therapy regimens was as follows in the HCV genotype 1 (GT1) cohort: IFN + ribavirin – 41.7%; DAAs + PegIFN + ribavirin – 77.4%; IFN-free regimens – 94.0%. Age older than 40 years, diabetes mellitus (DM), history of AVT failure (retreatment), and liver cirrhosis (LC) adversely affected the achievement of SVR. In the patients with HCV GT2 and GT3, the IFN + ribavirin combination allowed SVR achievement in 68.5% of patients, while IFN-free regimens were effective in 95.2% of patients. The predictive factors for achieving SVR were similar to those in the GT1 subgroup, except that the effect of age and DM did not reach statistical significance. Conclusions. The efficacy of DAAs in real clinical practice significantly exceeds the efficacy of IFN-based regimens in patients with various HCV infection genotypes. Achievement of SVR as a result of AVT reduces the likelihood of LC and HCC development. Key words: viral hepatitis, chronic hepatitis, antiviral therapy, peginterferon, interferon-free, dual therapy, triple therapy

1067. Interferon-free Hepatitis C Treatment Increases Surrogates of Cardiovascular Disease Risk in Black Veterans

BackgroundSustained virologic response (SVR) after hepatitis C virus (HCV) treatment with either Interferon (IFN)-based or IFN-free regimens with direct-acting antivirals (DAAs) has been shown to reduce cardiovascular disease (CVD) events in majority white populations stratified by ASCVD score. However, the effect of IFN-free therapy on lipid profiles after SVR, as an indirect measure of CVD risk, is unknown in Black patients.MethodsWe evaluated HCV-infected Veterans from the Baltimore VA who were treated with DAAs between 2015-2019. We performed a retrospective analysis comparing lipid profile changes following SVR among those with early stage (F0-F2) fibrosis and advanced liver disease (ALD, F3-F4 fibrosis) using two-tailed paired t-tests. Independent t-tests were used to assess differences in lipid profiles based on fibrosis stage in patients with HIV and Type II Diabetes Mellitus (DM2).ResultsOf those treated for HCV (n=1,528), 96% (n=1,474) achieved SVR. Demographics are shown in Table 1. Most patients were Black males (75%) and a minority (2.7%) received statin therapy during treatment (Table 1). Of 1,094 patients for whom data was available, an increase in total cholesterol (TC) and LDL (p< 0.01 for both) was seen an average of 17 months after SVR, regardless of fibrosis stage (Figure 1). A significant decrease in triglyceride levels (p=0.04) was also seen in the ALD group after SVR (Figure 1). Mean pre-treatment HCV RNA level was comparable between fibrosis groups (F0-F2: 6.35 logs, F3-F4: 6.37 logs, p=0.46). There were 101 and 436 patients with HIV and DM2, respectively, for whom pre-treatment liver fibrosis data was available. In both groups, there were significant increases in LDL (p=0.008 (HIV), p=0.003 (DM2)) among patients with ALD following SVR.Table 1. Baseline characteristics of treated HCV-infected persons who achieved SVR. Figure 1. Mean lipid profile parameters before and after HCV treatment for patients who achieved SVR. TC was measured a mean of 8.1 months (228 days, SD 333 days) before treatment and 17.4 months (488 days, SD 196 days) after SVR. LDL was measured a mean of 8 months (224 days, SD 284 days) before treatment and 17.5 months (492 days, SD 201 days) after SVR. *=differences in means using paired t-test were statistically significant with p<0.05. HCV= Hepatitis C Virus, SVR= Sustained Virologic Response TC=Total Cholesterol, HDL= High Density Lipoprotein, LDL= Lipoprotein, TG= Triglycerides. ConclusionIn a cohort of mostly Black HCV-infected Veterans, significant increases in TC, driven by increases in LDL, were seen after SVR regardless of fibrosis stage. In addition, patients with ALD and HIV or DM2, who have an inherently higher risk of CVD, had increased LDL levels, suggesting that these patients should be screened and treated for HCV prior to development of ALD. Correlates such as the ASCVD score should be considered in the timing of HCV treatment, in order to reduce the long-term risk of CVD.Disclosures Shyam Kottilil, MD PhD, Arbutus Pharmaceuticals (Grant/Research Support)Gilead Sciences (Grant/Research Support)Merck Inc (Grant/Research Support, Advisor or Review Panel member)

Timing of DAA Initiation After Curative Treatment and Its Relationship with the Recurrence of HCV-Related HCC.

Hepatitis C virus infection is a major cause of chronic hepatitis, leading to cirrhosis and hepatocellular carcinoma (HCC). Many studies agree that interferon (IFN)-based antiviral therapy can reduce the risk of HCC recurrence in patients with chronic hepatitis C who have achieved a sustained virological response (SVR). The recent introduction of direct-acting antivirals (DAA) has resulted in excitingly high SVR rates. However, as an IFN-free regimen, DAAs only exert antiviral activity without an immune response. The benefit of DAA-based regimens for HCC recurrence in patients with cirrhosis and following successful curative treatment remains controversial. Additionally, the time span between curative-intent therapy and the DAA regimen is an independent risk factor for HCC recurrence, irrespective of the DAA response. HCC patients who are eligible for potentially curative therapy by liver resection or ablation should defer DAA therapy; however, the accurate timing remains unclear. In this study, we reviewed the timing of DAA initiation after curative treatment and its effect on the recurrence of related HCC.

Successful DAA therapy for chronic hepatitis C reduces HLA-DR on monocytes and circulating immune mediators: A long-term follow-up study

IntroductionAfter DAA treatment for chronic hepatitis C infection, peripheral monocyte subsets from patients who achieved sustained virological response (SVR) reduced compared to healthy control. Improvement in inflammatory parameters and liver stiffness has been observed. However, little is known about the long-term impact of DAA treatment on peripheral monocyte subsets and immune mediators levels. ObjectivesWe aimed to examine peripheral monocyte subsets and immune mediators levels in Brazilian chronic HCV patients after long-term successful IFN-free SOF-based treatment. Material and methodsWe analyzed CD14++CD16-, CD14++CD16+ and CD14+CD16++ monocytes and 27 immune mediators by flow cytometry and analysis of multiple secreted proteins assay, respectively, in monoinfected chronic HCV patients receiving IFN-free sofosbuvir-based regimens followed before treatment, at SVR and one year after the end of treatment (1y). ResultsTwenty-one biomarkers decreased significantly at 1y and 55–80 % of patients this reduction at 1y. Experimented patients presented a greater modulation of immune mediators at 1y. HLA-DR expression significantly decreased on CD14++CD16- and CD14++CD16+ monocytes at 1y when compared to SVR. ConclusionsSuccessful DAA therapy did not modify monocyte subsets frequency but reduced monocyte activation at 1y and sustained the downregulation and restoration of circulating immune mediators, indicating that long-term reversal of inflammation status could occur after HCV eradication.

Impact of IFN-Free and IFN-Based Treatment on Blood Myeloid Dendritic Cell, Monocyte, Slan-DC, and Activated T Lymphocyte Dynamics during HCV Infection.

Chronic hepatitis C virus infection leads to the activation of innate immunity, a key component in HCV fibrosis. In the past, the use of IFN-based treatment regimens did not permit an adequate evaluation of the impact of HCV clearance on immune cells, because of their antiviral and immunomodulatory properties. The recent development of direct-acting antiviral (DAA) therapy, which is associated with high rates of sustained virological response, enables a more accurate analysis of the immunological modifications following HCV eradication. We studied the dynamics of blood myeloid dendritic cells, monocytes, slan-DCs, and T lymphocytes during IFN-free and IFN-based regimens in hepatitis C virus infection.

The Daclatasvir/Asunaprevir/Beclabuvir Combination Therapy for Chronic Hepatitis C Patients Experiencing Failure of IFN-Free DAA-Based Therapies

Background: Daclatasvir/asunaprevir/beclabuvir (DCV/ASV/BCV) combination therapy had been available for the treatment of chronic hepatitis C patients with genotype 1 (CHG1) in Japan. Our aim was to report the efficacy and safety of DCV/ASV/BCV in patients experiencing treatment failure with interferon (IFN)-free direct-acting antiviral agent (DAA)-based therapies, which have not been fully evaluated. Methods: We evaluated the efficacy and safety of 12-week DCV/ASV/BCV combination therapy for CHG1 patients experiencing failure of DCV/ASV and/or sofosbuvir/ledipasvir (SOF/LDV). Results: Nine patients were eligible for inclusion in this study. The previous IFN-free DAA-based therapies included DCV/ASV (n=7). SOF/LDV (n=1) and both DCV/ASV and SOF/LDV (n=1). The sustained virologic response at post-treatment week (PTW) 24 (SVR24) rate was 33.3% (3/9) and an SVR24 was obtained in patients who previously received DCV/ASV. Notably, virologic relapse occurred at PTW16 or 18 in 2 patients. “D168E or D168H in addition to Y93H”, “presumed L31 deletion (L31del) and/or P32del”, and “P29del” might contribute to the resistance to DCV/ASV/BCV combination therapy. One patient developed Grade 3 liver dysfunction but treatment could be completed with dose modification. Conclusions: The efficacy of DCV/ASV/BCV combination therapy in patients who experienced treatment failure with IFN-free DAA-based combination regimens was unsatisfactory, although the therapy was relatively well-tolerated. As virologic relapse occurred after PTW 12 in two cases, an SVR24 might be more suitable for judging viral eradication than an SVR12. The role of resistance-associated substitutions in patients who experience treatment failure with DCV/ASV/BCV combination therapy should be further evaluated.

Efficacy and safety of interferon-free regimens in patients affected by chronic hepatitis C and psychiatric disorders

The presence of psychiatric disorders (PD) in patients affected by chronic hepatitis C (CHC) was a major contraindication for the treatment with interferon (IFN)-based regimens. The novel IFN-free approach using the direct-acting antiviral agents (DAAs) is an interesting and promising chance for these subjects. In this retrospective analysis we focused the attention on the virological response and safety of CHC patients affected by PD and treated with IFN-free regimens.136 subjects were enrolled in this study. Treatment naïve were 78 (57.3), experienced 58 (42.6%). Major depression was present in 25 patients (18.4%), anxiety disorders in 37 (27.2%), bipolar disorders in 23 (16.9%), schizophrenia in 17 (12.5%), behavioral disturbance in 21 (15.4%), psychosis in 13 (9.5%). Psychoactive medication taken by patients were: benzodiazepines (n = 29, 21.3%), antidepressants (n = 24, 17.6%), neuroleptics (n = 29, 21.3%), mood stabilizers (n = 19, 14%), combinations of different drugs (n = 17, 12.5%). Sustained virological response at 12 weeks of follow-up (SVR12) was observed in 128 patients (94.1%), drop-out were 3 (2.2%). No adverse events or significant drug-related side-effects were reported.The treatment with novel IFN-free therapies against CHC were higher effective and well tolerated also in patients with PD taking psychoactive medications.

Evolution of HCV patient characteristics and DAA regimens in the German Hepatitis C Registry (DHC-R) in 2014 and 2015.

The urgent need in HCV-infected patients with liver disease mandated the rapid implementation of IFN-free DAA combination therapies following their regulatory approval in 2014 and 2015 without full knowledge of the optimal combinations and regimens. Investigating the evolution of the DAA utilization patterns and treatment outcomes could provide learnings for future situations. This was an analysis of a prospective observational database from the German Hepatitis C Registry (DHC-R) covering a period from May 2014 to September 2015. Adult patients had evidence of chronic HCV GT1 or GT4 infection and were treated with an IFN-free combination regimen of simeprevir (SMV) + sofosbuvir (SOF) or other IFN-free regimens: daclatasvir + sofosbuvir (DCV + SOF), ledipasvir/sofosbuvir (SOF/LDV), paritaprevir/r + ombitasvir ± dasabuvir (PrOD), with or without ribavirine (R). A total of 5496 subjects were followed during the period. During this period, clinical recommendations and treatment patterns evolved rapidly in response to new evidence from clinical trials and clinical routine and regulatory approval of additional regimens. High SVR12 rates were seen in this cohort, even in hard-to-treat patient subgroups. In the multivariate analysis, gender, age, advanced cirrhosis, and intensified treatment for cirrhotics were associated with treatment outcome. Despite limited knowledge of the optimal utilization of the newly approved DAA combinations and treatment durations as well as their comparative efficacy and safety profiles, high SVR rates were achieved regardless of the DAA combination. These outcomes were facilitated by the rapid adaptation of clinical recommendations. Future situations with high unmet medical need may follow a similar approach.

The metabolic fingerprints of HCV and HBV infections studied by Nuclear Magnetic Resonance Spectroscopy

Few studies are available on metabolic changes in liver injuries and this is the first metabolomic study evaluating a group of HCV-positive patients, before and after viral eradication via DAA IFN-free regimens, using 1H-NMR to characterize and compare their serum fingerprints to naïve HBV-patients and healthy donors. The investigation clearly shows differences in the metabolomic profile of HCV patients before and after effective DAA treatment. Significant changes in metabolites levels in patients undergoing therapy suggest alterations in several metabolic pathways. It has been shown that 1H-NMR fingerprinting approach is an optimal technique in predicting the specific infection and the healthy status of studied subjects (Monte-Carlo cross validated accuracies: 86% in the HCV vs HBV model, 98.7% in the HCV vs HC model). Metabolite data collected support the hypothesis that the HCV virus induces glycolysis over oxidative phosphorylation in a similar manner to the Warburg effect in cancer, moreover our results have demonstrated a different action of the two viruses on cellular metabolism, corroborating the hypothesis that the metabolic perturbation on patients could be attributed to a direct role in viral infection. This metabolomic study has revealed some alteration in metabolites for the first time (2-oxoglutarate and 3-hydroxybutrate) concerning the HCV-infection model that could explain several extrahepatic manifestations associated with such an infection.

Real World Experience of Chronic Hepatitis C Retreatment with Genotype Specific Regimens in Nonresponders to Previous Interferon-Free Therapy.

Background and Aim The development of interferon- (IFN-) free regimens substantially improved efficacy of treatment for HCV, but despite excellent effectiveness the failures still occur. The aim of our study was to evaluate the efficacy of retreatment with genotype specific direct acting antivirals- (DAA-) based regimens in nonresponders to previous IFN-free therapy. Materials and Methods Analysed population consisted of 31 nonresponders to IFN-free regimen, which received second IFN-free rescue therapy, selected from 6228 patients included in a national database EpiTer-2. Results Age and gender distribution were similar, whereas proportion of genotype 1b was slightly higher and genotype 4 lower in the whole population compared to studied one. Patients included in the study demonstrated much more advanced fibrosis. Primary therapy was discontinued in 12 patients, which were recognized as failures due to nonvirologic reason, whereas virologic reason of therapeutic failure was recognized in 19 patients which completed therapy. Overall sustained virologic response (SVR) rate was 81% and 86% in intent-to-treat (ITT) and modified ITT analysis, respectively (74% and 78% in virologic failures, 92% and 100% in nonvirologic failures). Resistance-associated substitutions (RAS) testing was carried out in 8 patients from the group of completed primary therapy and three of them had potential risk for failure of rescue therapy due to NS5A association, while two of them achieved SVR. Conclusions We demonstrated moderate effectiveness of genotype specific rescue therapy in failures due to virologic reason and high in those who discontinued primary therapy. Therefore rescue therapy with genotype specific regimens should be considered always if more potent regimens are not available.

Hepatitis C late relapse in patients with directly acting antiviral-related sustained virological response at week 12.

The aim of the present study was to identify, among the patients with failure to DAA regimen, those with a late relapse (after the achievement of a sustained virological response at week 12) and to characterize the clinical, epidemiological and virological features of these patients. A total of 129 HCV patients with non-response to an IFN-free regimen were enrolled. Sanger sequencing of NS3, NS5A and NS5B was performed at failure by home-made protocols. Of the 129 patients enrolled, 8 (6.2%) experienced a breakthrough, 15 (11.7%) non-response, 99 (76.7%) a relapse by week 12 after the end of DAA therapy, and 7 (5.4%) a late relapse (after week 12; median 24weeks, range 24-72). For two of the seven patients with a late relapse, a serum sample collected before the start of the DAA regimen was available; phylogenetic analysis showed no change in sequences of NS3, NS5A and NS5B regions, suggesting a reactivation of the initial HCV strain; for the remaining five patients, no serum collected before the DAA regimen was available, and thus, a re-infection cannot be excluded. Although a late relapse is infrequent, the study suggests a post-treatment follow-up of 72weeks.

TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy.

The aim of this study is to ascertain whether the TLL1 variant at rs17047200 is associated with the development of HCC after achieving sustained virological response (SVR) by interferon (IFN)-free therapy for chronic hepatitis C (CHC). A total of 1029 Japanese CHC patients with the following inclusion criteria were enrolled: (i) achieved SVR by IFN-free therapy, (ii) followed up at least 1year from the end of treatment (EOT) (median 104weeks), (iii) no history of hepatocellular carcinoma (HCC) by 1year from the EOT. Nineteen patients developed HCC (HCC group) and 1010 did not (non-HCC group). The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group (47.4% vs. 20.1%, P = 0.008). Multivariate analysis showed that higher levels of α-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC (HR = 3.22, P = 0.021 for α-fetoprotein > 4.6ng/ml; HR = 3.89, P = 0.036 for FIB-4 > 2.67; HR = 2.80, P = 0.026 for rs17047200 AT/TT). Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA (P = 0.006). Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA (P = 0.011 and 0.032, respectively). The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. It might be involved in hepatic fibrogenesis and thereby carcinogenesis.

Patients with HCV Genotype-1 who have Failed a Direct-Acting Antiviral Regimen: Virological Characteristics and Efficacy of Retreatment

This real-world clinical setting study characterized the virological patterns in genotype-1 patients failing interferon (IFN)-free regimens and evaluated the efficacy of re-treatment. A total of 73 consecutive patients failing IFN-free regimens were enrolled (17 genotype-1a and 56 -1b). At failure Sanger sequencing of NS3, NS5A and NS5B regions was performed by home-made protocols. In patients having failed an NS3 inhibitor, the prevalence of NS3-RASs was higher in the 10 with genotype-1a than in the 24 with genotype-1b (80% versus 41.6%). In patients treated with an NS5A inhibitor, the prevalence of NS5A-RASs was very high in the 14 with genotype-1a and the 27 with genotype-1b (78.6% and 92.5%, respectively). In patients having failed sofosbuvir, the prevalence of NS5B-RASs was more frequently identified in the 45 with genotype-1b than in the 10 with genotype-1a (37.7% versus 10%). The prevalence of NS5B-RASs in patients having failed dasabuvir was high in both genotypes, 66.6% in the 6 with genotype-1a and 45.5% in the 11 with genotype-1b. The 6 patients re-treated with genotype-1a less frequently (50%) showed sustained virological response (SVR) than the 18 with genotype-1b (88.8%; P=0.07). SVR was more frequent in the 21 patients with an effective second-line direct-acting antiviral (DAA) regimen than the 3 without (90.4% versus 0%; P<0.005). The prevalence of RASs was high in our real-world population. NS3, NS5A and NS5B sequencing seems mandatory in the choice of DAA re-treatment.