Sustained Virological Response In Patients Research Articles

Post-treatment levels of α-fetoprotein predict long-term hepatocellular carcinoma development after sustained virological response in patients with hepatitis C.

The rate of hepatocellular carcinoma (HCC) development is reportedly lower in patients with chronic hepatitis C virus (HCV) who have achieved a sustained virological response (SVR) than in patients who were unresponsive to therapy. However, the development of HCC is sometimes observed in patients with SVR. Therefore, we clarified the predictive power of clinical factors for HCC incidence in patients with SVR using receiver operating characteristic (ROC) curve analysis that takes time dependence into account. A total of 571 patients with HCV who achieved SVR with interferon-based therapy were enrolled. Univariate and multivariate Cox proportional hazards models and time-dependent ROC curves were used to analyze clinical factors associated with the development of HCC. Twenty-four patients developed HCC during the follow-up period (median duration, 9.0years). The 5-, 10-, 15-, and 20-year cumulative incidence rates for HCC were 1.7%, 4.8%, 5.8%, and 6.6%, respectively. Multivariate Cox proportional hazards models showed that older age (hazard ratio [HR], 3.648), male sex (HR, 7.560), lower platelet count at 24weeks after the end of treatment (SVR24) (HR, 3.939), and higher α-fetoprotein (AFP) at SVR24 (HR, 3.630) were independently associated with HCC development. In addition, time-dependent ROC analysis showed that, compared to platelet count at SVR24, AFP at SVR24 had higher predictive power for HCC incidence approximately 7years after SVR. Elevated AFP at SVR24 is a risk factor for HCC in patients with HCV, even those who achieve SVR. α-Fetoprotein is a good predictor of HCC development.

Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B

Anti-hepatitis C virus (HCV) therapy by interferon (IFN)-free regimen with oral direct-acting antiviral drugs are tolerable in aged patients, with fewer adverse effects than IFN-based therapies. We investigated the efficacy and tolerability of an IFN-free anti-HCV therapy in extremely aged patients, as well as the survival benefit of sustained virologic response (SVR). Following IFN-free therapy with daclatasvir and asunaprevir, tolerability and SVR rate were compared between 115 HCV genotype 1-infected patients aged 80years or older, 151 patients in their 70s (⩾70 and <80years), and 115 patients under the age of 70. One-year mortality and morbidity in patients aged ⩾80years were compared between SVR patients and propensity score-matched patients with persistent HCV infection. The SVR rate was 96.5% in patients ⩾80years, comparable to that in patients aged ⩾70 and <80years (95.4%) and patients aged <70years (93.9%). There were no differences in treatment discontinuation rate (2.6%, 1.3%, and 0.9%, respectively). One-year mortality was significantly lower in SVR patients (2.7%) than in patients with persistent HCV infection (15.3%, p=0.0016). Whereas 1-year mortality due to liver-related diseases was 8.1% in patients with persistent HCV infection who were aged ⩾80years, no SVR patients died from liver diseases within 1-year after the end of therapy. IFN-free therapy for HCV infection was associated with high tolerability and antiviral efficacy, even in patients aged ⩾80years. In addition, there seemed to be a survival benefit from the eradication of HCV in this population. IFN-free therapy with oral direct-acting antiviral drugs (daclatasvir and asunaprevir) for HCV infection showed similar tolerability and antiviral efficacy in patients aged ⩾80years as in younger patients (patients aged ⩾70 and <80years and patients aged <70years), with an SVR rate over 90% and no severe adverse effects. There was a survival benefit from the eradication of HCV even in patients aged ⩾80years.

Association between Leptin and Complement in Hepatitis C Patients with Viral Clearance: Homeostasis of Metabolism and Immunity.

BackgroundThe association between leptin and complement in hepatitis C virus (HCV) infection remains unknown.MethodsA prospective study was conducted including 474 (250 genotype 1, 224 genotype 2) consecutive chronic hepatitis C (CHC) patients who had completed an anti-HCV therapy course and undergone pre-therapy and 24-week post-therapy assessments of interferon λ3-rs12979860 and HCV RNA/genotypes, anthropometric measurements, metabolic and liver profiles, and complement component 3 (C3), C4, and leptin levels.ResultsOf the 474 patients, 395 had a sustained virological response (SVR). Pre-therapy leptin levels did not differ between patients with and without an SVR. Univariate and multivariate analyses showed that sex (pre- and post-therapy, p<0.001), body mass index (BMI) (pre- and post-therapy, p<0.001), and C3 levels (pre-therapy, p = 0.027; post-therapy, p = 0.02) were independently associated with leptin levels with or without HCV infection. Pre-therapy BMI, total cholesterol (TC), C4 levels, and the rs12979860 genotype were independently associated with pre-therapy C3 levels in all patients. Post-therapy BMI, alanine aminotransferase, TC, C4 levels, white blood cell counts, and hepatic steatosis were independently associated with the post-therapy C3 levels of SVR patients. Compared with pre-therapy levels, SVR patients showed higher 24-week post-therapy C4 (20.32+/-7.30 vs. 21.55+/-7.07 mg/dL, p<0.001) and TC (171.68+/-32.67 vs. 186.97+/-36.09 mg/dL, p<0.001) levels; however, leptin and C3 levels remained unchanged after therapy in patients with and without an SVR.ConclusionsLeptin and C3 may maintain immune and metabolic homeostasis through association with C4 and TC. Positive alterations in C4 and TC levels reflect viral clearance after therapy in CHC patients.

IL28B rs12980275 and HLA rs4273729 genotypes as a powerful predictor factor for rapid, early, and sustained virologic response in patients with chronic hepatitis C.

Single-nucleotide polymorphisms (SNPs) in the Interleukin-28B (IL28B) gene and rs4273729 in the human leukocyte antigen (HLA) gene in chronic hepatitis C (CHC) virus infection are important for predicting treatment outcome. In this study, the distribution of IL28B SNPs (rs12979860 and rs12980275) and HLA rs4273729 in rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) in HCV Iranian patients with CHC virus infection was assessed. IL28B genotyping and rs4273729 were performed using the amplification refractory mutation system (ARMS)-PCR and direct sequencing in 190 CHC virus infections, respectively. RVR, cEVR, and SVR were 53.2%, 78.9%, and 65.8%, respectively. Multivariate regression analysis demonstrated that the responses significantly predicted SVR in patients with age<40years (p=0.008), HCV genotypes (p=0.032), IL28B rs12979860 CC genotype (p<0.001), rs12980275 AA genotype (p<0.001), rs4273729 GG genotype (p<0.001), RVR (p<0.001) and cEVR (p=0.024). Three critical predictor factors based on RVR response were rs12979860 CC genotype (p=0.033), rs12980275 AA genotype (p<0.001) and rs4273729 GG genotype (p<0.001), while rs12980275 AA (p=0.003) and rs4273729 GG genotypes (p<0.001) predicted cEVR. For the first time in Iran, these results revealed that the rs12980275 and HLA rs4273729 are important for the treatment of CHC infection. These findings may help predict responses to CHC infection treatment and reduce the cost and side effects of therapy.

The Effect of IL28B Gene Polymorphism on Treatment Response in Iranian Patients with Hepatitis C Virus Infection

Background: The hepatitis C virus (HCV) is an important human pathogen affecting an estimated 120 - 170 million individuals in the world. Polymorphisms of the IL28B gene are strongly associated with sustained virological response in patients with chronic hepatitis C treated with peginterferon and ribavirin. Objectives: The aims of this study were to compare the allelic and genotypic frequencies of the IL28B rs12979860 polymorphism in sustained virological response in patients who did not respond to the standard of care treatment and to verify whether there is a correlation between the viral load and the IL28B rs12979860 polymorphism. Methods: This cross-sectional study was carried out on 75 HCV-infected patients, including 45 responders to treatment (group 1) and 30 nonresponders (group 2). We compared the allele and genotype frequencies of the IL28B rs12979860 between the two groups using the PCR-RFLP method. Results: The genotype frequencies of rs12979860 polymorphism in group 1 were CC (28.9%), CT (37.8%) and TT (33.3%) and in group 2 were CC (6.7%), CT (43.3%) and TT (50%). There was a significant difference in genotype frequencies of IL28B polymorphism between the two groups (P = 0.03). There was no significant association between the viral load and IL28B rs12979860 genotypes in either group 1 (P = 0.3) or group 2 (P = 0.2). Conclusions: Our findings indicate that patients with the homozygous CC genotype in the IL28B gene had a significantly higher rate of response to treatment than those with the TT or CT genotypes. Nor does the IL28B rs12979860 polymorphism affect the viral load.

Value of Sustained Virologic Response in Patients with Hepatitis C as a Function of Time to Progression of End-Stage Liver Disease.

Targeted intervention in patients with hepatitis C virus (HCV) closest to end-stage liver disease (ESLD) progression may offer an approach to treatment prioritisation whilst delivering benefits for patients and the healthcare system. In contrast to previous HCV economic analyses, this study aimed to estimate the health economic value of sustained virologic response (SVR) stratified by the patient's propensity to progress to ESLD. An HCV natural history model was adapted to estimate the value of avoiding ESLD complications following SVR, assessed as cost offsets and quality-adjusted life year (QALY) gains, as a function of time to ESLD at treatment initiation. These outcomes were used to estimate the financial value of achieving SVR, defined as the maximum investment that could be allocated without exceeding a willingness-to-pay threshold of £20,000/QALY. Regardless of time to ESLD onset, achieving SVR was beneficial, resulting in cost offsets and QALY gains, due to avoidance of ESLD complications. The value of achieving SVR was greatest in patients closest to ESLD onset, resulting in increased cost offsets and QALY gains (up to £50,901 and 9.56 QALYs). In patients closest to ESLD onset, the financial value of achieving SVR was £242,051, compared with £127,116 in patients furthest from onset. Standard cost-effectiveness evaluations may underestimate the value of treatment in HCV patients closest to ESLD development. Targeted intervention would promote efficient allocation of limited healthcare resources and reconcile concerns surrounding the affordability of new direct-acting antivirals, by minimising the number-needed-to-treat to maximise health benefit, whilst minimising healthcare expenditure.

Ultrasensitive HCV RNA Quantification in Antiviral Triple Therapy: New Insight on Viral Clearance Dynamics and Treatment Outcome Predictors.

ObjectivesIdentifying the predictive factors of Sustained Virological Response (SVR) represents an important challenge in new interferon-based DAA therapies. Here, we analyzed the kinetics of antiviral response associated with a triple drug regimen, and the association between negative residual viral load at different time points during treatment.MethodsTwenty-three HCV genotype 1 (GT 1a n = 11; GT1b n = 12) infected patients were included in the study. Linear Discriminant Analysis (LDA) was used to establish possible association between HCV RNA values at days 1 and 4 from start of therapy and SVR. Principal component analysis (PCA) was applied to analyze the correlation between HCV RNA slope and SVR. A ultrasensitive (US) method was established to measure the residual HCV viral load in those samples which resulted “detected <12IU/ml” or undetectable with ABBOTT standard assay, and was retrospectively used on samples collected at different time points to establish its predictive power for SVR.ResultsAccording to LDA, there was no association between SVR and viral kinetics neither at time points earlier than 1 week (days 1 and 4) after therapy initiation nor later. The slopes were not relevant for classifying patients as SVR or no-SVR. No significant differences were observed in the median HCV RNA values at T0 among SVR and no-SVR patients. HCV RNA values with US protocol (LOD 1.2 IU/ml) after 1 month of therapy were considered; the area under the ROC curve was 0.70. Overall, PPV and NPV of undetectable HCV RNA with the US method for SVR was 100% and 46.7%, respectively; sensitivity and specificity were 38.4% and 100% respectively.ConclusionHCV RNA “not detected” by the US method after 1 month of treatment is predictive of SVR in first generation Protease inhibitor (PI)-based triple therapy. The US method could have clinical utility for advanced monitoring of virological response in new interferon based DAA combination regimens.

Resistin reinforces interferon λ-3 to eliminate hepatitis C virus with fine-tuning from RETN single-nucleotide polymorphisms.

The effect of resistin (RETN) on the response to anti-HCV therapy remains unclear. A prospective cohort study was performed using 655 consecutive HCV patients, of whom 513 had completed a course of interferon-based therapy. Multivariate and GEE analyses revealed four RETN single-nucleotide polymorphisms (SNPs), rs34861192, rs3219175, rs3745367 and rs1423096, to be synergistically associated with resistin levels. After adjusting for co-factors such as interferon λ-3 (IFNL3)-rs12979860, the resistin level and the hyper-resistinemic genotype at the 4 RETN SNPs were positively and negatively associated with a sustained virological response (SVR), respectively. RETN-rs3745367 was in linkage disequilibrium with IFNL3-rs12979860. Compared to non-SVR patients, SVR patients had higher levels of pre-therapy resistin, primarily originating from intrahepatic lymphocytes, stellate cells, Kupffer cells, hepatic progenitor cells and hepatocytes. This difference diminished over the course of therapy, as only SVR patients exhibited a 24-week post-therapy decrease in resistin. Both resistin and IFNL3 mRNAs were upregulated, but only resistin mRNA was upregulated by recombinant resistin in peripheral blood mononuclear cells with and without hyper-resistinemic genotypes of the 4 RETN SNPs, respectively. Fine-tuned by RETN SNPs, intrahepatic, multi-cellular resistin reinforced IFNL3 in eliminating HCV via immunomodulation to counteract pro-inflammation. These results encourage the development of novel resistin-targeted anti-viral agents.

Pretreatment glucose status determines HCC development in HCV patients with mild liver disease after curative antiviral therapy

Although diabetes mellitus (DM) is known to increase the risk of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC), the impact of dynamic glucose status on HCC occurrence in chronic hepatitis C (CHC) patients receiving antiviral therapy is unclear. In total, 1112 biopsy-proven patients treated with peginterferon/ribavirin were enrolled in this study. Both pretreatment and post-treatment glucose status, including 75 g oral glucose tolerance test (OGTT), were measured to evaluate the association between glucose status and the development of HCC. Of the 1112 patients evaluated, 93 (8.4%) developed HCC >5183.8 person-years of follow-up (annual incidence rate: 1.79%). DM only influenced the risk of developing CC in patients with mild liver disease (F0-2) and a sustained virological response (SVR) but not in other patient subpopulations. Cox-regression analysis demonstrated that the strongest factor associated with HCC in patients with mild liver disease and SVR was the presence of DM (hazard ratio [HR]/95 % confidence intervals [CI]: 3.79/1.420-10.136, P = 0.008), followed by age (HR/CI: 1.06/1.001-1.117, P = 0.046) and platelet count (HR/CI: 0.989/0.979-1.000, P = 0.05). The percentages of SVR patients with F0-2 with normoglycemia, pre-DM, sub-DM (pre-sDM), and DM before treatment were 45.3% (n = 267), 29.9% (n = 176), 15.6% (n = 92), and 9.2% (n = 54), respectively. The percentages of HCC in patients with normoglycemia, pre-sDM, and DM were 1.1%, 3.7%, and 11.1%, respectively (trend P < 0.001). Sixteen of the 19 (84.2 %) HCC patients possessed glucose abnormality (including 6 patients with DM and 10 patients with pre-sDM) before antiviral therapy. Compared to patients with normoglycemia, the incidence of HCC increased gradually from pre-sDM (HR: 3.6, P = 0.05) to DM (HR: 11.6, P = 0.001) (adjusted trend P = 0.004). We concluded that DM is a critical determinant for the development of HCC in SVR patients with mild liver disease. Pre-sDM status carried an additional risk for HCC, and these patients should also be carefully monitored for HCC after viral eradication.

Rapid virological response assessment by Abbott RealTime hepatitis C virus assay for predicting sustained virological responses in patients with hepatitis C virus genotype 1 treated with pegylated-interferon and ribavirin

The lower limits of virus detection of hepatitis C virus (HCV) RNA detection assays are continuously improving. We aimed to assess the utility of more precise definition of 4th week viral load [rapid virological response (RVR)] in predicting sustained virological response (SVR) in HCV genotype 1 patients treated with pegylated-interferon (PEG-IFN) and ribavirin. Clinical data of treatment-naïve HCV genotype 1 patients were retrospectively collected from 2009 to 2014. Patients were grouped according to 4th week viral load as follows: undetectable (n = 90) and detectable but not quantifiable (< 12 IU/mL, n = 27). All patients received PEG-IFNα-2a or -2b and ribavirin for 24 weeks. Serum HCV RNA levels were measured by Abbott RealTime (ART; Abbott Molecular, Abbott Park, IL, USA) HCV assay. SVR was 95.5% and 63% in the undetectable group and < 12 IU/mL group of 4th week viral load, respectively. The between-group difference in SVR was significant (p < 0.001). We determined 4th week viral load was independently associated with SVR (odds ratio = 19.28; p = 0.002) and a good predictor of SVR [area under the curve (AUC) = 0.775; p = 0.001]. ART HCV assays had a stronger SVR predictive value in HCV genotype 1 patients, indicating that only the undetectable group of 4th week viral load patients measured by ART HCV assay should be considered for shorter treatment time (24 weeks) with PEG-IFN and ribavirin.

CD4 and CD4/CD8 ratio progression in HIV-HCV infected patients after achievement of SVR

BackgroundIn HIV-HCV co-infected patients, the long-term effects of HCV eradication on HIV disease progression are still unclear. ObjectivesThis study aims to determine if CD4 and CD4/CD8 ratio slopes improved after anti-HCV treatment in patients achieving a sustained virological response (SVR). Study designA total of 116 HIV-HCV co-infected patients, previously treated with Peg-IFN/RBV, were divided into two groups: SVR (55 patients who had achieved SVR), and non-SVR (61 patients). Retrospective data before and after anti-HCV therapy were obtained for all patients, with a median 8 year-follow-up. Multilevel mixed models were fitted to assess the trends over time of FIB-4 score, APRI score, CD4, CD8 cell count and CD4/CD8 ratio. ResultsMedian HIV-infection duration, HCV-RNA and GGT baseline levels were higher in non-SVR compared to the SVR group. A significantly decreased FIB-4 (p<0.001) and APRI trend (p<0.001) after SVR was observed in SVR patients compared to those non-SVR. After adjustment for HIV duration, there was no significant difference between the two groups for absolute CD4 (p=0.08) or percentage CD4 slope (p=0.6) over time. The CD4/CD8 ratio trend also demonstrated a similar progressive increase in both groups (p=0.2). During follow-up, six deaths were reported in the non-SVR group versus no death for the SVR group, while no difference in AIDS and non-AIDS events was observed. ConclusionsAchievement of SVR determines an important beneficial impact in terms of liver-related mortality and fibrosis regression, but does not seem to alter neither the slope of long term CD4 gain nor the CD4/CD8 ratio evolution in ART-treated HIV-HCV co-infected patients.

Outcomes of Interferon/Ribavirin Therapy in Patients with HCV Defined by Expression of Plasma Soluble Human Leukocyte Antigen-G but Not IL-37

BackgroundChronic hepatitis C virus (HCV) infection leads to life-threatening complications worldwide. Immunomodulation signals the response to virus clearance. The immune-suppressive molecule human leukocyte antigen-G (HLA-G) has been shown to function in inhibiting both innate and adaptive immune responses. The objective of this study was to investigate the expression of HLA-G and IL-37 in sustained virological response (SVR) and non-SVR HCV-positive patients before and after complete treatment with a combination of pegylated interferon (IFN) and ribavirin (RBV).Material/MethodsOur study included 132 chronic hepatitis C patents who received combined therapy with IFN-α and RBV. Both SVR and non-SVR patients were included. The end-of-treatment response was defined as undetectable HCV RNA at week 48. Patients with end-of-treatment response were detected by HCV RNA at 24 weeks after therapy. The expression levels of HLA-G and IL-37 at the end and 24 weeks after treatment were detected by ELISA.ResultsPlasma HLA-G and IL-37 were significantly increased in HCV-infected patients compared with healthy individuals before treatment. Furthermore, HLA-G in SVR patients was noticeably decreased after treatment, while HLA-G in non-SVR patients had no changes after treatment. Additionally, both in SVR and non-SVR patients, the expression of IL-37 was remarkably reduced compared with baseline after treatment.ConclusionsThese findings suggest that elevation of HLA-G and IL-37 in HCV may play an important role in response to combined therapy with IFN-α and RBV. Monitoring the expression of HLA-G during therapy could contribute to adjusting the treatment program of HCV-infected patients.

Improved Survival Among all Interferon-α-Treated Patients in HCV-002, a Veterans Affairs Hepatitis C Cohort of 2211 Patients, Despite Increased Cirrhosis Among Nonresponders.

As the era of interferon-alpha (IFN)-based therapy for hepatitis C ends, long-term treatment outcomes are now being evaluated. To more fully understand the natural history of hepatitis C infection by following a multisite cohort of patients. Patients with chronic HCV were prospectively enrolled in 1999-2000 from 11 VA medical centers and followed through retrospective medical record review. A total of 2211 patients were followed for an average of 8.5years after enrollment. Thirty-one percent of patients received HCV antiviral therapy, 15% with standard IFN/ribavirin only, 16% with pegylated IFN/ribavirin, and 26.7% of treated patients achieved sustained virologic response (SVR). Cirrhosis developed in 25.8% of patients. Treatment nonresponders had a greater than twofold increase in the hazard of cirrhosis and hepatocellular carcinoma, compared to untreated patients, whereas SVR patients were only marginally protected from cirrhosis. Nearly 6% developed hepatocellular carcinoma, and 27.1% died during the follow-up period. Treated patients, regardless of response, had a significant survival benefit compared to untreated patients (HR 0.58, CI 0.46-0.72). Improved survival was also associated with college education, younger age, lower levels of alcohol consumption, and longer duration of medical service follow-up-factors typically associated with treatment eligibility. As more hepatitis C patients are now being assessed for all-oral combination therapy, these results highlight that patient compliance and limiting harmful behaviors contribute a significant proportion of the survival benefit in treated patients and that the long-term clinical benefits of SVR may be less profound than previously reported.

The prevalence and impact of thrombocytopenia, anaemia and leucopenia on sustained virological response in patients receiving hepatitis C therapy: evidence from a large 'real world' cohort.

The aim of the study was to explore the extent of thrombocytopenia (TCP), anaemia and leucopenia in patients with hepatitis C and evaluate how they impact the management of antiviral therapy, the attainment of sustained virological response (SVR), and some therapy-related adverse events. The Scottish Hepatitis C Clinical Database was used in this retrospective study. The prevalence of TCP, anaemia and leucopenia was evaluated. The impact of the three deficiencies on antiviral therapy management, serious adverse events and SVR attainment was assessed in patients who received therapy. The prevalence of TCP, anaemia and leucopenia was 18.5, 0.9 and 0.2% among 4907 treated patients at baseline, increasing to 72, 25.8 and 5.4% during treatment, respectively. Dose reduction occurred in 29.3% of the patients without TCP; this percentage was higher in those with baseline TCP (53%) and in those who acquired it during treatment (35%). Similar results were found for anaemia and leucopenia. Baseline TCP (odds ratio=0.67, P<0.001) and baseline anaemia (odds ratio=0.43, P=0.03) were identified as risk factors associated with lower SVR rate; acquired TCP and anaemia were not associated with reduced SVR. Baseline TCP or anaemia increased the risk of dose cessation. Patients who acquired TCP, anaemia or leucopenia during treatment did not exhibit compromised SVR rates, whereas patients with TCP or anaemia at baseline did. The potential benefit of growth factors in maintaining SVR rate is likely to be confined to those with baseline TCP or anaemia rather than to those who acquire it during therapy, where dose reduction does not appear to reduce the chance of SVR.

Hepatitis C treatment failure is associated with increased risk of hepatocellular carcinoma.

Sustained virological response (SVR) to antiviral therapy for hepatitis C (HCV) reduces risk of hepatocellular carcinoma (HCC), but there is little information regarding how treatment failure (TF) compares to lack of treatment. We evaluated the impact of treatment status on risk of HCC using data from the Chronic Hepatitis Cohort Study (CHeCS-an observational study based in four large US health systems, with up to 7 years of follow-up on patients). Multivariable analyses were used to adjust for bias in treatment selection, as well as other covariates, followed by sensitivity analyses. Among 10 091 HCV patients, 3681 (36%) received treatment, 2099 (57%) experienced treatment failure (TF), and 1582 (43%) of these achieved sustained virological response (SVR). TF patients demonstrated almost twice the risk of HCC than untreated patients [adjusted hazard ratio (aHR) = 1.95, 95% confidence interval (CI) 1.50-2.53]; this risk persisted across all stages of fibrosis. Several sensitivity analyses validated these results. Although African Americans were at increased risk of treatment failure, they were at lower risk for HCC and all-cause mortality compared to White patients. SVR patients had lower risk of HCC than TF patients (aHR = 0.48, CI 0.31-0.73), whereas treatment - regardless of outcome - reduced all-cause mortality (aHR = 0.45, CI 0.34-0.60 for SVR patients; aHR = 0.78, CI 0.65-0.93 for TF patients).

Long-Term Outcomes of Hepatitis-C-Infected Patients Achieving a Sustained Virological Response and Undergoing Radical Treatment for Hepatocellular Carcinoma

Background and Aims: A sustained virological response (SVR) decreases the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C. We investigated the long-term outcomes of patients who developed HCC after achieving SVR with interferon therapy. Patients: Of 75 patients who developed HCC after SVR, 40 patients underwent radical therapies (SVR group). From 436 patients undergoing surgical resection for hepatitis C virus-positive HCC, 80 patients were randomly chosen as a control cohort, after adjusting for age, gender, and extent of hepatic fibrosis (non-SVR group). Patients were observed for a median of 5.08 years. Results: HCC recurrence was found in 16 SVR patients and in 66 non-SVR patients. The respective HCC recurrence rates of SVR and non-SVR patients were 23 and 56% at 3 years, 42 and 77% at 5 years, and 53 and 90% at 10 years (p = 0.001). The respective overall survival rates in the SVR and non-SVR groups were 93 and 68% at 5 years, 88 and 34% at 10 years, and 53 and 21% at 15 years (p = 0.001). Conclusion: Although SVR patients had a significantly lower HCC recurrence rate than the non-SVR patients, the cumulative recurrence rate of SVR patients increased to 86% at 15 years.

Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients.

Although interferon (IFN)-free antiviral therapy is expected to improve the treatment response for chronic hepatitis C, the effect on liver function and liver fibrosis is unknown. In this study, we analyzed the long-term follow up of liver function parameters and liver fibrosis markers in genotype 1b hepatitis C virus (HCV)-infected patients treated with daclatasvir and asunaprevir. Thirty patients were treated with daclatasvir and asunaprevir for 24weeks, and 26 patients achieved sustained virological response (SVR). We measured liver function parameters, serum alanine aminotransferase (ALT) and albumin levels and liver fibrosis markers, hyaluronic acid, type IV collagen and Mac-2-binding protein (M2BPGi) before and after (median, 27months; range, 17-47) completion of the treatment in SVR and non-SVR patients. We also measured serum α-fetoprotein (AFP) levels during the therapy and follow-up period. Pretreatment serum ALT and albumin levels and liver fibrosis markers were similar between SVR and non-SVR patients. Twenty-seven months after treatment, serum ALT and albumin levels significantly improved only in SVR patients. Although there was no change in non-SVR patients, platelet count and serum liver fibrosis markers significantly improved in SVR patients. Serum AFP levels rapidly decreased during the treatment in both SVR and non-SVR patients, but the change was significant only in SVR patients. Successful viral eradication by IFN-free daclatasvir and asunaprevir therapy could lead to improved liver function parameters and reduced liver fibrosis markers and AFP levels. This treatment has the potential to improve liver fibrosis and decrease the incidence of hepatocarcinogenesis.

Dynamic changes in CD45RA(-)Foxp3(high) regulatory T-cells in chronic hepatitis C patients during antiviral therapy.

CD4(+)Foxp3(+) regulatory T-cells (Treg) are known to accumulate under certain pathological conditions. This study was conducted to evaluate the characteristics of and dynamic changes in Treg cells in chronic hepatitis C (CHC) patients during antiviral therapy. One hundred and forty-five subjects were enrolled in this study, including 105 CHC patients and 40 healthy donors. The phenotypes and functions of Treg cells were analyzed by flow cytometry. A significant elevation in Treg cells was observed in the peripheral blood of CHC patients compared with healthy donors. Interestingly, compared with non-suppressive Treg (non-Treg) and resting Treg (rTreg) cells, activated Treg (aTreg) cells expressed higher levels of ectonucleotidase, CD39, and CD73. After treatment with interferon alpha (IFN-α) and ribavirin (RBV) in vitro, the frequencies of total Treg cells and aTreg cells in peripheral blood mononuclear cells (PBMC), as well as the levels of transforming growth factor beta (TGF-β) secreted by aTreg and non-Treg cells, were significantly decreased. Importantly, it was found that levels of aTreg cells in patients with a sustained virological response (SVR) were lower than in relapsed patients, suggesting that a high frequency of aTreg cells might be associated with a poor clinical outcome in HCV infection. These results demonstrate a decreasing trend in aTreg cells, which express higher levels of CD39, CD73, and TGF-β, in SVR patients during antiviral therapy.

Suppressor of cytokine signaling 1 expression in peripheral blood mononuclear cells of hepatitis C genotype 1 patients.

While new direct-acting antiviral therapies for hepatitis C virus (HCV) are the standard of care, interferon-α (IFN-α) remains a standard therapy in Taiwan based on its low cost and high response rate to IFN-α-based therapy. IFN-α exerts antiviral activity by inducing the expression of hundreds of genes that establish an antiviral state via Jak kinase (JAK)/signal transducers and activators of transcription (STAT) signaling. We quantified the transcript levels of JAK/STAT signaling genes in peripheral blood mononuclear cells of HCV genotype 1 patients and estimated the correlation between transcript levels and patient responses to IFN-α-based therapy. A total of 100 HCV genotype 1 naïve patients were enrolled. All patients received response-guided therapy for 24-48weeks with pegylated IFN-α and ribavirin. Peripheral blood mononuclear cells were collected before treatment. Twenty patients with sustained virological responses (SVR) and 20 patients without SVR were selected for a JAK/STAT signaling genes transcript analysis using multiplex reverse transcription-polymerase chain reaction. Transcripts that were upregulated or downregulated were further validated in 100 patients. Suppressor of cytokine signaling 1 (SOCS1) expression was upregulated in SVR patients compared with non-SVR patients (relative quantification=2.14) based on a multiplex reverse transcription-polymerase chain reaction analysis. We further analyzed SOCS1 expression in 100 patients. We found that SOCS1 expression did not differ significantly between SVR and non-SVR patients. Peripheral blood SOCS1 expression before treatment was not associated with SVR in HCV genotype 1 patients treated with pegylated IFN-α and ribavirin.

Predictors of sustained virological response in patients with hepatitis C virus genotype 3 infection.

Aim of the studyTo assess predictors of sustained virological response (SVR) in patients with chronic hepatitis C virus (HCV) genotype 3 treated with standard therapy.Material and methodsWe retrospectively investigated data of 116 consecutive treatment-naïve patients chronically infected with HCV genotype 3, treated with pegylated interferon alpha (PegIFNα) and ribavirin (RBV) for 24 weeks. HCV RNA at week 4 (rapid virological response – RVR) and week 12 (early virological response – EVR) were measured in 85 and 105 patients respectively. Liver biopsy data were available for 103 patients. The variables were compared between patients with an SVR and those without.ResultsOverall 70.7% of patients achieved an SVR. Pretreatment factors including younger age, mild liver fibrosis as well as normal values of gamma-glutamyl transferase (GGT) and platelet count were significantly associated with higher SVR rate in univariate analysis. In the multivariate analysis only baseline platelet count > 140 000/µl and normal GGT activity were correlated with higher SVR rate. At weeks 4 and 12 HCV RNA was undetectable in 34.1% and 84.8% of patients respectively. The SVR rate was significantly higher in patients with an RVR compared to those without (p = 0.002). Only 2 patients with a rapid and early virological response did not achieve an SVR; both had negative pretreatment prognostic factors.ConclusionsIn treatment-naïve patients with genotype 3 HCV infection, low baseline platelet count and elevated GGT activity were significantly associated with poor response to PegIFNα and RBV. Achieving a rapid and early virological response was associated with higher likelihood of an SVR.