Predictor Of Sustained Virological Response Research Articles

Serum microRNA-122 level correlates with virologic responses to pegylated interferon therapy in chronic hepatitis C

MicroRNA-122 (miR-122) facilitates hepatitis C virus replication in vitro. Serum miR-122 has been implicated as a biomarker for various liver diseases; however, its role in chronic hepatitis C remains unclear. To address this issue, 126 patients with chronic hepatitis C who completed pegylated IFN plus ribavirin therapy with sustained virologic response (SVR) or nonresponse (NR) were retrospectively included, and their pretreatment clinical profiles and treatment responses were collected. Serum miR-122 was quantified before and during treatment. Another 51 patients in SVR and NR groups were prospectively enrolled for validation. Serum miR-122 was found to be a surrogate for hepatic miR-122 and positively correlated with hepatic necroinflammation. Patients who showed complete early virologic response and SVR had significantly higher pretreatment serum miR-122 levels than those with NR (P = 0.001 and P = 0.008, respectively), especially in subgroups of patients with hepatitis C virus genotype 2 and IL-28B rs8099917 TT genotype. Patients with IL-28B TT genotype had significantly better treatment responses and higher pretreatment serum miR-122 level than those with GT or GG genotypes. Univariate analysis showed that pretreatment body mass index, γ-glutamyl transpeptidase, triglyceride, IL-28B TT genotype, and serum miR-122 are predictors for SVR. Multivariate analysis specifically in IL-28B TT genotype demonstrated that pretreatment serum miR-122 independently predicted SVR. The validation cohort confirmed a significantly greater pretreatment serum miR-122 level in patients with SVR compared with NR (P = 0.025). In conclusion, serum miR-122 may serve as a surrogate of hepatic miR-122, and a higher pretreatment serum miR-122 level can help predict virologic responses to pegylated IFN plus ribavirin therapy.

CCR5-Δ32 genotype does not improve predictive value of IL28B polymorphisms for treatment response in chronic HCV infection

IL28B polymorphisms strongly predict spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. A recent study proposed a 32-base pair deletion in the CC-chemokine receptor 5 (CCR5) gene (CCR5-Δ32) interacting with the IL28B polymorphisms to influence spontaneous HCV clearance. The aim of this study was to clarify the role of CCR5-Δ32 in treatment-induced clearance of chronic hepatitis C (CHC). A cross-sectional cohort of 813 Caucasian patients with CHC genotype 1 (365 responders and 448 non-responders) who had received standard of care dual therapy with interferon (IFN)-α and ribavirin (RBV) was genotyped for the CCR5-Δ32 and IL28B polymorphisms to examine their interaction with respect to treatment response. CCR5-Δ32 did not influence treatment-induced recovery to IFN-α/RBV in CHC, and did not improve prediction of sustained virological response in the context of the IL28B polymorphisms in a multivariate model. CCR5-Δ32 homozygotes were significantly more frequent in those with CHC than healthy controls in the European cohorts (2.9% vs 0.4%, P<0.0001), but not in Australians of European ancestry. In conclusion, CCR5-Δ32 does not influence treatment response in the context of IL28B polymorphisms. Although CCR5-Δ32 may affect viral clearance within closely controlled geographical and genetic environments, we found no effect in larger cohorts treated with dual therapy.

Psychological, lifestyle and social predictors of hepatitis C treatment response: a systematic review

To increase cure rates for Hepatitis C, barriers to treatment adherence and completion must be identified and overcome. This study systematically reviewed evidence on the psychological, lifestyle and social determinants of achieving viral eradication with antiviral therapy. An electronic search strategy was used to identify relevant studies that examined psychological, lifestyle and social factors related to achieving a sustained virological response (SVR). Thirty-four studies that matched our criteria were identified. Of the factors that predict response to treatment, Asian ethnicity was an independent predictor of SVR. We found an indirect relationship between diet and SVR, with non-responders to treatment consuming more polyunsaturated fatty acids, fats and carbohydrates than those who attained SVR. The effect of alcohol consumption relied on the amount consumed; fewer than 30 grams daily had no effect on SVR, whereas >70 grams daily had an adverse impact on a patient's ability to achieve SVR, with termination rates up to 44% in those who drank >2 drinks a day. Patients with psychiatric illnesses had comparable SVR rates to controls if they continued psychological therapy (average 42%), although discontinuation rates were high with 11 studies reporting rates from 14 to 48%. There are major gaps in current knowledge of the impact of variables such as diet, exercise, attitudes and coping skills on cure rates in chronic Hepatitis C. Those who drink limited amounts of alcohol or have psychiatric disorders should be offered treatment for their disease, with adjunctive education and support to improve treatment completion.

Role of Interleukin-28B Polymorphism as a Predictor of Sustained Virological Response in Patients with Chronic Hepatitis C Treated with Triple Therapy: A Systematic Review and Meta-Analysis

Chronic hepatitis C represents an important health problem. The aim of our meta-analysis was to establish the role of reference single nucleotide (rs) 12979860 allele of interleukin-28B (IL28B) CC versus CT+TT genotype (the most researched allele of IL28B) as a predictor of sustained virological response (SVR) in patients with chronic hepatitis C treated with triple therapy. The PubMed, MEDLINE, Lilacs, Scopus, Ovid, EMBASE, Cochrane and Medscape databases as well as abstract books from important gastroenterology and hepatology meetings were searched for all studies published until 15 July 2012 that analysed the relationship between the polymorphism of IL28B and SVR in patients with chronic hepatitis C, genotype 1, treated with pegylated interferon + ribavirin + direct antiviral agents (telaprevir or boceprevir). The following keywords were used: IL28B polymorphism, chronic hepatitis C, sustained virological response, SVR, triple therapy, telaprevir, boceprevir. Odds ratios (ORs) with 95 % confidence intervals were pooled from five study populations (1,641 cases) using a random-effects model. The SVR rate was significantly higher in patients with the CC genotype of IL28B than in those with non-CC genotypes (CT and TT): OR = 3.91 (95 % CI 2.11-7.28), p < 0.0001. Higher SVR rates were obtained in chronic hepatitis C patients with the CC genotype of IL28B, regardless of their therapeutic status (naïve patients: OR = 3.99 [95 % CI 1.67-9.51], p < 0.0001; and previously treated ones: OR = 2.15 [95 % CI 1.35-3.43], p = 0.001). IL28B polymorphism seems to influence the SVR rate in patients with chronic hepatitis C treated with triple therapy, but further studies are needed to clarify the mechanism and the influence of other factors on the SVR rates.

Prediction of efficacy to pegylated interferon‐α‐2b plus ribavirin in patients with genotype 2 hepatitis C virus using viral response within 2 weeks

Rapid virological response (RVR), defined as serum hepatitis C virus (HCV) RNA negativity at 4 weeks, is the most useful predictor of sustained virological response (SVR) to standard pegylated interferon (PEG IFN) plus ribavirin therapy for patients infected with genotype 2 HCV. The aim of the present study was to predict SVR using viral response within 2 weeks of therapy initiation. Of 64 HCV genotype 2 patients with a high viral load treated with standard PEG IFN-α-2b plus weight-based ribavirin for 24 weeks, 58 patients whose adherence was more than 67% were analyzed. RNA and core antigen levels were measured at four time points: the day of therapy initiation, the following day, and at 1 and 2 weeks. SVR was achieved in 73% (47/64) of patients. Univariate analysis of SVR contributing factors showed significant differences with age, bodyweight, white blood cell count, platelet count, fibrosis marker levels, baseline core antigen level and viral response. The area under the receiver-operator curve (AUC) of the core antigen level at 1 week (AUC, 0.940) was the highest among the significant SVR predicting factors. Setting 100 fmol/L as the cut-off value for core antigen level at 1 week, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy for predicting SVR were 100%, 86%, 96%, 100% and 97%, respectively, and for predicting RVR were 66%, 93%, 97%, 46% and 72%, respectively. The HCV core antigen level at 1 week after therapy initiation is the most useful predictor for SVR.

The prevalence of cirrhosis and hepatocellular carcinoma in patients with human immunodeficiency virus infection: Are the data found in this sample applicable to other settings?

We would like to thank Cusinato et al. for their thoughtful comments. The relative prevalence of hepatitis C virus (HCV) genotypes was 87% (genotype 1), 7% (genotype 2), 5% (genotype 3), and 1% (genotype 4). Clearly, HCV genotype is strongly associated with sustained virological response (SVR) rates and with the likelihood of receiving antiviral treatment. HCV genotype was also associated with development of cirrhosis or hepatocellular carcinoma (HCC) in our data set, but the results were not statistically significant. Specifically, for cirrhosis, the adjusted odds ratio (OR) was 0.74 (95% confidence interval [CI]: 0.52-1.06) for genotype 2 patients and 1.06 (95% CI: 0.71-1.56) for genotype 3 patients, relative to genotype 1 patients as the reference group. For HCC, the adjusted OR was 0.53 (95% CI: 0.16-1.73) for genotype 2 patients and 0.82 (95% CI: 0.25-2.7) for genotype 3 patients, relative to genotype 1 patients. We did not find the proportion of human immunodeficiency virus (HIV)/HCV coinfected patients who ever received antiviral treatment (18%) surprisingly low. Only 22% (36,898 of 170,119) of all HCV mono-infected patients who were in Veterans Affairs (VA) care in 2011 ever received antiviral treatment. Lack of antiviral treatment may be partly explained by the presence of absolute and relative contraindications to antiviral treatment, which may be more common in VA than non-VA patients, by the relatively low success rate of antiviral treatment and its significant side effects. It is beyond the scope of this work to examine the patient, provider, and facility predictors of receipt of antiviral treatment. However, it is crucial to point out that these represent treatment rates in an unselected population of HIV/HCV coinfected patients (i.e., all patients who were seen at least once in any VA facility throughout the country in year 2009) and cannot be compared with treatment rates from tertiary referral centers or prospectively followed cohorts of HIV-infected patients. A more-appropriate comparison would be the proportion of all patients with HIV/HCV coinfection in the entire United States who ever received antiviral treatment. Shire et al. reported that SVR rates to HCV antiviral treatment with pegylated interferon (Peg-IFN) and ribavirin (RBV) in HIV/HCV coinfected patients in five randomized controlled trials and two prospective cohort studies ranged from 27% to 44%. We reported that among all patients in VA care in 2009 who ever received antiviral treatment with either Peg-IFN or regular IFN with or without RBV (defined as at least two prescriptions of IFN), 17% achieved SVR. The lower SVR rate that we reported is the result of differences in treatment regimens and the fact that we did not report on results of clinical trials; rather, we reported SVR rates in unselected patients in a real-world setting. There are multiple viral, patient, provider, and facility factors that might account for these differences in SVR rates observed in clinical trials versus SVR rates observed in real clinical practice. The fact that we defined antiviral treatment as receipt of two or more prescriptions of IFN (“intention to treat”) also accounts for lower SVR rates, as Cusinato et al. rightly point out. An analysis of predictors of SVR is fairly complicated and not directly relevant to the presented research. We merely wanted to determine whether achieving SVR is associated with clinical outcomes (cirrhosis and HCC). George N. Ioannou M.D., M.S.*, Christopher L. Bryson M.D., M.S. , Noel S. Weiss M.D., Dr.P.H. , John D. Scott M.D., M.Sc.§, Edward J. Boyko M.D., M.P.H. , * Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, Division of Internal Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, WA, Department of Epidemiology, University of Washington, Seattle, WA, § Division of Infectious Diseases, University of Washington, Seattle, WA.

Expression of Biliverdin Reductase A in peripheral blood leukocytes is associated with treatment response in HCV-infected patients.

Background and AimsHepatitis C virus (HCV) infection is associated with systemic oxidative stress. Since the heme catabolic pathway plays an important role in antioxidant protection, we attempted to assess the gene expression of key enzymes of heme catabolism, heme oxygenase 1 (HMOX1), heme oxygenase 2 (HMOX2), and biliverdin reductase A (BLVRA) in the liver and peripheral blood leukocytes (PBL) of patients chronically infected with HCV.MethodsGene expressions (HMOX1, HMOX2, BLVRA) and HCV RNA were analyzed in PBL of HCV treatment naïve patients (n = 58) and controls (n = 55), with a subset of HCV patients having data on hepatic gene expression (n = 35). Based upon the therapeutic outcome, HCV patients were classified as either responders (n = 38) or treatment-failure patients (n = 20). Blood samples in HCV patients were collected at day 0, and week 12, 24, 36, and 48 after the initiation of standard antiviral therapy.ResultsCompared to the controls, substantially increased BLVRA expression was detected in PBL (p<0.001) of therapeutically naïve HCV patients. mRNA levels of BLVRA in PBL closely correlated with those in liver tissue (r2 = 0.347,p = 0.03). A marked difference in BLVRA expression in PBL between the sustained responders and patients with treatment failure was detected at week 0 and during the follow-up (p<0.001). Multivariate analysis revealed that BLVRA basal expression in PBL was an independent predictor for sustained virological response (OR 15; 95% CI 1.05–214.2; P = 0.046). HMOX1/2 expression did not have any effect on the treatment outcome.ConclusionOur results suggest that patients with chronic HCV infection significantly upregulate BLVRA expression in PBL. The lack of BLVRA overexpression is associated with non-responsiveness to standard antiviral therapy; whereas, HMOX1/2 does not seem to have any predictive potential.

A Comparison of Modified Directly Observed Therapy to Standard Care for Chronic Hepatitis C

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States. Effective treatments are available, however adherence to treatment is challenging. Modified directly observed therapy (mDOT) with weekly administration of pegylated interferon might improve adherence and outcomes for patients infected with chronic HCV. The purpose of this study was to compare two treatment protocols and examine predictors of sustained virologic response (SVR). This retrospective review compares HCV treatment outcomes in two outpatient clinics at an urban academic medical center. Gastroenterology fellows provided standard treatment (SC) in one clinic; a nurse practitioner administered weekly pegylated interferon injections weekly in a primary care clinic. All patients received oral ribavirin. Data was extracted from the medical records of all treated patients over a 5-year period. 155 treatment-naïve, chronically infected HCV patients were treated. Ninety-seven patients received mDOT treatment and 58 received standard care. Mean age was 46years. Genotype 1 represented 59% of the sample. The mDOT patients were significantly more likely to be younger (44 vs. 50years), have a history of injection drug use (93.1 vs. 50.0%), and be HIV-infected (13.5 vs. 2%) compared to SC patients. The overall SVR rate was 45.2% and did not differ between the groups in unadjusted analyses (p=0.95). Genotype was the only predictor of SVR. Patients treated by nurse practitioners trained in HCV care and seen weekly for interferon injections have comparable treatment outcomes to patients treated by specialists.

Association of IL 28b host gene polymorphisms with IFN responses in hepatitis C virus infected patients from eastern and north-eastern India

Background: Genome wide association studies have confirmed that SNPs at rs 12979860 C/T and rs 8099917 T/G are strongly associated in the rate of Sustained Virological Response (SVR). The prediction of SVR in patients before initiation of antiviral therapy is important to estimate the potential for treatment success.

Response to “Treatment guidelines for HCV genotype 1: mono for low, triple for high, and dual for ‘middle’?”

We appreciate the comments by Enomoto et al. regarding our review of the updated JSH guidelines for the treatment of chronic HCV infection [1]. Enomoto et al. note that triple therapy is poorly tolerated in elderly patients and may not be necessary to achieve sustained virological response (SVR) when viral loads are intermediate (HCV RNA of 5.0–5.4 log10IU/mL). In such patients, adequate sustained virological response rates may be achieved using conventional standard peg-interferon plus ribavirin combination therapy, whereas SVR rates decrease and/or treatment duration increases in patients with viral loads above this range. We agree, in principle, that conventional combination therapy may be sufficient or preferred for specific subgroups of patients. However, we feel that such decisions should be based on the discretion and experience of individual clinicians, whereas formal guidelines should favor simple and unambiguous treatment recommendations wherever possible, albeit at the expense of overly conservative recommendations in certain borderline cases. Enomoto et al. provide interesting data suggesting a sharp decline in SVR rate above 5.5 log10IU/mL in a retrospective analysis of their patients, although only 19 (10 %) of their patients belong to this intermediate viral load (5.0–5.4 log10IU/mL) group. However, these results should be replicated in prospective studies, as initial viral load in these patients might also be confounded with other factors, including age, sex, IL28B genotype, viral sub-genotype, Core70 and ISDR substitutions. Triple therapy is currently considered to be the best option for treatment of patients with moderate to high loads of genotype 1 HCV and is less sensitive than combination therapy to differences in prior treatment history or IL28B genotypes. While pre-treatment factors, such as initial viral load and IL28B genotype, are associated with treatment outcome, on-treatment predictors, such as early and rapid virological response, are better predictors of sustained virological response. Notably, rapid decrease in HCV RNA is also a hallmark of telaprevir therapy, which allows patients undergoing triple therapy to benefit from shorter duration of therapy (24 weeks versus 48 or more weeks of combination therapy). While many patients experience side effects of triple therapy, such as rash and anemia, that require dose reduction, ribavirin can be reduced by up to 80 %, if necessary, without significantly affecting SVR This author’s reply refers to the letter to the editor at doi:10.1007/s00535-013-0759-4.

Response to treatment in Brazilian patients with chronic hepatitis C is associated with a single-nucleotide polymorphism near the interleukin-28B gene

A single-nucleotide polymorphism (SNP) upstream of interleukin (IL)28B was recently identified as an important predictor of the outcome of chronic hepatitis C patients treated with pegylated interferon plus ribavirin (PEG-IFN/RBV). The aim of this study was to investigate the association between the IL28B gene polymorphism (rs12979860) and virological response in chronic hepatitis C patients. Brazilian patients (n = 263) who were infected with hepatitis C virus (HCV) genotype 1 and were receiving PEG-IFN/RBV were genotyped. Early virological response (EVR) (12 weeks), end-of-treatment response (EOTR) (48 weeks), sustained virological response (SVR) (72 weeks) and relapse were evaluated using conventional and quantitative polymerase chain reaction (PCR) assays. The frequency of the C allele in the population was 39%. Overall, 43% of patients experienced SVR. The IL28B CC genotype was significantly associated with higher treatment response rates and a lower relapse rate compared to the other genotypes [84% vs. 58% EVR, 92% vs. 63% EOTR, 76% vs. 38% SVR and 17% vs. 40% relapse rate in CC vs. other genotypes (CT and TT), respectively]. Thus, the IL28B genotype appears to be a strong predictor of SVR following PEG-IFN/RBV therapy in treatment-naïve Brazilian patients infected with HCV genotype 1. This study, together with similar research examining other SNPs, should help to define adequate protocols for the treatment of patients infected with HCV genotype 1, especially those with a poor prognosis.

Perihepatic lymph node enlargement is a negative predictor for sustained responses to pegylated interferon‐α and ribavirin therapy for Japanese patients infected with hepatitis C virus genotype 1

Although perihepatic lymph node enlargement (PLNE) is reportedly associated with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the significance of PLNE in interferon therapy for chronic hepatitis C. Between December 2004 and June 2005, 112 patients with hepatitis C virus (HCV) genotype 1 and HCV RNA of more than 100 KIU/mL were enrolled, who underwent pegylated interferon-α plus ribavirin therapy thereafter. PLNE was defined as a perihepatic lymph node of more than 1 cm in the longest axis by ultrasonography. The sustained virological response (SVR) rate was lower in patients with PLNE (4/22, 18.2%) than in those without (37/90, 41.1%; P = 0.045) and viral load decline was smaller in patients with PLNE than in those without (P = 0.028). The proportion of PLNE positive patients was the smallest in the SVR group (P = 0.033) among the patient groups divided by the treatment outcome. PLNE was retained as a negative predictor for SVR by multivariate logistic regression analysis (P = 0.012). Furthermore, PLNE was not significantly associated with the mutations at HCV core protein and at interferon sensitivity-determining region, or interleukin-28B polymorphism in 45 patients with HCV genotype 1, enrolled between December 2011 and March 2012. PLNE is a negative predictor for SVR in patients with HCV genotype 1 and HCV RNA of more than 100 KIU/mL treated with pegylated interferon-α plus ribavirin, independent of other known predictors for SVR.

IL‐28B polymorphisms and the response to antiviral therapy in HCV genotype 2 and 3 varies by ethnicity: a meta‐analysis

Studies of IL-28B genotype in patients with hepatitis C virus (HCV) genotype 2/3 infection have yielded conflicting results. The aim of this meta-analysis was to obtain a pooled odds ratio (OR) of the impact of IL-28B genotype on achieving sustained virologic response (SVR) in patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin. A meta-analysis with a random effects model was performed, and study heterogeneity and publication bias were assessed. Forty-three percent of the Caucasians (11 studies) and 86% of Asians (five studies) had the favourable IL-28B genotype. In Caucasians, the pooled OR of SVR with the favourable IL-28B genotype was 1.36 (95%CI: 0.98-1.88, P=0.07) in all patients and 1.55 (95%CI: 1.10-2.18, P=0.01) in patients treated with pegIFN and ribavirin for ≥24weeks. In Asians, the pooled OR of SVR in patients with the favourable IL-28B genotype was 1.99 (95%CI: 0.94-4.25, P=0.07). The favourable IL-28B genotype was also significantly associated with rapid virologic response (RVR) in both groups (Caucasians: OR: 1.82, 95%CI: 1.12-2.96, P=0.02; Asians: 2.39, 95%CI: 1.39-4.11, P=0.002), as well as the likelihood of an SVR in a subgroup of 350 Caucasian patients without an RVR (OR: 3.29, 95%CI: 1.67-6.51, P=0.001). The favourable IL-28B genotype is a statistically significant predictor of SVR and RVR in Caucasian patients treated with pegIFN and ribavirin for 24weeks. In contrast, the favourable IL-28B genotype is associated with RVR, but not SVR in Asian HCV genotype 2 patients.

Effects of IL‐28B gene polymorphism on response to peginterferon plus ribavirin combination therapy for genotype 2 chronic hepatitis C

AimInterleukin (IL)‐28B gene polymorphism is closely linked with treatment response to peginterferon plus ribavirin combination therapy for hepatitis C virus genotype 1. However, few studies have reported its effects on therapy for genotype 2. We aimed to examine the effects of IL‐28B gene polymorphism on treatment response in hepatitis C virus genotype 2 patients.MethodsIn a retrospective study of 101 patients infected with either genotype 2a (n = 65) or 2b (n = 36) and treated with peginterferon plus ribavirin, we investigated predictive factors for a sustained virological response (SVR), including genetic variations near the IL‐28B gene (rs8099917, rs11881222 and rs8103142) and clinical variables such as age, sex, body mass index, stage of fibrosis and drug adherence.ResultsUltra‐rapid virological response, rapid virological response (RVR), end‐of‐treatment response, SVR and relapse rates were 22.2%, 61.4%, 95.0%, 87.1% and 7.9%, respectively. In univariate analysis, RVR and IL‐28B single nucleotide polymorphisms (SNP) (rs8099917, rs11881222 and rs8103142) were significantly associated with SVR. In subgroup analysis, IL‐28B SNP were significantly associated with SVR in genotype 2a patients but not in genotype 2b patients. In multiple logistic regression analysis, RVR and IL‐28B SNP (rs8099917) were independently associated with SVR. Furthermore, IL‐28B SNP was significantly associated with relapse but RVR was not.ConclusionIn genotype 2 patients treated with peginterferon plus ribavirin combination therapy, IL‐28B gene polymorphism was a significant independent predictor of SVR as well as RVR. IL‐28B major allele may favor reduced relapse rates in patients with genotype 2 chronic hepatitis C.

Interleukin 28B-related polymorphisms: A pathway for understanding hepatitis C virus infection?

To analyze the role of rs12979860 and rs8099917 polymorphisms in hepatitis C virus (HCV) genotype 1 infection of Brazilians. A total of 145 adult patients diagnosed with genotype 1 chronic hepatitis C (CHC) who had completed a 48-wk regimen of pegylated-interferon α-2a or -2b plus ribavirin combination therapy were recruited from six large urban healthcare centers and 199 healthy blood donors (controls) from a single site between January 2010 and January 2012. Data on the patients' response to treatment was collected. Polymerase chain reaction-restriction fragment length polymorphism genotyping of the interleukin (IL)28B gene fragment encompassing the single nucleotide polymorphisms (SNPs) rs12979860 (C/T) and rs8099917 (T/G) was carried out for 79 of the CHC patients and 199 of the controls. Bi-directional amplicon sequencing of the two SNPs was carried out for the remaining 66 CHC patients. SNP rs12979860 genotyping was successful in 99.5% of the controls and 97.2% of the CHC patients, whereas the SNP rs8099917 genotyping was successful in 95.5% of the controls and 100% of the CHC patients. The genotype and allele distributions for both rs12979860 and rs8099917 were significantly different between the control and CHC patient groups, with significantly higher genotype frequencies of CC and TT in the controls (P = 0.037 and 0.046, respectively) and of TT and GG in the CHC patients (P = 0.0009 and 0.0001, respectively). Analysis of the CHC patients who achieved sustained virological response (SVR) to treatment (n = 55) indicated that the rs12979860 C allele and CC genotype were predictors of SVR (P = 0.02). No significant correlation was found between rs8099917 genotypes and treatment response, but carriers of the T allele showed significantly higher rates of SVR (P = 0.02). Linkage disequilibrium analysis of the group that achieved SVR showed a significant association between rs12979860 and rs8099917 (P = 0.07). The higher allele frequency of rs12979860 C and rs8099917 T observed in non-HCV-infected individuals may indicate a potential protective role for these IL28B-related polymorphisms.

Prediction of sustained virologic responses to combination therapy of pegylated interferon-α and ribavirin in patients with chronic hepatitis C infection

Background and Aim:Hepatitis C virus (HCV) infection is a major health problem worldwide. Genotype-4 is the most common genotype in Saudi Arabia. The response to treatment with pegylated interferon-α combined with ribavirin in chronic HCV infection varies. This study aimed at investigating the pre- and on-treatment predictors of sustained virologic response (SVR) in patients with chronic hepatitis C (CHC) infection.Patients and Methods:Clinical data of 48 patients with CHC treated with standard HCV antiviral combination therapy, between January 2005 and December 2010, at a Saudi University hospital, were retrospectively reviewed for age, sex, body mass index, liver enzymes, HCV-RNA viral load, liver biopsy, and response to treatment. The primary end point was SVR defined as undetectable HCV-RNA by polymerase chain reaction (PCR) 24 weeks after the end of treatment. Univariable logistic regression was used to explore the association between the different variables and SVR. These independent predictors of SVR were then analyzed with multivariable logistic regression analysis.Results:Of the 48 treated patients, 25 (52%) were females and 27 (56%) were Saudi. The mean age was 43 years (43 ± 10 years). Twenty-four (50%) had genotype-4, and 26 (54%) had liver biopsy. The overall SVR rate was 75% (36/48) and was 83.3% (20/24) among genotype-4 patients. Baseline factors associated with SVR identified by univariate logistic regression were genotype-4 and early viral response (EVR), defined as a drop of ≥2 log in serum HCV viral load after 12 weeks of initiation of combination therapy (P = 0.001). However, in stepwise regression analysis, the independent factor associated with the effect of antiviral therapy was genotype-4. When on-treatment variables were included, EVR (P = 0.003) and low baseline viral load (P = 0.048) were highly predictive of SVR.Conclusions:Of our HCV-treated patients, 75% had SVR. HCV genotype-4, EVR, and low baseline viral load were predictive of SVR.

Prediction of Sustained Virologic Response Based on Week 4 and Week 12 Response in Hepatitis C Virus Genotype 1 Patients Treated with Peginterferon and Ribavirin: Assessment in a Favorable IL28B Allele-Prevalent Area

Objectives: The aim of this study was to evaluate rapid virologic response (RVR) rate after peginterferon (PegIFN) and ribavirin (RBV) dual combination therapy in Korean hepatitis C virus (HCV) genotype 1 patients whose IL28B polymorphism is generally favorable. This study also assessed the value of RVR in predicting sustained virologic response (SVR). Methods: Treatment-naïve HCV genotype 1 patients who underwent initial treatment with either PegIFN-α-2a or α-2b and RBV were retrospectively evaluated. From 148 patients, 115 met inclusion criteria for the final analysis. Results: Overall RVR rate was 47.8% and SVR rate was 67.8% (78/115). Positive RVR had the highest positive predictive value (PPV) for achieving SVR, whereas it had the lowest negative predictive value (NPV). Undetectable HCV RNA at treatment week 12, namely complete early virologic response (cEVR), had high PPV as well as high NPV. Factors predisposing SVR were absence of liver cirrhosis and achievement of RVR or cEVR. Conclusion: This study showed RVR rate close to 50% in HCV genotype 1 patients treated with dual combination therapy in the region where favorable IL28B polymorphism is reported to be as high as 90%. Even for the patients who failed to achieve RVR, positive cEVR demonstrated a fair chance of achieving SVR.

Patients younger than forty years old with hepatitis C virus genotype–1 chronic infection had treatment responses similar to genotype–2 infection and not related to interleukin–28B polymorphism

Background and rationale. Age is one of the predictors for sustained virological response (SVR) when treating chronic hepatitis C (CHC) patients with pegylated-interferon/ribavirin (PegIFN/RBV). However, the treatment responses of the young patients had not been analyzed before. Therefore, we conducted this study to investigate the treatment responses of CHC patients younger than 40 years old (y/o).Material and methods. We retrospectively analyzed our prospective cohort of genotype 1 (GT1)- and genotype 2 (GT2)-CHC patients who received 24-week PegIFN/RBV treatment. We divided these patients into two groups according to their age younger or older than 40 y/o. Clinical parameters including viral responses and single nucleotide polymorphisms (SNPs) of interleukin–28B (IL28B) had been analyzed.Results. In GT1-CHC patients, the rapid, complete early viral response rates and the SVR rate were significantly higher in patients younger than 40 y/o. In GT–1 CHC patients younger than 40 y/o, the SVR rate was similar to the GT2-CHC patients, either with high or low baseline viral load. As for the SVR predictors, in CHC patients younger than 40 y/o, only BMI but not the genotype of HCV, not baseline viral load, and not IL28B SNP was the predictor.Conclusions. GT1-CHC patients younger than 40 y/o had SVR rate similar to GT2-CHC patients. The IL28B polymorphism had no impact on the SVR rate in these young GT1-CHC patients.

High effectiveness of peginterferon alfa-2a plus ribavirin therapy in Korean patients with chronic hepatitis C in clinical practice

Background/AimsIdentifying the impact of a patient's ethnicity on treatment responses in clinical practice may assist in providing individualized treatment regimens for chronic hepatitis C (CHC). The effectiveness of standard peginterferon plus ribavirin therapy and the need for triple combination therapy with protease inhibitors in Koreans remain matters of debate. These issues were investigated in the present study.MethodsThe clinical data of 272 treatment-naïve Korean CHC patients who were treated in a community-based clinical trial (Clinical Trial group; n=51) and in clinical practice (Cohort group; n=221), were analyzed and compared. All were treated with standard protocols of peginterferon alfa-2a plus ribavirin therapy.ResultsFor patients with hepatitis C virus (HCV) genotype 1, the sustained virological response (SVR) rates in the Clinical Trial and Cohort groups were 81% (21/26) and 55% (58/106), respectively, by intention-to-treat (ITT) analysis (P=0.02), and 100% (13/13) and 80% (32/40), respectively, in treatment-adherent patients (P=0.18). For patients with HCV genotype 2, the SVR rates in these two groups were 96% (24/25) and 88% (101/115), respectively, by ITT analysis (P=0.31). Adherence and treatment duration were independent predictors of SVR for genotypes 1 and 2, respectively (P<0.01 for each). Korean patients with CHC achieved high SVR rates with peginterferon alfa-2a plus ribavirin in both the clinical trial and clinical practice settings.ConclusionsMeasures to raise adherence to standard therapy in clinical practice may improve the SVR rates in these patients as effectively as adding protease inhibitors, thus obviating the need for the latter.

Efficacy of the retreatment of hepatitis C virus infections after liver transplantation: Role of an aggressive approach

A sustained virological response (SVR) is achieved by 30% of naive liver transplantation (LT) recipients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV). Almost no data are available about retreatment. The aim of this study was to assess the efficacy, tolerability, and SVR predictors of retreatment. Data were collected from 4 centers on the retreatment of prior nonresponders to standard therapy or PEG-IFN (with or without RBV) and relapsers. Seventy-nine of 301 treatment-experienced LT patients (26%), who had a median age of 59 years (range = 35-77 years) and were mostly male (72%) and infected with genotype 1 (87%), were retreated with PEG-IFN and RBV at a median of 6.9 years after LT. During the first course of therapy, 35% were treated with interferon, 49% received tacrolimus, 52% received steroids, and 49.5% were relapsers. Retreatment was started at a median of 1.9 years (range = 45 days to 8.2 years) after the end of the first course. The proportion of patients with cirrhosis increased from 10% to 37% (P < 0.001). In addition, in retreated patients, full initial RBV doses (P = 0.03), growth factors [erythropoietin (P < 0.001) and granulocyte colony-stimulating factor (P = 0.048)], and transfusions (P = 0.03) were used more frequently, and the treatment duration was longer (P = 0.03). An end-of-treatment response was achieved in 61%, whereas SVR, which was associated with improved survival, occurred in 28 (35%). The variables predicting SVR were age (P = 0.04), disease severity [fibrosis (50% with F0-F2 versus 26% with F3-4), P = 0.03; bilirubin, P = 0.006; platelet count, P = 0.03], adherence, and viral kinetics. None of the patients without an early virological response achieved SVR. There was a trend of prior relapsers achieving higher SVR rates than prior nonresponders. In conclusion, SVR, which was achieved by approximately one-third of the retreated patients, can be predicted with the same variables used for naive LT recipients (age, disease severity, adherence, and viral kinetics) and is associated with enhanced survival.