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1.  The Reduced Predictive Value of Interleukin 28b Gene Polymorphisms in a Cohort of Patients With Thyroiditis Developed During Antiviral Therapy for Chronic Hepatitis C: A Preliminary Study 
Hepatitis Monthly  2012;12(8):e6036.
Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-α and ribavirin treatment in patients with chronic hepatitis C. Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR).
To determine the role of IL28B genotypes in a cohort of hepatitis C patients who develop TD during treatment and its relationship to SVR.
Patients and Methods:
IL28B gene profiles including rs12979860, rs12980275 and rs 8099917 and their genotypes were determined in a cohort of 23 hepatitis C patients who developed TD during treatment and their relationship to SVR.
Out of 23 studies cases, 19 has one or more favorable genotypes, of which 15 (78.9%) achieved SVR. Eleven has all three unfavorable genotypes and yet achieved 72.7 % SVR. The presence of more than one favorable genotype only correctly predicts SVR vs. non- SVR in ~50 % of cases, i.e. by chance.
Despite the small number of subjects, the presence of one or more unfavorable IL28B genotype does not portend a poor SVR prognostic outcome. This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition.
PMCID: PMC3475014  PMID: 23087747
Polymorphism, Genetic; Hepatitis C; Thyroiditis
2.  Hepatitis C (chronic) 
BMJ Clinical Evidence  2010;2010:0921.
About 60% to 85% of people infected with hepatitis C virus will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions in treatment-naïve people with chronic hepatitis C infection, but without liver decompensation? What are the effects of interventions in people with chronic hepatitis C infection, but without liver decompensation, who have not responded to interferon treatment? What are the effects of interventions in people with chronic hepatitis C infection, but without liver decompensation, who relapse after interferon treatment? What are the effects of interventions in people with chronic hepatitis C infection who also have HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 35 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: interferon monotherapy; interferon alfa plus ribavirin; peginterferon monotherapy; and peginterferon plus ribavirin.
Key Points
Chronic hepatitis C virus (HCV) infection is defined as persistent, detectable serum HCV RNA for a period greater than 6 months, with or without derangement in liver function tests. About 60% to 85% of people infected with HCV will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population.Complications of chronic HCV infection include cirrhosis, compensated and decompensated liver disease, and hepatocellular carcinoma.Many people chronically infected with HCV remain asymptomatic, including a significant proportion of those who progress to cirrhosis, so routine screening of people in high-risk groups is advisable.
Interferon monotherapy produces a sustained virological response in both treatment-naïve people and people with cirrhosis or advanced fibrosis compared with placebo or no treatment. Interferon also improves liver histology, although it may not be effective in preventing hepatocellular carcinoma in people with cirrhosis.Efficacy is dependent on duration of treatment, with treatment for 12 months seeming more effective than treatment for 6 months. However, treatment for 12 months is associated with an increase in adverse effects.A dose of 6 MU of interferon three times weekly seems no more effective at achieving sustained virological response than 3 MU three times weekly, and is associated with an increased risk of adverse effects.
Adding ribavirin to interferon regimens further increases the likelihood of achieving sustained virological response, but also increases the risk of anaemia. Efficacy of combination therapy depends on genotype, with genotype 1-infected people typically requiring longer duration of treatment compared with genotype 2- and genotype 3-infected people.
Peginterferon monotherapy increases the proportion of treatment-naïve people who achieve sustained virological response compared with standard interferon monotherapy.
Adding ribavirin to peginterferon increases the likelihood of achieving sustained virological response compared with either peginterferon alone or standard interferon plus ribavirin. This is currently the standard recommended therapeutic approach.
In people previously non-responsive to interferon monotherapy, treatment with interferon alfa plus ribavirin increases the likelihood of achieving sustained virological response compared with interferon alone. This effect seems greater when the interferon dose is higher than 3 MU three times weekly, or the duration of the treatment is 12 months or greater.We don't know whether peginterferon as a monotherapy, or in combination with ribavirin, is effective in non-responders to interferon monotherapy. We don't know whether peginterferon plus ribavirin is more effective than interferon alfa plus ribavirin.
In people who relapse after interferon monotherapy, treatment with interferon plus ribavirin is more likely than interferon treatment alone to achieve sustained virological response (SVR). There is general consensus that peginterferon plus ribavirin is likely to improve the probability of achieving SVR in people who relapse after interferon monotherapy.We don't know whether peginterferon alone is effective at achieving SVR in people who relapse after interferon monotherapy.
In people co-infected with HCV and HIV, peginterferon plus ribavirin seems more effective than standard interferon plus ribavirin treatment or peginterferon alone at achieving SVR. Although interferon plus ribavirin seems less effective than peginterferon plus ribavirin, the proportion of people achieving SVR suggests that interferon plus ribavirin may be effective in people with HCV and HIV. We don't know whether interferon alone is effective in people co-infected with HCV and HIV.
PMCID: PMC2907607  PMID: 21718581
3.  Relevance of low viral load in haemodialysed patients with chronic hepatitis C virus infection 
AIM: To identify predictors of sustained virological response in hemodialysed patients treated by PEGinterferon α for chronic hepatitis C, genotype 1.
METHODS: The sustained virological response (SVR) rate, IL28B genotype, IFNL4 genotype, initial viral load (IVL) and other pretreatment variables in 39 end-stage renal disease patients (ESRD) on maintenance haemodialysis (HD) infected with hepatitis C virus (HCV), genotype 1b, were compared with a control group of 109 patients with normal kidney function treated within the same period. All the patients were treatment naïve and had well compensated liver disease. The ESRD patients received 135 μg of PEGylated interferon α-2a (PegIFN-α) weekly and a reduced dose of ribavirin (RBV) was administered to 23/39 patients with an initial haemoglobin level > 10 g/dL. Control group patients were given standard doses of PegIFN-α and RBV. SVR was assessed as HCV RNA negativity 24 wk post-treatment. A t-test or ANOVA were used for comparisons of the means and a χ2 test compared the frequencies. Logistic regression was used to determine significant predictors of SVR. Cutoff values for continuous variables were obtained from Receiver Operating Characteristic analysis.
RESULTS: The distribution of IL28B rs12979860 CC, CT and TT genotypes in the ESRD group was 28.2%, 64.1% and 7.7%, respectively, and 19.3%, 62.4% and 18.3% in the controls. The IFNL4 genotype was in almost absolute linkage disequlibrium with IL28B. The proportion of patients with a low IVL (< 600000 IU/mL) was significantly higher in the ESRD group than in the controls (28/39, 71.8% vs 51/109, 46.8%, P = 0.009), as was the proportion of patients with low IVL in IL28B CC carriers compared with non-CC carriers in the ESRD group (10/11, 90.9% vs 18/28, 64.3%, P = 0.0035). This difference was not found in the controls (7/22, 31.8% vs 44/87, 50.6%, P = 0.9). The overall SVR rate was 64.1% (25/39) in the ESRD group and 50.5% (55/109) in the control group (P = 0.19). 11/11 (100%) and 19/22 (86.4%) IL28B CC patients achieved SVR in the ESRD and control groups, respectively. A statistically significant association between SVR and IL28B and IFNL4 variants was found in both groups. The ESRD patients who achieved SVR showed the lowest IVL [median 21000, interquartile range (IQR): 6000-23000 IU/mL], compared with ESRD individuals without SVR (1680000, IQR: 481000-6880000, P = 0.001), controls with SVR (387000, IQR: 111000-1253000) and controls without SVR (905000, IQR: 451000-3020000). In ESRD, an IVL < 600000 IU/mL was strongly associated with SVR: 24/28 (85.7%) patients who achieved SVR had viraemia below this threshold.
CONCLUSION: Haemodialysis decreases the viral load, especially in IL28B CC genotype carriers. A low IVL was the strongest predictor of SVR in ESRD patients identified in multivariate analysis.
PMCID: PMC4427671  PMID: 25987772
End-stage renal disease; Hepatitis C virus genotype 1; Interferon alpha; IFNL4; Ribavirin
4.  An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C 
PLoS ONE  2011;6(7):e20904.
Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables.
HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC).
Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST∶ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study.
A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.
PMCID: PMC3132753  PMID: 21760886
5.  IL28B SNP rs12979860 Is a Critical Predictor for On-Treatment and Sustained Virologic Response in Patients with Hepatitis C Virus Genotype-1 Infection 
PLoS ONE  2011;6(3):e18322.
Single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) have received considerable interest for their association with sustained virological response (SVR) when treating patients of genotype-1 hepatitis C virus (GT1-HCV) chronic infection with pegylated interferon and ribavirin (PegIFN/RBV). This study was to investigate the predictive power of IL28B SNPs for on-treatment responses and SVR in treatment-naïve patients with GT1-HCV chronic infection.
Methodology/Principal Findings
We analyzed ten SNPs of IL28B in 191 treatment-naïve patients with GT1-HCV chronic infection who received PegIFN/RBV. In these patients, rapid virological response (RVR), early virological response (EVR) and SVR were achieved in 69.6%, 95.8% and 68.6% of the patients, respectively. Multivariate analysis (odds ratio; 95% confidence interval; P value) indicated age (0.96; 0.93–0.99; 0.012), low baseline viral load (4.65; 2.23–9.66; <0.001) and CC genotype of rs12979860 (7.74; 2.55–23.53; <0.001) but no other SNPs were independent predictors for SVR. In addition, none of the ten SNPs examined were associated with baseline viral load and stages of liver fibrosis. Regarding RVR, low baseline viral load (2.83; 1.40–5.73; 0.004) and CC genotype of rs12979860 (10.52; 3.45–32.04; <0.001) were two critical predictors. As for EVR, only CC genotype of rs12979860 (36.21; 6.68–196.38; <0.001) was the predictor. Similarly, for end of treatment response (ETR), CC genotype of rs12979860 (15.42; 4.62–51.18; <0.001) was the only predictor. For patients with RVR, only low baseline viral load (3.90; 1.57–9.68; 0.003) could predict the SVR. For patients without RVR, only rs12979860 (4.60; 1.13–18.65; 0.033) was the predictor for SVR.
rs12979860 is the critical predictor for RVR, EVR, ETR and SVR in treatment-naïve patients of GT1-HCV chronic infection. Furthermore, this SNP is the only predictor for SVR in patients without RVR. These results have provided evidence that rs12979860 is the ideal IL28B SNP for genetic testing in treating patients of GT1-HCV chronic infection.
PMCID: PMC3068186  PMID: 21479134
6.  Clinical Implications of Detectable Baseline Hepatitis C Virus-Genotype 1 NS3/4A-Protease Variants on the Efficacy of Boceprevir Combined With Peginterferon/Ribavirin 
Open Forum Infectious Diseases  2014;1(2):ofu078.
 We analyzed the impact of pretreatment variants conferring boceprevir-resistance on sustained virologic response (SVR) rates achieved with boceprevir plus peginterferon-α/ribavirin (P/R) for hepatitis C virus (HCV)-genotype-1 infection.
 NS3-protease-polymorphisms emerging coincident with virologic failure on boceprevir/P/R regimens were identified as resistance-associated variants (RAVs). Baseline samples pooled from 6 phase II or phase III clinical trials were analyzed for RAVs by population sequencing. Interferon (IFN)-responsiveness was predefined as >1 log reduction in HCV-RNA level during the initial 4-week lead-in treatment with P/R before boceprevir was added. The effective boceprevir-concentration inhibiting RAV growth by 50% (EC50) was determined using a replicon assay relative to the wild-type referent.
 Sequencing was performed in 2241 of 2353 patients (95.2%) treated with boceprevir. At baseline, RAVs were detected in 178 patients (7.9%), including 153 of 1498 genotype-1a infections (10.2%) and 25 of 742 genotype-1b infections (3.4%) (relative risk, 3.03; 95% confidence interval [CI], [2.01, 4.58]). For IFN-responders, SVR24 (SVR assessed 24 weeks after discontinuation of all study medications) rates were 78% and 76% with or without RAVs detected at baseline, respectively. For the 510 poor IFN-responders, SVR24 rates were 8 of 36 subjects (22.2% [11.7%, 38.1%]) when baseline RAVs were detected vs 174 of 474 subjects (36.7% [32.5%, 41.1%]) when baseline RAVs were not detected (relative likelihood of SVR24 [95% CI], 0.61 [0.32, 1.05]). Sustained virologic response was achieved in 7 of 8 (87.5%) IFN-nonresponders with baseline variants exhibiting ≤2-fold increased EC50 for boceprevir in a replicon assay, whereas only 1 of 15 (7%) IFN-nonresponders with baseline RAVs associated with ≥3-fold increased EC50 achieved SVR.
 Baseline protease-variants appear to negatively impact SVR rates for boceprevir/P/R regimens only when associated with decreased boceprevir susceptibility in vitro after a poor IFN-response during the lead-in period.
PMCID: PMC4281806  PMID: 25734146
boceprevir; hepatitis C-genotype 1; RAVs; resistance-associated variants
7.  DNA polymorphisms and response to treatment in patients with chronic hepatitis C: Results from the HALT-C trial 
Journal of hepatology  2008;49(4):548-556.
Certain host genetic polymorphisms reportedly affect the likelihood of a sustained virological response (SVR) to interferon treatment in subjects infected with hepatitis C virus (HCV). As part of the HALT-C trial we evaluated genetic associations among patients infected with HCV genotype 1 who had failed previous interferon treatment.
SVR was determined 24 weeks after completing treatment with pegylated interferon alfa-2a and ribavirin. Eight single nucleotide polymorphisms (SNPs) were selected on the basis of previously reported associations with treatment response. Genotypes were assessed by polymerase chain reaction-based assays. The percentage of patients who achieved SVR was determined for each genotype and for an IL-10 promoter diplotype.
Among 637 non-Hispanic Caucasian patients there were no significant associations between genotype for any individual SNP (IL10 -1082, IL10 -592, TNF -308, TNF -238, TGFB1 codon 25, CCL2 -2518, EPHX1 codon 113 and AGT -6) and SVR, but SVR was more common among the patients who were homozygous for the ACC IL-10 promoter diplotype (adjusted odds ratio, 3.24; 95% confidence interval, 1.33–7.78; p=0.001).
Among non-Hispanic Caucasian patients treated with peginterferon and ribavirin after failing previous treatment with interferon, homozygosity for the ACC IL-10 promoter diplotype was associated with SVR.
PMCID: PMC3903339  PMID: 18619701
hepatitis C; chronic/genetics; polymorphism; genetic; interferon-alpha/therapeutic use; gene frequency
8.  Evaluated outcomes in patients with Chronic Hepatitis C 
The objective of this study was to evaluate the real outcomes of chronic hepatitis C patients, who treated with interferon plus ribavirin (INF-RBV) and peg-interferon plus ribavirin (PEG-RBV).
Despite the PEG-RBV has become a standard treatment of hepatitis C virus (HCV) around the world; and in Iran too, but in developing countries like as Iran, INF-RBV is still used among some patients for treating HCV, due to the high costs of treatment with PEG-RBV.
Patients and methods
The present cross-sectional study was conducted on 77 naïve patients referred to a private gastroenterology clinic between years 2007 through 2009 in Tehran. Patients had participated in this study taking two types of combination therapies, based on standard protocol of the Iranian Ministry of Health. At the end of the treatment, sustain virological response (SVR) rate was evaluated.
The outcomes showed in INF-RBV treatment; 11.6%, 16.3% and 34.9% patients were suffered from relapse, lost follow-up their treatment and non-responder, respectively, and finally 37.2% of the patients reached SVR. In PEG-RBV treatment outcomes were as follows; 2.9%, 14.7% and 14.7% patients were non-responder, lost follow-up their treatment and suffered from a relapse, respectively, and 67.6% of the patients reached SVR. The multivariate-adjusted odds ratios of outcomes showed that treated with PEG-RIB and also genotype 3a than the others genotypes in this treated had more chance to achieved SVR.
The findings of the present study showed that the rate of SVR in patients who treated with PEG-RBV significantly was higher than patients who treated with INF-RBV. Also in PEG-RBV the chance of achieving SVR is higher among the patients with genotype 3a than among those with other genotypes.
PMCID: PMC4017542  PMID: 24834289
chronic hepatitis C; Interferon; Peg-interferon; Sustain Virological response
9.  Serum leptin and ghrelin in chronic hepatitis C patients with steatosis 
AIM: To determine the associations between leptin and ghrelin concentrations and sustained virological response (SVR) in chronic hepatitis C patients with steatosis.
METHODS: We retrospectively assessed 56 patients infected with hepatitis C virus (HCV) genotype-1 and 40 with HCV genotype-3. Patients with decompensated cirrhosis, and those with other causes of chronic liver disease, were excluded. Serum HCV-RNA concentrations were measured before the initiation of treatment; at weeks 12 (for genotype 1 patients), 24 and 48 during treatment; and 24 wk after the end of treatment. Genotype was determined using INNO-LIPA HCV assays, and serum leptin and ghrelin concentrations were measured using enzyme-linked immunosorbent assay. Biopsy specimens were scored according to the Ishak system and steatosis was graded as mild, moderate, or severe, according to the Brunt classification.
RESULTS: Overall, SVR was positively related to the presence of genotype-3, to biopsy-determined lower histological stage of liver disease, and lower grade of steatosis. Patients ≥ 40 years old tended to be less responsive to therapy. In genotype-1 infected patients, SVR was associated with a lower grade of liver steatosis, milder fibrosis, and an absence of insulin resistance. Genotype-1 infected patients who did not achieve SVR had significantly higher leptin concentrations at baseline, with significant increases as the severity of steatosis worsened, whereas those who achieved SVR had higher ghrelin concentrations. In genotype-3 infected patients, SVR was associated only with fibrosis stage and lower homeostasis model assessment insulin resistance at baseline, but not with the degree of steatosis or leptin concentrations. Genotype-3 infected patients who achieved SVR showed significant decreases in ghrelin concentration at end of treatment. Baseline ghrelin concentrations were elevated in responders of both genotypes who had moderate and severe steatosis.
CONCLUSION: Increased serum leptin before treatment may predict non-SVR, especially in HCV genotype-1 infected patients, whereas increased ghrelin may predict SVR in genotype-1.
PMCID: PMC3235593  PMID: 22171144
Hepatitis C virus; Steatosis; Leptin; Ghrelin; Sustained virological response
10.  Rapid normalization of alanine aminotransferase predicts viral response during combined peginterferon and ribavirin treatment in chronic hepatitis C patients 
The treatment for chronic hepatitis C (CHC) is removal of the virus in order to prevent progression to liver cirrhosis and hepatocellular carcinoma (HCC). Few data have been presented regarding the clinical significance of changes in the alanine aminotransferase (ALT) level in this context. We analyzed the patterns of changes in ALT level and investigated the relationship between the rapid normalization of ALT and sustained virologic response (SVR) after combined treatment with peginterferon and ribavirin.
CHC patients (n=370) were classified into four groups according to the initial ALT level and subsequent changes: (1) initially abnormal ALT level and sustained abnormal ALT level during treatment, (2) initially abnormal ALT level but achievement of ALT normalization, (3) initially normal ALT level and variable ALT abnormality during treatment, and (4) initially normal ALT level and sustained normalization of ALT level during treatment. We subdivided groups 1 and 2 into those with patterns of decreased and normalization of ALT, with or without rapid normalization. We checked the end-treatment response (ETR) and SVR rates in each group and the factors associated with SVR, including patterns of changes in ALT level.
A total of 168 patients completed the therapy (age=54.34±10.64 years [mean±SD], 95 males [56.5%], genotype 1:82 [48.8%]). SVR was achieved in 115 (68.45%) of the completely treated patients. The SVR rate was significantly lower in group 1 than in group 2 (37.8 vs. 81.6%, P<0.001), and significantly higher in the rapid normalization group than in the group without rapid normalization (78.5% vs. 41.2%, P<0.001). Multiple logistic regression analysis revealed that age (odds ratio [OR]=0.94, 95% confidence interval [CI]=0.91-0.98, P=0.005), viral genotype (OR=2.76, 95% CI=1.20-6.38, P=0.017), and initial hepatitis C virus RNA titer (OR=0.28, 95% CI=0.10-0.75, P=0.012) were identified as independent significant predictive factors for SVR.
The SVR rate is significantly associated with normalization, and especially rapid normalization of ALT. Rapid normalization of ALT by 4 weeks after treatment might be a useful response factor that is readily available in clinical practice, and especially for genotype 1 patients.
PMCID: PMC3326992  PMID: 22511902
Hepatitis C; Chronic; Ribavirin; Alanine transaminase; Peginterferon
11.  FTO rs9939609 polymorphism is associated with metabolic disturbances and response to HCV therapy in HIV/HCV-coinfected patients 
BMC Medicine  2014;12:198.
The Fat Mass and Obesity-Associated Protein (FTO) gene rs9939609 single nucleotide polymorphism (SNP) has been associated with obesity, metabolic syndrome, insulin resistance (IR), and type 2 diabetes mellitus in the general population. The aim of our study was to examine for the first time the association of the rs9939609 polymorphism with metabolic disturbances, liver disease and virologic response to hepatitis C virus (HCV) therapy with pegylated-interferon-alpha plus ribavirin (pegIFNα/RBV) in human immunodeficiency virus (HIV)/HCV coinfected patients.
We carried out a cross-sectional study in 261 patients, of whom 178 were subsequently treated with pegIFNα/RBV therapy. FTO rs9939609 and IFNL3 rs12980275 polymorphisms were genotyped by GoldenGate®. The main outcomes were: 1) metabolic disturbances: insulin resistance (homeostatic model assessment (HOMA-IR)) and overweight (body mass index (BMI)); 2) liver disease (Metavir score): significant fibrosis (F ≥2) and steatosis (>10% fatty hepatocytes); and 3) virologic response to HCV treatment: sustained virologic response (SVR).
The rs9939609 AA genotype was associated with higher values of BMI (adjusted arithmetic mean ratio (aAMR) = 1.08; 95% confidence interval (95%CI) = 1.03 to 1.14; P = 0.002) and HOMA-IR (aAMR = 1.32; 95%CI = 1.03 to 1.69; P = 0.027). Patients with an rs9939609 AA genotype had higher likelihoods of achieving values of BMI ≥27.5 kg/m2 (adjusted odds ratio (aOR) = 3.46; 95%CI =1.17 to 10.21; P = 0.024), HOMA-IR ≥2.5 (aOR = 2.09; 95%CI = 1.02 to 4.32; P = 0.045), significant fibrosis (aOR = 2.34; 95%CI =1.02 to 5.36; P = 0.045) and steatosis (aOR = 3.65; 95%CI = 1.29 to 10.36; P = 0.015). The rs9939609 AT/AA genotype decreased the likelihood of achieving SVR (aOR = 0.58; 95%CI = 0.34 to 0.99; P = 0.044). A decision tree was performed with the genotypes of HCV, IFNL3 and FTO. The incorporation of rs9939609 significantly improves the prediction of SVR (P <0.05). The overall accuracy was 68.2%.
Patients carrying the unfavourable AT/AA genotype of rs9939609 polymorphism had higher odds of metabolic disturbances and a lower likelihood of achieving successful virologic response to HCV therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0198-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4224698  PMID: 25367448
AIDS; Chronic hepatitis C; HCV therapy; Metabolism; Insulin resistance; Obesity; SNPs
12.  Differences in clinical outcomes among hepatitis C genotype 1-infected patients treated with peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin: a meta-analysis 
With the development of new direct acting antiviral (DAA) therapy for hepatitis C, the backbone peginterferon alpha used may be of importance in maximizing treatment outcomes. To this end, the rates of sustained virologic response (SVR), relapse, and treatment discontinuation among hepatitis C genotype 1-infected patients given peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin were determined using a meta-analysis.
Randomized trials examining peginterferon alpha-2a or peginterferon alpha-2b co-administered with ribavirin for 48 weeks were included. Data were extracted on SVR, relapse, and treatment discontinuations for treatment-naïve and treatment-experienced patients. Pooled proportions using fixed and random effects meta-analysis were calculated.
Twenty-six trials provided data on patients treated with peginterferon alpha-2a plus ribavirin, and 19 trials provided data on patients treated with peginterferon alpha-2b plus ribavirin. Five trials were direct head-to-head evaluations. In the subset of trials that included head-to-head evaluations, no significant differences were observed between the two treatments for treatment-naïve (relative risk [RR]: 1.07, 95% confidence intervals [CI]: 0.97–1.18) and treatment-experienced patients (RR: 1.27, 95% CI: 0.58–2.77). Using only active trial arms, a larger proportion of the treatment- naïve patients who were provided peginterferon alpha-2a plus ribavirin achieved a SVR (47%), which is greater than that of treatment-naïve patients who were provided peginterferon alpha- 2b plus ribavirin (40% SVR achievement); however, a larger proportion of treatment- experienced patients who were provided peginterferon alpha-2b plus ribavirin achieved a SVR (16%) when compared with treatment-experienced patients given peginterferon alpha-2a plus ribavirin (12% SVR achievement). A larger proportion of relapses occurred among both treatment-naïve and treatment-experienced patients given peginterferon alpha-2a plus ribavirin, when compared with treatment-naïve and treatment-experienced patients taking peginterferon alpha-2b plus ribavirin. The proportion of patients discontinuing treatment was greater among treatment-naïve patients taking peginterferon alpha-2a plus ribavirin, but smaller among treatment-experienced patients.
There are small differences in treatment outcomes for different types of peginterferon- alpha. Patient status and complexity of administration may differentiate clinical outcomes.
PMCID: PMC3304330  PMID: 22427726
hepatitis C; genotype 1; peginterferon; ribavirin; sustained virologic response; meta-analysis
13.  Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C: indirect evidence of a role of hepatitis C virus genotype 3 in steatosis 
Gut  2004;53(3):420-424.
Background and aim: Recent studies suggest that liver steatosis in chronic hepatitis C may be the expression of a direct cytopathic effect of hepatitis C virus (HCV), particularly in patients infected with genotype 3. To investigate this hypothesis, we studied the relationship between steatosis evolution and HCV clearance after antiviral treatment in patients with chronic hepatitis C and paired liver biopsies.
Methods: A total of 151 patients (37 with HCV genotype 3; 114 with HCV non-3 genotypes) were selected according to the following criteria: presence of steatosis at initial biopsy; no antiviral treatment prior to the first biopsy; antiviral treatment received between the two biopsies; body mass index (BMI) <28 kg/m2; absence of excessive alcohol intake; no serum hepatitis B surface antigen or human immunodeficiency virus antibodies; and absence of diabetes mellitus. Evolution of steatosis was examined by comparing steatosis grades between the two biopsies.
Results: Twenty five patients (16.5%) were sustained virological responders (SVR) to antiviral treatment. Steatosis evolution after antiviral treatment was as follows: improvement in 36% of cases; stability in 51%; and worsening in 13%. Steatosis improvement was significantly more frequent in SVR than in non-responders (NR) (64% v 31%; p<0.004). This significant difference occurred in patients infected with genotype 3 (91% v 19%; p<0.0001) but not in those infected with non-3 genotypes (43% v 34%; NS). Among the 25 SVR, improvement in steatosis was significantly more frequent in patients infected with genotype 3 than in those infected with non-3 genotypes (91% v 43%; p<0.04) whereas in NR, improvement in steatosis did not differ between those infected with genotype 3 and non-3 genotypes (19% v 34%; NS). In multivariate analysis, four factors were independently associated with steatosis improvement: sustained virological response to antiviral therapy (odds ratio (OR) 6.06 (95% confidence interval (CI) 1.61–22.9); p = 0.01), severe steatosis (OR 5.50 (95% CI 1.54–19.6); p = 0.01), HCV genotype 3 (OR 2.90 (95% CI 0.85–10.0); p = 0.07), and BMI >25 kg/m2 (OR 0.24 (95% CI 0.08–0.73); p = 0.02).
Conclusions: Our results showed significant improvement in steatosis in patients infected with HCV genotype 3, who achieved sustained viral clearance. This provides further evidence for direct involvement of HCV genotype 3 in the pathogenesis of hepatic steatosis.
PMCID: PMC1773974  PMID: 14960527
chronic hepatitis C; steatosis; interferon; hepatitis C virus genotype 3
14.  A Lower Serum Gamma-Glutamyltransferase Level Does Not Predict a Sustained Virological Response in Patients with Chronic Hepatitis C Genotype 1 
Gut and Liver  2012;7(1):74-81.
Low gamma-glutamyltransferase (GGT) level was shown to be an independent predictor of a sustained virological response (SVR) in chronic hepatitis C. We aimed to determine factors associated with high GGT level, and to evaluate whether low GGT level is an independent predictor of a SVR in chronic hepatitis C genotype 1.
We retrospectively reviewed our data of patients with chronic hepatitis C genotype 1 treated with pegylated interferon-α and ribavirin. Baseline features were compared between patients with normal and high GGT levels. Factors associated with high GGT level and those associated with a SVR were determined by univariate and multivariate analysis.
This study included 57 patients. Mean age was 52.28±9.35 years. GGT levels was elevated in 27 patients (47.4%). GGT levels were normal in 63.3% of the patients who achieved a SVR and in 40.7% of those who did not achieve a SVR (p>0.05). By multivariate logistic regression analysis, the presence of cirrhosis (odds ratio [OR], 9.41; 95% confidence interval [CI], 1.08 to 102.61) and female gender (OR, 6.77; 95% CI, 1.23 to 37.20) were significantly associated with high GGT level, and only rapid virological response was associated with a SVR (OR, 8.369; 95% CI, 1.82 to 38.48).
Low GGT level does not predict a SVR; however, it may be a predictor of high fibrosis scores.
PMCID: PMC3572324  PMID: 23423958
Chronic hepatitis C; Gamma-glutamyltransferase
15.  Durability of a sustained virological response in chronic hepatitis C patients treated with pegylated interferon alfa and ribavirin 
The Korean Journal of Hepatology  2011;17(3):183-188.
The reappearance rates of hepatitis C virus (HCV) RNA after a sustained virological response (SVR) have been reported to be 1-2%. We investigated the reappearance rate of HCV RNA after SVR in chronic hepatitis C (CHC) patients treated with pegylated interferon (PEG-IFN) and ribavirin.
In total, 292 CHC patients who achieved an SVR after PEG-IFN and ribavirin treatment were included. They were treated with subcutaneous injections of either PEG-IFN-α 2a or 2b plus ribavirin orally. Liver function tests and qualitative HCV RNA assays were performed every 6 months during the follow-up period after an SVR.
Among the 292 patients, 224 (genotype 1, 92; genotype non-1, 132) were followed up for more than 6 months after SVR. These 224 patients were aged 48.1±11.5 years (mean±SD), and 129 of them were male. The median follow-up duration was 18 months (range 6-60 months). The reappearance rate of HCV RNA during follow-up was 0%. Two patients who achieved an SVR developed hepatocellular carcinoma during the follow-up period.
An SVR was maintained in all CHC patients treated with PEG-IFN plus ribavirin during a median follow-up of 18 months. However, a screening test for hepatocellular carcinoma is needed for patients with an SVR.
PMCID: PMC3304656  PMID: 22102384
Durability; Sustained virological response; Chronic hepatitis C; Pegylated interferon; Ribavirin
16.  SVR12 is higher than SVR24 in treatment-naïve hepatitis C genotype 1 patients treated with peginterferon plus ribavirin 
Clinical Epidemiology  2014;6:49-58.
Randomized clinical trials (RCTs) of interventions for the hepatitis C virus have historically used sustained virological response (SVR) at 24 weeks after treatment (SVR24) as the key effect measure. However, recent RCTs investigating the efficacy of new direct acting agents (DAAs) have used SVR at 12 weeks after treatment (SVR12). While there is evidence to suggest SVR24 and SVR12 are similar in patients receiving new DAAs, this is unlikely to be true for patients receiving backbone peginterferon-ribavirin control treatment. Establishing the difference between SVR12 and SVR24 for patients receiving peginterferon-ribavirin treatment is therefore necessary to avoid biased interpretations of the benefits of newer DAAs.
We searched the MEDLINE®, Embase™, and Cochrane CENTRAL for RCTs with a peginterferon-ribavirin arm that used SVR24 and/or SVR12. As no RCTs reported on both, we pooled SVR12 and SVR24 proportions using conventional meta-analysis. Proportions were pooled separately for peginterferon alpha-2a and alpha-2b. Further, a Bayesian meta-regression model was employed to estimate the difference between SVR12 and SVR24.
Thirty-five RCTs including a peginterferon arm were identified. Twenty-four trials included a peginterferon alpha-2a plus ribavirin arms, of which 20 reported SVR24 and five reported SVR12. Seventeen trials included a peginterferon alpha-2b plus ribavirin arm, of which 16 reported SVR24 and one reported SVR12. Using Bayesian meta-regression, the pooled SVR12 was 6% higher than SVR24 with peginterferon alpha-2a (53% versus 47%) and 5% higher with peginterferon alpha-2b (45% versus 40%) and 95% credible intervals (CrIs) were only marginally overlapping. The meta-regression also demonstrated a marginally significant relative risk of 1.13 (95% CrI 0.99–1.26) of SVR12 versus SVR24. The conventional pairwise meta-analyses were consistent with these findings.
Considering the relatively large difference observed between SVR12 and SVR24, it seems reasonable to insist that future clinical trials report both to allow for complete transparency and clarity in their interpretation.
PMCID: PMC3897323  PMID: 24474846
sustained virological response; meta-regression; direct acting antivirals
17.  IL28B genetic variations are associated with high sustained virological response (SVR) of interferon-α plus ribavirin therapy in Taiwanese chronic HCV infection 
Genes and Immunity  2011;12(4):300-309.
Chronic hepatitis C virus (HCV) infection patients exhibit different sustained virological responses (SVRs) following the treatment with pegylated interferon-α (IFN-α) and ribavirin. Genome-wide association studies consistently linked SVR of IFN-α-based therapy to the IL28B single-nucleotide polymorphisms (SNPs) on chromosome 19q.13 in various populations. This study was undertaken to investigate the association of IL28B SNPs with SVR in a cohort of Taiwanese chronic HCV patients. Ten SNPs of IL28B were genotyped in 728 chronic HCV patients and 960 healthy controls. Genotype distributions, allele frequencies and haplotypes were tested for SVR and susceptibility in Taiwanese chronic HCV patients. Non-genotype 1 infection (adjusted P=3.3 × 10−12, odds ratio (OR) 0.179; 95% confidence interval (CI): 0.110–0.290) and low HCV viral load (<400 000 IU ml–1) (adjusted P=3.5 × 10−9, OR 0.299; 95% CI: 0.200–0.446) were two major factors identified for high SVR. Notably, eight IL28B SNPs including previously described disease-associated SNPs (Trend test P=0.005) were significantly associated with SVR. Our data indicate that IL28B polymorphisms are the essential contributing factors for high SVR in Taiwanese chronic HCV patients. Combination of virus genotyping and host genetic data may be used to select the optimal treatment regimes in IFN-based therapy.
PMCID: PMC3114195  PMID: 21346780
hepatitis C; sustained virological response; IL28B; single-nucleotide polymorphisms
18.  Retreatment with pegylated interferon alpha-2a and ribavirin in patients with chronic hepatitis C who have relapsed or not responded to a first course of pegylated interferon-based therapy 
Pegylated interferon (pegIFN) and ribavirin combination therapy remains the first-line treatment for chronic hepatitis C virus (HCV) infection. In contrast to the wealth of studies in treatment-naive patients, the effectiveness of retreatment in patients who have previously failed pegIFN-based therapy is largely unreported.
To assess the effectiveness of the retreatment of patients who have previously failed an initial course of pegIFN-based therapy with pegIFNα-2a and ribavirin.
A post-hoc analysis of a multicentre open-label study was performed. Patients received pegIFNα-2a and ribavirin at a dose of 800 mg/day and later 1000 mg/day to 1200 mg/day for 24 to 48 weeks at the discretion of the investigator. Outcomes at week 12 (early virological response [EVR]) and week 24 (sustained virological response [SVR]) were analyzed.
Eighty-seven patients who had relapsed after previous pegIFN-based therapy (n=28; 78% genotype 1) or were nonresponders (n=59; 71% genotype 1) were analyzed. Of the relapsers, 86% achieved an EVR and 68% achieved an SVR. In relapsers to pegIFN monotherapy (n=15) or pegIFN plus ribavirin (n=13), 60% and 77% achieved an SVR, respectively. Fibrosis and genotype did not affect the likelihood of SVR in relapsers although this may be the result of the relatively small number of patients. In previous nonresponders, an EVR was achieved in 53% but an SVR occurred in only 17%. In nonresponders to pegIFN monotherapy (n=9) and pegIFN plus ribavirin (n=50), 33% and 14% achieved an SVR, respectively. Genotype did not affect SVR in nonresponders. Only 10% with a METAVIR score of F3 or F4 on liver biopsy achieved an SVR.
Relapse after previous pegIFN-based therapy is associated with a strong probability of treatment success whereas retreatment of those with previous nonresponse does not.
PMCID: PMC2694653  PMID: 19319382
Failure; Hepatitis C; Nonresponse; Peginterferon; Relapse; Ribavirin; Treatment
19.  The impact of IL28B genotype on the gene expression profile of patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin 
Recent studies of CH-C patients have demonstrated a strong association between IL28B CC genotype and sustained virologic response (SVR) after PEG-IFN/RBV treatment. We aimed to assess whether IL28B alleles rs12979860 genotype influences gene expression in response to PEG-IFN/RBV in CH-C patients.
Clinical data and gene expression data were available for 56 patients treated with PEG-IFN/RBV. Whole blood was used to determine IL28B genotypes. Differential expression of 153 human genes was assessed for each treatment time point (Days: 0, 1, 7, 28, 56) and was correlated with IL28B genotype (IL28B C/C or non-C/C) over the course of the PEG-IFN/RBV treatment. Genes with statistically significant changes in their expression at each time point were used as an input for pathway analysis using KEGG Pathway Painter (KPP). Pathways were ranked based on number of gene involved separately per each study cohort.
The most striking difference between the response patterns of patients with IL28B C/C and T* genotypes during treatment, across all pathways, is a sustained pattern of treatment-induced gene expression in patients carrying IL28B C/C. In the case of IL28B T* genotype, pre-activation of genes, the lack of sustained pattern of gene expression or a combination of both were observed. This observation could potentially provide an explanation for the lower rate of SVR observed in these patients. Additionally, when the lists of IL28B genotype-specific genes which were differentially expressed in patients without SVR were compared at their baseline, IRF2 and SOCS1 genes were down-regulated regardless of patients' IL28B genotype. Furthermore, our data suggest that CH-C patients who do not have the SOCS1 gene silenced have a better chance of achieving SVR. Our observations suggest that the action of SOCS1 is independent of IL28B genotype.
IL28B CC genotype patients with CH-C show a sustained treatment-induced gene expression profile which is not seen in non-CC genotype patients. Silencing of SOCS1 is a negative and independent predictor of SVR. These data may provide some mechanistic explanation for higher rate of SVR in IL28B CC patients who are treated with PEG-IFN/RBV.
PMCID: PMC3296607  PMID: 22313623
HCV; Gene Expression; Pathway Analysis; IL28B; SOCS1; IRF2; chronic hepatitis C; HCV treatment
20.  Modeling Viral Evolutionary Dynamics after Telaprevir-Based Treatment 
PLoS Computational Biology  2014;10(8):e1003772.
For patients infected with hepatitis C virus (HCV), the combination of the direct-acting antiviral agent telaprevir, pegylated-interferon alfa (Peg-IFN), and ribavirin (RBV) significantly increases the chances of sustained virologic response (SVR) over treatment with Peg-IFN and RBV alone. If patients do not achieve SVR with telaprevir-based treatment, their viral population is often significantly enriched with telaprevir-resistant variants at the end of treatment. We sought to quantify the evolutionary dynamics of these post-treatment resistant variant populations. Previous estimates of these dynamics were limited by analyzing only population sequence data (20% sensitivity, qualitative resistance information) from 388 patients enrolled in Phase 3 clinical studies. Here we add clonal sequence analysis (5% sensitivity, quantitative) for a subset of these patients. We developed a computational model which integrates both the qualitative and quantitative sequence data, and which forms a framework for future analyses of drug resistance. The model was qualified by showing that deep-sequence data (1% sensitivity) from a subset of these patients are consistent with model predictions. When determining the median time for viral populations to revert to 20% resistance in these patients, the model predicts 8.3 (95% CI: 7.6, 8.4) months versus 10.7 (9.9, 12.8) months estimated using solely population sequence data for genotype 1a, and 1.0 (0.0, 1.4) months versus 0.9 (0.0, 2.7) months for genotype 1b. For each individual patient, the time to revert to 20% resistance predicted by the model was typically comparable to or faster than that estimated using solely population sequence data. Furthermore, the model predicts a median of 11.0 and 2.1 months after treatment failure for viral populations to revert to 99% wild-type in patients with HCV genotypes 1a or 1b, respectively. Our modeling approach provides a framework for projecting accurate, quantitative assessment of HCV resistance dynamics from a data set consisting of largely qualitative information.
Author Summary
Hepatitis C virus (HCV) chronically infects approximately 170 million people worldwide. The goal of HCV treatment is viral eradication (sustained virologic response; SVR). Telaprevir directly inhibits viral replication by inhibiting the HCV protease, leading to high SVR rates when combined with pegylated-interferon alfa and ribavirin. Telaprevir-resistant variants may be detected in the subset of patients who do not achieve SVR with telaprevir. While the clinical impact of viral resistance is unknown, typically the telaprevir-sensitive virus re-emerges after the end of treatment due to competition between the telaprevir-sensitive and resistant variants. Previous estimates of these competition dynamics were obtained from population sequence data, which are qualitative and have a limited sensitivity of ∼20%. We sought to improve these estimates by combining these data with clonal sequence data, which are quantitative and have a sensitivity of ∼5%, and using quantitative modeling. The resulting model, which was verified with an independent data set, predicted that the median time for telaprevir-resistant variants to decline to less than 1% of the viral population was ≤1 year. Our modeling approach provides a framework for accurately projecting HCV resistance dynamics from a dataset consisting of largely qualitative information.
PMCID: PMC4138032  PMID: 25101970
21.  Interleukin-28 and hepatitis C virus genotype-4: Treatment-induced clearance and liver fibrosis 
AIM: To investigate the association between interleukin-28B (IL28B) genotype and response to treatment and hepatic fibrosis in patients with hepatitis C virus (HCV) genotype 4.
METHODS: Two hundred and one HCV-genotype 4 patients were included. All patients were treated with Peginterferon alph2a/Ribavirin for 48 wk. End of treatment response (ETR) was defined as loss of detectable serum HCV RNA at the end of treatment. Sustained viral response (SVR) was defined as loss of detectable serum HCV RNA at the end of 24 wk follow up. Genotyping of IL28B rs12979860 was performed using the TaqMan assay. We used logistic regression to estimate the adjusted odds ratio (aOR) and 95%CI.
RESULTS: The study included 201 HCV-genotype 4 patients. The majority of patients were men (89.6%), with a median age of 47 years, inter-quartile range (40-51). Approximately 62.5% of patients had ETR, and 49.6% had SVR. Individuals who achieved SVR were more likely to be younger (χ2 = 4.91, P = 0.027), and less likely to have fibrosis (χ2 = 15.54, P < 0.0001), or inflammation (χ2 = 7.58, P = 0.006). The genotype distribution of rs12979860 was 36.2%, 49.0% and 14.8% for genotypes CC, CT, and TT, respectively. In these participants, rs12979860 genotype distribution did not differ by gender (P = 0.466), pretreatment viral load (P = 0.600), inflammation (P = 0.435), or fibrosis (P = 0.291). The frequencies of IL28B rs12979860 genotypes were TT (14.8%), CT (49.0%), and CC (36.2%). Compared to rs12979860 genotype TT, aORs (95%CI) for ETR and SVR were: CC genotype, [17.55 (5.34-57.69) and 5.92 (2.09-16.76), respectively]; CT genotype, [5.15 (1.80-14.78) and 2.48 (0.94-6.52), respectively]. In the current study, the patients who did not achieve ETR or SVR had a lower prevalence of rs12979860 CC (17.4% and 23.3%, respectively) than individuals who had ETR or SVR (47.9% and 47.2%, respectively). Individuals with rs12979860 CC genotype had approximately 6 times the odds of SVR compared to individuals with TT genotype (aOR = 5.92; 95%CI: 2.09-16.76). Similarly, patients with CT genotype had SVR more often than patients with TT genotype (aOR = 2.48; 95%CI: 0.94-6.52). Carrying at least one copy of the C allele (genotypes CT and CC) had almost 8 times the probability of ETR compared to those with genotype rs12979860 TT (aOR = 7.87; 95%CI: 2.84-21.82), and approximately 3 times the odds of SVR compared to those with genotype rs12979860 TT (aOR = 3.46; 95%CI: 1.37-8.74). In addition, data were consistent with a significant gene-dose relationship (aOR = 4.05/allele; 95%CI: 2.27-7.22). The association between rs12979860 genotype and SVR was similar among those who achieved and those who did not achieve SVR.
CONCLUSION: In HCV-genotype 4 patients, rs12979860 is a sensitive predictor of viral clearance, independent of viral load, age, gender or fibrosis, with no similar relation to severity of fibrosis.
PMCID: PMC3531686  PMID: 23323000
Genotype 4; Hepatic fibrosis; Hepatitis C virus; Interleukin-28B; rs12979860
22.  Achieving sustained virologic response in hepatitis C: a systematic review of the clinical, economic and quality of life benefits 
The goal of chronic hepatitis C treatment is to remove the virus to avoid progression of HCV-related disease. Sustained virologic response (SVR) is the most widely used efficacy endpoint in clinical studies of hepatitis C, and represents the eradication of HCV from the body. The aim of the current review was to examine the long-term clinical, economic and quality of life benefits associated with achieving SVR.
A systematic literature review was performed using the PubMed, EMBASE and Cochrane library databases to identify articles examining the clinical, economic and quality of life benefits associated with SVR, published in English language from 2002–2013. For inclusion studies were required to enroll ≥100 patients and to report clinical endpoints including hepatocellular carcinoma, overall- or liver-related mortality, or progression of disease/complications (e.g. portal hypertension, esophageal varices). Review of economic studies on cost/cost-effectiveness of achieving SVR were focused on studies assessing boceprevir/telaprevir plus pegIFN and ribavirin as this represents the current standard of care in several jurisdictions worldwide. Quality of life evidence was required to use validated quality of life instruments and provide a quantitative analysis of the impact of SVR versus no treatment or treatment failure.
SVR is durable with late relapse rates over 4–5 year periods being in the range of 1–2%. Patients who achieve SVR frequently demonstrate some regression of fibrosis/cirrhosis and have a substantially reduced risk for hepatocellular carcinoma (relative risk [RR] 0.1–0.25), liver-related mortality (RR 0.03–0.2) and overall mortality (RR 0.1–0.3) in comparison with no treatment or treatment failure. In the 5 years post-treatment, medical costs for patients achieving SVR are 13-fold lower than patients not achieving SVR. Patients who achieve SVR also have health state utility values that are 0.05 to 0.31 higher than non-responders to treatment.
SVR represents the fundamental goal of antiviral treatment for patients infected with chronic HCV, so as to reduce risk of liver disease progression. Achievement of SVR has implications beyond those of clearing viral infection; it is associated with improved long-term clinical outcomes, economic benefits and improved health-related quality of life.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0748-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4299677  PMID: 25596623
Sustained virologic response; Chronic hepatitis C, Cost, Quality of life, Utility, Morbidity, Mortality
23.  Sustained virological response based on rapid virological response in genotype-3 chronic hepatitis C treated with standard interferon in the Pakistani population 
AIM: To document the sustained virological response (SVR) in rapid virological responders (RVR) of genotype-3 chronic hepatitis C with standard interferon (SdIF).
METHODS: Hepatitis C genotype-3 patients during the period July 2006 and June 2007 were included. Complete blood counts, prothrombin time, ALT, albumin, qualitative HCV RNA were done. SdIF and ribavirin were given for 4 wk and qualitative HCV RNA was repeated. Those testing negative were allocated to group-A while the rest were allocated to group-B. Treatment was continued a total of 16 and 24 wk for group A and B respectively. HCV RNA was repeated after 24 wk of treatment. End virological and sustained virological responses were compared by χ2 test. ROC of pretreatment age, ALT and albumin were plotted for failure to achieve SVR.
RESULTS: Of 74 patients treated, RCV RNA after 16 wk of therapy became undetectable in 34 (45.9%) and was detectable in 40 (54.1%) and were allocated to groups A and B respectively. SVR was achieved in 58.8% and 27.8% in groups A and B respectively. SVR rates were significantly higher in patients who had RVR as compared to those who did not (P = 0.0; γ = 2). Both groups combined ETR and SVR were 70% and 33% respectively. ROC plots of pretreatment age, ALT and albumin for SVR showed only ALT to have a significantly large area under the curve.
CONCLUSION: SVR rates were higher in patients who had RVR with SdIF and high pre treatment ALT values correlated to probability of having RVR.
PMCID: PMC2703848  PMID: 18407597
Hepatitis C; Sustained virological response; Rapid virological responders; Chronic hepatitis
24.  Interleukin-28B gene non-TT allele strongly predicts treatment failure for genotype 1 infected chronic hepatitis C patients with advanced fibrosis: a case control study 
BMC Infectious Diseases  2015;15:156.
The role of single nucleotide polymorphisms (SNPs) of interleukin (IL)-28B in predicting therapeutic response of pegylated interferon (peg-IFN) plus ribavirin (PR) for genotype 1 infected chronic hepatitis C patients with advanced fibrosis (AF) is limited. The aim of this study is to assess its role in predicting sustained virologic responses (SVR) to treatment.
Forty-two patients with biopsy proven hepatitis C virus (HCV) related AF (group A; Ishak fibrosis score, ≥4) and 126 sex- and HCV genotype-matched patients without AF (group B; Ishak fibrosis score, ≤3) were recruited into study. All patients received PR therapy for 24 weeks. Baseline and on-treatment clinical, virological and host factors were evaluated for treatment efficacy.
The SVR rate was significantly lower in group A than group B patients with genotype 1 infection (24% vs. 53.3%; p = 0.011). However, it was similar in those with genotype non-1 infection (76.5% vs. 76.5%; p = 1.0). IL-28B rs8099917 genotype TT is the strongest predictor for SVR in genotype 1 infection. Patients who had TT genotype and achieved RVR in group A had similar SVR rates with those in group B (44.4% vs. 53.3%; p = 0.614). One third of patients in group A developed hematological adverse effects and had required modified doses during antiviral therapy.
In HCV genotype 1 infected AF receiving 24 weeks of PR treatment, patients with IL28B rs8099917 genotype TT, achieving RVR had similar SVR rate with those without AF. In contrast, patients with IL-28B rs8099917 non-TT genotype without achieving RVR are suggested to stop therapy.
PMCID: PMC4377185  PMID: 25888020
Advanced fibrosis; Chronic hepatitis C; Interleukin-28B; rs8099917; Sustained virologic response
25.  Association of serum vitamin B12 levels with stage of liver fibrosis and treatment outcome in patients with chronic hepatitis C virus genotype 1 infection: a retrospective study 
BMC Research Notes  2015;8:260.
Chronic hepatitis C (CHC) is a global health challenge. New therapeutic agents with excellent sustained virological response (SVR) rates are available mainly in developed countries, while the majority of CHC patients live in countries with low health budget. Predictors of therapeutic response are therefore necessary. Vitamin B12 appears to be involved in hepatitis C virus replication.
We therefore studied retrospectively the relationship between baseline serum vitamin B12 levels and clinical features in 116 CHC genotype 1 infected patients. Logistic regression models with univariate and multivariate analysis were used in the statistical analysis.
Baseline serum vitamin B12 levels were found to be positively associated with serum transaminase activities (AST, p = 0.002, ALT, p = 0.04), baseline viral load (p < 0.0001), stage of fibrosis (p = 0.0001) and favorable interferon-λ3/4 (IFNL3/IFNL4) rs12979860 genotypes (p = 0.04), and inversely with SVR (p < 0.001) as well as with rapid virological response (p = 0.001). Patients with baseline serum vitamin B12 levels below a cut-off value of 570 ng/L achieved a SVR rate of 59% with an odds ratio (OR) of 13.4 [confidence interval (CI) 4.3–41.9, p < 0.0001] compared to patients above the cut-off value. By combining serum vitamin B12 levels and IFNL3/IFNL4 rs12979860 genotypes, patients with baseline serum vitamin B12 levels below the cut-off value of 570 ng/L and IFNL3/IFNL4 rs12979860 CC genotype achieved a SVR rate of even 80% with an OR of 54 (CI 9.9–293, p < 0.0001) compared to patients above the cut-off value and non-CC-genotypes.
Our data suggest baseline serum vitamin B12 levels as useful noninvasive marker for characterizing CHC patients. They might further help to identify responders to a standard treatment.
PMCID: PMC4479221  PMID: 26109044
Hepatitis C; Genotype 1; Vitamin B12; Sustained virological response

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