Significant Predictors Of Sustained Virological Response Research Articles

Association between IFN-λ 3 Gene Polymorphisms and Outcome of Treatment with Direct Acting Antivirals in Chronic HCV-Infected Egyptian Patients

ABSTRACT Background: Single nucleotide polymorphisms (SNPs) of the interferon lambda 3 (IFN-λ 3) gene are associated with viral clearance and treatment response in chronic hepatitis C virus (HCV) infection. Aim: to assess whether specific IFN-λ 3 gene SNP, known as rs12979860 (C > T), could predict the outcome of treatment with direct acting antivirals (DAAs) among Egyptian patients with chronic HCV genotype 4 infection. Methods: Tetra-primer (ARMS-PCR) and PCR-RFLP methods were used for SNP genotyping in 100 chronic HCV-infected patients and 50 healthy subjects as control group. Results: The CC (wild type) genotype of rs12979860 was identified in 20 patients, 50% of them achieved sustained virological response (SVR). SNP genotype TT was found in 17 patients and only 2 of them (11.76%) were responders. The frequency of CT genotypes was significantly higher in responders than in non-responders (p= .021). In contrast, the frequency of TT genotypes was significantly higher in non-responders (42.85%, p< .001). On univariate and multivariate logistic regression analyses of the significant predictors of SVR, there were six predictive factors (Age, diabetes mellitus, AST, albumin, type of therapy and IFN-λ 3 genotype). Conclusion: The TT genotype and T allele were significantly associated with failure to achieve SVR. However, CT genotype of IFN-λ 3 (rs12979860) may be considered as a predictor for SVR in patients who received DAAs.

Assessment of interleukin 28B genotype as a predictor of response to combined therapy with pegylated interferon plus ribavirin in HCV infected Egyptian patients

Background and aimSingle nucleotide polymorphisms (SNPs) of interleukin 28B (IL28B) gene is associated with spontaneous clearance and variable response to combined therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C virus (HCV) infected patients. This study aimed at assessing the value of IL28B rs8099917 gene polymorphism in predicting sustained virological response (SVR) among HCV infected Egyptian patients treated with PEG-IFN and RBV. MethodsOur study was conducted on 153 chronic HCV infected patients treated with PEG-IFN and RBV. Genotyping of rs8099917 near the IL-28B gene was performed by Real Time PCR using Taq-Man probe assay. ResultsThe overall SVR was achieved in 49.6% of patients. Patients with TT genotype showed significantly higher SVR rate than minor allele (TG/GG) carriers (74% vs. 26%, P=0.004). Logistic regression analysis revealed that TT carriers had 2.8 higher chance for SVR achievement than G allele carriers TG/GG (OR=2.8, 95% CI=1.4–5.6, P=0.004). Younger age, male sex and low activity grading were significant predictors of SVR (P=0.003, P=<0.001 and P<0.001 respectively). High pretreatment AST levels and advanced liver fibrosis were negative predictors of SVR (P=0.04 and P<0.001 respectively). ConclusionIL28B genotype is a significant pre-treatment predictor of response to PEG-IFN/RBV in HCV infected Egyptian patients.

Efficacy of telaprevir-based therapy for difficult-to-treat patients with genotype 2 chronic hepatitis C in Japan.

This study assessed the efficacy and safety of telaprevir in combination with peginterferon-α-2b (PEG IFN) and ribavirin (RBV), for Japanese difficult-to-treat patients with hepatitis C virus (HCV) genotype 2 who had not achieved sustained virological response (SVR) during prior treatment. In total, 108 relapsed (median age, 59.0 years) and 10 non-responding (median age, 59.0 years) patients with genotype 2 HCV participated. Patients received telaprevir (750 mg, every 8 h) for 12 weeks and PEG IFN/RBV for 24 weeks. The SVR rates for relapsers and non-responders were 88.0% (95/108) and 50.0% (5/10), respectively. The SVR rates did not differ significantly between patients with rs8099917 TT and non-TT. The SVR rates for relapsers and non-responders with extended rapid viral response (eRVR) were 97.6% (82/84) and 100% (5/5), respectively. On the other hand, the SVR rates for relapsers and non-responders completing the treatment protocol were 98.4% (61/62) and 100% (5/5), respectively. The overall safety profiles of telaprevir-based regimens were similar for Japanese patients with genotype 1 and 2 HCV infection who experienced treatment failure. Telaprevir, in combination with PEG IFN/RBV, provided a high SVR rate for genotype 2 HCV, difficult-to-treat patients who had not achieved SVR during prior IFN-based treatment. The eRVR had a strong influence on the cure rate of telaprevir-based therapy. In addition, the continuation of telaprevir-based treatment for up to 24 weeks was a significant predictor of SVR.

Factors of Response to Pegylated Interferon/Ribavirin Combination Therapy and Mechanism of Viral Clearance

Objectives: This study explores viral factors of the interferon (IFN) and ribavirin (RBV) resistance-determining region (IRRDR), the IFN sensitivity-determining region (ISDR) and the core protein, and host factor interleukin 28B associated with response to pegylated IFN (PEG-IFN) and RBV combination therapy, and the correlation of viral and host factors with IFN-λ1. Methods: A total of 58 patients underwent PEG-IFN/RBV combination therapy for 48 weeks. The pretreatment factors associated with rapid virological response (RVR) and sustained virological response (SVR) were analyzed. Pretreatment IFN-λ1 serum levels were compared with the viral and host factors. Results: Univariate analysis showed that IRRDR ≥6 and ISDR ≥2 were significant pretreatment predictors of RVR, and multivariate analysis identified IRRDR ≥6 and hemoglobin as significant predictors of SVR. Pretreatment IFN-λ1 was significantly higher in the SVR group than in the non-SVR group and also in the IRRDR ≥6 group than in the IRRDR ≤5 group. Conclusions: IRRDR ≥6 was the only significant predictor of SVR and was correlated with IFN-λ1. High serum levels of IFN-λ1 may be conducive to effective PEG-IFN/RBV combination therapy because of the immunomodulatory system.

OC-041 IL28B haplotypes and IP-10 predict treatment response for recurrent HCV post transplant

IntroductionHepatitis C virus (HCV) recurrence post liver transplant (LT) is universal. Sustained virological response (SVR) rates post LT with pegylated interferon (PEG-IFN) and ribavirin (RIB) range between 26% and 50%...

Weight‐based high‐ and low‐dose ribavirin in combination with peginterferon α‐2b therapy for genotype 2 chronic hepatitis C: A randomized trial

The optimal ribavirin dose in the treatment of patients infected with hepatitis C virus (HCV) genotype 2 remains to be elucidated. We aimed to seek the optimal ribavirin dose required for this genotype in a randomized trial. We compared the efficacy and tolerability of the 24-week peginterferon α-2b (1.5 µg/kg/week) therapy in combination with a weight-based higher dose (600-1000 mg) and lower dose (400-800 mg) of ribavirin for genotype 2 patients. Noninferior margin was set at 10%. A total of 120 patients were randomized to a higher-dose or a lower-dose group. Sustained virological response (SVR) by intention-to-treat analysis was achieved in 47/58 (81.0%, 90% confidential interval [CI]: 72.6-89.5) patients in the higher-dose group and 41/60 (68.3%, 90% CI: 58.5-78.2) patients in the lower-dose group (difference, -12.7%; 90% CI, -25.7 to 0.3). Relapse rates were 10% and 21.6% in the higher-dose and the lower-dose groups, respectively. Multiple logistic regression analysis showed that ribavirin dose/kg body weight was the only significant predictor of SVR (≥9.5 mg/kg per day vs <9.5 mg/kg per day; odds ratio = 3.34; 95% CI, 1.41-7.92; P = 0.006). Twenty-one (36.2%) in the higher-dose group required ribavirin dose reduction because of anemia, whereas seven patients (11.7%) did in the lower-dose group (P < 0.01). Three of the higher-dose group and two of the lower-dose group required premature termination of therapy. Weight-based lower-dose ribavirin regimen was not equivalent to the higher-dose counterpart in the treatment of HCV genotype 2. We discourage treating these patients with low-dose ribavirin regimens. The peginterferon therapy in combination with ribavirin at a weight-based higher dose (600-1000 mg) remains the standard-of-care treatment for this genotype.

Hepatitis C virus genotype 4 with normal transaminases: histological changes, schistosomiasis and response to treatment.

Among individuals with chronic hepatitis C virus (HCV) infection, approximately 30% of patients show persistently normal alanine aminotransferase (PNALT). Individuals with PNALT have been historically excluded from antiviral treatment. However, some studies have reported sudden worsening of disease in patients with PNALT, suggesting the need to treat such individuals. To evaluate this further, we compared fibrosis severity and response to treatment in patients with PNALT to patients with abnormal ALT. In addition, we investigated whether liver histology and schistosomiasis affect response to treatment differently in those with PNALT and abnormal ALT. A retrospective cohort study of 176 HCV-Genotype 4 (HCV-G4) patients treated with pegylated interferon (PEG-IFN) and ribavirin. Of 176 cases studied, 53 (30.1%) had normal ALT. Prevalence of pretreatment severe fibrosis, sustained virological response (SVR) and relapse were not significantly different in patients with PNALT (26%, 66% and 5.7% respectively) compared to those with abnormal ALT (32.5%, 60.7%, and 6.6% respectively). Multivariable logistic regression revealed that pretreatment ALT, pretreatment viral load, inflammation and schistosomiasis were not significantly associated with SVR [OR (95% CI), 0.75 (0.34-1.65); 0.92 (0.61-1.37); 1.64 (0.64-4.18); 0.90 (0.44-1.84) respectively]. Severe fibrosis was the only significant predictor of SVR [OR (95% CI), 0.38 (0.14-0.99)]. PNALT does not reflect the degree of fibrotic changes or predict SVR. Furthermore, schistosomiasis is a predictor of neither fibrosis nor poor response in patients with PNALT. Severe fibrosis is a strong and independent predictor of response to treatment. Therefore, it is important to treat individuals with PNALT levels regardless of schistosomiasis.

Predictive Value of the Phosphorylation of Signal Transducers and Activators of Transcription in the Outcome of Interferon Therapy for Chronic Hepatitis C

Objective: Signal transducers and activators of transcription (STATs) play a critical role in antiviral defense. To better understand pegylated interferon (IFN)-α and ribavirin combination therapy resistance, we examined the STAT expression in the liver. Methods: We immunostained Phospho-STAT1 (P-STAT1) and Phospho-STAT3 (P-STAT3) in 59 hepatitis C virus (HCV)-infected liver tissues and compared the expression of these STATs proteins and the clinicopathological factors. Results: The number of P-STAT1 observed correlated significantly with the body mass index (BMI; p = 0.03) and homeostatic model assessment (p = 0.007). The number of P-STAT3 observed correlated significantly with the ALT level (p = 0.002) and platelet count (p = 0.002). The number of P-STAT1 nuclei in the sustained virological response (SVR) group was significantly larger than in the non-SVR group (p = 0.003). On multivariance analysis, the number of P-STAT1 nuclei (p = 0.004) and age (p = 0.016) were significant predictors of SVR. Conclusions: P-STAT1 in the liver tissue prior to IFN therapy correlated with an increased BMI and increased insulin resistance, and might be a useful predictor of HCV clearance by IFN therapy. On the other hand, P-STAT3 might play a critical role in the hepatocellular response against inflammatory damage.

Sustained Virological Response in the Antiviral Therapy of Chronic Hepatitis C: Is There a Predictive Value of Interferon-Induced Depression?

Background: The study objective was to determine the contribution of cytokine-induced depression to a predictive model of sustained virological response (SVR) in chronic hepatitis C. Methods: One hundred and one therapy-naïve hepatitis C virus (HCV) outpatients received treatment with peginterferon alfa-2b and ribavirin. Neuropsychiatric side effects were monitored prospectively (Hospital Anxiety and Depression Scale, DSM-IV criteria for major depression). SVR was defined as a failure to detect HCV by PCR 24 weeks after therapy. Results: SVR rate was 72.3% (73 of 101 patients). Classification data and the extent of interferon-induced depression were not significantly linked to SVR. Virus genotype (p = 0.045) and gender (p = 0.016) contributed significantly to a logistic regression model. Mean (p = 0.811) and maximum (p = 0.744) depression increases were no significant predictors of SVR. Major depression rates (DSM-IV criteria) were 12.3% (9 of 73 patients) in the subgroup with SVR and 10.7% (3 of 28) in patients without SVR. Conclusions: We found no significant association between depression and the efficacy of antiviral treatment in chronic hepatitis C. Interferon-induced depressive symptoms are important to be monitored and treated if necessary; however, they cannot be used to predict therapy success.

Interferon alpha plus ribavirin combination treatment of Japanese chronic hepatitis C patients with HCV genotype 2: A project of the Kyushu University Liver Disease Study Group

To determine the efficacy of an interferon alpha and ribavirin combination treatment for Japanese patients infected with hepatitis C virus (HCV) of genotype 2, a multi-center study was retrospectively analyzed. In total, 173 patients with HCV genotype 2 started to receive interferon-alpha subcutaneously thrice a week and 600-800 mg of ribavirin daily for 24 wk. The overall sustained virological response (SVR), defined as undetectable HCV RNA in serum, 24 wk after the end of treatment, was remarkably high by 84.4%, (146/173) by an intention-to-treat analysis. A significant difference in SVR was found between patients with and without the discontinuation of ribavirin (46.9% vs 92.9%), but no difference was found between those with and without a dose reduction of ribavirin. A significant difference in SVR was also found between patients with less than 16 wk and patients with 16 or more weeks of ribavirin treatment (34.8% vs 92.0%). The 24-wk interferon and ribavirin treatment is highly effective for Japanese patients with HCV genotype 2. The significant predictor of SVR is continuation of the ribavirin treatment for up to 16 weeks.

High Efficacy of Combination Therapy with Pegylated Interferon and Ribavirin in Hemophiliacs with Chronic Hepatitis C.

Pegylated interferon (Peg-IFN) plus ribavirin is the standard treatment for patients with chronic hepatitis C. In a multicenter open trial, we assessed the efficacy and tolerability of this treatment in 78 HIV negative hemophiliacs (age: 20–64 years) with persistently high transaminase values. Sixty-four were naïve and 14 were relapsers to IFN monotherapy. Cirrhosis was clinically detected in 12 patients (15%). HCV genotype was 1 in 69%, 2a/c in 14%, 3a in 14% and 4 in 3%. Peg-IFN alpha-2b was given subcutaneously at doses of 1.5 mcg/Kg/week for 48 weeks in genotypes 1 and 4 and for 24 weeks in genotypes 2 and 3; oral ribavirin at 800–1200 mg/day based on body weight. Treatment was stopped in patients with polymerase chain reaction positive HCV-RNA at month 6.Results: 11 patients (14%) withdrew for side effects (4) or non-compliance (7). Neutropenia (<500 cells/mmc), decompensated diabetes, ALT flares, and vomiting not responding to antiemetic drugs were reasons for treatment discontinuation. The median fall in hemoglobin levels was 3.1 g/dL. Weight loss (38%), fatigue (33%) and cephalalgia (15%) were frequent side effects. Thirty-two patients (41%) required dose reduction of ribavirin (23, 29%) or Peg-IFN (20, 26%). At the end of the 6-month follow-up, sustained virological response (SVR) was achieved in 43 patients (55%): 40/64 naïve (63%) and 3/14 relapsers (21%, p = 0.007). Five patients (6%), all relapsers to IFN monotherapy, had a virological breakthrough during treatment and 4 (5%) relapsed during the post-treatment follow-up period. SVR was obtained in 86% genotypes 2/3 and 43% genotypes 1/4 (p = 0.001). Predictors of SVR were evaluated by univariate analysis in the 64 naïve patients. SVR was significantly associated with HCV infection type 2 and 3 (86% vs 50% in HCV type 1 and 4; p = 0.008), absence of cirrhosis (97.5% vs 75% in non-responders; p = 0.02) and higher pre-treatment serum ALT levels (111 vs 75 IU/L in non-responders; p = 0.02). SVR rates did not differ in relation to patient's age, pretreatment HCV viremia, median disease duration and compliance to full-dose treatment.Conclusions: combination therapy with Peg-IFN plus ribavirin is the recommended therapeutic option for hemophiliacs with hepatitis C chronic infection. Relapsers to IFN monotherapy may benefit of re-treatment with Peg-IFN plus ribavirin achieving at least 20% SVR. Genotype 2 and 3 infection is the most significant predictor of SVR.