Hellstrand, K.

Impact of obesity on the bioavailability of peginterferon-α2a and ribavirin and treatment outcome for chronic hepatitis c genotype 2 or 3 (Article)

2012-05-24T00:00:00Z

Background and Aims: Having a body mass index above or equal to 30 kg/m2in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear. Methods: This study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 μg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC). Results: Patients with BMI ≥30 kg/m2showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140). Conclusions: Reduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.

IL28B polymorphisms predict reduction of HCV RNA from the first day of therapy in chronic hepatitis C (Article)

2011-11-01T00:00:00Z

Background & Aims: Single nucleotide polymorphisms (SNPs) associated with IL28B influence the outcome of peginterferon-α/ribavirin therapy of chronic hepatitis C virus (HCV) infection. We analyzed the kinetics of HCV RNA during therapy as a function of IL28B SNPs. Methods: IL28B SNPs rs8099917, rs12979860, and rs12980275 were genotyped in 242 HCV treatment-naïve Caucasian patients (67% genotype 1, 28% genotype 2 or 3) receiving peginterferon-α2a (180 μg weekly) and ribavirin (1000-1200 mg daily) with serial HCV-RNA quantifications. Associations between IL28B polymorphisms and early viral kinetics were assessed, accounting for relevant covariates. Results: In the multivariate analyses for genotype 1 patients, the T allele of rs12979860 (Trs12979860) was an independent risk factor for a less pronounced first phase HCV RNA decline (log100.89 IU/ml among T carriers vs. 2.06 among others, adjusted p <0.001) and lower rapid (15% vs. 38%, adjusted p = 0.007) and sustained viral response rates (48% vs. 66%, adjusted p <0.001). In univariate analyses, Trs12979860was also associated with a reduced second phase decline (p = 0.002), but this association was no longer significant after adjustment for the first phase decline (adjusted p = 0.8). In genotype 2/3 patients, Trs12979860was associated with a reduced first phase decline (adjusted p = 0.04), but not with a second phase decline. Conclusions: Polymorphisms in IL28B are strongly associated with the first phase viral decline during peginterferon-α/ ribavirin therapy of chronic HCV infection, irrespective of HCV genotype.

Response prediction in chronic hepatitis c by assessment of IP-10 and IL28B-related single nucleotide polymorphisms (Article)

2011-03-04T00:00:00Z

Background: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients. Methods and Findings: In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR. Conclusions: Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

Nonresponder patients with hepatitis C virus genotype 2/3 infection: A question of low systemic interferon concentrations? (Article)

2010-02-15T00:00:00Z

Twelve of 303 per-protocol patients were nonresponders in a 12-week versus 24-week treatment study of hepatitis C virus (HCV) genotype 2/3 infection. The nonresponders had significantly lower interferon concentrations, as well as significantly greater mean age, body mass index, and viral load. Suboptimal drug concentrations may thus contribute to lack of response to therapy in patients with infection due to HCV genotype 2/3.

A non-invasive fibrosis score predicts treatment outcome in chronic hepatitis C virus infection (Article)

2008-01-07T00:00:00Z

Objective. The results of a previous study suggest that an index calculated according to the formula (normalized ASAT×PK-INR)×100/thrombocyte count (×109/L; GUCI) may reflect liver fibrosis in patients with chronic hepatitis C virus (HCV) infection. The aims of the present study were (i) to validate the association between the Göteborg University Cirrhosis Index (GUCI) score and liver fibrosis and (ii) to evaluate the utility of this index in predicting the outcome of antiviral treatment. Material and methods. A total of 269 patients with chronic HCV infection, stratified according to HCV genotype (1/4 versus 2/3) participated in a phase III trial using pegylated interferon α-2a and ribavirin (DITTO study). Retrospective analyses of the baseline GUCI scores and assessments of pretreatment liver biopsies using the Ishak protocol were performed. Cut-off GUCI scores were calculated to distinguish patients with a high or low probability of sustained viral response (SVR). Results. Striking associations between GUCI and Ishak fibrosis stages (stages 0-2 versus stages 3-4, p=0.0002, stages 3-4 versus stages 5-6, p=0.002) were observed. In patients with genotype 1 or 4, a GUCI score below 0.33 was associated with a rapid viral response to antiviral treatment and an SVR rate of 80%. Ninety-two percent of patients (92/101) with a SVR had a pretreatment GUCI score below 1.11. Conclusions. Our results suggest that the GUCI score appropriately reflects the stage of liver fibrosis in HCV-infected patients, and predicts initial viral kinetics as well as treatment outcome in patients infected with HCV genotype 1 or 4.

Impact of disease severity on outcome of antiviral therapy in treatment-naïve patients with chronic hepatitis C [5] (Article)

2007-05-01T00:00:00Z

Predicting treatment outcome following 24 weeks peginterferon α-2a/ribavirin therapy in patients infected with HCV genotype 1: Utility of HCV-RNA at Day 0, Day 22, Day 29, and Week 6 [3] (Article)

2007-01-01T00:00:00Z

Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection (Article)

2007-01-01T00:00:00Z

Liver steatosis is highly prevalent in chronic hepatitis C virus (HCV) infection, especially in patients infected with genotype 3 virus, but its significance for the outcome of antiviral treatment is not fully understood. We have monitored steatosis in liver biopsies from 231 patients with chronic HCV infection who received pegylated recombinant interferon-alpha and ribavirin in a phase III study (DITTO trial). The degree of steatosis, along with relevant metabolic parameters, was correlated with the early disappearance of virus and with the final outcome of treatment. Our data suggest that the presence of steatosis impairs the early reduction of viral load during treatment in patients infected with HCV genotype 3 and non-3. Steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non-3 virus. Based on these findings, we propose that interventions aiming at reducing hepatic steatosis prior to the onset of antiviral therapy may be of benefit to patients infected with HCV of the non-3 genotypes. Patients infected with genotype 3, on the other hand, should be offered early antiviral treatment.