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 χ(2) 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.

The effect of severe hepatic impairment on the pharmacokinetics and haematological response of C.E.R.A.

AIM: To examine the effect of severe hepatic impairment (HI) on the pharmacokinetics (PK) and pharmacodynamics (PD) of the continuous erythropoietin receptor activator, C.E.R.A. METHODS: A non-randomised, multicentre, single-dose, open-label study in patients with HI (n=12) and healthy subjects (n=12). After 2 weeks of screening, participants received a single intravenous dose of C.E.R.A. (200 mug), and were then followed for approximately 8 weeks. The area under the concentration-time curve (AUC) from drug administration to last measurable concentration (AUC(last)), and maximum C.E.R.A. concentration (C(max)) were calculated to assess PK. The baseline-corrected area under the effect curve over 22 days (AUE(corr)) for reticulocyte count was the primary PD parameter. RESULTS: The PK profile was similar in patients and healthy subjects (AUC(last): 6678 vs 6985 ng*h/mL; C(max): 63 vs 75 ng/mL) C.E.R.A. produced a sustained erythropoietic response in bothgroups, with increases in reticulocyte counts peaking 7-9 days post-dose and returning to baseline by Day 22. Although mean AUE(corr) was 64% lower in patients, this may have been an artefact of higher baseline reticulocyte counts. Lower reticulocyte responses in patients did not translate into lower responses for haemoglobin, haematocrit or erythrocytes, suggesting that HI had no clinically relevant effect on the PD of C.E.R.A. C.E.R.A. was well tolerated. Four AEs (none considered drug related) were reported in three patients (mild myocardial ischaemia; mild pyrexia and liver transplant; severe bacterial peritonitis [serious AE]); no AEs were reported in healthy subjects. CONCLUSIONS: Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.

Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.

BACKGROUND/AIMS: Previous studies using standard interferon and ribavirin combination therapy suggested that patients infected with HCV-1 and a low pretreatment HCV-RNA level can be treated for 24 weeks without compromising sustained virologic response rates. The aim of the present study was to investigate this schedule in the era of pegylated interferon-alpha plus ribavirin. METHODS: Patients chronically infected with HCV-1 (n=235) and a screening viremia < or =600,000 IU/mL (real-time PCR) were treated with peginterferon alfa-2b 1.5 microg/kg subcutaneously once weekly plus ribavirin 800-1400 mg/day based on body weight for 24 weeks. RESULTS: End-of-treatment and sustained virologic response rates were 80 and 50%, respectively. The 48-week historical control (Manns et al., Lancet 2001;358:958-65) had similar end-of-treatment (74%) but higher sustained virologic response rates (71%). This difference was due to a high virologic relapse rate after 24 weeks of therapy (37%) compared with the historical control (4%). A subset of patients who had undetectable serum HCV-RNA at treatment week 4, however, achieved similar sustained virologic response rate (89%) as in the control group (85%). CONCLUSIONS: HCV-1 infected patients with a low baseline HCV-RNA concentration who become HCV-RNA negative at week 4 may be treated for 24 weeks without compromising sustained virologic response rates.