Karin Lindahl

High‐dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C

Improved treatment regimens for patients with chronic hepatitis C, genotype 1 and high viral load are needed. Increasing the dose of ribavirin has increased the response rate, but experience with doses of more than 1,200 mg/day is limited. The aim of this study was to investigate the safety and tolerance to treatment with a high and individualized dose of ribavirin in combination with peginterferon. Ten patients with chronic hepatitis C, genotype 1 and high viral load were treated with peginterferon alfa‐2a and ribavirin for 48 weeks in a prospective trial. The initial ribavirin dose was individualized and calculated from a pharmacokinetic formula based mainly on renal function. Ribavirin plasma concentrations were monitored, and the dose was adjusted to reach the target concentration. Hemoglobin was monitored, and patients were treated with erythropoietin and blood transfusions when indicated. After dose adjustments, the mean dose of ribavirin was 2,540 mg/day (range, 1,600‐3,600) at week 24. The main side effect was anemia, which was controlled with erythropoietin. Two patients required blood transfusions. One patient was withdrawn at week 24 because of a lack of viral response, and one patient at week 39 because of side effects, primarily interferon associated. At follow‐up (≥24 weeks posttreatment), nine of ten patients had undetectable HCV RNA and thus were cured by standard definitions. In conclusion, a high dose of ribavirin according to an individualized schedule is feasible but associated with more frequent and serious side effects such as anemia. The viral response merits further evaluation. (HEPATOLOGY 2005;41:275–279.)

Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients.

Summary.  Standard therapy for chronic hepatitis C (HCV) is pegylated interferon in combination with ribavirin. There is limited experience with either drug in dialysis [end stage renal disease (ESRD)]. Six haemodialysis patients, four with HCV genotype 1, one with genotype 4 and one genotype 2 were treated with pegylated interferon‐alfa‐2b (n = 4) and pegylated interferon‐alfa‐2a (n = 2) for 24–48 weeks according to genotype with a dose of 50 or 135 μg/week respectively. All patients were given reduced ribavirin doses, initially 200–400 mg/day. Ribavirin trough plasma concentrations were measured with a HPLC method previously developed for earlier treatment studies, aiming at a target concentration of 10–15 μmol/L. Interferon related side‐effects were common, in one patient peg‐alfa‐2b was permanently reduced to 50 μg every 9–10 days with improvement in tolerance. Average ribavirin dose was 170–300 mg/day. Ribavirin‐induced anaemia was treated with high doses of erythropoietin and low doses of iron. Blood‐transfusions were not needed. All patients became HCV‐RNA‐PCR negative during treatment which was completed or nearly completed in four patients. One patient terminated therapy prematurely due to pronounced interferon related side‐effects and another died of myocardial infarction probably not related to therapy. Three patients have remained HCV‐RNA negative with extended follow‐up, two of whom have had a successful kidney transplant. Pegylated interferons are likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin. However the pharmacokinetics and tolerability of both peg‐alfa‐2a and 2b need to be studied more closely in prospective studies before definite dosing recommendations can be made.

Dosage of ribavirin in patients with hepatitis C should be based on renal function: a population pharmacokinetic analysis.

A combination of interferon alfa and ribavirin is standard therapy for chronic hepatitis C virus (HCV). Ribavirin dosage is currently based on body weight. The aim of this study was to critically evaluate current dosage recommendations on the basis of a population pharmacokinetic analysis. The data consisted of 383 ribavirin plasma concentration samples collected from 63 patients undergoing treatment of HCV. Forty-four patients had normal range serum creatinine with an estimated glomerular filtration rate (GFR = estimated creatinine clearance) of 57–144 mL/min. Another 19 patients had renal impairment with a GFR of 5–57 mL/min. Population factors were age, gender, body weight, serum creatinine, and GFR. A population pharmacokinetic analysis with a two-compartment model was carried out using nonlinear mixed effect modeling. Ribavirin clearance was found to be linearly dependent on renal function with a small nonrenal clearance dependent on body weight and age. Estimated GFR was a significantly better predictor of ribavirin clearance than body weight alone. There remained a significant 40% interindividual variability in ribavirin total clearance not explained by estimated GFR and body weight. The volume of distribution was large and proportional to body weight (V = 44.3 × body weight), which resulted in a long half-life (100–500 hours, depending on GFR) and a long time to steady state (3–12 weeks). Ribavirin dosage should mainly be based on renal function and not, as currently recommended, on body weight alone. A ribavirin-dosing schedule based on GFR and body weight to reach an intended target concentration is proposed. Ribavirin monitoring may be useful for optimizing HCV treatment not only in patients with renal insufficiency but also in other patients considering the time to steady state and the interindividual variability in ribavirin clearance.

Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia.

Summary.  Ribavirin in combination with interferon alpha‐2 or pegylated interferon is the standard treatment for chronic hepatitis C. The current dosage recommendations for ribavirin are based on body weight (bw). Ribavirin is mainly eliminated by the kidneys and we have recently shown that ribavirin plasma concentrations are determined primarily by renal function. It is therefore reasonable to hypothesize that side‐effects of ribavirin, i.e. anaemia, should be more closely related to plasma concentrations of ribavirin than to the dose per kg bw. A total of 108 consecutive patients eligible for treatment of chronic hepatitis C were studied. Ribavirin concentrations in plasma were measured by high‐performance liquid chromatography (HPLC)‐UV after solid‐phase extraction in trough samples taken 4, 8 and 12 weeks after the treatment commenced. A total of 213 samples were obtained and the change in the haemoglobin level and the creatinine concentration was measured in addition to ribavirin. The dose of ribavirin per kg bw did not correlate with the drop in haemoglobin level induced by ribavirin. The concentration of ribavirin was non‐linearly related to the drop in the haemoglobin level as revealed by fitting a standard Hill equation type dose–response curve. The half maximal drop in haemoglobin was obtained at 4.4 μm. The results from this study suggest that the anaemia induced by ribavirin depends primarily on the concentration of ribavirin, and not on the dose per kg bw. This lends further support to the idea that ribavirin should be dosed according to renal function.

High-Dose Ribavirin Enhances Early Virological Response in Hepatitis C Genotype 1-Infected Patients.

Background: The aim of the study was to investigate whether patients with a previous nonresponse to standard of care treatment with ribavirin dosed according to body weight would respond to a high individualized dose of concentration-monitored ribavirin. Methods: Previous nonresponders to standard of care treatment with peginterferon (peg-IFN) and ribavirin were included. Ribavirin was dosed aiming at a plasma concentration of >15 &mgr;mol/L. The initial ribavirin dose was calculated from a formula based on renal function and body weight. Erythropoietin treatment was started 2 weeks before antiviral therapy. Results: Twenty patients (16 men and 4 women) with a mean age of 52 years were included. Sixty percent had advanced fibrosis. Eighty percent of patients achieved an early viral response, and 60% were negative for hepatitis C virus ribonucleic acid (HCV RNA) at treatment week 24. High-dose ribavirin resulted in a significantly increased HCV RNA drop at week 12 (mean: 3.13 versus 2.05 IU/mL; P < 0.001). Nine patients were negative for HCV RNA at the end of treatment, and 1 achieved sustained viral response. The final steady-state daily dose of ribavirin varied from 1400 to 4400 mg. Hemoglobin levels decreased during treatment, mean Hb 163, 134, and 110 g/L at week 0, 4, and 12, respectively. Two patients received blood transfusions. No other severe adverse events were recorded. Conclusions: An individualized high ribavirin dose resulted in a more pronounced early viral HCV RNA decline than a standard-dose ribavirin scheme. This regime is safe provided that close monitoring of anemia is undertaken and that treatment with erythropoietin is given.

Higher risk of renal disease in chronic hepatitis C patients: Antiviral therapy survival benefit in patients on hemodialysis

BACKGROUND & AIMS Several studies have shown that chronic hepatitis C (CHC) infection has a negative impact on kidney function, as well as survival, in patients with chronic kidney disease (CKD) or on hemodialysis. The aim of this nationwide registry study was to describe renal disease in Swedish patients with CHC. METHODS In the present study, patients were identified for CHC (B18.2) and CKD (N18) according to the International Classification of Diseases (ICD)-10 in the nationwide Swedish inpatient care day surgery (1997-2013) and non-primary outpatient care (2001-2013) patient registries. Hemodialysis was defined using the procedure code in the non-primary outpatient care. For each patient, up to five non-CHC diagnosed age/sex/place of residency-matched comparators were drawn from the general population at the time of diagnosis. Follow-up started at the date of CHC diagnosis and patients accrued person-time until, whichever came first, death, emigration or December 31st, 2013. RESULTS Between 2001 and 2013, 42,522 patients received a CHC diagnosis. Of these patients, 2.5% (1,077/45,222) were diagnosed with CKD during 280,123 person-years, compared with 0.7% (1,454/202,694) in the matched general population comparators (1,504,765 person-years), resulting in a standardized incidence ratio (SIR) of 4.0. There was a 3.3-7.0-fold risk of patients with CHC requiring hemodialysis. Overall, 17% of patients with CHC receiving hemodialysis were treated for CHC; 24% in the treated cohort died compared with 56% of the untreated cohort (p <0.0001), with antiviral treatment improving survival with an odds ratio of 3.901 (p = 0.001). CONCLUSIONS The results from this nationwide registry study showed that patients with CHC are at a higher risk of developing CKD. Furthermore, hepatitis C treatment seemed to improve survival for patients with CHC on hemodialysis compared with untreated patients. LAY SUMMARY Hepatitis C is an infectious disease that mainly infects the liver, but has also been shown to have negative effects on other organs. This nationwide study demonstrates an increased risk of hepatitis C patients developing reduced kidney function and the need for dialysis. The study also showed improved survival in dialysis patients who received antiviral treatment.

Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naïve patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-α (pegIFN-α), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-α, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-α. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log10 IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log10 IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-α and thus shortened treatment duration (P<0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P<0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an anti-viral effect differently regulated across IL28B genotypes. Trial Registration ClinicalTrials.gov NCT01226771