From the Division of Renal Medicine, Department of Clinical Science, and the Division of Infectious Diseases, Department of Medicine, Huddinge University Hospital, Karolinska Institutet, Stockholm, Sweden HEPATITIS C IN CHRONIC KIDNEY DISEASE AND KIDNEY TRANSPLANTATION: WITH SPECIAL REFERENCE TO EPI

Hepatitis C (HCV) is a clinical problem in infected kidney transplant patients but is also a cause of renal disease and vasculitis. Standard therapy for HCV is a combination of interferon and ribavirin. Renal patients have mostly been treated with interferon monotherapy since ribavirin has been contraindicated in renal insufficiency with a GFR (glomerular filtration rate) < 50 ml/min. A cohort of 520 HCV-negative and 51 HCV-positive patients transplanted between 1989 and 1997 at Huddinge University Hospital was studied with last follow-up 2002. The methods used were univariate Kaplan-Meier survival analysis and multivariate Cox proportional hazards model. We confirmed that HCV is an independent risk factor for both patient (p<0.0012) and graft-survival (p<0.0003) after kidney transplantation in line with previous studies. After adjusting for age, gender, diabetes, previous transplants, type of transplant and time in renal replacement therapy (RRT) HCV remained significantly more important than time in RRT for long-term outcome after kidney transplantation. This has not been well characterized before. The results lend support to the suggestion that successful anti-viral HCV therapy prior to transplantation may be preferable to an early transplant for long-term patient and graft survival after kidney transplantation. However, this remains to be confirmed in prospective studies. In order to optimise ribavirin therapy in patients with renal disease a high-performance liquid chromatography (HPLC) method for ribavirin plasma concentration measurement was developed. A trough level interval of 7-17μmol/L was found in 10 patients with normal renal function treated with interferon-alpha and ribavirin. The ribavirin monitoring method was used in 6 HCV infected dialysis patients in study and in 7 patients with renal insufficiency with HCV-related renal disease in study. The method enabled clinical use of ribavirin in combination with interferon-alpha in these patients with fair tolerability. However this required reduced ribavirin doses, close monitoring of ribavirin plasma concentrations and surveillance of side effects. Ribavirin-associated anaemia, the main side effect, was handled by means of medium-high doses of erythropoietin as well as low-dose iron therapy, thereby avoiding blood transfusions. Viral response during treatment in all 13 HCV replicating patients was 85%. Although the studies were small and uncontrolled ribavirin in addition to interferon-alpha is likely to have had an additive effect in renal insufficient patients. Overall 383 ribavirin samples from 63 patients were collected, 44 with normal serum creatinine and 19 with renal impairment with an estimated GFR of 5-57 ml/min. A population pharmacokinetic analysis was performed using non-linear mixed effect modelling (NONMEM) evaluating population factors as age, gender, body weight, serum creatinine and estimated GFR. Estimated GFR was found to be a significantly better predictor of ribavirin clearance than body weight alone. A small non-renal clearance dependant on body weight and age and a significant inter-individual 40 % variability in ribavirin total clearance remained, not explained by GFR and body weight. The results indicate that ribavirin should mainly be dosed on renal function and not on body weight alone. A dosing schedule is proposed based on these findings. Ribavirin monitoring is strongly recommended in renal patients. Further studies including patients with normal GFR should be of interest considering the inter-individual variability in ribavirin total clearance and in order to identify a possible therapeutic ribavirin target concentration for HCV infection.