Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment

Abstract

Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin. Patients with renal impairment (glomerular filtration rate [GFR] <90 mL/min) or who are dependent on dialysis often tolerate ribavirin treatment poorly, even after dose adjustments. However, most DAAs can be used at the normal dose because DAAs are not renally excreted. To date, grazoprevir plus elbasvir is the preferred DAA regimen in patients with renal impairment as data are pending for sofosbuvir patients with GFR <30 mL/min (as for ledipasvir and velpatasvir). However, sofosbuvir has been used in a small number of patients with severe renal impairment and, based on these trials, we recommend sofosbuvir 400 mg every day when no other DAA regimen is available. Ledipasvir and velpatasvir are not recommended in patients with severe renal impairment.

Fig. 1

Overview of the hepatic or non-enzymatic metabolism of drugs used for the treatment of hepatitis C: cytochrome P450 enzymes involved and biliary and/or renal excretion of drug (metabolites). Asterisk The site of metabolism is unknown but two metabolizing pathways are involved: (1) a reversible phosphorylation pathway; and (2) a degradative pathway involving deribosylation and amide hydrolysis. Plus or minus Sofosbuvir is extensively metabolized in the liver in the active metabolite GS-461203, followed by dephosphorylation which results in the inactive compound GS-331007. ASV asunaprevir, CYP cytochrome P450, DCV daclatasvir, DSV dasabuvir, EBV elbasvir, GRZ grazoprevir, LDV ledipasvir, OBV ombitasvir, PTV paritaprevir, RBV ribavirin, SIM simeprevir, SOF sofosbuvir, VPV velpatasvir

Fig. 2

Overview of the pathophysiological changes in patients with liver cirrhosis that influence drug metabolism and therefore the pharmacokinetics of drugs. CYP cytochrome P450, UGT uridine diphosphate-glucuronosyltransferase, ↓ indicates decrease, ↑ indicates increase