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.

Daclatasvir-based Treatment Regimens for Hepatitis C Virus Infection: A Systematic Review and Meta-Analysis

“…DCV is metabolized by liver CYP3A4 and is directly excreted via the biliary system. Single-dose pharmacokinetic studies have shown that DCV is well tolerated in patients with liver or renal failure without the need for dose adjustment (64, 65). …”

Management of Chronic Hepatitis C Virus Infection: A Consensus Report of the Study Group for Viral Hepatitis of the Turkish Society of Clinical Microbiology and Infectious Diseases-2017 Update

“…Her iki ilaç da hemodiyalizle serumdan uzaklaştırılamamaktadır (72). Yine de KHC'si olan hafif, orta ve ciddi böbrek yetmezliği bulunan hemodiyaliz ve periton diyalizi hastalarında GRZ/EBV kombinasyonu doz ayarlamasına gerek olmadan güvenli ve etkili bulunmuştur (83,84).…”

“…Önerilen dozda ASV ile hemodiyaliz hastalarında, böbrek fonksiyonları normal kontrollere göre maksimum serum konsantrasyonunun %28.6 arttığı, AUC'nin ise %10 azaldığı bildirilmektedir. Böbrek yetmezliği olan hastalarda her iki ilaç için de doz ayarlaması önerilmemekte ve bu hastalardaki kullanımın etkin ve güvenli olduğu bildirilmektedir (39,66,72,83).…”

“…Glomerüler filtrasyon hızı 30 ml/dakika'nın altında olan hastalarda ve diyalizi de içeren son dönem böbrek yetmezliği olanlarda SMV'nin güvenilirlik ve etkinliğiyle ilgili çalışma yapılmamıştır. Bununla birlikte SMV yüksek oranda proteine bağlı olması nedeniyle diyalizle anlamlı düzeyde uzaklaştırılmaz (39,66,83).…”

Current and future challenges in HCV: insights from an Italian experts panel

“…Grazoprevir and glecaprevir show a log magnitude of pharmacokinetic exposure increase in decompensated cirrhotic patients, while this is not the case for velpatasvir and elbasvir, although the latter is only available in combination with grazoprevir. It is thus apparent that NS5A inhibitors can be administered in case of decompensated cirrhosis, while protease inhibitors are not recommended or contraindicated in case of Child-Pugh stage B and C [28].…”