We read with great interest the article by Mauss et al. published in Hepatology. While renal impairment was not reported as a safety signal in phase III clinical trials, the authors alert our attention to a potential renal toxicity of first-generation antiproteases administered with peginterferon and ribavirin, especially in patients with risk factors for renal impairment. They demonstrate in telaprevir-treated patients a significant decrease of enhanced glomerular filtration rate (eGFR) (CKD EPI formula) during the first 12 weeks of treatment, but this decrease was early and completely reversible after discontinuation of the drug, before the 24th week of treatment. Comprehension of the mechanism of the decrease of eGFR is essential, as it might change monitoring of the patients.
In a recent article, Kunze et al. showed that interactions of telaprevir with drug transporters should not be neglected: telaprevir was shown to inhibit mostly the human renal drug transporter OCT2 (basal membrane of tubular cell), which interacts with creatinin tubular transport and is included in proximal tubular secretion.
Recently, Raffi et al., studying the efficacy and safety profile of both dolutegravir and raltegravir in human immunodeficiency virus (HIV)-infected patients, showed an increase of creatinin level only with dolutegravir. Dolutegravir and not raltegravir inhibits OCT2, which leads to a decrease of tubular secretion of creatinin and therefore increases concentrations of serum creatinin without affecting glomerular filtration. This inhibition of tubular secretion of creatinin has also been described with other antiretrovirals (ARVs), trimethoprim and cimetidine.
By analogy, the rapid and reversible decrease of calculated eGFR during telaprevir therapy could be due to the same mechanism involving OCT2. Even if we cannot provide proof of this hypothesis, we suggest that a mild or moderate reversible initial decrease of eGFR with telaprevir therapy is not always due to renal toxicity. However, as true renal toxicity may occur during treatment with peginterferon, ribavirin and potentially protease inhibitors, a careful monitoring of eGFR should be performed during all treatment. In our experience (not published data), the decrease of eGFR under telaprevir is quick, with a nadir before week 8 (20% on average) and is completely reversible after week 12. We suggest referring the patient to a nephrologist if the eGFR decreases for more than 20% before week 8 and goes on decreasing after, or does not increase after cessation of therapy.
Future studies concerning second-generation hepatitis C virus (HCV) direct antiviral drugs should take into account this potential decrease of eGFR.
Véronique Loustaud-Ratti, M.D.1,2 Paul Carrier, M.D.1 Chanlina Vong, M.D.1 Marie Essig, M.D., Ph.D.3,4
1Fédération d'Hépatologie, Service d'Hépato-gastroentérologie, Limoges, France
2Inserm UMR 1092, Faculté de Médecine de Limoges, Limoges, France
3Service de Néphrologie, Dialyse, Transplantation, Limoges, France
4Inserm UMR S850, Faculté de Médecine de Limoges, Limoges, France