Research Article: Treatment with direct-acting antivirals improves peripheral insulin sensitivity in non-diabetic, lean chronic hepatitis C patients

Date Published: June 6, 2019

Publisher: Public Library of Science

Author(s): Giacomo Gastaldi, Diana Gomes, Philippe Schneiter, Xavier Montet, Luc Tappy, Sophie Clément, Francesco Negro, Jee-Fu Huang.


Hepatitis C virus (HCV) infection is associated with insulin resistance, which may lead to type 2 diabetes and its complications. Although HCV infects mainly hepatocytes, it may impair insulin sensitivity at the level of uninfected extrahepatic tissues (muscles and adipose tissue). The aim of this study was to assess whether an interferon-free, antiviral therapy may improve HCV-associated hepatic vs. peripheral insulin sensitivity.

In a single-arm exploratory trial, 17 non-diabetic, lean chronic hepatitis C patients without significant fibrosis were enrolled, and 12 completed the study. Patients were treated with a combination of sofosbuvir/ledipasvir and ribavirin for 12 weeks, and were submitted to a 2-step euglycemic hyperinsulinemic clamp with tracers, together with indirect calorimetry measurement, to measure insulin sensitivity before and after 6 weeks of antivirals. A panel of 27 metabolically active cytokines was analyzed at baseline and after therapy-induced viral suppression.

Clamp analysis performed in 12 patients who achieved complete viral suppression after 6 weeks of therapy showed a significant improvement of the peripheral insulin sensitivity (13.1% [4.6–36.7], p = 0.003), whereas no difference was observed neither in the endogenous glucose production, in lipolysis suppression nor in substrate oxidation. A distinct subset of hepatokines, potentially involved in liver-to-periphery crosstalk, was modified by the antiviral therapy.

Pharmacological inhibition of HCV improves peripheral (but not hepatic) insulin sensitivity in non-diabetic, lean individuals with chronic hepatitis C without significant fibrosis.

Partial Text

Hepatitis C virus (HCV) infection is a major public health issue worldwide. The World Health Organization (WHO) has reported that HCV accounts for ~400,000 annual deaths globally, mostly due to end-stage complications of chronic liver disease, and vowed to eliminate HCV as a public health threat by the year 2030 [1]. This ambitious goal appears to be within reach thanks to the advent of potent and safe direct-acting antiviral-based regimens, resulting in a viral clearance in excess of 95% in most patients’ subgroups [2]. HCV clearance has been shown to be associated with the improvement of a wide array of clinical outcomes, such as hepatocarcinogenesis and liver-related mortality [3], but also with the restauration of innate immune responses [4] and an improved quality of life [5, 6].

In this study, we show that (i) the complete suppression of HCV replication induced by an IFNα-free regimen in lean chronic hepatitis C patients without significant fibrosis significantly improves the extrahepatic (but not the hepatic) insulin sensitivity, (ii) the improved glucose homeostasis bears no correlation with the transaminase decline, suggesting the HCV-induced extrahepatic IR and liver inflammation are probably disconnected from each other, (iii) HCV does not seem to interfere with the insulin effects on lipid metabolism in adipose tissue, and (iv) HCV modifies the circulating levels of factors likely involved in the pathogenesis of the decreased peripheral insulin sensitivity.