Hepatitis C Virus Eradication With Direct-acting Antiviral Improves Insulin Resistance

Francesco Paolo Russo; Alberto Zanetto; Martina Gambato; Ilaria Bortoluzzi; Ramona Al Zoairy; Enrica Franceschet; Federica De Marchi; Luca Marzi; Erica Nicola Lynch; Annarosa Floreani; Fabio Farinati; Benedikt Schaefer; Patrizia Burra; Heinz Zoller; Andrea Mega


J Viral Hepat. 2020;27(2):188-194. 

In This Article

Abstract and Introduction


Sustained virological response (SVR) after interferon-based therapy is associated with improvement of insulin resistance (IR) in HCV-infected patients. Few data are available in the direct-acting antivirals (DAAs) era, especially in cirrhotic patients. We prospectively evaluated the long-term effect of DAAs on IR. Patients treated with DAAs between May 2015 and December 2016 in 3 tertiary care centres were recruited. Patients with diabetes were excluded. Biochemical and virological data were collected at baseline, 12/24/48 weeks (W) after the end of therapy (EOT). Presence of IR was defined by a 'homeostasis model assessment index for IR' [HOMA-IR])> 2.5. Liver fibroscan was performed at baseline, at 24/48W after EOT. Hundred and thirty-eight patients were enrolled (mean age 58 years, M/F 85/53, GT1 61%, 68.8% cirrhotic). Sixty-eight patients (94/138) had IR. Patients with IR had significantly higher stiffness than patients without it (23 ± 12 vs 15 ± 8; P < .0001). SVR12 was achieved in 135 (98%) patients, and 124 (90%) patients reached the 48W post-EOT. At this time point, the percentage of patients with IR significantly decreased to 49% (P = 0,01). HOMA-IR was significantly lower than baseline (1.8 vs 3; P < .001), and this was related to a significant reduction of insulin level (11.7 ± 6.3 vs 16.4 ± 8.3). High BMI was associated with a significantly lower probability of achieving a non-IR status at 24W (P = .05) and 48W (P = .03). In conclusion, SVR following DAAs led to a significant reduction of IR, even in patients with cirrhosis. Nevertheless, IR can persist after the achievement of SVR, especially in patients with high BMI.


Approximately 1% of the world's population (about 170 million persons) is chronically infected with the hepatitis C virus (HCV).[1] Besides liver sequelae such as end-stage liver disease and hepatocellular carcinoma (HCC), chronic infection has been associated with multiple extra-hepatic manifestations which lead to increased morbidity and all-cause mortality rates.[2,3]

Hepatitis C virus can interfere with glucose homeostasis in different ways,[4,5] most of which involving insulin signalling.[6] Multiple and synergistic mechanisms are implied: degradation of insulin receptor substrate-1 (IRS-1), inhibition of insulin activity, increased glucose synthesis and release from hepatocytes.[7,8] In addition, hepatic inflammation and the production of pro-inflammatory cytokines (IL-8, IL-18, TNF-alfa) increase insulin resistance (IR) in muscles and visceral fat.[9] Hence, HCV-infected patients have a higher risk of developing insulin resistance (IR) and type II diabetes mellitus (T2DM) than their matched non-HCV counterparts (17%-25% and 40%-70%, respectively).[2,10–12] Metabolic comorbidities negatively affect patients' prognosis because of their independent association with progression of hepatic fibrosis and HCC development.[2] Furthermore, they also contribute to the increase in cardiovascular risk.[5]

Studies have shown an increase in the liver expression of IRS-1 after successful antiviral treatment with interferon (IFN)-based therapy, and there have been several reports of significant benefits in terms of IR reduction once sustained virological response (SVR) is achieved.[13–17] Eradication of the virus is not only associated with improvement of IR, but also with a significant reduction of T2DM and its complications.[18,19] The reduction of extra-hepatic manifestations of HCV ultimately leads to an improvement of patients' survival[20,21] and provides a significant public health benefit.[22]

After the widespread adoption of highly effective direct-acting antivirals (DAAs),[23] preliminary data from case series and cohort studies confirmed what previously described in the IFN era.[4,24–30] However, most of them were mono-centric and/or retrospective, with a relatively short duration of follow-up. Overall, the number of patients with cirrhosis was relatively small.

To overcome these drawbacks and to further analyse the long-term relationship between HCV eradication and IR, we performed a large multicentre prospective study aimed at assessing whether SVR after DAAs could improve the degree of IR in HCV-infected patients, including those with cirrhosis.