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


The natural history of chronic HCV infection is characterized by the development of several extra-hepatic manifestations that entail increased morbidity and mortality.[34–36] The wide mosaic of such manifestations has been described as 'HCV syndrome'[37] and represents the clinical expression of the biological effects of HCV.[38] The two major metabolic manifestations of the syndrome are insulin resistance and type II diabetes mellitus.[22,39–41] Previous data hypothesized a pilot role of HCV in favouring the development of IR, and IR was attributed to HCV active infection per se rather than to advanced liver fibrosis.[5,15,42,43] The development of IR in HCV-infected patients favours the development of hepatic steatosis and nonalcoholic fatty liver disease,[44] and both act as independent and synergistic risk factors for fibrosis progression and HCC development, regardless of the severity of the underlying liver disease.[39,45] Moreover, in the IFN era, the presence of baseline IR and/or T2DM was associated with a lower probability of achieving sustained virological response.[46]

In our study, baseline analysis confirmed the association between IR and HCV, with almost two-thirds of the entire cohort having HOMA-IR higher than 2.5. As expected, in accordance with a recent study by Adinolfi et al,[25] baseline IR did not affect efficacy of DAAs based antiviral therapy, with almost all the patients achieving SVR.

HCV eradication after IFN-based antiviral therapy has been associated with a reduced risk of developing de novo IR.[10] Furthermore, HCV patients with IR or T2DM who achieved SVR experienced an improvement of glucose homeostasis control.[20,22] However, one significant confounding factor of IFN-based studies was the frequent weight loss associated with IFN. Indeed, weight loss can lead to improvement of IR per se.[47]

In our cohort, during 1-year follow-up after the end of DAAs therapy, a significant number of patients who had IR at baseline showed an improvement of HOMA-IR. When we analysed the reason of this trend, we found that at 12W, 24W and 48W fasting glucose was not significantly lower than baseline value, whereas insulin progressively decreased at 12W, 24W and 48W after the EOT. The increased peripheral resistance to insulin activity is one of the main drivers of IR in HCV-infected patients and is induced by the pro-inflammatory cytokine milieu triggered by chronic hepatic injury.[6,9] Therefore, the decline of hepatic inflammation that follows HCV eradication could explain the significant reduction of IR after the achievement of SVR.

In accordance with the findings of Adinolfi et al,[25] the improvement of insulin sensitivity was independent of weight loss, further confirming the HCV-related chronic hepatitis as independent risk factor for the development of IR. On the contrary, high BMI significantly reduced the probability of IR improvement. Obesity is one of the main features of metabolic syndrome and is associated with IR.[48] HCV-infected patients who achieve SVR but remain overweight and/or insulin resistant might have an increased risk of liver and nonliver-related complications in the long term, and further studies with a longer follow-up are needed to address this issue in the DAAs era.

The percentage of patients becoming non-IR progressively increased from the achievement of SVR to the last follow-up, which was 1 year after the end of antiviral therapy; hence, other mechanisms not related to hepatic inflammation and peripheral resistance might be relevant. The achievement of SVR has a significant impact on the natural history of HCV-related disease, as it halters the progression and induces the regression of liver fibrosis.[49] In our study, we observed a progressive and significant increase of serum albumin, together with a parallel reduction of bilirubin. Moreover, there was a significant reduction in liver stiffness over time.

What are the implications of this phenomenon in terms of glucose homeostasis control? The liver plays a central role in all the metabolic processes in the body, and the improvement of hepatic function might have led to a better control of synthesis, storage and release of glucose, although we weren't able to find any significant reduction of blood fasting glucose over time.

In contrast with recent data by Adinolfi et al[25] and interestingly enough, presence of baseline cirrhosis was not associated with a lower probability of IR reversibility, further supporting the importance of HCV per se rather than advanced liver fibrosis in inducing IR. Different population characteristics and duration of follow-up might be the explanation for this difference, but further studies are needed to clarify this point.

The present study has some limitations. First of all, we evaluated IR by using HOMA-IR because of its clinical applicability. Therefore, no cellular and molecular evaluation underpinning the association between HCV status and IR was carried out. Secondly, the follow-up was relatively short, and a longer observation time is probably needed to properly assess the effects of HCV eradication on glucose homeostasis. Finally, in a relatively well-compensated cohort, 1-year follow-up is not enough to evaluate the impact of IR resolution in reducing the development of liver and nonliver related complications. In addition, our data should be interpreted with caution in more advanced patients that were not adequately represented in the present study.

In conclusion, we showed that HCV eradication following DAAs treatments is associated with a progressive reduction of insulin resistance, also in patients with advanced liver disease. Nevertheless, IR can persist after the achievement of sustained virological response, especially in patients with high body mass index. In such patients, nutritional support and dietetic intervention should be planned to improve glucose homeostasis and to avoid the complications of long-standing hyperinsulinemia. Further studies are now warranted to evaluate which is the impact of IR reversal on the natural history of hepatic and nonhepatic complications of HCV chronic infection, particularly in patients with advanced liver disease.