Among the various extrahepatic manifestations of hepatitis C virus (HCV) infection, Type 2 diabetes mellitus (DM) is one of the most common diseases associated with chronic HCV. There are strong lines of evidence supporting an epidemiologic link between DM and chronic hepatitis C (CHC). The higher prevalence of DM in CHC patients is observed all over the world. In Taiwan, large-scale studies have been reported showing the higher accumulated risk for DM in individuals with positive anti-HCV and the important role of HCV viremia, but not anti-HCV seropositivity alone, on the increased association with DM. With a prediabetic condition, namely, impaired fasting glucose and/or impaired glucose tolerance, oral glucose tolerance test can be used to diagnose DM more accurately; in fact, an additional 18.6% of DM patients who were diagnosed as having DM by oral glucose tolerance test were not initially considered to have DM based on fasting sugar level alone [1]. Insulin regulates glucose homeostasis, and insulin resistance (IR)—measured by the “gold standard” hyperinsulinemic–euglycemic clamp, or alternatively by the homeostasis model assessment-IR (HOMA-IR), which is used clinically—has a pivotal role in the pathogenesis of DM. IR has been reported to develop early in the course of HCV infection, and increased HOMA-IR was associated with more advanced fibrosis [2]. There was also a dose–response relationship between HCV RNA level and the presence of IR reported in Taiwan [3], which implicated the strong association between HCV and glucose metabolism.

Peginterferon alfa (PEG-IFN)/ribavirin combination therapy has remained the standard treatment regimen, especially in Asian countries despite the rapid development of novel direct-acting antivirals (DAAs), which are generally expensive. In Taiwan, the response-guided therapy is applied with a higher sustained virological response (SVR) rate for Genotype 1 (76–80%) and Genotype 2 (95%) compared with that used for patients in Western countries. The influence between IR or DM and antiviral therapy with PEG-IFN/ribavirin is interesting. Previous studies have shown the negative impact of DM on the response to PEG-IFN/ribavirin [4]. Similarly, studies have shown that IR is associated with a higher likelihood of failure to achieve an SVR in patients with different genotype infection [5] and [6]. Actually, the impact of IR on SVR has been reported in some special subgroups of patients, for example, difficult-to-treat patients, different HCV genotypes or races [7] and [8]. The specific association between lower IR and better response has made it possible to increase the SVR by targeting and improving the metabolic profiles related to IR, such as lifestyle modification or medications, prior to antiviral treatment.

For PEG-IFN/ribavirin therapy in CHC, another interesting issue is the impact of antiviral therapy on IR. With an existing property of immune modification, the emergence of IR and subsequent DM has been demonstrated with interferon-based therapy [9]. However, HCV core protein has a direct effect in inhibiting the insulin signaling pathway by upregulating suppressor cytokine signaling-3 or by dephosphorylation of AKT, a serine/threonine protein kinase B. Viral clearance might lead to improvement in insulin sensitivity and to glycemic control. Several studies have reported that reduced IR and subsequent improved glucose control after IFN therapy had been observed among patients with CHC who achieved SVR [10]. In Taiwan, our previous studies have shown that there was no significant decline in HOMA-IR even among those who achieved SVR. The significant decline of HOMA-IR after treatment was observed only in those patients with high pretreatment HOMA-IR, irrespective of SVR achievement [11], and successful eradication of HCV improves glucose abnormalities in prediabetic CHC patients [12]. In nondiabetic Taiwanese patients with CHC after Peg-IFN/ribavirin therapy, we have reported the insignificant decline of HOMA-IR in those responders. Nevertheless, a significant relief of pancreatic beta-cell function measured by the HOMA model (HOMA-%B: fasting insulin level (mU/mL)360/fasting plasma glucose (mg/dl)63) was noted, which may implicate the recovery in pancreatic beta-cell function earlier than that of IR after the response to Peg-IFN/ribavirin therapy [11].

In the current issue of the Advances of Digestive Medicine journal, Tseng et al investigated the change in IR from baseline, through the end of, and up to 24 weeks after the standard regimen with PEG-IFN plus ribavirin in 65 Taiwanese patients with CHC [13]. With the regimen of the National Health Insurance, which commenced in 1995, the current reimbursement for PEG-IFN/ribavirin therapy in Taiwan is as follows: 24 weeks for PEG-IFN/ribavirin for patients with a rapid virological response (RVR), 48 weeks for patients without an RVR and with a early virological response (EVR), and 16 weeks (the stopping rule) for patients without an EVR [14]. Forty-six (71%) patients achieved SVR. When the authors compared the changes in HOMA-IR and body mass index (BMI) during and after the antiviral therapy, a significant decrease in HOMA-IR was noted in patients with SVR (median value of 3.6, 1.4, and 1.3 at baseline, end of therapy, and 24 weeks after completing the therapy, respectively), but not in those without SVR (median value of 3.9, 2.1, and 2.2 at baseline, end of therapy, and 24 weeks after completing the therapy, respectively). With a significant decrease in BMI at the end of the therapy compared with baseline data in all treated 65 patients [median value (in kg/m2): 25.1 and 23.2 at baseline and end of therapy; for SVR patients, 24.4 and 22.9, and for non-SVR patients, 26.0 and 24.3, respectively], a significant decrease in BMI at 24 weeks after completing the therapy (compared with baseline data) was in contrast noted in patients without SVR (25.9 kg/m2) but not in those with SVR (24.3 kg/m2) at baseline, at the end of the therapy, and 24 weeks after completing the therapy, respectively. The authors concluded that antiviral therapy improves IR during HCV treatment, and the effectiveness in decreasing IR persists only in patients who achieve an SVR. Despite the limitations—the small number of cases, the lack of stratification of the pretreatment IR status by clinical diagnosis of DM or the medication, the results of improved IR without decrease of the BMI in patients with SVR support the role of antiviral therapy and the association between viremia and IR. Incidentally, the results of “insignificant” change in IR at 24 weeks after completing the therapy (3.9 to 2.2) with a significant decrease in BMI (26 to 25.9) in patients without SVR warrant further investigation as only 19 patients were enrolled in the study. Further large-scale studies with stratification of patients with different pretreatment IRs are necessary.

Anti-HCV therapy has experienced a tremendous progress in recent years. Several DAAs including three groups (viral protease NS3/4A inhibitors, viral RNA-dependent RNA-polymerase NS5B inhibitors, and the replicon complex NS5A inhibitors) have been approved, and interferon-free antiviral treatments have become available that achieve SVRs of more than 80–90% for most treatment groups. It is believed that in the near future, most patients with CHC will achieve virological clearance with the DAAs, enabling achievement of high SVR rates. Because DAAs have a different mechanism of anti-HCV effect, the association between the IR/glucose metabolism and the effectiveness, clinical course, and long-term outcomes deserve to be elucidated.

Conflicts of interest

The author declares no conflicts of interest.

References

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