The effect of sustained virological response by direct-acting antivirals on insulin resistance and diabetes mellitus in patients with chronic hepatitis C

KEYWORDS:

• DAAs
• chronic hepatitis C
• insulin resistance
• type 2 diabetes mellitus

Chronic hepatitis C virus (HCV) infection affects 1–2% of the world population and is a primary cause of liver morbidity and mortality including liver cirrhosis and hepatocellular carcinoma. Furthermore, HCV is directly or indirectly involved in HCV-associated extrahepatic manifestations such as lymphoproliferative processes, autoimmune conditions, and cardiovascular, renal, and nervous system diseases. Insulin resistance (IR) is a feature of HCV infection reported up to 70% of cases and is involved in changes in glucose metabolism and in the development of type 2 diabetes mellitus (T2DM) that is observed with a higher prevalence in patients with HCV infected compared to non-infected subjects [1]. IR and T2DM negatively affect both the progression of HCV-related liver disease and extrahepatic manifestations [2].

In experimental models, the HCV core protein has been shown to induce the development of IR [3]. In patients with HCV infection, the prevalence of IR is higher than that reported in hepatitis B virus infection and in the general population; in addition, IR develops independently of severity of the liver disease and is HCV-genotype–specific where the HCV genotype 1 and 4–infected patients showed the highest levels of IR, whereas the lowest prevalence was observed in HCV genotype 3 infection [1]. A correlation between serum HCV RNA levels and IR has been reported in HCV genotype 1 and 4 infection [1]. Furthermore, HCV has been shown to live and replicate within pancreatic β-cells causing distress [4]; a direct HCV interference with insulin signaling pathways has also been reported [5]. In addition, HCV contributes to IR by interfering with host genetic and environmental factors that induce cytokine imbalance and liver steatosis [1]. All these evidences seem to indicate that HCV plays a direct role in the development of IR. Given the postulate that HCV by itself induces IR, a logical hypothesis is that viral eradication should be associated with the improvement or reversion of the IR and associated conditions. So, the question is: is there any evidence that HCV clearance is associated with an improvement in IR and consequently an improvement in glycemic control and a decrease in the incidence of T2DM?

For almost 25 years, HCV treatment was based on interferon (IFN) that induced a sustained virological response (SVR) in 40–50% of patients. In the age of IFN-based treatment, the presence of IR or T2DM significantly reduced the rate of SVR to IFN [1]. Despite the negative impact of IR on SVR, there are evidence that patients who cleared HCV with IFN treatment had an improvement in IR and a reduced risk of developing de novo IR, T2DM [6], and HCV-associated extrahepatic manifestations.

In recent years, HCV treatment has been substantially changed with the introduction of all-oral IFN-free direct-acting antiviral (DAA) regimens that are safe and achieve SVR in 92–98% of cases. Contrary to what happens with IFN-based treatments, the presence of IR or T2DM does not change the SVR rate to DAA treatment. In view of the recent introduction of DAA regimens, it is obvious that there are limited data on the effects of viral eradication on the IR. Some data on the impact of DAAs on IR and related conditions have been published and seem to indicate a clear positive effect, but considering the short period of time and relatively few studies, these results deserve to be confirmed in larger future analyses.

In a recent study [7], changes in the IR were assessed prospectively in a population of nondiabetic patients with HCV genotype 1 infection and advanced liver disease treated or untreated with DAAs. The pretreatment, end-treatment, and 3-month posttreatment changes in the IR, β-cells function, serum insulin, and glucose levels were evaluated. The results of this study showed that clearance of HCV by DAAs was associated with a significant reduction in serum glucose and insulin levels and that there was a significant improvement in both insulin sensitivity and IR. In 76% of patients with SVR, either disappearance or a significant reduction in IR levels was observed, whereas no variation was shown in untreated patients. Furthermore, a significant improvement in pancreatic β-cell function was demonstrated [7]. Of interest was the observation that the improvement of the IR was independent of the degree of hepatic damage and the body mass index, while the effect was closely associated with the disappearance of HCV. These data confirm the direct pathogenic role of HCV genotype 1 in the induction of IR and demonstrate that HCV-related IR is a treatable condition. However, the results showed that non-regression of IR in SVR patients was closely associated with the highest degrees of liver cirrhosis, indicating the need to treat HCV infection in early stages of liver disease. It has been suggested that improvement of IR associated with HCV clearance may prevent pathological conditions associated with IR such as progression of liver fibrosis, development of T2DM, metabolic syndrome, and cardiovascular disease [7]. However, future studies will have to clarify this important issue.

In a large study in the real world, of which about half of the HCV patients were treated with DAAs, the nondiabetic patients achieved SVR and showed a 21% reduced risk of T2DM compared to those who did not achieve SVR during an average of 3.7 years of follow-up [8]. This study seems to suggest that the eradication of HCV by DAAs may have a positive impact on reducing the incidence of T2DM.

In view of the fact that HCV clearance is associated with a decrease in serum glucose levels and improves insulin secretion a question arises, what is the effect of treatment with DAAs in patients with established T2DM?  It is evident that there are limited data to adequately answer this question, even if the few studies seem to indicate a clear beneficial effect on the control of metabolic condition. An assessment was made in a study that enrolled a large number of HCV patients with T2DM treated with DAAs by comparing patients with SVR and those who did not [9]. The clearance of HCV by DAAs was associated with a significant improvement in glycemic control and a decrease in the amount of antidiabetic drugs and in particular of the insulin dose used [9].

An Italian study [10] aimed at the evaluation of fasting glucose and glycated hemoglobin values before and after DAA therapy in HCV patients with T2DM confirms the results of the previous study by strengthening the close link between HCV and diabetes. SVR induced a significant improvement in glycemic control, despite a significant weight gain and in 20.7% of SVR patients caused in a reduction or discontinuation of antidiabetic therapy [10]

Similar data have been reported in a large Egyptian study comprising HCV genotype 4–infected patients treated with DAAs [11]. Patients with improved glycemic control needed a reduction in antidiabetic drugs and insulin dose; the family history of diabetes, the presence of Child B cirrhosis, and the duration of diabetes were associated with non-improvement in glycemic control.

Based on these data, it has been suggested that diabetic patients treated with DAAs should be carefully monitored in the short time to reduce antidiabetic drugs in order to avoid hypoglycemic episodes [10].

Several other small retrospective studies [12–15] have shown a significant improvement of fasting plasma glucose and of glycated hemoglobin A1C in patients who achieved SVR with DAA treatment.

The overall data seem to indicate that clearance of HCV by DAAs unlocks the molecular and inflammatory pathways altered by the virus that cause IR and the alteration of glucose homeostasis. Prospective studies are needed to verify whether changes in glucose metabolism observed shortly after HCV clearance are maintained over a long-term period, considering also that many authors report an increase in body weight in these subjects.

Although the currently available data are insufficient to give a definitive judgment on the role of HCV clearance by DAA treatment on IR and glucose homeostasis, it seems evident that all available results are indicative that HCV clearance induces clear benefits on the alteration of homeostasis of glucose metabolism associated with HCV infection. In particular, the current data show an improvement in the IR and fasting glucose levels, a reduction in glycated hemoglobin levels, and a better control of blood glucose levels in diabetic patients with a significant lower antidiabetic dose than that required before HCV elimination. In addition, HCV clearance reduces the onset of de novo IR and T2DM. However, the data indicate that in patients with advanced cirrhosis or with a long-term diabetic history, there is no improvement in the IR or diabetes, underlining that there is a point of no return of the changes in glucose metabolism, and therefore, an early treatment is necessary to obtain maximum effects on IR and to improve diabetes. Furthermore, there is a need to identify HCV-infected diabetic patients in order to begin treatment with DAAs as early as possible to eliminate HCV to improve their glycemic control and possibly to reduce the faster progression of hepatic fibrosis observed in these patients as well as extrahepatic metabolic complications associated with the diabetes.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

The manuscript was not funded.