Successful Hepatitis C Antiviral Therapy Induces Remission of Type 2 Diabetes: A Case Report

Background

The World Health Organization estimates that approximately 185 million people are infected with HCV worldwide [1]. Diabetes is also a global health care challenge. Approximately 347 million individuals worldwide have diabetes, with type 2 diabetes accounting for 90% of all cases [2]. An association between these two chronic diseases was first recognized in 1994 and since then several epidemiological studies have demonstrated an increased prevalence of type 2 diabetes among HCV-infected patients compared with HBV infection, chronic liver disease from other causes, and healthy controls [3–8]. The mechanism by which HCV impairs glucose metabolism is not clear. Although alterations in insulin-signalling pathways have been implicated, the process is likely multifactorial, including host factors and HCV genotype [6].

The presence of insulin resistance and type 2 diabetes in HCV has been associated with poor response to interferonribavirin HCV antiviral therapy, acceleration of liver fibrosis, and increased risk of hepatocellular carcinoma (HCC) [9–12]. Several observational studies have demonstrated that eradication of HCV is associated with improved insulin sensitivity and may reduce the long-term risk of diabetes in this population [13–15]. Case reports have described improvements in glycemic control with treatment of HCV with both IFN/Ribavirin and IFN/Ribavirin/telaprevir; however, the improvements were limited to the treatment phase [16,17]. In both these cases, there was evidence of recurrence of diabetes once HCV anti-viral therapy ended. This is the first reported case to demonstrate complete remission of diabetes with viral clearance beyond the treatment phase.

Case Report

A 49-year-old man with no history of diabetes was referred to Endocrinology with polyuria, polydipsia, fasting blood sugar of 18 mmol/L, and a hemoglobin A1c (HbA1c) of 10% (Table 1). His past medical history included hemophilia, blood transfusion acquired HCV, non-alcoholic steatohepatitis, and early-stage cirrhosis. He had previously received pegylated-interferon/ribavirin (peg-IFN/rib) treatment for HCV and did not achieve a sustained virological response (SVR). The patient was diagnosed with type 2 diabetes and was started on Metformin 500 mg twice daily and Gliclazide 80 mg twice daily. Within a month, his HbA1c was 7.7% and fasting blood sugars ranged between 5–7 mmol/L. He continued to adhere to the prescribed treatment of oral agents over the next 2 years and maintained an HbA1c between 4.6 and 8.6%

In 2011, he was retreated with a 48-week course of peg-IFN/ rib plus a HCV protease inhibitor (boceprevir). His HbA1c at the start of treatment was 7.9%, with no change in diabetes medications. Antiviral response to HCV-therapy correlated with a significant improvement in glucose control based on random glucose levels and HbA1c measurements (Figure 1). He achieved a sustained virological response (free of viremia 6 months following completion of HCV treatment) and within a year of completing antiviral therapy no longer required diabetes medications. More than 2 years after the completion of HCV antiviral treatment, the patient remains aviremic and has maintained an HbA1c of 5.8% without diabetes medication. His weight remained relatively stable during this period with no significant lifestyle changes (Figure 1). In addition to the improvements in glucose metabolism described, we also observed decreasing levels of alpha-fetoprotein (AFP) during treatment, which paralleled the improvements in HbA1c (Figure 2).

Discussion

MECHANISMS FOR IMPAIRED INSULIN SENSITIVITY IN HCV INFECTION:

Despite extensive research in this area, the exact mechanism by which HCV impairs insulin sensitivity and leads to increased burden of diabetes is not well understood and is likely multifactorial. HCV infection is specific to the liver. However, insulin sensitivity appears to be impaired both in the liver and the periphery [20,21]. HCV impairs insulin signaling through direct and indirect mechanisms [22]. HCV directly impacts insulin signaling by interacting with specific proteins such as serine/threonine kinases that subsequently lead to inhibition or increased degradation of insulin signaling molecules [6,23]. HCV may also indirectly cause insulin resistance in the periphery by inducing the production of pro-inflammatory cytokines that impair insulin signaling pathways in uninfected tissues [20]. Changes in metabolic parameters described with chronic HCV infection differ by genotype, suggesting that the mechanisms by which these signaling molecules are impacted are genotype-dependent. Viral steatosis is more common among HCV-genotype 3-infected patients, and, in contrast, there is a higher prevalence of insulin resistance among HCV-genotype 1 and 4 infection [6,24].

HCV TREATMENT, INSULIN RESISTANCE, AND GLYCEMIC CONTROL:

Several observational studies have demonstrated that successful treatment of HCV with IFN/Ribavirin leads to improved insulin sensitivity and may reduce the long-term risk of type 2 diabetes [10,13–15]. Tahrani et al. reported a case of improved glycemic control and hypoglycemic episodes requiring cessation of diabetes therapies during treatment with IFNα-Ribavirin (Table 2) [16]. In contrast to our patient, the improvements in glycemic control were not maintained. After 24 weeks of treatment, HCV polymerase chain reaction remained positive and HCV treatment was stopped. Six months post-treatment, the glycemic control had deteriorated based on an HbA1c of 8.2%. The difference between the above-cited case and our patient may be due to the differences in antiviral treatment response and persistent viremia in the patient described above.

In recent years, the treatment of HCV has evolved rapidly with the development of direct-acting antiviral (DAA) therapies (protease inhibitors, NS5a inhibitors, and nucleotide and non-nucleotide polymerase inhibitors). The effect of DAA HCV treatments on insulin resistance and long-term risk of type 2 diabetes has yet to be clearly established. A randomized controlled trial of HCV mono-infected study participants receiving 14 days of monotherapy with the protease inhibitor Danoprevir found that serum HCV RNA and HOMA-IR correlated significantly (Spearman rho=0.379, p<0.0001) [25]. At the end of 14 days of Danoprevir monotherapy, the mean decrease in HCV RNA was 2.2±1.3 log10 IU/ml (p<0.0001) in patients who received the active drug (n=40), which correlated with a decrease in mean HOMA-IR score by 1.6±1.1 (p<0.0001). In contrast, HCVRNA and HOMA-IR remained unchanged in placebo recipients.

A recently published case report further suggests that telaprevir, a NS3/4A protease inhibitor, may improve glucose metabolism (Table 2) [17]. In this case, a patient developed recurrent episodes of hypoglycemia shortly after initiating triple therapy (IFN/Ribavirin and telaprevir), which required discontinuation of all diabetes medications. Similar to the previously described case, but in contrast with our patient, improvements in glycemic control were not maintained when antiviral therapy ended, despite achieving an SVR. While the differences in outcomes may be due to host factors, the authors of this case report suggest that the protease inhibitor may have a direct antidiabetic effect. Interestingly, our patient continued to show improvement in glucose metabolism post-treatment, with diabetes therapy being reduced and eventually discontinued over 12 months. This suggests a mechanism of impairment that extends beyond the direct viral effects of HCV or HCV therapy and improvements in glucose metabolism, which may reflect decreased inflammation and liver fibrosis with improved liver function. Further studies are needed to establish the mechanisms by which HCV induces insulin resistance and the effects that different HCV therapies have in improving glycemic outcomes.

HCV, INSULIN RESISTANCE, AND AFP:

In addition to the improvements in glucose metabolism described, we observed decreasing levels of alpha-fetoprotein (AFP) during treatment, which paralleled the improvements in HbA1c (Figure 2). AFP is an oncofetal protein associated with hepatic malignancies and liver regeneration [26,27]. HCV core protein, inflammation, necrosis, and hepatocellular injury have all been suggested as causes for elevated AFP levels in chronic HCV infection [26–29]. Although type 2 diabetes and insulin resistance have been identified as risk factors for the progression of liver fibrosis and development of hepatocellular carcinoma, the mechanism by which this occurs is not clear [9–12]. The relationship between AFP and insulin resistance was recently examined in a retrospective analysis of 300 HCV-infected patients [30]. This study demonstrated that whole-body insulin resistance and hepatic fibrosis correlated directly with elevated levels of AFP. In addition, this group conducted a pilot study examining the effects of a lifestyle modification program on insulin resistance and AFP levels. Lifestyle modification over a 3-month period correlated with improved insulin resistance and a reduction in AFP levels. The parallel improvements in AFP and glycemic control demonstrated in our patient are likely in part a reflection of resolving inflammation and hepatocellular injury. However, these findings draw attention to the need for further prospective studies to understand the relationship among insulin resistance, AFP, and hepatocarcinogenesis.

Conclusions

This case highlights the interaction between HCV and type 2 diabetes, as well as the potential reversibility of impaired glucose metabolism with viral eradication. It further suggests the need for close monitoring of glucose levels and the potential need for dose adjustments of diabetes therapies during treatment of HCV to prevent hypoglycemia. Studies are needed to delineate the impact of different HCV antiviral therapies on insulin signalling pathways and the potential for improving glucose metabolism. This knowledge will help inform patient care, guide therapeutic selection, and improve liver and metabolic outcomes for HCV-infected patients with type 2 diabetes.

Furthermore, this case highlights the association between insulin resistance and AFP levels. Although the improvements in both parameters with HCV antiviral therapy are in part a reflection of decreased inflammation and liver injury, additional evaluation for causative relationship(s) among HCV, insulin resistance, AFP, and HCC are necessary.