Glycemic Control in Patients Undergoing Treatment With Paritaprevir/Ombitasvir/Ritonavir and Dasabuvir for Chronic Hepatitis C Infection

Abstract

Background/Aim: Patients with hepatitis C virus (HCV)-associated cirrhosis are more prone to developing type 2 diabetes mellitus than patients with any other etiology of cirrhosis. The main objective of this study was to evaluate the impact of all oral antiviral treatment with ritonavir-boosted paritaprevir/ombitasvir and dasabuvir (OBV/PTV/r + DSV) in patients with chronic genotype 1b HCV infection.

Patients and Methods: We retrospectively evaluated 806 patients who underwent antiviral therapy between December 2015 and July 2019. The laboratory data analyzed were liver function tests, kidney function tests, HCV viremia, fasting glucose levels, and glycosylated hemoglobin.

Results: Patients with impaired glucose metabolism were predominantly male and of older age compared to patients with normal glucose tolerance, and also had higher levels of transaminases. Proteinuria and higher creatinine levels were found in patients with impaired glucose metabolism. Overall, we found a 98.01% rate of sustained virologic response (SVR), with a non-significant difference between patients with normal and abnormal glucose metabolism. A statistically significant difference in SVR rates in patients with low degrees of fibrosis (F0-F2) versus those with advanced degrees of fibrosis (F3-F4) was found in both groups. Antiviral treatment resulted in significant decreases in fasting glucose levels and glycosylated hemoglobin levels in all patients with impaired glucose metabolism at SVR.

Conclusion: Patients with pre-diabetes, as well as diabetic patients, achieved a better glycemic control after SVR obtained by ritonavir-boosted paritaprevir/ombitasvir and dasabuvir.

A direct relationship between chronic hepatitis C virus (HCV) and type II diabetes mellitus (DM) has been closely studied and current research suggests that DM is the most common extra hepatic manifestation of HCV (1). HCV is also implicated in atherosclerosis and can be associated with cardiovascular and all-cause mortality (2). Up to 33% of patients with chronic HCV infection also suffer from type 2 DM (3), and it is estimated that HCV infection increases the risk of DM by 1.8 (4). Mechanisms for this association are varied and linked to both the direct action of HCV and the effects of HCV-associated liver cirrhosis on glucose metabolism.

HCV infection is associated with background systemic inflammation and an increase in reactive oxygen species at the mitochondrial level, resulting in higher circulating levels of tumor necrosis factor alpha and other pro-inflammatory cytokines, which contribute to tissue insulin-resistance (5). Furthermore, HCV may be directly linked to insulin signaling. Studies have demonstrated that phosphorylation of insulin-stimulated tyrosine as well as the activity of phosphoinositide 3-kinase and protein kinase B (responsible for the majority of the metabolic effects of insulin) are down-regulated by HCV infection (6). HCV- infected beta pancreatic cells have morphological and functional defects, such as an altered insulin response to glucose. Also, pro-inflammatory cytokines disrupt insulin signaling and secretion and stimulate excessive gluconeogenesis (7,8).

Patients with HCV-associated cirrhosis are more prone to developing type 2 DM than patients with any other etiology of cirrhosis. It is estimated that over 50% of these patients will develop DM during the evolution of the infection and liver disease (9). The term “hepatogenous diabetes” has emerged, describing insulin-resistance and glucose intolerance in patients with advanced liver disease (10). A potential cause may be the impaired liver function in these patients, which reduces insulin extraction, corroborated with an excess of contra-insulin hormones (glucagon, insulin-like growth factor). However, cirrhotic patients present a progressive impairment of insulin secretion and hepatic insulin resistance, thus producing fasting hyperglycemia and a diabetic glucose tolerance profile (11).

Antiviral treatments also influence the relationship between HVC and DM. HCV treatment failure has been associated with a risk of developing insulin resistance of 2.8 times the risk in the general population (12). In contrast, studies have suggested that patients with DM have an accentuate progression of liver disease and lower responses to antiviral therapies than patients with normal glucose metabolism (13).

In transplant recipients, new-onset diabetes after transplantation has been described, strongly associated with immunosuppressive therapies such as corticosteroids and calcineurin inhibitors (14,15). In the era of direct-acting antiviral agents, which offer very high sustained virologic response rates with a short duration of treatment and self-limited side effects, the current research is aimed at the effects of these drugs on the comorbidities and complications of HCV infection (16).

The main objective of this study was to evaluate the impact of oral antiviral treatment with ritonavir-boosted paritaprevir/ombitasvir and dasabuvir (OBV/PTV/r + DSV) in patients with chronic genotype 1b HCV infection, the prevalent genotype in our country (17). Clinical trials have shown response rates of up to 99% in patients with chronic HCV hepatitis and compensated liver cirrhosis, rates confirmed by real-life studies. Current guidelines recommend a duration of treatment of 12 weeks in patients with advanced fibrosis and 8 weeks in treatment-naïve patients with low degrees of fibrosis (18).

Patients and Methods

This is a retrospective cohort study based on a cohort of patients who underwent treatment with OBV/PTV/r + DSV in a single Internal Medicine center, during December 2015-July 2019. All the treatments were approved by the National Healthcare Program. The study was approved by the local Ethical Committee (no. 22654/26.11.2015). No further approval was required as this was an observational trial, without impact in the medical management of the patients.

Data were retrieved by revision of medical charts, laboratory data and imaging, medical history, and physical examination. The following inclusion criteria were applied: Active HCV infection, determined by HCV-RNA [real-time PCR (TaqMan)]; Genotype 1b HCV; Various degrees of fibrosis, from F0 to F4, extimated by Fibromax^® and Fibroscan^®. Exclusion criteria for the current study were: Co-infection with HBV or HIV; Presence or history of decompensated cirrhosis (Child Pugh B and C), as this is a counter-indication for OBV/PTV/r + DSV; History of hepatocellular carcinoma; Diabetes mellitus secondary to corticoid therapy; Type 1 diabetes mellitus.

The antiviral treatment was administered as per protocol: OBV/PTV/r 12.5 mg/75 mg/50 mg, two pills once a day and DSV 250 mg twice a day. The duration of treatment was 24 weeks in patients with a history of liver transplantation and 12 weeks in all other patients. Virologic response at the end of treatment (EOT) and at 12 weeks after the end of treatment [sustained virologic response (SVR)] were defined as undetectable HCV-RNA.

Patients were monitored by liver function tests (aspartate aminotransferase AST, alanine aminotransferase ALT, total bilirubin TB, gamma- glutamyl-transpeptidase GGT, alkaline phosphatase, serum albumin), renal function tests (serum creatinine, urea, proteinuria), blood cell count, coagulation parameters, and alpha- feto-protein (AFP) before treatment administration. Standard imaging evaluation included Fibroscan and abdominal ultrasonography. In patients with high AFP values or suspicious liver ultrasonography, abdominal computed tomography (CT) or magnetic resonance imaging (MRI) were performed to exclude the presence of hepatocellular carcinoma. We determined fasting glucose levels in all patients. If there was a history of DM or if the patients presented hyperglycemia, glycosylated hemoglobin levels were measured at initiation, EOT, and SVR. Furthermore, when applicable, the same evaluation was performed at one year follow-up.

Overall, patients with impaired glucose metabolism were classified as having: glucose intolerance, type 2 DM with oral antidiabetic medication (OAD), and insulin-requiring type 2DM. Oral anti-hyperglycemic medication, insulin dosages, and all other concomitant medication were adjusted at the initiation of antiviral therapy in order to avoid possible drug-to-drug interactions and continued after the completion of antiviral treatment.

Statistical analysis was performed using statistical software SPSS 18.0 (SPSS Inc., Chicago, IL, USA). The primary endpoints of the study were the evaluation of fasting glucose levels and glycosylated hemoglobin levels after antiviral treatment. Numerical variables were expressed as mean±standard deviation and ANOVA test was used to compare them between groups. p-Values less than 0.05 were considered statistically significant.

Results and Discussion

A total of 806 patients fulfilled the inclusion criteria. Baseline characteristics are presented in Table I, with p-values evaluating the comparison between patients with normal and impaired glucose metabolism. Data revealed that patients with impaired glucose metabolism were predominantly male and of older age than patients with normal glucose tolerance. Prediabetes was found to be up to four times more frequent in HCV patients than in the general population (19); predisposing factors for prediabetes in HCV patients were older age and higher alanine transaminase (ALT) levels (20). In contrast, diabetes and insulin-resistance were associated with non-alcoholic steatohepatitis, which in turn may lead to an increase in liver enzymes as markers of hepatic inflammation, further increasing Fibromax and Fibroscan scores (21). Noticeably, in our cohort, patients with altered glucose tolerance or DM had higher levels of transaminases than those with normal glucose metabolism. There were no significant differences in the study groups regarding serum albumin and total bilirubin. This may be explained by the fact that our cohort included only patients with chronic hepatitis and compensated cirrhosis, as indicated in the treatment protocol for OBV/PTV/r + DSV. However, significant increases in gamma-glutamyl transferase (GGT) and alkaline phosphatase (AlkP) were noticed in the patients with altered glucose metabolism.

Table I. Baseline characteristics of the study cohort, depending on glucose metabolism alterations.

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; TB: total bilirubin; AlkP: alkaline phosphatase; AFP: alpha-fetoprotein; HbA1c: hemoglobin A1c; DM: diabetes mellitus.

Proteinuria and higher creatinine levels were found in patients with impaired glucose metabolism, most likely associated with diabetic nephropathy. A further in-depth analysis revealed that patients with known diabetes mellitus had a mean duration of disease of 12.2±10.8 years, thus explaining the presence of nephropathy and chronic kidney disease.

While the predominant degree of fibrosis was F4 in all study groups (50.78% in the normal glucose tolerance group and 66.66% in the altered glucose tolerance group) the statistical analysis revealed that patients with prediabetes or diabetes are more likely to associate with advanced liver disease. It has been demonstrated that insulin resistance correlates with the degree of liver fibrosis and portal inflammation and it also represents a risk factor for the development of hepatocellular carcinoma (22). Systemic inflammation associated with diabetes (23) may represent an underlying condition for the accelerated fibrosis in these patients.

SVR rates were consistent with those reported in current literature. Overall, we found a 98.01% rate of SVR, with a non-significant difference between patients with normal and abnormal glucose metabolism (98.63% versus 96.93%). There was a statistically significant difference in SVR rates in patients with low degrees of fibrosis (F0-F2) versus those with advanced degrees of fibrosis (F3-F4) in both groups (99.02% versus 98.53% in patients with normal glucose metabolism p=0.04, and 97.82% versus 96.77% in patients with altered glucose metabolism, p=0.04). Also, response rates between the two groups were significantly different in correlation with the degree of fibrosis, with lower rates in patients with impaired glucose metabolism. The difference in SVR rates in patients with hepatitis versus cirrhosis is well-known. A recent real-life analysis found SVR rates of 98.8% in non-cirrhotic patients versus 96.4% in cirrhotic patients (24). We have previously reported an SVR rate of 99.82% in a smaller group of patients (17). A retrospective analysis on more than 1,000 patients reported that SVR rates after all oral antiviral therapies vary with age, degree of fibrosis, and HCV genotype (25). No correlation was found between SVR rates and the presence of metabolic syndrome, its components (obesity, arterial hypertension, dyslipidemia, and type 2 DM) or body mass index. In contrast, a recent review (26) found a significant correlation between insulin resistance and progression of liver fibrosis which, as we have mentioned, has a strong impact on the virologic response. Furthermore, no correlation with the HCV genotype was found. Virologic response rates to interferon-based therapies were associated with the presence of abnormalities in glucose metabolism. Another review (27) found that, unlike in interferon-based therapies, response rates to direct acting antiviral therapies are not influenced by the presence of glucose abnormalities. In our study, we found similar virologic response rates in patients with and without glucose metabolism impairment, but differences between patients with low and high degrees of fibrosis.

The impact of SVR in diabetic and pre-diabetic patients is one of the most debated current issues. Data from our study showed that achieving SVR correlates with lover levels of fasting glucose and lower HbA1c levels, even up to one year after completion of treatment (Table II). Antiviral treatment in diabetic and prediabetic patients resulted in significant decreases in fasting glucose levels and glycosylated hemoglobin levels in all patients with impaired glucose metabolism at SVR. Patients with diabetes, either undergoing oral or insulin-based therapies also had better glycemic control at one year follow-up.

Table II. Impact of SVR on glycemic control.

*p-value>0.05; **0.01<p-value<0.05; ***p-value<0.01. HbA1c: Hemoglobin A1c; SVR: sustained virologic response; DM: diabetes mellitus; OAD: oral antidiabetic drugs.

The results of this study are consistent with literature data. A post-hoc analysis of phase 3 clinical trials (TOPAZ trials) on the effects on OBV/PTV/r + DSV on extrahepatic manifestations of HVC infection revealed that one year after treatment, completion serum glucose levels decreased by over 20% (on average by 4.3 mg/dl in patients with pre-diabetes and 34.2 mg/dl in patient with diabetes) (28). The reduction in glucose levels became obvious during the course of antiviral treatment and persisted at follow-up. The authors clearly indicated the limitations of their study as part of a retrospective analysis on clinical trials, including carefully selected patients, with results that may differ from real-life experience.

A large cohort study based on national electronic databases, comprising over 24,000 patients, found that eradication of HCV infection by using direct-acting antiviral agents is associated with better glycemic control in diabetic patients, demonstrated by a reduction in HbA1c levels and insulin doses (29). Antiviral treatment options in these patients included sofosbuvir/ledipasvir, sofosbuvir/ simeprevir and OBV/PTV/r + DSV. The analysis only considered the presence or absence of SVR in diabetic patients (2,435 patients), without comparison to patients with normal glucose metabolism. Besides demographic and laboratory data, the authors also evaluated changes in anti-diabetic medications before and after therapy. The decrease in HbA1c levels was significant in patients with SVR, particularly in patients with high baseline HbA1c. Furthermore, a decrease in the number of patients requiring insulin-therapy was noticed in patients with virologic response. Interestingly, the authors noted a weight increase in patients with SVR. Beside the possible positive effects of diabetes control on microvascular complications (nephropathy, neuropathy, retinopathy), HCV eradication may also positively influence cardiovascular risk by decreasing the pro-inflammatory status associated with the infection (30). However, HCV cure can result in increases in serum total cholesterol and LDL-cholesterol levels which may balance negatively the impact on atherosclerosis (31).

Several studies have evaluated the possibility of reduced risk of developing DM after HCV cure. A retrospective study on 2,800 patients monitored for a mean duration of 6.4 years found that risk factors for DM were older age, failure to obtain SVR, and advanced liver disease (32). New antidiabetic drugs with positive effects on liver steatosis and inflammation, such as inhibitors of sodium-glucose transporter 2 may have a beneficial impact on hepatic primary outcome in patients with chronic liver disease and DM (19). The majority of studies observed that the decrease in glycaemia and HbA1c levels is more noticeable in patients with type 2 DM as compared to those with pre-diabetes. One analysis of direct acting antiviral trials observed a rapid drop in glucose levels in patients with DM, a significant drop in patients with pre-diabetes, and a non-significant increase in glycaemia in patients with normal glucose metabolism (33).

Genotype 1 is the most studied in association with DM (19). In our country, the prevalence of genotype1b is 99.99% (17), therefore our analysis was based on these patients; the first approved antiviral treatment was OBV/PTV/r + DSV. However, many trials report similar results in patients with other genotypes or treatment regimens; the most studied therapeutic regimens are those based on sofosbuvir, as this molecule has a pan-genotypic antiviral action.

Very high rates of glycaemia and HbA1c level reduction have been reported in multicenter trials. For example, an Italian study found a decrease in glucose levels in 67% of patients and in HbA1 levels in 80% of patients (34). Prognostic factors associated with this decrease were identified: duration of DM under 7 years, negative family history for DM, and Child class A cirrhosis.

This dramatic reduction in glucose levels may lead to severe complications in diabetic patients such as hypoglycemia, especially in patients with impaired gluconeogenesis associated with advanced liver disease. It is estimated that up to 40% of patients treated with oral antidiabetics and even more patients treated with insulin regimens require dose reduction. One case report presented discontinuation of basal insulin at week 3 of treatment and ultimately discontinuation of bolus insulin during antiviral therapy in a patient undergoing treatment with sofosbuvir/ledispavir (34). In contrast, we have previously reported a case of new-onset diabetes with severe hyperglycemia during antiviral treatment with OBV/PTV/r + DSV in a kidney transplant recipient undergoing immuno-suppressive therapy with tacrolimus (15).

Conclusion

All oral antiviral therapies in chronic HCV infection have proven safe and effective in real life and clinical trials. Current research is based on evaluating the impact of these trials on the systemic complication of HCV infection. Recent trials suggest possible outcomes for diabetic patients in the setting of direct acting antiviral treatments. The conclusion of our real-life study is that patients with pre-diabetes as well as diabetic patients, achieve a better glycemic control after SVR obtained by OBV/PTV/r + DSV.

Conflicts of Interest

The Authors declare that they have no competing interests in relation to this study.

Authors’ Contributions

LT and AZ were responsible writing of the manuscript. XB and AMS were responsible for reviewing and editing of the manuscript. CPI, NB, RVT and CD made substantial contributions to the conception or design of the work. LI were responsible for the critically reviewed the manuscript. All Authors read and approved the final manuscript.