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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 4  |  Page : 1298-1304

Effect of diabetes mellitus on direct-acting antiviral drugs in chronic hepatitis C-infected patients


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Hepatology and Tropical Medicine, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt

Date of Submission06-Sep-2020
Date of Decision02-Dec-2020
Date of Acceptance17-Dec-2020
Date of Web Publication24-Dec-2021

Correspondence Address:
Mohammad S Abd Allah
MBBCh, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_296_20

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  Abstract 


Objective
To evaluate the role of direct-acting antiviral (DAA) agents used for treatment of hepatitis C virus (HCV) in diabetic Egyptian patients.
Background
There was a revolutionary reduction HCV epidemic in Egypt. Combinations of DAAs were reported to show high rates of sustained virological response (SVR) and pan-genotypic clinical efficacy in HCV genotypes.
Patients and methods
A prospective study was conducted on 200 consecutive patients with chronic HCV infection (100 diabetic and 100 nondiabetic) who attended the outpatient clinics of National Hepatology and Tropical Medicine Research Institute and received sofosbuvir plus daclatasvir with ribavirin for 12 and 24 weeks according to HCV treatment protocol issued by the National Committee for Control of Viral Hepatitis. All investigations were done before and after treatment.
Results
There was no significant difference between both groups regarding rapid virological response (P = 0.226) and SVR (P = 0.106). Overall, 24% of patients developed adverse effects during treatment and 76 (76%) patients were free in the diabetic group, whereas in the nondiabetic group, only eight patients developed adverse effects during treatment and 92 (92%) patients were free. So, the diabetic group had significantly higher adverse effects than the nondiabetic group (P = 0.005).
Conclusion
There was no significant difference between both groups regarding rapid virological response and SVR. Improvement of glycemic control with DAAs was seen more in younger patients without family history of type 2 diabetes mellitus and short duration of diabetes mellitus. DAAs have proven to be safe and effective. DAAs are well suited for nearly all infected patients, and many countries worldwide have taken on initial treatment scale-up strategies.

Keywords: direct-acting antiviral drugs, diabetes mellitus, Egyptian patients, hepatitis C virus


How to cite this article:
Dala AG, Saif SM, Abd Allah MS, Ezz EAA. Effect of diabetes mellitus on direct-acting antiviral drugs in chronic hepatitis C-infected patients. Menoufia Med J 2021;34:1298-304

How to cite this URL:
Dala AG, Saif SM, Abd Allah MS, Ezz EAA. Effect of diabetes mellitus on direct-acting antiviral drugs in chronic hepatitis C-infected patients. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:1298-304. Available from: http://www.mmj.eg.net/text.asp?2021/34/4/1298/333234




  Introduction Top


Chronic hepatitis C virus (HCV) infection is a major health-related burden in Egypt [1]. In Egypt, HCV prevalence rates reach 13% of the population, equating to an estimated 12 million Egyptians, of whom approximately eight million people are living with chronic hepatitis C without or with cirrhosis or liver cancer [2]. Chronic infection with HCV is the leading cause of end-stage liver disease, hepatocellular carcinoma, and liver-related death in Egypt [3]. However, with a recent introduction of genotype-4-effective direct-acting antivirals (DAA) in Egypt, there was has been a revolutionary reduction of HCV epidemic in Egypt; DAA combinations were reported to show high rates of sustained virological response (SVR) and pan-genotypic clinical efficacy in HCV genotypes 1–6 [4].

On the contrary, the current body of evidence shows higher prevalence of type 2 diabetes mellitus (T2DM) among patients with chronic HCV infection. It was proposed that HCV proteins increase serine and threonine phosphorylation of insulin receptor substrate-1, which contributes to insulin resistance. In addition, HCV proteins increase the release of proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, which then upregulate gluconeogenesis and enhance lipid accumulation in the liver [5].

Therefore, it is presumed that effective HCV management would result in improved glycemic control in diabetic patients. Recently, a growing body of evidence has shown a promising role of effective HCV eradication on glycemic control of diabetic patients; previous reports showed that the change in hemoglobin A1C was greater in those who achieved SVR (0.98%) with DAAs than in those who sustained treatment failure [6].

DAAs have shown superior safety and efficacy compared with interferon-based regimens (>95 vs. 40% cure rates, respectively), and revolutionized HCV treatment paradigms toward broader access to cure. The 69th World Health Assembly endorsed the global health sector strategy to eliminate HCV infection by 2030, which can become a reality with expanded use of DAAs. Here, authors described the current prospects of HCV eradication in the DAA era and ongoing challenges to achieve elimination goals [7]. Thus, the aim of this study was to evaluate the role of DAA used for treatment of HCV in diabetic Egyptian patients.


  Patients and methods Top


A prospective study was conducted on 200 consecutive patients with chronic HCV infection. The patients were visiting the outpatient clinics of National Hepatology and Tropical Medicine Research Institute and were recruited after obtaining their informed consent to receive sofosbuvir plus daclatasvir and ribavirin for 12 and 24 weeks according to HCV treatment protocol: oral sofosbuvir (400 mg once daily), oral daclatasvir (60 mg once daily), and weight-based oral ribavirin (1200 or 1000 mg/day if ≥75 or <75 kg body weight), correspondingly. Inclusion criteria were adult patient more than 18 years old and positive serology for HCV antibody by enzyme-linked immunosorbent assay and HCV viremia by PCR. Exclusion criteria were patients younger than 18 years or older than 75 years; pregnant or lactating women; history of hepatocellular carcinoma or other malignancies; current or past evidence of Child–Turcotte–Pugh score more than 8; hepatic encephalopathy or ascites; comorbid conditions such as poorly controlled diabetes, uncontrolled hypertension, or cardiovascular disease; history of solid organ transplantation; chronic use of systematically immunosuppressive agent; hypersensitivity to the recommended therapy; patients with any of the following laboratory abnormalities: serum bilirubin more than 3 mg/dl, serum albumin less than 2.8 g/dl, international normalized ratio more than or equal to 1.7, and platelet count less than 50 000/mm3; other cases of liver disease other than HCV such as coinfection with hepatitis B virus (HBV) or HIV; alcoholic or autoimmune disease; and serum creatinine more than 2.5 mg/dl [if creatinine was between 1.5 and 2.5 mg/dl, estimated glomerular filtration rate (eGFR) had been calculated and only patients with eGFR more than 30 ml/min were included]. Regarding ethical consideration, all the included patients signed consent after the agreement from Ethics Committee in Menoufia University and National Hepatology and Tropical Institute in Cairo before start of any study-related procedures. Patients who fulfilled the inclusion and exclusion criteria received sofosbuvir plus daclatasvir for 12 or 24 weeks and sofosbuvir plus daclatasvir with ribavirin for 12 weeks: oral sofosbuvir (400 mg once daily), oral daclatasvir (60 mg once daily), and weight-based oral ribavirin (1200 or 1000 mg/day if ≥75 or <75 kg body weight), correspondingly. Special criteria of the group of patients who received ribavirin were as follows: total serum bilirubin more than or equal to 1.2 mg/dl, serum albumin less than or equal to 3.5 g/dl, international normalized ratio more than or equal to 1.2, and platelet count less than or equal to 150 000/mm3.

All patients were classified into two groups: diabetic group included 100 diabetic patients with chronic hepatitis C infection and nondiabetic group included 100 nondiabetic patients with chronic hepatitis C infection. Before treatment, all patients were subjected to full history taking; complete physical examination; laboratory investigations, including complete blood picture, serum creatinine, liver function tests [albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin], alpha-fetoprotein, anti-HCV antibodies by enzyme-linked immunosorbent assay, quantitative HCV-RNA by PCR (by Taqman method, Q1A amp viral RNA, Mini Kit 50, Cat No 52904; Beckman Coulter, Beckman Coulter Life Sciences Headquarters, 5350 Lakeview Pkwy S Drive, Indianapolis, Indiana 46268, United States), hepatitis B surface antigen, and hemoglobin A1C; pelvi-abdominal ultrasound; ECG, echocardiograph for old age (>65 years); and liver stiffness measurement using the transient elastography. It was performed using the Fibroscan device (Echosens Version 13, 05/2009; software version 1.40). During treatment, the following were assessed: complete blood count, liver profile, creatinine after 4 weeks following treatment, and quantitative PCR for HCV-RNA after 4 weeks following treatment to confirm rapid virological response (RVR). After the treatment, the following were assessed: complete blood count, liver profile and creatinine at the end of treatment, and quantitative PCR for HCV-RNA after 12 weeks following treatment to confirm SVR. Patients were coded by a code number to maintain privacy of participants and confidentiality of the data. The results were used for research purpose only. The end point of the research was the investigations done 3 months after treatment. There were no risks on the participants as all procedures done were noninvasive.

Definitions of response are as follows: RVR is defined by HCV-RNA less than the lower limit of quantification 4 weeks after initiation of treatment, and SVR is defined HCV RNA less than the lower limit of quantification 12 weeks after the end of treatment.

Statistical analysis

Data entry, coding, and analysis were conducted using Statistical Package for the Social Sciences (Released 2017, IBM SPSS Statistics for Windows, version 25.0; IBM Corp., Armonk, New York, USA). Description of quantitative variables was in the form of mean and SD, and description of qualitative variables was by frequency and percentage. χ2 test, Mann–Whitney test, and Fisher exact test were used. P value less than or equal to 0.05 was set to be statistically significant [8],[9].


  Results Top


In the current study, the mean age of the studied group was 55.27 ± 7.9 years in the diabetic group and 49.28 ± 10.55 years in the nondiabetic group. They were 77 male and 23 females in the diabetic group and 64 male and 36 females in the nondiabetic group (P = 0.067). Moreover, 66 patients received sofosbuvir plus daclatasvir with ribavirin for 12 weeks in the diabetic group and 47 patients in nondiabetic group (P < 0.001). In addition, ALT and AST levels were significantly increased in diabetic group (71.70 ± 43.90 and 66.08 ± 42.86 U/l, respectively) than nondiabetic group (56.45 ± 44.5 and 54.88 ± 42.1 U/l, respectively) at baseline as well as at 4 weeks after treatment (33.82 ± 33.25 and 28.80 ± 13.24 U/l, respectively, in diabetic group and 25.29 ± 15.48 and 22.00 ± 11.13 U/l, respectively, nondiabetic group) [Table 1]. However, at week 4 of treatment, mean of hemoglobin (Hb) and white blood cells (WBCs) were significantly lower in diabetic group (12.36 ± 1.78 g/dl and 5.75 ± 1.96 c/mm3, respectively) than nondiabetic group (13.44 ± 1.69 g/dl and 6.37 ± 1.98 c/mm3, respectively). The mean serum creatinine level after 4 weeks of treatment was significantly increased in diabetic group (0.95 ± 0.21 mg/dl) than nondiabetic group (0.87 ± 0.19 mg/dl) (P = 0.004). Moreover, there were no statistically significant differences between the studied groups regarding platelets and liver functions at baseline and after 4 weeks of treatment [Table 2]. In addition, mean Hb, WBCs, and platelet were significantly lower in diabetic group (12.79 ± 1.83 g/dl, 5.55 ± 2.04 c/mm3, and 155.36 ± 61.18 c/mm3, respectively) than nondiabetic group (13.82 ± 1.33 g/dl, 6.38 ± 2.02 c/mm3 and 168.90 ± 56.65 c/mm3, respectively) at the end of treatment. Additionally, there were no statistically significant differences between the studied groups regarding liver functions and serum creatinine at the end of treatment [Table 3]. In the present study, there was no significant difference between both groups regarding RVR (P = 0.226) and SVR (P = 0.106). However, 24% of patients developed adverse effects during treatment in diabetic group, whereas only 8% of patients developed adverse effects during treatment in nondiabetic group [Table 4].
Table 1: Statistical comparison between the studied groups regarding baseline demographic, complete blood count, liver functions, and serum creatinine at baseline

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Table 2: Statistical comparison between the studied groups regarding complete blood count, liver functions, and serum creatinine at week 4

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Table 3: Statistical comparison between the studied groups regarding complete blood count, liver functions, and serum creatinine at the end of treatment

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Table 4: Statistical comparison between the studied groups regarding response to direct-acting antivirals and adverse effects to direct-acting antivirals

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  Discussion Top


In the current study, the age of the studied group was highly significant higher in diabetic group than nondiabetic group. They were 77 male and 23 females in the diabetic group and 64 male and 36 females in the nondiabetic group, with no significant difference. These agree with Niu et al. [10], who reported the highest prevalence of chronic HCV infection was at the age group 50–59 years, and the lowest prevalence was at age group of 0–9 years. Similarly, Miller et al.[11] reported that anti-HCV antibodies prevalence among Egyptian population increased with age to reach its highest prevalence at 50 years. Moreover, Elhawary et al.[12] showed that Egyptian patients with diabetes and chronic HCV infection were generally older. These findings support the idea that the induction of diabetes in HCV patients is progressive rather than abrupt, as reported by Chehadeh et al. [13]. Other studies suggest that HCV interferes with glucose metabolism independently of age, as reported by Kaabia et al. [14]. This observation was in disagreement with the study by Hashim et al. [15], which found that females had higher prevalence (52%) than males (48%). Our finding may be explained by that obesity is the major risk factor of T2DM in both sexes, but obesity is more common in women than men.

In the present study, mean Hb, WBCs and platelet were significantly lower in diabetic than nondiabetic groups at the end of treatment. Moreover, Sahin et al.[16] reported that chronic HCV infection is significantly associated with increased levels of Hb and hematocrit levels with poor clinical outcomes. Several hypotheses have been proposed to explain the pathogenesis including secretion of erythropoietin from regenerating liver cells, induced endogenous thrombopoietin secretion, and altered iron metabolism. On the contrary, Harrison[17] reported that DAA were found to be associated with high risk of anemia. Hb values less than 10 g/dl were found to occur in approximately 36% of patients receiving telaprevir-based triple therapy. Chen et al.[18] found that the Hb and hematocrit of patients with HCV were 10.5 1.6 g/dl and 31.6 4.7%, respectively, which were significantly higher than the 9.9 ± 1.4 g/dl and 29.7 ± 4% of patients with non-HBV/HCV infection.

In the present study, ALT and AST levels were significantly increased in diabetic group than nondiabetic group at baseline than nondiabetic group after 4 weeks of treatment. These agree with Hashim et al. [15], who found no significant improvement of ALT and AST during and after treatment, whereas there was a significant progressive increase of platelets. Normalization of alanine aminotransferase predicts successful antiviral treatment in patients with chronic hepatitis C, which showed a strong association between normal ALT values and SVR (70.6 vs. 72.6%, respectively), which was confirmed by George et al. [19]. Moreover, Kassem et al. [20], found that there were no statistically significant differences between the studied groups before initiation of therapy regarding laboratory investigations such as total bilirubin (mg/dl), WBCs (×103/μl), Hb (g), and platelets (×103/μl) and after 12 weeks of treatment.

In our results, mean serum creatinine level at 4 weeks of treatment was significantly increased in diabetic group than in nondiabetic group. Chen et al.[18] found that HCV infection was also associated with higher levels of AST and ALT as compared with negative for HCV. However, patients with HCV infection had lower platelet count than those with non-HBV/HCV. This agrees with Mada et al. [21], who found no difference in serum creatinine and eGFR levels at the beginning.

In addition, our results showed that there was no significant difference between both groups regarding RVR. These agree with Hum et al. [6], who found the rate of SVR among diabetic patients was 98%. Moreover, Dawood et al.[22] reported that chronic HCV infection is significantly associated with increased Hb and hematocrit levels with poor clinical outcomes. Several hypotheses have been proposed to explain the pathogenesis including secretion of erythropoietin from regenerating liver cells, induced endogenous thrombopoietin secretion, and altered iron metabolism. However, DAAs were associated with high risk of anemia. Hb values less than 10 g/dl occurred in ~36% of patients receiving telaprevir-based triple therapy, as reported by Harrison [17].

In the present study, diabetic group had significantly higher adverse effects than nondiabetic group. Similarly, Mada et al.[21] found that all patients completed antiviral therapy and subsequent follow-up (drop-out rate, 0%). Adverse events were recorded in a subset of patients; 58 individuals had at least one adverse event (AE). Most AEs were mild and were managed clinically without discontinuation of therapy. The most common AEs were fatigue, anemia, and headache. Severe anemia requiring reduction or discontinuation of ribavirin occurred in some cases. However, Franco et al.[23] reported that DAAs have shown superior safety and efficacy compared with interferon-based regimens (>95 vs. 40% cure rates, respectively) and revolutionized HCV treatment paradigms toward broader access to cure. Other studies suggest that successful treatment of chronic HCV infection with currently available DAA agents improves glycemic control in these diabetics [6],[24],[25],[26].


  Conclusion Top


There was no significant difference between both groups regarding RVR and SVR. Improvement of glycemic control with DAAs is seen more in younger patients without family history of T2DM and short duration of diabetes mellitus. DAAs have proven to be safe and effective. DAAs are well suited for nearly all infected patients, and many countries worldwide have taken on initial treatment scale-up strategies. These unprecedented efforts, albeit significant, face extraordinary challenges related to the high infection burden, stigma, and financial constraints.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Elgharably A, Gomaa AI, Crossey MM, Norsworthy PJ, Waked I, Taylor-Robinson SD. Hepatitis C in Egypt – past, present, and future. Int J Gen Med 2017; 10:1.  Back to cited text no. 1
    
2.
Kamal SM, Abdelhakam SA. Hepatitis C in Egypt. In hepatitis C in developing countries. London: Academic Press; 2018. 41–56.  Back to cited text no. 2
    
3.
Elghoroury EA, Maksoud SA, Kandil D, El Kafoury MR, Hassan EM, Awadallah E, et al. Expression of microRNAs-21 and-223 in hepatocellular carcinoma in hepatitis C virus infected Egyptian population. J Appl Pharma Sci 2017; 7:052–057.  Back to cited text no. 3
    
4.
Pawlotsky JM. Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens. Gastroenterology 2016; 151:70–86.  Back to cited text no. 4
    
5.
Parvaiz F, Manzoor S, Iqbal J, Sarkar-Dutta M, Imran M, Waris G. Hepatitis C virus NS5A promotes insulin resistance through IRS-1 serine phosphorylation and increased gluconeogenesis. World J Gastroenterol 2015; 21:12361.  Back to cited text no. 5
    
6.
Hum J, Jou JH, Green PK, Berry K, Lundblad J, Hettinger BD, et al. Improvement in glycemic control of type 2 diabetes after successful treatment of hepatitis C virus. Diabetes Care 2017; 40:1173–1180.  Back to cited text no. 6
    
7.
Weidner P, Boettche D, Zimmerer T, Burgermeister E, Teufel A, Ebert M, et al. Impact of direct acting antiviral (DAA) treatment on glucose metabolism and reduction of pre-diabetes in patients with chronic hepatitis C. J Gastrointestin Liver Dis 2018; 27:281–289.  Back to cited text no. 7
    
8.
Chan YH. Biostatistics 102: quantitative data parametric and non-parametric tests. Blood Press 2003; 140:79–83.  Back to cited text no. 8
    
9.
Chan YH. Biostatistics 103: qualitative data tests of independence. Singapore Med J 2003; 44:498–503.  Back to cited text no. 9
    
10.
Niu X, Fu N, Du J, Wang R, Wang Y, Zhao S, et al. Mir-1273g-3p modulates activation and apoptosis of hepatic stellate cells by directly targeting PTEN in HCV-related liver fibrosis. FEBS Lett 2016; 590:2709–2724.  Back to cited text no. 10
    
11.
Miller FD, Elzalabany MS, Hassani S, Cuadros DF. Epidemiology of hepatitis C virus exposure in Egypt: opportunities for prevention and evaluation. World J Hepatol 2015; 7:2849.  Back to cited text no. 11
    
12.
Elhawary EI, Mahmoud GF, El-Daly MA, Mekky FA, Esmat GG, Abdel-Hamid M. Association of HCV with diabetes mellitus. Virol J 2011; 8:367.  Back to cited text no. 12
    
13.
Chehadeh W, Abdella N, Ben-Nakhi A, Al-Arouj M, Al-Nakib W. Risk factors for the development of diabetes mellitus in chronic hepatitis C virus genotype 4 infection. J Gastroenterol Hepatol 2009; 24:42–48.  Back to cited text no. 13
    
14.
Kaabia N, Jazia EB, Slim I, Fodha I, Hachfi W, Gaha R, et al. association of hepatitis C virus infection and diabetes in central Tunisia. World J Gastroenterol 2009; 15:2778.  Back to cited text no. 14
    
15.
Hashim A, O'Sullivan M, Williams H, Verma S. Developing a community HCV service: project ITTREAT service for people who inject drugs. Prim Health Care Res Dev 2018; 19:110–120.  Back to cited text no. 15
    
16.
Sahin I, Arabaci F, Sahin HA, Ilhan M, Ustun Y, Mercan R, et al. Does hepatitis C virus infection increase hematocrit and hemoglobin levels in hemodialyzed patients? Clin Nephrol 2003; 60:401–404.  Back to cited text no. 16
    
17.
Harrison SA. Management of anemia in patients receiving protease inhibitors. Gastroenterol Hepatol 2012; 8:254.  Back to cited text no. 17
    
18.
Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 2008; 135:111–121.  Back to cited text no. 18
    
19.
George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology 2009; 49:729–738.  Back to cited text no. 19
    
20.
Kassem A, Mahmoud Aboelenin M, Abdelhamid Khedr M. Outcome of eradication of chronic hepatitis C virus infection with direct acting antiviral agents on blood sugar control and insulin resistance in patients with type 2 diabetes mellitus. Al-Azhar Med J 2018; 47:241–256.  Back to cited text no. 20
    
21.
Mada PK, Malus ME, Parvathaneni A, Chen B, Castano G, Adley S, et al. Impact of treatment with direct acting antiviral drugs on glycemic control in patients with hepatitis C and diabetes mellitus. Int J Hepatol 2020; 3:20–24.  Back to cited text no. 21
    
22.
Dawood AA, Nooh MZ, Elgamal AA. Factors associated with improved glycemic control by direct-acting antiviral agent treatment in Egyptian Type 2 diabetes mellitus patients with chronic hepatitis C Genotype 4. Diabetes Metab J 2017; 41:316–321.  Back to cited text no. 22
    
23.
Franco RA, Galbraith JW, Overton ET, Saag MS. Direct-acting antivirals and chronic hepatitis C: towards elimination. Hepatoma Res 2018; 6:11.  Back to cited text no. 23
    
24.
Ciancio A, Bosio R, Bo S, Pellegrini M, Sacco M, Vogliotti E, et al. Significant improvement of glycemic control in diabetic patients with HCV infection responding to direct-acting antiviral agents. J Med Virol 2018; 90:320–327.  Back to cited text no. 24
    
25.
Drazilova S, Janicko M, Skladany L, Kristian P, Oltman M, Szantova M, et al. Glucose metabolism changes in patients with chronic hepatitis C treated with direct acting antivirals. Can J Gastroenterol Hepatol 2018; 2:68.  Back to cited text no. 25
    
26.
Pavone P, Tieghi T, d'Ettorre G, Lichtner M, Marocco R, Mezzaroma I, et al. Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents. Clin Microbiol Infect 2016; 22:462–467.  Back to cited text no. 26
    



 
 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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