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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 31  |  Issue : 3  |  Page : 916-921

Glycemic control in type 2 diabetes mellitus and new hepatitis C virus genotype 4 therapy


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Ministry of Health, Cairo, Egypt

Date of Submission30-Jan-2017
Date of Acceptance24-Apr-2017
Date of Web Publication31-Dec-2018

Correspondence Address:
Raghda S El Meligy Matared
Shebin El-Kom 32511, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_104_17

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  Abstract 


Objective
The aim of this study was to evaluate the effect of glycemic control on the response to new therapy for hepatitis C virus infection (HCV) and the impact of the new HCV therapy on glycemic control in type 2 diabetes mellitus (T2DM) patients.
Background
HCV genotype 4 is prevalent in the Middle East, in Egypt, and in Central Africa. It is associated with an increased risk for T2DM as it causes insulin resistance. Direct pancreatic β-cell destruction, autoimmune injury, and other mechanisms associated with HCV are not entirely clear. HCV genotype 4 patients can be treated with interferon-free direct antiviral agents such as sofosbuvir (400 mg) and daclatasvir (60 mg) given daily for 12 weeks with or without ribavirin.
Patients and methods
Our study included 359 HCV patients who were divided into nondiabetic patients, controlled diabetic patients, and uncontrolled diabetic patients. These patients received anti-HCV treatment in Shebin El-Kom Teaching Hospital. They underwent tests for evaluation of glycated hemoglobin, HCV PCR, random blood sugar, liver function, creatinine levels, complete blood count, α-fetoprotein levels, and thyroid-stimulating hormone levels and an abdominal ultrasound.
Results
There was a highly significant response to HCV treatment in the nondiabetic group and a highly significant relapse in the uncontrolled diabetic group. There was also a highly significant decline in glycated hemoglobin levels at the end of treatment in both controlled and uncontrolled diabetic patients.
Conclusion
The successful treatment of HCV using new interferon-free direct antiviral agents has a significant beneficial effect on glycemic control in T2DM patients and also on thyroid-stimulating hormone levels.

Keywords: direct antiviral agents, genotype 4, hepatitis C virus, type 2 diabetes mellitus


How to cite this article:
El Kafrawy NA, Dawood AA, Nouh MZ, El Meligy Matared RS. Glycemic control in type 2 diabetes mellitus and new hepatitis C virus genotype 4 therapy. Menoufia Med J 2018;31:916-21

How to cite this URL:
El Kafrawy NA, Dawood AA, Nouh MZ, El Meligy Matared RS. Glycemic control in type 2 diabetes mellitus and new hepatitis C virus genotype 4 therapy. Menoufia Med J [serial online] 2018 [cited 2019 Mar 20];31:916-21. Available from: http://www.mmj.eg.net/text.asp?2018/31/3/916/248713




  Introduction Top


Chronic hepatitis C virus (HCV) infection is a global problem, in terms of both medical and socioeconomical aspects, as around 200 million people are infected with it worldwide[1].

There are 6 and 11 distinct HCV genotypes; genotype 4 occurs in the Middle East, Egypt, and Central Africa[2].

It was suggested that HCV infection is associated with an increased risk for type 2 diabetes mellitus (T2DM) as it causes insulin resistance (IR)[1].

Chronic HCV patients are three times more likely to develop T2DM than are HCV seronegative patients[3].

HCV-related IR/diabetes mellitus (DM) may include direct pancreatic β-cell destruction, autoimmune β-cell injury, and other mechanisms that are not entirely clear[4].

HCV genotype 4 patients can be treated with an Interferon-free combination of daily sofosbuvir (400 mg) and daily daclatasvir (60 mg) for 12 weeks with or without ribavirin[5].

This study proposed to examine the effect of the new therapy for HCV infection on glycemic control in T2DM patients infected with HCV.


  Patients and Methods Top


This study was carried out at Shebin El-Kom Teaching Hospital. A total of 359 HCV patients, aged from 18 to 75 years, were included in our study. They received sofosbuvir/daclatasvir ± ribavirin for 12 weeks. The patients were divided into three groups: group 1 included 126 nondiabetic patients; group 2 included 118 controlled T2DM patients; and group 3 included 115 uncontrolled T2DM patients. Patients falling under the following criteria were excluded: pregnant or breastfeeding, having total bilirubin level more than 3 mg/dl, having serum albumin less than or equal to 2.5 mg/dl, having international randomized ratio more than or equal to 1.8, having platelets less than 50 000, being of Child score more than class B7, and having hepatitis with hepatocellular carcinoma (HCC).

All patients were subjected to thorough history taking and underwent tests for evaluation of random blood sugar, alkaline transferase, aspartate transferase, international randomized ratio, prothrombin time, serum creatinine, complete blood picture, α-fetoprotein, HCV antibody, and thyroid-stimulating hormone (TSH). Both glycated hemoglobin (HbA1C), which was measured using the stanbio glycohemoglobin procedure (no. 0350) (stanbio laboratory, Boerne, TX, USA), and HCV PCR were measured at baseline (just before starting HCV treatment), at 12 weeks from the start of treatment, and 12 weeks after treatment completion. Ultrasonography was also carried out before the start of therapy.

The protocol of this study was approved by the ethical committee of our institution and all subjects gave informed consent to participate in this study.

Statistical analysis

Data were analyzed using the program for social science (SPSS), version 20.0. Quantitative data were expressed as mean ± SD and qualitative data as frequency and percentage. The following statistical tests were used as appropriate: the χ2-test, analysis of variance, the Wilcoxon signed-rank test, and the paired sample t-test. Correlations between variables were determined using Spearman's rank correlation coefficient (r). P values of 0.05 were taken as being statistically significant and values of 0.001 were taken as being statistically highly significant.


  Results Top


In our study the male to female ratio was 44.6: 55.4 [Figure 1].
Figure 1: Comparison between the three studied groups regarding gender.

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The mean age of the 359 HCV patients included in our study was 51 ± 11 years [Figure 2]. With regard to baseline parameters there were highly significant differences between the three studied groups in first HbA1C and random blood sugar (P < 0.001). Likewise, there was a significant difference between the three studied groups in portal vein diameter (P = 0.014) [Table 1].
Table 1: Comparison between the three studied groups regarding laboratory parameters

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Figure 2: Comparison between the three studied groups regarding age.

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We found that both the controlled and the uncontrolled diabetic group had higher moderate viremia compared with the nondiabetic group and that the controlled diabetic group had higher moderate viremia compared with the uncontrolled group [Figure 3].
Figure 3: Comparison between the three studied groups regarding degree of viremia before therapy.

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There was a highly significant response to new direct antiviral agents (DAAs) in nondiabetic patients with 100% response, whereas uncontrolled diabetics had a higher relapse rate, at 9.6% (P < 0.001) [Figure 4] and [Figure 5]. There was a difference in response to treatment among the three groups after 3 months from the start of treatment, with the nondiabetic group showing the highest response, at 100%, which is highly significant, and the uncontrolled group showing the highest relapse rate, at 9.6% (11 of 115 patients), which is again highly significant. In addition, 98.3% of controlled diabetic patients responded to treatment after 3 months of therapy compared with 90.4% of uncontrolled diabetic patients. Of the total number of patients, 96.3% had responded to treatment by 3 months. Sustained virological response (SVR) (after 6 months) was seen in 98.8% of responders (342 of 346) after 3 months of treatment [Table 2].
Figure 4: Comparison between the three studied groups regarding percentage of relapses and responders after 3 months from the start of hepatitis C virus treatment.

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Figure 5: Comparison between the three studied groups regarding percentage of relapses and sustained virologic responses after 6 months from the start of hepatitis C virus treatment.

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Table 2: Comparison between the three studied groups regarding degree of viremia before therapy, and response to therapy 3 and 6 months from the start of treatment

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There was a highly significant decline in TSH level in the nondiabetic group and in the controlled diabetic group after 3 and 6 months from the start of treatment compared with pretherapy levels, with a highly significant decline after 6 months than after 3 months from the start of treatment within groups. There was a highly significant decline in TSH level on HCV treatment after 3 and 6 months compared with pretherapy levels in the uncontrolled diabetic group [Table 3].
Table 3: Comparison between the three studied groups regarding thyroid-stimulating hormone level before therapy and after 3 and 6 months from the start of treatment

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In the nondiabetic group there was a highly significant increase in HbA1C levels after 3 months of start of treatment compared with pretherapy levels, but a significant decline in HbA1C occurred after 6 months from the start of treatment. In the controlled diabetic group there was a highly significant decline in HbA1C levels after 6 months from the start of treatment compared with pretherapy levels, with a highly significant decline in HbA1C level after 6 months than after 3 months. In the uncontrolled diabetic group there was a highly significant decline in HbA1C level after 3 and 6 months from the start of treatment compared with pretherapy levels, with a highly significant decline after 6 months than after 3 months from the beginning of treatment [Table 4].
Table 4: Comparison between the three studied groups regarding glycated hemoglobin level before therapy and after 3 and 6 months from the start of treatment

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In all studied groups there was a highly significant decline in HCV PCR after 3 and 6 months of treatment compared with that before therapy (P < 0.001) [Table 5]. The SVR in the nondiabetic group was 98.4%, that in the controlled diabetic group after excluding two cases that did not respond was 98.3%, and that in the uncontrolled diabetic group after excluding 10 nonresponders was 100% [Table 2]. There was a highly positive correlation between the first PCR and the first TSH [Table 6]. There was a highly positive correlation between the second PCR and the second HbA1C levels (P < 0.001) [Figure 6] whereas there was no positive correlation between the second PCR and the second TSH.
Table 5: Comparison between the effects of therapy on hepatitis C virus PCR among the three studied groups

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Table 6: Correlation between first PCR and first glycated hemoglobin and first thyroid-stimulating hormone levels (pretherapy levels)

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Figure 6: Correlation between the second PCR and the second glycated hemoglobin (HbA1C) 3 months after therapy.

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  Discussion Top


Roughly, each year 150–170 million people are diagnosed with HCV infection, and an estimated 350 000 people/year suffer from complications due to HCV, including fatty liver cirrhosis, HCC, and liver failure[6].

T2DM has a higher incidence in HCV-infected patients[7]. The development of T2DM during chronic hepatitis C increases the risk for HCC even in patients without cirrhosis and even after the eradication of HCV infection. It also contributes to the impairment of the response to antiviral therapy. The etiology of T2DM in HCV-infected individuals has been considered to be either liver-related T2DM resulting from advanced liver disease or virally mediated IR[8].

We found that both diabetic groups have higher moderate viremia compared with the nondiabetic group and that the controlled diabetic group had higher moderate viremia than did the uncontrolled group [Figure 1]. These findings are in agreement with those of Huang et al.[9], who documented that high HCV viral load, in patients infected with genotype 1 or 2, has been reported to be linked with increased risk for diabetes.

The lowest response was in the uncontrolled group [Table 1]; a similar result was seen in the study of Romeo-Gomez et al.[10], who postulated that HCV-infected patients with IR and DM seemed to be poorer responders to an anti-HCV regimen (interferon).

The response rate in our study to new DAAs was between 100% in nondiabetic patients and 98.3% in controlled diabetic patients [Table 2]. Similar outcomes were reported by European Association for the Study of the Liver[5], who stated that overall SVR rates are equally higher and above 90% in elderly and cirrhotic patients than usually seen in randomized clinical tests. There was a highly significant decline in TSH level with HCV treatment after 3 and 6 months compared with pretherapy levels in the three studied groups [Table 4]. This established that new interferon-free DAA therapies have a beneficial effect on thyroid function tests.

There was a highly significant increase in HbA1C levels after 3 months compared with pretherapy levels [Table 5]. This could be due to the presence of three patients who developed new-onset diabetes with treatment with DAAs. These results are in agreement with those of Premji et al.[11], who reported adverse glycemic event in their case study, which had two patients who had new-onset DM related to the combination therapy of ledipasvir/sofosbuvir, either independently or in combination. This adverse effect is not mentioned in the current drug product information.

There was a significant decline in HbA1C levels in the nondiabetic group after 6 months compared with that after 3 months from the start of treatment [Table 5].

In the controlled diabetic group there was a highly significant decline in HbA1C level after 6 months from treatment compared with pretherapy levels and that after 3 months. There was a highly significant decline in HbA1C level after 6 months than after 3 months from the start of treatment.

In the uncontrolled diabetic group there was a highly significant decline in HbA1C level after 3 and 6 months compared with pretherapy levels, and a highly significant decline in HbA1C level after 6 months than after 3 months from the start of treatment.

This shows that successful eradication of HCV helps in control of T2DM, in agreement with the findings of Raymond et al.[12], who presented a case of poorly controlled insulin-dependent diabetes in which DAA therapy for mixed genotype 1a/1b HCV led to a dramatic improvement in glycemic control. This improvement in insulin requirements and HbA1C persisted following viral clearance despite an increase in the patient's BMI.


  Conclusion Top


Our work highlights the importance of successful eradication of the globally prevalent problem of HCV infection, augmenting the secondary benefits of new interferon-free DAA regimens in T2DM HCV-infected patients. Likewise, our work supports the significant connection between HCV and T2DM.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yoneda M, Saito S, Ikeda T, Fujita K, Mawatari H, Kirikoshi H, et al. Hepatitis C virus directly associates with insulin resistance independent of the visceral fat area in non-obese and nondiabetic patient. J Viral Hepatol 2007; 14:600–607.  Back to cited text no. 1
    
2.
Pybus OG, Barnes E, Taggart R, Lemey P, Markov PV, Rasachak B, et al. Genetic history of hepatitis C virus in East Asia. J Virol 2009; 83:1071–1082.  Back to cited text no. 2
    
3.
Hammerstad SS, Grok SF, Shira HJ, Grock F, Lee HJ, Hasham A, et al. Diabetes and hepatitis C: a two-way association. Front Endocrinol (Lausanne) 2015; 6:134.  Back to cited text no. 3
    
4.
Stepanova M, Lam B, Younossi YM, Srishord K, Younossi ZM. Association of hepatitis c with insulin resistance and type 2 diabetes in US general population. The impact of the epidemic of obesity. J Viral Hepatol 2012; 19:341–345.  Back to cited text no. 4
    
5.
European Association for the Study of the Liver. EASL Recommendations for treatment of hepatitis C 2015. J Hepatol 2015; 63:199–236.  Back to cited text no. 5
    
6.
Cacoub P, Comarmond C, Domont F, Savey L, Desbois AC. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis. 2016; 3:3–14.  Back to cited text no. 6
    
7.
Meissner EG, Lee YJ, Osinusi A, Sims Z, Qin J, Sturdevant D, et al. Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients. Hepatology 2015; 61:790–801.  Back to cited text no. 7
    
8.
Vanni E, Bugianesi E, Saracco G. Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: myth or reality? Dig Liver Dis 2016; 48:105–111.  Back to cited text no. 8
    
9.
Huang JF, Dai CY, Hwang SJ, Ho CK, Hsiao PJ, Hsieh MY, et al. Hepatitis C viremia increases the association with type 2 diabetes mellitus in a hepatitis B and C endemic area: an epidemiological link with virological implication. Am J Gastroenterol 2007; 102:1237–1243.  Back to cited text no. 9
    
10.
Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmerón J, Diago M, Fernández-Rodríguez CM, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology 2005; 128:636– 641.  Back to cited text no. 10
    
11.
Premji R, Roopnarinesingh N, Qazi N, Nylen ES. New-onset diabetes mellitus with exposure to ledipasvir and sofosbuvir. J Investig Med High Impact Case Rep. 2015; 3:2324709615623300.  Back to cited text no. 11
    
12.
Raymond AN, Nicole T, Arun J. Markedly Improved glycemic control in poorly controlled type 2 diabetes following direct acting antiviral treatment of genotype 1 hepatitis C. Case Rep Hepatol 2016; 7807921:3.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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