Skip to main content
Download PDF

HCV infection characteristics, treatment uptake and outcomes in patient with diabetes mellitus

BMC Endocrine Disorders volume 22, Article number: 277 (2022) Cite this article

Abstract

Background

The interplay between HCV, DM, and DAA therapy is poorly understood. We compared HCV infection characteristics, treatment uptake, and treatment outcomes in patients with and without DM. 

Methods

A retrospective cohort study was conducted using data from The Ottawa Hospital Viral Hepatitis Program. Statistical comparisons between diabetes and non-diabetes were made using χ2 and t-tests. Logistic regression analyses were performed to assess predictors of DM and SVR.

Results

One thousand five hundred eighty-eight HCV patients were included in this analysis; 9.6% had DM. Patients with DM were older and more likely to have cirrhosis. HCC and chronic renal disease were more prevalent in the DM group. Treatment uptake and SVR were comparable between groups. Regression analysis revealed that age and employment were associated with achieving SVR. Post-SVR HCC was higher in DM group.

Conclusion

The high prevalence of DM in our HCV cohort supports screening. Further assessment is required to determine if targeted, early DAA treatment reduces DM onset, progression to cirrhosis and HCC risk. Further studies are needed to determine if optimization of glycemic control in this population can lead to improved liver outcomes.

Peer Review reports

Summary

The interplay between HCV, DM, and DAA therapy is poorly understood. We compared HCV infection characteristics, treatment uptake, and treatment outcomes in patients with and without DM. Nearly 10% of patients with HCV had DM. These individuals were older, more likely have cirrhosis and possessed more comorbidities. DM patients were less likely to report unhealthy behaviours. Treatment uptake and SVR rates were comparable between both DM and non-DM groups.

Introduction

Hepatitis C virus (HCV) infects over 100 million people and is a leading cause of liver-related morbidity and mortality [1, 2]. Diabetes mellitus (DM) affects an estimated 425 million people and can result in serious health complications [3]. Insulin resistance and DM adversely impact the course of liver disease, accelerating the rate of hepatic fibrosis and increasing the risk of hepatocellular carcinoma (HCC) [4, 5]. DM may also impact the likelihood of achieving sustained virological response (SVR) with HCV antiviral therapy [6,7,8]. With regard to diminished interferon treatment efficacy, insulin resistance impairs TNF signalling, thus blocking STAT-1 translocation and interferon-stimulated gene production which is critical to HCV antiviral activity [9].

DM is an extrahepatic complication of chronic HCV infection [10,11,12,13,14,15,16]. Evidence suggests that insulin resistance is the primary mechanism by which HCV induces DM [17,18,19,20,21]. According to experimental and clinical studies, HCV may interact with glucose metabolism to promote insulin resistance through various pathogenic processes: direct inhibition of insulin signalling [22], decreased incretin hormones [23], overproduction of proinflammatory cytokines [24, 25], oxidative stress [26], and pancreatic ß-cell dysfunction [27, 28].

Improved glycemic control may be attained in individuals achieving SVR with direct acting antiviral (DAA) therapy [29,30,31]. Publications have demonstrated early declines in fasting blood glucose and glycated hemoglobin during [32] and after [33] HCV treatment. Furthermore, the results of a prospective case-control study showed an improvement in pancreatic β-cell function following the clearance of HCV by DAAs [34]. Although the exact effects of HCV clearance on DM are unresolved, they are thought to involve alterations in glucose metabolism and insulin signalling [35, 36]. Suggested mechanisms include interrupting inflammatory pathways to restore glucose homeostasis [37] and increasing the hepatic expression of insulin receptor substrates [38].

In an effort to further evaluate the interplay between HCV, DM, and DAA therapy, we evaluated predictors of DM in a cohort of people living with chronic HCV. Furthermore, we compared HCV infection characteristics, treatment uptake, and treatment outcomes between patients with and without DM in our cohort receiving care at a regional HCV referral center.

Methods

Study design and population

We conducted a retrospective cohort study of patients assessed by The Ottawa Hospital Viral Hepatitis Program (TOH) between January 2014 and March 2020 (Ottawa Health Science Network Research Ethics Board #2004-196). TOH is a publicly funded, multidisciplinary program that provides comprehensive HCV care to individuals in Eastern Ontario, Western Quebec, and Nunavut, Canada. Consenting patients 18 years of age and older with chronic HCV infection (defined as HCV RNA positive at least 6 months after acute infection) were included in this analysis. Data from patient medical records was abstracted using standardized data collection forms and entered in the TOH Viral Hepatitis Program Database.

Independent variables

DM status served as the primary independent variable. DM was defined as a diagnosis of either type 1 or type 2 DM as reported within patient health records. Covariates included (a) baseline characteristics (age at first clinical assessment, year of first visit to the clinic, sex, race, immigration status, HCV genotype and fibrosis stage); (b) baseline laboratory values (HCV RNA, hemoglobin, platelets, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, creatinine, liver stiffness in kilopascals, Control Attenuation Parameter (CAP score)); (c) social determinants of health (employment status, alcohol use history, incarceration history, injection drug use (IDU) history, and recreational drug use history); and (d) comorbidities (HIV co-infection, psychiatric illness, chronic renal disease, and HCC). Liver stiffness was assessed by transient elastography (Fibroscan) where a measure over 12.5 kPa was deemed evidence of cirrhosis. Fibroscan results were converted to the METAVIR scoring system where “F0” signified no fibrosis and “F4” signified cirrhosis [39]. CAP score was measured in dB/m by transient elastography where a result of 300 dB/m or more was considered evidence of steatosis [40].

Dependent variables

Dependent variables included (1) Predictors of DM, (2) HCV treatment uptake and (3) HCV treatment outcomes as a function of DM status. HCV treatment initiation was defined as the provision of a DAA prescription. If more than one course of therapy was received, then the most recent round of therapy was considered. HCV treatment outcomes were evaluated in accordance to two main variables. The first was SVR, defined as HCV RNA negativity 12 weeks or more post-treatment. Crude SVR was calculated among patients who received at least one dose of DAA therapy. A treatment completion analysis was used to determine SVR among patients who completed a DAA therapy course and had post-treatment HCV RNA testing results available. The second was the incidence of newly diagnosed HCC cases at 12 and 24 months post-treatment. The enrollment of new participants was censored in March 2019. However, HCV treatment uptake and treatment outcomes data were collected until March 2020.

Statistical analysis

All statistical analyses were performed using SAS Enterprise Guide (version 9.4m SAS Institute, Cary, NC). The distribution of baseline sociodemographic, laboratory, and clinical measures by patient DM status were described using the respective means (standard deviation [SD]) and proportions. Statistical comparisons between the two groups were made using χ2 tests for categorical variables and t-tests for continuous variables. Characteristics of patients who initiated and did not initiate DAA therapy were assessed by stratifying participants in accordance with DM status. Predictors of DM and SVR were assessed by logistic regression analysis adjusted for covariates and potential confounders. All significance tests were two-sided and p-values <0.05 were deemed statistically significant.

Results

HCV infection characteristics

One thousand five hundred and eighty-eight HCV-infected patients were included in this analysis. One hundred and fifty-three (9.6%) were diagnosed with DM (Table 1). Numerically, DM patients were more likely to be male (70.6%), between the ages of 60-69 years (38.6%) and Black (9.8%) at baseline assessment. Patients with DM were older, more likely to have advanced fibrosis and more likely to be infected with HCV genotypes 1b, 2, and 4. Only age predicted a diagnosis of DM by multivariate analysis (Table 2).

Table 1 Baseline characteristics and HCV treatment outcomes compared between DM and non-DM patients
Full size table
Table 2 Predictors of diabetes diagnosis at baseline
Full size table

The prevalence of several social determinants of health differed between DM and non-DM groups (Table 1). In the DM group there was a lower prevalence of alcohol use, incarceration, IDU and recreational drug use histories. Certain differences were observed in the proportion of concurrent co-morbidities between groups (Table 1). DM patients had a higher prevalence of chronic renal disease and HCC at baseline assessment. Individuals with DM were more likely to be cirrhotic at the time of DAA initiation. Mean baseline CAP score was higher in DM patients suggesting a greater burden of non-alcoholic steatohepatitis. Of note, the prevalence of HIV co-infection and psychiatric illness were similar.

Treatment initiation

Of 1,588 patients, 1,072 (67.5%) initiated DAA therapy during the period of evaluation (Table 1). The initiation of DAA treatment was higher in the DM group compared with non-DM group (86.9% versus 65.4%, p<0.001). Within patients with DM, patient characteristics were similar between those who started DAA treatment and those who did not (data not shown). In contrast, initiating DAA in non-DM group was associated with older mean baseline age, genotype 1 infection, cirrhosis, Caucasian race, history of alcohol use and history of psychiatric illness (data not shown).

Treatment outcomes

Crude SVR was comparable between DM (90.1%) and non-DM groups (86.8%) (Table 1). Likewise, SVR in those completing post-treatment HCV RNA testing was high and similar by group (96.7% vs 98.5%). By univariate analysis, DM status, older age and being employed were associated with achieving SVR (Table 3). After adjustment, age and employment status remained significant predictors of SVR. Of note, 77% of our DM group were on diabetes medications at the time of treatment. In an exploratory analysis, pharmacological treatment for diabetes did not impact SVR. The presence of steatosis as measured by transient elastography CAP score did not influence SVR.

Table 3 Predictors of Sustained Virologic Response in HCV treatment recipients
Full size table

Although our analysis was limited by low frequency of events, the prevalence of newly diagnosed HCC was numerically higher in the DM group compared to the non-DM group at both 12 (0.8% versus 0.2%) and 24 (2.3% versus 0.6%) months post-treatment.

Discussion

Our analysis utilized data from a cohort of HCV patients of which nearly 10% had DM. This proportion is within previously reported estimates ranging from 5.9-43.2% among HCV cohorts [41,42,43]. It also aligns with the global and Canadian DM prevalence among the general population (9.3%) [3, 44]. As a regional comparison, the prevalence of diabetes in Ontario was estimated to be 8.7% in 2016 [45]. Older age predicted DM in our cohort of people living with chronic HCV but not HCV genotype or race (Table 2). The prevalence of impaired fasting glycemia and DM has been demonstrated to increase with aging [46, 47]. Several groups have speculated that this is largely due to the age-related decrease in beta cell proliferation and enhanced sensitivity to apoptosis [48].

Our demographic results were comparative to those of other studies that reported HCV-infected with DM to be older [49,50,51] and numerically more likely to be non-Caucasian [51, 52] relative to non-diabetes patients (Table 1). DM patients in our cohort were more likely to be infected with genotypes 1b, 2, and 4. These findings are only partially in agreement with other studies who report higher frequencies of genotypes 1 [53], 3a [53,54,55,56] and 4 [53, 56] among DM patients. In this study, DM were less likely to engage in unhealthy lifestyle behaviours relative to non-diabetes patients. Similar observations have been made in Canadian studies comparing the behaviours of immigrant and non-immigrant patients with HCV [57,58,59]. Of note, there was a higher proportion of immigrants in the DM group.

A greater prevalence of baseline HCC and chronic renal disease was noted in those with DM. The higher mean age of our DM group may, at least in part, explain this finding. Another explanation is the pathophysiological association between DM, HCV, and chronic renal disease [60,61,62,63,64]. We found the prevalence of HIV co-infection to be similar in DM and non-DM patients. This result was unexpected as it contradicts previous studies that report DM to be more common in HIV-HCV co-infection [43, 60, 65]. A possible explanation for this finding is that the HIV patients included in our cohort were younger. We also found the prevalence of psychiatric illness to be comparable between the groups. This result is in contrast with other evidence that suggests an association between DM and mental health conditions [66,67,68,69]. The relationship between HCV, DM, and comorbidities may be partially attributed to psychosocial factors such as socioeconomic status. Given that we did not capture data in this realm, we were unable to explore how patient socioeconomic status influenced our findings.

In this cohorts there was a higher prevalence of cirrhosis in the diabetes group. This observation is consistent with previous literature [70, 71] and supports researchers that have found insulin resistance to accelerate fibrogenesis in HCV-infected subjects [72, 73]. DM is also associated with steatosis which also contributes to liver fibrosis [74]. It is noteworthy that the CAP score, a measure of liver steatosis, was greater among diabetes patients.

Collectively, the heightened risk of HCC, chronic renal disease and cirrhosis among patients with diabetes suggests that DM is linked to worse baseline health among patients with HCV. Santos speculated that this may be understood by considering the age at which HCV-infected patients with diabetes engage in care. In a prospective cohort analysis, DM was revealed to independently predict delayed access to HCV services. This represents a paradox, whereby people who are already at higher risk of advanced fibrosis are those that present late to care - a scenario that increases their risk of accelerated disease progression. The paradox is further complicated by the fact that DM is more prevalent within low socioeconomic groups [75]. These findings emphasize the need to pursue more timely testing and treatment for HCV among diabetes patients. As DM is more prevalent in socially deprived groups, specific screening strategies are recommended to address HCV within these subpopulations.

We found a greater proportion of DM patients initiated DAA therapy. This finding is likely confounded by cirrhotic state as patients with cirrhosis are more likely to be prescribed treatment for HCV; especially in the early era of DAA therapy when reimbursement was often dictated by fibrosis stage.

Historically, insulin resistance and DM have served as negative predictors of SVR in patients receiving interferon-based HCV treatment [6,7,8]. Fortunately, studies consistently demonstrate that new DAA therapies yield high SVR in nearly all patients with chronic HCV [76,77,78]. Our data showed that SVR rates were high in both the DM and non-DM patients. We found that being employed was associated with achieving SVR. This result is expected, as it aligns with previous studies that report employment to predict healthy lifestyle behaviours [79] and adherence to treatment [80, 81]. We also found that increased age at first assessment was associated with achieving SVR. This may be explained by the fact that substance abuse and mental health issues among treatment-seeking, older adults are generally less prevalent and less severe [82, 83]. Additionally, older adults tend to report more social support, more adaptive coping, and fewer barriers to treatment, relative to younger patients [82, 84]. Of note, genotype, cirrhosis and steatosis were not identified as predictors of SVR in DAA recipients.

We found that DM patients had a greater prevalence of newly diagnosed HCC after completing DAA therapy. Though limited by low frequency of events, these results suggest that HCC is more likely to develop in DM patients, even after HCV infection is cleared. Several studies have sought to investigate the incidence of HCC in cured HCV patients [85,86,87,88]. DM has rarely been found to predict HCC in individuals who achieve DAA-induced SVR [89]. Rather, reports suggest that older age [90] and baseline cirrhosis [90, 91] are predictors of HCC development post-treatment. This could explain why we observed an increased prevalence of HCC in diabetes patients with viral clearance as individuals in this group were older with more advanced fibrosis prior to initiating therapy. The increased prevalence of HCC post-SVR emphasizes the importance of early HCV treatment to prevent the development of initial cirrhosis as well as the need the maintain long-term, post-treatment HCC surveillance in patients with baseline cirrhosis [92, 93].

Several limitations are recognized in this retrospective study. Our analysis could be biased by missing data. However, there was minimal missingness for core variables including sex, age, comorbidities and fibrosis assessment. We were not able to account for patients with pre-diabetes (IFG/IGT) and undiagnosed diabetes. We were also unable to differentiate between type 1 and type 2 diabetes and how these may impact liver outcomes differently as type 1 is due to insulin deficiency as opposed to insulin resistance. However, the vast majority had type 2 diabetes. Sociodemographic data was self-reported. This could have introduced some degree of bias, particularly with respect to histories of incarceration, alcohol, and drug use. We were unable to consider certain variables that may affect the association between DM, HCV and DAA therapy including central obesity, glycemia control, insulin resistance-related inflammatory effects and specific diabetic medications [94, 95].

Conclusions

DM is at least as common in those living with HCV as in the general population. This high prevalence as well as the burden of cirrhosis and HCC in this population support current calls for diabetes screening in those living with HCV. HCV screening should be considered in diabetic patients as well. We speculate that earlier HCV detection, treatment and cure could prevent progression to cirrhosis and reduce HCC risk. Further assessment is required to determine if targeted, early DAA treatment with cure may also reduce DM incidence. Additionally, studies are needed to determine if early diagnosis of DM and optimization of glycemic control may also help to modify HCV complication and improve liver outcomes in this population.

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due to privacy considerations but are available from the corresponding author on reasonable request.

Abbreviations

DAA:

Direct Acting Antiviral

DM:

Diabetes mellitus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

IDU:

Intravenous drug use

SVR:

Sustained virological response

TOH:

The Ottawa Hospital

References

  1. Diaz HM, Mindiola AL, Aldana AG. Pathophysiology of hepatitis C and diabetes mellitus: Towards the cure of two epidemics in the 21st century. Revista Colombiana de Gastroenterologia. 2019;34(3):274–83.

    Google Scholar 

  2. Lanini S, Easterbrook PJ, Zumla A, Ippolito G. Hepatitis C: global epidemiology and strategies for control. Clin Microbiol Infect. 2016;22(10):833–8.

    Article  CAS  PubMed  Google Scholar 

  3. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019;157:107843.

    Article  PubMed  Google Scholar 

  4. Bose SK, Ray R. Hepatitis C virus infection and insulin resistance. World J Diabetes. 2014;5(1):52–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and Hepatitis C: A Two-Way Association. Front Endocrinol (Lausanne). 2015;6:134.

    Article  Google Scholar 

  6. Konishi I, Horiike N, Hiasa Y, Tokumoto Y, Mashiba T, Michitaka K, Miyake Y, Nonaka S, Joukou K, Matsuura B, et al. Diabetes mellitus reduces the therapeutic effectiveness of interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C. Hepatol Res. 2007;37(5):331–6.

    Article  CAS  PubMed  Google Scholar 

  7. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361(6):580–93.

    Article  CAS  PubMed  Google Scholar 

  8. Romero-Gomez M, Del Mar Viloria M, Andrade RJ, Salmeron J, Diago M, Fernandez-Rodriguez CM, Corpas R, Cruz M, Grande L, Vazquez L, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128(3):636–41.

    Article  CAS  PubMed  Google Scholar 

  9. El-Zayadi AR, Anis M. Hepatitis C virus induced insulin resistance impairs response to anti viral therapy. World J Gastroenterol. 2012;18(3):212–24.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Antonelli A, Ferri C, Fallahi P, Sebastiani M, Nesti C, Barani L, Barale R, Ferrannini E. Type 2 diabetes in hepatitis C-related mixed cryoglobulinaemia patients. Rheumatology (Oxford). 2004;43(2):238–40.

    Article  CAS  Google Scholar 

  11. Bilić-Ćurčić I, Roguljić H, Ivandić M, Včev A, Smolić R, Smolić M. Hepatitis C-Associated Diabetes Mellitus. In: Smolic M, Vcev A, editors. Update on Hepatitis C. Wu G: IntechOpen; 2017. p. 48–55.

    Google Scholar 

  12. Jadoon NA, Shahzad MA, Yaqoob R, Hussain M, Ali N. Seroprevalence of hepatitis C in type 2 diabetes: evidence for a positive association. Virol J. 2010;7:304.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lecube A, Hernandez C, Genesca J, Simo R. Glucose abnormalities in patients with hepatitis C virus infection: Epidemiology and pathogenesis. Diabetes Care. 2006;29(5):1140–9.

    Article  CAS  PubMed  Google Scholar 

  14. Mason AL, Lau JY, Hoang N, Qian K, Alexander GJ, Xu L, Guo L, Jacob S, Regenstein FG, Zimmerman R, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;29(2):328–33.

    Article  CAS  PubMed  Google Scholar 

  15. Montano-Loza AJ, Sultan A, Falanga D, Loss G, Mason AL. Immunogenetic susceptibility to diabetes mellitus in patients with liver disease. Liver Int. 2009;29(10):1543–51.

    Article  PubMed  Google Scholar 

  16. White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49(5):831–44.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, Taniguchi E, Kumemura H, Hanada S, Maeyama M, et al. Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol. 2004;165(5):1499–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol. 2014;61(1 Suppl):S69-78.

    Article  PubMed  Google Scholar 

  19. Pazienza V, Vinciguerra M, Andriulli A, Mangia A. Hepatitis C virus core protein genotype 3a increases SOCS-7 expression through PPAR-{gamma} in Huh-7 cells. J Gen Virol. 2010;91(Pt 7):1678–86.

    Article  CAS  PubMed  Google Scholar 

  20. Persico M, Russo R, Persico E, Svelto M, Spano D, Andolfo I, La Mura V, Capasso M, Tiribelli C, Torella R, et al. SOCS3 and IRS-1 gene expression differs between genotype 1 and genotype 2 hepatitis C virus-infected HepG2 cells. Clin Chem Lab Med. 2009;47(10):1217–25.

    Article  CAS  PubMed  Google Scholar 

  21. Serfaty L. Metabolic Manifestations of Hepatitis C Virus: Diabetes Mellitus, Dyslipidemia. Clin Liver Dis. 2017;21(3):475–86.

    Article  PubMed  Google Scholar 

  22. Aytug S, Reich D, Sapiro LE, Bernstein D, Begum N. Impaired IRS-1/PI3-kinase signaling in patients with HCV: a mechanism for increased prevalence of type 2 diabetes. Hepatology. 2003;38(6):1384–92.

    Article  CAS  PubMed  Google Scholar 

  23. Itou M, Kawaguchi T, Taniguchi E, Sumie S, Oriishi T, Mitsuyama K, Tsuruta O, Ueno T, Sata M. Altered expression of glucagon-like peptide-1 and dipeptidyl peptidase IV in patients with HCV-related glucose intolerance. J Gastroenterol Hepatol. 2008;23(2):244–51.

    Article  CAS  PubMed  Google Scholar 

  24. Knobler H, Zhornicky T, Sandler A, Haran N, Ashur Y, Schattner A. Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association. Am J Gastroenterol. 2003;98(12):2751–6.

    Article  CAS  PubMed  Google Scholar 

  25. Lecube A, Hernandez C, Genesca J, Simo R. Proinflammatory cytokines, insulin resistance, and insulin secretion in chronic hepatitis C patients: A case-control study. Diabetes Care. 2006;29(5):1096–101.

    Article  CAS  PubMed  Google Scholar 

  26. Mitsuyoshi H, Itoh Y, Sumida Y, Minami M, Yasui K, Nakashima T, Okanoue T. Evidence of oxidative stress as a cofactor in the development of insulin resistance in patients with chronic hepatitis C. Hepatol Res. 2008;38(4):348–53.

    Article  CAS  PubMed  Google Scholar 

  27. Masini M, Campani D, Boggi U, Menicagli M, Funel N, Pollera M, Lupi R, Del Guerra S, Bugliani M, Torri S, et al. Hepatitis C virus infection and human pancreatic beta-cell dysfunction. Diabetes Care. 2005;28(4):940–1.

    Article  PubMed  Google Scholar 

  28. Wang Q, Chen J, Wang Y, Han X, Chen X. Hepatitis C virus induced a novel apoptosis-like death of pancreatic beta cells through a caspase 3-dependent pathway. PLoS One. 2012;7(6):e38522.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. El Badry M, Ali D, Eltaweel N, Abdel-Wahed M. Effect of eradication of HCV infection by direct-acting antivirals in diabetic HCV-infected patients as regards glycemic control. Egyptian Liver J. 2020;10(54):1–7.

  30. Hum J, Jou JH, Green PK, Berry K, Lundblad J, Hettinger BD, Chang M, Ioannou GN. Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus. Diabetes Care. 2017;40(9):1173–80.

    Article  PubMed  Google Scholar 

  31. Pashun RA, Shen NT, Jesudian A. Markedly Improved Glycemic Control in Poorly Controlled Type 2 Diabetes following Direct Acting Antiviral Treatment of Genotype 1 Hepatitis C. Case Reports Hepatol. 2016;2016:7807921.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Pavone P, Tieghi T, d’Ettorre G, Lichtner M, Marocco R, Mezzaroma I, Passavanti G, Vittozzi P, Mastroianni CM, Vullo V. Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents. Clin Microbiol Infect. 2016;22(5):462 e461-463.

    Article  Google Scholar 

  33. Fabrizio C, Procopio A, Scudeller L, Dell’Acqua R, Bruno G, Milano E, Milella M, Saracino A, Angarano G. HCV and diabetes: towards a “sustained” glycaemic improvement after treatment with DAAs? Clin Microbiol Infect. 2017;23(5):342–3.

    Article  CAS  PubMed  Google Scholar 

  34. Adinolfi LE, Nevola R, Guerrera B, D’Alterio G, Marrone A, Giordano M, Rinaldi L. Hepatitis C virus clearance by direct-acting antiviral treatments and impact on insulin resistance in chronic hepatitis C patients. J Gastroenterol Hepatol. 2018;33(7):1379–82.

    Article  CAS  PubMed  Google Scholar 

  35. Hashim A, Kandeel H, El-Mola K, El-Raey F, Attia M. Effect of new direct-acting antiviral drugs on insulin resistance and glycemic control after treatment of chronic hepatitis C virus infection in type 2 diabetic patients. Al-Azhar Assiut Medical Journal. 2017;15(4):187–95.

    Article  Google Scholar 

  36. Weidner P, Boettche D, Zimmerer T, Burgermeister E, Teufel A, Ebert MPA, Antoni C. 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(3):281–9.

    Article  PubMed  Google Scholar 

  37. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11(2):183–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kawaguchi T, Ide T, Taniguchi E, Hirano E, Itou M, Sumie S, Nagao Y, Yanagimoto C, Hanada S, Koga H, et al. Clearance of HCV improves insulin resistance, beta-cell function, and hepatic expression of insulin receptor substrate 1 and 2. Am J Gastroenterol. 2007;102(3):570–6.

    Article  PubMed  Google Scholar 

  39. Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group Hepatology. 1996;24(2):289–93.

    CAS  Google Scholar 

  40. Myers RP, Pollett A, Kirsch R, Pomier-Layrargues G, Beaton M, Levstik M, Duarte-Rojo A, Wong D, Crotty P, Elkashab M. Controlled Attenuation Parameter (CAP): a noninvasive method for the detection of hepatic steatosis based on transient elastography. Liver Int. 2012;32(6):902–10.

    Article  PubMed  Google Scholar 

  41. Bigam DL, Pennington JJ, Carpentier A, Wanless IR, Hemming AW, Croxford R, Greig PD, Lilly LB, Heathcote JE, Levy GA, et al. Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation. Hepatology. 2000;32(1):87–90.

    Article  CAS  PubMed  Google Scholar 

  42. Imazeki F, Yokosuka O, Fukai K, Kanda T, Kojima H, Saisho H. Prevalence of diabetes mellitus and insulin resistance in patients with chronic hepatitis C: comparison with hepatitis B virus-infected and hepatitis C virus-cleared patients. Liver Int. 2008;28(3):355–62.

    Article  CAS  PubMed  Google Scholar 

  43. Visnegarwala F, Chen L, Raghavan S, Tedaldi E. Prevalence of diabetes mellitus and dyslipidemia among antiretroviral naive patients co-infected with hepatitis C virus (HCV) and HIV-1 compared to patients without co-infection. J Infect. 2005;50(4):331–7.

    Article  PubMed  Google Scholar 

  44. Diabetes Statistics in Canada [http://www.diabetes.ca/how-you-can-help/advocate/why-federal-leadership-is-essential/diabetes-statistics-in-canada]

  45. Government of Canada, “Data Blog: Diabetes in Canada” Health-Infobase. 2019. https://healthinfobase.canada.ca/datalab/diabetes-blog.html.

  46. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. In: Edited by Services UDoHaH. Atlanta: Centers for Disease Control and Prevention; 2011.

    Google Scholar 

  47. Hosseini Z, Whiting SJ, Vatanparast H. Type 2 diabetes prevalence among Canadian adults - dietary habits and sociodemographic risk factors. Appl Physiol Nutr Metab. 2019;44(10):1099–104.

    Article  PubMed  Google Scholar 

  48. Tschen SI, Dhawan S, Gurlo T, Bhushan A. Age-dependent decline in beta-cell proliferation restricts the capacity of beta-cell regeneration in mice. Diabetes. 2009;58(6):1312–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Elhawary EI, Mahmoud GF, El-Daly MA, Mekky FA, Esmat GG, Abdel-Hamid M. Association of HCV with diabetes mellitus: an Egyptian case-control study. Virol J. 2011;8:367.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Petit JM, Bour JB, Galland-Jos C, Minello A, Verges B, Guiguet M, Brun JM, Hillon P. Risk factors for diabetes mellitus and early insulin resistance in chronic hepatitis C. J Hepatol. 2001;35(2):279–83.

    Article  CAS  PubMed  Google Scholar 

  51. Banks DE, Bogler Y, Bhuket T, Liu B, Wong RJ. Significant disparities in risks of diabetes mellitus and metabolic syndrome among chronic hepatitis C virus patients in the U.S. Diabetes Metab Syndr. 2017;11 Suppl 1:S153–8.

    Article  PubMed  Google Scholar 

  52. Thuluvath PJ, John PR. Association between hepatitis C, diabetes mellitus, and race a case-control study. Am J Gastroenterol. 2003;98(2):438–41.

    PubMed  Google Scholar 

  53. Moucari R, Asselah T, Cazals-Hatem D, Voitot H, Boyer N, Ripault MP, Sobesky R, Martinot-Peignoux M, Maylin S, Nicolas-Chanoine MH, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134(2):416–23.

    Article  CAS  PubMed  Google Scholar 

  54. Farshadpour F, Taherkhani R, Ravanbod MR, Eghbali SS. Prevalence and Genotype Distribution of Hepatitis C Virus Infection among Patients with Type 2 Diabetes Mellitus. Med Princ Pract. 2018;27(4):308–16.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Memon MS, Arain ZI, Naz F, Zaki M, Kumar S, Burney AA. Prevalence of type 2 diabetes mellitus in hepatitis C virus infected population: a Southeast Asian study. J Diabetes Res. 2013;2013:539361.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Chehadeh W, Kurien SS, Abdella N, Ben-Nakhi A, Al-Arouj M, Almuaili T, Al-Mutairi O, Al-Nakib W. Hepatitis C virus infection in a population with high incidence of type 2 diabetes: impact on diabetes complications. J Infect Public Health. 2011;4(4):200–6.

    Article  PubMed  Google Scholar 

  57. Cooper CL, Read D, Vachon ML, Conway B, Wong A, Ramji A, Borgia S, Tam E, Barrett L, Smyth D, et al. Hepatitis C virus infection characteristics and treatment outcomes in Canadian immigrants. BMC Public Health. 2020;20(1):1345.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Cooper CL, Thavorn K, Damian E, Corsi DJ. Hepatitis C Virus Infection Outcomes Among Immigrants to Canada: A Retrospective Cohort Analysis. Ann Hepatol. 2017;16(5):720–6.

    Article  PubMed  Google Scholar 

  59. Greenaway C, Makarenko I, Tanveer F, Janjua N. Addressing hepatitis C in the foreign-born population: A key to hepatitis C virus elimination in Canada. Canadian Liver Journal. 2018;1(2):34–50.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Butt AA, McGinnis K, Rodriguez-Barradas MC, Crystal S, Simberkoff M, Goetz MB, Leaf D, Justice AC. Veterans Aging Cohort S: HIV infection and the risk of diabetes mellitus. AIDS. 2009;23(10):1227–34.

    Article  PubMed  Google Scholar 

  61. Collaboration GBDCKD. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–33.

    Article  Google Scholar 

  62. Dyal HK, Aguilar M, Bartos G, Holt EW, Bhuket T, Liu B, Cheung R, Wong RJ. Diabetes Mellitus Increases Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Virus Patients: A Systematic Review. Dig Dis Sci. 2016;61(2):636–45.

    Article  CAS  PubMed  Google Scholar 

  63. Hwang JC, Jiang MY, Lu YH, Weng SF. Impact of HCV Infection on Diabetes Patients for the Risk of End-Stage Renal Failure. Medicine (Baltimore). 2016;95(3):e2431.

    Article  Google Scholar 

  64. Iovanescu VF, Streba CT, Ionescu M, Constantinescu AF, Vere CC, Rogoveanu I, Mota E. Diabetes mellitus and renal involvement in chronic viral liver disease. J Med Life. 2015;8(4):483–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Jain MK, Aragaki C, Fischbach L, Gibson S, Arora R, May L, Vardhineni K, Lee WM. Hepatitis C is associated with type 2 diabetes mellitus in HIV-infected persons without traditional risk factors. HIV Med. 2007;8(8):491–7.

    Article  CAS  PubMed  Google Scholar 

  66. Ali S, Stone M, Skinner TC, Robertson N, Davies M, Khunti K. The association between depression and health-related quality of life in people with type 2 diabetes: a systematic literature review. Diabetes Metab Res Rev. 2010;26(2):75–89.

    Article  PubMed  Google Scholar 

  67. Chima CC, Salemi JL, Wang M. Mejia de Grubb MC, Gonzalez SJ, Zoorob RJ: Multimorbidity is associated with increased rates of depression in patients hospitalized with diabetes mellitus in the United States. J Diabetes Complications. 2017;31(11):1571–9.

    Article  PubMed  Google Scholar 

  68. Cols-Sagarra C, Lopez-Simarro F, Alonso-Fernandez M, Mancera-Romero J, Perez-Unanua MP, Mediavilla-Bravo JJ, Barquilla-Garcia A, Miravet-Jimenez S. Work Group of Diabetes S: Prevalence of depression in patients with type 2 diabetes attended in primary care in Spain. Prim Care Diabetes. 2016;10(5):369–75.

    Article  PubMed  Google Scholar 

  69. Roy T, Lloyd CE. Epidemiology of depression and diabetes: a systematic review. J Affect Disord. 2012;142(Suppl):S8-21.

    Article  PubMed  Google Scholar 

  70. Desbois AC, Cacoub P. Diabetes mellitus, insulin resistance and hepatitis C virus infection: A contemporary review. World J Gastroenterol. 2017;23(9):1697–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Raff EJ, Kakati D, Bloomer JR, Shoreibah M, Rasheed K, Singal AK. Diabetes Mellitus Predicts Occurrence of Cirrhosis and Hepatocellular Cancer in Alcoholic Liver and Non-alcoholic Fatty Liver Diseases. J Clin Transl Hepatol. 2015;3(1):9–16.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George J. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression [corrected]. Gastroenterology. 2003;125(6):1695–704.

    Article  CAS  PubMed  Google Scholar 

  73. Petta S, Camma C, Di Marco V, Alessi N, Cabibi D, Caldarella R, Licata A, Massenti F, Tarantino G, Marchesini G, et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. Am J Gastroenterol. 2008;103(5):1136–44.

    Article  CAS  PubMed  Google Scholar 

  74. Miyaaki H, Ichikawa T, Taura N, Miuma S, Shibata H, Isomoto H, Takeshima F, Nakao K. Predictive value of the fibrosis scores in patients with chronic hepatitis C associated with liver fibrosis and metabolic syndrome. Intern Med. 2011;50(11):1137–41.

    Article  PubMed  Google Scholar 

  75. Santos M, Protopopescu C, Delarocque-Astagneu E, Petrov-Sanchez V, Di Beo V, Larrey D, Baudoin M, Dorival C, Bureau M, Fontaine H, et al. Late presentation for HCV care: time to target people with diabetes and/or hazardous alcohol use (ANRS CO22 HEPATHER cohort). Liver Int. 2022;42(1):38–49.

    Article  PubMed  Google Scholar 

  76. Asselah T, Marcellin P, Schinazi RF. Treatment of hepatitis C virus infection with direct-acting antiviral agents: 100% cure? Liver Int. 2018;38(Suppl 1):7–13.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Drazilova S, Gazda J, Janicko M, Jarcuska P. Chronic Hepatitis C Association with Diabetes Mellitus and Cardiovascular Risk in the Era of DAA Therapy. Can J Gastroenterol Hepatol. 2018;2018:6150861.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Stine JG, Wynter JA, Niccum B, Kelly V, Caldwell SH, Shah NL. Effect of Treatment with Direct Acting Antiviral on Glycemic Control in Patients with Diabetes Mellitus and Chronic Hepatitis C. Ann Hepatol. 2017;16(2):215–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Virtanen P, Vahtera J, Broms U, Sillanmaki L, Kivimaki M, Koskenvuo M. Employment trajectory as determinant of change in health-related lifestyle: the prospective HeSSup study. Eur J Public Health. 2008;18(5):504–8.

    Article  PubMed  Google Scholar 

  80. Nachega JB, Uthman OA, Peltzer K, Richardson LA, Mills EJ, Amekudzi K, Ouedraogo A. Association between antiretroviral therapy adherence and employment status: systematic review and meta-analysis. Bull World Health Organ. 2015;93(1):29–41.

    Article  PubMed  Google Scholar 

  81. Younossi ZM, Stepanova M, Henry L, Nader F, Younossi Y, Hunt S. Adherence to treatment of chronic hepatitis C: from interferon containing regimens to interferon and ribavirin free regimens. Medicine (Baltimore). 2016;95(28):e4151.

    Article  CAS  Google Scholar 

  82. Lemke S, Moos RH. Prognosis of older patients in mixed-age alcoholism treatment programs. J Subst Abuse Treat. 2002;22(1):33–43.

    Article  PubMed  Google Scholar 

  83. Mejldal A, Andersen K, Bilberg R, Moller S, Nielsen AS. DSM-5 Latent Classes of Alcohol Users among Treatment Seeking Older Adults. Subst Use Misuse. 2020;55(8):1214–22.

    Article  PubMed  Google Scholar 

  84. Wieben ES, Nielsen B, Nielsen AS, Andersen K. Elderly alcoholics compared to middle-aged alcoholics in outpatient treatment - 6-month follow-up. Nord J Psychiatry. 2018;72(7):506–11.

    Article  PubMed  Google Scholar 

  85. Kozbial K, Moser S, Al-Zoairy R, Schwarzer R, Datz C, Stauber R, Laferl H, Strasser M, Beinhardt S, Stattermayer AF, et al. Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment. Liver Int. 2018;38(6):1028–35.

    Article  CAS  PubMed  Google Scholar 

  86. Nahon P, Layese R, Bourcier V, Cagnot C, Marcellin P, Guyader D, Pol S, Larrey D, De Ledinghen V, Ouzan D, et al. Incidence of Hepatocellular Carcinoma After Direct Antiviral Therapy for HCV in Patients With Cirrhosis Included in Surveillance Programs. Gastroenterology. 2018;155(5):1436-1450 e1436.

    Article  PubMed  Google Scholar 

  87. Ogawa E, Furusyo N, Nomura H, Dohmen K, Higashi N, Takahashi K, Kawano A, Azuma K, Satoh T, Nakamuta M, et al. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment. Aliment Pharmacol Ther. 2018;47(1):104–13.

    Article  CAS  PubMed  Google Scholar 

  88. Romano A, Angeli P, Piovesan S, Noventa F, Anastassopoulos G, Chemello L, Cavalletto L, Gambato M, Russo FP, Burra P, et al. Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: A prospective population study. J Hepatol. 2018;69(2):345–52.

    Article  CAS  PubMed  Google Scholar 

  89. Mecci AJ, Kemos P, Leen C, Lawson A, Richardson P, Khakoo SI, Agarwal K, Mutimer D, Rosenberg WM, Foster GR, et al. The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis. Aliment Pharmacol Ther. 2019;50(2):204–14.

    Article  CAS  PubMed  Google Scholar 

  90. Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M, George J, Dore GJ. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression. J Hepatol. 2017;67(6):1204–12.

    Article  CAS  PubMed  Google Scholar 

  91. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2017;153(4):996-1005 e1001.

    Article  CAS  PubMed  Google Scholar 

  92. Negro F, Alaei M. Hepatitis C virus and type 2 diabetes. World J Gastroenterol. 2009;15(13):1537–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Su PY, Chen YY, Yen HH, Huang SP, Liu IL, Zeng YH, Hsu YC, Siao FY. Strategy for the Micro-Elimination of Hepatitis C among Patients with Diabetes Mellitus-A Hospital-Based Experience. J Clin Med. 2021;10(11):2509.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Gonzalez-Reimers E, Lopez-Prieto J, Quintero-Platt G, Pelazas-Gonzalez R, Aleman-Valls MR, Perez-Hernandez O. de-la-Vega-Prieto MJ, Gomez-Rodriguez MA, Martin-Gonzalez C, Santolaria-Fernandez F: Adipokines, cytokines and body fat stores in hepatitis C virus liver steatosis. World J Hepatol. 2016;8(1):74–82.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30(3):734–43.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all patients consenting to be included in this analysis.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Ottawa Hospital Research Institute, G12-501 Smyth Road, Ottawa, ON, K1H 8L6, Canada

    Marina Angel, Yelena Petrosyan, Mary-Anne Doyle & Curtis Cooper

  2. Department of Medicine, University of Ottawa, Ottawa, ON, K1H 8L6, Canada

    Mary-Anne Doyle & Curtis Cooper

  3. School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, K1G 5Z3, Canada

    Curtis Cooper

Authors
  1. Marina Angel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yelena Petrosyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary-Anne Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Curtis Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MA and CC were responsible for concept design, data interpretation and manuscript preparation. MD was responsible for data interpretation and manuscript preparation. YP performed data analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Curtis Cooper.

Ethics declarations

Ethics approval and consent to participate

The study was approved by the Ottawa Hospital Research Institute’s Ottawa Health Science Network Research Ethics Board study #2004-196. Research involving human data was performed in accordance with the Declaration of Helsinki. Informed consent to participate in study 2004-196 was obtained from all subjects.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Angel, M., Petrosyan, Y., Doyle, MA. et al. HCV infection characteristics, treatment uptake and outcomes in patient with diabetes mellitus. BMC Endocr Disord 22, 277 (2022). https://doi.org/10.1186/s12902-022-01198-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12902-022-01198-x

Keywords

  • Hepatitis C
  • Diabetes
  • Direct Acting Antiviral Treatment

BMC Endocrine Disorders

ISSN: 1472-6823

Contact us