The Effect of Viral Clearance Achieved by Direct-Acting Antiviral Agents on Hepatitis C Virus Positive Patients with Type 2 Diabetes Mellitus: A Word of Caution after the Initial Enthusiasm
Abstract
:1. Introduction
2. Experimental Section
- (1)
- Does SVR achieved by DAAs significantly prevent the onset of IR and DM?
- (2)
- Does HCV clearance with DAAs lead to significant improvement of glycometabolic control in patients with DM? If so, is this control maintained over the long term?
- (3)
- Does SVR-related glycometabolic improvement induce de-escalation/withdrawal of antidiabetic therapy?
- (4)
- Do DAA-induced glycemic changes determine a significant clinical impact on the outcome of DM and its complications?
- (5)
- What is the clinical impact of DAA-induced SVR on the incidence of HCC in diabetic patients?
3. Results and Discussion
3.1. Does SVR Achieved by DAAs Significantly Prevent the Onset of Insulin Resistance and DM?
3.2. Does HCV Clearance with DAAs Lead to Significant Improvement of Glycometabolic Control in Patients with DM? If so, is This Control Maintained over the Long Term?
3.3. Does SVR-Related Glycometabolic Improvement Determine De-Escalation/Withdrawal of Antidiabetic Therapy?
3.4. Do DAA-Induced Glycemic Changes Determine a Significant Clinical Impact on the Outcome of DM and its Complications?
3.5. What is the Clinical Impact of DAA-Induced SVR on The Incidence of HCC in Diabetic Patients?
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Negro, F.; Forton, D.; Craxì, A.; Sulkowski, M.S.; Feld, J.J.; Manns, M.P. Extrahepatic Morbidity and Mortality of Chronic Hepatitis C. Gastroenterology 2015, 149, 1345–1360. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- White, D.L.; Ratziu, V.; El-Serag, H.B. Hepatitis C infection and risk of diabetes: A systematic review and meta-analysis. J. Hepatol. 2008, 49, 831–844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Naing, C.; Mak, J.W.; Ahmed, S.I.; Maung, M. Relationship between hepatitis C virus infection and type 2 diabetes mellitus: Meta-analysis. World J. Gastroenterol. 2012, 18, 1642–1651. [Google Scholar] [CrossRef] [PubMed]
- Antonelli, A. Hepatitis C virus infection and type 1 and type 2 diabetes mellitus. World J. Diabetes 2014, 5, 586. [Google Scholar] [CrossRef] [Green Version]
- Fabiani, S.; Fallahi, P.; Ferrari, S.M.; Miccoli, M.; Antonelli, A. Hepatitis C virus infection and development of type 2 diabetes mellitus: Systematic review and meta-analysis of the literature. Rev. Endocr. Metab. Disord. 2018, 19, 405–420. [Google Scholar] [CrossRef]
- Negro, F. Facts and fictions of HCV and comorbidities: Steatosis, diabetes mellitus, and cardiovascular diseases. J. Hepatol. 2014, 61, S69–S78. [Google Scholar] [CrossRef]
- Kaddai, V.; Negro, F. Current understanding of insulin resistance in hepatitis C. Expert Rev. Gastroenterol. Hepatol. 2011, 5, 503–516. [Google Scholar] [CrossRef]
- 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, 1499–1508. [Google Scholar] [CrossRef] [Green Version]
- 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, 1217–1225. [Google Scholar] [CrossRef] [Green Version]
- 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, 1678–1686. [Google Scholar] [CrossRef]
- Vanni, E.; Abate, M.L.; Gentilcore, E.; Hickman, I.; Gambino, R.; Cassader, M.; Smedile, A.; Ferrannini, E.; Rizzetto, M.; Marchesini, G.; et al. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology 2009, 50, 697–706. [Google Scholar] [CrossRef]
- Gastaldi, G.; Gomes, D.; Schneiter, P.; Montet, X.; Tappy, L.; Clément, S.; Negro, F. Treatment with direct-acting antivirals improves peripheral insulin sensitivity in non-diabetic, lean chronic hepatitis C patients. PLoS ONE 2019, 14. [Google Scholar] [CrossRef] [PubMed]
- Cacoub, P.; Desbois, A.C.; Comarmond, C.; Saadoun, D. Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: A meta-analysis. Gut 2018, 67, 2025–2034. [Google Scholar] [CrossRef] [PubMed]
- Hum, J.; Jou, J.H.; Green, P.K.; Berry, K.; Lundblad, J.; Hettinger, B.D.; Chang, M.; Ioannou, G.N. Improvement in Glycemic Control of Type 2 Diabetes After Successful Treatment of Hepatitis C Virus. Diabetes Care 2017, 40, 1173–1180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ciancio, A.; Bosio, R.; Bo, S.; Pellegrini, M.; Sacco, M.; Vogliotti, E.; Fassio, G.; Bianco Mauthe Degerfeld, A.G.F.; Gallo, M.; Giordanino, C.; 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Drazilova, S.; Janicko, M.; Skladany, L.; Kristian, P.; Oltman, M.; Szantova, M.; Krkoska, D.; Mazuchova, E.; Piesecka, L.; Vahalova, V.; et al. Glucose Metabolism Changes in Patients with Chronic Hepatitis C Treated with Direct Acting Antivirals. Can. J. Gastroenterol. Hepatol. 2018, 2018. [Google Scholar] [CrossRef] [Green Version]
- Gilad, A.; Fricker, Z.P.; Hsieh, A.; Thomas, D.D.; Zahorian, T.; Nunes, D.P. Sustained Improvement in Type 2 Diabetes Mellitus is Common After Treatment of Hepatitis C Virus with Direct-acting Antiviral Therapy. J. Clin. Gastroenterol. 2019, 53, 616–620. [Google Scholar] [CrossRef] [PubMed]
- Weidner, P.; Boettche, D.; Zimmerer, T.; Burgermeister, E.; Teufel, A.; Ebert, M.P.A.; 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, 281–289. [Google Scholar]
- Li, J.; Gordon, S.C.; Rupp, L.B.; Zhang, T.; Trudeau, S.; Holmberg, S.D.; Moorman, A.C.; Spradling, P.R.; Teshale, E.H.; Boscarino, J.A.; et al. Sustained virological response does not improve long-term glycaemic control in patients with type 2 diabetes and chronic hepatitis C. Liver Int. 2019, 39, 1027–1032. [Google Scholar] [CrossRef]
- Abdel Alem, S.; Elsharkawy, A.; Fouad, R.; Adel, E.; Abdellatif, Z.; Musa, S.; Nagy, A.; Hussein, M.S.; Yosry, A.; Esmat, G. Improvement of glycemic state among responders to Sofosbuvir-based treatment regimens: Single center experience. J. Med. Virol. 2017, 89, 2181–2187. [Google Scholar] [CrossRef]
- Dawood, A.A.; Nooh, M.Z.; Elgamal, A.A. 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. [Google Scholar] [CrossRef] [PubMed]
- Morales, A.L.; Junga, Z.; Singla, M.B.; Sjogren, M.; Torres, D. Hepatitis C eradication with sofosbuvir leads to significant metabolic changes. World J. Hepatol. 2016, 8, 1557–1563. [Google Scholar] [CrossRef] [PubMed]
- Ikeda, A.; Ikeda, K.; Takai, A.; Takahashi, K.; Ueda, Y.; Marusawa, H.; Seno, H.; Inagaki, N.; Kokuryu, H. Hepatitis C Treatment with Sofosbuvir and Ledipasvir Accompanied by Immediate Improvement in Hemoglobin A1c. Digestion 2017, 96, 228–230. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Beig, J.; Orr, D.; Harrison, B.; Gane, E. Hepatitis C Virus Eradication with New Interferon-Free Treatment Improves Metabolic Profile in Hepatitis C Virus-Related Liver Transplant Recipients. Liver Transpl. 2018, 24, 1031–1039. [Google Scholar] [CrossRef] [Green Version]
- 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, 342–343. [Google Scholar] [CrossRef] [Green Version]
- Pashun, R.A.; Shen, N.T.; Jesudian, A. Markedly Improved Glycemic Control in Poorly Controlled Type 2 Diabetes following Direct Acting Antiviral Treatment of Genotype 1 Hepatitis C. Case Rep. Hepatol. 2016, 2016. [Google Scholar] [CrossRef] [Green Version]
- Pavone, P.; Tieghi, T.; d’Ettorre, G.; Lichtner, M.; Marocco, R.; Mezzaroma, I.; Passavanti, G.; Vittozzi, P.; Mastroianni, C.M.; Vullo, V. Rapid decline of fasting glucose in HCV diabetic patients treated with direct-acting antiviral agents. Clin. Microbiol. Infect. 2016, 22, e1–e3. [Google Scholar] [CrossRef] [Green Version]
- Carnovale, C.; Pozzi, M.; Dassano, A.; D’Addio, F.; Gentili, M.; Magni, C.; Clementi, E.; Radice, S.; Fiorina, P. The impact of a successful treatment of hepatitis C virus on glyco-metabolic control in diabetic patients: A systematic review and meta-analysis. Acta Diabetol. 2019, 56, 341–354. [Google Scholar] [CrossRef]
- Saab, S.; Barnard, A.; Challita, Y.; Adeniyi, A.; Aziz, A.; Choi, G.; Durazo, F.A.; El-Kabany, M.M.; Han, S.-H.B.; Busuttil, R.W. Impact of Sustained Viral Response with Direct-Acting Agents on Glycemic Control and Renal Function in Hepatitis C Liver Transplant Recipients. Exp. Clin. Transplant. 2018, 16, 419–424. [Google Scholar]
- Teegen, E.M.; Dürr, M.; Maurer, M.M.; Eurich, F.; Vollbort, A.; Globke, B.; Bahra, M.; Blaeker, H.; Pratschke, J.; Eurich, D. Evaluation of histological dynamics, kidney function and diabetes in liver transplant patients after antiviral treatment with direct-acting antivirals: Therapy of HCV-recurrence. Transpl. Infect. Dis. 2019, 21. [Google Scholar] [CrossRef]
- Stine, J.G.; Wynter, J.A.; Niccum, B.; Kelly, V.; Caldwell, S.H.; Shah, N.L. Effect of treatment with direct acting antiviral on glycemic control in patients with diabetes mellitus and chronic hepatitis C. Ann. Hepatol. 2017, 16, 215–220. [Google Scholar] [CrossRef] [PubMed]
- Chaudhury, C.S.; Sheehan, J.; Chairez, C.; Akoth, E.; Gross, C.; Silk, R.; Kattakuzhy, S.; Rosenthal, E.; Kottilil, S.; Masur, H.; et al. No Improvement in Hemoglobin A1c Following Hepatitis C Viral Clearance in Patients with and without HIV. J. Infect. Dis. 2017, 217, 47–50. [Google Scholar] [CrossRef] [PubMed]
- Huang, J.-F.; Huang, C.-F.; Yeh, M.-L.; Dai, C.-Y.; Hsieh, M.-H.; Yang, J.-F.; Huang, C.-I.; Lin, Y.-H.; Liang, P.-C.; Lin, Z.-Y.; et al. The outcomes of glucose abnormalities in chronic hepatitis C patients receiving interferon-free direct antiviral agents. Kaohsiung J. Med. Sci. 2017, 33, 567–571. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shiffman, M.L.; Gunn, N.T. Impact of hepatitis C virus therapy on metabolism and public health. Liver Int. 2017, 37, 13–18. [Google Scholar] [CrossRef]
- Salomone, F.; Catania, M.; Montineri, A.; Bertino, G.; Godos, J.; Rizzo, L.; Magrì, G.; Li Volti, G. Hepatitis C virus eradication by direct antiviral agents improves glucose tolerance and reduces post-load insulin resistance in nondiabetic patients with genotype 1. Liver Int. 2018, 38, 1206–1211. [Google Scholar] [CrossRef]
- Elhelbawy, M.; Abdel-Razek, W.; Alsebaey, A.; Hashim, M.; Elshenawy, H.; Waked, I. Insulin resistance does not impair response of chronic hepatitis C virus to direct-acting antivirals, and improves with the treatment. Eur. J. Gastroenterol. Hepatol. 2019, 31, 16–23. [Google Scholar] [CrossRef]
- Adinolfi, L.E.; 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, 1379–1382. [Google Scholar] [CrossRef]
- Gualerzi, A.; Bellan, M.; Smirne, C.; Tran Minh, M.; Rigamonti, C.; Burlone, M.E.; Bonometti, R.; Bianco, S.; Re, A.; Favretto, S.; et al. Improvement of insulin sensitivity in diabetic and non diabetic patients with chronic hepatitis C treated with direct antiviral agents. PLoS ONE 2018, 13. [Google Scholar] [CrossRef]
- de Andrade, V.G.; da Yamashiro, F.S.; Oliveira, C.V.; Moreira, A.; Winckler, F.C.; Silva, G.F. Insulin resistance reduction after sustained virological response with direct acting antiviral: Not every population improves. Arq. Gastroenterol. 2018, 55, 274–278. [Google Scholar] [CrossRef]
- Meissner, E.G.; Lee, Y.-J.; Osinusi, A.; Sims, Z.; Qin, J.; Sturdevant, D.; McHutchison, J.; Subramanian, M.; Sampson, M.; Naggie, S.; 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. [Google Scholar] [CrossRef] [PubMed]
- Doyle, M.-A.; Galanakis, C.; Mulvihill, E.; Crawley, A.; Cooper, C.L. Hepatitis C Direct Acting Antivirals and Ribavirin Modify Lipid but not Glucose Parameters. Cells 2019, 8, 252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Butt, A.A.; Yan, P.; Aslam, S.; Shaikh, O.S.; Abou-Samra, A.-B. Hepatitis C Virus Treatment with Directly Acting Agents Reduces the Risk of Incident Diabetes -Results from ERCHIVES. Clin. Infect. Dis. 2019. [Google Scholar] [CrossRef]
- El-Serag, H.B.; Christie, I.C.; Puenpatom, A.; Castillo, D.; Kanwal, F.; Kramer, J.R. The effects of sustained virological response to direct-acting anti-viral therapy on the risk of extrahepatic manifestations of hepatitis C infection. Aliment. Pharmacol. Ther. 2019, 49, 1442–1447. [Google Scholar] [CrossRef] [PubMed]
- Mahale, P.; Engels, E.A.; Li, R.; Torres, H.A.; Hwang, L.Y.; Brown, E.L.; Kramer, J.R. The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection. Gut 2018, 67, 553–561. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Zhang, T.; Gordon, S.C.; Rupp, L.B.; Trudeau, S.; Holmberg, S.D.; Moorman, A.C.; Spradling, P.R.; Teshale, E.H.; Boscarino, J.A.; et al. Impact of sustained virologic response on risk of type 2 diabetes among hepatitis C patients in the United States. J. Viral Hepat. 2018, 25, 952–958. [Google Scholar] [CrossRef]
- Roccaro, G.A.; Mitrani, R.; Hwang, W.-T.; Forde, K.A.; Reddy, K.R. Sustained Virological Response Is Associated with a Decreased Risk of Posttransplant Diabetes Mellitus in Liver Transplant Recipients with Hepatitis C-Related Liver Disease. Liver Transpl. 2018, 24, 1665–1672. [Google Scholar] [CrossRef] [Green Version]
- Lenters-Westra, E.; Schindhelm, R.K.; Bilo, H.J.G.; Groenier, K.H.; Slingerland, R.J. Differences in interpretation of haemoglobin A1c values among diabetes care professionals. Neth. J. Med. 2014, 72, 462–466. [Google Scholar]
- Van Der Meer, A.J.; Veldt, B.J.; Feld, J.J.; Wedemeyer, H.; Dufour, J.F.; Lammert, F.; Duarte-Rojo, A.; Heathcote, E.J.; Manns, M.P.; Kuske, L.; et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA J. Am. Med. Assoc. 2012, 308, 2584–2593. [Google Scholar] [CrossRef]
- Tada, T.; Kumada, T.; Toyoda, H.; Kiriyama, S.; Tanikawa, M.; Hisanaga, Y.; Kanamori, A.; Kitabatake, S.; Yama, T.; Tanaka, J. Viral eradication reduces all-cause mortality in patients with chronic hepatitis C virus infection: A propensity score analysis. Liver Int. 2016, 36, 817–826. [Google Scholar] [CrossRef]
- Carrat, F.; Fontaine, H.; Dorival, C.; Simony, M.; Diallo, A.; Hezode, C.; De Ledinghen, V.; Larrey, D.; Haour, G.; Bronowicki, J.P.; et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: A prospective cohort study. Lancet 2019, 393, 1453–1464. [Google Scholar] [CrossRef]
- Hsu, Y.-C.; Lin, J.-T.; Ho, H.J.; Kao, Y.-H.; Huang, Y.-T.; Hsiao, N.-W.; Wu, M.-S.; Liu, Y.-Y.; Wu, C.-Y. Antiviral treatment for hepatitis C virus infection is associated with improved renal and cardiovascular outcomes in diabetic patients. Hepatology 2014, 59, 1293–1302. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, J.; Gordon, S.C.; Rupp, L.B.; Zhang, T.; Trudeau, S.; Holmberg, S.D.; Moorman, A.C.; Spradling, P.R.; Teshale, E.H.; Boscarino, J.A.; et al. Sustained virological response to hepatitis C treatment decreases the incidence of complications associated with type 2 diabetes. Aliment. Pharmacol. Ther. 2019, 49, 599–608. [Google Scholar] [CrossRef] [PubMed]
- Mehta, D.A.; Cohen, E.; Charafeddine, M.; Cohen, D.E.; Bao, Y.; Sanchez Gonzalez, Y.; Tran, T.T. Effect of Hepatitis C Treatment with Ombitasvir/Paritaprevir/R + Dasabuvir on Renal, Cardiovascular and Metabolic Extrahepatic Manifestations: A Post-Hoc Analysis of Phase 3 Clinical Trials. Infect. Dis. Ther. 2017, 6, 515–529. [Google Scholar] [CrossRef] [PubMed]
- Petta, S.; Adinolfi, L.E.; Fracanzani, A.L.; Rini, F.; Caldarella, R.; Calvaruso, V.; Cammà, C.; Ciaccio, M.; Di Marco, V.; Grimaudo, S.; et al. Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis. J. Hepatol. 2018, 69, 18–24. [Google Scholar] [CrossRef]
- Feng, B.; Eknoyan, G.; Guo, Z.-S.; Jadoul, M.; Rao, H.-Y.; Zhang, W.; Wei, L. Effect of interferon-alpha-based antiviral therapy on hepatitis C virus-associated glomerulonephritis: A meta-analysis. Nephrol. Dial. Transplant. 2012, 27, 640–646. [Google Scholar] [CrossRef] [Green Version]
- Saadoun, D.; Pol, S.; Ferfar, Y.; Alric, L.; Hezode, C.; Si Ahmed, S.N.; de Saint Martin, L.; Comarmond, C.; Bouyer, A.S.; Musset, L.; et al. Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis. Gastroenterology 2017, 153, 49–52. [Google Scholar] [CrossRef] [Green Version]
- Rehermann, B. Pathogenesis of chronic viral hepatitis: Differential roles of T cells and NK cells. Nat. Med. 2013, 19, 859–868. [Google Scholar] [CrossRef] [Green Version]
- Durante-Mangoni, E.; Zampino, R.; Marrone, A.; Tripodi, M.F.; Rinaldi, L.; Restivo, L.; Cioffi, M.; Ruggiero, G.; Adinolfi, L.E. Hepatic steatosis and insulin resistance are associated with serum imbalance of adiponectin/tumour necrosis factor-α in chronic hepatitis C patients. Aliment. Pharmacol. Ther. 2006, 24, 1349–1357. [Google Scholar] [CrossRef]
- Serres, L.; Vasseur, P.; Tougeron, D.; Gand, E.; Chagneau-Derrode, C.; Charier, F.; Rochd, S.; Silvain, C. Cardiovascular events in chronic hepatitis C: Prognostic value of liver stiffness evolution. Eur. J. Gastroenterol. Hepatol. 2015, 27, 1286–1292. [Google Scholar] [CrossRef]
- González-Reimers, E.; Quintero-Platt, G.; Martín-González, C.; Pérez-Hernández, O.; Romero-Acevedo, L.; Santolaria-Fernández, F. Thrombin activation and liver inflammation in advanced hepatitis C virus infection. World J. Gastroenterol. 2016, 22, 4427–4437. [Google Scholar] [CrossRef] [PubMed]
- Di Marco, V.; Calvaruso, V.; Ferraro, D.; Bavetta, M.G.; Cabibbo, G.; Conte, E.; Cammà, C.; Grimaudo, S.; Pipitone, R.M.; Simone, F.; et al. Effects of Viral Eradication in Patients with HCV and Cirrhosis Differ with Stage of Portal Hypertension. Gastroenterology 2016, 151, 130–139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- van der Meer, A.J.; Feld, J.J.; Hofer, H.; Almasio, P.L.; Calvaruso, V.; Fernández-Rodríguez, C.M.; Aleman, S.; Ganne-Carrié, N.; D’Ambrosio, R.; Pol, S.; et al. Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication. J. Hepatol. 2017, 66, 485–493. [Google Scholar] [CrossRef] [PubMed]
- Nahon, P.; Bourcier, V.; Layese, R.; Audureau, E.; Cagnot, C.; Marcellin, P.; Guyader, D.; Fontaine, H.; Larrey, D.; De Lédinghen, V.; et al. Eradication of Hepatitis C Virus Infection in Patients with Cirrhosis Reduces Risk of Liver and Non-Liver Complications. Gastroenterology 2017, 152, 142–156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Toyoda, H.; Kumada, T.; Tada, T.; Kiriyama, S.; Tanikawa, M.; Hisanaga, Y.; Kanamori, A.; Kitabatake, S.; Ito, T. Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection. J. Gastroenterol. Hepatol. 2015, 30, 1183–1189. [Google Scholar] [CrossRef] [PubMed]
- Huang, C.-F.; Yeh, M.-L.; Huang, C.-Y.; Tsai, P.-C.; Ko, Y.-M.; Chen, K.-Y.; Lin, Z.-Y.; Chen, S.-C.; Dai, C.-Y.; Chuang, W.-L.; et al. Pretreatment glucose status determines HCC development in HCV patients with mild liver disease after curative antiviral therapy. Medicine 2016, 95. [Google Scholar] [CrossRef]
- Hung, C.-H.; Lee, C.-M.; Wang, J.-H.; Hu, T.-H.; Chen, C.-H.; Lin, C.-Y.; Lu, S.-N. Impact of diabetes mellitus on incidence of hepatocellular carcinoma in chronic hepatitis C patients treated with interferon-based antiviral therapy. Int. J. Cancer 2011, 128, 2344–2352. [Google Scholar] [CrossRef]
- El-Serag, H.B.; Kanwal, F.; Richardson, P.; Kramer, J. Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. [Erratum appears in Hepatology. 2016 Sep;64,1010; PMID: 27541070]. Hepatology 2016, 64, 130–137. [Google Scholar] [CrossRef] [Green Version]
- Hedenstierna, M.; Nangarhari, A.; Weiland, O.; Aleman, S. Diabetes and Cirrhosis Are Risk Factors for Hepatocellular Carcinoma after Successful Treatment of Chronic Hepatitis C. Clin. Infect. Dis. 2016, 63, 723–729. [Google Scholar] [CrossRef] [Green Version]
- Matsuura, K.; Sawai, H.; Ikeo, K.; Ogawa, S.; Iio, E.; Isogawa, M.; Shimada, N.; Komori, A.; Toyoda, H.; Kumada, T.; et al. Genome-Wide Association Study Identifies TLL1 Variant Associated with Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. Gastroenterology 2017, 152, 1383–1394. [Google Scholar] [CrossRef] [Green Version]
- Arase, Y.; Kobayashi, M.; Suzuki, F.; Suzuki, Y.; Kawamura, Y.; Akuta, N.; Kobayashi, M.; Sezaki, H.; Saito, S.; Hosaka, T.; et al. Effect of type 2 diabetes on risk for malignancies includes hepatocellular carcinoma in chronic hepatitis C. Hepatology 2013, 57, 964–973. [Google Scholar] [CrossRef]
- Yamada, R.; Hiramatsu, N.; Oze, T.; Urabe, A.; Tahata, Y.; Morishita, N.; Kodama, T.; Hikita, H.; Sakamori, R.; Yakushijin, T.; et al. Incidence and risk factors of hepatocellular carcinoma change over time in patients with hepatitis C virus infection who achieved sustained virologic response. Hepatol. Res. 2019, 49, 570–578. [Google Scholar] [CrossRef] [PubMed]
- Kozbial, K.; Moser, S.; Al-Zoairy, R.; Schwarzer, R.; Datz, C.; Stauber, R.; Laferl, H.; Strasser, M.; Beinhardt, S.; Stättermayer, A.F.; et al. Follow-up of sustained virological responders with hepatitis C and advanced liver disease after interferon/ribavirin-free treatment. Liver Int. 2018, 38, 1028–1035. [Google Scholar] [CrossRef] [PubMed]
- Romano, A.; Angeli, P.; Piovesan, S.; Noventa, F.; Anastassopoulos, G.; Chemello, L.; Cavalletto, L.; Gambato, M.; Russo, F.P.; 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, 345–352. [Google Scholar] [CrossRef] [PubMed]
- Calvaruso, V.; Cabibbo, G.; Cacciola, I.; Petta, S.; Madonia, S.; Bellia, A.; Tinè, F.; Distefano, M.; Licata, A.; Giannitrapani, L.; et al. Incidence of Hepatocellular Carcinoma in Patients with HCV-Associated Cirrhosis Treated with Direct-Acting Antiviral Agents. Gastroenterology 2018, 155, 411–421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mariño, Z.; Darnell, A.; Lens, S.; Sapena, V.; Díaz, A.; Belmonte, E.; Perelló, C.; Calleja, J.L.; Varela, M.; Rodriguez, M.; et al. Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: Relevance of non-characterized nodules. J. Hepatol. 2019, 70, 874–884. [Google Scholar] [CrossRef] [PubMed]
- 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, 104–113. [Google Scholar] [CrossRef] [Green Version]
- Nahon, P.; Layese, R.; Bourcier, V.; Cagnot, C.; Marcellin, P.; Guyader, D.; Pol, S.; Larrey, D.; De Lédinghen, 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, 1436–1450. [Google Scholar] [CrossRef] [Green Version]
- Kanwal, F.; Kramer, J.; Asch, S.M.; Chayanupatkul, M.; Cao, Y.; El-Serag, H.B. Risk of Hepatocellular Cancer in HCV Patients Treated with Direct-Acting Antiviral Agents. Gastroenterology 2017, 153, 996–1005. [Google Scholar] [CrossRef] [Green Version]
- Mecci, A.J.; Kemos, P.; Leen, C.; Lawson, A.; Richardson, P.; Khakoo, S.I.; Agarwal, K.; Mutimer, D.; Rosenberg, W.M.; Foster, G.R.; et al. The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis. Aliment. Pharmacol. Ther. 2019, 50, 204–214. [Google Scholar] [CrossRef]
- Singer, A.W.; Reddy, K.R.; Telep, L.E.; Osinusi, A.O.; Brainard, D.M.; Buti, M.; Chokkalingam, A.P. Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: A retrospective cohort study. Aliment. Pharmacol. Ther. 2018, 47, 1278–1287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nkontchou, G.; Cosson, E.; Aout, M.; Mahmoudi, A.; Bourcier, V.; Charif, I.; Ganne-Carrie, N.; Grando-Lemaire, V.; Vicaut, E.; Trinchet, J.-C.; et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J. Clin. Endocrinol. Metab. 2011, 96, 2601–2608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lai, S.-W.; Chen, P.-C.; Liao, K.-F.; Muo, C.-H.; Lin, C.-C.; Sung, F.-C. Risk of hepatocellular carcinoma in diabetic patients and risk reduction associated with anti-diabetic therapy: A population-based cohort study. Am. J. Gastroenterol. 2012, 107, 46–52. [Google Scholar] [CrossRef] [PubMed]
- Tseng, C.H. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver Int. 2018, 38, 2018–2027. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.; Harmsen, W.S.; Mettler, T.A.; Kim, W.R.; Roberts, R.O.; Therneau, T.M.; Roberts, L.R.; Chaiteerakij, R. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology 2014, 60, 2008–2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hamdane, N.; Juhling, F.; Crouchet, E.; El Saghire, H.; Thurmann, C.; Oudot, M.A.; Bandiera, S.; Saviano, A.; Ponsolles, C.; Roca Suarez, A.A.; et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology 2019, 156, 2313–2329. [Google Scholar] [CrossRef] [Green Version]
- Perez, S.; Kaspi, A.; Domovitz, T.; Davidovich, A.; Lavi-Itzkovitz, A.; Meirson, T.; Holmes, J.A.; Dai, C.Y.; Huang, C.F.; Chung, R.T.; et al. Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet. 2019, 15. [Google Scholar] [CrossRef]
Author, Year (ref.) | Type of Study | Design | No. of Patients with SVR | No. of Control Patients | HOMA-IR Change (p) | Follow-up |
---|---|---|---|---|---|---|
Salomone et al. 2018 [36] | Observational | Prospective | 32 | N.A. | −1.4 (<0.001) | 12 weeks |
Elhelbawy et al. 2019 [37] | Observational | Prospective | 465 (24% with DM) | 46 | −1.09 (<0.001) | 12 weeks |
Adinolfi et al. 2018 [38] | Case-control | Prospective | 68 | 65 | −2.66 (<0.001) | 12 weeks |
Gualerzi et al. 2018 [39] | Observational | Prospective | 82 | N.A. | −0.62 (<0.001) | 12/24 weeks |
Andrade et al. 2018 [40] | Observational | Prospective | 75 | N.A. | −0.76 (0.02) | 12 weeks |
Meissner et al. 2015 [41] | Phase 2 clinical trial | Prospective | 33 | 17 | Not significant | 36 weeks |
Doyle et al. 2019 [42] | Observational | Prospective | 23 | N.A. | −0.3 (0.32) | 24 weeks |
Author, Year (Reference) | Type of Study | Design | No. of Patients with SVR | No. of Control Patients | DM Incidence in SVR Patients | DM Incidence in Control Patients | p-Value | Follow-up |
---|---|---|---|---|---|---|---|---|
Butt et al. 2019 [43] | Observational | Retrospective | 21279 | 4764 | 9.9/1000 persons/year | 20.9/1000 persons/year | <0.001 | 6 years |
El-Serag et al. 2019 [44] | Observational | Retrospective | 41711 | 3549 | 21.0/1000 persons/year | 23.1/1000 persons/year | 0.86 | 2 years |
Li et al. 2018 [46] | Observational | Retrospective | 3748 | 1397 | 6.2% | 21.7% | 0.0003 | 3.7 years |
Roccaro et al. 2019 [47] | Observational | Retrospective | 31 | 225 | 9.7% | 23,0% | 0.02 | 41,2 months |
Author, Year (Reference) | Type of Study | Design | No. of Diabetic pts | Mean Glycemic Change (p) | Mean HbA1c Level Change (p) | Follow-up |
---|---|---|---|---|---|---|
Ciancio et al. 2018 [15] | Observational | Prospective | 101 | −18.0 md/dL (0.002) | −0.5% (<0.001) | 12 weeks |
Abdel Alem et al. 2017 [20] | Observational | Retrospective | 65 | −11.5 mg/dL (0.005) | –0.5% (<0.001) | 24 weeks |
Dawood et al. 2017 [21] | Clinical trial | Open label | 378 | −23.4 mg/dL (N.A.) | −0.45% (N.A.) | 12 weeks |
Bejg et al. 2018 [24] | Observational | Retrospective | 38 | –19.8 mg/dL (0.01) | −0.2% (0.03) | 24–44 weeks |
Pavone et al. 2016 [27] | Observational | Retrospective | 27 | −52.7 mg/dL (0.0007) | −2.0% (0.02) | 8 weeks |
Weidner et al. 2018 [18] | Observational | Retrospective | 28 | −22 mg/dL (0.04) | −0.29% (0.04) | 0–44 weeks |
Gilad et al. 2019 [17] | Observational | Retrospective | 122 | Not determined | −0.6% (0.001) | 1.5 years |
Hum et al. 2017 [14] | Observational | Retrospective | 2435 | Not determined | −0.37% (0.03)* | 48 weeks |
Morales et al. 2016 [22] | Observational | Retrospective | 23 | Not determined | −0.53% (<0.005) | 24 weeks |
Ikeda et al. 2017 [23] | Observational | Prospective | 13 | Not determined | −0.2% (<0.01) | 12 weeks |
Pashum et al. 2016 [26] | Case report | – | 1 | Not determined | −5.8% (N.A.) | 24 weeks |
Li et al. 2019 [19] | Observational | Retrospective/Prospective | 192 | Not determined | −2.3 (<0.001) | 24 weeks |
Fabrizio et al. 2017 [25] | Observational | Retrospective | 59 | –20 mg/dl (<0.001) | Not determined | 24 weeks |
Drazilova et al. 2018 [16] | Observational | Retrospective | 88 | −21 mg/dl (<0.0001) | Not determined | 12 weeks |
Author, Year (Reference) | Type of Study | Design | No. of Diabetic pts | Mean Glycemic Change (p) | Mean HbA1c Level Change (p) | Follow-up |
---|---|---|---|---|---|---|
Stine et al. 2017 [31] | Observational | Retrospective | 26 | Not determined | −0.25% (0.27) | 12 weeks |
Saab et al. 2018 [29] | Observational | Retrospective | 30 | N.A. (0.32) | Not determined | 27 months |
Teegen et al. 2019 [30] | Observational | Retrospective | 32 | Not determined | −0.7% (0.1) | 31 months |
Chaudhury et al. 2018 [32] | Observational | Prospective | 41 | −6 mg/dl (0.21) | −0.1% (0.29) | 28 months |
Huang et al. 2017 [33] | Clinical trial | Prospective | 13 | Not determined | –0.1% (0.17) | 3−15 months |
Author, Year (Reference) | Type of Study | Design | De-Escalation/Withdrawal of Oral Hypoglycemic Agents, n/total (%) | De-Escalation/Withdrawal of Insulin Therapy, n/total (%) | Follow-up (EOT) |
---|---|---|---|---|---|
Hum et al. 2017 [14] | Observational | Retrospective | 85/1630 (5.2%) | 72/900 (8.0%) | 12 months |
Ciancio et al. 2018 [15] | Observational | Prospective | 8/19 (41.2%) | 13/46 (28.2%) | 12 weeks |
Dawood et al. 2017 [21] | Clinical trial | Open label | 17/378 (4.4%) | 61/378 (16.1%) | 12 weeks |
Morales et al. 2016 [22] | Observational | Retrospective | 2/16 (12.5%) | N.A. | 24 weeks |
Ikeda et al. 2017 [23] | Observational | Prospective | 2/6 (33.3%) | 1/6 (16.6%) | 12 weeks |
Bejg et al. 2018 [24] | Observational | Retrospective | 2/26 (7.6%) | 10/26 (38.4%) | 24–44 weeks |
Fabrizio et al. 2017 [25] | Observational | Retrospective | 0/31 (0.0%) | 1/16 (6.2%) | 12–24 weeks |
Pavone et al. 2016 [27] | Observational | Retrospective | 2/10 (20.0%) | 4/15 (26.6%) | 8 weeks |
Drazilova et al. 2018 [16] | Observational | Retrospective | 0/13 (0.0%) | 3/17 (17.6%) | 12 weeks |
Teegen et al. 2019 [30] | Observational | Retrospective | N.A. | 2/32 (6.25%) | 30.6 months |
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ribaldone, D.G.; Sacco, M.; Saracco, G.M. The Effect of Viral Clearance Achieved by Direct-Acting Antiviral Agents on Hepatitis C Virus Positive Patients with Type 2 Diabetes Mellitus: A Word of Caution after the Initial Enthusiasm. J. Clin. Med. 2020, 9, 563. https://doi.org/10.3390/jcm9020563
Ribaldone DG, Sacco M, Saracco GM. The Effect of Viral Clearance Achieved by Direct-Acting Antiviral Agents on Hepatitis C Virus Positive Patients with Type 2 Diabetes Mellitus: A Word of Caution after the Initial Enthusiasm. Journal of Clinical Medicine. 2020; 9(2):563. https://doi.org/10.3390/jcm9020563
Chicago/Turabian StyleRibaldone, Davide Giuseppe, Marco Sacco, and Giorgio Maria Saracco. 2020. "The Effect of Viral Clearance Achieved by Direct-Acting Antiviral Agents on Hepatitis C Virus Positive Patients with Type 2 Diabetes Mellitus: A Word of Caution after the Initial Enthusiasm" Journal of Clinical Medicine 9, no. 2: 563. https://doi.org/10.3390/jcm9020563