THE COURSE OF HEPATITIS C INFECTION AND RESPONSE TO ANTI-VIRAL THERAPY IN PATIENTS WITH THALASSEMIA MAJOR AND HEPATITIS C INFECTION: A LONGITUDINAL, PROSPECTIVE STUDY.
Main Article Content
Keywords
hepatitis C, thalassemia, liver fibrosis progression, transient elastography, serum fibrosis markers
Abstract
Background/Aims: The course of hepatitis C infection (HCV) in patients with thalassemia has not been adequately studied and management has not been optimized. The current prospective longitudinal study assessed the clinical course, outcome, progression and management of recently acquired HCV in patients with transfusion dependent thalassemia major versus acute HCV without thalassemia.
Methods: A well-characterized cohort of patients with thalassemia and recent HCV infection or recent HCV without thalassemia were enrolled and prospectively followed. The blood transfusion needs and chelating agents were determined. Liver functions tests, HCV-RNA, iron and ferritin levels were measured. Patients with chronic HCV evolution received treatment for HCV. The fibrosis progression rate was determined in chronic HCV patients with or without thalassemia by paired liver biopsies or serial transient elastography (TE), or serum markers of liver fibrosis. Liver iron content (LIC) was assessed by R2 MRI.
Results: Self-limited acute HCV was observed in 17% of patients with acute HCV and thalassemia versus 35% of patients without thalassemia (P=0.031). The fibrosis progression rates were significantly higher in patients with chronic HCV and thalassemia compared to those with chronic HCV alone (1.14±0.48) and (0.35±0.14) (P < 0.0001) respectively. A direct linear correlation was observed between the fibrosis progression rate and each of LIC (R=+0.67; P=0.01) and ferritin (R=0.77; P<0.01). In patients with chronic HCV and thalassemia, the sustained virologic response (SVR) to pegylated interferon based therapy and direct antiviral agents (DAAS) were 33% and 82% respectively (P=), while in chronic HCV patients without thalassemia, the SVR rates to PEG-IFN/RBV and DAAs were 51% and 92% respectively. Five patients with concomitant HCV and thalassemia died during the study due to cardiac causes (n=3) and liver cancer (n=2).
Conclusions: Patients with acute HCV and thalassemia have low rates of spontaneous resolution of HCV infection and the majority develop chronic HCV. Direct acting antiviral combinations are associated with high SVR rates and low adverse event in treatment naïve and experienced patients with chronic HCV and thalassemia. Liver fibrosis is accelerated in thalassemia patients with chronic HCV, therefore, early diagnosis, treatment with DAAs, adequate iron chelation and non-invasive monitoring liver status are recommended to prevent cirrhosis and hepatocellular carcinoma.
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References
1. Lavanchy D. The global burden of hepatitis C. Liver Int 2009; 29:74 81.
2. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2015; 5:558–567.
3. Gower E, et al. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61(1):S45–57.
4. Kamal SM, Nasser IA. Hepatitis C genotype 4: what we know and what we don’t yet know. Hepatology 2008; 47:1371–1383
5. Angelico M, Renganathan E, Gandin C, Fathy M, Profili MC, Refai W, et al. Chronic liver disease in Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections. J Hepatol 1997; 26: 236-243.
6. Talaat M, Afifi S, Reaves E, Abu Elsood H, El-Gohary A, Refaey S, Hammad R, Abdel Fadeel M, Kandeel A. Evidence of sustained reductions in the relative risk of acute hepatitis B and C virus infections, and the increasing burden of hepatitis a virus infection in Egypt: comparison of sentinel acute viral hepatitis surveillance results, 2001–17. BMC Infect Dis. 2019; 19: 159.
7. Westbrook R.H. Dusheiko. G. Natural history of hepatitis C J Hepatol 2014; 61 (1 Suppl) : S58-S68
8. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with hepatitis C. Lancet 1997;349:825-832.
9. Newsum AM, Kooij KW, Boyd A, Smit C, Wit FWNM, van der Meer JTM, Prins M, Reiss P, van der Valk M; MOSAIC study group, ATHENA observational HIV cohort and NVHB-SHM hepatitis working group. Progression of liver fibrosis following acute hepatitis C virus infection in HIV-positive MSM. AIDS. 2019; 1;33(5):833-84.
10. Pol S, Haour G, Fontaine H. Dorival C, Petrov-Sanchez V, Bourliere M, J. Capeau J, Carrieri P, Larrey D, Larsen C, Marcellin, Pawlostky JM, Nahon F, Zoulim P, Cacoub P, de Ledinghen V, Mathurin P, Negro F, Pageaux GP, Yazdanpanah Y. Wittkop L, Zarski JP, Carrat F, For The French Anrs Co22 Hepather Cohor. The negative impact of HBV/HCV coinfection on cirrhosis and its consequences. Aliment Pharmacol Ther. 2017 Dec;46(11-12):1054-1060.
11. Kamal SM, Rasenack JW, Bianchi L, Al Tawil A, El Sayed Khalifa K, Peter T, Mansour H, et al. Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4 (+) T-cell and cytokine response. Gastroenterology 2001; 12: 646-656.
12. Kamal SM, Graham CS, He Q, Bianchi L, Tawil AA, Rasenack JW, et al. Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis. J Infect Dis 2004; 189:1140-1150.
13. Origa R. ?-Thalassemia. Genet Med. 2017 Jun;19(6):609-619.
14. Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R. Cardiovascular function and treatment in ß-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013. 128(3):281-308
15. De Sanctis V, Soliman AT, Yassin MA, Di Maio S, Daar S, Elsedfy H, Soliman N, Kattamis C. Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment. Acta Biomed. 2018 Feb 16;89(2-S):6-15
16. De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Soliman NA, Elalaily R, Kattamis C Endocrine profile of ?-thalassemia major patients followed from childhood to advanced adulthood in a tertiary care center.Indian J Endocrinol Metab. 2016 Jul-Aug;20(4):451-9.
17. De Sanctis V, Kattamis C, Canatan D, Soliman AT, Elsedfy H, Karimi M, Daar S, Wali Y, Yassin M, Soliman N, Sobti P, Al Jaouni S, El Kholy M, Fiscina B, Angastiniotis M. ?-Thalassemia Distribution in the Old World: an Ancient Disease Seen from a Historical Standpoint. Mediterr J Hematol Infect Dis. 2017 Feb 20;9(1):e2017.
18. Elalfy MS, Adly A, Awad H, Tarif Salam M, Berdoukas V, Tricta F. Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: A randomized controlled trial.Am J Hematol. 2018 Feb;93(2):262-268.
19. Ragab L, Helal S, Zaghloul N, El-Raziky M, Afifi R, Musallam KM, Taher AT Clinicovirologic analysis of hepatitis C infection in transfusion-dependent ?-thalassemia major children. 2010; Int J Lab Hematol 32:184–190
20. El-Beshlawy A, Youssry I. Prevention of hemoglobinopathies in Egypt. Hemoglobin. 2009;33 Suppl 1:S14-20
21. Said F, El Beshlawy A, Hamdy M, El Raziky M, Sherif M, Abdel kader A, Ragab Intrafamilial transmission of hepatitis C infection in Egyptian multitransfused thalassemia patients. J Trop Pediatr. 2013;59(4):309-13.
22. Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani D, Giardini C, Galimberti M, Polchi P, Lucarelli G.. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343(5):327-331
23. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. 2004; Haematologica 89:1187–1193
24. Bedossa P, Dargère D and Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003; 38:1449–1457
25. Castera L. Non-invasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142:1293–302.
26. Rossi E, Adams L, Prins A, et al. Validation of the FibroTest biochemical markers scores in assessing liver fibrosis in hepatitis C patients. Clin Chem 2003; 49(3):450-4.
27. Johansen JS, Moller S, Price PA, et al. Plasma YKL-40 a new potential marker of fibrosis in patients with alcoholic cirrhosis? Scand J gastroenterol 1997; 32: 582-90.
28. Karsdal MA, Hjuler ST, Luo Y, Rasmussen DG, Nielsen MJ, Leeming DJ, Goodman Z, Arch RH, Patel K, Schuppan D. Assessment of liver fibrosis progression and regression by a serological collagen turnover profile. Am J Physiol Gastrointestinal Liver Physiol. 2019 Jan 1;316(1):G25-G31
29. Scheuer P.J., Williams R., Muir A.R. Hepatic pathology in relatives of patients with haemochromatosis. J. Pathol. Bacteriol. 1962;84:53–64
30. Rowe JW, Wands JR, Mezey E, Waterbury LA, Wright JR, Tobin J, Andres R. Familial hemochromatosis: characteristics of the precirrhotic stage in a large kindred. Medicine (Baltimore). 1977 May;56(3):197-211.
31. Alustiza JM, Castiella A, De Juan MD, Emparanza JI, Artetxe J, Uranga M. Iron overload in the liver diagnostic and quantification. Eur J Radiol. 2007; 61:499–506.
32. Bedossa, P. & Poynard, T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology, 1996; 24, 289– 293.
33. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997 Mar 22;349(9055):825-32.
34. Deuffic-Burban S, Poynard T, Valleron AJ. Quantification of fibrosis progression in patients with chronic hepatitis C using a Markov model. J Viral Hepat. 2002;9(2):114-22.
35. Poynard T, Vergniol J, Ngo Y, Foucher J, Munteanu M, Merrouche W, Colombo M, Thibault V, Schiff E, Brass CA, Albrecht JK, Rudler M, Deckmyn O, Lebray P, Thabut D, Ratziu V, de Ledinghen V; FibroFrance Study Group; Epic3 Study Group; Bordeaux HCV Study Group. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and transient elastography (FibroScan®). J Hepatol. 2014;60(4):706-14
36. Kennedy P, Wagner M, Castéra L, Hong CW, Johnson CL, Sirlin CB, Taouli B. Quantitative Elastography Methods in Liver Disease: Current Evidence and Future Directions. Radiology: 2018; 286 ( 3): 738-763
37. Rose C, Vandevenne P, Bourgeois E, Cambier N, Ernst O. Liver iron content assessment by routine and simple magnetic resonance imaging procedure in highly transfused patients. Eur J Haematol. 2006 Aug;77(2):145-9
38. Tipirneni-Sajja A, Song R, McCarville MB, Loeffler RB, Hankins JS, Hillenbrand CM.Automated vessel exclusion technique for quantitative assessment of hepatic iron overload by R2*-MRI. J Magn Reson Imaging. 2018 Jun;47(6):1542-1551
39. Kamal SM, Kassim SK, Ahmed AI, Mahmoud S, Bahnasy KA, Hafez TA, Aziz IA, Fathelbab IF, Mansour HM. Host and viral determinants of the outcome of exposure to HCV infection genotype 4: a large longitudinal study. Am J Gastroenterol. 2014 Feb;109(2):199-211.
40. Sharaf Eldin N, Ismail S, Mansour H, et al. Symptomatic acute hepatitis C in Egypt: diagnosis, spontaneous viral clearance, and delayed treatment with 12 weeks of pegylated interferon alfa?2a. PLoS One. 2008; 3( 12): e4085.
41. Bakr I, Rekacewicz C, El Hosseiny M, Ismail S, El Daly M, El-Kafrawy S, Esmat G, Hamid MA, Mohamed MK, Fontanet A. Higher clearance of hepatitis C virus infection in females compared with males. Gut. 2006 Aug;55(8):1183-7.
42. Santantonio T, Medda E, Ferrari C, Fabris P, Cariti G, Massari M, Babudieri S, Toti M, Francavilla R, Ancarani F, Antonucci G, Scotto G, Di Marco V, Pastore G, Stroffolini T. Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy. Clin Infect Dis. 2006;43:1154–9.
43. Jauncey M, Micallef JM, Gilmour S, et al. Clearance of hepatitis C virus after newly acquired infection in injection drug users. Jjj Infect Dis. 2004; 190 (7): 1270? 1274.
44. Zhang M, Rosenberg PS, Brown DL, Preiss L, Konkle BA, Eyster ME, Goedert JJ. Second Multicenter Hemophilia Cohort Study. Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia. Blood 2006; 107: 892– 7.
45. Lai ME, Origa R, Danjou F, Leoni GB, Vacquer S, Anni F, Corrias C, Farci P, Congiu G, Galanello R. Natural history of hepatitis C in thalassemia major: a long-term prospective study. Eur J Haematol. 2013; 90(6):501-7.
46. Kamal SM, Fouly A, Mohamed MK, Lamonti S, Gohary M, Koziel MJ, Afdhal NA. Peginterferon alpha-2b therapy with and without ribavirin in patients with thalassemia: A randomized study. Journal of Hepatology. 2006;44 (2): S217
47. Harmatz P, Jonas MM, Kwiatkowski JL, Wright EC, Fischer R, Vichinsky E, et al. Safety and efficacy of pegylated interferon alpha-2a and ribavirin for the treatment of hepatitis C in patients with thalassemia. Haematologica. 2008;93(8):1247–51
48. Sandoughdaran S, Alavian SM, Sharafi H, Behnava B, Salimi S, Mehrnoush L, Karimi Elizee P, Keshvari M. Efficacy of prolonged treatment with pegylated interferon (Peg-IFN) and ribavirin in thalassemic patients with hepatitis C who relapsed after previous Peg-IFN-Based Therapy. Hepat Mon. 2015. 13;15(1):e23564.
49. Origa R, Ponti ML, Filosa A, Galeota Lanza A, Piga A, Saracco GM, Pinto V, Picciotto A, Rigano P, Madonia S, Rosso R, D'Ascola D, Cappellini MD, D'Ambrosio R, Tartaglione I, De Franceschi L, Gianesin B, Di Marco V, Forni GL; Italy for THAlassemia and hepatitis C Advance - Società Italiana Talassemie ed Emoglobinopatie (ITHACA-SITE). Treatment of hepatitis C virus infection with direct-acting antiviral drugs is safe and effective in patients with hemoglobinopathies. Am J Hematol. 2017 Dec;92(12):1349-1355.
50. Mehta R, Kabrawala M, Nandwani S, Desai P, Bhayani V, Patel S, Parekh V. Safety and Efficacy of Sofosbuvir and Daclatasvir for hepatitis C virus infection in patients with ?-thalassemia major. J Clin Exp Hepatol. 2018;8(1):3-6.
51. Mangia A, Sarli R, Gamberini R, Piga A, Cenderello G, Piazzolla V, Santoro R, Caruso V, Quarta A, Ganga R, Copetti M, Forni G. Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion-dependent thalassaemia and HCV genotype 1 or 4 infection. Aliment Pharmacol Ther. 2017; 46(4):424-431
52. Maira D, Cassinerio E, Marcon A, Mancarella M, Fraquelli M, Pedrotti P, Cappellini MD. Progression of liver fibrosis can be controlled by adequate chelation in transfusion-dependent thalassemia (TDT). Ann Hematol. 2017; 96(11):1931-1936.
53. Ferraioli G, Lissandrin R, Tinelli C, Scudeller L, Bonetti F, Zicchetti M, Longo F, Murgia M, Bernuzzi S, Zecca M, Casula P, Piga A, Filice C. Liver stiffness assessed by transient elastography in patients with ? thalassaemia major. Ann Hepatol. 2016; 15(3):410-417.
2. Shepard CW, Finelli L, Alter MJ. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2015; 5:558–567.
3. Gower E, et al. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61(1):S45–57.
4. Kamal SM, Nasser IA. Hepatitis C genotype 4: what we know and what we don’t yet know. Hepatology 2008; 47:1371–1383
5. Angelico M, Renganathan E, Gandin C, Fathy M, Profili MC, Refai W, et al. Chronic liver disease in Alexandria governorate, Egypt: contribution of schistosomiasis and hepatitis virus infections. J Hepatol 1997; 26: 236-243.
6. Talaat M, Afifi S, Reaves E, Abu Elsood H, El-Gohary A, Refaey S, Hammad R, Abdel Fadeel M, Kandeel A. Evidence of sustained reductions in the relative risk of acute hepatitis B and C virus infections, and the increasing burden of hepatitis a virus infection in Egypt: comparison of sentinel acute viral hepatitis surveillance results, 2001–17. BMC Infect Dis. 2019; 19: 159.
7. Westbrook R.H. Dusheiko. G. Natural history of hepatitis C J Hepatol 2014; 61 (1 Suppl) : S58-S68
8. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with hepatitis C. Lancet 1997;349:825-832.
9. Newsum AM, Kooij KW, Boyd A, Smit C, Wit FWNM, van der Meer JTM, Prins M, Reiss P, van der Valk M; MOSAIC study group, ATHENA observational HIV cohort and NVHB-SHM hepatitis working group. Progression of liver fibrosis following acute hepatitis C virus infection in HIV-positive MSM. AIDS. 2019; 1;33(5):833-84.
10. Pol S, Haour G, Fontaine H. Dorival C, Petrov-Sanchez V, Bourliere M, J. Capeau J, Carrieri P, Larrey D, Larsen C, Marcellin, Pawlostky JM, Nahon F, Zoulim P, Cacoub P, de Ledinghen V, Mathurin P, Negro F, Pageaux GP, Yazdanpanah Y. Wittkop L, Zarski JP, Carrat F, For The French Anrs Co22 Hepather Cohor. The negative impact of HBV/HCV coinfection on cirrhosis and its consequences. Aliment Pharmacol Ther. 2017 Dec;46(11-12):1054-1060.
11. Kamal SM, Rasenack JW, Bianchi L, Al Tawil A, El Sayed Khalifa K, Peter T, Mansour H, et al. Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4 (+) T-cell and cytokine response. Gastroenterology 2001; 12: 646-656.
12. Kamal SM, Graham CS, He Q, Bianchi L, Tawil AA, Rasenack JW, et al. Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis. J Infect Dis 2004; 189:1140-1150.
13. Origa R. ?-Thalassemia. Genet Med. 2017 Jun;19(6):609-619.
14. Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R. Cardiovascular function and treatment in ß-thalassemia major: a consensus statement from the American Heart Association. Circulation. 2013. 128(3):281-308
15. De Sanctis V, Soliman AT, Yassin MA, Di Maio S, Daar S, Elsedfy H, Soliman N, Kattamis C. Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment. Acta Biomed. 2018 Feb 16;89(2-S):6-15
16. De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Soliman NA, Elalaily R, Kattamis C Endocrine profile of ?-thalassemia major patients followed from childhood to advanced adulthood in a tertiary care center.Indian J Endocrinol Metab. 2016 Jul-Aug;20(4):451-9.
17. De Sanctis V, Kattamis C, Canatan D, Soliman AT, Elsedfy H, Karimi M, Daar S, Wali Y, Yassin M, Soliman N, Sobti P, Al Jaouni S, El Kholy M, Fiscina B, Angastiniotis M. ?-Thalassemia Distribution in the Old World: an Ancient Disease Seen from a Historical Standpoint. Mediterr J Hematol Infect Dis. 2017 Feb 20;9(1):e2017.
18. Elalfy MS, Adly A, Awad H, Tarif Salam M, Berdoukas V, Tricta F. Safety and efficacy of early start of iron chelation therapy with deferiprone in young children newly diagnosed with transfusion-dependent thalassemia: A randomized controlled trial.Am J Hematol. 2018 Feb;93(2):262-268.
19. Ragab L, Helal S, Zaghloul N, El-Raziky M, Afifi R, Musallam KM, Taher AT Clinicovirologic analysis of hepatitis C infection in transfusion-dependent ?-thalassemia major children. 2010; Int J Lab Hematol 32:184–190
20. El-Beshlawy A, Youssry I. Prevention of hemoglobinopathies in Egypt. Hemoglobin. 2009;33 Suppl 1:S14-20
21. Said F, El Beshlawy A, Hamdy M, El Raziky M, Sherif M, Abdel kader A, Ragab Intrafamilial transmission of hepatitis C infection in Egyptian multitransfused thalassemia patients. J Trop Pediatr. 2013;59(4):309-13.
22. Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani D, Giardini C, Galimberti M, Polchi P, Lucarelli G.. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med. 2000;343(5):327-331
23. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. 2004; Haematologica 89:1187–1193
24. Bedossa P, Dargère D and Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003; 38:1449–1457
25. Castera L. Non-invasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142:1293–302.
26. Rossi E, Adams L, Prins A, et al. Validation of the FibroTest biochemical markers scores in assessing liver fibrosis in hepatitis C patients. Clin Chem 2003; 49(3):450-4.
27. Johansen JS, Moller S, Price PA, et al. Plasma YKL-40 a new potential marker of fibrosis in patients with alcoholic cirrhosis? Scand J gastroenterol 1997; 32: 582-90.
28. Karsdal MA, Hjuler ST, Luo Y, Rasmussen DG, Nielsen MJ, Leeming DJ, Goodman Z, Arch RH, Patel K, Schuppan D. Assessment of liver fibrosis progression and regression by a serological collagen turnover profile. Am J Physiol Gastrointestinal Liver Physiol. 2019 Jan 1;316(1):G25-G31
29. Scheuer P.J., Williams R., Muir A.R. Hepatic pathology in relatives of patients with haemochromatosis. J. Pathol. Bacteriol. 1962;84:53–64
30. Rowe JW, Wands JR, Mezey E, Waterbury LA, Wright JR, Tobin J, Andres R. Familial hemochromatosis: characteristics of the precirrhotic stage in a large kindred. Medicine (Baltimore). 1977 May;56(3):197-211.
31. Alustiza JM, Castiella A, De Juan MD, Emparanza JI, Artetxe J, Uranga M. Iron overload in the liver diagnostic and quantification. Eur J Radiol. 2007; 61:499–506.
32. Bedossa, P. & Poynard, T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology, 1996; 24, 289– 293.
33. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997 Mar 22;349(9055):825-32.
34. Deuffic-Burban S, Poynard T, Valleron AJ. Quantification of fibrosis progression in patients with chronic hepatitis C using a Markov model. J Viral Hepat. 2002;9(2):114-22.
35. Poynard T, Vergniol J, Ngo Y, Foucher J, Munteanu M, Merrouche W, Colombo M, Thibault V, Schiff E, Brass CA, Albrecht JK, Rudler M, Deckmyn O, Lebray P, Thabut D, Ratziu V, de Ledinghen V; FibroFrance Study Group; Epic3 Study Group; Bordeaux HCV Study Group. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest™) and transient elastography (FibroScan®). J Hepatol. 2014;60(4):706-14
36. Kennedy P, Wagner M, Castéra L, Hong CW, Johnson CL, Sirlin CB, Taouli B. Quantitative Elastography Methods in Liver Disease: Current Evidence and Future Directions. Radiology: 2018; 286 ( 3): 738-763
37. Rose C, Vandevenne P, Bourgeois E, Cambier N, Ernst O. Liver iron content assessment by routine and simple magnetic resonance imaging procedure in highly transfused patients. Eur J Haematol. 2006 Aug;77(2):145-9
38. Tipirneni-Sajja A, Song R, McCarville MB, Loeffler RB, Hankins JS, Hillenbrand CM.Automated vessel exclusion technique for quantitative assessment of hepatic iron overload by R2*-MRI. J Magn Reson Imaging. 2018 Jun;47(6):1542-1551
39. Kamal SM, Kassim SK, Ahmed AI, Mahmoud S, Bahnasy KA, Hafez TA, Aziz IA, Fathelbab IF, Mansour HM. Host and viral determinants of the outcome of exposure to HCV infection genotype 4: a large longitudinal study. Am J Gastroenterol. 2014 Feb;109(2):199-211.
40. Sharaf Eldin N, Ismail S, Mansour H, et al. Symptomatic acute hepatitis C in Egypt: diagnosis, spontaneous viral clearance, and delayed treatment with 12 weeks of pegylated interferon alfa?2a. PLoS One. 2008; 3( 12): e4085.
41. Bakr I, Rekacewicz C, El Hosseiny M, Ismail S, El Daly M, El-Kafrawy S, Esmat G, Hamid MA, Mohamed MK, Fontanet A. Higher clearance of hepatitis C virus infection in females compared with males. Gut. 2006 Aug;55(8):1183-7.
42. Santantonio T, Medda E, Ferrari C, Fabris P, Cariti G, Massari M, Babudieri S, Toti M, Francavilla R, Ancarani F, Antonucci G, Scotto G, Di Marco V, Pastore G, Stroffolini T. Risk factors and outcome among a large patient cohort with community-acquired acute hepatitis C in Italy. Clin Infect Dis. 2006;43:1154–9.
43. Jauncey M, Micallef JM, Gilmour S, et al. Clearance of hepatitis C virus after newly acquired infection in injection drug users. Jjj Infect Dis. 2004; 190 (7): 1270? 1274.
44. Zhang M, Rosenberg PS, Brown DL, Preiss L, Konkle BA, Eyster ME, Goedert JJ. Second Multicenter Hemophilia Cohort Study. Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia. Blood 2006; 107: 892– 7.
45. Lai ME, Origa R, Danjou F, Leoni GB, Vacquer S, Anni F, Corrias C, Farci P, Congiu G, Galanello R. Natural history of hepatitis C in thalassemia major: a long-term prospective study. Eur J Haematol. 2013; 90(6):501-7.
46. Kamal SM, Fouly A, Mohamed MK, Lamonti S, Gohary M, Koziel MJ, Afdhal NA. Peginterferon alpha-2b therapy with and without ribavirin in patients with thalassemia: A randomized study. Journal of Hepatology. 2006;44 (2): S217
47. Harmatz P, Jonas MM, Kwiatkowski JL, Wright EC, Fischer R, Vichinsky E, et al. Safety and efficacy of pegylated interferon alpha-2a and ribavirin for the treatment of hepatitis C in patients with thalassemia. Haematologica. 2008;93(8):1247–51
48. Sandoughdaran S, Alavian SM, Sharafi H, Behnava B, Salimi S, Mehrnoush L, Karimi Elizee P, Keshvari M. Efficacy of prolonged treatment with pegylated interferon (Peg-IFN) and ribavirin in thalassemic patients with hepatitis C who relapsed after previous Peg-IFN-Based Therapy. Hepat Mon. 2015. 13;15(1):e23564.
49. Origa R, Ponti ML, Filosa A, Galeota Lanza A, Piga A, Saracco GM, Pinto V, Picciotto A, Rigano P, Madonia S, Rosso R, D'Ascola D, Cappellini MD, D'Ambrosio R, Tartaglione I, De Franceschi L, Gianesin B, Di Marco V, Forni GL; Italy for THAlassemia and hepatitis C Advance - Società Italiana Talassemie ed Emoglobinopatie (ITHACA-SITE). Treatment of hepatitis C virus infection with direct-acting antiviral drugs is safe and effective in patients with hemoglobinopathies. Am J Hematol. 2017 Dec;92(12):1349-1355.
50. Mehta R, Kabrawala M, Nandwani S, Desai P, Bhayani V, Patel S, Parekh V. Safety and Efficacy of Sofosbuvir and Daclatasvir for hepatitis C virus infection in patients with ?-thalassemia major. J Clin Exp Hepatol. 2018;8(1):3-6.
51. Mangia A, Sarli R, Gamberini R, Piga A, Cenderello G, Piazzolla V, Santoro R, Caruso V, Quarta A, Ganga R, Copetti M, Forni G. Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion-dependent thalassaemia and HCV genotype 1 or 4 infection. Aliment Pharmacol Ther. 2017; 46(4):424-431
52. Maira D, Cassinerio E, Marcon A, Mancarella M, Fraquelli M, Pedrotti P, Cappellini MD. Progression of liver fibrosis can be controlled by adequate chelation in transfusion-dependent thalassemia (TDT). Ann Hematol. 2017; 96(11):1931-1936.
53. Ferraioli G, Lissandrin R, Tinelli C, Scudeller L, Bonetti F, Zicchetti M, Longo F, Murgia M, Bernuzzi S, Zecca M, Casula P, Piga A, Filice C. Liver stiffness assessed by transient elastography in patients with ? thalassaemia major. Ann Hepatol. 2016; 15(3):410-417.