PATIENTS WITH HAEMOGLOBINOPATHIES AND CHRONIC HEPATITIS C: A REALLY DIFFICULT TO TREAT POPULATION IN 2016?
Main Article Content
Keywords
Thalassemic Syndromes, HCV, Treatment, DAAs
Abstract
Background & objectives: In the past, patients with haemoglobinopathies were at high risk for acquiring hepatitis C virus (HCV) due to multiple transfusions before HCV screening. In these patients the coexistence of haemochromatosis and chronic hepatitis C (CHC) often leads to more severe liver disease. We assessed the HCV prevalence, clinical characteristics and outcome in this setting with particular attention to the response to treatment including therapies with the new direct acting antivirals (DAAs).
Methods: The medical records of 81 consecutive patients followed the last 15 years were reviewed retrospectively.
Results: 43/81 (53%) patients were anti-HCV positive including 31/43 (72.1%) with CHC (HCV-RNA positive; age 25±7 years; 45.2% with genotype 1b; 19.4% cirrhotics; baseline ferritin 887 ng/ml; range: 81-10.820). Thirty patients received IFN-based therapy with or without ribavirin with sustained virological response (SVR) in 14/30 (46.7%). Eleven patients (9 non-responders to IFN-based therapies, 1 relapser and 1 naïve) received treatment with DAAs (SVR: 100%). 3/11 patients increased their transfusion needs while 1/11 reported mild arthralgias. No drug-drug interactions between DAAs and chelation agents were observed as attested by the stability of ferritin levels during treatment.
Conclusions: More than 1/3 of patients with haemoglobinopathies suffered from CHC. Response rates to antiviral treatment seem to be similar to other patients with CHC, while treatment with DAAs was very effective and safe even in difficult to treat patients (most null responders with severe fibrosis) suggesting that this group of HCV patients should no longer be regarded as a difficult to treat.
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References
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[2] Papatheodoridis G, Thomas HC, Golna C, Bernardi M, Carballo M, Cornberg M, Dalekos G, Degertekin B, Dourakis S, Flisiak R, Goldberg D, Gore C, Goulis I, Hadziyannis S, Kalamitsis G, Kanavos P, Kautz A, Koskinas I, Leite BR, Malliori M, Manolakopoulos S, Mati?i? M, Papaevangelou V, Pirona A, Prati D, Raptopoulou-Gigi M, Reic T, Robaeys G, Schatz E, Souliotis K, Tountas Y, Wiktor S, Wilson D, Yfantopoulos J, Hatzakis A. Addressing barriers to the prevention, diagnosis and treatment of hepatitis B and C in the face of persisting fiscal constraints in Europe: report from a high level conference. J Viral Hepat 2016;23 (Suppl 1):1-12.
[3] Di Marco V, Capra M, Angelucci E, Borgna-Pignatti C, Telfer P, Harmatz P, Kattamis A, Prossamariti L, Filosa A, Rund D, Gamberini MR, Cianciulli P, De Montalembert M, Gagliardotto F, Foster G, Grangè JD, Cassarà F, Iacono A, Cappellini MD, Brittenham GM, Prati D, Pietrangelo A, Craxì A, Maggio A; Italian Society for the Study of Thalassemia and Haemoglobinopathies; Italian Association for the Study of the Liver.. Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel. Blood. 2010;116:2875-83.
[4] Hershko C. Pathogenesis and management of iron toxicity in thalassemia. Ann N Y Acad Sci. 2010;1202:1-9.
[5] Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G, Lucarelli G. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood. 2002;100:17-21.
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[7] EASL recommendations on treatment of Hepatitis C 2015. J Hepatol. 2015;63:199-236.
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[9] Donohue SM, Wonke B, Hoffbrand AV, Reittie J, Ganeshaguru K, Scheuer PJ, Brown D, Dusheiko G. Alpha interferon in the treatment of chronic hepatitis C infection in thalassaemia major. Br J Haematol. 1993;83:491-497.
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[11] Di Marco V, Lo Iacono O, Almasio P, Ciaccio C, Capra M, Rizzo M, Malizia R, Maggio A, Fabiano C, Barbaria F, Craxi A. Long-term efficacy of alpha interferon in beta-thalassemics with chronic hepatitis C. Blood. 1997;90: 2207-12.
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[13] Butensky E, Pakbaz Z, Foote D, Walters MC, Vichinsky EP, Harmatz P. Treatment of hepatitis C virus infection in thalassemia. Ann N Y Acad Sci 2005; 1054: 290-299.
[14] Alavian SM, Tabatabaei SV. Treatment of chronic hepatitis C in polytransfused thalassaemic patients: a meta-analysis. J Viral Hepat. 2010;17:236-244.
[15] Vafiadis I, Trilianos P, Vlachogiannakos J, Karagiorga M, Hatziliami A, Voskaridou E, Ladas SD. Efficacy and safety of interferon-based therapy in the treatment of adult thalassemic patients with chronic hepatitis C: a 12 years audit. Ann Hepatol. 2013;12:532-8.
[16] Kalafateli M, Kourakli A, Gatselis N, Lambropoulou P, Thomopoulos K, Tsamandas A, Christofidou M, Zachou K, Jelastopoulou E, Nikolopoulou V,Symeonidis A, Dalekos GN, Lambropoulou-Karatza C, Triantos C. Efficacy of interferon a-2b monotherapy in b-thalassemics with chronic hepatitis C. J Gastrointestin Liver Dis. 2015;24:189-96.
[17] Gatselis NK, Rigopoulou E, Stefos A, Kardasi M, Dalekos GN. Risk factors associated with HCV infection in semi-rural areas of central Greece. Eur J Intern Med. 2007;18:48-55.
[18] Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1:431-35.
[19] Gatselis NK, Zachou K, Norman GL, Tzellas G, Speletas M, Gabeta S, Germenis A, Koukoulis GK, Dalekos GN. IgA antibodies against deamidated gliadin peptides in patients with chronic liver diseases. Clin Chim Acta 2012; 413:1683-8.
[20] Kaffe ET, Rigopoulou EI, Koukoulis GK, Dalekos GN, Moulas AN. Oxidative stress and antioxidant status in patients with autoimmune liver diseases. Redox Rep 2015;20:33-41.
[21] Norman GL, Gatselis NK, Shums Z, Liaskos C, Bogdanos DP, Koukoulis GK, Dalekos GN. Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma. World J Hepatol 2015;7:1875-83.
[22] Kountouras D, Tsagarakis NJ, Fatourou E, Dalagiorgos E, Chrysanthos N, Berdoussi H, Vgontza N, Karagiorga M, Lagiandreou A, Kaligeros K, Voskaridou E,Roussou P, Diamanti-Kandarakis E, Koskinas J. Liver disease in adult transfusion dependent beta-thalassaemia patients: investigating the role of iron overload and chronic HCV infection. Liver Int 2013;33:420-7.
[23] Triantos C, Kourakli A, Kalafateli M, Giannakopoulou D, Koukias N, Thomopoulos K, Lampropoulou P, Bartzavali C, Fragopanagou H, Kagadis GC, Christofidou M, Tsamandas A, Nikolopoulou V, Karakantza M, Labropoulou-Karatza C. Hepatitis C in patients with ?-thalassemia major. A single-centre experience. Ann Hematol 2013;92:739-46.
[24] Prati D, Poli F, Farma E, Picone A, Porta E, Mattei C, Zanella A, Scalamogna A, Gamba A, Gronda E, Faggian G, Livi U, Puricelli C, Viganò M, Sirchia G. A multicenter prospective study on the risk of acquiring liver disease in anti-hepatitis C virus negative patients affected from homozygous beta-thalassemia. Blood. 1998;92:3460-64.
[25] Christofidou M, Lambropoulou-Karatza C, Dimitracopoulos G, Spiliopoulou I. Distribution of hepatitis C virus genotypes in viremic patients with beta-thalassemia. Eur J Clin Microbiol Infect Dis. 2000;19:728-30.
[26] Lai ME, Origa R, Daniou F, Leoni GB, Vacquer S, Anni F, Corrias C, Farci P, Conqiu G, Galanello R. Natural history of hepatitis C in thalassemia major: a long-term prospective study. Eur J Hematol. 2013;90:501-7.
[27] Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48:418-31.
[28] Lingala S, Ghany MG. Natural history of hepatitis C. Gastroenterol Clin North Am. 2015;44:717-34.
[29] Sherker AH, Senosier M, Kermack D. Treatment of transfusion-dependent thalassemic patients infected with hepatitis C virus with interferon alpha-2b and ribavirin. Hepatology. 2003;37:223.
[30] Poynard T, Marcellin P, Lee SS, NiederauC, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352:1426-32.
[31] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa?2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-82.
[32] Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications Gut. 2006;55:1350–59.
[33] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR,Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211–21.
[34] Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R, Lalezari J, Younes ZH, Pockros PJ, Di Bisceglie AM, Arora S, Subramanian GM, Zhu Y, Dvory-Sobol H, Yang JC,Pang PS, Symonds WT, McHutchison JG, Muir AJ, Sulkowski M, Kwo P; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483–93.
[35] Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, Shiffman ML, Schiff E, Ghalib R, Ryan M, Rustgi V, Chojkier M, Herring R, Di Bisceglie AM, Pockros PJ, Subramanian GM, An D, Svarovskaia E, Hyland RH, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Pound D, Fried MW; ION-3 Investigators.. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879–88.
[36] Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, Weiland O, Aguilar H, Xiong J, Pilot-Matias T, DaSilva-Tillmann B, Larsen L, Podsadecki T,Bernstein B.. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370:1594–1603.
[37] Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, Tam E, Marinho RT, Tsai N, Nyberg A, Box TD, Younes Z, Enayati P, Green S, Baruch Y,Bhandari BR, Caruntu FA, Sepe T, Chulanov V, Janczewska E, Rizzardini G, Gervain J, Planas R, Moreno C, Hassanein T, Xie W, King M, Podsadecki T, Reddy KR; PEARL-III Study; PEARL-IV Study.. ABT-450/rombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983–92.
[1] Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333–42.
[2] Papatheodoridis G, Thomas HC, Golna C, Bernardi M, Carballo M, Cornberg M, Dalekos G, Degertekin B, Dourakis S, Flisiak R, Goldberg D, Gore C, Goulis I, Hadziyannis S, Kalamitsis G, Kanavos P, Kautz A, Koskinas I, Leite BR, Malliori M, Manolakopoulos S, Mati?i? M, Papaevangelou V, Pirona A, Prati D, Raptopoulou-Gigi M, Reic T, Robaeys G, Schatz E, Souliotis K, Tountas Y, Wiktor S, Wilson D, Yfantopoulos J, Hatzakis A. Addressing barriers to the prevention, diagnosis and treatment of hepatitis B and C in the face of persisting fiscal constraints in Europe: report from a high level conference. J Viral Hepat 2016;23 (Suppl 1):1-12.
[3] Di Marco V, Capra M, Angelucci E, Borgna-Pignatti C, Telfer P, Harmatz P, Kattamis A, Prossamariti L, Filosa A, Rund D, Gamberini MR, Cianciulli P, De Montalembert M, Gagliardotto F, Foster G, Grangè JD, Cassarà F, Iacono A, Cappellini MD, Brittenham GM, Prati D, Pietrangelo A, Craxì A, Maggio A; Italian Society for the Study of Thalassemia and Haemoglobinopathies; Italian Association for the Study of the Liver.. Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel. Blood. 2010;116:2875-83.
[4] Hershko C. Pathogenesis and management of iron toxicity in thalassemia. Ann N Y Acad Sci. 2010;1202:1-9.
[5] Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G, Lucarelli G. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood. 2002;100:17-21.
[6] Di Marco V, Capra M, Gagliardotto F, Borsellino Z, Cabibi D, Barbaria F, Ferraro D, Cuccia L, Ruffo GB, Bronte F, Di Stefano R, Almasio PL, Craxì A. Liver disease in chelated transfusiondependent thalassemics: the role of iron overload and chronic hepatitis C. Haematologica. 2008;93:1243-6.
[7] EASL recommendations on treatment of Hepatitis C 2015. J Hepatol. 2015;63:199-236.
[8] European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55:245–264.
[9] Donohue SM, Wonke B, Hoffbrand AV, Reittie J, Ganeshaguru K, Scheuer PJ, Brown D, Dusheiko G. Alpha interferon in the treatment of chronic hepatitis C infection in thalassaemia major. Br J Haematol. 1993;83:491-497.
[10] Telfer PT, Garson JA, Whitby K, et al. Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients. Br J Haematol. 1997;98:850-855.
[11] Di Marco V, Lo Iacono O, Almasio P, Ciaccio C, Capra M, Rizzo M, Malizia R, Maggio A, Fabiano C, Barbaria F, Craxi A. Long-term efficacy of alpha interferon in beta-thalassemics with chronic hepatitis C. Blood. 1997;90: 2207-12.
[12] Li CK, Chan PK, Ling SC, Ha SY. Interferon and ribavirin as frontline treatment for chronic hepatitis C infection in thalassaemia major. Br J Haematol. 2002;117:755-8.
[13] Butensky E, Pakbaz Z, Foote D, Walters MC, Vichinsky EP, Harmatz P. Treatment of hepatitis C virus infection in thalassemia. Ann N Y Acad Sci 2005; 1054: 290-299.
[14] Alavian SM, Tabatabaei SV. Treatment of chronic hepatitis C in polytransfused thalassaemic patients: a meta-analysis. J Viral Hepat. 2010;17:236-244.
[15] Vafiadis I, Trilianos P, Vlachogiannakos J, Karagiorga M, Hatziliami A, Voskaridou E, Ladas SD. Efficacy and safety of interferon-based therapy in the treatment of adult thalassemic patients with chronic hepatitis C: a 12 years audit. Ann Hepatol. 2013;12:532-8.
[16] Kalafateli M, Kourakli A, Gatselis N, Lambropoulou P, Thomopoulos K, Tsamandas A, Christofidou M, Zachou K, Jelastopoulou E, Nikolopoulou V,Symeonidis A, Dalekos GN, Lambropoulou-Karatza C, Triantos C. Efficacy of interferon a-2b monotherapy in b-thalassemics with chronic hepatitis C. J Gastrointestin Liver Dis. 2015;24:189-96.
[17] Gatselis NK, Rigopoulou E, Stefos A, Kardasi M, Dalekos GN. Risk factors associated with HCV infection in semi-rural areas of central Greece. Eur J Intern Med. 2007;18:48-55.
[18] Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1:431-35.
[19] Gatselis NK, Zachou K, Norman GL, Tzellas G, Speletas M, Gabeta S, Germenis A, Koukoulis GK, Dalekos GN. IgA antibodies against deamidated gliadin peptides in patients with chronic liver diseases. Clin Chim Acta 2012; 413:1683-8.
[20] Kaffe ET, Rigopoulou EI, Koukoulis GK, Dalekos GN, Moulas AN. Oxidative stress and antioxidant status in patients with autoimmune liver diseases. Redox Rep 2015;20:33-41.
[21] Norman GL, Gatselis NK, Shums Z, Liaskos C, Bogdanos DP, Koukoulis GK, Dalekos GN. Cartilage oligomeric matrix protein: A novel non-invasive marker for assessing cirrhosis and risk of hepatocellular carcinoma. World J Hepatol 2015;7:1875-83.
[22] Kountouras D, Tsagarakis NJ, Fatourou E, Dalagiorgos E, Chrysanthos N, Berdoussi H, Vgontza N, Karagiorga M, Lagiandreou A, Kaligeros K, Voskaridou E,Roussou P, Diamanti-Kandarakis E, Koskinas J. Liver disease in adult transfusion dependent beta-thalassaemia patients: investigating the role of iron overload and chronic HCV infection. Liver Int 2013;33:420-7.
[23] Triantos C, Kourakli A, Kalafateli M, Giannakopoulou D, Koukias N, Thomopoulos K, Lampropoulou P, Bartzavali C, Fragopanagou H, Kagadis GC, Christofidou M, Tsamandas A, Nikolopoulou V, Karakantza M, Labropoulou-Karatza C. Hepatitis C in patients with ?-thalassemia major. A single-centre experience. Ann Hematol 2013;92:739-46.
[24] Prati D, Poli F, Farma E, Picone A, Porta E, Mattei C, Zanella A, Scalamogna A, Gamba A, Gronda E, Faggian G, Livi U, Puricelli C, Viganò M, Sirchia G. A multicenter prospective study on the risk of acquiring liver disease in anti-hepatitis C virus negative patients affected from homozygous beta-thalassemia. Blood. 1998;92:3460-64.
[25] Christofidou M, Lambropoulou-Karatza C, Dimitracopoulos G, Spiliopoulou I. Distribution of hepatitis C virus genotypes in viremic patients with beta-thalassemia. Eur J Clin Microbiol Infect Dis. 2000;19:728-30.
[26] Lai ME, Origa R, Daniou F, Leoni GB, Vacquer S, Anni F, Corrias C, Farci P, Conqiu G, Galanello R. Natural history of hepatitis C in thalassemia major: a long-term prospective study. Eur J Hematol. 2013;90:501-7.
[27] Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48:418-31.
[28] Lingala S, Ghany MG. Natural history of hepatitis C. Gastroenterol Clin North Am. 2015;44:717-34.
[29] Sherker AH, Senosier M, Kermack D. Treatment of transfusion-dependent thalassemic patients infected with hepatitis C virus with interferon alpha-2b and ribavirin. Hepatology. 2003;37:223.
[30] Poynard T, Marcellin P, Lee SS, NiederauC, Minuk GS, Ideo G, Bain V, Heathcote J, Zeuzem S, Trepo C, Albrecht J. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet. 1998;352:1426-32.
[31] Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa?2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-82.
[32] Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications Gut. 2006;55:1350–59.
[33] Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR,Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211–21.
[34] Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R, Lalezari J, Younes ZH, Pockros PJ, Di Bisceglie AM, Arora S, Subramanian GM, Zhu Y, Dvory-Sobol H, Yang JC,Pang PS, Symonds WT, McHutchison JG, Muir AJ, Sulkowski M, Kwo P; ION-2 Investigators. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:1483–93.
[35] Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, Shiffman ML, Schiff E, Ghalib R, Ryan M, Rustgi V, Chojkier M, Herring R, Di Bisceglie AM, Pockros PJ, Subramanian GM, An D, Svarovskaia E, Hyland RH, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Pound D, Fried MW; ION-3 Investigators.. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879–88.
[36] Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, Weiland O, Aguilar H, Xiong J, Pilot-Matias T, DaSilva-Tillmann B, Larsen L, Podsadecki T,Bernstein B.. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370:1594–1603.
[37] Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, Tam E, Marinho RT, Tsai N, Nyberg A, Box TD, Younes Z, Enayati P, Green S, Baruch Y,Bhandari BR, Caruntu FA, Sepe T, Chulanov V, Janczewska E, Rizzardini G, Gervain J, Planas R, Moreno C, Hassanein T, Xie W, King M, Podsadecki T, Reddy KR; PEARL-III Study; PEARL-IV Study.. ABT-450/rombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983–92.