2016, Number 3
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Ann Hepatol 2016; 15 (3)
Management of gastroesophageal varices in cirrhotic patients: current status and future directions
Toshikuni, N, Takuma, Y, Tsutsumi, M
Language: English
References: 92
Page: 314-325
PDF size: 192.58 Kb.
Text Extraction
Bleeding from gastroesophageal varices (GEV) is a serious event in cirrhotic patients and can cause death. According to the explosion theory, progressive portal hypertension is the primary mechanism underlying variceal bleeding. There are two approaches for treating GEV: primary prophylaxis to manage bleeding or emergency treatment for bleeding followed by secondary prophylaxis.
Treatment methods can be classified into two categories: 1) Those used to decrease portal pressure, such as medication (i.e., nonselective â-blockers), radiological intervention [transjugular intrahepatic portosystemic shunt (TIPS)] or a surgical approach (i.e., portacaval shunt), and 2) Those used to obstruct GEV, such as endoscopy [endoscopic variceal ligation (EVL), endoscopic injection sclerotherapy (EIS), and tissue adhesive injection] or radiological intervention [balloon-occluded retrograde transvenous obliteration
(BRTO)]. Clinicians should choose a treatment method based on an understanding of its efficacy and limitations. Furthermore, elastography techniques and serum biomarkers are noninvasive methods for estimating portal pressure and may be helpful in managing GEV. The impact of these advances in cirrhosis therapy should be evaluated for their effectiveness in treating GEV.
REFERENCES
Martell M, Coll M, Ezkurdia N, Raurell I, Genesca J. Physiopathology of splanchnic vasodilation in portal hypertension. World J Hepatol 2010; 2: 208-20.
Sanyal AJ, Bosch J, Blei A, Arroyo V. Portal hypertension and its complications. Gastroenterology 2008; 134: 1715-28.
La Mura V, Nicolini A, Tosetti G, Primignani M. Cirrhosis and portal hypertension: The importance of risk stratification, the role of hepatic venous pressure gradient measurement. World J Hepatol 2015; 7: 688-95.
Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985; 5: 419-24.
Dell’era A, Bosch J. Review article: the relevance of portal pressure and other risk factors in acute gastro-oesophageal variceal bleeding. Aliment Pharmacol Ther 2004; 20 (Suppl. 3): 8-15; discussion 16-7.
Moitinho E, Escorsell A, Bandi JC, Salmeron JM, Garcia-Pagan JC, Rodes J, Bosch J. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology 1999; 117: 626-31.
Monescillo A, Martinez-Lagares F, Ruiz-del-Arbol L, Sierra A, Guevara C, Jimenez E, Marrero JM, et al. Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding. Hepatology 2004; 40: 793-801.
Kovalak M, Lake J, Mattek N, Eisen G, Lieberman D, Zaman A. Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database. Gastrointest Endosc 2007; 65: 82-8.
North Italian Endoscopic Club for the S, Treatment of Esophageal V. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988; 319: 983-9.
Garcia-Pagan JC, Barrufet M, Cardenas A, Escorsell A. Management of gastric varices. Clin Gastroenterol Hepatol 2014; 12: 919-28 e1; quiz e51-2.
Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications, and outcomes. Gastroenterology 2002; 122: 1620-30.
Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet 2003; 361: 952-4.
Bruno S, Zuin M, Crosignani A, Rossi S, Zadra F, Roffi L, Borzio M, et al. Predicting mortality risk in patients with compensated HCV-induced cirrhosis: a long-term prospective study. Am J Gastroenterol 2009; 104: 1147-58.
D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999; 19: 475-505.
Siramolpiwat S. Transjugular intrahepatic portosystemic shunts and portal hypertension-related complications. World J Gastroenterol 2014; 20: 16996-7010.
Orloff MJ, Hye RJ, Wheeler HO, Isenberg JI, Haynes KS, Vaida F, Girard B, et al. Randomized trials of endoscopic therapy and transjugular intrahepatic portosystemic shunt versus portacaval shunt for emergency and elective treatment of bleeding gastric varices in cirrhosis. Surgery 2015; 157: 1028-45.
Khuroo MS, Khuroo NS, Farahat KL, Khuroo YS, Sofi AA, Dahab ST. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophagealvariceal bleeding. Aliment Pharmacol Ther 2005; 21: 347-61.
Thiele M, Krag A, Rohde U, Gluud LL. Meta-analysis: banding ligation and medical interventions for the prevention of rebleeding from oesophageal varices. Aliment Pharmacol Ther 2012; 35: 1155-65.
Shi KQ, Liu WY, Pan ZZ, Ling XF, Chen SL, Chen YP, Fan YC, et al. Secondary prophylaxis of variceal bleeding for cirrhotic patients: a multiple-treatments meta-analysis. Eur J Clin Invest 2013; 43: 844-54.
Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and beta-blockers: a randomized controlled trial. J Hepatol 2011; 54: 1161-7.
Mishra SR, Chander Sharma B, Kumar A, Sarin SK. Endoscopic cyanoacrylate injection versus beta-blocker for secondary prophylaxis of gastric variceal bleed: a randomised controlled trial. Gut 2010; 59: 729-35.
Park JK, Saab S, Kee ST, Busuttil RW, Kim HJ, Durazo F, Cho SK, et al. Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) for Treatment of Gastric Varices: Review and Meta-Analysis. Dig Dis Sci 2015; 60: 1543-53.
Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver D, Practice Parameters Committee of the American College of G. Prevention and management of gastroesophagealvarices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46: 922-38.
de Franchis R, Baveno VIF. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63: 743-52.
Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992; 16: 1343-9.
Lopez-Mendez E, Uribe M. Beta blockers in portal hypertension. Are they really a good option? Ann Hepatol 2006; 5: 86-91.
Banares R, Moitinho E, Piqueras B, Casado M, Garcia-Pagan JC, de Diego A, Bosch J. Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology 1999; 30: 79-83.
Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, Heinisch BB, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013; 62: 1634-41.
Hernandez-Gea V, Aracil C, Colomo A, Garupera I, Poca M, Torras X, Minana J, et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with beta-blockers. Am J Gastroenterol 2012; 107: 418-27.
Ge PS, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol 2014; 60: 643-53.
Funakoshi N, Duny Y, Valats JC, Segalas-Largey F, Flori N, Bismuth M, Daures JP, et al. Meta-analysis: beta-blockers versus banding ligation for primary prophylaxis of esophageal variceal bleeding. Ann Hepatol 2012; 11: 369-83.
Gluud LL, Krag A. Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst Rev 2012; 8: CD004544.
Zhang C, Thabut D, Kamath PS, Shah VH. Oesophageal varices in cirrhotic patients: from variceal screening to primary prophylaxis of the first oesophageal variceal bleeding. Liver Int 2011; 31: 108-19.
van Buuren HR, Rasch MC, Batenburg PL, Bolwerk CJ, Nicolai JJ, van der Werf SD, Scherpenisse J, et al. Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899]. BMC Gastroenterol 2003; 3: 22.
Saad WE, Darcy MD. Transjugular Intrahepatic Portosystemic Shunt (TIPS) versus Balloon-occluded Retrograde Transvenous Obliteration (BRTO) for the Management of Gastric Varices. Semin Intervent Radiol 2011; 28: 339-49.
Ryan BM, Stockbrugger RW, Ryan JM. A pathophysiologic, gastroenterologic, and radiologic approach to the management of gastric varices.Gastroenterology 2004; 126: 1175-89.
Seewald S, Sriram PV, Naga M, Fennerty MB, Boyer J, Oberti F, Soehendra N. Cyanoacrylate glue in gastric variceal bleeding. Endoscopy 2002; 34: 926-32.
Kang EJ, Jeong SW, Jang JY, Cho JY, Lee SH, Kim HG, Kim SG, et al. Long-term result of endoscopic Histoacryl (Nbutyl- 2-cyanoacrylate) injection for treatment of gastric varices. World J Gastroenterol 2011; 17: 1494-500.
Santos MM, Tolentino LH, Rodrigues RA, Nakao FS, Rohr MR, de Paulo GA, Kondo M, et al. Endoscopic treatment of esophageal varices in advanced liver disease patients: band ligation versus cyanoacrylate injection. Eur J Gastroenterol Hepatol 2011; 23: 60-5.
Ljubicic N, Biscanin A, Nikolic M, Supanc V, Hrabar D, Pavic T, Boban M. A randomized-controlled trial of endoscopic treatment of acute esophageal variceal hemorrhage: N-butyl-2-cyanoacrylate injection vs. variceal ligation. Hepatogastroenterology 2011; 58: 438-43.
Barclay S, Cameron I, Stewart I, Forrest E. Massive hemorrhage from a pulmonary vein-esophageal fistula: a late complication of Histoacryl glue injection. Gastrointest Endosc 2009; 70: 1037-8.
Kanagawa H, Mima S, Kouyama H, Gotoh K, Uchida T, Okuda K. Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration. J Gastroenterol Hepatol 1996; 11: 51-8.
Azoulay D, Castaing D, Majno P, Saliba F, Ichai P, Smail A, Delvart V, et al. Salvage transjugular intrahepatic portosystemic shunt for uncontrolled variceal bleeding in patients with decompensated cirrhosis. J Hepatol 2001; 35: 590-7.
Orloff MJ, Isenberg JI, Wheeler HO, Haynes KS, Jinich-Brook H, Rapier R, Vaida F, et al. Emergency portacaval shunt versus rescue portacaval shunt in a randomized controlled trial of emergency treatment of acutely bleeding esophageal varices in cirrhosis—part 3. J Gastrointest Surg 2010; 14: 1782-95.
Orloff MJ. Fifty-three years’ experience with randomized clinical trials of emergency portacaval shunt for bleeding esophageal varices in Cirrhosis: 1958-2011. JAMA Surg 2014; 149: 155-69.
Chau TN, Patch D, Chan YW, Nagral A, Dick R, Burroughs AK. “Salvage” transjugular intrahepatic portosystemic shunts: gastric fundal compared with esophageal variceal bleeding. Gastroenterology 1998; 114: 981-7.
Paik CN, Kim SW, Lee IS, Park JM, Cho YK, Choi MG, Chung IS. The therapeutic effect of cyanoacrylate on gastric variceal bleeding and factors related to clinical outcome. J Clin Gastroenterol 2008; 42: 916-22.
Tan PC, Hou MC, Lin HC, Liu TT, Lee FY, Chang FY, Lee SD. A randomized trial of endoscopic treatment of acute gastric variceal hemorrhage: N-butyl-2-cyanoacrylate injection versus band ligation. Hepatology 2006; 43: 690-7.
Garcia-Pagan JC, Caca K, Bureau C, Laleman W, Appenrodt B, Luca A, Abraldes JG, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med 2010; 362: 2370-9.
Garcia-Pagan JC, Di Pascoli M, Caca K, Laleman W, Bureau C, Appenrodt B, Luca A, et al. Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study. J Hepatol 2013; 58: 45-50.
Sauerbruch T, Mengel M, Dollinger M, Zipprich A, Rossle M, Panther E, Wiest R, et al. Prevention of Rebleeding from Esophageal Varices in Patients with Cirrhosis Receiving Smalldiameter Stents vs.Hemodynamically Controlled Medical Therapy. Gastroenterology 2015.
Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, Cortez C, Perreault P, et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004; 126:469-75.
Puente A, Hernandez-Gea V, Graupera I, Roque M, Colomo A, Poca M, Aracil C, et al. Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review. Liver Int 2014; 34: 823-33.
Garcia-Pagan JC, Navasa M, Bosch J, Bru C, Pizcueta P, Rodes J. Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology 1990; 11: 230-8.
Hung HH, Chang CJ, Hou MC, Liao WC, Chan CC, Huang HC, Lin HC, et al. Efficacy of non-selective beta-blockers as adjunct to endoscopic prophylactic treatment for gastric variceal bleeding: a randomized controlled trial. J Hepatol 2012; 56: 1025-32.
Lo GH, Liang HL, Chen WC, Chen MH, Lai KH, Hsu PI, Lin CK, et al. A prospective, randomized controlled trial of transjugular intrahepatic portosystemic shunt versus cyanoacrylate injection in the prevention of gastric variceal rebleeding. Endoscopy 2007; 39: 679-85.
Rios Castellanos E, Seron P, Gisbert JP, BonfillCosp X. Endoscopic injection of cyanoacrylate glue versus other endoscopic procedures for acute bleeding gastric varices in people with portal hypertension. Cochrane Database Syst Rev 2015; 5: CD010180.
Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, Escorsell A, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007;133: 481-8.
Vorobioff J, Groszmann RJ, Picabea E, Gamen M, Villavicencio R, Bordato J, Morel I, et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology 1996; 111: 701-9.
Triantos CK, Nikolopoulou V, Burroughs AK. Review article: the therapeutic and prognostic benefit of portal pressure reduction in cirrhosis. Aliment Pharmacol Ther 2008; 28: 943-52.
Bureau C, Peron JM, Alric L, Morales J, Sanchez J, Barange K, Payen JL, et al. “A La Carte” treatment of portal hypertension: Adapting medical therapy to hemodynamic response for the prevention of bleeding. Hepatology 2002; 36: 1361-6.
Sharma P, Kumar A, Sharma BC, Sarin SK. Early identification of haemodynamic response to pharmacotherapy is essential for primary prophylaxis of variceal bleeding in patients with ‘high-risk’varices. Aliment Pharmacol Ther 2009; 30: 48-60.
Colecchia A, Montrone L, Scaioli E, Bacchi-Reggiani ML, Colli A, Casazza G, Schiumerini R, et al. Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis. Gastroenterology 2012; 143: 646-54.
Berzigotti A, Seijo S, Arena U, Abraldes JG, Vizzutti F, Garcia-Pagan JC, Pinzani M, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis. Gastroenterology 2013; 144: 102-111 e1.
Takuma Y, Nouso K, Morimoto Y, Tomokuni J, Sahara A, Toshikuni N, Takabatake H, et al. Measurement of spleen stiffness by acoustic radiation force impulse imaging identifies cirrhotic patients with esophageal varices. Gastroenterology 2013; 144: 92-101 e2.
Sharma P, Kirnake V, Tyagi P, Bansal N, Singla V, Kumar A, Arora A. Spleen stiffness in patients with cirrhosis in predicting esophageal varices. Am J Gastroenterol 2013; 108: 1101-7.
Procopet B, Berzigotti A, Abraldes JG, Turon F, Hernandez-Gea V, Garcia-Pagan JC, Bosch J. Real-time shear-wave elastography: applicability, reliability and accuracy for clinically significant portal hypertension. J Hepatol 2015; 62: 1068-75.
Choi SY, Jeong WK, Kim Y, Kim J, Kim TY, Sohn JH. Shearwave elastography: a noninvasive tool for monitoring changing hepatic venous pressure gradients in patients with cirrhosis. Radiology 2014; 273: 917-26.
Sun HY, Lee JM, Han JK, Choi BI. Usefulness of MR elastography for predicting esophageal varices in cirrhotic patients. J Magn Reson Imaging 2014; 39: 559-66.
Shin SU, Lee JM, Yu MH, Yoon JH, Han JK, Choi BI, Glaser KJ, et al. Prediction of esophageal varices in patients with cirrhosis: usefulness of three-dimensional MR elastography with echo-planar imaging technique. Radiology 2014; 272:143-53.
Thabut D, Imbert-Bismut F, Cazals-Hatem D, Messous D, Muntenau M, Valla DC, Moreau R, et al. Relationship between the Fibrotest and portal hypertension in patients with liver disease. Aliment Pharmacol Ther 2007; 26: 359-68.
Poynard T, Vergniol J, Ngo Y, Foucher J, Munteanu M, Merrouche W, Colombo M, et al. Staging chronic hepatitis C in seven categories using fibrosis biomarker (FibroTest) and transient elastography (FibroScan(R)). J Hepatol 2014; 60: 706-14.
Vorobioff JD, Groszmann RJ. Prevention of portal hypertension: from variceal development to clinical decompensation. Hepatology 2015; 61: 375-81.
Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, Escorsell A, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353: 2254-61.
Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52: 886-93.
Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, Washington MK, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 2013; 381: 468-75.
Poynard T, McHutchison J, Manns M, Trepo C, Lindsay K, Goodman Z, Ling MH, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002; 122: 1303-13.
Mallet V, Gilgenkrantz H, Serpaggi J, Verkarre V, Vallet-Pichard A, Fontaine H, Pol S. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med 2008; 149: 399-403.
D’Ambrosio R, Aghemo A, Rumi MG, Ronchi G, Donato MF, Paradis V, Colombo M, et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 2012; 56: 532-43.
Roberts S, Gordon A, McLean C, Pedersen J, Bowden S, Thomson K, Angus P. Effect of sustained viral response on hepatic venous pressure gradient in hepatitis C-related cirrhosis. Clin Gastroenterol Hepatol 2007; 5: 932-7.
Bruno S, Crosignani A, Facciotto C, Rossi S, Roffi L, Redaelli A, de Franchis R, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology 2010; 51: 2069-76.
Bourliere M, Bronowicki JP, de Ledinghen V, Hezode C, Zoulim F, Mathurin P, Tran A, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015; 15: 397-404.
Charlton M, Everson GT, FlammSL, Kumar P, Landis C, Brown RS, Jr., Fried MW, et al. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease. Gastroenterology 2015.
Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, Shiffman ML, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370: 1973-82.
Hezode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, de Ledinghen V, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013; 59: 434-41.
Hezode C, Fontaine H, Dorival C, Zoulim F, Larrey D, Canva V, De Ledinghen V, et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology 2014; 147: 132-42. e4.
Poynard T, Vergniol J, Ngo Y, Foucher J, Thibault V, Munteanu M, Merrouche W, et al. Staging chronic hepatitis B into seven categories, defining inactive carriers and assessing treatment impact using a fibrosis biomarker (FibroTest(R)) and elastography (FibroScan(R)). J Hepatol 2014; 61: 994-1003.
Poynard T, Moussalli J, Munteanu M, Thabut D, Lebray P, Rudler M, Ngo Y, et al. Slow regression of liver fibrosis presumed by repeated biomarkers after virological cure in patients with chronic hepatitis C. J Hepatol 2013; 59: 675-83.
Nagaoki Y, Aikata H, Kobayashi T, Fukuhara T, Masaki K, Tanaka M, Naeshiro N, et al. Risk factors for the exacerbation of esophageal varices or portosystemic encephalopathy after sustained virological response with IFN therapy for HCV-related compensated cirrhosis. J Gastroenterol 2013; 48: 847-55.
Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013; 123: 1887-901.
N JT, Dranoff JA, Schuppan D, Friedman SL. Strategies and endpoints of antifibrotic drug trials: Summary and recommendations from the AASLD Emerging Trends Conference, Chicago, June 2014. Hepatology 2015.
Jaroszewicz J, Flisiak-Jackiewicz M, Lebensztejn D, Flisiak R. Current drugs in early development for treating hepatitis C virus-related hepatic fibrosis. Expert Opin Investig Drugs 2015: 1-11.