Telbivudine in combination with adefovir versus adefovir monotherapy in HBeAg-positive, lamivudine-resistant chronic hepatitis B

Hepatology International - Tập 6 - Trang 696-706 - 2011
Sang-Hoon Ahn1, Young-Oh Kweon2, Seung-Woon Paik3, Joo-Hyun Sohn4, Kwan-Sik Lee5, Dong Joon Kim6, Teerha Piratvisuth7, Man Fung Yuen8, Anuchit Chutaputti9, You-Chen Chao10, Aldo Trylesinski11, Claudio Avila11
1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
2The Kyungpook National University Hospital, Daegu, Korea
3Department of Medicine/Gastroenterology, Samsung Medical Centre, Seoul, Korea
4Division of Gastroenterology, Hanyang University Guri Hospital, Suwon, Korea
5Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
6Hallym University Sacred Heart Hospital, Chuncheon, Korea
7NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
8Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong
9Phramongkutklao Hospital, Bangkok, Thailand
10Tri-Service General Hospital, Taipei, R.O.C
11Novartis Pharma AG, Basel, Switzerland

Tóm tắt

Lamivudine (LAM) resistance is common on lamivudine monotherapy for chronic hepatitis B. This study examined the safety and efficacy of telbivudine (LDT) given with adefovir (ADV) versus ADV monotherapy in patients with chronic, lamivudine-resistant HBV infection. An open-label, 96 week study with planned recruitment of 150 HBeAg-positive, lamivudine-experienced Asian patients with a confirmed YMDD resistance mutation, randomized 1:1 to receive ADV alone or with LDT. The study was terminated early due to difficulty in enrolling monotherapy patients. At termination, 42 patients had received study medication for 8–61 weeks. Due to incomplete enrolment, summary statistics only were prepared, without significance testing. A total of 42 patients underwent rescue therapy (switch to ADV or LDT + ADV; n = 21 per group). Median treatment duration was 48 weeks in both groups. HBV DNA changes from baseline were greater in the LDT + ADV arm at all time points (Week 48: −7.4 log10 vs. −4.9 log10 copies/ml), and serum DNA was undetectable (<300 copies/mL) at week 48 in 38.5% (5/13) on LDT + ADV versus 0% (0/9) on ADV monotherapy Two patients (9.6%) on ADV monotherapy experienced virologic breakthrough without evidence of ADV resistance, but none on LDT + ADV; and no confirmed ADV resistance was observed in any on-treatment sample. HBeAg loss occurred in three patients on LDT + ADV and one patient on ADV monotherapy through week 48. Safety profiles were similar between the arms. LDT + ADV combination treatment showed better outcomes against lamivudine resistant HBV than ADV alone, with a similar safety profile.

Tài liệu tham khảo

Coates JA, Cammack N, Jenkinson HJ, Mutton IM, Pearson BA, Storer R, Cameron JM. The separated enantiomers of 2′-deoxy-3′-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob Agents Chemother 1992;36:202–205 Doong SL, Tsai CH, Schinazi RF, Liotta DC, Cheng YC. Inhibition of the replication of hepatitis B virus in vitro by 2′, 3′-dideoxy-3′-thiacytidine and related analogues. Proc Natl Acad Sci USA 1991;88:8495–8499 Locarnini S. Primary resistance, multidrug resistance, and cross-resistance pathways in HBV as a consequence of treatment failure. Hepatol Int 2008;2:147–151 Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, Brown N, Condreay LD. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology 1998;27:1670–1677 Yuen MF, Fung J, Wong DK, Lai CL. Prevention and management of drug resistance for antihepatitis B treatment. Lancet Infect Dis 2009;9:256–264 Yuen MF, Seto WK, Chow DH, Tsui K, Wong DK, Ngai VW, Wong BC, Fung J, Yuen JC, Lai CL. Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease. Antivir Ther 2007;12:1295–1303 Hadziyannis SJ, Papatheodoridis GV, Dimou E, Laras A, Papaioannou C. Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2000;32:847–851 Liaw YF, Chien RN, Yeh CT. No benefit to continue lamivudine therapy after emergence of YMDD mutations. Antivir Ther 2004;9:257–262 Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology 1999;30:567–572 Chen CH, Lee CM, Lu SN, Wang JH, Tung HD, Hung CH, Chen WJ, Changchien CS. Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants. J Hepatol 2004;41:454–461 Papatheodoridis GV, Dimou E, Laras A, Papadimitropoulos V, Hadziyannis SJ. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease. Hepatology 2002;36:219–226 Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, Rizzetto M, Craxi A. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 2004;40:883–891 De Clercq E. Acyclic nucleoside phosphonates in the chemotherapy of DNA virus and retrovirus infections. Intervirology 1997;40:295–303 Asmuth DM, Nguyen HH, Melcher GP, Cohen SH, Pollard RB. Treatments for hepatitis B. Clin Infect Dis 2004;39:1353–1362 Ying C, De Clercq E, Nicholson W, Furman P, Neyts J. Inhibition of the replication of the DNA polymerase M550 V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir. J Viral Hepat 2000;7:161–165 Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney WE. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV. Antivir Ther 2005;10:625–633 Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, Gibbs CS, Brosgart C, Fry J, Namini H, Katlama C, Poynard T. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study. Lancet 2001;358:718–723 Perrillo R, Schiff E, Yoshida E, Statler A, Hirsch K, Wright T, Gutfreund K, Lamy P, Murray A. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 2000;32:129–134 Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, Tillmann HL, Samuel D, Zeuzem S, Lilly L, Rendina M, Villeneuve JP, Lama N, James C, Wulfsohn MS, Namini H, Westland C, Xiong S, Choy GS, Van Doren S, Fry J, Brosgart CL. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology 2003;38:1419–1427 Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, Tobias H. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008;6:1315–1341 Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, Guan R, Lau GK, Locarnini S. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008;2:263–283 European Association For The Study Of The Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2009;50:227–242 Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–662 Yeon JE, Yoo W, Hong SP, Chang YJ, Yu SK, Kim JH, Seo YS, Chung HJ, Moon MS, Kim SO, Byun KS, Lee CH. Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil. Gut 2006;55:1488–1495 Lee YS, Suh DJ, Lim YS, Jung SW, Kim KM, Lee HC, Chung YH, Lee YS, Yoo W, Kim SO. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 2006;43:1385–1391 Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, Plym M, Pokornowski K, Yu CF, Angus P, Ayres A, Bartholomeusz A, Sievert W, Thompson G, Warner N, Locarnini S, Colonno RJ. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother 2004;48:3498–3507 Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, Wichroski MJ, Xu D, Yang J, Wilber RB, Colonno RJ. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 2009;49:1503–1514 van der Poorten D, Prakoso E, Khoo TL, Ngu MC, McCaughan GW, Strasser SI, Lee AU. Combination adefovir-lamivudine prevents emergence of adefovir resistance in lamivudine-resistant hepatitis B. J Gastroenterol Hepatol 2007;22:1500–1505 Peters MG, Hann HH, Martin P, Heathcote EJ, Buggisch P, Rubin R, Bourliere M, Kowdley K, Trepo C, Gray DD, Sullivan M, Kleber K, Ebrahimi R, Xiong S, Brosgart CL. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 2004;126:91–101 Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 2007;45:307–313 Vassiliadis TG, Giouleme O, Koumerkeridis G, Koumaras H, Tziomalos K, Patsiaoura K, Grammatikos N, Mpoumponaris A, Gkisakis D, Theodoropoulos K, Panderi A, Katsinelos P, Eugenidis N. Adefovir plus lamivudine are more effective than adefovir alone in lamivudine-resistant HBeAg- chronic hepatitis B patients: a 4-year study. J Gastroenterol Hepatol 2010;25:54–60 Chan HL, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM, Chao YC, Myers RP, Minuk GY, Jeffers L, Sievert W, Bzowej N, Harb G, Kaiser R, Qiao XJ, Brown NA. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med 2007;147:745–754 Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, Heathcote EJ, Manns M, Bzowej N, Niu J, Han SH, Hwang SG, Cakaloglu Y, Tong MJ, Papatheodoridis G, Chen Y, Brown NA, Albanis E, Galil K, Naoumov NV. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009;136:486–495 Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–539. Fung J, Lai CL, Yuen JC, Wong DK, Tanaka Y, Mizokami M, Yuen MF. Adefovir dipivoxil monotherapy and combination therapy with lamivudine for the treatment of chronic hepatitis B in an Asian population. Antivir Ther 2007;12:41–46 Lampertico P, Vigano M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology 2007;133:1445–1451 Buti M, Elefsiniotis I, Jardi R, Vargas V, Rodriguez-Frias F, Schapper M, Bonovas S, Esteban R. Viral genotype and baseline load predict the response to adefovir treatment in lamivudine-resistant chronic hepatitis B patients J Hepatol. 2007;47:366–372 Lee JM, Park JY, Kim DY, Nguyen T, Hong SP, Kim SO, Chon CY, Han K-H, Ahn SH. Long-term adefovir dipivoxil monotherapy for up to 5 years in lamivudine-resistant chronic hepatitis B. Antivir Ther 2010;15:235–241 Chen E-Q, Wang L-C, Lei J, et al. Meta-analysis: Adefovir dipivoxil in combination with lamivudine in patients with lamivudine-resistant hepatitis B virus. Virol J 2009; 6.(doi:10.1186/1743-422X-6-163). Ijaz S, Arnold C, Dervisevic S, Mechurova J, Tatman N, Tedder RS, Naoumov NV. Dynamics of lamivudine-resistant hepatitis B virus during adefovir monotherapy versus lamivudine plus adefovir combination therapy. J Med Virol 2008;80:1160–1170 Bartholomeusz A, Locarnini SA. Antiviral drug resistance: clinical consequences and molecular aspects. Semin Liver Dis 2006;26:162–170 Turner D, Brenner B, Wainberg MA. Relationships among various nucleoside resistance-conferring mutations in the reverse transcriptase of HIV-1. J Antimicrob Chemother 2004;53:53–57 Qi X, Xiong S, Yang H, Miller M, Delaney WE. In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther 2007;12:355–362 Yatsuji H, Noguchi C, Hiraga N, Mori N, Tsuge M, Imamura M, Takahashi S, Iwao E, Fujimoto Y, Ochi H, Abe H, Maekawa T, Tateno C, Yoshizato K, Suzuki F, Kumada H, Chayama K. Emergence of a novel lamivudine-resistant hepatitis B virus variant with a substitution outside the YMDD motif. Antimicrob Agents Chemother 2006;50:3867–3874 Lacombe K, Ollivet A, Gozlan J, Durantel S, Tran N, Girard PM, Zoulim F. A novel hepatitis B virus mutation with resistance to adefovir but not to tenofovir in an HIV-hepatitis B virus-co-infected patient. AIDS 2006;20:2229–2231 Tyzeka (telbivudine) Prescribing Information. Available at: http://www.pharma.us.novartis.com/product/pi/pdf/tyzeka.pdf Accessed 6 July 2010. Yoo BC, Kim JH, Chung YH, Lee KS, Paik SW, Ryu SH, Han BH, Han JY, Byun KS, Cho M, Lee HJ, Kim TH, Cho SH, Park JW, Um SH, Hwang SG, Kim YS, Lee YJ, Chon CY, Kim BI, Lee YS, Yang JM, Kim HC, Hwang JS, Choi SK, Kweon YO, Jeong SH, Lee MS, Choi JY, Kim DG, Kim YS, Lee HY, Yoo K, Yoo HW, Lee HS. Twenty-four-week clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology 2007;45:1172–1178 Warner N, Locarnini S. The antiviral drug selected hepatitis B virus rt181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology 2008;48:88–98 Castel H, Osiowy C, Heathcote EJ, Willems B, Villeneuve JP. Is viral load at week 48 predictive of adefovir resistance in HBV patients receiving adefovor for lamivudine resistance? J Hepatol 2008;48(suppl 2):A684–A685 Kwon HC, Cheong JY, Cho SW, Choi JM, Hong SP, Kim SO, Yoo WD. Emergence of adefovir-resistant mutants after reversion to YMDD wild-type in lamivudine-resistant patients receiving adefovir monotherapy. J Gastroenterol Hepatol 2009;24:49–54 Division of AIDS table for grading severity of adult adverse experiences (August 1992). Available at: http://rsc.tech-res.com/Document/safetyandpharmacovigilance/Table_for_Grading_Severity_of_Adult_AEs_v01a.pdf Accessed 6 July 2010.