Clinical Trial Results of New Therapies for HBV: Implications for Treatment Guidelines

ABSTRACT

Currently approved treatments for chronic infection with hepatitis B virus (HBV) are limited by low rates of sustained response, side effects, and in some cases, the emergence of drug resistance. Thus, new treatments, characterized by more potent antiviral effects less toxicity, and minimal or no risk of resistance, are needed. During the last few years, several agents have been developed that have increased potency and reduced potential for resistance-among them, entecavir and pegylated interferons. In addition, several novel anti-HBV agents recently evaluated in phase II clinical trials, such as tenofovir, clevudine, telbivudine, pradefovir, and valtorcitabine, appear to be promising agents for the treatment of chronic hepatitis B. This article describes the clinical experience with new antiviral agents and the implications of the trial results for practice guidelines.

KEYWORDS

Hepatitis B - entecavir - pegylated interferon - nucleoside analogue

REFERENCES

• 1 Hepatitis B Foundation . What is hepatitis B?.  Statistics. 2005;  18
• 2 Lai C L, Ratziu V, Yuen M F, Poynard T. Viral hepatitis B.  Lancet. 2003;  362 2089-2094
• 3 Moyer L A, Mast E E. Hepatitis B: virology, epidemiology, disease, and prevention, and an overview of viral hepatitis.  Am J Prev Med. 1994;  10(suppl) 45-55
• 4 World Health Organization .Department of Communicable Disease Surveillance and Response. Hepatitis B-an introduction. http://Available at: www.who.int/emc-documents/hepatitis/docs/whocdscsrlyo20022/introduction/introduction.html Last update: January, 2005 Accessed May 5, 2005
• 5 Cihlar T, Lin D C, Pritchard J B, Fuller M D, Mendel D B, Sweet D H. The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1.  Mol Pharmacol. 1999;  56 570-580
• 6 Lok A S. New treatment of chronic hepatitis B.  Semin Liver Dis. 2004;  24(suppl 1) 77-82
• 7 Marcellin P. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.  N Engl J Med. 2003;  348 808-816
• 8 Santantonio T, Mazzola M, Iacovazzi T, Miglietta A, Guastadisegni A, Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine.  J Hepatol. 2000;  32 300-306
• 9 Tassopoulos N C, Volpes R, Pastore G et al.. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group.  Hepatology. 1999;  29 889-896
• 10 Food and Drug Administration .Center of Drug Evaluation and Research. Approval Letter: Baraclude™. http://Available at: www.fda.gov/cder/foi/appletter/2005/021797,021798ltr.pdf Last update: 2005 Accessed 2005
• 11 Hadziyannis S J, Papatheodoridis G V. Emerging treatments in chronic hepatitis B.  Expert Opin Emerg Drugs. 2004;  9 207-221
• 12 Colonno R J, Genovesi E V, Medina I et al.. Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection.  J Infect Dis. 2001;  184 1236-1245
• 13 de Man R A, Wolters L M, Nevens F et al.. Safety and efficacy of oral entecavir given for 28 days in patients with chronic hepatitis B virus infection.  Hepatology. 2001;  34 578-582
• 14 Innaimo S F, Seifer M, Bisacchi G S, Standring D N, Zahler R, Colonno R J. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus.  Antimicrob Agents Chemother. 1997;  41 1444-1448
• 15 Lai C L, Rosmawati M, Lao J et al.. Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection.  Gastroenterology. 2002;  123 1831-1838
• 16 Seifer M, Hamatake R K, Colonno R J, Standring D N. In vitro inhibition of hepadnavirus polymerases by the triphosphates of BMS-200475 and lobucavir.  Antimicrob Agents Chemother. 1998;  42 3200-3208
• 17 Wolters L M, Hansen B E, Niesters H G, Dehertogh D, de Man R A. Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B.  J Hepatol. 2002;  37 137-144
• 18 Chang T T, Gish R, de Man R et al.. Entecavir is superior to lamivudine for the treatment of HBeAg (+) chronic hepatitis B: results of phase III study ETV-022 in nucleoside-naive patients.  Hepatology. 2004;  40(suppl 1) 193A
• 19 Shouval D, Lai C-L, Cheinquer H et al.. Entecavir demonstrates superior histologic and virologic efficacy over lamivudine in nucleoside-naive HBeAg (-) chronic hepatitis B: results of phase III trial ETV-027.  Hepatology. 2004;  40(suppl 1) 728A
• 20 Sollano J, Schiff E, Carrilho F et al.. Entecavir is well-tolerated for treatment of chronic hepatitis-B: phase III safety analysis in nucleoside-naive and lamivudine-refractory patients.  Hepatology. 2004;  40 665A
• 21 Package Insert .Baraclude. http://Available at: www.fda.gov/cder/foi/label/2005/021797,021798lbl.pdf Last update: 2005 Accessed April 4, 2005
• 22 Sherman M, Yurdaydin C, Sollano J et al.. Entecavir is superior to continued lamivudine for the treatment of lamivudine-refractory, HBeAg (+) chronic hepatitis B: results of phase III study ETV-026.  Hepatology. 2004;  40(suppl 1) 664A
• 23 Rosmawati M, Schiff E, Parana R et al.. Entecavir is superior to lamivudine at reducing HBV DVA in patients with chronic hepatitis B regardless of baseline alanine aminotransferase levels.  Hepatology. 2004;  40(suppl 1) 656A
• 24 Colonno R J, Rose R E, Levine S M et al.. Entecavir (ETV) resistance is not observed in nucleoside-naive subjects and is observed infrequently by week 48 in lamivudine-refractory subjects with chronic HBV infection.  J Hepatol. 2005;  , In press
• 25 Tenney D J, Langley D R, Oliver A J et al.. Hepatitis B virus resistance to entecavir involves novel changes in the viral polymerase.  Hepatology. 2004;  40 245A
• 26 Warner N, Locarnini S A, Colledge D et al.. Molecular modelling of entecavir resistant mutations in the hepatitis B virus polymerase selected during therapy.  Hepatology. 2004;  40(suppl 1) 245A , (abst 183)
• 27 Colonno R J, Rose R, Levine S M et al.. Emergence of entecavir resistant hepatitis B virus after one year of therapy in phase II & III studies is only observed in lamivudine refractory patients.  Hepatology. 2004;  40(suppl 1) 661A
• 28 Chang T T, Hadziyannis S, Cianciara J et al.. Sustained viral load and ALT reduction following 48 weeks of entecavir treatment in subjects with chronic hepatitis B who have failed lamivudine.  Hepatology. 2002;  36 300A
• 29 Honkoop P, de Man R A. Entecavir: a potent new antiviral drug for hepatitis B.  Expert Opin Investig Drugs. 2003;  12 683-688
• 30 Chen C J, Yang H I, Su J et al.. Elevated serum level of hepatitis B virus DNA is an independent risk factor for hepatocellular carcinoma: a long-term follow-up study in Taiwan.  J Hepatol. 2005;  45(suppl 1) , abst 35A
• 31 Chen G, Lin W, Shen F M et al.. Viral load as a predictor of liver disease in chronic hepatitis B infection.  Hepatology. 2004;  40 594A
• 32 Yang H I, Lu S N, Liaw Y F et al.. Hepatitis B e antigen and the risk of hepatocellular carcinoma.  N Engl J Med. 2002;  347 168-174
• 33 Bonino F, Rosina F, Rizzetto M et al.. Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe.  Gastroenterology. 1986;  90(suppl 5 pt 1) 1268-1273
• 34 Di Bisceglie A M. Long-term outcome of interferon-alpha therapy for chronic hepatitis B.  J Hepatol. 1995;  22 65-67
• 35 Eddleston A. Interferons in the treatment of chronic hepatitis B virus infection.  Med Clin North Am. 1986;  (suppl) 25-30
• 36 Korenman J, Baker B, Waggoner J, Evert J E, Di Bisceglie A M, Hoofnagle J H. Long-term remission of chronic hepatitis B after alpha-interferon therapy.  Ann Intern Med. 1991;  114 629-634
• 37 Perry C M, Jarvis B. Peginterferon-alpha-2a (40 kD): a review of its use in the management of chronic hepatitis C.  Drugs. 2001;  61 2263-2288
• 38 Glue P, Fang J W, Rouzier-Panis R for the Hepatitis C Intervention Therapy Group et al,. Pegylated interferon-alpha. 2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data.  Clin Pharmacol Ther. 2000;  68 556-567
• 39 Cooksley W G, Piratvisuth T, Lee S D et al.. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.  J Viral Hepat. 2003;  10 298-305
• 40 Lindsay K L, Trepo C, Heintges T et al.. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.  Hepatology. 2001;  34 395-403
• 41 Reddy K R, Wright T L, Pockros P J et al.. Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C.  Hepatology. 2001;  33 433-438
• 42 Chan H L, Leung N W, Hui A Y et al.. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone.  Ann Intern Med. 2005;  142 240-250
• 43 Janssen H L, van Zonneveld M, Senturk H et al.. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.  Lancet. 2005;  365 123-129
• 44 Lau G K, Piratvisuth T, Luo K X et al.. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.  N Engl J Med. 2005;  352 2882-2695
• 45 Marcellin P, Lau G K, Bonino F et al.. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.  N Engl J Med. 2004;  351 1206-1217
• 46 Bonino F, Lau G, Marcellin P, Hadzyannis S. The first detailed analysis of predictors of response in HBeAg-negative chronic hepatitis B: data from a multicenter, randomized, partially double-blind study of peginterferon alfa-2A (40KD) PEGASYS®) alone or in combination with lamivudine vs lamivudine alone.  Hepatology. 2005;  40(suppl 1) 659A
• 47 Lampertico P, Del Ninno E, Vigano M et al.. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy.  Hepatology. 2003;  37 756-763
• 48 Manesis E K, Hadziyannis S J. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.  Gastroenterology. 2001;  121 101-109
• 49 Wursthorn K, Buggisch P, Zoellner B et al.. Combination therapy of peginterferon alfa-2b and adefovir dipivoxil in chronic hepatitis B leads to a strong suppresison of cccDNA and high rates of HBe and HBs seroconversion.  J Hepatol. 2005;  45(suppl 1) , abst 76
• 50 Hodge R A. Telbivudine/Torcitabine Idenix/Novartis.  Curr Opin Investig Drugs. 2004;  5 232-241
• 51 Han S H, Leung N WY, Teo E K et al.. Results of a one-year international phase IIB trial of LDT, and LDT plus lamivudine, in patients with chronic hepatitis B.  J Hepatol. 2004;  40 16
• 52 Lai C L, Lim S G, Brown N A et al.. A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection.  Hepatology. 2004;  40 719-726
• 53 Lai C L, Brown N A, Myers M et al.. Valtorcitabine provides potent suppression of hepatitis B virus in patients with chronic hepatitis B: results of a phase I/II clinical trial (abst 24). Presented at: the 55th Annual Meeting of the American Association for the Study of Liver Disease October 29-November 2, 2004 Boston, MA;
• 54 Buti M, Esteban R. Entecavir, FTC, L-FMAU, LdT and others.  J Hepatol. 2003;  39(suppl 1) S139-S142
• 55 Gish R G, Trinh H, Leung N et al.. Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study.  J Hepatol. 2005;  43 60-66
• 56 Gish R G, Leung N W, Wright T L et al.. Dose range study of pharmacokinetics, safety, and preliminary antiviral activity of emtricitabine in adults with hepatitis B virus infection.  Antimicrob Agents Chemother. 2002;  46 1734-1740
• 57 Gish R, Leung N, Wang C et al.. Antiviral activity, safety, and incidence of resistance in chronically infected hepatitis B patients (CHB) given once daily emtricitabine for 2 years.  Hepatology. 2003;  38 372A
• 58 Shiffman M L, Ng T M, Krastev Z et al.. A double-blind, placebo-controlled trial of emtricitabine (ftc, Emtriva) administered once-daily for treatment of chronic hepatitis B virus (HBV) infection (abst 22). Presented at: the 55th Annual Meeting of the American Association for the Study of Liver Disease October 29-November 2, 2004 Boston, MA;
• 59 Cossart Y E. Australia antigen and hepatitis in renal units.  Proc Eur Dial Transplant Assoc. 1972;  9 235-242
• 60 Davis H L. DNA vaccines for prophylactic or therapeutic immunization against hepatitis B virus.  Mt Sinai J Med. 1999;  66 84-90