, Volume 65, Issue 11, pp 1451–1460 | Cite as

Drugs in Development for Hepatitis B

Leading Article


The management of chronic hepatitis B (CHB) has improved dramatically over the last decade with the development of new drugs such as lamivudine and adefovir dipivoxil, in addition to the now standard interferon (IFN)-α therapy. These new drugs can achieve a significant reduction or inhibit replication of hepatitis B virus (HBV) DNA during therapy. However, in the majority of patients, particularly in those who are hepatitis B e antigen (HBeAg)-negative, the sustained off-therapy suppression of HBV DNA is rare. For this reason, several new antiviral and immunomodulatory agents are currently being evaluated.

Among the immunomodulatory agents, pegylated IFNα (peginterferon-α) has been shown to be more effective for HBeAg-positive CHB than either lamivudine or standard IFNα monotherapy, particularly in those patients infected by HBV genotypes A and B. The new antivirals entecavir, tenofovir disoproxil fumarate and telbivudine exhibit a more potent viral inhibitory effect than the currently approved drugs (IFNs, lamivudine and adefovir dipivoxil). However, the emergence of viral resistance has been witnessed and this could be one of the major limitations to the clinical use of these new drugs, particularly during prolonged therapy.

In HBeAg-negative patients it is more and more common for oral antiviral therapy to be administered for prolonged periods, as the sustained off-therapy response rates of short-term therapy are very low. Different studies are currently evaluating combination therapy, using lamivudine with adefovir dipivoxil or peginterferon-α with lamivudine; the preliminary results show virological responses no better than those achieved by monotherapy. However, as combination therapy is associated with a low likelihood of developing HBV drug resistance, this could result in a higher virological response during prolonged therapy.

In the near future the most realistic therapeutic option for the majority of patients with CHB will be long-term use of these new, more potent antiviral drugs, if they can achieve good safety profiles while maintaining low resistance rates at affordable costs.



The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.


  1. 1.
    EASL International Consensus Conference on Hepatitis B. J Hepatol 2003; 39 Suppl. 1: S3–25Google Scholar
  2. 2.
    Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000 — summary of a workshop. Gastroenterology 2001: 120: 1828–53PubMedCrossRefGoogle Scholar
  3. 3.
    Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2001; 34: 617–24PubMedCrossRefGoogle Scholar
  4. 4.
    Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology 2001: 34: 1225–41PubMedCrossRefGoogle Scholar
  5. 5.
    Hoofnagle JH, Dusheiko GM, Seeff LB, et al. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med 1981; 94: 744–8PubMedGoogle Scholar
  6. 6.
    Fattovich G, Rugge M, Brollo L, et al. Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 1986; 6: 167–72PubMedCrossRefGoogle Scholar
  7. 7.
    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: 168–74PubMedCrossRefGoogle Scholar
  8. 8.
    Hadziyannis SJ. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment. Vir Hep Rev 1995; 1:7–36Google Scholar
  9. 9.
    Hunt CM, McGill JM, Allen ML, et al. Clinical relevance of hepatitis B virus mutations. Hepatology 2000; 31: 1037–44PubMedCrossRefGoogle Scholar
  10. 10.
    Bonino F, Rosina F, Rizzetto M, et al. Chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology 1986; 90: 1268–73PubMedGoogle Scholar
  11. 11.
    Brunetto MR, Giarin M, Oliveri F, et al. Wild type and e antigen-minus hepatitis B virus in course of chronic hepatitis. Proc Natl Acad Sci U S A 1991; 88: 4186–90PubMedCrossRefGoogle Scholar
  12. 12.
    Cooksley WG, Piratvisuth T, Lee SD, 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: 298–305PubMedCrossRefGoogle Scholar
  13. 13.
    Janssen HLA, von Zonneveld M, Senturk H, et al. Pegylated interferon α-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005 Jan 8; 365(9454): 123–9PubMedCrossRefGoogle Scholar
  14. 14.
    Lau G, Piratvisuth T, Luo KX, et al. Peginterferon alfa2a monotherapy and in combination with lamivudine is more effective than lamivudine monotherapy in HBeAg-positive chronic hepatitis B: results from a large, multinational study. Hepatology 2004; 40 Suppl. 1: 171AGoogle Scholar
  15. 15.
    Marcellin P, Lau GKK, 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: 1206–17PubMedCrossRefGoogle Scholar
  16. 16.
    Yamanaka G, Wilson T, Innaimo S, et al. Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus. Antimicrob Agents Chemother 1999; 43: 190–3PubMedGoogle Scholar
  17. 17.
    Nevens F, de Man RA, Chua D, et al. Effectiveness of a low dose of entecavir in treating recurrent viremia in chronic hepatitis B [abstract]. Hepatology 2000; 32 Suppl.: 377AGoogle Scholar
  18. 18.
    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. Gastroenterology 2002; 123: 1831–8PubMedCrossRefGoogle Scholar
  19. 19.
    de Man RA, Wolters L, Nevens F, et al. A study of oral entecavir given for 28 days in both treatment-naive and pre-treated subjects with chronic hepatitis [abstract]. Hepatology 2000; 32 Suppl.: 376AGoogle Scholar
  20. 20.
    Tassopoulos N, Hadziyannis S, Cianciara J, et al. Entecavir is effective in treating patients with chronic hepatitis B who have failed lamivudine therapy [abstract]. Hepatology 2001; 34: 340ACrossRefGoogle Scholar
  21. 21.
    Chang TT, Gish R, de Man R, et al. Entecavir is superior to lamivudine for the treatment of HBeAg positive chronic hepatitis B: results of phase III study ETV-022 in nuclesoide naive patients [abstract]. Hepatology 2004; 40 Suppl. 1: 193AGoogle Scholar
  22. 22.
    Shouval D, Lai CLL, Cheinquer H, et al. Entecavir demosntrates superior histologic and virologic efficacy over lamivudine in nucleoside-naive HBeAg-negative chronic hepatitis B: results of phase III trial ETV-027 [abstract]. Hepatology 2004; 40 Suppl. 1: 728AGoogle Scholar
  23. 23.
    Sherman M, Yurdaydin C, Sollano J, et al. Entecavir is superior to continued lamivudine for the treatment of lamivudine-refractory, HbeAg-positive chronic hepatitis B: results of phase III study ETV-026 [abstract]. Hepatology 2004; 40 Suppl. 1: 664AGoogle Scholar
  24. 24.
    Delanay WE, Yang H, Sabogal A, et al. In vitro cross-resistance testing of adefovir, lamivudine, telvibudine, entecavir and other anti-HBV compounds against four major mutational patterns of lamivudine-resistant HBV [abstract]. Hepatology 2004; 40 Suppl. 1: 244AGoogle Scholar
  25. 25.
    Korba BE, Schinazi RF, Cote P, et al. Effect of oral administration of emtricitabine on woodchuck hepatitis virus replication in chronically infected woodchucks. Antimicrob Agents Chemother 2000; 44: 1757–60PubMedCrossRefGoogle Scholar
  26. 26.
    Ladner SK, Miller TJ, Otto MJ, et al. The hepatitis B virus M539V polymerase variation responsible for 3TC resistance also confers cross-resistance to other nucleoside analogues. Antiviral Chemother 1998; 9: 65–72Google Scholar
  27. 27.
    Wang C, Correy L, Leung N, et al. Antiviral activity of 48 weeks of emtricitabine (FTC) treatment in patients with HBeAg negative/HBV DNA positive chronic hepatitis B (CHB) [abstract]. Hepatology 2001; 34: 323ACrossRefGoogle Scholar
  28. 28.
    Shiftman ML, Ng TM, Krastev Z, et al. A double-blind, placebo-controlled trial of emtrcitabine (FTC, Emtriva) administered once-daily for treatment of chronic Hepatitis B virus infection [abstract]. Hepatology 2004; 40 Suppl. 1: 172ACrossRefGoogle Scholar
  29. 29.
    Lau G, Cooksley H, Ribeiro RM, et al. Randomized, double, blind study comparing adefovir dipivoxil plus emtricitabine combination therapy versus adefovir alone in HBeAg-positive chronic hepatitis B: efficacy and mechanisms of treatment response [abstract]. Hepatology 2004; 40 Suppl. 1: 272AGoogle Scholar
  30. 30.
    Han SH, Leung NWY, Teo EK, et al. Results of a one-year international phase IIb trial of LdT, and LdT plus lamivudine in patients with chronic hepatitis B [abstract]. Hepatology 2004; 40 Suppl. 1: 16CrossRefGoogle Scholar
  31. 31.
    Chu CK, Boudinot FD, Peek SF, et al. Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent. Antivir Ther 1998; 3 Suppl. 3: 113–21PubMedGoogle Scholar
  32. 32.
    Peek SF, Cote PJ, Jacob JR, et al. Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-beta, 1-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax). Hepatology 2001; 33: 254–66PubMedCrossRefGoogle Scholar
  33. 33.
    Abdelhamed AM, Kelley CM, Miller TG, et al. Comparison of anti-hepatitis B virus activities of lamivudine and clevudine by a quantitative assay. Antimicrob Agents Chemother 2003; 47: 324–36PubMedCrossRefGoogle Scholar
  34. 34.
    Marcellin P, Mommeja-Marin H, Sacks SL, et al. A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B. Hepatology 2004; 40: 140–8PubMedCrossRefGoogle Scholar
  35. 35.
    Marcellin P, Leung N, Hann H-WL, et al. A phase II, randomized trial evaluating the safety, pharmacokinetics and antiviral activity of clevudine for 12 weeks in patients with chronic hepatitis B [abstract]. Hepatology 2004; 40 Suppl. 1: 652ACrossRefGoogle Scholar
  36. 36.
    Benhamou Y, Poynard T. Treatment of chronic hepatitis B virus infection in patients co-infected with human immunodeficiency virus. J Hepatol 2003; 39 Suppl. 1: S194–9PubMedCrossRefGoogle Scholar
  37. 37.
    Lessells R, Leen C. Management of hepatitis B in patients coinfected with the human immunodeficiency virus. Eur J Clin Microbiol Infect Dis 2004; 23: 366–74PubMedCrossRefGoogle Scholar
  38. 38.
    Benhamou Y. Antiretroviral therapy and HIV/hepatitis B virus coinfection. Clin Infect Dis 2004; 38 Suppl. 2: S98–103PubMedCrossRefGoogle Scholar
  39. 39.
    Dore GJ, Cooper DA, Pozniak AL, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis 2004; 189: 1185–92PubMedCrossRefGoogle Scholar
  40. 40.
    Lerbaek A, Kristiansen TB, Katzenstein TL, et al. Tenofovir treatment in an unselected cohort of highly antiretroviral experienced HIV positive patients. Scand J Infect Dis 2004; 36: 280–6PubMedCrossRefGoogle Scholar
  41. 41.
    Benhamou Y, Bochet M, Thibault V, et al. 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: 718–23PubMedCrossRefGoogle Scholar
  42. 42.
    Van Bömmel F, Wünche T, Mauss S, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant Hepatitios B virus infection. Hepatology 2004; 40: 1421–5PubMedCrossRefGoogle Scholar
  43. 43.
    Standring DN, Bridges EG, Placidi L, et al. Antiviral beta-L-nucleosides specific for hepatitis B virus infection. Antivir Chem Chemother 2003; 12 Suppl. 1: 119–29Google Scholar
  44. 44.
    Bryant ML, Bridges EG, Placidi L, et al. Antiviral L-nucleosides specific for hepatitis B virus infection. Antimicrob Agents Chemother 2001; 45: 229–35PubMedCrossRefGoogle Scholar
  45. 45.
    le Guehier F, Pichoud C, Jamard C, et al. Characterization of the antiviral effect of 2′3′-dideoxy-2′-3′didehydro-beta-L-5-fluo-rocytidine in the duck hepatitis B virus infection model. Antimicrob Agents Chemother 2000; 44: 111–22CrossRefGoogle Scholar
  46. 46.
    Delaney W, Yang H, Miller M, et al. Lamivudine-resistant HBV is cross-resistant to L-dT and L-dC in vitro. J Hepatol 2002; 36 Suppl. 1: 89CrossRefGoogle Scholar
  47. 47.
    Lai C-L, Lim SG, Brown NA, et al. A dose-finding study of once-daily oral telvivudine in HBeAg-positive patients with chronic hepatitis B virus infection. Hepatology 2004; 40: 719–26PubMedCrossRefGoogle Scholar
  48. 48.
    Lai C-L, Leung NWY, Teo E-K, et al. Results of a one-year international phase IIb comparative trial of telbivudine, lamivudine, and the combination, in patients with chronic hepatitis B [abstract]. Hepatology 2003; 38 Suppl. 1: 262ACrossRefGoogle Scholar
  49. 49.
    Neumman AV, Zhou XJ, Boehme RE, et al. Viral dynamics for LDT (Telbuvidine) treated Hepatitis B patients: high degree of initial inhibition with dose-dependent second phase HBV clearance suggests a new model for HBV dynamics [abstract]. Hepatology 2004; 40 Suppl. 1: 246AGoogle Scholar
  50. 50.
    Lai CL, Brown N, Myers M, et al. Valtorcitabina provides potent suppression of hepatitis B virus in patients with chronic hepatitis B: results of a phase I/II clinical trial. J Hepatol 2004; 40 Suppl. 1: 173AGoogle Scholar
  51. 51.
    Shaw T, Locarnini S. Combination chemotherapy for hepatitis B virus: the final solution? Hepatology 2000; 32: 430–2PubMedCrossRefGoogle Scholar
  52. 52.
    Mailliard ME, Gollan JL. Suppressing hepatitis B without resistance: so far, so good. N Engl J Med 2003; 348: 848–50PubMedCrossRefGoogle Scholar
  53. 53.
    Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 2004; 2: 87–10652PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Liver UnitHospital General Universitari Vall d’HebronBarcelonaSpain

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