Current Treatment of Chronic Hepatitis B: Benefits and Limitations

Robert P. Perrillo

doi:10.1055/s-2005-915647

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2005; 25: 20-28
DOI: 10.1055/s-2005-915647

Current Treatment of Chronic Hepatitis B: Benefits and Limitations

Robert P. Perrillo¹

¹Director, Academic Affairs, Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, Louisiana

Abstract

ABSTRACT

Nucleoside analogue therapy allows safe, long-term suppression of hepatitis B virus (HBV) and is a major milestone in the treatment of chronic hepatitis B. Entecavir has recently been approved by the U.S. Food and Drug Administration and is not only more potent than lamivudine and adefovir, but it is also associated with a very low rate of drug resistance. Peginterferon, which has been shown to be more potent than conventional interferon, has recently been licensed in Europe and in the United States. Despite these advances, however, the clinician still faces several challenges in treating this relatively complex disorder. Controversies and unresolved issues remain, including the question of whether the thresholds for alanine aminotransferase and HBV DNA levels recommended in the published treatment guidelines are too restrictive. Another complication is the differing levels of sensitivity and dynamic range of the assays for serum HBV DNA. Finite courses of treatment are associated with low rates of virologic response, but drug resistance occurs when nucleoside analogue monotherapy is used long term. The role for combination therapy remains unclear. Much has been accomplished over the past decade, but much remains to be done.

KEYWORDS

Hepatitis B - clinical trials - nucleoside analogues - interferon

Volltext

Referenzen

REFERENCES

1 Lok A SF, McMahon B J. Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: update of recommendations. Hepatology. 2004; 39 857-861
2 Liaw Y-F, Leung N, Guan R et al.. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int. 2005; 25 472-489
3 EASL Jury . EASL International Consensus Conference on Hepatitis B: 13-14 September 2002, Geneva, Switzerland: consensus statement (long version). J Hepatol. 2003; 39 S3-S25
4 Chu C-J, Hussain M, Lok A SF. Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology. 2002; 36 1408-1415
5 Manensis E K, Papatheodoridis G V, Sevastianos V et al.. Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection. Am J Gastroenterol. 2003; 98 2261-2267
6 Perrillo R P, Lai C L, Liaw Y F et al.. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002; 36 186-194
7 Piton A, Poynard T, Imbert-Bismut F for the MULTIVIRC Group et al.. Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. Hepatology. 1998; 27 1213-1219
8 Yang L M, Xu K C, Zhao Y L et al.. Clinical significance of liver biopsy in chronic hepatitis B patients with persistently normal transaminase. Chin J Dig Dis. 2002; 3 150-153
9 Keeffe E B, Dieterich D T, Han S-HB et al.. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004; 2 87-106
10 Yao J, Beld M, Oon L et al.. Multicenter evaluation of the VERSANT hepatitis B virus DNA 3.0 assay. J Clin Microbiol. 2004; 42 800-806
11 Lewin S R, Ribeiro R M, Walters T et al.. Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed. Hepatology. 2001; 34 1012-1020
12 Dienstag J L, Goldin R D, Heathcote E J et al.. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003; 124 105-117
13 Lok A SF, Lai C-L, Leung N et al.. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003; 125 1714-1722
14 Liaw Y F, Sung J JY, Chow W C et al.. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004; 351 1521-1531
15 Locarnini S. Molecular virology and the development of resistant mutants: implications for therapy. Semin Liver Dis. 2005; 25(suppl 1) 9-19
16 Richman D. The impact of drug resistance on the effectiveness of chemotherapy for chronic hepatitis B. Hepatology. 2000; 32 866-867
17 Sung J JY, Lau J Y, Zeuzem S et al.. A randomized double-blind phase II study of lamivudine (LAM) compared to lamivudine plus adefovir dipivoxil (ADV) for treatment naïve patients with chronic hepatitis B (CHB): week 52 analysis. J Hepatol. 2003; 38(suppl 2) 25 , (abst)
18 Perrillo R P. Interferon in the management of chronic hepatitis B. Dig Dis Sci. 1993; 38 577-593
19 Nair S, Perrillo R. Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?. Hepatology. 2001; 34 1021-1026
20 Cooksley G, Manns M, Lau G KK et al.. Effect of genotype and other baseline factors on response to peginterferon alfa-2a (40 KD) (Pegasys^®) in HBeAg-positive chronic hepatitis B: results from a large, randomized study. J Hepatol. 2005; 42 30 , (abst)
21 Cooksley W G. Treatment with interferons in patients with hepatitis B. Semin Liver Dis. 2004; 24(suppl 1) 45-54
22 Janssen H LA, van Zonneveld M, Zeuzem S et al.. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomized trial. Lancet. 2005; 365 123-129
23 Lau G, Piratvisuth T, Luo K X et al.. PEGinterferon alfa-2a (40KD) (Pegasys^®) 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 171A
24 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
25 Piratvisuth T, Luo K-X, Marcellin P et al.. Effect of ALT flares on efficacy and safety of PEGinterferon alfa-2a (40KD) (Pegasys^®), PEGinterferon alfa-2a plus lamivudine and lamivudine in HBeAg-positive chronic hepatitis B (CHB). J Hepatol. 2005; 42 189 , (abst)
26 Westland C, Delaney W IV, Yang H et al.. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology. 2003; 125 107-116
27 Kao J H, Wu N H, Chen P J et al.. Hepatitis B genotypes and the response to interferon therapy. J Hepatol. 2000; 33 998-1002
28 Chu C J, Keeffe E B, Han S H et al.. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003; 125 444-451
29 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
30 Lai C-L, Leung N WY, 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. Hepatology. 2003; 38 262A
31 Wright T L. Clinical trial results and treatment resistance with lamivudine in hepatitis B. Semin Liver Dis. 2004; 24(suppl 1) 31-36
32 Dienstag J L, Schiff E R, Wright T L et al.. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999; 341 1256-1263
33 Liaw Y F, Leung N WY, Chang T T et al.. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology. 2000; 119 172-180
34 Thio C L. Hepatitis B in the human immunodeficiency virus-infected patient: epidemiology, natural history, and treatment. Semin Liver Dis. 2003; 23 125-136
35 Marcellin P, Chang T T, Lim S G et al.. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003; 348 808-816
36 Hadziyannis S J, Tassopoulos N C, Heathcote E J et al.. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003; 348 800-807
37 Marcellin P, Chang T, Lim S et al.. Increasing serologic, virologic and biochemical response over time to adefovir dipivoxil (ADV) 10 mg in HBeAg+ chronic hepatitis B (CHB) patients. J Hepatol. 2005; 42 31 , (abst)
38 Hadziyannis S, Tassopoulos N, Chang T T et al.. Three year study of adefovir dipivoxil demonstrates sustained efficacy in presumed precore mutant chronic hepatitis B (CHB) patients in a long term safety and efficacy study (LTSES). J Hepatol. 2004; 40 17 , (abst)
39 Hadziyannis S, Tassopoulos N, Heatheate E J et al.. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. 2005; 352 2673-2681
40 Angus P, Vaughan R, Xiong S et al.. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology. 2003; 125 292-297
41 Perrillo R, Hann H-W, Mutimer D et al.. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology. 2004; 126 81-90
42 Peters M G, Hann H W, Martin P et al.. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004; 126 91-100
43 Schiff E R, Lai C-L, Hadziyannis S et al.. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003; 38 1419-1427
44 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
45 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 a phase III study ETV-022 in nucleoside-naïve patients. Hepatology. 2004; 40(suppl 1) 193A , (abst)
46 Shouval D, Lai C-L, Cheinquer H et al.. Entecavir demonstrates superior histologic and virologic efficacy over lamivudine in nucleoside-naïve HBeAg (-) chronic hepatitis B: results of a phase III trial ETV-027. Hepatology. 2004; 40 728A , (abst)
47 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
48 Colonno R, Rose R E, Levine S M et al.. Entecavir (ECV) resistance is not observed in nucleoside-naïve subjects and is observed infrequently by week 48 in lamivudine-refractory subjects with chronic HBV infection. J Hepatol. 2005; 42 173 , (abst)
49 Shiffman M, 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. Hepatology. 2004; 40 172A , (abst 22)
50 Raffi F, Snow A, Borroto-Esoda K et al.. Anti-HBV activity of emtricitabine (FTC) in patients co-infected with HIV and hepatitis B virus (abst 215). Programs and abstracts of the 2nd IAS Conference on Pathogenesis and Treatment July 13-16, 2003 Paris, France;
51 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. 2002; 36 372A
52 van Bommel F, Wunsche T, Mauss S et al.. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004; 40 1421-1425
53 Ristig M B, Crippin J, Aberg J A et al.. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis. 2002; 186 1844-1847
54 Nelson M, Portsmouth S, Stebbing J et al.. An open-label study of tenofovir in HIV-1 and hepatitis B virus co-infected individuals. AIDS. 2003; 17 F7-10
55 Kuo A, Dienstag J L, Chung R T. Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin Gastroenterol Hepatol. 2004; 2 266-272
56 Perrillo R P. Overview of treatment of hepatitis B: Key approaches and clinical challenges. Semin Liver Dis. 2004; 24(suppl 1) 23-29
57 Sung J JY, Lai J Y, Zeuzem S et al.. A randomized double-blind phase II study of lamivudine compared to lamivudine plus adefovir dipivoxil for treatment naive patients with chronic hepatitis B: week 52 analysis. J Hepatol. 2003; 38(suppl 2) 25 , (abst)
58 Lai C L, Leung N W, Teo E et al.. Phase IIb extended-treatment trial of telbivudine (LdT) vs lamivudine vs combination treatment in hepatitis B patients: two-year results. Gastroenterology. 2005; 128(suppl 2) 320A
59 Chan H L-Y, Leung N W-Y, Hui Ay. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-α2b and lamivudine with lamivudine alone. Ann Intern Med. 2005; 142 240-250

Robert P PerrilloM.D.

1514 Jefferson Highway, Section of Gastroenterology and Hepatology

Ochsner Clinic Foundation, New Orleans, LA 70121

eMail: rperrillo@ochsner.org