How to compare antivirals in the treatment of chronic hepatitis B?
© Ozaras and Leblebicioglu; licensee BioMed Central Ltd. 2009
- Received: 02 February 2009
- Accepted: 02 March 2009
- Published: 02 March 2009
After the use of antiviral drugs in the treatment of hepatitis B virus (HBV) infection, we found new therapeutic options for non-responders to interferon (IFN). Additionally, those could not be treated previously by IFN, such as cirrhotics have been given effective antivirals. However, the parameters to determine the efficacy, the outcome measures, and the duration of the treatment emerged as unresolved issues by the treatment with antivirals. Resistance to antivirals is also a challenge and its definition, detection, and management are new controversial topics in the area of HBV treatment.
Now, the clinician has a wider choice of antivirals: in addition to IFNs, lamivudine, adefovir, entecavir, telbivudine, and tenofovir have been approved for treating chronic HBV infection [1, 2]. As the HBV treatment studies are published, we see several comparisons of the antivirals [3–5]. Updated EASL guideline gave the comparisons of the HBV drugs . However comparing efficacies or other aspects of two or more antivirals in a simple way may give misleading results.
Differing characteristics of the studies comparing the response rates in HBeAg-positive patients
Pegylated-IFN-α2a, 180 μg once Weekly
Lamivudine 100 mg/d
Adefovir 10 mg/d
Entecavir 0.5 mg/d
Telbivudine 600 mg/d
Tenofovir 300 mg/d
Mean age (years)
31.6 to 35
Male gender (%)
74 to 79
Asian race (%)
57 to 87
272 to 463
Conventional IFN 11%, lamivudine 11%
Conventional IFN 11%/IFN 13% and lamivudine 3%/NA
IFN (24% among all arms)
IFN 13% and lamivudine 3%
IFN 17%, lamivudine or emtricitabine 5%
Baseline HBV-DNA (log10 cp/ml)
9.5 to 10.1
102 to 159
Baseline necro-inflammatory score
7.3 to 7.7
Baseline fibrosis score
2.2 to 2.3
Genotypes (%, A/B/C/D/others)
7/30/58/4/1 (ref 8) 28/22/25/15/11 (ref 9)
Treatment duration (weeks)
48 to 52
Virological response criterion (HBV DNA level)
<400 cp/ml (ref 8), <0.7 MEq/ml (ref 10), <300 cp/ml (ref 10)
ALT is another issue: Baseline mean ALT levels may not be comparable. Additionally, ALT level as an inclusion criterion varied: greater than 1 time the upper limit of the normal range for pegylated interferon , 1.3 times for entecavir  and telbivudine , and 1.2 times for adefovir .
Patient numbers, genotype distributions, treatment durations, previous treatment, and probably many other differences exist among the studies compared, discouraging to make a head-to-head comparison. Asian race for example, is associated with poor response to interferon treatment , and the rate of this race is highest in pegylated IFN study.
Considering the role of high ALT and low DNA on treatment response, a comparison of efficacy of any two drugs should include the details of distribution of these parameters in the study population. Only the telbivudine study described the stratification of the patients according to DNA levels.
Resistance is another important issue in the treatment of HBV with antivirals. The published clinical trials have used varying definitions of efficacy, failure, and resistance based on different measures of virologic responses . If we analyze the resistance outcomes in the studies, we see that although some studies included all patients to the tests for antiviral resistance [16, 17] some others included only those with a viral rebound [18, 19]. The methods used to detect the resistance also differ: Although the majority of the studies used direct sequencing , restriction fragment length polymorphism  and line-probe, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry  were used in some others. Study design differs in the studies and reported resistance rates should be evaluated regarding the design. In entecavir study, patients who had a response (defined by an HBV DNA level below 0.7 megaequivalents [MEq] per milliliter and HBeAg loss) or a nonresponse (defined by an HBV DNA level of 0.7 MEq per milliliter or greater) discontinued study treatment at week 52 . Patients who had only a virologic response (defined by an HBV DNA level below 0.7 MEq per milliliter and no HBeAg loss) were offered continued study therapy for up to 96 weeks. This design, especially discontinuation of the therapy in nonresponders may decrease the risk of resistance. This unique feature of the study may underestimate the resistance.
Studies in HBeAg-negative patients may have similar problems, especially in inclusion criteria and response definitions . A review defined virological response as "decrease of serum HBV DNA to PCR-undetectable levels (preferably) or <2000 IU/mL (4 log10 copies/mL) . The entecavir study used "HBV DNA <300 copies/ml by PCR assay"  and the adefovir study used "<400 copies/ml" . Clevudine study, finally, used hybride capture with lower limit of detection of <4700 copies/mL and then if it remains undetectable, used PCR with lower limit of detection of 300 copies/mL .
A simple comparison of several drugs in differing study characteristics may not give reliable conclusive information to the reader. Unless randomizing the patients in the same study design, it seems difficult to compare the efficacies of any given drugs. When giving such comparisons, the reader should be warned against the difference among study characteristics and better, the main differences should also be included.
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- Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology. 2007, 45: 507-39. 10.1002/hep.21513View ArticlePubMedGoogle Scholar
- European Association For The Study Of The Liver: EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol. 2009, 50: 227-42. 10.1016/j.jhep.2008.10.001View ArticleGoogle Scholar
- 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: 1315-41. 10.1016/j.cgh.2008.08.021View ArticlePubMedGoogle Scholar
- Dusheiko G, Antonakopoulos N: Current treatment of hepatitis B. Gut. 2008, 57: 105-24. 10.1136/gut.2005.077891View ArticlePubMedGoogle Scholar
- Papatheodoridis GV, Manolakopoulos S, Dusheiko G, Archimandritis AJ: Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. Lancet Infect Dis. 2008, 8: 167-78. 10.1016/S1473-3099(07)70264-5View ArticlePubMedGoogle Scholar
- European Association for the Study of the Liver: EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol. 2009, 50:Google Scholar
- Feld JJ, Ghany MG: Evolution of therapy for chronic hepatitis B: progressing from the simple to the complex. Ann Intern Med. 2007, 147: 806-8.View ArticlePubMedGoogle Scholar
- Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group: Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005, 352: 2682-95. 10.1056/NEJMoa043470View ArticlePubMedGoogle Scholar
- Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, BEHoLD AI463022 Study Group: A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006, 354: 1001-10. 10.1056/NEJMoa051285View ArticlePubMedGoogle Scholar
- Lai CL, Gane E, Liaw YF, Thongsawat S, Wang Y: Telbivudine vs. lamivudine for chronic hepatitis B: first-year results from the international phase III Globe trial [Abstract]. Hepatology. 2005, 42: 748A-10.1002/hep.20930.View ArticleGoogle Scholar
- Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Adefovir Dipivoxil 437 Study Group: Adefovir dipivoxil for the treatment of hepatitis B e antigen positive chronic hepatitis B. N Engl J Med. 2003, 348: 808-16. 10.1056/NEJMoa020681View ArticlePubMedGoogle Scholar
- Marcellin P, Heathcote EJ, Buti M, Gane E, de Man RA, Krastev Z: Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008, 359: 2442-55. 10.1056/NEJMoa0802878View ArticlePubMedGoogle Scholar
- Valsamakis A: Molecular Testing in the Diagnosis and Management of Chronic Hepatitis B. Clin Microbiol Rev. 2007, 20: 426-39. 10.1128/CMR.00009-07PubMed CentralView ArticlePubMedGoogle Scholar
- Lai CL: Antiviral therapy for hepatitis B and C in Asians. J Gastroenterol Hepatol. 1999, 14 (Suppl): S19-21.View ArticlePubMedGoogle Scholar
- Pawlotsky JM, Dusheiko G, Hatzakis A, Lau D, Lau G, Liang TJ, Locarnini S, Martin P, Richman DD, Zoulim F: Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach. Gastroenterology. 2008, 134: 405-15. 10.1053/j.gastro.2007.11.036PubMed CentralView ArticlePubMedGoogle Scholar
- Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF: Entecavir res6istance is rare in nucleoside naive patients with hepatitis B. Hepatology. 2006, 44: 1656-1665. 10.1002/hep.21422View ArticlePubMedGoogle Scholar
- Westland C, Yang H, Delaney WE, Gibbs C, Miller M, Wulfsohn M: Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology. 2003, 38: 96-103. 10.1053/jhep.2003.50288View ArticlePubMedGoogle Scholar
- Colonno R, Rose F, CJ B: High barrier to resistance results in no emergence of entecavir resistance in nucloside-naive subjects during the first two years of therapy [Abstract 490]. J Hepatol. 2006, 44 (Suppl 1): S182-10.1016/S0168-8278(06)80490-3.View ArticleGoogle Scholar
- Lai C, Gane E, Liaw Y-F, Thongawat S, Wang Y, Heathcote E: Telbivudine (LDT) vs. lamivudine for chronic hepatitis B: first-year results from the International Phase III Globe Trial [Abstract]. Hepatology. 2005, 42 (Suppl): 748A-Google Scholar
- Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, Liaw YF, Mizokami M, Kuiken C, : Antiviral drugresistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007, 46: 254-65. 10.1002/hep.21698View ArticlePubMedGoogle Scholar
- Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER: Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003, 125: 1714-1722. 10.1053/j.gastro.2003.09.033View ArticlePubMedGoogle Scholar
- Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K: Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol. 2006, 44: 283-290. 10.1016/j.jhep.2005.10.018View ArticlePubMedGoogle Scholar
- Ozaras R, Leblebicioglu H, Eroglu C: To define virological response in hepatitis B e antigen-negative patients. Hepatology. 2008, 47: 1425- 10.1002/hep.22233View ArticlePubMedGoogle Scholar
- Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z: Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006, 354: 1011-20. 10.1056/NEJMoa051287View ArticlePubMedGoogle Scholar
- Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M: Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003, 348 (9): 800-7. 10.1056/NEJMoa021812View ArticlePubMedGoogle Scholar
- Yoo BC, Kim JH, Kim TH, Koh KC, Um SH, Kim YS: Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology. 2007, 46: 1041-8. 10.1002/hep.21800View ArticlePubMedGoogle Scholar