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Long-term efficacy and emergence of multidrug resistance in patients with lamivudine-refractory chronic hepatitis B treated by combination therapy with adefovir plus lamivudine

  • Original Article—LIVER, PANCREAS, and BILIARY TRACT
  • Published:
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Abstract

Background

Few studies have investigated the emergence of multidrug resistance to adefovir dipivoxil (ADV) plus lamivudine (LAM) combination therapy for patients with LAM-refractory chronic hepatitis B (CHB). In this retrospective study, we investigated the long-term clinical course of these patients with or without multidrug resistance mutations.

Methods

We analyzed 406 Japanese patients with LAM-refractory CHB treated with combination therapy with follow-up for a median of 5.4 (0.5–9.5) years. Multidrug resistance of hepatitis B virus (HBV) DNA was analyzed using direct sequencing or cloning methods at baseline and viral breakthrough or insufficient decline during combination therapy.

Results

Ratio of patients with undetectable serum HBV DNA levels (<2.6 log copies/mL) during combination therapy was 63, 72, 75, 79, 82, 80 and 85 % at years 1 through 7, respectively. Substitutions associated with multidrug resistance were identified in 11 patients (2.7 %) at baseline, and in 12 patients (3 %) during therapy. HBV DNA levels of patients with rtA181S mutation at baseline and emergence of rtA181T + rtN236T double mutation or a wide variety of mutations during combination therapy could not be suppressed. Moreover, using ultra-deep sequencing, rtA181T/V mutations were detected at baseline in 7 of 10 patients with emergent multidrug resistance during combination therapy, although 6 of these 7 patients had very low frequency (<1 %) variants.

Conclusion

Long-term ADV plus LAM combination therapy is effective in LAM-refractory patients. However, HBV DNA levels of the patients with multidrug resistance at baseline or during combination therapy sometimes could not achieve complete suppression or were re-elevated after a decrease.

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Abbreviations

HBV:

Hepatitis B virus

IFN:

Interferon

NA:

Nucleoside/nucleotide analogues

LAM:

Lamivudine

ADV:

Adefovir dipivoxil

ETV:

Entecavir

TDF:

Tenofovir disoproxil fumarate

CHB:

Chronic hepatitis B

HBeAg:

Hepatitis B e antigen

ALT:

Alanine aminotransferase

HBsAg:

Hepatitis B surface antigen

PCR:

Polymerase chain reaction

CLEIA:

Chemiluminescent enzyme immunoassay

rt:

Reverse transcriptase

VBT:

Viral breakthrough

AST:

Aspartate aminotransferase

CI:

Confidence interval

Pt:

Patient

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Acknowledgments

This study was supported in part by an Grant-in-Aid for Scientific Research (C) (Grant Number 24590999) from the Japan Society for the Promotion of Science, and by an Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan

    Fumitaka Suzuki, Tetsuya Hosaka, Yoshiyuki Suzuki, Norio Akuta, Hitomi Sezaki, Tasuku Hara, Yusuke Kawamura, Masahiro Kobayashi, Satoshi Saitoh, Yasuji Arase, Kenji Ikeda & Hiromitsu Kumada

  2. Okinaka Memorial Institute for Medical Research, Tokyo, Japan

    Fumitaka Suzuki

  3. Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan

    Mariko Kobayashi, Sachiyo Watahiki & Rie Mineta

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  1. Fumitaka Suzuki
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Correspondence to Fumitaka Suzuki.

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Supplementary material (DOC 24 kb)

535_2013_864_MOESM2_ESM.tif

Supplementary Figure. Cumulative clearance of HBe antigen in patients treated with ADV plus LAM (Kaplan–Meier method). (TIFF 92 kb)

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Suzuki, F., Hosaka, T., Suzuki, Y. et al. Long-term efficacy and emergence of multidrug resistance in patients with lamivudine-refractory chronic hepatitis B treated by combination therapy with adefovir plus lamivudine. J Gastroenterol 49, 1094–1104 (2014). https://doi.org/10.1007/s00535-013-0864-4

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  • DOI: https://doi.org/10.1007/s00535-013-0864-4

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