The rtL180M Mutation of Hepatitis B Virus Closely Associates with Frequent Virologic Resistance to Adefovir Dipivoxil Therapy

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The rtL180M Mutation of Hepatitis B Virus Closely Associates with Frequent

Virologic Resistance to Adefovir Dipivoxil Therapy

Yoon-Seon Lee, Young-Hwa Chung, Jeong A. Kim, Young Joo Jin, Won Hyung Park,

Sung Eun Kim, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young Suk Lim, Han Chu Lee,

Yung Sang Lee, Dong Jin SuhDOI: 10.1111/j.1440-1746.2011.06853.x

© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell

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Journal of Gastroenterology and Hepatology

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Author Information

Department of Internal Medicine, University of Ulsan College of Medicine, Asan

Medical Center, Seoul, Korea

*Correspondence: Young-Hwa Chung, M.D., Ph.D. Department of Internal Medicine

University of Ulsan College of Medicine, Asan Medical Center 86,

Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Korea Tel: +82-2-3010-3184 Fax:

+82-2-476-0824 E-mail: yhchung@...

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is an Accepted Article that has been peer-reviewed and approved for publication

in the Journal of Gastroenterology and Hepatology, but has yet to undergo

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Article”; doi: 10.1111/j.1440-1746.2011.06853.x

Abstract

Background/Aim: We intended to investigate the effects of preexisting mutations

at reverse transcriptase region of hepatitis B virus (HBV) on the occurrence of

virologic breakthrough (VB) to adefovir dipivoxil (ADV) in patients with

lamivudine (LAM)-resistant chronic hepatitis B (CHB).

Methods: Ninety-seven patients with LAM-resistant CHB were treated with ADV at a

dose of 10mg daily and followed for a median period of 13 months. Just before

the initiation of ADV therapy, the whole length of reverse transcriptase region

of serum HBV-DNA was sequenced using direct sequencing.

Results: All patients contained genotype C HBV and mutations in the YMDD motif,

specifically, YIDD (65%), YVDD (28%) or both (7%). The rtL180M and rtL80V/I

mutations were identified in 68% and 69%, respectively. The cumulative

probability of VB was 19% and 27% at 1 and 2 years, respectively. There was no

difference in occurrence of VB with regard to types of YMDD mutation or

rtL80V/I. However, interestingly, patients containing rtL180M experienced VB

during ADV monotherapy more frequently than those not carrying rtL180M (2-yr

cumulative probability of virologic breakthrough: 37% vs. 3% at 2 years, P <

0.01). On multivariate proportional-hazards analysis, rtL180M (HR, 8.62; 95%

CI, 1.08-69.09; P = 0.042) and decrease in HBV-DNA for 1 year of treatment (HR,

0.69; 95% CI, 0.51-0.95; P = 0.024) are independently associated with VB.

Conclusions: The rtL180M mutation of Hepatitis B virus as well as small decrease

in HBV-DNA after 1 year of treatment may be closely associated with frequent

occurrence of virologic resistance to ADV in patients with LAM-resistant CHB.