Antiviral Efficacy of Lamivudine/Adefovir Combination Therapy in Chronic Hepatitis B Patients with Resistance to Lamivudine and Adefovir Consecutively

Hyun Joo Suh; Moon Kyung Park; Hyang Ie Lee; Geum Yeon Gwak; Seung Woon Paik; Byung Chul Yoo; Joon Hyeok Lee; Kwang Cheol Koh

doi:10.4166/kjg.2009.53.5.305

Journal List > Korean J Gastroenterol > v.53(5) > 1006547

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Suh, Park, Lee, Gwak, Paik, Yoo, Lee, and Koh: Antiviral Efficacy of Lamivudine/Adefovir Combination Therapy in Chronic Hepatitis B Patients with Resistance to Lamivudine and Adefovir Consecutively

Original Article

Korean J Gastroenterol 2009;53(5):305-310.

Published online: 21 February 2009

DOI: https://doi.org/10.4166/kjg.2009.53.5.305

Antiviral Efficacy of Lamivudine/Adefovir Combination Therapy in Chronic Hepatitis B Patients with Resistance to Lamivudine and Adefovir Consecutively

Hyun Joo Suh, M.D., Moon Kyung Park, M.D., Hyang Ie Lee, M.D., Geum Yeon Gwak, M.D., Seung Woon Paik, M.D., Byung Chul Yoo, M.D., Joon Hyeok Lee, M.D., Kwang Cheol Koh, M.D.

Department of Internal Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea

Correspondence to: Joon Hyeok Lee, M.D. Department of Internal Medicine, Samsung Medical Center, 50, Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea Tel: +82-2-3410-3409, Fax: +82-2-3410-3849 E-mail: liverjhlee@skku.edu

Received 18 December 2008 Accepted 27 December 2008

Abstract

Background/Aims

The aim of this study was to elucidate the antiviral efficacy of lamivudine (LMV)-adefovir (ADV) combination therapy in chronic hepatitis B patients who showed resistance to LMV and ADV consecutively.

Methods

A retrospective review was performed in eighteen patients with chronic hepatitis B who developed virologic breakthroughs during LMV-ADV sequential monotherapy and treated with LMV-ADV combination therapy.

Results

The median duration of follow up was 17 months (range, 6-27) after the start of LMV-ADV combination therapy. Mean HBV DNA level in log₁₀ IU/mL was 6.08±0.95, 4.05±1.66, 3.17±1.58, 3.18±2.16, and 2.35±1.52 at 0, 3, 6, 12, and 24 months, respectively. Sixteen patients (88.9%) showed HBV DNA reduction below detection limit (＜20,000 IU/mL). HBeAg seroconversion was observed in one patient (7.1%) after 8 months of combination therapy. Virologic breakthrough occurred in only one patient after 21 months of combination therapy. Viral rebound occurred in two patients at 12 months and 14 months of combination therapy. Normalization of serum ALT was achieved in twelve patients (66.7%). Primary non-response was observed in two cases (11.1%).

Conclusions

LMV-ADV combination treatment was effective in 88.9% of patients with resistance to LMV and ADV in a short-term follow up. It may be applied as a bridge therapy until another effective anti-viral regimen becomes available.

Keywords: Hepatits B, Chronic, Drug therapy, Combination, Lamivudine, Adefovir

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Fig. 1.

A flow chart illustrating the outcome of Lamivudine-Adefovir combination therapy in HBV infected patients with sequential resistance.∗ Chronic hepatitis B, fall of HBV DNA below 20,000 IU/mL and normal alanine aminotransferase levels after 3 months of entecavir therapy. ^† Compensated liver cirrhosis, 5 log₁₀ IU/mL of HBV DNA and mildly elevated alanine aminotransferase levels but no compensation during LMV/ADV combination therapy for 18 months. ADV, adefovir; LMV, lamivudine.

Fig. 2.

Mean log changes in serum HBV DNA levels during Lamivudine-Adefovir combination therapy. HBV DNA declined rapidly at initial 3 months of combination therapy then slowly decreased throughout the observation period.

Fig. 3.

Mean ALT changes in serum HBV DNA levels during Lamivudine-Adefovir combination therapy. ALT declined rapidly at initial 3 months of treamemt and gradually declined throughout the observation period.

Table 1.

Baseline Characteristics of Patients with Lamivudine-Adefovir Combination Therapy

	Total (n=18)
Age in years, median (range)	52 (24-62)
Male:Female	14:4
Median duration of follow-up in month (range)	17 (6-27)
Liver disease
Chronic hepatitis B	7
Liver cirrhosis, compensated	8
Liver cirrhosis, decompensated	3
Prior ADV therapy in months,	18 (6-26)
median (range)
HBeAg (%)
Positive	14 (77.8)
Negative	4 (22.2)
Log₁₀ HBV DNA IU/mL, mean (± SD)	6.09 (±0.95)
Serum ALT in IU/L, mean (± SD)	167.78 (±154.65)
Genotypic resistance to LMV	16^∗
rtM204I	5
rtM204I/rtL180M	5
rtM204V/rtL180M	3
rtM204I/rtM204V/rtL180M	2
Genotypic resistance to ADV	6
rtA181V	3
rtA181T	1
rtN236T	1
rtA181V/rtN236T	1

^∗ One of these patients was revealed to have genotypic resistance to lamivudine but subtype of YMDD mutation had not been identified. ADV, adefovir; LMV, lamivudine.

Table 2.

Clinical Course of Lamivudine-Adefovir Combination Therapy

HBV DNA undetectable	16/18 (88.9%)
(＜20,000 IU/mL)
3 ^rd month	5
6 ^th month	5
9 ^th month	2
12 ^th month	1
24 ^th month	3
Normalization of serum ALT	12/18 (66.7%)
(＜40 IU/mL)
3 ^rd month	5
6 ^th month	2
9 ^th month	2
12 ^th month	3
24 ^th month	0
HBeAg seroconversion	1/14 (7.1%)
Virologic breakthrough	1/16 (6.3%)
Viral rebound	2/16 (12.5%)
Primary non-response	2/18 (11.1%)

ADV, adefovir; LMV, lamivudine.

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