Efficacy of Tenofovir-based Rescue Therapy for Patients with Drug-resistant Chronic Hepatitis B

Kanghyug Choi; Han Min Lee; Baek Gyu Jun; Sae Hwan Lee; Hong Soo Kim; Sang Gyune Kim; Young Seok Kim; Boo Sung Kim; Soung Won Jeong; Jae Young Jang; Young Don Kim; Gab Jin Cheon

doi:10.4166/kjg.2015.65.1.35

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Choi, Lee, Jun, Lee, Kim, Kim, Kim, Kim, Jeong, Jang, Kim, and Cheon: Efficacy of Tenofovir-based Rescue Therapy for Patients with Drug-resistant Chronic Hepatitis B

Original Article

Korean J Gastroenterol 2015;65(1):35-42.

Published online: 4 October 2015

DOI: https://doi.org/10.4166/kjg.2015.65.1.35

Efficacy of Tenofovir-based Rescue Therapy for Patients with Drug-resistant Chronic Hepatitis B

Kanghyug Choi^∗,, Han Min Lee^∗,, Baek Gyu Jun, Sae Hwan Lee, Hong Soo Kim, Sang Gyune Kim¹, Young Seok Kim¹, Boo Sung Kim¹, Soung Won Jeong², Jae Young Jang², Young Don Kim³, Gab Jin Cheon³

Departments of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea

¹Bucheon Hospital, Bucheon, Soonchunhyang University College of Medicine, Gangneung, Korea

²Seoul Hospital, Seoul, Soonchunhyang University College of Medicine, Gangneung, Korea

³Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, Korea

Correspondence to: Sae Hwan Lee, Liver Clinic, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 330-903, Korea. Tel: +82-41-570-3692, Fax: +82-41-574-5762, E-mail: stevesh@sch.ac.kr

^∗ These two authors have equally contributed to this work.

Received 24 August 20147 October 2014 Accepted 31 October 2014

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

Tenofovir disoproxil fumarate (TDF) plays a pivotal role in the management of drug-resistant chronic hepatitis B. However, it remains unclear whether TDF-nucleoside analogue combination therapy provides better outcomes than TDF monotherapy. This study aimed to compare the efficacy of TDF monotherapy with that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B.

Methods

This retrospective cohort study included 76 patients receiving TDF-based rescue therapy for more than 12 months. Suboptimal response was defined as serum HBV-DNA level of >60 IU/mL during prior rescue therapy. Multi-drug resistance was defined as the presence of two or more drug resistance-related mutations confirmed by mutation detection assay. The relationship between baseline characteristics and virologic response (HBV DNA <20 IU/mL) at 12 months were evaluated using logistic regression analysis.

Results

Fifty-five patients (72.4%) were suboptimal responders to prior rescue therapy, and 26 (34.2%) had multi-drug resistance. Forty-two patients (55.3%) received combination therapy with nucleoside analogues. Virologic response at 12 months was not significantly different between the TDF monotherapy group and TDF-nucleoside analogue combination therapy group (p=0.098). The serum HBV DNA level was reduced to −4.49±1.67 log₁₀ IU/mL in the TDF monotherapy group and to −3.97±1.69 log₁₀ IU/mL in the TDF-nucleoside analogue combination therapy group at 12 months (p=0.18). In multivariate analysis, female sex (p=0.032), low baseline HBV-DNA level (p=0.013), and TDF monotherapy (p=0.046) were predictive factors for virologic response at 12 months.

Conclusions

TDF monotherapy showed similar efficacy to that of TDF-nucleoside analogue combination therapy in patients with drug-resistant chronic hepatitis B.

Keywords: Hepatitis B, Drug resistance, Tenofovir, Virologic response

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Fig. 1.

Mean (95% CI) changes in serum HBV DNA levels between TDF monotherapy group and TDF-nucleoside analogue combination therapy group.

Fig. 2.

Mean (95% CI) changes in serum HBV DNA levels according to adefovir dipivoxil resistance-associated mutations. ADV-R, adefovir dipivoxil resistance-associate mutation.

Table 1.

Baseline Characteristics of the Study Population

Characteristic	Total (n=76)	TDF monotherapy (n=34)	TDF-nucleoside analogues combination therapy (n=42)	p-value
Age (yr)	50 (20–74)	48 (33–65)	50 (22–74)	0.988
Male	56 (73)	23 (41)	33 (58)	0.282
Antiviral agents in naïve state
Lamivudine	54 (71)	22 (65)	32 (76)	0.273
Clevudine	7 (9)	2 (6)	5 (12)
Telbivudine	5 (5)	3 (9)	2 (5)
Entecavir	7 (9)	5 (14)	2 (5)
Adefovir dipivoxil	3 (4)	2 (6)	1 (2)
Prior rescue therapy	55 (72)	23 (67)	32 (76)	0.408
Cirrhosis	14 (18)	8 (23)	6 (14)	0.301
ALT (IU/L)	31 (13–417)	32 (13–332)	30 (15–417)	0.645
Creatinine (mg/dL)	0.9 (0.3-1.3)	0.9 (0.3-1.3)	1 (0.5-1.3)	0.327
HBeAg-positivity	62 (81)	26 (42)	36 (58)	0.432
HBV DNA (log₁₀ IU/mL) ^a	4.4 (1.8-7.9)	4.76±1.7	4.54±1.76	0.224

Values are presented as median (range), n (%), or mean±SD.

TDF, tenofovir disoproxil fumarate.

Table 2.

Baseline Mutation Patterns and Virologic Response

Drug resistance	Genotypic mutations	n	VR12
LAM, 38 (50.0)	rt180	4	30 (78.9
	rt204I	11
	rt180+ rt204I	5
	rt180+ rt204V	13
	rt180+ rt204I/V	5
ADV, 12 (15.8)	rt181A	4	9 (75.0
	rt181A+ rt236T	8
LAM-ADV, 5 (6.6)	rt180+ rt181A	1	3 (60.0
	rt180+ rt181A+ rt204V	3
	rt181A+ rt204I	1
LAM-ETV, 17 (22.4)	rt204I+ rtT184	1	12 (70.6
	rt204VvrtT184	1
	rt180+ rt204V+ rtT184	3
	rt180+ rt204I/V+ rtT184	1
	rt180+ rt204I/V+ rtI169	1
	rt180+ rt204V+ rtT184+ rtI169	3
	rt180+ rt204V+ rtS202	7
LAM-ADV-ETV, 4 (5.3)	rt181A+ rt204I+ rtT184	2	4 (100)
	rt180+ rt181A+ rt204I/V+ rtT184	1
	rt180+ rt181A+ rt204V+ rt236T+ rtS202+ rtM250	1

Values are presented as n only or n (%).

LAM, lamivudine; ADV, adefovir dipivoxil; ETV, entecavir; VR12, viro logical response at month 12.

Table 3.

Predictive Factors for Virological Response at 12 Months

Factor	Univariate		Multivariate
Factor	OR (95% CI)	p-value	OR (95% CI)	p-value
Age (>50 yr)	1.93 (0.65-5.69)	0.231
Gender (male)	0.12 (0.02-0.97)	0.047	0.08 (0.01-0.81)	0.032
Cirrhosis	4.91 (0.59-40.47)	0.139	6.64 (0.63-69.4)	0.114
Prior rescue therapy	0.44 (0.11-1.72)	0.242
Combination with nucleoside	0.38 (0.12-1.21)	0.104	0.23 (0.05-0.97)	0.046
Presence of adefovir dipivoxil resistance-associated mutations	0.99 (0.31-3.22)	0.987
Mutation on rt236	2.33 (0.26-20.3)	0.443
Multi-drug resistance	0.76 (0.25-2.28)	0.632
HBeAg-positive	0.24 (0.02-1.99)	0.186	0.21 (0.02-2.14)	0.186
HBV DNA (<4.3 log₁₀ IU/mL)	4.62 (1.35-15.7)	0.014	6.05 (1.47-24.9)	0.013

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