Multidrug-Resistant Hepatitis B Virus Resulting From Sequential Monotherapy With Lamivudine, Adefovir, and Entecavir: Clonal Evolution During Lamivudine Plus Adefovir Therapy

BACKGROUND & AIMS: Whether multidrug-resistant (MDR) hepatitis B virus (HBV) harbors mutations co-located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. METHODS: Sera were obtained from 6 patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. RESULTS: Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV-resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in 5 patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V ± rtN236T mutations, which were detected in the absence of rtM204 and ETVresistant mutations in 37 clones (94.9%). Only 2 clones (5.1%) harbored both rtA181T/V and ETV-resistant mutations. The rtA181T/V mutation emerged after reversion from ETVii resistant mutants to wild-type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. CONCLUSIONS: The majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co-localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for MDR patients.

Author dc:creator

• 김, 순선

Contributors dc:contributor

• 조, 성원
• 대학원 의학과
• 105547

• Chronic hepatitis B
• Clonal sequencing
• HBV DNA
• Multidrug resistance
• Viral genome
• 만성 B형간염
• 다약제 내성
• 바이러스 게놈

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000014802
000000014802

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/8654