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


CONCLUSIONS
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.
Department of Hepatology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan, fumitakas@toranomon.gr.jp.
Fumitaka
F
Suzuki
Tetsuya
T
Hosaka
Yoshiyuki
Y
Suzuki
Norio
N
Akuta
Hitomi
H
Sezaki
Tasuku
T
Hara
Yusuke
Y
Kawamura
Masahiro
M
Kobayashi
Satoshi
S
Saitoh
Yasuji
Y
Arase
Kenji
K
Ikeda
Mariko
M
Kobayashi
Sachiyo
S
Watahiki
Rie
R
Mineta
Hiromitsu
H
Kumada
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D044466:Asian People; D004279:DNA, Viral / Q000097:blood*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
D004279:DNA, Viral; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C053001:adefovir; D000225:Adenine