title: Virologic breakthrough in a patient with chronic hepatitis B by combination treatment with tenofovir disoproxil fumarate and entecavir.
abstract: Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients in the USA and Europe. No confirmed report of resistance selection during treatment with TDF in treatment-naïve and nucleoside/nucleotide analog-treated chronic hepatitis B patients has yet been reported. Here, we report for the first time a patient with chronic hepatitis B and cirrhosis who emerged with virologic breakthrough during combination therapy with TDF and entecavir (ETV), against ETV-resistant virus. A 51-year-old Japanese woman with hepatitis B e-antigen (HBeAg), whose genotype was C, received ETV monotherapy continuously followed by TDF and ETV combination therapy, because her HBV DNA levels had been >3.5 log copies/mL. At the start of combination therapy, amino acid substitutions of the reverse transcriptase (rt) gene, rtL180M, rtT184I/M, and rtM204V, were detected. After this, serum HBV DNA decreased to less than 2.1 log copies/mL and remained at this level until 31 months of combination therapy, when it again began to increase. Amino acid substitutions of rtL180M, rtS202G, and rtM204V emerged and were associated with an increase in serum HBV DNA at virologic breakthrough. Long-term therapy with TDF against the ETV-resistant virus has the potential to induce virologic breakthrough and resistance, and careful follow-up should be carried out.
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan ; Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors: Fumitaka
authors: F
authors: Suzuki
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Hitomi
authors: H
authors: Sezaki
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Norio
authors: N
authors: Akuta
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Yoshiyuki
authors: Y
authors: Suzuki
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Yusuke
authors: Y
authors: Kawamura
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Tetsuya
authors: T
authors: Hosaka
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Masahiro
authors: M
authors: Kobayashi
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Satoshi
authors: S
authors: Saitoh
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Yasuji
authors: Y
authors: Arase
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Kenji
authors: K
authors: Ikeda
authors: Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan.
authors: Mariko
authors: M
authors: Kobayashi
authors: Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan.
authors: Sachiyo
authors: S
authors: Watahiki
authors: Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan.
authors: Rie
authors: R
authors: Mineta
authors: Research Institute for Hepatology, Toranomon Branch Hospital, Kawasaki, Japan.
authors: Yukiko
authors: Y
authors: Suzuki
authors: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors: Hiromitsu
authors: H
authors: Kumada
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000235:genetics / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D000068698:Tenofovir; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; C413685:entecavir; D006147:Guanine; D000068698:Tenofovir; D000225:Adenine
keywords: hepatitis B virus; resistant