title: Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies.
abstract: OBJECTIVE
  To evaluate the long-term efficacy adefovir (ADV)-based combination therapies in entecavir (ETV)-resistant chronic hepatitis B (CHB) patients.
  
  
  METHODS
  Fifty CHB patients with genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV (ADV/ETV, n = 23) or ADV plus lamivudine (LMV) (ADV/LMV, n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus (HBV) DNA levels were measured by real-time PCR and logarithmically transformed for analysis. Cumulative rates of virologic response (VR; HBV DNA < 20 IU/mL) were calculated using the Kaplan-Meier method, and the difference was determined by a log-rank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR, respectively.
  
  
  RESULTS
  Baseline median HBV DNA levels were 5.53 (2.81-7.63) log10 IU/mL. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27 (12-45) mo. Overall, cumulative VR rates at 6, 12, 24, and 36 mo were 26%, 36%, 45%, and 68%, respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates (35%, 43%, 65%, and 76%, respectively) than those with the ADV/LAM combination (18%, 30%, 30%, and 62%, respectively; P = 0.048). In the multivariate analysis, low baseline HBV DNA levels (< 5.2 log10 IU/mL) and initial virologic response at 3 mo (IVR-3; HBV DNA < 3.3 log10 IU/mL after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period, the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.
  
  
  CONCLUSIONS
  If tenofovir is not available, ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers, and may be continued if IVR-3 is achieved.
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Hyoung Su
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Yim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Myoung Kuk
authors.initials: MK
authors.lastname: Jang
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Suh
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Yeon Seok
authors.initials: YS
authors.lastname: Seo
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Sang Jong
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Sae Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Sang Gyune
authors.initials: SG
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Jung Il
authors.initials: JI
authors.lastname: Lee
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: In Hee
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Tae Yeob
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Jin-Wook
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Sook-Hyang
authors.initials: SH
authors.lastname: Jeong
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Young Kul
authors.initials: YK
authors.lastname: Jung
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Park
authors.affiliation: Hyoung Su Kim, Myoung Kuk Jang, Ji Won Park, Department of Internal Medicine, Hallym University College of Medicine, Seoul 134-701, South Korea.
authors.forename: Seong Gyu
authors.initials: SG
authors.lastname: Hwang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000627:therapeutic use*; D019562:Viral Load; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000225:Adenine
keywords: Adefovir; Chronic hepatitis B; Entecavir; Lamivudine; Resistance