Covalently closed-circular hepatitis B virus DNA reduction with entecavir or lamivudine.
OBJECTIVE
To investigate the reduction in hepatitis B virus (HBV) covalently closed-circular DNA (cccDNA) with entecavir (ETV) or lamivudine (LAM).


METHODS
This analysis included patients who had participated in the randomized Phase III study ETV-022 comparing ETV vs LAM in nucleos(t)ide-naive, HBeAg-positive patients. Patients received ETV (0.5 mg daily) or LAM (100 mg daily) for a minimum of 52 wk. Patients were eligible to participate in this sub-study if they had paired biopsies at baseline and week 48 with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA. The main objective was to compare changes in hepatic HBV cccDNA and total hepatic HBV DNA at week 48 of ETV or LAM treatment, which was a secondary endpoint of study ETV-022. Additional post hoc analyses included linear regression analyses to assess associations of baseline levels and on-treatment changes of cccDNA with other baseline factors [sex, age, serum HBV DNA, alanine aminotransferase (ALT), Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBV genotype], or on-treatment factors (changes from baseline at week 48 in serum HBV DNA, ALT, Knodell necroinflammatory score, Ishak fibrosis score, total hepatic HBV DNA, and HBeAg loss at week 48).


RESULTS
Overall, 305 patients (ETV = 159; LAM = 146) of ETV-022 had paired baseline and week 48 liver biopsies with evaluable measurements for hepatic HBV cccDNA and total hepatic HBV DNA, and were included in this analysis. Baseline demographics and disease characteristics were comparable between the two arms. After 48 wk, ETV resulted in significantly greater reductions in hepatic HBV cccDNA [-0.9 log10 copies/human genome equivalent (HGEq) vs -0.7 log10 copies/HGEq; P = 0.0033] and total hepatic DNA levels (-2.1 log10 copies/HGEq vs -1.6 log10 copies/HGEq; P < 0.0001) than LAM. Virologic, biochemical, and histologic response rates at week 48 were also greater with ETV than with LAM. Baseline HBV cccDNA levels were positively associated with baseline levels of serum HBV DNA and total hepatic HBV DNA, and negatively associated with HBV genotype F. On-treatment changes in HBV cccDNA levels were negatively associated with baseline levels of serum HBV DNA and baseline ALT, and were positively associated with on-treatment changes in the levels of serum HBV DNA, total hepatic HBV DNA levels, and ALT, change in Knodell necroinflammatory score, and HBeAg loss.


CONCLUSIONS
Forty-eight weeks of ETV resulted in greater reductions in cccDNA and total hepatic HBV DNA than LAM, but long-term therapy may be needed for cccDNA elimination.
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Scott
S
Bowden
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Stephen
S
Locarnini
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Ting-Tsung
TT
Chang
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
You-Chen
YC
Chao
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Kwang-Hyub
KH
Han
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Robert G
RG
Gish
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Robert A
RA
de Man
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Miao
M
Yu
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Cyril
C
Llamoso
Scott Bowden, Stephen Locarnini, Victorian Infectious Diseases Reference Laboratory, Victoria 3000, Australia.
Hong
H
Tang
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D004270:DNA, Circular / Q000187:drug effects*; D004279:DNA, Viral / Q000097:blood / Q000187:drug effects*; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006509:Hepatitis B / Q000175:diagnosis / Q000188:drug therapy* / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D016014:Linear Models; D008099:Liver / Q000187:drug effects* / Q000821:virology; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult
D000998:Antiviral Agents; D015415:Biomarkers; D004270:DNA, Circular; D004279:DNA, Viral; D019259:Lamivudine; C413685:entecavir; D006147:Guanine
Antiviral suppression; Hepatitis B virus; Intrahepatic hepatitis B virus DNA; Nucleos(t)ide analog therapy; Virologic cure