Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B.
OBJECTIVE
Lamivudine treatment is associated with frequent development of resistant hepatitis B virus (HBV) and loss of treatment benefit. In preclinical and phase II studies, entecavir demonstrated potent antiviral activity against lamivudine-resistant HBV.


METHODS
In this phase III, double-blind trial, hepatitis B e antigen-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine) were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks. Two coprimary end points were assessed at 48 weeks: histologic improvement and a composite end point (HBV branched DNA <0.7 MEq/mL and alanine aminotransferase [ALT] <1.25 times the upper limit of normal).


RESULTS
Histologic improvement occurred in 55% (68/124) of entecavir-treated vs 28% (32/116) of lamivudine-treated patients (P < .0001). More patients on entecavir than lamivudine achieved the composite end point: 55% (77/141) vs 4% (6/145), respectively (P < .0001). Mean change from baseline in HBV DNA was -5.11 log(10) copies/mL for entecavir-treated patients and -0.48 log(10) copies/mL for lamivudine-treated patients (P < .0001). Virologic rebound because of entecavir resistance substitutions occurred in 2 of 141 of entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment.


CONCLUSIONS
In patients with lamivudine-refractory chronic hepatitis B, switching to entecavir provides superior histologic improvement, viral load reduction, and ALT normalization compared with continuing lamivudine, with a comparable adverse event profile.
Sherman
Morris
M
Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada. Dr.Morris.sherman@uhn.on.ca
Yurdaydin
Cihan
C
Sollano
Jose
J
Silva
Marcelo
M
Liaw
Yun-Fan
YF
Cianciara
Janusz
J
Boron-Kaczmarska
Anna
A
Martin
Paul
P
Goodman
Zachary
Z
Colonno
Richard
R
Cross
Anne
A
Denisky
Gail
G
Kreter
Bruce
B
Hindes
Robert
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D005260:Female; D005500:Follow-Up Studies; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006513:Hepatitis B e Antigens / Q000032:analysis / Q000276:immunology*; D006515:Hepatitis B virus / Q000187:drug effects*; D019694:Hepatitis B, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011336:Probability; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D019562:Viral Load
D006513:Hepatitis B e Antigens; D019259:Lamivudine; C413685:entecavir; D006147:Guanine