Lamivudine for patients with chronic hepatitis B and advanced liver disease.
BACKGROUND
The effectiveness of antiviral therapy in preventing disease progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis is unknown.


METHODS
Patients with chronic hepatitis B who had histologically confirmed cirrhosis or advanced fibrosis were randomly assigned in a 2:1 ratio to receive lamivudine (100 mg per day) or placebo for a maximum of five years. Of 651 patients, 436 were assigned to receive lamivudine and 215 to receive placebo. The primary end point was time to disease progression, defined by hepatic decompensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, bleeding gastroesophageal varices, or death related to liver disease. An independent data and safety monitoring board monitored the progress of the study and performed interim analyses of the data.


RESULTS
We randomly assigned 651 patients (98 percent Asian and 85 percent male) to receive lamivudine or placebo. The study was terminated after a median duration of treatment of 32.4 months (range, 0 to 42) owing to a significant difference between treatment groups in the number of end points reached. End points were reached by 7.8 percent of the patients receiving lamivudine and 17.7 percent of those receiving placebo (hazard ratio for disease progression, 0.45; P=0.001). The Child-Pugh score increased in 3.4 percent of the patients receiving lamivudine and 8.8 percent of those receiving placebo (hazard ratio, 0.45; P=0.02), whereas hepatocellular carcinoma occurred in 3.9 percent of those in the lamivudine group and 7.4 percent of those in the placebo group (hazard ratio, 0.49; P=0.047). Genotypic resistance YMDD mutations developed in 49 percent of the patients treated with lamivudine, and the Child-Pugh score was more likely to increase in patients with these mutations than in the other patients treated with lamivudine (7 percent vs. <1 percent). Overall, 12 percent of the patients in the lamivudine group and 18 percent of the patients in the placebo group reported serious adverse events.


CONCLUSIONS
Continuous treatment with lamivudine delays clinical progression in patients with chronic hepatitis B and advanced fibrosis or cirrhosis by significantly reducing the incidence of hepatic decompensation and the risk of hepatocellular carcinoma.
Liaw
Yun-Fan
YF
Liver Research Unit, Chang Gung Memorial Hospital and University, Taipei, Taiwan. liveryfl@so-net.net.tw
Sung
Joseph J Y
JJ
Chow
Wan Cheng
WC
Farrell
Geoffrey
G
Lee
Cha-Ze
CZ
Yuen
Hon
H
Tanwandee
Tawesak
T
Tao
Qi-Min
QM
Shue
Kelly
K
Keene
Oliver N
ON
Dixon
Jonathan S
JS
Gray
D Fraser
DF
Sabbat
Jan
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000517:prevention & control; D018450:Disease Progression; D004311:Double-Blind Method; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008113:Liver Neoplasms / Q000401:mortality / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D012720:Severity of Illness Index
D000998:Antiviral Agents; D019259:Lamivudine