Prognostic indicators of breakthrough hepatitis during lamivudine monotherapy for chronic hepatitis B virus infection.
BACKGROUND
Breakthrough hepatitis (BTH), defined as a flare of transaminases alanine aminotransferase [ALT]) can occur during lamivudine monotherapy for hepatitis B virus (HBV) infection. There have been many reports of lamivudine-resistant mutations within the C domain of the viral reverse transcriptase; however, the appearance of these mutants is not necessarily correlated with BTH during lamivudine therapy.


RESULTS
Entire serial HBV genomic sequences before and during lamivudine therapy for 4 patients with BTH and 1 patient without BTH were analyzed and showed changes in the pre-S region. These changes may be associated with ALT flares. Further investigation in a cohort of 36 patients with a median treatment period of 25 months showed that 21 patients had a rise in HBV-DNA titer, of whom 18 had BTH. Univariate statistical analyses showed that possible prognostic indicators for the occurrence of BTH were pre-S deletions ( P = 0.03) and L180M/M204L mutations ( P = 0.04). By multivariate Cox regression analyses, significant variables were pre-S deletions (hazard ratio, 0.17; 95% confidence internal (CI), 0.044-0.66) and precore mutations (hazard ratio, 5.70; 95% CI, 1.74-18.71) prior to the commencement of lamivudine monotherapy. Interestingly, BTH occurred after the selection of the wild-type species in the pre-S region during lamivudine monotherapy.


CONCLUSIONS
These results suggest that patients with HBV pre-S deletion mutants should be monitored carefully during lamivudine therapy.
Tanaka
Yasuhito
Y
Department of Clinical Molecular Informative Medicine, Nagoya City University Medical School Graduate School of Sciences, Kawasumi 1, Mizuho, 467-8601 Nagoya, Japan.
Yeo
Anthony E T
AE
Orito
Etsuro
E
Ito
Kiyoaki
K
Hirashima
Noboru
N
Ide
Tatsuya
T
Sata
Michio
M
Mizokami
Masashi
M
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use*; D002872:Chromosome Deletion; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D011498:Protein Precursors / Q000235:genetics; D012044:Regression Analysis
D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D011498:Protein Precursors; C050807:presurface protein 2, hepatitis B surface antigen; D019259:Lamivudine