Lamivudine resistance and other mutations in the polymerase and surface antigen genes of hepatitis B virus associated with a fatal hepatic failure case.
OBJECTIVE
Resistance to lamivudine therapy of chronic hepatitis B virus (HBV) infection occurs by mutation in the YMDD motif of the reverse transcriptase (rt) domain (rtM204V/I) of the virus polymerase, and is usually accompanied by rtL180M mutation. Here we investigated virological factors associated with hepatic failure in a 58-year-old male, chronically HBV-infected patient who died after 33 months of lamivudine therapy.


METHODS
Nucleotide sequencing was performed from one sample collected before and two samples collected during lamivudine therapy.


RESULTS
A peak of alanine aminotransferase and aspartate aminotransferase levels occurred after 19 months of lamivudine treatment, associated with the rtM204I mutation. After 32 months, the rtM204V mutation was predominant, accompanied by the lamivudine-resistant rtL180M mutation. Furthermore, two rare polymerase (rtS117Y and rtV142A) and three HBsAg (L109I, F134L, and I208T) substitutions were observed. At that time, the patient was hospitalized with hepatic decompensation, followed by hepatic failure, and died one month later. HBV-DNA was detected at moderate levels (8.3 x 10(4)-2.6 x 10(6) copies/mL) throughout.


CONCLUSIONS
The results suggest that substitutions in polymerase (rtS117Y, rtV142A) and surface antigens (L109I, F134L, and I208T), associated with lamivudine-resistant mutations at positions 180 and 204, were involved in this case of fatal hepatitis B.
Bottecchia
Marcelle
M
Molecular Virology Laboratory, Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
Ikuta
Nilo
N
Niel
Christian
C
Araujo
Natalia M
NM
O
Kycia M R
KM
Gomes
Selma A
SA
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000009:adverse effects*; D002908:Chronic Disease; D004279:DNA, Viral; D024882:Drug Resistance, Viral / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects*; D017093:Liver Failure / Q000235:genetics / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D054334:Viral Regulatory and Accessory Proteins
D000998:Antiviral Agents; D004279:DNA, Viral; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D019259:Lamivudine; D012194:RNA-Directed DNA Polymerase