4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

HEPATITIS B VIRUS DRUG RESISTANCE: LESSONS FOR HIV TREATMENT FAILURE

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):3 (Abstract 1

S Locarnini and A Bartholomeusz
Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia

The genomes of hepatitis B virus (HBV) and HIV both encode a reverse transcriptase (RT). The HBV genome is a 3.2-kb double-stranded DNA which is organized into four overlapping open reading frames. In HBV, the polymerase protein gene includes four functional regions: a terminal protein involved in priming DNA synthesis, a spacer region, the RT conserved catalytic domains and the RNaseH domain. The polymerase gene overlaps the other three HBV proteins in a frame- shifted manner. The region which encodes the conserved catalytic domains (F, A–E) of the RT overlaps the envelope protein HBsAg. Within the HBV RT there is an insertion of 47 amino acids between the A and B functional domains, which corresponds to the ‘a’ determinant of the envelope gene, the neutralization epitope. This insertion in the HBV polymerase has no homologue in other polymerase proteins. Thus, mutations in the viral RT selected due to antiviral drug resistance can result in changes in HBsAg and vice versa; in other words immune-based therapies such as hepatitis B immune globulin (HBIG) can select neutralization escape mutants (G145R and P120T in HBsAg) with altered HBV RT. Following the widespread use of lamivudine and famciclovir for the treatment of HBV infections, a number of different famciclovir-and lamivudine-associated mutations have been recognized. In patients who have also received HBIG as well as these antiviral agents, multiple-mutated HBVs are now being identified. In some patients at viral breakthrough, the viral loads are 0.5–1.0 log greater than pre-treatment level. Lamivudine-resistance is typically associated with a change at M550I/V in the viral polymerase (the M184V/I in HIV), and in in vitro assays these lamivudine-resistance mutants replicate poorly. However, a second change at L526M in the B domain has been detected in conjunction with M550V, which appears to partially restore replication competence and increase drug-resistance. In addition to this mutation, changes at L426V/I, T474N (P120T in HBsAg) and W/R499Q (G145R in HBsAg) have been selected in the presence of lamivudine alone, lamivudine+HBIG and famciclovir+HBIG, respectively, which have a higher replication capacity than wild-type virus, and tend to be associated with more aggressive liver disease. The implications for these mutations and other mutations in the A and B domains, as well as the A-B interdomain detected in the clinical setting, will be developed against the present modelling status of nucleoside analogue resistance in HIV.

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2000-06-12
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