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AZT co-resistance in HIV strains harboring the 3TC 184V mutation.
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written by Douglas Mayers, M.D.
published on HIVresistanceWeb: February 1, 1998
The dual nucleoside combination of AZT/3TC has
been remarkably effective in suppressing HIV-1 replication for prolonged
periods of time despite the rapid emergence of high level 3TC resistance
in treated patients. Mechanisms suggested to explain this seeming
anomaly include:
1. The 184V mutation, which causes
3TC-resistance, suppresses AZT resistance leading to prolonged
activity due to the AZT component of the combination regimen.
2.
The 184V mutation leads to a 7-fold increase in fidelity of the reverse
transcriptase enzyme which could potentially lead to decreased
generation of viral quasispecies and inability of the virus to escape
both drug and immune pressure.
Evidence to support both of these
mechanisms has been presented by different groups.
This study by
Nijhuis and colleagues carefully evaluates the relationship of drug
resistance (by both drug susceptibility testing and evolution of
resistance mutations) to changes in viral load and CD4 cell counts in
four patients harboring the 184V mutation who were treated with combination AZT/3TC.
The study found no difference in the rate or pattern of
emergence of AZT-associated resistance mutations in these patients,
suggesting that increased reverse transcriptase fidelity due to the 184V
mutation was not the mechanism responsible for prolonged antiviral effect. The study
did find, however, that multiple reverse transcriptase mutations were
necessary to produce high level AZT-resistance (compared with HIV-1
isolates from patients treated with AZT monotherapy) in the presence of
the 184V mutation. It seems, therefore, that 3TC resistance can prolong
drug susceptibility to AZT by requiring the development of additional
resistance mutations, and that this results in a more durable antiviral
effect.
Ultimately, if viral replication persists in the
presence of the AZT/3TC combination, these additional mutations will
develop, leading to resistance to both drugs and loss of antiviral
activity. This bolsters the rationale for the use of
AZT/3TC/protease inhibitor combinations to potently suppress viral
replication below the levels necessary to allow emergence of resistance
to any single agent in the drug combination.
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