|How and why does
Competition within the prevailing environment
|wThe competitive edge depends on the prevailing environment
of the virus; use of one or more suppressive antiretrovirals changes the
environment to favour other populations over the wild-type.
|wPopulations with even a very small degree of resistance to
one or more of the drugs used will quickly seize the bulk of the residual
replication under therapy; these so-called ‘escape mutants’ may not cause
regimen failure directly, but will provide the ‘backbone’ for further,
stepwise accumulation of mutations increasing the degree of resistance to
give an eventual outgrowth.
|wUse of multiple drugs in a regimen significantly delays the
development of resistance in two ways:
|•By markedly reducing the likelihood of there being a
pre-existing escape mutant in the quasispecies, particularly if more than a
single mechanistic class is employed.
|•By reducing residual replication by a much greater amount
than that derived from only one or two drugs.
|wIn principle, a sufficient number of drugs in a regimen
might be expected to suppress replication to such a degree that, even were an
escape mutant to eventually emerge, it would be functionally disabled and
|wHowever, to date, no combination of drugs has proved to be
‘resistance-proof’ in this way.