Biology Reference
In-Depth Information
adequate drug potency, nonadherence, and still unknown factors. Indeed, in-
complete adherence is the most common cause of virologic failure (the level of
adherence needed to maintain an adequate response is higher than that de-
scribed for any other disease) ( Haubrich et al., 1999).
Adherence should be assessed and reinforced as a routine part of manage-
ment. However, many ways of improving adherence are being investigated, but
they remain largely empiric ( Paterson et al., 2000).
Any discussions on salvage strategies requires a previous de®nition of pa-
rameters of treatment failure. For the adherent patient on an initial treatment
regimen, con®rmed detectable plasma HIV-1 RNA should be considered evi-
dence of treatment failure. Continued treatment with the same regimen in this
situation will eventually lead to development of high-level drug resistance,
and diminishes the likelihood that salvage regimens will be successful. Thus, for
the patient with clear treatment options, early switching could maximize the
chances for therapeutic success of the next treatment regimen and preserve
future options.
The situation di¨ers for patients who are highly treatment experienced and
for whom fewer options remain. In such cases, a more conservative approach
may be warranted. Usually, virologic escape is followed by immunologic dete-
rioration and eventually clinical evolution. However, the time lag between HIV
RNA rebound and clinical failure varies from patient to patient, and it has be-
come clear that CD4
cell count may remain high even in the presence of a
clear rebound in HIV RNA. Before making any decisions about changes in
antiretroviral treatment, it is important to determine why the current regimen is
failing to avoid choosing an inappropriate remedy. In particular, factors such
as drug resistance, inadequate drug exposure due to poor adherence, absorption
and pharmacokinetics, and persistence of HIV in viral reservoirs all represent
major causes of failure that should be deeply investigated before switching to a
di¨erent regimen.
Unfortunately, due to the large degree of cross-resistance occurring within
all antiretroviral drug classes, limited options actually exist, especially for
patients experiencing their second or third failure. In this heavily pretreated
population, both observational and prospective studies have shown quite dis-
appointing results of any investigated salvage regimens.
New strategies in the management of treatment failure are being inves-
tigated, including structured treatment interruptions, new combinations (triple
PI, dual NNRTI), exploiting drug ``hypersusceptibility'' (which has been de-
scribed with zidovudine, abacavir, NNRTIs, amprenavir, and saquinavir), and
reduced viral ®tness. Indeed, the scienti®c basis for continuing activity of drugs
in failing regimens ( Deeks et al., 2001) is supported by data that suggested that
drug-resistant viruses were less ®t than wild-type ranging from a 3.3 to 36.1%
relative loss of ®tness. Interestingly, the less ®t the mutant virus during therapy
the more rapidly wild-type virus rebounds when a treatment interruption was
started. Whether the loss of ®tness could be exploited more in salvage patients
is one area of study that should be intensi®ed.
