Biology Reference
In-Depth Information
Role of Resistance Testing
In the next years, a widespread di¨usion of genotypic resistance testing is ex-
pected. Though representing a major advantage for the management of HIV
patients, the routine use of these tests in the clinical setting has yet to be vali-
dated. In general, whereas resistance is generally a good predictor of likely
failure of a drug, susceptibility is no guarantee of success. It is becoming a
common belief, therefore, that these assays have their major application in
predicting which drugs not to use rather than which are likely to be successful.
Their best current application is therefore the design of salvage regimens. In-
deed, several retrospective and a few prospective studies have shown that a
higher response rate is likely to occur when a salvage regimen is selected on the
basis of genotype or phenotype testing results.
Indeed, the major advantage of resistance testing availability is that the
results can also help sparing drugs when a new regimen has to be designed.
Although the general principle of changing all drugs in the new combination
keeps all its validity, in some cases, drug failure may not imply resistance to all
agents in that combination and therapeutical options may be limited. In these
settings, changing one drug only may restore sensitivity to the whole regimen.
However, there are several inherent limitations that should be kept in con-
sideration when interpreting the results of both phenotypic and genotypic
esistance testing, such as their ability to measure only the predominant viral
species and the fact that some mutations conferring signi®cant resistance to one
drug may actually increase viral susceptibility to a second, unrelated agent
( Hirsch et al., 2000).
Finally, transmission of drug-resistant virus at primary HIV infection and
identi®cation of drug-resistant virus in previously untreated patients is a grow-
ing phenomenon. Data from the United States show that the prevalence of
high-level resistance to NNRTI and PIs has increased in the last year compared
with 1996±1998. Ten- or greater fold resistance to NNRTI has increased from 1
to 7%, and for PIs from 2 to 6%. In Europe, drug resistance rates seems to have
gone down in Switzerland, although clusters of primary HIV infection are oc-
curring. In France, during 1999, the frequency of drug resistance was 6.5% for
NNRTIs, 3.7% for NRTIs, and 2.8% for the PI. Continuing surveillance is re-
quired and many authors suggest that drug resistance testing should be per-
formed in patients with primary HIV infection before initiating antiretroviral
therapy.
NEW TREATMENT STRATEGIES
Currently, 15 antiretroviral agents are approved or available through expanded
access programs, while there are at least 23 new drugs in clinical development
that are expected to become available within the next 3 years. Several of them
belong to the already well-known classes of reverse transcriptase inhibitors and
protease inhibitors, and are characterized by higher potency and/or tolerability
