Biology Reference
In-Depth Information
and/or better pharmacokinetic pro®le compared with existing drugs. Further-
more, in some cases they show antiviral activity also against HIV strains that
are no longer sensitive to previous antiretroviral agents.
A second group of new antiretrovirals consists of drugs acting on di¨erent
viral targets. The most advanced drugs in development are virus-attachment
inhibitors and fusion inhibitors that block de novo infection and cell-to-cell
virus transmission. A further class of drugs includes the integrase inhibitors,
which prevent the integration of viral DNA into the host DNA.
New drugs with improved tolerability and pharmacokinetic pro®le are eagerly
awaited. However, the major advances in antiretroviral therapy are expected
from the development of new treatment strategies.
Simplification of Therapy
Given the complexity of many current treatment regimens and the di½culties
in treatment adherence experienced by many patients, the question of treatment
simpli®cation naturally arises from practical issues.
Unfortunately, the results so far available have been disappointing, at least
for the studies that have been published and in which potent antiretroviral
treatment with three or four drugs was started and continued for 3±6 months.
Patients in whom plasma HIV-1 RNA was successfully suppressed to below the
limit of detection were then randomized to continue the ``induction'' regimen or
switch to a ``maintenance'' regimen consisting of fewer drugs. In all trials, the
results were disappointing, patients randomized to maintenance regimens ex-
periencing signi®cantly higher rates of virologic failure as compared with those
who remained on their initial therapy. However, several factors could account
for the poor outcome of these studies: the duration of induction treatment, the
virologic cuto¨ adopted for the switch to a simpli®ed regimen, the low potency
of both induction and maintenance regimens. While teaching us that potency
must not be sacri®ed solely for the sake of improved adherence, the failure of
the simpli®cation strategies so far investigated should not discourage us from
designing further trials, the key issue being design of ``simpler'' rather than
``weaker'' regimens (Montaner, 1999). A variation on the theme of induction
maintenance may be starting with one proven, potent regimen, then switching
to avoid or ameliorate toxicity and/or adherence. Although numbers of drugs
in the regimen may not change, dosing regimen and/or pill burden may be
better.
Examples of this strategy include switching from PI (plus or minus ritonavir)
plus dual NRTI combination to NNRTI/dual NRTI or triple NRTI and from
PI or NNRTI/dual NRTI combinations to a PI/NNRTI.
Treatment Intensification
Despite major success, the toxicity and complexity of the currently available
antiretroviral drug regimens represent a major barrier to adherence and repre-
