Biology Reference
In-Depth Information
able alternative to PI-containing combinations in terms of potency. Besides the
advantage of deferring the introduction of PIs, NNRTI-containing regimens
may also allow for a lower pill burden and therefore improved adherence. The
main disadvantage of NNRTIs is the ease and rapidity with which resistance
develops to the individual drugs in this class if they are used in the context of a
regimen that is not maximally suppressive and the very strong likelihood that
cross-resistance within this class of drugs will follow.
The use of three NRTIs to ``spare'' both PIs and NNRTIs has recently been
proposed. Most data refer to the combination of abacavir, zidovudine, and
lamivudine, which has shown durable antiviral activity (after 48 wks of treat-
ment), equivalent to that of a ``standard'' two NRTI plus one PI regimen (e.g.,
zidovudine/lamivudine/indinavir), in treatment-naive patients. This combina-
tion, however, could be less e¨ective in patients with high baseline plasma viral
loads. The main attraction of a three NRTI regimen is deferral of the use of
PIs, while also sparing the NNRTI and placing only a single class of anti-
retroviral drugs ``at risk'' for the development of resistance. Once again, the
long-term e½cacy and toxicity of multinucleoside regimens remains unknown
and there is concern over the potential possibility of selecting for multinucleo-
side-resistant variants of HIV and over the possibility of a cumulative nucleo-
side toxicity.
In planning ®rst-line therapy, the following considerations may apply: for
patients with viral loads <100,000 copies/ml, PI, NNRTI, or triple NRTI
(w/ABC) based regimens are probably comparable options in terms of e½cacy.
For patients with high viral loads, more data are needed regarding e½cacy of
triple NRTI abacavir (Ziagen, ABC) (w/ABC) regimens.
A major cause for concern is the evidence from several clinical trials that 20±
40% only of previously untreated patients achieve complete virologic suppres-
sion (de®ned as plasma HIV-1 RNA below the limits of detection), even with
the currently available potent regimens. Evidence from several laboratories
making use of sensitive molecular assays suggests persistent virus replication in
lymphoid tissues of at least some of these patients. Such persistent replication
may be responsible for the occasional ``blips'' in plasma HIV-1 RNA that are
observed in some patients. Intermittent nonadherence, interindividual variation
in pharmacokinetics, drug-to-drug interactions, and inadequate potency of cur-
rent regimens could concur in determining persistent virus replication. Given the
high rate of HIV-1 replication, the concern is that any residual turnover could
lead to rapid repopulation of the HIV reservoirs. Therefore, the use of anti-
retroviral combinations that produce high activity on viral reservoirs (anatom-
ical and cellular) is also being explored as a tool to improve overall e½cacy.
COMPLICATIONS OF ANTIRETROVIRAL THERAPY
Important factors that negatively impact long-term outcomes are complications
of therapy and its recently emerged untoward e¨ects, speci®cally metabolic/fat
abnormalities and mitochondrial toxicity (which has several manifestations
Search WWH ::




Custom Search