DRUG THERAPY OF
The replicative cycle of HIV
presents many opportuni-ties for the targeting of antiviral agents. The drugs
in clinical use are classified as nucleoside reverse tran-scriptase inhibitors
(NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide
reverse transcriptase inhibitors (NTRTIs), and protease in-hibitors (PI).
Single agents are seldom used
to treat HIV infec-tion. Instead, multidrug
therapy is used to counteract the rapid
mutation rate of HIV and to minimize drug toxic-ity. Highly active
antiretroviral therapy (HAART) uses combinations
of reverse transcriptase inhibitors and protease inhibitors (Table 51.1). In
this system, drugs working by different mechanisms produce a sequential
blockade of steps required for viral reproduction.
It is difficult for the HIV to
simultaneously develop mutants that provide it with resistance to the multiple
drugs that act via different mechanisms. However, even with mul-tidrug
regimens, it has been estimated that viruses in 85% of infected people develop
resistance to one or more of the antiretroviral agents. Therefore, it is
neces-sary to produce drugs that either inhibit this resistance or find
compounds that produce no resistance.
New drugs are being targeted
against drug-resistant HIV strains. In addition, a variety of drugs under
devel-opment act as inhibitors of viral fusion or viral entry into the host
cell. New agents designed to inhibit viral integrase have shown promise in
early clinical trials. Current therapies do not enhance the host defense
sys-tem; this may account for their incomplete effective-ness. Protection of
the host immune mechanism might increase the efficacy of other drugs that
inhibit viral replication.