Drug Therapy of HIV Infection

DRUG THERAPY OF HIV INFECTION

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.