Drug Therapy Of Hiv Infection

The replicative cycle of HIV presents many opportunities 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 inhibitors (PI).

Single agents are seldom used to treat HIV infection. 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

LT ABLE 51.1 Antiretroviral Drug Combinations Used in HAART

Combinations of Choice

2 NRTIs and 1 PI 2 NRTIs and 1NNRTI 2 NRTIs and 1 PI with ritonavir 2 NRTIs and abacavir

Secondary Alternatives

1 PI, 1 NRTI, and 1NNRTI

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 multidrug 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 necessary 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 development 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 system; this may account for their incomplete effectiveness. Protection of the host immune mechanism might increase the efficacy of other drugs that inhibit viral replication.

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