The most significant advance in the medical management of HIV-1 infection

has been the treatment of patients with antiviral drugs, which can suppress
HIV-1 replication to undetectable levels. The discovery of HIV-1 as the
causative agent of AIDS together with an ever-increasing understanding of
the virus replication cycle have been instrumental in this effort by providing
researchers with the knowledge and tools required to prosecute drug
discovery efforts focused on targeted inhibition with specific pharmacological
agents. To date, an arsenal of 24 Food and Drug Administration (FDA)approved drugs are available for treatment of HIV-1 infections. These drugs
are distributed into six distinct classes based on their molecular mechanism
and resistance profiles: (1) nucleoside-analog reverse transcriptase inhibitors
(NNRTIs), (2) nonnucleoside reverse transcriptase inhibitors (NNRTIs), (3)
integrase inhibitors, (4) protease inhibitors (PIs), (5) fusion inhibitors, and (6)
coreceptor antagonists. In this article, we will review the basic principles of
antiretroviral drug therapy, the mode of drug action, and the factors leading
to treatment failure (i.e., drug resistance).
BASIC PRINCIPLES OF ANTIRETROVIRAL THERAPY

Before 1996, few antiretroviral treatment options for HIV-1 infection existed.
The clinical management of HIV-1 largely consisted of prophylaxis against
common opportunistic pathogens and managing AIDS-related illnesses. The
treatment of HIV-1 infection was revolutionized in the mid-1990s by the
development of inhibitors of the reverse transcriptase and protease, two of
three essential enzymes of HIV-1, and the introduction of drug regimens that
combined these agents to enhance the overall efficacy and durability of
therapy. A timeline of antiretroviral drug development and approval for
human use is described in Figure 1.