Basic Concepts in HIV Therapeutics

Considerable progress has been made during the past twenty years in the development of effective treatment against HIV-1, the agent of AIDS. Today, there are more than twenty agents commercialized that target various steps in the viral life cycle (Figure 21.1). These drugs, used in combination, inhibit two or more steps of the viral cycle: viral entry (fusion inhibitors, coreceptor antagonists), reverse transcription (nucleoside analog and nonnucleoside inhibitors), integration into the host genome (anti-integrases), and viral polyprotein processing (protease inhibitors). The need for combination antiretroviral therapy (ART) is determined by the ease of viral escape from the selective pressure when confronted with single antiretroviral agents. The ability to escape from drug pressure is, in turn, the result of rapid mutation rates due to a viral polymerase (the reverse transcriptase) that lacks proofreading activity.

HIV treatment is highly standardized, with defined criteria for its initiation and detailed knowledge on comparative efficacy (1). Decisions to initiate ART are primarily based on the degree of immunosuppression (generally defined by the numbers of CD4+ T cells – the target of HIV-1 – in blood), with additional consideration given to the levels of viral replication (defined by the level of viremia – viral genome copy numbers per milliliter), and the presence of clinical symptoms. In the absence of treatment, most individuals infected with HIV-1 will have progression of immunosuppression, leading to AIDS-related opportunistic infections and cancer. Individuals progress to AIDS over a mean of eight years after infection; however, rates of progression are highly variable among individuals.