The pharmacotherapy of HIV infection is a rapidly moving field. Three-drug combinations are the minimum standard of care for this infection, so current agents constitute several thousand possible regimens. Knowing the essential features of the pathophysiology of this disease and how chemotherapeutic agents affect the virus and the host is critical in developing a rational approach to therapy. Unique features of this drug class include the need for lifelong administration to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not used properly.
PATHOGENESIS OF HIV-RELATED DISEASE
Human immunodeficiency viruses (HIVs) are lentiviruses, a family of retroviruses evolved to establish chronic persistent infection with gradual onset of clinical symptoms. Replication is constant following infection, and although some infected cells may harbor nonreplicating virus for years, in the absence of treatment there generally is no true period of viral latency following infection. Humans and nonhuman primates are the only natural hosts for these viruses.
There are 2 major families of HIV. Most of the epidemic involves HIV-1; HIV-2 is more closely related to simian immunodeficiency virus (SIV) and is concentrated in western Africa. HIV-1 is genetically diverse, with at least 5 distinct subfamilies or clades. HIV-1 and HIV-2 have similar sensitivity to most antiretroviral drugs, although the non-nucleoside reverse transcriptase inhibitors (NNRTIs) are HIV-1-specific and have no activity against HIV-2.
VIRUS STRUCTURE. HIV is a typical retrovirus with a small RNA genome of 9300 base pairs. Two copies of the genome are contained in a nucleocapsid core surrounded by a lipid bilayer, or envelope, that is derived from the host cell plasma membrane (Figure 59-1). The viral genome encodes 3 major open reading frames: gag encodes a polyprotein that is processed to release the major structural proteins of the virus; pol overlaps gag and encodes 3 important enzyme activities—an RNA-dependent DNA polymerase or reverse transcriptase with RNAase activity, protease, and the viral integrase; and env encodes the large transmembrane envelope protein responsible for cell binding and entry. Several small genes encode regulatory proteins that enhance virion production or combat host defenses. These include tat, rev, nef, and vpr.
Replicative cycle of HIV-1 and sites of action of available antiretroviral agents. Available antiretroviral agents are shown in blue. cDNA, complementary DNA; gp120 + gp41, extracellular and intracellular domains, respectively, of envelope glycoprotein; mRNA, messenger RNA; RNase H, ribonuclease H; RT, reverse transcriptase. (Adapted from Hirsch MS, D'Aquila RT. Therapy for human immunodeficiency virus infection. N Engl J Med, 1993; 328:1686–1695.)
VIRUS LIFE CYCLE (see Figure 59-1). HIV tropism is controlled by the envelope protein gp160 (env). The major target for env binding is the CD4 receptor present on lymphocytes and macrophages, although cell entry ...