46 Chemotherapy
drugs for HIV
HIV belongs to a family of retroviruses where the genetic information is held as RNA. Consequently, the first step in viral replication is the synthesis of DNA from RNA by viral reverse transcriptase. HIV gains entry to immune system cells by binding to surface proteins (CCR5 on macrophages and dendritic cells; CD4 on T helper cells, macrophages and dendritic cells). The infection eventually destroys the cells of the immune system and at this stage the acquired immunodeficiency syndrome (AIDS) occurs. HIV/AIDS is a major pandemic (although overwhelmingly centred on sub-Saharan Africa, where up to 35% of the adult population is infected with HIV). Because the viral genome can be incorporated into the host genome (a provirus that can be activated at a later date), and can linger in sites less available to drugs (e.g. the brain), it can remain secluded from antiviral actions. Most currently available antiviral agents are only effective while the virus is replicating. There are four major drug classes used in the treatment of HIV with differing targets (Fig. 3.46.1):
Fig. 3.46.1 Human immunodeficiency virus (HIV). (A) A virion; (B) cell entry; (C) interference with viral replication.
No one drug is completely effective in HIV and there is the potential for the development of drug resistance. A combination of drug classes, known as highly active antiretroviral therapy (HAART), minimizes this potential. A typical HAART combination would involve two nucleoside reverse transcriptase inhibitors (NRTI) with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or one or two protease inhibitors. This approach has greatly extended patient survival but the regimen is complex, patient compliance can be an issue and a lifelong commitment to take these medications is required because of the presence of latent virus. There can be unwelcome drug interactions and variations in penetration of drug into reservoir sites such as the brain. In addition the side-effect profile is considerable and drug resistance can still develop.
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