Antiretroviral therapy: reverse transcriptase inhibition

a great extent this is still the case, as AZT remains the drug most commonly prescribed as the initial treatment and the agent with which new therapies are typically compared. However, in most other respects the field has grown enormously, with major changes having occurred in both practical and theoretical drug development. Clinically, dideoxynucleoside reverse transcriptase (RT) inhibitors remain the mainstay of practice. The results of landmark clinical trials have changed the indications and dose recommendations for AZT, and the alternative agents dideoxyinosine (ddl) and dideoxycytidine (ddC) are now available to physicians even while clinical trials to define their precise roles are ongoing. Information derived from studies of newer, nonnucleoside RT inhibitors, agents which act at other stages in the viral life cycle, and combination therapies will likely produce major changes in the chemotherapeutic approach to the control of established HIV infection. Antiviral agent development in the field of human retrovirology is a particular challenge. In addition to the basic but often difficult principle of developing an agent that will attack a unique target in the viral life cycle but be relatively nontoxic for the human host, there are the additional hurdles posed by the integration of HIV into the host cell genome, its capacity for persistence and latency, the complexity of the viral replication scheme, and the potential for antiviral agent resistance. This challenge, however, is being met by an intensive basic research effort which has resulted in a fundamental understanding of the molecular biology of HIV (31). The present knowledge of the viral life cycle and the complex genomic organization of HIV have created opportunities for rational and unique drug design which are among 'he most hopeful avenues for current and future drug development. A familiarity with the replication scheme of HIV is thus crucial to a full appreciation of antiviral chemotherapy.