S25   New Antiretroviral Drugs

Roy Gulick
Weill Medical Coll. of Cornell Univ., New York, NY

Antiretroviral drug combinations have changed the natural history of HIV infection, resulting in dramatic improvements in HIV-related morbidity and mortality. However, despite the current availability of 15 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens have limitations. As many as 60% of patients may experience treatment failure of current antiretroviral regimens, due to difficulties with adherence, toxicity and/or drug resistance. Newer drugs and drug combinations are needed to improve the ease of administration, tolerability, and antiretroviral activity (against both wild type virus and resistant virus) of the current drugs. The ease of administration may be improved by developing drugs that are administered orally, require a minimal number of pills per dose, are given once or twice daily or have few, if any, restrictions on food intake. Tolerability may be improved by identifying drugs with fewer short-term and long-term side effects and minimal drug-drug interactions. Antiretroviral activity may be improved by enhancing the pharmacokinetic properties of the antiretroviral agents, identifying new agents with increased inherent antiretroviral activity, or developing agents with novel mechanisms of action. Promising agents are in development in existing classes of antiretroviral drugs: nucleoside analogue reverse transcriptase inhibitors (nRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). Newer formulations and fixed-dose combinations of existing drugs also are becoming available. In addition, promising agents are in development that have new mechanisms of action: nucleotide analogue reverse transcriptase inhibitors (ntRTI) and entry inhibitors (e.g., fusion inhibitors, chemokine receptor inhibitors). Additional novel targets (e.g., HIV integrase, TAT protein, CD4 receptor) provide opportunities for future drug development. Further improvements in HIV therapy will result from continued, coordinated efforts in both basic and clinical research.