Non-nucleoside reverse transcriptase inhibitors in the treatment of human immunodeficiency virus infection

Abstract

The human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic maintains its inexorable spread across the globe; approximately 13,000 new infections occur each day, and an estimated 27.9 million people worldwide have been infected [1]. Of these infections, 26 million (~ 93%) have occurred in developing countries, approximately one million in North America, and more than 450,000 in Europe. In the absence of a vaccine or effective prevention efforts, spread of the virus is likely to continue. Efficacious treatments are needed to treat the increasing number of those infected. Since the discovery of AIDS in 1981 and the causative agent, HIV, in 1983, remarkable progress has been made in understanding the pathogenesis of the disease and in the development of therapeutic agents. The ability to quantitate the level of HIV in blood and other tissues (viral load measurement) has advanced studies in pathogenesis, monitoring of disease progression, and response to therapy in patients. Recent studies have demonstrated that the virus replicates at extraordinarily high levels, producing millions of viral particles in an infected person daily, with resultant loss of key cells of the immune system, the CD4+ T-lymphocytes [2,3]. These [2,3]. These cells are critical components of the cellular immune system and their destruction leads to immune compromise, followed by disease and death. Chemotherapy using antiretroviral drugs is the only treatment that has so far proved useful. Combinations of antiretroviral agents have led to improved immune function, delay of disease progression and increased survival in patients [4]. The first antiretroviral, zidovudine (AZT, ZDV), was licensed in 1987. Since then, eight other drugs have been launched, some at unprecedented speed. Recent studies have shown that antiretroviral combinations including protease inhibitors can lead to dramatic increases in CD4+ T-lymphocyte levels and decreases in viral load [5,6]. These results have led to new optimism in the scientific community, and in those affected by the disease. However, the ability of HIV to mutate and evade both the host immune response and the effect of antiviral drugs continues to confound research efforts. Factors limiting the effectiveness of available drugs include the development of viral resistance, drug toxicity, drug interactions and cost. More effective treatments are needed that can combine potent antiviral activity, ease of administration and minimal toxicity.