Current approaches to treatment for HIV-1 infection

The last 3 years have seen a dramatic fall in mortality and morbidity from HIV infection. Four factors have contributed to this: an improved understanding of the pathogenesis of HIV infection; the availability of tests that could measure plasma viral burden; the development of new and more powerful drugs such as the protease and non-nucleoside reverse transcriptase inhibitors; and the completion of large clinical endpoint trials that conclusively demonstrated that potent antiretroviral combinations significantly delayed the progression of HIV disease and improved survival. Typical antiretroviral regimen now consist of at least three agents: one or two protease inhibitors or a non-nucleoside reverse transcriptase inhibitor combined with two nucleoside analogs. The goal of therapy is to reduce measurable plasma viral burden to undetectable levels. Viral load testing has made it possible to individualize therapy and to more accurately determine the best time to initiate or change therapy, long before declining CD4+ counts would have given evidence of active viral replication. However, despite the impressive progress to date, there remain significant shortcomings with current treatment. Even with the most potent regimens available, there exists a proportion of patients (perhaps 20 - 50% of treated individuals) who fail to have complete and durable virologic responses to therapy. The shortcomings of current regimens are particularly evident in patients with high plasma HIV-1 RNA levels, extensive prior treatment, and advanced disease. Complexity, short- and long-term toxicities, cross-resistance, and drug-drug interactions all complicate current regimens. Viral resistance is increasingly encountered in clinical practice and transmission of resistant virus is well-documented. In addition, there remain concerns about the ability of the virus to evade current therapies, whether in viral reservoirs in non-lymphoid compartments or in lymphoid tissue, such as resting memory T cells. Thus there remains a need for new therapies as well as new strategies using existing drugs.