Advances in antiretroviral therapy over the past decade have improved the management of human immunodeficiency virus-1 (HIV-1) infection. Currently, the principal goals of antiretroviral phar-macotherapy require continuous drug therapy (1) to ensure maximal and prolonged suppression of viral loads, (2) to restore CD4 lymphocyte cell counts, (3) to improve quality of life, and (4) to reduce morbidity and mortality related to HIV infection and acquired immunodeficiency syndrome (AIDS).
Therapeutic success and efficacy ultimately depend on patient adherence to antiretroviral therapy that produces minimal side effects and offers simple dosing regimens. However, success with available protease inhibitors is limited by several factors, including complicated dosing schedules and intolerable side effects.
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In general, protease inhibitors (PIs) are well known for their metabolic adverse drug effects (ADEs) such as lipid abnormalities, impaired glucose tolerance, insulin resistance, and an increased risk of lipodystrophy. Gastrointestinal (GI) side effects (e.g., drug intolerance, nausea, vomiting, and diarrhea) are also characteristic of this drug class.
All of the aforementioned ADEs make it difficult for patients to adhere to antiretroviral regimens. Poor compliance with any combination therapy that includes a PI is likely to result in an increased risk of emerging PI-resistant variants and treatment failure. In general, poor compliance with highly active antiretroviral therapy (HAART) has significant consequences, including:
Several studies have concluded that greater than 95% adherence is required to achieve adequate therapeutic respon-ses. In 1999, amprenavir (Agenerase®, GlaxoSmithKline) was the fifth PI to be approved by the Food and Drug Administration (FDA). Current HIV treatment guidelines do not advocate the use of amprenavir as the sole PI in patients, partly because of concerns of a high pill burden (16 capsules/day) and the potential for poor compliance.
On October 21, 2003, the FDA approved yet another PI, a prodrug of amprenavir—fosamprenavir calcium (Lexiva™, GlaxoSmithKline/Vertex)— in combination with other antiretro-viral agents for the treatment of HIV-1 infection in adults. Fosamprenavir was evaluated in two major clinical trials to determine its efficacy, safety, and potential benefits when used in a PI-based regimen.