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I. OVERVIEW OF HIV INFECTION AND ITS TREATMENT
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There are currently several million people taking chronic combination antiretroviral therapy to suppress human immunodeficiency virus (HIV) infection, including >3 million in sub-Saharan Africa alone. This is an amazing achievement for a disease that was uniformly fatal and with few treatment options just two decades ago. Combination antiretroviral therapy prolongs life and prevents progression of disease caused by HIV. The pharmacotherapy of HIV infection is a rapidly moving field. In 2009, 24 antiretroviral drugs were available in the U.S. Three-drug combinations are the minimum standard of care for this infection, so current agents constitute several thousand possible regimens. The long-term management of a patient on antiretroviral therapy can be daunting, even for experienced healthcare providers. Knowing the essential features of the pathophysiology of this disease and how chemotherapeutic agents affect the virus and the host is critical in developing a rational approach to therapy. Unique features of this drug class include the need for lifelong administration to control virus replication and the possibility of rapid emergence of permanent drug resistance if these agents are not used properly.
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Increasingly, the public health impact of this epidemic has shifted to those regions least able to afford treatment. Because combination antiretroviral therapy has the capacity to improve the quality of human health and to produce near-normal life expectancies (Lee et al., 2001), there is a strong impetus to provide these drugs to as many infected individuals as possible. Through a combination of increased foreign aid, access to generic antiretrovirals, and willingness on the part of legacy pharmaceutical companies to allow violation of intellectual property law for this class of drugs, HIV treatment is now a possibility for much of the world. Because the number of effective treatment options is large, emphasis is shifting from efficacy to long-term convenience, tolerability, and safety. One outcome has been the development of single tablet fixed-dose combinations of drugs that can be taken orally once or twice a day. Because treatment is taken for years if not decades, the potential adverse effects of each drug take on increasing importance.
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Pathogenesis of HIV-Related Disease
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Human immunodeficiency viruses (HIV) are lentiviruses, a family of mammalian retroviruses evolved to establish chronic persistent infection with gradual onset of clinical symptoms. Unlike herpesviruses, replication is constant following infection, and although some infected cells may harbor nonreplicating virus for years, in the absence of treatment there generally is no true period of viral latency following infection (Greene and Peterlin, 2002). Humans and nonhuman primates are the only natural hosts for these viruses.
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There are two major families of HIV. Most of the epidemic involves HIV-1; HIV-2 is more closely related to simian immunodeficiency virus (SIV) and is concentrated in western Africa. HIV-1 is genetically diverse, with at least five distinct subfamilies or clades. HIV-1 and HIV-2 have similar in vitro sensitivity ...