Recognizing Lower Extremity Effects Of Antiretroviral Drugs

By Robert G. Smith, DPM, MSc, RPh, CPed

     Acquired immune deficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) continues to be a major health problem worldwide. The Centers for Disease Control and Prevention (CDC) has estimated that approximately 40,000 people in the United States become infected with HIV each year.1 Human immunodeficiency virus infection and severe HIV-related disease have become leading causes of illness and death in the U.S. The cumulative estimated number of diagnoses of AIDS through 2005 in the United States and dependent areas was 988,376.2      The management of HIV/AIDS involves the complex coordination of many healthcare professionals. Better treatments have led to an increase in the number of people in the United States who are living with AIDS.2 In 2005, the estimated number of people living with AIDS in the United States was 437,982.2 The podiatric physician can provide education to the public regarding lower extremity manifestations of AIDS.3 Indeed, podiatric physicians can play an important role by identifying patients who are infected with HIV by being alert to the specific lower extremity signs and symptoms that may signal the presence of the infection.3 Further, podiatrists may be uniquely positioned to identify adverse effects from highly active antiretroviral therapy that affect the lower extremities of HIV-infected patients.

A Helpful Primer On Antiretroviral Therapy

     Currently, the available antiretroviral drugs used to treat patients with HIV infections are divided into four categories: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) and entry inhibitors.4 Integrase inhibitors, a new class of antiretroviral drugs, are currently undergoing studies.5,6      Each class of HIV medications fights HIV in a different way. The primary difference among each class is the stage of HIV replication. The nucleoside reverse transcriptase inhibitors are synthetic analogs of naturally occurring deoxyribonucleosides that are phosphorylated intracellularly. They work by interfering with the HIV virus reverse transcriptase enzyme system that is responsible for viral replication by terminating chain elongation. Members of the non-nucleoside reverse transcriptase class are structurally diverse and have similar mechanisms of action. They inhibit the reverse transcriptase enzyme system directly without having to be intracellularly activated by binding to the system itself and making it unavailable for use by the virus. Both NRTIs and NNRTIs decrease transcription of HIV RNA to DNA.      The protease inhibitors are synthetic agents that are very potent and more active against the reverse transcriptase system when compared to both NRTI and NNRTI classes. Protein inhibitors target the protease enzyme, which cuts up long chains of genetic material into smaller pieces to complete viral replication. They act at the end of the HIV virus life cycle, resulting in the formation of immature non-infectious virons by preventing cleavage of the Gag-pol polyprotein. Fusion inhibitors, also known as entry inhibitors, work by blocking an important step in the process of HIV entry into the CD4+ cells known as fusion. By blocking the fusion, entry inhibitors may prevent HIV from entering and infecting CD4+ cells.4

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