HIV is the virus that causes acquired immune deficiency syndrome (AIDS). HIV kills or damages cells in the body's immune system, gradually destroying the body's ability to fight infection and certain cancers. An estimated 1,039,000 to 1,185,000 persons in the United States were living with HIV/ AIDS at the end of 2003 (221).
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV and the most common class of agents in the treatment of HIV infection. Since the introduction of zidovudine (AZT) in 1987, a relatively large number of compounds have been developed for the treatment of HIV-induced AIDS. Antiretroviral drugs act at different stages of the HIV life cycle and are classified based on their structure and site of action. The four classifications are as follows: (1) fusion or entry inhibitors, (2) reverse transcriptase inhibitors, (3) integrase inhibitors, and (4) protease inhibitors (PIs). Reverse transcriptase inhibitors are sub-classified as nucleoside reverse transcriptase inhibitors, non-nucleoside reverse tran-scriptase inhibitors, and nucleotide reverse transcriptase inhibitors. Standard treatment of HIV infection involves a combination of several antiretroviral drugs and is known as highly active anti-retroviral therapy (HAART). Combination HIV therapy, where multiple medications with anti-HIV activity are combined in one fixed dose, are widely used for treatment of HIV and AIDS in order to avoid increasing expression of resistance to the drugs when they are administered alone. Because of HAART therapy, the medial survival time of HIV/AIDS patients now exceeds 10 years.
Despite the progress made in the treatment of HIV infection, the virus can become sequestered certain regions of the body such as the CNS. While HAART therapy can eradicate the systemic viral load in HIV patients undergoing treatment, discontinuation of therapy is associated with a high incidence of relapse of re-infection from these reservoir sites and the potential for resistance development. Furthermore, HIV infection causes devastating structural damage to the brain, and as the disease progresses viral load in the brain ultimately leads to dementia (222). Current HAART medications are unable to achieve sufficient drug levels in the CNS due to poor permeability across the BBB. These drugs are substrates for BBB efflux transporters, thereby limiting access of these medications to the brain. Thus, delivering therapeutically relevant levels of antiviral medications to the CNS is of paramount importance for treating AIDS patients.
To address this deficiency and improve therapeutic outcomes in HIV patients, investigators are looking towards nanotechnology-based drug delivery systems. The potential impact of nanoparticulate drug carriers on HIV therapy are described in recent reviews (223,224). These formulations are designed to facilitate complete eradication of viral load from the CNS and other reservoir sites. Multilayer nanosystems (formulations containing particles 500 nm) are capable of encapsulating a variety of compounds, improving oral bioavailability, and promoting efficient delivery and residence in tissues to allow for drug internalization. These lipophilic systems can be modified in terms of size, surface charge, and surface composition to control drug release and target specific regions of the body. The application of nanosystems to deliver HIV medications to the CNS was discussed previously in this chapter.
Nanocarrier-based drug delivery systems have been shown to improved antiviral drug delivery to intracellular reservoirs (lymphocytes, macrophages) as well as anatomical areas such as the lymph nodes (223). For CNS delivery, nanoparticulate formulations could be designed to combine HAART medications with efflux transporter inhibitors to enhance BBB uptake. This is an area of interest for formulation scientists, where the ultimate goal is to achieve complete eradication of HIV in infected patients.
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