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RESEARCH PRODUCT

Future Perspectives in NNRTI-Based Therapy: Bases for Understanding Their Toxicity

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Continuous administration of the drugs included under the term Highly Active Antiretroviral Therapy (HAART) has turned AIDS into a chronic disease, at least in developed countries (Panos et al., 2008). The initial development of these drugs was particularly rapid and focused on clinical efficacy before all other considerations. However, as the disease has come under control, there has been growing emphasis on the long-term adverse effects associated with this therapy. The first drug for the treatment of HIV infection, zidovudine (AZT), was approved in 1987. The number of other antiretroviral drugs already approved for use or under development continues to grow, and the primary aim of researchers in the field is to improve their efficacy, safety and tolerability. Currently, there are 25 licensed antiretroviral drugs that belong to 6 different families: eight nucleoside (nucleotide) reverse transcriptase inhibitors (N[t]RTI) which inhibit competitively the viral reverse transcriptase, four non-nucleoside reverse transcriptase inhibitors (NNRTI), which produce a direct inhibition of the reverse transcriptase and a reduction in its catalytic activity, ten protease inhibitors (PI), which inactivate the HIV protease and prevent the generation of new viruses capable of infecting other cells, one fusion inhibitor, which prevents the fusion of the virus envelope with the host-cell membrane, one CCR5 inhibitor, which blocks the interaction of the virus with one of its receptors on the host cell, and, finally, one integrase inhibitor, whose function is to block viral DNA integration in the nuclear genome. HAART aims to slow the rate of viral replication to the point of reducing the viral load and producing a significant immune system reconstitution that increases circulating levels of CD4+ T cells. HAART usually combines the three major families of drugs: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. According to current guidelines, HAART regimens for initial treatment consist of two N(t)RTI plus either a NNRTI or a boosted PI (Hammer et al., 2008). NNRTI-based regimens have been in use for over a decade now, with the NNRTI of choice being Nevirapine (NVP) (for first line therapy in countries with limited resources) and Efavirenz (EFV) (for the treatment of naive patients). Although considered to be safe and well-