Antiretroviral therapy for HIV infection dates back to 1987 when the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine was first introduced to the market. Dramatic improvements in morbidity and mortality were noted with the addition of drugs capable of inhibiting different targets in the HIV replication cycle, such as protease inhibitors (PI, first approved in 1995), additional NRTIs, and non-nucleoside reverse transcriptase inhibitors (NNRTI, first approved in 1996). Apart from NRTIs, PIs and NNRTIs, fusion (& entry) inhibitors are the fourth class of antiretroviral therapy. NNRTIs differ from NRTIs in that they directly bind to reverse transcriptase, non-competitively inhibiting enzymatic activity. Of the more than twenty approved antiretroviral drugs, only three NNRTIs plus one fixed dose combination including one NNRTI are currently approved. These NNRTIs have several therapeutic limitations including the development of HIV strains that are resistant to other drugs within the class, unacceptable adverse side effects, reproductive toxicity which limits the use of the compounds in women of childbearing potential, and drug-to-drug interactions. Despite major efforts in developing novel NNRTIs during the last years, many projects have failed. New insight into the molecular and structural mechanisms by which such mutations confer resistance is driving the development and and refinement of novel compounds capable of maintaining antiviral activity against both wild-type and drug-resistant HIV strains. Further improvements consist in once daily oral dosing and more favourable toxicology profiles. The most advanced representative (etravirine) of such novel NNRTIs currently is under regulatory review by the FDA and the EMEA and at least eight further NNRTIS are in clinical stages of development.

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