Improving non-nucleoside reverse transcriptase inhibitors for first-line treatment of HIV infection: the development pipeline and recent clinical data.

Abstract

Efavirenz non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy or boosted protease inhibitor (PI)-based therapy are currently recommended as first-line regimens for the treatment of HIV infection. Although the available therapy options are efficacious and well-tolerated in the majority of patients, treatment durability is still limited by drug-related side effects, inadequate patient adherence and the development of drug resistance. PI-based regimens have higher tablet loads, more complicated drug interactions and have been associated with gastrointestinal side effects and metabolic abnormalities. NNRTI-based regimens are efficacious, but have a low genetic barrier to resistance and have been associated with rash, hypersensitivity reactions and central nervous system side effects. There is, therefore, still a need for first-line antiviral agents that facilitate patient adherence and allow durable suppression of viral replication. The next-generation NNRTIs in development include rilpivirine (TMC-278), UK-453061, RDEA-806, IDX-899 and MK-4965. These NNRTIs demonstrate significant advantages over efavirenz, and may improve treatment options for first-line therapy. A number of other structurally diverse compounds that inhibit common NNRTI-resistant mutant viruses are also under investigation. In this review, the desirable features of a next-generation NNRTI for treatment-naïve patients are discussed, as well as the properties of the NNRTIs that are currently in development.

• Authors: Zachary K Sweeney, Klaus Klumpp
• Journal: Current opinion in drug discovery & development (Curr Opin Drug Discov Devel) Vol. 11 Issue 4 Pg. 458-70 (Jul 2008) ISSN: 1367-6733 [Print] England
• PMID: 18600563 (Publication Type: Journal Article, Review)

Chemical References

• Anti-HIV Agents
• IDX 899
• Indoles
• Nitriles
• Phosphinic Acids
• Pyrimidines
• Reverse Transcriptase Inhibitors
• Rilpivirine

Topics

• Animals
• Anti-HIV Agents (adverse effects, chemistry, therapeutic use)
• Drug Design
• Humans
• Indoles (adverse effects, chemistry, therapeutic use)
• Molecular Structure
• Nitriles (therapeutic use)
• Phosphinic Acids (adverse effects, chemistry, therapeutic use)
• Pyrimidines (therapeutic use)
• Reverse Transcriptase Inhibitors (adverse effects, chemistry, therapeutic use)
• Rilpivirine
• Structure-Activity Relationship
• Treatment Outcome