title: 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.affiliation: Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. zachary.sweeney@roche.com
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D015394:Molecular Structure; D009570:Nitriles / Q000627:therapeutic use; D010721:Phosphinic Acids / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D000068696:Rilpivirine; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; C534138:IDX 899; D007211:Indoles; D009570:Nitriles; D010721:Phosphinic Acids; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D000068696:Rilpivirine