title: Safety and efficacy of tenofovir/IQP-0528 combination gels - a dual compartment microbicide for HIV-1 prevention.
abstract: Tenofovir (TFV) is a nucleotide reverse transcriptase inhibitor and IQP-0528 is a non-nucleoside reverse transcriptase inhibitor that also blocks virus entry. TFV and IQP-0528 alone have shown antiviral activity as microbicide gels. Because combination therapy will likely be more potent than mono-therapy, these drugs have been chosen to make a combination microbicide gel containing 2.5% TFV/1% IQP-0528. Safety and efficacy testing was done to evaluate five prototype combination gels. The gels retained TZM-bl cell and ectocervical and colorectal tissue viability. Further, the epithelium of the ectocervical and colorectal tissue remained intact after a 24h exposure. The ED(50) calculated from the formulations for IQP-0528 was ~32nM and for TFV was ~59nM and their inhibitory activity was not affected by semen. The ED(50) of TFV in the combination gels was ~100-fold lower than when calculated for the drug substance alone reflecting the activity of the more potent IQP-0528. When ectocervical and colorectal tissue were treated with the combination gels, HIV-1 p24 release was reduced by ≥1log(10) and ≥2log(10), respectively. Immunohistochemistry for the ectocervical tissues treated with combination gels showed no HIV-1 infected cells at study end. With the increased realization of receptive anal intercourse among heterosexual couples often in conjunction with vaginal intercourse, having a safe and effective microbicide for both mucosal sites is critical. The safety and efficacy profiles of the gels were similar for ectocervical and colorectal tissues suggesting these gels have the potential for dual compartment use.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. cdezzutti@mwri.magee.edu
authors.forename: Charlene S
authors.initials: CS
authors.lastname: Dezzutti
authors.forename: Cory
authors.initials: C
authors.lastname: Shetler
authors.forename: Alamelu
authors.initials: A
authors.lastname: Mahalingam
authors.forename: Shweta R
authors.initials: SR
authors.lastname: Ugaonkar
authors.forename: Garry
authors.initials: G
authors.lastname: Gwozdz
authors.forename: Karen W
authors.initials: KW
authors.lastname: Buckheit
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D058956:Administration, Mucosal; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D063065:Organophosphonates / Q000494:pharmacology* / Q000633:toxicity; D011744:Pyrimidinones / Q000494:pharmacology* / Q000633:toxicity; D000068698:Tenofovir; D046509:Tissue Culture Techniques; D014622:Vaginal Creams, Foams, and Jellies / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000890:Anti-Infective Agents; C573126:IQP-0528; D063065:Organophosphonates; D011744:Pyrimidinones; D014622:Vaginal Creams, Foams, and Jellies; D000068698:Tenofovir; D000225:Adenine