Vaginal Microbicide Film Combinations of Two Reverse Transcriptase Inhibitors, EFdA and CSIC, for the Prevention of HIV-1 Sexual Transmission

• Published in: Pharmaceutical research 2015-09, Vol.32 (9), p.2960-2972
• Main Authors: Zhang, Wei, Hu, Minlu, Shi, Yuan, Gong, Tiantian, Dezzutti, Charlene S., Moncla, Bernard, Sarafianos, Stefan G., Parniak, Michael A., Rohan, Lisa C.
• Format: Article
• Language: English
• Subjects: Administration, Intravaginal; Anti-HIV Agents - pharmacology; Anti-Infective Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Cell Line; Chemistry, Pharmaceutical - methods; Diazonium Compounds - pharmacology; Disease prevention; Disease transmission; Drug Therapy, Combination - methods; Farnesol - analogs & derivatives; Farnesol - pharmacology; Female; HIV; HIV Infections - drug therapy; HIV Infections - microbiology; HIV Infections - prevention & control; HIV-1 - drug effects; Human immunodeficiency virus; Humans; Indoles - pharmacology; Lactobacillus; Lactobacillus - drug effects; Lentivirus; Medical Law; Pharmacology; Pharmacology/Toxicology; Pharmacy; Research Paper; Retroviridae; Reverse Transcriptase Inhibitors - pharmacology; Vagina - microbiology
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-015-1678-2

Purpose EFdA is a potent nucleoside reverse transcriptase inhibitor (NRTI) with activity against a wide spectrum of wild-type and drug resistant HIV-1 variants. CSIC is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with demonstrated anti-HIV properties important for use in topical prevention of HIV transmission. The objective of this study was to develop and characterize film-formulated EFdA and CSIC for use as a female-controlled vaginal microbicide to prevent sexual transmission of HIV. Methods Assessments of EFdA- and CSIC-loaded films included physicochemical characteristics, in vitro cytotoxicity, epithelia integrity studies, compatibility with the normal vaginal Lactobacillus flora and anti-HIV bioactivity evaluations. Results No significant change in physicochemical properties or biological activity of the combination films were noted during 3 months storage. In vitro cytotoxicity and bioactivity testing showed that 50% cytotoxic concentration (CC 50 ) of either EFdA or CSIC was several orders of magnitude higher than the 50% effective concentration (EC 50 ) values. Film-formulated EFdA and CSIC combination showed additive inhibitory activity against wild type and drug-resistant variants of HIV. Epithelial integrity studies demonstrated that the combination vaginal film had a much lower toxicity to HEC-1A monolayers compared to that of VCF®, a commercial vaginal film product containing nonoxynol-9. Polarized ectocervical explants showed films with drug alone or in combination were effective at preventing HIV infection. Conclusions Our data suggest that vaginal microbicide films containing a combination of the NRTI EFdA and the NNRTI CSIC have potential to prevent HIV-1 sexual transmission.