Next generation microbicides may be broad-spectrum multipurpose prevention technologies with improved efficacy and safety. CAPRISA-004 showed that 1% TFV vaginal gel prevented HIV-1 and HSV-2. Here we compare the in vitro and in vivo safety and efficacy profile of 1% TFV gel versus a microbicide gel (MZC) containing 50 mM MIV-150 (M), 14 mM zinc acetate (Z) and 3% carrageenan (CG).
Increased HSV-2 susceptibility in mice (n=20), TEER in Caco-2 cells, and macaque vaginal explant histology were used to estimate damage to epithelia. XTT and Cyquant were used to evaluate in vitro cytotoxicity in TZM-bls and PBMCs. Anti-HIV activity was tested against HIV-1 lab strains (n=5), primary isolates and multidrug resistant strains/clones (n=28) in TZM-bls or PBMCs. CC_50 and IC_50 values were used to estimate therapeutic indexes (TI=CC_50/IC_50). Anti-SHIV-RT activity (10^4 TCID_50/explant) of diluted gels was assessed in macaque vaginal explants. In vivo anti-HSV-2 activity (5x103 pfu/mouse, n=20/treatment) was evaluated in mice (gel applied 1 h before and after HSV-2 vaginal challenge). Levels of TFV and TFV-DP in mouse cervicovaginal tissues were quantified by LC-MS/MS. Fisher's exact test (P<0.05) was used for statistical comparison in all HSV-2 murine models. Kruskal-Wallis and Dunn's Multiple Comparison test (P<0.05) in the explant model.
Both gels were safe. However, diluted 1% TFV reduced TEER values in Caco-2 monolayers. MZC showed greater in vitro antiviral activity (2 to 80-fold) than 1% TFV gel against HIV-1 in TZM-bls. Both gels showed good TI (>25-800) in PBMCs, except for one and two MDR HIVs with 1%TFV and MZC, respectively. MZC fully protected explants from SHIV-RT (p<0.009) with greater anti-SHIV-RT activity than 1% TFV gel. MZC fully protected mice from HSV-2 (p<0.0001), but the 1% TFV gel did not. The lack of protection could be associated with sub-therapeutic levels of TFV and TFV-DP in mouse tissues.
MZC is a promising microbicide candidate for clinical use.