including the unanticipated finding of increased HIV acquisitionA

The microbicide field had faced setbacks in clinical trials, including the unanticipated finding of increased HIV acquisition in one of two recent phase III clinical trials of cellulose sulphate. To date, preclinical safety studies have included in vitro (outside the human body) measurements of cell viability and effects on lactobacilli, rabbit vaginal irritation, and a few macaque studies, while phase I safety studies in humans have looked for signs of irritation, assessed colposcopic abnormalities, measured inflammatory cytokines, or cultured specific bacteria. This innovative study assessed changes in electrical resistance and effects on junctional proteins in the vaginal epithelium when each of four microbicides was applied. The authors found that polarized cells provide a relatively impervious barrier to HIV migration through the epithelium. It is encouraging that neither PMPA (tenofovir) nor PRO 2000 0.5% disrupted epithelial tight junctions or activated inflammatory pathways. Both of these candidates are currently in trials: CAPRISA 004 and MDP 301, respectively. The results of these trials will help better determine the place of this methodology in the safety evaluation of future microbicide candidates but based on this report it does warrant serious consideration.