HIV infectionor TDF.103,104 An IVR based on DPV, a potent NNRTI

HIV infectionor TDF.103,104 An IVR based on DPV, a potent NNRTI, has also been designed.105 An IVR incorporating DPV is currently undergoing two different Phase III clinical trials: ASPIRE (A Study to Prevent Infection with a Ring for Extended Use), conducted by the MTN in several sub-Saharan countries, and the Ring Study (IPM 027), the outcome of which will be known in 2015. Additionally, IVR incorporating DPV and the CCR5 inhibitor maraviroc has also been formulated, which is undergoing Phase I safety and pharmacokinetic studies (MTN 013).Multipurpose technologiesTo enhance the acceptability and adherence of vaginal/rectal microbicides, MPTs are being developed that aim simultaneously to inhibit HIV-1 infections and other STIs. In this direction, the Population Council is developing MPTs that may be effective against HIV-1, human papilloma virus, and HSV-2 using a combination of MIV-150, carrageenan, and zinc acetate.107,108 Various combinations of MIV-150, carrageenan, and zinc acetate have shown efficacy in preventing both vaginal and rectal transmission of RT-SHIV and HSV-2.Ponesimod 109,110 Further, MPTs that are capable of preventing sexual transmission of HIV-1 and also have contraceptive efficacy are being developed, and will have greater acceptability among women.111,Challenges in microbicide developmentSeveral microbicide clinical trials based on the successful in vitro anti-HIV efficacy of the microbicide candidates, however, have failed to demonstrate in vivo efficacy, presenting (except the CAPRISA 004 trial) the discrepancies between the in vitro and in vivo data.Imdevimab A reevaluation of the current microbicide-development paradigm and a renewed approach for preclinical testing systems that can predict negative outcomes of microbicide clinical trials is necessary.PMID:23724934 There are at least two important issues: (1) the microbicide should not have any effect on vaginal mucosa, and (2) the microbicide should not generate any proinflammatory response. To determine preclinical efficacy as well as safety of the candidate topical microbicides, human cervical and colorectal explant cultures have been developed.113,114 Further, a three-dimensional in vitro human vaginal epithelial cell model has been developed that mimics human stratified squamous epithelium with microvilli, tight junctions, microfolds, and mucus.115 Using this model, N-9 treatment led to an increase in tumor necrosis factor-associated apoptosis as well as biomarkers of cervicovaginal inflammation.115 Thereis a need to develop additional cell-based and explant-based models for discovering new biomarkers of cervicovaginal inflammation for assessment of microbicide safety before clinical evaluation can be initiated.116 For testing the safety and efficacy of the microbicide candidates, the absence of a validated animal model is a major obstacle. The animal models used currently (the mouse HSV-2 model, the rabbit vaginal irritation index, and the macaque SIV model) have substantial differences from humans. However, recent advances include the development of humanized murine models, which allow better vaginal and rectal HIV efficacy-challenge studies.117 To evaluate proinflammatory response and disruption of mucosal integrity by a candidate microbicide that may facilitate transepithelial viral penetration as well as replication, a Th17-based mouse model has been developed for preclinical assessment. 118 The sheep cervicovaginal tract, which comprises stratified squamous epithelium similar t.