Historical development of vaginal microbicides to prevent sexual transmission of HIV in women: from past failures to future hopes

Abstract

Infection with human immunodeficiency virus (HIV) remains a global public health concern and is particularly serious in low- and middle-income countries. Widespread sexual violence and poverty, among other factors, increase the risk of infection in women, while currently available prevention methods are outside the control of most. This has driven the study of vaginal microbicides to prevent sexual transmission of HIV from men to women in recent decades. The first microbicides evaluated were formulated as gels for daily use and contained different substances such as surfactants, acidifiers and monoclonal antibodies, which failed to demonstrate efficacy in clinical trials. A gel containing the reverse transcriptase inhibitor tenofovir showed protective efficacy in women. However, the lack of adherence by patients led to the search for dosage forms capable of releasing the active principle for longer periods, and hence to the emergence of the vaginal ring loaded with dapivirine, which requires a monthly application and is able to reduce the sexual transmission of HIV. The future of vaginal microbicides will feature the use of alternative dosage forms, nanosystems for drug release and probiotics, which have emerged as potential microbicides but are still in the early stages of development. Protecting women with vaginal microbicide formulations would, therefore, be a valuable tool for avoiding sexual transmission of HIV.

Vaginal Formulations for Prevention of Sexual Transmission of HIV

“…It was subsequently discovered that this inefficacy was due to the formation of a semen-derived enhancement of the virus infection that increased the infectious capacity of the virus in the presence of seminal fluid [13]. This study highlights the importance of evaluating the efficacy of microbicides in the presence of semen [4].…”

“…The most common pharmaceutical dosage forms for the vaginal administration of drugs are gels, capsules, ovuli and tablets, although vaginal rings and films are rapidly gaining ground [4]. The first trials of vaginal microbicides mainly explored vaginal gels, but the current trend focuses more on vaginal rings and sustained-release tablets, which could prolong protection time.…”

“…Vaginal microbicides have been defined as "any agent included in a topical formulation designed to prevent the spread of sexually transmitted pathogens either through cell death, inactivation of cell mechanisms, inhibition of viral replication, the formation of a physical barrier between cells and pathogens, or by enhancing the natural protection mechanisms of the cervix and vagina" [4].…”

“…Microbicides that include antiretroviral drugs can be classified into entry inhibitors or viral enzyme inhibitors [4]. Of particular interest in this group is Tenofovir, an inhibitor of the reverse transcriptase of the virus, which was part of the first microbicide that proved its effectiveness in preventing the transmission of HIV, and has now become the most widely-studied drug for this purpose [3,5].…”

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

“…The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginallyadministered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women (Malcolm et al, 2015;Notario-Pérez et al, 2017;Thurman et al, 2013;Traore et al, 2018). In 2016, the results of two parallel Phase III clinical studies conducted across multiple sites in Africa were reported for the lead candidate microbicide product, a matrix-type silicone elastomer vaginal ring offering 28-day continuous release of the non-nucleoside reverse transcriptase inhibitor dapivirine (Baeten et al, 2016;Chen et al, 2018).…”