Abstract
The development of topically applied products capable of preventing vaginal and rectal transmission of HIV-1 has been on-going for nearly 20. years. Despite this, only one clinical trial has demonstrated protection against sexual transmission of HIV-1 in women. This review covers the development of microbicides, also referred to as topical pre-exposure prophylaxis (PrEP), through three stages. The first stage focused on nonspecific agents, including surfactants such as nonoxynol-9 (N-9), to prevent HIV-1 transmission. Unfortunately, N-9 enhanced susceptibility to sexual transmission of HIV-1 when evaluated for efficacy. Soon thereafter, other nonspecific agents (polyanions) were quickly moved into large efficacy trials. Due to a lack of coordination among investigators and funders, a large investment was made in a class of compounds shown ultimately to be ineffective, although poor adherence may have contributed to these findings. The second stage involved the assessment of the antiretroviral drug tenofovir, formulated as a vaginal gel, which was found to be modestly effective in a Phase IIb trial (CAPRISA-004) when dosed in a coitally-dependent manner. In another Phase IIb trial, VOICE (MTN-003), tenofovir gel was found to be ineffective when dosed once-daily in a coitally-independent manner. Based on pharmacokinetic data, it was concluded the participants were poorly adherent to this dosing regimen, leading to a lack of efficacy. Tenofovir gel is currently in a Phase III safety and efficacy trial in South Africa (FACTS-001), using the coitally-dependent dosing regimen employed in CAPRISA-004. We are now in the third stage of microbicide research. The antiretroviral drug dapivirine is currently in two Phase III safety and efficacy studies formulated as a vaginal ring. It is hoped that the once-monthly dosing regimen will lead to higher adherence than found in the VOICE study. It is now clear that product adherence could be the greatest challenge to demonstrating topical (and to a similar extent oral) PrEP. Novel dosage forms should play a role in creating products that women will use correctly.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 391-400 |
| Number of pages | 10 |
| Journal | Antiviral Research |
| Volume | 99 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 2013 |
Funding
Topical HIV-1 prevention science is supported by a patchwork of public funding through the NIH, USAID and private donors, in particular the Bill and Melinda Gates Foundation, with support from the pharmaceutical industry in the form of providing licenses to antiretrovirals, but little or no financial investment. Because of serial clinical failures and the inability until recently to recognize that adherence, behavior and product demand are the main hurdles in this field, significant doubt has been raised concerning the concept of topical HIV-1 prevention. This is reflected in the potential unwillingness of donors to fund clinical studies of HIV-1 prevention technologies beyond the three current Phase III trials (TFV 1% gel and DPV IVR). Further support of HIV-1-only products will depend strongly on the outcomes of these trials. However, the donors are not completely backing off, and are now actively pointing to the need for combination ARV-contraceptive options, for the reasons discussed above. This work was supported by Cooperative Agreement GPO-A-00-08-00005-00 from the United States Agency for International Development (USAID) (DRF) and a subaward via CONRAD (PFK). The views expressed by the authors do not necessarily reflect those of USAID.
Keywords
- Adherence
- Intravaginal rings
- Microbicide
- Multipurpose prevention technologies
- Pre-exposure prophylaxis
- Vaginal gels
ASJC Scopus subject areas
- Virology
- Pharmacology
