November 15, 2013
A vaginal ring that delivers both tenofovir for HIV prevention and levonorgestrel for contraception, a gel containing the experimental antiretroviral IQP-0528 designed for both vaginal and rectal use, and a gel combining tenofovir and the anti-herpes drug acyclovir were among the new HIV prevention technologies presented at the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition this week in San Antonio.
The field of biomedical HIV prevention has seen major advances in recent years. Pre-exposure prophylaxis (PrEP) using oral tenofovir or Truvada can dramatically reduce the risk of HIV infection, but it only works with good adherence. Researchers are exploring other delivery methods that may be more convenient and encourage better adherence than daily pills. Multipurpose prevention technologies -- for example, combining protection against HIV and other sexually transmitted infections, or HIV protection and contraception -- is another way to encourage consistent use.
Patrick Kiser from Northwestern University, Meredith Clark from CONRAD, and colleagues are working on an intravaginal ring designed to deliver a combination of tenofovir and the hormonal contraceptive levonorgestrel for 90 days.
Studies have already shown that a 1% tenofovir vaginal gel applied before and after sex decreases HIV infection risk for women. Putting tenofovir in an intravaginal ring would allow it to be left in place longer. This type of ring was shown to protect monkeys from vaginal exposure to an HIV-like virus. Adding a contraceptive could address two needs at once.
"We saw the urgent need to make this dual-protection intravaginal ring because a majority of the world's unintended pregnancies occur within resource-poor regions where the HIV/AIDS pandemic is most prevalent, such as sub-Saharan Africa," Clark explained in an AAPS press release.
But putting tenofovir and levonorgestrel together in a ring is tricky because they have different release rates and biochemical properties: Tenofovir is hydrophilic, meaning it attracts water, while levonorgestrel is hydrophobic, or naturally repels water. (This article from MIT explains the difference.)
To solve this problem, the researchers developed a segmented polyurethane ring with separate reservoirs that can deliver both drugs simultaneously. Using tubes of different lengths to change the amount of drugs released, they were able to achieve target levels of both tenofovir and levonorgestrel. After optimizing segments for each drug, they tested the combination rings in rabbits and sheep, showing that tenofovir levels in vaginal tissue and fluid were similar to those obtained with 1% tenofovir gel in human clinical trials.
"Products only work when they are used," said CONRAD's David Friend. "By having a ring that can remain in the body for up to 90 days, our hope is that this ring will offer a solution to increase adherence, and therefore provide greater protection against HIV while also preventing pregnancy."
CONRAD and collaborators expect to start Phase 1 clinical trials in early 2014 using the combination ring and one containing tenofovir alone.
In another presentation, Anthony Ham and colleagues from ImQuest BioSciences described the development of DuoGel, a microbicide gel containing IQP-0528 -- an experimental antiretroviral that acts as both an NNRTI and an HIV entry inhibitor -- that is designed for both vaginal and rectal use.
"It is recognized that both vaginal and rectal intercourse occur during the same sexual act, so a single product that is safe for both compartments makes sense in terms of convenience, which is likely to result in higher compliance," Ham explained in another AAPS press release. "In addition, these DuoGels will be much safer products for HIV prevention in males practicing receptive anal intercourse."
The researchers developed various IQP-0528 gel formulations using excipients (inactive carrier compounds) approved for both vaginal and rectal administration. They tested the gels' biochemical properties, drug release, toxicity, and anti-HIV activity in laboratory cell cultures and cervical and rectal tissue explants (tissue samples kept alive in a lab). The best DuoGel formulation showed no toxicity to cells or normal vaginal bacteria at the highest concentration tested, and caused no loss of viability in cervical or rectal tissue.
Acceptability and adherence are now being evaluated using a placebo DuoGel without the active ingredient. The researchers are preparing the current gel for animal studies and hope to begin Phase 1 human clinical trials in early 2015. In the next stage, they plan to create a multidrug DuoGel that contains IQP-0528 plus tenofovir.
Finally, researchers from SRI International reported on the development of a vaginal gel combining tenofovir and acyclovir, which is used to treat and prevent outbreaks of genital herpes.
The team developed gels made with different combinations of two polymers, Pluronic F-127 and Noveon AA1. One gel, dubbed SR-2P, retained its structure when diluted with fluids and subjected to "mild simulated coital stress." It showed good adhesion to pig vaginal tissue and caused little or no irritation in a mouse model.
Because tenofovir is compatible with Noveon AA1 while acyclovir is compatible with Pluronic F-127, the researchers are working on a dual syringe that can administer the two drug/polymer mixes from separate compartments.
Liz Highleyman is a freelance medical writer and editor-in-chief of HIVandHepatitis.com.