ICAAC 2014: Tenofovir Vaginal Ring and Nanoparticle Gel Are Protective in Animal Studies

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A vaginal ring that dispenses tenofovir protected all 6 macaque monkeys exposed to an HIV-like virus, while a heat-sensitive vaginal gel containing tenofovir nanoparticles prevented infection of mice, researchers reported at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy last week in Washington, DC.

A once-daily pill containing tenofovir and emtricitabine (Truvada) has been shown to be highly effective for pre-exposure prophylaxis (PrEP) to protect against HIV sexual transmission, but researchers are exploring several other methods of delivering antiretrovirals for PrEP in an effort to maximize acceptability, convenience, and adherence for a range of populations.

Pod-IVR Vaginal Ring

JM Smith from the U.S. Centers for Disease Control and Prevention (CDC) and colleagues reported findings from a trial of a vaginal ring that uses novel "pod-IVR" technology to provide sustained release of multiple drugs -- in this case tenofovir and emtricitabine -- at independent controlled rates.

The study included 6 female pigtailed macaques with normal menstrual cycles that were fitted with intravaginal rings containing tenofovir disoproxil fumarate (65 mg) and emtricitabine (68 mg); the rings were exchanged every 2 weeks. (One treated macaque was replaced for "non-compliance.") In addition, 3 untreated macaques served as real-time controls and 6 historical untreated control monkeys were also included in the statistical analysis.

Starting 1 week after insertion of the first ring, the macaques were given once-weekly vaginal exposures of a hybrid simian-human immunodeficiency virus (SHIV162p3) for 16 weeks or until infection was confirmed by detectable plasma HIV RNA. Plasma viral load was tested weekly and drug levels in vaginal fluid were measured each time the rings were exchanged.

All 6 macaques with vaginal rings remained uninfected through 16 weeks of exposure over 4 menstrual cycles and for 2 weeks thereafter. They also had undetectable SHIV DNA provirus in peripheral blood mononuclear cells (PBMCs), indicating that a viral reservoir was not established. In contrast, all control monkeys without vaginal rings became infected after a median of 4 exposures. Tenofovir and emtricitabine were released from the rings at median rates of 0.68 and 2.50 mg/day, respectively, in a 28-day pharmacokinetic analysis.

"Successful PrEP regimens require good adherence and delivery of protective antiretroviral levels, and should have the capacity to deliver multiple drugs," the researchers summarized. "The pod-IVR design fulfills these requirements and provides complete protection from SHIV infection in a rigorous animal model and does not require adherence to daily dosing."

They added that the pod-IVR platform has a significant advantage in terms of flexibility in development and scalability in manufacturing because most fabrication steps are identical regardless of which specific drugs are inserted into the pods. They noted that a vaginal ring sized for humans could hold a total drug volume of 2 g, which would allow for rings that last 4 weeks or longer.

The National Institutes of Health recently awarded $20 million to a consortium that will further develop the pod-IVR technology, testing various combinations of antiretroviral drugs to determine which are most effective when delivered together for PrEP.

Tenofovir Nanoparticles

In earlier-stage research, CJ Destache from Creighton University and colleagues tested a vaginal gel containing tenofovir nanoparticles.

While the CAPRISA 004 trial found that a 1% tenofovir vaginal gel applied before and after sex was associated with a 39% lower risk of HIV acquisition overall and a 54% reduction among women who achieved the best adherence, other studies of tenofovir gel have produced mixed and at best modest results. "Vaginal gel leakage and poor tenofovir permeability may in part, be responsible for these results," the investigators suggested.

In an attempt to remedy this, the researchers developed a thermosensitive gel that remains liquid at room temperature but increases in viscosity at body temperature. It contains tenofovir disoproxil fumarate in tiny particles made from poly lactic-co-glycolic acid polymer that slowly release the drug over time. The gel is designed to be "coitus-independent," meaning it can be inserted well before having sex, which would improve convenience and women's control over its use.

The gel was tested in humanized BLT (hu-BLT) mice with engrafted human thymus and liver tissue and hematopoietic stem cells, which makes them susceptible to HIV infection (normal mice are not). A total of 13 modified mice were randomly assigned to receive thermosensitive gel containing 0.1% or 0.5% tenofovir -- equivalent to 1 or 5 mg/mL, respectively -- or a control gel without active drug.

At 4 and 24 hours after gel administration, the mice were vaginally exposed to 2 transmitted/founder strains of HIV-1 (WITO.c/2474 and SUMA.c/2821). Blood was drawn weekly for plasma viral load measurement for 4 weeks following exposure. At week 4, the mice were tested for HIV DNA in PBMCs. Finally, the animals were killed and levels of HIV p24 antigen were measured in vaginal tissue. 

All 10 mice treated with either strength of the active tenofovir nanoparticle gel had no detectable plasma HIV viral load through 4 weeks of follow-up after vaginal exposure. These mice also had undetectable HIV DNA in PBMCs and no evidence of HIV p24 in vaginal tissue. All 3 mice receiving the inactive control gel, however, had detectable plasma viral load within 1 to 2 weeks post-exposure.

"[Tenofovir] nanoparticles in thermosensitive gel offers sustained and coitus-independent prevention from vaginal contraction of HIV-1 in a hu-BLT mouse model," the researchers concluded. "The use of vaginal thermosensitive gel containing [tenofovir] nanoparticles offers sustained protection against heterosexual transmission of HIV."

9/16/14

References

JM Smith, P Srinivasan, JA Moss, et al. Complete Protection In Macaques From Multiple Simian-human Immunodeficiency Virus Exposures With Pod-intravaginal Rings Delivering An Antiretroviral Combination. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract H-998.

CJ Destache, AA Date, Y Zhe, et al. Topical Application of Tenofovir DF Nanoparticles Prevents HIV-1 Vaginal Transmission in Humanized-BLT Mice. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract H-997.