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Tenofovir/Emtricitabine Vaginal Ring Protects Monkeys Against HIV-Like Virus

A vaginal ring that releases tenofovir and emtricitabine -- the antiretroviral drugs in the Truvada PrEP pill -- maintained protective drug levels over 4 months, and all macaque monkeys that received the ring were protected from infection with an engineered HIV-like virus, researchers reported in the June 8 edition of PLoS ONE. A human study of a different type of tenofovir ring showed that it maintained protective drug levels in genital fluid and blood over 14 days.

Pre-exposure prophylaxis using oral tenofovir and emtricitabine has been shown to dramatically lower the risk of HIV infection among people who take it regularly. However, risk reduction has been greatest among gay men in clinical trials to date, while studies of women have shown a smaller protective effect associated with poorer adherence and perhaps biological factors that affect drug levels in genital fluid and tissues.

Offering PrEP in other forms -- such as long-lasting injectables, vaginal gels, or rings -- may make it easier for some people to use it consistently. However, so far studies of topical (externally applied) PrEP have demonstrated only modest effectiveness. For example, a pair ofstudies presented at this year's Conference on Retroviruses and Opportunistic Infections showed that vaginal rings containing the NNRTI drug dapivirine offered about 30% efficacy, though they were more effective in women over age 25.

Priya Srinivasan from the Centers for Disease Control and Prevention (CDC) and colleagues performed an animal study to evaluate a novel "pod" intravaginal ring that can deliver tenofovir and emtricitabine at independently controlled rates.

The study included 12 female pigtailed macaque monkeys with normal menstrual cycles. 6 of the monkeys were fitted with silicone vaginal rings containing 65 mg tenofovir disoproxil fumarate (TDF) and 68 mg emtricitabine, while 3 control animals received no rings; 6 historical controls were also included in the analysis. Rings were exchanged every 2 weeks for 18 weeks.

The monkeys were vaginally exposed to once-weekly low doses (50 TCID₅₀) of SHIV162p3, an engineered simian-human virus similar to HIV, starting 1 week after the first ring was inserted and repeated for 16 weeks. Vaginal rings were exchanged 3 days before the next viral exposure.

The researchers found that all 6 macaques that received active vaginal rings were protected against infection throughout the study, while all 3 real-time control animals became infected after a median of 5 SHIV exposures, as were the 6 historical controls after a median of 4 exposures.

"The first efficacy study of sustained release vaginal delivery of TDF in combination with [emtricitabine], the only drugs FDA-approved for HIV PrEP, in the gold standard preclinical model demonstrated complete protection from productive SHIV infection," the study authors concluded. "These results support the significant translational potential of the [TDF-emtricitabine] pod-intravaginal ring as a non-vaccine biomedical prevention strategy for female-controlled HIV prevention in resource-poor regions."

In their discussion the researchers explained that the pod ring design overcomes some limitations of reservoir or matrix ring designs by enabling customizable, individually controlled drug release rates from each pod. In a prior study, pod rings demonstrated stable drug release rates while reservoir or matrix rings exhibited significant variability in daily release rates over time.

The press release added that research on the pigtailed macaque model is "particularly relevant" because of its similarities with the human menstrual cycle, vaginal architecture, and vaginal microbiome.

"Up to this point, topical pre-exposure prophylaxis (PrEP) against HIV has been marginally successful in recent clinical trials with low adherence rates being a primary factor for failure," study co-author Marc Baum said in an Oak Crest Institute of Science press release. "Our hypothesis has been that controlled, sustained release of antiretroviral drug combinations could overcome these low adherence rates if the product itself could remain protective for extended periods of time. This study has shown that the drug combination and the versatile drug delivery system that we have designed can indeed remain protective for over 4 and a half months."

"In contrast to daily therapies, sustained release approaches to drug delivery have special appeal for use in the developing world: they are less expensive on a per-patient, per-day basis, they require less infrastructure to provide to the community, and they can be more effective," Baum added.

First Human Study of Tenofovir Ring

A related study published in the March 13 edition of AIDS evaluated the safety and pharmacokinetics of a different type of tenofovir vaginal ring in women; this early study did not assess efficacy.

Marla Keller from Albert Einstein College of Medicine conducted the first randomized human trial of a polyurethane vaginal ring that releases TDF from a reservoir.

This study included 30 healthy, sexually abstinent women age 18-45; 15 received tenofovir-releasing vaginal rings and 15 used placebo rings without active drug. The researchers measured drug concentrations in cervical-vaginal fluid, rectal secretions, blood plasma, and dried blood spots over 14 days of continuous ring use and 7 days of follow-up after removal; a cervical tissue biopsy sample was taken on day 14.

Steady-state tenofovir concentrations in cervical-vaginal fluid were observed in various vaginal locations both proximal to (behind) and distal to (in front of) the ring by 1 day after insertion. Tenofovir half-life after ring removal was about 12 hours, and median drug concentrations remained above 1000 ng/mL for 2 to 4 days after removal. Tenofovir was detected in all but one of the rectal samples.

The median tissue concentration of tenofovir and tenofovir diphosphate (the active form of the drug) in cervical biopsies at 14 days after ring insertion were 5.4 ng/mg and 120  fmoL/mg, respectively.

Cervical-vaginal fluid collected from the cervix at 1 week and 2 weeks after insertion of tenofovir rings demonstrated significant protection against ex vivo (outside the body) HIV exposure in the laboratory, with inhibitory activity exceeding 90%.

11 of 14 participants (78%) had detectable tenofovir diphosphate concentrations in dried blood spots 14 days after insertion of the tenofovir rings, suggesting that these may provide a surrogate marker of adherence in clinical trials.

The vaginal rings were generally safe and well-tolerated. There were 43 total adverse events -- mostly mild (grade 1) -- with twice as many in the active ring group as in the placebo ring group (29 vs 12). 8 events (vaginal discharge) were deemed to be product-related, with 6 of them occurring in the tenofovir ring group. One woman withdrew from the study, but the rest all said the vaginal ring was acceptable and easy to use.

"A TDF intravaginal ring is safe, well tolerated, and results in mucosal tenofovir concentrations that exceed those associated with HIV protection," the researchers concluded. "The findings support further clinical evaluation of this TDF intravaginal ring."

6/16/16

References

P Srinivasan, JA Moss, M Gunawardana, JM Smith, et al. Topical Delivery of Tenofovir Disoproxil Fumarate and Emtricitabine from Pod-Intravaginal Rings Protects Macaques from Multiple SHIV Exposures. PLoS ONE 11(6):e0157061. June 8, 2016.

MJ Keller, PM Mesquita, MA Marzinke, et al. A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring. AIDS 30(5):743-751.

Other Source

Oak Crest Institute of Science. Topical Application of Antiretroviral Drug Combination Prevents Transmission of (S)HIV. Press release. June 11, 2016.