New Rings, Gels, and Films Show Promise in Microbicide Trials
Experimental vaginal microbicides—products such as gels, films, or flexible rings worn inside the vagina—were the focus of two studies reported Tuesday at the 21st Conference on Retroviruses and Opportunistic Infections.
As Beatrice Chen of the University of Pittsburgh explained, vaginal rings are promising candidates for microbicide products for several reasons. First, they can offer sustained delivery of the anti-HIV drug. Second, they require little action on the part of the user; “once you place the vaginal ring, don’t need to think about it,” Chen said. And finally, they are discreet and private.
Indeed, these advantages could allow individuals to protect themselves against HIV infection when condoms are not an option—for example, when a receptive partner is not in a position to negotiate condom use for vaginal or anal sex, or when a mixed-HIV-status couple is trying to conceive. (In addition, sustained-delivery products like rings could help get around adherence challenges.)
Chen presented findings from the first-in-humans clinical trial assessing safety, pharmacokinetics (PK; how the body absorbs and distributes a drug), and pharmacodynamics (PD; how the drug acts on the body) of vaginal rings containing maraviroc and a combination of maraviroc and dapivirine.
Dapivirine is an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) that blocks a key stage in the HIV lifecycle. Phase 3 clinical trials in African countries are already testing dapivirine alone in drug-releasing vaginal rings. Maraviroc is currently approved for HIV treatment (brand name Selzentry) and is a CCR5 antagonist; taken orally, it prevents the virus from entering and infecting immune system cells via the CCR5 protein on the cell surface, but it has not previously been studied for vaginal use in humans.
As Chen explained, the trial enrolled 48 HIV-negative women, aged 18 to 40, at three U.S. sites: The Fenway Institute in Boston, the University of Pittsburgh, and the University of Alabama at Birmingham. Women in the trial were randomly assigned to use a vaginal ring containing either dapivirine, maraviroc, both agents, or a placebo for 28 days, followed by 24 days without the ring. Study participants were sexually abstinent; the trial was not designed to detect efficacy (how well a drug or product works in a controlled study setting).
Adherence (whether the ring was kept in place as directed) was measured by self-report and residual drug levels in rings that were collected after the initial 28-day period of use. The research team assessed PK and PD by measuring levels of dapivirine and maraviroc in samples of blood plasma and vaginal fluid.
In addition, researchers took multiple biopsies of cervical tissue immediately after ring removal on day 28 and on three subsequent visits during and after the 24-day “washout” period. These tissue samples were examined for drug levels and used to perform “explant challenges,” in which the samples were exposed to HIV in the laboratory to see whether they were susceptible to infection.
“All four rings were generally safe,” Chen reported. “We found no difference in the number of participants with genitourinary adverse events [unwanted effects] as compared by study arm.” Most adverse events were mild to moderate, and most were unrelated to the study products.
Adherence was high: 94% of women reported keeping the ring in place for the full 28 days. The researchers measured levels of both drugs remaining in the rings after removal and found residual drug levels to be consistent with self-reported ring use.
Comparison of dapivirine and maraviroc levels in plasma, vaginal fluid, and cervical tissue suggested that the rings released maraviroc less efficiently than the researchers had hoped. For example, maraviroc levels in vaginal fluid were 2–10 times lower than dapivirine levels.
Dapivirine, on the other hand, appeared to be released efficiently and also showed promise of efficacy in the explant challenge. “Fresh cervical tissue from dapivirine and combination ring users showed a significant linear correlation between dapivirine levels in the tissue and protective effect against HIV replication,” Chen said. “The higher the dapivirine level, the less likely it was that HIV was replicating in cervical tissue” in the lab. Maraviroc levels, however, appeared to be too low to have the same protective effect against HIV.
“We have hope that continued development of the maraviroc ring may show promise for further studies,” Chen concluded.
Katherine Bunge, also from the University of Pittsburgh, reported results from a safety, PK, and PD trial of gel and dissolvable film formulations of dapivirine—the first study of a vaginal film containing a microbicidal drug in humans.
Films have the advantage of being discreet, portable, and easier to store than gels, and can be inserted in the vagina without an applicator, Bunge explained. The study enrolled 60 HIV-negative women who were randomized to receive a placebo gel, dapivirine gel, placebo film, or dapivirine film. Participants were directed to use the product daily for seven days.
Although 60 participants were involved in the study, a handful were ultimately excluded from the analysis. Some women in the film arms acknowledged that they found the product difficult to insert and, Bunge explained, “at the time of the genital biopsies, we actually observed that five women had film on the external genitalia…which was clear evidence of inappropriate film placement.” Once the study was unblinded (when the researchers learned which participants had been using study drug vs. placebo), it was discovered that all five women were in the dapivirine film arm, and the team opted to exclude them from the data analysis to avoid artificially skewing the study results.
The remaining arms of the study included 10 women receiving dapivirine film, 14 with placebo film, 15 receiving dapivirine gel, and 16 with placebo gel. The mean age of women in the study was 26.7 years. Retention in the study was 98%.
The researchers checked dapivirine levels in cervicovaginal fluid, genital tissue, and plasma to evaluate PK and PD, and also assessed whether gel or film use in vivo (in living participants) would confer protection to biopsied tissue exposed to HIV in the lab.
Dapivirine gel and film were considered generally safe. The proportion of participants experiencing grade 2 (moderate) and higher adverse events deemed related to study product were comparable across all study arms. Two moderate adverse events were reported, but both occurred in placebo users. The most commonly reported adverse events were vaginal discharge and odor.
Plasma concentrations of dapivirine from gel and film products were found to be comparable—and, importantly, were comparable to concentrations seen with dapivirine-releasing vaginal rings. Drug concentrations in cervical and vaginal tissues appeared to favor the gel formulation; dapivirine gel yielded four-fold higher levels in tissues, a result that Bunge admitted was surprising given the comparable plasma levels. The presence of extra gel adhering to the tissues may account for this unexpected difference.
“So we know that the drug got to the tissue,” Bunge said. “The big question is whether or not the drug actually protected against HIV infection.” Presenting on only vaginal tissue explants, she noted that tissue from the dapivirine groups, both film and gel, had significantly lower measures of HIV infectivity than the placebo-exposed samples.
“This proof-of-concept study demonstrated that quick-dissolving films can effectively deliver antiretrovirals to genital tissues at concentrations similar to sustained-delivery systems such as the vaginal ring,” Bunge concluded. “While we all acknowledge that sustained-delivery systems have some clear advantages, we do have to also concede that women likely would like choice. This form could provide a lower-cost, on-demand microbicide product for women.”
The second antiretroviral film trial is now enrolling, she added, with a slightly larger film designed to be easier to place correctly in the vagina.
41: Safety and Pharmacokinetics/Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings
Beatrice A. Chen, Lori Panther, Craig Hoesley, Craig Hendrix, Ariane van der Straten, Marla Husnik, Lydia E. Soto-Torres, Annalene Nel, Sherri Johnson, Charlene S. Dezzutti
Background: Vaginal rings offer sustained multi-drug delivery for pre-exposure prophylaxis of HIV infection. A dapivirine (DPV) vaginal ring, an NNRTI, is in Phase III trials. Maraviroc (MVC), a CCR5 co-receptor antagonist, is approved for oral HIV treatment but has not been studied intravaginally. This trial evaluated the safety and pharmacokinetic/pharmacodynamics of vaginal rings containing DPV and MVC alone or in combination compared to placebo.
Methodology: We conducted a multi-site, double-blind, randomized, placebo-controlled trial in 48 HIV-negative sexually abstinent women to evaluate vaginal rings containing 25 mg DPV plus 100 mg MVC, DPV only, MVC only or placebo used for 28 days followed by 24 days off product. Safety was assessed by adverse events (AE). Adherence was assessed by self-report and residual drug levels in returned rings. DPV and MVC plasma and vaginal fluid levels were quantified. Cervical biopsies were obtained on day 28 immediately after ring removal to quantify drug and for the HIV ex vivo challenge assay.
Results: Mean age was 29.6 years (range 20-40); 50% were white and 38% were black. Retention was 98% at the final visit. There were 33 grade 1 and one grade 2 related genitourinary AEs from 22 women with no difference between each of the treatment arms and placebo arm. There were 20 grade 2 or higher AEs from 13 women, of which two grade 2 AEs were related to study product. Ninety-four percent were fully adherent by self-report; ring use was confirmed by residual drug levels. Plasma DPV Cmax was not significantly different between DPV and DPV/MVC users (272 vs 294 pg/mL, respectively). MVC plasma concentrations were below limits of quantification (LOQ). Day 28 mean DPV vaginal fluid levels were 14.9 .g/mL and 10.0 .g/mL in DPV and DPV/MVC users, respectively. Day 28 mean DPV tissue levels were 0.6 .g/mL and 1.6 .g/mL in DPV and DPV/MVC users. Day 28 mean MVC vaginal fluid levels were 6.7 .g/mL and 1.1 .g/mL in MVC and DPV/MVC users. Only 4 of 24 MVC and DPV/MVC users had tissue levels above LOQ for MVC.. Fresh cervical tissue from DPV and DPV/MVC users showed a significant inverse linear relationship between HIV replication and tissue DPV drug levels.
Conclusions: Vaginal rings were safe and well tolerated. DPV but not MVC delivered by a vaginal ring for 28 days blocked HIV-1 infection in cervical tissue. There was a linear correlation between DPV levels in tissue and protective effect. These data suggest that delivery of NNRTIs via vaginal rings is a viable approach for HIV prevention.
42LB: FAME-02: A Phase I Trial To Assess Safety, PK, and PD of Gel and Film Formulations of Dapivirine
Katherine E. Bunge, Charlene S. Dezzutti, Ingrid Macio, Craig W. Hendrix, Lisa C. Rohan, Mark A. Marzinke, Brid Devlin, Leslie A. Meyn, Hans M. L. Spiegel, Sharon L. Hillier
Background: Film formulations of topical microbicides have theoretical advantages over gels and intravaginal rings. Relying on physiologic fluids to dissolve, the product may provide more efficient drug delivery while minimizing disruption of innate immune defenses, product application may ensure privacy while avoiding leakage, and the cost associated with scale up of vaginal films compares favorably to gels. In this first in human trial of a film for delivery of ARVs, we sought to compare the safety, PK, and PD of film and gel formulations of dapivirine versus placebo.
Methodology: 60 healthy HIV negative women were randomized to placebo gel, dapivirine (0.05%) gel, placebo film, or dapivirine (1.25mg) film. Participants were instructed to use product daily for seven days. Adverse event (AE) data were collected via questionnaire and physical exam at two follow-up visits. The proportion of participants experiencing Grade 2 and higher AEs deemed related to study product were compared across treatment arms using Fisher’s exact test. After seven daily doses plasma dapivirine levels were measured. Cervical and vaginal biopsies obtained 2-4 hours after the last dose were analyzed for tissue drug levels or were exposed to HIV-1 in an ex-vivo challenge model. Tissue HIV infection was monitored by p24 levels in culture supernatant.
Results: The mean age of the participants was 26.7 years; 53.3% of evaluable participants were white and 36.7% black. There were two Grade 2 related AEs; both were in the placebo film group. Five of 29 women assigned to film were noted to have visible film at or outside of the introitus just prior to biopsies which suggested poor film placement; all were in the active film arm. Women randomized to gel and film products had comparable plasma dapivirine levels (302.47 vs 227.13 pg/ml) after one week. However, tissue levels of dapivirine were 4 times higher in the gel users when compared to film users, possibly due to residual gel product adherence to the tissue surface. Both active products when placed correctly were protective against HIV-1 infection in the ex-vivo challenge model (Figure 1).
Conclusions: This proof of concept study demonstrated that the dapivirine film was safe and released dapivirine to plasma and genital tissue at levels comparable to the dapivirine gel and intravaginal ring. While safe and effective when placed correctly, the dapivirine film was difficult to insert for some women, and further development is needed to optimize ease of placement for this dosage form.