Three new trials, published in CID, highlight potential for intravaginal rings.
Those fighting for more enhanced measures for HIV prevention seems at least a step closer to achieving victory.
A series of 3 clinical trials published on October 4, 2018, in Clinical Infectious Diseases (CID) evaluated the safety and efficacy of MK-2048/vicriviroc (MK-4176)/MK-2048A and dapivirine intravaginal rings designed to deliver sustained-release formulations of antiretroviral therapy for HIV prophylaxis in women. And, in general, the results were positive—notable, given that it is believed that these devices offer the potential for improved adherence over pill-based prophylaxis.
Indeed, adherence to pre-exposure prophylaxis (PrEP) has generally varied from trial to trial among women in Africa, for example, ranging from 28% to 37%.
“Topical microbicides and systemic options for PrEP offer women multiple potential strategies to prevent sexual HIV acquisition,” lead author of one of the trials Craig J. Hoesley, MD, Senior Associate Dean for Medical Education and Chair, Department of Medical Education, University of Alabama School of Medicine told Contagion®.
In the phase 1 MTN-027 trial, Dr. Hoesley and colleagues evaluated the safety and pharmacokinetics of intravaginal rings containing MK-2048 and/or vicriviroc (MK-4176) in a single-blind, randomized, placebo-controlled design. The trial enrolled 48 women, who were administered intravaginal rings containing vicriviroc (182 mg), and/or MK-2048 (30 mg), or placebo and used them continuously for 28 days. For all subjects, the authors recorded adverse events and measured drug concentrations in plasma, vaginal fluid, cervical tissue, and rectal fluid.
Overall, they found no differences in genitourinary adverse events between treatment arms compared with placebo. Furthermore, in both single and combination intravaginal rings, the study drugs achieved peak concentrations in vaginal fluids. However, the trial also revealed that the antiviral activity of vicriviroc and/or MK-2048 “was not correlated with tissue-associated drug concentrations,” they write. In all, 77% of the study subjects adhered to the prescribed treatment time of 28 days.
“[Our] paper demonstrated the combination drug ring was safe and acceptable but tissue-associated vicriviroc and/or MK2048 did not inhibit HIV infection in ex-vivo challenge assays,” Dr. Hoesley explained. “This suggests future studies are needed to determine the optimal drug release and concentration profiles of VCV and MK-2048 needed to achieve protection from HIV acquisition.”
A second phase 1 trial, MTN-028, evaluated the safety and pharmacokinetics of the 2 intravaginal rings in 19 HIV uninfected women. As in the first trial, study participants were randomized to receive either a low-dose (91 mg of vicriviroc; 10 mg of MK-2048) or original-dose (182 mg of vicriviroc; 30 mg of MK-2048) ring, which they used for 28 days. Adverse events were documented, and drug concentrations were assessed in the plasma, cervicovaginal fluid, and cervical tissue of study participants.
The authors of the second trial reported that all adverse events recorded among the participants were grade 1 or 2 (application site pain, vulvovaginal pruritis, and dysmenorrhea in the low-dose arm and diarrhea and vaginal discharge in the original-dose arm)—meaning that, overall, they were safe and well-tolerated—and that there were no statistically significant differences in related genitourinary adverse events or grade ≥2 adverse events observed. Vicriviroc and MK-2048 concentrations rose rapidly in both groups, but there were higher plasma and cervical tissue area under the concentration-time curve (AUC) findings in the original-dose arm. There were similar cervicovaginal fluid AUCs in both arms. Plasma and cervicovaginal fluid concentrations for both drugs fell rapidly following ring removal.
“Our findings suggest that vaginal rings containing vicriviroc/MK-2048 are safe and well-tolerated when tested in women,” noted lead author Albert Liu, MD, MPH Clinical Research Director, Bridge HIV, and Population Health Division, San Francisco Department of Public Health. “These studies highlight the potential for rings containing other drug regimens and formulations to be developed and tested with the goal of further expanding HIV prevention options in women.”
Finally, a phase 2A clinical trial of another intravaginal ring delivering the microbicide dapivirine or placebo in 96 HIV-negative postmenopausal women yielded similarly positive results. In this trial, intravaginal rings containing 25 mg of dapivirine or placebo were administered for a period of 12 weeks, and study subjects were assessed for adverse events and drug concentrations in plasma and vaginal fluid, with steady-state concentrations assessed at 4, 8, and 12 weeks.
In all, the authors found no differences in the proportion of women with related grade 2 or higher reproductive system adverse events (dapivirine: 8%, placebo: 13%) or grade 3 or higher adverse events (dapivirine: 6%, placebo: 0%), although in the dapivirine arm 3% of the enrolled subjects “declined to resume product use” because of adverse events. Overall, median dapivirine concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) remained constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4.
However, these are not the only positive findings associated with the dapivirine ring. According to Dr. Hoesley, 2 phase 3 trials of the device in Africa have demonstrated efficacy (based on up to a 31% reduction in HIV incidence) due in large part to consistent adherence. All 3 intravaginal rings evaluated to date “have been found to have a favorable acceptability profile” among study subjects, he added.
“Of the papers in CID, the dapivirine vaginal ring phase 2a study provides safety and acceptability data for post-menopausal women, [which] will be beneficial for regulatory approval,” Dr. Hoesley continued. “The phase 1 MK-2048/vicriviroc intravaginal ring studies speak to the potential for combination…based on the clinical rationale for combining antiretroviral drugs with different mechanisms of action to increase the breadth of protection against resistant HIV strains as well as potentially protect against emergence of resistant HIV viral strains.”
“Currently the field is conducting a number of different studies to advance the science of vaginal rings for HIV prevention,” added Dr. Liu. “The Microbicide Trials Network is conducting studies of rings containing higher dose strengths of dapivirine, extended duration—90-day—rings containing dapivirine or tenofovir, and a combination ring with dapivirine-levonorgestrel for HIV prevention and contraception. There are also studies testing vaginal ring use in pregnancy and breastfeeding. Vaginal rings are a really promising approach to HIV prevention. They offer women a discreet prevention option that is easy to use and one in which they can take charge of protecting themselves against HIV.”
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous health care-related publications. He is the former editor of Infectious Disease Special Edition.