Microbicide Development Hinges on New Products Administered in New Ways
Non-specific or antiretroviral-based vaginal gels failed to work but new formulations offer hope.
By Mary Rushton
Nearly a decade ago billionaire philanthropist Bill Gates, appearing before 20,000 people at the 16th International AIDS Conference, urged the world to accelerate the search for a microbicide. “This could mark a turning point in the epidemic, and we have to make it an urgent priority,” he said on the opening night of the biannual conference in Toronto.
The Bill & Melinda Gates Foundation had already given close to US$2 billion to support HIV/AIDS projects and considered development of an AIDS vaccine its top priority. But with HIV incidence static, and the development of an effective vaccine several years away, Gates said microbicides along with oral antiviral drugs to prevent HIV transmission—a then still hypothetical strategy dubbed pre-exposure prophylaxis or PrEP—were necessary to help reduce the rate of HIV infections.
Gates wasn’t alone in sounding the call. Former US President Bill Clinton’s foundation was primarily focusing on helping to make antiretroviral (ARV) drugs affordable for millions of HIV-infected individuals in developing countries. But at the conference they too broadcasted the need for vaginal microbicides—defined then as gels or creams women applied to the vagina prior to intercourse to prevent sexual transmission of HIV.
How far the field of microbicides has progressed since then is a pipeline half-full, pipeline half-empty situation. Unlike the army of positive findings that led the US Centers for Disease Control and Prevention (CDC) and most recently the World Health Organization to recommend oral PrEP for all high-risk, HIV-uninfected individuals (seeNew Global Goals and Guidelines Aim to Eliminate AIDS, IAVI Report, Vol. 19, No. 3), the results from so-called topical microbicide candidates have been largely disappointing thus far (see PrEP Works, IAVI Report, Vol. 19, No. 1). Only one trial of a topical vaginal microbicide to date showed any efficacy and follow-up studies have failed to confirm the candidate’s protective effect. The biggest reason: women don’t use it. Or as researchers say, there is poor adherence. While poor adherence has been a factor in some oral PrEP studies, the inability of volunteers to use a topical microbicide gel consistently—particularly high-risk young women in the setting of clinical trials—has essentially sidelined the development of topical microbicide gels.
Yet the microbicide pipeline remains quite robust with attention now focused on new formulations that are less user-dependent. Two pivotal Phase III trials are assessing the efficacy of a vaginal ring containing the ARV dapivirine (DPV) that slowly releases the experimental drug over one month, freeing women from having to apply the gel around sex to be protected. Intra-vaginal rings that simultaneously protect against infection with HIV and herpes simplex virus (HSV), while also preventing pregnancy, are also in development. And while vaginal gels may no longer be considered optimal, microbicide gels applied rectally are still being explored as a potential approach for use by both men and women who engage in anal intercourse. One candidate has just completed testing in a Phase II trial and additional studies are being planned.
Other new methods for delivering microbicides include vaginal films which can deliver multiple broadly neutralizing antibodies (bNAbs)—infection-fighting proteins that can neutralize most of the HIV isolates in circulation—or other ARVs such as integrase inhibitors, which could provide several days of protection from HIV with a single application. “I’m really excited about all the new technologies,” says Sharon Hillier, a professor of medicine in the Department of Obstetrics, Gynecology and Reproductive Sciences at the University of Pittsburgh and principal investigator of the Microbicide Trials Network (MTN), a worldwide clinical trials network funded by the US National Institutes of Health.
The need for HIV prevention options is as important as ever, Hillier and others stress. According to the Joint United Nations Programme on HIV/AIDS’s 2014 Gap Report, nearly half of the 5,000 HIV cases reported daily across the globe occur in women and adolescent girls, despite the proven efficacy of oral PrEP. “You know, there are many methods of contraception and no one ever questions whether another one should come on the market because the need is huge,” says Zeda Rosenberg, the founding Chief Executive Officer of the International Partnership for Microbicides (IPM), a non-profit product-development partnership. “One would argue the need is going to be huge for HIV/AIDS for a very long time. Just look at the rate of new infections among women. Even with the rollout of medical male circumcision and the rollout of treatment, in general it has not taken one ding. The number of new infections in women in sub-Saharan Africa remains alarmingly high.”
An evolving pipeline
The field of microbicide research has been one of peaks and valleys. The earliest microbicide candidates—an assortment of spermicides, surfactants, HIV entry inhibitors, and acid buffer gels which keep vaginal pH at protective levels—all failed to protect against HIV. The reasons they didn’t work varied by candidate, and in some cases still aren’t entirely clear. Repeated use of the spermicide Nonoxynol-9 (N-9) and the entry inhibitor cellulose sulfate (CS) in microbicide trials were found to actually increase risk of HIV transmission because they disrupt the protective genital epithelial barrier, thereby making it easier for HIV particles to get across (see Some Candidate Microbicides Can Damage Epithelia, IAVI Report, Vol. 12, No. 2). Another microbicide candidate known as PRO 2000—a water-based topical gel composed of 0.5% of a synthetic polyanionic polymer designed to bind nonspecifically to viruses and bacteria—initially looked promising. Ultimately it was found ineffective in preventing HIV infection, most likely because the seminal plasma reduced the effectiveness of PRO 2000, but also perhaps because the microbicide candidate reduced protective mucosal immune mediators (Int. J. Infec. Dis. 15, 10, e656, 2011). SAVVY, a surfactant microbicide gel, was also ineffective in preventing HIV infection and was associated with a higher incidence of reproductive adverse events (Int. J. Infec. Dis. 15, 10, e656, 2011).
In 2009, microbicide researchers thought they had a winner with a topical PrEP candidate containing a gel formulation of the antiretroviral tenofovir (TDF). The CAPRISA 004 trial, involving 889 high-risk South African women, showed the candidate reduced HIV incidence by 39 percent and HSV-2 acquisition by 51 percent when used in a coitally dependent manner. Volunteers were instructed to insert the applicator containing gel within 12 hours before sex and as soon as possible, but within 12 hours, after sex. They were also instructed not to exceed more than two doses in a 24-hour period (see Microbicides Finally Gel, Securing Spotlight at the International AIDS Conference, IAVI Report, Vol. 14, No. 4). Principal investigator and director of the Centre for the AIDS Programme of Research in South Africa (CAPRISA) Salim Abdool Karim, who presented the results at the International AIDS Society meeting in Vienna in 2009, said that with this level of efficacy, mathematical models indicated that the gel could prevent 1.3 million new HIV infections and over 800,000 deaths in South Africa alone. His presentation received a standing ovation, which even given the more positive news in HIV research of late is still a rare occurrence.
Not only were these results good news for the field of microbicides, they provided the first clinical evidence that PrEP, topical or otherwise, could be an effective strategy in blocking HIV. Researchers were ebullient. But two confirmatory trials proved disappointing. Neither the FACTS 001 study designed to evaluate the original CAPRISA 004 peri-coital approach in 2,059 high-risk women from South Africa, nor the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial involving 5,029 high-risk women that evaluated both oral and topical PrEP regimens at sites in South Africa, Zimbabwe, and Uganda, showed a reduction in HIV infections among women who used the TDF gel. In both trials poor adherence was the apparent reason that the approaches were not effective.
Based on returned vaginal applicators and a self-reported number of sex acts, investigators who led the FACTS 001 study determined that women used the TDF gel during just 50 to 60 percent of sex acts per month. And only 13 percent used it at least 80 percent of the time. A total of 123 HIV infections occurred during the three-year study, 61 in the microbicide arm and 62 in the placebo group. Analysis of HSV-2 incidence is still ongoing, according to CONRAD, the health research organization that sponsored the study.
The VOICE trial, conducted by the MTN, evaluated the effectiveness of both daily oral and daily topical TDF as well as daily oral Truvada—a combination pill containing TDF and the ARV emtricitabine (FTC)—and reached the same conclusion as FACTS 001. The gel arm was halted after an independent Data Safety Monitoring Board (DSMB) determined that the rate of new infections was the same (6 percent) in the microbicide and placebo arms during the course of a year. Investigators also halted the oral TDF arm after a separate DSMB said it would be unlikely this trial would be able to show that this strategy was effective. Investigators continued to evaluate oral Truvada until the end of the study, but ultimately found that ineffective as well (see The VOICE Results, Loud and Clear: Adherence Matters, IAVI Report Blog, March 4, 2013). Meanwhile, multiple others trials established the efficacy of orally administered TDF and FTC in preventing HIV infection among men who have sex with men (MSM), men and women in heterosexual serodiscordant couples in which one partner is HIV infected, and heterosexual men and women recruited individually rather than as a couple.
The VOICE and FACTS 001 trials showed, however, that there was a disconnect between what women were reporting and what they were actually doing with the gels and pills. Over the course of the study, women reported remarkably high adherence to PrEP and the counts of returned tablets and used gel applicators—another measure of adherence—seemed to support what the women were saying. But quarterly blood samples from a sub-group of randomly selected participants told a different story. Detectable levels of TDF were found in just 25 percent of samples from the microbicide group, 28 percent from the oral Truvada group, and 30 percent from the oral TDF group, suggesting poor adherence across the board. The lowest drug levels were found in those under age 25, the subgroup of women at greatest risk of contracting HIV, researchers noted. The results were consistent with FEM-PrEP, a Phase III study of oral Truvada conducted in 1,951 high-risk women in Africa that was also stopped for futility (see PrEP Trial in Women Halted Due to Doubts That It Could Show Efficacy, IAVI Report, Vol. 15, No. 2).
This remarkably poor adherence had researchers puzzled. A VOICE sub-study led by study investigator Ariane van der Straten of RTI International in San Francisco, uncovered some troubling revelations last year. Her study suggested many of the women had strong reservations about daily PrEP and misconceptions about the study drugs and the dangers of research. Interviews with about 102 randomly selected women revealed that some of the women were afraid of the stigma associated with taking a daily ARV-based regimen used primarily by people already infected with HIV. Others thought the regimens would make them infertile or increase their risk of HIV infection. Some objected to the vaginal wetness created by the microbicide gel. “Some women indicated that the lack of real-time monitoring allowed them to mislead the staff and not take their products … while several women minimized the consequences of their own behavior in the context of a large, blinded trial, counting on others for compliance,” the investigators of the sub-study analysis noted (PLoS One, doi: 10.1371/journal.pone.0089118, 2014).
Hillier said in retrospect some of the findings were not that unexpected. “Given the long-standing fears some women had about ARVs, the stigma surrounding the use of oral ARVs, and the fact that some women just didn’t like the wetness of the gels, it’s not necessarily surprising that they made those decisions. What is clear is that we need alternatives to oral daily tablets and vaginal gels.”
When publishing the final results of the VOICE trial this past February, researchers concluded that products that do not require daily use, including sustained delivery of antiretroviral agents from vaginal rings or injections, might be a better option for women (NEJM 372, 509, 2015).
The ring cycle
Attention in the microbicide field is now focused on just those types of strategies. Researchers are eagerly awaiting the results from two pivotal Phase III studies testing a monthly vaginal ring containing 25 milligrams of DPV, the experimental ARV developed by Janssen Sciences Ireland UC (formerly Tibotec Pharmaceuticals). This drug was never approved or licensed as an HIV treatment because it isn’t absorbed well when administered orally. But DPV does build up well in vaginal tissue. In 2004, Tibotec granted IPM rights to develop DPV as a microbicide and they are now leading one of the efficacy trials of the drug administered via a vaginal ring that slowly releases it over the course of a month. The Ring Study, as this trial is known, involves 1,959 women from South Africa and Uganda.
Investigators from the MTN are leading the other efficacy trial of a DPV vaginal ring. This trial, known as ASPIRE—an acronym for “A Study to Prevent Infection with a Ring for Extended Use”—involves 2,629 women at 15 clinical trial sites in Malawi, Uganda, South Africa, and Zimbabwe. The first efficacy results from these studies are expected in 2016, perhaps as early as the annual Conference on Retroviruses and Opportunistic Infections (CROI) in February. If the results are favorable, IPM plans to seek regulatory approval and licensure of the ring as soon as possible, says Rosenberg, adding that DPV would only be the start. There are many other ARVs and combinations of ARVs that could be delivered vaginally in this manner she says, mentioning integrase inhibitors, protease inhibitors, and the CCR5-inhibitor Maraviroc, among others.
The dapivirine ring is made of a flexible silicone material measuring 2 ¼ inches in diameter. It sits high up in the vagina. Rings have been used for hormonal contraception since 2001. But figuring out the correct concentration of drug to put in the ring for HIV prevention—enough to prevent HIV infection but at the same time minimizing systemic exposure—is a balancing act. Data presented last year at CROI by University of Pittsburgh researcher Beatrice Chen, study chair of the MTN-013/IPM 026 Phase I trial evaluating the safety, acceptability, and drug absorption qualities of a vaginal ring, found that a vaginal ring containing DPV blocked HIV infection of cervical tissue samples, but a ring containing the CCR5-inhibitor Maraviroc was not absorbed enough by vaginal tissues to be effective.
Because the bioavailability of DPV is higher in the vaginal compartment when delivered via a ring than when taken orally, less of the drug needs to be used to be effective, says Thesla Palanee-Phillips, Director of Clinical Trials at the Wits Reproductive Health and HIV Institute in Johannesburg, South Africa, and protocol co-chair of ASPIRE.
“Studies have shown that the ring can deliver high concentrations of active drug to vaginal tissue for a month or longer with only trace amounts of the drug being absorbed elsewhere in the body,” says Palanee-Phillips. “What this means is that when used as a vaginal microbicide for the inhibition of vaginal transmission of HIV-1, much lower doses of DPV may be used than those used for a systemic, therapeutic indication.”
Other modes of delivery
Vaginal rings are furthest along in the pipeline, but other delivery methods are also being developed. Another microbicide strategy involves delivering antibodies grown in tobacco plants using a vaginal film the size of a small Band-aid. This approach is now in early stage clinical testing in the US. The vaginal film, which contains the bNAb VRC01 and a second antibody that neutralizes HSV-1 and 2, is inserted manually into the vagina by the woman.
The trial will be conducted in multiple phases, beginning with a study involving single use of the films in eight women to monitor safety and the release of the antibodies in the vagina. In this phase, the film will be placed by the doctor. In the second phase, 15 women will insert a new vaginal film every day for seven days, while a control group of 15 women will insert a placebo film daily.
To develop this approach, Deborah Anderson, a professor of obstetrics/gynecology and microbiology at Boston University School of Medicine who is leading the program, is working with scientists from San Diego-based Mapp Biopharmaceuticals—the maker of the ZMAPP experimental antibody therapy used to treat Ebola infection during the latest outbreak—and Kentucky Bioprocessing, which uses tobacco plants to express human monoclonal antibodies, or “plantibodies” (see Cape Town Connections, IAVI Report, Vol. 18, No. 4). A previous study conducted in Europe tested the safety of vaginal use of a single HIV-specific “plantibody” in women and found no adverse side effects. Anderson says their program is the first one to use a formulated cocktail of antibodies. They are also considering adding more potent and broadly neutralizing HIV antibodies to the mix, including an anti-sperm antibody that could be used as a contraceptive. Anderson says the HIV-specific bNAbs being tested in the second generation version are ones that block both cell-associated and cell-free virus transmission.
Anderson’s collaborators at the Yerkes National Primate Center in Atlanta have also used a vaginal ring to release bNAbs in non-human primates. “The HIV antibodies were released at levels correlating with protection for over two weeks,” she said. “We’re hoping we can get one that releases in women out to a month, which will improve adherence.”
The field of rectal microbicides is also moving forward. Ian McGowan, a University of Pittsburgh professor of medicine who has been leading rectal microbicide trials at the MTN for years, says MSM are much less averse to using a rectal gel because the vast majority of them use lubricants anyway, making the product more acceptable. Some men have expressed concerns about having to use applicators to deliver the product, says McGowan. To put it bluntly, they would rather squeeze the gel on their fingers and apply it directly to the penis.
Whether this would deliver enough drug to the rectal mucosa is unknown, so the MTN has designed a microbicide study to find out. In the trial MSM will either insert the DPV gel into the rectum using an applicator or apply the gel with their finger. Samples of rectal tissue will be collected from volunteers to look for the presence of DPV and to see whether the rectal tissue can resist infection when the tissue biopsies are incubated with HIV in vitro.
The MTN has also completed a Phase II study of approximately 200 MSM and transgendered women in Peru, Thailand, South Africa, and the US that compared daily and peri-coital rectal use of a tenofovir gel with oral Truvada. Results are expected in 2016. McGowan said the group is still determining which product to test in a Phase III study. Whatever is decided the study design will be complicated by the success of oral PrEP. That’s because for ethical reasons, anyone entering an HIV prevention study in a country where PrEP is the standard of care must now be offered PrEP. “If [enrollees] use oral PrEP at the levels we want them to it becomes virtually impossible to develop another product,” says McGowan.
To determine the practicality of a Phase III rectal microbicide trial, MTN recently received approval to conduct a study involving MSM and transgendered women that will offer volunteers oral PrEP, but also randomize volunteers into a placebo-controlled study of a rectal gel containing an ARV, most likely DPV. “If everyone says, ‘great, thanks for the oral PrEP, love it, use it every day,’ that will answer one question about operational feasibility of a Phase III trial,” says McGowan.
Regardless of which vaginal or rectal microbicides move forward and in which settings, adherence will remain an issue. Investigators have already incorporated some of the lessons learned from previous studies and adopted new methods of screening and monitoring volunteers.
The ASPIRE study devised social engagements and group meetings to help the volunteers be more open about any difficulties they have using the ring. Other events either included or were exclusively for male partners. Researchers also monitored adherence more regularly to gauge how things were going as the trial progressed. “Without compromising the blinded, placebo-controlled nature of the study, blood samples and used rings were tested routinely for drug availability. These data were pooled according to trial sites as well as the study overall so that challenges with use could be addressed as they became apparent,” said Palanee-Phillips.
Meanwhile FHI 360, which led the FEM-PrEP trial and has been involved in microbicide research for over two decades, was just awarded funding from the US Agency for International Development (USAID) to advance microbicide introduction, including the development of a community health clinic model that encourages the consistent and safe use of microbicides. A central theme of the CHARISMA project—which will be led by RTI and carried out in five African countries—is to counter harmful gender norms that interfere with microbicide or oral PrEP use, including partner violence. The idea is to set up an environment where PrEP can be used without the “taint of stigma” attached to it. “We have a lot of work to do to understand that dynamic,” acknowledges Tim Mastro, director of Global Health, Population and Nutrition at FHI 360 and a longtime PrEP researcher.
FHI is leading a separate USAID-funded project called OPTIONS to develop a product delivery platform for current and future microbicide candidates as well as oral ARV-based HIV intervention.
“It is important that we continue to move forward,” says Mastro. “Science generates new evidence, which generates new questions. Look, the Pill came out nearly 60 years ago and we’re still looking for ways to improve contraception. We’ll be defining prevention options for decades to come so it is important to continue to make advances. There are still large issues related to adherence that need to be sorted out.”
Funds are tight
Money is another challenge. Like many global health programs, funding for microbicide research is constrained. A report released earlier this year by the HIV Vaccines & Microbicides Resource Tracking Working Group found that global investment in microbicide research and development declined by US$17 million last year, to $193 million, and has been declining since 2012. The National Institutes of Health, which accounts for about 59 percent of microbicide research spending, reduced its support last year by about $4 million, but the largest drop-off came from the Bill & Melinda Gates Foundation, which reduced funding from $19.2 million to $7.6 million.
Still other agencies stepped up their support. USAID boosted its support for microbicide and PrEP research significantly in recent years. Funding rose from $35 million in 2011 to $45 million in 2014, according to the HIV Vaccines & Microbicides Resource Tracking Working Group.
Future funding of microbicide research will likely hinge on the outcome of ASPIRE and The Ring Study. “If the dapivirine ring works, it opens up huge opportunities in product development, but if it doesn’t work we’ll need to find out why,” says Mitchell Warren, executive director of AVAC, the HIV prevention advocacy group based in New York City. “Perhaps we’ll find DPV was not the right drug or women just didn’t like the ring. It’s a remarkable but anxious time for those of us in advocacy.”
Sheryl Zwerski, director of the Prevention Sciences Program at the US National Institute of Allergy and Infectious Disease’s Division of AIDS, says interest in microbicide research has not been lost in the after-glow of oral PrEP or the push toward treatment as prevention. “Microbicides are still a very important and key strategy,” she said. “If you think about it, what may be taken up by a gay man in Harlem might not be the same as for a woman in South Africa. Our philosophy is to go and try and provide different strategies.”
McGowan concurred. “I really believe we need a prevention tool box,” he says. “Some people will embrace gels, some will embrace pills, and some will want long-acting injections, so we do need to strive for diversity in prevention options.”
Long-acting, injectable ARVs are another strategy being investigated for both treatment and prevention. These drugs persist in the body for far longer than daily formulations, suggesting they may be a potential solution to the adherence problem. But because they linger in the body longer, the pharmacokinetics of the drugs need to be sorted out as well.
GSK744 and rilpivirine are two compounds being studied as long-acting PrEP products. A recent study found that a monthly injection of GSK744 protected monkeys against repeat intra-vaginal challenge with a simian/human immunodeficiency virus hybrid over an 11-week period (Sci. Trans. Med. 7, 270, 2015). Clinical trials are now being conducted in HIV-infected men and women to determine the correct dosages of both GSK744 and rilpivirine before studying the drugs in efficacy trials.
Another HIV prevention tool that also shows promise is the passive administration of bNAbs—delivering antibodies directly into the body via injection to prevent infection. A Phase I safety trial now underway in HIV-uninfected men and women is assessing different doses of the bNAb VRC01.
The variety of ARV and antibody-based strategies demonstrates how far the field has come in developing new HIV prevention strategies. But it has also blurred the lines between microbicides and PrEP, and even vaccines which also aim to induce bNAbs. This complicates how funding is tracked and raises questions about how products shown to be effective should be marketed and explained to a lay public that may not understand all these distinctions.
Warren says the most important questions ought to be what are the active drugs being used and how are they being delivered. “People do get caught up on all of this, but personally, for me, I think of it all as PrEP,” Warren says.
Mary Rushton is a freelance writer based in Cambridge, Massachusetts.