Wringing out HIV
Results from efficacy studies of a new approach to HIV prevention were the biggest news to emerge from this year’s Conference on Retroviruses and Opportunistic Infections.
By Michael Dumiak
Last summer more than 2,500 women from Malawi, South Africa, Uganda, and Zimbabwe completed their participation in a three-year clinical trial designed to show whether a vaginal ring—a silicone ‘o’ containing an experimental antiretroviral (ARV) that is inserted into the vagina—could reduce a woman’s risk of contracting HIV. This was the larger of two simultaneous efficacy studies to determine whether this approach to pre-exposure prophylaxis (PrEP), the use of ARVs in healthy individuals to ward off HIV infection, would work.
Results from these two studies were presented recently at the Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, one of the largest annual meetings of HIV scientists and clinicians. The results show that a vaginal ring containing an ARV known as dapivirine (DPV) does prevent women from acquiring HIV, but how well it works depends on how compliant the volunteers were and this varied greatly by age in both studies.
Overall, behavioral issues related to PrEP loom large and they were a major topic of discussion at CROI. Other approaches that aim to circumvent adherence issues also received top billing, including studies involving direct injection of anti-HIV proteins known as broadly neutralizing antibodies as a means of HIV prevention and the development of long-lasting ARVs that may be applicable for both treatment and prevention of HIV infection.
Aspiring to protection
The two efficacy trials of the DPV-containing vaginal rings were: A Study to Prevent Infection with a Ring for Extended Use, or ASPIRE trial (MTN-020), and what’s called The Ring Study. ASPIRE, led by the National Institutes of Health (NIH)-funded Microbicide Trials Network, was the larger trial with 2,629 volunteers enrolled at 15 study sites: nine in South Africa, three in Zimbabwe, two in Malawi, and one in Uganda. This trial took place from August 2012 to June of 2015. The Ring Study was led by the International Partnership for Microbicides (IPM) and involved 1,959 women volunteers in South Africa and Uganda.
DPV-containing vaginal ring development dates back to 2002 with the founding of IPM, which holds the global license for DPV. The experimental ARV was never licensed for HIV treatment. Volunteers in both trials were counseled to use the ring continuously and return each month for collection of the spent device, to obtain a fresh one, to be tested for pregnancy, HIV, and other sexually transmitted diseases, and to receive HIV prevention and risk-reduction counseling. Follow-up was for a minimum of one year.
Results from ASPIRE and The Ring Study differed only slightly in their overall protection rates, with ASPIRE showing an overall 27 percent reduction in HIV infection and The Ring Study showing a reduction of 31 percent. But the trials showed vastly differing rates of protection when analyzed by age. In ASPIRE, women aged 18 to 21 showed no overall reduction in HIV risk, whereas in The Ring Study it was only 15 percent. However, there was a 56 percent reduction in risk for women ages 22 to 26, and a 51 percent reduction among women ages 27 to 45 in the ASPIRE trial. The Ring Study showed 37 percent efficacy in women older than 21.
The main reason the protective effect varied so greatly was adherence. Adherence was significantly lower among younger women who happen to be at the highest risk of contracting HIV. “We really wanted those numbers to be higher. We were disappointed, too, originally,” says Annlene Nel, IPM’s Paarl, South Africa-based chief medical officer. Even so, the researchers behind the studies say the results are compelling enough to pursue licensure of the DPV ring for HIV prevention in women.
To receive regulatory approval, the group needed two pivotal trials showing statistically significant efficacy. “We’ve got that,” says Nel. “It is modest efficacy. We know that, very much so. But look at the burden of disease in the communities where we are conducting this trial. It is significant. If you can prevent a third of women from contracting HIV, over 10 years you prevent thousands of women from becoming HIV positive. Long term you can really change the incidence.”
Development of the ring itself comes directly from the effort to improve adherence—insert the ring and forget about it, as opposed to oral PrEP, which requires women take a pill on a daily basis. But adherence is still an issue with the ring.
Nel and other researchers suspect non-adherence had to do with volunteers being leery about the safety and efficacy of the product. “There may also be rumors in the community. A negative influence really spreads. And when there’s a change of partner, there’s a fear component where they will not disclose and then they might just remove the ring.”
Sheena McCormack, a clinical epidemiologist at the Medical Research Council Clinical Trials Unit at the University College of London, says the rings are a new beast altogether, and there are issues around vaginal practices that may influence their use. “Women do like to wash after sex. It’s possible they take the ring out to do that. It might be something that doesn’t fit with their culture, doing that with the ring in,” she says.
But even though adherence remains an issue, many researchers are optimistic about the DPV ring as an additional HIV prevention option for women. Robin Shattock is an immunologist and mucosal infection expert at the Imperial College of London who is researching combination prevention approaches. This includes ARV-based gels or rings as well as the use of broadly neutralizing monoclonal antibodies. He suggests there are some things that may help improve upon the results of the two ring trials. “When the ring was being designed, they could have put more drug into the ring. I think more drug probably would have given higher efficacy in women that used it,” he says. “That can be improved.”
A combination of drugs may also provide better protection. Shattock says combining the ring with a contraceptive, as IPM plans to do, would be a no-brainer. “Women may then be using it for the convenience of contraception, and to have a contraceptive ring that also provides some level of protection against HIV may be more appealing than thinking, ‘I’m at risk and need to have something that will stop me from getting HIV.’” For any of the PrEP regimens, adherence is the key to efficacy. “For these things to work, people need to use them,” Shattock says.
Bruce Walker, an immunologist and director of the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology (MIT), and Harvard, says tools need to be independent of behavior. “We need things that are going to work in women at the most vulnerable periods of their lives. The fact the ring didn’t really work in women before age 25 is a disappointing finding. I’m less optimistic about that being part of a solution for HIV infection,” he says. “The more you can take behavior out of the equation, the more successful these interventions are going to be.”
Three of the 15 clinics in the ASPIRE trial were located in Zimbabwe, serving 678 of the study volunteers. Nyaradzo Mgodi of the University of Zimbabwe served as clinical researcher directing the study. “In Zimbabwe we have a saying, home is a woman. We want to take care of women because this is how you make steps in promoting public health. I’m happy about the results,” Mgodi says.
She thinks that in Zimbabwe a ring has a better shot of being used, even given the adherence questions. “Most young women in Zimbabwe are unemployed. Some of them have secondary education. They are homemakers, they take care of their family and extended family,” Mgodi says. “Any day they may be asked to go to rural areas to look after a sick relative, or attend a funeral, or go to a church conference.” Mgodi recalls the VOICE trial that tested oral PrEP in sub-Saharan Africa. “The volunteers used to say they would forget sometimes to take their tablets. They want something which is less user-dependent, so I think this will be good.”
IPM is pushing ahead with an open-label, follow-on study of Ring Study volunteers, and is also in discussions for a similar open-label study for ASPIRE participants. Open-label studies may positively influence adherence, according to the University of Washington’s Jared Baeten, who led the ASPIRE study. Baeten says what is important now is to understand who are the populations that would use a pill, and who are the populations that would not use a pill but might use a ring. Meanwhile, the group is compiling data for a submission dossier which, if things go as planned, should be delivered to the European Medical Association and regional southern African regulators either by the end of this year or in the first quarter of 2017.
Researchers to antibodies: Stick around
Another realm of prevention research discussed at CROI centers on the hundreds of anti-HIV proteins or antibodies researchers have isolated in resent years. These antibodies are capable of knocking out a broad swath of HIV strains circulating around the globe, earning them the moniker of broadly neutralizing antibodies (bNAbs). These antibodies are the types that vaccine researchers ideally wish to induce through immunization.
In the meantime, researchers including John Mascola, director of the National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center, want to determine whether directly injecting these antibodies into people may be able to protect them from HIV infection, an approach referred to as passive administration. To optimize the antibodies for this purpose, researchers are attempting to improve their potency and staying power so that less antibody is necessary to protect and it sticks around for a longer time.
Within the next couple years, Mascola says, antibodies targeting four major sites on the virus are likely to be in passive-administration studies. The question now is what amount of antibody is sufficient to prevent HIV infection. To determine this, researchers are now enrolling volunteers in a Phase IIb study, known as the Antibody-Mediated Prevention (AMP) Study. “Can a passively infused antibody prevent HIV in humans?” Mascola asked. “That’s what needs to be studied and answered.” AMP will be a placebo-controlled study of an antibody identified by NIAD researchers. The antibody, known as VRC01, will be administered every two months in 2,700 men who have sex with men and transgendered people in North and South America, and 1,500 women in sub-Saharan Africa.
Mascola says there are many reasons to pursue passive administration: there’s a reasonable chance it will work; that because the antibodies are human antibodies they are likely to be well-tolerated; and that a single shot could potentially deliver long-term protection against HIV, reducing some of the reliance on adherence that is required for oral PrEP or even the vaginal rings. The ultimate goal, he says, is a sub-cutaneous injectable antibody that could be given every three to four months and safely and effectively protect high-risk individuals from HIV infection. “That’s where the field is trying to go,” Mascola says.
To do so, any eventual product needs to meet specific targets: it will need to cover 98 to 99 percent of all HIV strains, which may require a combination of bNAbs, cost about as much as ARV-based PrEP, and be injectable every three to four months. These elements, Mascola says, are already achievable in the lab.
Another long-lasting approach to HIV treatment and prevention involves a new generation of incredibly durable ARVs. Jay Grobler, director of infectious disease biology at pharmaceutical company Merck, presented data at CROI on a long-acting, experimental drug known as MK-8591, which the company licensed from Japanese company Yamasa. Grobler said the drug has the potential for once-weekly oral administration as well as much longer-acting parenteral administration that could persist for up to a year. The drug is being explored for both HIV treatment and prevention.
Grobler reported results from Phase I studies of MK-8591, which he says showed the drug persisted even longer and had better antiviral activity in humans than in either laboratory studies or animal experiments. Following a single oral dose, Merck researchers saw a very rapid uptake of the drug, with high concentrations reached in blood within an hour.
Merck considers the drug an ideal candidate for low-dose parenteral formulations, either by injection or patch, which release effective drug levels for up to 180 days. There is potential for the long-acting ARV to even provide coverage for up to a year’s time. This would greatly reduce the burden of therapy.
David Margolis, director of drug development at ViiV, the HIV joint venture between GlaxoSmithKline and Pfizer, has been overseeing another long-acting HIV therapeutic—in this case, combining two licensed ARVs (cabotegravir and rilpivirine) that were developed as once-daily pills. In the LATTE program, for which Margolis presented the second round of study results at CROI, researchers are testing the combination as an injectable, long-acting HIV treatment.
LATTE 2, a 32-week study aimed at establishing safety and efficacy of the combination and to set a dosing schedule for future trials, involved 286 volunteers randomized to receive gluteal shots of the ARVs either every four weeks or every eight weeks. A third group took oral doses of the two drugs daily.
Volunteers with the highest level of virologic success were in the group that received shots every eight weeks (95% as compared to 91% in the daily oral dosing group). Volunteer satisfaction was also higher for the injection than the oral dosing. The next step, Margolis says, is a 48-week dose-selection for upcoming Phase III trials.
The long-acting ARV combination outlined by Margolis could be a “game changer” for treatment and prevention once implemented, according to Steve Deeks, a clinician at the University of California at San Francisco who specializes in HIV inflammation. However, in Deeks’ view the data with MK-8591 could be an even more exciting approach to treatment and prevention. “It is potent and can be formulated for very long-acting delivery methods, due to the limited amount of drug needed to block HIV,” the San Francisco clinician says. “This data was a complete surprise and quite novel.”
Michael Dumiak reports on global science, technology, and public health and is based in Berlin.
This article is based on a full report from CROI, which appeared in IAVI Report, Volume 20, Issue 1.