HIV Field’s Current Contours Show in Boston
HIV prevention was the top story at CROI 2016, but issues of adherence and uptake still loom large in the battle to stop HIV’s spread.
By Michael Dumiak
Last summer more than 2,500 women across the sub-Saharan nations of Malawi, South Africa, Uganda, and Zimbabwe completed their participation in a three-year clinical trial of a monthly vagina
l ring containing an experimental antiretroviral (ARV) known as dapivirine (DPV). It was the larger of two simultaneous efficacy studies of vaginal rings as pre-exposure prophylaxis, or PrEP—the use of ARVs in healthy individuals to ward off HIV infection.
Researchers gathered for this year’s Conference on Retroviruses and Opportunistic Infections (CROI), held Feb. 21-26 in Boston, heard firsthand the results of these two efficacy studies. Overall, the rings were 27 percent to 31 percent effective in reducing the incidence of HIV infection in women ages 18 to 45. The broader implications of this and other HIV prevention strategies set the tone at this year’s CROI. Behavioral issues still loom large and researchers discussed how to reach younger, more vulnerable people with HIV prophylaxis, including daily oral PrEP, which so far shows much higher efficacy than the ring.
Meanwhile some of the newer ARVs in development may offer another option for both treating and preventing HIV infection.
Aspiring to protection
The DPV ring was tested simultaneously in two placebo-controlled efficacy trials: 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, is 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. The budget for each trial was approximately US$72 million.
DPV-containing vaginal ring development dates back to 2002 with the founding of IPM, which launched in order to develop antiretroviral-based microbicides for prophylaxis in mother-to-child transmission and to prevent sexual transmission between adults as well.
The ring is itself, which has been used for contraception, is essentially a silicone ‘o,’ which contains 25 milligrams of DPV, a non-nucleoside reverse transcriptase inhibitor never licensed for treatment. The ring is designed to slowly release drug over one month of use. IPM holds a global dapivirine license from Janssen R&D Ireland, one of the Janssen Pharmaceutical companies of Johnson & Johnson, which originally developed the drug as the independent biotechnology company Tibotec.
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 looked at more closely and 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. Among older women, 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. 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 women in the 18 to 21 age group. “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.
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. It would be a huge difference coming down from 8 percent to 4 percent.”
The ring has many supporters in the HIV community, many of whom expressed their support in Boston. But some there also questioned the ring’s very clearly reduced effectiveness in younger women and the overarching problem with adherence. Development of the ring itself comes directly from the effort to improve adherence—insert the ring and forget about it. But adherence is still an issue.
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.
Finding the best drug
One critique of the overall ring results is that the protective effect was lowest in the young, sexually active women who are at great risk of HIV infection. Another is that the existing alternative, oral PrEP with the drug Truvada (a combination of the ARVs tenofovir and emtricitabine), is between 92 and 99 percent effective in preventing HIV infection when used consistently. Some wonder what accounts for this gap in efficacy.
“I have some questions around the drug. Would we have seen a different result if it had been a tenofovir ring or another drug that once released stays in the genital tract a little bit longer?” McCormack asks. She is co-principal investigator of the Microbicides Development Program and was chief investigator for the PROUD trial, which studied the use of oral PrEP in men who have sex with men.
Dapivirine and tenofovir are very different drugs, McCormack says. Oral PrEP acts systemically, so it takes longer to get into genital tissues; a vaginal ring releases a smaller amount of drug locally so there are high levels in the genital tissues but lower drug levels elsewhere. It’s altogether hard to differentiate which is more effective, given all the behavioral factors affecting use.
“It is clear that oral tenofovir, when used daily, has a higher level of efficacy,” says Robin Shattock, an immunologist and mucosal infection expert at the Imperial College of London. “That’s really when you are taking it every day.” Still, Shattock, who is researching combination prevention approaches, including ARV-based gels or rings as well as the use of broadly neutralizing monoclonal antibodies, is optimistic about the dapivirine ring’s chances. “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 who 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. The funders—the Bill & Melinda Gates Foundation, UK’s Department for International Development, and other European nations—appear to support this plan.
Response to the ring results stands in marked contrast to the disappointment over the RV144 vaccine trials which showed that a combination of two vaccine candidates reduced HIV infection rates among volunteers by 31 percent. Shattock says the overall gloomy reaction to the RV144 trial and the apparent enthusiasm for the DPV ring, despite similar overall efficacy rates, is due to the science.
“It’s an important first step and there are some obvious steps to take to improve it,” Shattock says of the ring. There are many other possible drugs that can be explored, and most importantly, researchers understand how they work. Human behavior is more complicated, but the science is not such a hard issue as it is with vaccines. “The contrast with the Thai trial is that to this day I don’t think anyone really understands what the mechanistic correlates are,” Shattock says. “You have lots of immune correlates that reduce risk of infection, but we don’t know the mechanism. So to know where to go next takes guesswork.”
| A coda for Ebola |
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For the better part of 18 months, the world’s largest Ebola outbreak to date raged through the western African nations of Liberia, Sierra Leone, and Guinea. It devastated villages and families, set the world on edge, and prompted a desperate global health response, heroic in the moment and in some cases criticized afterward for being sluggish. During all this, three vaccine candidates emerged into public view and went through quickly organized clinical trials. Safety and efficacy data emerged last fall (see When Ebola Returns, Will the World be Ready?, IAVI Report, Issue 4, 2015) and the trials continue to yield valuable information, as presented in February at the Conference on Retroviruses and Opportunistic Infections (CROI). Researchers shared Phase II clinical trials results for the two leading vaccine candidates tested during the 2014-2016 outbreak. The first, a vesicular stomatitis virus-vectored replication-competent vaccine (rVSV-ZEBOV) from Merck and the Public Health Agency of Canada, was tested in Guinea and Sierra Leone. The other was a chimpanzee adenovirus-vectored DNA vaccine (ChAd3-EBO-Z) from GlaxoSmithKline and the National Institutes of Health, which was tested in Liberia. Also discussed at CROI was the Ebola treatment ZMapp, a triple monoclonal antibody cocktail tested in all three nations. The Merck and GSK candidates came under the collaborative umbrella representing dozens of international and local agencies in what’s called PREVAIL: PREVAIL I is the effort covering the two vaccine candidates, PREVAIL II covered the ZMapp treatment effort, and PREVAIL III is an ongoing effort to gauge Ebola’s longer-term impact on survivors of the virus. Fatorma Bolay, director of the Liberian Institute for Biomedical Research, pointed out that both vaccine candidates are well tolerated and immunogenic, as has been reported previously. But further analysis of the data is now bringing other aspects into focus: for instance, the trial shows that six percent of volunteers entered the study with detectable levels of Ebola antibodies, suggesting they had been infected with the virus before but had no known history of the disease. The candidates also |
seemed to induce antibodies at different rates. The ChAd3 candidate produced immune responses in week one in 13 percent of volunteers, the VSV in nine percent, and the placebo in six percent. But by the end of one month, 87 percent of ChAd3-vaccinated individuals developed an antibody response, while 94 percent of VSV-vaccinated individuals did, and only seven percent of placebo recipients had Ebola antibodies. Meanwhile three studies of thousands of Ebola survivors are ongoing. Early data from these efforts provide evidence for a possible syndrome that develops in Ebola survivors, signs that Ebola can cause unrecognized and asymptomatic infection, and growing confirmation of the potential of Ebola to be transmitted through sexual transmission. “There are still many gaps in our knowledge of Ebola,” says Gene Richardson, a Stanford field researcher. Bolay and Mosoka Fallah, of the Liberian health ministry, also reported that in the PREVAIL vaccine volunteer group totaling 1,500, 5.2 percent were HIV infected, which is unexpectedly high, according to the National Institute of Allergy and Infectious Diseases. The reported HIV incidence rate in the country overall is 1.9 percent, according to Bolay. This raises questions about whether the incidence is just much higher among younger people or if the estimated incidence doesn’t reflect the actual size of the HIV epidemic in these west African countries. —M.D.Getting word out on PrEP
Given the imprimatur of top health officials and its well-established efficacy, one would think oral PrEP would be a settled issue. But getting at-risk individuals to actually use it is very much a work in progress.
Gilead first launched Truvada for the treatment of HIV-infected adults in the US in August 2004. Based on results from the iPrEx and Partners PrEP clinical trials testing the drug for HIV prevention, the US Food and Drug Administration approved Truvada in 2012 as the first oral PrEP drug. That same year the World Health Organization recommended daily oral PrEP use for serodiscordant couples and also noted the scientific consensus emerging that PrEP reduces the risk of sexual acquisition and transmission of HIV regardless of population or setting. The institution later recommended oral PrEP for all high-risk individuals.
Since then, however, uptake is slower than expected. By the summer of 2014, Johns Hopkins University HIV epidemiologist Chris Beyrer was telling the Guardian that Truvada, to that point, was a “boutique intervention.” This was partly due to cost in the US, where it carried a price tag of between $8,000 and $14,000 a year, although Gilead was offering subsidies for those without private insurance. Daily adherence was also being seen as an impediment. These factors were at play especially in minority and poor communities.
The US Centers for Disease Control and Prevention (CDC) estimates 185,000 new HIV infections in the US could be prevented by expanding testing, treatment, and, notably, oral PrEP.
In Chicago and London, efforts are underway to address the lag in PrEP uptake. Chicago’s PrEP effort, as outlined by Jim Pickett of the AIDS Foundation Chicago, involves a social and promotional campaign launched in February. Pickett and Chicago health officials were able to enlist volunteer help from a global advertising agency to create a professionally-designed, data-driven marketing, social media, and publicity campaign for PrEP in Chicago.
Pickett says that in 2015 the number of new HIV infections reported in Chicago dipped under 1,000 for the first time since the epidemic began, with 973 new cases occurring in 2014. That’s about half of the peak number reported in 2001. But there are disparities: half of new cases are among black people, and of the women who do contract the virus, most of them are black. Three of four new infections are among gay or bisexual men in Chicago; half of this number are black men and another 25 percent are latino.
A CDC study shows 77 percent awareness of oral PrEP in Chicago, but further surveying shows of those aware, only 14 percent had obtained subscriptions. Of those surveyed who were aware of PrEP but did not have a prescription, half reported having unprotected anal intercourse. “We’re missing the boat,” Pickett says. For his crew in Chicago, time will tell how effective PrEP marketing can be. A second wave of the campaign launches this summer.
Elsewhere, researchers, clinicians, and advocates are also beginning to think about how to incorporate oral PrEP in order to reduce incidence of HIV among the subgroups of individuals at highest risk of infection. In the last decade HIV infections have risen across Europe by 33 percent among men who have sex with men, while falling 61 percent among heterosexuals from countries with generalized HIV epidemics and declining by 36 percent among those injecting drugs. In Europe there’s a new urgency for early diagnosis of HIV and other sexually transmitted infections. Since McCormack and her colleagues reported in 2015 on the PROUD study showing up to 85 percent effectiveness for Truvada, some 6,000 new HIV infections have been diagnosed in the UK. “Over half of them have been seen previously in the clinic and could have been offered PrEP,” McCormack said during her CROI presentation. “PrEP has to be part of the vision for the future.”
McCormack says a small clinic on Dean Street in the Soho neighborhood of London called Dean Street Express, which offers faster, more self-directed testing for HIV and other sexually transmitted infections, may be a natural place to promote PrEP. Dean Street Express neither looks nor feels like a clinic. An aid sets up a client with swabs. The client goes into the screening room, where a digital presentation on the mirror explains how to do the testing. The samples go into a container, which goes into a pneumatic tube. Test results are delivered in six hours by text message.
The UK National Health Service (NHS) is in the process of considering Truvada for listing, which would make PrEP free for UK residents. It is becoming a heated debate, though.
Cutting half life in half
Another realm of prevention research discussed at CROI centers on the hundreds of broadly neutralizing antibodies (bNAbs) researchers have isolated from HIV-infected individuals in recent years. These antibodies, which can effectively neutralize a broad swath of HIV isolates, 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’ Vaccine Research Center, want to determine whether directly injecting these antibodies into people may be able to block HIV infection, an approach referred to as passive administration. To optimize the antibodies for this purpose, researchers are attempting to improve the potency and half-life of these antibodies so that less antibody is necessary and it stays around for a longer time. “The consideration for using the antibodies for prevention has been that we may be able to test them on an interval of about every two months,” Mascola said.
Two antibodies targeting the CD4 binding site (VRC01 and 3BNC117) are already in Phase I passive administration studies. Michel Nussenzweig and colleagues at Rockefeller University have started Phase I studies with the antibody 10-1074; Mascola expects studies with PGT121 to begin within the next year. These two antibodies target different vulnerability sites on the virus. Other antibodies, including PGDM1400, CAP256-VRC26, and 10e8, will probably take a year to 18 months to get into the clinic. Within the next couple years, Mascola says, antibodies targeting four major sites on the virus are likely to be in passive-administration studies.
He reported that in Phase I trials VRC01 lingered at titers of up to 10 micrograms per ml in serum for about two months. The question now is whether that concentration of antibody is sufficient to prevent HIV infection. A Phase IIb study, the Antibody-Mediated Prevention (AMP) Study, opened enrollment this month under the umbrella of both the HIV Prevention and Vaccine Trial Networks. “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 VRC01 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. The aim is to associate the level of antibody in a volunteer’s plasma with the level of protection and therefore define the optimum dosage.
“If that level turns out to be fairly reasonable, a therapeutic range that we might expect, it translates into the possibility of giving an antibody subcutaneously,” Mascola says. Muscle itself could, potentially, be lured into secreting antibody for weeks or months at a time, providing medium-to-long-term protection. “Knowledge of protection in a human setting would tell us something about neutralizing antibody levels and what a vaccine might need to elicit in order to protect.”
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, that a single shot could potentially deliver long-term protection, and that clinical efficacy would propel this approach into mainstream use. 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 given subcutaneously every three to four months. These elements, Mascola says, are already achievable in the lab. The bNAb N6 neutralizes more broadly than VRC01, only missing three percent of viruses as opposed to VRC01’s 13 percent, and is much more potent. Other antibodies can be engineered in order to boost their potency, and combining antibodies, at least in the lab, shows it is possible to gain 100 percent coverage and account for the diversity of HIV.
There is also reason to be optimistic about efforts to improve the half-life of the antibodies. Mascola uses an example from AstraZeneca subsidiary Medimmune, which is investigating a monoclonal antibody called motavizumab (the company had pursued it for respiratory syncytial virus infection unsuccessfully, but continues to work with it). A 2012 trial of mutated motavizumab, motavizumab-YTE, extended the half-life of the antibody for up to six months at 10 micrograms per ml of serum. “That’s a remarkable feature one would hope to take advantage of for prevention studies,” he says.
The VRC scientists introduced mutations into VRC01 to improve its half-life and are now testing the modified antibody in a Phase I trial. “We will know soon if we can take the half-life from about two months of therapeutic range out to four, five, or six months.”
| Complex and persistent |
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Each HIV particle may be alike, but Melbourne immunologist Sharon Lewin’s coming to conclude that every HIV infection persists in its own way. “We’re hearing a lot more about the complexity of how and where HIV persists,” Lewin says, sitting for a minute in one of the huge halls of the John Hynes Convention Center at the recently held Conference on Retroviruses and Opportunistic Infections (CROI). “The initial dogma was that there was a long-lived resting pool of cells where HIV persisted indefinitely. We’re seeing now that there’s no one way that HIV persists. It probably persists differently in different immune cells in tissue and blood.” This is the central question for those pursuing an HIV cure: in order to rid a person of HIV, researchers need to understand exactly how the virus gets into specific cells, why it stays there, and how to flush it out. They’ll need to flush it out because all indications are that if antiretroviral treatment stops, it’s only a matter of time before this latent reservoir of HIV-infected cells causes viral rebound. “There’s not one flavor of latency. We’re trying to dig it out: in naïve T-cells, T-follicular helper cells, in proliferating T-cells. They all look very different,” Lewin says. Her lab at the University of Melbourne is able to mimic, in vivo, what she says is one of the latest wrinkles in persistence. Emory’s Nitasha Kumar, a researcher formerly in Lewin’s group, presented results at CROI demonstrating that latency can be established in non-proliferating and proliferating cells. Lewin says the implication is that virus persists not just in non-dividing cells, but also in cells that can proliferate. The virally infected proliferating T-cells divide, and make new infected T-cells. “The virus is intact, yet it doesn’t destroy the cell, which challenges a long held dogma in the field,” Lewin says. Many researchers believed if a virus was intact, then proliferation would activate the virus and therefore kill the cell. As it turns out, Lewin says, it appears that latency can be established in proliferating cells in vitro and that these cells are long lived. So if researchers are only looking for latency in long-lived resting cells, they may be missing another reservoir of the virus. —M.D. |
Long-lasting inhibition
Extending the half-life of ARVs also looks more promising. Jay Grobler, director of infectious disease biology at pharmaceutical company Merck, presented data at CROI on a long-acting, experimental nucleoside reverse transcriptase inhibitor 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 prophylaxis.
Grobler reported results from Phase I pharmacokinetic studies of MK-8591, which he says showed the drug had an even greater intracellular persistence and antiviral activity than was observed in in vitro studies and in rhesus macaques. Following a single oral 50 milligram-per-kilogram dose, Merck researchers saw a very rapid uptake of the molecule, with high concentrations reached in blood within an hour. Concentrations stayed over 10 micrograms per ml for more than a week; the absorbed drug has a half-life in monkeys of more than 50 hours.
In the Phase I dosing study, volunteers received varying doses of MK-8591 (10, 30, and 100 milligrams) once a week for three weeks. “At that 10-milligram dose we’ve already exceeded the target drug concentration with the SIV monkey model,” he says. “One week after dosing, the trough concentrations exceeds that target twofold.” Doses of up to 400 mg were well tolerated.
Merck considers the molecule ideal 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. Either way, this type of treatment would greatly reduce the burden of therapy. As prophylaxis, it could potentially eliminate the reliance on behavior, which has proven problematic even with the monthly rings.
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 the ARVs cabotegravir, an integrase inhibitor, with rilpivirine, a non-nucleoside reverse transcriptase inhibitor. Both were developed as once-daily pills. But in the LATTE program (Lancet Inf. Dis. 10, 1145-55, 2015), for which Margolis in Boston presented the second round of study results, 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 cabotegravir and rilpivirine daily.
The trial volunteers had suppressed viral loads of less than 50 copies per ml prior to the injection of the ARVs. Maintenance of virologic success was steady over 32 weeks, Margolis said: by the end of the study, 95 percent of those receiving injections every eight weeks, 94 percent of those getting shots every four weeks, and 91 percent of those on oral dosing met virological success, which was an undetectable viral load under 50 copies per ml of blood. Volunteer satisfaction was higher for the injection than the oral dosing: 90 versus 71 percent reported satisfaction. The next step, Margolis says, is a 48-week dose-selection for upcoming Phase III trials.
The long-acting cabotegravir/rilpivirine 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. “The CROI data confirm what most of us expected to see with these regimens. This is an important, but not a particularly new story,” he says. MK-8591, however, could be in Deeks’ view 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. “In contrast to the cabotegravir-related data at CROI, this data was a complete surprise and quite novel. I find it amazing that 10 mg of a drug could have such a potent and sustained effect.”
Michael Dumiak reports on global science, technology, and public health and is based in Berlin.
ecently formed non-profit venture is focused on rational design of vaccines against a variety of challenging pathogens.
accine design efforts today. Koff is responsible for driving IAVI’s Protocol studies, which helped researchers gain a better understanding of HIV disease among African cohorts as well as the immune responses that develop in response to infection, and also allowed researchers to identify the types of bNAbs that researchers surmised would be vital to vaccine-induced protection. During one of the Protocol studies, researchers collected samples from thousands of HIV-infected volunteers in Africa, India, Australia, Thailand, the UK, and the US. These samples are proving to be a treasure trove for vaccine researchers. In partnership with biotech companies, IAVI and its partners in the NAC were able to isolate dozens of very potent and broadly neutralizing antibodies from these samples. Identification of these antibodies then led to identification of multiple targets on the virus that were not identified previously. Burton calls the collection of these samples “absolutely crucial to the vaccine field.” The antibodies isolated from these volunteers and the viral epitopes they target, are now the basis of much of the HIV vaccine design and development efforts taking place in labs around the world (see image at right). “The knowledge that has been gained on the HIV Envelope on the molecular level and the knowledge that has been gained with the antibodies is like an inflection point in the field,” says Koff. “We know so much more now.”
marily through increasing dialogue and facilitating collaborations among the major players in the field. The Enterprise doesn’t fund research, sponsor trials, or develop candidates, rather it troubleshoots issues and provides forums for the field to reach consensus on critical issues. The Enterprise’s Timely Topics in HIV Vaccine Research, launched in 2012, regularly convenes expert panels to analyze and respond to unresolved questions that encroach upon vaccine development. The series kicked off with a session on the ethics of pediatric clinical trials (Science 300, 2036, 2003). Another recent topic was therapeutic vaccines, which figure prominently in the emerging field of HIV cure research. Lately, innovation and product development issues are at the forefront. A boot camp held last year by the Enterprise for vaccine researchers and product development experts looked at different ways to incorporate a more industrial-like approach in the vaccine discovery process (see In Brief, IAVI Report, Vol. 19, No. 4).
But the Enterprise found its footing with Snow, a self-proclaimed gadfly with enormous credibility in the field. Snow’s passion for ending the epidemic is matched only by his willingness to ask tough questions without apology. Though not a scientist, his roots in AIDS vaccine research run deeper than many. In what he calls a “personal journey,” Snow’s involvement in the famous activist group ACT-UP and with community advisory boards for clinical trials led him to co-found AVAC in 1995. He also sits on the AIDS Vaccine Research Subcommittee of the US National Institute of Allergy and Infectious Diseases (NIAID), and the US National Institutes of Health’s (NIH) Vaccine Research Center Scientific Advisory Working Group. Snow also served on the Enterprise’s original council and as treasurer of its board when it received its first round of funding.