header-backissues

 

In Brief

Spending Increases for HIV Vaccine Research, But Concern Rife for Future

In a tumultuous and conflict-ridden year when scientists have felt fraught enough to take to the streets and demonstrate, overall funding for a preventive HIV vaccine actually increased slightly over previous years, bringing it to the highest level in a decade according to the Resource Tracking for HIV Prevention Research and Development Working Group (RTWG).

Even so, the overall budget picture for HIV-related research and development is mixed. Global funding levels show signs of weakness with overall HIV prevention research and development investment dropping slightly from the year before, continuing a slow but steady downward trend. Major figures in the HIV research community, both in research and in policy roles, are expressing doubt and concern about future resources. Meanwhile, in Washington the White House moved to try and slash the budget for the US National Institutes of Health (NIH), the largest single source of HIV-related research funding, stirring opposition in the US Congress and setting up what will be a hard fight over the US federal budget in the coming weeks.

Worry about where future resources will come from furrowed many brows in Paris earlier this summer at the 9th International AIDS Society’s Conference on HIV Science (IAS 2017; see Decisive Moments in Wake of Paris). “There’s still a funding shortfall,” says Marijke Wijnroks, interim director of the Global Fund to Fight AIDS, Tuberculosis and Malaria. “If we are serious about ending AIDS as a public health threat, we should be able to make the funding available to do it.”

Since 2004, the RTWG has tracked trends in research and development investment for biomedical HIV prevention options, with the global advocacy group AVAC leading a group secretariat that includes IAVI and the Joint United Nations Programme on HIV/AIDS (UNAIDS).

The total funding for preventive HIV vaccines in 2016 came in at US$894 million, up from $859 million the year before. This was the largest gross investment since 2007’s $961 million, the summer before the last global financial crisis hit. This year’s boost in vaccine funding came mostly at the hands of the NIH, which invested at its highest level since 2000. This increase, according to the RTWG report, was due to the agency’s support for the first HIV vaccine efficacy trial to begin in a decade—the HVTN 702 Phase III study in South Africa testing a modified version of the vaccine regimen that was tested in Thailand and showed a modest 31 percent efficacy.

Even as the funding for HIV vaccine R&D climbed by $34 million overall, public sector investment from European sources was the lowest since 2001, at $38.5 million. About $11 million of that is committed to two five-year programs aiming to test early stage vaccine candidates.

Overall investment in HIV prevention research and development efforts seem to be slowing, according to the RTWG report: funding fell to $1.17 billion, down $35 million from the year before. Other reports surfacing over the summer covering HIV efforts also painAntibody bluegreent a mixed picture. Funding levels from donor governments that provide bilateral programs and contributions for low- and middle-income countries to the Global Fund fell to $7.5 billion in 2015 from $8.6 billion in 2014, marking the first decrease in five years, according to a report from the Kaiser Family Foundation (KFF) and UNAIDS. Figures for 2016 are at $7 billion. “Donor government funding for HIV continues to be on the decline,” KFF Vice President Jen Kates, director of Global Health and HIV Policy, said in a statement as the report came out. “Recent proposed cuts from the US, amidst other competing demands on donor budgets, will likely contribute to an ongoing climate of uncertainty around funding for HIV going forward.”

The alarm caused by US President Donald Trump’s original proposal for drastic decreases in the NIH budget were tempered over recent weeks as legislators made it clear they will resist deep retrenchment for the institute and other public health outlays. While administration officials called for a $5.8 billion to $7.5 billion cut in NIH funding, US Senate appropriations call instead for a $2 billion overall increase for the NIH, with increased contributions for Gavi, the Vaccine Alliance, PEPFAR, and the Global Fund. These numbers will fluctuate as the budget is hammered out, but for now the proposed cuts appear to lack congressional support.

Concerns remain, however, over sustained investment in HIV treatment and prevention programs and in the R&D needed to reach what for many is the ultimate goal, to bring the epidemic to an end. Not only are two clinical trials for HIV vaccine candidates progressing to advanced stages, there are long-acting antiretrovirals under study, a vaginal ring employing the antiretroviral dapivirine is under review by the European Medicines Agency, daily oral PrEP (pre-exposure prophylaxis) delivery is becoming more commonplace, investment in HIV cure research climbed in 2016 by $60 million, and more than half of the world’s 36 million people living with HIV are on regular antiretroviral treatment. That last figure alone marks a startling jump from 15 years ago, says Michel Sidibé, executive director of UNAIDS, when the World Health Organization’s “3X5” initiative—which aimed to get three million people living with HIV on antiretroviral treatment by 2005—seemed like a moon shot and, indeed, did not meet its goal on time. At the Paris conference health officials from Swaziland, once a place with the highest HIV prevalence in the world, were able to show that ramped-up treatment, testing, and adult male circumcision brought incidence down by 44 percent and that two-thirds of the country’s infected population has fully suppressed virus.

All of this, leaders in the field say, points to the need for sustained investment. “Any cuts—any cuts—to funding jeopardizes our results,” Sidibé declared to a crowded room in Paris. “We are breaking the backbone of this epidemic. It is a moment we should never, never let go. It is a moment for winning. It is not a moment for losing.” —Michael Dumiak

Michael Dumiak reports on global science, public health and technology and is based in Berlin.

 

 

Longer-acting HIV Prevention Methods: Take Two Antibodies and Call Me in Six Months?

“An ounce of prevention is worth a pound of cure,” so Benjamin Franklin once said. Weighing the benefits of prevention in HIV suggests a few more ounces are needed. There are several ways to effectively protect against HIV infection: condoms, voluntary adult male circumcision, and daily oral pre-exposure prophylaxis (PrEP)—which entails giving antiretrovirals (ARV) to healthy, uninfected individuals. But what all of these methods except circumcision have in common is that they require the user to do exactly that, use them. And to do so consistently. This, researchers recognize, is not always what happens, even in clinical trials when volunteers receive frequent reminders about adherence and its importance. Demonstration studies of oral PrEP and clinical trials of an ARV-containing vaginal ring show that compliance is imperfect for a variety of reasons. Some individuals are reluctant to even begin using oral PrEP because it demands daily use to be effective (see PrEParing to Prevent HIV).

This is why researchers are focusing on developing longer-acting HIV prevention strategies, a topic discussed at a day-long meeting at The New York Academy of Sciences (NYAS) on September 22, just after the close of the United Nations General Assembly. While a vaccine that provides durable, high-level protection would be the ultimate long-acting HIV prevention modality, other strategies have the advantage of being closer to fruition. “Long-acting anti-HIV prophylactic agents are critical tools in our fight against the epidemic, and that must be developed within the next decade,” says Emilio Emini, director of the HIV program at the Bill & Melinda Gates Foundation (BMGF), which co-presented the NYAS meeting.

Funders, advocates, and scientists who gathered at the NYAS meeting discussed the various prevention strategies under study, including long-acting ARVs for oral PrEP, vaginal rings containing ARVs, implantable devices capable of releasing ARVs or antibodies, or injections of antibodies that are engineered to last for longer periods. “We have never had as robust a pipeline for HIV prevention in clinical trials, let alone in early product development as well,” says Mitchell Warren, executive director of AVAC, the HIV prevention advocacy group based in New York City.

The long-acting ARV that is the farthest along in development is the investigational drug cabotegravir (CAB LA), a long-acting injectable integrase strand transfer inhibitor. ViiV Healthcare, a company specializing in HIV that is owned by GlaxoSmithKline, Pfizer, and Shinogi Limited, is developing CAB LA for both HIV prevention and treatment. A Phase III efficacy trial of CAB LA for prevention (HPTN 083) is testing injections of CAB LA every two months head to head against placebo and daily, oral Truvada, made by pharmaceutical company Gilead, which is the current state-of-the-art PrEP drug. The trial started at the end of last year and will involve 4,500 volunteers. This is the first injectable PrEP drug to be evaluated in an efficacy trial.

Another ARV in development by Gilead for both treatment and prevention is known as GS-CA1. This experimental drug is a capsid inhibitor that prevents HIV’s nuclear material from entering cells. Preclinical data on subcutaneous administration of this experimental ARV was presented earlier this year at the Conference on Retroviruses and Opportunistic Infections. The company is planning to test GS-CA1 in clinical trials by next year. Gilead is also testing F/TAF, a combination of emtricitabine and a derivative of the drug tenofovir—the two drugs that make up Truvada—known as tenofovir alafenamide to see whether this newer drug combo, which is already licensed for treatment, is also effective for PrEP. F/TAF has a much longer intracellular half life and the company is now comparing oral administration of F/TAF with Truvada in a PrEP trial known as the DISCOVER study. Another long-acting ARV slated for HIV prevention trials is MK-8591, an adenosine nuclease analog developed by Merck.

In addition to developing new compounds, researchers are also focusing on delivery systems that might be able to provide prolonged release of HIV drugs inside the body. These include using implantable devices similar to those used for hormonal contraception that either need to be removed surgically or that could biodegrade, or using self-assembled gels that act as long-acting injectables. The biotechnology company Intarcia Therapeutics, backed by a US$140 million grant from BMGF, is now developing an implantable drug-delivery pump for HIV based on one they already developed to treat type 2 diabetes.

Another approach is to use antibodies that can neutralize a broad swathe of the HIV variants in circulation, so-called broadly neutralizing antibodies (bNAbs), to prevent HIV. There is evidence that some of the recently isolated bNAbs can protect against infection in animal studies and there is already a Phase IIb efficacy study of one of these bNAbs (VRC01) underway: the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID) is running the antibody-mediated prevention or AMP study involving 4,200 volunteers from seven countries. This is rapid progress given the first crop of new bNAbs was reported less than 10 years ago, says John Mascola, head of the VRC and a co-organizer of the NYAS meeting.

Results from the AMP study should come in 2019 or 2020 and will answer many preliminary questions about the role of bNAbs in prophylaxis, including whether they are feasible as a biologic and how much antibody is needed for protection.

Meanwhile, scientists are exploring introducing mutations into bNAbs to improve their staying power, thereby reducing the frequency of injections necessary to afford lasting and effective protection against HIV, while at the same time, improving their potency so a lower dose is needed. It is possible or even likely that a combination of bNAbs might be required so the lower the antibody dose, the less it will cost to manufacture the proteins on a large scale. Bruce Kerwin, vice president of drug product design at Just Biotherapeutics, says that to feasibly provide bNAbs for HIV prevention in sub-Saharan Africa the cost would need to be around $20 per gram of antibody. Right now the cost is more like $150 to $200 per gram, so researchers have a way to go. But studies suggest it might be possible to get there. “The potential to improve antibodies is quite remarkable,” says Mascola.

Introducing a single mutation (known as the LS mutation) into VRC01 for example, increases the half life more than four-fold as compared to plain VRC01. This engineered antibody can even be administered subcutaneously rather than by intra-muscular injection and still maintain high levels for extended periods of time. The long-term goals is to administer the antibodies only every four to six months.

Another promising effort to create more broad and potent antibodies involves engineering existing bNAbs so that they recognize multiple epitopes on HIV, as recently reported by researchers from pharmaceutical company Sanofi, in collaboration with NIAID, Harvard Medical School, The Scripps Research Institute, and The Ragon Institute (Science 2017, doi: 10.1126/science.aan8630). These tri-specific antibodies neutralized more broadly than any single bNAb identified to date and also afforded complete protection against a mixture of hybrid HIV/simian immunodeficiency virus (SIV) challenge viruses in non-human primate studies. Clinical studies will determine how immunogenic these tri-specific antibodies will be in humans.

But even as research into these longer-acting prevention strategies progresses, there are still looming questions. One is how to sustain or even increase funding when so much of the current focus is on scaling up ARV treatment. There is also the larger question of what the individuals at highest risk of HIV infection, particularly in sub-Saharan Africa, will ultimately want or choose to use to protect themselves. Researchers are hopeful that answers to that question will come from implementation studies for existing or potential strategies, like the vaginal ring containing the experimental ARV dapivirine that was found to be 27 percent effective in protecting against HIV in two large clinical trials. Researchers at the International Partnership for Microbicides (IPM) and their partners are starting a trial next year in adolescent girls to see whether they prefer to use the ring or daily, oral PrEP. At the same time they are seeking licensure for the dapivirine ring from the European Medicines Agency, which allows them to apply for simultaneous pre-qualification by the World Health Organization. IPM also started a trial earlier this year testing a dapivirine ring that only needs to be swapped out every three months.

AVAC is now working on two implementation studies for oral PrEP, one funded by BMGF and the other by the United States Agency for International Development. Daily oral PrEP received approval from the US Food and Drug Administration in 2012 and there are now more than 200,000 PrEP users, which Warren says does not represent a failure in implementation, but more work is necessary as most of these PrEP users are in the US and Europe. Uptake in Africa is happening more slowly. “We don’t fully know what people want,” he says. “This is not just a product development conversation, it’s a product delivery conversation. Just because we develop it doesn’t make it so.” Warren says that creating demand for new products is key, something that just seems to be starting in earnest for PrEP.

Warren suggests that determining how and by whom these existing or longer-acting prevention approaches in development will be used needs to be studied in large implementation studies, not the smaller ones done to date. “Let’s be ready to spend tens of millions of dollars on product introduction,” and do so earlier than what happened with oral PrEP, says Warren. “Asking questions three years after a product is registered is too late.” —Kristen Jill Kresge, Managing Editor