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Why a promising new approach to HIV prevention could lose funding

A battle is brewing in the HIV research world about the best way to prevent HIV transmission. On one side are drugs that target the tissue where exposure to the virus occurs — think a gel or douche. On the other is a whole-body approach. Think a pill or a shot.

At the heart of the debate is a tall, square-jawed scientist in wire-rimmed glasses who still carries himself like a military man: Dr. Craig Hendrix. Hendrix’s career has touched every part of the HIV prevention world. He’s analyzed data to prove how well HIV treatment and prevention drugs work. He’s studied pills, long-acting injectables and a vaginal ring. As a former Air Force lieutenant colonel, Hendrix taught other military doctors how to counsel enlisted men and officers about safer sex and to take an accurate sexual history without ever directly talking about homosexuality. This was during the Don’t Ask, Don’t Tell years.

And while he continues to work on all manner of HIV prevention drugs, it’s a bottle filled with medicated liquid that Hendrix has helped develop that he sees as important to HIV prevention among gay men. Used as an enema — or a rectal douche, as it’s called in gay circles — it could prevent HIV. But it’s a gamble that the National Institutes of Health may not be willing to throw its substantial funding muscle behind.

NIH officials have announced that after 2020, they don’t plan to fund topical HIV prevention products like douches or gels, unless they can protect the whole body, or early studies show they could substantially reduce HIV risk. That could put the douche Hendrix’s team is developing out in the cold. And Hendrix and others in the field remain skeptical, and wonder whether the NIH’s new approach is the best for those at risk.

“You have to be a believer to spend time making a new drug,” Hendrix said. “But then you have to be a skeptic of your own data.”

Cutting HIV off at the pass

To understand the scientific and funding debate, you first have to understand how the HIV virus infects the human body. Contrary to popular belief, it’s not an instantaneous, inevitable event.

It takes six weeks for an HIV infection to show up on a typical HIV antibody test. During that time, there are lots of places where scientists are trying to intervene, said Luis J. Montaner, an immunologist and director of the HIV-1 Immunopathogenesis Laboratory at the Wistar Institute in Philadelphia.

Think of it like driving a car. Sounds simple: get in the car and go. But stop and break down the steps, and you see there are lots of places where the process can fail: Grab your keys, and open the door to the garage or the car. Is there enough fuel in your gas tank? Do your starter and motor work? Is there a clear path from wherever you’re parked to the road? If you get stuck at any of these steps, you’re stranded.

“There are a thousand simple tasks that can make driving a car impossible,” Montaner said. “HIV is the same way.”

Let us count the ways HIV could be blocked: If the person living with HIV is on effective treatment, multiple large studies have shown that they in effect can’t transmit the virus.

If the virus does come into contact with another person, it must find a crack in the armor of the body — some fissure, some space in the mucosal linings, that allows it to sneak into a person’s tissue.

If it gets into the tissue, it still has to set up shop inside local immune cells and start replicating before it finally travels to the lymph nodes and blood, where it finds cells to hijack and use as incubators for the virus.

If you block HIV from any step of the hijacking process, whether locally in the vagina or rectum, or in the bloodstream and lymph nodes, you can stop an HIV infection.

“You have multiple shots at goal,” Montaner said, “depending on where you want to intercede.”

‘Something that people want to take’

Unsurprisingly, scientists have created schools of thought around these different prevention approaches. One camp is targeting the tissue where people are exposed to HIV — the rectum or the vagina, for instance — to try to prevent HIV from getting into the rest of the body in the first place. For that, you need a gel, a film, or a topical product of some kind that can reliably coat the area and block infection or replication.

Others are targeting the whole body, betting that if the virus somehow slips past local defenses, a system-wide approach will still do the trick. For that approach, you have to take pills or shots or an implant that slowly releases a drug into the bloodstream.

Both approaches can work, said Dr. John Brooks, senior medical advisor of the CDC’s Center for HIV/AIDS Prevention. It’s just that we tend to prefer some approaches for one condition over another.

You’re not likely to rub a gel on your forehead to treat a headache, even though only your head hurts; you’d probably pop an aspirin or ibuprofen.

But if you get a cut on your arm, you probably won’t be prescribed an antibiotic just for a scrape; you’ll smear a salve across it instead.

Those are the ways you can prevent HIV, too: One is through the whole body, called systemic protection; the other applies that protection to the site of exposure, and is known as topical protection.

“There are advantages and disadvantages to each,” Brooks said.

Pills can be easy to take and may be better for people at high risk for disease, because they protect the entire body, Brooks said. On the other hand, a disadvantage of oral drugs is that you are bathing every cell in your body in that medicine. That means it can build up in organs like the liver or kidneys. That’s exactly what it’s supposed to do, but it can have the effect of potentially damaging organs. That’s true for the HIV prevention drug Truvada (tenofovir/emtricitabine, made by Gilead Sciences), which can cause bone mineral density loss and temporary kidney trouble.

Topical drugs, on the other hand, won’t impact your kidney or liver, because they don’t enter the bloodstream in enough quantity to build up in organs. But they can’t help you if HIV somehow escapes the site where you were exposed, either.

“Topical drugs tend to have a high level of patient satisfaction if they are easy to use and not messy,” Brooks said. “We are a nation of pill poppers, but a lot of people, if you tell them they can choose between a drug that’s distributed into their whole body or one that can work just where you need it… They will consider which they might prefer.”

The key, Brooks said, is that, however you deliver them, the drugs “have to be safe, they have to work, and they have to be something that people want to take.”

Stumbling blocks

Right now, NIH’s National Institutes of Allergy and Infectious Diseases (NIAID) is deciding where to put its money after 2020. For nearly two years, Dr. Carl Dieffenbach, director of NIAID’s Division of AIDS, has been telling researchers and advocates that his department is coming down strongly on the side of whole-body protection, especially for young people and men who have sex with men.

“From my perspective, there’s plenty of time between now and 2020 to do work in the classical [topical protection, or] microbicide field,” he said. “But long term, we really need to think about what’s best for people.”

What’s best for people, especially young people, may not be what they want, he said—if what they want isn’t as effective as what’s already out there. Truvada, for instance, has been found to be more than 90 percent effective when used consistently, in the landmark iPrEx Truvada prevention study and in follow-ups. Acquiring HIV when you’re taking Truvada is so rare that it’s become the subject of individual case reports at prestigious HIV conferences.

It’s so effective, in fact, that the HIV prevention field has changed how it conducts studies: Now, many studies don’t have a placebo arm. Instead, participants are offered Truvada because it would be unethical not to offer people a prevention method that works.

“We don’t want a product that works for 20 percent of people; that’s the equivalent of it not working,” said Dr. Anthony Fauci, NIAID’s director. “If you have a product where you’ve tried every which way but Sunday and the best you can do is 45 percent… You’ve got to do better than that. That’s unfair to people.”

It’s been a challenge to develop topical drugs that deliver the highest levels of effectiveness. The drugs developed so far, all of them for vaginal protection, have faced stumbling blocks. In some cases, women have found them too gooey to want to use. In another, bacteria that naturally exist in the vagina was found to be “gobbling up” tenofovir, the HIV prevention drug researchers were testing.

And while rectally applied HIV prevention drugs are just now making it into human studies, those options present challenges, too. For one thing, the more alkaline pH of the rectum leads to slight inflammation that may draw more immune cells to the surface. These are the cells that HIV hijacks, so the virus has more opportunities to infect.

The lining of the rectum is also incredibly delicate. There are only six inches of nerve endings in the rectum, above which any damage wouldn’t be felt. One man described the rectum lining as “thin as a wet paper bag.”

Plus, there’s just more of it. The colon is five feet long. Would a prevention method need to efficiently coat the whole five feet to prevent HIV topically? And how long would it need to last? These are questions that HIV researchers are now tackling.

“It’s not tenable,” Fauci said. “Someone’s got to come up with a better idea to prevent infection through rectal exposure.”

A positive signal

Hendrix isn’t so sure about that. In fact, when NIAID asked for comments about its restructuring of HIV prevention funding after 2020, Hendrix sent the Division of AIDS’ Dieffenbach an 11-page letter, which included nine pages of references, notes and scientific data that he says shows that applying HIV prevention drugs directly to the rectum, via a douche, a gel or a lube, is not only safe and desired by those most at risk, including young gay black men in the southern United States, but also highly effective.

He argues that researchers like himself and Kenneth Palmer at the University of Louisville in Kentucky have learned from vaginal prevention trials and have created new, better and potentially more effective drugs than those that have gone before them.

In research presented in March at the Conference on Retroviruses and Opportunistic Infections (CROI), the U.S.’s largest HIV conference, Hendrix’s colleague Francois Villinger of the University of Louisiana, divided macaques into four groups of six. One batch served as a control group that received no drug. The next was a group that received daily oral tenofovir, one part of the HIV prevention drug Truvada. The other two received rectal douches of varying concentrations. Then, an hour after dosing with the douche or last dose of the pill, the researchers exposed the animals to a human-simian hybrid virus of HIV, directly to the rectum.

The idea was to test whether the douche would be at least as good as current oral HIV prevention pills.

After eight weeks, the results were in: tenofovir received topically delivered tissue concentration levels of tenofovir more than six times higher than taking a pill. Perhaps this is no surprise, since applying a drug right to tissue concentrates the drug at that location, as opposed to taking a pill and waiting for enough drug to circulate through the whole body before it builds up in the rectum.

But the next part was important: The rectally applied douche actually prevented HIV more than the pills, Hendrix said.

Of all the macaques that received the high-dose douche, one acquired HIV. By comparison, three monkeys that received oral drug also contracted the virus. The low-dose douche was far less effective. It’s too soon to draw conclusions from such a small study, one not done in humans. But it is a positive signal that Hendrix said is “exciting” to pursue.

“The question is, can [rectal] concentrations be high enough to make up for not having systemic protection? We don’t know what the answer to that is,” he said. “Based on animal studies we’ve completed and some in analysis, I think we can make the case that topical application can be as good or better than oral dosing.”

Hendrix has moved on from macaques. He’s currently enrolling 18 gay and bisexual men and transgender women to use the medicated rectal douche every time they have sex. Then, he’s going to test their rectal and plasma drug concentration levels and look to see if it’s safe to use, and how protective the drug is to first the tissue and then the blood.

His is one of at least seven topical rectal prevention drugs now in development. Hendrix suggested if one works, future clinical trials might test how effective a douche loaded with more than one drug might be to protect people from HIV.

But it would be 2020 before researchers would be anywhere close to starting a Phase III trial—the trials that actually test effectiveness after a drug has been proven safe in earlier trials.

“If the [NIH’s] request for applications [for HIV prevention study funding after 2020] is written in such a way that it’s not welcoming of microbicide studies and doesn’t also have people familiar with microbicide science [awarding the funds], there’s no way to pull off the study,” he said. “No matter what we show, if they exclude microbicide expertise, there’s no way to advance any of the… products now in development.”

Funding a ‘good idea’

NIH’s Fauci said Hendrix and other microbicide researchers shouldn’t be so worried.

“I can tell you, if someone comes up with a good, innovative idea, it will get funded,” Fauci said. “You can take that to the bank.”

But what is a good idea? If Phase II trials are successful for Hendrix’s douche, would that qualify? It’s too soon to tell.

As for Hendrix’s specific study, Dieffenbach is intrigued but cautious.

“There may be enough drug delivered rectally to lead to protection,” he said. “We look forward to the data from similar Phase II studies in humans.”

For Hendrix, this is a shame—not because he thinks microbicides are the answer, but because the topical drugs could support the use of other drugs, like injectable prevention drugs now in development.

For instance, Hendrix is on the team developing the injectable HIV prevention drug cabotegravir. The drug is designed to be given every eight weeks, and has so far been shown to be safe. But it’s also been found to linger in the systems of people who used it for more than a year after their last injection—but at levels that are too low to protect anyone. In previous studies, low levels of drugs have been associated with the creation of viruses that resist treatments.

“The long-acting methods have liabilities and advantages compared to oral Truvada,” Hendrix said. “We’re going to want a backup method.”

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