With several long-acting HIV treatments in the works, the newest drugs emphasize convenience

Lionel Hillard’s boss asked him to come into his office. It was the late 1980s in Dallas. The then 29-year-old was a medical assistant at a busy clinic with a room full of patients. But the doctor who ran it said he needed to talk with him about the results of his routine blood work.

“He said, ‘Lionel, you are HIV positive,’ ” Hillard recalls.

Hillard held it together for the rest of the workday, then broke down when he got home. He had been working with people with HIV for years, in an era when that diagnosis often meant a rapid march to death. “I was working with people who were HIV positive and was teaching their families how to let them go,” Hillard says. Now, he had to counsel himself.

Somehow, Hillard survived. And in the nearly 30 years since his diagnosis, he has seen HIV go from certain killer to treatable to one-pill-a-day preventable. It’s remarkable, he says, but it’s not enough.

Hillard, now 58, is an advocate for people living with HIV, engaged and active in understanding the newest treatments. He has participated in clinical trials, including one for Trogarzo, an injectable HIV drug for people whose viruses have become resistant to older therapies. He takes it regularly, heading to his doctor for an injection every 2 weeks. Theratechnologies’ Trogarzo is one of a growing number of injectable HIV drugs, both approved and in development, that promise efficacy, as well as discretion for those scared to live openly with their HIV status. An injection, some say, resolves the constant reminder of HIV status that taking a daily pill brings.

The rise of injectables is emblematic of a gradual culture change for people with access to good HIV care. Although still a serious illness, HIV has effectively become a chronic disease in the US, manageable by adherence to medication. While scientists work on a practical cure for HIV that can treat the largest number of people, some pharma companies are still chasing new HIV drug targets and trying to make treatment more meaningful and long acting. Drugmakers tell C&EN that for the injectables in their pipelines, the idea is convenience over a lifetime of use.

Convenience. After decades of pills, including the canonical triple therapy, Hillard likes how that sounds.

“It gives you the freedom that you don’t have to think about it—oh, did I remember to take my pill today?” he says. “I believe there will be a drawn attraction to the injectable and not having to carry these pills around.”

Injectables fill drug pipelines

At a recent international conference on retroviruses, much of the buzz among the thousands in attendance was around successes in treating and preventing HIV infection in areas where it is practically endemic.

HIV is a bigger problem outside the US than in it, says John Mellors, an HIV physician-scientist at the University of Pittsburgh who is a key organizer of the Conference on Retroviruses and Opportunistic Infections (CROI), held most recently in Seattle. In some African countries, public health personnel struggle with stigma, access to health care, adherence to medications, and burgeoning resistance to available drugs, often on a much larger scale than in the US.

“We’re approaching a crossroads right now because the first line of therapy that’s been chugging along for more than 15 years globally is running out of gas because of resistance,” he told C&EN after the conference. “Small molecules are very effective, but we need backups.”

Among those backups are a growing number of long-acting drugs, including at least nine injectables, in clinical development.

Mellors is confident that at least one new injectable will be approved as a treatment for people who are newly diagnosed with HIV, and he believes that the injectables’ once-per-month dosages will help deal with the issue of compliance—getting people to take their medications on time to keep their viral loads low and resistance at bay.

“We are fallible as human beings and we don’t always do that,” Mellors says of taking daily pills.

At CROI, ViiV Healthcare released Phase III data from two trials of an injectable treatment consisting of cabotegravir and rilpivirine. Cabotegravir is a new molecule that blocks the HIV integrase enzyme, a protein critical in helping HIV insert its genome into the DNA of the T cell it infects (J. Med. Chem. 2013, DOI: 10.1021/jm400645w). Rilpivirine, already approved as a pill, is part of an older class of drugs called nonnucleoside reverse transcriptase inhibitors. It’s a small molecule that binds to and blocks HIV’s reverse transcriptase, the enzyme that allows the virus to copy its genetic material and replicate (Virus Res. 2008, DOI: 10.1016/j.virusres.2008.01.002. The two, when packaged together for intramuscular injection, can last in the body for 1 month or longer.

After 48 weeks, most of the 1,250 people enrolled in two international trials of the injectable duo were able to suppress HIV comparably to people who were taking the standard HIV treatment of a single pill with three drugs in it. One trial focused on people who successfully treated their HIV with other medicines before switching to the injectable, while the other enrolled only people who were newly diagnosed.

People in both trials reported few side effects, says Kimberly Smith, a physician who leads medical development for ViiV. As part of the trial, patients that had taken pills in the past were asked which—pills or the long-acting injectable—they prefer.

The results were telling.

“In one of our studies, it was 97% of patients who said they preferred long acting, and the other one, it was 99%,” Smith says.

These survey results echo what Gary Sinclair, an infectious disease doctor in Dallas, is seeing in the clinic. Sinclair, who previously worked at a pharma company, runs clinical trials at Prism Health North Texas, one of the largest providers of HIV services in the Dallas–Fort Worth area. The clinic has been involved in multiple HIV drug trials, including the one for Trogarzo, the injectable that Hillard takes, and another injectable, currently in progress.

“The long-acting injectables are being pushed by patient preference,” he says.

But Sinclair is cautious of claims that injectable treatments will solve the adherence and resistance problems. If patients miss an injection, he says, he doesn’t have the staff or funding to track them down. As the concentration of the drug in their bodies slowly wanes, the viral loads may start to creep up. At a certain point, the amount of drug circulating in those patients’ bodies won’t be enough to outright destroy the virus but will be enough to put survival pressure on it, possibly leading to resistance. He says this window of “suboptimal inhibition” will be longer for injectables than pills, which are metabolized quickly.

That theory might soon be put to the test. ViiV expects that the cabotegravir-rilpivirine injectable will be available by the start of 2020.

In the meantime, other injectables are in early phases of testing. Some of the compounds attack targets in HIV that have been notoriously tough to drug.

Attendees at CROI got a first glimpse of how one of those new drugs works in humans. At the meeting, Gilead Sciences reported early safety data on GS-6207, an inhibitor of the HIV capsid, an inner core structure that protects the virus’s RNA genome and delivers it into the T cell it has infected. GS-6207 stops capsid formation by nestling between two capsid proteins in the repeating hexamer that is characteristic of the structure, and it works at several different points in the life cycle of the viral particle.

Developing GS-6207 took more than a decade, and it is the first capsid inhibitor to make it into clinical trials. “From a chemical standpoint, it’s been a tough nut to crack,” says Diana Brainard, Gilead senior vice president of HIV research.

In the Phase I trial, the team tested doses ranging from 30 to 450 mg in four groups of 10 healthy people each to understand the pharmacokinetics of the molecule. There were few side effects. The drug stayed at consistent levels in the body for about 6 weeks and seemed to last in some cases for more than 24 weeks.

Early tests suggest GS-6207 is active against several mutated strains of HIV that are resistant to other treatments. The Gilead team is now trying to figure out whether the capsid inhibitor should be packaged with another drug to augment its efficacy. Although it’s being tested now as a treatment, GS-6207 could ultimately be used to prevent infection, Brainard says.

“With the capsid inhibitor, once we better understand its antiviral properties and pharmacokinetics to the fullest, we can think how to use it in prevention,” she says.

Paths to a cure

The advances in HIV treatment have made it a disease that thousands of people are living with worldwide, but researchers still hope they can one day find a cure. Academic and industry researchers are working on a few different ideas that could not just suppress but eradicate the virus.

Although drugs can reduce viral load to levels that are undetectable, and thus untransmittable (what public health messaging calls U = U), if a person stops taking them, viral loads can rebound. That’s because of what HIV often leaves behind in a cell that it doesn’t kill—a copy of itself.

That copy is called a provirus, and it is a DNA version of HIV’s RNA genome that is inserted into the DNA of the cell it infects. These infected cells lie dormant until awoken by the right trigger, causing the embedded HIV genome to begin replicating. Virus particles form anew, bud, and disperse to infect new cells.

Eliminating cells with a hidden provirus is key to curing HIV, says Robert Siliciano, an infectious disease researcher at Johns Hopkins University School of Medicine. His team has created a test that doesn’t just measure the number of proviral particles in a person who is living with HIV but can also determine which of those particles are most capable of making a fresh virus. Most proviruses, he says, are too mutated to ever become active viruses if woken up.

This more accurate measure of the viral reservoir is critical to curing HIV. Without it, researchers don’t really know how strong curative measures need to be or how well they are working.

For example, in a strategy called “kick and kill” or “shock and kill,” researchers use different compounds to stimulate cells harboring dormant HIV, trying to kick-start virus production so that the immune system can then act on those cells. A more accurate measure of potentially competent viruses could aid these efforts. Siliciano’s test is being optimized by a spin-off company, Accelevir Diagnostics.

Some of the molecules being tested in kick-and-kill strategies ramp up cellular gene activity in the hopes of waking up the dormant viral DNA within. Others try to induce gene expression by globally stimulating immune cells. And others being tested for their ability to wake up latent HIV are drugs that are used in cancer immunotherapy.

The challenge with some of these efforts is that many people whose HIV is well controlled are relatively healthy, and waking up the latent reservoir could make them quite sick before any treatment cures them.

“We’re trying to gently induce that reservoir and not cause a lot of collateral damage, and then reduce it,” says Brian Johns, who works on HIV cures for ViiV Healthcare. He prefers the term “induce and reduce” over “kick and kill.” “The trick is to lower the reservoir to the point that the patient’s immune system can control the virus.”

One promising avenue in the kill category is broadly neutralizing antibodies, called such because they appear to kill HIV even as it mutates within its host. The antibodies themselves are highly mutated, seemingly formed through an iterative process in which they change to respond to subtle genetic alterations in the part of HIV they recognize. Scientists hope that, if successful in clinical trials, these antibodies might work in a wide swath of the HIV population.

More than a dozen clinical trials of broadly neutralizing antibodies are underway, including at least one at Prism Health in Dallas.

Developing them into treatments has involved some engineering, first to make them last longer than they would naturally and also to build novel antibodies that recognize more than one conserved spot in HIV. Another goal has been to improve these antibodies’ ability to spur the immune system to keep working against HIV after the antibodies have been metabolized.

Researchers from Rockefeller University are enrolling people with HIV in a trial of a pair of human-derived antibodies with mutations added to improve longevity. Meanwhile, the National Institutes of Health and Sanofi expect to have an engineered trispecific broadly neutralizing antibody, which interacts with three parts of the HIV envelope, in clinical trials by the end of 2019.

NIH and United BioPharma have developed yet another approach. Their antibody binds to CD4, the main molecule that HIV uses to enter T cells, and was shown to be safe in a small trial. Importantly, the therapy seems to overcome some of the resistance issues that have been seen in trials of other broadly neutralizing antibodies.

Groups at Temple University and the University of Pennsylvania are separately exploring the use of gene editing to reduce infection. Efforts include using CRISPR to remove sections of integrated simian immunodeficiency virus from infected cells or using an mRNA-based zinc finger nuclease technology to cut out parts of CCR5, a molecule on the surface of T cells that HIV uses to gain entry. A small trial of the zinc finger–based therapy found a modest delay in viral rebound in patients on no other treatment, but a few people in the trial had low levels of circulating virus for up to 10 months.

Another method involves cell engineering: taking a person’s T cells, isolating and enriching for the ones that are specific to HIV, treating the cells with small interfering RNAs to turn off CCR5 plus different isolates of HIV, and then giving the T cells back to the person they came from. American Gene Technologies has used the method to isolate cells from people living with HIV, and according to the firm’s CEO, Jeff Galvin, tests in mice indicate that the modified cells are not toxic. Galvin claims the method is less dangerous than a bone marrow transplant, the only way so far that anyone has been able to cure HIV, and the company hopes to be in early clinical trials within the next few months.

“We’re pretty confident that we’re going to be able to achieve this, that we’re going to be able to make people permanently immune to HIV,” Galvin says.

But the University of Pittsburgh’s Mellors, who thinks broadly neutralizing antibodies are the most promising step toward a cure, takes a more cautious stance regarding complicated cures. He wants to see whether the protocols are practical and the steps involved can be scaled up. Between 100 billion and 1 trillion cells in the body are susceptible to HIV. He says researchers studying cures might need to deliver these technologies to every susceptible cell—will they be able to?

“People love their technology, but whether it can do the job requires proof of concept in large animal models and then eventually people. And those have got to be scalable or it’s not going to have a huge impact,” he says.

A question of access

The development of longer-acting HIV treatments comes as US president Donald J. Trump and federal health officials vow to end HIV in the US within 10 years. Although HIV is more prevalent elsewhere in the world, the Centers for Disease Control and Prevention says that some 38,000 people in the US were newly infected with HIV in 2017. In a speech given at the recent CROI, Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, said that this number has remained steady for some time. The groups most at risk? Men who have sex with men, intravenous-drug users, young black men, and in general, people of color.

Ending HIV in the US will take more than new drugs, Fauci says. If every person diagnosed with HIV could get on therapy and everyone at risk could access preventive care, HIV infection could end. But, he says, “we have an implementation gap in the US.”

That gap is something Sinclair sees constantly in Dallas. Dallas, like many southern cities, still suffers from an entrenched stigma against same-sex relationships that drives many people underground and keeps them from getting tested until they are so sick, they have little choice. But the gap is also a bit of political will.

“For whatever reason in the South, we don’t seem to be as interested, and therefore, we’re not as aggressive about quickly identifying patients who are infected,” Sinclair says of public health infrastructure.

Prism Health has about 2,600 patients, of which 2,300 are living with HIV. Because many are on treatment, the perception among people who are at highest risk, and perhaps policy makers, is that HIV is not an issue anymore. But Sinclair says that he still gets patients in the clinic who are incredibly sick—whose HIV has killed off all their CD4+ T cells and who have toxoplasmosis, histoplasmosis, tuberculosis, and other diseases.

“I can think of five within the last month that have required the full breadth of my infectious disease training,” he says. “We still have about 10% of our patients coming through as though we are in 1985.”

While patients like Lionel Hillard exemplify how drugmakers see injectables being used in the fight against HIV, even he cautions that adherence might not be easy for some people.

“As opposed to taking pills, which you can take anywhere, the mind-set is coordinating your life to get stuck every 2 weeks,” Hillard says about Trogarzo.

Sinclair, while hopeful for his patients who are up to date on developments in HIV treatment, is not sure that the new wave of injectable HIV treatments will work for some of Prism Health’s hardest cases, the ones prone to drug resistance—for example, people who are homeless or have substance abuse issues, or those with homes and jobs but no stable insurance coverage for drugs that can cost hundreds of dollars per month.

“We tend to have a population that tends to stop and start treatment a lot. We might have a bigger interest in the regimens that can bill themselves as having a demonstrated high genetic barrier to resistance,” he says. “Everybody is claiming to have them.”