To look at Nelson Vergel, you would never guess what he has been through. For 35 years, he has kept up a relentless fight against HIV, but his muscular physique is that of a man decades younger. Regular workouts, fatty breakfasts of arepas stuffed with cheese and eggs — a staple of his native Venezuela — and 32 massive pills a day have kept him fit and driven the virus from his blood. And yet, all is not well.
Four years ago, Vergel developed and beat lymphoma. He has irritable bowel syndrome, chronic diarrhea, and severe fatigue, and in 2015, he had surgery on his right hand for a nerve disorder; he still can use only one finger on that hand to type. “Chemo was nothing compared to that,” he says.
Vergel, 59, attributes most of these conditions to his low CD4 count, a key marker of immune function in HIV-positive people. He is what’s known as an immunologic non-responder (INR) — someone whose immune system does not rebound even after years of antiretroviral therapy. There are tens of thousands of these non-responders in the U.S., whose low CD4 numbers put them at much higher risk of heart attacks, stroke, cancers, secondary infections such as tuberculosis, and death. And yet, drug companies and researchers aren’t actively pursuing new treatments that would boost their immunity, leaving people like Vergel feeling neglected.
“The field is moving on, to be honest with you,” he told STAT. Vergel and a group of other HIV/AIDS activists are hoping to change that, by drawing attention to their situation and persuading the Food and Drug Administration to grant non-responders orphan disease status.
Nobody knows exactly how many INRs like Vergel there are, but they are likely to number fewer than 200,000 in the U.S., where there are roughly 1.1 million people with HIV. (The proportion of INRs is likely to be higher elsewhere in the world, where the burden of HIV is higher and access to drugs more difficult.). The small number in the U.S. may paradoxically offer the best hope for non-responders — the cutoff for orphan status, a special designation that gives drug makers incentives to develop medications for rare diseases, is 200,000 people.
Many non-responders have trajectories like Vergel’s. The Houston resident was infected at age 24, but it was years before he realized it was HIV that had caused him to experience the mysterious flu-like symptoms. Over the next decade, he took a series of HIV drugs, one at a time, and became resistant to each. Then came the combination therapies, which also never worked for very long. It was 2012 before the drugs became sophisticated enough, and Vergel began taking enough of them, that the virus in his body came under control.
His CD4 count when he began therapy was around 190 cells per cubic milliliter of blood. (The normal range is 500 to 1,500.) The number typically rebounds significantly in response to antiretroviral drugs. Vergel’s did not.
Seeking orphan drug status
The drug pipeline didn’t always look so bleak for non-responders. About a decade ago, there were several trials testing treatments for boosting immunity in INRs. But after some high-profile and expensive failures, companies have steered well clear.
An orphan drug designation might help these companies lower their risks. The label comes with substantial financial incentives for a drug’s sponsor, including tax credits and waivers for the “user fees” the agency typically collects on new drug applications. It also means an accelerated approval timeline: Companies would be able to enroll fewer participants than in the typical large Phase 3 clinical trial — perhaps fewer than 100 compared with the usual thousands.
Without these advantages, said Dr. Steve Deeks, professor of medicine at the University of California, San Francisco, “the cost of getting through to Phase 3 is so high and the risk of failure is so high, that no one’s going there.”
Vergel and other activists have set up meetings with FDA officials and with biotech companies to try and broker an orphan drug designation — and the appropriate clinical trial designs — for treatments for non-responders.
The FDA said it is, in theory, fully supportive of this approach to help non-responders. “Our best guess is the sponsor [company] would be able to provide sufficient support in the published literature that the population of INRs in the U.S. is smaller than 200,000 people,” said Jeff Murray, deputy director of the FDA’s Division of Antiviral Products.
It’s up to a drug maker to take the first step, however, and none has yet applied for orphan drug status for a treatment for INRs. But one biotech company, called Revimmune, said it would begin exploring how to do so after STAT brought the possibility to its attention.
Before any company can move forward, it must first be able to define who exactly fits the definition of an INR and how best to measure the effect of a drug on non-responders.
“We can’t start looking for solutions or drugs if we don’t have a really solid definition of the group,” said Dr. Irini Sereti, chief of the HIV Pathogenesis Section at the National Institute of Allergy and Infectious Diseases. “Almost every paper you read has used a different definition.”
One analysis by Treatment Action Group, an advocacy organization based in New York, found 14 definitions of INRs across 20 studies. And these definitions can, in turn, affect estimates of the prevalence.
For example, a 2014 study of more than 5,500 people estimated that about 15 percent of people who began taking antiretroviral therapy with a CD4 count of less than 200 didn’t show an increase in those cells three years later. Another study in 2018 of about 1,600 people found that 27 percent of people had a CD4 count below 350 six years after beginning treatment.
These studies broadly agree that older age and a low CD4 count at the start of treatment are the strongest predictors of poor immune recovery. But they also each report a different frequency of problems that can occur in INRs.
Dr. Virginia Sheikh, a medical officer in the FDA’s Division of Antiviral Products, is working with colleagues to analyze pooled data submitted to the agency for antiretroviral drugs to gain a clearer picture of non-responders. Still, even with a conservative estimate, the number of INRs in the U.S. is unlikely to be higher than 200,000, she said.
Few drugs in pipeline
About a decade ago, the immune molecule interleukin-2 seemed to be a promising treatment for non-responders. Two large Phase 3 clinical trials showed that interleukin-2 successfully boosts the numbers of CD4 cells. But it turned out to increase a subtype of the cells that suppress immunity, instead of enhancing it, and delivered no clinical benefit for the participants.
Then, a French company called Cytheris developed an experimental product based on another immune molecule called interleukin-7. This therapy dramatically increased CD4 levels and enhanced immunity in early testing with INRs. But the company went bankrupt in 2013, before it could test its approach further.
Deeks was involved in another trial with non-responders, a small pilot study led by California-based Sangamo Therapeutics. That trial involved extracting CD4 cells from an HIV-positive person, editing the cells to knock out CCR5 — a protein HIV needs to infect the cells — and infusing these modified CD4 cells back into the person. The approach worked: “The CD4 count went up dramatically and quickly,” Deeks said, and stayed up for years.
Matt Sharp, one of the trial’s participants and an HIV activist, was in the audience of a 2011 conference where Sangamo presented the results. Like Vergel, Sharp had taken antiretroviral drugs for decades but his CD4 count had stayed depressed. When the Sangamo slide went up, Sharp was stunned to see increases in CD4 counts in most of the participants.
“There was this phenomenal doubling of CD4 cells in almost every patient,” he recalled. His CD4 level was around 200 at the start of the study, he said, but has stayed at nearly 500 ever since. His health, too, has been better than before.
Despite these promising effects, however, Sangamo chose not to pursue the method any further for INRs. Like many others in HIV research these days, the company is instead exploring the method as a cure for HIV. A new trial about to get underway may include people with low CD4 counts but is not specific to non-responders, said Rafick-Pierre Sékaly, a professor of pathology at Case Western Reserve University School of Medicine who is leading the trial.
One other positive development for INRs is that Revimmune, the company that licensed Cytheris’ interleukin-7 technology, has been testing it for other conditions. The company had not considered renewing its focus on HIV, but after hearing about the orphan drug designation, Michel Morre — the French scientist who led Cytheris and is now chief scientific officer of Revimmune — said that seems like a viable approach. “It is certainly something we should consider,” he said.
Vergel welcomes this news: “I was disappointed to find out the development of this option for HIV had been halted, so I am happy that it may be reconsidered for INRs,” he said.
In the meantime, Vergel is giving talks about INRs to patients and clinicians, and is trying to stay optimistic. “This message is my most important mission,” he said. “I don’t want this to be left behind.”
Correction: An earlier version of this story wrongly described the kind of cancer Vergel developed and had an incorrect title for Dr. Virginia Sheikh, an FDA medical officer.
Published on STAT