Rethinking the Definition of Cure as Patients With HIV Wait

Heather Boerner

March 13, 2020

BOSTON — A year ago, a man living with HIV walked into the exam room of Maile Young Karris, MD, from the UC San Diego Medical Center. He had seen on the news that there was a cure for HIV, and asked Karris: "How can I get it?"

Karris, who specializes in HIV primary care, explained that although one man — then known as the London patient — had been off medication for 18 months and remained in remission, that cure, if it were really a cure, was not available to him or, really, to any other patient with HIV.

"I'm often very hopeful. I believe we will get there," she told Medscape Medical News. "We're sort of just one scientific advance away."

But back then, she had to explain that the London patient, like the Berlin patient before him, had to get to the point of almost dying from cancer before the stem cell transplant that changed his immune system was even a possibility, and that both men had undergone a painful and invasive immunologic makeover.

So when it was reported at the virtual Conference on Retroviruses and Opportunistic Infections (CROI) 2020 that the London patient, now identified as Adam Castillejo, is still in remission a year later, even the researcher who performed the transplant was willing to say it's probably a cure.

But that likely won't change the way Karris or other HIV providers care for patients.

A New Definition of Cure

When Ravindra Gupta, MD, from University College London, presented the case of the London patient at CROI 2019, he was very careful to say "remission", not "cure".

But when he presented the case at CROI this year, he called it a cure, and he and his colleagues, in their report of the evidence published in the Lancet HIV, state that "these findings probably represent the second recorded HIV-1 cure."

In May 2016, Castillejo received a stem cell transplant to treat stage 4 Hodgkin's lymphoma, a non-AIDS-defining cancer. That transplant, like the one that Timothy Ray Brown, the so-called Berlin patient, received contained stem cells with two genetic mutations that remove the CCR5 receptor from the surface of the T-cell. Without that receptor, most HIV strains can't invade cells and, therefore, can't proliferate.

When Gupta presented preliminary findings last year, Castillejo had only been off HIV treatment for 18 months and was nearly 2 years out from his transplant. Back then, the team only took blood samples, but they showed that HIV wasn't present.

Then, just last month, samples from Castillejo — including blood, plasma, semen, and tissue from his rectum, cecum, sigmoid colon and terminal ileum, and auxiliary lymph nodes — were subjected to DNA, RNA, and other testing to see if the virus really was gone.

Although Castillejo's T-cell count is starting to approach where it had been before the transplant, there is no evidence that HIV is replicating in the blood, semen, or tissue samples tested, Gupta reported.

There were remnants of HIV genetic sequences in T-cells and in lymph node samples, though.

"Those can be regarded as so-called fossils," artifacts of past infection, not proof that HIV was still alive in his system, the researchers explain in the published report.

The findings are exciting, said Sharon Lewin, MBBS, PhD, from the Peter Doherty Institute for Infection and Immunity at the University of Melbourne in Australia, who was not involved in the study.

"It makes me think about a new definition of cure," she told Medscape Medical News. It's "the idea that clearing intact virus is what we're doing. And people may well have defective remnants of the virus, but that defective remnant can't replicate."

Of course, this is all still conjecture, she acknowledged. No one knows how long someone has to follow a person like Brown or Castillejo to know for sure that it will never come back. But she seems reassured that Castillejo had made it past the 27-month mark, which is when the viral load of the Mississippi baby rebounded.

Testing and Stigma

When Gupta presented data on the London patient last year, "it was electric," said Rajesh Gandhi, MD, from Massachusetts General Hospital in Boston. "I think most of us remember where we were."

So it's probably not a surprise that people living with HIV were also electrified. It was a topic that popped up in many exam rooms, which some clinicians blamed on newspapers headlines such as "HIV Is Reported Cured in a Second Patient."

https://twitter.com/drmt/status/1106275009289441280

And even for patients who weren't asking directly for a stem cell transplant, the question of cure was urgent for many of them.

"I think most of my patients weren't thinking that it is so easy that they want to go through the rigors of chemotherapy," Gandhi told Medscape Medical News. But "people have definitely come in to my clinic asking: 'What type of cure research are you doing?'"

Gandhi said he directs patients back to what does work: a single pill a day to control HIV.

Right now, Gandhi has a patient who has had both cancer and HIV. The cancer is now gone, but the HIV remains. The patient shared his cancer diagnosis with family but still hasn't disclosed his HIV status.

"He could get all the support from his family around cancer, but he never could share his HIV diagnosis," Gandhi said. "I think this is what motivates people to ask about the London patient and the Berlin patient."

People are still afraid of HIV.

Karris has noticed the same thing. Not long ago, a woman came to the clinic and reported that her partner had pulled a knife on her.

"He'd found her HIV meds in her purse and looked it up," Karris explained. "He took a knife to her because she didn't disclose. He said he was going to cut off her fingertips."

The woman has a suppressed viral load, meaning she can't transmit the virus to her partner. California changed its criminal code in 2017 to make HIV nondisclosure a misdemeanor instead of a felony.

"People are still afraid of HIV," Karris said. "Some people hate the idea that they have HIV. This is one reason people stop taking medicine. They tell me: 'I hate coming here. I don't feel sick. And when I come to the clinic, I'm reminded I'm sick. When I take my meds, I'm reminded I'm sick'."

For patients who feel that way, she has three things to offer. One is the concept of undetectable equals untransmittable, meaning that they aren't putting the people they care about in the position to acquire HIV. That's been transformational for many patients, she said.

The second is that new HIV medications are coming soon that will be taken every month or every other month. "That seems helpful for them," she said. "They like the idea of coming in once a month. Then they don't have to think about it every day."

And finally, she said, she's excited to share a new tidbit, also presented at this year's CROI, that people who have CD4 a T-cell count of at least 500 cells/mm3 when they start taking medication now have an average lifespan just 3 years less than those in the general public.

"The gap is closing between people living with HIV and those without," she said. "I try to communicate that. It can be mind-blowing for them, to see that they could live as long as anyone else."

Conference on Retroviruses and Opportunistic Infections (CROI) 2020: Abstract 346. Presented March 10, 2020.

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