乌鸦传媒

GLASGOW, Scotland -- A combination approach will likely be needed in order to achieve either a sustained functional or a "sterilizing" cure for HIV, experts said here.

This approach to a "functional cure" would look toward induction, followed by remission and maintenance -- similar to the approaches to treatment in the oncology space. HIV researchers may also be able to benefit from current research in oncology, particularly in immunotherapy, they said.

But any research into a cure in humans is a balancing act of risks and benefits, as it likely involves taking a patient off antiretroviral therapy (ART) and seeing how long it takes between treatment for the virus to rebound.

"We have learned from antiretroviral therapy that expecting one agent to do all the work is probably not going to be sufficient," said Sarah Fidler, MD, of Imperial College and Imperial College NHS Trust in London, speaking at the International Congress on HIV Drug Therapy ().

She began her talk with a discussion of the Timothy Brown -- who has been cured of HIV for 9 years after treatment involving chemotherapy, and having a particularly lucky genetic mutation. But she said this approach is "not scalable and actually quite dangerous."

The key to any clinical trial examining HIV cure is "analytical treatment interruption," she said. This involves questions about how frequently to test viral load, what are the risks of transmission, and how long to wait before treatment re-initiation. There is currently no point-of-care viral load test, Fidler said.

"For patients, if you control [their HIV] for a couple weeks off therapy, that's all very interesting, but it doesn't cause any life-changing outcomes," she said. "And we can't say to our patients 'oh look, we can't grow virus in our test tubes, so you can interrupt treatment and we know the virus won't come back.'"

Fidler also touched on the "shock and kill" (or "kick and kill") strategy, which combines "latently reversing agents with an HIV-specific immune response that will kill the latently activated cell." Her group recently conducted the , the first randomized trial examining this approach, but found no difference in total HIV DNA or viral outgrowth by study arm, she said.

Broadly neutralizing antibodies (BNAbs), which provide a "vaccinal effect," are another strategy being explored, she continued. Next-generation BNAbs have extended half-lives, for up to 3 to 6 months. She added that this approach is being studied in prevention as well as cure. One study found an up to 19-week delay in rebound versus historical controls.

Dual BNAb therapy is currently in the pipeline, as "combined antibodies seem to work." But Fidler added that this is effective only among people whose virus is susceptible to antibodies.

"It could likely be a more scalable approach than the interventions Timothy Brown had," she noted.

Piggybacking Off Cancer Immunotherapy Research

In a second talk, Steven Deeks, MD, of the University of California, San Francisco, opened by discussing the recent Nobel Prize-winning research by James Allison, PhD, for cancer immunotherapy. Deeks said that HIV researchers had investigated several types of immunotherapy in the earlier days of HIV, but "largely failed" in HIV due to high disease burden, ineffective T-cells, inflammation, and counter-regulatory immunosuppression.

"Our group in San Francisco had done research on CAR-T cells [back in the 1990s]," he said. "Just like we're seeing now with the PD-1 blockade, those technologies are slowly coming back into the HIV world."

He described HIV infection on ART as "persistent low-level inflammation, where chronic inflammation causes chronic upregulation," similar to the situation in cancer. Deeks said this is why these pathways have been "aggressively targeted by oncologists -- if we block pathways, the T-cells will work better and cure cancer."

But studies of PD-1 therapy have mostly been confined to HIV patients with cancer, as opposed to all patients with HIV -- due to the safety profile of these therapies, he said. However, controlled studies of HIV outside cancer are now being planned, he added.

"There have been a couple reports of people that when they have PD-1 therapy given to them, there's a remarkable drop in HIV DNA, possibly because the immune system is being revved up to work better," Deeks noted. "[HIV researchers] are stealing a lot of ideas from oncologists."

But like Fidler, Deeks agreed that given the many barriers to success, the best strategy is likely a combination approach.

"Our group [at UCSF] got fed up with all the experimental medicine studies," he said, adding that their group received FDA approval to perform a study that treats patients with a variety of approaches, including therapeutic vaccines, vaccine adjuvants, reservoir reduction, and BNAbs.

"There's going to be multiple failures, there have been some failures already. That's the way medicine advances," Deeks said.

Given the variety of ongoing research, Fidler predicted that there may be a "functional cure" for HIV in the next 5 to 10 years, but "unless some amazing new treatment comes along, we have to wait a lot longer for a [full] cure."

But one participant seemed to put the whole discussion into perspective with his somewhat rhetorical question: "I don't want to be a nihilist, but I am a clinician," he said. "Let's say we invest billions of dollars and come up with a safe and sterilizing cure. What's the point of curing someone and taking them off ART just to put them on PrEP?"

Comment