'Beautiful, Long-Lived' HIV Suppression With Combo bNAbs

Heather Boerner

September 26, 2018

Nine of 11 people living with HIV maintained "beautiful, long-lived" viral suppression after receiving two broadly neutralizing antibodies (bNAbs) against HIV, nearly tripling the mean time to viral rebound seen in studies of a single bNAb.

"This research confirms what we all thought we knew: We need combination antibody therapy for HIV suppression," said Trevor Crowell, MD, PhD, from Johns Hopkins School of Medicine in Baltimore and the US Military HIV Research Program, who was not involved in the study.

"We've learned this lesson before with ART and we're now seeing it play out with an immune-based intervention for HIV treatment," he told Medscape Medical News.

This could mean that the future of treatment-free remission will look more like current antiretroviral therapy combinations than a one-and-done shot that suppresses HIV indefinitely.

The bNAb combination has been described in two recent publications (Nature. 2018;561:479-484 and Nat Med. Published online September 26, 2018).

HIV B-Cell Coevolution

When someone acquires HIV, the immune system is mostly silent. But it wakes up over time and starts to mount an attack against the virus. That attack, heralded by B-cells, comes in the form of antibodies designed to stall or stop different steps of HIV infection.

The trouble is, just as one antibody starts to gain a foothold, the virus morphs, eliminating the spot on its sugary outer envelope where the antibody works. The B-cells try another antibody, and another, each time trying to stop HIV and each time working for a bit before the virus evolves to evade the system.

The bad news is that the immune system rarely gets a leg up on the virus. The good news, though, is that scientists have been examining these B-cells to identify antibodies that are both potent and work on a range of HIV viruses.

That's how researchers at Rockefeller University in New York City, who reviewed hundreds of HIV envelopes, found 3BNC117 and 10-1074, two antibodies that target two different spots on those envelopes.

Both antibodies have been studied individually, and each time they suppressed the virus, at least in some patients. But each time the virus rebounded, as it did in previous bNAb monotherapy studies, and sometimes it developed resistance to that antibody.

"That's similar to what happened when single antiretroviral drugs were given many years ago," said investigator Marina Caskey, MD. "So it was not necessarily a surprise that, when treated with combination antibodies, patients successfully maintained viral suppression, similar to what happened with ART."

What did surprise her, Caskey said, "was how long we were able to maintain suppression."

Triple the Time and Still Going

A previous study demonstrated that HIV was suppressed for up to 10 weeks without antiretroviral therapy in patients who received 3BNC117 alone (Nature. 2016;535:566-560). And in patients with detectable viral loads who received 10-1074 alone, the mean half-life was 12.8 days (Nat Med. 2017;23:185-191). The administration of VRC01, another widely studied antibody, suppressed HIV for about 5.6 weeks (N Engl J Med. 2016;375;2037-2050).

For the combination of 3BNC117 plus 10-1074, administered three times over 6 weeks, the mean time to viral rebound was 21 weeks. "That's 4 months from the last dose of antibodies," Caskey emphasized.

But that's not all. As with all antibody studies thus far, different people reacted to the antibodies in different ways. Two people rebounded — one at 5 weeks and one at 7 weeks — and were later found to have resistance to one or the other antibody.

"There seems to be a higher bar to 3BNC117 resistance than to 10-1074 resistance," Caskey pointed out. "What we saw in this study was that for people who responded, the virus only came through once 3BNC117 washed out."

Determining who is prone to resistance to these antibodies could lead to a more effective treatment. "This is one of the challenging areas we need to work out," she said.

A "Glimmer of Hope"

When the study ended at 30 weeks, two of the 11 participants were still virally suppressed. These are the ones who "provide a glimmer of how HIV remission is really possible," Crowell said.

The participants have chosen to stay off treatment and the team continues to follow them.

What is it about these two people that has allowed them to stay virally suppressed? It could be a combination of the person's particular virus, the specifics of that person's immune system, and how the antibody administration itself changes the way the immune system sees the virus, Caskey explained.

"We're in the early days of understanding this," she added. When these antibodies bind to the virus, "they label and signal to the rest of the immune system that this is something it has to eliminate. So even though it's not a vaccine per se, it can have a vaccinal effect."

So even though it's not a vaccine per se, it can have a vaccinal effect.

But that doesn't mean everyone should run out and start asking for the 4-month treatment for HIV. A lot more work needs to be done, said Caskey.

Much larger studies with more diverse populations (only one woman participated in the trial) are needed to determine if the results were particular to the participants or if they are more generalizable. And a test is needed that will identify who is at risk for resistance before the bNAbs are administered.

In fact, Caskey and her colleagues are conducting larger studies, which are currently in the enrolment stage.

This is not a cure, she emphasized. But it is also not the end of the development of combination bNAb therapy, said Anthony Fauci, MD, from the National Institutes of Allergies and Infectious Diseases.

"These are standard antibodies, and they suppressed the virus for a median of 21 weeks," Fauci said. "If you use the same proof of principle and longer-acting antibodies, it means it's possible you could give an antibody twice a year, nothing else, and continue to suppress the virus."

This study was funded by the Bill and Melinda Gates Foundation, the European Research Council, the German Center for Infection Research, the Heisenberg-Program of the DFG, and the National Institutes of Health. Crowell, Caskey, and Fauci have disclosed no relevant financial relationships.

Follow Medscape on Twitter @Medscape and Heather Boerner @HeatherBoerner

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