BOSTON – Long-term control of HIV without the need for ongoing antiretroviral therapy (ART), even though it is not a cure, would be a major milestone for HIV treatment. At the Conference on Retroviruses and Opportunistic Infections (CROI) this week, researchers suggested that it may be possible to find treatments that induce such long-term control, through a combination of ART and broadly neutralizing antibodies (bNAbs).

BOSTON – Long-term control of HIV without the need for ongoing antiretroviral therapy (ART), even though it is not a cure, would be a major milestone for HIV treatment. At the Conference on Retroviruses and Opportunistic Infections (CROI) this week, researchers suggested that it may be possible to find treatments that induce such long-term control, through a combination of ART and broadly neutralizing antibodies (bNAbs).

Hopes that early ART alone, if initiated early enough, could prevent formation of a viral reservoir and allow patients to discontinue ART after a time have not been sustained. There are currently two known children, one living in France and one in South Africa, who have been able to stay off of antiretroviral drugs without experiencing viral rebound.

But statistically speaking, such rebound is just about inevitable.

At the CROI conference, Man Chan, a statistician at University College London's Clinical Trials Unit, presented data from 183 infants who began treatment within 12 weeks of birth in the CHER trial, and whose treatment was interrupted after either 40 or 96 weeks.

Though one child in the CHER trial has remained suppressed for 8.5 years since discontinuing ART, 80 percent of the children had experienced viral rebound by four months after treatment interruption, and the virus had rebounded in 182 within eight months.

What's more, researchers have no idea why the one child did not rebound, or what determined how long the other 182 were able to control the virus. Neither age at treatment onset nor treatment duration was associated with the time to viral rebound.

"ART does not induce elite controller status – ART is doing something different, even when started three days after infection," Malcolm Martin, chief of the laboratory of molecular medicine at the National Institute of Allergy and Infectious Diseases (NIAID), told the audience at the conference in a session titled "Stop it Now: Targeting Early Infection Events."

However, several recent studies by Martin and others suggest that long-term control might be achieved by combining ART and broadly neutralizing antibodies.

In 2017, Martin and his colleagues reported that treating monkeys with one of two broadly neutralizing antibodies, 3BNC-117 or 10-1074, delayed the onset of detectable virus in the blood by two to six months.

And although all animals did eventually have detectable virus in their blood, six of 11 animals were ultimately able to re-suppress the virus to undetectable levels, meaning they became elite controllers.

Martin said at CROI that his team is trying to extend that window of opportunity – "treating at day three is absurd" from a clinical perspective, he acknowledged.

But he said he thinks that the window of opportunity to make a difference is bigger than three days.

One reason is that his team's working hypothesis is that during treatment with a bNAb, "we're not actually preventing the initial infection."

That infection means there are viral particles around that form immune complexes with antibodies, and those complexes activate dendritic cells, which contribute to viral control over the long haul.

A study presented at CROI by researchers at Beth Israel Deaconess Medical Center also showed that combining the bNAb PGT-121 with an innate immune stimulant was able to convert roughly half of macaques into elite controllers. (See BioWorld, March 8, 2018.)

But bNAbs are not the only type of antibody that can combine with ART to improve the ability to control HIV. Also in the Stop It Now session, NIAID investigator James Arthos gave an overview of his work on a monoclonal antibody targeting the T-cell surface molecule alpha-4-beta-7 integrin (Alpha4beta7).

Arthos and his colleagues have shown that treating infected monkeys with an antibody to Alpha4beta7 early after infection had long-term effects on the number and activity of helper T cells.

And in 2016, Arthos and colleagues showed that when monkeys receiving ART were also treated with the antibody, they were ultimately able to stop taking both ART and the antibody.

Why the antibody works is still unclear. Alpha4beta7 is a gut-homing receptor, and the GI tract is a major site of viral replication and helper T-cell destruction early in HIV infection. The team, which was led by Emory University's Aftab Ansari, had originally hypothesized that blocking Alpha4beta7 would prevent helper T cells from going to the gut, and HIV would find fewer cells to infect. Entyvio (vedolizumab, Takeda Pharmaceutical Co. Inc.), an FDA-approved antibody for the treatment of ulcerative colitis and inflammatory bowel disease, works by reducing inflammation in the gut. But in their study, Arthos and his team found that there were high levels of helper T cells in their animals' guts after treatment.

HIV levels were still detectable in the animals that were treated with the antibody and subsequently taken off ART – as Arthos phrased it, they "keep blipping."

But the antibody enabled the animals to control infection "in a way that just ART doesn't," he said. "ART-alone animals die when ART is withdrawn."

A phase I trial testing whether Entyvio is safe and will affect the ability HIV-infected individuals on ART to control the virus is currently ongoing.