Broadly Neutralizing Antibodies Delayed Rebound in HIV Patients Who Stopped ART

SAN FRANCISCO — Most patients with HIV who received two broadly neutralizing antibodies (bNAbs) after pausing antiretroviral therapy (ART) avoided rebound for 5 months, a randomized trial showed.

At 20 weeks from analytical treatment interruption (ATI), 75% of participants who received bNAbs had not rebounded compared with 8.8% of those who received placebo (HR 0.09, 95% CI 0.04-0.21, P<0.0001), reported Sarah Fidler, PhD, MBBS, of Imperial College London, at the Conference on Retroviruses and Opportunistic Infections (CROI).

The median time to rebound was 62.3 weeks for the participants who received bNAbs. At 48 weeks, 57% of those who received bNAbs had not rebounded compared with 5% of those who received placebo. At 72 weeks, these rates were 39% versus 5%, respectively.

“We show that two long-acting broadly neutralizing antibodies can tend to maintain viral control for a long time after stopping treatment, and longer than has previously been demonstrated,” Fidler said. “They’re safe and seem to be working to reduce the size of the reservoir through immune activation.”

Three patterns of virological responses to bNAbs emerged during the study. The first was a rapid rebound within 20 weeks occurring in 23.5% of patients; half of these patients had envelope sequences predicting resistance to the antibody 10-1074 at rebound. The second pattern was a delayed rebound in which 48% of participants rebounded by week 72. The remaining seven participants (24%) remained undetectable past 72 weeks.

Fidler noted during a press conference that results from another study had shown that those who did not rebound “have a marked reduction in measures of their HIV reservoir, the pool of cells that harbor the sleeping virus that can prevent ART from curing HIV.” With regards to how the bNAbs control the reservoir virus, another poster presented at CROI showed that “bNAbs seem to be activating the immune system, and this immune activation is associated with viral control,” she said.

Athe Tsibris, MD, of Harvard Medical School and Brigham and Women’s Hospital in Boston, told MedPage Today that “it’s exciting that they can see reduction in rebound viremia well after these antibodies have cleared out of people’s systems.”

“I really do wonder if, even in people who are virologically suppressed, they’re managing to clear out HIV-infected cells,” he added.

While the long-term viability of this approach remains an open question, Tsibris said these steps are helping to figure out the “fundamental science behind the observation and see if there’s anything that we can learn eventually for a cure or for a treatment that is less common than people taking pills every day.”

The next step would be to identify better, more potent antibodies that can neutralize more broadly across HIV strains and test those to see if similar results occur, Tsibris said. “I think these early studies are very important to get a good proof of principle,” he noted. “Conventional wisdom says the virus should rebound as soon as that antibody is gone, and yet they’re showing that it does not, and I think that is the key finding that we have to explain in studies.”

The trial involved 68 participants who had been virally suppressed on ART for at least 12 months before enrollment and had a CD4 count greater than 500 cells/µL or a CD4:8 ratio greater than 1 at enrollment.

All had to be willing to access pre-exposure prophylaxis (PrEP) and additional appropriate protection to prevent transmission of HIV. Participants with co-infections or comorbidities were excluded, as were those who were predicted to have resistance to the monoclonal antibody 10-1074 based on envelope DNA sequencing.

The participants were all cisgender men with an average age of 39.5. Most (85%) were white, and average CD4 count at enrollment was 800 cells/µL. Most had HIV clade B (80%), and 6% had clade A.

All participants underwent ATI, with half receiving an infusion of placebo, and half receiving one infusion of two broadly neutralizing antibodies, 3BNC117-LS and 10-1074-LS. Participants could opt to receive a second blinded dose after 20 weeks.

The primary endpoint of viral rebound was defined as >1,000 copies/mL for 6 consecutive weeks, >100,000 copies/mL for two readings 1 week apart, or instances outside either of those criteria that were reviewed by an independent panel.

Conditions for restarting ART included viral rebound, a CD4 count dropping to below 350 cells/µL, clinical symptoms attributable to ATI, participant preference, or concerns over risk mitigation for transmission.

There were eight serious adverse events, including one death, but none were related to the antibodies or ATI, and there were no infusion reactions. No participants restarted ART due to CD4 count decline, and no HIV transmission occurred. Participants’ peak viral load was a median 55,245 copies/mL in the bNAbs group and a median 1,000,000 copies/mL in the placebo group, for an overall median of 63,525.

Nearly all participants (94%) achieved viral suppression within 12 weeks after restarting ART. Five participants who had a peak viral load greater than 1,000,000 copies/mL at rebound took 2 to 24 weeks to achieve viral suppression.

Please enable JavaScript to view the

comments powered by Disqus.