乌鸦传媒

An attempt to "shock and kill" the latent reservoir of HIV using an investigative neutralizing antibody and an anticancer agent together failed to make a significant impact, researchers reported here.

After 48 weeks, there was no change in the size of the HIV reservoir with romidepsin (Istodax) -- an anti-lymphoma agent -- either alone or used together with 3BNC117, a neutralizing antibody, reported Ole Sogaard, MD, PhD, of Aarhus University Hospital in Denmark.

In his presentation of the so-called ROADMAP study at the virtual Conference on Retroviruses and Opportunistic Infections (CROI), Sogaard said: "Latency reversal with currently available agents and boosting of autologous HIV-specific immunity may not be very effective in long-term suppressed patients."

He and his colleagues sought to determine if the shock-and-kill strategy of using broadly neutralizing antibodies prior to latency reversal could help eliminate infected cells by coaxing the cells from their reservoirs.

In the ROADMAP study, that strategy failed, Sogaard said. The primary endpoint was the days to viral rebound during analytical treatment interruption, defined as plasma HIV RNA greater than 200 copies/mL on two consecutive measurements, or days to re-initiation of antiretroviral therapy in participants who restarted antiretroviral therapy before viral rebound.

In his pre-recorded presentation for the coronavirus pandemic-canceled CROI meeting, Sogaard said the study found:

• No evidence of a decline in the size of the reservoir in either group

• No clear delay in time to viral rebound

• No induction of HIV-specific immunity following 3BNC117 infusions in patients on combination antiretroviral therapy

• No detrimental effect of romidepsin on HIV-specific immunity

Commenting on the study, Joseph McGowan, MD, medical director of the Northwell Health HIV Service Line Program in Manhasset, New York, told 乌鸦传媒 that the shock-and-kill strategy was one of the first adopted to reduce the HIV reservoir, but to date it has been disappointing.

Some of the concerns raised, he said, have been the lack of ability of tested agents to adequately "shock" HIV more completely from its deep-seated hiding places -- agents with higher potency and reduced toxicity would be needed, he explained.

In addition, the "killing" would have to be enhanced, for which the neutralizing antibody was added. Other agents, such as vaccines and immune checkpoint inhibitors, are also being explored, he said. "Unfortunately, more work is needed if this will emerge as a viable cure option."

McGowan noted that researchers continue to seek ways of eliminating the reservoirs, and thus perhaps be able to cure patients, even though current HIV treatment does successfully suppress the virus. "We have very potent and reasonable safe treatment options today, but they require a high level of lifelong commitment and adherence, which is a challenge," he said. "The issues of mental illness, substance use, health insurance, health literacy, unstable housing, and employment are huge challenges to a lifetime of therapy adherence."

"Also, long-term toxicity, although reduced, is still a problem for many people, especially as the population of people living with HIV and AIDS continues to age," McGowan continued. "Increased weight, insulin resistance, lipid changes, platelet activity, etc. are issues that continue to plague our current regimens and for which we have incomplete appreciation of etiology and long-term impact. So, if you add the burden of chronic concomitant medication for diabetes, hypertension, and other diseases of aging to the challenge of antiretroviral adherence, it becomes even more difficult to sustain. Cure will certainly be a challenge, but I believe it should remain a critical goal. It is also a strong motivator to maintain viral suppression until that end is achieved."

For the , the researchers randomized 11 patients to receive romidepsin plus 3BNC117 and nine to romidepsin alone; patients were treated for 24 weeks.

Sogaard explained that 3BNC117 is a broadly neutralizing antibody targeting the CD4-binding site on the HIV-1 env protein. He added that the antibody has been safe and well tolerated in studies involving more than 100 individuals, and data indicate that it facilitates the elimination of HIV env-expressing cells.

in the U.S. for treatment of lymphomas.