For the last few years, there has been great excitement in the HIV field about broadly neutralizing antibodies that target the virus. However, when only a single antibody against the virus is given, HIV often mutates or changes to become resistant. For that reason, combinations of antibodies against HIV are being studied. An alternative approach is to target the human receptor for the virus, CD4. The antibody ibalizumab, does just that — by targeting CD4, ibalizumab blocks HIV from entering cells. Ibalizumab was recently approved for treatment of HIV that is resistant to other medications. Now, results of a study of a new antibody, UB-421, have been published.
UB-421 also targets CD4, like ibalizumab, but it aims at a different part of CD4. Instead of testing it against multidrug-resistant HIV, the researchers in this study did something interesting. They focused on substituting the antibody for standard oral HIV treatment.
They enrolled 29 people who were on oral HIV therapy and gave them the antibody by IV infusion, and then stopped oral ART a week after the first infusion was administered. This was followed by multiple doses of the antibody for 8 or 16 weeks.
What I think is interesting and exciting about the study is that essentially all of the participants maintained viral suppression for anywhere from 8 to 16 weeks with infusions of the antibody. The reason this single antibody is working is probably because it is targeting the human CD4 receptor, which does not change or mutate like the virus does.
Now, a couple of cautionary notes to mention. About half of the participants did have a mild rash, and it was transitory. But one person had to stop the antibody because of the rash. About a quarter of participants had low levels of detectable HIV, but it did not exceed the threshold of 200 copies. So, that is promising, but it is something that needs to be watched.
What I took away from this study was that if you give an antibody directed against CD4, it can maintain virologic suppression, at least in the short-term. Now, what needs to be done is to see if the antibody works in a larger number of people and for a longer time. This trial should prompt bigger and longer studies.
How this antibody might be used if larger and longer studies show it to be safe and effective, still needs to be determined. Would it be used for people whose virus has become resistant to first- and second-line therapy, and now need a third-line — like ibalizumab? Would the antibody be used to replace oral daily therapy? UB-421 is given through an IV, so it is less convenient than oral therapy because the patient must come into the office to receive an IV infusion rather than taking a pill. There are also new investigational antiretrovirals, cabotegravir plus rilpivirine, that are given by injection into a muscle, which may be easier than an IV. Those new injectable drugs are likely to be submitted to the FDA this year; we will see what the FDA says but, if approved, those injections may be another option rather than daily pills for some people.
There are other possibilities with UB-421. If the antibody has an effect on the immune system and HIV reservoir, that would be exciting. And if they could make the antibody, or another antibody, that could be engineered to last not 1 week, not 2 weeks but for many months, that would be a major advance. We are not there yet but this is an area to explore for the future.
What I am excited about in general is, even after decades of advances in ART, we continue to develop new approaches and new medicines. It is not like the HIV field is resting on its laurels. As we continue to make advances, however, let us not forget: We need to make sure everyone with HIV has access to the life-saving medicines that we have available right now.
Rajesh T. Gandhi, MD
Vice chair, HIV Medicine Association
Director of HIV clinical services and education,
Massachusetts General Hospital
Professor of medicine, Harvard Medical School
Disclosures: Gandhi reports receiving education grants to his institution (Massachusetts General Hospital) from Gilead Sciences, Janssen, Theratechnologies and Viiv Healthcare, and serving on scientific advisory boards for Gilead and Merck.