From the Journals

Broadly neutralizing antibody VRC01 fails to sustain HIV viral suppression


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Passive immunization against HIV using the broadly neutralizing antibody VRC01 is associated with a delay in plasma viral rebound in individuals undergoing interruption of antiretroviral therapy, according to a new study, but the viral suppression is not sustained.

Two open-label trials investigated the impact of different dosing regiments of VRC01 in a total of 24 patients who were taking a break from antiretroviral therapy, according to a paper published Nov. 9 in the New England Journal of Medicine.

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VRC01 targets the CD4 binding site on the HIV envelope glycoprotein. In vitro data suggested the antibody had strong neutralizing capabilities, and studies in animal models showed it was able to prevent HIV transmission.

Katharine J. Bar, MD, of the Penn Center for AIDS Research at the University of Pennsylvania, Philadelphia, and her coauthors suggested broadly neutralizing antibodies such as VRC01 could target the persistent viral reservoir that leads to rapid viral rebound as soon as antiretroviral therapy is stopped (N Engl J Med. 2016 Nov 9. doi: 10.1056/NEJMoa1608243).

However, in these two studies, VRC01 did not achieve durable viral suppression. Overall, participants in both trials were significantly more likely than historical controls to maintain viral suppression 4 weeks after interrupting antiretroviral therapy (38% and 80% vs. 13%) but this difference was no longer significant by week 8.

In one trial – the A5340 – 12 of the 13 participants with data that could be evaluated showed viral rebound to more than 200 copies/mL by week 8, and in the second NIH trial, the median time to rebound of 40 copies/mL was 39 days.

All participants showed similar plasma levels of VRC01 that had been observed in previous trials – significantly above 50 mcg/mL for 8 weeks in the A5340 trial and above 100 mcg/mL in the NIH trial. Plasma VRC01 levels were consistently above 50 mcg/mL even at the time of viral rebound, except in one patient.

Researchers performed post hoc analyses of the sequence diversity at the time of viral rebound and compared these to samples from eight participants taken before initiation of antiretroviral therapy.

“Sequence-based and neutralization analyses suggest that VRC01 can restrict the clonality of rebounding virus in some participants, selecting for pre-existing resistance, and drive the emergence of VRC01-resistant virus,” the authors wrote.

However, they pointed out that the early years of antiretroviral drug development showed how quickly resistance could develop in a single-agent situation. Since that time, a multiagent approach directed at different targets has achieved much more potent and sustained viral suppression.

“Analogous to current regimens of highly successful combination ART that targets multiple HIV gene products, our data suggest that immunotherapy will probably require multiple bNAbs [broadly neutralizing antibodies] that target different sites on the HIV envelope glycoprotein,” the authors concluded.

The study was supported by the National Institute of Allergy and Infectious Diseases, the Penn Center for AIDS Research, the Penn Clinical Trials Unit, the University of Alabama at Birmingham Center for AIDS Research, the UAB Clinical Trials Unit, the AIDS Clinical Trials Group Statistical and Data Analysis Center, a Ruth L. Kirschstein National Research Service Award, and the National Institutes of Health.

Two authors declared personal fees from pharmaceutical industry outside the submitted work, and one author served as a contractor to the NIH through Columbus Technologies. No other conflicts of interest were declared.

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