VRC01, an antibody that targets the HIV CD4 binding site, modestly delays viral rebound in patients with HIV who have discontinued antiretroviral therapy (ART), but does not maintain viral suppression through 8 weeks, according to results from two phase 1 clinical trials.
The results, published online November 9 in the New England Journal of Medicine, also suggested that VRC01 may select for preexisting VRC01-resistant virus and drive the emergence of new resistance.
Because ART suppresses HIV replication without eradicating the virus, viral rebound usually begins within days of stopping ART. Preliminary studies have suggested that broadly neutralizing antibodies may be able to control infection, but the new data show antibody combinations may be needed.
Experts advise that combination therapy is probably the way to go. One such study in monkeys suggests that combination therapy with an immune stimulating agent and an experimental HIV vaccine may provide a functional cure for HIV by controlling it without the need for ART. Results from that study were also published online November 9 in Nature.
VRC01 May Slow Rebound
The first study with VRC01, called the AIDS Clinical Trials Group (ACTG), was led by Katharine Bar, MD, and Pablo Tebas, MD, from the ACTG and the Penn Center for AIDS Research, and took place at the University of Pennsylvania and the University of Alabama. It included 14 male participants who received up to three doses of intravenous VRC01 (40 mg/kg) given 1 week before discontinuing ART, and then every 3 weeks after that, for up to three doses.
The second trial took place at the National Institutes of Health (NIH) in Bethesda, Maryland, and was led by Anthony Fauci, MD, Michael Sneller, MD, and Tae-Wook Chun, PhD. It included 10 participants (eight men, two women) who received intravenous VRC01 (40 mg/kg) 3 days before stopping ART, 14 and 28 days after interrupting ART, and once monthly after that.
Participants in both trials did not receive prescreening for sensitivity to VRC01.
Patients restarted ART following predefined criteria showing viral rebound or decreased CD4 counts. In the ACTG, the median time off ART was 6 weeks, whereas in the NIH trial it was 8 weeks.
No serious adverse events occurred. However, despite maintaining intended serum VRC01 concentrations, all participants experienced viral rebound by or before 8 weeks.
Participants in the ACTG had a median time to rebound of 4 weeks, whereas those in the NIH trial experienced viral rebound by a median of 5.6 weeks.
In both trials, VRC01 suppressed the virus at week four compared with historical controls. However, by week eight, the difference became nonsignificant.
Further analyses evaluating virus populations before starting ART, as well as before and after interrupting ART, showed that preexisting viral resistance was common, and suggested that VRC01 may exert selective pressure to further drive resistance.
The authors note that VRC01 resistance represents a "considerable challenge" to using broadly neutralizing antibodies such as VRC01 to treat HIV infection. Future clinical trials may need to consider prescreening for resistance.
"Our findings highlight an important consideration for the design of future clinical trials of passive immunotherapy in HIV-infected persons," they write. "Analogous to current regimens of highly successful combination ART that targets multiple HIV gene products, our data suggest that immunotherapy will probably require multiple [broadly neutralizing antibodies] that target different sites on the HIV envelope glycoprotein."
Given the issue of viral resistance to broadly neutralizing antibodies and the expense of producing such therapeutics, Marina Caskey, MD, from the Laboratory of Molecular Immunology, Rockefeller University, New York City, and colleagues, ask in a linked perspective whether scientists should even bother exploring this therapeutic avenue.
However, they described several advantages associated with the approach. Antibodies have naturally long half-lives compared with small-molecule drugs, and they can be further lengthened through genetic engineering techniques. Thus, passive immunization with antibodies may be needed just two or four times per year, whereas the best small-molecule drugs require administration every 2 months.
In addition, long-acting drugs may select for resistant viruses. Individuals who become infected with strains that are resistant to small-molecule drugs likely will not respond to ART regimens that contain the same drug classes. Antibodies that are in development, however, have different targets than standard antiretrovirals, so people who become infected with viruses that are resistant to such drugs may still respond to treatment.
Broadly neutralizing antibodies also have potential immune-enhancing aspects that may help control viral replication and decrease the size of the latent viral reservoir, raising the possibility of HIV eradication.
To decrease resistance that either preexists or develops over the course of treatment, the perspective authors also point out that a combination of antibodies may be needed.
They conclude, "Ongoing studies aim to explore their use for HIV-1 prevention and immunotherapy in infected persons."
Combinations Appear Active in SIV Model
The results of one such study suggest combination may be more effective, at least in animals, researchers report in a paper published November 9 in Nature.
"The objective of our study was to identify a functional cure for HIV — not to eradicate the virus, but to control it without the need for ART," lead author Dan Barouch, MD, PhD, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School in Boston, Massachusetts, said in an institute press release.
The idea was to draw latent viruses out of hiding by stimulating the immune system, then use the vaccine to induce immune responses that can kill the virus.
The 2-year study was conducted in 36 rhesus macaques infected with simian immunodeficiency virus, the monkey form of HIV. After receiving 6 months of ART, the monkeys received experimental vaccines alone, an immune stimulant alone, or a vaccine plus stimulant combination. Results showed that combination treatment was more effective than vaccine or immune stimulation alone.
After discontinuing ART, animals that received combination treatment showed evidence of delayed viral rebound. All of these animals also showed decreased viral loads, and one third of them had undetectable virus levels.
"If all the animals' viral loads had been undetectable, that would have been a home run," Dr Barouch also said in the press release. "But the fact that all animals showed a reduction in viral load and three out of nine were undetectable, that's a solid base hit. It's definitely something that we can work from."
The study was funded by the National Institute of Allergy and Infectious Diseases, Penn Center for AIDS Research, the Penn Clinical Trials Unit, the University of Alabama at Birmingham (UAB) Center for AIDS Research, the UAB Clinical Trials Unit, the ACTG Statistical and Data Analysis Center, and a Ruth L. Kirschstein National Research Service Award. Dr Tebas reports receiving personal fees from Merck and other support from GlaxoSmithKline. One coauthor reports receiving personal fees from Gilead Sciences, Alexion, The Medicines Company, and Cempra. Another coauthor reports personal fees from Columbus Technologies. Two other coauthors are employees of Janssen Diseases and Vaccines. Two other coauthors are employees of Gilead Sciences. One coauthor of the perspective reports pending patents related to antibody therapeutics. The other authors have disclosed no relevant financial relationships.
Nature. Published online November 9, 2016. Abstract
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Cite this: Neutralizing Antibody Modestly Effective in Patients With HIV - Medscape - Nov 09, 2016.