A broadly neutralizing antibody (bnAb) failed to prevent overall HIV-1 acquisition better than placebo, but analyses of certain isolates offered early evidence that bnAb prophylaxis can be effective, researchers reported.
In studies conducted in the Americas, Europe, and sub-Saharan Africa of high-dose or low-dose VRC01 infusions, the incidence of HIV-1 infection/100 person-years was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group of the HVTN 704/HPTN 085 trials for an estimated prevention efficacy of 26.6% (95% CI −11.7 to 51.8, P=0.15), according to Lawrence Corey, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and HVTN 704/HPTN 085 and HVTN 703/HPTN 081 co-authors.
And in the HVTN 703/HPTN 081 trials, the incidence per 100 person-years was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (8.8% estimated prevention efficacy, 95% CI −45.1 to 42.6 P=0.70), they reported in the New England Journal of Medicine.
“Our trials were designed to evaluate whether long-term administration of a bnAb (VRC01) could prevent HIV-1 acquisition, whether susceptibility of the circulating viruses in the community to the bnAb would influence prevention efficacy according to subtype or gender, and whether we could determine the in vitro level of VRC01 neutralization sensitivity of viruses as a biomarker of protection,” the authors explained. “VRC01 did not prevent overall HIV-1 acquisition in either of our trials.”
They added that “Similar to what has been seen with first-generation antiretroviral therapy, innate resistance and selection of resistant isolates over time mitigate the effect of this treatment as a single preventive therapeutic agent.”
However, they pointed out that “Our data suggest that VRC01 applied pressure on the circulating strains of virus at the earliest stages of acquisition and may have suppressed infection in the tissue, with emergence of resistant isolates over time.”
In an editorial accompanying the study, Bruce D. Walker, MD, of the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University in Cambridge, offered a good news-bad news take on the results.
“The good news is that this strategy can indeed prevent [HIV-1] acquisition, but the caveat is that in the majority of participants it did not, and these findings have important implications for future prevention efforts,” he stated.
The “logistically complex and impressively conducted trials,” were ultimately not able to show significant VRC01-mediated protection in general, Walker explained. But “[t]he frequency of transmission of VRC01-sensitive viruses, defined as those with an 80% inhibitory concentration of less than 1 µg per milliliter, was 0.20 per 100 person-years among participants receiving VRC01, significantly lower than the 0.86 per 100 person-years in the placebo group,” he noted.
Walker stressed a couple of take-home messages from the research. First, passive immunization with VRC01 offered some protection against HIV-1 acquisition, “but only against viruses that were highly sensitive to the antibody,” he said.
“The trials also showed that serum neutralization titer, as measured with a standardized high throughput assay, may be predictive of protection, thereby providing an important metric for future trials,” Walker added.
Corey and co-authors enrolled at-risk cisgender men and transgender persons in the Americas and Europe (HVTN 704/HPTN 085) and at-risk women in sub-Saharan Africa (HVTN 703/HPTN 081), who were randomly assigned to receive infusions every 8 weeks of VRC01 at a dose of either 10 or 30 mg/kg or placebo, for a total of 10 infusions.
“VRC01 is a human IgG1 monoclonal antibody that has demonstrated in vitro neutralizing activity against approximately 90% of a diverse panel of HIV strains. It is a next-generation bNAb that targets a conserved region of the CD4 binding site on the HIV envelope gp120,” according to the NIH.
For the current trials, HIV-1 testing was done every 4 weeks, and the VRC01 80% inhibitory concentration (IC80) of acquired isolates was measured with the TZM-bl assay.
The authors reported the following:
- HIV-1 infection in 2,699 participants in HVTN 704/HPTN 085: 32 in the low-dose group, 28 in the high-dose group, 38 in the placebo group.
- HIV-1 infection in 1,924 participants in HVTN 703/HPTN 08: 28 in the low-dose group, 19 in the high-dose group, 29 in the placebo group.
Corey’s group also conducted a prespecified analyses that pooled data across the trials and found that the incidence of infection with VRC01-sensitive isolates (IC80 <1 μg/mL)/100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients for an estimated prevention efficacy of 75.4% (95% CI 45.5 to 88.9).
“The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates,” they stated.
As for treatment-related adverse events (AEs), moderate to severe AEs were observed in 1.2% of the people in HVTN 704/HPTN 085 and in 3.0% of the people in HVTN 703/HPTN 081. Half a dozen deaths occurred in both groups, but none were deemed to be related to VRC01 or placebo, according to the authors.
Corey’s group noted that other highly potent antibodies are currently in development, and bnAb combinations — 3BNC117-LS-J and 10-1074-LS-JPGT121.414.LS and VRC07-523LSPGT121, PGDM1400, 10-1074, and VRC07-523LS — are also under evaluation.
And VRC01 may have other potential applications. For instance, a March 2020 study looked at how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in a small group of “acutely treated and durably suppressed” patients, and the authors reported that “Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly.”
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VRC01, a human IgG1 monoclonal antibody, did not prevent overall HIV-1 acquisition more effectively than placebo in at-risk cisgender men and transgender persons in the Americas and Europe and in at-risk women in sub-Saharan Africa.
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Analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that broadly neutralizing antibody prophylaxis can be effective.
Shalmali Pal, Contributing Writer, BreakingMED™
The trials were supported by the National Institute of Allergy and Infectious Diseases (NIAID) and the Intramural Research Program/NIAID.
Corey reported no relationships relevant to the contents of this paper to disclose.
Cat ID: 339
Topic ID: 338,339,284,339,730,190,27,192,151,925
