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INFILTRATION OF VRC01 INTO THE CEREBROSPINAL
FLUID IN
HUMANS IN THE RV397 STUDY
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CROI 2020
Poster pdf attaced here
Download the PDF here
Madhu Prabhakaran1, Sandeep Narpala1, Lucio Gama1, Donn J. Colby2,3, Phillip Chan2, Carlo Sacdalan2, Khunthalee Benjapornpong2,
Jintanat Ananworanich2,3, Nittaya Phanupak2, Suteeraporn Pinyakorn3, Trevor A. Crowell3, Serena Spudich4, Adrian
1Vaccine Research Center, National Institutes of Health, USA; 2SEARCH - Thai Red Cross AIDS Research Centre, Thailand; 3US Military HIV Research Program, Walter Reed
Army Institute of Research, Silver Spring, MD, USA; 4Yale University, USA
abstract
HIV may persist in the central nervous system (CNS) despite antiretroviral therapy (ART), creating a barrier to HIV eradication. Novel strategies to reduce the latent HIV reservoir may need to cross the blood brain barrier (BBB) into the cerebrospinal fluid (CSF). Targeting the CD4 binding site, VRC01 is a broadly neutralizing antibody (bNab) capable of potently neutralizing over 90% of HIV-1 strains.
The RV397 study conducted in Bangkok, Thailand was a randomized, double-blind, placebo-controlled trial that randomized participants who initiated suppressive ART during acute HIV infection to receive VRC01 40mg/kg or placebo intravenously every 3 weeks during analytic interruption of ART (ATI). CSF samples were collected at two time points from 3 participants who received VRC01: pre-infusion and 2-4 days after first detectable plasma viral load. VRC01 levels were quantified using a standardized sensitive Singulex single molecule counting technology with a lower limit of quantitation (LLOQ) of 50pg/ml for VRC01. CSF VRC01 concentration was compared to concurrent plasma level for each participant.
Three males, aged 18-47 years, initiated ART during acute HIV (Fiebig stages 1 or 2) and were on ART for at least 28 months before ATI. Pre-infusion, pre-ATI, CSF HIV RNA was <80 copies/ml, CSF WBC <2 cells/μl, CSF protein <38 mg/dL, blood HIV RNA <20 copies/ml and CD4 >400 cells/μL. Post ATI, post-VRC01 infusion CSF HIV RNA was <80 copies/ml, CSF WBC <2 cells/μl, CSF protein <43 mg/dL, blood HIV RNA 418-1789 copies/ml and CD4 T >400 cells/μl. VRC01 levels in CSF were below LLOQ preinfusion and ranged between 0.35 - 0.75ug/ml post-infusion (see Table). Concurrent VRC01 levels in plasma were 200-600ug/ml, indicating a 100-1000 fold lower penetration into the CNS compartment.
We report here the successful quantification of the bNab VRC01 in the CSF from 3 persons living with HIV. The bioavailability of this potent and broad HIV monoclonal antibody in the CNS is critical considering that the CNS can facilitate the generation of resistant HIV quasi-species that are distinct from virus in systemic circulation. These results thus serve to inform the design of immunotherapies to target HIV infection in the CNS.
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