Presentation Details
| Seroprevalence and Seroconversion among People with Hemophilia A in the United States: Observations from the SAAVY (Seroprevalence of AAV antibodY) Study Amy Shapiro1, Leonard A.Valentino2, 3, David Hinds4, Manil Vaghela5, Erin Goodman4, Karim Iskander4, George Dela Cerda 4, Kim Schafer6, Steven Pipe7. 1Indiana Hemophilia Thrombosis Center, Indianapolis, IN, USA.2National Bleeding Disorders Foundation, New York, NY, USA.3Rush University, Chicago, IL, USA.4BioMarin Pharmaceutical, Novato, CA, USA.5BioMarin Pharmaceutical, London, United Kingdom.6Hemostasis and Thrombosis Center, UC Davis Health, Sacramento, CA, USA.7Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, MI, USA |
Abstract
Background: Pre-existing immunity against adeno-associated virus (AAV) can restrict patient eligibility to AAV-mediated gene therapy, yet published data on AAV seroprevalence and seroconversion among people with hemophilia A (PwHA) are limited. Objective: To quantify the seroprevalence of antibodies to AAV5, AAV6, and AAV8 (including antibody titers) and seroconversion over time among PwHA. Methods: US adult PwHA in the observational SAAVY study were assessed for the presence of AAV antibodies at an initial blood draw (baseline) and randomized to have a follow-up assessment at either 3- or 6-months after the initial draw. Seroprevalence was described as the proportion and 95% confidence intervals (CI) of participants with antibodies to an AAV serotype at baseline. Seroconversion was described as the proportion of participants changing AAV serostatus between baseline and follow-up. Seroconversions from AAV– (no antibodies) to AAV+ (presence of antibodies) and AAV+ to AAV– were described separately. Antibody titers as measured by serial dilution were described among participants with antibodies (AAV+ participants). Results below the minimum required dilution (<20) were imputed as 20 for summary statistics. Results: 106 participants had a baseline serostatus assessment. The mean age of participants was 45 years (standard deviation= 15 years) and the population was comprised of 47% with severe, 19% with moderate, and 34% with mild hemophilia A. 34.0% of participants (95% CI: 25.0%-43.8%) had AAV5 antibodies, 37.7% (28.5%-47.7%) had AAV6 antibodies, and 41.5% (32.0%-51.5%) had AAV8 antibodies at baseline. 45 and 41 of the 106 participants had a 3-month or 6-month re-assessment, respectively (n=20 were lost to follow-up). Zero of the 27 participants who were AAV5– at baseline and re-assessed at 3-months seroconverted to AAV5+, while 1 of the 27 (3.7%) AAV5– participants at baseline and re-assessed at 6-months seroconverted. Seroconversion was similar for AAV8 (1/29, 3.4% at 3-months; 1/19, 5.3% at 6-months), but higher for AAV6 at 6-months (1/28, 3.6% at 3-months; 4/23, 17.4% at 6-months). Seroconversion from AAV+ to AAV– was more frequently observed than AAV– to AAV+ for AAV5 and AAV8, though not for AAV6: AAV 5 (4/18, 22.2% at 3-months; 1/14, 7.1% at 6-months); AAV6 (1/17, 5.9% at 3-months; 1/18, 5.6% at 6-months); AAV8 (3/16, 18.8% at 3-months; 6/22, 27.3% at 6-months). Antibody titers were lowest for AAV5, followed by AAV6 and AAV8: median [interquartile range] AAV5 titer, 46.5 [20.0-129.5]; AAV6 titer, 899.5 [121.0-3072.5]; AAV8 titer, 176.5 [38.5-498.5]. Conclusions: Trends in seroprevalence between AAV serotypes and antibody titers were consistent with previous seroprevalence estimates for the US, with the AAV5 having a lower seroprevalence relative to AAV6 or AAV8. Seroconversion from AAV+ to AAV– was more frequently observed than AAV– to AAV+. Factors associated with seroconversion require further exploration, as well as exploration of seroconversion beyond 6-months. Though based on small numbers, data from the SAAVY study strengthen growing evidence that PwHA without AAV antibodies are likely to remain AAV– over a 6-month period.
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