CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

782

Simulation Modeling of Hepatitis B Virus Disease Progression, Hepatitis Flares, and Functional Cure Amir Mohareb 1 , Virginia Talbot 1 , Arthur Y. Kim 1 , Maya Hajny Fernandez 1 , Anders Boyd 2 , Kenneth A. Freedberg 1 , Emily Hyle 1 1 Massachusetts General Hospital, Boston, MA, USA, 2 Amsterdam University Medical Centers, Amsterdam, Netherlands Background: Nearly 300 million people have chronic hepatitis B infection (HBV), which can result in hepatic complications (e.g., cirrhosis and hepatocellular carcinoma [HCC]) and mortality. Our objective was to develop and validate an HBV simulation model to examine disease progression, treatment, and cure. Methods: We developed an HBV simulation model with nine health states: HBV-uninfected; no fibrosis; moderate/severe fibrosis; cirrhosis; HCC; end-stage liver disease; hepatitis flare (ALT >3x upper limit of normal); HBV surface antigen (HBsAg) loss; and death. We incorporated anti-HBV effects of tenofovir as lowering incidence of fibrosis, cirrhosis, HCC, and hepatitis flare. Input parameters included: progression to fibrosis or cirrhosis (0.3-2.5/100 person years [PYs]), incidence of HCC (0.05-0.42/100 PYs), hepatitis flares (2.0-10.0/100 PYs), and functional cure (1.0/100 PYs). We modeled the risk reduction with tenofovir for fibrosis/cirrhosis (0.37), HCC (0.59), and hepatitis flares (0.15). Model outcomes included the cumulative incidence of fibrosis, cirrhosis, HCC, HBsAg loss, and survival. We simulated the benefits of tenofovir therapy and the effects of tenofovir cessation for a cohort with HBV genotype B or C and mean starting age of 40 years. We also validated the model to simulate HCC incidence in a population of African origin. Results: Consistent with data from the Western Pacific region, 10-year cumulative incidence of fibrosis, cirrhosis, and HCC in untreated HBV would be 27.5%, 7.3%, and 1.0%, respectively. Uninterrupted tenofovir therapy would reduce liver-related complications and improve 10-year survival for an adult cohort with genotype B or C (97.7% v. 95.1% without treatment). After tenofovir cessation, people would have an increased risk of hepatitis flares (53% over 12 months) but a higher rate of HBsAg loss (1.9% at 12 months), consistent with HBV treatment cessation studies. Model validation produced equivalent HCC projections to a published cohort of people of African origin (10-year cumulative incidence 2.33% v. 2.45%, root-mean-square error 0.126). Conclusions: We developed and validated an HBV simulation model that incorporates the impact of treatment and its cessation on clinical outcomes; when used in conjunction with established HIV models, it can also be used to simulate HIV-HBV coinfection. This model will help to address clinical and policy questions such as HBV cure, the risks and benefits of tenofovir cessation, and pre-exposure HIV prophylaxis.

783

HIV/HCV Coinfection: Extracellular Vesicles Modulate NK Functionality in Relation to Liver Fibrosis Ariel A. Osegueda 1 , Alan Adamczyk 1 , Luz Leicaj 1 , Leonel Cruces 1 , Lucía Baquero 1 , Paula Benencio 2 , Tomas Langer 1 , Virginia Gonzalez Polo 1 , Matías Ostrowski 1 , Natalia Laufer 1 1 Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Buenos Aires, Argentina, 2 University of Buenos Aires, Buenos Aires, Argentina Background: Plasma extracellular vesicles (pEV) play a role modulating the immune response. In HIV/HCV coinfection, NK cells are crucial in eliminating activated hepatocellular stellate cells, responsible for progression to liver fibrosis (LF). We previously showed that in individuals with advanced LF (F4), NK cells presented an exhausted phenotype and impaired functionality even after elimination of HCV by direct-acting antivirals (DAA). Here, we aimed to characterize the effect on NK cell functionality of pEV from individuals with HIV/ HCV and mild (METAVIR score F0/F1) or advanced LF (F4). We hypothesized that F4 pEV will have a negative impact on NK cells functionality. Methods: pEV were purified by size exclusion chromatography from 2 mL of plasma from F0/F1 (n=5) and F4 (n=5) individuals at baseline (before DAA), EoT (end of treatment) and >= 1 year after successful treatment and from healthy controls (n=4). pEV were resuspended in 60 uL of PBS. PBMC were isolated from healthy donors and incubated for 1 hour with 30 uL of pEV suspension from each condition before conducting the NK cell functionality assay. After pEV incubation, PBMC (1x10 6 ) were cocultured with K562 at a 10:1 ratio (1:1 NK:K562) for 2 hours. NK cell degranulation was evaluated by FACS analysis of CD107a, CD3, CD56 expression and a cell viability marker. We report NK relative degranulation as the ratio between NK CD107a+ in each condition and NK CD107a+ in absence of pEV. Data was analyzed using nonparametric statistics. Results: We found that pEV from all participants, including healthy donors, consistently reduced NK CD107a expression, compared to NK cells in the absence of pEV. However, pEV from individuals with advanced liver fibrosis exhibited a higher suppressive effect on NK cell functionality than those from healthy donors (0.70 vs 0.88; p=0.03) and individuals with mild fibrosis at baseline (0.70 vs 0.85; p=0.03). The inhibitory effect of pEV on NK cell cytotoxicity was lower at EoT and at >= one year after EoT than baseline, for both groups. Conclusions: We show evidence that pEV from individuals with advanced LF could play a role in the overall exhausted phenotype observed in NK cells from this group. This context could be one of the factors associated with little or no improvement of LF in individuals with F4 LF after eliminating HCV by DAA treatment. Further characterization of the composition of pEV could reveal therapeutic targets to reverse NK cell dysfunction and mitigate fibrosis in individuals with F4 LF. In Vitro and In Vivo Immunogenicity of a Dendritic Cell-Based Vaccine Targeting HBV Epitopes Nour Ghazzaui 1 , Mathieu Surenaud 1 , Guillaume Hypolite 1 , Florence Picard 1 , Émile Foucat 1 , Anaïs Kembou 1 , Marie-Laure Plissonnier 2 , Mireille Centlivre 1 , Fabien Zoulim 2 , Aurélie Wiedemann 2 , Véronique Godot 1 , Yves Lévy 1 , Sylvain Cardinaud 1 1 Vaccine Research Institute, Créteil, France, 2 Institut national de la santé et de la recherche médicale (Inserm), Paris, France Background: Persistent chronic HBV infection is associated with impaired functional T-cell specific responses and a lack of memory T-cells against core (C), polymerase (P), and envelope proteins (S). Therapeutic vaccination is aimed to relieve exhausted T-cells and to stimulate recall memory T-cells. We have developed an antigen-presenting cell (APC)-targeting approach allowing the delivery of specific antigens through a mAb targeting the CD40 receptor. Methods: HBV C, P, and S proteins (genotype Dayw) were screened in silico to identify immunogenic and conserved epitopes. Six selected peptides were fused to a humanized anti-CD40 IgG4 mAb. The immunogenicity of the resulting CD40.HBV vaccines was evaluated in hCD40 transgenic mice in a prime/boost regimen (10mcg/mouse with 50mcg of Poly-ICLC). IgG binding to S and C was measured via Luminex assay, while T-cell immunity was assessed using IFN-γ ELISpot. Additionally, PBMCs from NUC-treated chronically infected donors (CHB, n=19) were stimulated in vitro with 1nM to 10nM of the vaccine, and the expansion of functional CD4+ and CD8+ memory T-cells was analyzed by FACS. Results: Two peptides from S and 2 from C were selected and successfully conjugated with the CD40 mAb (CD40.HBV(S/C)), or the non-targeting IgG4 control mAb (IgG4.HBV(S/C)) while 2 peptides from P were associated with a second vaccine (CD40.HBV(P)). The co-injection of CD40.HBV(S/C) and CD40.

Poster Abstracts

784

CROI 2025 232