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Pre- and Post-Bulevirtide Biopsies Show HDV RNA Drops in Liver Track With Drops in Blood
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EASL Congress 2024, June 5-8, 2004, Milan
Mark Mascolini
Paired pre- and posttreatment liver biopsies in a trial of bulevirtide with or without pegylated interferon-alfa2α (pegIFN) showed "a strong correlation" between HDV RNA declines in liver and blood [1]. The greatest off-treatment virologic response in liver came with the highest bulevirtide dose assessed, 10 mg daily, plus pegIFN weekly.
Researchers from the University Medical Center Hamburg-Eppendorf reminded colleagues of the sparse treatment options for HDV infection, which teams with HBV to cause the most severe form of viral hepatitis. Scant medications to treat HDV infection include off-label (unlicensed) pegIFN and (in Europe) 2 mg of subcutaneous bulevirtide daily for adults with chronic HDV infection and compensated liver disease.
To get a better understanding of bulevirtide's liver impact in people with HDV, researchers involved in the open-label, randomized, phase 2b MYR204 trial compared pretreatment and 24-week posttreatment biopsies of people who took 10 mg of bulevirtide subcutaneously daily for 96 weeks with pegIFN (180 ug weekly), 2 mg of bulevirtide daily plus pegIFN for 96 weeks, 10 mg of bulevirtide daily without pegIFN for 96 weeks, or pegIFN alone for 48 weeks [2]. Researchers collected 42 paired pre- and posttreatment liver biopsies to assess levels of HDV RNA and HBV RNA and host gene expression. They gathered 50 paired biopsy samples for immunohistochemistry for HDV antigen (HDAg) and HDAg-positive cell counts. And they assessed biochemical and virologic parameters in peripheral blood.
HDV RNA levels in liver fell from baseline to 24 weeks after the end of treatment (study week 120) in almost all 42 biopsy study participants. The biggest off-treatment drop in HDV RNA came in 11 people taking 10 mg of bulevirtide daily plus pegIFN (-3.16 log10 vs -1.99 log10 in 14 people getting 2 mg of bulevirtide daily with pegIFN). Eight of 11 people (73%) getting 10 mg of bulevirtide daily plus pegIFN versus 8 of 14 (57%) getting 2 mg daily plus pegIFN had undetectable HDV RNA in liver.
After 72 weeks of treatment, serum HDV RNA fell most among people getting 10 mg of bulevirtide plus pegIFN, followed by 2 mg of bulevirtide plus pegIFN, 10 mg of bulevirtide without pegIFN, and pegIFN alone. At week 120, 24 weeks after the end of treatment, serum HDV loads had rebounded in all three bulevirtide groups. At that point median loads had dropped 3.48 log10 IU/mL with 10 mg of bulevirtide plus pegIFN, 3.13 log10 IU/mL with 2 mg of bulevirtide plus pegIFN, and 2.01 log10 IU/mL with 10 mg of bulevirtide without pegIFN.
Among people taking bulevirtide, HDAg-positive cell numbers fell from pretreatment levels in all three treatment groups. People taking 10 mg of bulevirtide daily with pegIFN had the biggest median fall (-1.85 log10 IU/mL, 67% below the lower limit of quantitation [LLOQ]), followed by 2 mg of bulevirtide daily plus pegIFN (-0.98 log10 IU/mL, 44% below LLOQ), and 10 mg daily without pegIFN (-0.77 log10 IU/mL, 8% below LLOQ).
HDV RNA levels in liver correlated strongly with number of HDAg-positive cells (r = 0.85, P < 0.0001), a finding suggesting bulevirtide lowers the number of HDV-infected cells in liver. Change from baseline in HDAg-positive cells correlated even more strongly with change from baseline in liver HDV RNA (r = 0.96, P < 0.0001). Change from baseline serum HDV RNA correlated with change from baseline liver HDV RNA (r = 0.82, P < 0.0001), and serum HDV RNA correlated with liver HDV RNA (r = 0.34, P = 0.0027).
In contrast, HBV RNA levels did not change significantly between baseline and 24 weeks after treatment ended. But total HDV RNA fell modestly in the combination treatment arms.
The researchers recorded low expression of inflammatory chemokines and cytokines after bulevirtide/pegIFN combination therapy and with pegIFN monotherapy 24 weeks after the end of treatment. But reduced mRNA expression of the chemokine CXCL10 correlated with HDV RNA in the liver (r = 0.67, P < 0.0001) and with alanine aminotransferase (ALT, r = 0.75, P < 0.0001).
The investigators stressed that paired pretreatment and posttreatment analysis of liver biopsies in people taking the HDV and HBV entry inhibitor bulevirtide disclosed a strong correlation between falling HDV RNA in liver and blood. They stressed that, as in HDV studies in blood, these liver analyses found the highest rate of off-treatment virologic responses in people taking 10 mg of bulevirtide daily plus weekly pegIFN.
References
1. Allweiss L, Volmari A, Manuilov D, et al. Bulevirtide in combination with pegylated interferon alfa-2a shows a sustained off-treatment response in the liver. EASL Congress 2024, June 5-8, 2004, Milan. Abstract OS-122.
2. ClinicalTrials.gov. study to assess efficacy and safety of bulevirtide in combination with pegylated interferon alfa-2a in participants with chronic hepatitis delta (CHD. ClinicalTrials.gov ID NCT03852433.
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