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Fast Response to REP 2139-Mg in 3 With HDV/HBV and Decompensated Cirrhosis
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EASL Congress 2023, June 21-24, Vienna
Mark Mascolini
Case studies of 3 people with hepatitis D virus (HDV) and hepatitis B virus (HBV) coinfection and decompensated cirrhosis showed rapid responses to REP 2139-Mg, a novel subcutaneous agent with multiple mechanisms, plus tenofovir disoproxil (TDF), for 48 weeks [1]. Researchers from Hôpital Beaujon AP-HP in Clichy and colleagues at other French centers, proposed that functional cure of HDV/HBV "appears achievable for the first time in this special population" [1].
Because liver transplantation remains the only treatment for people with chronic HDV infection and decompensated cirrhosis, French investigators tested the safety and efficacy of a novel agent, REP 2139-Mg, which disrupts HDV antigen function and blocks assembly and secretion of HBV subviral particles. (HDV propagation depends on coinfection with HBV). They combined REP 2139-Mg provided by the Replicor Compassionate Access Program [2] at a subcutaneous dose of 250 mg weekly with 245 mg of oral TDF daily and have administered the drugs under close observation to 3 people with chronic HDV infection and decompensated cirrhosis.
Patient 1 was a 56-year-old Caucasian woman, Patient 2 a 56-year-old African woman, and Patient 3 a 47-year-old African man. Alanine aminotransferase levels were well above normal in all three people (168, 64, and 89 U/L respectively), and HDV RNA levels measured 1.09 x 10(7), 4285, and 34,138 IU/mL . HBV DNA levels were undetectable in all 3 people, while HBsAg concentrations (indicating active HBV infection) were 1177 IU/mL in Patient 1, 4270 IU/mL in Patient 2, and 1273 IU/mL in Patient 3.
Patient 1 carried HDV genotype 1 and had decompensated cirrhosis with a Child-Pugh score of B8, portal hypertension, and ascites. Ultrasound confirmed reversal of ascites at REP 2139-Mg treatment week 4 and HBsAg loss at week 10. HBsAg seroconversion came at week 14 (27 mIU/mL rising to 478.5 mIU/mL at week 30). HDV RNA has not been detectable since week 20, the same point at which ALT returned to normal.
Patient 2 had HDV genotype 5 and had responded to HDV therapy with bulevirtide and pegylated interferon. HDV relapse occurred 1 year after she stopped bulevirtide and her condition progressed to decompensated cirrhosis with a Child-Pugh score of C11, portal hypertension, ascites, hepatocellular carcinoma (HCC), edema, and pronounced fatigue. Ultrasound at treatment week 4 showed reversal of ascites, while peripheral edema and fatigue improved markedly.
This patient had a successful liver transplant for HCC at REP 2139-Mg treatment week 10. Before the transplant, HDV RNA became undetectable at week 6. HBsAg had dropped to 1.75 IU/mL, and hepatitis B surface antibody (anti-HBs) measured 8 mIU/mL.
Patient 3 had HDV genotype 5 and decompensated cirrhosis marked by a Child-Pugh score of C10, portal hypertension, ascites, and hepatic encephalopathy. An antiviral response had not become evidence at treatment week 4. Although the researchers noted a significant reversal of ascites at week 6, ascites returned apparently because of the patient's poor diet.
No significant adverse events arose in any of these 3 people, who tolerated weekly subcutaneous dosing well.
The researchers concluded that weekly subcutaneous REP 2139-Mg plus daily TDF can promote rapid reversal of ascites in people with HDV/HBV and decompensated cirrhosis. The findings need confirmation in more people with decompensated cirrhosis and HDV/HBV. But if these early results point to a functional cure for people with HDV/HBV and decompensated cirrhosis, as these researchers proposed, many in this group might be spared the trauma and risks of liver transplantation.
References
1. Stern C, De-Freitas C, Bazinet M, et al. Safety and efficacy of REP 2139-Mg in association with TDF in chronic hepatitis delta patients with decompensated cirrhosis. EASL Congress 2023, June 21-24, Vienna. Abstract SAT-183.
2. ClinicalTrials.gov. Replicor Compassionate Access Program (RCAP). ClinicalTrials.gov identifier NCT05683548. https://clinicaltrials.gov/study/NCT05683548
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