Introduction

Chronic infection with the hepatitis D virus (HDV) may lead to rapid progression towards liver cirrhosis and portal hypertension. For this study, we characterized the cohort of Austrian HDV patients and their response to bulevirtide (BLV) treatment.

Aims & Methods

We included anti-HDV positive patients who visited one of six participating Austrian hepatology centers from 2020 onwards. At baseline (BL), demographic, clinical and laboratory data, endoscopy and imaging reports, liver stiffness measurement (LSM) and liver steatosis assessment (using controlled attenuation parameter, CAP) were recorded. If available, hepatic venous pressure gradient (HVPG) and histologic assessment of liver biopsies were included. In a subset of patients, single nucleotide polymorphisms (SNPs) in IL28B, PNPLA3, SERPINA1 and NTCP were assessed. Patients without BLV treatment were characterized at last contact. Patients who received treatment with BLV were evaluated for biochemical response (BR, defined by normalization of ALT), virological response (VR, negative HDV RNA PCR or ≥2log decline in viral load), or combined response (CR, meeting both BR+VR) every 24 weeks (W24, W48, W72, W96).

Results

Overall, 84 anti-HDV positive patients were included (median age 45.5 years [IQR 37-56), 58.3% male, median BMI 25.0 [IQR 21.4-29.0]), of which 59 (70.2%) had detectable HDV RNA. Nine (10.7%) patients reported daily alcohol intake. Eleven (13.1%) patients were coinfected with HIV and 17 (20.2%) had anti-HCV antibodies. A LSM ≥10 kPa was found in 36 (54.4% of 66) of patients and ≥25 kPa in 9 (13.6%). Liver biopsy showed F4 fibrosis in 19 (52.8% of 36) of patients. Esophageal varices were found in 15/61 (15.4%) in endoscopy and 12/50 (19.4%) had signs of portal hypertension on imaging reports. Median HVPG was 10 mmHg (IQR 6.75-15.5, n=28) and eleven (13.1%) patients were decompensated at baseline. Median MELD was 8 points (IQR 6-10). No polymorphisms were found regarding SERPINA1 or NTCP, while for PNPLA3 we found C/C n=15 (37.5%), C/G n=22 (55.0%) and G/G n=3 (7.5%); and for IL28B we found C/C n=17 [49.9%], C/T n=16 (43.2%) and T/T n=4 (10.8%).
Of 59 viremic patients, 50 were started on treatment with BLV (median treatment duration 17 [7.5-24] months). BR rates at W24, W48, and W96 were 27/46 (58.7%), 28/38 (73.7%), and 16/22 (72.7%). VR rates at M6, M12, and M24 were 15/46 (32.6%), 24/38 (63.2%), and 15/22 (68.2%). CR rates at M6, 12, and M24 were 10/46 (21.7%), 18/38 (47.4%), and 11/22 (50.0%). At W48 BLV treatment led to a decline of ALT (p<0.001), HDV RNA (p<0.001), and LSM (p < 0.006).
SNPs in either PNPLA3 or IL28B did not affect treatment outcomes. Ten patients who achieved clearance of HDV discontinued BLV, of which 4 relapsed and were restarted on BLV. Pegylated interferon alfa-2a was added to BLV treatment in 13 (26%) patients after a median of 10 (7-18) months. During follow-up, three (3.6%) patients – all without BLV treatment - were diagnosed with hepatocellular carcinoma and overall, five (6.0%) patients died, of which four deaths were liver-related.

Conclusion

Our Austrian HDV patient cohort showed a substantial burden of cirrhosis and signs of portal hypertension – still we observed high and steadily increasing rates of virologic and biochemical response to BLV treatment. Liver stiffness – as a surrogate of the risk for liver-related events – decreased significantly at W48.

Disclosure

M.P., M.Str., A.F.S., S.R., A.M., L.D., E.A. have nothing to disclose.
M.S. received travel support from MSD, Sandoz, BMS, AbbVie and Gilead; and speaking honoraria from BMS and Gilead.
C.S. received travel support from Gilead, Abbvie, Galápagos, and Gebro; speaking honoraria from Abbvie and Gilead; and payments for consulting from Gilead.
D.B. received travel support from Gilead and AbbVie; speaking honoraria from AbbVie and Siemens and grant support from Gilead and AbbVie.
A.M. received grant support from Abbvie and Gilead; speaking honoraria from Abbvie, Gilead, Janssen, Roche, Intercept, and MSD; consulting/advisory board fees from Abbvie, Gilead, Janssen, Roche, Intercept, Norgine, and MSD; and travel support from Abbvie, Gilead and Roche.
M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Madrigal, Novartis, Phenex, Pliant, Regulus, and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept, as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid filed by the Medical Universities of Graz and Vienna.
M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Collective Acumen, Echosens, Gilead, Takeda, and W. L. Gore & Associates and received travel support from AbbVie and Gilead.
H.Z. has received grant support and honoraria for lecturing and consulting fees from Vifor, the manufacturer of ferric carboxymaltose.
M.G. received grant support from Abbvie, Gilead, and MSD; speaking honoraria from Abbvie, Gilead, Janssen, Roche, Intercept, and MSD; consulting/advisory board fees from Abbvie, Gilead, Janssen, Roche, Intercept, Norgine, AstraZeneca, Falk, Shionogi, and MSD; and travel support from Abbvie and Gilead.
T.R. served as a speaker and/or consultant and/or advisory board member speaking honoraria from AbbVie, Bayer, Boehringer-Ingelheim, Gilead, Intercept, MSD, Roche, Siemens, and W. L. Gore & Associates and received travel support from AbbVie, Boehringer-Ingelheim, Gilead, and Roche as well as grants/research support from AbbVie, Boehringer-Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Philips Healthcare, Pliant, Siemens, and W. L. Gore & Associates.
M.J. served as a speaker and/or consultant for Gilead.