Mathematical modeling of HDV RNA, HBsAg, and ALT kinetics in patients with compensated cirrhosis: Insights from 96 Weeks of bulevirtide monotherapy.

BACKGROUND & AIMS: Bulevirtide (BLV) 2 mg/day is approved for the treatment of compensated chronic hepatitis D virus (HDV) infection in Europe; however, understanding HDV-RNA, HBsAg and ALT dynamics under 96 weeks of BLV monotherapy is lacking.

APPROACH &

RESULTS

38 HDV-infected patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) received BLV. HDV, ALT, and HBsAg were measured at baseline, weeks 4, 8 and every 8 weeks thereafter. Mathematical modeling was used to explain the observed HDV, ALT, and HBsAg kinetics. Median baseline HDV, HBsAg, and ALT were 5.1 log IU/ml [IQR:4.0-5.8], 3.7 log IU/ml [IQR:3.4-3.9] and 90 U/L [IQR:55-150], respectively. During therapy, patients fit into four main HDV kinetic patterns: biphasic (n = 7), flat-partial response, FPR (n = 18), viral breakthrough, VB (n = 6) and non-responder (n = 7). ALT normalization was achieved in 29 patients (76%) at a mean of 11.9 (95% CI: 5.9-17.9) weeks. HBsAg remained at pre-treatment levels. Modeling indicated that BLV inhibited infection with efficacy η = 80% (95% CI:62-91%) and that HDV-infected cell half-life t1/2 = 11.6 (95% CI:6.6-16.6) days. BLV efficacy was less than the critical drug efficacy (ηc) for most patients (32/38) explaining the high rates of FPR, VB, and nonresponse despite a prolonged course of BLV.

CONCLUSIONS

The HDV FPR and VB observed in patients during 96 weeks of BLV are consistent with the modeling prediction that BLV 2 mg/day is suboptimal (η≤ηc) in a high percentage of patients (84%) with compensated cirrhosis and CSPH and therefore is unlikely to achieve cure even with prolonged duration of therapy.