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Mathematical modeling of HDV RNA, HBsAg, and ALT kinetics in patients with compensated cirrhosis: Insights from 96 Weeks of bulevirtide monotherapy.
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Mhlanga Adquate, Shekhtman Louis, Cotler Scott J, Wasserman Ori, Degasperi Elisabetta, Anolli Maria Paola, Uceda Renteria Sara Colonia, Sambarino Dana, Borghi Marta, Perbellini Riccardo, Facchetti Floriana, Callegaro Annapaola, Dahari Harel, Lampertico Pietro
Аннотация
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.
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.