Abstract

Background and Aims: Bulevirtide (BLV) is a novel antiviral drug against hepatitis D virus (HDV) that was conditionally approved in Europe in 2020. While it recently was suggested that BLV treatment discontinuation may be considered for patients who achieve long-term HDV RNA suppression (PMID:35514008), a computational approach may help to define the required duration of BLV therapy. Here we analyze HDV RNA kinetics in 7 patients undergoing BLV therapy and examine whether mathematical modeling could potentially be used to predict a finite duration of BLV therapy.

 

Methods: Seven chronic HDV-infected patients receiving BLV monotherapy at two clinics in Vienna were included. HDV RNA was quantified by a sensitive PCR assay throughout treatment. ALT and HBsAg data were frequently collected in 7/7 and 3/7 patients, respectively. A recently developed mathematical model (AASLD 2022: late breaking abstract 5031) accounting for HDV RNA, HBsAg and ALT dynamics during BLV treatment was used to predict the time to reach <1 virus copy in the entire extracellular body fluid (BF).

 

Results: Median pretreatment HDV RNA, ALT, and HBsAg were 5.0 log IU/mL [interquartile range, IQR 1.7], 44 U/L [IQR 69.5], and 3.1 log IU/mL [IQR 1.0], respectively. Two patients had normal ALT levels at pretreatment. A delay in HDV RNA decline was seen in 4/7 patients at the beginning of therapy, lasting between 2 and 7 weeks. All 7 patients experienced a rapid phase of HDV decline (median of 0.11 log/week [IQR 0.09]) with a median duration of 14.7 weeks [IQR 13.3] and median magnitude of decline of 2.2 log cp/mL [IQR 0.8]. Thereafter, 2 patients experienced a 2nd slower phase of HDV decline (termed biphasic) of whom only one patient reached HDV undetectable (Fig. 1a). In the remaining 5 patients HDV RNA levels dropped to a subsequent lower viral plateau (termed flat partial response) throughout therapy (Fig. 1b). The two biphasic patients were both young (29 and 30 years old) without cirrhosis, while all flat-partial patients had a median age of 51 [IQR 14] and had cirrhosis. ALT normalized (Female<35 U/L; Male<50 U/L) in all but one (biphasic) patient during therapy. Five patients had normal ALT levels by week 24, and one patient by week 36. In 5/6 of these patients, HDV viral load declined > 2 log from pre-treatment levels before ALT normalization. HBsAg remained at pre-treatment levels. In the mathematical model, the predicted values fit well the measured values (Fig. 1). In the biphasic patient who achieved undetectable HDV RNA levels, the model accurately predicted that a duration of ~100 weeks is required to achieve <1 virus copy in the BF (Fig. 1a).

 

Conclusion: The developed viral kinetic model provides an initial step toward to guide individualized BLV therapy allowing finite treatment durations in patients with HDV.