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The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USANetwork Science Institute, Northeastern University, Boston, MA, USA
The entry inhibitor bulevirtide (BLV) received conditional approval from the EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult-to-treat patients with HDV-related cirrhosis is presently unknown. Herein, we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to 3 years on a compassionate use program.
published a unique case study on hepatitis D virus (HDV) RNA kinetics under entry-inhibitor bulevirtide (BLV) monotherapy in 3 patients. Historically, mathematical modeling of viral hepatitis kinetics predicts a monophasic viral decline under antiviral treatment that blocks virus infection. Modeling suggests that the monophasic decline is driven by the rate of loss/death of virus productive-infected cells (parameter δ, Fig. 1A). Indeed, assuming that BLV’s only mode of action (MOA) is blocking HDV entry/infection (assuming η∼100%, Fig. 1A),
the model (Fig. 1A) fits well with the measured HDV data in patients 2 and 3 (Fig. S1) but not in patient 1, in whom a transient viral increase was seen during the first 4 weeks of treatment, consisting of a 0.4 log increase from pretreatment HDV-RNA level at week 2, followed by a monophasic HDV decline thereon (Fig. 1B). Such a transient viral increase can also be noticed in several hepatitis B virus (HBV) mono-infected patients treated with BLV 10 mg/day,
suggesting that this transient viral increase may occur in some patients treated with BLV for both HBV and HDV. The nature of this early transient viral increase under BLV treatment is not known.
Conceivably, the transient viral increase can be explained if one assumes that in addition to blocking viral infection, BLV also enhances viral production (parameter κp, Fig. 1A) or reduces viral clearance from circulation (parameter θ, Fig. 1A). The latter two theoretical BLV MOAs can fit data from patient 1 well, with BLV enhancing viral production by κp∼3.5-fold (Fig. 1B) or reducing viral clearance by θ∼66% (Fig. 1B). It is unlikely that BLV enhances viral production since BLV blocks the binding site of the human sodium taurocholate co-transporting polypeptide on the HBV envelope, thereby inhibiting the entry of the virus into hepatocytes.
However, reducing viral clearance by BLV may be a more plausible MOA if viral clearance from the circulation is interrupted by BLV blocking viral entry into hepatocytes. In that case, it is possible that there was a modest effect on patients 2 and 3 that was not recognized due to infrequent sampling (Fig. S2). We recently showed for hepatitis C virus (HCV) that, in some patients, the liver not only produces virus but also clears virus from the circulation,
supporting the notion that blocking viral entry could reduce viral clearance by the liver in patient 1. In patients 2 and 3, other mechanisms of viral clearance (e.g., adaptive-immune response) that were not affected by BLV may have played a major role.
Reminiscent of the notion of predicting the duration of anti-HCV treatment needed to reach <1 virus copy in a patient’s total extracellular-body fluid (BF),
modeling predicts <1 HDV copy per BF after 75, 50 and 90 weeks of 10 mg/day BLV in patients 1, 2 and 3, respectively (Fig. S3). Thus, modeling may explain, retrospectively, why patient 1 had viral rebound after 52 weeks of BLV and suggests that patients 2 and 3 who were treated for 144 weeks already reached HDV clearance in BF.
We further investigated in silico the predicted effect of BLV on slowing HDV viral clearance from the circulation in combination with other drugs that are predicted to block HDV viral production, i.e. parameter ε in Fig. 1A (e.g., interferon-α, lonafarnib, and nucleic-acid polymers, Fig. 1C) that we have previously shown to cause a biphasic HDV decline.
) will lead to a slower viral decline (Fig. 1C) compared to BLV monotherapy (Fig. 1C). However, BLV plus drugs with low efficacy (ε = 50%) will first lead to a slower viral decline during the first phase compared to BLV monotherapy (Fig. 1D), but later (∼11 weeks, Fig. 1D) BLV-based therapy will cause a higher suppression of HDV compared to therapy that blocks viral production without BLV. In patients in whom BLV will not or will only moderately slow HDV clearance (θ∼20%), modeling predicts enhanced viral decline under combination therapy compared to BLV monotherapy (Fig. S4), indicating the importance of including BLV in future anti-HDV regimens.
Studies in experimentally tractable in vivo systems might be able to dissect the mechanism underlying the apparent increases in HDV and HBV viremia under BLV and to ultimately gain an in-depth understanding of BLV’s MOA.
Future BLV perturbation experiments and theoretical modeling during HBV/HDV chronic infection are needed.
In conclusion, the monophasic HDV decline observed in 2 patients is consistent with the known MOA of BLV as an entry inhibitor. The transient increase in HDV in a third patient with initiation of BLV raises the possibility that blocking HDV entry into the liver has a secondary effect of reducing viral clearance by the liver.