Bulevirtide‐based treatment strategies for chronic hepatitis delta: A review

Chronic hepatitis Delta (CHD) is a rare and severe form of chronic viral hepatitis. Until recently, the only therapeutic approach has been the off‐label use of a 48 weeks course of PegInterferon alpha (PegIFNα), that was characterized by suboptimal efficacy and burdened by significant side effects that limited treatment applicability in patients with advanced liver disease. In July 2020, European Medicines Agency (EMA) conditionally approved the entry inhibitor Bulevirtde (BLV) at the dose of 2 mg/day for the treatment of adult patients with compensated CHD. Efficacy and safety of BLV in CHD have been evaluated in clinical trials either as monotherapy or in combination with PegIFNα. These results were confirmed by real‐life studies, which also evaluated long‐term BLV monotherapy in patients with advanced compensated cirrhosis. Notwithstanding these promising results there are still several issues to be addressed, such as the optimal duration of the treatment, the rates of off‐therapy responses, as well as the long‐term clinical benefits. This review summarizes updated and current literature data about clinical trials and real‐life studies with BLV monotherapy and/or in combination with PegIFNα.

The Phase 3, open-label, multicentre MYR301 study investigated efficacy and safety of BLV monotherapy in a large cohort of 150 HDV patients. As per study design. patients were randomized 1:1:1 to receive a 48 weeks delayed treatment with BLV 10 mg/day for 96 weeks (Arm A), BLV 2 mg/day for 144 weeks (Arm B) or BLV 10 mg/day for 144 weeks (Arm C). Interim study results were reported at Week 48: primary endpoint was combined response, while secondary endpoints included rates of HDV RNA undetectability, ALT normalization and changes in liver stiffness. Inclusion of patients with compensated (Child Pugh Score [CPT]-A6) cirrhosis was allowed and stratified across the three arms. At study start, mean age was 42 years, 57% males, 99% HDV genotype 1, 83% HBV genotype D, 10% HBeAg positive, 60% receiving NUC treatment, 56% previously treated with PegIFNα. Cirrhosis accounted for 47% in each study arm, mean liver stiffness was 14    reported; fatigue (n = 7), pruritus (n = 3) and injection site reaction (n = 1) were the most common side effects. De novo decompensation occurred in two cases. 15 Germany also reported long-term outcomes at Weeks 52, 56 and 68 in three patients receiving BLV 2 mg/day monotherapy. All patients achieved a virological response at Week 24, that was maintained throughout Week 68 in two cases, while the other experienced HDV RNA breakthrough at Week 40. 16 The Italian real-life study investigated safety and efficacy of BLV monotherapy 2 mg/day in 18 patients with compensated cirrhosis (CPT-A) and clinically significant portal hypertension (CSPH).
HBsAg >1 Log decline at Week 72 was achieved in 40% of patient receiving PegIFNα + BLV 2 mg vs. 13% for BLV 5 mg and 10 mg vs.
4% for PegIFNα monotherapy. 27% of patients treated with PegIFNα + BLV 2 mg and 7% of patients treated with PegIFNα + BLV 10 mg experienced HBsAg loss. Off-therapy HDV RNA responses at Week 72 were observed in patients achieving HBsAg decline. 9 Overall, 124 CHD patients (35% with cirrhosis) in three arms of the phase 2 MYR204 study received PegIFNα-based strategies in combination with BLV. As per study design, patients were randomized to receive: PegIFNα monotherapy for 48 weeks (n = 24 patients); PegIFNα + BLV 2 mg/day for 48 weeks, followed by 48 weeks of BLV 2 mg monotherapy (n = 50 patients); PegIFNα + BLV 10 mg/ day for 48 weeks, followed by 48 weeks of BLV 10 mg monotherapy (n = 50 patients). Following 24 weeks of treatment, median HDV RNA decline in the PegIFNα monotherapy arm was 2.01 LogIU/ml, while combination with BLV strategy resulted in a more pronounced decline in HDV RNA (3.78 LogIU/ml in BLV 2 mg vs. 4.11 LogIU/ml in BLV 10 mg). Virological response at Week 24 was achieved in 38% vs. 88% and 92% in the PegIFNα monotherapy vs. combination with BLV 2 mg and 10 mg, respectively. Rates of HDV RNA undetectability were 13% vs. 24% vs. 34%, respectively. Only 13% of patients treated with PegIFNα monotherapy showed a biochemical response, in contrast to 30% and 24% of patients in the combination BLV groups. Rates of combined response were 30% and 24% in the PegIFNα + BLV 2 mg and PegIFNα +10 mg, respectively. 10 Main results of clinical trials with PegIFNα + BLV combination are summarized in Figure 3. and 71% at month 12 and 18, respectively (HDV RNA undetectable in 61% and 57%). Rates of combined response were 22% at month 12, rising to 41% at month 18. Patients in group D received BLV + PegIFNα for 12 months followed by BLV monotherapy: a virological response was achieved by 95% of patients at month 12 (HDV RNA undetectable in 77%) and was maintained in 74% of patients (HDV RNA undetectable 61%) at month 18 (BLV monotherapy ongoing, 6 months after PegIFNα discontinuation). Rates of combined response were 50% and 55% at months 12 and 18, respectively.
Overall, 6 patients discontinued IFN treatment, while, as expected, rates of side effects were significantly higher with BLV + PegIFNα combination than BLV monotherapy. 13 Main results of real-life studies with PegIFNα + BLV combination are summarized in Figure 4.

| SA FE T Y
In clinical trials and real-life reports, BLV monotherapy was well tolerated: no serious adverse events (SAEs) related to study drug F I G U R E 3 Virological, biochemical and combined response rates of BLV + PegIFNα combination in clinical trials.
were observed reported in clinical trials, as well as side effects leading to treatment discontinuation. Also in real-life studies, rates of BLV discontinuation due to side were negligible, except for some experiences (French ATU). In the MYR301 study, mild and dose-dependent injection-site reactions were reported: 6% in the BLV 2 mg/day arm vs. 26% in the BLV 10 mg/day group. In real-life experiences, injection site reactions were rarely observed with the 2 mg/day dose. As expected by BLV mechanism of action, increase of bile acids due to NTCP receptor blockage was reported in both clinical and real-life studies: in the vast majority of cases, the bile acid increase was fully asymptomatic. Recently, a case of immediate-type hypersensitivity reaction to BLV was described in an Austrian compensated cirrhotic patient: progressive pruritus, swelling of the upper extremities, face, lips and dyspnoea were indicative of type-1 allergic reaction. These symptoms immediately resolved after treatment discontinuation; however, as the patient had a strong clinical need for BLV administration, a desensitization strategy was applied and led to continue BLV treatment without any further complications. 20 The addition of PegIFNα to BLV was associated with expected PegIFNα-related side effects, resulting in increased rates of treatment discontinuation in patients receiving BLV combination with PegIFNα compared to BLV monotherapy alone. However, many issues have still to be solved: first of all, optimal treatment duration is currently unknown. While a finite treatment duration could be envisaged with addition of PegIFNα to enhance response rates, many HDV patients are not PegIFNα candidates due to advanced liver disease and could require a prolonged BLV monotherapy treatment approach. More studies are needed to characterize mechanisms of viral control, define predictors of response and criteria for BLV discontinuation. This is of crucial importance in patients with advanced cirrhosis, where flares associated with viral relapse after BLV discontinuation could result in liver decompensation.

| SUMMARY AND CON CLUS IONS
While EMA approval suggests that treatment should be continued as long as a clinical benefit is demonstrated, more data are needed in order to assess long-term outcomes with BLV treatment and define robust treatment endpoints associated with significant benefits in term of liver-related mortality and survival.

AUTH O R CO NTR I B UTI O N S
Concept and design, interpretation of the data, drafting the article and critical revision: ED, MPA, PL.

FU N D I N G I N FO R M ATI O N
None.

F I G U R E 4
Virological, biochemical and combined response rates of BLV + PegIFNα combination in real-life studies.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Elisabetta Degasperi: Advisory Board: AbbVie; Speaking and teaching: Gilead, MSD, AbbVie. Maria Paola Anolli: nothing to disclose.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C A L A PPROVA L
All authors approved the final version of the manuscript.