Chronic Hepatitis D—What Is Changing?

David Yardeni; Theo Heller; Christopher Koh

Disclosures

J Viral Hepat. 2022;29(4):240-251. 

In This Article

Investigational Therapies for HDV

Interferon Lambda

The effectiveness of interferon at mounting a significant immune response has been shown in multiple clinical trials. However, the main caveats to its use are the adverse events affecting nearly every organ. IFN-lambda is a novel type 3 interferon, which binds to a unique receptor highly expressed on hepatocytes but much less so on hematopoietic cells and CNS cells.[59] This finding translates to a superior safety profile due to its restricted receptor expression with also far less reported autoimmune events. Clinical trials performed on HBV and HCV patients receiving IFN-lambda displayed a somewhat comparable efficacy with as postulated significantly less AEs.[60,61] In the Lambda Interferon MonoTherapy (LIMT) study in HDV study, 14 and 19 patients with HDV were randomized to receive either 180 or 120 μg of weekly SC PEG-IFN-lambda for 48 weeks respectively[62] (Table 2). At the end of treatment, 7 (50%) and 4 (21%) patients from the high- and low-dose groups achieved a >2log IU/ml decline in HDV RNA. Unquantifiable HDV RNA was found in 5 (36%) and 3 (16%) patients from the high- and low-dose groups. Interestingly, the effect was sustained at 24 weeks post-treatment. Most AEs reported were mild flu-like symptoms; however, six patients experienced varying degrees of hyperbilirubinemia, which resolved at dose reduction and discontinuation. A phase 3 study, titled LIMT-2 is scheduled to begin recruitment in 2022 and will include 48 weeks of treatment with weekly 180 μg of PEG-IFN-lambda.[63] These recent study findings have made PEG-IFN-lambda an attractive alternative to PEG-IFN-α as either a monotherapy or as a part of a combination therapy as will be discussed next.

Lonafarnib—Prenylation Inhibitor

Prenylation is a post-translational and site-specific modification of proteins that facilitates protein–protein and protein–membrane interactions. In 1992, Glenn et al.[25] identified that prenylation of the carboxy terminus of the large HDAg was a necessary step for facilitating HDAg binding to HBsAg and subsequent HDV virion assembly. Farnesyltransferase inhibitors were shown in the following years to inhibit HDV-like particles in in vitro cell lines and animal models.[64,65] A proof-of-concept clinical trial demonstrated that the oral farnesyltransferase inhibitor lonafarnib (LNF) administered either at 100 or 200 mg twice daily for 28 days led to statistically significant HDV viral load declines compared with placebo[66] (Table 2). HDV RNA negativity was not achieved. However, a highly linear relationship was demonstrated between LNF serum concentration and HDV RNA log decline, suggesting that using higher concentrations of the drug may have an even greater antiviral effect. AEs were significant for nausea, diarrhoea and weight loss. In the lonafarnib with and without ritonavir in HDV-1 (LOWR HDV-1) study, the cytochrome P450-3A4 inhibitor, ritonavir (RTV), allowed a lower LNF dose to be used whilst achieving higher levels of postabsorption LNF.[67] Fifteen patients received either LNF 200 or 300 mg twice daily for 12 weeks, 100 mg three times daily for 5 weeks, 100 mg twice daily with RTV for 8 weeks and LNF 100 mg twice daily with PEG-IFN-α for 8 weeks. At the end of treatment, the LNF + RTV group achieved a mean decline of 3.19 log IU/ml in HDV RNA with fewer adverse events. In the LNF with PEG-IFN-α group, a mean decline of 2.97 log IU/ml at the end of treatment was seen. Interestingly, at post-treatment follow-up, two patients receiving 300 and 200 mg of LNF twice daily were found to be HDV RNA-negative following a brief ALT elevation. In the following dose-finding LOWR HDV-2 study, 39 patients were randomized to receive either LNF at "high dose": 75–100 mg twice daily or 100–150 mg once a day or "low dose": 25–50 mg twice daily with RTV 50–100 mg twice a day or 100 mg once a day for 12, 24 or 48 weeks.[68] Additional 19 patients received "triple therapy" consisting of 25 or 50 mg of LNF twice a day with 100 mg of RTV twice a day and weekly injections of SC PEG-IFN-α for 24 or 48 weeks. The study results revealed that HDV suppression took place in all arms. Superior results were seen in the triple therapy arms. Seven patients' HDV RNA became unquantifiable and three patients became HDV RNA-negative at the end of treatment with two patients maintaining a negative HDV RNA at 24 weeks post-treatment. Efficacy results at 12 weeks of treatment from the "high-dose" group were similar to the "low-dose" group and thus only the "low-dose" group completed 24 weeks of treatment. At the end of treatment, 5 (36%) patients achieved unquantifiable HDV RNA and 1 patient became HDV RNA-negative at week 24. Mild-to-moderate gastrointestinal AEs continued to dominate with only three serious AEs reported, all classified as unlikely related to LNF. The LOWR-3 study was a double-blinded randomized placebo-controlled study in which 21 patients were randomized to 50, 75 and 100 mg of LNF with a 100 mg of RTV or placebo for 12 or 24 weeks.[69] All patients received NAs to prevent HBV from flaring. Following 12 weeks of placebo treatment, the placebo group was randomized to 12 further weeks of LNF and RTV. After 12 weeks of treatment, a median decrease of 1.6, 1.33 and 0.83 log IU/ml was seen in the 50, 75 and 100 mg of LNF respectively. HDV RNA increased by a mean of 0.75 log IU/ml in the placebo group. Only one patient achieved undetectable HDV RNA. LOWR-4 was an open-label, dose escalation study designed to investigate if rapid step-wise increases in LNF can allow higher doses.[70] Fifteen patients were given 50 mg of LNF with 100 mg of RTV twice daily. After a minimum of 6 weeks, 10 patients were able to tolerate a dose increase of LNF to 100 mg twice a day. Five patients were able to maintain the dose for the full 24-week treatment. At the end of treatment, mean HDV RNA decline was 1.58 ± 1.38 log IU/ml. One patient became HDV RNA-negative. Gastrointestinal AEs were once again rated as mild to moderate. A single serious AE was termed unrelated. Delta Liver Improvement and Virologic Response in HDV (D-LIVR) is a currently active multicenter double-blinded phase 3 study combining LNF treatment with interferon alpha (NCT03719313). Recruited patients are randomized to receive 50 mg of LNF with 100 mg RTV twice a day with and without PEG-IFN-α for 48 weeks compared with PEG-IFN-α monotherapy and placebo.

Combination of Interferon Lambda and Lonafarnib

The recently completed Lambda InterFeron combo Therapy (LIFT) study was an open-label study in which two investigational approaches were combined,[71] weekly injections of the novel PEG-IFN-lambda along with twice daily dosing of 50 mg LNF with 100 mg RTV. Twenty-six patients completed 12 weeks of treatment and 22 completed 24 weeks of treatment. HDV RNA declined by a mean of 3.36 log IU/ml at week 12 and by 3.23 log IU/ml at treatment week 24. Eleven (50%) patients achieved undetectable or unquantifiable HDV RNA at week 24. Interestingly, five patients were able to maintain this status at 24 weeks post-therapy; of them, three maintained a negative HDV RNA. All patients suffered from mild-to-moderate gastrointestinal AEs. Four patients discontinued therapy due to hyperbilirubinemia.

Nucleic Acid Polymers

Nucleic acid polymers (NAPs) are negatively charged oligonucleotides with broad-spectrum inhibitory activity against viruses. Their mechanism of action is not entirely clear; however, it is assumed to be driven by their interaction with hydrophobic surfaces of viral and nonviral alpha helices, which have a similar structure.[72] In 2013, an in vitro study displayed antiviral activity of NAPs on primary duck hepatocytes infected with duck HBV (DHBV).[73] These findings were followed by an in vivo study assessing the effect of the NAP REP 2055 on ducks with persistent DHBV.[74] Results showed a significant decline of ~2 log in serum DHBsAg and ~3 logs in DHBV DNA. In the proof-of-concept REP 101 and REP 102 studies, 8 and 12 patients with chronic HBV from Bangladesh were given REP 2055 and a modified calcium chelate complex formulation of REP 2055 termed REP 2139-Ca.[75] Patients were given weekly IV dosing of study drugs at escalating doses resulting in HBsAg and HBV DNA reductions. Activity of NAPs in HDV patients was evaluated in the open-label phase 2 REP 301 study held in Moldova[76] (Table 2). Twelve enrolled patients received 500 mg of IV REP 2139 once weekly for 15 weeks followed by a combination of weekly IV 250 mg of REP 2139 and 180 μg of SC PEG-IFN-α for another 15 weeks. This was followed by further treatment with weekly 180 μg of SC PEG-IFN-α for 33 weeks. At the end of treatment 9 (75%), patients became HDV RNA-negative and 10 (83.3%) patients experienced a ≥2 log IU/ml reduction in HDV RNA. Interestingly, 5 (42%) patients became HBsAg-negative. At 1-year follow-up after treatment, 7 (58%) patients remained HDV RNA-negative whilst HBsAg loss was maintained for responsive patients. During the study, 1 patient discontinued therapy due to PEG-IFN-α-induced hepatic decompensation, which resolved following the study's drug discontinuation. Eleven patients continued long-term surveillance in the REP 301-LTF study. Results from the extended follow-up of 3.5 years recently reported show that 7 (64%) of patients remained HDV RNA-negative and 4 (36%) remained HBsAg-negative.[77] Other than the aforementioned hepatic decompensation, AEs reported during the REP 301 study were mostly hematological with most patients suffering from thrombocytopenia (83%) and neutropenia (67%). Four (33%) patients suffered a serious AE: alanine and aspartate aminotransferase elevation, elevated bilirubin and thrombocytopenia. All were attributed to PEG-IFN-α therapy. No serious AEs were reported to be related to NAP treatment during the initial REP 301 study and throughout the extended follow-up of REP 301-LTF.

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