From the AGA Journals

Nucleoside polymers show early promise in HBV

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One step closer to a cure

Dr. Manhal Izzy

Since the advent of the curative direct-acting antiviral therapy for hepatitis C, increased efforts have been devoted toward finding a cure for chronic hepatitis B. The integration of hepatitis B virus (HBV) into the host genome is a major barrier to the complete cure (eradication of HBV DNA from hepatocytes and serum). Consequently, functional cure (sustained clearance of HBV surface antigen with viral DNA eradication from serum) has become the sought after outcome in clinical trials. Current treatment of active hepatitis B targets viral DNA suppression mostly using life-long oral nucleos(t)ide analogue or infrequently using 1-year course of interferon. Both of these therapies have been generally successful in suppressing serum levels of HBV DNA but functional cure rates have been minimal. In the current study, Bazinet and colleagues evaluated tenofovir disoproxil fumarate and pegylated interferon-alpha in conjunction with weekly administration of either of two investigational nucleic acid polymers (REP 2139-Mg or its rapidly cleared analogue REP 2165-Mg) in a randomized phase 2 trial for 48 weeks followed by up to 48 weeks off any therapy. Notably, the functional cure rate observed on follow-up was 39%, compared with 0% on tenofovir or tenofovir and interferon when used before adding the study medications. No serious adverse events were associated with either investigational drug. As expected, interferon-related thrombocytopenia and neutropenia developed. This study offers promising safety and efficacy data and it brings us one step closer to functional cure on the path of one day achieving the holy grail of complete cure of HBV.


Manhal Izzy, MD, is assistant professor of medicine, Vanderbilt University Medical Center, division of gastroenterology, hepatology, and nutrition, and transplant hepatology at the Vanderbilt Clinic, Nashville, Tenn. He has no conflicts.


 

FROM GASTROENTEROLOGY

For patients with chronic hepatitis B virus (HBV) infection, triple-combination therapy with tenofovir disoproxil fumarate, pegylated interferon alfa-2a (TDF-pegIFN), and either of two investigational nucleic acid polymers was tolerable and led to long-term functional cures in an open-label phase 2 trial.

The addition of either REP 2139 or REP 2165 to backbone TDF-pegIFN therapy produced functional cures in 39% of patients without lessening HBV DNA control or exacerbating treatment-induced neutropenia or thrombocytopenia, said Michel Bazinet, MD, of Replicor in Montreal and his associates. “Increases in levels of transaminases were significantly more frequent (P < .001 vs. controls) and greater (P = .002 vs. controls) in the nucleic acid polymer groups but did not produce symptoms, correlated with [an] initial decrease in hepatitis B surface antigen [HBsAg], and normalized during therapy and follow-up,” the investigators wrote in Gastroenterology.

Nucleic acid polymers (NAPs) suppress the assembly and secretion of HBV subviral particles. NAP monotherapy is active against HBV but usually does not provide long-term virologic control. In a small study, adding pegIFN or thymosin alpha-1 to an investigational NAP achieved functional control (HBsAg positive, HBV DNA ≤ 2000 IU/mL, and normal alanine aminotransferase levels) in eight of nine patients.

Building on these findings, two triple-combination NAP regimens were evaluated in 40 noncirrhotic HB envelope antigen–negative adults with chronic HBV infection. After 24 weeks of TDF monotherapy, participants were randomly assigned to either 48 weeks of REP 2139 or REP 2165 plus backbone therapy with TDF and pegIFN, or 24 weeks of backbone therapy followed by 48 weeks of triple-combination treatment. Patients were then followed without treatment for 24-48 weeks.

Backbone TDF-pegIFN therapy produced no HBsAg seroconversions, and HBsAg levels dropped by more than 1 log10 IU/mL in only three patients. In contrast, triple-combination NAP therapy produced undetectable HBsAg and HBsAg seroconversions (up to 233,055 mIU/mL) for 60% of patients. Among 36 patients followed for 24-48 weeks after completing treatment, 78% maintained virologic control and 39% showed functional cures (HBsAg < 0.05 IU/mL, undetectable HBV DNA, and normal ALT). “Additional follow-up is planned to confirm the long-term stability of [these] outcomes,” the researchers said.

Both NAPs were formulated with chelated magnesium to improve their tolerability. Although 95% of patients experienced transaminase flares, these “self-resolved or declined during continuing NAP therapy and normalized in 32 of 34 (94%) of participants completing 48 weeks of follow-up,” the researchers said. In keeping with prior studies, transaminase flares were associated with early declines in HBsAg but not with altered liver function or liver disease symptoms.

The study was conducted at three sites in Maldova. Most participants were men with HBV genotype D infection. “During follow-up, viral rebound occurred in participants [in whom] HBsAg was still detectable at the end of 48 weeks of combination therapy (≥ 57.9 IU/mL), who did not complete therapy, or [for whom] HBsAg clearance occurred very late in therapy,” the researchers wrote. Thus, “persistent exposure to pegIFN while HBsAg is cleared may be important for the establishment of virologic control and functional cure.” They recommended evaluating NAP plus nucleos(t)ide analogue (NUC) therapy to assess response in the absence of pegIFN. Such studies should enroll “NUC-experienced participants with well-controlled HBV DNA.”

Replicor provided funding. Dr. Bazinet and the senior investigator reported that they are employees and shareholders of Replicor and have invented patents that Replicor holds. One coinvestigator reported compensation from Replicor to his institution. The remaining 11 coinvestigators reported having no relevant disclosures.

SOURCE: Bazinet M et al. Gastroenterology. 2020 Mar 5. doi: 0.1053/j.gastro.2020.02.058.

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