木瓜直播

In adults with chronic hepatitis B infection receiving viral suppression therapy, coupling an investigational small interfering RNA therapy with an immunomodulator led to substantial declines in blood levels of hepatitis B surface antigen (HBsAg), according to a randomized phase II trial.

Out of five medication regimens given for 48 weeks in the open-label Piranga study, combination xalnesiran plus pegylated interferon alfa-2a (Pegasys) therapy had the best results when it came to the proportion of people who achieved a decrease in HBsAg to below 0.05 IU per/mL at 24 weeks after end of treatment.

In that group, 23% met that primary efficacy endpoint, as compared with anywhere from 0% with nucleoside or nucleotide analogue (NA) therapy alone to 3-12% with xalnesiran alone or plus ruzotolimod.

The promising findings with the approach did have two caveats, however: the durability of HBsAg loss appears to be a challenge, and only people who had an HBsAg level below 1,000 IU/mL at screening managed to show HBsAg loss with or without seroconversion, reported Jinlin Hou, MD, of Nanfang Hospital at Southern Medical University in Guangzhou, China, and colleagues in the .

"To address these challenges, a potential approach could be to specifically target adaptive immunity and restore HBV-specific exhausted T cells," the authors suggested.

"Combination regimens containing checkpoint inhibitors are being explored in chronic hepatitis B, including a liver-targeted locked nucleic acid that degrades programmed death ligand 1 expression and is being evaluated in combination with xalnesiran in other groups of the Piranga platform trial," they noted.

In Piranga, Hou and colleagues had sought to find among the tested treatments a regimen that brings chronic hepatitis B patients closer to a functional cure, defined as off-treatment sustained undetectable levels of both hepatitis B virus (HBV) DNA and HBsAg.

Xalnesiran is an investigational small interfering RNA that silences multiple transcripts from the HBV genome. Ruzotolimod, also investigational, is a toll-like receptor 7 agonist selectively activated in the liver. Peginterferon alfa-2a is a form of recombinant interferon already indicated to treat chronic hepatitis B infection in people who show signs of liver damage.

"Combining drugs with different target engagement can provide a synergistic effect on viral suppression and immune control, leading to functional cure," the study authors wrote.

As for safety, the researchers reported that grade 3/4 adverse events were "not uncommon" in the trial.

"These results herald a new era for combination therapy to treat chronic HBV infection and raise questions about how and when to assess response and how to balance the probability of response with the likelihood of durable clinical benefit and risk of side effects," commented Harry L.A. Janssen, MD, PhD, of Erasmus MC University Medical Center in Rotterdam, the Netherlands, and Milan J. Sonneveld, MD, PhD, of the Toronto Centre for Liver Disease at University Health Network's Toronto General Hospital, in an .

Patients were only eligible for the Piranga study if they demonstrated virologic suppression with NA therapy (HBV DNA below 20 IU/mL following at least 12 months of entecavir [Baraclude], tenofovir alafenamide [Biktarvy], or tenofovir disoproxil fumarate [Viread]). The participants were randomly assigned to one of five treatment groups for 48 weeks of treatment, followed by 48 weeks of follow-up observation.

At 24 weeks after end of treatment, the primary efficacy results were as follows for the five groups:

• Xalnesiran 100 mg alone (n=30): 7% of people met criteria for HBsAg loss
• Xalnesiran 200 mg alone (n=30): 3%
• Xalnesiran 200 mg plus ruzotolimod 150 mg (n=34): 12%
• Xalnesiran 200 mg plus pegylated interferon alfa-2a 180 μg (n=30): 23%
• Nucleoside or nucleotide analogue (NA) alone (n=36): 0%

Across the five groups, grade 3/4 adverse events occurred in 17%, 10%, 18%, 50%, and 6%, respectively. The most common high-grade adverse event was an elevated alanine aminotransferase (ALT) level, which was logged in 43-83% of the participants who received xalnesiran. Increased aspartate aminotransferase levels occurred in 20-70% of these participants.

Hou and colleagues reported an erosion in the response to xalnesiran/pegylated interferon alfa-2a after treatment was withdrawn: durability of HBsAg loss decreased from 78% to 56% between 24 weeks and 48 weeks after the end of treatment.

This finding of a risk of relapse undermines "the choice of functional cure as an endpoint for these agents, at least when assessed relatively early after the withdrawal of therapy," wrote Janssen and Sonneveld.

"Future trials could evaluate whether alternative treatment regimens, such as drugs with different target engagement, could increase the likelihood of response," the pair suggested. The editorialists also noted the importance of gathering more data "on the durability of the effect achieved with new agents that directly interfere with HBsAg production."

, spread through bodily fluids, is the most common liver infection in the world. Acute infections can turn chronic in some cases and cause liver damage, cirrhosis, liver cancer, and even death. A hepatitis B vaccine is recommended for all children as soon as possible after birth.

The Piranga study enrolled 159 participants with chronic hepatitis B infection from July 2020 to November 2021.

Inclusion criteria included an ALT level no more than 1.5 times the upper limit of the normal range for at least 6 months before screening. Participants were not enrolled if they had HIV or another hepatitis type, or if they had clinically significant liver fibrosis or cirrhosis or hepatocellular carcinoma.

Baseline characteristics were similar across the randomly assigned groups in age, BMI, HBsAg levels, hepatitis B DNA levels, ALT levels, and duration of previous NA treatment. Participants were 94% Asian, majority men, and 70% hepatitis B e antigen-negative at enrollment.

Participants randomized to xalnesiran received it subcutaneously every 4 weeks. Patients receiving ruzotolimod took it orally every other day, and peginterferon alfa-2a was given subcutaneously weekly. Participants continued taking oral NA therapy daily until meeting the criteria for stopping.

HBsAg seroconversion remained 24 weeks after the end of treatment in 20% of those given xalnesiran plus peginterferon alfa-2a, compared to 3% with xalnesiran 100 mg, 3% with xalnesiran plus ruzotolimod, and none in the other two groups. At 48 weeks after end of treatment, 17% of those receiving xalnesiran plus peginterferon alfa-2a retained seroconversion.

Hou and co-authors acknowledged study limitations including the lack of patients assigned ruzotolimod or peginterferon alfa-2a alone, the small samples across treatment groups, and the absence of longitudinal immunologic and intrahepatic assessments as part of the protocol.

Comment