HBV serum RNA kinetics during nucleic acid polymers based therapy predict functional cure.

Area of Science:

• Hepatology
• Virology
• Pharmacology

Background:

• Serum HBV RNA is a marker for cccDNA transcriptional activity in hepatocytes.
• Combination therapy of tenofovir-disoproxil-fumarate (TDF) and pegylated-interferon-alpha-2a (pegIFN) with nucleic-acid polymer (NAP) shows promise for functional cure in chronic HBV.
• Understanding HBV RNA kinetics is crucial for optimizing treatment strategies.

Purpose of the Study:

• To characterize HBV RNA kinetics during combination therapies involving TDF and pegIFN, with or without NAP.
• To investigate the relationship between HBV RNA kinetic patterns and treatment outcomes, including functional cure.
• To assess the predictive value of early HBV RNA levels for treatment response.

Main Methods:

• A phase-II clinical trial (REP401) involving 40 participants with chronic HBV.
• Participants received 48 weeks of triple combination therapy (TDF + pegIFN + NAPs) or sequential TDF/dual therapy followed by triple therapy.
• HBV RNA levels were measured every 4 weeks using the Abbott RUO assay.

Main Results:

• Novel HBV RNA kinetic patterns were observed, including stable levels, new plateaus, and transient increases followed by declines.
• Introduction of NAPs led to a decline in HBV RNA in participants with elevated plateaus.
• Failure to reach the lower limit of quantification (LLoQ) for HBV RNA by 16 weeks predicted functional cure with 100% accuracy.
• A significantly longer HBV RNA half-life was observed in the virological rebound group compared to partial and functional cure groups (5.7 vs. 2.7 weeks).

Conclusions:

• HBV RNA kinetics provide valuable insights into cccDNA activity during antiviral therapy.
• Early HBV RNA kinetics, particularly the time to reach LLoQ, can predict functional cure.
• Shorter HBV RNA half-life is associated with achieving partial or functional cure, suggesting more effective cccDNA inactivation.