Prolonged antiviral therapy reduces HBV cccDNA
medwireNews: Long-term treatment with nucleos(t)ide analogs (NAs) can lead to a marked decline in levels of covalently closed circular DNA (cccDNA) in hepatitis B surface antigen (HBsAg)-positive patients with chronic hepatitis B virus (HBV) infection, research indicates.
The study “disproves the standard concept that cccDNA is ‘resistant’ to nucleos(t)ide analogue therapy” and suggests that viral replication capacity is “very low” after prolonged therapy, say the study authors.
But they add: “Whether cccDNA depletion is sustained and associated with better patient outcome requires further study.”
Of note, the reduction in HBsAg levels was less marked and HBsAg production appeared to be independent of viral replication, leading the team to question the validity of using HBsAg seroclearance as the “ideal” endpoint of therapy.
Among 129 patients enrolled in NA clinical trials with available liver biopsy samples at baseline and 1 year after initiating antiviral therapy, 43 consented to a third biopsy after a minimum 5 years of continuous treatment.
Treatment with NAs for a median duration of 126 months led to a significant 2.94 log decrease in median cccDNA levels relative to baseline, equating to a 99.98% reduction (p<0.0001). And just under half (49.00%) of the participants had cccDNA levels below the detection limit (<0.005 copies/cell).
By contrast, although median serum HBsAg levels at the most recent assessment were significantly lower than at baseline (p<0.0001), there was only a 0.54 log or 71.46% decrease, and just one patient had undetectable serum HBsAg at this timepoint.
Moreover, serum HBsAg levels remained high in patients with undetectable cccDNA, which, the researchers explain, “can be interpreted as reflecting very little or no viral replication activity,” and were comparable to HBsAg levels in patients with detectable cccDNA.
“This suggests that by the time of the third liver biopsies, the serum HBsAg levels were independent of viral replication,” Ching-Lung Lai, from The University of Hong Kong, and fellow investigators write in the Journal of Hepatology.
Nothing that just 10–12% of chronic HBV patients achieve HBsAg seroclearance with current therapies, they observe: “If HBsAg particles are produced in the host hepatocytes even when there is no active viral replication, and the findings of the present study supported this view, then HBsAg seroclearance may never be achievable in the majority of patients.”
In light of their findings, Lai et al suggest that cccDNA depletion be investigated as a potential endpoint of treatment.
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