The promise of epigenetic editing strategies in functionally curing chronic hepatitis B virus infections

Chronic hepatitis B (CHB) is a major global health issue that remains without a cure due to the persistence of covalently closed circular DNA (cccDNA) and integrated DNA (intDNA) in hepatitis B virus (HBV) infected hepatocytes. Standard therapies suppress replication but do not eliminate these viral DNA reservoirs, enabling viral and disease persistence. Nuclease-based gene editing can disrupt HBV genomes but has the risk of (off-target) mutagenesis across the many, variable intDNA loci, while immunotherapies can provoke hepatic toxicity. Here, we review epigenetic strategies that transcriptionally silence HBV without altering the DNA sequence. We compare broad-acting epidrugs with locus-specific epigenetic editing that targets chromatin modifiers to HBV regulatory elements using programmable zinc-finger proteins (ZFPs), transcription activator-like effectors (TALEs), or deactivated CRISPR-Cas9 (dCas9). Indirect repressors and direct editors reduce HBV RNA, DNA, and antigens from cccDNA and, in some contexts, intDNA, with improved specificity relative to epidrugs. We evaluate academic and industrial advances against three criteria: longevity, specificity, and delivery feasibility, and highlight promising preclinical programs pursuing durable, liver-restricted silencing. Collectively, precision epi-editing offers a potentially safer route than gene editing to functionally cure CHB by stably repressing cccDNA and intDNA, provided that specificity and durability are further improved through optimized effectors, delivery strategies, and clinically relevant models.