Carey et al. recently proposed that HBV pregenomic RNA (pgRNA) is a sensitive indicator of covalently closed circular DNA (cccDNA) transcription status in patients receiving nucleos(t)ide analogue therapy (NA) for hepatitis B. pgRNA is transcribed from the cccDNA minichromosome and therefore reflects a product of cccDNA transcriptional activity and its prevalence within HBV-infected cells. They observed that some patients reached pgRNA negativity 12 months of NA, suggesting a surprisingly rapid decline in transcriptional activity/prevalence of cccDNA.