One‐quarter of chronic hepatitis D patients reach HDV‐RNA decline or undetectability during the natural course of the disease

Summary Background Spontaneous HDV‐RNA fluctuations, assessed by nonstandardised in‐house assays, have been reported during the course of chronic hepatitis delta (CHD). Aims To evaluate changes in serum HDV‐RNA concentrations in untreated CHD patients and correlate these changes with other HBV markers. Methods A total of 323 consecutive serum samples from 56 CHD patients (detectable HDV‐RNA) followed for >3 years were retested for HDV‐RNA levels by a sensitive technique using the first WHO international HDV‐RNA standard. Quantitative HBsAg, HBV‐DNA, and HBV‐RNA were also determined. Results Most participants were male, middle‐aged, white European, and HBeAg‐negative (82%). Almost half had liver cirrhosis and 64% were receiving nucleos(t)ide analogues. At inclusion, median‐HDV‐RNA was 5.3 (4.2‐6.5) log10IU/mL, HBsAg 4.0 (3.5‐4.3) log10IU/mL, and HBV‐DNA 1.6 (1.0‐2.6) log10IU/mL; ALT values were normal in 13 (23%). During a mean follow‐up of 5.6 (3‐16) years, 14 (25%) showed ≥2log10 HDV‐RNA decline, including 11 (20%) who spontaneously achieved undetectable HDV‐RNA. Four patients (7%) lost HBsAg, with undetectable HDV‐RNA. The remaining 42 (75%) had persistently detectable HDV‐RNA. During follow‐up, patients with a ≥2log10 HDV‐RNA decline showed a greater HBsAg drop (−0.7 ± 1.1 vs −0.09 ± 0.9 log IU/mL; P = 0.039) than those with a