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

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) log IU/mL, HBsAg 4.0 (3.5-4.3) log IU/mL, and HBV-DNA 1.6 (1.0-2.6) log IU/mL; ALT values were normal in 13 (23%). During a mean follow-up of 5.6 (3-16) years, 14 (25%) showed ≥2log 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 ≥2log 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 <2 log HDV-RNA decline. Overall, ALT and HBV-DNA levels decreased over time. There were no differences in clinical outcomes between groups.

Conclusions: One-quarter of untreated CHD patients showed a ≥2log decline in HDV-RNA and 20% reached HDV-RNA undetectability during a mean follow-up of 5.6 years. The decline was associated with ALT decrease. These findings have implications for designing new therapies for CHD.