Editorial: natural history of hepatitis delta virus‐induced liver disease ‐ less severe today but still needs attention

Chronic hepatitis delta virus (HDV) infection is potentially the most severe form of viral hepatitis. Hepatitis B virus (HBV)HDV coinfection was linked to fulminant hepatitis in the 1980s.1 A particular fast pace of cirrhosis development had been reported for chronic hepatitis delta (CHD).1 These severe forms are less often observed in recent years.24 Support for a milder CHD course is described recently in Alimentary Pharmacology and Therapeutics. In that study, Palom et al5 report a retrospective multicentre study on a CHD cohort of 56 patients with compensated liver disease followed longitudinally for a mean duration of 5.6 (316) years. Twothirds were on nucleos(t)ide analogue (NA) treatment. At baseline, patients had platelet counts of ≥90 × 109/L. Despite this, patients were not treated with interferons, the only available treatment. This has enabled the authors to assess the natural history of the disease, a strength of the study. However, it is of concern that patients with the most severe form of viral hepatitis were followed without treatment. Primary endpoint of the study was a ≥2 log10 decline and/or HDV RNA undetectability. Of 56 patients, 14 (25%) patients reached this endpoint, whereas 42 did not. NAtreated patients were similar in both groups. No baseline characteristic predicted the primary endpoint. This may have been due to low patient numbers. Median followup was longer (8.0 years) in those with ≥2 log10 HDV RNA decline vs those without (3.3 years) (P = 0.026). Interestingly, no difference in clinical outcomes was observed in the two groups. Data are of interest and add support to observations of a milder CHD course since spontaneous ≥2 log10 HDV RNA decline was associated with larger quantitative HBsAg decline, HBsAg clearance in four patients, undetectable HDV RNA in 11 patients and more frequent normalisation of ALT. Potential effect of longterm NA treatment in some patients can only be speculated.6 However, the fact that ≥2 log10 HDV RNA decline was not associated with better clinical outcome suggests that disease progression such as hepatic decompensation may have led to decrease in serum HDV RNA in some patients.7 Overall, the study supports evidence that CHD runs a milder course than in the past. Severe forms in the 1980s were attributed to emergence of more pathogenic strains of HDV as a consequence of rapid circulation of the virus in intravenous drug user communities and the interplay with wildtype (HBeAg positive) HBV,3 both of which have decreased today in western countries. In such countries, HDV is, similar to the past, a disease of highrisk groups but in variance with the past, main risk factor today is migration from endemic countries.8 In this context, a clinician today should be aware of viral factors affecting disease severity. Genotype 3 (G3) HDV observed in South America leads to more severe, and G2 and G5 HDV seen in Asia and Africa, respectively, lead to milder disease compared to G1 HDV.1,9 Contribution of the host immune system to severity of CHD is less understood.10