Long-term Therapy of Chronic Delta Hepatitis With Peginterferon Alfa

T. Heller; Y. Rotman; C. Koh; S. Clark; V. Haynes-Williams; R. Chang; R. McBurney; P. Schmid; J. Albrecht; D. E. Kleiner; M. G. Ghany; T. J. Liang; J. H. Hoofnagle


Aliment Pharmacol Ther. 2014;40(1):93-104. 

In This Article

Abstract and Introduction


Background. Chronic delta hepatitis virus (HDV) infection rapidly progresses to cirrhosis. Treatment with peginterferon for up to 2 years is often without durable response.

Aim. To examine the efficacy and safety of long-term peginterferon in achieving a durable response.

Methods. Treatment was initiated with 180 μg/week of peginterferon alfa-2a with titration to a maximal tolerable dose, for up to 5 years. Liver biopsies and hepatic venous pressure gradients (HVPG) were evaluated at baseline, 1, 3 and 5 years. The primary endpoint was histological improvement or loss of serum HDV and HBsAg at 3 years.

Results. Thirteen patients were treated for a median of 140 weeks (6–260) with an average peginterferon dose of 180 μg/week (90–270). At baseline, most had advanced disease (median Ishak fibrosis = 3) with portal hypertension (HVPG = 10.2 ± 6 mmHg). Five of 13 patients (39%) achieved the primary endpoint, with three seroconverting for HBsAg after 24, 37 and 202 weeks of treatment. Histological inflammation improved after 1 year, (median HAI: 10 vs. 7, P = 0.01) with persistence in 4/5 patients at 3 years (median HAI: 7.5). Greatest improvements occurred in the first year. Baseline bilirubin and HBsAg levels were significantly lower in virological responders than nonresponders. After 12 weeks, virological responders had a significant decline in HBsAg (1.5 log10 IU/mL, P = 0.05).

Conclusion. Despite increased doses and duration of therapy, treatment of chronic HDV with peginterferon remains unsatisfactory. Quantitative measures of HBsAg may be an important biomarker of early response to peginterferon therapy in chronic delta hepatitis virus infection.


The hepatitis D (delta hepatitis) virus (HDV) is the smallest pathogenic animal virus known to infect humans with an estimated 15–20 million chronically infected worldwide.[1] The virus is an incomplete RNA virus, which is composed of a 1.7 kb single-stranded circular genomic RNA, virally encoded small and large delta antigens, and a surrounding lipid envelope of hepatitis B surface antigen (HBsAg).[2,3] Propagation in humans only occurs in individuals infected with hepatitis B virus (HBV), either via superinfection or co-infection.[4]

The hepatitis D (delta hepatitis) virus infection has been described to be endemic in various regions throughout the world.[1,5] Compared to patients mono-infected with HBV, patients co-infected with HDV suffer more severe chronic hepatitis and progress more rapidly to cirrhosis.[6–8] In addition, those with HDV are at higher risk for hepatic decompensation leading to death and the development of hepatocellular carcinoma (HCC) compared to individuals with HBV alone.[9–11] Thus, HDV shares epidemiological patterns and clinical features with hepatitis B, but tends to be more severe.

Currently, no satisfactory or FDA approved therapy exists for HDV infection. The American Association for the Study of Liver Diseases (AASLD) guidelines suggest the use of alpha interferon as therapy for chronic HDV infection.[12] However, alpha interferon therapy is generally unsatisfactory and poorly tolerated; serum aminotransferase levels normalise in only 40–70% of treated patients and relapse occurs in 60–97% of patients. Long-term treatment with alpha interferon has been reported to be beneficial and preliminary evidence with 96 weeks of peginterferon-based therapy appears safe.[13,14] Instances of a complete response to therapy, defined as a loss of HDV RNA and HBsAg and development of anti-HBs, have been reported, although rarely. Thus, standard preparations of alpha interferon are an unsatisfactory therapy for chronic hepatitis D and are limited by poor tolerance and a relatively low long-term response rate.

In this study, we examined the utility of long-term high-dose pegylated alpha interferon in patients with chronic hepatitis D and evaluated its effect on hepatic histology, safety and tolerability.