EDITORS
HEPATOLOGY ELSEWHERE Kris Kowdley, Seattle, WA
Geoffrey McCaughan, Newtown, Australia
Christian Trautwein, Aachen, Germany
Reviving Pegylated Interferon as a incomplete virus with an extraordinarily small RNA
Therapeutic Agent for Hepatitis D: genome (1.7 kb) encoding two hepatitis D antigens
No More Room for Nucleos(t)ides? (HDAgs): a small, 24-kDa HDAg and a bigger, 27-kDa
HDAg.1 Viral replication is possible only in hepatitis B
Wedemeyer H, Yurdaydı`n C, Dalekos GN, Erhardt A, virus (HBV)–infected cells because hepatitis B surface
Çakalog˘lu Y, Deg˘ertekin H, et al.; for HIDIT Study antigen (HBsAg) is needed as a lipid layer around the
Group. Peginterferon plus adefovir versus either drug protein-RNA complex of HDV. Because of this unique
alone for hepatitis delta. N Engl J Med 2011;364:322- method of replication, HDV has obtained its own genus
331. (Reprinted with permission.) (Deltavirus). Five percent of all HBV-positive patients
are expected to be HDV-positive, although we should
Abstract keep in mind that there are significant regional differen-
BACKGROUND: Chronic infection with hepatitis B virus and ces in prevalence. Chronic delta hepatitis can cause the
hepatitis delta virus (HDV) results in the most severe form of viral most severe form of viral hepatitis known to date,2 and
hepatitis. There is no currently approved treatment. We investi- a standard therapy regimen has not been established yet.
gated the safety and efficacy of 48 weeks of treatment with peginter- Two paths of infection and two subsequent courses of
feron alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone,
disease are possible: a coinfection with hepatitis B (with
and adefovir dipivoxil alone. METHODS: We conducted a
randomized trial in which 31 patients with HDV infection received a high risk of fulminant hepatitis and a 95% chance of
treatment with 180 lg of peginterferon alfa-2a weekly plus 10 mg the clearance of both viruses) and a superinfection with
of adefovir daily, 29 received 180 lg of peginterferon alfa-2a preexisting hepatitis B (with the possibility of fulminant
weekly plus placebo, and 30 received 10 mg of adefovir alone hepatitis and/or severe chronic disease). Patients with
weekly for 48 weeks. Follow-up was conducted for an additional chronic hepatitis B who acquire an HDV superinfection
24 weeks. Efficacy end points included clearance of HDV RNA,
normalization of alanine aminotransferase levels, and a decline in
have a high risk of developing liver cirrhosis.3,4
levels of hepatitis B surface antigen (HBsAg). RESULTS: The pri- For Hep-Net International Delta Hepatitis Interven-
mary end point—normalization of alanine aminotransferase levels tion Trial I (HIDIT-I), Wedemeyer et al.5 recruited 90
and clearance of HDV RNA at week 48—was achieved in two patients with chronic hepatitis B and D coinfections
patients in the group receiving peginterferon alfa-2a plus adefovir from multiple centers in Germany, Greece, and Turkey
and two patients in the group receiving peginterferon alfa-2a plus and compared three different therapy regimens: pegy-
placebo but in none of the patients in the group receiving adefovir
alone. At week 48, the test for HDV RNA was negative in 23% of
lated interferon alfa-2a (PEG-IFNa2a) and a placebo
patients in the first group, 24% of patients in the second, and none (n ¼ 29), PEG-IFNa2a and adefovir (ADV; n ¼ 32),
of those in the third (P¼0.006 for the comparison of the first and and ADV alone (n ¼ 30) for 48 weeks. Eighty patients
third groups; P¼0.004 for the comparison of the second and completed the study (89%), and follow-up was per-
third). The efficacy of peginterferon alfa-2a was sustained for 24 formed for another 24 weeks. Among others, the pri-
weeks after treatment, with 28% of the patients receiving peginter- mary and secondary endpoints were the normalization
feron alfa-2a plus adefovir or peginterferon alfa-2a alone having
negative results on HDV-RNA tests; none of the patients receiving
of alanine aminotransferase levels, the clearance of
adefovir alone had negative results. A decline in HBsAg levels of HDV RNA, and a significant decline in HBsAg levels.
more than 1 log10 IU per milliliter from baseline to week 48 was Wedemeyer et al.5 found that 48 weeks of therapy with
observed in 10 patients in the first group, 2 in the second, and PEG-IFNa2a, alone or in combination with ADV, signifi-
none in the third (P<0.001 for the comparison of the first cantly reduced HDV RNA levels, with 28% of the patients
and third groups and P¼0.01 for the comparison of the first clearing the virus within 24 weeks of the end of therapy.
and second). CONCLUSIONS: Treatment with peginterferon alfa-
2a for 48 weeks, with or without adefovir, resulted in sustained
Treatment with ADV alone had no significant effect on
HDV RNA clearance in about one quarter of patients with HDV HDV clearance after 24 weeks, although the suppression
infection. of HBV DNA under therapy was best in the ADV group.
These results are consistent with earlier studies evaluating
Comment PEG-IFN as an effective therapeutic agent.6,7
Since its discovery in 1977 by Rizzetto et al., hepatitis HDV has (at least) eight different genotypes. These
delta virus (HDV) has been known as a special and eight different clades have specific distributions in
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Fig. 1. Different therapeutic agents have been evaluated over the last 20 years for delta hepatitis. Interferon (pegylated or not pegylated) has
been used as a therapeutic agent since 1991, and there have been promising results in multiple studies over the last years. On the other hand,
although nucleos(t)ides are the standard therapy for hepatitis B, efforts to prove their therapeutic effect for HDV infections have failed. Studies
with more potent nucleos(t)ides are currently under way, and a possibly positive effect of combination therapy has to be evaluated. Prenylation
inhibitors might become therapeutic options in the future,19 and after promising preclinical results with the HBV/HDV entry inhibitor Myrcludex B
(indicated by asterisks in the figure), we are awaiting the first clinical data. In addition, this figure illustrates the different interactions of HDV
with hepatocytes and HBV. To date, delta hepatitis is considered an immune-mediated disease involving hepatocytes as MHC class II presenting
cells and cytotoxic CD4þ T cells.12,21 Cytopathic effects have been discussed in the past, but they do not seem to be the main pathological
mechanisms of HDV infection. The inhibition of IFN-a signaling seems to be an important factor not only in the persistence of chronic disease
but also in successful resistance against interferon therapy.22 With clusterin activation23 and NF-jB activation,24 more mechanisms are known to
be involved in hepatic inflammation and hepatocellular carcinoma development caused by HDV infection. Abbreviations: Enh, enhancer; IFN-a,
interferon-a; IFNAR, interferon-a/b receptor; JAK1, Janus kinase 1; MHC, major histocompatibility complex; NF-jB, nuclear factor kappa B; 2,5-
OAS, 20 ,50 -oligoadenylate synthetase; PKR, protein kinase R; STAT, signal transducer and activator of transcription; Tyk2, tyrosine kinase 2.
different regions of the world.8 In all patients of this HBV genotype D and HDV genotype 1. More studies
study, genotype 1 was detected. Genotype 1 is character- need to be conducted to obtain more information about
istic for Caucasian patients from Europe and can cause variations in therapy and efficacy for different
severe chronic disease. Different pathological effects de- genotypes.
pendent on the different genotypes have been discussed Several different treatment regimens for treating
in the past (see Fig. 1 for further details). Because the patients with hepatitis D have been evaluated in the
clinical course of the disease can differ with the geno- past.11 Nucleosides and nucleotides were ineffective for
type,9 we do not know whether positive data on the HDV infections in multiple studies. For genotypes 1
effects of PEG-IFNa2a treatment can be assigned to the and 2, Aslan et al.12 previously postulated a primary
other genotypes. Furthermore, with the influence of immune-mediated disease with elevated levels of CD4þ
eight different HBV genotypes known to date10 (30 T cells, and this makes an immunomodulatory com-
patients of the study population were tested for their pound such as interferon a reasonable therapeutic
HBV genotype, and all had genotype D), this study can choice. In 1991, the first 12-month interferon treatment
provide reliable results only about coinfections with study was published by Rizzetto’s group; a biochemical
