Reviving pegylated interferon as a therapeutic agent for hepatitis D: No more room for nucleos(t)ides?


  • Potential conflict of interest: Nothing to report.

Wedemeyer H, Yurdaydìn C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, et al.; for HIDIT Study Group. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 2011;364:322-331. (Reprinted with permission.)


BACKGROUND: Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in the most severe form of viral hepatitis. There is no currently approved treatment. We investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and adefovir dipivoxil alone. METHODS: We conducted a randomized trial in which 31 patients with HDV infection received treatment with 180 μg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, 29 received 180 μg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen (HBsAg). RESULTS: The primary end point—normalization of alanine aminotransferase levels and clearance of HDV RNA at week 48—was achieved in two patients in the group receiving peginterferon alfa-2a plus adefovir and two patients in the group receiving peginterferon alfa-2a plus 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 patients in the first group, 24% of patients in the second, and none of those in the third (P=0.006 for the comparison of the first and third groups; P=0.004 for the comparison of the second and third). The efficacy of peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of the patients receiving peginterferon alfa-2a plus adefovir or peginterferon alfa-2a alone having negative results on HDV-RNA tests; none of the patients receiving adefovir alone had negative results. A decline in HBsAg levels of more than 1 log10 IU per milliliter from baseline to week 48 was observed in 10 patients in the first group, 2 in the second, and none in the third (P<0.001 for the comparison of the first and third groups and P=0.01 for the comparison of the first and second). CONCLUSIONS: Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir, resulted in sustained HDV RNA clearance in about one quarter of patients with HDV infection.


Since its discovery in 1977 by Rizzetto et al., hepatitis delta virus (HDV) has been known as a special and incomplete virus with an extraordinarily small RNA genome (1.7 kb) encoding two hepatitis D antigens (HDAgs): a small, 24-kDa HDAg and a bigger, 27-kDa HDAg.1 Viral replication is possible only in hepatitis B virus (HBV)–infected cells because hepatitis B surface antigen (HBsAg) is needed as a lipid layer around the protein-RNA complex of HDV. Because of this unique method of replication, HDV has obtained its own genus (Deltavirus). Five percent of all HBV-positive patients are expected to be HDV-positive, although we should keep in mind that there are significant regional differences in prevalence. Chronic delta hepatitis can cause the most severe form of viral hepatitis known to date,2 and a standard therapy regimen has not been established yet.

Two paths of infection and two subsequent courses of disease are possible: a coinfection with hepatitis B (with a high risk of fulminant hepatitis and a 95% chance of the clearance of both viruses) and a superinfection with preexisting hepatitis B (with the possibility of fulminant hepatitis and/or severe chronic disease). Patients with chronic hepatitis B who acquire an HDV superinfection have a high risk of developing liver cirrhosis.3, 4

For Hep-Net International Delta Hepatitis Intervention Trial I (HIDIT-I), Wedemeyer et al.5 recruited 90 patients with chronic hepatitis B and D coinfections from multiple centers in Germany, Greece, and Turkey and compared three different therapy regimens: pegylated interferon alfa-2a (PEG-IFNα2a) and a placebo (n = 29), PEG-IFNα2a and adefovir (ADV; n = 32), and ADV alone (n = 30) for 48 weeks. Eighty patients completed the study (89%), and follow-up was performed for another 24 weeks. Among others, the primary and secondary endpoints were the normalization of alanine aminotransferase levels, the clearance of HDV RNA, and a significant decline in HBsAg levels.

Wedemeyer et al.5 found that 48 weeks of therapy with PEG-IFNα2a, alone or in combination with ADV, significantly reduced HDV RNA levels, with 28% of the patients clearing the virus within 24 weeks of the end of therapy. Treatment with ADV alone had no significant effect on HDV clearance after 24 weeks, although the suppression of HBV DNA under therapy was best in the ADV group. These results are consistent with earlier studies evaluating PEG-IFN as an effective therapeutic agent.6, 7

HDV has (at least) eight different genotypes. These eight different clades have specific distributions in different regions of the world.8 In all patients of this study, genotype 1 was detected. Genotype 1 is characteristic for Caucasian patients from Europe and can cause severe chronic disease. Different pathological effects dependent on the different genotypes have been discussed in the past (see Fig. 1 for further details). Because the clinical course of the disease can differ with the genotype,9 we do not know whether positive data on the effects of PEG-IFNα2a treatment can be assigned to the other genotypes. Furthermore, with the influence of eight different HBV genotypes known to date10 (30 patients of the study population were tested for their HBV genotype, and all had genotype D), this study can provide reliable results only about coinfections with HBV genotype D and HDV genotype 1. More studies need to be conducted to obtain more information about variations in therapy and efficacy for different genotypes.

Figure 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 CD4+ 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-α 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-κB activation,24 more mechanisms are known to be involved in hepatic inflammation and hepatocellular carcinoma development caused by HDV infection. Abbreviations: Enh, enhancer; IFN-α, interferon-α; IFNAR, interferon-α/β receptor; JAK1, Janus kinase 1; MHC, major histocompatibility complex; NF-κB, nuclear factor kappa B; 2,5-OAS, 2′,5′-oligoadenylate synthetase; PKR, protein kinase R; STAT, signal transducer and activator of transcription; Tyk2, tyrosine kinase 2.

Several different treatment regimens for treating patients with hepatitis D have been evaluated in the past.11 Nucleosides and nucleotides were ineffective for HDV infections in multiple studies. For genotypes 1 and 2, Aslan et al.12 previously postulated a primary immune-mediated disease with elevated levels of CD4+ T cells, and this makes an immunomodulatory compound such as interferon a reasonable therapeutic choice. In 1991, the first 12-month interferon treatment study was published by Rizzetto's group; a biochemical response was found, although a virological response was not achieved.13 In 2006, the first data for a small group (n = 16) treated with PEG-IFNα2b were presented,6 and a sustained virological response was shown in 43% of the patients. Wedemeyer et al.5 have now put hepatitis D therapy with PEG-IFN back into the limelight. Their data demonstrate that PEG-IFN is at present the only reasonable therapeutic option for HDV infection.

What is the Remaining Significance of Nucleos (t)ide Therapy?

HDV coinfection leads to hepatitis B e seroconversion and low HBV DNA levels, which are typical signs of delta hepatitis dominating an HBV infection.14 This constellation can cause severe hepatitis with a high risk of decompensating end-stage liver disease or hepatocellular carcinoma development, and this makes optimal treatment necessary. In light of the current results and previous studies already showing the ineffectiveness of nucleos(t)ide therapy, we are faced with the question whether there is any role for these compounds in treating patients chronically coinfected with hepatitis B and hepatitis D. ADV has lost its role as a first-line therapy for chronic hepatitis B over the last years, and to date, there are no available data addressing the prognosis of treatment with entecavir or tenofovir in these cases. Anyway, although no significant suppression of HBsAg was noticed in the PEG-IFN–alone group, HDV RNA clearance was achieved to the same degree found in the PEG-IFN and ADV group. In addition, HBsAg levels could be further reduced with combination therapy. In this cohort, HDV replication correlated with serum HBsAg levels.15 HBsAg reduction might be a prognostic factor for possible clearance in the future because HDV needs HBsAg as an envelope protein. Thus, is there a reasonable indication for combination therapy? With respect to HBsAg levels, this therapeutic scheme had the most profound effect. Because an HBsAg decline is a positive predictor of successful therapy in hepatitis B e antigen–positive patients with chronic hepatitis B monoinfections,16 combination therapy might also be favorable in HBV/HDV-coinfected patients with hepatitis B e antigen and/or a high viral load. A positive effect provided by combination therapy in these patients must be evaluated in future studies. An ongoing Hep-Net study (HIDIT-II) is evaluating a possible regimen involving tenofovir and PEG-IFNα2a.

Who Should Be Treated?

Taking into consideration the present study as well as future studies, we believe that all patients with HDV infections and without contraindications should be evaluated for PEG-IFN therapy. Because patients undergoing interferon therapy are at high risk for adverse events and long treatment intervals are needed with a probable effectiveness of only 25%, it is important to identify prognostic factors to determine treatment outcomes. In 2007, Wedemeyer17 evaluated different cytokine patterns in patients participating in this study. He showed that differences in the T cell response discriminated between responders and nonresponders. Also, as mentioned before, an HBsAg decline might be a prognostic factor of the virological response. Reliable parameters are needed to provide valuable predictions of therapeutic success early during treatment and to determine the necessary duration of therapy.


Future studies should be performed to determine whether combination therapy is an option in patients with chronic hepatitis B and D coinfections. Currently, HIDIT-II is recruiting patients to compare PEG-IFN plus tenofovir to PEG-IFN plus a placebo. Because an earlier trial achieved promising results in patients coinfected with human immunodeficiency virus, HBV, and HDV,18 we are looking forward to discovering whether the therapy response can be improved, although the treatment duration was significantly longer in that study (median = 6 years). Because a decline in HBsAg levels during therapy is a potential prognostic parameter for these patients, longer treatment intervals have to be considered.

Finally, novel treatment options include prenylation inhibitors19 and HBV entry inhibitors, which are currently in early clinical development. They might be treatment options in the future. HBV/HDV entry inhibitors (e.g., Myrcludex B) have been successfully tested in preclinical studies, and clinical trials have to be conducted to determine whether these novel compounds can be successfully used.20 Because 15 to 20 million people are infected with HDV worldwide and immigration from areas of high endemicity mainly to Europe is a growing problem, successful therapeutic regimens are desperately needed.