Hepatitis delta virus (HDV) is a defective single- stranded RNA virus that needs co-infection with hepatitis B virus (HBV) to replicate. ¹,² The need is limited to the Hepatitis B surface antigen (HBsAg), which is required to encapsidate the HDV genome for viral morphogenesis. The virus was first discovered in Italy in the mid-1970s during a major outbreak of hepatitis D in the Mediterranean basin. ³

Although HDV suppresses HBV replication, chronic HDV co-infection significantly enhances the mortality and morbidity from cirrhosis and hepatocellular carcinoma in HBsAg carriers. ⁴,⁵ The prevalence of HDV infection in industrialized countries has declined as a result of anti-HBV vaccination; however, epidemiologic data show that HDV-related diseases persist in several regions of the world. ³

High dose of recombinant standard interferon (IFN) is currently the standard anti-HDV therapy. Although pegylated IFN (peginterferon) has been shown to be significantly superior to standard IFN in the treatment of both chronic hepatitis C and B, its superiority has not been elucidated in the therapy. ⁶,⁷ Randomized controlled studies (RCTs) of HDV disease that have compared peginterferons at any dose with high dose of standard IFN in a head- to- head manner are lacking. Furthermore, although the addition of oral agents to IFN-based therapy might help to reduce intrahepatic HBV cccDNA-a template for HBsAg production-thus diminishing the HBsAg ⁸,⁹ available to HDV to encapsidate and propagate infection, RCTs conducted so far have failed to show that combination therapy with lamivudine, ribavirin, or adefovir improves the efficacy compared with IFN monotherapy. ¹⁰,¹¹,¹²,¹³,¹⁴ The data regarding combination therapy with other potent anti-viral agents are not available yet.

Several studies in the literature have evaluated different doses and treatment duration of anti-HDV therapy with standard or peginterferon; however, they generally lack enough sample power, some are old, and others contain scattered information. In this review, we have summarized and pooled the results of these studies in an effort to reach a reliable estimate of efficacy and safety of both standard and peginterferon in anti-HDV therapy.

Search methods for identification of studies

An electronic search through Medline, EMBASE, Scopus, the Cochrane Central Register of Controlled Trials, and ISI Web of Knowledge was performed using combination of following terms: "HDV" or "Hepatitis D virus" or "Hepatitis Delta", and "interferon," "interferon alpha- 2a," interferon alpha-2b," "peginterferon," "peginterferon alpha-2a," "peginterferon alpha-2b," and "sustained virological response" or "SVR" to locate articles concerning treatment of HDV infection. The brand names of IFN such as "Pegasys," "Pegintron," "PDferon B," and "Intron A" were also tried, and the references of reviews and interventional trials retrieved were skimmed to locate other relevant studies. Temporal limits were not applied to our search strategy.

Data collection and abstraction

Titles and abstracts of all potentially relevant citations were screened by two authors separately (BB and SVT). Thereafter, the full texts of all selected reports were retrieved and assessed according to the predefined inclusion and exclusion criteria. Data from studies that met the inclusion criteria were extracted by two investigators separately and were rechecked by the third one (SMA). Decision about inclusion or exclusion of studies and predefined assumptions was made and agreed by all authors before running the meta-analysis. Characteristic data of the studies were abstracted using standard questionnaires.

Data synthesis

All analyses were performed in Mix 2.0 professional software for meta-analysis in Excel. ¹⁵ Data of all the included patients were analyzed based on the intention- to- treat principle, irrespective of compliance or follow-up. To manage missing data, we used the worst case scenario analysis; since there was a positive outcome (virological response), all patients with missing data were counted as non-responders. The results are presented as a non- comparative index, the proportion who achieved SVR with 95% confidence interval (CI).

The meta-analysis was performed using the Freeman- Tukey double arcsine transformation in random effects model of DerSimonian and Laird method. ¹⁶ The random effects model provides a more conservative estimate of significance. This model operates under the assumption that included studies are only a random sample of all the studies that will be conducted, so that heterogeneity between individual studies will result in a wider CI of the summary estimate. Therefore, using the DerSimonian and Laird random effects model, the reported summary estimate was calculated as an average of the individual study results weighted by the inverse of their variance. ¹⁶

The estimate of heterogeneity was taken from the Mantel- Haenszel model; under the null hypothesis of the test of heterogeneity, there is no difference in treatment effect between groups (this follows a c2 distribution with k−1 degree of freedom, where k is the number of studies contributing to the meta-analysis). Study results were considered heterogeneous if the resultant P-value was less than 0.1. ¹⁷ I2 was also used to provide a measure of the degree of inconsistency between the studies′ results. Its quantity describes the percentage of total variation across studies, which is due to heterogeneity rather than chance. I2 lies between 0% and 100%. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity. ¹⁸

Outcome measure

The outcome measure was the SVR, i.e., HDV-RNA remaining undetectable at least 6 months after treatment cessation, regardless of HBsAg or hepatitis B e antigene (HBeAg) loss or seroconversion. The SVR is the most desired treatment outcome of HDV infection and is considered a surrogate marker of liver HDV-Ag loss. Patients who normalize liver enzymes or undergo liver histological improvement but do not have SVR are still at greater significant risk of liver cirrhosis and hepatocellular carcinoma.

To evaluate the safety of anti-HDV therapy, we considered the number of patients who did not complete the treatment for any reasons as an index of safety. To this regard, we considered patients who discontinued treatment due to personal reasons also as treatment failures.

Eligibility criteria

Randomized and non-randomized controlled clinical trials and cohort studies were considered. Patients who had both HBsAg and HDV-RNA in serum were included if they had received at least 48 weeks of peginterferon alpha-2a, -2b or other recombinant IFN-alpha with various dose schedules. The diagnosis of chronic HDV infection required the presence of antibody to HDV (anti-HDV) for at least 6 months prior to the study and HDV-RNA detectable in serum (qualitative or quantitative methods) at the start of therapy. Only the studies which reported HDV-RNA status with a sensitive enough polymerase chain reaction (PCR) method at least 6 months after cessation of therapy were considered. The studies with previous antiviral therapy older than 6 months, study dose modification, administration of growth factors, and seropositivity for HCV and HIV without immunodeficiency syndrome were allowed. Patients were not considered if: (1) they had history of decompensated liver disease including ascites, bleeding esophageal varices, hepatic encephalopathy, bilirubin level >4 mg/dl, serum albumin level <3 g/dl, prothrombin time >4 seconds longer than the control, platelet count <50,000- 100,000/mm ³ , a leukocyte count <3000/mm ³ , granulocyte count <1500/mm ³ ; (2) they had significant co-morbidities such as autoimmune diseases, hemoglobinopathies, chronic kidney disease (serum creatinine level >1.7 mg/dl), immune-deficient status due to AIDS or immunosuppressant medications; (3) they had received oral anti-nucleoside analogs such as adefovir, lamivudine, or ribavirin; or (4) they had positive liver biopsy staining for HDV-Ag but negative for serum HDV-RNA.

Results of the search

We found 45 reports of anti-HDV therapy. Thirty-one studies were excluded for the following reasons: administration of human lymphoblastoid IFN, ¹⁹,²⁰ no-report of HDV-RNA status, at least 24 weeks after completion of treatment, ²¹,²²,²³,²⁴,²⁵,²⁶,²⁷ combination therapy with ribavirin, ¹⁴ short duration of treatment, ²⁸,²⁹,³⁰,³¹,³² combination therapy with lamivudine, ¹¹,²³,³³ case report or letter, ³⁴,³⁵,³⁶,³⁷,³⁸,³⁹ retrospective design, ²¹,⁴⁰ and duplicate publication of the same patients′ data ⁴¹,⁴²,⁴³,⁴⁴,⁴⁵ Figure 1.Figure 1

Process of study identification

The sum of clinical data indicates that HDV co-infection increases the morbidity and mortality of liver disease significantly in HBsAg carriers, compared with HBV infection alone; unfortunately, however, therapy against the HDV remains a critical and unmet need.

The potent nucleic analogs currently used for the treatment of HBV-adefovir, entecavir, telbivudine, and tenofovir - were not efficacious against HDV; this virus lacks any replicative function of its own that could be targeted by these drugs which selectively block the reverse transcription of the HBV. Early studies have shown that the less potent HBV agents, lamivudine and famcyclovir, as well as ribavirin, a drug active against RNA viruses (such as the HDV), were also of no therapeutic use.

IFN, first used empirically in the 1980 on the wake of its partial efficacy in HBV disease, remains the only approved therapy for hepatitis B. However, the use of IFN is still based on accepted common practice rather than on precise guidelines based on RCTs. We therefore performed this study to evaluate the true therapeutic potential of IFN in chronic hepatitis D. Our meta-analysis suggests that approximately one-fifth and one-third of those who receive standard and peginterferon have a chance of sustained HDV eradication. Furthermore, a sub-analysis did not indicate that extending the duration of peginterferon therapy for 2 years was more effective than the standard 48-week therapy. The major limitations to this meta-analysis are the variability of the design of the studies that made use of standard IFN and the clinical heterogeneity across treatment regimens; we could not identify even two such studies which adopted similar therapy regimens. Given this problem and in view of the few number of patients treated in each study, no definite conclusion on the superiority of peginterferon over standard IFN for anti-HDV therapy could be reached. However, because of the similar safety index between standard and peginterferon and the slightly higher rate of SVR with peginterferon, considering also its weekly administration and the better compliance of the patient, peginterferon alpha-2a or -2b for 48 weeks appears to be a preferable option for anti-HDV therapy.

This systematic review indicates that the literature lacks sufficient evidence to make precise recommendations for treatment of HDV infections. The meta-analysis of these studies shows that standard dose of peginterferon might be more effective than high dose of standard interferon.