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Nucleic acid polymers: much-needed hope for hepatitis D? - Comment
  Lancet Gastroenterology& Hepatology - *Dulce Alfaiate, Francesco Negro Department of Pathology and Immunology, University of Geneva, Geneva 1211, Switzerland (DA); and Divisions of Gastroenterology and Hepatology and Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland (FN)
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In the Lancet Gastroenterology & Hepatology, Michel Bazinet and colleagues1 describe the results of a phase 2 clinical trial on the safety and efficacy of combined treatment with the nucleic acid polymer REP 2139 and pegylated interferon alfa-2a for treatment of patients with chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection.
Chronic hepatitis D is considered the most severe and most difficult form of chronic viral hepatitis to treat. Despite affecting an estimated 15-20 million people worldwide, often in impoverished settings, the allocation of resources for the treatment of chronic hepatitis D is low compared with other chronic infections of similar prevalence.2 At present, pegylated interferon alfa-2a is the only approved therapy for chronic hepatitis D, for which only a minority of patients are eligible because of the known safety issues of the drug.3 Moreover, response rates are poor and late relapses are common, highlighting the urgent need for new therapeutic strategies.4
Nucleic acid polymers have shown antiviral activity against HBV, both in experimental models and in a proof-of-concept clinical trial.5 The proposed mechanism of action involves both the inhibition of viral entry and, most importantly, the blockade of hepatitis B virus surface antigen (HBsAg) release and secretion of subviral particles, enabling restoration of the host immune response against the virus.5 Because HDV is a defective virus that also depends on HBsAg for its assembly and is hypothesised to use the subviral particle secretion pathway for its egress,6 these molecules are very attractive candidates to target HDV.
In this proof-of-principle trial by Bazinet and colleagues,1 12 patients, all without cirrhosis, received REP 2139, first as monotherapy for 15 weeks and then combined with pegylated interferon alfa-2a for another 15 weeks, followed by a 33 week course of pegylated interferon alfa-2a monotherapy. Substantial declines in both HBsAg concentrations and HDV RNA were observed by the end of REP 2139 monotherapy, which remained stable in most patients for 1 year after treatment withdrawal. The regimen also appeared to be relatively safe, despite the induction of pronounced alanine aminotransferase flares in some patients, which might limit the applicability of the treatment for patients with cirrhosis. Although these results appear promising, a more thorough evaluation of these molecules is warranted to validate their use.
First, the results of this uncontrolled study must be confirmed by a randomised controlled trial that includes at least a pegylated interferon alfa-2a monotherapy arm. Indeed, although all patients were reported to have had HDV infection for more than 1 year before treatment and the decline of HDV RNA and HBsAg concentrations was faster than that expected during the natural course of disease, data on IgM antibodies against hepatitis B core antigen were not provided. Thus, the possibility that some enrolled patients had a protracted acute HDV infection that spontaneously cleared cannot be excluded.
Second, the possibility of late relapses must be carefully ruled out, not only because they are common in patients with chronic hepatitis D infection who receive pegylated interferon alfa-2a,4 but also because in the authors' previous study7 on the efficacy of REP 2139 in patients with chronic HBV infection, relapses occurred as late as 123 weeks after treatment withdrawal, supporting the possibility of a transient, incomplete viral clearance. Long-term follow-up will also allow the risk of complications associated with the intrahepatic accumulation of viral products to be investigated.
Beyond the clinical implications, this study raises interesting questions about the effects of nucleic acid polymers on the life cycle of HDV. In most patients a steep decline in serum HDV RNA was observed before the introduction of pegylated interferon alfa-2a, which is consistent with the proposed inhibition of HBsAg assembly and egress by nucleic acid polymers, although this mechanism of action remains to be investigated in the context of HDV infection. More importantly, in some patients, the HDV RNA decrease occurred irrespective of HBsAg decline, and preceded the increase in alanine aminotransferase concentration that occurred after the introduction of pegylated interferon alfa-2a, which indicates that substantial lysis of infected cells is an unlikely explanation. Furthermore, direct inhibition of HDV replication by nucleic acid polymers has been excluded in vitro,8 and the induction of the intracellular innate immune response has been ruled out in primary hepatocytes.9 In view of the likely accumulation of HDV viral components inside hepatocytes, indirect antiviral effects might be considered-eg, inhibition of viral replication induced by the large isoform of the HDV antigen.10 Studies that investigate intrahepatic viral markers are required to clarify the mechanism by which serum HDV RNA is decreased. The results of Bazinet and colleagues' study indicate that some degree of control of HBsAg secretion is necessary to maintain a virological response after treatment withdrawal because HDV rebound occurred only in patients in whom HBsAg loss was not achieved.
Although the results of the study by Bazinet and colleagues must be interpreted with caution, they indicate that nucleic acid polymers might represent a promising new therapy that provides effective, long-lasting, and safe control of chronic hepatitis D infection.

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