Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy

Summary

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible “trial endpoints”) that could be used across different clinical trials.

Introduction

Chronic hepatitis delta (CHD) has been designated an orphan disease in the European Union and in the US.¹ In these areas CHD is observed mainly in high-risk groups such as intravenous drug users, sex workers and immigrants from hepatitis delta virus (HDV) endemic areas. The latter represent areas and countries such as the former Soviet republics, Western Pacific islands, Mongolia, Pakistan, Afghanistan, countries of sub-Saharan Africa, Mediterranean and Eastern European countries such as Turkey, Romania and Albania, and areas close to the Amazon river in South America.² The causative agent of CHD, HDV, contains the smallest genome of any animal virus and needs the helper function of the hepatitis B virus (HBV) to propagate and to cause disease in humans.[3], [4], [5], [6] Eight genotypes of HDV have been described based on 19–38% sequence variation.[7], [8] Determination of HDV genotype and the global distribution of these genotypes may be important as they may affect disease prognosis and treatment outcome. For example, HDV genotype 2 appears to have a milder course than genotype 1,⁹ and genotype 3 has been associated with a more severe form of the disease.¹⁰ Furthermore, genotype 5 may be associated with outcomes similar to genotype 2, with a milder form of disease and may also respond better to interferon alpha (IFNα).¹¹ Interestingly, genotype 3 may also respond better to IFNα.¹² Among these genotypes, genotype 1 has a worldwide distribution whereas genotypes 2 and 4 are seen mainly in the Far East, genotype 3 in northern South America and genotypes 5 to 8 have only been seen in Africa.

CHD represents the most severe form of chronic viral hepatitis. Not surprisingly, many patients with compensated liver disease entering clinical studies in CHD have already reached the stage of cirrhosis. In studies from HIV-HDV coinfected patients, HDV was found to be independently associated with an increase in mortality.[13], [14] This may justify a more aggressive treatment approach with a rebalanced risk/benefit ratio compared to HBV or HCV monoinfection. Despite this, treatment of CHD has not changed since the 1980s and consists of the off-label use of IFNα or pegylated (peg)-IFNα with a viral response observed in only 25 to 30% of genotype 1 patients.¹⁵ However, considering the possibility of late relapse after discontinuation of IFN treatment, as will be discussed, the true viral response rate to IFN is almost certainly even lower. The low response rate is not unexpected. Studies in transfected cell lines suggested a general insensitivity of HDV RNA replication to IFNα.[16], [17] Interferons may be effective at a very early stage of infection when HDV is entering hepatocytes rather than at the stage of established intracellular hepatocyte HDV infection.[17], [18] Human pharmacokinetic studies were supportive of these in vitro studies and a much longer delay was observed before PegIFNα had an effect on HDV RNA compared to HCV RNA or HBV DNA (8.5 days vs. 10 to 20 hours, respectively).¹⁹ At present, there is no approved therapy for CHD and without new treatment options many patients will die from liver disease, with liver transplantation providing the only hope of rescue.

Treatment of chronic hepatitis D infection has not changed since the 80s and is suboptimal, with poor response rates and limited efficacy.

However, after many years of silence there are now attempts to develop new treatments in CHD. Four approaches have raised most of the attention, with the efficacy and safety of drugs linked to these approaches currently being tested in phase II trials. These compounds include an HBV-specific entry inhibitor, a prenylation inhibitor, nucleic acid polymers and interferon lambda (IFNλ).[20], [21], [22], [23] In addition, there are several new treatments aimed at inducing functional cure of HBV, which could also be beneficial for HDV if HBV surface antigen (HBsAg) seroconversion is achieved. These include immunomodulatory approaches such as the use of Toll-like receptor ligands, therapeutic HBV vaccines and check point inhibitors, as well as novel antivirals such as the use of small interfering RNAs, capsid assembly modulators and gene editing approaches.²⁴

The aim of all forms of treatment in chronic viral hepatitis is to prevent the development of complications of liver disease such as hepatocellular carcinoma, cirrhosis and decompensation, and ultimately death. Surrogate markers of treatment efficacy are used if the overall aim of treatment can be achieved. These surrogates have been well defined for both chronic hepatitis B and chronic hepatitis C[25], [26] but not for CHD. The main objective of this report is an attempt by a group of experts in the field to come up with reasonable and realistic recommendations with regard to treatment goals, which could be used as trial endpoints that will represent a clinically meaningful basis for conditional approval of new drugs in CHD – a disease that may not be curable and in which long-term placebo controlled studies with hard endpoints are not feasible.