Hepatitis delta virus propagation enabled by hepatitis C virus—Scientifically intriguing, but is it relevant to clinical practice?

Abstract

In vitro cell culture experiments and animal models have demonstrated that hepatitis delta virus (HDV) can theoretically propagate being enveloped by human pathogenic viruses other than hepatitis B virus (HBV), namely hepatitis C virus (HCV) and dengue virus. However, the clinical relevance of these findings and whether HDV replication occurs in real‐world hepatitis B surface antigen (HBsAg)–negative HCV patient cohorts remain unknown. To this aim, we analysed 323 HCV‐RNA–positive and HBsAg‐negative sera for the presence of HDV‐RNA and anti‐HDV antibodies (anti‐HDV). All 323 (100%) samples were negative for HDV‐RNA. Interestingly, 8/316 samples tested positive for anti‐HDV. The HBV serology of these eight patients showed a positive result for HBV core antibodies (anti‐HBc) indicating a seroconversion of an acute HBV infection in the past. None of the anti‐HBc–negative patients were positive for anti‐HDV. Our results indicate a distinctly low probability of replicative HDV infection in HCV mono‐infected patients in Germany. Current German clinical guidelines rightly recommend performing HDV screening only in HBsAg‐positive patients. However, larger studies on this subject should be performed in regions that are endemic for chronic HBV/HDV as well as HCV infections.

Interplay between Hepatitis D Virus and the Interferon Response

“…Another study showed that HDV RNP could be packaged into the envelope proteins of vesiculo-, flavi-, and hepaciviruses in vitro, allowing the egress of HDV RNPs from cells and subsequent entry into cell lines expressing the respective receptors [ 87 ]. It is controversial whether HDV is able to use the envelopes of non-hepadnaviruses for dissemination in patients [ 88 , 89 , 90 ]. HBV envelope-independent spread may play a yet-unknown role in HDV persistence in CHD patients and challenge the effect of drugs interfering with HD virion production or de novo virus entry.…”

New insights into HDV persistence: The role of interferon response and implications for upcoming novel therapies

“…73 However, two other studies didn't find any HBV-independent HCV/HDV co-infection in more than 2000 HCV individuals. 74,75 Larger studies on this subject are needed in regions with high prevalence of chronic HBV/HDV and HCV and regions where parental infection routes have been studied and are known. Similarly, more investigations are needed to clarify whether HDV-like agents spread with the help of viruses other than hepadnaviruses in respective infected hosts.…”

Hepatitis Delta Virus (HDV) and Delta-Like Agents: Insights Into Their Origin

“…However, the clinical relevance of these findings remain uncertain. A recent study that involved 323 HCV RNA positive and HBsAg-negative patients could only detect HDV markers in eight HBV core antibody (anti-core) positive patients (evidence of past acute HBV infections) and not among the remaining HBV core antibody negative patients suggesting the occurrence of replicative HDV infections in HCV mono-infected patients is low ( Pflüger et al, 2020 ). A similar study investigating a cohort of 160 Venezuelan patients infected with HCV in the absence of molecular markers for HBV detected two patients with anti-HDAg antibodies, and for one patient low-level circulating HDV RNA ( Chemin et al, 2020 ), also indicating that if HCV provides helper functions, it does not seem to be an effective or potent helper virus.…”