Identification, diagnosis and management of persistent Hepatitis E virus infection
File(s)
Author(s)
Ankcorn, Michael James
Type
Thesis
Abstract
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in the
UK and leads to persistent HEV infection in immunosuppressed individuals. The
prevalence and clinical outcomes of persistent HEV are unknown in the UK. It is
hypothesized that persistent HEV is an under-recognised disease in the UK, that
screening of high-risk immunocompromised patients will be cost-effective and
enhanced surveillance of persistent HEV cases will identify pragmatic parameters
for clinical monitoring.
Within this study, the prevalence of HEV infection was investigated in three distinct
immunocompromised cohorts. A commercial assay for detecting HEV antigen
(HEV-Ag) was explored for use as a screening assay and monitoring tool. A cost-effectiveness analysis modelled the impact of annual HEV screening in solid organ
transplant (SOT) recipients. The diagnostic findings and clinical outcomes were
reported on a case series of persistent HEV infections across England and Wales
and whole genome sequencing (WGS) was utilized to explore viral mutations with
and without antiviral pressure.
This work demonstrates that persistent HEV infections are under-recognised in
transplant recipients, with biochemical abnormalities often attributed to other
causes by clinicians. Viraemia rates were similar to other European studies among
SOT recipients. HEV-Ag had both high sensitivity and specificity as a screening
assay for persistent HEV infections. The annual screening of SOT recipients either
by RNA or HEV-Ag testing is projected to be cost-effective for the NHS. The case
series showed that a broad range of immunosuppressed patients are at risk of
persistent infection, however the magnitude of risk in antibody-deficient patients
and those with a haematological malignancy were lower than in SOT. Finally, WGS
revealed the emergence of mutations in the RNA-dependent RNA polymerase
region associated with clinical phenotypic resistance to ribavirin. However, further
optimization of HEV sequencing is required to investigate samples with lower HEV
viral loads.
UK and leads to persistent HEV infection in immunosuppressed individuals. The
prevalence and clinical outcomes of persistent HEV are unknown in the UK. It is
hypothesized that persistent HEV is an under-recognised disease in the UK, that
screening of high-risk immunocompromised patients will be cost-effective and
enhanced surveillance of persistent HEV cases will identify pragmatic parameters
for clinical monitoring.
Within this study, the prevalence of HEV infection was investigated in three distinct
immunocompromised cohorts. A commercial assay for detecting HEV antigen
(HEV-Ag) was explored for use as a screening assay and monitoring tool. A cost-effectiveness analysis modelled the impact of annual HEV screening in solid organ
transplant (SOT) recipients. The diagnostic findings and clinical outcomes were
reported on a case series of persistent HEV infections across England and Wales
and whole genome sequencing (WGS) was utilized to explore viral mutations with
and without antiviral pressure.
This work demonstrates that persistent HEV infections are under-recognised in
transplant recipients, with biochemical abnormalities often attributed to other
causes by clinicians. Viraemia rates were similar to other European studies among
SOT recipients. HEV-Ag had both high sensitivity and specificity as a screening
assay for persistent HEV infections. The annual screening of SOT recipients either
by RNA or HEV-Ag testing is projected to be cost-effective for the NHS. The case
series showed that a broad range of immunosuppressed patients are at risk of
persistent infection, however the magnitude of risk in antibody-deficient patients
and those with a haematological malignancy were lower than in SOT. Finally, WGS
revealed the emergence of mutations in the RNA-dependent RNA polymerase
region associated with clinical phenotypic resistance to ribavirin. However, further
optimization of HEV sequencing is required to investigate samples with lower HEV
viral loads.
Version
Open Access
Date Issued
2021-11
Date Awarded
2022-07
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
McClure, Myra
Tedder, Richard
Sponsor
NHS Blood and Transplant
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)