Summary of the British Transplantation Society UK ...and significant liver fibrosis. The British Transplantation Society (BTS) has developed Guidelines for “Hepatitis E & Solid Organ

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Summary of the British Transplantation Society UK Guidelines for

Hepatitis E and Solid Organ Transplantation

Dr Stuart McPherson, Consultant Hepatologist, Liver Transplant Unit, The Newcastle upon

Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle

university, UK

Dr Ahmed M Elsharkawy, Consultant Hepatologist, Liver Transplant Unit, Queen Elizabeth

Hospital, Birmingham, UK

Dr Michael Ankcorn, Clinical Research Fellow in Virology, Virus Reference Department,

National Infection Service, Public Health England/NHS Blood and Transplant, Colindale,

London, UK

Dr Samreen Ijaz, Deputy Head, Blood Borne Virus Unit, Virus Reference Department,

National Infection Service, Public Health England, Colindale, London UK

Mr James Powell, Consultant Transplant Surgeon, Royal Infirmary of Edinburgh, UK

Dr Ian Rowe, Honorary Consultant Hepatologist, University of Leeds and Liver Unit, St

James‟ Hospital, Leeds, UK

Prof Richard Tedder, Division of Infection and Immunity, University College London and

Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public

Health England, Colindale, London, UK

Dr Peter A Andrews, Chair of BTS Standards Committee and Consultant Nephrologist, SW

Thames Renal & Transplantation Unit, Surrey, UK

http://guide.medlive.cn/




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Correspondence address:

Dr Stuart McPherson

Consultant Hepatologist,

The Liver Unit,

Level 6,

Freeman Hospital,

Freeman Road,

Newcastle upon Tyne, NE7 7DN, U.K.

Telephone: +44 (0) 191 233 6161

Email: [email protected]

All authors contributed to the BTS guideline document and to this summary of the guideline.

All have reviewed and approved the final document.

The authors received no support for the writing of either the BTS guideline or this paper

based upon it.





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Potential conflicts of interest:

Dr Stuart McPherson – speaker, consultancy or travel support from AbbVie, BMS, Gilead,

MSD, Novartis and Roche

Dr Ahmed Elsharkawy - speaker, consultancy, research grant or travel support from Abbvie,

Astellas, BMS, Chiesi, Gilead and MSD

Dr Ian Rowe – speaker or travel support from AbbVie, Bayer and Norgine

Mr James Powell – none

Dr Michael Ankcorn – none

Dr Samreen Ijaz – none

Prof Richard Tedder – none

Dr Peter Andrews – none





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Abstract

The incidence and prevalence of hepatitis E virus (HEV) infection has increased in many

developed countries over the last decade, predominantly due to infection with genotype 3

(G3) HEV. Infection with HEV G3 is important in transplant recipients because it can persist

in immunosuppressed individuals, leading if untreated to the development of chronic hepatitis

and significant liver fibrosis. The British Transplantation Society (BTS) has developed

Guidelines for “Hepatitis E & Solid Organ Transplantation” to inform clinical teams and

patients about hepatitis E, to help increase the recognition of persistent hepatitis E infection,

and to provide clear guidance on its management. This guideline was published on the BTS

website in June 2017 and aims to review the evidence relating to the diagnosis and

management of persistent hepatitis E in solid organ transplant recipients, and the methods of

prevention of HEV infection. In line with previous guidelines published by the BTS, the

guideline has used the GRADE system to rate the strength of evidence and recommendations.

This article includes a summary overview of hepatitis E and transplantation with key

references, and the statements of recommendation contained within the guideline. It is

recommended that the full guideline document is consulted for complete details of the

relevant references and evidence base. This may be accessed at https://bts.org.uk/guidelines-

standards/

Keywords: guideline; hepatitis E; transplantation, transplant





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Introduction

The incidence and prevalence of hepatitis E virus (HEV) infection has increased in many

developed countries over the last decade, predominantly due to infection with genotype 3

(G3) HEV. Infection with HEV G3 is important in transplant recipients because it can persist

in immunosuppressed individuals, leading if untreated to the development of chronic hepatitis

and significant liver fibrosis. As there are currently no international guidelines on the

management of hepatitis E in transplant recipients, the British Transplantation Society (BTS)

has developed guidelines to inform clinical teams and patients about hepatitis E, to help

increase the recognition of persistent hepatitis E infection, and to provide clear guidance on

its management. The following includes an overview of hepatitis E and transplantation with

key references, and the statements of recommendations contained within the BTS guideline.

Overview of Hepatitis E and Solid Organ Transplantation

Epidemiology of HEV

Hepatitis E virus (HEV) belongs to the genus Hepevirus in the Hepeviridae family and

infects humans and a range of animal hosts (1). Four major HEV genotypes infect humans

(G1 to G4). The epidemiological picture, transmission routes and reservoirs, as well as

clinical features and outcome differ significantly depending on the region of the world and

accordingly, the HEV genotype (2). G1 and G2 are restricted to the human host and occur

primarily in Asia and Africa. G3 has a worldwide distribution and is associated with infection

in humans, pigs and other mammalian species. G4 only infects humans and pigs, principally

in South East Asia.





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HEV G1 and G2 viruses remain major public health concerns in resource poor settings,

where HEV is thought to be responsible for >50% of cases of viral hepatitis. The virus is

transmitted via the faecal-oral route through the consumption of contaminated food and

water. Reported mortality rates from endemic areas are significant, ranging from 0.5 to 4%

(2). Infection with G1 and G2 is self-limiting and persistent infection does not occur.

HEV G3 and G4 are zoonotic infections, being transmitted to humans from an animal

reservoir. Case-control studies have indicated that the consumption of pork products

(particularly processed products) and game meat are associated with HEV infection (3, 4).

Enhanced surveillance data from England collected over 10 years indicate there has been a

recent rise in indigenous G3 infection (5). Seroprevalence rates in the general population of

England is high at ~13% (6) and estimates of burden in the general population suggest as

many as 200 000 HEV infections occur per year and that these account for around 600-800

cases of hepatitis in England. Persistent HEV infection is increasingly recognised, probably

reflecting increased awareness and testing. Public Health England surveillance shows these

infections occur across a broad range of immunosuppressed patient groups (solid organ

transplantation, haematopoietic stem cell transplantation, haemato-oncology and HIV-

infected).

Data from the selective screening programme implemented by NHS Blood and Transplant in

March 2016 indicate that 1 in 2500 donations are HEV RNA positive (data correct in

February 2017). An investigation undertaken in England in recipients of HEV-containing

blood components showed that 18 (42%) of 43 went on to develop HEV infection, giving an

approximate risk of transfusion-related HEV infection of 1 in 5000 (7). As a result, universal

screening of all blood components for HEV is now recommended by the UK Advisory

Committee for the Safety of Blood, Tissues and Organs (SaBTO) on the basis of superior cost

effectiveness of universal over selective testing for HEV (8).





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The transplant patient may acquire HEV in 2 ways, either through diet or through the receipt

of substances of human origin including organs and blood components (9). Cross sectional

studies assessing the prevalence of HEV infection in cohorts of transplant recipients indicate

that detectable HEV RNA (indicating current viremia) ranged from 0-3.2% (10). A recent

study at a single centre in the UK found the point prevalence of HEV viremia in transplant

recipients was 16/2418 (0.7%) (manuscript submitted). It has been previously estimated that

the annual risk of acquiring HEV in the UK is approximately 1 in 500 to 1000 (7).

Clinical Features

Acute Hepatitis E

The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to

fulminant liver failure. Symptoms, if they occur, include general malaise, abdominal pain,

anorexia, nausea and fever and are followed by the onset of jaundice accompanied by dark

urine, pale stools and pruritis (11). Most infections are self-limiting. Acute hepatitis E in

patients with underlying liver disease may lead to decompensation and a poor outcome (12-

14), and very rarely fulminant liver failure (15, 16). A number of extrahepatic manifestations

linked both to acute and to persistent hepatitis E infection have been reported including

thrombocytopenia, glomerulonephritis and a range of neuropathologies (17).

Persistent HEV Infection

Reported cases of persistent HEV infections are almost always been due to G3 HEV

(although G4 has been reported (18)). The clinical features of persistent HEV infection are

often unremarkable. Liver transaminases are usually only modestly raised and few patients

present with any symptoms (11, 19). Once infected, 60% of solid organ transplant recipients

fail to clear the virus and are at risk of developing chronic hepatitis (11, 19). Liver biopsy

shows rapid progression of liver fibrosis with 10% of patients progressing to cirrhosis over a

few years (11).





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Diagnosis of Hepatitis E

Acute hepatitis E cannot be clinically distinguished from other causes of acute hepatitis.

Diagnosis of HEV infection can be undertaken using methods for detecting antibody, antigen

and RNA (20-22). Importantly, laboratory diagnosis of acute or persistent HEV in

immunosuppressed individuals must be through detection of the virus itself, either through

HEV RNA testing or HEV antigen testing, as antibody detection in the immunosuppressed

population is not a reliable marker of infection (11). Viral RNA can be detected a few weeks

before the onset of clinical symptoms in both blood and stool samples. In an

immunocompetent host viremia lasts on average for 8 weeks, becoming undetectable in blood

approximately 3 to 4 weeks after the onset of symptoms. Viral shedding in stool continues

beyond plasma viral clearance in both acute and treated persistent infection (23).

The clinical diagnosis of persistent hepatitis E infection is challenging, as such infections are

largely asymptomatic (11, 19). Testing strategies for identifying individuals with persistent

infection are not clear and mean that infection can remain undiagnosed for years. Clinicians

must have a high index of suspicion for infection and should investigate raised liver enzymes

of any degree with reflex HEV RNA testing. Typically ALT levels are between 100-200 U/L

in transplant recipients with HEV infection, but patients with may also present with

minimally raised liver enzymes or enzymes within the upper normal range (11, 19). Persistent

HEV infection can be misdiagnosed as drug-induced liver injury (24), rejection (in liver

transplants) (25) or graft versus host disease, so careful assessment is needed of all liver

enzyme abnormalities in transplant recipients.

Management of HEV infection posttransplant

The initial management of acute infection in solid organ transplant recipients should include

careful observation and monitoring of HEV RNA levels, serology, and liver enzymes.





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Clearance of infection occurs spontaneously in more than 30% of cases (11). Where possible,

a reduction in immunosuppression should be considered. If HEV RNA clearance from the

blood and stool has not been achieved by 3 months then persistent infection is likely to occur

and the patient should be managed as having persistent HEV infection. There may be specific

cases where early antiviral therapy with ribavirin is indicated, such as patients who develop

severe liver dysfunction (jaundice and coagulopathy) or extrahepatic manifestations, although

evidence for this is currently limited (26-29).

Persistent HEV G3 infection causes a chronic hepatitis that can progress rapidly (3-5 years)

to cirrhosis in approximately 10% of infected solid organ transplant recipients so it is

important that it is treated (11). Individuals with persistent HEV infection (documented or

estimated duration of infection of greater that 3 months) should be actively managed with the

aim of achieving a sustained virological response (HEV RNA nondetected in plasma and

stool 6 months after completing treatment).

If not already attempted in the acute phase, first line management of persistent HEV infection

is a strategic reduction in immunosuppression which can lead to clearance of HEV infection

in approximately 30% of individuals with persistent HEV (11). Different classes of

immunosuppressant drugs have different effects on HEV replication. Overall, current

evidence suggests that calcineurin and mTOR inhibitors may contribute to persistence of

HEV replication in hepatocytes and the development of persistent HEV, whereas

corticosteroids appear to have no effect on viral replication, and mycophenolate may have an

inhibitory effect on HEV replication in vitro (11, 30-34). Therefore, strategic modification of

immunosuppression might help with viral clearance. Further studies are awaited to help

define the role of modification of immunosuppression in persistent HEV. It is important to

recognise that changes in immunosuppression can precipitate rejection in more immunogenic

individuals so the risk of rejection versus the potential benefits of modification of

immunosuppression must be carefully balanced.





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Ribavirin

The second line treatment for persistent HEV, after modification of immunosuppression, is

ribavirin. Several studies have demonstrated efficacy of ribavirin in the treatment of

persistent HEV, with sustained virological response rates (SVR; HEV RNA negative 6

months post treatment) ranging from 63-78% with 3-6 months of ribavirin treatment (31, 32,

35-38). Initial studies used different doses and duration of ribavirin so the optimum duration

remains unknown. More recent studies, using a more standardised protocol of 3 months of

ribavirin treatment using creatinine-clearance adjusted dosing, showed SVR rates of 63% (31,

32). These studies also demonstrated that on-treatment virological response may predict

outcome from treatment. Kamar et al showed that a fall in HEV RNA at day 7 of treatment

with ribavirin predicted SVR following 3 months of ribavirin (31). In that study falls of 0.5

log copies/mL or 1 log copies/mL at day 7 of ribavirin treatment had positive predictive

values for SVR of 88% and 100% respectively. Therefore, assessment of day 7 virological

response could be incorporated into treatment algorithms to help determine treatment course

length (ie, those with a favourable response at day 7 could be treated for 3 months with

ribavirin and those with a slower virological response probably require a longer course, such

as 6 months). However, this was a small study and requires validation.

Another important study showed that persistent HEV shedding in stool, even after clearance

from the plasma, strongly predicted relapse following 3 months of treatment with ribavirin

(32). Therefore, assessment of stool HEV RNA to ensure it is negative before stopping

ribavirin treatment can significantly reduce the risk of relapse. A suggested algorithm for the

treatment of HEV is shown in Figure 1.

The most frequent side effect of ribavirin is a hemolytic anemia, which requires intervention

in approximately 40% (dose reduction, epoetin or blood transfusion) (35). Therefore, patients

require regular monitoring of hemoglobin while on treatment.





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Treatment failure with ribavirin treatment

Approximately 40% of transplant recipients with persistent HEV relapse after 3 months of

treatment with ribavirin (31, 32). Potential reasons for treatment failure include the need for

dose reduction, insufficient duration of treatment to ensure HEV is cleared from both blood

and stool, and the development of ribavirin associated mutations (G1634R mutation in the

RdRp domain of the ORF1 protein is associated with ribavirin treatment failure) (38, 39). The

majority of patients who relapse will respond to a longer course of treatment with ribavirin,

even those harboring the G1634R mutation (37). Therefore, retreatment with a longer course

of ribavirin should be considered for patients who relapse, and treatment continued until the

HEV RNA is negative in blood and stool on 2 tests at least 1 month apart. Retreatment for 6

months with ribavirin will be sufficient for many patients to achieve a sustained virological

response, but some will require longer treatment (36). There are occasional reports of very

resistant cases of HEV with multiple mutations that confer resistance to ribavirin who have

persisting HEV viremia despite continued treatment (40). This emphasises the importance of

ensuring the patient receives effective treatment on their first course of treatment where

possible.

For cases of ribavirin-refractory persistent HEV, treatment with PEG-interferon could be

considered as there are case reports of successful clearance of persistent HEV with PEG-

interferon in transplant recipients (75% SVR in 8 patients treated for 3-12 months) (35).

However, PEG-interferon is well known to increase the risk of rejection in transplant

recipients, so close monitoring is required.





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Process of Writing and Methodology

The British Transplantation Society (BTS) Guidelines for Hepatitis E and Solid organ

Transplantation were posted online in June 2017 (41). They were written by a team with

wide representation from UK clinicians under the auspices of the BTS Standards

Committee and were produced in line with the BTS Clinical Practice Guideline

Development policy (available at http://www.bts.org.uk/) (42). In brief, a systematic

review of the relevant literature and synthesis of the available evidence was

commissioned from selected clinical experts working to the standards of the above

document. Draft chapters were produced by expert authors and reviewed for content,

and modified to house style by the editorial committee. This was followed by peer group

appraisal and expert review. Following revision of the text, appropriate levels of

evidence were added to the recommendations by editorial and author consensus. The

draft of the document was placed on the BTS website in April 2017 for a period of open

consultation, to which clinicians and patient groups were actively encouraged to

contribute. Following a further round of editorial review, the final document was posted

in June 2017.

The last date of formal literature review was Dec 2016, although additional references

were included during the review process.

The guideline used the GRADE system to rate the strength of evidence and the strength

of recommendations (Table 1) (43). This approach is consistent with that adopted by

previous BTS guidelines. It is recognized that the evidence base in this area of clinical

practice is weak, and the grading of the recommendations reflects this. The guidelines

are designed to indicate areas of agreement where they exist, and to suggest good

practice where they do not. As such, it is hoped that they will stimulate debate audit,

research, and changes in practice, as well as a providing a reference point to current

clinical practice.





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The guideline comprises 54 pages and is freely available at https://bts.org.uk/guidelines-

standards/ . Given the lack of a consistent evidence base the guideline does not attempt

to be proscriptive or to define a standard of care. However, to be of value, it must

indicate areas where the evidence or consensus of opinion is strong. Therefore, each

section of the guideline is prefaced by one or several „statements of recommendation‟,

which are explained and referenced in the subsequent text.

Table 1. Summary of the GRADE system (43)

For each recommendation, the quality of evidence has been graded as one of:

A (high)

B (moderate)

C (low)

D (very low)

For each recommendation, the strength of recommendation has been indication as one of:

Level 1 (we recommend)

Level 2 (we suggest)

Not graded (where there is not enough evidence to allow formal grading)





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STATEMENTS OF RECOMMENDATIONS

Hepatitis E Biology and Disease

We recommend that:

• Virus specific tests, including HEV RNA and/or antigen detection, must be used to

diagnose HEV infection in transplant recipients as antibody detection is unreliable in

immunosuppressed individuals. (1B)

We suggest that:

• All clinicians managing transplant recipients should receive specific training about

HEV (acute and persistent) as its prevalence is increasing and the clinical consequences of

infection can be significant. (Not graded)

Testing of Solid Organ Donors for Hepatitis E

We recommend that:

• All solid organ donors are screened for HEV in line with the UK Advisory Committee

for the Safety of Blood, Tissues and Organs (SaBTO) recommendations. (1C)

We suggest that:

• The detection of HEV viremia in a donor is not an absolute contra-indication to use of

an organ from that donor, but will inform clinical management decisions posttransplant. (2C)





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• Individuals who become infected with HEV through transplantation are managed

according to recommendations pertaining to other persistently infected individuals. (2C)

Prevention of Hepatitis E in Solid Organ Transplant Recipients

We recommend that:

• Individuals must receive written advice regarding the risk of HEV from undercooked

meat (particularly processed pork) before and after transplantation. (1D)

Surveillance and Screening for HEV in Solid Organ Transplant Recipients

We recommend that:

• Potential recipients of solid organ transplants do not need routine screening for HEV

infection. There may be specific instances where testing for HEV is indicated

pretransplantation, such as in an immunosuppressed individual with raised liver enzymes.

(D1)

• Solid organ transplant recipients with liver transaminases above the upper limit of

normal or symptoms suggestive of HEV infection are tested for HEV using an HEV RNA or

an antigen assay. (1C)





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We suggest that:

• Transplant recipients have a plasma sample taken at the time of transplantation and

stored for a minimum of 1 year that could be tested retrospectively for HEV or other

infections. (2D)

Treatment of Acute Hepatitis E in a Patient on the Transplant List

We suggest that:

• Individuals with unexplained acute on chronic or acute liver failure should be tested

for HEV. (2C)

• Treatment with ribavirin is considered for patients with cirrhosis who develop

hepatitis E when on the liver transplant waiting list. (2D)

Management of HEV Infection in Solid Organ Transplant recipients

Newly diagnosed or acute HEV infection

We suggest that:

• The initial management of newly diagnosed or acute HEV infection in solid organ

transplant recipients includes observation and monitoring of HEV RNA levels and liver

enzymes as more than 30% will spontaneously clear the infection within 3 months. Dynamic

viral monitoring and antibody profiling may help clinical decision-making. (2C)





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• A strategic reduction in immunosuppression is considered in patients with acute or

persistent HEV as this may facilitate viral clearance, but the risk of rejection should be

carefully assessed. (2C)

• Early treatment with ribavirin may be considered in specific cases of acute hepatitis E,

such as patients who develop severe liver dysfunction (jaundice and coagulopathy) or extra-

hepatic manifestations, although evidence for this recommendation is currently limited. (2D)

Persistent HEV infection

We recommend that:

• Persistent HEV infection is diagnosed when HEV RNA is detectable in blood or stool

for more than 3 months after the onset of relevant symptoms, raised liver enzymes, or from

the first positive HEV RNA test. (1C)

• Individuals with persistent HEV infection (documented or estimated duration of

infection of more than 3 months) receive treatment with ribavirin with the aim of achieving

sustained virological response (HEV RNA not detected in plasma and stool 6 months after

completion of treatment). (1C)

• A baseline quantitative HEV RNA assessment is undertaken on both plasma and stool

at the start of treatment. (1C)

• Treatment with ribavirin should continue for at least 3 months for solid organ

transplant recipients with persistent HEV infection. For most individuals 3-6 months of

ribavirin treatment will suffice. (1C)





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• Monthly HEV RNA testing in plasma and stool is undertaken until a decision is made

to stop treatment. (1C)

• Ribavirin is continued until stool tests are negative for HEV RNA on 2 occasions 1

month apart, as continued shedding of HEV in stool is an important factor predicting relapse

after ribavirin treatment. (1C)

• A test of sustained virological response is conducted by testing plasma and stool

samples for HEV RNA at 3 and 6 months after stopping antiviral therapy. (1C)

• Regular haemoglobin monitoring is conducted during ribavirin therapy as haemolytic

anaemia is a common treatment-related side effect. Ribavirin dose reduction may be required

during treatment to maintain an adequate haemoglobin concentration. Epoetin therapy and/or

blood transfusion may be indicated to allow continued antiviral therapy without avoidable

drug reduction. (1A)

• PEG-interferon should not be used as first line for the treatment of persistent HEV in

transplant recipients as there is a moderate risk of precipitating organ rejection. (1D)

We suggest that:

• Assessment of the change in plasma HEV RNA after 7 days of ribavirin treatment

may help predict the chance of achieving sustained virological response after 3 months of

ribavirin treatment. We therefore suggest quantitative testing of a plasma sample taken at day

7 of ribavirin treatment to help determine the likely length of treatment required. (2C)

• To minimise treatment-related side-effects, the dosage of ribavirin is adapted

according to creatinine clearance, estimated using the Cockcroft-Gault equation. (2C)





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• Patients with persistent HEV who relapse after a first course of ribavirin are retreated

for at least 6 months with ribavirin at dosages toward the higher dose range, where tolerated.

(2D)

• Routine baseline sequencing of HEV for mutations is not indicated prior to antiviral

treatment as the significance of mutations has not been determined. (2D)

• PEG-interferon treatment may be considered in cases of ribavirin-refractory persistent

HEV infection. However, patients will require very close monitoring for rejection. (2D)





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ACCEPTED





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ACCEPTED





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Figure 1

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Documents

Summary of the British Transplantation Society UK ...and significant liver fibrosis. The British Transplantation Society (BTS) has developed Guidelines for “Hepatitis E & Solid Organ