Approach

​Treatment of HEV infection will depend on the clinical situation, particularly if the patient is immunosuppressed. Acute HEV infection typically does not require treatment other than supportive care as it resolves spontaneously in almost all patients.[1][2]​​ However, it is important to note that acute HEV infection in pregnancy in endemic areas can lead to acute liver failure in upwards of 20% of women.[10]​ Acute HEV infection in solid organ transplant recipients has been shown to resolve spontaneously in over 30% of cases; a reduction of immunosuppression in these patients should be considered wherever possible to assist with viral clearance.​[25][54]​​ There is no specific treatment for acute hepatitis E, but antiviral therapy with ribavirin may be considered in patients with severe acute HEV infection to prevent progression to hepatic decompensation, and in patients with acute-on-chronic liver failure.[2]

In people with chronic HEV infection, such as recipients of solid organ transplants, treatment may involve adjustment/reduction of immunosuppression in the first instance, with the addition of ribavirin if HEV infection persists.[2][25]

If indicated, ribavirin is given for 3 months, but can be extended to 6 months if HEV remains detectable in serum or stool following 3 months of treatment.

Treatment with peginterferon alfa may be considered in liver transplant recipients on a case-by-case basis if HEV RNA is still positive after 6 months of ribavirin.[2][25]

Consider specialist nephrology review for renal investigation if the patient has recent deterioration of renal function or significant proteinuria.[2]

Consider referral to a neurologist if the patient has neurological manifestations related to HEV infection.

Acute HEV infection

For acute HEV infection, give supportive care, alongside monitoring of liver enzymes and liver function. This is typically all that is required if the patient is immunocompetent.[2]

  • Advise the patient to rest, consume adequate nutrition and fluids, avoid drinking alcohol, and check with their physician before taking drugs that may potentially cause hepatic damage (e.g., paracetamol).[1]

  • Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to food handling practices.

Some patients, such as those with chronic liver disease, people with weakened immune systems, and older people, can experience more severe infection. These patients may require closer observation to monitor for deterioration in liver function.[32]

Consider reduction of immunosuppression therapy (wherever possible) in patients with solid organ transplant who have acute HEV infection, to assist with viral clearance.​[25][54]​ Acute HEV infection in solid organ transplant recipients has been shown to resolve spontaneously in over 30% of cases.​[25][54]

Consider treatment with ribavirin for patients with severe acute HEV infection, patients who are at increased risk of progression to hepatic decompensation, and those with acute-on-chronic liver failure.[2]

  • Case reports of ribavirin in acute HEV infection (or acute HEV infection occurring in underlying liver disease) suggest that liver enzymes may rapidly normalise, with HEV RNA levels becoming undetectable within days of initiation of treatment.[62]

  • Women of childbearing age, and men who may have sex with women of childbearing age, should be counselled regarding the use of contraception during treatment with ribavirin and after treatment has stopped.

Refer patients who develop signs that may be suggestive of acute liver failure to a transplant centre for monitoring and consideration of a liver transplant.[63] See Acute liver failure.

Pregnant women

Acute HEV infection in pregnancy in endemic areas can lead to acute liver failure in upwards of 20% of women.[10]

Perform frequent monitoring of signs and symptoms as well as biochemical parameters in all pregnant women with acute HEV infection, under the combined management of the obstetric and specialist hepatology teams. Consider hospital admission for pregnant women with symptomatic acute HEV infection on a case-by-case basis.[1][15]​​​ Based on clinical experience in practice, indications for admission include evidence of deteriorating liver function and concern for fetal viability. Also consider hospital admission for pregnant women with solid organ transplant who have acute HEV infection (seek expert advice).

Treatment in a high-dependency treatment setting may be required for symptomatic pregnant patients, and transfer to a transplant centre will be required if signs of liver failure are present.[2]

If hospital admission is not indicated:

  • Advise the patient to rest, avoid drinking alcohol, consume adequate nutrition and fluids, and check with their physician before taking drugs that may potentially cause hepatic damage (e.g., paracetamol)[1]

  • Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to food handling practices.

Note that ribavirin is contraindicated in pregnancy.

Chronic HEV infection

The vast majority of patients with chronic HEV infection are immunosuppressed, with the condition most commonly being found in recipients of solid organ transplants. The goal of treatment in patients with chronic HEV infection is sustained viral eradication.

Where possible, decrease immunosuppression therapy at diagnosis of chronic HEV infection in recipients of solid organ transplants.[2][25][41]​​

  • A systematic review of data from 21 studies of immunocompromised patients with HEV infection showed that reduction of immunosuppressive drugs induced clearance of HEV in 32% of patients.[64]

  • A retrospective analysis of data from 17 centres from the US and Europe, including 85 recipients of solid organ transplants who were chronically infected with HEV, noted that 32.1% achieved viral clearance when the dose of immunosuppressive drugs was reduced.[54]

Give ribavirin for 3 months to patients in whom HEV replication persists 3 months after detection of HEV RNA, and to transplant recipients with chronic HEV infection in whom reduction of immunosuppression is not possible or is unsuccessful.[2][41]​​​ There have been no placebo-based trials for the use of ribavirin in chronic HEV infection; treatment recommendations are based on the results of case reports and case series.[57][65][66]​​[67]​​​​​​​

  • One meta-analysis of the effect of ribavirin in 395 immunosuppressed patients with chronic HEV infection found that 301 patients (76%) achieved a sustained viral response following 3 months of therapy.[64]

  • A retrospective, multi-centre case series assessing the effects of ribavirin in 59 solid organ transplant recipients treated for a median of 3 months demonstrated a 78% sustained viral response rate in these patients.[67] Another study of 6 recipients of kidney transplants with chronic HEV infection found that HEV RNA was undetectable in the serum of all patients after 3 months of ribavirin.[57]

  • Ribavirin is associated with adverse effects, particularly dose-dependent anaemia. Regular monitoring of FBCs is required in all patients, and a dose reduction, with or without transfusion, may be required in patients who develop anaemia.[2][25]

Regularly assess response to ribavirin with serum alanine aminotransferase (ALT) and HEV RNA in stool and serum.

  • Stop ribavirin if HEV RNA in both stool and serum are negative as this indicates a sustained viral response; note that stool HEV RNA may remain positive long after serum HEV RNA is negative, hence the requirement for stool HEV testing to avoid relapse.

  • Continue ribavirin for a further 3-6 months if there is persistence of HEV RNA in either stool or serum following the initial 3 months of treatment.[2][41]

Consider switching to peginterferon alfa 2a in liver transplant recipients, on a case-by-case basis, if HEV RNA is still positive after 6 months of ribavirin.[2]​​[25][41]​​​ Peginterferon alfa 2a may also be considered as an alternative to ribavirin in these patients, on a case-by-case basis, if ribavirin is not tolerated.[41]

  • Peginterferon alfa may be considered based on efficacy in small case series, but is associated with the risk of rejection in solid organ transplant recipients except liver transplant.[2]

  • Treatment of these patients with peginterferon alfa should only be performed at, or in consultation with, a transplant centre.

In immunosuppressed patients who have not had a solid organ transplant, such as those with HIV or haematological disorders, a handful of case reports/small series have shown some efficacy with treatment with peginterferon alfa, ribavirin, or a combination of the two drugs.[68][69][70]​​​​​

  • One systematic review of studies that identified 13 immunosuppressed patients with chronic HEV infection who were treated with peginterferon alfa noted a rapid virological response in four patients (31%); 11 patients (84%) achieved sustained viral response.[64] However, acute transplantation rejection occurred in two patients during treatment.[64]

Peginterferon alfa may cause or aggravate fatal or life-threatening infectious, neuropsychiatric, autoimmune, and ischaemic disorders. Monitor patients closely.

Advise all patients with chronic HEV to avoid drinking alcohol, and check with their physician before taking drugs that may potentially cause hepatic damage (e.g., paracetamol).[1]

Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to food handling practices.

Pregnant women

Monitor pregnant women with chronic HEV infection, under the combined management of the obstetric and specialist hepatology teams. Consider hospital admission on a case-by-case basis. Based on clinical experience in practice, indications for admission include evidence of deteriorating liver function and concern for fetal viability.

Provide pregnant women with supportive care, if needed. Advise the patient to avoid drinking alcohol, consume adequate nutrition and fluids, and check with their physician before taking drugs that may potentially cause hepatic damage (e.g., paracetamol).[1]

Counsel the patient on hand hygiene to prevent transmission of HEV, particularly with respect to food handling practices. Note that ribavirin and peginterferon alfa are contraindicated in pregnancy due to their potential teratogenic effects.

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