Hepatitis E virus infection: signs, symptoms and management

Hepatitis E virus (HEV) is the most common cause of acute hepatitis in the UK^[1]
. Around 20 million HEV infections occur annually worldwide, with more than 3 million symptomatic cases and around 44,000 HEV-related deaths^[2]
. Large outbreaks of HEV are often seen in developing countries, but some sporadic cases are now being identified in developed nations^[3]
. Chronic infection with HEV most commonly occurs in patients who are either immunosuppressed or immunocompromised.

HEV has at least four different genotypes: 1, 2, 3, and 4^[2]
. Genotypes 1 and 2 occur most commonly in developing countries in Africa and Asia, whereas genotypes 3 and 4 primarily cause infections in developed nations^[2]
.

This article will outline the difference between acute and chronic HEV infection, as well as the complications associated with the disease.

Transmission

HEV is predominantly transmitted by faecal contamination of drinking water as a result of poor sanitation^[2],[4]. Other routes of transmission include consumption of contaminated food, such as raw or undercooked meat (e.g. pork and shellfish) derived from infected animals^{[5],[6],[7],[8]}
and through transfusion of infected blood products (which is more common in highly endemic areas^[9]
).

A 2014 UK study that evaluated 225,000 blood donations identified 79 donations that were positive for HEV genotype 3 RNA, which were used to prepare 129 blood components — of which 62 were transfused^[10]
. The results showed 43 recipients received HEV-infected transfusions with 42% of patients developing detectable HEV RNA. Consequently, since April 2017, all blood donations in Ireland and the UK are routinely screened for HEV RNA.

Diagnosis

Signs and symptoms

Acute HEV infection

Infection with HEV generally leads to an acute, self-limiting infection and patients are often asymptomatic. Patients who develop symptoms tend to present with non-specific symptoms that are not clinically distinguishable from other types of acute viral hepatitis, including: 

• Jaundice;
• Malaise;
• Anorexia;
• Nausea;
• Vomiting;
• Abdominal pain;
• Hepatomegaly;
• Pruritus;
• Arthralgia.

A small proportion of patients develop acute liver failure, and women who are pregnant at the time of infection are at greatest risk. 

Chronic HEV infection

A chronic infection is defined by the persistence of HEV RNA in the serum and stool for greater than six months. Patients who are immunosuppressed (following solid organ or bone marrow transplants), and patients with haematological disorders, HIV or conditions requiring heavy doses of immunosuppressive drugs are most susceptible to developing chronic HEV infection^[11]
. 

Although HEV infection is mainly associated with features of liver disease, extrahepatic manifestations are increasingly recognised; however, causality remains to be established in some cases (see Table 1). 

Laboratory diagnosis

The incubation period of HEV is around 15–60 days^[11]
. Three weeks after infection, HEV RNA can be detected in the blood and stools, which occurs shortly before the onset of symptoms. For patients with acute infection, HEV RNA can be detected in the blood for 3–6 weeks, and shedding in the stool can occur for 4–6 weeks.

Definitive diagnosis of HEV infection is usually based on the detection of specific immunoglobulin (Ig) M antibodies to the virus in the patient’s blood^[2]
. IgM antibodies, which are short-lived and detected over 4–6 months, appear first. They are followed by the appearance of IgG antibodies, which are long-lasting and have increasing antibody avidity over time.

It is important to test for HEV in any patient presenting with biochemical evidence of hepatitis, irrespective of travel history, because patients with HEV in developed countries can have a locally acquired infection. 

Differential diagnosis

Patients presenting with elevated aminotransferases (with or without symptoms of hepatitis) have a broad range of differential diagnoses (see Table 2). Drug-induced liver injury (DILI) is an important differential diagnosis of acute HEV^[12]
. In a UK retrospective study of patients with criterion-referenced DILI, 13% of patients with acute HEV were misdiagnosed as having DILI^[13]
, highlighting the importance of testing for HEV in patients with this diagnosis.

Management

The management of HEV depends on the immune status of the patient, and whether it is an acute or chronic infection.

Acute HEV infection

There is no specific treatment for acute HEV infection and, in most cases, the virus clears spontaneously. In the rare occurrence of acute liver failure, admission to intensive care or liver transplantation may be required. Early antiviral therapy with ribavirin may shorten the course of the disease and reduce the overall morbidity, but there are limited data to support this in the acute setting^[14]
.

Pregnant women with HEV are at an increased risk of acute liver failure, foetal loss and mortality^[2]
. These patients should be referred immediately for specialist care.

Chronic HEV infection

This generally only occurs in patients who are immunosuppressed or immunocompromised, and is usually owing to infection with genotype 3 HEV. The aim of treatment is to achieve HEV RNA eradication in both serum and stool (i.e. sustained virologic response [SVR]) 12 weeks after cessation of treatment. Although patients who achieve SVR are cured, they remain at risk of reinfection.

Dose reduction should be the initial step for patients taking immunosuppressants. In a study by Kamar N et al., solid organ transplant recipients with chronic HEV infection, in whom the virus spontaneously cleared, had lower tacrolimus levels and a lower daily steroid dose compared with patients who remained viraemic^[15]
. This study led to the concept of reducing immunosuppressive therapy in patients with chronic HEV infection, particularly patients taking therapeutic agents targeting T-cells^[15],[16]
.

There are several case reports and case series supporting the use of ribavirin for the treatment of HEV in solid organ transplant recipients^{[17],[18],[19],[20]}
, although there are side effects and contraindications that should be considered (see Box). In a multicentre, retrospective study, 59 solid organ transplant recipients with HEV infection received ribavirin for a median duration of 3 months (range: 1–18 months) at a median dose of 600mg/day (range: 29mg–1200mg/day). SVR was achieved by 78% of patients^[20]
. Patients who relapsed after treatment were re-treated for a longer period of 6 months, with one patient receiving 12 months of treatment, and achieved SVR. Doses of ribavirin were adjusted according to kidney function. Although the optimal dose and duration of ribavirin are unknown, a three-month course is an appropriate duration unless patients are heavily immunosuppressed or remain viraemic after one month of treatment^[20]
(see Figure 1).

There are some data to suggest that patients with non-transplant immunosuppression (e.g. patients with underlying haematological disorders) with chronic HEV infection can also be successfully treated with ribavirin or pegylated-interferon-alpha, or a combination of both^{[21],[22],[23],[24],[25]}
.

Pegylated-interferon-alpha

A three-month course of pegylated-interferon-alpha 2a and 2b has been successfully used to treat a small number of liver transplant recipients who failed treatment with ribavirin, as well as one haemodialysis patient^{[27],[28],[29]}
. However, because of concerns about the immunostimulatory effect, it is generally contraindicated in patients with kidney, pancreas, heart or lung transplantations, owing to the risks of precipitating acute rejection^[11]
. 

Sofosbuvir

Although developed as treatment for hepatitis C, it has been reported that sofosbuvir has some activity against HEV RNA replication in vitro and has an additive antiviral effect with ribavirin^[30]
. However, when a hepatitis C/HEV co-infected patient received a 12-week course of sofosbuvir and daclatasvir, they did not achieve virologic clearance of HEV^[31]
. Therefore, it remains unknown if the observations made in vitro will translate into clinical efficacy in vivo.

Prevention

When travelling to regions with poor hygiene and sanitation, and where HEV is endemic, basic recommendations to prevent traveller’s diarrhoea should be adhered to. Pharmacists and healthcare professionals can advise patients that this includes avoiding:

• Water where the purity is unknown;
• Salads;
• Uncooked fruit;
• Unpasteurised dairy products;
• Raw or undercooked meat and seafood.

Furthermore, strict hygiene measures should be followed, such as washing hands thoroughly.

The risk of HEV patient-to-patient transmission is unknown. Sexual transmission in men who have sex with men has been described in two studies^[32],[33]
, but in a study with HIV co-infected patients, there was no evidence of sexual transmission^[34]
.

A recombinant vaccine against HEV was licensed in China in 2011 and has shown to prevent 97% of episodes of symptomatic acute HEV^[35]
. Long-term follow-up showed that the vaccine induced antibodies against HEV and provided protection against HEV for up to 4.5 years^[36]
. The vaccine is safe for use in pregnancy^[37]
 but data are still needed for efficacy in immunocompromised individuals and those with chronic liver disease. There is currently no vaccine licensed for use in the UK.