Hepatitis E: when to treat and how to treat Zaigham Abbas, Rafia Afzal

Antiviral Therapy 2013; 10.3851/IMP2705 Submission date Acceptance date Publication date

30th June 2013 7th October 2013 5th November 2013

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2013 International Medical Press

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Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705

Review Hepatitis E: when to treat and how to treat Zaigham Abbas1*, Rafia Afzal1 1

Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan *Corresponding author e-mail: [email protected]

SUMMARY: Hepatitis E virus (HEV) generally causes a self-limited acute infection and treatment remains supportive. However, severe hepatitis or fulminant hepatic failure may occur, more so during pregnancy. It is an important cause of acuteon-chronic liver failure in endemic areas. Chronic HEV infection and progressive disease has been reported in recipients of solid organ transplants, hematological malignancies, HIV patients and those on hemodialysis. Clearance of HEV may occur after reducing immunosuppressive therapy, especially those targeting T cells, in about one third of cases. Antiviral therapy should be considered for patients for whom immunosuppressive therapy cannot be reduced and for those who do not achieve viral clearance after reducing immunosuppression. The patients with severe infection, fulminant hepatic failure and acute-on-chronic infection should be considered for ribavirin monotherapy to expedite the viral clearance and recovery. Although ribavirin therapy is contraindicated in pregnancy owing to teratogenicity, the risks of untreated HEV to the mother and fetus are high and treatment may be offered. A twelve week course of peginterferon, ribavirin, or a combination of the two agents leads to viral clearance in about two-third of patients with chronic hepatitis E. Three to twelve month treatment with peginterferon clears virus in liver transplant recipients and patients on hemodialysis. In kidney and heart transplant patients where interferon may lead to organ rejection, ribavirin may be given. Accepted 7 October 2013, published online 5 November 2013 Hepatitis E is estimated to cause 70, 000 deaths world-wide every year [1] and is probably the most common cause of acute viral hepatitis universally [2]. Hepatitis E virus is mainly an enterically transmitted RNA virus, which usually causes a self-limiting disease with spontaneous viral clearance [3]. The most common route of transmission is via consumption of water contaminated with feces. However, it may also be transmitted through some uncommon routes including; zoonotic transmission [4], transfusion of infected blood products [1] and perinatal transmission from mother to neonate [5]. Hepatitis E is an endemic disease in developing countries owing to unsatisfactory personal hygiene and sanitary conditions and until recently it was not observed in Western world. Domestically acquired sporadic cases have now been increasingly reported in developed countries owing to swinerelated hepatitis E virus (HEV) genotypes 3 and 4. To date, at least four HEV genotypes have been

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 recognized, of which genotype 1 and 2 are known to cause hepatitis E epidemics and sporadic cases in developing part of the world while, genotypes 3 and 4 are thought to involve in the occurrence of sporadic cases both in the developed and developing countries [6].

The clinical spectrum of hepatitis E The clinical spectrum of the disease may range from mild sub-clinical disease, acute self-limiting infection which resolves spontaneously, to acute liver failure which has high mortality particularly among pregnant patients [7]. Symptomatic disease is most common among individuals aged between 15 and 40 years [1]. However, acute-on-chronic hepatitis precipitated by HEV in patients with underlying chronic liver disease is also a well-known clinical entity [8] requiring prompt intervention. Chronic HEV infection refers to detectable HEV RNA in serum or stools of the patient and persistently elevated serum ALT levels for more than 6 months. Chronic infection with HEV and progressive liver disease and cirrhosis [9] has now been increasingly reported in recent past. Chronic sequelae of HEV infection have been observed most commonly among immune-compromised individuals i.e. organ-transplant recipients [9–14], patients receiving cancer chemotherapy [15], and HIV-infected patients [16–18]. Occurrences of chronic HEV infection have also been observed among patients undergoing hemodialysis [19,11]. It has been estimated that approximately 61% of the solid organ transplant recipients develop chronic hepatitis E after HEV exposure [12,20,21].

Treatment: Acute hepatitis E Acute hepatitis E usually follows a self-limiting course which only requires symptomatic treatment but not uncommonly it may take a severe acute form (also in immune-compromised individuals) with the rapid development of acute fulminant hepatitis [22]. Severe acute hepatitis E and fulminant hepatitis may require treatment with an antiviral agent in addition to the supportive care [8,23–25]. HEV-related acuteon-chronic hepatitis should also be treated. The aim of the treatment is to accelerate the viral clearance and complement body immune responses against the virus to preclude the development of acute liver failure and its grave consequences. An immune-competent individual with hepatitis E may show rapid recovery if treated with an antiviral agent [25].

Treatment options for severe acute infection: Ribavirin monotherapy has been found beneficial in the treatment of severe acute hepatitis E in both immune-competent and immune-compromised patients with prompt viral clearance and rapidly improved liver function [8,23–25]. However, an optimal therapeutic dose and duration has yet to be determined (Table 1). Glycyrrhizin has been known for its antiviral property and has been used for the treatment of hepatitis B and C [26,27]. Tandon et al determined its efficacy for the treatment of acute hepatitis E.

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 Glycyrrhizin has been found to be effective in bringing biochemical and clinical improvement in HEVinfected patients with essentially no treatment side-effects [28]. The authors didn’t report the status of viral replication prior and following glycyrrhizin therapy and reporting merely clinical and enzymatic improvement following treatment. This makes the study inconclusive and less convincing in advocating the benefit of this treatment. Although ribavirin therapy is contraindicated in pregnancy owing to teratogenicity, the risks of untreated HEV to the mother and fetus are high and treatment may be offered. Since, evidence is available regarding ribavirin administration during pregnancy associated with no adverse maternal and fetal outcome [29–31], its use for the treatment of hepatitis E may therefore be advocated to prevent hepatitis E related fulminant hepatitis in expectant mothers.

Chronic hepatitis E HEV is a non-cytopathic, immune-provoking virus which is kept controlled and cleared by the host’s cellmediated immunity [32]. Chronic HEV infection if left untreated may invariably progress to cirrhosis particularly among patients who are immune-compromised [7,9,33]. However, prompt recognition and proper treatment of hepatitis E may abate the risk of developing hepatitis E-related progressive liver disease. Chronic HEV infections in immune-compromised individuals may thus be benefited by reducing the dose of immunosuppressants especially those targeting T cells and augmenting cellular immune responses. All immune-compromised patients including those who are on hemodialysis should undergo screening for HEV for the purpose of prompt recognition of HEV exposure.

Treatment options for chronic hepatitis E To date, there are no approved treatment regimens for HEV and the therapeutic options available are all experimental. There are some case reports and small case series advocating the beneficial role of some therapeutic options. Treatment options available for acute and chronic hepatitis E are few, all depicting variable responses. • Reduction of immunosuppression • Ribavirin • Valgancyclovir • Pegylated interferon • Combination therapy with ribavirin and pegylated interferon

Reduction of immunosuppressive therapy: Reduction of immunosuppressive therapy should be the first and foremost step taken in an attempt to clear HEV in organ transplanted patients (particularly liver and renal transplant recipients) [23,13] and those with immune-suppression [15]. It has been estimated that about one third of the patients achieve

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 viral clearance following reduction in the doses of immune-suppressants and/or modifications of the immunosuppressive regime (Table 2). Moal et al [13] have reported even a higher percentage (about 50%) of the patients achieving viral clearance after reduction of immune-suppression. But this is of little value in heart and lung transplant recipients owing to higher risk of rejection. Transplanted patients with a higher risk of rejection and those unresponsive to reduction in immune-suppression should therefore be treated with an appropriate antiviral agent. Moreover, Tacrolimus-based immunosuppressive therapy has been found associated more with the development of chronic hepatitis E than cyclosporine-based regime [12,20]. So cyclosporine may be an alternative to tacrolimus in these cases.

Ribavirin: Ribavirin has been found efficacious for the treatment of chronic hepatitis E in the cases of solid organ transplant recipients, including renal, lung, heart and pancreas transplanted patients where interferon treatment may result in the rejection of transplanted organ (Table 3). Junge et al [34] reported the first case of liver transplanted pediatric patient who was successfully treated with ribavirin for his chronic hepatitis E. The optimal duration for ribavirin therapy is yet to be established. Twelve weeks therapy successfully clears the virus in most cases. However, there may be a virological relapse after the cessation of treatment [35]. A longer treatment duration (of about 20 weeks) is thus advocated [23,36] assuming it may be associated with a lower risk of HEV relapse, considering the treatment of hepatitis C where prolonged viral suppression has been associated with lower relapse rate [37]. Another issue still awaiting settlement is optimal ribavirin dose for the treatment of chronic hepatitis E. A ribavirin dose of 600 mg daily has been found satisfactory in most of the cases of hepatitis E, a dose reduction owing to treatment related side-effects i.e. anemia has been observed associated with viral rebound and resistance as reported by Pisckhe et al [23,36], suggesting unnecessary dose reductions should be avoided unless inevitable.

Valgancyclovir: Valgancyclovir when used, in conjunction with reduced immunosuppressive therapy has also shown HEV clearance in a liver transplanted patient co-infected with human herpes virus-6 [38].

Pegylated interferon monotherapy or combination: After modified immunosuppressive therapy, liver transplant recipients with chronic hepatitis E have been most benefited when treated with pegylated interferon for about three to twelve months [39,40]. An optimal dose and duration of therapy are still needed to be addressed, however, weekly doses of 1-1.5 g/ kg of pegylated interferon alpha 2b and 135 g of pegylated interferon alpha have shown favorable outcome (Table 4). A twelve-week course of peginterferon, ribavirin, or a combination of the two agents leads to viral clearance in about two-third of patients with chronic hepatitis E [15,17,19,35,39,41–43].

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 Chronic HEV- infected patient undergoing hemodialysis may be benefited with both ribavirin monotherapy [11] as well as pegylated interferon [19]. Patients with hematological malignancies including, myelomonocytic leukemia [15] and hairy cell leukemia [43] have also been treated successfully with ribavirin montherapy and peg-interferon respectively. Sustained virological response was also achieved with both the regimes. Co-infection with hepatitis E in HIV patients has recently been known and subjected to treatment using ribavirin monotherapy [18,44], pegylated interferon alone [16] as well as a combination therapy with ribavirin and pegylated interferon [17]. A 24-week course of treatment has been employed with favorable outcome. A prompt recognition and early treatment of hepatitis E in HIV patients is of immense importance since HEV has been associated with rapid development of cirrhosis in these patients [18]. Furthermore, ribavirin has an added advantage over pegylated interferon in treating hepatitis E in HIV patients presenting with decompensated liver disease.

The future dimensions The available evidence should only be regarded as pilot observations that need to be verified with larger randomized trials. In immune-competent patients with severe complications of acute HEV infection such as ALF, ALF in pregnant women and ACLF, ongoing viral replication has been inferred rather than convincingly demonstrated. Small, uncontrolled case series documenting ‘benefit of antiviral therapy’ are not very convincing in the absence of documented ongoing viral replication or documentation that clinical improvement coincided with suppression of viral replication by the drug used. HEV replication is well documented in immune-suppressed patients with chronic hepatitis E, but it may be that the chronicity occurs only in some genotypes, though in those genotypes it appears that patients with immunosuppression are more likely to develop chronicity than immunocompetent patients. There is a need to document HEV genotype in future therapeutic interventions. Almost all cases of chronic HEV have been seen with HEV genotype 3 infection in immunosuppressed patients [47]. A recent report from Lucknow, where genotype 1 infection is the norm in both sporadic and epidemic situations, documented the absence of chronicity in immune-suppressed populations [48]. There are some other unanswered questions. What should be the ideal duration of treatment? When does virus become undetectable on treatment? Should we retreat in case of relapse? What are the risks of reduction of immunosuppression versus adverse events related to the intervention? Would pegylated interferon in combination with ribavirin be a preferable option over monotherapy with either agent?

Conclusion: There is no approved therapeutic option available for the treatment of hepatitis E, different case reports and series have advocated the beneficial role of ribavirin, pegylated interferon and a combination of the

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 both agents, but larger controlled trials and longer follow-ups are still required to establish the efficacies of these therapeutic regimes. Moreover, reduction of immunosuppressive therapy should remain the firstline therapeutic option when treating chronic hepatitis E in immune-suppressed and transplanted patients. Less documented treatment options including glycyrrhizin and valgancyclovir need further evaluation of their potential role in hepatitis E. In expectant mothers, ribavirin treatment may be offered to prevent fulminant hepatitis and its fatal outcome.

Disclosure statement Authors do not have any conflicts of interest to disclose related to this article Any funding did not support this work.

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Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 Table 1: Treatment of acute hepatitis E Authors Subjects Number Drug of patients Pisckhe S Severe 1 Ribavirin et al, acute HEV2013 [23] genotype-1e infection (immunecompetent) Del Bello Acute HEV 1 Ribavirin A et al, in a liver 2012 [24] transplant recipient Gerolami Severe 1 Ribavirin R et al, acute HEV 2011 [25] in an immunecompetent pt Goyal R HEV4 Ribavirin et al, induced 2012 [8] acute-onchronic liver failure Tandon A Acute 22 Glycyrrhizin et al, hepatitis E 2002 [28] with moderate to severe liver disease HEV, hepatitis E virus; SVR, sustained virologic response

Dose

600 mg/day

Duration of therapy

End point/ response

6 weeks

HEV clearance

400 mg/day

3 months

HEV clearance and sustained virologic response

1200mg/day

3 weeks

HEV clearance

200- 600 mg/day

60 ml daily through IV route

3-24 weeks (median= 12 weeks)

Treatment was stopped once significant clinical and biochemical improvement noted (30-45 days)

4 of 4 patients cleared the virus

Clinical improvement in all the patients Normalization of ALT and AST in 19 pts within 30 days of the commencement of therapy

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 Table 2: Reduction of immunosuppression to clear Hepatitis E Authors Subjects Number Time of of clearance of patients HEV: median (months) + range Kamar N et al, Solid organ 56 19.5 (10-106) 2011 [12] transplant recipients

End point/ response

18 (32.1%) of 56 patients achieved viral clearance and SVR

Moal V et al, 2013 [13]

Renal transplant recipients

12

39 (17-86)

6 (50%) of 12 pts achieved viral clearance; 1 experienced acute graft rejection following dose reduction of immunosuppressants

Kamar N et al, 2010 [20]

Solid organ transplant recipients Solid organ transplant recipients

16

19 (14-23)

4 (25%) of 16 pts achieved viral clearance

14

6 (3-30)

3 (21.4%) of 14 patients achieved viral clearance; all three were liver transplant recipients

Pischke S et al, 2013 [23]

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 Table 3: Antiviral therapy for chronic hepatitis E Authors Subjects Number Drug of patients Junge N Child (liver 1 Ribavirin et al, 2013 transplant Monotherapy [34] recipient) (RMT)

dose

duration

End point/ response

400 mg/ day

6 months

Viral clearance

Kamar N et al, 2010 [35]

Kidney transplant recipients

6

RMT

600-800 mg/day

3 months

6 of 6 pts achieved viral clearance while SVR was achieved in 4 pts, 2 relapsed after treatment

Pisckhe S et al, 2013 [23]

Solid organ transplant recipients

11

RMT

600-1000 mg/day

5 months

Viral clearance and SVR achieved in 9 subjects; 2 showed no clearance

Pisckhe S et al [36]

Heart transplant recipients

4

RMT

600-800 mg/day

5 months

SVR in 3; treatment failure in 1 patient after ribavirin dose reduction

Mallet V et al, 2010 [41]

Kidney and pancreas transplant recipient; idiopathic CD4 positive T lymphocytopenia

2

RMT

12mg/ kg body weight daily

3 months

Viral clearance in both

Chaillon A et al, 2011[42]

Heart transplant recipient

1

RMT

17 mg/kg/day

3 months

Viral clearance and SVR

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 de Niet A et al, 2012 [45]

Renal transplant recipient

1

RMT

800 mg bid

3 months

Viral clearance and SVR

RiezebosBrilman A et al, 2013 [10]

Lung transplant recipients

2

RMT

400 mg bid

4 months

2 of 2 patients cleared the virus

Im GY et al, 2013 [11]

Pancreas and kidney transplant recipient on hemo-dialysis

1

RMT

200 mg/ day

10 months

Viral clearance and SVR achieved

Koning L et al, 2013[18] Neukman K et al, 2013 [18]

Heart transplant recipients

4

RMT

Doses not mentioned

3-9 months

3 of 4 paients cleared the virus

Patients with HIV

2

RMT

1000-1200 mg/day

6 months

2 of 2 patients cleared the virus

Hajji H et al, 2013 [44] Alric L, 2011 [15]

Patient with HIV

1

RMT

800 mg/ day

3 months

Viral clearance and SVR achieved

Patient with chronic indolent myelomonocytic leukemia

1

RMT

600 mg/day

3 months

Viral clearance and SVR achieved

Te HS et al, 2013 [38]

Concurrent HEV and human herpes virus-6 (HHV-6) infection in a liver transplant recipient

1

Valganciclovir

900 mg PO bid

8 weeks

Viral clearance of both the viruses

Publication: Antiviral Therapy; Type: Review DOI: 10.3851/IMP2705 Table 4: Interferon montherapy or combination for the treatment of chronic hepatitis E Authors Subjects Number Drug dose duration of patients Kamar N Patient on 1 PEG-IFN 2a 3 months 135 g / week et al, 2010 Hemodialysis [19]

End point / response

Viral clearance and sustained virologic response

Kamar N et al, 20 [39]

Liver transplant recipients

3

PEG-IFN 2a

135 g/week

3 months

Viral clearance in all and SVR achieved in 2 pts, 1 relapsed after treatment

Haagsma EB, 2010 [40]

Liver transplant recipients

2

PEG-IFN 2b

1.5 g/kg/wk

12 and 4 months respectively

Viral clearance and SVR in both the patients

Alric L, 2010 [43]

Patient with hairy cell leukemia

1

PEG-IFN 2b

1.0 g/kg/wk

3 months

Viral clearance achieved with SVR

Jagjit Singh GK et al, 2013 [16]

Patient with HIV

1

PEG-IFN 2a

180 g/ wk

24 weeks

Viral clearance achieved with SVR

Ollier L, 2009 [46]

Patient with non-Hodgkin lymphoma Patient with HIV

1

IFN

Dose not mentioned

3 months

1

Combination of pegylated interferon and ribavirin

PEG-INF 135 g/wk; ribavirin 1000 mg/day for 6 weeks followed by 500 mg/day for additional 6 weeks

PEG-INF alone for 6 months; followed by combination of PEG-INF and ribavirin for 12 weeks

Patient improved clinically but HEV RNA remained detectable Viral clearance achieved

Dalton HR, 2011 [17]

IFN, interferon; PEG-IFN, pegylated interferon;