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Herpes simplex virus load to monitor antiviral treatment after liver transplantation for acute herpetic hepatitis

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©2012 International Medical Press 1359-6535 (print) 2040-2058 (online) 401 Antiviral Therapy 2012; 17:401–404 (doi: 10.3851/IMP1922)

Herpes simplex virus (HSV) hepatitis is an uncommon cause of acute liver failure (ALF), primarily affecting immunocompromised patients. So far, 148 cases have been published, of which 9 underwent liver transplanta- tion (LT). The reported post-transplant survival is poor, with over 60% dying in the first year. Dosing and duration of antiviral therapy after LT are not established. Concerns include both the risk of hepatic recurrence after LT and

emergence of viral resistance during prolonged therapy.

HSV DNA plasma levels might be helpful to monitor ther- apeutic response and guide duration of therapy. We pre- sent a case of ALF complicating a primary HSV-1 infection in an immunocompetent host, who required emergency LT. We further discuss the value of measuring serial HSV DNA plasma loads to monitor antiviral therapy.

Acute herpes simplex virus (HSV) hepatitis is a rare cause of acute liver failure (ALF), with only 148 reported cases [1–8]. Because of the poor prognosis it has been suggested to initiate specific antiviral therapy as soon as HSV hepatitis is suspected, while waiting for virological confirmation [9]. Liver transplantation (LT) has been reported in only nine cases for acute HSV hep- atitis, with a poor post-transplant survival, as only one- third survived the first year [5,8]. Recurrence of HSV infection in the allograft is a particular concern with uncertainties remaining for both duration and dose of the antiviral treatment. Prolonged antiviral therapy has been suggested to promote emergence of resistant strains that subsequently could lead to recurrence in the allograft [10]. As a consequence, the post- transplant management of such cases is particularly difficult. We report the rare case of a primary HSV-1 hepatitis in an immunocompetent host leading to ALF and LT, and describe the use of HSV viral loads to monitor the effec- tiveness of the post-transplant antiviral treatment.

Case report

A 64-year-old male was admitted for fever, abdominal pain and stomatitis, in the absence of cutaneous lesions.

The evolution was remarkable for pancytopenia, acute renal failure and rapid development of ALF with pro- found encephalopathy requiring LT. No predisposing immunosuppression was detected. A large screening for viral infections (including hepatitis A, B and C viruses, HIV, cytomegalovirus, Epstein–Barr virus and parvovi- rus B19), as well as toxic causes (paracetamol) and auto- immune diseases (antibodies against S-M2, S-LKM1, S-LC1, S-SLA and S-actine) was negative. Liver histo- pathology revealed important necrosis surrounded by hepatocytes with intranuclear inclusions (Figure 1A).

Immunohistochemistry was positive for HSV-1-2, in the absence of specific immunoglobulin (Ig)M and IgG (Fig- ure 1B). HSV-1 DNA was positive at 64.5 million cop- ies/ml plasma using a type-specific TaqMan real-time PCR previously shown to detect between 10 and 100

Case report

Herpes simplex virus load to monitor antiviral treatment after liver transplantation for acute herpetic hepatitis

Juan Ambrosioni1,2,3, Laurent Kaiser1,3, Emiliano Giostra2,4, Pascal Meylan5, Gilles Mentha2, Christian Toso2, Muriel Genevay-Infante6, Laura Rubbia-Brandt6, Christian van Delden1,2*

1Service of Infectious Diseases, Department of Medical Specialities, University Hospitals of Geneva, Geneva, Switzerland

2Service of Transplantation, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland

3Laboratory of Virology, University Hospitals of Geneva, Geneva, Switzerland

4Service of Gastroenterology, Department of Medical Specialities, University Hospitals of Geneva, Geneva, Switzerland

5Institut de Microbiologie, University Hospital Lausanne, Lausanne, Switzerland

6Service of Clinical Pathology, Department of Genetic Medicine and Laboratory, University Hospitals of Geneva, Geneva, Switzerland

*Corresponding author e-mail: Christian.vanDelden@hcuge.ch

Introduction

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©2012 International Medical Press 402

J Ambrosioni et al.

genome HSV copies/ml [11]. Intravenous acyclovir was initiated at doses equivalent to 30 mg/kg/day, adjusted to renal function, followed by oral valaciclovir with a rapid decrease in HSV-1 DNAemia (Figure 2). Tran- siently, foscarnet was added for suspicion of acyclovir resistance since the patient developed HSV DNA posi- tive skin lesions while on acyclovir therapy. However, viral cultures from these lesions remained negative.

Amplification of the thymidine kinase gene from blood samples was unsuccessful since viral load at that time was too low. Thus, in the absence of proof of acyclovir resistance, foscarnet was discontinued to avoid toxicity.

In order to prevent recurrence of HSV DNAemia and secondary graft infection, long-term valacyclovir was given as secondary prophylaxis at a dose equivalent to 1 g/day adapted to the renal function. To monitor the effectiveness of this treatment, we measured HSV DNAemia every second week. Post-LT, both HSV DNA levels and HSV-1-2 antigens in graft biopsies remained undetectable (Figure 2). The patient was discharged 4 months after transplantation but developed many com- plications including graft rejection, multiple polymicro- bial bacteraemia and infected bilioma, finally leading to death 8 months post-transplantation. The last liver biopsy, performed the day before death, was negative for HSV-1-2 antigen detection. There was no clinical evidence of HSV recurrence in other organs. Autopsy was declined by the family.

Discussion

Including our case, 149 cases of HSV hepatitis have been reported so far. This infection is a rare cause of ALF. Indeed a large study including 360 cases of ALF reported that HSV accounted for only 1.4% of them [9]. Most of these cases occurred during primary infec- tions. Herpetic hepatitis is more frequent during infec- tions in immunocompromised hosts. Indeed 80 out of the 149 (54%) published cases occurred in immuno- compromised patients, and 45 of them in solid organ transplant recipients. HSV-2 was responsible for 62%

of cases [1–8]. Interestingly, the present patient had no apparent immunosuppression and, in the absence of specific IgM and IgG, we retained the diagnosis of primary infection, despite his advanced age. Whether severe cases such as our patient, without apparent immunosuppression, have an unknown immunological defect including polymorphisms in Toll-like receptors (TLR) remains speculative [12]. Indeed both TLR2 and TLR9 have been recently identified as responsible for the innate immune response to HSV, however, so far, the lack of TLR signalling has not been associated with an increase in HSV replication [13,14].

The global reported prognosis of acute herpetic hepatitis is poor; indeed 55% of cases (82/149) were diagnosed at autopsy. This might be due to late suspicion of the disease and delayed specific treatment. If herpetic

A B

Figure 1. Liver biopsy

(A) The recipient’s pre-transplant liver biopsy shows marked necrosis with disappearance of the normal tissue architecture. Intranuclear inclusions are seen in numerous hepatocytes (hematoxylin and eosin, original magnification ×400). (B) Immunohistochemistry staining for herpes simplex virus-1-2 is positive both for nuclear and cytoplasmic viral inclusions (original magnification ×600).

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HSV load to monitor antiviral treatment for acute herpetic hepatitis

Antiviral Therapy 17.2 403

hepatitis is suspected, treatment should be promptly initiated. Liver transplantation for HSV hepatitis was performed in 10 cases including our patient [5,8] and 6 of them died within the first year, which compares badly to the 85% expected 1-year survival after LT [15].

However, in only one case was death considered related to recurrent HSV infection and multi-organ failure [10].

Moldovan B et al. [16], based on the Scientific Registry of Transplant Recipients (USA), recently reported a bet- ter recovery in children than in adults both prior and post-LT for HSV hepatitis. HSV likely reaches the liver by haematogenous spread, but the factors determin- ing HSV viraemia are poorly understood. HSV virae- mia appears to be limited to primary HSV infections and more frequent during herpes genitalis, with up to 50% of patients having detectable HSV DNAemia at that time [17]. As a consequence, it has been sug- gested that blood donors with primary HSV infection should be excluded from donation. In one small series of liver transplant recipients for herpetic hepatitis, HSV DNA or HSV culture was positive from blood samples at admission in three out of five cases, but viral DNA quantification was not performed [9]. So far, a corre- lation between hepatic replication and HSV DNAemia

has not been established. Clinical implications of HSV viraemia have just recently started to be investigated. In a retrospective study, hepatitis was the most frequent clinical finding in patients with HSV viraemia [18]. The same study reported an extremely wide range of blood HSV DNAemia (from 8.1×101 to 2.6×109 HSV cop- ies/ml) in patients with disseminated infection. In the case presented here, the initial HSV viral load was very elevated (64.5×106 copies/ml), probably reflecting high viral load during acute primary infection.

In LT recipients for HSV hepatitis, recurrence of HSV viraemia with allograft infection is a major concern.

Therefore, long-term suppressive antiviral therapy has been proposed [7,19]. In our case, the viral load rap- idly decreased following transplantation and initiation of specific antiviral treatment, and stayed undetectable suggesting efficient long-term suppression of viral repli- cation by valacyclovir (Figure 2). Whether a positive pre- transplant HSV DNAemia, despite antiviral treatment, should influence the timing of LT is unclear. Indeed sev- eral published cases, including our case, showed a signifi- cant reduction of viral load post-LT [8]. These observa- tions suggest that the removal of the infected liver, being a major reservoir for HSV, might be highly effective in 0

1 2 3 4 5 6 7 8 9

0 5 10 15 20 25 30 35

HSV DNA, log10 copies/ml

Weeks after transplantation Cutaneous

lesions (+) by PCR HSV-1-2

Oral valacyclovir IV foscarnet

IV acyclovir

Detection limit

Figure 2. HSV-1 DNA plasma load and antiviral therapy

Shown is the plasma herpes simplex virus (HSV)-1 DNA load (log10) according to time post-liver transplant. Periods of various antiviral therapies and presence of PCR- positive cutaneous lesions are indicated. IV, intravenous. +, positive.

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J Ambrosioni et al.

©2012 International Medical Press 404

reducing the viral load, arguing against delaying LT once indicated [8]. Interestingly, post-LT extrahepatic HSV disease during acyclovir treatment, and despite undetect- able viraemia, has been described [8]. This also occurred in our patient, leading to fear of resistance to acyclovir.

Why in these cases acyclovir was able to prevent recur- rence in the allograft but not extrahepatic disease is unclear. Development of acyclovir resistance has been reported during prolonged post-LT acyclovir therapy [10]. In that case, sequencing of the HSV strain recovered from the allograft showed a base insertion in the thy- midine kinase gene resulting in acyclovir resistance not present in the initial strain. Unfortunately, plasma DNA determinations before and after the recurrence of herpes infection were not performed. Because we feared break- through viraemia due to the development of acyclovir resistance, we continued to monitor viral DNA levels until the patient’s death. Based on our experience, serial HSV DNA load determinations might be as a useful tool for post-LT monitoring of antiviral treatment and sur- veillance for breakthrough viraemia. Interestingly, HSV liver infections in immunocompromised patients are not always aggressive: transient liver enzyme elevations without compromised liver function have been reported in isolated cases [20]. In such situations, once other more frequent causes of liver tests alteration have been ruled out and in the absence of positive serology, determina- tion of plasma HSV DNAemia could also be considered to establish the diagnosis.

To conclude, our case illustrates the potential utility of plasma HSV DNA load determinations for diagnosis and monitoring therapy for HSV hepatitis, particularly fol- lowing LT. Considering the serious prognosis of this dis- ease, samples should be rapidly sent to the laboratory and empiric antiviral treatment initiated whenever herpetic hepatitis is suspected. Prospective studies will be required to determine factors influencing the outcome of liver transplantation for herpetic hepatitis and should help to select patient with a better post-transplant prognosis.

Acknowledgements

CT was supported by a SCORE grant from the Swiss National Science Foundation

Disclosure statement

The authors declare no competing interests.

References

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2. Basse G, Mengelle C, Kamar N, et al. Disseminated herpes simplex type-2 (HSV-2) infection after solid-organ transplantation. Infection 2008; 36:62–64.

3. Grimm B, Padberg B, Ruhstaller T, Fleisch F, von Moos R. Fatal herpes simplex virus hepatitis in a patient with esophageal cancer under radiochemotherapy. Onkologie 2008; 31:620–622.

4. Hori T, Ogura Y, Okamoto S, et al. Herpes simplex virus hepatitis after pediatric liver transplantation. Transpl Infect Dis 2010; 12:353–357.

5. Norvell JP, Blei AT, Jovanovic BD, Levitsky J. Herpes simplex virus hepatitis: an analysis of the published literature and institutional cases. Liver Transpl 2007;

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Clin Transplant 2009; 23 Suppl 21:37–41.

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9. Ichai P, Roque Afonso AM, Sebagh M, et al. Herpes simplex virus-associated acute liver failure: a difficult diagnosis with a poor prognosis. Liver Transpl 2005; 11:1550–1555.

10. Longerich T, Eisenbach C, Penzel R, et al. Recurrent herpes simplex virus hepatitis after liver retransplantation despite acyclovir therapy. Liver Transpl 2005; 11:1289–1294.

11. Meylan S, Robert D, Estrade C, et al. Real-time PCR for type-specific identification of herpes simplex in clinical samples: evaluation of type-specific results in the context of CNS diseases. J Clin Virol 2008; 41:87–91.

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Accepted 12 May 2011; published online 21 October 2011

AVT-11-CR-2082_Ambrosioni.indd 404 09/02/2012 17:05:19

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