Ribavirin Therapy in Immunodeficient Patients with Chronic Hepatitis E Virus Infection

  

    
Variable 
    
Value 
  
  

    
Age-year (range) 
    

  
  

    
Median 
    
45 (21-79)
  
  

    
Sex-no. (%) 
    

  
  

    
Male 
    
6 (55)
  
  

    
Female 
    
5 (45)
  
  

    
Immunosuppression at time    of ribavirin initiation-no. (%) 
    

  
  

    
Glucocorticoid 
    
10 (83)
  
  

    
Tacrolimus 
    
9 (75)
  
  

    
Mycophenolate Mofetil 
    
3 (25)
  
  

    
Methotrexate 
    
1 (8)
  
  

    
Azathioprine 
    
1 (8)
  
  

    
Rituximab 
    
1 (8)
  
  

    
Sirolimus 
    
1 (8)
  
  

    
Interval between    diagnosis of chronic HEV and ribavirin initiation – days (range) 
    

  
  

    
Median 
    
91 (1-293)
  
  

    
Indication to cease    treatment-no. (%) 
    

  
  

    
2 x negative serum and    stool RNA PCR 4 weeks apart 
    
6 (50)
  
  

    
2 x negative serum RNA    PCR 4 weeks apart 
    
4 (33)
  
  

    
1 x negative serum RNA    PCR 
    
1 (8)
  
  

    
Normal ALT 
    
1 (8)
  
  

    
Duration of successful    course of therapy-no. (%) 
    

  
  

    
3 months 
    
3 (27)
  
  

    
3.5 months 
    
3 (27)
  
  

    
5 months 
    
2 (18)
  
  

    
6 months 
    
1 (9)
  
  

    
10.5 months 
    
1 (9)
  
  

    
14 months (re-treatment    course for relapse) 
    
1 (9)
  
  

    
Sustained virological    response-no. (%) 
    

  
  

    
Negative stool and serum    RNA PCR 6 months 
    
6 (55)
  
  

    
Negative serum RNA PCR 6    months 
    
2 (18)
  
  

    
Negative serum RNA PCR 6    months, stool RNA PCR 3 months 
    
1 (9)
  
  

    
Negative serum RNA PCR 3    months 
    
1 (9)
  
  

    
Normal ALT 6 months 
    
1 (9)
  

Table 1: Demographic, clinical and treatment characteristics of the patients.

11 patients were identified with chronic HEV infection during the study period, 55% of whom were male, with an age range 21-79 y at diagnosis. All of these patients were immunosuppressed, due to either long term drug therapy (10 patients) or haematological malignancyrelated immune paresis. The HEV genotype was not routinely measured for our patients.

82% of patients were SOT recipients (renal (n=7), liver (n=2)). The median time from receiving a SOT to chronic HEV diagnosis was 64 months (range 12-168 months). One patient with neuro-sarcoidosis was receiving immunosuppressive therapy with methotrexate and prednisolone.

At the point of diagnosis of chronic HEV, 91% (n=10) of patients were medicated with at least 2 immunosuppressants. Immunosuppressant therapy included tacrolimus (n=9) prednisolone (n=10), mycophenolate mofetil (n=2), azathioprine (n=2), methotrexate (n=1), rituximab (n=1) and sirolimus (n=1). Prior to ribavirin treatment, patients’ trough tacrolimus level was 6.5 μgL^-1 with a median of 6 μgL^-1 and a range of 1.6-8.4 μgL^-1.

Only the 2 liver transplant patients had a history of prior intrinsic liver disease (biliary atresia and autoimmune hepatitis). 91% (n=10) had pre-existing renal disease (80% CKD 2, 20% CKD 3). 7 of these 10 patients were renal transplant recipients and 2 were liver transplant recipients. There were no reported extra-hepatic manifestations of HEV infection.

When chronic HEV was diagnosed, 73% of patients (n=8) had an asymptomatic transaminitis and 27% (n=3) had clinical symptoms alongside a biochemical hepatitis such as abdominal pain, lethargy, weakness or diarrhoea.

Prior to treatment, the mean lymphocyte count was 1.68 10⁹L^-1 (range 0.53-3.95 10⁹L^-1, RR 1.00-4.00 10⁹L^-1), mean platelet count 256 10⁹L^-1 (range 138-355 10⁹L^-1, RR 150-400 10⁹L^-1), and mean ALT 112 UL^-1 (range 18-219 UL^-1, RR 10-60 UL^-1).

Treatment

11 patients received a total of 12 courses of ribavirin treatment, since viral relapse occurred in 1 patient necessitating re-treatment.

The median time between the diagnosis of chronic HEV infection and the initiation of the first course of ribavirin therapy was 91 days (range 1-293 days). At the time of treatment initiation, 7 patients had detectable serum HEV RNA for at least 6 months but 4 patients had been infected for longer than 6 months. The serum HEV RNA was checked in all patients immediately before treatment and an additional baseline stool HEV RNA PCR was checked in 6 of 11 patients.

The main reason for the delay in the initiation of therapy from the point of diagnosis of chronic HEV was to monitor for spontaneous clearance, which did not occur in any of the patients. Three of the 10 patients who were immunosuppressed had their immunosuppressant therapy reduced (tacrolimus) or an agent ceased (sirolimus/ azathioprine) but this was unsuccessful in each case.

Ribavirin treatment was initially commenced at a median daily dose of 1000 mg, with a range of 800-1200 mg. The starting doses were prescribed based on body weight and all the patients were treatment naïve.

Criteria for stopping treatment

EASL 2018 guidance4 recommends assessment of HEV RNA in the serum and stool after 12 weeks of treatment and if the RNA is undetectable in both, then to stop the ribavirin. Most of these patients were treated before the publication of this guideline and so the indications to cease therapy varied, however all patients were treated for a minimum of 3 months. In all but 2 courses of treatment, 2 consecutive negative HEV RNA tests, tested 4 weeks apart, were required to stop treatment.

In 5 patients a negative stool and serum HEV RNA result 4 weeks apart was used as an indication to cease therapy; in 4 patients, 2 negative serum HEV RNA PCR results 4 weeks apart was used; normalisation of the ALT was used in 1 patient and 1 patient’s therapy was stopped due to haemolytic anaemia in the context of 1 negative serum HEV RNA sample after 3 months of treatment-this was the only patient in whom the virus recurred (Table 1).

The patient with HEV recurrence had neuro-sarcoidosis and was being treated with methotrexate when his ribavirin was stopped. Seven months after cessation he developed biochemical hepatitis and was found to have positive HEV RNA in his serum, stool and cerebrospinal fluid. The methotrexate was switched to mycophenolate mofetil with no subsequent evidence of viral clearance and so he was recommenced on ribavirin. 14 months later, once he had 2 consecutive stool and serum samples negative for HEV RNA 4 weeks apart, his ribavirin was stopped. During this period, his stool HEV RNA was intermittently negative.

The mean ribavirin treatment duration, including the second course of therapy for 1 patient (n=12), was 5.3 months with a median of 3.5 months and a range of 3-14 months. 10 of 12 courses of ribavirin lasted for 3-6 months, 1 course lasted 6-12 months and 1 lasted longer than 12 months (Table 1). The mean treatment duration of the successful courses was 5 months with a median of 3.5 months and a range of 3-14 months.

The main treatment duration (4.67 months) was shorter in the 3 patients who had their immunosuppression reduced pre-treatment compared to those who did not (6.2 months).

Adverse events

Anaemia complicated ribavirin therapy in 92% (n=11) of courses, requiring dose reduction in 5 patients and 1 patient needed a blood transfusion (4 units) during the course of treatment. The median daily dosage of ribavirin was 900 mg with a range of 600-1200 mg.

One patient experienced nausea and fatigue was documented during 4 courses of therapy.

Treatment outcome (Table 1)

SVR was confirmed by undetectable HEV RNA in both stool and serum at 6 months post treatment completion in 6 of the 11 patients; 3 of 11 had a negative serum HEV RNA PCR 6 months after the end of treatment, 1 of whom had a negative stool HEV RNA PCR 3 months after the end of treatment; 1 patient had a negative serum HEV RNA PCR 3 months after the end of treatment and 1 patient had not had any HEV testing after the end of treatment due to non-attendance but the ALT remains in the normal range.

The mean ALT, 6 months after the end of treatment, was 17.6 UL^-1 (range 8-29 UL^-1).

Evaluation of liver fibrosis

6 of the 11 patients had a pre-treatment FibroscanTM as a noninvasive assessment of fibrosis, which showed the absence of cirrhosis in all but 1 patient, whose scan was difficult to evaluate due to polycystic liver disease (score of 15.3 kPa). The median FibroscanTM score of the other 5 patients was 5.2 kPa with a range of 2.5-6.3 kPa.

2 further patients had undergone liver biopsy to investigate abnormal liver blood tests prior to screening for chronic HEV. Both these biopsies took place in July 2013 and showed an idiopathic chronic hepatitis but no evidence of fibrosis.

10 out of 11 patients had a FibroscanTM during therapy with ribavirin, which showed no fibrosis in 6 patients (<7kPA). One patient had a reading of 7.6 kPA but did not attend a follow up scan. One patient had a reading of 7.2 kPA which normalised to 5.7 kPA post treatment. Two patients had readings of above 10 kPA; 1 had a post treatment transient elastography by ARFI scan which was normal (5.57 kPa, normal <5.7 kPa) and the other had a follow-up ARFI scan showing a stiffness of 9.1 kPa. This patient has polycystic liver disease which was thought to be the reason for the elevated readings. No patients had evidence of cirrhosis by transient elastography assessment after completion of ribavirin therapy.

Discussion

This relatively small retrospective case series contributes to the growing experience of the diagnosis and management of chronic HEV infection in immunosuppressed patients. In particular, we considered the utility of a 3 month monitoring period post diagnosis (to define chronic infection) and looked at the effect on treatment outcome of different stopping criteria. We also sought to describe further the pattern of chronic HEV infection in this group.

The majority of patients observed with chronic HEV presented as an asymptomatic transaminitis highlighting the importance of vigilant monitoring in patients receiving immunosuppression. Patients should be counselled that they cannot be reassured by an absence of symptoms.

All cases of chronic HEV in our treatment series developed in immunosuppressed patients, consistent with previous observations that chronic HEV in immunocompetent individuals is rare [5]. SOT recipients constituted the majority of chronic HEV cases observed in our series and all were treated with tacrolimus.

Kamar et al. identified that tacrolimus therapy is the main predictive factor for chronic HEV in SOT recipients. This may be related to a greater immunosuppressive effect compared with cyclosporine due to down regulation of T-cell responses against the virus [2]. Similarly, Choi et al. observed this association in renal transplant recipients who developed chronic HEV [6].

It has been postulated that a low platelet count is an independent predictive factor of chronic hepatitis in the HEV infection [7], although most patients in our series had a normal platelet count (mean 256 109L^-1).

In contrast with other studies, none of our patients achieved SVR with reduction of immunosuppression alone and all were treated with ribavirin. Interestingly none of the patients cleared the virus spontaneously during a 3 month post diagnosis monitoring period, as recommended by the EASL 2018 clinical practice guidelines, which states to consider treatment after this time frame [8].

These practice guidelines had not yet been published when some of the earlier patients in our series were treated, thus there was heterogeneity in treatment stopping decisions. In 9 out of 11 ribavirin-naïve patients, cessation of treatment was guided by 2 negative serum HEV RNA PCR results 4 weeks apart, with parallel negative stool HEV RNA PCR results also available for 5 of these patients. None of these 9 patients relapsed. One patient, however, had a negative serum HEV RNA PCR and normal ALT 2 months after starting treatment but had persistent positive stool HEV RNA. Had the stool not been tested and the biochemistry/single negative serum HEV RNA PCR sample been used to guide treatment cessation, the patient may well have relapsed without the more prolonged course of treatment (6 months) which they eventually received.

Furthermore, the only patient who required ribavirin retreatment for HEV relapse had just a single serum HEV RNA used as a marker of viral clearance for their initial course (i.e. without stool test). The same patient had fluctuating stool HEV RNA positivity during re-treatment, resulting in a markedly prolonged (14 months), but successful re-treatment course. These results highlight the value of using 2 consecutive stool HEV RNA tests, 4 weeks apart, as a marker of SVR in immunosuppressed patients.

For the 10 patients who did not require re-treatment, the mean duration of the ribavirin course was 4.6 months (Figure 1).

    

    

    Figure 1: Duration of therapy for those who did not require re-treatment (n=10).