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Determining the therapeutic range for ribavirin in transplant recipients with chronic hepatitis E virus infection

Abstract The aim of this study was to define the therapeutic range for ribavirin (RBV) in transplant recipients with chronic hepatitis E virus (HEV) infection. In this retrospective multicentre cohort study, data of adult transplant recipients with chronic HEV infection, who had been treated with RBV monotherapy between 01‐3‐2008 and 01‐08‐2018, were included. ROC curve analyses were performed, and the half‐maximal effective RBV concentration was calculated to determine a representative therapeutic range. In 96 patients, RBV monotherapy for a median of three months resulted in a sustained virologic response in 63.5% of the patients, while 88.5% of the patients developed anaemia. RBV plasma concentrations at steady state were significantly higher in clinical responders compared with clinical non‐responders: median 1.96 (IQR 1.81‐2.70) versus 0.49 (IQR 0.45‐0.73) mg/L, P = .0004. RBV caused a dose‐dependent haemoglobin reduction with higher RBV plasma concentrations resulting in more haemoglobin reduction. The therapeutic range for RBV for chronic HEV infection in transplant recipients ranges between 1.8 and 2.3 mg/L.


Ribavirin (RBV) for chronic hepatitis E virus (HEV) infection in im-
munocompromised patients is associated with a sustained virologic response (SVR) of around 80%. 1 The use of RBV is, however, limited by its side effects, which include haemolytic anaemia and a decrease in glomerular filtration rate (GFR). 2 Ribavirin is mainly excreted by the kidneys and has a long halflife (approximately 300 hours). Therefore, RBV steady-state plasma concentrations are not reached until week 8. In patients infected with HCV, a relationship has been described between RBV plasma concentrations, SVR and anaemia. 3 The aim of this study was to investigate the association between RBV plasma concentrations and virologic response and anaemia in transplant recipients with a chronic HEV infection.

| Study design and setting
This was a retrospective multicentre study in which four hospitals The decision to treat HEV with RBV, the starting and maintenance dose of RBV and the timing of RBV plasma concentrations measurements were determined by the treating physician. No formal therapeutic drug monitoring (TDM) protocol for RBV was implemented in any of the participating hospitals.
A waiver was given for this retrospective study by the Medical Ethics Committee of the Erasmus MC (MEC-2018-1326).

| Response assessment
A SVR was defined as an undetectable level of HEV RNA in serum at least 6 months after completion of RBV therapy. 4 Since 6 months after the completion of therapy, RBV is washed out, and we examined the relationship between viral kinetics during RBV treatment and RBV exposure to assess clinical response. Clinical response was defined as a decrease of the HEV RNA load between two measurements with at least a factor 2. Further referred to as "clinical response" in this manuscript. A rise in the HEV RNA load was defined as "clinical non-response". Declines in HEV RNA load without at least a factor 2 (n = 5) were not included. Only the first RBV plasma concentration at steady state was included in the analysis. For the determination of the lower limit of the therapeutic range, plasma concentrations of patients with at least 90 days between the diagnosis of HEV infection and initiation of RBV therapy were included.

| Toxicity assessment
Toxicity of RBV was determined based on the percentage reduction of the haemoglobin (Hb) concentration during a RBV plasma concentration measurement compared to the Hb concentrations at the initiation of RBV therapy (baseline) for each patient. Anaemia was defined as a haemoglobin concentration <8.5 mmol/L (men) and <7.5 mmol/L (women). For the toxicity analysis and determination of the upper limit of the therapeutic range, every plasma concentration was included.

| Statistical analysis
Variables are described with descriptive statistics, and differences

| Patients and ribavirin therapy
A total of 92 HEV-infected SOT and 4 HSCT recipients were included. The characteristics of the 96 patients are depicted in Table 1. RBV monotherapy for a median of 3 (range 1-44) months resulted in a SVR in 63.5% of the patients. In total, 324 RBV plasma samples were included, of which 68 samples of 40 patients were RBV steadystate plasma concentrations.

| Therapeutic effect of ribavirin
The RBV plasma concentrations at steady state were not different between patients with or without SVR ( Figure S1  AUC = 0.75 (95% CI 0.628 to 0.871, P < .0001), Figure 1A). This decreased to 1.10 mg/L with a sensitivity of 89% and specificity 65%.
The ROC curve analysis revealed no differences when HSCT recipients were excluded.

| Ribavirin and toxicity
Eighty-five (88.5%) patients developed anaemia during RBV therapy. Twelve (12.5%) patients needed a blood transfusion because Hb concentrations dropped below 5.0 mmol/L. During RBV treatment, 24 (25%) patients had an increasing Hb concentration due to the use of erythropoiesis-stimulating agents or a blood transfusion.
RBV caused Hb reduction regardless of the dose. Figure 1B

| DISCUSS ION
Here, we show that a steady-state RBV therapeutic range of 1. Based on our toxicity analysis, regular monitoring of Hb, and adjusting the dose accordingly, is sufficient to prevent RBV-related toxicity. A reduction of the dose is desirable in case the Hb concentration drops > 15%. RBV should than be stopped for 2 weeks and restarted at half the initial dose.
In SOT recipients or when MPA is not used as an immunosuppressive agent, one might aim for higher RBV concentrations.
Furthermore, in case of severe toxicity of RBV, a lower limit of the therapeutic range of 1.1 mg/L might be targeted. We recommend to aim for the lower limit of 1.80 mg/L when treatment-naive patients start treatment with RBV for chronic HEV.