Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience

ORIGINAL ARTICLE

VIROLOGY

Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience M.-C. Tsai1,2, C.-H. Chen1, P.-L. Tseng1,2, C.-H. Hung1, K.-W. Chiu1, J.-H. Wang1, S.-N. Lu1,2, C.-M. Lee1,2, K.-C. Chang1, Y.-H. Yen1,2, M.-T. Lin1,2, Y.-P. Chou1 and T.-H. Hu1 1) Division of Hepato-Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Centre and 2) Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taiwan

Abstract This study aims to assess the nephrotoxicity and efficacy of tenofovir disoproxil fumarate (tenofovir), telbivudine and entecavir. A retrospective study of 587 patients with chronic hepatitis B treated with tenofovir (n = 170), telbivudine (n = 184) and entecavir (n = 233) for at least 1 year. Renal function and efficacy were assessed. The estimated glomerular filtration rate (eGFR) decreased significantly in the tenofovir group after a mean of 17 months treatment (from 92.2 to 85.6 mL/min/1.73 m2, p < 0.001), but increased in the telbivudine group after a mean of 32 months of treatment (from 86.1 to 95 mL/min/1.73 m2, p < 0.001). There was no significant change in eGFR in the entecavir group after a mean of 44 months. By multivariate analysis, pre-existing renal insufficiency (p = 0.003), tenofovir (p = 0.007) and diuretic treatment (p = 0.001) were independent predictors for renal function deterioration. Cumulative virological breakthrough was 0% in tenofovir after 2 years, 3.4% in entecavir after 7 years and 22.9% in telbivudine after 5 years. Liver cirrhosis (p = 0.008) and virological breakthrough (p = 0.040) were independently associated with increased risk of hepatocellular carcinoma development. Tenofovir may lead to deterioration in renal function as assessed by serial eGFR measurements. Although telbivudine appeared to be associated with an improvement in eGFR, it was associated with high rates of virological breakthrough, which was an independent risk factor for HCC development. With low rates of virological breakthrough and preservation of renal function, entecavir could be the best choice among these three agents. Clinical Microbiology and Infection © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Keywords: Entecavir, estimated glomerular filtration rate, renal function, telbivudine, tenofovir Original Submission: 11 January 2015; Revised Submission: 17 May 2015; Accepted: 26 May 2015 Editor: G. Antonelli Article published online: 5 June 2015

Corresponding author: T-H. Hu, Division of HepatoGastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung Medical Centre, 123, Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung Hsien, 833, Taiwan E-mail: [email protected]

Introduction The aim of chronic hepatitis B (CHB) treatment is to achieve sustained viral suppression of hepatitis B virus (HBV) replication, with loss of hepatitis B e antigen (HBeAg) or more

preferably, hepatitis B surface antigen (HBsAg) [1]. Although nucleotide/nucleoside analogues are effective in suppressing HBV replication, they cannot eradicate the virus. Therefore, most patients require long-term treatment. Long-term efficacy, safety, drug resistance and cost are major considerations in determining which nucleoside analogues should be considered as first-line treatment. Tenofovir disoproxil fumarate (tenofovir) was approved by the US Food and Drug Administration in 2001 as the first nucleotidic reverse transcription inhibitor for the treatment of human immunodeficiency virus (HIV) infection, and was subsequently approved for the treatment of CHB in 2008. In HIVinfected patients, despite clinical trials of tenofovir

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addition, the cumulative rate of hepatocellular carcinoma (HCC) was analysed.

demonstrating an excellent safety profile [2], concerns have been raised about the potential risk of nephrotoxicity with long-term use. Tenofovir is an acyclic nucleotide analogue structurally similar to adefovir, which has been shown to be nephrotoxic [3,4]. Nephrotoxicity with tenofovir has been demonstrated, including increases in serum creatinine and blood urea nitrogen, decrease in serum phosphate, and glycosuria, proteinuria and phosphaturia [5]. In HIV-infected patients, tenofovir therapy has been associated with a modest decline in serum creatinine clearance; cessation of tenofovir may help to normalize creatinine clearance [6,7]. However, in CHB, no patients in a pivotal 48-week study developed renal toxicity [8]. Furthermore, realworld studies showed no major changes in renal function in tenofovir-naive CHB patients [9–14]. In contrast to tenofovir, nucleoside analogues including entecavir and telbivudine did not show renal toxicity at supranormal doses in rat studies [5,15]. It has been shown that the estimated glomerular filtration rate (eGFR) in CHB patients was increased via an unknown mechanism after telbivudine treatment [16]. Moreover, in patients with compensated and decompensated cirrhosis, long-term telbivudine therapy improved renal function, especially in patients at increased risk of renal impairment [17]. Our previous study found that an improvement of eGFR was noted in a telbivudinetreated group compared with an entecavir group after 2 years of treatment [18]. To date, there has been no study from the real world comparing the renal function and efficacy among tenofovir-, telbivudine- and entecavir-treated patients. Therefore, the aim of this study is to assess the renal safety and efficacy of tenofovir, telbivudine and entecavir in naive CHB patients in a real world setting.

Data analysis Data are presented as means ± SD, proportions, or median (range). Categorical variables were analysed by the chi-squared or Fisher’s exact test. Student t test and Mann-Whitney U test were used to examine continuous variables with normal and skewed distributions, respectively. The direct and indirect renal function, including eGFR, serum phosphate, urine phosphate, microalbumin and total protein were analysed using the paired t test for each group. A univariate and multivariate linear regression was used to assess the factors predictive of renal function deterioration. The R2 value was used to assess the strength of this correlation. The cumulative rates of HBeAg seroconversion and HCC were analysed using the Kaplan– Meier method and the log-rank test, respectively. All statistical analyses were performed using SPSS 17.0. All p values of <0.05 were accepted as statistically significant.

Patients and methods

Results

This retrospective, single-centre cohort study enrolled 587 CHB treatment-naive patients commenced on tenofovir (n = 170), telbivudine (n = 184) or entecavir (n = 233) at the Chang Gung Memorial Hospital, Kaohsiung Medical Centre for a minimum of 1 year from November 2006 through December 2012. For each patient, medical records were reviewed to obtained demographic information, baseline CHB characteristics, and comorbidities including diabetes mellitus, hypertension, history of renal transplantation and pre-existing renal insufficiency. Nephrotoxicity on treatment was assessed by serial measures of renal function, including serum creatinine and eGFR. Starting in July 2011, serum phosphate and urine phosphate, creatinine, microalbumin and total protein were assessed at each clinic visit. Treatment efficacy was assessed by alanine transaminase (ALT) normalization, HBeAg seroconversion rate, HBV DNA levels and virological breakthrough. In

Clinical characteristics at baseline The baseline characteristics of the three study groups are shown in Table 1. The 587 patients were predominately male (71.7%), gender split and mean age were similar for each group. Patients in the telbivudine group had higher incidence of HCC at baseline (23.9% versus 15.0% versus 12.4%, p = 0.009) and lower baseline serum HBV DNA (p = 0.003). The median duration of follow up was 12 months (mean 16.6 months, range 12–24 months), 36 months (mean 31.2 months, range 12–60 months) and 36 months (mean 43.4 months, range 12–84 months) in the tenofovir, telbivudine and entecavir groups, respectively.

Definitions Pre-existing renal insufficiency was defined as a baseline eGFR of <60 mL/min/1.73 m2, as calculated by the Modification of Diet in Renal Disease (MDRD) equation. The MDRD equation is: eGFR = 186 × (creatinine)−1.154 × (age)−0.203 × (0.742 if female) [19]. Renal function deterioration was defined as a decrease in eGFR from baseline to the last visit. Each serum creatinine level, from baseline to the last visit, was confirmed by using the average of three samples taken. Values from patients with sepsis or gastrointestinal bleeding were excluded from analysis.

Comparison of eGFR change The changes in eGFR during treatment in the entecavir, telbivudine, and tenofovir groups are shown in Fig. 1. Overall, the

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TABLE 1. Baseline demographics and characteristics of study patients

Age (years) Male (%) ALT (IU/L) ALT > 2 × ULN (%) ALT > 5 × ULN (%) HBeAg-positive (%) Liver cirrhosis (%) Child–Pugh classification A B C HCC (%) HBV DNA (log copies/ mL) Creatinine (mg/dL) eGFR stage (%) <30 mL/min/1.73 m2 30–59 mL/min/1.73 m2 60–90 mL/min/1.73 m2 >90 mL/min/1.73 m2 Diabetes mellitus (%) Hypertension (%) Renal transplantation (%) Chemotherapy (%)

Tenofovir (n [ 170)

Telbivudine Entecavir (n [ 184) (n [ 233)

51.8 ± 11.9 121 (71.2%) 161.4 ± 280.7 78 (45.9%) 31 (18.2%) 39 (22.9%) 80 (47.1%)

54.2 ± 14.6 132 (71.9%) 172.7 ± 310.5 88 (47.8%) 37 (20.1%) 33 (17.9%) 102 (55.4%)

52.8 ± 12.4 168 (72.1%) 171.8 ± 275.4 125 (53.6%) 55 (23.6%) 61 (26.2%) 118 (50.6%)

78 (97.5%) 1 (1.3%) 1 (1.3%) 21 (12.4%) 6.4 ± 1.9

86 (84.3%) 15 (14.7%) 1 (1%) 44 (23.9%) 5.7 ± 1.8

109 (92.4%) 7 (5.9%) 2 (1.7%) 35 (15.0%) 6.2 ± 1.5

0.9 ± 0.3

0.9 ± 0.3

1.0 ± 0.3

1 10 75 82 21 (12.5%) 24 (14.3%) 4 (2.4%) 18 (10.6%)

2 16 79 70 28 (15.2%) 17 (9.2%) 0 11 (6%)

2 24 119 61 28 (12.0%) 39 (16.7%) 19 (8.2%) 4 (1.7%)

p value 0.919 0.979 0.759 0.259 0.401 0.168 0.284 0.014

0.009 0.003 0.056 0.012

0.603 0.083 < 0.001 0.001

Data were expressed as mean ± SD, or n (%). Abbreviations: ALT, alanine transaminase; HBeAg, hepatitis B-e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; Cr, creatinine; eGFR, estimated glomerular filtration rate; UNL, upper limit of normal.

eGFR in the tenofovir group decreased significantly compared with baseline over the 2-year treatment period. In the entecavir group, the eGFR was stable in the first 3 years, but significantly improved at the 4th and 5th year marks (p = 0.002 and p = 0.003, respectively). In the telbivudine group, the eGFR increased significantly in the first 4 years (Fig. 1a). In a subgroup analysis in those with a baseline eGFR >90 mL/min/1.73 m2, there was no significant change in renal function after 5 years of treatment in the entecavir and telbivudine groups, whereas eGFR decreased in the tenofovir group (from 109.6 to 99.4 mL/ min/1.73 m2, p < 0.001 and from 109.6 to 101 mL/min/1.73 m2, p 0.008 in the 1st and 2nd years, respectively) (Fig. 1b). In patients with baseline chronic kidney disease stage II (eGFR 60–90 mL/min/1.73 m2), there were significant increases in eGFR in the telbivudine and entecavir groups after 5 years of treatment. In contrast, there was a significant decrease in eGFR in the tenofovir group (from 79 to 72.8 mL/min/1.73 m2, p = 0.034) after 2 years of treatment (Fig. 1c). Fig. 2 shows the change in eGFR between baseline and last visit. There was a significant decrease in the tenofovir group after a mean of 16.6 months of treatment (from 92.2 to 85.6 mL/min/1.73 m2, p < 0.001). In contrast, the telbivudine group had a significant increase after a mean of 31.2 months of treatment (from 86.1 to 95 mL/min/1.73 m2, p < 0.001). In a sub-analysis of patients with baseline eGFR >90 mL/min/ 1.73 m2, only the tenofovir group had a significant decrease in eGFR (from 109.5 to 101.4 mL/min/1.73 m2, p < 0.001). In

FIG. 1. Comparison the estimated glomerular filtration rate (eGFR) between entecavir (ETV), telbivudine (LdT) or tenofovir (TDF) -naive chronic hepatitis B (CHB). (a) Overall; (b) in eGFR >90 mL/min/1.73 m2 (c) in chronic kidney disease stage II.

patients with baseline chronic kidney disease stage II (eGFR 60–90 mL/min/1.73 m2), the tenofovir group still showed significant decrease (from 79 to 73.7 mL/min/1.73 m2, p < 0.001), but there was an increase in the telbivudine and entecavir groups (in telbivudine group, from 74.6 to 91.7 mL/min/ 1.73 m2, p < 0.001; in entecavir group, from 75.8 to 82.5 mL/

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min/1.73 m2, p < 0.001). To ensure that the deterioration of renal function in the tenofovir group was not being confounded by a subset of patients who underwent chemotherapy treatment for concomitant cancer (such as for colon cancer and breast cancer), we excluded these patients from the analysis and the renal function deterioration remained significant (from 91 to 85.2 mL/min/1.73 m2, p < 0.001) (Fig. 2d). Predictive factors for renal function deterioration We defined renal function deterioration as those patients whose eGFR decreased between baseline and last visit. Univariate linear regression indicated that Child–Pugh class B and C versus A (p = 0.033), pre-existing renal insufficiency (p = 0.056), tenofovir treatment (p < 0.001), higher HBV DNA level (p = 0.005), virological breakthrough (p = 0.011), and diuretic treatment (p = 0.058) were significant predictors of renal function deterioration (Table 2). After multivariate linear regression pre-existing renal insufficiency, diuretics and tenofovir treatment (adjusted R2 value, 0.48; p = 0.003, p = 0.001 and p = 0.007, respectively) remained as independent predictors of renal function deterioration (Table 2). Comparison of serum phosphate, urine phosphate, microalbumin and total protein among the entecavir, telbivudine and tenofovir groups In July 2011 we commenced regular testing for other makers of renal function, including serum phosphate, urine phosphate, urine creatinine, urine microalbumin and urine total protein at each clinical visit. These other markers of renal function were not significantly changed after 2 years of treatment in the tenofovir, telbivudine, and entecavir groups (see Supplementary material, Table S1). During 2 years of treatment, de novo hypophosphataemia (defined as serum phosphate 2.5 mg/dL) occurred in four (8.2%), one (5.3%) and one (1.8%) patients in the tenofovir, telbivudine and entecavir groups, respectively. In addition, there was no correlation between hyperphosphaturia and hypophosphataemia.

FIG. 2. Comparison the change of estimated glomerular filtration rate (eGFR) between entecavir (ETV), telbivudine (LdT), or tenofovir (TDF)-naive chronic hepatitis B (CHB) from baseline to last visit. (a) Overall, (b) in eGFR >90 mL/min/1.73 m2, (c) in chronic kidney disease stage II, (d) without chemotherapy.

Efficacy of entecavir, telbivudine and tenofovir in CHB patients The rates of ALT normalization, HBV DNA undetectability and the cumulative resistance among the entecavir, telbivudine and tenofovir groups are shown in the Supplementary material (Fig. S1). The rates of ALT normalization in the entecavir, telbivudine and tenofovir groups ranged from 78% to 100%, 76% to 80% and 77% to 88% respectively across 7, 5 and 2 years of treatment; rates of HBV DNA undetectability ranged from 92.7% to 100%, 82% to 100% and 85% to 97% respectively; and the cumulative virological breakthrough was 3.4%, 22.9% and 0% in the entecavir, telbivudine and tenofovir groups,

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TABLE 2. Univariate and multivariate linear regression of predictive factors for renal function progressiona Multivariatec

Univariate Variable

β

SE

Age (years) −0.077 0.079 Sex (Male vs. Female) −1.741 2.168 ALT (>80 vs. 80 U/L) 0.602 1.952 HBeAg (positive vs. negative) 1.393 2.31 Cirrhosis (Yes vs. No) −0.02 1.954 Child–Pugh Classification 10.343 4.833 (B and C vs. A) HCC (Yes vs. No) −0.074 2.55 Nucleoside analogues (tenofovir 10.749 2.055 vs. entecavir or telbivudine) HBV DNA (log copies/mL) 1.545 0.549 Virological breakthrough −10.765 4.208 (Yes vs. No) Pre-existing renal insufficiencyb 6.171 3.223 (Yes vs. No) Diabetes mellitus (Yes vs. No) 2.635 2.822 Hypertension (Yes vs. No) 1.475 2.777 Diuretics (Yes vs. No) 8.929 4.692 Chemotherapy (Yes vs. No) 7.708 4.096 Renal transplantation history 4.459 4.798 (Yes vs. No)

β

p

SE

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(HR = 3.855, 95% CI 1.061–14.006, p = 0.040) and diabetes mellitus (HR = 2.690, 95% CI 1.043–6.938, p = 0.041) as independent risk factors for the HCC development (see Supplementary material, Table S2).

p

0.332 0.423 0.758 0.546 0.992 0.033 0.933 <0.001 8.32

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Discussion

3.055

0.007

0.056 10.272 4.207

0.003

0.351 0.595 0.058 16.991 5.189 0.085 0.353

0.001

0.005 0.011

Abbreviations: β, β-coefficience; SE, standard error; ALT, alanine transaminase; HBeAg, hepatitis B-e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma NAs, nucleotide/nucleoside analogs. a Definition of renal function progression: decreased eGFR from baseline to the last visit. b Definition of pre-existing renal insufficiency: baseline eGFR 60 mL/min/1.73 m2. c Adjusted multiple R2 = 0.48.

respectively. There were no significant differences between the entecavir, telbivudine, and tenofovir groups in HBeAg seroconversion (see Supplementary material, Fig. S2a). Baseline ALT 200 IU/L predicted HBeAg seroconversion (p = 0.002; see Supplementary material, Fig. 2b) in univariate analysis, and was the only independent predictive factor for HBeAg seroconversion (hazard ratio (HR) = 2.149, 95% CI 1.273–3.626, p = 0.004). Comparison of HCC development among entecavir, telbivudine and tenofovir groups Of the 487 treated patients without HCC at baseline, HCC was diagnosed in 104 patients during treatment. The median duration of follow up was 24 months (mean 31.4 months). Five patients who developed HCC in the first year of treatment were excluded leaving 482 patients; 197 in the entecavir group, 138 in the telbivudine group and 147 in the tenofovir group (Fig. 3). The overall cumulative incidence rates of HCC were 4.2% and 8.6% at years 3 and 5, respectively (Fig. 3a). Log-rank test revealed a significantly higher incidence of HCC development in the telbivudine group compared with the entecavir group (p = 0.001, Fig. 3b). Further analysis also found that there was a significant difference in HCC development between groups with and without virological breakthrough (p = 0.001, Fig. 3c) and liver cirrhosis (p < 0.001, Fig. 3d). Multivariate analysis revealed liver cirrhosis (HR = 15.769, 95% CI 2.081–119.506, p = 0.008), virological breakthrough

Renal function is an important issue in the use of the two oral antiviral agents telbivudine and tenofovir. There is increasing evidence that telbivudine may impart a protective effect on renal function by unknown mechanisms [16–18]. A study by Liang et al. showed significant reductions of serum angiotensinconverting enzyme during monotherapy with telbivudine in CHB patients [20]. As we know, angiotensin-converting enzyme plays an important role in the renin–angiotensin aldosterone regulatory system, with known downstream effects on systemic vasoconstriction and renal sodium and renal fluid retentions, which might explain the possible mechanism of renal function modulation in telbivudine treatment [20]. In contrast to the possibility of telbivudine improving renal function, tenofovir is thought to be associated with deterioration of renal function. Studies have shown that tenofovir has been associated with nephrotoxicity in HIV/HBV co-infected patients [21–23]; however, nephrotoxicity in HBV monoinfected patients, treated with tenofovir is less commonly observed compared with tenofovir-treated HIV patients [4,9–13]. In the current study, we found that tenofovir treatment resulted in significant decrease in eGFR in CHB patients after a mean of 17 months of treatment. Multivariate analysis indicated that pre-existing renal insufficiency, concomitant diuretic therapy and tenofovir treatment were independent risk factors for renal function deterioration. These results are similar to those reported by Gish et al. [9], which compared tenofovir and entecavir treatment. Here, pre-existing renal insufficiency is a risk factor for renal function progression; however, tenofovir therapy is not associated with significantly different changes in renal function compared with entecavir therapy [9]. Nucleoside analogues undergo renal clearance predominantly in their unaltered forms. Therefore, in patients with poor renal function, dose reduction or increased dose intervals are recommended. In the present study, even though the dose of antiviral agents was adjusted according to guidelines in all patients with renal insufficiency (defined as eGFR 60 mL/min/1.73 m2), renal insufficiency remained a risk factor for renal function deterioration during tenofovir treatment. This reinforces the need for clinicians to be aware of CHB patients with pre-existing renal insufficiency or being treated with diuretics. It is worth noting that virological breakthrough was an independent risk factor for HCC development in this study. In

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CHB patients treated with lamivudine, drug resistance was reported to be a risk factor for developing long-term complications, including HCC development [24]. A systematic review of 21 studies including 3881 treated patients demonstrated that higher incidence rates of HCC (7.5% versus 2.3%, p < 0.001) in non-responding patients or in patients who experience viral breakthrough even if HBV replication is subsequently suppressed by rescue therapy compared with those who experienced remission [25]. A Japanese study that compared two groups, entecavir-treated and non-rescued lamivudine cirrhotic patients (September 1995 to September 2007), showed greater HCC suppression in the entecavir group compared with the non-rescued lamivudine patients [26]. In the present study, experience of viral breakthrough is an independent predictor of HCC development. It should be noted that of the 35 patients who experienced breakthrough, 32 were from the telbivudine group and three from the entecavir group. This is the first study showing that telbivudine treatment was associated with a higher incidence of HCC compared with entecavir and tenofovir. Telbivudine is still used in some countries, mostly because of its relative low cost. Based on the present study, telbivudine should not be recommended as first-line therapy because of the increased rate of virological breakthrough and HCC development after long-term treatment. Its use may be limited to chronic inactive carriers or HBV core antibody-positive patients undergoing chemotherapy for a fixed course as prophylaxis [21,27]. Limitations of our study include short median follow-up time of tenofovir-treated patients, plus its retrospective, nonrandomized design. Results and conclusions must therefore be interpreted accordingly. A prospective study with a longer follow-up time is warranted to more accurately detect differences in the renal function changes in entecavir-, telbivudineand tenofovir-treated patients. In conclusion, tenofovir is associated with renal function deterioration as measured by eGFR in CHB patients, especially in those with pre-existing renal insufficiency and receiving diuretics. Although telbivudine was associated with renal function improvement, its utility is limited by high rates of virological breakthrough, which was an independent risk for HCC development. Based on these results, when considering HCC development and renal function deterioration, entecavir could be the best choice among these three agents.

FIG. 3. Comparison cumulative hepatocellular carcinoma (HCC) incidence in naive chronic hepatitis B (CHB). (a) Overall, (b) between entecavir, telbivudine, and entecavir, (c) between virological breakthrough and non-virological breakthrough, and (d) between cirrhosis and non-cirrhosis. Clinical Microbiology and Infection © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved, CMI, 22, 95.e1–95.e7

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Transparency declaration There is no conflict of interest to disclose for all authors.

Acknowledgements This study was supported by grants CMRPG8D0221 from Chang Gung Memorial Hospital, Taiwan. In addition, we thank Dr Michael C. Wallace, School of Medicine and Pharmacology at the University of Western Australia, for his editorial assistance.

Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.cmi.2015.05.035

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