© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 1010–1015 DOI: 10.1111/ctr.12410
Clinical Transplantation
Entecavir treatment in kidney transplant recipients infected with hepatitis B Yap DYH, Yung S, Tang CSO, Seto WK, Ma MKM, Mok MMY, Kwan LPY, Chan GCW, Choy BY, Yuen MF, Chan TM. Entecavir treatment in kidney transplant recipients infected with hepatitis B. Abstract: Although nucleotide/side analogs improve the clinical outcome of hepatitis B surface antigen-positive (HBsAg+) kidney transplant recipients (KTR), a significant proportion of subjects have developed resistance to lamivudine (LAM). We retrospectively analyzed the efficacy and tolerability of entecavir (ETV) in HBsAg+ KTR at Queen Mary Hospital during 2005–2013. Twenty-one patients (10 treatment-na€ıve, 11 with LAM resistance) were included (duration of ETV treatment 34.7 22.9 months, range 6–75 months). ETV treatment led to a decline of hepatitis B virus (HBV) DNA titer compared to baseline and is more significant in the treatment-na€ıve group (treatment-na€ıve: p = 0.028, 45 U/L for women lasting over six months. Circulating HBV DNA level was measured with
Normally distributed continuous variables were expressed as mean standard deviation and compared with paired or unpaired t-test, while non-normally distributed ones were expressed as median and range and analyzed with Wilcoxon or Mann–Whitney test. Categorical data were expressed as frequencies and percentages and compared with chi-squared test. Longitudinal data between groups were compared using Wilcoxon rank-sum test and intragroup comparison of paired variables by Wilcoxon signed-ranks test. Patient and graft survival, time-to-undetectable HBV DNA, and time-to-ALT normalization were estimated by Kaplan–Meier method. Data analyses were generated by SPSS for windows version 18 (SPSS, Chicago, IL, USA) and Prism version 5 (San Diego, CA, USA), and p-values were two-sided.
Results Patient characteristics
Twenty-one HBsAg+ KTR (10 treatment-na€ıve and 11 with LAM-resistant HBV infection) were included (Table 1). Two patients were excluded in this study (one due to concomitant HCV infection and one due to chronic alcoholism). The duration
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Yap et al. Table 1. Characteristics of 21 ETV-treated HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance Treatment-na€ıve (n = 10) Age (yr) 54.6 5.7 Sex (F/M) 3/7 Previous mode of 8/2 dialysis (PD/HD) Type of kidney transplant Deceased donor 5 Live donor 5 Duration of follow-up after transplantation (months) 184.7 141.2 Immunosuppressive treatment at initiation of ETV (baseline) Prednisolone 10 CYA 5 TAC 2 MMF 4 AZA 1 mTOR inhibitors 1 Baseline HBeAg status () 2/8 Baseline ALT (U/L) 45.0 (25.0–361.0) Baseline HBV DNA (copies/mL) 1.2 9 105 (1.7 9 102–1.6 9 108) Baseline serum creatinine level (lM) 173.8 136.8
LAM-resistant (n = 11)
Overall (n = 21)
50.3 5.1 2/9 7/4
52.3 5.7 5/16 15/6
7 4 180.7 89.3
12 9 182.6 113.9
11 9 1 3 1 1 2/9 36.0 (14.0–46.0) 1.2 9 106 (7.3 9 103–2.7 9 107) 150.2 67.3
21 14 3 7 2 2 4/17 37.0 (14–361) 9.6 9 105 (1.7 9 102–1.6 9 108) 161.4 104.0
AZA, azathioprine; HD, hemodialysis; mTOR inhibitor, mammalian target of rapamycin inhibitors; PD, peritoneal dialysis.
of follow-up after initiation of ETV was 34.7 22.9 months (treatment-na€ıve 24.9 24.5 months, LAM-resistant 43.5 18.1 months, p = 0.061). ETV treatment was not interrupted during follow-up and was continued at the time of writing. Nineteen (65.5%) patients had ETV treatment for more than 12 months and 11 (45.8%) patients for more than 24 months. The actual dose of ETV administered was 0.43 0.12 mg/d in treatment-na€ıve subjects and 0.66 0.34 mg/d in the LAM-resistant group. Effect of ETV treatment on HBV virological parameters
Baseline median HBV DNA level was 9.6 9 105 copies/mL (1.7 9 102–1.6 9 108 copies/mL) (treatment-na€ıve: 1.2 9 105 copies/mL [1.7 9 102–1.6 9 108 copies/mL]; LAM-resistant: 1.2 9 106 copies/ mL [7.3 9 103–2.7 9 107 copies/mL], p = 0.179) before ETV was started. Treatment with ETV led to a 3-log reduction of HBV DNA level after three months (Fig. 1). In the treatment-na€ıve group, HBV DNA dropped from 1.2 9 105 copies/ mL (1.7 9 102–1.6 9 108 copies/mL) to 1.2 9 102 copies/mL (0–1.4 9 102 copies/mL) after 12 months (p = 0.028) and became undetectable after 24 and 36 months (p < 0.001 for both, compared with baseline). In the LAM-resistant group, median HBV DNA decreased from 1.2 9 106 copies/mL (7.3 9 103–2.7 9 107 copies/mL) to 1.8 9 102 copies/mL (0–5.9 9 103 copies/mL), 7.0 9 102 copies/
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Fig. 1. Serial HBV DNA levels after ETV treatment in 21 HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance.
mL (0–1.4 9 103 copies/mL), and 1.3 9 102 copies/mL (0–1.3 9 103 copies/mL) after 12, 24, and 36 months, respectively (p = 0.273, 0.180, and 0.109, respectively compared with baseline). Treatment-na€ıve patients had significantly lower HBV DNA levels compared with the LAM-resistant group at 12, 24, and 36 months (p = 0.039, 0.048, and 0.036, respectively). Cumulative rate of undetectable HBV DNA was 60%, 100%, and 100% in
Entecavir in HBV+ kidney transplantation treatment-na€ıve patients and 27%, 45%, and 45% for LAM-resistant patients, at 12, 24, and 36 months, respectively. Time-to-undetectable HBV DNA was 15.7 4.6 months in treatment-na€ıve patients and 24.5 4.2 months in LAM-resistant patients (p = 0.230). Serial HBV DNA levels did not differ between patients receiving standard dose of ETV and those given renal-adjusted doses (p = 0.564). No virological breakthrough was observed in treatment-na€ıve patients. In the LAMresistant group, two patients had resurgence of HBV DNA after 20.0 3.5 months, and both were confirmed to have genotypic ETV resistance. Four patients (two treatment-na€ıve and two LAM-resistant) were HBeAg+ at baseline and one sero-converted after 20 months. Effect of ETV treatment on liver biochemistry
Baseline median ALT level before ETV treatment was 45.0 U/L (25.0–361.0 U/L) and 36.0 U/L (14.0–46.0 U/L) for treatment-na€ıve and LAMresistant patients, respectively (p = 0.217). ALT level decreased after ETV treatment (Fig. 2). For treatment-na€ıve patients, the median ALT level decreased to 18.5 U/L (15.0–30.0 U/L), 18.0 U/L (17.0–21.0 U/L), and 18.0 U/L (12.0–24.0 U/L) after 12, 24, and 36 months, respectively (p = 0.002, 0.041, and 0.047 compared with baseline). For LAM-resistant patients, the median ALT level decreased to 26.0 U/L (6.0–51.0 U/L), 17.0 U/L (13.0–56.0 U/L), and 15.5 U/L (12.0– 83.0 U/L) after 12, 24, and 36 months, respectively
Fig. 2. Serial ALT levels after ETV treatment in 21 HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance.
(p = 0.094, 0.215, and 0.195 compared with baseline). Ninety percent of patients achieved normal liver biochemistry. ALT levels did not differ between treatment-na€ıve and LAM-resistant patients at 12, 24, and 36 months (p = 0.335, 0.363, and 0.470, respectively). Mean time-to-ALT normalization was 12.6 3.7 months in treatment-na€ıve patients and 28.2 3.5 months in the LAM-resistant group (p = 0.317). ALT levels did not differ between patients receiving standard dose and those on renal-adjusted dose of ETV (p = 0.512). In patients who developed ETV resistance, the ALT level increased from 13.5 4.9 to 42.0 28.2 U/L. Clinical outcomes and ETV tolerability
One patient had chronic active hepatitis despite ETV treatment for 36 months, which was not associated with ETV resistance. None of the patients showed de novo clinically evident cirrhosis or liver tumor during follow-up. Four patients died – three from pneumonia and one from pancreatic cancer. The patient survival rate after 12, 24, and 36 months was 90%, 90%, and 90%, respectively, for treatment-na€ıve patients and 100%, 100%, and 86%, respectively, for LAM-resistant patients (p = 0.643). Serum creatinine and eGFR at 36 months did not differ significantly from baseline (161.4 104.0 and 136.8 46.5 lM, respectively, p = 0.401; 53.0 23.6 and 56.7 22.5 mL/min/ 1.73 m2, respectively, p = 0.426; Fig. 3). The graft survival rate was 100%, 100%, and 100%, respectively, at 12, 24, and 36 months for both groups.
Fig. 3. Serial serum creatinine levels after ETV treatment in 21 HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance.
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Yap et al. Discussion
ETV is a potent nucleoside analog that is effective in suppressing the replication of wide-type and LAM-resistant HBV (20, 22). There are limited data regarding the use of ETV in immunosuppressed KTR, especially in the setting of LAM resistance. Our results showed that ETV treatment was effective and well tolerated in these patients. Suppression of HBV replication by ETV was more effective in treatment-na€ıve patients compared with those who had LAM resistance. The high efficacy in treatment-na€ıve KTR was in line with the experience in the general population (25–27). Suppression of HBV DNA was accompanied by biochemical improvement. Normalization of transaminase levels occurs within a few months of treatment and was sustained for at least three yr, without emergence of drug resistance (20). The latter presents a distinct advantage compared with LAM (1, 12, 14). As LAM was the first oral nucleoside analog available, there is a significant number of HBsAg+ KTR who have developed LAM resistance. Before the availability of alternative nucleoside/tide analogs, it was the practice to continue with LAM treatment despite the emergence of drug resistance. Subsequently, combined adefovir and LAM treatment or substitution with tenofovir was the recommended treatment (15, 16, 28, 29). However, both adefovir and tenofovir are nephrotoxic and have been associated with allograft dysfunction (17–19). In contrast, ETV is non-nephrotoxic. Our current data demonstrated that ETV can be considered as treatment for KTR with LAM resistance, especially in patients with impaired renal allograft function, as it resulted in clinically meaningful viral suppression and improvement in liver biochemistry. The latter can occur despite persistence of HBV DNA at a detectable level. Here, we observed a difference in treatment response between treatment-na€ıve and LAM-resistant patients. Whether such discrepancy might be related to host or viral factors remains speculative. In this context, ETV also demonstrated higher efficacy in treatmentna€ıve patients than LAM-resistant patients in the general population (20–22). Nevertheless, the emergence of ETV resistance remains a concern (22), and whether the resistance rate might increase further with longer follow-up requires further investigation. While liver-related morbidities and mortality were not observed during ETV treatment for approximately three yr, further data are required on the long-term outcomes. ETV is predominantly eliminated by renal excretion (62–73%) (30).
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Therefore, we down-adjusted the ETV dose in patients with impaired renal allograft function in view of the reduced drug elimination rate. In this context, we were concerned whether reducing the dose of ETV due to renal impairment might adversely impact its antiviral efficacy, and the result from this study was reassuring. Although these preliminary data appeared promising, the small sample size and retrospective nature of our study limit a definitive conclusion on the efficacy and tolerability of ETV and its long-term clinical impact in KTR. In summary, the results in this study suggested that ETV is well tolerated in KTR, and allograft function was stable after three yr of ETV treatment. In treatment-na€ıve subjects, ETV treatment was highly effective in suppressing HBV viral load, which was accompanied by normalization of ALT. ETV treatment suppressed HBV DNA to undetectable levels in approximately half of the patients with prior LAM resistance, and the improvement in liver biochemistry was comparable to treatmentna€ıve patients, although ETV resistance subsequently developed in about 20% of patients. Acknowledgement Dr. Susan Yung is supported by the funding from Yu Chiu Kwong Professorship in Medicine awarded to Prof. Tak Mao Chan.
References 1. CHAN TM, FANG GX, TANG CS, CHENG IK, LAI KN, HO SK. Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology 2002: 36: 1246. 2. PIRSON Y, ALEXANDRE GP, YPERSELE C. Long-term effect of HBS antigenemia on patient survival after renal transplantation. N Engl J Med 1977: 296: 194. 3. PARFREY PS, FORBES RD, HUTCHINSON TA et al. The clinical and pathological course of hepatitis B liver disease in renal transplant recipients. Transplantation 1984: 37: 461. 4. HARNETT JD, ZELDIS JB, PARFREY PS et al. Hepatitis B disease in dialysis and transplant patients. Further epidemiologic and serologic studies. Transplantation 1987: 44: 369. 5. BANG BK, YANG CW, YOON SA et al. Prevalence and clinical course of hepatitis B and hepatitis C liver disease in ciclosporin-treated renal allograft recipients. Nephron 1995: 70: 397. 6. PARFREY PS, FORBES RD, HUTCHINSON TA et al. The impact of renal transplantation on the course of hepatitis B liver disease. Transplantation 1985: 39: 610. 7. FORNAIRON S, POL S, LEGENDRE C et al. The long-term virologic and pathologic impact of renal transplantation on chronic hepatitis B virus infection. Transplantation 1996: 62: 297. 8. CHAN TM, WU PC, LI FK, LAI CL, CHENG IK, LAI KN. Treatment of fibrosing cholestatic hepatitis with lamivudine. Gastroenterology 1998: 115: 177.
Entecavir in HBV+ kidney transplantation 9. DURLIK M, GACIONG Z, ROWINSKA D et al. Long-term results of treatment of chronic hepatitis B, C and D with interferon-alpha in renal allograft recipients. Transpl Int 1998: 11(Suppl 1): S135. 10. ROSTAING L, MODESTO A, BARON E, CISTERNE JM, CHABANNIER MH, DURAND D. Acute renal failure in kidney transplant patients treated with interferon alpha 2b for chronic hepatitis C. Nephron 1996: 74: 512. 11. FILIK L, KARAKAYALI H, MORAY G et al. Lamivudine therapy in kidney allograft recipients who are seropositive for hepatitis B surface antigen. Transplant Proc 2006: 38: 496. 12. YAP DY, TANG CS, YUNG S, CHOY BY, YUEN MF, CHAN TM. Long-term outcome of renal transplant recipients with chronic hepatitis B infection-impact of antiviral treatments. Transplantation 2010: 90: 325. 13. FABRIZI F, DULAI G, DIXIT V, BUNNAPRADIST S, MARTIN P. Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: meta-analysis of clinical trials. Transplantation 2004: 77: 859. 14. CHAN TM, TSE KC, TANG CS, LAI KN, HO SK. Prospective study on lamivudine-resistant hepatitis B in renal allograft recipients. Am J Transplant 2004: 4: 1103. 15. DAUDE M, ROSTAING L, SAUNE K et al. Tenofovir therapy in hepatitis B virus-positive solid-organ transplant recipients. Transplantation 2011: 91: 916. 16. TSE KC, YAP DY, TANG CS, YUNG S, CHAN TM. Response to adefovir or entecavir in renal allograft recipients with hepatitic flare due to lamivudine-resistant hepatitis B. Clin Transplant 2010: 24: 207. 17. KRUMMEL T, PARVEZ-BRAUN L, FRANTZEN L et al. Tenofovir-induced acute renal failure in an HIV patient with normal renal function. Nephrol Dial Transplant 2005: 20: 473. 18. LAMPERTICO P, VIGANO M, FACCHETTI F et al. Long-term add-on therapy with adefovir in lamivudine-resistant kidney graft recipients with chronic hepatitis B. Nephrol Dial Transplant 2011: 26: 2037. 19. LAI HW, CHANG CC, CHEN TH, TSAI MC, CHEN TY, LIN CC. Safety and efficacy of adefovir therapy for
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lamivudine-resistant hepatitis B virus infection in renal transplant recipients. J Formos Med Assoc 2012: 111: 439. YUEN MF, SETO WK, FUNG J, WONG DK, YUEN JC, LAI CL. Three years of continuous entecavir therapy in treatment-naive chronic hepatitis B patients: VIRAL suppression, viral resistance, and clinical safety. Am J Gastroenterol 2011: 106: 1264. TENNEY DJ, ROSE RE, BALDICK CJ et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 2009: 49: 1503. SHERMAN M, YURDAYDIN C, SIMSEK H et al. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 2008: 48: 99. NANKIVELL BJ, GRUENEWALD SM, ALLEN RD, CHAPMAN JR. Predicting glomerular filtration rate after kidney transplantation. Transplantation 1995: 59: 1683. HO SK, YAM WC, LEUNG ET et al. Rapid quantification of hepatitis B virus DNA by real-time PCR using fluorescent hybridization probes. J Med Microbiol 2003: 52: 397. HU TH, TSAI MC, CHIEN YS et al. A novel experience of antiviral therapy for chronic hepatitis B in renal transplant recipients. Antivir Ther 2012: 17: 745. LAI CL, SHOUVAL D, LOK AS et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006: 354: 1011. CHANG TT, GISH RG, DE MAN R et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006: 354: 1001. KAMAR N, MILIOTO O, ALRIC L et al. Entecavir therapy for adefovir-resistant hepatitis B virus infection in kidney and liver allograft recipients. Transplantation 2008: 86: 611. FONTAINE H, VALLET-PICHARD A, CHAIX ML et al. Efficacy and safety of adefovir dipivoxil in kidney recipients, hemodialysis patients, and patients with renal insufficiency. Transplantation 2005: 80: 1086. MATTHEWS SJ. Entecavir for the treatment of chronic hepatitis B virus infection. Clin Ther 2006: 28: 184.
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Clin Transplant 2014: 28: 1010–1015 DOI: 10.1111/ctr.12410
Clinical Transplantation
Entecavir treatment in kidney transplant recipients infected with hepatitis B Yap DYH, Yung S, Tang CSO, Seto WK, Ma MKM, Mok MMY, Kwan LPY, Chan GCW, Choy BY, Yuen MF, Chan TM. Entecavir treatment in kidney transplant recipients infected with hepatitis B. Abstract: Although nucleotide/side analogs improve the clinical outcome of hepatitis B surface antigen-positive (HBsAg+) kidney transplant recipients (KTR), a significant proportion of subjects have developed resistance to lamivudine (LAM). We retrospectively analyzed the efficacy and tolerability of entecavir (ETV) in HBsAg+ KTR at Queen Mary Hospital during 2005–2013. Twenty-one patients (10 treatment-na€ıve, 11 with LAM resistance) were included (duration of ETV treatment 34.7 22.9 months, range 6–75 months). ETV treatment led to a decline of hepatitis B virus (HBV) DNA titer compared to baseline and is more significant in the treatment-na€ıve group (treatment-na€ıve: p = 0.028, 45 U/L for women lasting over six months. Circulating HBV DNA level was measured with
Normally distributed continuous variables were expressed as mean standard deviation and compared with paired or unpaired t-test, while non-normally distributed ones were expressed as median and range and analyzed with Wilcoxon or Mann–Whitney test. Categorical data were expressed as frequencies and percentages and compared with chi-squared test. Longitudinal data between groups were compared using Wilcoxon rank-sum test and intragroup comparison of paired variables by Wilcoxon signed-ranks test. Patient and graft survival, time-to-undetectable HBV DNA, and time-to-ALT normalization were estimated by Kaplan–Meier method. Data analyses were generated by SPSS for windows version 18 (SPSS, Chicago, IL, USA) and Prism version 5 (San Diego, CA, USA), and p-values were two-sided.
Results Patient characteristics
Twenty-one HBsAg+ KTR (10 treatment-na€ıve and 11 with LAM-resistant HBV infection) were included (Table 1). Two patients were excluded in this study (one due to concomitant HCV infection and one due to chronic alcoholism). The duration
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Yap et al. Table 1. Characteristics of 21 ETV-treated HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance Treatment-na€ıve (n = 10) Age (yr) 54.6 5.7 Sex (F/M) 3/7 Previous mode of 8/2 dialysis (PD/HD) Type of kidney transplant Deceased donor 5 Live donor 5 Duration of follow-up after transplantation (months) 184.7 141.2 Immunosuppressive treatment at initiation of ETV (baseline) Prednisolone 10 CYA 5 TAC 2 MMF 4 AZA 1 mTOR inhibitors 1 Baseline HBeAg status () 2/8 Baseline ALT (U/L) 45.0 (25.0–361.0) Baseline HBV DNA (copies/mL) 1.2 9 105 (1.7 9 102–1.6 9 108) Baseline serum creatinine level (lM) 173.8 136.8
LAM-resistant (n = 11)
Overall (n = 21)
50.3 5.1 2/9 7/4
52.3 5.7 5/16 15/6
7 4 180.7 89.3
12 9 182.6 113.9
11 9 1 3 1 1 2/9 36.0 (14.0–46.0) 1.2 9 106 (7.3 9 103–2.7 9 107) 150.2 67.3
21 14 3 7 2 2 4/17 37.0 (14–361) 9.6 9 105 (1.7 9 102–1.6 9 108) 161.4 104.0
AZA, azathioprine; HD, hemodialysis; mTOR inhibitor, mammalian target of rapamycin inhibitors; PD, peritoneal dialysis.
of follow-up after initiation of ETV was 34.7 22.9 months (treatment-na€ıve 24.9 24.5 months, LAM-resistant 43.5 18.1 months, p = 0.061). ETV treatment was not interrupted during follow-up and was continued at the time of writing. Nineteen (65.5%) patients had ETV treatment for more than 12 months and 11 (45.8%) patients for more than 24 months. The actual dose of ETV administered was 0.43 0.12 mg/d in treatment-na€ıve subjects and 0.66 0.34 mg/d in the LAM-resistant group. Effect of ETV treatment on HBV virological parameters
Baseline median HBV DNA level was 9.6 9 105 copies/mL (1.7 9 102–1.6 9 108 copies/mL) (treatment-na€ıve: 1.2 9 105 copies/mL [1.7 9 102–1.6 9 108 copies/mL]; LAM-resistant: 1.2 9 106 copies/ mL [7.3 9 103–2.7 9 107 copies/mL], p = 0.179) before ETV was started. Treatment with ETV led to a 3-log reduction of HBV DNA level after three months (Fig. 1). In the treatment-na€ıve group, HBV DNA dropped from 1.2 9 105 copies/ mL (1.7 9 102–1.6 9 108 copies/mL) to 1.2 9 102 copies/mL (0–1.4 9 102 copies/mL) after 12 months (p = 0.028) and became undetectable after 24 and 36 months (p < 0.001 for both, compared with baseline). In the LAM-resistant group, median HBV DNA decreased from 1.2 9 106 copies/mL (7.3 9 103–2.7 9 107 copies/mL) to 1.8 9 102 copies/mL (0–5.9 9 103 copies/mL), 7.0 9 102 copies/
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Fig. 1. Serial HBV DNA levels after ETV treatment in 21 HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance.
mL (0–1.4 9 103 copies/mL), and 1.3 9 102 copies/mL (0–1.3 9 103 copies/mL) after 12, 24, and 36 months, respectively (p = 0.273, 0.180, and 0.109, respectively compared with baseline). Treatment-na€ıve patients had significantly lower HBV DNA levels compared with the LAM-resistant group at 12, 24, and 36 months (p = 0.039, 0.048, and 0.036, respectively). Cumulative rate of undetectable HBV DNA was 60%, 100%, and 100% in
Entecavir in HBV+ kidney transplantation treatment-na€ıve patients and 27%, 45%, and 45% for LAM-resistant patients, at 12, 24, and 36 months, respectively. Time-to-undetectable HBV DNA was 15.7 4.6 months in treatment-na€ıve patients and 24.5 4.2 months in LAM-resistant patients (p = 0.230). Serial HBV DNA levels did not differ between patients receiving standard dose of ETV and those given renal-adjusted doses (p = 0.564). No virological breakthrough was observed in treatment-na€ıve patients. In the LAMresistant group, two patients had resurgence of HBV DNA after 20.0 3.5 months, and both were confirmed to have genotypic ETV resistance. Four patients (two treatment-na€ıve and two LAM-resistant) were HBeAg+ at baseline and one sero-converted after 20 months. Effect of ETV treatment on liver biochemistry
Baseline median ALT level before ETV treatment was 45.0 U/L (25.0–361.0 U/L) and 36.0 U/L (14.0–46.0 U/L) for treatment-na€ıve and LAMresistant patients, respectively (p = 0.217). ALT level decreased after ETV treatment (Fig. 2). For treatment-na€ıve patients, the median ALT level decreased to 18.5 U/L (15.0–30.0 U/L), 18.0 U/L (17.0–21.0 U/L), and 18.0 U/L (12.0–24.0 U/L) after 12, 24, and 36 months, respectively (p = 0.002, 0.041, and 0.047 compared with baseline). For LAM-resistant patients, the median ALT level decreased to 26.0 U/L (6.0–51.0 U/L), 17.0 U/L (13.0–56.0 U/L), and 15.5 U/L (12.0– 83.0 U/L) after 12, 24, and 36 months, respectively
Fig. 2. Serial ALT levels after ETV treatment in 21 HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance.
(p = 0.094, 0.215, and 0.195 compared with baseline). Ninety percent of patients achieved normal liver biochemistry. ALT levels did not differ between treatment-na€ıve and LAM-resistant patients at 12, 24, and 36 months (p = 0.335, 0.363, and 0.470, respectively). Mean time-to-ALT normalization was 12.6 3.7 months in treatment-na€ıve patients and 28.2 3.5 months in the LAM-resistant group (p = 0.317). ALT levels did not differ between patients receiving standard dose and those on renal-adjusted dose of ETV (p = 0.512). In patients who developed ETV resistance, the ALT level increased from 13.5 4.9 to 42.0 28.2 U/L. Clinical outcomes and ETV tolerability
One patient had chronic active hepatitis despite ETV treatment for 36 months, which was not associated with ETV resistance. None of the patients showed de novo clinically evident cirrhosis or liver tumor during follow-up. Four patients died – three from pneumonia and one from pancreatic cancer. The patient survival rate after 12, 24, and 36 months was 90%, 90%, and 90%, respectively, for treatment-na€ıve patients and 100%, 100%, and 86%, respectively, for LAM-resistant patients (p = 0.643). Serum creatinine and eGFR at 36 months did not differ significantly from baseline (161.4 104.0 and 136.8 46.5 lM, respectively, p = 0.401; 53.0 23.6 and 56.7 22.5 mL/min/ 1.73 m2, respectively, p = 0.426; Fig. 3). The graft survival rate was 100%, 100%, and 100%, respectively, at 12, 24, and 36 months for both groups.
Fig. 3. Serial serum creatinine levels after ETV treatment in 21 HBsAg+ KTR including 10 subjects without prior antiviral treatment and 11 patients who had received prior treatment with LAM and had developed drug resistance.
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Yap et al. Discussion
ETV is a potent nucleoside analog that is effective in suppressing the replication of wide-type and LAM-resistant HBV (20, 22). There are limited data regarding the use of ETV in immunosuppressed KTR, especially in the setting of LAM resistance. Our results showed that ETV treatment was effective and well tolerated in these patients. Suppression of HBV replication by ETV was more effective in treatment-na€ıve patients compared with those who had LAM resistance. The high efficacy in treatment-na€ıve KTR was in line with the experience in the general population (25–27). Suppression of HBV DNA was accompanied by biochemical improvement. Normalization of transaminase levels occurs within a few months of treatment and was sustained for at least three yr, without emergence of drug resistance (20). The latter presents a distinct advantage compared with LAM (1, 12, 14). As LAM was the first oral nucleoside analog available, there is a significant number of HBsAg+ KTR who have developed LAM resistance. Before the availability of alternative nucleoside/tide analogs, it was the practice to continue with LAM treatment despite the emergence of drug resistance. Subsequently, combined adefovir and LAM treatment or substitution with tenofovir was the recommended treatment (15, 16, 28, 29). However, both adefovir and tenofovir are nephrotoxic and have been associated with allograft dysfunction (17–19). In contrast, ETV is non-nephrotoxic. Our current data demonstrated that ETV can be considered as treatment for KTR with LAM resistance, especially in patients with impaired renal allograft function, as it resulted in clinically meaningful viral suppression and improvement in liver biochemistry. The latter can occur despite persistence of HBV DNA at a detectable level. Here, we observed a difference in treatment response between treatment-na€ıve and LAM-resistant patients. Whether such discrepancy might be related to host or viral factors remains speculative. In this context, ETV also demonstrated higher efficacy in treatmentna€ıve patients than LAM-resistant patients in the general population (20–22). Nevertheless, the emergence of ETV resistance remains a concern (22), and whether the resistance rate might increase further with longer follow-up requires further investigation. While liver-related morbidities and mortality were not observed during ETV treatment for approximately three yr, further data are required on the long-term outcomes. ETV is predominantly eliminated by renal excretion (62–73%) (30).
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Therefore, we down-adjusted the ETV dose in patients with impaired renal allograft function in view of the reduced drug elimination rate. In this context, we were concerned whether reducing the dose of ETV due to renal impairment might adversely impact its antiviral efficacy, and the result from this study was reassuring. Although these preliminary data appeared promising, the small sample size and retrospective nature of our study limit a definitive conclusion on the efficacy and tolerability of ETV and its long-term clinical impact in KTR. In summary, the results in this study suggested that ETV is well tolerated in KTR, and allograft function was stable after three yr of ETV treatment. In treatment-na€ıve subjects, ETV treatment was highly effective in suppressing HBV viral load, which was accompanied by normalization of ALT. ETV treatment suppressed HBV DNA to undetectable levels in approximately half of the patients with prior LAM resistance, and the improvement in liver biochemistry was comparable to treatmentna€ıve patients, although ETV resistance subsequently developed in about 20% of patients. Acknowledgement Dr. Susan Yung is supported by the funding from Yu Chiu Kwong Professorship in Medicine awarded to Prof. Tak Mao Chan.
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