- Email: [email protected]
Clinical and Virologic Courses of Hepatitis B Surface Antigen-Negative and Hepatitis B Core or Hepatitis B Surface Antibody-Positive Renal Transplant Recipients
Clinical and Virologic Courses of Hepatitis B Surface Antigen-Negative and Hepatitis B Core or Hepatitis B Surface Antibody-Positive Renal Transplant Recipients K. Nishimura, H. Kishikawa, Y. Yoshida, N. Ueda, S. Nakazawa, K. Yamanaka, T. Hirai, and Y. Ichikawa ABSTRACT Recent findings suggest that reactivation of hepatitis B (HB) virus (HBV) in renal transplantation recipients with a past HBV infection is an important cause of morbidity and mortality. In the present study, we reviewed the clinical and virologic courses of past HBV infections in recipients following renal transplantation. We retrospectively analyzed pretransplant HB surface antigen (HBsAg), HB core antibody (HBcAb), HB surface antibody (HBsAb), and HBV deoxyribonucleic acid (DNA) levels in 147 patients who underwent renal transplantation at our institution between September 2000 and November 2011. Thirty-four (23.1%) of the patients were diagnosed with a past HBV infection. The mean age of patients with a past HBV infection was significantly older than that of those without (48.4 vs 41.1 years, P ⫽ .002), while the duration of hemodialysis (HD) was significantly longer (138 vs 79.5 months, P ⫽ .027) and ratio of cadaveric transplantation procedures was higher (41.2% vs 21.2%, P ⫽ .035). During the follow-up period after renal transplantation, HBsAg was negative, HBV DNA was undetectable, and serum alanine aminotransferase level was normal in all patients. There were no statistically differences for graft and patient survival, and serum creatinine level between patients with and without a past HBV infection. Our results indicate that a past HBV infection is significantly associated with older age, longer duration of HD, and cadaveric transplantation. However, no HBV reactivation occurred in our previously infected patients, and the presence of HBcAb or HBsAb positivity did not influence graft or patient survival or renal function following renal transplantation. ELL-ESTABLISHED EVIDENCE showing the possible development of life-threatening complications from hepatitis B (HB) virus (HBV) reactivation after renal transplantation has been presented, while the risk of that reactivation in recipients showing a serologic pattern of past HBV infection [HB surface antigen (HBsAg)-negative and HB core or HB surface antibody (HBcAb or HBsAb)positive] has recently been emphasized.1,2 The purpose of this study was to retrospectively analyze the clinical and virologic courses of recipients with a past HBV infection following renal transplantation.
W
MATERIALS AND METHODS We retrospectively analyzed pretransplant HBsAg, HBcAb, HBsAb, and HBV deoxyribonucleic acid (DNA) levels in 147 patients who underwent renal transplantation at our institution between September 2000 and November 2011. The mean age at transplantation was 42.8 years (19 –73) and the mean follow-up period after
transplantation was 60.5 months (0 –135). We evaluated clinical outcomes and clinicovirologic factors associated with HBV reactivation in those patients after renal transplantation.
RESULTS
Thirty-four (23.1%) of the patients were diagnosed with a past HBV infection. At the time of transplantation, 12, 5, and 17 were positive for HBcAb, HBsAb, and both, respectively, while HBV DNA was undetectable in all. Furthermore, the mean levels of alanine aminotransferase (ALT) From the Department of Kidney Transplantation Center, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Hyogo, Japan. Address reprint requests to Kenji Nishimura, MD, PhD, Department of Renal Transplantation Center, Hyogo Prefectural Nishinomiya Hospital, 13-9, Rokutanji-cho, Nishinomiya, 6620918, Japan. E-mail: [email protected]
0041-1345/13/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.01.093
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1600
Transplantation Proceedings, 45, 1600 –1602 (2013)
HEPATITIS B AND TRANSPLANT RECIPIENTS
1601
Table 1. Comparison of Clinical Backgrounds Between Patients With and Without Past HBV Infection
Age (y) Sex (male/female) Post-transplant follow-up duration (mo) Duration of dialysis (mo) Living donor (%) HCV-positive (%) Calcinurin inhibitor (number of TAC/CyA) Transfusion (%) Diabetes melitus (%) Mean serum creatinine (mg/dL)
for graft and patient survival and serum creatinine level between patients with and without a past HBV infection (Fig. 1).
Past HBV Infection (n ⫽ 34)
No Past HBV Infection (n ⫽ 113)
P Value
48.4 19/15 57.1
41.1 75/38 62
.002 .36 .55
138 0.59 5.9 18/16
79.5 0.79 9.4 60/53
.027 .035 .73 .99
32.4 11.8 1.5
29.2 16.8 1.49
.89 .66 .66
DISCUSSION
In other reports, HB has been suggested to be clinically resolved in patients even when showing a serologic pattern indicating a past HBV infection. However, those patients have recently been recognized to be latently infected with an episomal form of HBV accompanied by ongoing viral replication and a few nucleotide mutations in the precore and core regions.3 Reactivation of HBV infection in such patients has been reported to occur in association with immunosuppressive therapy, while some cases have been shown to have fulminant forms of HBV infection.4 Berger et al reported that 228 of 1512 renal recipients were diagnosed with resolved HBV infection; reactivation of HBV infection after renal transplantation was observed in 2 (0.9%).2 Blanpain et al suggested that the incidence of HBV reactivation among patients with anti-HBs and antihepatitis B core antibodies is about 5%.5 In the present study, no incidence of reactivation of HBV infection in 34 with a past HBV infection of 147 renal recipients was found, and those patients also maintained normal liver enzyme levels. Moreover, there were no statistically differences for graft and patient survival and serum creatinine level between patients with and without a past HBV infection. Our findings suggest that the ratio of reactivation of HBV infection in renal transplantation recipients with a past HBV infection is low and that the prognoses of patient, graft, and liver function in those patients are not affected by such a past infection. Therefore, a favorable prognosis can
HBV, hepatitis B virus; HCV, hepatitis C virus; TAC, tacrolimus; CyA, cyclosporine.
were normal (13.6 IU/mL). A comparison of clinical backgrounds between patients with and without past HBV infection is shown in Table 1. The mean age of those with a past HBV infection was significantly older than that of those without a past infection (48.4 vs 41.1 years, P ⫽ .002), while the duration of hemodialysis (HD) was significantly longer (138 vs 79.5 months, P ⫽ .027) and the ratio of cadaveric transplantation procedures was higher (41.2% vs 21.2%, P ⫽ .035). There were no statistically significant differences regarding serum creatinine level between patients with and without a past HBV infection. During the follow-up period after renal transplantation, HBsAg was negative, HBV DNA was undetectable, and ALT level was normal in all patients. There were no significant differences
A
B
% 100
%
100
80
80 P=0.40
60 40
60 40
Past HBV infection
20
P=0.37
Past HBV infection
20
Non-past HBV infection
Non-past HBV infection
0
0 0
2 Fig 1.
4
6
8
10
year
0
2
4
6
8
Graft (A) and patient (B) survival with and without a previous hepatitis B virus (HPB) infection.
10
year
1602
be expected, though the possibility of reactivation must be kept in mind. During the clinical course of de novo related hepatitis after chemotherapy, serum ALT level was reported to be increased after 1 or more months after elevation of serum HBV-DNA level.6 Therefore, it is thought that severe hepatitis can be prevented from developing even if nucleoside antiviral agents are administered when HBV-DNA is determined using a TaqMan polymerase chain reaction (PCR) method once a month, as that method has a higher level of sensitivity. The Japanese guidelines for prevention of HBV infection reactivation induced by immunosuppressive therapy or chemotherapy in patients with a past HBV infection who develop an immunosuppressed state, such as renal transplantation recipients, recommend to measure HBV-DNA with the TaqMan PCR method once a month and also administer several oral nucleoside antiviral agents if HBV-DNA increases beyond the sensitivity of the assay.7 However, many renal recipients in Japan have a history of HBV infection, as confirmed in our study, in which 23.1% of our patients were diagnosed with a past HBV infection. We think that it is not realistic to monitor HBV-DNA once a month in such patients based on medical and economic considerations, but rather recommend about once every 3 months. In conclusion, our results indicate that past HBV infection is significantly associated with older age, longer dura-
NISHIMURA, KISHIKAWA, YOSHIDA ET AL
tion of HD, and cadaveric transplantation. Among the present patients, none experienced HBV reactivation, and positivity for HBcAb or HBsAb did not influence graft or patient survival or renal function following renal transplantation. REFERENCES 1. Chaubo C, Hot A, Chevallier-Queyron P, et al. Kidney transplant and cryptic hepatitis. Lancet. 2009;373:2082. 2. Berger A, Preiser W, Kachel HG, et al. HBV reactivation after kidney transplantation. J Clin Virol. 2005;32:162. 3. Marusawa H, Uemoto S, Hijikata M, et al. Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology. 2000;31:488. 4. Borentain P, Colson P, Coso D, et al. Clinical and virological factors associated with hepatitis B virus reactivation in HBsAgnegative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer. J Viral Hepat. 2010;17:807. 5. Blanpain C, Knoop C, Delforge ML, et al. Reactivation of hepatitis B after transplantation in patients with pre-existing antihepatitis B surface antigen antibodies: report on three cases and review of the literature. Transplantation. 1998;66:883. 6. Hui CK, Cheung WW, Zhang HY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006;131:59. 7. Tsubouchi H, Kumada H, Kiyosawa K, et al. Prevention of immunosuppressive therapy or chemotherapy-induced reactivation of hepatitis B virus infection-joint report of the intractable liver diseases study group of Japan and the Japanese study group of the standard antiviral therapy for viral hepatitis. Kanzo. 2009;50:38.
W
MATERIALS AND METHODS We retrospectively analyzed pretransplant HBsAg, HBcAb, HBsAb, and HBV deoxyribonucleic acid (DNA) levels in 147 patients who underwent renal transplantation at our institution between September 2000 and November 2011. The mean age at transplantation was 42.8 years (19 –73) and the mean follow-up period after
transplantation was 60.5 months (0 –135). We evaluated clinical outcomes and clinicovirologic factors associated with HBV reactivation in those patients after renal transplantation.
RESULTS
Thirty-four (23.1%) of the patients were diagnosed with a past HBV infection. At the time of transplantation, 12, 5, and 17 were positive for HBcAb, HBsAb, and both, respectively, while HBV DNA was undetectable in all. Furthermore, the mean levels of alanine aminotransferase (ALT) From the Department of Kidney Transplantation Center, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Hyogo, Japan. Address reprint requests to Kenji Nishimura, MD, PhD, Department of Renal Transplantation Center, Hyogo Prefectural Nishinomiya Hospital, 13-9, Rokutanji-cho, Nishinomiya, 6620918, Japan. E-mail: [email protected]
0041-1345/13/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2013.01.093
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1600
Transplantation Proceedings, 45, 1600 –1602 (2013)
HEPATITIS B AND TRANSPLANT RECIPIENTS
1601
Table 1. Comparison of Clinical Backgrounds Between Patients With and Without Past HBV Infection
Age (y) Sex (male/female) Post-transplant follow-up duration (mo) Duration of dialysis (mo) Living donor (%) HCV-positive (%) Calcinurin inhibitor (number of TAC/CyA) Transfusion (%) Diabetes melitus (%) Mean serum creatinine (mg/dL)
for graft and patient survival and serum creatinine level between patients with and without a past HBV infection (Fig. 1).
Past HBV Infection (n ⫽ 34)
No Past HBV Infection (n ⫽ 113)
P Value
48.4 19/15 57.1
41.1 75/38 62
.002 .36 .55
138 0.59 5.9 18/16
79.5 0.79 9.4 60/53
.027 .035 .73 .99
32.4 11.8 1.5
29.2 16.8 1.49
.89 .66 .66
DISCUSSION
In other reports, HB has been suggested to be clinically resolved in patients even when showing a serologic pattern indicating a past HBV infection. However, those patients have recently been recognized to be latently infected with an episomal form of HBV accompanied by ongoing viral replication and a few nucleotide mutations in the precore and core regions.3 Reactivation of HBV infection in such patients has been reported to occur in association with immunosuppressive therapy, while some cases have been shown to have fulminant forms of HBV infection.4 Berger et al reported that 228 of 1512 renal recipients were diagnosed with resolved HBV infection; reactivation of HBV infection after renal transplantation was observed in 2 (0.9%).2 Blanpain et al suggested that the incidence of HBV reactivation among patients with anti-HBs and antihepatitis B core antibodies is about 5%.5 In the present study, no incidence of reactivation of HBV infection in 34 with a past HBV infection of 147 renal recipients was found, and those patients also maintained normal liver enzyme levels. Moreover, there were no statistically differences for graft and patient survival and serum creatinine level between patients with and without a past HBV infection. Our findings suggest that the ratio of reactivation of HBV infection in renal transplantation recipients with a past HBV infection is low and that the prognoses of patient, graft, and liver function in those patients are not affected by such a past infection. Therefore, a favorable prognosis can
HBV, hepatitis B virus; HCV, hepatitis C virus; TAC, tacrolimus; CyA, cyclosporine.
were normal (13.6 IU/mL). A comparison of clinical backgrounds between patients with and without past HBV infection is shown in Table 1. The mean age of those with a past HBV infection was significantly older than that of those without a past infection (48.4 vs 41.1 years, P ⫽ .002), while the duration of hemodialysis (HD) was significantly longer (138 vs 79.5 months, P ⫽ .027) and the ratio of cadaveric transplantation procedures was higher (41.2% vs 21.2%, P ⫽ .035). There were no statistically significant differences regarding serum creatinine level between patients with and without a past HBV infection. During the follow-up period after renal transplantation, HBsAg was negative, HBV DNA was undetectable, and ALT level was normal in all patients. There were no significant differences
A
B
% 100
%
100
80
80 P=0.40
60 40
60 40
Past HBV infection
20
P=0.37
Past HBV infection
20
Non-past HBV infection
Non-past HBV infection
0
0 0
2 Fig 1.
4
6
8
10
year
0
2
4
6
8
Graft (A) and patient (B) survival with and without a previous hepatitis B virus (HPB) infection.
10
year
1602
be expected, though the possibility of reactivation must be kept in mind. During the clinical course of de novo related hepatitis after chemotherapy, serum ALT level was reported to be increased after 1 or more months after elevation of serum HBV-DNA level.6 Therefore, it is thought that severe hepatitis can be prevented from developing even if nucleoside antiviral agents are administered when HBV-DNA is determined using a TaqMan polymerase chain reaction (PCR) method once a month, as that method has a higher level of sensitivity. The Japanese guidelines for prevention of HBV infection reactivation induced by immunosuppressive therapy or chemotherapy in patients with a past HBV infection who develop an immunosuppressed state, such as renal transplantation recipients, recommend to measure HBV-DNA with the TaqMan PCR method once a month and also administer several oral nucleoside antiviral agents if HBV-DNA increases beyond the sensitivity of the assay.7 However, many renal recipients in Japan have a history of HBV infection, as confirmed in our study, in which 23.1% of our patients were diagnosed with a past HBV infection. We think that it is not realistic to monitor HBV-DNA once a month in such patients based on medical and economic considerations, but rather recommend about once every 3 months. In conclusion, our results indicate that past HBV infection is significantly associated with older age, longer dura-
NISHIMURA, KISHIKAWA, YOSHIDA ET AL
tion of HD, and cadaveric transplantation. Among the present patients, none experienced HBV reactivation, and positivity for HBcAb or HBsAb did not influence graft or patient survival or renal function following renal transplantation. REFERENCES 1. Chaubo C, Hot A, Chevallier-Queyron P, et al. Kidney transplant and cryptic hepatitis. Lancet. 2009;373:2082. 2. Berger A, Preiser W, Kachel HG, et al. HBV reactivation after kidney transplantation. J Clin Virol. 2005;32:162. 3. Marusawa H, Uemoto S, Hijikata M, et al. Latent hepatitis B virus infection in healthy individuals with antibodies to hepatitis B core antigen. Hepatology. 2000;31:488. 4. Borentain P, Colson P, Coso D, et al. Clinical and virological factors associated with hepatitis B virus reactivation in HBsAgnegative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer. J Viral Hepat. 2010;17:807. 5. Blanpain C, Knoop C, Delforge ML, et al. Reactivation of hepatitis B after transplantation in patients with pre-existing antihepatitis B surface antigen antibodies: report on three cases and review of the literature. Transplantation. 1998;66:883. 6. Hui CK, Cheung WW, Zhang HY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006;131:59. 7. Tsubouchi H, Kumada H, Kiyosawa K, et al. Prevention of immunosuppressive therapy or chemotherapy-induced reactivation of hepatitis B virus infection-joint report of the intractable liver diseases study group of Japan and the Japanese study group of the standard antiviral therapy for viral hepatitis. Kanzo. 2009;50:38.