Title: Long-Term Outcome of Hepatitis B-Positive Renal Allograft Recipients after
Development of Antiviral Treatment
Authors: Kyung Sun Park1, Duck Jong Han2, Jae Berm Park2, Jung Sik Park1, Su-Kil Park1
1 Division of Nephrology, Department of Internal Medicine, University of Ulsan College of
Medicine, Asan Medical Center
2 Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center
KSP participated in research design, performed research, data analysis and wrote article; DJH
and JBP helped design research and provided urine and blood samples from kidney
transplantation candidates; JSP participated in research design; SKP participated in research
design, data analysis and project supervisor.
The authors declare no conflict of interest.
There is no funding source.
Word counts of Abstract and Text are 200 and 2692, respectively.
There are 2 Tables and 3 Figures.
Running Title: Long-term outcome of HBV-positive renal recipients
Correspondence: Su-Kil Park, MD, PhD.
Division of Nephrology, Department of Internal Medicine
University of Ulsan college of Medicine, Asan Medical Center
388-1 Poongnap-2 dong, Songpa-gu, Seoul, 138-736, South Korea
Phone: +82-2-3010-3263; Fax: +82-2-3010-6963; E-mail: skpark@amc.seoul.kr
1
ABSTRACT
Background/Aims: Hepatitis B virus (HBV) infection can adversely affect the clinical
outcome of kidney transplantation (KT). Short-term efficacy of lamivudine has been
demonstrated for chronic hepatitis B in KT recipients (KTR).
Methods: To clarify the long-term impact of antiviral treatment for HBV-positive KTR, we
retrospectively reviewed 94 HBV-positive (male 73%) and 282 age-sex matched HBVnegative patients who underwent KT from February 1997 to November 2009, after
lamivudine had come into wide use.
Results: Mean follow-up was 75.7 months. Fifty-six patients received antiviral agent for
prophylaxis, and other 18 for HBV reactivation. During follow-up, 15 died, with 5 deaths
being HBV related. Although the patient survival rate was lower for HBV-positive than HBVnegative KTRs (89% vs. 94% at 5 years, 78% vs. 88% at 10 years, p=0.031), graft survival
was comparable (86% vs. 92% at 5 years, 73% vs. 81% at 10 years, p=0.113). Of the 26
hepatitis B e antigen (HBeAg)-positive patients, 14 experienced HBV reactivations, but all
survived with stable liver chemistry, except for one who died of hepatocellular carcinoma.
Among 57 HBeAg-negative patients, 12 died, whereas the remaining 45 survived without
hepatic dysfunction.
Conclusion: Long-term outcomes of HBV-positive KTRs may be favorable after antiviral
agents have been introduced.
Keywords: Hepatitis B, Kidney transplantation, Lamivudine
2
Short summary
We clarified the long-term outcomes of hepatitis B-positive renal allograft recipients who
underwent transplantation after antiviral agents had come into wide use in a relatively large
cohort with long duration after kidney transplantation. Treatment of hepatitis B-positive renal
allograft recipients with antiviral agents still resulted in lower patient survival rates in
HBsAg-positive than in HBsAg-negative KT recipients. However, graft survival was not
adversely affected by HBV infection.
3
INTRODUCTION
Hepatitis B virus (HBV) infection has been recognized as a major concern for kidney
transplantation (KT). Immunosuppressive therapy after KT enhances viral replication and
may lead to liver-related complications, including chronic active hepatitis, cirrhosis and
hepatocellular carcinoma (HCC), thus increasing the morbidity and mortality of renal
allograft recipients (KTRs) [5, 7, 8, 15, 16, 18, 20]. Liver biopsy has been recommended for
HBV-positive patients to identify high risk patients for hepatic decompensation after KT [19].
If the biopsy shows severe hepatitis or cirrhosis, KT is not recommended [11]. Although KT
is usually acceptable in patients with mild hepatitis, HBV infection is associated with a
significant risk of hepatic failure after KT in these patients.
Lamivudine, the (-) enantiomer of 2’-3’ dideoxy-3’-thiacytidine, is a potent inhibitor of
HBV replication [14] and is a safe and effective therapy for chronic hepatitis B (CHB) in
KTRs [9, 13, 17, 21]. Preemptive or prophylactic treatment with lamivudine before hepatic
dysfunction has shown favorable outcomes in KTRs, including reduction in viral load,
improvements in liver chemistry and prevention of permanent histological deterioration [2, 6].
Other agents used to treat CHB after KT include adefovir, a nucleotide analogue of adenosine
monophosphate, and entecavir, a carbocyclic analogue of 2’-deoxyguanosine [22, 23].
However, these uncontrolled studies assessed only short-term outcomes after transplantation.
The long-term impact of these antiviral agents in HBV-positive KTRs has not been clarified.
We therefore retrospectively investigated the long-term outcomes of HBV-positive KTRs
who underwent KT after antiviral agents had come into wide use, focusing on changes in
liver chemistry and serological viral markers, such as HBV DNA and hepatitis B e antigen
(HBeAg). We also evaluated patient and graft survival compared with HBV-negative KTRs.
PATIENTS AND METHODS
4
This study was approved by the institutional review board of Asan Medical Center, which
has obtained certification from FERCAP (Forum for Ethical Review Committees in Asia and
the Western Pacific).
Populations
Since 1997, lamivudine has been used at our center to treat HBV-positive KTRs. The case
records of the 1863 patients who underwent KT between February 1997 and November 2009
at Asan Medical Center were reviewed; among these, 102 (5.5%) tested positive for hepatitis
B surface antigen (HBsAg) before transplantation. After exclusion of 8 patients who
underwent kidney-liver co-transplantation, 94 subjects (69 males, 73%) were included. To
compare patient and graft survival, we selected as a control group 282 age- and sex-matched
HBV-negative patients who underwent KT after 1997.
Data collection
Data were obtained from the electronic medical recording system of Asan Medical Center.
Data collected included baseline demographic characteristics, biochemical liver profile,
serological viral markers such as HBsAg, HBeAg, antibody against HBeAg (anti-HBe), HBV
DNA and antibody against hepatitis C virus (anti-HCV), induction and maintenance
immunosuppression, acute rejection episodes, date and cause of death and date of graft loss.
HBsAg, HBeAg and anti-HBe were measured by immunoradiometric assays. HBV DNA titer
in serum was measured by hybridization or real-time polymerase chain reaction (PCR). A
serum concentration of HBV DNA of > 0.5 pg/mL determined by hybridization or > 50
copies/mL HBV DNA determined by real-time PCR was considered a positive result.
Baseline liver histology was obtained for most of the patients immediately before
transplantation.
5
Definitions
Prophylaxis in this study means that the serum alanine aminotransferase (ALT)
concentrations is normal when the antiviral drug is prescribed at the time of transplantation,
which includes post treatment cases before transplantation. HBV reactivation was defined as
an increase of serum ALT two times greater than the upper limit of normal with new
appearance of HBV DNA or more than 2-log elevation of HBV DNA titer without other
cause of hepatic dysfunction such as alcohol, medication or toxin. Biochemical response
(BCR) to antiviral treatment was defined as decreased serum ALT within normal limits (< 40
IU/L). HBeAg seroconversion was defined as the clearance of HBeAg and the appearance
anti-HBe. HBeAg reversion was defined as the reappearance of lost HBeAg. Acute rejection
was considered when clinically suspected or biopsy-proven. Patient death with functioning
kidney was included in graft loss.
Antiviral treatment
Lamivudine (100 mg daily) was used as the initial therapy before adefovir or entecavir was
available. Patients who had developed HBV reactivation with suspicion of lamivudine
resistance were maintained on lamivudine before the availability of adefovir or entecavir.
After these agents were available, these patients were added on adefovir (10 mg daily) or
switched to entecavir (1 mg daily), after consultation with a hepatologist. Dosages were
adjusted according to allograft function.
Antiviral prophylaxis was at the discretion of each clinician because there were no clear
guidelines for prophylaxis of HBV-positive KTRs. Moreover a patient’s finances were crucial
because prophylactic antiviral agents for HBV-positive KTRs are not covered by health
insurance in Korea.
6
Lamivudine resistance
The most common mutation that causes lamivudine resistance involves the substitution of
methionine in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the HBV DNA
polymerase by valine or isoleucine rtM204V/I, the so-called ‘YMDD mutation’[14]. Direct
sequencing of HBV DNA and PCR–restriction fragment length polymorphism (RFLP)
analysis were used to detect lamivudine resistance.
Immunosuppression
Patients were administered 500 mg methylprednisolone intravenously during surgery and
were then tapered. Maintenance immunosuppression consisted of low-dose prednisolone and
cyclosporine or tacrolimus and azathioprine or mycophenolate mofetil. Acute rejection was
treated with intravenous methylprednisolone.
Statistical analysis
All statistical analyses were performed with SPSS software (Statistical Package for the
Social Science, version 18.0). Quantitative and qualitative variables were compared using
Student’s t-test and Chi-square test. Patient and graft survival were analyzed using the
Kaplan-Meier method and compared using the log rank test. A p-value < 0.05 was considered
statistically significant.
RESULTS
Baseline Characteristics
The mean age of the 94 HBV-positive patients was 40.5 years, and the mean follow-up was
75.7 months ranging from 1 to 162 months (Table 1). None of these patients was positive for
7
anti-HCV. At transplantation, 26 patients were positive and 57 were negative for HBeAg,
whereas no information was available for the other 11. In addition, 32 were positive and 51
were negative for HBV DNA, with no information available for the other 11. Mean serum
ALT was 19.4 IU/L. Liver biopsies were performed in 71 patients, with histology showing
mild inflammation in 67, moderate to severe hepatitis in 2 and cirrhosis in 2. Of the 94
patients, 52 received antiviral prophylaxis, 48 with lamivudine and 4 with entecavir, just
before transplantation and 4 were receiving antiviral treatment, 3 with lamivudine and 1 with
entecavir, for HBV reactivation that had occurred before transplantation. Both patients with
cirrhosis were prescribed antiviral prophylaxis, 1 with lamivudine and 1 with entecavir.
Seventy patients received renal grafts from living donors and 24 from deceased donors.
Twenty one donors (7 living, 14 deceased) were positive for HBsAg.
Patient and Graft survival
During follow-up, 15 patients died, 5 of HBV-related causes. The 5- and 10-year survival
rates of these patients were 89% and 78%, respectively (Fig. 1A). Graft losses developed in
19 patients, with 5- and 10-year graft survival rates of 86% and 73%, respectively (Fig. 1B).
The log rank test showed that patient survival rate was significantly lower in HBV-positive
patients than in HBV-negative controls (p = 0.031) but that graft survival rates were
comparable (p = 0.113).
Subgroup analysis of patient and graft survival according to donor HBV positivity, recipient
HBeAg and HBV DNA positivity, and antiviral prophylaxis was performed. The 10-year
survival rates of patients who received allograft from HBV-positive and HBV-negative
donors were 55% and 83%, respectively (p = 0.985), and the 10-year graft survival rates were
39% and 80% (p = 0.404), respectively. Moreover, there was no significant difference in
patient and graft survival rates between subgroups that did and did not receive antiviral
8
prophylaxis. Interestingly, HBeAg-positive and HBV DNA-positive subjects had better
outcomes than HBeAg-negative and HBV DNA-negative patients, respectively. This may be
resulted from significantly younger age of HBeAg-positive patients (42 vs. 36, p = 0.007). In
multivariate analysis, HBeAg and HBV DNA were not significant factor for patient and graft
survival. The 5- and 10-year survival rates of each subgroup are summarized in Table 2.
Outcomes of hepatitis B virus infection
Of the 26 HBeAg-positive patients, 14 were receiving antiviral prophylaxis at
transplantation (Fig. 2). HBV reactivation occurred in 8 at a mean 46.0 months (range, 7 to
140 months) after transplantation. Four of these had the YMDD mutation and were switched
to adefovir. Of these, 3 achieved BCR, at 1, 5 and 10 months after HBV reactivation,
respectively, and the fourth showed no further progression of hepatic dysfunction. The
remaining 4 patients who were maintained on first-line agents achieved BCRs 3, 6, 6 and 6
months after HBV reactivation, respectively. Eighty months after KT, 1 of these 4 patients
acquired HBeAg clearance without seroconversion. Although YMDD mutation was also
detected in two other patients who did not experience HBV reactivation, they were
maintained on lamivudine. Their liver chemistry remained stable for 70 and 139 months,
respectively.
Twelve HBeAg-positive patients did not receive antiviral prophylaxis. Of these, 6 showed
HBV reactivation at a mean 61.3 months (range, 9 to 107 months) after KT. After lamivudine
treatment, all showed BCR, at a mean 10.7 months, (range 4 to 23 months) after reactivation.
Two patients experienced a second episode of HBV reactivation due to the YMDD mutation.
Both were switched to adefovir and achieved a second BCR. One patient was diagnosed with
HCC 96 months after KT and died 17 months later. During a mean follow-up of 99 months
(range, 1 to 162 months) after KT, 25 HBeAg-positive patients survived without hepatic
9
failure or HCC.
Of 57 HBeAg-negative patients, 35 were started on antiviral prophylaxis (Fig. 3). HBV
reactivation occurred in 14 of these 35 patients at a mean 39.1 months (range 3 to 102
months) after KT. The YMDD mutation was detected in 11 of these patients, who were
switched to adefovir or entecavir. BCRs were observed in 13 patients at a mean 4.9 months
(range 1 to 16 months) after reactivation. Three patients died of hepatic failure at 20, 90 and
105 months after KT, respectively. Two patients experienced second episodes of HBV
reactivation, at 20 and 100 months after KT, respectively. After management with adefovir or
entecavir, their hepatic function remained stable. HCC developed in 2 patients at 4 and 31
months after KT. One died of cytomegalovirus pneumonia, whereas the second remains alive.
Another 4 patients died of pulmonary thromboembolism, postoperative complications and
pneumonia, at 2, 8, 8 and 68 months after KT, respectively. On this progress, 4 patients
experienced HBeAg reversion and 1 patient showed HBsAg clearance.
Of 22 HBeAg-negative patients who did not receive antiviral prophylaxis, 14 experienced
HBV reactivation at a mean 10.3 months (range 3 to 46 months) after KT. After treatment
with lamivudine or entecavir, all showed BCR, at a mean 6.2 months (range 2 to 28 months)
after reactivation. Four experienced a second episode of HBV reactivation, at 14, 40, 41 and
63 months, respectively, after KT. Of these, 1 died 75 months after KT and the other 3
patients have survived without hepatic dysfunction. An additional 3 subjects also died, at 7,
45 and 132 months after KT. Three patients showed HBeAg reversion, at 6, 12 and 32 months,
respectively, after KT.
Of 11 patients for whom data about HBeAg were not available, 7 received lamivudine
prophylaxis. Of these, 1 patient experienced HBV reactivation 24 months after KT due to a
YMDD mutation. This patient showed a BCR after treatment with adefovir for 10 months.
Two patients died at 2 and 43 months after KT.
10
DISCUSSION
We found that HBsAg was present in 5.5% of KTRs, similar to that of the general
population in Korea [12]. The outcome of HBV-positive KTRs has been unclear. Prior to the
development of lamivudine, HBV infection was reported to have a negative effect on KT.
After transplantation, immunosuppressive agents can activate HBV proliferation, resulting in
chronic hepatitis, liver cirrhosis and HCC [7, 15, 16, 20], contributing to poor patient and
graft survival in KTRs [5, 8, 18]. After the introduction of antiviral agents such as lamivudine,
adefovir and entecavir, the clinical courses of these patients have changed. Lamivudine has
shown short-term efficacy on suppression of HBV replication and normalization of ALT for
reactivated CHB after transplantation [2, 6, 9, 13, 17, 21]. Indeed, we found that 13 of 14
HBeAg-positive and 27 of 28 HBeAg-negative patients with HBV reactivation achieved
BCRs to antiviral agents.
Preemptive or prophylactic treatment with lamivudine before hepatic dysfunction has also
been shown effective [2, 6]. Patients who received preemptive or prophylactic therapy had a
significantly lower recurrence of hepatitis B viremia (1/10 for 24 months) than untreated
patients or patients treated only after HBV reactivation (3/6 for 48 months) [6]. Moreover,
preemptive lamivudine not only showed virologic and biochemical efficacy but also
improved the survival of HBV-positive KTRs [2]. We found, however, that HBV reactivation
occurred in 8 of 14 HBeAg-positive (mean duration 46.0 months) and 14 of 35 HBeAgnegative patients (mean duration 39.1 months) who received antiviral prophylaxis and that
antiviral prophylaxis did not affect patient or graft survival. Because our patients were
followed-up for much longer time after transplantation, our findings suggest that antiviral
prophylaxis is less effective in the long-term prevention of HBV reactivation and
improvement of long-term survival after transplantation. Moreover, we found that 4 of 13
11
HBeAg-positive and 11 of 30 HBeAg-negative patients who received lamivudine prophylaxis
developed YMDD mutations. In this respect, more potent drugs with less resistance such as
adefovir, entecavir or tenofovir might be more attractive for long-term prophylactic use.
There are several studies described the efficacy of these agents for HBV-positive KTRs [3, 4,
10]. However these are small and larger prospective studies are needed to clarify the longterm efficacy and safety of these agents for HBV-positive KTRs.
Long-term improvements in patient and/or graft survival of HBV-positive KTRs have also
been observed [1, 2, 24]. For example, HBV-positive patients had similar renal allograft
survival and reduced patient survival rates compared with HBV-negative controls [2]. In
addition, the 10-year patient and graft survival rates of lamivudine-treated HBV-positive
recipients were comparable to those of HBV-negative patients, although all HBV-positive
recipients showed lower 10-year patient and graft survival rates than HBV-negative patients
[1]. Another recent study in China showed similar results, in that antiviral treatment was
associated with significantly improved patient survival, although survival rates were lower in
HBV-positive than in HBV-negative subjects transplanted during the same period [24]. In
comparison, we found that the 10-year patient and graft survival rates of HBV-positive KTRs
transplanted after 1997 were 78% and 73%, respectively. Although patient survival rates were
lower than in HBV-negative controls, graft survival rates became comparable after antiviral
agents were introduced.
Our findings also showed information about the long-term natural history of CHB after KT,
especially in liver chemistry and changes in HBV serology. In a report involving 151 HBVpositive KTRs [5], the rates of HBsAg and HBeAg clearance over a mean 125 months (range,
1 to 320 months) were 3% and 30%, respectively, suggesting that immunosuppressive agents
may decrease the rate of clearance of HBsAg and HBeAg and may increase the rate of
HBeAg reversion. According to the 2007 American Association for the Study of Liver
12
Disease practice guidelines of chronic hepatitis B [14], the annual rates of clearance of
HBeAg and HBsAg in the general HBV-positive population are 8-12% and 0.5%,
respectively. Moreover, approximately 4% to 20% of inactive carriers will experience HBeAg
reversion. We found that only 1 of 26 HBeAg-positive patients experienced HBeAg clearance
80 months after transplantation without HBeAg seroconversion. Seven patients showed
HBeAg reversion at a mean 25.1 months, (range 4 to 70 months) after transplantation.
HBsAg clearance was observed in only 1 patient 73 months after transplantation.
In conclusion, treatment of HBV-positive KTRs with antiviral agents still resulted in lower
patient survival rates in HBV-positive than in HBV-negative KTRs. However, graft survival
was not adversely affected by HBV infection. Furthermore, we clarified the long-term natural
history of HBV-positive KTRs in a relatively large cohort with long duration after
transplantation. Further investigations are needed to assess the relationship between
prophylactic or preemptive therapy with newer antiviral agents and long-term survival,
especially regarding the incidence of antiviral resistance.
13
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17
Mean age; years (SD)
Sex, male
HBsAg(+)
HBsAg(-)
n = 94
n = 282
40.5 (10.6)
40.4 (11.5)
0.928
69
207
1.000
75.7 (1-162)
78.6 (1-163)
0.624
70
220
0.478
P
Duration of transplant;
months (range)
Donor
living
mean age; years (SD)
40.5 (9.5)
sex; male
49
HBsAg; positive
21
0
6
0
0
0
HBV DNA; positive
anti-HCV; positive
HBeAg; positive
26
HBV DNA; positive
32
Mean ALT; IU/L (SD)
19.4 (11.4)
Liver biopsy; available
71
mild
67
moderate to severe
2
cirrhosis
2
0
Antiviral agent
lamivudine
51
entecavir
5
Table 1. Baseline demographic and clinical characteristics of the study population
18
Table 2. Patient and graft survival rates
Patient survival (%)
5 year
All
89
10 year
Graft survival (%)
p
78
5 year
86
Donor HBV
10 year
73
0.985
0.404
positive
100
55
87
39
negative
88
83
88
80
HBeAg
0.019
0.033
positive
92
92
100
87
negative
87
71
79
64
HBV DNA
0.031
0.091
positive
97
97
90
84
negative
86
71
82
67
Antiviral prophylaxis
0.137
0.726
received
87
66
83
74
not received
94
86
91
76
19
p
Figure legends
Figure 1 Patient (A) and graft (B) survival rates of HBsAg-positive renal allograft recipients
compared with age/sex-matched HBsAg-negative controls.
Figure 2 Clinical outcomes of HBeAg-positive renal transplant recipients.
*1 patient showed HBeAg clearance without seroconversion 80 months after renal
transplantation.
Figure 3 Clinical outcomes of HBeAg-negative renal recipients.
†2 patients developed HBeAg reversion, with 1 showing HBeAg seroconversion 25 months
after reversion.
‡2 patients developed HBeAg reversion.
*3 patients developed HBeAg reversion, with 1 showing HBeAg seroconversion 16 months
after reversion.
§1 patient was treated with adefovir in place of lamivudine due to a YMDD mutation, and 1
was treated with entecavir in place of adefovir.
₤10, 2 and 2 patients received lamivudine, entecavir and conservative therapy, respectively.
€2 and 2 patients were treated with lamivudine and adefovir, respectively.
¶1 patient showed HBsAg loss 73 months after renal transplantation.
20