Comparison of hepatitis B prophylactic outcomes in living donor liver transplantation recipients who meet the Milan or UCSF criteria

Chengdu, China

Comparison of hepatitis B prophylactic outcomes in living donor liver transplantation recipients who meet the Milan or UCSF criteria

Li Jiang, Lu-Nan Yan, Tian-Fu Wen, Bo Li and Jia-Yin Yang

Chengdu, China

BACKGROUND:The tumor burden before liver transplantation indicates that hepatitis B virus (HBV) may hide in the extrahepatic and micrometastatic sites which serve as a source of HBV replication. Currently, many liver transplant centers, especially in Western countries, use the Milan or UCSF criteria to select patients with hepatocellular carcinoma for liver transplantation. This study was undertaken to compare the HBV prophylactic outcomes in two groups of living donor liver transplantation (LDLT) recipients. Patients in group A met the Milan criteria and those in group B exceeded the Milan criteria but were within the UCSF criteria.

METHODS:A database of adult-to-adult right-lobe LDLT performed at our institution for HBV-related hepatocellular carcinoma within the Milan or UCSF criteria between June 2002 and May 2012 was used to compare the HBV prophylactic outcomes between patients within the Milan criteria (group A, 41 patients) and those exceeding the Milan criteria but within the UCSF criteria (group B, 19 patients).

RESULTS:The 1-, 3-, and 5-year survival rates were similar between groups A and B (87.8%, 85.1% and 74.0% vs 73.3%, 61.1% and 61.1%, respectively,P=0.067). HBV recurred in 1 patient in 3.1 months after LDLT in group A and in 2 patients in group B (1 in 11.9 months and 1 in 24.1 months after LDLT). The 1-, 3-, and 5-year HBV recurrence rates were 2.6%, 2.6% and 2.6% in group A, and 7.3%, 17.9% and 17.9% in group B, respectively (P=0.118).

CONCLUSION:LDLT recipients who exceed the Milan criteria but remain within the UCSF criteria may have post-transplantHBV prophylactic outcomes similar to those who meet the Milan criteria.

(Hepatobiliary Pancreat Dis Int 2013;12:494-499)

living donor;liver transplantation; hepatitis B virus; hepatocellular carcinoma; antiviral therapy

Introduction

Liver transplantation (LT) is a widely accepted treatment for patients with hepatocellular carcinoma (HCC). Prior to the introduction of the Milan criteria, the survival rate of patients undergoing LT for HCC was low, and the 5-year survival rate was less than 40%.[1,2]In 1996, Mazzaferro et al[3]proposed the Milan criteria (a single tumor ≤5 cm or a maximum of 3 tumors ≤3 cm), which showed a post-LT survival rate similar to that for those who undwent LT for nonmalignant liver diseases.[4]Yao et al[5]at the University of California, San Francisco later proposed the UCSF criteria (a single tumor ≤6.5 cm or a maximum of 3 tumors ≤4.5 cm or a cumulative tumor size ≤8 cm) for the expansion of the tumor size limits for LT. In selected patients based on the two criteria, both the 5-year survival rate and tumor-free survival rate exceeded 50%. Thus, many liver transplant centers, especially in Western countries, use the Milan or UCSF criteria to select patients with HCC for LT.

In China, chronic hepatitis B virus (HBV) infection is the primary cause of HCC, the overall prevalence of hepatitis B surface antigen (HBsAg) is about 7%.[6]Approximately half of the LTs were performed in patients with HCC, and 85% of whom were coinfected with HBV at LT. Prevention of HBV recurrence is essential after LT in these HBV-related HCC patients, since complete eradication of HBV after LT is rarelypossible.

Prophylactic use of lamivudine (LAM) and lowdose hepatitis B immunoglobulin (HBIG) is currently regarded as a cost-effective regimen, in which LAM, a nucleoside analogue, reduces HBV viral load whereas HBIG removes wild-type and possibly mutant HBV strains,[7]and has been accepted in many transplant centers. In our center, the post-LT HBV prophylaxis protocol comprises LAM and individualized low-dose intramuscular (IM) HBIG. The outcome of our regimen is very promising in deceased donor liver transplantation (DDLT) for HBV-related benign end-stage liver diseases (ESLDs) (excluding HCC).[8]However, compared with HBV-related benign ESLDs, the tumor burden prior to LT as well as lymphovascular invasion on the explants may indicate that HBV may hide in the extrahepatic and micrometastatic sites, which may serve as a source of HBV replication for HBV-related HCC recipients.

In an attempt to identify whether different selection criteria for HCC in transplantation had similar impacts on post-transplant HBV recurrence or not, we compared the prophylactic effects of our regimen on post-transplant HBV recurrence between the living donor liver transplantation (LDLT) recipients meeting the Milan criteria and those exceeding the Milan but within the UCSF criteria.

Methods

Patients

We used a database of adult-to-adult right-lobe LDLT procedure performed at our institution for HBV-related HCC between June 2002 and May 2012 for this analysis. Patients enrolled in our study had tumors within the Milan or UCSF criteria at LDLT and had no evidence of coinfection with hepatitis C, hepatitis D or human immunodef i ciency virus. Their pre-LDLT antiviral strategy was to use LAM according to the pre-LDLT HBV DNA level. Finally, a total of 60 consecutive adult patients were enrolled in this study. The patients were monitored until July 2012 or their death, and their medical records were retrospectively reviewed.

Study groups

According to the LT criteria for HCC, patients were divided into 2 groups: group A comprised those who met the Milan criteria; group B consisted of the patients who exceeded the Milan criteria but were within the UCSF criteria.

Clinical practice

Living donations were voluntary and altruistic in all cases. All procedures were approved by the Ethics Committee of West China Hospital and were in accordance with the ethical guidelines of theDeclaration of Helsinki. Before LDLT, both living donors and recipients were informed the anticipated morbidity and mortality rates based on our experience. We exclusively procured the right-lobe liver graft without the middle hepatic vein (MHV) when performing hepatectomy for a living donor. In principle, the requirement for graft to body weight ratio (GBWR) was ≥0.8%, and for residual donor liver volume was ≥40%.

Immunosuppression

A combination of cyclosporine- or tacrolimus- and mycophenolate-based immunosuppression was used. The tacrolimus dose was adjusted to 7-12 ng/mL for the fi rst postoperative month and 3-7 ng/mL thereafter. Cyclosporine dose ranged from 250 to 350 ng/mL for the fi rst postoperative month, followed by 100 to 180 ng/mL for the next 5 months, and then 50 to 150 ng/ mL thereafter. Prednisone was generally discontinued within 3 months after LDLT.

Hepatitis B prophylaxis protocol and hepatitis B evaluation

All patients were treated with a combination of HBIG (Yuandashuyang Pharmaceutical Co., Ltd., Chengdu, China) and LAM for HBV prophylaxis after LDLT. Two thousand international unit (IU) HBIG was administered intramuscularly during the anhepatic phase, followed by 800 IU daily for the next 6 days and weekly for the rest of 3 weeks in the fi rst postoperative month. According to the monitored serum antibody to hepatitis B surface antigen (anti-HBs), HBIG dose was adjusted thereafter to maintain anti-HBs titers >100 IU/ L. Detailed descriptions of our institutional hepatitis B prophylaxis protocol and hepatitis B evaluation process have been published in previous studies.[8,9]HBV recurrence was def i ned as the reappearance of either HBsAg or HBV DNA in the serum.

Statistical analysis

SPSS 17.0 statistical software (SPSS Inc., Chicago, IL, USA) was used to analyze the relevant data. Categorical data were presented as number (percent) and compared using the Chi-square test or Fisher's exact test. Continuous variables were expressed as mean±standard deviation (SD), and were analyzed using Student'sttest. Survival curves and HBV recurrence were estimated using the Kaplan-Meier method and differences among ordered categories were determined by the log-ranktest. The Cox proportional hazards model was used to test potential predictors of HBV recurrence after LDLT. Univariate results were reported as hazard ratios with 95% conf i dence intervals. AP<0.05 was considered statistically signif i cant.

Results

Characteristics of recipients and their donors

Forty-one patients with HCC meeting the Milan criteria were enrolled into group A, whereas 19 patients who exceeded the Milan criteria but were within the UCSF criteria were included in group B. The clinical features of recipients in both groups are shown in Table 1. The related data were not statistically signif i cant between the two groups. A total of 60 adult donors volunteered to donate their right-lobe liver graft without MHV. Their characteristics are shown in Table 2. The grafts of GBWR <0.8% were used in 2 recipients in group A and 2 in group B. Twenty-two (53.7%) donors in group A and 9 (47.4%) in group B were HBsAb positive. Six (14.6%) donors in group A and 2 (10.5%) in group B were positive for hepatitis B core antibody (HBcAb). No death occurred in the donors. Other related data were also not statistically signif i cant between groups A and B (Table 2).

Patient survival

Eight patients died (none died during the fi rst month after LDLT) during a mean follow-up period of 44.3±24.7 months (range 1.1-86.4) in group A and 7 died (including 2 patients who died during the fi rst month after LDLT) during a mean follow-up period of 29.1± 25.5 months (range 0.9-83.1) in group B. The leadingcauses of death for each group are shown in Table 3, and the survival curve for each group is shown in Fig. 1. The 1-, 3-, and 5-year survival rates were similar between groups A and B (87.8%, 85.1% and 74.0% vs 73.3%, 61.1% and 61.1%, respectively,P=0.067).

Table 1.Characteristics of transplanted patients

Table 2.Characteristics of living donors

Table 3.Leading causes of death for recipients

Fig. 1.Post-LDLT survival curves in groups A and B (log-rank test) (P=0.067).

Table 4.Clinical features of the patients with HBV recurrence after transplantation

Fig. 2.Cumulative probabilities of post-LDLT HBV recurrence in groups A and B (log-rank test) (P=0.118).

Fig. 3.Cumulative probabilities of post-LDLT HCC recurrence in groups A and B (log-rank test) (P=0.004).

HBV and HCC recurrence

During the follow-up period, HBV recurred in 1 patient (3.1 months after LDLT) in group A and 2 in group B (1 in 11.9 months and 1 in 24.1 months after LDLT). Cumulative probabilities of HBV recurrence in groups A and B were not statistically signif i cant (Fig. 2). The 1-, 3-, and 5-year HBV recurrence rates were 2.6%, 2.6% and 2.6% in group A, and 7.3%, 17.9% and 17.9% in group B, respectively (P=0.118). One of these 3 patients who showed recurrence of HBV died from severe pulmonary infection. Thyrosine-methionine-aspartate-aspartate (YMDD) mutants (rtM204V+rtL180M) were detected in 2 of the 3 recipients who experienced HBV recurrence. Details of these 3 patients with posttransplant HBV recurrence are listed in Table 4. In univariate analysis, the YMDD mutant after LDLT was found to be the predictive factor for post-transplant HBV recurrence (Table 5).

Table 5.Univariate analysis of factors associated with HBV recurrence after LDLT

During the follow-up period, 1 patient in group A and 4 in group B had HCC relapse after LDLT. The mean HCC recurrence time was 16.7±24.2 months (range 0.8-59.0) after LDLT. Group B had higher rates of HCC recurrence after transplantation than group A (Fig. 3). The 1-, 3-, and 5-year HCC recurrence rates were 0, 2.9% and 2.9% in group A, and 18.0%, 18.0% and 59.0% in group B, respectively (P=0.004). The 5 patients with recurred HCC had no HBV recurrence.Four patients with HCC recurrence died, and the remaining patient was alive at the time of analysis, or 2 months after the diagnosis of HCC recurrence.

Discussion

The role of HCC in post-transplant HBV recurrence has attracted more attention of researchers in recent years. Faria et al[10]in 2008 found that HCC was associated with HBV reinfection after LDLT. Recently, Xu et al[11]also reported a similar relationship between the presence of HCC at transplantation and post-transplant HBV recurrence. One potential theoretical explanation may be that a large tumor burden on the explants may hide the virus in extrahepatic and micrometastatic sites, which may serve as a factor for HBV reinfection.

Therefore, we exclusively investigated whether different selection criteria for HCC in LDLT had similar impacts on post-transplant HBV recurrence or not. As shown in Fig. 2, patients who met the Milan criteria had a rate of HBV recurrence after LDLT similar to those who exceeded the Milan but were within the UCSF criteria. Our study demonstrated that the UCSF criteria neither signif i cantly decreased the survival rate of recipients after LDLT nor increased the risk of HBV recurrence after transplantation, although the UCSF criteria represent a larger tumor burden than the Milan criteria.

There are different viewpoints about the predictive value of HBV DNA status at transplantation on HBV recurrence. Some studies[12-14]demonstrated that the level of viral replication before transplantation was an important predictor for prophylaxis success regardless of the prophylactic protocol. Marzano et al[12]suggested that the serum HBV DNA titers in active replicating patients should be less than 105copies/mL at transplantation in order to signif i cantly reduce the risk of HBV recurrence. On the other hand, others found that the high HBV DNA level before transplantation was not correlated with HBV recurrence after LT.[15-17]In our study, no signif i cant correlation was found between HBV DNA levels and HBV reinfection after LDLT. This may be related to the small sample size. In addition, it is noteworthy that the studies reporting a correlation between HBV DNA status and HBV recurrence after transplantation usually included other HBV-related ESLDs, such as decompensated liver cirrhosis and fulminant hepatitis B, not just HBV-related HCC. Therefore, the predictive effect of HBV DNA status of patients with HBV-related HCC on HBV recurrence after transplantation still needs further verif i cation by large prospective and controlled trials.

The predictive effect of pre-LDLT hepatitis B e antigen (HBeAg) status on HBV recurrence remains controversial. Steinmüller et al[16]found that HBV recurrence after transplantation was signif i cantly related to the preoperative HBeAg status. Patients in the HBeAg positive group had a higher recurrence rate than those in the HBeAg negative group. However, some studies did not fi nd this correlation.[15,18]In our study, no signif i cant difference was observed between the recipients with positive HBeAg and those with negative HBeAg.

Likewise, the inf l uence of HCC recurrence after transplantation on HBV recurrence is still controversial. Some studies[15,18,19]reported that HCC recurrence after transplantation was a stronger predictor of HBV reinfection. Wong et al[20]provided a theoretical foundation for this prediction that the covalently closed circular DNA, the main form of HBV DNA isolated from HCC tissues, suggesting that HBV replication also may occur in tumor cells. In addition, the occurrence of HBV replication at occult extrahepatic metastatic sites may lead to HBV reinfection. However, others[12,13,21]did not fi nd the association between HCC recurrence and HBV reinfection after transplantation. We did not fi nd a statistically signif i cant correlation between post-LDLT HCC recurrence and HBV reinfection.

LDLT may produce risk to living donors. No donor mortality was seen in our study. All the 8 donors with positive HBcAb did not experience fulminant hepatitis after hepatectomy. Our data showed that donor safety can be ensured, with acceptable outcomes for living donors.

Limitations of our study include its retrospective nature and relatively small sample size, which are important factors that should be considered to draw conclusions. Therefore, our arbitrary conclusion is that LDLT recipients who exceed the Milan but remain within the UCSF criteria may have HBV prophylactic outcomes and a survival rate after transplantation, similar to those who meet the Milan criteria. Larger, prospective, multi-center controlled trials, with longer follow-up periods, are needed to compare the prophylactic effects on HBV recurrence after transplantation between LDLT patients who meet the Milan criteria and those who meet the UCSF criteria. Nevertheless, to our knowledge this is the fi rst study to analyze the inf l uence of the different selection criteria for HCC in LDLT on HBV recurrence after transplantation. This study provides adequate preliminary data for future studies.

In conclusion, our study demonstrated that combined therapy with LAM and individualized lowdose IM HBIG provides a similar prophylactic effect onHBV recurrence after LDLT between patients who meet the Milan criteria and the UCSF criteria.

Contributors:YLN and LB proposed the study. JL and WTF performed research and wrote the fi rst draft. YJY collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. YJY is the guarantor.

Funding:This study was supported by a grant from the National Natural Science Foundation of China (81170456).

Ethical approval:All procedures were approved by the Ethics Committee of West China Hospital and were in accordance with the ethical guidelines of theDeclaration of Helsinki.

Competing interest:No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received November 22, 2012

Accepted after revision April 18, 2013

AuthorAff i liations:Liver Transplantation Center, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, China (Jiang L, Yan LN, Wen TF, Li B and Yang JY)

Jia-Yin Yang, MD, Liver Transplantation Center, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, China (Tel/Fax: 86-28-85422871; Email: yangjiayinhx@163. com)

© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(13)60078-8