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. Kiyici, M. Yilmaz, M. Akyildiz, C. Arikan, U. Aydin, D. Sigirli, D. Nart, F. Yilmaz, T. Ozacar, Z. Karasu,nd M. Kilic

ABSTRACT

Background/Aims. Hepatitis B virus (HBV) and hepatocellular carcinoma (HCC)recurrences affect both patient and graft survivals post–orthotopic liver transplantation(OLT) in HBV patients with HCC. We analyzed the relationship between HBV and HCCrecurrence in a large cohort of HBV-OLT patients with versus without HCC.Methods. Two hundred eighty-seven HBV patients with OLT (72 also with HCC) wereincluded in the study. Mean follow-up in the post-OLT period was 31.7 � 24.7 (range,3–119) months.Results. Post-OLT HBV recurrence observed in 10.1% of patients was more prevalentamong the HCC group; 23.6% versus 5.5% in patients with and without HCC, respectively.The mean interval for the development of HBV recurrence was 39.5 � 28.5 (range, 2–99)months. Among 72 HCC patients, 8 patients (11.1%) had recurrent HCC, and 7 of themalso had HBV recurrence. The mean interval for the development of HCC recurrence was11.2 � 7.85 (range, 2–23) months after OLT. OLT patients with HCC with tumorsexceeding the Milan criteria had worse 1-, 3-, and 5-year survival rates than patients withHCC meeting the Milan criteria. HBV and HCC recurrence-free survivals were signifi-cantly lower in patients with HCC and HBV recurrence, respectively. In the 7 patients withboth HCC and HBV recurrence, mean HBV recurrence time was 9.42 � 6.75 months andmean HCC recurrence time was 9.57 � 6.75 months. There was a strong correlationbetween HBV and HCC recurrence times. Cox proportional hazards regression analysisshowed that only HCC recurrence was a significant independent predictor of HBVrecurrence (P � .001; hazard ratio [HR] � 26.94; 95% confidence interval [CI] �10.81–67.11). On the other hand, HBV recurrence (P � .013; HR � 5.80; 95% CI �1.45–23.17) and nodule count (P � .014; HR � 13.08; 95% CI � 1.70–100.83) weresignificant predictors of HCC recurrence.Conclusions. HBV and HCC recurrences demonstrate a close relationship in patients

with OLT.

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IVER transplantation is the treatment of choice inadvanced cirrhotic patients with hepatocellular carci-

oma (HCC). In addition to eliminating the precancerousiver before development of de novo HCC foci, liverransplantation can cure the underlying liver disease. How-ver, survival after transplantation for HCC was disappoint-ng before the institution of the Milan criteria for selectingandidates for orthotopic liver transplantation (OLT).1

ith application of this policy, the overall survival is nowomparable, but perhaps slightly lower than that of patients

ithout HCC who undergo OLT.2 3

2008 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 40, 1511–1517 (2008)

In contrast, the outcomes of OLT for hepatitis B virusHBV)–related cirrhosis was dismal in the early 1990s withigh rates of reinfection with HBV (approximately 80%–00%) and 2-year survival rates of about 50%.3 Introduc-ion of effective therapies, such as hepatitis B immunoglob-

From the Ege University, Organ Transplantation Center, Izmir,urkey.Address reprint requests to Murat Kilic, Associate Professor,

ge University Medical Faculty, Organ Transplantation Center,

5100, Bornova, Izmir, Turkey. E-mail: murat.kilic@ege.edu.tr

0041-1345/08/$–see front matterdoi:10.1016/j.transproceed.2008.03.156

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1512 KIYICI, YILMAZ, AKYILDIZ ET AL

lin (HBIG) and antivirals (lamivudine, adefovir, andntecavir), revealed effective means to prevent HBV recur-ence and significantly improve the outcomes of OLT inBV patients.4

HBV infection is a leading cause of HCC worldwide, ie,pproximately 53% of HCC cases are related to HBV.5,6

In this study, we analyzed the relationship betweenecurrences of HBV and HCC among patients undergoingLT for HBV cirrhosis.

ATIENTS AND METHODSatients

wo hundred eighty-seven HBV patients (233 males [M], 54emales [F]; mean age, 47.8 � 8.37; range, 24–65 years) with OLTere included in the study. One hundred twenty of the transplan-

ations were performed from deceased donors and 167 from livingonors between April 1995 and January 2007. Within the studyohort, 50 patients (17.8%) had chronic hepatitis B � D and 6atients (2.1%) had chronic hepatitis B � C coinfections.There were 72 patients with HCC who were older than the

atients without HCC. There were no differences in the gender ortiology of cirrhosis between the 2 groups (Table 1).

mmunosuppression

enerally, the immunosuppressive regimen consisted of cal-ineurin inhibitors and steroids. Methyl-prednisolone 500 mg in-ravenous (IV) was given for the first day and the tapered from 100g to 10 mg in the following 2 months. Steroids were discontinuedithin 6 months to 1 year. Blood concentrations of tacrolimus andyclosporine were targeted to 10–15 ng/mL and 200–300 mg/mL inhe early postoperative period and 5–10 ng/mL and 100–200

Table 1. Characteristics of OLT Patients With andWithout HCC

ParametersPatients

Without HCCPatients With

HCC P

215 72ge (y) 41.9 � 6.78 52.3 � 6.52 .0001enderM/F (n) 172/43 61/11 .375

tiology of cirrhosis (n)Chronic hepatitis B 171 59 .847Chronic hepatitis B � D 39 12Chronic hepatitis B � C 5 1BV recurrence-positive

(n, %)12 (5.5) 17 (23.6) .00001

utcome: dead/alive 37/178 8/64 .218ean survival (months �

SEM)95.31 � 3.60 69.65 � 4.42 .276

urvival (%)1 y 85 95 .3453 y 83 905 y 82 68ilan criteria and 1-, 3-,

and 5-yr survival (%)Meeting Milan (n � 37) — 97/93/93 .042*Exceeding Milan (n � 35) 93/89/54

s*P indicates significance of survival between HCC patients meeting and

xceeding Milan criteria.

g/mL in the long-term, respectively. In case of acute cellularejection, the dose of calcineurin inhibitors was increased or pulseteroid (500 mg IV) treatment was administered. If calcineurinephrotoxicity/neurotoxicity was observed, either mycophenolateofetil was added to the regimen or the patients were switched to

irolimus.

BV Characteristics and Prophylaxis of Recurrence

reoperative HBeAg, anti-HBe, and qualitative HBV-DNA posi-ivity and serum quantitative HBV-DNA levels were not differentetween HBV recurrent and nonrecurrent patients (P � .05).Patients with positive HBV-DNA prior to OLT received lami-

udine (100 mg/d) or lamivudine � adefovir (10 mg/d) combinationn cases of lamivudine resistance. After OLT, patients receivedamivudine and/or adefovir � low-dose HBIG combination. Allatients were given 4000 IU HBIG in the anhepatic phase in theperating room followed by 800–1600 IU intramuscular (IM) or500 IU IV. HBIG daily until serum hepatitis B surface antigenHBsAg) became negative and antibody to hepatitis B surfacentigen (anti-HBs) became positive with titer of � 200 IU/L.ong-term follow-up of serum anti-HBs was performed at weekly

and then monthly) intervals and minimum serum titer of anti-HBsas kept �50 IU/L. Lamivudine (and adefovir) were continued

ndefinitely. Reappearance of serum HBsAg was accepted as HBVecurrence criteria. Adefovir (10 mg/d) was added to the treatmentn recurrent HBV patients.

ollow-up for HCC Recurrence

ll HCC patients were investigated for extra-hepatic spread ofumor preoperatively using whole-body computerized tomography/agnetic resonance imaging (CT/MRI) and bone scan. Milan

riteria, which were used before January 2002 to select HCCatients for liver transplantation, included a single tumor not �5m in diameter, or less than 3 tumors with the largest not �3 cm,nd no invasion of blood vessels or lymph nodes.1 University ofalifornia San Francisco (UCSF) criteria were used after January002 and included a single tumor not �6.5 cm, or less than 3umors with the largest not �4.5 cm and a total tumor burden lesshan 8 cm in diameter.7 After OLT, patients were regularlyollowed up at the outpatient clinic. Liver ultrasonography anderum �-fetoprotein (AFP) levels were monitored every 3 monthsn the first year; follow-up intervals were extended to every 6

onths in the second year post-OLT. Whole-body CT/MRI andone scan were repeated whenever HCC recurrence was suspected.iagnosis of recurrent HCC was confirmed with biopsy.

efinitions of End-Points

he following definitions were used as end-points in the presenttudy: outcome, proportion of all deaths due to any cause toemaining living patients in the long-term follow-up after OLT;CC recurrence, diagnosis of recurrent HCC at the graft or

xtra-hepatic sites during follow-up; and HBV recurrence, reap-earance of HBsAg after initial disappearance from serum ofatients with HBV-related OLT.

tatistical Analyses

ll data entry and statistical analyses were performed with SPSSor Windows version 13 (SPSS, Chicago, Ill, United States). Theumeric categorical variables were compared using Pearson chi-

quare test, whereas nonparametric continuous data were com-

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HEPATITIS B AND HCC 1513

ared using Mann-Whitney U test. Cox regression analysis waserformed to determine the parameters predicting HBV recur-ence. A receiver operator characteristics (ROC) analysis waserformed to determine the discriminative abilities of parameterso predict HBV recurrence. Continuous and normally distributedata were represented as mean values � standard deviations withalues of P � .05 considered statistically significant.

ESULTSubjects

e retrospectively analyzed records of 287 HBV-OLTatients. Mean follow-up for the post-OLT period was1.7 � 24.7 (range, 3–119) months.

BV Recurrence

ost-OLT HBV recurrence was observed among 10.1% ofatients. The mean interval for the development of HBVecurrence was 39.5 � 28.5 (range, 2–99) months. HBVecurrence rates at 1, 2, 3, and 5 years were 2.0%, 3.8%,.5%, and 8.3%, respectively. HBV recurrence was morerevalent in the HCC group. HBV recurrence rates were3.6% versus 5.5% in patients with versus without HCC,espectively (Table 1).

CC Characteristics and Recurrence

mong 72 HCC patients, 8 patients (11.1%) displayedecurrent HCC. Among these 8 patients, 7 also had HBVecurrence (Fig 1). There were no differences in meanatient age or gender between HCC recurrence-negativend recurrence-positive groups. The mean HCC noduleount was higher and the mean HCC nodule size was largern the recurrent HCC patients. Tumor stages were compa-able between recurrent and nonrecurrent patients. Fur-hermore, there were more patients with poor tumor dif-erentiation and major vascular invasion in the recurrentCC group. Patients were then analyzed according toilan and UCSF criteria for HCC. Patients with tumors

xceeding these 2 systems tended to have HCC recurrence,lthough only Milan criteria reached statistical significance.inally, as expected, recurrent HCC patients demonstratedpoorer prognosis with a higher rate of mortality (Table 2).

ig 1. Flow diagram of frequencies of HCC and HBV recur-

aences in patients with OLT.

The mean interval for the development of HCC recur-ence in the study cohort was 11.2 � 7.85 (range, 2–23)onths after OLT and HCC recurrence rates at 1 and 2

ears were 5.5% and 11.1%, respectively.

utcome and Survival

verall survivals at 1, 3, and 5 years were 88%, 85%, and0%, respectively. Outcomes, overall mean survival ratesnd 1-, 3-, and 5-year survival rates were comparableetween patients with versus without HCC. In contrast,LT patients with HCC in whom the tumors exceeded theilan criteria showed worse 1-, 3-, and 5-year survival rates

han patients with HCC meeting the Milan criterial (Table 1).Patients with HCC exceeding the Milan criteria were

etermined to have more frequent recurrences than pa-ients with HCC meeting the Milan criteria. Although nottatistically significant, the same was observed for patientsith HCC exceeding the UCSF criteria. Outcomes wereoor in recurrent HCC patients (Table 2).Post-OLT survival analysis of patients with HBV-related

irrhosis with HCC revealed that neither HCC nor HBVelapse affected overall patient survivals significantly (Fig 2nd 3). In contrast, HBV and HCC recurrence-free surviv-ls were significantly different in patients with HCC versusBV recurrence (Figs 4 and 5).

actors Predicting HCC and HBV Recurrence

n 7 patients with both HCC and HBV recurrence, meanBV recurrence time was 9.42 � 6.75 months and meanCC recurrence time was 9.57 � 6.75 months. Two patients

howed HBV recurrence first (2nd vs 3rd and 7th vs 13thonths) and 2 patients had HCC recurrence first (12th vs

5th and 2nd vs 5th months). The remaining 3 patients hadBV and HCC recurrence in the same month (3rd, 16th,

nd 18th months). Correlation analysis demonstrated atrong correlation between HBV and HCC recurrenceimes (P � .016; r � 0.847; Fig 6).

Cox regression analysis was performed to determinehether age, gender, etiology of cirrhosis, or HCC recur-

ence predicted HBV recurrence. Cox regression modelncluding age, gender, etiology of cirrhosis, and HCCecurrence was significant (P � .001). Cox proportionalazards regression analysis showed that only HCC recur-ence was a significant independent predictor of HBVecurrence (P � .001; hazard ratio [HR] � 26.94; 95%onfidence interval [CI] � 10.81–67.11), whereas age, gen-er, and etiology of cirrhosis were not significant (P � .05).he HR is the relative risk attributable to an increase by 1nit in the level of a prognostic variable; hence, it can betated that HCC recurrence increases the risk of HBVecurrence 26.94-fold.

ROC analysis was performed to determine the discrimi-ative abilities of HCC nodule size and count to predictCC recurrence. Optimal cut-off value was 3.5 cm for

odule size (P � .03; area under the curve [AUC] � 0.68)

nd 5 for nodule count (P � .03; AUC � 0.68). Variables

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1514 KIYICI, YILMAZ, AKYILDIZ ET AL

ere then entered into multivariate analysis after categori-ation according to their cut-off values.

Backward stepwise Cox regression analysis was per-ormed for HCC recurrence. Age, gender, etiology ofirrhosis, nodule size and count, meeting Milan and UCSFriteria, and HBV recurrence were taken as independentariables. The final Cox regression model included meetingCSF criteria, nodule size/count, and HBV recurrence.ox proportional hazards regression analysis showed thatBV recurrence (P � .013; HR � 5.80; 95% CI �

.45–23.17) and nodule count (P � .014; HR � 13.08; 95%I � 1.70–100.83) were significant predictors of HCC

ecurrence, whereas age, gender, etiology of cirrhosis, nod-le size, and meeting Milan and UCSF criteria were notredictors (P � .05).

ISCUSSION

majority of the adult liver transplantations in Turkey aressociated with cirrhosis secondary to chronic hepatitis B.8

he mean prevalence of chronic hepatitis B is approxi-ately 6.9% in the general population. It is also a major

ause of HCC in this country. HBV recurrence after liverransplantation is universal in the absence of adequate

Table 2. Tumor Characte

Parameters HCC Recurrence-Ne

o. of patients 64atient age (y) 47.6 � 8.42ender (M/F) 54/10o. of nodules (n, %)1 23 (36)2–3 17 (27)�4 24 (37)

ize of largest tumor (cm) (n, %)�2 26 (40)2.1–5.0 32 (50)5.1–6.5 5 (8)�6.6 1 (2)

umor stage (n, %)T1 11 (17)T2 4 (6)T3 30 (47)T4 19 (30)

umor differentiation (n, %)Well 18 (28)Moderate 37 (58)Poor 9 (14)

ascular invasion (n, %)No 40 (63)Yes 24 (37)ilan criteria (n, %)Meeting/exceeding 37 (58)/27 (42CSF criteria (n, %)Meeting/exceeding 38 (59)/26 (41utcome (n, %)Alive 58 (91%)Dead 6 (9%)

rophylaxis, which today is generally instituted as long-term s

BIG plus lamivudine/adefovir combination. Posttrans-lantation. HBV recurrence has been reported in the

iterature to be approximately 4%–10%.9,10 Our HBVecurrence rates were comparable to reported rates in theiterature, but it is obvious that HBV recurrences are up to

times more prevalent among patients with HCC afterLT. This is important, because HBV recurrence shows a

egative impact on both patient and graft survivals. Theumulative corticosteroid dose and the chemotherapy usedor HCC have been demonstrated to be risk factors forBV recurrence.4 However, the same corticosteroid doseas used in both recurrent and nonrecurrent patients andhemotherapy was not instituted in HCC patients in theresent study.Post-OLT survivals among patients with HBV with and

ithout HCC was previously demonstrated to be similar,11

hich was also observed in the present study (data nothown). In the literature, some of the factors associatedith HCC recurrence included the presence of cirrhosis,

umor size �5 cm, more than 5 nodules, vascular infiltra-ion, and male gender.12 Tumor staging was reported as onef the most important predictive factors for patient out-ome,13 which supports the usage of the Milan criteria to

s of Patients With HCC

HCC Recurrence-Positive P

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HEPATITIS B AND HCC 1515

ately 10%–60% of HCC patients have recurrences afterLT.14,15 In accordance with this literature, the results of

he present study showed that HBV and HCC recurrenceslosely correlated among post-OLT patients and that recur-ences of HBV and HCC reduced HCC and HBV recurrence-ree survivals, respectively. Correlation analysis demonstratedstrong correlation between HBV and HCC recurrence times

P � .016; r � 0.847) (Fig 6). HbsAg positivity may indicateumor recurrence as well as HBV recurrence in patientsndergoing OLT for HBV-associated HCC. Undetectableicrometastatic HCC cells can repopulate and may induce

he recurrence of both HBV and HCC after liver transplan-ation. Ou et al reported a similar relationship betweenBV and HCC in non-OLT patients. In their study, 128CC recurrences were observed in 147 HBV patients and

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ecurrence. a

nly 8 HCC recurrences were observed in 15 non-HBVatients after hepatectomy (�2 � 11.501; P � .001).16

HBV interacts with the host hepatocyte after entrancento it. A replicative form of HBV DNA, termed covalentlylosed circular DNA (cccDNA), accumulates in the hepa-ocyte nuclei in chronic hepatitis B. It has also been recentlyemonstrated that cccDNA is the predominant form ofBV DNA in the tumor tissues.15

HBV integrates its viral genes into the host cell generallyuring acute hepatitis B.17 This integration can induceome important rearrangements and/or partial deletions inenes regulating cellular signal transduction, proliferation,nd viability.18 For example, it has been found recently thatuman telomerase reverse transcriptase, which is the majoreterminant of telomerase activity in human cells, is tar-eted in many HCCs associated with HBV infection.19,20 It

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nd without HBV recurrence.

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1516 KIYICI, YILMAZ, AKYILDIZ ET AL

s well documented that telomerase is associated withuman cell immortalization and oncogenesis.21 Other pro-osed mechanisms of development of HCC by integratedBV-DNA into host DNA are HBx gene and family ofreS2 activators. The HBx gene activates a variety ofifferent promoter elements and interferes with signalingascades, triggering activation of some transcription factors.urthermore, the HBx gene is involved in the control of cellycle, proliferation, and apoptosis. HBx protein is consid-red to be a crucial protein for HBV-associated carcino-enesis.22,23 Mutations in the HBx gene were determinedore frequently in HCC patients than in chronic hepatitis

atients.24,25 HBx genome encodes another family of pro-eins with regulatory function, the PreS2 activators. Theyind to and activate protein kinase C – a in the cytoplasm,hich in turn triggers a signal cascade that exerts a tumorromoter–like function,26 demonstrated in a transgenicouse model.27

HCC is a systemic disorder. AFP messenger RNAmRNA) is detected in bone marrow using polymerasehain reaction (PCR) analysis after curative hepatectomy inatients with HCC and, furthermore, it has been observedhat AFP mRNA in the bone marrow and systemic circu-ation during the perioperative period predict patient sur-ival and recurrence after curative hepatic resection28 andfter living donor liver transplantation29 for HCC.

Recurrences of HCC after liver transplantation occurver a wide range of times (43–3204 days). This wideormant phase suggests that tumor cells may persist in aormant state for long periods before becoming clinicallyvident.12

A new carcinogenic model for development of HCC haseen proposed. In this model, HCC (and gastric cancer) isroposed to derive from transdifferentiation of adult bone

ig 6. Correlation between HBV and HCC recurrence times inost-OLT patients with both HCC and HBV recurrence. Spear-an’s correlation coefficient (0.847) is significant at the 0.05 level

2-tailed).

arrow stem cells.30,31 Therefore, HCC recurrence afterhh

LT appears to be caused by metastatic cells that gondetected before surgery, and circulate before taking upesidence in the graft, or they may be derived from adultone marrow cells,32 which have the potential to differen-iate into mature hepatocytes and ultimately to HCC.

In conclusion, in this study we demonstrated a relation-hip between HBV and HCC recurrences in patients withLT. This observation was supported by several statistical

nalyses, including Cox regression analysis and correlationnd survival analysis. Based on our results, it is suggestedhat reappearance of HBsAg can be used as a surrogatearker for the development of HCC recurrence in OLT

atients with HBV and HCC.

CKNOWLEDGMENTS

e are thankful to Murat Cakir, MD, for his assistance in thetatistical analysis of this study.

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enesis. J Clin Virol 34(suppl 1):S75, 200523. Chan HL, Sung JJ: Hepatocellular carcinoma and hepatitisvirus. Semin Liver Dis 26:153, 200624. Fang ZL, Ling R, Wang SS, et al: HBV core promoterutations prevail in patients with hepatocellular carcinoma from

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11