Beijing, China

HBV recurrence lowered by lamivudine/HBIG combination therapy in liver transplant patients: ten-year experience

Chun-Hui Yuan, Dian-Rong Xiu, Bin Jiang, Zhi-Fei Li, Lei Li, Shi-Bing Song and Tong-Lin Zhang

Beijing, China

BACKGROUND:Lamivudine and hepatitis B immunoglobulin (HBIG) are widely used to treat patients with hepatitis B recurrence after liver transplantation. However, the outcomes are inconclusive. The present study was undertaken to evaluate the effect of combined therapy on patients with hepatitis B recurrence after liver transplantation.

METHODS:Twenty-two patients with hepatitis B recurrence after liver transplantation from August 2000 to October 2011 were enrolled in this study. Of these patients, 16 received lamivudine plus HBIG (combination therapy group) and 6 were treated with lamivudine alone (lamivudine-treated group). The clinical features were matched in the two groups. HBV recurrence parameters, HBsAg clearance rate, patient survival rate, and survival time were compared.

RESULTS:The average time of follow-up was 47.2 months (range 13-99). Signif i cant difference was noted in the HBsAg clearance rate in the lamivudine-treated and combination therapy groups (50% vs 93.8%,P<0.05). There was no signif i cant difference in the time of HBV recurrence, patient survival rate and survival time between lamivudine-treated and combination therapy groups (P>0.05).

CONCLUSION:Compared with lamivudine monotherapy, combination therapy signif i cantly increased the HBsAg clearance rate in patients with HBV recurrence after liver transplantation.

(Hepatobiliary Pancreat Dis Int 2013;12:149-153)

hepatitis B virus;recurrence; lamivudine; hepatitis B immunoglobulin; liver transplantation

Introduction

Hepatitis B virus (HBV) recurrence causes a deadly liver failure, which is one of the main factors leading to death of liver recipients.[1-3]Effective treatment for HBV recurrence can signif i cantly improve the survival of these patients.[4,5]It is well known that lamivudine and hepatitis B immunoglobulin (HBIG) are widely used to treat patients with hepatitis B recurrence after liver transplantation.[6,7]However, the outcomes in these patients treated with the combination of lamivudine and HBIG are not clear. The present study was undertaken to evaluate the eff i ciency of combination therapy with lamivudine and HBIG in patients with HBV recurrence after liver transplantation.

Methods

Three hundred and ninety-six patients with end-stage HBV-related liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC), underwent liver transplantation in the Liver Transplantation Center of Third Hospital, Peking University from August 2000 to October 2011. After the transplantation, liver function, serologic parameters and HBV DNA level were tested monthly in the fi rst 6 months, then every two months in the second 6 months, and then every 3 months. Hepatitis B serologies, including HBsAg, hepatitis B e antigen (HBeAg), and antibody to HBeAg (anti-HBe) were measured using commercially available enzymelinked immunosorbent assay. HBV DNA level was measured using transcription-mediated amplif i cation assay (TMA, SRL, Tokyo, Japan) or PCR assay (Amplicor HBV Monitor assay, SRL) and expressed as IU/mL. The sensitivity of the assay was approximately 500-5000 IU/mL.

HBV recurrence was def i ned as HBsAg positive or elevated HBV DNA (>104IU/L) level. Six patients withhepatitis B recurrence who were treated with lamivudine alone (100 mg/d, orally) and matched for clinical features were selected (lamivudine-treated group) as controls. Sixteen patients with hepatitis B recurrence received lamivudine plus HBIG therapy (lamivudine 100 mg/d and high dosage of HBIG, combination therapy group). The treatment was continued until plasma HBV DNA concentration less than 100 IU/L (Table 1). The combination therapy and lamivudinetreated groups were compared with respect to changes in HBV recurrence parameters, HBsAg clearance rate, patient survival rate, and survival time.

Table 1.Different treatments and prognosis of patients with HBV recurrence

Statistical analysis

Statistical analysis was performed with JMP software 5.01J (SAS Institute Inc., Cary, NY, USA). Continuous variables were expressed as mean±SD or median and range. Fisher's exact test, Student'sttest, and the Mann-WhitneyUtest were performed as appropriate. The survival rate was compared by the logrank test. All signif i cant levels were determined using two-tailed tests, andPvalues <0.05 were considered statistically signif i cant.

Results

Demographics and clinical data

Twenty-two patients (16 males and 6 females) were included in this study. Ten liver recipients had liver cirrhosis, eight had HCC, three had subacute severe hepatitis, and one had acute severe hepatitis pre-transplantation (Table 1). Eighteen patients were HBsAg positive, and 4 patients had elevated HBV DNA (>104IU/L) (Table 2). Eleven patients were HBsAg (+), HBV DNA (+); 7 patients were HBsAg (+), HBV DNA (-); 4 patients HBsAg (-), HBV DNA (+). The average age of the transplant recipients was 50.4 years (range 35-69). Details about the patient demographics and HBsAg clearance time are shown in Table 3.

HBV recurrence

The average time of HBV recurrence in lamivudinetreated and combination therapy groups were 11.3 and 17.3 months, respectively (P=0.208). Eleven patients with HBV recurrence had an ALT level twice above the upper limit of normality (normal <40 mmol/L). HBV DNA levels were 7.0×104, 5.0×105, 5.8×104and 1.6×105IU/L, respectively, which were signif i cantly high in 4 HBsAg-negative patients (Tables 1, 2).

Table 2.Status of patients with HBV recurrence after LT

Table 3.Baseline characteristics of patients after HBV recurrence

HBsAg clearance and survival

Three patients in the lamivudine-treated group had been conf i rmed HBsAg clearance at the 8th, 11th, and 33rd month, respectively. They survived for 99, 90, 73 months after liver transplantation. In the other 3 patients who did not achieve HBsAg clearance, one survived for 97 months after transplantation, one died from liver failure 18 months after transplantation, and another died from hepatorenal syndrome 24 months after transplantation (Table 1). Four patients (66.7%) survived with normal liver function during the followup.

In the combination therapy group, HBsAg converted to negative in 15 patients. Among the 15 patients, 10 survived with normal liver function at a mean followup of 13 to 68 months after transplantation, 3 survived with abnormal liver function 24-73 months, one died from transplantation HCC recurrence with normal liver function 43 months after transplantation, and one died from liver failure 48 months after transplantation. One patient with persistent HBsAg positive survived 55 months after transplantation. The total average patient survival rate was 81.2%. The patient survival rate at 1-, 3-and 5-year was 100%, 81%, and 69%, respectively.

Compared with the lamivudine-treated group, patients in the combination therapy group had a signif i cantly higher HBsAg clearance rate (93.8% vs 50%,P=0.046). However, there was no signif i cant difference in the time of HBsAg seroconversion between the two groups (P=0.084). There was also no signif i cant difference in patient survival rate and survival time between the lamivudine-treated and combination therapy groups (P=0.292).

Discussion

Prophylaxis is always better than treatment for any infection,[8-10]particularly in HBV transplant recipients. Combined prophylaxis of nucleotide analogues and HBIG signif i cantly decreases the HBV recurrence and improves the prognosis of HBV infection in transplant patients.[11,12]With the combination of nucleotide analogue and HBIG, HBV recurrence rate after liver transplantation is decreased signif i cantly.[13,14]However, HBV recurrence in liver recipients is still a challenge. A trial[1]of 166 patients revealed that serologic HBV recurrence was diagnosed in 82% of patients without treatment, 48% of patients treated with HBIG alone, 67% of patients treated with lamivudine alone, and 11% of patients treated with lamivudine and HBIG. Effective treatment for HBV recurrence in transplant patients means more survivors. However, reports on this special population and long-term follow-up are still rare.

Lamivudine is a safe and effective drug in treating recipients with recurrent hepatitis B in a short time.[6,15]Fontana et al[4]reported that at a median of 6-month therapy, 72% initially responded with undetectable HBV DNA. However, 45% developed a viral breakthrough after a median of 15 months of lamivudine therapy. The increasing resistance rate represents a rather challenging problem.[16,17]Data[15]showed the resistance rates at 1st, 2nd and 3rd year of lamivudine therapy were 27%, 40% and more than 50%. Lamivudine resistant cases follow a relatively milder course compared with those of wild HBV recurrence.[18]

Han et al[19]analyzed 23 patients with HBV recurrence (mean follow-up of 41 months), 37.5% of patients receiving lamivudine/HBIG combination therapy cleared HBsAg, whereas the clearance rate is 18% in patients receiving lamivudine monotherapy and 0% (zero of two patients) in those having HBIG treatment. The mean time to HBsAg clearance in the lamivudine/HBIG combination therapy and lamivudine monotherapy groups was 1.7 and 8.0 months, respectively. In our study, the HBsAg clearance rate in patients receiving combination therapy was signif i cantly higher than that in patients treated with lamivudine (P=0.046). Our data were consistent with those reported by Anselmo et al.[1]The 1-, 3-, and 5-year survival rates in our study was 100%, 81% and 69%, respectively, which were similar to those reported elsewhere.[9]

Compared with HBIG or lamivudine monotherapy for HBV recurrence, the combination treatment with lamivudine and HBIG signif i cantly decreased patients' mortality rate. However, no statistical differences were found in the survival rate of patients (P=0.292) and survival time between the two groups. The optimal result of combination therapy may be due to the synergistic effect, i.e. lamivudine inhibits HBV production and HBIG decreases mutations in the pre S/S and YMDD regions.[20]

The most common cause of death for liver transplant patients is recurrent HBV infection (64%), followed by HCC recurrence (23%).[1]HBV recurrence may be accompanied by complications such as chronic rejections which may rapidly lead to hepatic failure.[21]Lamivudine and HBIG are reported to signif i cantly decrease the mortality caused by HBV recurrence.[19]In Han's study, although 6 of 23 HBV recurrent patients died after combination therapy with lamivudine and HBIG, none of them died from graft failure related to HBV recurrence. In our study, 2 patients (33%) in the lamivudine-treated group died from HBV recurrence, but there was no death in the combination therapy group because of HBV recurrence. Our results indicated that combination therapy is more effective than the method with a single agent, and an aggressive treatment for HBV recurrence is necessary in transplant patients.

In summary, combination therapy with lamivudine and HBIG increases HBsAg clearance rate in HBV recurrent patients after liver transplantation. Hence we advocate aggressive treatment after HBV recurrence, especially the combination therapy with lamivudine and HBIG.

Contributors:YCH, XDR and ZTL proposed the study. YCH and XDR performed research and wrote the fi rst draft. LZF and LL collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. XDR is the guarantor.

Funding:This study was supported by a grant from the National Natural Science Foundation of China (30872556).

Ethical approval:Not needed.

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 June 26, 2012

Accepted after revision February 20, 2013

AuthorAff i liations:Department of General Surgery, Peking University Third Hospital, Beijing 100191, China (Yuan CH, Xiu DR, Jiang B, Li ZF, Li L, Song SB and Zhang TL)

Dian-Rong Xiu, MD, PhD, Department of General Surgery, Peking University Third Hospital, Beijing 100191, China (Tel: 86-10-82267338; Fax: 86-10-62010334; Email: ychdoctor@163.com)

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

10.1016/S1499-3872(13)60024-7