New Era of Liver Transplantation for Hepatitis B

Abstract

Objective

To evaluate the variables affecting orthotopic liver transplantation (OLT) outcome for hepatitis B virus (HBV) in a large patient cohort over a 17-year period.

Summary Background Data

Historically, OLT for chronic HBV infection has been associated with aggressive reinfection and poor survival results. More recently, OLT outcome has been improved with the routine use of antiviral therapy with either hepatitis B immune globulin (HBIg) or lamivudine; however, HBV recurrence remains common. The authors studied the factors affecting HBV recurrence and outcome of transplantation, including the effects of combination viral prophylaxis with HBIg and lamivudine.

Methods

A retrospective review of 166 OLT recipients for chronic HBV over a 17-year period at a single center was performed. Median follow-up was 29 months. HBV recurrence was defined by HBsAg seropositivity after OLT. HBIg monotherapy was used in 28 (17%) patients, lamivudine monotherapy in 20 (12%), and HBIg and lamivudine combination in 89 (54%); 29 (17%) did not receive any HBV prophylaxis. Hepatocellular carcinoma (HCC) was present in 43 patients (26%) and urgent United Network for Organ Sharing (UNOS) status was assigned to 27 patients (16%). Univariate and multivariate analyses were performed to identify factors that affected OLT outcome.

Results

Overall 1-, 3-, and 5-year patient survival rates were 85.8%, 73.6%, and 71.8%, respectively. As expected, HBV recurrence-free survival rates were significantly lower than overall survival rates (76.4%, 58.7%, and 48.3%). When compared with a nontreated cohort, OLT recipients receiving combination viral prophylaxis with HBIg and lamivudine showed markedly reduced HBV recurrence rates and significantly improved 1- and 3-year recurrence-free survival rates. By univariate estimates, patient survival was reduced in the presence of HCC, in the Asian population, and urgent candidates by UNOS classification. Graft loss rates were significantly increased in urgent OLT candidates, Asians, patients with pretransplant positive DNA, and in the presence of HCC. Factors that were significant by univariate analysis or thought to be clinically relevant were subjected to multivariate analysis. By multivariate estimates, urgent UNOS or presence of HCC adversely affected patient and graft survival rates, whereas combination prophylactic therapy strongly predicted improved patient and graft survival rates as well as recurrence-free survival rates.

Conclusions

Orthotopic liver transplantation for HBV under combination viral prophylaxis results in survival rates equivalent to other indications. Pretransplant viral replication, UNOS status, and the presence of HCC are all sensitive markers for posttransplantation outcome. Viral prophylactic therapy has effectively reduced HBV recurrence and prolonged survival outcomes. The combination of HBIg and lamivudine is the prophylactic regimen of choice.

Chronic hepatitis B virus (HBV) infection is a common cause of advanced liver disease and has become a worldwide public health issue. It is estimated that 1.25 million people in the United States and more than 300 million people worldwide are chronically infected with HBV. ¹ Further, chronic HBV infection is a well-recognized risk factor for the development of hepatocellular carcinoma (HCC), which is becoming a more prevalent clinical problem, especially in HBV-endemic areas.

Orthotopic liver transplantation (OLT) is the most effective therapeutic modality for patients with decompensated end-stage liver disease. However, OLT for HBV-related liver disease has been historically associated with high viral recurrence rates and poor patient survival. ^2–4 Recurrence was noted to be highest among patients with markers of active viral replication. ^5,6 Other reports identified possible factors associated with poorest outcome, such as Asian race and presence of concomitant HCC. ^2,7 As a consequence, HBV cirrhosis was considered by some centers to be an absolute contraindication to OLT. ⁸ This position was reevaluated when reports from the EUROHEP study in 1993 showed that long-term administration of hepatitis B immunoglobulin (HBIg) substantially reduced HBV recurrence and prolonged survival. ⁵ Several other studies have also shown an improved outcome with aggressive passive HBIg immunoprophylaxis. ^9–11 Despite favorable results with HBIg alone, HBV still recurs in 16% to 52% of recipients. ^12,13 Further, the use of high-dose intravenous HBIg may be limited by patient tolerability and economic constraints. ^14,15

Lamivudine, a nucleoside analog, exhibits antiviral activity through inhibition of HBV-related DNA polymerase. Several trials have shown the safety and efficacy of lamivudine in the both the treatment of chronic HBV infection and recurrence prophylaxis after transplantation. ^16,17 Despite this, results from long-term follow-up have been limited by the development of resistant strains and allograft reinfection rates of 36%. ¹⁸ In fact, a recent study by Petit et al ¹⁹ found persistent HBV infection by sensitive polymerase chain reaction and enzyme-linked immunosorbent assay techniques in all patients receiving lamivudine therapy despite undetectable HBV DNA levels by standard dot-blot hybridization.

Given the recurrence rates with single-agent therapy, several centers have investigated a combination of HBIg and lamivudine as a prophylactic regimen against HBV recurrence after OLT. ^20–24 The rationale for combination immunoprophylaxis comes from theoretical considerations suggesting that a synergistic effect would reduce the selective pressure for resistant viral strains to emerge. Inhibition of viral replication with lamivudine would reduce the likelihood that a high viral load would overwhelm the binding capacity of HBIg, thus allowing more rapid viral clearance. Further, the humoral immunity provided by HBIg may confine the virus to extrahepatic sites, where viral replication is not as efficient, thereby lowering the chance for lamivudine-resistant strains to emerge. Although these reports have shown the effectiveness of combination prophylaxis against HBV recurrence, post-OLT outcome has not been previously studied in a large population of patients with chronic hepatitis B receiving HBIg and lamivudine.

This study retrospectively evaluated a single center’s experience with a large cohort of patients who underwent OLT for HBV-related chronic liver disease over a 17-year period. We examined the effects of both HBIg and lamivudine viral prophylactic therapy on HBV recurrence and the outcome of OLT. We further analyzed the factors that may influence patient and graft survival.

METHODS

Patients

From September 1984 to April 2001, 166 adults underwent OLT at the Dumont-UCLA Transplant Center for end-stage liver disease secondary to chronic HBV infection. Patients undergoing transplants for fulminant liver failure caused by hepatitis B were excluded from analysis. We performed a retrospective review of the UCLA transplant database and patients’ medical records. Patients were divided into four treatment groups according to HBV prophylaxis therapy: no treatment (n = 29), HBIg monotherapy (n = 28), lamivudine monotherapy (n = 20), and HBIg and lamivudine combination therapy (n = 89). Of the 89 patients who received combination viral prophylaxis, 29 were started on lamivudine before transplantation and 71 remained on HBIg therapy beyond 6 months after OLT.

Clinical Variables

For the univariate models, clinically relevant patient variables were analyzed including patient age, United Network for Organ Sharing (UNOS) status, Asian race, gender, preoperative HBeAg, preoperative HBV DNA, and HCC status, in addition to the four antiviral treatment groups (no treatment, HBIg alone, lamivudine alone, combination therapy). Preoperative HBV DNA status was included only in the univariate analysis because there were insufficient data to include in the multivariate models. Provisional Cox proportional hazard multivariate models for death rate, graft loss rate, and recurrence/death rate (recurrence-free survival) were determined by simultaneously controlling for viral prophylaxis and six other potential covariates: age, Asian race, urgent UNOS status, female sex, HCC, and preoperative HBeAg. Age groups were dichotomized at 49 for comparison, which simply represents the median value in this dataset. In these three models, the no-treatment group served as the referent group for antiviral therapy. A rate ratio (RR) less than 1.0 indicates a lowering of rates compared with the referent group, and an RR greater than 1.0 indicates an elevated rate compared with the referent group.

Diagnosis and Definitions

Hepatitis B was diagnosed before OLT by HBsAg seropositivity and/or polymerase chain reaction for detection of HBV DNA. Recurrent HBV was diagnosed by HBsAg seropositivity after transplantation. We defined graft failure as either patient death or retransplantation. Analysis for HBV genotypic mutations is not routinely performed at our center and therefore was not included as a factor in the present study. Currently, HBsAg is monitored every 2 weeks after hospital discharge or as deemed necessary by the patient’s transplant hepatologist. Long-term HBIg therapy was defined as adherence to either a fixed or pharmacokinetic-guided therapy for 6 months beyond the initial hospital stay.

Candidates for OLT were considered as urgent or nonurgent recipients according to their medical condition before transplantation, as defined by the UNOS categories. From 1990 to 1994, urgent recipients included status 4 patients, whereas nonurgent patients included status 3, 2, and 1. After November 1994, status designation was modified by UNOS on two other occasions. Urgent recipients included either status 1 or 2A and nonurgent recipients included status 2, 2B, 3, or 4, according to the designated UNOS criteria at the time of transplantation.

HBIg and Lamivudine Dosing

HBIg (North American Biologicals, Boca Raton, FL) was administered using the following fixed dosing protocol to most patients before 1998: 10,000 U intravenous during the anhepatic phase, then 10,000 U/d intravenous for 7 days, then 10,000 U intravenous every month thereafter. After 1998, HBIg dosing was administered at a dose of 10,000 U intravenous during the anhepatic phase of OLT and 2000 U/d intravenous for 6 days, then 1,560 U intramuscular with the dosing frequency titrated to trough serum titers of HBsAb IgG. Lamivudine was administered orally after OLT at 150 mg/d indefinitely. In the lamivudine monotherapy group, all patients were maintained on treatment from the time of transplant until the time of follow-up, and three patients (15%) started therapy before OLT. Twenty-nine of the combination therapy patients (33%) received lamivudine before the transplant. In this retrospective study, lamivudine therapy was routinely given to OLT candidates with decompensated liver disease and/or evidence of active viral replication.

Immunosuppression

Maintenance immunosuppression regimens consisted of either a triple cyclosporine-based drug regimen that included Sandimmune or Neoral, azathioprine, and prednisone or dual tacrolimus-based immunosuppression comprising tacrolimus and prednisone. In 1996, Neoral was routinely substituted for Sandimmune. Routine use of tacrolimus was initiated at our institution in 1994. On the day of transplantation, patients were started on a rapid steroid taper according to our standard protocol. One gram of Solu-Medrol (methylprednisolone) was administered intravenously for the first day and rapidly tapered to 20 mg/d over 1 week. Oral prednisone was started on day 8 (20 mg/d) and tapered over 2 months to 5 mg/d. From 1995, steroids were discontinued at 6 months in HBV patients who did not exhibit rejection episodes.

Statistical Analysis

Survival curves were computed using the Kaplan-Meier method. Proportions were compared using the chi-square test. The log-rank test for trend was used when comparing survival curves across ordered categories. Univariate and multivariate assessment of drug treatment and covariates were carried out by computing the crude rates per 100 person-years of follow-up and by using the Cox proportional hazards model with two-way interactions permitted. Covariates found significant in bivariate analyses controlling for drug treatment and/or thought to be important on biomedical grounds were included as candidates for multivariate Cox model analysis. Variables were retained in the multivariate Cox model after backwards stepdown elimination using a liberal P < .10 criterion for variable retention. All analyses were carried out using the SAS system (SAS Institute Inc., Cary, NC). P < .05 was considered statistically significant.

RESULTS

Patient Characteristics

Patient characteristics are listed in Table 1. The median age was 49 (range 12–73) years. Median follow-up time was 29 (range 4–204) months. This patient population included 136 male patients and 30 female patients. Urgent UNOS status was assigned to 27 patients (16%) before transplantation. Forty-three patients (26%) were diagnosed with concomitant HCC by either preoperative workup or incidentally by explant histology. Before OLT, all patients were HBsAg positive and 43 were HBeAg positive. HBV DNA was tested by dot-blot hybridization in 89 patients, and 23 of these were found to be positive at the time of transplantation. A total of 55 of 142 patients tested showed evidence of active viral replication by HBeAg and/or HBV DNA before OLT. The remaining 24 patients did not have available data on markers of pretransplant viral replication status. Serologic HBV recurrence occurred in 57 patients and 40 patients died during follow-up. Of the 166 patients studied, 23 (14%) required retransplantation. Only the results from initial transplantation were included in this study.

Table 1. DEMOGRAPHICS

HBV, hepatitis B virus; HCC, hepatocellular cancer; UNOS, United Network for Organ Sharing.

Causes of Posttransplant Death

Twenty-four of 40 deaths (68%) were attributable to recurrent HBV infection and 4 were due to recurrent HCC (10%). Four patients died of unknown causes (10%) and four patients died of causes unrelated to HBV or HCC (sepsis 1, metastatic lung cancer 1, hemorrhagic stroke 1, cardiomyopathy 1). Of the 24 deaths related to HBV recurrence, 13 occurred in the no-treatment group (46%), 9 in the HBIg monotherapy group (23%), none in the lamivudine monotherapy group, and 2 in the combination prophylaxis group (8%). Two of the nine HBV recurrence-related deaths in patients receiving HBIg monotherapy were maintained on long-term therapy. Considering the patients with concomitant HCC, the most common cause of death was related to recurrent HBV infection (64%), followed by HCC recurrence (23%).

Causes of Retransplantation

Of the 23 patients requiring a second transplant, 13 transplants (56%) were performed within 30 days of the initial OLT. The most common cause of early retransplantation was primary nonfunction (n = 8); delayed nonfunction occurred in four patients and one patient had hepatic artery thrombosis. Beyond 30 days, the primary cause of retransplantation was recurrent hepatitis B (n = 8), followed by chronic rejection (n = 1) and hepatic artery thrombosis (n = 1). Considering patients who were retransplanted secondary to HBV recurrence, three retransplants occurred in the nontreated group, two occurred in each of the HBIg and lamivudine monotherapy groups, and only one occurred in the combination prophylaxis group. The median time to retransplantation for recurrent HBV was 30.5 months.

HBV Recurrence

Serologic HBV recurrence was diagnosed after OLT in 82% of the nontreated patients, in 48% of the HBIg alone group, and in 67% of the lamivudine monotherapy patients. Of the 89 patients administered combination therapy, HBsAg reappearance occurred in 10 (11%). Considering the 28 patients who received HBIg monotherapy for whom recurrence data were available, 10 were maintained on long-term therapy and 15 terminated therapy within 6 months. Four of the 10 (40%) long-term HBIg monotherapy patients had HBV recurrence, whereas 9 of 15 (60%) receiving short-term treatment had recurrence.

Of the patients who had recurrence while receiving combination therapy, further analysis revealed that only 2 of these 10 patients adhered to the established protocol. One patient had recurrence in the immediate postoperative period, which we believe indicated infection with resistant HBV, and the other patient had recurrence shortly after cytotoxic chemotherapy for HCC. The remaining eight patients elected to discontinue HBIg or were noncompliant with lamivudine treatment. A total of 71 patients in this group received both lamivudine and indefinite, pharmacokinetic-guided HBIg therapy, with only 2 showing clinical reinfection. Therefore, the actual incidence of HBV recurrence for combination prophylaxis under the current treatment protocol at UCLA is 2.8%.

Table 2 reports a bivariate analysis with crude HBV recurrence rates per 100 person-months compared with both pretransplant HBeAg and HBV DNA, thus accounting for follow-up time and reliable markers of viral replication. As expected, HBsAg recurrence was higher in nontreated HbeAg-positive patients compared with those who were HBeAg negative (recurrence rate 39.0 vs. 4.56;P = .0041). However, there was no difference in the recurrence rate between HbeAg-positive versus -negative patients in either the HBIg monotherapy group (2.13 vs. 2.44;P = .056) or those receiving lamivudine alone (1.92 vs. 1.37;P = .18). Interestingly, the recurrence rate was zero in the combination therapy group despite HBeAg seropositivity. Similar effects were observed with pretransplant HBV DNA status (see Table 2). In nontreated patients, the HBV recurrence rate was significantly higher in the HBV DNA-positive group compared with the HBV DNA-negative patients (9.57 vs. 0.65;P = .041). Combination therapy lowered HBV recurrence in HBV DNA-positive patients compared with no treatment (9.57 vs. 0.32;P = .06), but this difference only approached significance, likely because of sample size error. Under combination prophylaxis, the rate of HBV recurrence was identical regardless of pretransplant HBV DNA status (0.32). Recurrence rates for monotherapy were not included secondary to insufficient HBV DNA data for analysis in these groups.

Table 2. HBsAg RECURRENCE RATE PER 100 PERSON-MONTHS

HBIg, hepatitis B immune globulin.

Overall Patient and Graft Survival

Kaplan-Meier patient and graft survival estimates for the entire patient population included in the study period, from 1984 to 2001, are shown in Figure 1. Overall patient survival rates from the date of the first transplant at 1, 3, and 5 years were 85.8%, 73.6%, and 71.8%, respectively. Considering patients with no serologic HBV recurrence, overall survival rates at 1 and 3 years were 97.8% and 88.7%, respectively, which compared favorably with survival of HBsAg recurrence-positive patients (1-, 3-, and 5-year survival rates of 73%, 58%, and 55%, respectively).

Figure 1. Outcome of liver transplantation after serologic recurrence of hepatitis B virus. Overall patient survival (diamonds) compared with survival with (triangles) and without recurrence (boxes).

Graft survival analysis that included all causes of graft failure and/or patient deaths showed graft survival rates of 73.2%, 69.3%, and 61.5% at 1, 3 and 5 years, respectively (Fig. 2). When considering grafts in patients who showed no recurrence of HBsAg during follow-up, 1- and 3-year graft survival rates were 93.7% and 85.7%; for those with recurrence, the 1-, 3-, and 5-year graft survival rates were lower at 64.3%, 50.1%, and 41.3%, respectively.

Figure 2. Outcome of liver transplantation after serologic recurrence of hepatitis B virus. Overall graft survival (diamonds) compared with survival with (triangles) and without recurrence (boxes).

Effects of Viral Prophylaxis on HBV Recurrence-Free Survival

Overall 1-, 3-, and 5-year recurrence-free survival rates were 75.6%, 58.7%, and 39.2% (Fig. 3). Figure 4 illustrates recurrence-free survival rates for each treatment group. Of the 29 patients with no prophylactic therapy, 1- and 3-year recurrence-free survival rates were 44.8% and 15.8%, respectively. HBIg monotherapy patients had 1-, 3-, and 5-year survival rates of 60.5%, 36.4%, and 31.2%, respectively. In the lamivudine monotherapy group, 1-, 3-, and 5-year survival rates were 75%, 65%, and 55%, respectively. In patients receiving HBIg and lamivudine combination therapy, recurrence occurred in only 11% (10/89), and 1- and 3-year survival rates were 93.7% and 83.3%, respectively.

Figure 3. Overall Kaplan-Meier recurrence-free patient survival curve after liver transplantation for hepatitis B.

Figure 4. Kaplan-Meier recurrence-free patient survival estimates after liver transplantation for hepatitis B stratified according to viral prophylaxis therapy: no treatment (diamonds), hepatitis B immune globulin monotherapy (boxes), lamivudine monotherapy (triangles), and combination therapy (circles).

Predictors of Patient and Graft Survival by Univariate Analysis

Preoperative recipient variables were studied for their impact on survival outcomes after transplantation. The seven recipient variables were age group (older than 49 or younger than 49), gender, Asian race, urgent UNOS status, diagnosis of HCC, preoperative HbeAg, and HBV DNA. The effects of viral prophylactic therapy were also analyzed by univariate methods. These variables were dichotomized at their median value for comparison. The outcomes reported include death rate, graft loss rate, and death/recurrence rate. We examined both death and recurrence together as an outcome measurement because this represents the converse of what we believe is the most clinically relevant outcome, recurrence-free survival. In this approach, either an increased rate of death or rate of recurrence or both could possibly account for an observed difference.

By univariate comparison, an increased risk of death after OLT was significantly associated with urgent UNOS status (RR 3.16;P = .008), Asian race (RR 2.32;P = .01), and concomitant HCC (RR 3.04;P = .0007) (Table 3). Age and preoperative markers of active viral replication did not appear to influence the overall death rate. Similarly, graft loss was not only affected by Asian race (RR 1.82;P = .044), HCC (RR 2.38;P = .004), and urgent UNOS status (RR 2.45;P = .023), but also by positive HBV DNA (RR 2.831;P = .0283). As shown in Table 3, the two factors that were shown to affect death or recurrence ratio (i.e., recurrence-free survival) were age older than 49 (RR 0.60;P = .0383) and positive preoperative HBV DNA (RR 2.71;P = .0145). Therefore, ignoring other variables, Asian race and the presence of HCC portend a worse overall patient and graft survival, whereas preoperative HBV DNA serves as a sensitive marker for HBV recurrence and graft failure. Considering viral prophylaxis therapy groups, lamivudine monotherapy and combination prophylaxis significantly improved patient and graft survival as well as recurrence-free survival. However, this effect was not observed with HBIg treatment alone. This is not surprising given the fact that several patients prematurely terminated HBIg therapy, and nine of the HBV recurrence-related deaths occurred in this group. Univariate comparison was then performed for the subgroup of HBIg monotherapy patients who remained on treatment for greater than 6 months. The observed reduction in overall death rate and graft loss rate approached significance, but the recurrence/death rate was significantly improved with long-term HBIg monotherapy (RR 0.15;P = .009).

Table 3. UNIVARIATE RATE RATIOS

HBIg, hepatitis B immune globulin; HBV, hepatitis B virus; HCC, hepatocellular cancer; UNOS, United Network for Organ Sharing.

Predictors of Patient and Graft Survival by Multivariate Analysis

Variables found to have an impact on survival (P < .1) univariately, or those thought to be relevant, were analyzed by Cox multivariate regression analysis (Table 4). The effects of preoperative HBV DNA and lamivudine monotherapy could not be assessed due to excessive data censorship when simultaneously considering other variables. Factors included in analysis were age, HCC, gender (female sex), UNOS status (urgent), combination therapy, HBeAg, and Asian race. The positive effect of the drug combination on all three measured outcomes (death, graft loss, or recurrence/death rate ratios) was statistically significant after controlling for HCC, UNOS status, and Asian race. Presence of HCC and urgent UNOS status were found to have an adverse impact on the death and graft loss rate; however, the death/recurrence rate was significantly affected only by presence of HCC. Controlling for other covariates, Asian race, gender, age, and preoperative HBeAg did not significantly affect patient, graft, or recurrence-free survival (data not shown).

Table 4. MULTIVARIATE RATE RATIOS

HBIg, hepatitis B immune globulin; HCC, hepatocellular cancer; UNOS, United Network for Organ Sharing.

DISCUSSION

This retrospective study represents one of the largest series of liver transplantation outcome for hepatitis B infection from a single center. Our results confirm that recurrence of HBV infection after liver transplantation clearly portends a worse prognosis. At our institution, in HBV-infected patients with no serologic evidence of recurrence after OLT, we have achieved overall patient survival rates of 98% and 89% and graft survival rates of 94% and 86% at 1 and 3 years of follow-up. In comparison, recurrence of HBV leads to 1- and 3-year patient survival rates of 73% and 58% and graft survival rates of 64% and 50%, respectively. These results agree with other reports of worsened OLT outcome related to HBV recurrence ⁴ and underscore the critical importance in preventing viral reinfection in patients who undergo liver transplantation for chronic hepatitis B. However, such is not the case with liver transplantation for hepatitis C infection. A recent study by Ghobrial et al ²⁵ from this center showed that for patients who underwent OLT for chronic hepatitis C, viral recurrence does not confer a lower overall patient or graft survival.

Our results further confirm that pretransplant evidence of active viral replication increases the risk of HBV recurrence after transplantation. However, this effect was observed only in patients not receiving any prophylactic therapy, whereas HBV recurrence in each of the three treatment groups studied (HBIg alone, lamivudine alone, HBIg plus lamivudine) was unchanged by viral replication status (HBV DNA and HBeAg). The issue of active viral replication before transplantation was shown by Samuel et al ⁵ to be an important factor affecting HBV recurrence, regardless of immunoprophylaxis therapy. The apparent contradiction in our data most likely relies on the fact that we examined HBV recurrence rates in a much smaller cohort of patients using a bivariate analysis, whereas Samuel et al’s study used a Cox regression model controlling for several different potential covariates. In addition, seropositivity of HBsAg after transplantation, regardless of follow-up time, was defined as recurrence of viral infection and thus a treatment failure. Of the patients who did not clear viral infection or who had recurrence shortly after OLT, HBV recurrence may relate to infection with a mutant viral strain or some other undefined factor. However, it is not routine practice at our center to perform viral genotyping, and therefore our study is not suited to distinguish between both entities.

Univariate analysis of recipient factors identified Asian race, presence of HCC, and urgent UNOS status as three significant variables that adversely affected patient and graft survival after OLT for HBV. Surprisingly, these variables were not significant when considering death and recurrence simultaneously (death/recurrence rate). However, this finding may reflect the fact that a large proportion of Asians (59%), those with HCC (65%), and urgent UNOS patients (55%) were treated with combination therapy such that a reduction in HBV recurrence offset the increase in overall incidence of death in these groups. HBV DNA status significantly increased graft loss and death/recurrence risk ratios but was not shown to significantly affect the overall death rate. Because all causes of graft loss were included in this analysis, including both retransplantation and death, this shows that HBV DNA status is a predictive factor for HBV recurrence and contributes to graft loss by a higher rate of retransplantation. Unlike with lamivudine alone, the effects of HBIg monotherapy on transplantation outcome were not improved compared with the nontreated group. The variability of HBIg dosing during this early period undoubtedly accounts for this finding, as evidenced by a significant improvement in recurrence-free survival when analyzing long-term HBIg alone. The benefits of HBIg monotherapy are well established. Nyman et al ¹⁰ reported that indefinite high-dose immune prophylaxis with HBIg lowered recurrence rates to 23% and significantly improved patient and graft survival compared with an untreated cohort. Pruett et al, ²⁶ in a study of 40 liver transplants, also showed the importance of “indefinite” HBIg therapy for chronic HBV. Under an aggressive protocol of intravenous HBIg titrated to pharmacokinetic parameters, they reported HBV recurrence in only nine grafts, all of which were HBeAg positive, and an outcome equivalent to OLT for other diagnoses.

Multivariate analysis considered covariates found to be significant in the univariate comparison (Asian race, UNOS status, HCC, age, and combination therapy group). As expected, presence of HCC and candidates in urgent need of liver transplantation were independent factors predicting lower patient and graft survival rates. Pretransplantation UNOS status is a well-recognized recipient factor that has been shown to predict outcome after OLT. ^27,28 In addition, Wong et al ²⁹ found that the poor OLT outcome observed for HCC in the setting of chronic HBV was related to allograft reinfection, not tumor recurrence. These findings correlate well with our data, in which the predominant cause of death in the patients with HCC was related to recurrence of HBV (64%), not HCC. This effect is unrelated to other potential factors, such as adjuvant chemotherapy or viral therapy, and may be caused by defects in cell-mediated immunity and cytokine production present in patients with HCC. ³⁰

The main finding of this study was that by using a combination of long-term immune prophylaxis with HBIg and antiviral therapy with lamivudine, HBV recurrence after OLT has been lowered to 2.8% and recurrence-free survival rates at 1 and 3 years were 92% and 81%, respectively. This is far superior to untreated patients, who had 1- and 3-year recurrence-free survival rates of 45% and 16% and an incidence of HBV recurrence of more than 80%. These results were supported by multivariate regression analysis showing that combination therapy independently predicts improved patient, graft, and recurrence-free survival after OLT. Our findings concur with several studies that show improved results with combination prophylaxis. ^20–24 Markowitz et al ²¹ found no evidence of HBV recurrence at 1.1 years of follow-up in 14 patients using intravenous HBIg combined with lamivudine. Ten of the 14 patients received lamivudine before surgery, four of whom were HBV DNA positive. Further, Han et al ²³ addressed the concerns over the high cost of intravenous HBIg in an economic analysis of a large cohort of hepatitis B transplant recipients. Results from this retrospective review revealed that combination prophylaxis prevented reinfection in all 59 patients studied and was more cost-effective than HBIg monotherapy, considering the cost of recurrent HBV. Reports using pre- and posttransplant lamivudine with postoperative intramuscular HBIg have also been shown to reduce pretransplant viral replication and prevent HBV recurrence. ^22,24

Although the present study has shown a significant benefit to combination therapy, the optimal dosing schedule for this regimen is not yet established. Our current protocol uses intramuscular HBIg, with the dosing frequency adjusted to maintain trough serum HBsAb levels greater than 500 IU/L for the first 6 months, more than 150 IU/L for up to 1 year, then greater than 100 IU/L thereafter. However, adherence to this regimen is not without disadvantages, both logistic and economic. Our protocol also includes the administration of pretransplant lamivudine to patients with positive HBV DNA, positive HbeAg, and/or decompensated liver disease. We have previously shown that short-term lamivudine therapy before transplantation is effective in converting HBV DNA-positive patients to negative status. ²¹ Another recent study by Yao et al ³¹ observed that lamivudine treatment in patients with decompensated HBV cirrhosis resulted in a clinical improvement before OLT as well as a survival benefit after OLT. However, considering longer wait list times, the risk of inducing viral resistance with long-term administration of lamivudine is an important concern. Other issues that should be addressed in the development of antiviral therapies for HBV include not only the optimal dosing and duration of HBIg, but also the inconvenience and economic constraints of this therapy. In addition, the role of other nucleoside analogs, such as adefovir, especially in the treatment or prevention of lamivudine resistance, awaits clinical investigation. It is important that future clinical trials identify new approaches to HBV prophylaxis that will reduce the disadvantages of current protocols while maintaining the excellent results currently seen with HBIg and lamivudine combination therapy.

Discussion

DR. RICHARD J. HOWARD (Gainesville, FL): The bottom line of this paper is that it is now safe to perform liver transplantation in patients who have liver failure from hepatitis B. Furthermore, the results are similar to those who don’t have hepatitis B, as long as they receive two-drug therapy.

It wasn’t so long ago, as Dr. Busuttil reminded us, that many surgeons were reluctant to transplant patients who had hepatitis B and insurance companies refused to pay for patients who had liver failure from viral diseases. That wasn’t as important for patients with hepatitis B because they account for a small fraction of the total patients needing liver transplantation. But they also refused to pay for transplantation for patients who had liver failure from hepatitis C. Currently, in some centers such as ours, that is the most common cause for patients needing liver transplantation.

I would just remind the audience that there are currently 18,000 patients on the UNOS waiting list awaiting liver transplantation. This year there will be approximately 5,000 liver transplants done.

It has been estimated by one of our hepatologists that because of the lag time between the development of hepatitis C, with which there are about 3.5 million people infected in our country this year, and the time that the patients end up needing a liver transplantation from cirrhosis, that in 2020 there will be 70,000 people on the waiting list from hepatitis C alone. So it is going to become a worse issue. But at least it is safe to do so now.

The findings are similar to a paper we presented last year discussing liver transplantation in patients who had hepatocellular carcinoma and those who were DNA positive and were treated with a two-drug regimen, had a 5-year survival in the 70% range, whereas those who weren’t treated had a 5-year survival of only approximately 20%. So drug therapy is needed.

The lessons we have learned from treating AIDS and HIV infection are similar to treating patients with hepatitis; that is, strategies for treating the virus by interfering with multiple biochemical pathways require multidrug regimens. And currently, AIDS patients are treated with a three- or four-drug regimen. We treat patients with hepatitis B with a two-drug regimen. And as more drugs become available, probably they will be added to the drug regimen.

I would like to ask the author a couple of questions.

I assume these were historic controls; that is, he wouldn’t treat patients currently with no drug regimen who had hepatitis B. How does he decide whether the change is the result of the drug regimen or just the fact that transplantation has gotten substantially better since the 1980s currently?

What would he do as new drug regimens come along? How does he decide whether to add drugs? How long are patients going to be treated? Are they all going to require lifelong therapy?

Finally, what does this do for the cost of therapy after transplantation? These regimens can be extremely expensive, added to an already expensive cost of immunosuppression.

Currently, in Florida at least, some of our patients are nontransplantable, not because they don’t have their transplant covered—although there are some of those also—but because the insurance companies won’t pay for long-term drug treatment. And it is a real tragedy. What will he do with those patients?

I thank the Society for the privilege of the floor. It was an extremely good presentation from a transplant center that does more transplants currently than anyone in the world.

DR. TIMOTHY L. PRUETT (Charlottesville, VA): I would like to thank the authors for the opportunity to read the manuscript. It had several other bits of information which weren’t in the presentation. I would like to commend Ron on a very nice talk.

Unlike other organs that we transplant, the primary problem of liver transplantation is recurrent disease. We don’t see a lot of falloff from chronic rejection. The problems in this field are a little bit different from those in kidney, heart, and lung disease.

The learning message that came out this presentation is that indefinite therapy seems to be important. The problem with indefinite treatment in any kind of microbiologic system is that mutations occur. The virus, in this case, will find ways to escape. Hepatitis B can escape through an immunologic mechanism which was initially described in neonates after vaccination, by which anti-HBs becomes ineffective and more recently long-term lamivudine therapy can induce a mutation in a polymerase catalytic region and the drug becomes ineffective. The interesting part about hepatitis B is that the gene sequences for these products (HBsAg and polymerase) completely overlap. The hepatitis B epitope for HBsAg is in the same area as is the one for the polymerase region, which is where the YMDD mutation occurs. With HBIg alone inducing mutations to the immunoglobulin, YMDD mutations have been simultaneously described. On the flip side, the use of antivirals has resulted in changes mimicking those seen from immune pressure.

If pretransplant therapy results in significant viral changes, we may be in a position where there are no good drugs to impair hepatitis B from infecting the liver. It has become part and parcel of our routine hepatology management of patients on the list to put patients on lamivudine. And the rate of mutation and subsequent resistance to the drug can be about 20% to 30% a year. And with current wait times being between 1 and 3 to 4 years, the risk of HBV mutation is substantial.

So with all that as a prelude, I would like to ask a few questions.

One, does UCLA have a policy regarding the pretransplant use of lamivudine after the generation of resistant viruses? Several groups have recommended stopping lamivudine.

The second is, the therapeutic goal for hepatitis B immunoglobulin in our hands has always been the elimination of surface antigen. This has been highly variable between patients even on lamivudine. In the manuscript you recommend, particularly because of cost issues, early conversion to intramuscular use of hepatitis B immune globulin. I was wondering whether that was always effective. Do you always reduce the surface antigen and clear it? If you don’t, do you revert back to IV immune globulin and how long? In what percentage of people do you have problems in achieving the therapeutic goal of surface antigen negativity in the serum?

I find the observation that hepatocellular carcinoma is a predictor for long-term viral failure is very interesting. There have been several models in which antiviral therapy seems to reduce the risk for development of hepatocellular carcinoma, but not the converse (making the virus more prone to resistance). Was that all just viral recurrence death, or was it a combination of tumor recurrence in combination with viral recurrence after the use of chemotherapy in those patients? Do you think there is really something specific about the combination of virus and hepatocellular carcinoma which is a bad predictor? If so, will you change your approach to that?

I thank the Society for the opportunity of the floor and to review this very interesting paper.

DR. RONALD W. BUSUTTIL (Los Angeles, CA): Thank you, Richard, and thank you, Tim.

The first question that Dr. Howard asked related to whether a time factor had an impact on our results. Because this was a span of 17 years, we also were concerned with this issue. Thus, we analyzed results for a disease that does not recur, namely primary biliary cirrhosis, and compared our results from 1984 through 1991 to 1992 through 2001. As you can see, there was no difference, negating the era of transplantation as a causative factor in our results. We believe that the time issue had no impact on the improved results that we obtained with lamivudine and HBIg, which was utilized in the latter part of the series.

The second question relates to newer drug regimens. I believe at the present time we are very comfortable with lamivudine and HBIg. As new drugs become available, we will probably consider using them if their therapeutic index is favorable regarding decreasing mutation and if their cost-benefit is favorable. Dr. Pruett has already alluded to this.

However, I believe it is important to point out that in our entire series, we have only had two patients that have developed a YMDD mutant. In fact, in one of those patients we maintained them on HBIg and lamivudine and this patient continues to do well, and is now 4 years out. Thus, I am not sure how problematic YMDD mutations are going to be in the long term, although we are vigilant for their development.

Dr. Howard mentioned the cost of the prophylaxis regime. Obviously, cost containment is a very important issue in liver transplantation. It is one of the more costly procedures that any hospital undertakes. However, if you look at a cost analysis and compare the cost per patient who recurs versus the cost of a patient that does not recur because of the use of lamivudine and HBIg, you clearly have an advantage in those patients receiving the prophylaxis.

We give lamivudine pretransplant to three types of patients: 1) those are active viral replicators, 2) patients who have HCC, and 3) patients with decompensated liver disease. The stable patients are given lamivudine immediately after transplant.

Regarding intramuscular therapy, we have altered our protocol to intramuscular therapy because we have found that we can get by with less HBIg than the usual intravenous dose of 10,000 units. By doing so we have avoided some of the toxicities that we see with intravenous HBIg, and certainly some of the cost concerns that we see when you give the large intravenous doses.

The use of intramuscular HBIg has been very effective in our hands. Using this particular regimen outlined in our manuscript, 74% of our patients did not require any additional HBIg; 25% required supplementation with IV therapy to maintain the desired titers that we were looking for.

I would like to thank the discussants for their comments and thank the Association for the privilege of the floor.