EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Hepatitis B core antibody immunoglobulin G seropositivity is evidence of past exposure to hepatitis B virus. Donor or recipient hepatitis B core antibody positivity may pose a risk of reactivation, especially early after liver transplant. Although most centers advocate using antiviral agents plus hepatitis B immunoglobulin, some have recently relied on antivirals only as prophylaxis after liver transplant. Here, we retrospectively investigated patient survival in hepatitis B core antibody-positive recipients, comparing those treated with antivirals plus hepatitis B immunoglobulin versus antivirals alone.

Materials and Methods: After Internal Review Board approval, we reviewed medical records of deceased-donor liver transplant recipients between 1995 and 2013. Demographic characteristics, transplant indication, hepatitis B core antibody status, time to death, and type of posttransplant prophylaxis were recorded. We also recorded whether donors showed hepatitis B core antibody positivity. Patients who died within 30 days of liver transplant were excluded.

Results: There were 148 hepatitis B core antibody-positive recipients. Prophylaxis was given to 75 recipients after transplant: 8 (5%) received hepatitis B immunoglobulin, 22 (15%) received antivirals, and 45 (30%) received the combination. There were 34 deaths: 3 (38%) in hepatitis B immunoglobulin only, 3 (14%) in antiviral only, 8 (18%) in the combination, and 20 (27%) in no prophylaxis groups. One- and 5-year survival rates were similar for binary comparisons among prophylaxis groups (P > .05).

Conclusions: Preliminary results support the current practice of using hepatitis B immunoglobulin plus antivirals for prophylaxis after liver transplant. The similar survival benefit with the combination versus antiviral agents alone suggests equal effectivity for prophylaxis posttransplant. However, a clear benefit of antivirals was not evident in our analysis. Future larger prospective studies are warranted to identify potential benefits of using antivirals alone as prophylaxis after liver transplant and to further clarify their role as the sole prophylactic regimen.

Key words : Hepatitis B, Oral antivirals, HBIG, Liver transplant

Liver transplant with replicating hepatitis B virus (HBV) infection was considered to be an absolute contraindication in the early 1990s. High recurrence of HBV infection, sometimes approaching 80%, resulted in early graft loss and carried mortality rates as high as 50%.¹ In the United States, the 3-year survival rate of patients with HBV infection who received liver transplants was reported to be 55%, before the availability of hepatitis B immunoglobulin (HBIG). With the introduction of HBIG, outcomes after transplant have considerably improved, decreasing the recurrence of HBV from 75% to 36% and simultaneously improving liver transplant survival.^2-4 The availability of HBIG also has resulted in an increased number of available organs for liver transplant. In the past, donors who had been exposed to HBV and possessed hepatitis B core antibody (HBcAb) immunoglobulin G seropositivity with either negative or positive hepatitis B surface antigen (HBsAg) status were at risk of transmitting de novo HBV to the recipients. After transplant, these recipients were at increased risk of recurrence of HBV infection due to immunosuppressive course. The coexisting HBsAg status of a liver transplant recipient, if positive, carried added risk of recurrence after transplant. The availability of HBIG and nucleoside or nucleotide analogues has limited graft infection to < 5% and improved survival of liver transplant recipients.

Although the exact mechanism of action of HBIG is unclear, it is thought to reduce hepatocyte infection by binding to the HBV viral particles in the blood circulation.⁵ Some investigators also point toward its efficacy and its ability to modulate the local immune response by decreasing T-cell and dendritic cell function and cytokine production.⁶ For optimal outcomes, patients possessing HBcAb, with or without presence of HBsAg, required high-dose, long-term HBIG in combination with nucleoside or nucleotide analogue antivirals. The reported recurrence of HBV infection after transplant using this strategy was < 10%.⁷ However, higher cost of HBIG, adverse effects, and lack of availability worldwide has provided the impetus for the development of alternative cost-effective regimens. The per-year cost for HBIG is estimated to be $50 000 if given by intravenous route daily for the first week and monthly later.⁸ Adverse effects may vary with the dose of therapy and may include muscle ache, flushing, and headache.⁹

For the above-mentioned reasons, different combinations of HBIG and antiviral agents have been tried with variable success rates. Gane and associates studied 147 HBV patients and showed that administration of HBIG ranging from 400 to 800 IU intramuscularly in combination with lamivudine resulted in a recurrence rate of 1% at year one and 4% at year five.¹⁰ This regimen was reported to have 10% less cost than the high-dose traditional regimen. The trend of combination therapy continued to be the standard care in several centers in the United States and worldwide until recently, when a few centers in Asia began using novel antiviral agents alone for posttransplant prophylaxis. Fung and associates studied 80 patients with chronic HBV infection. All patients received entecavir therapy without HBIG. Of the studied patients, 91% lost HBsAg after 2 years.¹¹ These findings point toward a trend of gradually weaning of HBIG from the current standard practice, which has long been the traditional cornerstone of immunoprophylaxis against HBV in liver transplant recipients.

In the present retrospective study, we explored the efficacy of HBIG alone versus HBIG combined with nucleoside or nucleotide analogue antiviral agents in HBcAb-positive liver transplant recipients. Our aim was to elucidate whether HBIG alone or antiviral agents alone or the combination should be made the standard regimen for immunoprophylaxis of liver transplant recipients exposed to HBV.

Materials and Methods

After Institutional Review Board approval, electronic medical records of adults who underwent deceased-donor liver transplant between January 1995 and January 2013 were retrospectively reviewed. All patients were adult (> 18 y old) transplant recipients who underwent deceased-donor liver transplant at the Johns Hopkins Hospital (Baltimore, MD, USA). Patients who received living-donor liver transplants, had acute liver failure, or died within 30 days of liver transplant were excluded.

We identified 148 liver transplant recipients with HbcAb-positive status. The electronic patient records were used to retrieve recipient demographics. Donor information was retrieved from the United Network for Organ Sharing database. Recipient demographics retrieved included age at transplant, race, sex, and transplant indication. We used the explant histopathology results and medical records to confirm the indication for liver transplant.

We categorized patients who received prophylaxis after liver transplant into 3 treatment groups: (1) combination therapy (HBIG and antiviral agents), (2) HBIG only, and (3) antiviral agents only. The types of nucleoside or nucleotide analogue used as the antiviral agent also were recorded. The insufficient number of recipients precluded a subgroup analysis. Donor characteristics included donor HbcAb status. The primary outcome measured was posttransplant survival.

All data were entered in Microsoft Excel (Microsoft Corp. Richmond, VA, USA), with statistical analyses performed using STATA 12.0 (StataCorp LP, College Station, TX, USA). Survival of patients was defined as time of transplant to study termination time. Survival analyses were performed using Kaplan-Meier curves. Log-rank tests were used to analyze the differences in survival. P < .05 was considered statistically significant. We also performed a Cox regression analysis, using time to death or end of study period as the dependent outcome variable to calculate the hazards for mortality outcome.

There were 148 HBcAb-positive patients who received liver transplant during the study period. The median age at liver transplant was 53 years (interquartile range, 9 y). All recipients were HbcAb positive. Most patients were white (52.7%), followed by African American (33.1%). Twenty-four donors (16.2%) were HbcAb positive, whereas 122 donors (82.4%) were HbcAb negative (Table 1).

The HbcAb status of 2 donors was unknown. Forty-five recipients (30.1%) received a combination of HBIG and antiviral agents, whereas 22 recipients (14.7%) were treated with antiviral agents only. Only 8 recipients (5.3%) received HBIG only (Table 1, Figure 2). Indications for transplant varied among our study population. Most received a liver transplant because they were hepatitis C virus positive (62 patients [41.9%]). Thirty-five recipients (23.6%) had combined hepatitis C virus infection and alcoholic cirrhosis. Only 29 recipients (19.6%) had a primary diagnosis of HBV infection (Table 1).

Univariate regression analysis was performed using sex, age at time of transplant, recipient surface antigen status, donor core status, hepatitis C virus status, hepatocellular carcinoma status, and various treatment groups as covariates. The univariate analysis did not yield any significant predictor of mortality (Table 2). Multivariate regression was not performed because of the nonsignificant association between the covariates in the univariate analysis.

There were 34 patients who died during the median time frame of 4.1 years (interquartile range, 5.7 y). We compared 1-year and 5-year survival rates in patients who received the combination therapy versus HBIG or antiviral agents alone (Figure 1). Comparison of 1-year survival between the combination therapy and antiviral agents alone revealed no survival difference (log-rank test; P = .91). Comparison of the combination with HBIG alone also did not reveal a survival difference (log-rank test; P = .69). Similarly, comparison of 5-year survival revealed no difference between the combination therapy versus antiviral agents alone or combination therapy versus HBIG alone (Figure 1).

Liver transplant is the main treatment for patients with end-stage liver disease and hepatocellular carcinoma. Chronic HBV infection is one of the most common infectious diseases resulting in end-stage liver disease and hepatocellular carcinoma.^12-14Liver transplant recipients with prior exposure to HBV are at increased risk of reinfection and graft failure. Currently, the use of HBIG with antiviral drugs is standard of care for prophylaxis against HBV recurrence. Our findings revealed that HBIG with antiviral therapy is equally efficacious versus antiviral therapy alone in HbcAb-positive recipients who receive HBV prophylaxis after liver transplant. These findings are congruent with the recent report by Fung and associates, which revealed the efficacy of entecavir monotherapy for HBV prophylaxis.¹¹

Hepatitis B immunoglobulin use may exert a protective action against HBV through several mechanisms. These may include neutralizing the viral particles by way of binding, cell death of infected hepatocytes, and decreasing inflammation by reducing cytokine production.^5,6 In 1991, both Muller and associates and Samuel and associates published the beneficial effects of HBIG in HBV-positive liver transplant recipients.^3,15 Less than 20% HBV recurrence has been shown with HBIG treatment. These historical data were followed by other studies showing the beneficial effects of HBIG after liver transplant. Nucleoside or nucleotide analogue antiviral agents against HBV replication became available in the latter part of the 1990s and soon became another viable option to prevent the recurrence of HBV after liver transplant. It was shown that the addition of lamivudine with HBIG was more effective than HBIG monotherapy.⁷ Subsequently, in 2 different studies, Grellier and associates and Mutimer and associates reported the prophylactic effect of lamivudine without HBIG.^16,17 This was then followed by studies from other groups in the late 2000s on newer antiviral agents, with these antiviral regimens also being effective without HBIG after liver transplant.^11,18-22 Fung and associates studied 80 patients with chronic HBV. These patients received entecavir monotherapy, with 90% having negative HBsAg status 2 years after liver transplant.¹¹ Similarly, Stravitz and associates demonstrated that the tenofovir plus emtricitabine combination prevented the recurrence of HBV after transplant. Their sample consisted of 32 patients who received grafts for HBV-related diseases.1 In another study, Ahn and Cohen studied 28 patients who underwent liver transplant. This group showed that nucleoside or nucleotide analogue antiviral therapy alone was effective in limiting HBV after transplant.9 These studies may pave a way toward an HBIG-free regimen for HBV prophylaxis to be used in the near future.

Initially, it was suggested that HBIG prophylaxis should continue lifelong. With the introduction of potent antiviral regimens (ie, entecavir and tenofovir), HBIG can now be stopped early and prophylaxis can continue with antiviral agents only. Although decreasing the required dose of HBIG is financially feasible, discontinuation of HBIG is still controversial.²³ The combination of HBIG plus antiviral agents can be continued for several years or indefinitely. However, cost and compliance are considered to be the major obstacles. More recently, antiviral agents in combination with low-dose intramuscular administration of HBIG has been proposed, but the optimal duration of HBIG is yet to be defined.^10,24,25 In a recent study, Akcam and associates reported that the combination of low-dose HBIG plus antiviral therapy was effective against HBV recurrence.¹²

Our present study showed no differences in survival in the use of antiviral agents alone versus the combination of HBIG plus antivirals 1 and 5 years after liver transplant. In addition, we found no difference in survival between the use of HBIG alone versus the HBIG plus antiviral combination. At this point, which treatment should be selected for HBV prophylaxis? In the lamivudine era, there was a risk of lamivudine resistance. Presently, the more potent antiviral agents (entecavir and tenofovir) are being used for HBV prophylaxis in the absence of HBIG administration. In this study, we did not explore the recurrence rates of HBV and limited our investigation to the effect of HBV after exposure, as evidenced by HBcAb positivity, on overall posttransplant short-term (1 year) and long-term (5 year) survival. In this limited retrospective study, there was no additional effect of HBIG on survival.

The present guidelines recommend no prophylaxis for HBcAb-positive liver transplant recipients with HBsAg-negative status who receive a liver from an HBcAb- and HBsAg-negative donor. Prophylaxis with HBIG and antiviral agents is indicated if the recipient is HBsAg and HBcAb positive, regardless of donor status. In this case, the timing of HBIG administration (ie, short-term vs long-term therapy) is decided by the HBV DNA at the time of transplant. If HBV DNA is positive at the time of liver transplant, then long-term HBIG therapy is warranted. If the donor is HBcAb positive and HBsAg negative and the recipient is HBsAg negative, then antiviral therapy without HBIG is recommended to prevent HBV recurrence.²⁶ Our results investigated outcomes of liver transplant recipients who were HBcAb positive, with 25% of the recipients having HBsAg-positive status. Limited sample sizes for different categories precluded subgroup survival analyses.

There are several limitations of our study. First, the retrospective nature of the study may have limited our inference of causality. Second, we did not explore the efficacy of interventions on graft survival. Third, we did not explore HBV recurrence in various intervention groups. Finally, our limited sample size for various intervention groups within different HBV exposure categories severely limited our analyses. Despite these limitations, our study provides evidence regarding HBV prophylaxis and suggests a possible role of antiviral therapy alone in the near future.

In conclusion, among liver transplant recipients previously exposed to HBV and with HBcAb-positive status, there were no differences in short-term and long-term survival benefits with the combination of HBIG and antiviral agents versus antiviral agents alone. At this time, it is too early to point toward the effectiveness of antiviral agents alone in HBV prophylaxis after transplant. The role of potent antiviral agents needs to be further studied either alone or in conjunction with minimal dose of HBIG. Although our findings may substantiate emerging evidence regarding the use of novel antiviral agents such as entecavir and tenofovir and their role for HBV prophylaxis after liver transplant, prospective and randomized controlled trials may be warranted to confirm further these findings.

Volume: 15 Issue: 2 April 2017

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