Case study:Managing HBV Infection Following Liver Transplant

StephenW

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Case Study:
Managing HBV Infection Following Liver Transplant                              (Course HBV6.17)                                                                         
Published on December 09, 2011 Tx Reporter e-Newsletter                                          
                                            
                                      
            Faculty: Mindie Nguyen, MD
Medical Writer: Nancy J. Nordenson, MT (ASCP), MFA
            
                                                                                                                                             

                    
                                                        
     

            

Patient Description

     

A 52-year-old Asian man underwent an orthotopic liver transplant for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). At the time of HCC diagnosis—approximately 1.5 years prior to his transplant—the patient had been started on entecavir 0.5 mg daily for indication of HCC, elevated HBV DNA viral level (1.2 million IU/mL), and mildly elevated alanine aminotransferase (52 U/L). He was hepatitis B e antigen (HBeAg) negative. He responded well to therapy, with an undetectable HBV DNA for at least 9 months prior to the transplant. Comorbidities include diabetes mellitus and hypertension, both controlled with medication.

     

The patient had an uneventful liver transplant and postoperative course. He received induction intravenous hepatitis B immunoglobulin (HBIg) according to center protocol (20,000 IU over 1 hour daily for 6 days) to target a trough hepatitis B surface antibody (anti-HBs) level of approximately 500 IU/L for the first week. He also received ongoing entecavir. After the first week, the anti-HBs target level was reduced to 100 to 150 IU/L, as per center protocol. There was no acute rejection. At his 1-month follow-up visit, the patient's only immunosuppressant was tacrolimus with an average trough level of approximately 10 to 12 ng/mL.

     

At his 3-month follow-up visit, the patient asked if he could stop HBIg and/or entecavir since he has been doing well and has a high deductible with his insurance coverage.

   

Clinical Decision Point 1: HBV Prophylaxis 3 Months Posttransplant

     

Question 1: Which of the following would be the most appropriate recommendation at this time?

• Stop HBIg
• Stop entecavir
• Continue HBIg and entecavir
  

         

Discussion

     

(c) In the era prior to posttransplant HBV prophylaxis, recurrent HBV infection was the most common cause for reduced survival in patients undergoing orthotopic liver transplant due to HBV-related liver disease.1 Eighty percent of HBV-infected transplant recipients developed HBV reinfection,1 and survival at 1 and 5 years was 71% and 53%, respectively.2 Current HBV prophylaxis with long-term HBIg plus a nucleos(t)ide analog has significantly improved outcomes, preventing reinfection in more than 90% of patients in the first 2 years posttransplant1 and increasing the 1-year survival to 87% and the 5-year survival to 76%.2 Although studies have explored limiting the duration of posttransplant prophylaxis, it is advisable not to discontinue either HBIg or entecavir in this patient at this time. He is only 3 months posttransplant and his history of HCC places him at higher risk of HBV recurrence,3 despite undetectable HBV DNA levels prior to transplant.

               

What impact does HBeAg status have on the risk of HBV recurrence posttransplant?

      

HBIg has been central to the prevention efforts of recurrent chronic hepatitis B posttransplant since the early 1990s. In a retrospective multicenter European study published by Samuel et al in 1993, 372 consecutive HBsAg-positive patients who underwent a liver transplant were evaluated for HBV recurrence.4 Of the 359 patients for whom information on HBIg administration is available, 209 received long-term HBIg monotherapy (6 or more months), 83 received short-term HBIg monotherapy (2 or fewer months), and 67 received no HBIg. In multivariate analysis, long-term administration of HBIg was an independent predictor of a lower risk of HBV recurrence. The 3-year risk of HBV recurrence posttransplant was 36% in patients who received long-term HBIg compared with 74% in patients who received short-term HBIg and 75% in patients who received no HBIg (P <.001, long-term HBIg versus short-term and no HBIg combined). Other independent predictors of a lower risk of HBV recurrence in multivariate analysis were hepatitis D virus superinfection and acute liver disease. Univariate analysis identified these same predictors as well as the absence of HBV DNA and absence of HBeAg prior to transplant.

     

Lamivudine was the first nucleoside analog to be combined with HBIg for HBV prophylaxis in the posttranplant setting. Initial small cohort studies of lamivudine monotherapy in this setting showed promising results at 1 year.1 However, prolonged therapy resulted in YMDD mutations, leading to HBV recurrence in 22% to 50% of patients over follow-up of 16 to 38 months.1 Subsequent studies found improved outcomes when HBIg and lamivudine were combined.1 With combination therapy, not only is the risk of HBV recurrence within 2 years cut to 10% or less, but also HBV DNA levels are typically negative several years after transplant.1

     

A recent meta-analysis compiled data from 20 studies (22 comparisons)—including randomized-controlled and nonrandomized clinical trials, prospective one-arm trials with historic controls, and retrospective and prospective cohort studies—to compare the efficacy of HBIg monotherapy, nucleoside analog monotherapy (lamivudine or adefovir), or HBIg/nucleoside analog combination therapy in preventing HBV recurrence in HBV-infected liver transplant recipients.5 Among the 22 comparisons, 10 compared HBIg monotherapy to combination therapy, nine compared nucleoside analog monotherapy to combination therapy, and three compared HBIg monotherapy to nucleoside analog monotherapy. The findings showed the superiority of combination therapy compared with HBIg alone in the primary outcome, HBV recurrence defined as reappearance of serum HBsAg, and in secondary outcomes, including overall mortality, HBV-related mortality, occurrence of HBV-related active liver disease, and reappearance of serum HBV DNA. The relative risk of HBV recurrence with the combination of HBIg plus a nucleoside analog compared with HBIg monotherapy was 0.28 (0.12–0.66); similarly, the relative risk of HBV recurrence with combination therapy compared with nucleoside analog monotherapy was 0.31 (0.22–0.44).

     

More potent antiviral agents with high genetic barriers to resistance, such as entecavir or tenofovir combined with HBIg, are now preferred in the posttransplant setting, particularly in patients with pre-existing resistant mutations, due to the risk of multidrug resistant mutations.6 In general, tenofovir is a good choice in patients with lamivudine exposure and potential resistance prior to transplant.6 Entecavir is a good choice in patients with high HBV DNA levels prior to transplantation or when there is concern about nephrotoxicity.6 Although lamivudine has worked well in this setting for many years, it is not the treatment of choice. With the current trend being to remove HBIg earlier and earlier, the risk of exposing patients to potential antiviral resistance with lamivudine may complicate their antiviral treatment when HBIg is removed. Although data from large-sample clinical trials of entecavir and tenofovir in the posttransplant setting are lacking, small cohort studies support their use when combined with HBIg.7,8

     

The prophylactic efficacy of HBIg combined with a nucleoside analog appears to be due to their different and synergistic mechanisms of action.5 While HBIg's mechanism has not been clearly elucidated, it likely binds to and neutralizes circulating virions and induces lysis of infected hepatocytes, thereby inhibiting cell-to-cell infection.5,9 In contrast, nucleos(t)ide analogs reduce viral load in the liver and extrahepatic sites by direct antiviral activity.5

     

Transplant centers vary according to the dosing, frequency, and method of HBIg administration used, duration of HBIg, and duration of antiviral therapy.1 In general, however, the traditional approach is to administer HBIg intravenously at a dose of 10,000 U during the anhepatic phase at the time of orthotopic transplant. It is continued daily at this or a lower dose during the first postoperative week to maintain an anti-HBs titer of greater than 500 IU/L. A nucleos(t)ide analog is also administered according to the dose recommended in product labeling. The amount of HBIg needed thereafter may vary according to pretransplant HBV DNA levels, with the amount needed potentially reduced in patients with undetectable levels. Patients with undetectable HBV DNA levels prior to transplant may be maintained thereafter at an anti-HBs titer of 100 to 150 IU/L. Patients with detectable HBV DNA levels prior to transplant should receive HBIg at a sufficient dose and frequency to achieve an anti-HBs titer greater than 500 IU/L for the first month, a titer greater than 250 IU/L through the third month or longer, followed by a titer greater than 100 to 150 IU/L thereafter.

     

Two approaches exist for HBIg dosing. The first approach is to titrate the HBIg dose and/or frequency to a target anti-HBs titer.1 The second approach is to administer HBIg at a fixed schedule and at a dose high enough to ensure an anti-HBs titer higher than the target.1 Two modes of HBIg administration also exist: intravenous and intramuscular. Intramuscular administration is less costly compared with intravenous, yet has similar pharmacokinetic properties6 and may be an option for patients who can be maintained on the limited amount of HBIg that can be delivered in a single injection.1 In a study of 59 HBV-infected liver transplant recipients who were prospectively followed after being switched from intravenous HBIg to intramuscular HBIg in combination with lamivudine, 58/59 (98.3%) patients were HBsAg negative after a median follow-up period of 511 days.10 One third of patients, however, needed a median of one supplemental intravenous HBIg infusion to maintain sufficient antibody titers.10

     

The traditional approach of using high-dose intravenous HBIg (10,000 IU/day then on-demand targeting "protective" anti-HBs trough titer >500 IU/L) has been challenged by recent studies showing a similar HBV recurrence rate with low-dose intramuscular HBIg in combination with a nucleos(t)ide analog. A prospective study from Australia and New Zealand reported efficacy and safety data of a low-dose HBIg strategy in which patients received 400 to 800 U HBIg by intramuscular injection daily for 1 week posttransplant then monthly thereafter in combination with lamivudine.11 The study followed 147 patients for a median of 1860 days and found the risk of HBV recurrence to be 1% at 1 year and 4% at 5 years.11 A more recent review of data from the National Institutes of Health 15-center study on &quotrevention of HBV Recurrence after Liver Transplantation" reported on outcomes of various prophylactic strategies in 187 patients who received livers between 2001 and 2007.12 All but six patients received both HBIg and a nucleos(t)ide analog. In order of frequency, the HBIg regimens used were intramuscular low dose (39%), intravenous high dose (25.1%), intravenous low dose (21.4%), and HBIg of finite duration (12.3%; median, 12 months). The groups were similar in terms of pretransplant HBV DNA levels, HBeAg status, use of antiviral therapy, and virologic breakthrough. The overall rate of HBV recurrence was 6.9% after a median follow-up of 42 months and 9% after 5 years. Five-year recurrence rates were comparable across the four groups: intravenous high dose, 10%; intravenous low dose, 3%; intramuscular low dose, 10%; and finite duration, 14% (P = .733).

     

Due to this patient's concern about cost, he could switch from intravenous to intramuscular HBIg. The cost of intramuscular HBIg, however, would still easily exceed the deductible that this patient is trying to avoid.

               

What are the adverse effects of HBIg?

   

Case Continues

     

The patient returned for his 1-year follow-up visit. He reported that he had been doing well, which was consistent with laboratory and HCC surveillance findings. His graft function was stable with liver enzymes within normal range. His calculated creatinine clearance was 60 mL/minute. His recent serum alpha-fetoprotein and surveillance computed tomography scan were negative for evidence of recurrent HCC. His HBV DNA level was undetectable and HBsAg was negative.

            

What is the HBV monitoring protocol for patients posttransplant?

        

Clinical Decision Point 2:  Duration of HBV Prophylaxis

     

Question 2: Since the patient is now more than 1 year from liver transplant, which of the following is the most reasonable option for HBV prophylaxis for him at this time?

   

• Stop HBIg and entecavir
• Stop HBIg and add tenofovir
• Continue HBIg and entecavir
• "b" or "c"
  

         

Discussion

     

(d) Efforts to reduce therapy—particularly dose or duration of HBIg—after a reasonable period of time in low-risk patients are the subject of ongoing evaluation. Studies evaluating alternative strategies have primarily been done in low-risk patients, with none focused exclusively on patients with transplant due to HCC. As noted above, the presence of HCC increases the risk of HBV recurrence posttransplant, with one study reporting a greater than three-fold higher risk.3 Although the patient had undetectable HBV DNA prior to transplant and at 1 year posttransplant, which would otherwise place him in a category of low risk for HBV recurrence, his HCC diagnosis continues to be a significant risk factor. Therefore, it would not be reasonable to discontinue all prophylaxis for this patient, but it would be reasonable to consider replacing HBIg with tenofovir or to continue as he has with both HBIg and entecavir.

               

Why does HCC increase the risk of HBV recurrence?

        

Since most cases of HBV recurrence developed during the first year, the potential for HBIg discontinuation after 1 or 2 years is a legitimate question.4 Saab et al conducted a retrospective single-center study that followed 61 liver transplant recipients who converted to combination therapy with a nucleoside analog (lamivudine or entecavir) and a nucleotide analog (adefovir or tenofovir) after having received intramuscular HBIg plus lamivudine for at least 12 months.13 HBV infection recurred in two patients (3.3%) at 3.1 and 16.6 months after conversion. Among the 23 patients with a diagnosis of HCC prior to transplant, one patient had recurrence of HCC posttransplant but without HBV recurrence. These data suggest that the combination of a nucleoside analog and a nucleotide analog provide effective prophylaxis 12 months posttransplant and are a reasonable option at this time point, particularly in patients who are compliant with oral medication and for whom close laboratory monitoring could identify evidence of recurrence. The low numbers of patients with HCC, however, also suggest that it would be reasonable to await application of these results to the HCC population.

     

Some investigators have sought to discontinue HBIg earlier than 1 or 2 years posttransplant. Teperman et al reported preliminary data on 37 liver transplant recipients (stable at least 12 weeks posttransplant) who were treated with HBIg plus emtricitabine and tenofovir for 24 weeks, then randomized to emtricitabine and tenofovir with or without HBIg.14 Forty percent of patients had a diagnosis of HCC and 47% had detectable HBV DNA at transplant. At the time of reporting, 35 patients had reached week 72 and 28 had reached week 92. One patient in the nonHBIg group reported a transient increase in HBV DNA at week 84 visit only, consistent with a period of nonadherence.

     

Buti et al compared HBV recurrence in 29 HBV-infected liver transplant recipients who were randomized to receive either HBIg plus lamivudine for 1 month posttransplant followed by lamivudine monotherapy or long-term HBIg plus lamivudine for 17 months.15 The study found that the efficacy of both approaches was comparable with no patients experiencing recurrence. Only one of the study patients had a diagnosis of HCC, however, limiting the application of these data to the HCC population.

     

Complete discontinuation of all HBV prophylaxis has been evaluated in selected transplant recipients (ie, those with undetectable HBV DNA at transplant and no intrahepatic total and cccDNA) with evidence of success.16 However, this approach is not standard-of-care for any patient group.

     

Stratifying patients by risk of HBV recurrence is helpful when making decisions regarding nontraditional prophylactic strategies. Risk factors for recurrence in addition to presence of HCC are shown in the Table.

         

Table. Risk Factors for HBV Recurrence in HBV-Infected Liver Transplant Recipient3

   

Higher pretransplant HBV DNA level (levels greater than 103 copies/mL)

Presence of HCC

No pretransplant antiviral therapy

Posttransplant viral mutation

            

Case Continues

     

On a follow-up visit 2 years later, the patient's blood pressure was 156/82 mmHg. His current medications include: metformin 500 mg BID, lisinopril 5 mg QD, entecavir 0.5 mg QD, tacrolimus 1.0 mg BID, and HBIg intramuscular. His diabetes mellitus was under fair control with an HbA1c level of 6.2%. His calculated creatinine clearance was noted to be 45 mL/minute. Urinalysis revealed no significant sediments. Liver enzymes were normal and HBV DNA was undetectable by polymerase chain reaction. His trough tacrolimus level was 8.2 ng/mL.

         

Clinical Decision Point 3: Management of Impaired Renal Function

     

Question 3: Which of the following would be the best management approach?

• Optimize blood pressure control
• Reduce entecavir to 0.5 mg every other day
• Decrease tacrolimus dosage and maintain patient at a lower therapeutic level with or without addition of a second nonnephrotoxic immunosuppressant as needed and as appropriate
• All of the above
  

         

Discussion

     

(c) Multiple indicators of possible nephrotoxicity are present in the findings of this patient's 2-year posttransplant follow-up visit and are a matter of concern. Uncontrolled hypertension is a well-known cause of renal failure.17 His systolic blood pressure is elevated above the target value of <130/80 mmHg for patients with diabetes mellitus.18 Optimal blood pressure control is important to prevent progressive loss of renal function.17 More specifically, his creatinine clearance has fallen since his 1-year follow-up visit and is now below the acceptable threshold (>50 mL/min) for entecavir administration at the standard dosage19 and is at the level that defines chronic kidney disease in individuals with diabetes.18 While entecavir is not nephrotoxic, it is excreted primarily by the renal system and the dosage needs to be adjusted with renal impairment.19 Tacrolimus, while an effective immunosuppressive agent, is well known for its nephrotoxicity.20 Immunosuppression requirement decreases with time from transplant and therapeutic levels for maintenance therapy can be individualized with close monitoring.

     

Based on these clinical findings, three actions should be taken. First, his blood pressure medication should be adjusted to reach his target value. Second, his entecavir dose should be adjusted. Product labeling approved by the FDA recommends dosage adjustment if the creatinine clearance is less than 50 mL/min.19 The dosage should be reduced to 0.25 mg once daily or 0.5 mg every 48 hours.19 Thirdly, the tacrolimus dosage should be adjusted. Immunosuppression requirement decreases with time from transplant and therapeutic levels can be individualized with close monitoring. Tacrolimus product labeling recommends considering a dosage at the lower end of the therapeutic dosing range in patients who have received a liver transplant and have renal impairment. Further reductions in dose below the targeted range may be required.20 If another oral nucleoside or nucleotide were used, such as lamivudine or tenofovir, their dosage should be adjusted according to renal function as well.

               

What are the considerations for use of anti-HBV nucleoside and nucleotide analogs in patients who are receiving posttransplant immunosuppressants?

     

Case Continues

     

The patient's tacrolimus dose was reduced with a new target trough level of approximately 6 ng/mL. His creatinine clearance stabilized at 50 to 60 mL/min, and his blood pressure returned to good control. Entecavir dosing was increased back to 0.5 mg/day.

                 

How should the expectation of adherence to prescribed HBV prophylaxis be discussed with a patient who is this far after transplant and feeling well?

         

Conclusion

     

HBV prophylaxis is an integral part of managing HBV-infected liver transplant recipients. Current strategies account for a significantly reduced incidence of HBV recurrence and subsequent related morbidity and mortality. While no guidelines currently exist regarding HBV prophylaxis following liver transplantation, the key components of prophylaxis include long-term administration of HBIg and a nucleos(t)ide analog. The precise dosing and administration protocols vary among transplant centers, and the development of new strategies to minimize cost and exposure to HBIg while maintaining efficacy is an ongoing focus of research. An important consideration for the clinician when selecting nontraditional prophylactic strategies is the individual patient's risk level for HBV recurrence. In addition, while focusing on reducing the risk of HBV recurrence in the HBV-infected liver transplant patient over the long term, care must be taken to monitor renal function, and if needed, to make adjustments to medication dosing schedules as needed to prevent progression of impairment.

        




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