Abbreviations
- anti‐HBc
hepatitis B core antibody
- anti‐HBs
hepatitis B surface antibody
- BMD
bone mineral density
- HB
hepatitis B
- HBsAg
hepatitis B surface antigen
- HBV
hepatitis B virus
- Hep B‐CpG
hepatitis B‐cytosine phosphoguanine
- hgbNA
high genetic barrier nucleos(t)ide analogue
- LAM
lamivudine
- LFT
liver function test
- NASH
nonalcoholic steatohepatitis
- TAF
tenofovir alafenamide
- TDF
tenofovir disoproxil fumarate
The incidence of hepatitis B virus (HBV) infection in the United States has increased in recent years, and organ procurement from patients who are hepatitis B core antibody (anti‐HBc) positive is a means to expand the donor pool.1 We present a patient who underwent combined deceased donor liver and kidney transplant from an anti‐HBc‐positive donor who developed breakthrough hepatitis B viremia 4.5 years after transplant while receiving lamivudine (LAM) prophylaxis. We provide a review on HBV preventive practices in these patients and emphasize advances in antiviral drug prophylaxis and immunization.
Case Report
A 78‐year‐old woman with a history of nonalcoholic steatohepatitis (NASH) cirrhosis and end‐stage renal disease who underwent combined deceased donor liver and kidney transplant from an anti‐HBc‐positive donor was found to have newly detectable serum HBV DNA on surveillance laboratory results 4.5 years after transplantation while receiving LAM prophylaxis with adherence corroborated by pharmacy refill history.
The patient was initially diagnosed with NASH cirrhosis in 2009. In 2015, she was admitted with hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding. She was placed on the transplant waitlist with a Model for End‐Stage Liver Disease–Sodium score of 24. Her pretransplant HBV serological markers were notable for negative hepatitis B surface antigen (HBsAg), undetectable hepatitis B surface antibody (anti‐HBs), negative anti‐HBc, negative hepatitis B e‐antigen, and negative hepatitis B e‐antibody.
The patient underwent combined deceased donor liver and kidney transplant a month after listing from an HBsAg‐negative, anti‐HBc‐positive donor and was started on prophylactic entecavir posttransplant. Other prophylactic antimicrobials included dapsone and valganciclovir. Her induction immunosuppression consisted of basiliximab and methylprednisolone, and her immunosuppressant regimen consisted of cyclosporine, mycophenolate mofetil, and prednisone. Posttransplant history was notable for mild biopsy‐proven acute cellular rejection 5 months posttransplant that resolved with a 3‐day course of methylprednisolone.
The patient remained on entecavir for HBV prophylaxis from 2015 to mid‐2016. Entecavir was stopped because of cost and transitioned to LAM. She continued to follow up regularly with transplant surgery and hepatology with liver function tests (LFTs) and HBV DNA level monitoring every 6 months, except for a 15‐month lapse between mid‐2018 and late 2019 because of missing an outpatient appointment because of a hospital admission.
In late 2019, 4.5 years after her combined liver‐kidney transplant and 3 years after switching to LAM prophylaxis, the patient was found to have HBV viremia with a peak viral load of 17 million IU/mL while taking tacrolimus, mycophenolate mofetil, and prednisone 5 mg daily. Her LFTs remained within normal range, and she was asymptomatic. A hepatitis B resistance profile (Quest Diagnostics, San Juan Capistrano, CA) revealed HBV genotype C and polymerase mutation rendering resistance to LAM and telbivudine (M204I) and susceptibility to adefovir and entecavir.
The patient was started on tenofovir disoproxil fumarate (TDF) and transitioned to tenofovir alafenamide (TAF) a month later given concerns for renal and bone mineral density (BMD) complications with indefinite therapy. While receiving TAF, the HBV viral load decreased to 190 IU/mL in early 2020 and the patient remained asymptomatic and without LFT elevation.
Discussion
This case demonstrates a patient who acquired de novo HBV infection after kidney and liver transplant from an anti‐HBc‐positive donor despite LAM prophylaxis. Breakthrough HBV infection while taking LAM prophylaxis and development of LAM resistance highlight the importance of indefinite HBV DNA surveillance every 3 to 6 months in these patients.2
Isolated anti‐HBc positivity can signify four distinct scenarios (Table 1). Although the risk for breakthrough HBV infection after liver transplant from an anti‐HBc‐positive donor while receiving prophylaxis is low, this risk is highest in noninfected, nonimmune (anti‐HBc‐ and anti‐HBs‐negative) recipients and lowest in anti‐HBs and/or anti‐HBc‐positive recipients.3 Although rituximab has been associated with increased risk for HBV reactivation,4 there is no reported link between basiliximab, which was used for induction immunosuppression in this patient, and HBV reactivation. In a study of 631 anti‐HBc‐positive kidney transplant recipients who received basiliximab, antithymocyte globulin, or a combination of antithymocyte globulin and rituximab as induction therapy and received no HBV prophylaxis, 2 patients showed evidence of HBV reactivation after kidney transplant.5 One patient received antithymocyte globulin and methylprednisolone for induction immunosuppression, and the other patient received basiliximab and methylprednisolone for induction immunosuppression. Because of the low numbers, further analyses regarding risk factors for HBV reactivation could not be performed.
TABLE 1.
Interpretation of Select Hepatitis B Serologies
| Tests | Results | Interpretation |
|---|---|---|
| HBsAg | Negative | Nonimmune, noninfected (susceptible) |
| Anti‐HBc | Negative | |
| Anti‐HBs | Negative | |
| HBsAg | Negative | Immune as a result of natural infection |
| Anti‐HBc | Positive | |
| Anti‐HBs | Positive | |
| HBsAg | Negative | 4 possibilities |
| 1. Recovery from acute infection | ||
| 2. Distant infection with disappearance of anti‐HBs | ||
| 3. Occult chronic infection with undetectable HBsAg as a result of mutation | ||
| 4. False positive; nonimmune, noninfected (susceptible) | ||
| Anti‐HBc | Positive | |
| Anti‐HBs | Negative |
Current guidelines from the American Society of Transplantation recommend indefinite antiviral prophylaxis with LAM for nonimmune recipients of liver transplants from anti‐HBc‐positive donors because it is most cost‐effective.2 A concern with this approach is the development of breakthrough HBV infection with long‐term LAM therapy, leading some guidelines to preferentially recommend newer generation nucleos(t)ide analogues with higher genetic barrier to resistance, such as TDF, TAF, or entecavir.6, 7 TAF, a prodrug of tenofovir, undergoes activation intracellularly, thereby decreasing plasma tenofovir levels and the deleterious effects on renal function and BMD.6 TAF can be administered if creatinine clearance remains greater than 15 mL/min, whereas TDF is not recommended for patients with creatinine clearance less than 60 mL/min. Dose‐adjusted entecavir is an option for patients with more advanced renal dysfunction but should be avoided in the presence of LAM resistance because of increased risk for entecavir resistance over time.6 Although these newer agents are options for antiviral prophylaxis, their use can be limited by their higher cost and lack of insurance coverage (Table 2). Notably, hepatitis B immune globulin administration is not required in combination with antiviral prophylaxis to prevent HBV infection in recipients of livers from anti‐HBc‐positive donors.8
TABLE 2.
Profile of Commonly Used Nucleos(t)ide Analogues
| Nucleos(t)ide Analogue | Daily Dose* | Key Characteristics | Annual Cost† (as of October 2020) |
|---|---|---|---|
| LAM | 100 mg | High rate of resistance with prolonged use | $5,872.85 |
| Adefovir dipivoxil | 10 mg | Effective against LAM‐resistant mutants, although some resistance seen with prolonged use | $13,829.85 |
| Entecavir | 0.5 mg | hgbNA, yet resistance more likely in LAM‐resistant mutants | $16,202.35 |
| TDF | 300 mg | hgbNA without documented resistance in patients with HBV monoinfection | $14,793.45 |
| TAF | 25 mg | hgbNA without documented resistance in patients with HBV monoinfection, decreased renal and BMD toxicity as compared with TDF | $17,118.50 |
Daily dose for adults with normal renal function.
Generic drug pricing (from UpToDate, Waltham, MA; accessed on November 4, 2020).
Immunization can be effective in the prevention of HBV infection in recipients of liver transplants from anti‐HBc‐positive donors.9 Pretransplant anti‐HBs levels >1000 IU/L are associated with sustained anti‐HBs levels >100 IU/L posttransplant and greater protection against HBV infection.9 Factors associated with suboptimal vaccine response include older age, male sex, comorbidities, including diabetes mellitus, cirrhosis, body mass index ≥25 kg/m2, and smoker status.10 Immunization should ideally occur prior to the onset of chronic liver disease and before liver transplantation. The new recombinant hepatitis B vaccine (Hep‐CpG, HEPLISAV‐B) has a better seroprotective rate than conventional recombinant hepatitis B vaccines (Energix‐B, Recombivax HB) even in patients expected to have decreased immune response (Table 3).11
TABLE 3.
Hepatitis B Vaccines
| Vaccine | Key difference | Administration* | Advantages |
|---|---|---|---|
| Recombivax HB/Energix‐B | Aluminum adjuvant | 40 μg at standard (0, 1, and 6 months) or accelerated (0, 1, 2, and 12 months) schedules | Available worldwide |
| Well studied in all populations | |||
| Heplisav‐B | Immunostimulatory adjuvant (HepB‐CpG) | 20 μg at 0 and 1 month | Two‐dose series |
| Quicker seroprotection† | |||
| Increased immunogenicity† |
Recommended dosing for individuals with immunocompromising condition, such as chronic liver disease.
As compared with Energix‐B vaccine.
In summary, LAM prophylaxis is a reasonable and cost‐effective approach to prevent HBV infection in treatment‐naive, nonimmune recipients of anti‐HBc‐positive donors. However, LAM resistance with prolonged use, particularly in nonimmune recipients, is an important concern and requires surveillance. We did not find a link between basiliximab use and subsequent HBV reactivation in the literature. Newer generation nucleos(t)ide analogues with high genetic barrier to resistance are alternatives to LAM presuming insurance coverage. The use of HEPLISAV‐B can protect against HBV and should be administered as early as possible in patients with chronic liver disease. These HBV preventive strategies can optimize outcomes for liver transplant recipients who receive organs from anti‐HBc‐positive donors, and they allow for safer expansion of the donor organ pool.
Potential conflict of interest: Nothing to report.
References
- 1.Verna EC, Schluger A, Brown RS Jr. Opioid epidemic and liver disease. JHEP Rep 2019;1:240‐255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Huprikar S, Danziger‐Isakov L, Ahn J, et al. Solid organ transplantation from hepatitis B virus‐positive donors: consensus guidelines for recipient management. Am J Transpl 2015;15:1162‐1172. [DOI] [PubMed] [Google Scholar]
- 3.Munoz SJ. Use of hepatitis B core antibody‐positive donors for liver transplantation. Liver Transpl 2002;8(10 Suppl. 1):S82‐S87. [DOI] [PubMed] [Google Scholar]
- 4.Kim IK, Kim BG, Kim W, et al. Clinical prediction of failure of Lamivudine prophylaxis for hepatitis B virus‐infected patients undergoing cytotoxic chemotherapy for malignancy. Antimicrob Agents Chemother 2012;56:5511‐5519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Querido S, Weigert A, Adragão T, et al. Risk of hepatitis B reactivation in hepatitis B surface antigen seronegative and core antibody seropositive kidney transplant recipients. Transpl Infect Dis 2019;21:e13009. [DOI] [PubMed] [Google Scholar]
- 6.Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Clin Liv Dis 2018;12:33‐34. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Chang MS, Olsen SK, Pichardo EM, et al. Prevention of de novo hepatitis B in recipients of core antibody‐positive livers with lamivudine and other nucleos(t)ides: a 12‐year experience. Transplantation 2013;95:960‐965. [DOI] [PubMed] [Google Scholar]
- 8.Fung J, Wong T, Chok K, et al. Long‐term outcomes of entecavir monotherapy for chronic hepatitis B after liver transplantation: results up to 8 years. Hepatology 2017;66:1036‐1044. [DOI] [PubMed] [Google Scholar]
- 9.Wang SH, Loh PY, Lin TL, et al. Active immunization for prevention of de novo hepatitis B virus infection after adult living donor liver transplantation with a hepatitis B core antigen‐positive graft. Liver Transpl 2017;23:1266‐1272. [DOI] [PubMed] [Google Scholar]
- 10.Herta T, Petroff D, Engelmann C, et al. Hepatitis B vaccination in patients with liver cirrhosis evaluated for liver transplantation ‐ a simple intervention ensures high adherence. Ann Transpl 2019;24:527‐531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Rhee Y, Sha BE, Santos CAQ. Optimizing vaccination in adult patients with liver disease and liver transplantation. Clin Liv Dis 2020;15:63‐68. [DOI] [PMC free article] [PubMed] [Google Scholar]