The risk of de novo hepatitis B virus infection is lower after liver transplant using hepatitis B core antibody-negative donors into negative recipients versus hepatitis B core antibody-positive donors but can occur. Here, we present a 34-year-old male patient with acute de novo hepatitis B virus that developed 7 months after successful liver transplant. The case we report here is the first in the literature with regard to both switch from tenofovir to entecavir treatment and the presentation of de novo acute hepatitis B virus after liver transplant. The switch in treatment protocol resulted in significant improvements in serologic and biochemical levels, and the patient was discharged from the hospital on day 35 after admittance.
Key words : Acute liver failure, Entecavir, Fulminant disease, Tenofovir
Risk of de novo hepatitis B virus (HBV) infection is extremely low after transplant of liver grafts from hepatitis B core antibody (anti-HBc)-negative donors to hepatitis B surface antigen (HBsAg)-negative recipients, with incidence that ranges from 0% to 1.7%.1 Therefore, the ideal way to care for this patient group is still a debated subject. Here, we present a case of acute de novo HBV that developed 7 months after liver transplant.
A 34-year-old male patient presented to our liver transplant center with signs and symptoms of toxic hepatitis. His history was notable for alcohol intake 3 days per week for 15 years; he had also been taking some admixtures to boost his condition during the past 3 months. Biochemical analyses showed the following: HbsAg negative, hepatitis B e antigen (HbeAg) negative, anti-HBc total negative, anti-HBs negative, anti-Hbe negative, ammonia level of 264 μg/dL, alanine aminotransferase (ALT) level of 56 U/L, aspartate aminotransferase (AST) level of 76 U/L, total bilirubin of 1.65 mg/dL, alkaline phosphatase of 255 U/L, gamma-glutamyltranspeptidase (GGT) of 155 U/L, and lactate dehydrogenase level of 366 U/L.
The patient underwent right lobe living-donor liver transplant from his 38-year-old sister (anti-HBc total negative, anti-HBs negative, and HBsAg negative). Because he developed signs of posttransplant tacrolimus-associated neurotoxicity, low-dose tacrolimus and everolimus were started, with the patient discharged uneventfully on day 14. His biochemical tests were all normal at 1, 3, and 5 months. At 7 months posttransplant, however, the following biochemistry and serology results were obtained: AST of 384 U/L, ALT of 496 U/L, total bilirubin of 0.48 mg/dL, international normalized ratio of 1.54, tacrolimus level of 8.6 ng/mL, everolimus level of 5.2 ng/mL, HbsAg of 5374 sample-cutoff ratio, HbeAg of 1.2 sample-cutoff ratio positive, anti-HBc immunoglobulin M of 40.3 sample-cutoff ratio, hepatitis D virus RNA polymerase chain reaction (PCR) negative, and HBV DNA PCR result of 26.9 billion copies/mL.
The patient was admitted to allow close monitoring and was started on a treatment protocol that consisted of bed rest, liver-protective diet, low-dose tacrolimus, and 245 mg tenofovir. Levels of ALT and AST continued to increase during treatment, and bilirubin level started to increase significantly from week 2 onward. Tenofovir treatment was therefore stopped; because enzyme levels did not drop, entecavir dose of 0.5 mg/day was commenced a few days later on the recommendation of the hepatology council. This new treatment protocol resulted in significant improvements in serologic and biochemical levels (HBV DNA PCR of 42 million copies/mL, AST of 70 U/L, ALT of 109 U/L, GGT of 209 U/L, bilirubin of 2.8 mg/dL, international normalized ratio of 1.2). The patient was discharged on tacrolimus (2 mg/day) and entecavir (0.5 mg/day) on day 35. Follow-up biochemistry and serology results 3 months after discharge were as follows: HBsAg negative, anti-HBs level of 919 IU/mL, AST of 36 U/L, ALT of 40 U/L, total bilirubin of 0.8 mg/dL, GGT of 62 U/L, and alkaline phosphatase of 110 U/L. Changes in liver function tests are shown in Figures 1 to 3.
The rate of de novo HBV rises considerably after liver transplant with anti-HBc-positive donors in the absence of prophylaxis. Although the risk of de novo HBV infection is lower after liver transplant using anti-HBc-negative donors, there is however a limited number of publications about the treatment of these patients.1 Douglas and associates1 reported that only 2 patients (0.5%) developed de novo acute HBV infection after liver transplant from 323 anti-HBc-negative donors.
One of the patient groups known to have relatively worse prognosis is transplant patients who receive immunosuppressive therapy. The clinical course of HBV infection depends on the balance between the host’s defense and the virus’s replication ability. This balance usually works against the host among patients who use immunosuppressive agents, and the risk of contracting HBV infection or HBV reactivation is increased. The main problem in these patients is the potential for rejection of the transplanted liver due to stopping immunosuppressive treatment or when the dose is temporarily reduced. To avoid this experience, we opted to reduce the immunosuppressive doses rather than completely stop administration.
Acute liver failure develops in less than 1% to 5% of patients with acute HBV infection.2,3 That is, because acute HBV infection is mostly a self-limiting disease, many patients fare well solely with rest and a liver-protective diet, without commencing antiviral treatment. However, there is an indication for starting antiviral treatment for patients who have fulminant and severe acute HBV infection.4 Guidelines from the Asian Pacific Association for the Study of the Liver (APASL) recommend using antiviral treatment for fulminant or severe acute HBV infection.2 The European Association for the Study of the Liver (EASL) guidelines advocate that starting a highly potent antiviral treatment early in the course of fulminant or severe acute HBV infection will prevent the disease from progressing to acute liver failure.3 The recommendations of both guidelines regarding HBV infection are mostly for nontransplant patients with HBV. However, it should be noted that transplant patients may have a relatively worse prognosis. The indications for starting antiviral treatment should be more flexible and treatment monitoring should be stricter among these patients.
Despite the general trend for the treatment of acute HBV infection to use potent antiviral agents with lower resistance rate, such as tenofovir and entecavir, published guidelines have yet to reach a consensus. Mantzoukis and associates5 analyzed the recommendations of the two guidelines (EASL and American Association for the Study of Liver Diseases) for the medical treatment of acute HBV infection. According to the EASL guidelines, entecavir and tenofovir are the most appropriate agents. This guideline states that antiviral treatment should be continued for at least 3 months after anti-HBs appear or at least 12 months after anti-HBe appear. Guidelines from the American Association for the Study of Liver Diseases recommend that lamivudine or telbivudine be used when the expected treatment duration is short. Otherwise, entecavir is the most appropriate therapeutic agent. Treatment should be continued until HBsAg becomes negative or should be indefinite when transplant is contemplated. In our view, among patients who develop de novo acute HBV infection after liver transplant, antiviral treatment should be continued for 6 to 12 months after HBsAg becomes negative. Our approach with the patient presented here was based on that principle.
The major guidelines in hepatology fall short for guiding treatment of de novo acute or fulminant HBV after liver transplant. It is the most prudent approach to reduce the intensity of immunosuppressive treatment as much as possible and to start an antiviral agent among patients who acquire de novo acute HBV infection after liver transplant. However, the main complication among these patients is hepatocyte cell death or destruction as a result of apoptosis, and antiviral treatment can worsen hepatocyte injury by aggravating or intensifying the underlying HBV infection. Although some publications have reported the switch between tenofovir and entecavir for the treatment of chronic HBV, no study has yet investigated the switch between these 2 agents for the treatment of acute de novo HBV infection. The case we report here is the first in the literature with regard to both switch from tenofovir to entecavir treatment and the presentation of de novo acute HBV after liver transplant.
Volume : 16
Issue : 5
Pages : 635 - 637
DOI : 10.6002/ect.2018.0072
From the 1Department of Surgery and Liver Transplant Institute and the
of Gastroenterology and Hepatology, Inonu University Faculty of Medicine,
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Sami Akbulut, Department of Surgery and Liver Transplant Institute, Inonu University Faculty of Medicine, Elazig Yolu 10. Km, Malatya 44280, Turkey
Phone: +90 422 3410660
Figure 1. Blood Aspartate Aminotransferase and Alanine Aminotransferase Levels During Tenofovir and Entecavir Treatment
Figure 2. Blood Gamma-Glutamyltranspeptidase and Alkaline Phosphatase Levels During Tenofovir and Entecavir Treatment
Figure 3. Blood Total Bilirubin Level During Tenofovir and Entecavir Treatment