Managing HBV Infection Following Liver Transplant: Expert Q&A

Prior to the introduction of effective prophylactic therapy, liver transplantation in patients infected with hepatitis B virus (HBV) resulted in high rates of viral recurrence, allograft loss, and mortality.^1,2 One retrospective study found the risk of HBV recurrence to be as high as 75% in liver transplant patients who were not given immunoprophylaxis.³

Therapeutic advances in the past 2 decades have drastically changed the outlook for patients infected with HBV, turning liver transplantation into a routine procedure.⁴ The introduction of hepatitis B immunoglobulin (HBIg) and nucleoside analogues has significantly reduced HBV recurrence: with HBIg and lamivudine and/or adefovir combination therapy, the risk of recurrent HBV infection is estimated to be <10%.¹ Combination treatment with HBIg and nucleoside analogues with high genetic barrier to resistance, such as entecavir and tenofovir, reduced the risk of HBV recurrence even more — to <5%.⁵ Furthermore, hepatocellular carcinoma, as opposed to liver decompensation, has become the primary indication for liver transplantation.⁶

In an interview with Infectious Disease Advisor, Norah A. Terrault, MD, MPH, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco (UCSF), discussed the recent advances and remaining challenges in managing HBV infection in patients undergoing liver transplantation.

Infectious Disease Advisor: What is the primary indication for liver transplantation in patients with HBV infection?

Norah A. Terrault, MD, MPH: In our transplant center at UCSF, as in others throughout the United States, the majority of patients with HBV have liver cancer as the primary indication for liver transplantation.⁷ The other group of patients in whom we perform liver transplants are patients with acute liver failure due to hepatitis B and those with decompensated cirrhosis. For those with decompensated cirrhosis, these are frequently patients with HBV who present very late to care and who have been undiagnosed and untreated for a very long time.

However, anyone who is engaged in care and having their hepatitis B appropriately managed is generally at low risk of getting decompensated cirrhosis, because current guidelines recommend that patients who have cirrhosis and HBV continue with antiviral therapy for life. Long-term suppressive antiviral therapy would be expected to prevent progression of cirrhosis and decompensated liver disease.

Infectious Disease Advisor: In what percentage of patients does HBV infection recur following liver transplant?

Dr Terrault: With current prophylactic therapies, which have been available for more than 2 decades, recurrence rates are less than 5%. And even in those roughly 5% of patients who get reinfected, we are able to control the progression of infection and injury to the liver because our antiviral therapies are very effective. The number of patients who develop recurrent HBV and actually lose their graft is essentially zero as long as the patient has access to antiviral therapy.

Infectious Disease Advisor: Which prophylactic strategies are currently recommended to prevent recurrent HBV infection following liver transplant, and how effective are they?

Dr Terrault: There is variability from center to center as to what prophylactic therapy is provided. On one end of the spectrum, some centers use antiviral drugs, such as entecavir and tenofovir, only. This approach has been most broadly used in Asia, where the cost and access to HBIg are more limited and where clinicians have more experience with using antivirals alone. In the United State and Europe, we tend to use a combination of HBIg plus antivirals. HBIg is introduced at the time of the surgery and continued for some period of time posttransplant — the duration of HBIg use can be highly variable between centers — from as little as 5 days to several months or years for some patients. Since there have been no randomized controlled trials, the optimal duration of HBIg use is not known and these decisions are mostly based on center practices.

So basically, all patients with hepatitis B who undergo liver transplant receive prophylactic therapy using antiviral therapy (nucleos(t)ide analogues), typically starting pretransplant, continuing posttransplant for life, and some will receive HBIg for variable periods posttransplant.

Infectious Disease Advisor: Which factors influence the choice of prophylactic therapies.

Dr Terrault: The cost of HBIg likely influences treatment practices, as well as availability. Additionally, HBIg is less convenient for patients and providers because it requires intravenous, intramuscular, or subcutaneous administration. In addition to the cost and availability issues, there are some patient characteristics that influence the decision-making about whether to use HBIg as a component of prophylactic therapy. Patients with high risk of recurrent HBV may be better served by combination HBIg plus antivirals, while those with low risk for HBV recurrence may be treated with antivirals alone.

Patients who are at low risk for recurrent HBV include those who have a very low viral load at the time of transplant and patients who don’t have coinfection with hepatitis delta virus (HDV) or human immunodeficiency virus (HIV). Patients in this group may be treated with a very short course of HBIg⁸ or maybe none at all.⁹ Patients at higher risk of recurrence would include patients with HDV or HIV coinfection. In our transplant program, we continue HBIg lifelong in patients who have HDV. Patients with HIV are another group at higher risk of HBV recurrence [and suitable for longer regimens of HBIg], because patients with HIV often have drug-resistant HBV, which leaves them with limited drug options should infection recur.

Infectious Disease Advisor: What are some of the clinical predictors of failed prophylaxis?

Dr Terrault: Historically, the level of viral load at the time of transplant was the best predictor of HBV recurrence. In the current era of prophylaxis, I think the viral load is less important. Data from the Hong Kong group have shown that even patients with a high viral load can undergo successful prophylaxis with antivirals (without use of HBIg). So, I think the viral load is important, but it is not an all-or-none type of predictor of prophylaxis failure. Other patients at potentially higher risk of prophylaxis failure are those who have pre-existing drug-resistant HBV and who have been heavily pretreated and maybe have resistant variants or can develop resistant variants to the antivirals or HBIg. Again, the current prophylaxis combinations make this situation infrequent. Finally, lack of adherence to prophylactic therapy is a recognized reason for prophylaxis failure.

Infectious Disease Advisor: Which questions and challenges still remain in managing HBV infection in liver transplant patients?

Dr Terrault: I think one of the important remaining questions is whether all transplant patients need prophylaxis. There are some patients who may be HBV-free, meaning that the pretransplant antiviral therapy combined with liver transplantation led to clearance of HBV. An interesting study done in Italy took patients who had been on long-term prophylaxis with HBIg and antivirals, and then gradually withdrew the HBIg, and then the antivirals, and showed that a proportion of those patients could be managed without prophylaxis. This study presents a really interesting question and challenge at the same time: Do all liver transplant patients with HBV need lifelong prophylaxis? Can we develop new diagnostic tools to determine whether the patient receiving prophylaxis really needs it? I see this as the remaining area for research. In the future, more insights into who is at risk for recurrence and who is not may allow us to avoid prophylaxis in a select group of patients or at least stop it after a certain amount of time, rather than committing everybody to lifelong therapy. But right now, we are doing extremely well; patients have excellent outcomes and we use prophylactic therapy with a high degree of success.

References

1. Coffin CS, Terrault NA. Management of hepatitis B in liver transplant recipients. J Viral Hepat. 2007;14(Suppl 1):37-44.
2. Jiménez-Pérez M, González-Grande R, Mostazo Torres J, González Arjona C, Rando-Muñoz FJ. Management of hepatitis B virus infection after liver transplantation. World J Gastroenterol. 2015;21(42):12083-12090.
3. Samuel D, Muller R, Alexander G, et al. Liver transplantation in European patients with the hepatitis B surface antigen.N Engl J Med. 1993;329(25):1842-1847.
4. Mohanty SR, Cotler SJ. Management of hepatitis B in liver transplant patients. J Clin Gastroenterol. 2005;39(1):58-63.
5. Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review.Am J Transplant. 2013;13(2):353-362.
6. Al-Hamoudi W, Elsiesy H, Bendahmash A, et al. Liver transplantation for hepatitis B virus: decreasing indication and changing trends. World J Gastroenterol. 2015;21(26):8140-8147.
7. Flemming JA, Kim WR, Brosgart CL, Terrault NA. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology. 2017;65(3):804-812.
8. Radhakrishnan K, Chi A, Quan DJ, Roberts JP, Terrault NA. Short course of postoperative hepatitis B immunoglobulin plus antivirals prevents reinfection of liver transplant recipients. Transplantation. 2017;101(9):2079-2082.
9. 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(4):1036-1044.