A recently published study suggests that it may be possible to provide effective hepatitis B virus (HBV) prophylaxis following liver transplantation by using a combination of oral antiviral agents with only short-term hepatitis B immunoglobulin (HBIG) therapy. According to the investigators, the prophylactic use of effective oral antiviral agents may obviate the inconvenience and cost associated with HBIG infusion in liver transplant recipients at risk of HBV recurrence.¹

Posttransplant prophylaxis is widespread because without it, HBV recurrence is nearly universal and associated with rapid graft failure, need for retransplantation, and increased mortality.^2-5 The gold standard for posttransplant HBV prophylaxis has been periodic infusion of HBIG in conjunction with an oral antiviral agent, which has proven effective in reducing HBV recurrence, even for patients with replicative infection at the time of transplant.⁶ However, HBIG is cumbersome, expensive, and not devoid of side effects (eg, headaches, backache, and flushing) or the potential to induce HBsAg mutations. Therefore, an alternative strategy in preventing HBV recurrence without long-term HBIG therapy would be advantageous. In this era of potent antiviral agents, many clinicians believe, albeit anecdotally, that some patients may come off HBIG and be maintained on an oral agent(s) alone. The recently published article by Nath et al¹ is the first to report the outcomes of a small number of patients who received short-term HBIG without HBIG maintenance therapy.

The investigators retrospectively reviewed medical records of 14 HBV-infected patients who underwent liver transplantation at the University of Minnesota between October 2002 and July 2005. All had received intravenous HBIG 10,000 IU at the time of surgery and the same HBIG dose daily during the first week after transplantation, in conjunction with lamivudine 100 mg/d. They then discontinued HBIG and began taking adefovir 10 mg/d with continued lamivudine therapy. One patient received tenofovir/lamivudine rather than adefovir/lamivudine due to established lamivudine resistance pretreatment. All patients were HBsAg positive, 79% were HBV DNA positive, 35% were HBeAg positive, and one was positive for hepatitis delta at the time of transplantation. One half received antiviral therapy prior to the transplantation. (Six patients took lamivudine and one with a documented lamivudine-resistance mutation was given adefovir.) All 14 patients had functioning grafts at the time of hospital discharge.

Oral combination therapy was well tolerated posttransplant, without any discontinuations due to side effects or tolerability issues. After a mean follow-up of 14 months, 13/14 patients remained HBsAg negative. The one patient who had a return of HBsAg had high pretreatment HBV DNA levels and received lamivudine only for a limited duration prior to transplantation. Seven patients underwent liver biopsy, and none had histologic evidence of HBV recurrence. Although they did not perform a detailed cost analysis, investigators pointed out that the annual cost of HBIG at their institution is $59,600 (which includes only drug costs and not costs associated with administration), compared with $9800 for lamivudine/adefovir at the doses used in their study.

Although this proof-of-concept study by Nath et al¹ is not a randomized, controlled trial, the rarity of HBV recurrence strongly suggests the feasibility of using effective oral antiviral agents without HBIG maintenance therapy following liver transplantation. A preliminary report by Wong et al⁷ also suggested a low rate of recurrence when HBIG maintenance was withdrawn and patients were maintained only on oral antiviral therapy. In that study, 15 patients received initial prophylaxis with HBIG and antiviral agents and six received HBIG monotherapy for a median of 82 months before beginning lamivudine. All eventually discontinued HBIG: four during the first year posttransplantation, four in years 2 to 3, and 13 after the third year. Only one patient had recurrence (HBsAg positivity) and another had transient appearance of HBV DNA up to 3.3 log₁₀ copies/mL without HBsAg positivity. Both patients had lamivudine-resistance mutations.

Oral therapy, including newer antiviral agents, may represent a more cost-effective and convenient alternative to long-term intravenous HBIG maintenance therapy, and avoids the drawbacks of HBIG. While a randomized trial to confirm these provocative results is eagerly awaited, oral antiviral agents may be a safe and effective alternative for hepatitis B prophylaxis in liver transplant recipients, particularly if their viremia is under control at the time of transplantation.

References

1. Nath DS, Kalis A, Nelson S, Payne WD, Lake JR, Humar A. Hepatitis B prophylaxis post-liver transplant without maintenance hepatitis B immunoglobulin therapy. Clin Transplant. 2006;20:206-210.
2. Davies SE, Portmann BC, O'Grady JG, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology. 1991;13:150-157.
3. Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology. 1991;13:619-626.
4. O'Grady JG, Smith HM, Davies SE, et al. Hepatitis B virus reinfection after orthotopic liver transplantation. Serological and clinical implications. J Hepatol. 1992;14:104-111.
5. Belle SH, Beringer KC, Murphy JB, Detre KM. The Pitt-UNOS Liver Transplant Registry. Clin Transpl. 1992:17-32.
6. Sawyer RG, McGory RW, Gaffey MJ, et al. Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization. Ann Surg. 1998;227:841-850.
7. Wong SN, Chu C-J, Wai C-T, et al. Low risk of HBV recurrence post-liver transplantation (OLT) in patients maintained on nucleoside(t)e analogue (NA) therapy after withdrawal of hepatitis B immune globulin (HBIG) [abstract 782]. Presented at: 57th annual meeting of the American Association for the Study of Liver Diseases; October 27–31, 2006; Boston, Mass.