Entecavir or tenofovir monotherapy prevents HBV recurrence in liver transplant recipients: A 5-year follow-up study after hepatitis B immunoglobulin withdrawal

Abstract

Background

Recent data suggest that oral third-generation nucleos(t)ide analogs (NA) monoprophylaxis following hepatitis B immunoglobulin (HBIg) withdrawal may be effective to prevent HBV reinfection after liver transplantation (LT).

Patients and methods

Between 01/2010 and 03/2012, all HBV monoinfected and HBV/HDV co-infected LT patients followed in our centre withdrew HBIg ± NA and were commenced on either ETV or TDF as monotherapy.

Results

Seventy-seven patients were included in the study (55% TDF, 45% ETV). Group A comprised 69 HBV monoinfected patients and Group B 8 HBV/HDV co-infected patients. After HBIg withdrawal, Groups A and B patients were followed for 69 (range 13–83) months and 61 (range 31–78) months, respectively. No Group B patients had HBsAg or HBV DNA recurrence, while 6 (9%) Group A patients became HBsAg-positive after a median of 18 (range 1–40) months. The cumulative 5-year incidence of HBsAg recurrence was 9%. All 6 patients demonstrated undetectable HBV-DNA levels and stable graft function during 30 months of additional follow-up. In 3/6 patients, seroconversion was transitory, while the remaining 3 showed HBsAg levels <0.13 IU/mL over the entire period of observation. Pre-LT HCC emerged as the strongest predictor of HBsAg recurrence.

Conclusion

HBIG can be safely discontinued in HBsAgpositive LT recipients and replaced by ETV or TDF monotherapy.

Introduction

Hepatitis B virus (HBV) infection still represents a global major health problem associated with significant morbidity and mortality [1]. The highest rates of chronic infection are found in sub-Saharan Africa, East Asia (5–10% of the adult population), southern parts of Eastern/Central Europe, the Middle East and the Indian subcontinent (2–5%). However, significant immigration flows have resulted in higher rates of hepatitis B diagnosis in North-Western Europe and North America, where historically less than 1% of the native population is chronically infected [1]. Consequently, HBV-associated liver disease has represented an important indication for liver transplantation (LT) (5–10%) in Europe and the United States over the last 20 years [2].

Until recent years, long-term prophylaxis combining hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogues (NAs), was considered the standard of care to prevent HBV recurrence after LT. Several studies and meta-analyses have confirmed their synergistic effect in obtaining long-term HBsAg negativity in more than 90% of HBV liver recipients [3], [4], [5].

The availability of third-generation NAs, entecavir (ETV) and tenofovir (TDF), which provides a more potent viral suppression and higher genetic barrier to resistance compared to previous NAs (lamivudine, adefovir, telbivudine, emtricitabine), led to the proposal of alternative strategies for prophylaxis against HBV reinfection of the allograft after LT, with the aim of eliminating the need for long-term HBIg administration [6], [7], [8], [9], [10], [11], [12], [13], [14]. The majority of the published data report that HBIg-free treatment regimens have promising results with rates of HBV recurrence similar to those achieved with combination prophylaxis. However, most of the studies had significant limitations including small patient cohorts, inclusion of selected patients (e.g. low-risk subjects) only, short periods of follow-up, a variety of different antiviral approaches after HBIg discontinuation and a lack of information on the recipients’ pre-LT virological profile (e.g. virus genotype, drug-resistance mutations, HBsAg titre). Furthermore, only a minority recorded quantitative HBsAg (qHBsAg) kinetics after recurrence, which could prove useful to predict post-LT outcomes.

Nevertheless, these early reports encouraged the American (AASLD), European (EASL) and Asian Pacific (APASL) Association for the Study of the Liver to incorporate the option of HBIg withdrawal into their clinical guidelines for recipients considered at low-risk of HBV recurrence (i.e. patients with low or undetectable HBV DNA levels before LT and no history of drug-resistant HBV) [15], [16], [17].

In this study, we therefore aimed to investigate the long-term effectiveness and safety of third-generation NA monoprophylaxis in preventing HBV reinfection after HBIg withdrawal in stable LT recipients, and to characterize patients’ clinical and virological indices (e.g. qHBsAg) after HBsAg recurrence.