ETV and TDF are the most recently introduced Nucs with both high antiviral potency and high barriers to resistance. TDF/FTC, TDF, and ETV are all safe and effective antiviral treatment in patients with decompensated liver disease and achieved undetectable HBV DNA (<400 copies/ml) at 48 weeks of treatment in 70.5, 87.8 and 72.7 % of the patients respectively [118]. In a recent study of ETV monoprophylaxis pre and post-LT, HBsAg reappeared in 18/80 patients (22.5 %) by 2 years post-LT, However, all of the patients with HBV DNA <5 log₁₀ IU/ml and HBsAg <3 log₁₀ IU/ml at the time of LT achieved HBsAg seroclearance ad none had genotypic antiviral resistance [38]. In a subsequent report including 362 patients, 176 (49 %), 142 (39 %), and 44 (12 %) were treated with LAM, ETV, and combination therapy (predominantly LAM + ADV) respectively at the time of transplant. The rate of HBsAg seroclearance and HBV DNA suppression to undetectable levels at 8 years was 88 and 98 %, respectively. Overall 8-year survival was not different among the three treatment groups [37]. Wadhawan et al. [119] conducted a prospective trial to evaluate Nuc with HBIG regimen in 89 patients between 2005 and 2012, in which only patients with HBV DNA levels >2000 IU/ml were given HBIG (n = 14). Of the remaining 75 patients not receiving HBIG, 19 patients received LAM + ADV, 42 received ETV, 12 received TDF, and 2 received ETV + TDF. At the last follow-up (median = 21 months), 66 patients cleared HBsAg with a HBV recurrence rate of 12 %, and without mortality due to HBV recurrence. Based on these, current data did not recommend LAM monotherapy for post LT prophylaxis due to inadequate potency and high resistance rates. There are now increasing number of reports of HBIG-free antiviral prophylaxis in using ETV or TDF alone or in combination. A completely HBIG-free protocol seems to be better adopted for patients who are HBV DNA negative at the time of LT [37, 38, 93].

Withdrawal of all antiviral prophylaxis with no maintenance HBIG o r Nuc therapy can be considered in patients whose intrahepatic HBV DNA, and cccDNA are controlled below the positive titers. A study [122] included 30 patients who were transplanted 64–195 months earlier and were HBsAg-positive, HBeAg and HBV-DNA negative at LT. After verification of no detectable intrahepatic total HBV DNA and ccc-DNA by liver biopsy, all patients underwent HBIG withdrawal and continued LAM with monthly HBsAg and HBV-DNA monitoring and sequential liver biopsies. Thereafter, those with confirmed intrahepatic total and ccc-DNA undetectability 24 weeks after stopping HBIG also underwent LAM withdrawal and were followed-up without prophylaxis. Five of these 30 became HBsAg-positive during a median follow-up of 28.7 months (range 22–42) after LAM withdrawal, but none of these patients experienced clinically relevant events. Of the patients with HBsAg reappearance, one remained HBsAg-positive with detectable HBV-DNA and was successfully treated with TDF. HBsAg-positivity in the remaining patients was transient and followed by anti-HBs seroconversion. They conclude that patients with undetectable HBV viremia at LT and no evidence of intrahepatic total and cccDNA may safely undergo the cautious weaning of prophylaxis. In such a strategy, LAM is cheap and the cost effectiveness on the management of reactivated HBV may be high.

It was reported that a high reinfection rate of HBV may accelerate the progression of disease, which resulted in a 5-year survival rate of less than 50 % [3, 123, 124]. The availability and advances in the prophylactic therapies have changed such outcomes of LTRs. In a retrospective study of HBV-infected adults undergoing primary LT in the USA between 1987 and 2002, the 1-year survival probability significantly improved from 71 % in year 1987–1991 to 87 % in year 1997–2002, and the corresponding 5-year survival rate increased from 53 to 76 % (P < 0.01) [4]. A large study in 5912 HBV-related LT in Europe over 20 years (1988–2010) showed that the patient and graft survival at 1 and 3 years before 1995 was significantly lower (73%, 65 % and 69 %, 60 %, respectively) when compared with year 1996–2000 (86 %, 81 % and 83 %, 75 %, respectively; each P < 0.001), year 2001–2005 (88 % , 83 % and 84 %, 79 %, respectively; each P < 0.001), and year 2006–2010 (86 %, 81 % and 83 %, 77 %, respectively; each P < 0.001) [125]. This incremental improvement in survival over time reflects the influence of the newer Nuc of ETV and TDF.

After prophylaxis with post-LT HBIG + Nuc, patients’ survival continued to improve as 90 % 1-year patient survival was reported in 2007 [126], and 1, 3, 5, and 10 years survival of 93.9, 90.0, 86.9, and 84.1 %, respectively, in 2012 [127]. Even with a totally HBIG-free regimen, patient survival in LTRs could reach 95, 88, and 83 % at 1, 5, and 8 years under potent Nuc prophylaxis [37]. The impact of HBV recurrence on the survival after LT is no longer a significant problem.

Regarding donor factors, HBsAg-positive liver grafts can be transplanted to patients with HBV-related diseases [128–130]. Given the shortage of donors, the use of HBV positive grafts in patients with HBV-unrelated diseases could expand the donor pool. A recent study in 42 HBsAg-negative patients using HBsAg-positive liver grafts showed no differences in complications and the patient and graft survivals were comparable to those receiving HBsAg-negati ve grafts. However, HBsAg persisted after transplant in all patients that received HBsAg-positive grafts though no HBV flare-ups were observed under Nuc therapy with/without HBIG combination [131]. Another study [130] reviewed the outcome of 92 LT using allografts from HBsAg-positive donors in the USA (1990–2009). Allograft and patient survival were comparable between the HBsAg-positive and HBsAg-negative (n = 82108) allografts. Utilization of HBsAg-positive liver grafts seems not to increase postoperative morbidity and mortality in the LTR. However, there remains concern of the use of HBsAg-positive live donors, because of the risk of postoperative reactivation and possible liver failure in the donors.

The use of anti-HBc-positive liver grafts is another solution to the current deceased donor shortage. However, the major concern of transplanting such grafts is the transmission of de novo HBV infection to non-HBV recipients. A systematic review [132] including 13 studies showed a 2.7 % incidence of de novo HBV infection during a median period of 25.4 months in patients receiving LAM monotherapy and 3.6 % in patients receiving HBIG + LAM combination therapy during a median period of 31.1 months. Another systematic review [133] including 39 studies showed recurrent HBV infection in 11 % of HBsAg-positive LTRs who received anti-HBc-positive grafts, while survival was similar to HBsAg-positive recipients of anti-HBc-negative grafts. Furthermore, if LTRs did not receive any anti-HBV prophylaxis, de novo HBV infection developed in 47.8 % of 186 HBV naïve recipients, significantly higher than 15.2 % of 138 recipients with serological markers of past HBV infection (P < 0.001) or 9.7 % (3/31) of recipients with successful pre-LT vaccination (P < 0.001) [134–138]. A study showed that LTRs maintained on ADV therapy had a numerically higher rate (15 %, 5 of 33) of de novo HBV infection than patients maintained on LAM (8 %, 5 of 62) [139]. LAM may be the most cost-effective option for prophylaxis of de novo HBV infection from anti-HBc-positive liver grafts, when compared with newer antivirals (ETV or TDF) [140]. HBIG seems to be unnecessary either as monotherapy or in combination with LAM.

The active immunization of post-LT recipients with HBV vaccine has been tried. Earlier studies reported a successful response to HBV vaccination after LT [141, 142]. However, most studies of post-LT HBV vaccination were of low response rates [143–145]. Patients who were not chronic HBV carriers used to respond well to vaccination. In contrast, the effect of vaccination was disappointing in patients with liver cirrhosis due to immune tolerance [146, 147]. In addition, donors from their spouses with high anti-HBs titers before donation may respond well to vaccine. They undergo adoptive immune transfer from the donor [148, 149]. A study has shown that a high anti-HBs titer (>1000 IU/l) in donors is essential for protective adoptive transfer [150]. Pre-LT HBV vaccination for candidate living donors may facilitate improved post-LT vaccine responses in recipients with liver cirrhosis. LAM or HBIG prophylaxis after LT may be also associated with recurrence due to escape mutants in which secon d generation recombinant HBV vaccine is not effective [151]. Third-generation recombinant pre-S containing vaccine Sci-B-Vac™ is effective in about 50 % in prevention HBV recurrence due to escape mutants [152].

Notably, considering the extremely high rates of de novo HBV infection after LT in HBV naïve recipients [133] and the successful prevention of de novo HBV infection by pre-LT vaccination [134–138], HBV vaccination should be offered to all naïve HBV patients pre-LT to minimize the need for post-transplant Nuc prophylaxis. Vaccination post-LT may be also tried to enable withdrawal of Nuc prophylaxis if mounting a protective anti-HBs response. However, HBV vaccination alone (without any Nuc) post-LT has been reported to be ineffective in preventing de nov o HBV infection [133].

Besides RT, there is less data available for other non-liver organ transplantation [229, 230]. HBV reactivation after heart transplantations was common but usually well controlled with LAM treatment. HBsAg-positive donor hearts were safely transplanted into anti-HBs-positive recipients; Therefore, HBV carrier status should not contraindicate heart transplantation [230]. It is also reasonable to consider recommendations similar to that for the RT setting [28–33]. Among these, bone marrow transplantation (BMT) is the most serious one that should be briefly addressed. Immunosuppression in BMT can result in reactivation not only among HBV patients, but also in those immune to HBV. Among patients with resolved hepatitis B before BMT, the anti-HBs titer may decline and serum HBV DNA may become detectable [231]. Chemotherapy which was used before BMT may further reactivate HBV infection. An earlier study reported 100 Hong Kong patients undergoing chemotherapy for lymphoma and found that the development of HBV-related hepatitis in 13 (48 %) of 27 HBsAg-positive patients; 2 (3.9 %) of 51 HBsAg-negative, anti-HBc-positive patients; and none (0 %) of 22 HBsAg-negative, anti-HBc-negative patients [232]. A study of 137 consecutive patients (23 HBsAg-positive, 37 anti-HBs-positive, and 77 negative for HBV) who underwent hematopoietic cell transplantation (HCT) showed that hepatitis due to HBV reactivation was more common in HBsAg-positive patients than in HBsAg-negative patients (hazard ratio, 33.3; P < 0.0001). Furthermore, HBsAg-positive patients with detectable HBV DNA before HCT had a significantly higher risk of hepatitis flare than HBsAg-positive patients without detectable HBV DNA (adjusted hazard ratio, 9.35; P = 0.012) [233]. It has also been reported that adoptive transfer of immunity against HBV leading to clearance of HBV infection was found in patients undergoing BMT in which the donors had recovered from prior HBV infection or had been actively immunized against hepatitis B [233, 234]. Overall, prophylactic antiviral therapy is recommended for all HBsAg-positive patients undergoing BMT regardless of HBV DNA status, and should be continued for at least 6 months or longer according to baseline serum HBV DNA levels [235–238]. Finally, transplanting avascular organs such as the cornea carries very low risk of HBV transmission, even from HBsAg-positive donors [239–241]. Antiviral prophylaxis is not recommended for this transplant setting.