HBIG is burdened by its high costs and a suboptimal effectiveness in monotherapy. It has been demonstrated that beginning parenteral HBIG immediately after LT leads to a significant reduction in graft infection and an increase in 3-year survival [16]. Nevertheless, despite several solid immunological-acting pathways, HBIG should not be used in monotherapy since high rates of post-LT HBV recurrence have been reported in LT recipients treated with this strategy. On the other hand, lamivudine post-LT monotherapy leads to high rates of HBV recurrence, while the combination of HBIG and lamivudine has been seen to be an effective recurrence prophylaxis [17, 18]. Those patients who develop resistance to lamivudine during combined HBIG and lamivudine prophylaxis are commonly treated with tenofovir monotherapy rather than adefovir add-on, especially in view of the cost-effectiveness and safety issues. In short, if appropriately combined with available NUCs, HBIG use can be optimized in terms of costs and feasibility by administering lower doses and preferring intramuscular injections to intravenous regimens. As regards dose minimization or even prophylactic treatment withdrawal, this was prospectively explored in a study in which a gradual HBIG withdrawal was followed by antiviral discontinuation in patients not showing covalently closed circular HBV DNA in liver biopsy. At follow-up, more than 80 % of patients did not present HBV recurrence [19]. Recently, the efficacy of monotherapy with entecavir was examined in 80 subjects who underwent LT for HBV, showing cumulative rates of HBsAg clearance of 91 % after 2 years and almost 100 % of HBV DNA undetectable patients [20]. This approach might be taken into account in subjects who at the time of LT are HBeAg negative/HBV DNA undetectable. The vaccination strategy should be adopted since so far the studies including the use of adjuvanted vaccines are not encouraging [21]. Finally, the complete withdrawal of post-LT HBV prophylaxis in selected low-risk populations can be hypothesized, but is still debated and insufficiently explored.

A real de novo HBV infection post-LT is an extremely rare event. On the other hand, suboptimal adherence to the pharmacological prophylaxis and resistance phenomena might lead to HBsAg reappearance after an initial fade-out. If serum HBV DNA also becomes detectable, the antiviral therapy should be promptly started so as to avoid chronic liver injury development and progression, to prevent graft loss, and to reduce complication onset and mortality. The possible strategies should be tailored according to the virological and clinical characteristics of HBV recurrence. In particular, entecavir or tenofovir is used as an effective option if HBIG resistance occurs, taking into consideration that lamivudine resistance should be treated with tenofovir rather than entecavir, which might develop resistance as well. On the other hand, starting tenofovir should be evaluated carefully in patients with renal failure, especially considering proteinuria and previous tubular damage. When necessary, although there are no extensive data to support this approach, the combination of these two analogues can be considered if complex resistance features emerge [22].

Over the years, the expansion of the donor pool has been proposed to allow greater LT access, and this was extended to HBsAg-negative/hepatitis B core antigen-antibody (anti-HBc)-positive donors, ideally allocating these organs to already HBsAg-positive liver recipients, previously undergoing immunoprophylactic HBV regimen [23]. In fact, an extensive review of the studies using livers from anti-HBc-positive donors in HBsAg-negative recipients revealed the probability of de novo HBV infection in recipients who did not receive immunoprophylaxis in anti-HBc-/anti-HBs-patients, of 15 % in anti-HBs+ and/or anti-HBc+, and of less than 2 % in anti-HBc–/anti-HBs+ recipients. In anti-HBc+ graft recipients, HBIG is not necessary, while lamivudine monotherapy seems to ensure satisfactory low rates of graft infection (<3 %).

In conclusion, the combination of antiviral drugs and low-dose HBIG can effectively prevent HBV recurrence in almost all LT recipients. HBIG discontinuation can be taken into consideration, maintaining the NUCs in those patients who do not have apparent risk factors for recurrence and who had low or undetectable HBV DNA levels before LT. These prophylactic and therapeutic approaches have drastically modified the natural history and the prognosis of both pre-LT and post-LT HBV-related settings.

Hepatitis C virus (HCV) infection can lead to cirrhosis and its complications and represents the main indication for LT, at least in the Western countries [24]. Unfortunately, in HCV RNA-positive patients, the recurrence of HCV infection after LT is universal [25, 26] and may lead to cirrhosis in approximately 30 % of recipients after 5 years [27]. The severity of the infection is unpredictable and often associated with additional clinical and histological features (e.g., cholestasis, de novo autoimmunity, coinfections), determining a more rapid progression versus advanced illness and possible graft loss. LT patients who undergo antiviral therapy have been shown to have a longer survival, better histological and hemodynamic long-term features, and a lower rate of decompensation [28–31], especially when a sustained virological response (SVR) is achieved. However, dual antiviral therapy with pegylated interferon (PegIFN) and ribavirin (RBV) seems to be poorly effective in this population [32]. Direct-acting antiviral agents (DAA) such as protease inhibitors (PI) have been seen to ameliorate the rate of SVR in pre-LT genotype 1 patients, both treatment naive and experienced [33, 34]. Recently, several experiences have been reported regarding the use of the new antiviral agents in LT recipients, focusing not only on the likelihood of achieving higher SVR rates with the new antiviral regimens but also on the complex issue of immunosuppressant drug handling, drug interactions, and increase of renal and hematopoietic toxicity [35–38]. These data confirmed that, also in post-LT hepatitis C settings, similar SVR rates to those of non-LT patients can be achieved by triple regimens with PI, peginterferon, and ribavirin. Moreover, satisfactory SVR rates have been obtained despite several adverse events such as anemia, neutropenia, rash, and renal failure. The worldwide growing experience with the use of telaprevir and boceprevir in LT recipients with HCV recurrence has significantly helped clinicians in the use of new DAAs, especially in awareness on the drug-drug interaction issue and the possible induction of plasma cell hepatitis during triple IFN-based regimens, sometimes with acute rejection-like onset resulting in graft loss or in fatal outcome [39–41]. On the other hand, it is possible that the high costs of oncoming potent IFN-free regimens will be prohibitive for many developing countries which will continue to rely on PIs such as boceprevir and telaprevir [42]. Another issue which is still controversial is when to start treating the HCV recurrence [43]. The preemptive antiviral therapy after up to 6 months should be taken into consideration when rapidly progressive features emerge. The decision to treat post-LT HCV recurrence is often taken according to the histological characteristics (presence of fibrosis) at the 1-year liver biopsy, but at the same time, the individual patient’s predictive factors of response should be carefully evaluated. The positive predictive characteristics associated with SVR are genotypes 2 or 3, mild fibrosis, young donor age, low baseline level of viremia, early viral clearance, and both donor and recipient CC polymorphism of IL28B [44–47]. The immunosuppressive regimen with cyclosporin has also been seen to be associated with SVR [48], but in triple regimens, especially those containing telaprevir, these data should be reviewed.

Undoubtedly, the oncoming era of HCV treatment has begun with the approval of several DAAs with different viral targets [49]. These drugs will likely very soon guarantee simplified treatment schedules and high tolerability and might avoid the use of interferon. Sofosbuvir is a potent all-oral-dosing nucleotide analogue inhibitor of HCV polymerase activity, with excellent virological response rates obtained in randomized controlled studies employing combination schedules with RBV, with or without PegIFN, in both naive and experienced HCV patients [50]. Currently, sofosbuvir is becoming more and more available worldwide but, besides the cost-related limitations, it should be noted that in LT settings, the experience is still limited. The preliminary data of a compassionate US program, utilizing sofosbuvir in LT recipients with a severe recurrence of HCV infection, were recently presented [51, 52], showing good clinical outcomes, a global clinical and MELD improvement; however, the relapse rate was not negligible, indicating that the treatment regimen should be maximally optimized in this seriously ill LT population, probably by combining sofosbuvir with another potent DAA. No drug-drug interactions with calcineurin inhibitors are expected during SOF administration [53, 54], but in a single center experience, awareness of significant tacrolimus/cyclosporine trough level reduction when sofosbuvir is administered in LT recipients has already emerged [55].

Indeed, the future perspectives of HCV-related viral hepatitis in pre-LT and post-LT settings will soon drastically change, thanks to the rich pipeline of new antiviral agents. However, some issues not present until now will affect real clinical practice and will require expert dedication in this complex setting. Among these, in addition to the time to treat and the duration of treatment, the most important are cost-effectiveness, choice of one DAA rather than another, drug-drug interactions, patients’ eligibility for treatment, and viral resistance management. These features underline the importance of continuing to identify the predictive factors of good outcomes of antiviral treatment and of the global clinical outcomes in HCV-related viral hepatitis pre- and post-LT.