HBV and HCV Infection Prophylaxis in Liver Transplant Recipients

Abstract

Liver transplantation is the treatment of choice for patients with liver cirrhosis caused by viruses (HCV, HBV, and HBV + HDV) in end-stage liver disease. However, liver transplantation is complicated by the risk of recurrent infection, which significantly affects the graft and patient survival, the main risk factor for the development of recurrent viral infection being the viral load at the time of transplant. The development of antiviral drugs and effective prophylactic regimens using hepatitis B immunoglobulins have significantly improved hepatitis B outcomes after liver transplantation. Hepatitis B virus (HBV) reinfection after liver transplantation (LT) may favor the recurrence of hepatocellular carcinoma (HCC), and combination therapy with hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analog may reduce HBV recurrence after LT. In patients transplanted for HCV infection due to the availability of direct-acting antivirals, the survival of transplanted patients is comparable to that of transplants performed for alcoholic liver disease and even better than the survival evaluated in patients with hemochromatosis or hepatitis B infection. However, current approaches continue to be hampered by the extremely high cost of treatment and the emergence of drug-resistant viral mutations.

1. Introduction

Chronic hepatitis B (CHB), which is the primary cause of hepatocellular carcinoma, currently represents a major threat to public health since it may result in potentially fatal complications [1]. According to the World Health Organization epidemiological reports, 296 million people were living with CHB infection in 2019, with an annual incidence of 1.5 million and an estimated mortality of 820,000 people [2].

Current CHB therapies based on nucleos(t)ide analogues (NUCs) are effective in minimizing viral load but are curable in less than 5% of cases [3]. The only effective treatment for decompensated CHB cirrhosis, whether or not it is exacerbated by HCC, is orthotopic liver transplantation (OLT) [4]. A common indication for OLT at the moment is CHB, which accounts for 30% of all OLT procedures in Asia and 10% in Europe and the USA [5]. The key indicators for liver transplantation (LT) in patients with chronic hepatitis B (CHB) infection are severe episodes of infection and long-term consequences, such as decompensated cirrhosis and hepatocellular carcinoma (HCC) [1]. However, in areas where infection persists to be prevalent, CHB tends to be among the most prevalent primary liver conditions for LT [6].

Due to the high likelihood of HBV recurrence following OLT, which causes graft losses and a dismal survival rate of less than 40% after 5 years, CHB was historically regarded as a contraindication [4]. A long-term antiviral preventative medication is required since liver transplantation is not a curative treatment for CHB infection [5]. The primary objective of antiviral prophylaxis is to avoid reactivation, rather than recurrence or reinfection, because the virus is never entirely destroyed after transplant [7]. Oral nucleos(t)ide analogs (NUCs), which have been accessible since 1998, are considered to be the most efficient HBV suppressants with a small probability of developing resistance [8]. A nucleotide analogue (NA) was used as an antiviral medication both pre- and post-transplant when the spontaneous risk for HBV re-infection was previously over 80% [8]. The introduction of hepatitis B immunoglobulins (HBIG) and several generations of NUC over the past three decades has modified the prophylaxis schedule advised by the majority of worldwide hepatic societies [9].

In 90–100% of individuals, the combination of both prevents HBV recurrence. According to theory, ongoing therapy could reduce the risk of HCC while additionally delaying the onset of cirrhosis, decompensation, and acute flares [10].

In worldwide studies, 5% of HBV-infected people were additionally discovered to have exposure to the hepatitis delta virus (HDV) [10]. This article discusses the present level of research regarding the treatment and prevention of post-LT recurrent HBV and HDV infections, as well as the effect that these infections have on liver allograft outcomes [10].

HCV infection is one of the most common causes of liver transplantation, as it currently accounts for 40% of persistent liver damage in the United States. The newly transplanted graft will become infected during transplant reperfusion if the infection is neglected before surgery [11]. Eliminating the viral infection before transplant is now the greatest way to avoid the recurrence of the graft itself with HCV after the procedure [12].

In HBV/HCV-coinfected LT recipients, reinfection was decreased by hepatitis B immune globulin (HBIG) [13]. Due to their ability to prevent HCV infection within human hepatocytes and lower viral loads in experimental animals, two HCV-neutralizing human monoclonal antibodies showed an in vitro advantage [12]. There is an urgent need for more research on HCIGs, and several studies are already being conducted. Following a liver transplant, what is referred to as “prophylaxis” for recurrent HBV and HCV is disputable, suppressive rather than preventative, and is likely to continue for a lifetime [14].

2. Chronic hepatitis B infection

The Hepadnaviridae family includes the small DNA virus known as the hepatitis B virus (HBV) [15]. Eight genotypes of HBV, ranging from A to H, have been identified, each with a unique geographic distribution [16]. The infectious HBV virion (Dane particle) is a spherical, double-shelled structure with a diameter of 42 nm [15]. It is made up of an inner nucleocapsid which is composed of hepatitis B core antigen (HBcAg) combined with virally encoded polymerase and the viral DNA genome, as well as a lipid envelope containing HBsAg [17]. The partly double-stranded DNA virus HBV reverse converts pre-genomic ribonucleic acid (RNA) into DNA throughout its life cycle [17]. The genome comprises an external phospholipid envelope and an internal nucleocapsid core encoded by the overlapping C, X, P, and S open reading frames [18].

The pathogenic virion known as Dane particles expresses the envelope protein HBsAg on their surface. The presence of HBsAg in the bloodstream is evidence of active HBV infection [15]. Anti-HBc antigen identification suggests acute, chronic, or cured infection but not immunity caused by vaccination and demonstrates previous contact with HBV [19]. The detection of HBeAg along with viral replication in progress is suggestive of the individual’s infectiousness. Anti-HBs are a sign of healing and vaccination against HB infection, either through the HB vaccine or disease [19].

HBV is transmitted from mother to child after exposure being exposed to infected blood or bodily fluids or through sexual contact. Additionally, HBV can live and remain contagious on wet surfaces at ambient temperature for a couple of weeks [20]. The primary and most reliable method of preventing HBV exposure is vaccination (WHO 2019a). Since its introduction in 1982, the HBV vaccination has significantly reduced the number of HBV infections worldwide [2].

Hepatitis B (HB) is a serious health threat that can manifest as acute, chronic, severe liver failure, and malignancy, resulting in high morbidity and mortality despite the existence of efficient immunizations and therapeutic options [15]. Chronic infections are most prevalent in immunocompromised patients and are age-related in terms of risk and prognosis. It is generally accepted the theory according to which the infection contracted in youth will evolve into chronic infection [19]. Acute infections are typically cleared in individuals with impaired immunity, while 90% of babies, 30–50% of children under the age of five, and 5–10% of adults suffer from chronic infections [19]. The typical manifestations of an acute infection, which may persist for 2–3 months, include fever, jaundice, abdominal discomfort, nausea, and vomiting [5]. The age of the person at the moment of infection, the manner of acquiring, ethnic background, and the genotype all affect the typical course of chronic HBV in children, which is characterized by the persistence of HBsAg for a period of time exceeding 6 months. Although acute liver disease may develop in young adults, chronic hepatitis is infrequent in this demographic group [21]. A high probability of the occurrence of chronic infections with evolution towards liver cirrhosis is specific to hemodialysis patients who have coinfection with the HIV virus [21].

Chronic HBV develops in an unpredictable way via four stages with clinically distinct symptoms, while there is occasionally overlapping [4]. The immune-tolerant stage, which may persist for years but the majority of patients exit around the teenage years, is characterized by low hepatic inflammation in the majority of children regardless of an elevated rate of HBV replication [22]. The immune clearance phase, which comes after this one, is marked by liver damage as well as phases involving moderate and elevated HBV replication as the body’s defense mechanism works to eliminate HBV [23]. A child may reach the chronic inactive carrier stage if they seroconvert (go from being HBeAg negative to HBeAb positive) after eliminating the virus. Despite the fact that this condition is typically regarded as benign, 20–30% of individuals may experience HBV reactivation in the presence of immunodeficiency or HBV mutation. To determine the stage of infection and to assess the host immunological response, it is required to continually track levels of HBV genetic material and alanine transaminase (ALT) [23].

Considering the clinical manifestations and symptoms of chronic HBV may prove nonexistent or subtle, a complete evaluation of the patient’s risk elements and medical records is necessary for the diagnosis.

The most effective way to evaluate inflammatory processes, fibrosis extent, the existence of additional sources of liver illnesses, and to track the progression of the disease following therapy is by liver biopsy [24]. The immune clearance phase is marked by portal inflammatory disorders, interface hepatitis, and varied fibrosis, although biopsy evidence of liver inflammation is limited in the immunological-tolerant phase [24]. Whilst neither of the noninvasive indicators is currently regularly advised as standard testing, they are being studied as a means of determining the degree of liver fibrosis in HBV patients [21]. Simple or non-invasive indicators have been demonstrated to be helpful in patients with chronic HBV, such as the aspartate aminotransferase (AST)-platelet ratio index and the fibrosis-4 index based on platelets, ALT, AST, and age [25].

Patients suffering from cirrhosis from an infection with HBV are at increased risk for developing HCC. On an annual basis, 600,000 people die globally from cirrhosis, hepatocellular cancer, acute liver failure from recent infections, or reactivation in chronic carriers [26]. 10% of liver transplants are for chronic hepatitis B infections, although the graft could become reinfected as a result [26].

Infections with HBV can occur in liver transplant recipients in two distinct manners [10]:

• De-Novo infection: in patients without previous serological proof of HBV infection. This generally happens as a result of HBV transmission from a donor who has tested positive for the hepatitis B core antibody (anti-HBc). Additionally, seronegative donors may spread an “occult” HBV infection [10].

• Re-infection: following a liver transplant, a compromised immune system leads to a spike in HBV multiplication. Re-infection probability has a direct connection with the replication of HBV prior to LT. Two scenarios may lead to a re-infection: (1) circulating HBV particles or (2) excessive production of immunological HBV particles (escaped mutants) in extrahepatic places like the peripheral blood mononuclear cells, which is referred to as the “Immune Pressure mechanism” [10].

Increased HBV DNA levels than those from de novo infections are linked to re-infection.

Serum HBsAg and HBV DNA are biomarkers of recurrence cancer of the liver, one of the side effects of recurrent HBV. Re-infection can, in rare instances, progress into fibrosing cholestatic hepatitis, a subtype of the disease marked by early fibrosis [27]. Nevertheless, candidates for LT for chronic HBV illness must have anti-viral prophylaxis.

3. Prevention of post-transplant HBV recurrence

Because of the substantial likelihood of HBV reappearance following OLT, which can lead to graft failures and a dismal survival rate after 5 years of below 40%, CHB was formerly regarded as a contraindication [28]. Hepatitis B immunoglobulins (HBIG) and several generations of NUC have modified the prophylactic protocol adopted to avoid HBV recurrence during the past thirty years. The risk of HBV recurrence following OLT, determined by HBsAg positive in the serum, is presently below 10% when third-generation NUC and HBIG perfusions are used together. In consideration of this, the majority of worldwide hepatic societies advise using this combination preventive strategy [29]. Due to the substantial expense of the administration of HBIG by i.v. infusion or s.c. injection, minimizing the HBIG preventive measures period is taken into consideration in certain groups of patients according to the absence of risk factors like pre-OLT viral load, HDV coinfections, and when optimal patient compliance to treatment is ensured [30]. For the prevention of HBV recurrence, NUC monotherapy without HBIG has been documented in various trials. After using NUCs with an elevated barrier to resistance, these research investigations stated a rate of detectable HBsAg in serum of 8–10% after a period of time of 2–8 years post OLT, which was linked to sustained suppression of the virus and a lack of virologic recurrence [2].

There are a number of established risk factors for HBV recurrence before LT: HBeAg positive and a detectable blood HBV DNA level. Additional warning signs for HBV re-infection include simultaneous HDV infection or human immunodeficiency virus (HIV) infection, HCC before LT, limited adherence to antiviral therapy, and antiviral medication resistance [10].

Prior to the development of HBV prevention, confirmations of recurrence were frequent. The prophylactic period first began with HBIG alone, which was later utilized alongside antivirals. Antivirals are now also utilized on their own. The therapy combinations, however, vary per facility and are always changing [10].

In order to prevent HBV recurrence, HBIG, a polyclonal antibody targeting HBsAg, was developed in the last decades of the nineteenth century. It was ground-breaking research by Samuel et al. that indicated a significant decrease in HBV recurrence, from 75% in patients getting no medication or short-term HBIG therapy to 33% in those undergoing long-term IV HBIG medication, and was linked to better graft and patient outcomes. As a result, there was no agreement on the frequency, dosage, or length of HBIG [31].

Additionally, it presented drawbacks such as higher expenses, resistance, the need for intravenous infusion, a lack of accessibility, the requirement for follow-ups and lab monitoring, local and systemic adverse reactions, and the inability to achieve appropriate protective anti-HBs concentrations for individuals [18]. As a result of these limitations and the development of antivirals that work in concert with HBIG, their usage as monotherapy was discontinued [32].

Initial investigations on LAM as a monotherapy revealed up to 18% recurrence over 3 years of treatment [33]. However, monotherapy with strong antivirals showed encouraging outcomes. These outcomes offer a more cost-effective approach to reduce HBIG consumption. Benefits should not be extrapolated,However, monotherapy should only be administered to a small number of lowrisk individuals under close observation [2].

NAs altered the HBV LT management environment. They reduced the recurrence incidence by less than 10% when combined with HBIG [34]. The initial type of NA was LAM, and its inaugural successful investigation was made public in 1998 by Markowitz and associates from the UCLA Medical Center [35]. A more extensive patient follow-up in Italian research by Marzano et al. that revealed 4% recurrence with the same combo treatment provided more evidence for this [35]. This motivated doctors to combine different NAs, and a meta-analysis revealed that a combo of adefovir dipivoxil (ADV) and HBIG is better than HBIG/LAM [10]. The adoption of more recent NAs with strong genetic resistance barriers, such as entecavir (ETV) or tenofovir disoproxil fumarate (TDF), followed. Nevertheless, among individuals who have been exposed to LAM, ETV is linked to high resistance, and TDF safety concerns regarding bone and renal function are quite important [36]. Tenofovir alafenamide (TAF), a tenofovir prodrug, is, therefore, an option for patients with these worries [36].

Different reduced doses and methods were investigated, which were provided intramuscularly (IM) every day for 1-week post-transplantation and monthly due to HBIG’s restrictions (cost, IV mode of administration) [37]. Additionally, it was more than 90% less expensive than a high-dose prescription. Furthermore, trials using subcutaneous (SC) injections of HBIG revealed improved satisfaction among patients, less pain, and over 90% adherence to maintaining protective anti-HBs blood concentration [38]. Only individuals with minimal viral load before to transplant have been shown to benefit from low-dosage HBIG, according to studies. Therefore, the dose should be customized for each patient while anti-HBs levels are continuously monitored [10].

Until NAs were developed, HBIG was administered as monoprophylaxis at a high dose to stop the recurrence of HBV following LT. LMV, ADV, or any one of these medications plus HBIG were initially administered to avoid HBV recurrence after LT following the introduction of NAs [39]. Since LMV and ADV have poor effectiveness and a high incidence of resistance development, they are currently not suggested as the best primary preventive treatment [40]. Effective and well-tolerated in preventing HBV recurrence after LT is ETV or TDF combined with HBIG. Another approach that is currently used involves starting an HBIG/NA combination, stopping HBIG, and continuing NA as a monotherapy [41].

As a result, the findings demonstrate the effectiveness of high susceptibility barrier antivirals and provide evidence in favor of the possibility of stopping HBIG if the cost is minimal. In individuals who had high levels of detectable HBV DNA after transplant, had HCC as a sign of needing a transplant, or were coinfected with HDV, it should be maintained for a longer period [41]. After LT, there are center-specific rehabilitation alternatives, but there are also several suggestions from societies all across the world. The American Association for the Study of Liver Diseases (AASLD) advises against ever using HBIG monotherapy [42]. They emphasize that treatment should last a lifetime and that ETV or TDF should constitute the chosen antiviral medication due to reduced resistance with prolonged usage [42].

For end-stage liver disease/HCC caused by HBV/HDV, liver transplantation is the gold standard therapy, with results that are on parity with those of the other criteria. The proper care and primary prevention of viral recurrence are essential to its effectiveness [43]. Presently, either the transplant center or the transplant region determines the prevention and treatment of recurrent HBV/HDV [2]. However, considering the information together, it is reasonable to assume that the strategy for therapy should be customized to the particular features of every patient. Importantly, the dosage and duration of HBIG should be based on the patient’s HBV viral level at the time of transplantation [37]. However, the stronger antivirals (ETV, TDF, and TAF) have to be used as first-line medications and kept up throughout life, whether in combination or as monotherapy [20].

4. Recipients of anti-hepatitis B core-positive livers

Due to the enormous number of patients on the waiting list for liver transplantation and the limited number of donors, the facilities were built to accommodate the use of liver transplants from donors who had positive anti-HBc antibodies [44]. Most of these donors had previously been infected with HBV (anti-HBc positive and hepatitis B surface antigen [HBsAg] negative) [45]. Liver grafts from HBc antibody-positive patients should be transplanted into HBsAg-positive patients before transplantation as they will usually receive post-transplant prophylaxis to prevent re-infection with HBV due to the shortage of adequate liver grafts, there are cases in which patients without HBV infection received livers from donors with positive anti-HBc antibodies [41]. For recipients without a history of chronic HBV infection, the risk of graft-related HBV infection is decreased with antiviral prophylaxis. Graft-related infection is defined as the appearance of HBV surface antigen and detectable HBV DNA in the recipient [10]. HBV infection can be acquired from the liver of the anti-HBc-positive donor due to the persistence of HBV covalently closed circular DNA (cccDNA) in the donor’s liver, which can be reactivated secondary to recipient immunosuppression [2].

The risk of graft-related hepatitis B infection from an anti-HBc-positive donor liver varies with the recipient’s HBV status. Patients who have not been infected with HBV (HBs Agnegative, anti-HBc negative, and anti-HBs antibodies negative), people with immunity due to vaccination (HBs Ag negative, anti-HBc negative, and anti-HBs positive), and patients who have passed through HBV infection with spontaneous healing (anti-HBc positive, HBsAg negative) [46].

The combined administration of Human anti-hepatitis B Immunoglobulin (HBIG) and nucleotide(z)ide analogues (tenofovir, entecavir, and lamivudine) for an indefinite period, with the maintenance of an anti-HBs titer of more than 100–150 IU/ml in people with HBV DNA negative and 500 IU/ml in people with positive HBV DNA in pre-TH represents the universal prophylactic regimen recommended for preventing HBV reinfection of the graft [41].

The recommended initial regimen consists of the administration of HBIG 10,000 IU i/v during the anhepatic phase, followed by 2000–10,000 IU i.v. daily in the first post-transplant week, with subsequent administrations being adjusted to maintain the Anti-HBs titer above 100–150 IU/ml in pre-transplant HBV DNA negative patients and over 500 IU/ml in pre-transplant HBV DNA positive patients [6].

All recipients of anti-HBc-positive liver grafts should receive lifelong antiviral prophylaxis and the antiviral agent should be initiated at the time of transplantation. Initially, an antiviral agent with a low resistance barrier (Lamivudine) was used for antiviral prophylaxis, then entecavir or tenofovir alafenamide (TAF), due to its efficacy, tolerability, and high barrier to resistance [44].

Cholongitas, Papatheodoridis, and Burroughs showed in a study published in 2010, on a group of >900 patients who received a positive HBc graft, that approximately 20% of recipients with negative HBsAg left without antiviral prophylaxis presented de novo infection and that patient the probability was lower in those who went through HBV infection (anti-HBc/anti-HBs) [47].

5. HVB/HDV coinfection

Reinfection prophylaxis in patients transplanted for HBV and HDV co-infection is not very clear due to the fact that the presence of HBsAg is mandatory for viral replication of HDV [10]. Thus, the recurrence of post-transplant HBV infection, in patients with pre-transplant HBV/HDV co-infection, can lead to re-infection of the liver graft, including delta virus, which complicates the post-transplant evolution [48]. Some guidelines recommend long-term administration of HBIG prophylaxis usually combined with a nucleotide/nucleoside inhibitor. Older studies evaluated the efficacy of long-term combination HBIG with LAM as prophylaxis for transplant patients for HBV/HDV co-infection [41]. No recurrence of HBV/HDV co-infection was observed in either group, however, the authors concluded that a preference for the HBIG-LAM combination was a cost-effective treatment. Option [49].

Approved treatment for HBV monoinfection such as nucleoside/nucleotide inhibitors does not affect HDV viral load and currently, there is no globally approved treatment for HDV [50]. Pegylated Interferon Alpha (PEG-IFN-alpha) has been used for decades to treat HDV infections and has shown a virologic response rate of up to 30%, with use limited by severe adverse effects that have compromised therapy and its use among patients with decompensated liver disease or in the post-transplant setting [51]. Recently, Bulevirtide, a lipopeptide that blocks the binding of HBsAg-coated particles to the sodium taurocholate cotransporter polypeptide (NTCP), which is the cellular entry receptor for both HBV and HDV, was approved by the EMA at a dose of 2 mg/day, subcutaneous injection, in patients with HDV coinfection [52]. Clinical studies have confirmed the efficacy and safety of Bulevirtide, even in patients with advanced-stage compensated cirrhosis [51].

However, the duration and dose of the antiviral treatment have not yet been precisely established. More studies are needed to understand the mechanisms of virologic response, build models to predict therapeutic response, determine discontinuation criteria, and test drug efficacy and safety in special populations such as transplant patients [41]. Two investigational drugs, PEG-IFN and Lonafarnib, are currently in phase III, but these drugs, as well as Bulevirtide, are not been tested in transplant patients; specific prophylaxis for transplant patients for HBV/HDV co-infection is not yet available, but because HBV needs HBV to infect hepatocytes and replicate, the primary goal of post-transplant prophylaxis in patients with HDV co-infection is to prevent HBV relapse [52].

Caccamo et al. compared HBIG monotherapy with the combination of lamivudine and HBIG and found no cases of HDV recurrence in either group and suggested combination therapy as a more cost-effective option because this strategy allows the use of lower doses of expensive HBIG [53]. The use of NUC alone rarely leads to the loss of HBsAg, and this increases the chances of HDV infection developing in new hepatocytes, although the manifestation of HDV infection is difficult without complete HBV reactivation [53]. However, there is no known effective treatment for HDV infection in the post-transplant setting, and lifelong combination therapy of high-barrier NUC and HBIG is the recommended prophylaxis [2].

6. Hepatocellular carcinoma

Patients with HBV infection and hepatocarcinoma have a higher risk of recurrence of HBV infection than those without neoplasia at the time of transplantation [54]. The way in which a neoplasia recurrence occurs could be explained by the persistence of extrahepatic metastatic cells, which are difficult to eradicate and act as a reservoir for the hepatitis B virus [55].

Hepatitis B virus (HBV) reinfection after liver transplantation (LT) may favor the recurrence of hepatocellular carcinoma (HCC), and combination therapy with hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogues may reduce HBV recurrence after LT [5]. Before effective prophylaxis was available, HBV reinfection often led to early graft cirrhosis with a 2-year mortality rate of 50% [26].

The current antiviral prophylactic regimen of hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogues has decreased viral recurrence and dramatically improved clinical outcomes after LT for HBV [25]. The pathological progression of HBV-induced liver injury to hepatocellular carcinoma (HCC) is well documented. Unfortunately, historically, up to 40% of patients have experienced tumor recurrence after LT [56].

Lamivudine (LAM) monotherapy has recently been shown to delay the progression of advanced liver disease and the subsequent development of HCC in nontransplant patients. Moreover, survival has been improved with a combination of HBIG and nucleoside/nucleotide analogues in patients undergoing liver transplants for HBV-associated disease [5]. Previous research suggests that the successful treatment of HBV is associated with improved survival and a reduction in HCC recurrence after transplantation. Whether the combination of HBIG and antivirals has a direct antineoplastic effect that is distinct from the suppression of viral replication is not known [37].

7. Patients receiving HBsAg-positive grafts

Since the early nineties, researchers have been studying the potential of liver transplant from HBsAg-positive patients because of the lack of patients who could have become donors; so, they decided to use grafts from sources they have not used before for patients who have been diagnosed with cirrhosis and hepatocellular carcinoma [57].

From 1994 to 2006, 8.5% of about 35,000 adult transplant recipients in the United States received anti-HBc-positive grafts due to the presence of occult infection of some of the grafts [58]. The first transplant with an HBsAg-positive graft was reported in 1994 when a critically ill woman received a seropositive graft [44]. She has done the profilaxis with HBV immunoglobuline but shortly after that she was found with liver dysfunction and diagnosed with chronic hepatitis B [59]. This case report has been followed by an unicentric study on 10 patients from 2005 to 2009 [59]. Patients who underwent surgery for liver transplant for HBV–related disease have never cleared the HBs Antigen; some of them cleared the HBs Antigen and others tested positive for HBV whereas they never tested positive for it before [38]. All in all, none of the patients have had hepatitis, mostly because HBV replication was controlled by the antiviral therapy [38].

A retrospective analysis of a larger study back in the early 2000 has also confirmed that 78 of 92 patients have received HBs antigen-positive grafts, but the recipients already had a history of HBV infection [44].

These results were confirmed by Chinese researchers who have done a retrospective study on about 370 patients who underwent liver transplants from 2010 to 2013, and a few of them (N = 42) received an HBs-positive graft. Post-transplant follow–up has shown similar liver function in both of the two groups and the complications—such as acute rejection, liver dysfunction, and biliary complications—were similar. They concluded that doctors all over the world should abandon the administration of hepatitis B immunoglobuline in favor of antiviral therapy [60].

On the other hand, other case report suggested that even after immunoglobuline profilaxis was used in association with Lamivudine and Adenofovir, some patients remained positive for HBs antigen [61]. The therapy has been switched to pegylated interferon and after that to Tenofovir. None of them seemed to work so the patient has revealed symptoms of cirrhosis and has been listed again for liver transplant. Nowadays, the British transplant society’s guidelines suggests that HBs antigen-positive liver donation is possible because of antiviral drugs such as Entecavir or Tenofovir because they can successfully stop the replication of the virus and prevent graft damage [61]. All the patients should be tested for VHD co-infection because a positive test means the transplant will not be possible because of the high risk of liver cirrhosis after transplant.

Therefore, the British researchers recommend [62]:

• that only in case of emergency HBs antigen-positive liver will be used for a HBs antigen-negative patient

• patient who underwent surgery for a liver transplant and got a positive graft, should be treated with entecavir or tenofovir since the surgery

• HBs antigen-positive livers can be transplanted to HBs antigen-negative patients only if the co-infection with VHD virus is not present

• HB immunoglobuline is not recommended anymore

8. Hepatitis C infection and recurrence post-transplant

The initial evaluation of HVC-infected patients involves a full clinical and biological evaluation of the patient so that we can start antiviral therapy. Sometimes patients discover the infection when the fibrosis is already advanced [63]. Furthermore, patients should get an ultrasonography and an upper endoscopy twice every year so that their medical team can screen them for hepatocellular carcinoma or spot the esophageal varices [63].

Since 40% of the chronic liver disease in the United States is caused by HCV, this infection becomes one of the most common indications for liver transplant. If the infection is not treated before the surgery, the new liver will get infected when the graft is reperfused and it could cause graft failure [11]. Without antiviral therapy before the transplant, the evolution of the graft is variable. In most cases, patients who have not been cured before the surgery will develop histologic damage. On the other hand, some of them will develop cirrhosis shortly after the transplant [48].

Although disease disease-free patient is the targeted patient for transplant, there a critically ill patients on the transplant list who have decompensated cirrhosis, and the antiviral therapy is not suitable for them, so it would be a lot more beneficial to postpone treatment until after the transplant [64]. Furthermore, patients with child C cirrhosis have a lower response to antiviral therapy so this implies there is a higher risk of resistance to the antivirals. The virus could also mutate and the therapy regimen would get even more complicated. All in all, the decision to treat HCV should be individualized. The target is to increase life expectancy with treatment before or after liver transplant (Table 1) [65].

Antiviral therapy BEFORE transplant	Postponed therapy – after transplant
Compensated cirrhosis and HCC Decompensated cirrhosis but no HCC when the MELD score is relatively low (e.g., <20) and there are no other conditions such as severe portal hypertension that warrant prompt transplantation Decompensated cirrhosis and HCC when expected wait time for transplantation is more than 3–6 months	Advanced decompensated cirrhosis with an anticipated wait time less than 3 months Decompensated cirrhosis and HCC with an anticipated wait time less than 3–6 months

Table 1.

International liver transplantation society recommends [66].

Due to the availability of Direct Acting Antivirals, transplanted patient’s survival is comparable with the one regarding the transplants performed for alcohol liver disease and even better than the survival rate for patients with hemochromatosis or hepatitis B infection [66].

The only test necessary for patient medical management is the direct identification of the HCV virus to determine whether a patient has an active infection with HCV. Regardless of this, HCV is currently diagnosed in two stages: first, HCV antibodies (anti-HCV) are detected using both centralized laboratory tests or rapid diagnostic tests to identify exposure to the virus secondly, for individuals with anti-HCV positive, active HCV infection has been established by nucleic acid testing (NAT) or HCV core antigen (HCVcAg) detection [67].

After patients are stabilized post-transplant, it is recommended to test for HCV RNA [68].

The specific expenses of each test determine whether anti-HCV screening is necessary before HCV RNA and/or HCVcAg testing. This two-step diagnosis process will probably continue until the price of an HCV RNA or HCVcAg test is drastically decreased [67].

For the treatment of hepatitis C, telaprevir (TVR), a protease inhibitor, is used with pegylated interferon alfa-2b and ribavirin in a Japanese study. TVR significantly inhibits CYP3A4 and CYP3A5. Effective TVR therapy for liver transplant recipients who experienced a relapse of hepatitis C while undergoing immunosuppressive medication was reported [69].

All liver transplant recipients with detectable viremia should be treated because they can achieve sustained virologic response and the rate of liver fibrosis progression will be lower. If the conventional therapy does not work, the patients could be listed again for transplant, although the prognosis is generally poor [68].

Patients with detectable HCV viremia at the time of transplant are certain to have recurrent infection of the transplanted liver allograft, which can result in a variety of diseases ranging from asymptomatic chronic infection to an aggressive fibrosing cholestatic hepatitis. Recurrent HCV is a primary cause of allograft loss, morbidity, and death in the post-transplant population because it is more frequent in this group [70].

American and European Associations of Studying Liver Diseases (AASLD and EASL) recommendations for treating recurrent HCV infection after transplant are listed in the Table 2 [71].

Genotype	AASLD/IDSA	EASL
1	Ledipasvir + sofosbuvir + ribavirin for 12 weeks	Sofosbuvir + daclatasvir +/− ribavirin for 12–24 weeks
	Ledipasvir + sofosbuvir for 24 weeks (alternate regimen if ribavirin intolerant or ineligible)	Sofosbuvir + simeprevir +/− ribavirin for 12 weeks (alternate regimen)
	Sofosbuvir + simeprevir +/− ribavirin for 12 weeks (alternate regimen)	—
	Paritaprevir + ritonavir + ombitasvir + dasabuvir for 24 weeks (alternate regimen)	—
2	Sofosbuvir + ribavirin for 24 weeks	Sofosbuvir + ribavirin for 12–24 weeks
3	Sofosbuvir + ribavirin for 24 weeks	Sofosbuvir + daclatasvir +/− ribavirin for 12–24 weeks
4	Ledipasvir + sofosbuvir + ribavirin for 12 weeks	Sofosbuvir + daclatasvir +/− ribavirin for 12–24 weeks
	Ledipasvir + sofosbuvir for 24 weeks (alternate regimen if ribavirin intolerant or ineligible)	Sofosbuvir + simeprevir +/− ribavirin for 12 weeks (alternate regimen)
5	—	Sofosbuvir + daclatasvir +/− ribavirin for 12–24 weeks
6	—	Sofosbuvir + daclatasvir +/− ribavirin for 12–24 weeks

Table 2.

Antiviral strategies in the treatment of human and animal viral infections.