Viral Hepatitis in Solid Organ Transplant Recipients

Viral hepatitis in organ transplant recipients may be caused by a number of different viruses. Of these, the most important infectious agents are hepatitis B (HBV) and hepatitis C virus (HCV). Other possible causes include cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), Epstein Barr virus (EBV), adenovirus, and parvovirus B19. This section will concentrate on HBV and HCV; discussions of other pathogens can be found in the appropriate sections of these guidelines. The issues related to viral hepatitis in organ transplant recipients are complex, and the approach to management depends on a variety of donor and recipient characteristics. The organ transplanted is the most important of these characteristics. The approach to liver transplant patients is significantly different from that of nonhepatic organ transplant recipients with viral hepatitis. Epidemiology and risk factors: Over 350 million people are infected with HBV worldwide. As a result, approximately 1 million die from complications related to cirrhosis and/or hepatocellular carcinoma (HCC) (1, 2). Given the high percentage of foreign-born individuals in the United States, it is estimated that over 2 million are infected with HBV (3). Successful therapy with nucleos(t)ide analogues can reduce the risk of hepatic decompensation and HCC, prolong transplant free survival and allow some patients to be removed from transplant lists (4-7). However, HBV infection still remains an important indication for orthotopic liver transplantation (OLT) and accounts for ∼10% of OLTs in the United States. Prior to the era of antiviral prophylaxis (1980s, early 1990s), 80% of the patients experienced HBV reinfection after OLT, resulting in a 50% 2-year post-OLT mortality (8-11). Although the major source of viral replication (the liver) is removed, circulating virions in extrahepatic sites (peripheral blood mononuclear cells (PBMCs), blood) reinfect the newly transplanted liver soon after OLT (12-14). With the advent of hepatitis B immunoglobulin (HBIG) and the first oral antiviral agent for HBV, lamivudine (LAM), in the mid-late 1990s, graft reinfection became the exception rather than the rule and patient/graft survival became comparable or even superior to that of other OLT indications (15, 16). While uncommon, viral resistance to antiviral therapy and HBIG is a leading cause of HBV-related graft dysfunction (17-19). Other established risk factors for recurrence include high viral load (>2 × 104 IU/mL [105 copies/mL]) at OLT, high levels of immunosuppression (IS), HBeAg positivity, and noncompliance. Recurrence is uncommon in patients receiving OLT for fulminant HBV or those with concurrent hepatitis delta infection as such patients typically have lower viral loads (20-23). Diagnosis: HBV recurrence is typically defined as the reappearance of HBsAg after OLT. This is generally associated with detectable HBV DNA in the blood, although viremia may occur in the absence of HBsAg antigenemia. The significance of this latter event is unknown as HBV DNA may be detectable in low levels in the sera, liver, and PBMCs of OLT recipients (24, 25); however detectable HBV DNA, particularly at higher levels, in the absence of HBsAg raises the possibility of recurrence with the emergence of a hepatitis B surface antigen escape mutant (26). Both HBsAg and HBV viremia occur prior to biochemical or histological changes. The histology of recurrence is similar to that of pretransplant HBV infection with one exception—fibrosing cholestatic hepatitis (FCH). Now exceedingly rare in the setting of peritransplant viral control, FCH was fairly common in the preprophylaxis era. It is characterized by high viral titers, a destructive cholestatic hepatitis on histology and is associated with a high mortality with or without retransplantation (27). Monitoring protocols for HBV recurrence after OLT are variable among transplant centers. HBsAg and DNA should be performed at least every 3 months even with HBIG and oral antiviral therapy. Although newer, more potent antiviral agents or combination therapy may be associated with a low potential for resistance, currently there are insufficient data to allow for less-frequent monitoring. Anti-HBs titers are often monitored in patients receiving HBIG therapy, to confirm adequate levels (>100 IU/L; >500 IU/L early after OLT or high HBV DNA) or to decide on redosing. If HBV recurs on appropriate prophylaxis, either noncompliance or antiviral/HBIG resistance should be suspected and appropriate resistance testing should be performed to guide further antiviral therapy. Recommendation: Quarterly monitoring of HBsAg and HBV DNA should be performed in HBV-positive liver transplant recipients, regardless of prophylaxis regimen (III) Treatment: Pretransplant: Antiviral therapy prior to OLT, particularly if HBV DNA can be reduced to undetectable or at least <2 × 104 IU/mL, reduces the risk of HBV recurrence. A detailed discussion of pre-transplant HBV therapy is beyond the scope of these guidelines. In general however therapy should be with a potent nucleos(t)ide analogue or combination therapy and based on published guidelines (28-30). Interferon therapy is not recommended in decompensated cirrhotic patients given the risk of precipitating hepatitis flares and further decompensation. Posttransplant recurrence: For recurrent HBV infection despite prophylaxis (see Prophylaxis below), HBIG should be discontinued and oral antiviral therapy tailored based on data obtained from resistance testing. Monotherapy with drugs associated with unacceptably high long-term resistance rates (LAM, telbivudine [LdT], adefovir [ADV]) is not recommended as first line in transplant recipients. However, combination therapy for LAM resistant patients by using the addition of ADV or tenofovir (TDF) before or after OLT lowers viral load, improves liver function and may stabilize or improve histology (31-35). Recent FDA approvals of potent antiviral agents with low resistance rates (entecavir [ETV], TDF) are likely to replace older agents but need to be studied in a prospective fashion in transplant recipients. Prevention/prophylaxis: Advances in antiviral prophylaxis have dramatically improved the outcome of transplantation in HBV-infected recipients. Hepatitis B immunoglobulin, a polyvalent anti-HBs antibody preparation, binds to intracellular and circulating virions to prevent graft reinfection. A landmark trial in 1993 demonstrated significant improvement in graft reinfection rates with long-term IV HBIG therapy (36%) compared to short term (74%) or no HBIG (75%) therapy (22). However, higher recurrence rates with HBIG monotherapy occurred in patients with high HBV DNA at the time of OLT (25, 36-41). Similarly, LAM monotherapy improves the rate of recurrence over no prophylaxis, although the development of resistance results in recurrence in 10%–50% within 1–3 years after OLT (5, 23). Combination therapy with IV HBIG and LAM is highly efficacious in preventing graft reinfection (<10%) (41-46). The major drawbacks of long-term IV HBIG therapy are the cost, the inconvenience of ongoing IV infusions and the need for continued anti-HBs monitoring. More recently, investigators have reported low rates of recurrence with low-dose IV (400 IU–800 IU vs. 10 000 IU in high dose) or IM HBIG, particularly in those with undetectable HBV DNA at the time of OLT (23, 44, 47-51). In addition, recurrence rates of < 10% have been demonstrated with short-term (< 6 months) use of HBIG, typically with continued use of oral antiviral therapy, in patients with undetectable DNA at OLT (15, 52). Low recurrence rates have also been demonstrated in patients given combination antiviral therapy (LAM + ADV) prior to OLT and continued post-OLT with or without the use of postoperative HBIG therapy (31, 53); however there are currently insufficient data to recommend post-OLT prophylaxis with nucleos(t)ide analogues alone in the absence of HBIG. The choice of antiviral agent should be based on antiviral exposure history, resistance testing and the principles of HBV therapy pre-OLT. In those with low (< 2 × 104 IU/mL) or undetectable HBV DNA at transplant, short-term or even no HBIG therapy may be considered in the context of indefinite antiviral therapy with low resistance. Further research is required to determine the role of newer more potent antivirals versus combination antiviral therapy in the prevention of HBV recurrence and need for HBIG post-OLT. Another attempted strategy to perhaps allow discontinuation of HBIG and/or antiviral therapy is vaccination of HBV-positive recipients. A number of studies have shown inconsistent anti-HBs response rates following standard or high-dose HBV vaccination (54-57). One study demonstrated high titer anti-HBs (>721 IU/mL) in 16 of 20 patients following recombinant adjuvant HBsAg vaccination and HBIG was discontinued successfully in these patients (55). These findings have not since been replicated and further research is needed to evaluate this novel approach. Recommendations: In HBsAg-positive recipients, post-OLT prophylaxis should include potent nucleos(t)ide analogue therapy ± HBIG (IV or IM). Discontinuation of HBIG may be considered in patients with low or undetectable HBV DNA at transplant (II-2). Antiviral therapy, preferably combination therapy or monotherapy with low known resistance, should be continued indefinitely post-OLT (III). Anti-HBc-positive donors: With efforts to expand the donor pool, anti-HBc-positive donors have been increasingly utilized. Without prophylaxis, recipients of anti-HBc-positive, HBsAg-negative liver grafts experience high rates of primary HBV infection. Oral antiviral therapy is effective prophylaxis, with or without HBIG, in recipients of these organs and should be continued indefinitely posttransplant, unless HBV DNA negativity can be confirmed in the serum and liver tissue of the donor (58-62). Rarely, despite prophylaxis, late HBV infection with antiviral-resistant virus has been described. The role of routine HBsAg and/or HBV DNA monitoring in recipients of anti-HBc-positive grafts is unclear; however unexplained aminotransferase elevation should be investigated with HBsAg and HBV DNA to rule out HBV infection. Recommendation: In general, recipients of anti-HBc-positive donors should receive anti-HBV prophylaxis indefinitely (II-2) Infection control issues: HBV uninfected, nonimmune OLT candidates should be vaccinated for HBV as early as possible pre-OLT. The percentage of patients who successfully seroconverts, however, is suboptimal (16%–62%), even with double dose regimens, and many (37%–73%) lose anti-HBs within the first year following OLT (63-69). All household and sexual contacts of HBV-infected recipients should be vaccinated and have documentation of anti-HBs seroconversion. HBV-infected recipients should not share razorblades, toothbrushes, or other personal items that may be contaminated with even small amounts of blood (III). Epidemiology and risk factors: There are approximately 4 million hepatitis C virus (HCV) infected individuals in the United States and more than 170 million globally (70). Worldwide hepatitis C is currently the leading indication for OLT. The number of patients developing end-stage liver disease and requiring liver transplantation for HCV is expected to steadily increase over the next 10–15 years (71). The majority of OLT recipients develop evidence of histological recurrence within 5 years of OLT, with a smaller but significant percentage (10%–25%) developing cirrhosis within this same time frame (72, 73). Fibrosing cholestatic hepatitis, similar to that seen in the early days of HBV transplantation, fortunately only occurs in a small percentage of patients. Fibrosis progression is accelerated after OLT and is best predicted by performing early (1–2 years post-OLT) liver biopsies (74, 75). While the overall, 5-year patient (70%) and graft survival (57%) in HCV-infected OLT recipients is acceptable, it remains inferior to patient (77%) and graft survival (68%) in HCV-uninfected recipients (77). Once recurrent HCV cirrhosis occurs, 40% decompensate within 1 year, resulting in a 1- and 4-year patient survival of only 66% and 33%, respectively (73, 76). Retransplantation for HCV-induced graft failure is associated with particularly poor outcomes and might not be considered in higher risk recipients with advanced age, renal insufficiency, high MELD, deconditioned status and aggressive early (<1 year) HCV recurrence (78-87). Risk factors for accelerated HCV recurrence are displayed in Table 1. The most consistently identified and strongest predictors of recurrence are IS therapy for acute rejection (i.e. intravenous corticosteroids, lymphodepleting antibodies), CMV infection, preservation injury and older recipient and donor age (88-96). In general, induction therapy with either lymphocyte depleting or nondepleting (IL-2 inhibitors) antibodies does not appear to increase the risk of recurrence (97-100). However, the use of lymphocyte depleting antibodies for treatment of steroid-refractory rejection profoundly increases the risk of an aggressive HCV recurrence and FCH. More controversial and less clearly defined risks for recurrence include pre-OLT viral load, HCV genotype (1b), donor/recipient HLA differences, and the use of donors after cardiac death (90, 96, 101-105). Even more controversial are the effects of different maintenance IS agents and steroid tapering regimens. The weight of current data does not support a significant difference in recurrence rates with the use of tacrolimus compared to cyclosporine, even though cyclosporine has well recognized in vitro anti-HCV effects (106-112). Other adjunctive agents, such as mycophenolate mofetil, rapamycin and azathioprine, have not been shown to definitively impact the risk of recurrence (113-116). Recent data support complete steroid avoidance with induction therapy or a slow tapering schedule of steroids in HCV+ recipients to avoid precipitating a more aggressive early recurrence seen with rapid steroid withdrawal (98, 117-121). This practice, however, is not universally agreed upon. Finally, the effect of live donors (LDLT) and HCV+ donors on recurrence has recently been While early a higher rate of recurrence following data have these The use of HCV+ donors for HCV+ recipients also does not appear to impact recurrence rates The use of genotype 1 HCV+ donors 1 recipients however, not Diagnosis: function are common in HCV+ recipients and not HCV recurrence from other the is liver may not be in other causes of early graft dysfunction from HCV recurrence and may also the of While evidence is not most liver biopsies to for evidence of histological recurrence and HCV therapy for patients who develop recurrence 3 or by Other include of the hepatic and blood or While a and may not be in OLT recipients, an by has been shown to progression to more advanced disease and the development of This also with anti-HCV therapy after OLT with a higher and for advanced in HCV+ recipients in to other of these appear to an of disease the need for further or Recommendation: of early or histological recurrence and/or by liver and are of disease progression and may be in the to HCV therapy (II-2) Treatment: Pretransplant: of HCV viremia resulting in a response prior to OLT may the need for OLT and reduce the risk of HCV recurrence. With the current standard of HCV therapy, genotype 1 and genotype of patients While based therapy is generally in cirrhotic it is and often in decompensated patients with advanced liver disease an approach in and are at low and advanced to levels was shown to improve allow for continued treatment OLT, and an that after OLT However, this approach is more in 1 cirrhotic patients with disease and associated with a risk of infectious complications with (< 10% in genotype 1 patients with more advanced of histological recurrence with or + after OLT is only in of recipients and is associated with high rates of discontinuation to A reported a and rate for standard + and + regimens, respectively A major in an rate is the to to the high of renal in HCV + OLT recipients Although reported high rates of a study of early post-OLT prophylaxis and therapy not an increase in the risk of acute rejection Prevention/prophylaxis: A general in HCV + OLT recipients is to avoid that might rapid such as acute use of older or donors and CMV infection. IS tapering of agents and or is more likely to to a lower of HCV recurrence and acute This however, is more than and not based on HCV therapy after OLT has not clearly been shown to the of recurrence In addition, postoperative use of ± results in low a high of complications infection, and is therapy is not currently recommended in Hepatitis C immunoglobulin has been shown to lower HCV but does not HCV viremia or the risk of recurrence Infection control issues: to HBV, HCV-infected recipients should avoid toothbrushes, or other that may be contaminated with even small amounts of blood and in of HCV is rare and seen in individuals who in The use of to prevent HCV in is can particularly in with high HCV but this risk is low In to HBV, an HCV has not been successfully to prevent Epidemiology and risk factors: With current infection control and the of the of HBV in patients on has in and and of HBV on is uncommon in the majority of For the most HBsAg can be to standard risk factors in sexual although to be reported The of HBV in other nonhepatic transplant candidates has not been well studied but likely the older studies have shown a significant risk of death in HBsAg-positive renal transplant recipients This has been to HBV-related liver disease as well as an risk of In transplantation, to of patients will develop cirrhosis within years In one however, the 5-year survival was and not significantly different from those without HBV more studies in renal and cardiac transplantation have demonstrated outcomes in HBsAg-positive patients with nucleos(t)ide analogue therapy Recommendation: In the current era of potent antiviral therapy for HBV, hepatitis B infection should not be considered a to nonhepatic (II-2). In nonhepatic recipients with of HBV infection ± anti-HBs there is a low risk of HBV Although uncommon, has been associated with rapid progression to cirrhosis and death Hepatitis B uninfected, patients nonhepatic may donor The HBsAg-positive donor a high risk of to recipients although outcomes have been with prophylaxis (see The risk of HBV from an anti-HBc-positive nonhepatic donor is significantly lower (< than that of hepatic donors from anti-HBc-positive donors can be with and appropriate to prevent (II-2) (see Diagnosis: The of HBV on the same and in the (28-30). Recommendations: for HBV should be at the time transplant and include anti-HBs and All patients with HBV on nucleos(t)ide analogue therapy should liver and HBV DNA monitoring every months and HBsAg testing (III). of organs from a HBsAg or anti-HBc-positive donor should monitoring at least every 3 months with liver and HBV DNA As in the HBsAg-positive patients should have an if of the liver is and for of every 6 months (III) (28-30). Treatment: candidates with HBV should be to determine the need for therapy prior to The management of HBV is and beyond the scope of this however, should be based on published guidelines (28-30). In general, treatment with a potent nucleos(t)ide for renal function as is to the potential for resistance therapy should be as it is generally in those with and associated with a low rate of response in Recommendation: candidates with HBV should be for the need for therapy prior to transplantation based on published guidelines in the (III). Prevention/prophylaxis: As in liver transplantation, HBV uninfected, nonhepatic candidates who are nonimmune should be vaccinated for HBV as early in the of disease as possible (III). In those with end-stage renal the who develop a antibody response 10 however, is suboptimal even with rates with renal function There are data with to the of hepatitis B vaccination in and transplant however small rates of and respectively Recommendation: HBV uninfected, nonhepatic candidates who are nonimmune should be vaccinated for HBV as early in the of disease as possible (III). recipients with HBV who are not on antiviral therapy prior to transplant should be on nucleos(t)ide analogue therapy at transplant to prevent Antiviral therapy should be continued indefinitely The only agent well studied in the setting of is LAM however, associated with a high risk of resistance at 5 Given the need for therapy and the risk of a in an if resistance despite the of should be given to a more potent antiviral or TDF) to the potential for resistance, particularly in those with high viral load or advanced Recommendations: recipients with HBV who are not on antiviral therapy prior to transplant should be on nucleos(t)ide analogue therapy at transplant and continued indefinitely to prevent (II-2). In those with high viral load or advanced should be given to using a more potent antiviral or TDF) to the potential for resistance (III). In those with of HBV infection ± anti-HBs there is a low risk of HBV While data are the approach to management in these either antiviral prophylaxis or monitoring should be to the risk associated with HBV If nucleos(t)ide analogues are not recipients should testing for HBV DNA and every 1–3 months with antivirals if HBsAg or if HBV DNA of an organ from a HBsAg regardless of should receive prophylaxis with HBIG and a nucleos(t)ide analogue The of prophylaxis required is however, it is recommended that the nucleos(t)ide analogue be continued If the HBsAg and HBV DNA may be given to HBIG months In recipients of an organ from an anti-HBc-positive the risk of is if the recipient is and no further prophylaxis is needed In HBV nonimmune recipients of an anti-HBc-positive prophylaxis with LAM other antiviral or HBIG should be of HBV DNA in the donor may be to further guide If the donor HBV DNA is or prophylaxis should be continued with HBIG for at least months or LAM for at least months If the donor is HBV DNA prophylaxis can be but routine monitoring should with liver HBsAg and HBV DNA every 3 months for at least months or Recommendations: may be given to using organs from an HBsAg-positive donor with prophylaxis and (III). In HBV nonhepatic recipients of an anti-HBc-positive no prophylaxis is needed (II-2). In HBV nonhepatic recipients of an anti-HBc-positive prophylaxis with either LAM months) or HBIG months) should be (II-2). Infection control issues: HBsAg-positive patients should not share personal items that may be contaminated with even small amounts of blood and contacts should be vaccinated and have documentation of anti-HBs seroconversion. Epidemiology and risk factors: The of HCV infection in candidates for nonhepatic by organ the of HCV in patients with end-stage renal disease has been to that of the general however with to routine infection control and of blood the has over the in The of HCV infection in organ transplant candidates to the nonhepatic recipients, the impact of HCV on transplant outcomes has been studied most in renal transplant recipients. In this the rate of progression has been shown to be accelerated compared to individuals Although early data no significant difference in patient and graft survival and renal recipients, more studies an impact of HCV infection on patient and graft survival The impact of HCV infection on and or more years after The survival is approximately lower in compared to renal transplant recipients. however, survival is improved compared to on and poor outcomes occur in those with advanced at transplant candidates and recipients with to 2 or liver disease at have a low risk of progression of liver disease In addition to the impact on recipients of a renal have an risk of graft dysfunction and There are no long-term studies the impact of HCV on outcomes of small or recipients. in these have no difference in patient and graft survival likely to the short-term and small on the renal transplant there is likely an risk of death beyond 5 years in other nonhepatic however, further studies are needed to the Diagnosis: The of hepatitis C infection on the same and in the for antibody to HCV should be at the time transplant using a The has improved compared to older and are rare even in the setting of IS However, in transplant candidates or recipients with HCV and unexplained liver HCV testing to rule out testing should be In those with HCV HCV should be to confirm current infection. The HCV genotype should be in patient considered a potential for HCV therapy (see is for of complications of liver disease such as and In HCV infection, the liver remains the for the of hepatic and as well as the of the is recommended in the of nonhepatic candidates with HCV to guide antiviral treatment those who may be considered for liver) transplant and those who are for nonhepatic to advanced liver disease Recommendations: for antibody to HCV should be at the time of transplant using a and HCV should be to confirm current infection in those found to be antibody is recommended in the of nonhepatic candidates with HCV to guide management (II-2). Treatment: of HCV in nonhepatic recipients is generally to a significant risk of acute rejection therapy transplant has been associated with often steroid in to of patients and results in Even after renal prior to retransplantation has been to be associated with acute rejection to the risk of precipitating therapy should be in However, therapy has been reported transplant and may be considered on a in those with disease following of the potential risks and Recommendations: In recipients of therapy should be (III). In renal transplant recipients, therapy may be considered on a by in those with significant disease and following of the potential risks and Prevention/prophylaxis: In to HBV, there is no HCV to prevent The of prevention in this is prevention to the impact of HCV infection on transplant Given the risks associated with therapy as well as the accelerated progression of hepatic and risk of and mortality in HCV-infected nonhepatic recipients, patients should be for therapy prior to of HCV transplant has been shown to have a on outcomes HCV therapy in renal transplant however, is associated with suboptimal rates and a higher rate of and discontinuation to than in the general With standard the rate is and from to with monotherapy of the studies are small and many have not reported response by small have the use of in combination with therapy in patients with HCV and poor renal function Given the data however, remains in patients with a < guidelines that renal transplant candidates with HCV should liver as of without advanced should be for transplant however therapy should be considered prior to with or cirrhosis should therapy and may be for transplant if an is with decompensated cirrhosis are generally not considered candidates for renal transplant but may be considered for transplant the management of and transplant candidates with HCV are further data are the principles and data from the renal transplant may be to guide A liver should be as of the in those infected with In transplant HCV therapy is to the effect (i.e. risk of with disease may be for transplant, those with advanced or cirrhosis are generally not considered candidates for cardiac transplantation Although there are no published data on the outcome of transplant in recipients, this is generally considered a However, some transplant using the liver to guide the for and/or of therapy pretransplant One small has shown that transplant candidates can and be for HCV prior to transplantation Recommendations: transplant candidates should be for for HCV therapy prior to transplant (II-2). A approach to the and management of HCV infected nonhepatic transplant candidates is in 1 (III). approach to the management of HCV-infected nonhepatic transplant The of HCV in organ donors that of the general and transplantation of an organ an recipient results in HCV at the time of transplantation may have a particularly early aggressive with a high risk of death from infectious complications and FCH Although early small studies no impact of an nonhepatic organ an studies have demonstrated a significant risk of death beyond 2 years Recommendations: Given the current era of organ and risk of death on the an organ may be considered for transplantation, with an recipient or in The use of organs recipients should generally be to poor however, this may be considered with in patients a transplant (III). Infection control issues: with HCV should not share personal items that may be contaminated with even small amounts of and

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