Viral Hepatitis in Solid Organ Transplantation

A number of hepatotrophic viruses affect organ transplant candidates and recipients. The most important agents causing acute and chronic hepatitis are hepatitis B virus (HBV), with or without hepatitis delta virus (HDV), and hepatitis C virus (HCV). In addition, hepatitis E virus (HEV), previously thought to only cause acute, self-limited infection in the developing world, is emerging as an increasing cause of chronic hepatitis in transplant recipients in industrialized countries. Management of viral hepatitis in transplant candidates and recipients is complex and highly depends on the organ transplanted, particularly for HBV and HCV, and the donor/recipient status. This chapter will focus primarily on the epidemiology, diagnosis, treatment and prevention of the primary hepatotrophic viruses (A-E) after hepatic and nonhepatic organ transplantation. HAV is a nonenveloped RNA virus and a member of the picornavirus family. It is largely transmitted person-to-person by the fecal–oral route, although blood borne transmission can occur 1, 2. High-income regions of the world have very low HAV endemicity levels and a high proportion of nonimmune adults, whereas in low-income regions with high endemicity most adults are immune on the basis of prior infection 3. Worldwide, approximately 1.4 million cases of hepatitis A are reported each year; however, the true incidence is estimated to be 3–10 times higher. HAV vaccines have been licensed since 1992 and vaccination of susceptible, at-risk individuals (e.g. pre- and postorgan transplantation) is advised based on national guidelines 4. Acute HAV infection is generally self-limited, but the risk of fulminant hepatic failure increases with age 5. Young children are frequently asymptomatic, whereas older children and adults may develop a range of clinical manifestations from mild anicteric infection to fulminant hepatic failure. Those with underlying chronic liver disease of any etiology are at increased risk of fulminant disease and those who are nonimmune should be vaccinated 4. The estimated fatality rate for HAV is low (<1.5%). Among those who develop fulminant hepatic failure, 35–40% will spontaneously recover, whereas others usually survive after liver transplantation (LT) (6, 7). Rarely, HAV recurs after transplantation 8, 9. HBV is a DNA hepadnavirus transmitted parenterally, sexually and vertically. Worldwide, it infects ∼400 million individuals and causes over one million deaths per year 10, 11. The prevalence can be high (≥8%), intermediate (2–7%) or low (<2%) depending on the geographic region 12. With an increase in immigrants from endemic countries, it is now estimated that >2 million HBV-infected individuals reside in the United States, of which ∼5000 per year die from complications 13. However, the ability to effectively prevent HBV infection by immunization and treat the disease with antiviral therapy represent major advances of modern medicine. Even so, HBV infection still remains an important indication for LT. Before the early 1990s and available HBV prophylaxis, untreatable recurrent HBV disease occurred in most recipients undergoing LT for this indication 14-16. Some developed a rapid, fibrosing cholestatic hepatitis (FCH) variant that led to poor early survival rates 17-20. A dramatic shift occurred in the mid-late 1990s with the advent of hepatitis B immunoglobulin (HBIG) and the first oral antiviral drug for HBV, lamivudine (LAM). Combination therapy (HBIG + LAM), without graft reinfection, became the rule resulting in advances in survival that now supersede other indications 21, 22. More recently, nucleos(t)ide analogues (tenofovir, TDF; entecavir; ETV) with high barriers to resistance have been shown to rescue patients from liver failure and need for LT, as well as allow for excellent outcomes without recurrence post-LT 23-27. Even with risk factors, e.g. high viral load at OLT (>2 × 104 IU/mL; HBeAg positivity), recurrence is now exceedingly rare. When recurrence occurs, the typical causes are noncompliance to antiviral therapy and/or HBIG, or resistance if an older agent (LAM; adefovir, ADV) is used as monotherapy 28-30. Patients with fulminant HBV or concurrent HDV have a low incidence of recurrence, given their characteristic low viral loads 31-34. HBV recurrence has been historically defined as the reappearance of HBsAg after LT, although patients on antiviral prophylaxis and not HBIG may develop HBsAg positivity without actual recurrence (DNA undetectable, normal biochemistry and histology). The reverse may also occur, i.e. low levels of viremia in the absence of HBsAg positivity, either spontaneously or due to HBsAg escape mutants during HBIG therapy 35-37. The histology of recurrence is similar to that of pretransplant HBV (Figure 1), with the exception of FCH. This now uncommon entity is defined as rapidly progressive cholestasis, fibrosis and multi-organ failure 38. All patients should be followed post-LT by a clinician (hepatologist, infectious disease, other) experienced in the management of HBV infection. Although monitoring protocols for HBV recurrence vary among centers, HBsAg and DNA should be performed at least every 3 months within the first year and every 6 months thereafter even with prophylaxis. In patients receiving HBIG, it is typical to follow anti-HBs titers with a predose goal of >100 or >500 IU/L in those with low or high DNA at LT, respectively. More frequent anti-HBs titers and dosing intervals should be performed if levels remain below these thresholds. Central to the prevention of HBV recurrence post-LT is adequate pre-LT viral control (Table 1). Although seven drugs are licensed for HBV therapy, including interferon alfa (IFNα), pegylated interferon alfa-2a (PegIFNα-2a), telbivudine, LAM, ADV, TDF and ETV, only the latter two are advisable in patients with hepatic decompensation, due to high efficacy and low resistance. HBV DNA reduction to undetectable, or at least <1 × 105 IU/mL, with a potent nucleos(t)ide analogue having high barrier to resistance (TDF, ETV) reduces the risk of HBV recurrence 39-42. Combination nucleoside/nucleotide [i.e. TDF/emtricitabine (FTC); TDF+ETV; LAM+ADV] therapy is often used by centers pre- and post-LT but the published data do not support any benefit of this approach over potent monotherapy. Rarely, antiviral therapy can lead to mitochondrial dysfunction and lactic acidosis requiring urgent discontinuation 43, 44. Entecavir needs to specifically be taken on an empty stomach. A more detailed review of HBV therapy pre-LT can be found in current national guidelines 45. HBV recurrence after LT is the result of failed prophylaxis (see below), either due to noncompliance or the development of drug/HBIG resistance. LAM resistance may occur in up to 50% of LT recipients and predisposes patients to ETV resistance long-term 46. Resistance to ADV is seen in up to 30% at 5 years before LT, although this has not been shown to lead to a higher rate of TDF resistance or loss of efficacy 47. However, the typical strategy is to either switch classes of drugs with high barrier to resistance or add the other class agent, resulting in combination therapy 48-54. The latter combination approach is often practiced anecdotally but again not proven to be more effective. HBIG is typically discontinued in patients with recurrent HBV. The nucleotide agents ADV and TDF may cause proximal renal tubular injury in a small percentage of patients, although this has mainly been seen in HIV infected populations 55, 56. Renal function should be monitored and dose adjustments made for all agents. Many centers still use combination therapy with HBIG and LAM that effectively prevents HBV recurrence (Table 1; Refs. 57-62). However, LAM resistance and the cost and inconvenience of intravenous HBIG have motivated a recent trend toward alternative preparations or HBIG withdrawal in conjunction with potent oral antivirals. Intramuscular HBIG is less expensive and represents an acceptable alternative to IV, particularly in patients with low HBV DNA at LT 34, 59, 63-67. In this group, HBIG can be safely withdrawn postoperatively (6–12 months) in conjunction with continued oral antiviral therapy 21, 68. Similar low recurrence rates have also been reported with combination therapy (LAM + ADV) before and after OLT, even without HBIG therapy 48, 69. Others have reported the use of newer, potent antiviral agents (TDF, ETV) ± HBIG, even in patients who are viremic at OLT 70-75. That being said, it is still currently recommended to give, at minimum, a short course of HBIG in combination with indefinite antiviral therapy with high barriers to resistance. One recent interesting study showed patients with undetectable HBV DNA at LT and no evidence of latent intrahepatic total and cccDNA may safely undergo full weaning of prophylaxis, although larger studies are needed before recommending this biopsy-driven approach 76. Vaccination as a strategy to allow discontinuation of HBIG or antivirals has yielded unreliable results and is not advisable. Antiviral prophylaxis is not necessary for anti-HBc positive "alone" recipients (i.e. sAg and HBV DNA negative), unless perhaps in situations of intense immunosuppressive therapy (i.e. lymphodepletion) 77-80. Anti-HBc positive donors have been increasingly used to expand the donor pool, although without prophylaxis they pose a 34–86% risk of transmitting HBV infection to unexposed (HBsAg negative) LT recipients 81. Oral antiviral therapy ± HBIG is effective prophylaxis for recipients who are HBsAg negative ± anti-HBc positive (Table 1). Lamivudine may be more effective than HBIG 82 and is preferred by many centers for logistical ease and cost. Although not standard of care, the available data suggest that discontinuation of prophylaxis can be considered in certain situations with careful monitoring: (1) donor serum, if available, is HBV DNA negative; (2) recipient is vaccinated or exposed pre-LT and maintains anti-HBs positivity post-LT and (3) recipient is vaccinated post-LT (∼12 months) and maintains anti-HBs positivity 81, 83-88. Rarely, HBV infection despite LAM or ADV has been reported in recipients of anti-HBc positive organs 82, although there are insufficient data to recommend newer agents as primary prophylaxis compared to rescue therapy for breakthrough 89. Routine HBsAg and/or HBV DNA monitoring in prophylaxed recipients of anti-HBc positive grafts may not be necessary, although transaminase elevations should prompt these investigations to exclude HBV infection. All HBV noninfected, nonimmune patients with cirrhosis should be vaccinated, as de novo HBV infection can lead to decompensated liver failure. Even with double dose regimens, the percentage who successfully seroconvert is suboptimal (16–62%), and many (37–73%) lose anti-HBs within the first year after LT 90-96. Thus, repeat or booster vaccination should be attempted at ∼12 months post-LT with the goal of sero-conversion. All household and sexual contacts of HBV-infected recipients should be vaccinated. HBV-infected recipients should not share with others personal items that may be contaminated with blood, such as toothbrushes, razor blades, nail clippers, etc. The prevalence of chronic HBV infection and markers of prior HBV in nonhepatic solid organ transplant (SOT) candidates and recipients vary widely by population and geographic region 97. In Western countries, the strict institution of infection control practices and HBV vaccination in patients on dialysis has led to a decline in the prevalence of chronic HBV, which now ranges between 0% and 6.6% 97. In contrast, a registry study of dialysis patients in Asia-Pacific countries found a prevalence of HBsAg positivity ranging between 1.3% and 14.6% 98. Although incident cases of HBV acquired on dialysis are considered uncommon, particularly in the U.S. and Europe, transmissions and outbreaks are still reported and reflect a need for ongoing education, case identification and management 99, 100. There are no data with regards to the prevalence of chronic HBV in thoracic organ transplant candidates/recipients. It is likely that the prevalence and risk factors for HBV mirrors that of the general background population, with mother-to-child transmission and early childhood horizontal acquisition being the major risk factors in those in or born in highly endemic regions. Parenteral and sexual transmission are the dominant modes of transmission in areas of low endemicity 101. The risk of reactivation of HBV in HBsAg positive renal transplant recipients, in the absence of antiviral prophylaxis, ranges from 50% to 94% 102-104. Historically, before the era of effective antiviral therapy, nonhepatic SOT in recipients with chronic HBV infection was associated with substantial reductions in patient and graft survival due to rapidly progressive liver disease 105-108. Several recent studies in both renal and cardiac transplantation have showen excellent outcomes in HBsAg positive patients managed with antiviral therapy 109-114. The prevalence of markers of prior HBV infection (HBsAg negative but anti-HBc positive, with or without positive anti-HBs) is significantly higher than the prevalence of chronic HBV in any given population. In the U.S. population, the estimated prevalence of HBsAg is 0.27%, whereas that of positive ant-HBc is 4.7% 115. In nonhepatic SOT recipients with markers of past HBV infection there is a risk of reactivation, although this is low and estimated to be at most 5% 116, 117. The natural history of reactivation in this setting seems to be a loss of the protective anti-HBs (if present at baseline) followed by a rise in HBV DNA and then seroreversion to a positive HBsAg state. It generally occurs early, within the first year, after transplant. Although the overall risk of reactivation in this setting is low, when it does occur, rapid progression and death due to liver disease have been described in the absence of antiviral therapy 117. The diagnosis of HBV relies on the same serologic and virologic assays used in the nontransplant population 39, 45, 118. As in all patients with chronic HBV, there is an increased risk of hepatocellular carcinoma (HCC). Nonhepatic SOT who are HBsAg positive should undergo HCC surveillance based on published guidelines 118, 119. A nonhepatic SOT candidate identified to be HBsAg positive during assessment should be evaluated for the need for therapy before transplant. The management of HBV is complex and requires lifelong monitoring and follow-up whether or not antiviral therapy is initiated, and thus referral to a specialist with expertise in the management of HBV is recommended. Therapy should be based on guidelines published for the management of HBV in the general population 39, 45, 118. In those with indications for therapy before SOT, LAM is no longer recommended as first line therapy due to the high risk of resistance, unless more potent agents are unavailable. Treatment with a potent nucleos(t)ide analogue, such as ETV or TDF adjusted for renal function as needed, should be used given the need for long-term therapy and to limit the risk of future resistance. It has been suggested that ETV may be preferred over TDF in the renal transplant population due to the lack of nephrotoxicity 45. Interferon or peginterferon is not recommended due to poor tolerability, bone marrow suppression and a low rate of response in immunocompromised hosts. The risk of HBV reactivation persists as long as patients remain on immunosuppressive therapy. Thus, once treatment is initiated pretransplant, it should be continued up to the time of transplant and indefinitely posttransplant as long as the patient remains on immunosuppressive therapy. If the recipient comes off immunosuppression (e.g. return to dialysis due to failed renal graft), the need for ongoing HBV therapy should be reviewed and any consideration of discontinuation of antiviral therapy should follow national guidelines 45. As in the general population, nonhepatic SOT candidates initiated on therapy for chronic HBV should undergo regular follow-up and monitoring for response to antiviral therapy and continue HCC surveillance 39, 45, 118. Nonimmune nonhepatic SOT candidates/recipients are at risk for acquisition of HBV through the usual risk factors, but also importantly via transmission from an organ donor. In many circumstances, vaccination with documented seroconversion can protect against donor-transmitted HBV (see below). Although the proportion of those with end-stage renal disease who will seroconvert, even to double dose HBV vaccine, is suboptimal, 55–67% will respond 120. Response rates are higher in those with lesser degrees of renal dysfunction and certainly better pre- than posttransplant 121. Amongst thoracic organ transplant candidates, response rates to HBV vaccine seem similarly suboptimal (45–53%) but still worthwhile 101, 122. If HBV vaccine was not given before transplant, consideration should be given to vaccination posttransplant. The rate of seroconversion to a protective titre of positive anti-HBs in the renal transplant population has been found to be 17–36% 123, 124. As described previously, the risk of reactivation of HBV in HBsAg positive renal transplant recipients, in the absence of antiviral prophylaxis, ranges from 50% to 94% 102-104. In the era before effective HBV antiviral therapy, this resulted frequently in rapidly progressive liver disease and an increased risk of graft loss and death 105-108. As LAM was the first available oral antiviral for HBV, this is the agent that has been used in most studies 110, 125. Although LAM has been shown to significantly improve patient survival after renal transplant (83% vs. 34% at 20 years), its use and impact is limited by a high (60–70%) risk of resistance over 4–5 years 125. As such, despite the improvement in overall survival, there remains an increased risk of liver-related mortality in HBsAg positive renal transplant recipients managed with LAM 125. In light of these data 126, ETV or TDF are recommended to limit the potential for resistance, with LAM or ADV reserved for those without other options 45. Interferon-based therapy is contraindicated posttransplant due to the risk of rejection. In those with markers of past HBV infection (HBsAg negative, anti-HBc positive ± anti-HBs positive), there is a low (∼5%) risk of HBV reactivation 116, 117. Data are lacking regarding the optimal approach in this situation. Given the absence of data and the low overall risk, routine antiviral prophylaxis in this group cannot be recommended. Some centers use prophylaxis in patients felt to be at increased risk (e.g. anti-HBc alone, intense immunosuppression). Alternatively, some have advocated monitoring of HBV DNA and institution of pre-emptive antiviral therapy if the DNA progressively rises 45. The challenge with this strategy is that there are no data regarding the optimal frequency of monitoring or the HBV DNA threshold at which antiviral therapy should be initiated. Given the natural history of reactivation, in those who are both anti-HBc and anti-HBs positive, some centers monitor only anti-HBs over the first 12 posttransplant months because as long as this remains above protective titres, there is a negligible risk of reactivation. Hepatitis B uninfected, nonimmune patients undergoing nonhepatic SOT may acquire donor derived HBV. The HBsAg positive donor carries a high risk of transmission to recipients although satisfactory outcomes have been described generally with the use of combined HBIG and antiviral prophylaxis 127-130. The duration of prophylaxis required is unknown, although lifelong nucleos(t)ide analogue therapy has been suggested 127. If the HBsAg and HBV DNA remain negative, consideration may be given to discontinuing HBIG 6–12 months posttransplant. The risk of HBV transmission from an anti-HBc positive nonhepatic donor is significantly lower than that of hepatic donors, ranging from 0% to 5.2% in different studies 131, 132. Renal and thoracic organs from anti-HBc positive donors have been safely used with strategies to minimize the risk of transmission 127, 133, 134. In recipients of a nonhepatic organ from an anti-HBc positive donor, the risk of transmission is negligible if the recipient is immune 127, 133, thus highlighting the importance of pretransplant immunization. In HBV nonimmune recipients of an anti-HBc positive organ, the risk of transmission is to be to the of HBV DNA present in the or of the organ donor. As such, assessment of HBV DNA in the donor may the need for prophylaxis 127. Although the optimal duration of prophylaxis is unknown, the risk is thought to be to the early posttransplant of donor HBsAg positive SOT recipients should not share personal items that may be contaminated with even small of All contacts should be for HBV, vaccinated if nonimmune and have of anti-HBs is an RNA to hepatitis and viruses is on and an RNA resulting in a of that challenge It is the cause of million and million cases of chronic hepatitis in the United and world, have the risk of hepatitis in Western countries, but cases continue to occur to who have with and transmissions In the Western world, and are the most followed by and 3. The other are primarily seen in the and Worldwide, hepatitis C is a indication for LT. The number of patients requiring LT for is to in the years followed by a decline due to advances in treatment and after LT is and injury is in the graft compared to the rate this recipients with have patient and graft survival compared with recipients and both with primary or repeat transplantation due to only occurs in and is associated with poor outcomes (Figure progression is by early (6–12 months liver recurrent cirrhosis occurs, within year is and is often not considered in those with renal failure, and early recurrence The risk factors for recurrence are high dose immunosuppressive therapy for acute concurrent HIV or older donor/recipient viral load and injury or In to recipients, treatment of acute is associated with increased mortality and graft loss in recipients with risk It is however, that or increase the risk of recurrence when used primarily as therapy There has been recent in donor/recipient C or being of progressive and response to therapy post-LT risk factors for recurrence the use of donors after cardiac death or donors and the of therapy data have a or no to early recurrence, although this is not There has been some in the of in fibrosis progression in recipients, although data suggest a higher risk of mortality in this setting The use of donors for recipients results in outcomes similar to the use of an donor However, the use of donors for or any positive donor recipients should be studies also that outcomes are if donors over age are used compared to donors or if donors are used for recipients the of the LT RNA rapidly from the The rate of RNA decline after likely due to to its hepatocellular RNA levels then increase rapidly after the first at year, can higher levels than In the first 6 acute hepatitis of occurs in approximately of recipients, with developing cholestatic occurs in at years after LT and up to 30% to fibrosis or cirrhosis by year 5 Thus, the standard for diagnosis is liver with the that it may not other causes from early after LT and may fibrosis centers liver at defined time (i.e. to monitor for recurrence the need for treatment 3 or that are less used hepatic and blood and for of fibrosis has been shown to the development of progressive and and with antiviral therapy liver with or can fibrosis and may be for fibrosis although are widely available in the United a virologic response with pre-LT antiviral therapy may the need for OLT and the risk of However, this comes at a due to poor patient and depending on the of hepatic and the A low dose approach of and to levels may improve and an that is usually after OLT, of pre-LT viral is However, this approach is most effective in patients and is associated with a high risk of infectious complications with benefit in Thus, treatment should be limited to decompensated patients with and primarily and 3 infection. In two first became available for use in combination with and for the treatment of HCV, even in cirrhosis Although there are no current published data in decompensated patients, a number of centers are to this therapy with the goal of viral before LT. It is not currently if the overall benefit will the and it is likely that of oral antiviral agents without or will be more in this population. therapy or within a after OLT has not been shown to the of recurrence The study compared the and efficacy of pre-emptive of within after LT only an recurrence at was similar in the prophylaxis and Similar results shown with and other Given the and lack of virologic therapy is not currently advisable in clinical centers the development of recurrence, typically by or liver treatment of recurrence with + is only in of recipients and is associated with high rates of discontinuation due to A major in an acceptable rate is the to due to renal and Although some have not shown an increase in the risk of acute with a recent study reported a rate of graft dysfunction that was associated with poor patient and graft survival of of injury on such as was the risk for the development of this Thus, careful review of liver for alternative other than may suggest the need to therapy and therapy in this situation. a number of at recent

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