Liver transplantation in adults: Evaluation and prevention of Hepatitis D virus reinfection in liver transplant recipients

INTRODUCTION — 

Hepatitis D virus (HDV) infection is caused by a defective virus. Individuals with clinical manifestations of HDV are dually infected with hepatitis B virus (HBV) infection. Although HDV can replicate autonomously, the simultaneous presence of HBV is required for complete virion assembly and secretion.

Despite the availability of antiviral therapy for patients with HBV, some patients with HBV/HDV coinfection develop progressive liver disease and require liver transplantation. HDV reinfection in liver transplant recipients is rare because post-transplant prophylaxis with a nucleos(t)ide analog alone or in combination with hepatitis B immune globulin (HBIG) is an effective strategy for preventing HBV reinfection.

For most patients with acute HBV and acute HDV coinfection, the clinical course is characterized by a self-limited acute hepatitis and overall good prognosis. However, some patients may develop acute liver failure or progression to chronic hepatitis and cirrhosis. In contrast to HBV infection alone, chronic HBV/HDV coinfection has been associated with more rapid progression to cirrhosis and increased risk of hepatocellular carcinoma [1]. In addition, patients with HBV/HDV coinfection may develop decompensated cirrhosis and need liver transplantation at a younger age than patients with HBV infection alone [2-4].

This topic will review HDV reinfection following liver transplantation. Issues related to liver transplantation in patients with HBV infection alone is discussed separately. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)

The pathogenesis, clinical manifestations, prevention, and treatment of HDV infection are discussed separately. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection" and "Treatment and prevention of hepatitis D virus infection".)

Prevention and management of other infections following liver transplantation are discussed separately. (See "Infectious complications in liver transplantation".)

PATHOGENESIS — 

HDV is a defective virus that is dependent upon hepatitis B virus (HBV) for envelopment, virion assembly, and secretion. In general, HDV infection occurs only in the presence of HBV infection [5]. Thus, reinfection with HDV alone following liver transplantation is usually short-lived and is not associated with recurrent liver disease unless HBV reinfection occurs subsequently. Observational studies on the clinical course of HDV reinfection have provided important insights into the biology of HDV replication and the pathogenesis of HDV-related liver disease. (See 'Clinical features of HDV reinfection' below and "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection", section on 'Pathogenesis'.)

In vitro experiments using cell cultures have shown that HDV can replicate in the absence of HBV but that the virions cannot be released from the cells [6-8]. In addition, studies in woodchucks demonstrated that HDV infection of the liver can be achieved by inoculating woodchucks with sera containing a high ratio of HDV to woodchuck hepatitis virus (WHV) particles. However, productive infection occurred only when the animals were subsequently administered a highly infectious dose of WHV [9]. In addition, humanized animal models suggested that latent HDV infection was rescued by superinfecting animals with HBV, leading to the appearance of high titers of HDV RNA in serum and an increasing number of hepatocytes expressing HDV antigen (HDAg), and the newly produced HDV virions were infectious in naive chimeric mice [10].

It is possible that for liver transplant recipients who have HDV reinfection alone, HBV was present but went undetected because of masking of hepatitis B surface antigen (HBsAg) by hepatitis B immunoglobulin (HBIG) [11]. Although early studies found that HBV DNA was undetectable both in sera and in liver tissues [12], one study demonstrated the presence of HBV DNA by polymerase chain reaction, indicating that small amounts of HBV are present at the time of HDV reinfection [11]. Another study showed rapid early decline in HDV RNA in parallel with HBsAg during the first few days post-transplant, but HDAg stained positive in transplanted livers in 6 of 26 patients for up to 19 months after transplant, despite an absence of HBV DNA in the liver and HBsAg and HDV RNA (using a very sensitive RT-PCR assay) in the serum [13]. These data support the concept that latent HDV reinfection can occur in patients with no evidence of HBV reinfection. However, traces of HBV are likely present in these situations and HDV reinfection can become overt if prevention or suppression of HBV reinfection fails.

With the availability of nucleos(t)ide analogues with low rates of resistance (ie, entecavir or tenofovir), many transplant centers no longer routinely use HBIG to prevent HBV reinfection in patients transplanted for HBV infection alone. However, use of HBIG in combination with an antiviral agent may be important for patients transplanted for HBV/HDV coinfection. (See 'Strategies to prevent HDV reinfection' below.)

Studies performed before the widespread use of antiviral prophylaxis have described long-term outcomes after liver transplantation for HDV-related cirrhosis in the absence of antiviral agents [12,14]. These studies showed that in the absence of antiviral therapy, long-term HBIG alone can decrease the risk of HBV/HDV reinfection.

CLINICAL FEATURES OF HDV REINFECTION — 

Most patients with HDV reinfection alone are asymptomatic. However, those with HDV/hepatitis B virus (HBV) reinfection may present with symptoms of recurrent hepatitis.

HDV reinfection alone — In patients with HDV reinfection without markers of HBV reinfection, serum aminotransferase levels usually remain normal and there is no evidence of hepatitis on liver biopsy. In a study that included 61 patients who were transplanted for HDV infection and remained hepatitis B surface antigen (HBsAg) negative post-transplant, 47 patients (77 percent) had normal grafts, seven (12 percent) had acute or chronic rejection, and seven (12 percent) had acute or chronic hepatitis on liver biopsies that were performed at least two years post-transplantation [12]. All patients with biopsy-proven hepatitis were negative for markers of HDV and HBV infection. However, six patients were positive for hepatitis C antibody, suggesting that hepatitis C infection may have been the cause of the hepatitis.

Latent HDV reinfection activated by HBV reinfection — In some patients, HBV reinfection lags behind HDV reinfection by a few months. When HBV reinfection occurs (ie, reappearance of HBsAg), HBV replication reactivates latent HDV [15,16]. Clinical manifestations are similar to simultaneous coinfection with HBV/HDV and include hepatitis and progression to chronic liver disease.

Simultaneous HDV and HBV reinfection — Simultaneous reinfection with HDV and HBV after transplantation is usually accompanied by recurrent hepatitis and expression of HDV antigen (HDAg) in the liver graft [12,15,17]. In a study of seven patients who were transplanted for HDV infection and developed simultaneous HDV and HBV reinfection, four patients subsequently became HBsAg negative, either spontaneously or after antiviral therapy with adenine arabinoside 5'-monophosphate (ARA-AMP) [12]. Among these four patients, liver biopsy was normal in two patients and showed chronic hepatitis without cirrhosis in two patients. For three patients who remained HBsAg positive, liver biopsy showed chronic active hepatitis without cirrhosis after 51 to 70 months post-transplant.

Another series presented detailed histopathologic evaluation of nine patients with HDV and HBV reinfection [15]. Two types of lesions were observed. Some patients had productive HBV reinfection with hepatic expression of HDAg, HBsAg, and HBcAg and necroinflammatory changes typical of acute viral hepatitis. However, other patients had hepatic expression of HDAg and HBsAg but not HBcAg. The histologic changes at this stage were mainly degenerative: hepatocyte ballooning, micro- and macro-vesicular steatosis, and eosinophilic alterations of the cytoplasm were seen with little evidence of inflammation. The histologic picture in the latter patients became predominantly necroinflammatory when markers of HBV replication appeared. These patients appear to demonstrate a propensity of HDV to suppress HBcAg expression [17].

MONITORING FOR HDV POST-TRANSPLANT — 

Testing for HDV RNA should only be performed in patients with HBV/HDV coinfection if they have evidence of HBV reinfection post-transplant. Routine monitoring for HDV reinfection is not needed in those without HBV reinfection, since reinfection with HDV alone is not clinically significant. (See 'HDV reinfection alone' above and "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection", section on 'Diagnostic tests'.)

After transplant, we monitor patients for HBV reinfection by measuring HBsAg and HBV DNA every one to three months during the first year after transplant and every 6 to 12 months thereafter. We also check these markers if there is unexplained elevation in aminotransferases. HBV reinfection is diagnosed if there is reappearance of HBsAg or HBV DNA. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'Surveillance post-transplant'.)

In patients with HBV reinfection, we monitor serum HDV RNA every three months for the first year and then every six months thereafter.

The diagnosis of HBV/HDV coinfection is made by detecting HDV RNA in serum and/or HDAg in the liver graft (eg, if a liver biopsy was performed) [12]. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection", section on 'Diagnostic tests'.) [12]. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection", section on 'Diagnostic tests'.)

MANAGEMENT IF REINFECTION OCCURS

Pharmacologic therapy — Specific treatment for HDV reinfection has not been evaluated and is generally not necessary because HDV reinfection in the absence of HBV reinfection is usually self-limited and not associated with recurrent hepatitis. In addition, reinfection with both HBV and HDV is rare with the use of long-term antiviral prophylaxis (ie, entecavir or tenofovir) [18-21]. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'Strategies to prevent HBV reinfection'.)

Although pegylated interferon is used for treating HDV infection in the nontransplant setting, data on interferon therapy for HDV reinfection are lacking. In addition, use of interferon may increase the risk of acute T-cell mediated (cellular) rejection. Emerging therapies such as bulevirtide or lonafarnib show promise for treating HDV reinfection in transplant recipients, but clinical data in this setting are limited [22,23]. Management of HDV infection, including data on efficacy and safety of drug therapy, is presented separately. (See "Treatment and prevention of hepatitis D virus infection".)

Retransplantation — Studies on retransplantation for progressive liver disease related to HDV reinfection are lacking. In an observational study including 76 patients with HDV-related cirrhosis who underwent liver transplantation, none of the recipients required retransplantation because of recurrent liver disease related to HBV or HDV reinfection [12].

STRATEGIES TO PREVENT HDV REINFECTION — 

Preventing HDV reinfection relies on the strategies used to prevent HBV reinfection. HDV reinfection alone is short-lived, unless it is reactivated by HBV replication [24]. Specific prophylaxis for HDV reinfection is not available. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)

Preventing HBV reinfection — The most effective method for preventing HDV reinfection is to prevent hepatitis B virus (HBV) reinfection with long-term antiviral prophylaxis. We agree with society guidelines that recommend a combination of an antiviral agent (eg, tenofovir or entecavir) plus prophylaxis with hepatitis B immunoglobulin (HBIG) post-transplant [25]. Data from observational studies suggested that post-transplant prophylaxis with these agents was associated with negligible rates of HDV reinfection [26,27]. In a study of 128 patients who were transplanted for HBV/HDV coinfection and received prophylaxis with an antiviral agent plus HBIG, there were no cases of HDV recurrence after mean follow-up of 30 months [26]. Detailed information on dosing and administration of antiviral agents and HBIG for prevention of HBV reinfection post-liver transplant is presented in a separate topic review. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'Strategies to prevent HBV reinfection'.)

Antiviral therapy should be continued indefinitely. However, the duration of HBIG is unclear and usually depends on the specific transplant center. Some centers withdraw HBIG soon after transplant (eg, 6 to 12 months) since data suggest that HBIG can be safely withdrawn after liver transplantation as long as nucleos(t)ide analog is continued indefinitely, and there is strict adherence to antiviral therapy [4,28-33]. As an example, in an analysis of six studies that included 98 patients who were transplanted for HBV/HDV cirrhosis, the rate of HBV/HDV reinfection in those who received long-term prophylaxis with an antiviral agent alone after discontinuing HBIG was 2 percent over a median follow-up of two to 20 years [4]. However, some guidelines, such as the European Association for the Study of the Liver Guidelines, do not support withdrawal of HBIG, especially during the first 24 months [34].

Unclear role of HDV specific therapies — The role of HDV-specific therapies for preventing HDV reinfection post-transplant has not been established.

●Eradicating HDV prior to transplant – Eradicating HDV prior to transplant could potentially reduce the risk of reinfection post-tranplant. However, for patients with HDV-related cirrhosis, we typically do not use high-dose interferon to eradicate HDV prior to liver transplantation due to the limited efficacy of treatment and the risk of drug-related toxicity [35]. (See "Treatment and prevention of hepatitis D virus infection", section on 'Patients with advanced fibrosis or cirrhosis'.)

Studies of emerging therapies such as bulevirtide and lonafarnib have shown promise for decreasing HDV RNA and alanine aminotransferase levels pre-transplant. Available data have suggested that bulevirtide was safe, decreased HDV RNA levels, and improved liver function in patients with compensated cirrhosis [22,23]. In patients with decompensated cirrhosis (mostly Child class B), small case series have also shown that bulevirtide was safe [29-33], with some patients recompensating, but data are very limited. (See "Treatment and prevention of hepatitis D virus infection", section on 'Antiviral therapy for treatment of HDV'.)

●Antiviral therapy post-transplant – The role of bulevirtide in the post-transplant setting has not been systematically tested. A case report of treatment of HDV infection after kidney transplantation showed that bulevirtide was well tolerated, despite some asthenia [36]; however, there was a potential interaction between bulevirtide and tacrolimus (but not with everolimus), leading to its increased serum levels. Further studies, including randomized trials, are needed to evaluate the safety and efficacy of bulevirtide in preventing HDV reinfection post-transplant before it can be recommended for use in the clinical setting. (See "Treatment and prevention of hepatitis D virus infection".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Liver transplantation".)

SUMMARY AND RECOMMENDATIONS

●Background – In general, hepatitis D virus (HDV) infection occurs only in the presence of hepatitis B virus (HBV) infection. Thus, reinfection with HDV alone following liver transplantation is usually short-lived and is not associated with recurrent liver disease unless HBV reinfection occurs simultaneously or subsequently. (See 'Pathogenesis' above.)

●Clinical course – The clinical course of liver transplant recipients with HDV reinfection depends on whether the recipient has HBV coinfection. In patients with HDV reinfection alone, serum aminotransferase levels usually remain normal and there is no evidence of hepatitis on liver biopsy. However, recipients with HBV/HDV coinfection usually have recurrent hepatitis and expression of HDV antigen (HDAg) in the liver graft. (See 'Clinical features of HDV reinfection' above.)

●Monitoring and diagnosis – Testing for HDV RNA should only be performed in patients who have evidence of HBV reinfection. Routine monitoring for HDV reinfection is not needed in those without HBV reinfection, since reinfection with HDV alone is not clinically significant. (See 'HDV reinfection alone' above.)

We monitor for HBV reinfection by measuring HBsAg and HBV DNA every one to three months during the first year after transplant and every 6 to 12 months thereafter. We also check these markers if there is unexplained elevation in aminotransferases. Monitoring for HBV in the post-transplant setting is discussed in a separate topic review. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'Surveillance post-transplant'.)

In patients with HBV reinfection (ie, reappearance of HBsAg or HBV DNA), the diagnosis of HBV/HDV coinfection is made by detecting HDV RNA in serum and/or HDAg in the liver graft. (See 'Monitoring for HDV post-transplant' above.)

●Management – Treatment for HDV reinfection alone is not necessary because HDV reinfection in the absence of HBV reinfection is usually self-limited and not associated with recurrent hepatitis. (See 'Management if reinfection occurs' above.)

Management of HBV reinfection in liver transplant recipients is presented separately. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'HBV reinfection'.)

●Prevention – Preventing HDV reinfection relies on the strategies used to prevent HBV reinfection. For patients with HBV/HDV cirrhosis who undergo liver transplantation, we suggest immunoprophylaxis with hepatitis B immunoglobulin (HBIG) in addition to antiviral prophylaxis with a nucleos(t)ide analog rather than antiviral prophylaxis alone (Grade 2C). This approach is effective for preventing HBV reinfection, and without HBV reinfection, HDV reinfection remains latent. (See 'Strategies to prevent HDV reinfection' above and "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'Strategies to prevent HBV reinfection'.)

We continue the antiviral agent lifelong. The optimal duration of HBIG is unclear and is usually guided by transplant center protocol.