INTRODUCTION — Hepatitis D virus (HDV) infection is uncommon in the United States. Less than 3 percent of patients with acute hepatitis B virus (HBV) infection are coinfected with HDV. Based on studies conducted more than 20 years ago, it was estimated that approximately 70,000 individuals in the United States are chronic carriers of HDV and that as many as 1000 individuals die of HDV-related liver disease each year [1]. In a study analyzing the National Health and Nutrition Examination Survey (NHANES) database, 42 percent of adults in the United States who tested positive for hepatitis B surface antigen (HBsAg) were also positive for HDV antibody (anti-HDV), suggesting a much higher burden of HDV infection [2]. However, these results were based on projection from 113 HBsAg positive individuals who may not be representative of the general population, and there were concerns about false positive results with the assay that was used.
The clinical course of infection with HDV, which generally occurs only in patients coinfected with HBV, is highly variable [1,3]. As an example, although coinfection with HDV and HBV usually causes self-limited acute hepatitis, a high incidence of fulminant hepatic failure has been reported among intravenous drug users [3]. Similarly, superinfection of HDV in HBV carriers may be clinically inapparent or it may manifest as an exacerbation of preexisting chronic hepatitis with rapid progression to cirrhosis [4].
Since medical management of HDV-related liver disease has limited efficacy, some patients will require liver transplantation [5,6].
This topic will review hepatitis D virus reinfection following liver transplantation. The pathogenesis, clinical manifestations, prevention, and treatment of HDV infection are discussed separately. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection" and "Treatment and prevention of hepatitis D virus infection".)
TYPES AND RATES OF REINFECTION — Reinfection with hepatitis D virus (HDV) alone following liver transplantation is usually short-lived and not associated with recurrent liver disease unless hepatitis B virus (HBV) reinfection occurs subsequently. However, HDV reinfection can occur in the absence of markers of HBV reinfection, an observation that has provided important insights into the biology of HDV replication and the pathogenesis of HDV-related liver disease.
Three types of reinfection with HDV with very different clinical courses have been observed following liver transplantation:
●HDV reinfection without evidence of HBV reinfection
●HDV reinfection followed by HBV reinfection
●Simultaneous HDV and HBV reinfection
HDV is a defective virus that is dependent upon HBV for envelopment, virion assembly, and secretion. In general, HDV infection occurs only in the presence of HBV infection [7]. However, experience with liver transplantation has revealed that HDV reinfection can occur in the absence of markers of HBV reinfection. (See "Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection".)
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 [8-10]. 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 high infectious dose of WHV [11].
It is possible that, in patients who have HDV reinfection alone after transplantation, HBV was present but not detected because of masking of HBsAg by hepatitis B immunoglobulin (HBIG) [12]. Although early studies found that HBV DNA was undetectable both in sera and in liver tissues [13], 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 [12]. 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 in the absence of HBV DNA in the liver and HBsAg and HDV RNA in the serum for up to 19 months after transplant [14]. 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.
Occurrence of HDV reinfection was illustrated in a French study of 76 patients transplanted for HDV-related cirrhosis [13]. Of the four patients who received short-term HBIG, one died prematurely and the remaining three all had simultaneous HDV and HBV reinfection. Among the 72 patients who received long-term (>2 months) HBIG, four patients died prematurely. Of the remaining 68 patients:
●Seven patients (10 percent) had simultaneous HDV and HBV reinfection
●53 patients (78 percent) remained HBsAg negative but had evidence of HDV reinfection during the first post-transplant year (ie, detectable serum HDV RNA and/or hepatic HDAg). However, only 5 percent of those patients had persistent HDV infection at two years.
The outcome is different when long-term HBIG is not given. A combined Italian and Belgian study, for example, evaluated 27 patients transplanted for HDV-related cirrhosis, only five of whom received long-term HBIG prophylaxis [15]. Six patients died prematurely. Of the 21 patients who were followed:
●Five (24 percent) had no evidence of HDV or HBV reinfection
●Five (24 percent) had HDV reinfection only
●Six (28 percent) had HDV reinfection followed by HBV reinfection
●Five (24 percent) had simultaneous HDV and HBV reinfection
With the availability of nucleos(t)ide analogues with low rates of resistance (entecavir or tenofovir), many transplant centers no longer routinely use HBIG to prevent HBV reinfection; however, use of HBIG may be important for patients transplanted for HDV. (See 'Prevention of HDV reinfection' below.)
DIAGNOSIS OF REINFECTION — Hepatitis D virus (HDV) RNA and markers of hepatitis B virus (HBV) infection (HBsAg, HBeAg and HBV DNA) become undetectable shortly after transplantation in patients who receive hepatitis B immunoglobulin (HBIG) prophylaxis [13]. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)
In patients who are not reinfected with HDV, IgM anti-HDV becomes undetectable within a few weeks but IgG anti-HDV may persist for up to 18 to 24 months posttransplantation [15]. As a result, a positive result in the commercial anti-HDV assay (which detects total anti-HDV) is not necessarily indicative of HDV reinfection.
HDV reinfection is diagnosed by the detection of HDV RNA in serum and HDAg in liver [16]. Unfortunately, tests for HDV RNA in serum are not routinely available and not all pathology laboratories routinely stain for HDAg in liver sections.
In patients with apparent HDV reinfection alone, HBsAg and IgM anti-HDV remain undetectable by conventional assays, hepatitis D viremia may be intermittent, and only a few hepatocytes (<5 percent) express HDAg. However, studies in which PCR has been used to detect HBV DNA have challenged the existence of isolated HDV reinfection, since low levels of HBV DNA and the presence of a typical HDV virion with an HBsAg envelope have been detected in some patients [12]. Furthermore, studies in chimpanzees showed that HDV alone is incapable of inducing latent HDV infection in the absence of HBsAg [12]. The diagnosis may be difficult to establish since HDV reinfection alone is usually not accompanied by recurrent hepatitis.
In patients with HDV reinfection who are also reinfected with HBV, there is reappearance of HBsAg and IgM anti-HDV. In addition, hepatitis D viremia is consistently detected and there is more widespread expression of HDAg in the liver. In contrast to patients with HBV reinfection alone, patients with HDV and HBV reinfection are frequently negative for markers of HBV replication (ie, HBeAg and HBV DNA) in the serum [7,17].
CLINICAL COURSE OF HDV REINFECTION — The clinical course of patients with hepatitis D virus (HDV) reinfection varies with the type of reinfection. In general, the outcome is favorable compared with patients with hepatitis B virus (HBV) reinfection alone.
HDV reinfection without evidence of HBV reinfection — 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 (figure 1).
In the French study described above, of the 61 patients who remained HBsAg negative, 47 (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 posttransplantation [13]. All of the patients with hepatitis on biopsy were negative for markers of HDV and HBV infection. However, six were positive for hepatitis C antibody, suggesting that hepatitis C infection may have been the cause of the hepatitis.
HDV reinfection followed by HBV reinfection — In some patients, HBV reinfection lags behind HDV reinfection by a few months. The return of HBV infection, as determined by the reappearance of HBsAg, is accompanied by recurrent hepatitis and progression to chronic liver disease [18,19]. These studies suggest that HDV is not directly cytopathic and that HBV is an essential cofactor in the development of hepatitis.
Simultaneous HDV and HBV reinfection — Coinfection after transplantation is invariably accompanied by recurrent hepatitis and massive expression of HDAg in the graft (figure 2). In the French study, four of seven patients with simultaneous HDV and HBV reinfection subsequently became HBsAg negative, either spontaneously or after antiviral therapy [13]. In these four patients, the last liver biopsies were normal in two and showed chronic hepatitis without cirrhosis in two. All three patients who remained HBsAg positive had chronic active hepatitis without cirrhosis on their biopsies 51 to 70 months posttransplant.
Another series presented detailed histopathologic evaluation of nine patients with HDV and HBV reinfection [18]. Two types of lesions were observed:
●Patients with productive HBV reinfection had hepatic expression of HDAg, HBsAg, and HBcAg and necroinflammatory changes typical of acute viral hepatitis.
●Patients with non-replicative HBV reinfection 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 very 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 [20].
Serial liver biopsies showed that four of nine patients who had persistent HDV and HBV reinfection progressed to cirrhosis during a follow-up period of 12 to 35 months (mean 20 months).
OUTCOMES OF PATIENTS TRANSPLANTED FOR HEPATITIS D — The overall outcomes following liver transplantation are better in patients with hepatitis D virus (HDV) compared with those transplanted for hepatitis B virus (HBV) alone (figure 3) [13,15,21-24]. The presence of HDV infection appears to provide a protective effect against HBV reinfection, possibly via suppression of HBV replication [25,26]. The presence of HDV may also inhibit hepatitis C virus replication and recurrence of hepatitis C virus in liver transplant recipients who are coinfected with hepatitis B, C, and D virus [27,28]. In the nontransplant setting, HDV also appears to inhibit HCV replication by an as yet unknown mechanism [29].
In addition to a lower rate of HBV reinfection, patients with HDV reinfection have higher survival rates and do not appear to develop fulminant hepatitis or fibrosing cholestatic hepatitis. In the EUROHEP study, for example, the presence of HDV infection pretransplant was an independent predictor of a lower risk of graft reinfection and of increased patient survival [21]:
●The risk of recurrence of HBV among patients transplanted for cirrhosis was 67 percent in those with HBV infection alone versus 32 percent in those coinfected with HDV
●The actuarial one- and three-year survival rates of patients who had HBV reinfection were 68 percent and 44 percent, respectively, among those transplanted for HBV-related cirrhosis, and 86 percent and 83 percent, respectively, among those transplanted for HDV-related cirrhosis (p<0.001) [21]. Similar findings were noted in the French study: the actuarial five-year survival rate of patients transplanted for HDV-related cirrhosis was 88 percent [13].
Earlier studies on liver transplantation for hepatitis D virus were conducted during an era when HBIG was the only prophylactic therapy to prevent HBV reinfection. Subsequent studies using HBIG in combination with long-term use of a nucleos(t)ide analogue have demonstrated very low rates of HDV reinfection. In two studies including a total of 162 patients who underwent liver transplantation for HBV with HDV coinfection, prophylaxis with HBIG and nucleos(t)ide analogue was associated with rates of HDV reinfection ranging from 0 to 3 percent [30-32].
PREVENTION OF HDV REINFECTION — The most effective means of preventing hepatitis D virus (HDV) reinfection is to prevent hepatitis B virus (HBV) reinfection, since HDV reinfection alone is abortive unless it is subsequently rescued by HBV reinfection [13]. Specific prophylaxis for HDV reinfection is not available. Furthermore, pretransplant elimination of HDV appears unlikely due to the lack of sustained efficacy and significant toxicity of long-term, high-dose interferon therapy in patients with HDV-related cirrhosis [33]. (See "Treatment and prevention of hepatitis D virus infection".)
The combination of hepatitis B immunoglobulin (HBIG) and antiviral therapy is highly effective prophylaxis for HBV reinfection. In the EUROHEP study, the three-year actuarial risk of HBV reinfection for patients transplanted for HDV-related cirrhosis was much lower among those who received long-term HBIG compared with those who received no or short-term HBIG (17 versus 70 and 54 percent, respectively, p<0.001) [21]. The risk of HBV reinfection in HDV-positive patients who received long-term HBIG was lower compared with HDV-negative patients (17 versus 56 percent, p<0.001). This is most likely explained by the suppressive effect of HDV on HBV replication [25,26]. The three-year actuarial risk of HBV reinfection for patients transplanted for fulminant hepatitis D who received long-term HBIG was 34 percent.
Nucleos(t)ide analogues for HBV (eg, lamivudine, adefovir, entecavir, telbivudine, and tenofovir) have been evaluated for the prevention of HBV reinfection in patients transplanted for hepatitis B. None of these drugs is effective in suppressing HDV replication. Nucleos(t)ide analogues alone in the absence of HBIG have been shown to be effective in preventing HBV reinfection in patients with HBV infection alone [34]. Given that HBsAg may remain detectable in serum for many years despite undetectable HBV DNA in patients who received nucleos(t)ide analogue alone without HBIG for prevention of HBV reinfection, it is possible that HDV reinfection may not be prevented.
There is no effective treatment for recurrent hepatitis D virus infection, and we agree with society guidelines that recommend combination of long-term HBIG and nucleos(t)ide analogues to prevent HBV and HDV reinfection [35]. However, a review of five studies involving 81 patients transplanted for HBV/HDV infection found that one patient had recurrent HBV/HDV disease after withdrawal of HBIG, while six patients had detectable HBsAg but no evidence of recurrent HBV/HDV disease [31,32,36]. These data have suggested that HBIG may not be necessary or only needed for a short duration for all patients transplanted for HBV/HDV cirrhosis and that recurrence of HDV disease cannot occur when HBV infection is controlled by nucleos(t)ide analogues. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients".)
TREATMENT OF HDV REINFECTION — Specific treatment for HDV reinfection has not been evaluated and is probably not necessary since HDV reinfection in the absence of HBV reinfection is usually self-limited and not associated with recurrent hepatitis. Reinfection with both HBV and HDV is uncommon with the use of nucleos(t)ide analogues (entecavir or tenofovir) with low rates of resistance which are given pretransplant to suppress HBV replication and continuation of plus entecavir or tenofovir post-transplant.
Several drugs are in clinical trials for treatment of HDV infection, but these drugs have not been studied in the setting of transplantation. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients" and "Treatment and prevention of hepatitis D virus infection".)
●Interferon alfa has demonstrated activity against HBV and HDV in the nontransplant setting, but it is largely ineffective for recurrent HBV infection alone following transplantation [33,37].
●The efficacy of lamivudine, adefovir, entecavir, telbivudine, and tenofovir in the treatment of patients with recurrent hepatitis B and D has not been examined; however, data in non-transplant setting indicate that these drugs are not effective in suppressing HDV replication. (See "Treatment and prevention of hepatitis D virus infection".)
RETRANSPLANTATION — Experience with retransplantation for severe recurrent disease is limited. In the French study, 3 of 76 patients were retransplanted for other causes; no deaths or retransplantation related to hepatitis B virus or hepatitis D virus reinfection was noted [13].
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
●Three types of reinfection with hepatitis D virus (HDV) have been observed following liver transplantation:
•HDV reinfection without overt evidence of hepatitis B virus (HBV) reinfection
•HDV reinfection followed by HBV reinfection
•Simultaneous HDV and HBV reinfection
●In patients with apparent HDV reinfection alone, HBsAg and IgM anti-HDV remain undetectable by conventional assays, hepatitis D viremia may be intermittent, and only a few hepatocytes (<5 percent) express HDAg. (See 'Diagnosis of reinfection' above.)
●In patients with HDV reinfection who are also reinfected with HBV, there is reappearance of HBsAg and IgM anti-HDV. In addition, hepatitis D viremia is consistently detected and there is more widespread expression of HDAg in the liver. (See 'Diagnosis of reinfection' above.)
●The clinical course of patients with HDV reinfection varies with the type of reinfection. In general, the outcome is favorable compared with patients with HBV reinfection alone. (See 'Clinical course of HDV reinfection' above and 'Outcomes of patients transplanted for hepatitis D' above.)
●The most effective means of preventing HDV reinfection is to prevent HBV reinfection, since HDV reinfection alone is abortive unless it is subsequently rescued by HBV reinfection. Hepatitis B immunoglobulin should be used in combination with nucleos(t)ide analogues in this setting. (See 'Prevention of HDV reinfection' above.)
●Specific treatment for HDV reinfection has not been evaluated and is probably not necessary since HDV reinfection in the absence of HBV reinfection is usually self-limited and not associated with recurrent hepatitis. (See 'Treatment of HDV reinfection' above.)
