SEARCH

SEARCH BY CITATION

Keywords:

  • Liver failure;
  • HBV;
  • Nucleoside analogue

Abstract

  1. Top of page
  2. Abstract
  3. Diagnosis of hepatitis B virus reactivation
  4. Management of hepatitis B virus reactivation
  5. Prevention of hepatitis B virus reactivation
  6. Conclusion
  7. Conflicts of interest
  8. References

Reactivation of hepatitis B is characterized by a sudden increase in hepatitis B virus (HBV) replication in a patient with prior evidence of resolved or inactive HBV infection. Although HBV reactivation can occur spontaneously, it usually occurs after chemotherapy, immunosuppression (organ transplantation) or an alteration in immune function (therapy for autoimmune disease, human immunodeficiency virus infection). The clinical presentation cases can vary, ranging from a subclinical, asymptomatic course to severe acute hepatitis and even death. Although reactivation of HBV is mainly found in HBsAg-positive patients, it can be observed in serologically recovered anti-hepatitis B core antibody (HBc)-positive, HBsAg-negative patients. Serum HBV DNA typically increases during immune suppression, followed by a disease flare and HBV DNA clearance following immune restoration after immune suppression is stopped. In organ transplant recipients, without immune reconstitution, high HBV DNA levels can lead to fibrosing cholestatic hepatitis related to the direct cytopathic effect of HBV. Several randomized, controlled trials and meta-analyses have shown that reactivation can be prevented by lamivudine prophylaxis. Screening for HBsAg and anti-HBc should be performed before beginning immunosuppressive treatment and routine prophylaxis is recommended in HBsAg-positive patients. The optimal duration of prophylaxis remains to be determined. In anti-HBc-positive patients with or without anti-hepatitis B surface antigen, alanine transaminase and HBV DNA levels should be closely monitored and antiviral therapy should be started when HBV reactivation is confirmed. The use of new more potent nucleos(t)ides analogues with lower resistance rates would seem to be logical; however, experience with these drugs in the prophylaxis and treatment of severe HBV reactivation is limited.

Hepatitis B virus (HBV) reactivation is characterized by the sudden reappearance or increase in HBV replication in a patient with prior evidence of resolved or inactive HBV infection (1). The clinical presentation of the disease can vary, ranging from a subclinical, asymptomatic course to severe acute hepatitis, fulminant liver failure, fibrosing cholestatic hepatitis and even death. Although HBV reactivation can occur spontaneously, it usually occurs following chemotherapy, immunosuppression or an alteration in immune function. Reactivation is more common when chemotherapy regimens include corticosteroids or rituximab (2). However, it has also been reported after intra-arterial chemoembolization for hepatocellular carcinoma (HCC) (3), immunosuppressive therapies such as infliximab or other anti-tumour necrosis factor α (TNFα) therapies for rheumatoid arthritis or inflammatory bowel disease (4, 5), human immunodeficiency virus (HIV) infection (6, 7) and immunosuppressive therapies for organ transplantation (8). Reactivation is marked by an increased immunological response to HBV because of increased HBV replication during immunosuppression (9). Although reactivation of HBV during chemotherapy mainly occurs in HBsAg-positive patients, it can be observed in serologically recovered anti-hepatitis B core antibody (HBc)-positive, HBsAg-negative patients leading to HBsAg seroreversion (10). HBsAg, anti-HBc and HBV DNA testing should be performed in patients who are going to receive prophylactic immunosuppressive therapy, so that patients at risk can be treated with nucleos(t)ides analogues (NUCs) especially lamivudine (LAM), to reduce the rate of HBV reactivation, the severity of associated hepatitis flares and mortality (11–14). Acute flares in chronic hepatitis B can also be observed during antiviral therapy as a result of a viral breakthrough or non-compliance. This review will focus on the diagnosis, management and prevention of severe HBV reactivation. Reactivation of HBV infection after liver transplantation will not be treated in this review.

Diagnosis of hepatitis B virus reactivation

  1. Top of page
  2. Abstract
  3. Diagnosis of hepatitis B virus reactivation
  4. Management of hepatitis B virus reactivation
  5. Prevention of hepatitis B virus reactivation
  6. Conclusion
  7. Conflicts of interest
  8. References

Covalently closed circular DNA, the main template for the transcription of viral mRNAs, persists in the liver even of patients with successful cellular and humoral control of HBV infection (i.e. HBsAg-negative patients). Immunosuppression influences cellular and humoral immune responses and may lead to HBV reactivation. For example, among the different factors that may impair immune control, the humoral arm is profoundly affected by rituximab and HIV infection interferes with the cellular immune response (15). Furthermore, prednisone may enhance viral replication via additional direct mechanisms. In vitro corticosteroid use has been shown to increase HBV DNA and RNA synthesis via the presence of a glucocorticoid receptor binding sequence that increases glucocorticoid-dependent activity of the HBV enhancer (16).

Typically, reactivation begins with a sudden increase in viral replication during immune suppression (Fig. 1) (17). Diagnostic markers of this phase are an increase in serum HBV DNA more than one log above baseline, anti-HBc IgM, and HBeAg. The second phase develops when immunosuppression is withdrawn. Immune restoration is followed by a rapid immune-mediated destruction of HBV-infected hepatocytes leading to acute liver failure, chronic hepatitis or cirrhosis. Diagnostic markers of this phase are aminotransferase levels three times above the upper limit of normal and even jaundice. HBV DNA levels may start to decrease during this phase. In organ transplant recipients, without immune reconstitution, high HBV DNA levels can lead to fibrosing cholestatic hepatitis related to a direct cytopathic effect of HBV (18).

image

Figure 1.  Course of HBV reactivation during immunosuppressive therapy. Adapted from Xunrong et al. (17). ALT, alanine transaminase; HBV, hepatitis B virus.

Download figure to PowerPoint

Reactivation of HBV has been described following chemotherapy, immunosuppression or alterations in the immune function (Table 1). The frequency of HBV reactivation is especially high in countries with a high prevalence of HBV infection. Reactivation of HBV during chemotherapy mainly occurs in HBsAg-positive patients but can also be observed in serologically recovered anti-HBc-positive, HBsAg-negative patients leading to HBsAg seroreversion (10, 19).

Table 1.   Different causes of hepatitis B virus reactivation
  1. TNF, tumour necrosis factor.

• Spontaneous: mainly HbeAg-negative patients
• Cancer chemotherapy all drugs but increase frequency with corticosteroids, rituximab
• Immune modulation for autoimmune conditions: use of TNFα blockers in inflammatory bowel disease, rheumatoid arthritis
• Human immunodeficiency infection
• Solid organ transplantation: kidney, heart, lung
• Bone marrow transplantation
• During antiviral B therapy: breakthrough, non–compliance

Hepatitis B virus reactivation during anticancer therapy or bone marrow transplantation

Hepatitis B virus-related complications can delay or require changes in chemotherapy, thus reducing the chance of cure. The first description of HBV reactivation during antitumour chemotherapy was reported by Wands et al. (20). The exact risk of reactivation has not been clearly defined and is thought to range from 20 to 50% with a 30% mortality rate (10, 13, 19, 21). Lok and colleagues, found that reactivation in 27 HBsAg-positive patients with lymphoma undergoing chemotherapy was 48%; furthermore, reactivation was associated with the development of jaundice in 22% of patients and 20% of them died. Two out of 51 patients (4%) with serological evidence of resolved HBV infection (HBsAg negative and anti-HBc positive) developed HBV reactivation with the reappearance of HBsAg in serum (10). A large meta-analysis of the role of LAM prophylaxis including a total of 424 control patients found an overall HBV reactivation rate of 50% (range 24–88%) (13). Known risk factors of HBV reactivation have been described and include HBV DNA level before therapy (i.e. >105 copies/ml) (22–24), HBeAg positivity (23), concomitant use of steroids, anthracyclines or rituximab (2), male sex (10), younger age, diagnosis of lymphoma or breast cancer and prechemotherapy alanine transaminase (ALT) levels (19). In a prospective study of 50 patients with non-Hodgkin's lymphoma who were randomized to receive either the standard steroid-containing regimen or a steroid-free regimen, the cumulative incidence of HBV reactivation was significantly higher in the steroid-containing arm (73 vs. 38%; P=0.03). However, patients in the steroid free-arm had a significantly lower rate of remission and overall survival (25). Lymphomas are one of the main groups of malignancies associated with HBV reactivation in HBsAg-positive patients. Although the risk is lower, other tumours associated with the occurrence of reactivation include breast, lung and gastrointestinal cancer.

Recently, several case reports have described severe hepatitis flares associated with rituximab (9). In 12 case reports of HBV reactivation because of rituximab therapy, the overall mortality rate was 83%, with five documented cases in patients who were HBsAg negative before therapy (2, 9, 19). In a study from Hong Kong, eight out of 244 HBsAg-negative lymphoma patients became HBV DNA positive from reactivation of a past HBV infection (26). Three patients progressed to fuminant hepatitis and one died. Rituximab was part of the chemotherapy regimen in seven of the eight patients. HBV reactivation occurred more than 1 year after the final administration of rituximab in some patients.

The rate of HBV reactivation after allogenic bone marrow transplantation varies between 14 and 50% (27, 28). Suggested risk factors include corticosteroid use, lack of anti-hepatitis B surface antigen (HBs) in the donor and graft vs. host disease. Conversely, there have been fewer reports in autologous bone marrow transplantation. Several studies have provided further evidence that immunization of donors may induce HBV immunity in recipients within several days to weeks after transplantation (29).

Hepatitis B virus reactivation during immunosuppression for non-malignant diseases

Reactivation of HBV is uncommon during immunosuppression with low doses of corticosteroids, azathioprine or methotrexate. TNFα blockers have shown to be effective for the treatment of immune-modulated diseases such as Crohn's disease, rheumatoid arthritis and psoriasis (15). One mechanism that could facilitate HBV reactivation during TNFα blocker use is their influence on B cell function. However, it is unclear whether the risk of reactivation is the same with all TNFα antagonists. Most cases have been associated with the more potent monoclonal antibodies infliximab or adalimumab rather than etanercept. The largest study on this topic evaluated HBV reactivation in 80 patients with Crohn's disease (4) in whom HBV markers were prospectively determined before infliximab infusion. Three patients with chronic HBV infection were identified in this study; two developed severe HBV reactivation after the withdrawal of therapy, one of whom died. There was no evidence of HBV reactivation in the third patient who was treated with LAM at the onset of infliximab therapy. In addition to this study, more than a dozen documented cases of severe HBV reactivation following infliximab administration have been reported in the literature (30). Prophylactic treatment with LAM appears to be effective in preventing reactivation or adverse clinical events in patients receiving anti-TNFα.

Hepatitis B virus reactivation have been described with non-biological immunosuppressive therapy such as corticosteroids or methotrexate as well as with infliximab in patients with rheumatoid diseases (5). LAM prophylaxis has been shown to be effective in preventing reactivation of HBV during infliximab therapy in some patients.

Hepatitis B virus reactivation after solid organ transplantation

Before the development of antiviral prophylaxis, HBV reactivation rates in HBsAg-positive patients after solid organ transplantation were above 50% (8). Patients are now routinely tested for HBsAg and anti-HBc before transplantation, and if positive, considered for antiviral B prophylaxis and long-term antiviral treatment with second-generation antiviral nucleos(t)ides. The risk of HBV reactivation is negligible (<1%) in patients with resolved HBV infection independent of their anti-HBs status (31).

Hepatitis B virus reactivation in human immunodeficiency virus-infected patients

In Europe and the US, 6–14% of HIV-infected patients have HBV co-infection leading to an unfavourable outcome of liver disease. HBV/HIV co-infection is associated with an accelerated progression of liver fibrosis and cirrhosis, an increased frequency of reactivation and liver decompensation, HCC and liver-related mortality (6, 7). Hepatitis flares may be more frequent following highly active antiretroviral treatment because of immune restoration (32). Reactivation episodes may also be related to discontinuation of drugs with anti-HIV and HBV activity (33).

Spontaneous hepatitis B virus reactivation

The natural history of chronic hepatitis B includes spontaneous flares that mainly occur in HBeAg-negative patients (34). These flares can be mistaken for episodes of acute hepatitis and are characterized by high HBV DNA and ALT levels, increased disease activity and positivity of IgM anti-HBc. The reasons and risk factors for reactivated infection are not well known.

Hepatitis B virus reactivation during antiviral B therapy

The efficacy of first-generation NUCs is limited by the emergence of resistant mutant strains leading to reactivation and deterioration of hepatitis B. Reactivation may also occur because of non-compliance to therapy. Several studies have shown that HBV is more rapidly suppressed in patients who receive additional antiviral therapy during the phase of genotypic resistance than in those treated during the phase of phenotypic resistance (35).

Management of hepatitis B virus reactivation

  1. Top of page
  2. Abstract
  3. Diagnosis of hepatitis B virus reactivation
  4. Management of hepatitis B virus reactivation
  5. Prevention of hepatitis B virus reactivation
  6. Conclusion
  7. Conflicts of interest
  8. References

The clinical presentation of the disease can vary from a subclinical, asymptomatic course to severe acute hepatitis, fulminant liver failure and even death. Patients with cirrhosis are more likely to develop hepatic decompensation. Spontaneous resolution of viral replication may occur.

In cases of severe acute hepatitis, aggressive supportive therapy and discontinuation of cytotoxic chemotherapy have been the mainstay of treatment. LAM has been reported to be effective in cases of hepatic decompensation during HBV reactivation (36). However, despite LAM, HBV-associated mortality has been reported in up to 20% of HBsAg-positive patients who are treated. It has been suggested that this may be because antiviral administration was not begun until after severe liver impairment had already occurred (21, 37). Adefovir has also been used as a first-line therapy for HBV reactivation (38).

Hepatitis B virus fulminant hepatitis is serious and results in death or transplantation in 80% of individuals. Liver transplantation may be indicated depending on the underlying tumoural disease. The goals of treatment in patients with end-stage HBV liver disease are to improve liver function, preventing the need for liver transplantation and in patients who require transplantation to decrease the risk of post-transplantation HBV recurrence. The main way to achieve these goals is to obtain sustained viral suppression and reduce viral activity in the liver. Approved therapies for HBV include: interferon, LAM, adefovir, tenofovir and entecavir. Interferon is not recommended in patients with decompensated disease because of the risk of infectious complications. Although LAM significantly decreases HBV DNA levels, in these cases it does not significantly improve clinical and biochemical outcome compared with the placebo (39). Clinical improvement is slow in patients with decompensated liver disease and no benefit may be observed in the first 3–6 months of therapy. In a prospective study, 32 of 154 (21%) patients on the list for transplantation and receiving LAM died, with most deaths (25 of 32; 78%) occurring during the first 6 months of therapy (40). In multivariate analysis, elevated serum bilirubin, elevated creatinine and serum HBV DNA >10copies/ml before treatment were independent predictors of 6-month mortality. Thus, transplantation is a critical component of management in patients with advanced liver failure whatever the antiviral response. Like LAM, it takes approximately 6 months for patients to show clinical benefits with adefovir or entecavir so transplantation must be considered in patients with advanced liver decompensation (41, 42). New NUCs (i.e. entecavir and tenofovir) have more potent antiviral efficacy and a lower resistance rate. Although they are recommended for the treatment of HBV infection in patients with end-stage liver disease, experience with these drugs is limited in this setting (1, 43). A study has shown that five of 16 patients with decompensated HBV-related disease (MELD score >20) developed symptomatic lactic acidosis after receiving entecavir for 4–240 days, resulting in death in a patient with fulminant hepatitis B (44). Although the mechanisms of toxicity are unclear, concomitant drugs, comorbidities and other host factors may alter drug pharmacokinetics. A recent study has described the use of entecavir in 36 patients with spontaneous severe acute exacerbation of hepatitis B compared with 117 LAM historical controls (45). In this cohort, entecavir was independently associated with an increased short-term mortality (11 vs. 2% of deaths within 30 days of therapy, P=0.028) compared with LAM despite higher rates of virological (71 vs. 40% of patients achieved undetectable HBV DNA) and biochemical response at week 48. These findings suggest that rapid virological suppression may lead to an increased immune response and worsen liver injury. All antiviral therapies have not been shown to improve short-term mortality in patients with severe HBV reactivation. Short-term mortality depends mainly on the degree of hepatic necrosis rather than viral load (46, 47).

Prevention of hepatitis B virus reactivation

  1. Top of page
  2. Abstract
  3. Diagnosis of hepatitis B virus reactivation
  4. Management of hepatitis B virus reactivation
  5. Prevention of hepatitis B virus reactivation
  6. Conclusion
  7. Conflicts of interest
  8. References

Lamivudine prophylaxis significantly reduced the number of HBV-related ALT flares, liver failure, deaths and cessations of chemotherapy in HBsAg-positive patients by (11, 14, 15). Two prospective, randomized, controlled trials of LAM prophylaxis to prevent HBV reactivation in HBsAg-positive patients undergoing chemotherapy for malignant lymphoma have been published. They have shown significantly fewer cases of HBV reactivation during chemotherapy when LAM is given preventively compared with LAM given therapeutically (11, 12). In the study by Lau et al. (11), reactivation occurred in eight of 15 control subjects (53%) but zero of 15 patients given LAM prophylaxis (P=0.002). Seven of the eight episodes of reactivation were accompanied by hepatitis (80%), two were icteric (25%) and one was fatal (12%). In a study by Hsu et al. (12), three patients (12%) out of 26 receiving LAM prophylaxis developed HBV reactivation (two of them were found to harbour LAM-resistant HBV) compared with 14 of 25 control patients (56%) (P=0.002). Five control patients developed jaundice but the cases of reactivation in the prophylactic group were mild. It is important to note that HBV reactivation was also common after therapy was stopped (2 months after completion of chemotherapy): 19% in the prophylactic group and 14% in the therapeutic group. A meta-analysis of 14 studies including 275 patients in the preventive LAM group and 475 control participants showed that the relative risk of both HBV reactivation and HBV-related hepatitis with prophylactic LAM ranged from 0.00 to 0.21 (reduced risk by 79–100%) in patients undergoing chemotherapy (13). None of the patients in the preventive LAM group developed HBV-related hepatic failure (0 of 108 patients vs. 21 of 162 patients), and there were four deaths from HBV (four of 208 patients vs. 27 of 394 patients) in the preventive LAM group. In another meta-analysis including 21 studies, the authors demonstrated a clear benefit of LAM prophylaxis for clinical and virological HBV reactivation, overall mortality, HBV-related mortality and interruptions or discontinuations of immunosuppressive treatment (14).

The optimal duration of LAM prophylaxis has not been defined. Disease exacerbation can occur after LAM is discontinued in patients with high pretreatment HBV DNA levels. Close follow-up of patients with serial serum ALT and HBV DNA level monitoring is advised after discontinuation of LAM prophylaxis. Clinical guidelines recommend long-term antiviral therapy and the administration of second-generation NUCs (i.e. entecavir or tenofovir) in patients with high pretreatment HBV DNA levels (1, 43).

The development of resistant mutants is a potential concern during prolonged use of prophylactic LAM. At present, reports on LAM resistance in haemato-oncological patients with HBV reactivation are scarce.

The algorithm for the management of hepatitis B in patients receiving chemotherapy is reported in Figure 2 (1, 43, 48). Before chemotherapy, patients should be screened for serological HBV markers and HBV DNA levels in case of HBsAg and/or anti-HBc positivity. HBV vaccination is recommended in seronegative patients. In HBsAg-positive patients, pre-emptive treatment should be initiated whatever the HBV DNA levels and continued for 6–12 months after immunosuppressive therapy is discontinued. Entecavir or tenofovir are preferable in patients with an initial viral load >2000 IU/ml. ALT and HBV DNA levels should be closely monitored in anti-HBc-positive patients with or without anti-HBs, and antiviral therapy should be started when HBV reactivation is confirmed. Anti-HBs titres should be monitored closely in anti-HBs-positive patients because a decrease in anti-HBs can precede seroreversion. Therapy is not needed as long as anti-HBs titres are protective.

image

Figure 2.  Algorithm for the management of hepatitis B in patient receiving chemotherapy or immunosuppressive therapy. Modified according to Lalazar et al., EASL and AASLD clinical pracice guidelines (1, 43, 48). ALT, alanine transaminase; HBV, hepatitis B virus.

Download figure to PowerPoint

Conclusion

  1. Top of page
  2. Abstract
  3. Diagnosis of hepatitis B virus reactivation
  4. Management of hepatitis B virus reactivation
  5. Prevention of hepatitis B virus reactivation
  6. Conclusion
  7. Conflicts of interest
  8. References

Hepatitis B virus reactivation is a common complication in HBsAg-positive patients undergoing immunosuppressive therapy but is also less frequently observed in serologically recovered anti-HBc-positive, HBsAg-negative patients. The clinical presentation of the disease varies, ranging from a subclinical, asymptomatic course to severe acute hepatitis. Routine screening should be performed for HBsAg and anti-HBc before beginning immunosuppressive treatment. Prophylactic therapy with NUCs has been shown to significantly decrease the incidence and the overall morbidity of HBV reactivation in HBsAg-positive patients, compared with later administration. ALT and HBV DNA levels should be closely monitored in anti-HBc-positive patients with or without anti-HBs and antiviral therapy can be started when HBV reactivation is confirmed. LAM significantly decreases HBV DNA levels in cases of severe acute hepatitis, but does not result in a significant clinical and biochemical improvement compared with placebo. All antiviral therapies have not been shown to improve short-term mortality because this depends mainly on the degree of hepatic necrosis rather than viral load. The use of new more potent NUCs (i.e. entecavir and tenofovir) with a lower resistance rate seems logical; however, experience with these drugs in the prophylaxis and treatment of severe HBV reactivation is limited.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Diagnosis of hepatitis B virus reactivation
  4. Management of hepatitis B virus reactivation
  5. Prevention of hepatitis B virus reactivation
  6. Conclusion
  7. Conflicts of interest
  8. References

Didier Samuel is a consultant for Gilead Sciences and Bristol-Myers Squibb. Bruno Roche has declared no potential conflicts.

References

  1. Top of page
  2. Abstract
  3. Diagnosis of hepatitis B virus reactivation
  4. Management of hepatitis B virus reactivation
  5. Prevention of hepatitis B virus reactivation
  6. Conclusion
  7. Conflicts of interest
  8. References