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HBV reactivation
dysfunction results in an association with immune-related side effects; hepatotoxicity is not uncommon and usually relates to an autoimmune-type hepatitis.61 Hepatitis relat- ed to exacerbation of HBV infection has also been report- ed in patients who were subsequently found to be HBsAg positive.62,63 The risk of reactivation in those who are only anti-HBc positive is thought to be low.9 Interestingly, checkpoint inhibitors are also being investigated in the treatment of chronic hepatitis B by potentially overcom- ing the T-cell exhaustion that is observed.64
Venetoclax, a small molecule inhibitor of BCL-2 which is over-expressed in malignant B cells, is used in refractory cases of CLL. No specific cases of HBV reactivation have been reported, but as venetoclax decreases total white cell counts and can cause lymphopenia in addition to neu- tropenia, it may be capable of inducing reactivation. Similarly, azacitidine and decitabine are hypomethylating agents which have been increasingly used to treat acute myeloid leukemia (AML), especially in the elderly. Their potential to cause myelosuppression raises the potential risk of reactivation, but as yet no reports have emerged. With all these novel agents, reports or series of their use and safety in patients with chronic or resolved hepatitis B are warranted.
Management of hepatitis B virus reactivation
Screening
Ideal management and prevention of HBV reactivation includes both stringent identification of at risk patients prior to initiation of any immunosuppressive therapy, and appropriate consideration of prophylactic antiviral treat-
Figure 1. Key points summarizing rec- ommendations. HSCT: hematopoietic stem cell transplantation; HBV: hepatitis B virus; anti-HBc: anti-hepatitis B core; anti-HBs: anti-hepatitis B surface; HBsAg: hepatitis B surface antigen.
ment. As the majority of people with chronic or past HBV are not aware of their infection, it has been strongly rec- ommended by several international societies and guide- lines that all patients should be screened for HBV prior to commencing any immunosuppressive therapy.4,9,25,65 Given the significant risk of reactivation associated with resolved HBV infection and certain regimens, this should include testing for both HBsAg and anti-HBc antibody. Testing for anti-HBs antibodies may also be beneficial, as those with- out anti-HBs are considered to be at even higher risk. However, at the moment, no recommendations have been made concerning stratifying management according to anti-HBs presence or titer.
If during screening a new HBsAg-positive patient is identified, he or she should be referred to an appropriate specialist hepatitis service to undergo full assessment, regardless of the plans for immunosuppression. Assessment will focus on defining the phase of HBV infec- tion (Table 1), differentiating between chronic HBV infec- tion and chronic hepatitis, and staging the liver disease with a combination of imaging, liver biopsy, and/or non- invasive methods such as transient elastography (FibroScan). Patients positive for anti-HBc antibody may also require assessment, as they may still present with advanced liver disease, even in the absence of active HBV viremia. In rare cases, anti-HBc positivity may also repre- sent true occult HBV infection, where the patient is HBsAg-negative but has positive serum HBV DNA. This can be due to virus mutations in surface antigen rendering it undetectable with standard HBsAg assays or, more com- monly, strongly suppressed but active viral replication.66 Such patients are managed the same as those who are HBsAg-positive.
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