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Hepatitis B reactivation during or after direct acting antiviral therapy - implication for susceptible individuals
  Expert Opin Drug Saf. 2017 Jun
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Pooled results of a systematic review have demonstrated that HBV reactivation following immunosuppressive therapy for cancer causes hepatitis in 33.4%, liver failure in 13.0% and leads to death in 6.7% (150). A more recent meta-analysis and systematic review of HBV reactivation following chemotherapy for solid organ cancers found that HBV reactivation ranged from 4-68%. Owing to this significant risk and potentially severe consequences, HBV prophylaxis is now recommended according to the HBV status and the immunosuppressive regimen (151). This strategy reduces the risk of HBV reactivation (odds ratio 0.12), HBV hepatitis (4%, odds ratio 0.18), fulminant hepatic failure (0%) and death (2%) (150, 152).

The FDA issued a warning following 24 cases of HBV reactivation during DAA therapy for HCV, including individuals with inactive, occult and past HBV infection. Clinical presentations ranged from asymptomatic fluctuations in HBV DNA to fulminant hepatic failure, liver transplantation and death. The mechanism is unknown.
Areas covered
HCV/HBV coinfection is common, particularly in regions endemic for HBV. HCV and HBV utilize host factors to support replication; both viruses evade/impair host immunity. Clinical presentations of HBV reactivation during DAAs are summarized. Other causes of HBV reactivation are revisited and recent data regarding HBV reactivation are presented.
Expert opinion
HBV reactivation during DAAs for HCV occurs, with life-threatening consequences in some individuals. The risk of HBV reactivation is observed in all HBV stages. The rapid removal of HCV likely alters and liberates host-viral +/− viral-viral interactions that lead to increased HBV replication. As immune reconstitution occurs with HCV removal, host recognition of HBV DNA likely ensues followed by vigorous host immune responses leading to liver injury (HBV flare). These cases highlight the importance of HBV testing prior to initiating DAA therapy, the need for close monitoring of HBV during therapy and timely administration of anti-HBV therapy to prevent serious sequelae.
The development of all oral interferon-free combination direct-acting antivirals (DAAs) has revolutionized the treatment of chronic hepatitis C virus infection (HCV), affording extremely high cure rates (>95%) with few adverse events. Since their approval by many drug regulatory agencies worldwide, these agents are now widely available in many countries as first line therapy for HCV. The registration studies for these agents did not include individuals with a history of hepatitis B virus infection (HBV), another hepatotropic virus that is often found in patients with HCV owing to their shared transmission routes. Recently, at least 24 cases of hepatitis B virus (HBV) reactivation have been reported to the United States Food and Drug Administration (FDA) Event Reporting System or published in the literature in individuals undergoing DAA therapy for HCV infection who also have a past or current history of HBV infection (1-8). This resulted in the FDA issuing a safety alert for risk of HBV reactivation during DAA therapy in these patients, requiring a boxed warning to be added to the drug label, the most prominent warning. It has long been recognized that immunosuppressive therapy may reactive HBV, and hence prophylactic therapy is recommended in patients undergoing immunosuppressive therapy. However, HBV reactivation in the context of DAAs for HCV has been an unexpected sequelae, as DAA were not known to be directly immunomodulatory with their mechanism of action specifically targeting HCV non-structural proteins that are critical in the replication cycle of HCV.
Prevalence of HCV and HBV infection
Chronic HCV (CHC) infection and chronic HBV (CHB) infection remain significant global concerns. The majority of individuals (>75%) exposed to HCV do not spontaneously clear virus and develop chronic infection (18), and more than 185 million individuals are infected worldwide (12, 19). In addition there are more than 248 million individuals with chronic HBV infection globally, defined as positive HBV surface antigen (HBsAg) seroprevalence (20). In contrast to HCV, age of acquisition of HBV is a critical determinant of likelihood of the development of chronic HBV. Perinatally acquired HBV results in chronic HBV in over 90% of infants (21), and between 20-60% develop chronic HBV if acquired from 6 months to 5 years of age (22, 23), whereas the minority (5%) of adults who acquire HBV develop chronic HBV (23).
The majority of individuals are asymptomatic from HCV and/or HBV infection, with many experiencing non-specific symptoms such as intermittent vague right upper quadrant pain and fatigue, often only developing significant symptoms when end-stage liver disease has already been established. Therefore, many individuals with HCV or HBV may not seek medical attention resulting in under-diagnosis of CHC and CHB. The prevalence of CHB is also further under-recognized due to lack of diagnosis of occult HBV when using HBsAg as a marker of CHB. Occult HBV is a form of CHB characterized by positive HBV DNA levels but negative HBsAg serology. High prevalence areas of HCV and HBV are often found in low-income countries where the infrastructure may not exist or be possible for testing and/or reporting.

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