Optimizing HBV Management During Anti-CD20 Antibodies
Optimizing HBV Management During Anti-CD20 Antibodies
Hepatitis B virus (HBV) reactivation is common during anti-CD20 containing chemotherapy, even
 in HBsAg-negative patients with only prior HBV exposure. The optimal timing of commencing
 antiviral therapy and the interval of clinical monitoring is uncertain. 25% of the Hong Kong
 population has prior HBV exposure. The investigators plan monitor this cohort of patients and
 determine (1) the optimal time point for starting antiviral therapy based on the progression
 of HBV reactivation, and (2) the optimal interval of clinical monitoring.
The use of immunosuppressive cytotoxic therapy in patients with chronic hepatitis B virus
 (HBV) infection is known to be associated with potentially fatal HBV reactivation.
 Prophylactic nucleoside analogue therapy has been shown to reduce the rates of HBV
 reactivation in hepatitis B surface antigen (HBsAg)-positive subjects, and is now recommended
 in current treatment guidelines.

 Patients who are negative for HBsAg and anti-HBsAg antibody (anti-HBs) may be naïve to HBV.
 Nonetheless in HBV-endemic regions, such patients might have been infected with HBV and
 achieved HBsAg seroclearance. Prior HBV exposure is evidenced by the presence of positive
 antibody to the hepatitis B core antigen (anti-HBc). Hence although a HBsAg-negative,
 anti-HBc positive state may represent resolved HBV infection, it could also represent occult
 HBV infection with HBV persisting at low replicative levels following HBsAg seroclearance.
 Reactivation of HBV is then possible.

 Rituximab, ofanumumab and obinutuzumab are chimeric monoclonal antibodies against the B-cell
 surface antigen CD20, and are used extensively in B-cell lymphoid malignancies and many
 non-malignant immune-mediated diseases in the fields of rheumatology, dermatology, neurology
 and nephrology.Previous retrospective and prospective studies have found the rates of HBV
 reactivation in HBsAg-negative, anti-HBc positive individuals who undergo anti-CD20 antibody
 containing chemotherapy to vary between 8.9 and 23.8%. This variation can be partially
 explained by the use of different definitions of HBV reactivation, including a combination of
 biochemical hepatitis, HBsAg seroreversion, or HBV DNA levels over a certain threshold.
 Another important factor was the lack of regular monitoring following commencement of
 anti-CD20 antibodies. In view of these discrepancies, our research team conducted a
 prospective study in which HBsAg-negative, anti-HBc positive lymphoma patients were monitored
 at 4-week intervals for up to 2 years following commencement of rituximab. Using a detectable
 serum HBV DNA level as the definition of HBV reactivation, the 2-year cumulative reactivation
 rate was 41.5%. Anti-HBs negativity was significantly associated with a higher risk of HBV
 reactivation.

 Despite previous accurate description of the rate of HBV reactivation, many clinical
 questions remain :

 1. Which is the better strategy for HBsAg-negative, anti-HBc positive patients receiving
 anti-CD20 antibodies - prophylactic antiviral therapy for all patients, or regular
 clinical monitoring and prescription of antiviral therapy when needed? Although
 prophylactic antiviral therapy has been proven effective, one needs to consider the high
 seroprevalence of anti-HBc in the HBV-endemic regions of East Asia that could reach 40%.
 Based on our two studies of rituximab and hematopoietic stem cell transplantation, the
 seroprevalence of anti-HBc in Hong Kong was between 26.4 and 27.6%. Universal
 prescription of antiviral therapy for all HBsAg-negative, anti-HBc positive individuals
 might not be cost-effective. At the same time, a recent technical review by the American
 Gastroenterological Association stated that based on current evidence, they "had no
 comment" on whether routine clinical monitoring could substitute prophylactic antiviral
 therapy.

 2. If routine clinical monitoring were chosen, what is the optimal interval of monitoring?
 A current recommendation of every 1-3 months was based on expert opinion only. To answer
 this question, a prospective study is needed to observe the serial changes in HBV DNA
 levels over time in patients following the development of detectable HBV DNA, with each
 time epoch assessed for its suitability in monitoring.

 3. Are all HBV reactivations clinically relevant? Our previous study only provided the rate
 of HBV DNA detectability, and did not describe its subsequent clinical progression. Will
 patients continue to have serial increases in HBV DNA level leading to biochemical
 hepatitis and/or HBsAg seroreversion, or do HBV DNA levels remain relatively low? A
 recent study found discrepancies between the rates of HBsAg seroconversion and HBV DNA
 ≥2,000 IU/mL (10.3% and 17.9% respectively), implying not all patients with HBV DNA
 detectability proceed to a progressive increase in HBV DNA levels, HBsAg seroreversion
 or biochemical hepatitis. Serial prospective data on this with respect to the cyclical
 treatment regimen of anti-CD20 antibodies are lacking.

 The investigators propose a prospective observational study to answer these clinical
 questions and provide a concise management strategy for the large number of patients
 prescribed anti-CD20 antibodies containing therapy for both malignant and non-malignant
 diseases
Inclusion Criteria:

 1. Age ≥18 years.

 2. Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.

 3. HBsAg-negative, anti-HBc positive patient receiving anti-CD20 containing chemotherapy
 with or without antibody to the hepatitis B surface antigen (anti-HBs).

 4. Baseline normal serum alanine amiontransferase (ALT) (≤30 U/L for men, ≤19 U/L for
 women).

 Exclusion Criteria:

 1. Concomitant liver diseases including chronic hepatitis C and D infection, Wilson's
 disease, autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing
 cholangitis.

 2. Significant alcohol intake (>30 grams per day).

 3. History of prior anti-HBV therapy, hematopoietic stem-cell transplantation, anti-CD20
 antibody therapy, anti-CD52 antibody therapy or anti-tumour necrosis factor antibody
 therapy.

 4. Baseline detectable HBV DNA (≥10 IU/mL). These patients will be started on
 prophylactic entecavir.