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Hepatitis B Reactivation with Novel Agents in Non-Hodgkin’s Lymphoma and Prevention Strategies

  • Oluwatobi O. Ozoya1,
  • Lubomir Sokol2 and
  • Samir Dalia*,3
Journal of Clinical and Translational Hepatology 2016;():-

DOI: 10.14218/JCTH.2016.00005

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Abstract

Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines. Non-Hodgkin’s lymphoma is the most common hematological malignancy, and certain patients undergoing therapy are at increased risk of HBV reactivation. Rituximab, a monoclonal antibody, is well studied in HBV reactivation, but newer agents have been implicated as well. Here, we review novel agents suspected in HBV reactivation and effective strategies to prevent HBV reactivation. Fifteen years of literature were reviewed in order to better understand the reactivation rates of hepatitis B in patients with non-Hodgkin’s lymphoma. Anti-CD20 antibodies continue to be the main medications that can lead to HBV reactivation, and HBV reactivation rates have decreased with increased awareness. HBV reactivation is uncommon when using other novel agents. Entecavir and lamivudine remain the agents of choice to prevent HBV reactivation in high risk patients. In conclusion, the immunosuppressive effect of NHL and its therapy provide a pathway for HBV reactivation, especially in patients treated with anti-CD20 antibody. Since many HBV positive patients are often excluded from clinical trials of novel agents in NHL, more aggressive post-market surveillance of new agents, well-designed best practice advisories, and timely case reports are needed to reduce the incidence of HBV reactivation. Lastly, large prospective investigations coupled with well-utilized best practice advisories need to be conducted to understand the impact of more potent novel NHL therapy on HBV reactivation.

Keywords

Hepatitis B virus, HBV reactivation, Non-Hodgkin’s lymphoma, Rituximab, Anti-CD20 antibody, Best practice advisories

Introduction

Hepatitis B virus (HBV) is a DNA virus that resides exclusively in human reservoirs and is transmitted through body fluids. The infective form remains prevalent globally despite available prophylactic immunization. Endemicity is present in Asia, Africa, the Middle East, parts of Eastern Europe, and South America, and up to 400 million people are chronically infected.1 Although the United States is non-endemic for HBV, up to 1 million people have chronic HBV, and the risk of acute infection persists. Estimated age-adjusted prevalence in the US is 4.7% for core antibody (anti-HBc) and 0.27% for surface antigen (HBsAg).2 In addition, HBsAg prevalence rate is thought to be 0.75% in those who receive immunosuppressive therapy and is highest among those with co-infection of the human immunodeficiency virus (HIV).3 Vaccination efforts have contributed to the decrease in anti-HBc prevalence rate from 1.9% in 1999 to 0.6% in 2006 for those aged 6 to 19 years. Among adults older than 50 years of age, the prevalence rate decreased marginally from 7.7% in 1999 to 7.2% in 2006.2 Moreover, HBV has been implicated in the incidence of non-Hodgkin’s lymphoma (NHL),47 which increases with advancing age for all race and gender subgroups.8,9

NHL is one of the most prevalent hematological malignancies globally and contributed to over 190,000 deaths in 2008.10 NHL is also common in the US, where almost 20,000 patients will die from this disease each year, despite available chemotherapy.11 Cytotoxic chemotherapy, which is highly immunosuppressive, has been linked to reactivation of HBV infection in seropositive and seronegative cases (undetectable anti-HBc and anti-HB surface antigens).1218 The mechanisms underlying HBV reactivation in NHL therapy include the active roles of acquired viral genomic mutations, chronic viral infection, immunosuppression, and exaggerated immune response following cessation of chemotherapy.7,1921 The definition of HBV reactivation can vary, but it must include a 10-fold rise in HBV DNA in a patient with past or latent HBV infection and/or levels > 10,000 copies/mL (4 log copies/mL).7,22,23 A serum transaminase level three times the upper limit of normal or alanine aminotransferase (ALT) over 100 IU/L7,19,24 in a patient with known HBV seropositivity may also be considered HBV reactivation.22 HBV reactivation is important in patients treated for NHL, as it increases the likelihood of stopping therapy, may lead to liver failure, and can increase the risk of mortality.2426

Chemo-immunotherapy induced HBV reactivation can be preventable if detected early. A vast majority of the NHL literature on HBV reactivation has focused on rituximab. With the advent of newer immunotherapy agents, less is understood about the incidence and prevention of HBV reactivation. This review aims to summarize recent data on the reactivation of HBV with novel agents in NHL therapy and effective methods to prevent HBV reactivation in these patients.

Review Criteria

Relevant articles for this review were identified by searching PubMed, Embase, Ovid Medline, and Scopus using the following terms, alone and in combination: “Hepatitis B reactivation”, “novel agents”, “Non-Hodgkin’s lymphoma”, “immunosuppression”, “immunocompromised host”, “immunosuppressive agents”, “hepatitis B”, “hepatitis B virus”, “HBV”, “reactivation”, “management” and “prevention”. Full text articles of all selected studies were retrieved, and if a paper was selected for inclusion, the bibliographic references were scrutinized to identify additional relevant studies. The period of the search was restricted to a 15 year period to limit the search to novel agents in the treatment of NHL (2000–2015).

Hepatitis B reactivation in NHL therapy

Hepatitis B reactivation in susceptible individuals has been linked with chemotherapy through amplification of viral replication and immune function recovery following chemotherapy induced-immunosuppression.20,21,26,27 Reactivation is also attributable to profound immunosuppression induced by lymphocytotoxic monoclonal antibodies27,28. In the largest study (10,729 patients) on HBV reactivation in patients receiving chemotherapy, predictors included male gender, race (Asian, Black), rituximab use, and presence of hepatitis B risk factors. The risk of reactivation was high in individuals with anti-HBc or anti-HBs and even higher in those with seropositive HBsAg.28

The severity of chemotherapy-induced HBV reactivation in NHL has been categorized as low risk with azathioprine and methotrexate moderate risk with commonly used cytotoxic chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), high-dose corticosteroids (prednisolone > 20 mg), and fludarabine. Patients who received anti-CD20 monoclonal antibodies, such as rituximab, were at the highest risk for HBV reactivation.29,30

Among the monoclonal anti-CD20 antibodies, rituximab-associated HBV reactivation has been the most commonly reported event.7,20,26 Two meta-analyses have demonstrated more than a five-fold increased risk of HBV reactivation with rituximab chemotherapy based on HBcAb serum level (risk ratio (RR) of 5.52, 95% confidence interval (CI) 2.05–14.85, p < 0.001)12 and odds ratio (OR) of 5.73, 95% CI 2.01–16.33; Z = 3.33, p < 0.001.13 The first published meta-analysis reported a 55% liver failure rate,13 while another reported that 43% of participants developed adverse hepatic-related events.7 In addition, early studies on HBV reactivation rates from rituximab combined chemotherapy reported rates up to 56%, especially in HBV endemic regions.22,31,32 However, more recent studies have reported lower reactivation rates (< 2.7%) and lower mortality rates,14,15,33,34 even in high prevalent regions. This discrepancy may be explained by improved defined criteria and awareness of HBV reactivation.14,35 In addition, reactivation rates may be reduced due to early diagnosis and increased knowledge of the management of chronic hepatitis B and the associated HBV reactivation in oncologic therapy.30,36

In addition to rituximab, ofatumumab was included in the Food and Drug Administration (FDA) reactivation warning 4 years after its approval in 2009.24,37 A search of the FDA Adverse Event Reporting System database yielded 32 cases of rituximab-associated HBV reactivation and one case associated with ofatumumab (http://www.fda.gov/Drugs/DrugSafety/ucm366406.htm). Data in support of ofatumumab in HBV reactivation is still sparse, and a recent European Phase IV trial in advanced chronic lymphocytic leukemia (CLL) categorically reported no case of HBV reactivation in patients treated with ofatumumab.38 Obinutuzumab, recently approved by the FDA for CLL in 2013, has a black box warning for HBV reactivation. However, no published data exist to support this report.39,40 A search from the FDA Adverse Event Reporting System database did not yield any data to support this report (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111085.htm#O; http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm373263.htm). A Japanese Phase I study of obinutuzumab in refractory B-cell NHL excluded patients with seropositive HBV status,41 thereby precluding the usefulness of identifying adverse events through clinical trials.42

Although there is no FDA warning yet, few case reports of HBV reactivation have been reported with other monoclonal agents used to treat NHL. Alemtuzumab (anti-CD52) therapy, mainly used in CLL, increased HBV DNA level to 7.3 log copies/mL in one patient,43 while mogamulizumab in adult T-cell leukemia-lymphoma increased HBV DNA to a range of 2.1 to 9.1 log copies/mL during therapy for four different patients.44,45 Other novel agents, such as the small molecule inhibitors [Bruton’s kinase (BTK) inhibitors and phosphatidylinositol 3-kinase delta inhibitors (PI3Kδ)], have been linked to the occurrence of autoimmune hepatitis, but it is unclear if HBV reactivation can occur.20,46,47 Idelalisib, a potent, small-molecule inhibitor of PI3Kδ has demonstrated favorable treatment response in patients with indolent NHL who are refractory to rituximab and other previous chemotherapy.48,49 Asymptomatic elevated transaminase levels was reported in 47%–48% of such patients, and 13%–25% had grade 3 elevations, although most cases resolved following dose reduction.48,49 It is unclear if these are negligible laboratory abnormalities or an indication that patients with HBV risk factors treated with PI3Kδ inhibitors may develop overt HBV reactivation.50,51 Clinical trials of these agents in combination with rituximab are underway, and the outlook in regard to HBV reactivation is guarded until more post-market surveillance data emerge.42,52Table 1 summarizes confirmed and suspected novel agents with HBV reactivation sequela.

Table 1.

Novel agents and HBV reactivation status

aAgentTargetIndicationHBV reactivation StatusData source References
Monoclonal antibodies
Rituximab*CD20Relapsed or refractory indolent lymphoma maintenance therapy in B-cell NHLFDA boxed warningFDA AERS1315,30,31,37
Ofatumumab*CD20Relapsed/refractory CLLFDA boxed warningFDA AERS37,38
Obinutumumab*CD20Rituximab-refractory patientsFDA boxed warningFDA AERS3941
Alemtuzumab§CD52Refractory B-CLL+HBVr but no FDA warning yetCase reports27,43
Mogamulizumab§CC chemokine receptorAggressive adult T-cell leukemia-lymphoma (ATL) and peripheral T-cell lymphoma+HBVr but no FDA warning yetCase reports44,45
Small molecule inhibitors
Ibrutinib§BTK inhibitorsLow-grade NHLImmune hepatitisClinical trials46,47
Idelalisib§PI3Kδ inhibitorsRelapsed/Refractory low-grade NHLImmune hepatitis/ TransaminitisClinical trials46,47

Prevention Strategies

HBV screening, best practice advisories, and HBV vaccination

Screening for both HBV reactivation and HBV risk factors is the first step in preventing reactivation in patients undergoing therapy for NHL.28,30,53 Organizational policies on screening have significantly increased screening rates over the last 6 years from 20% to 90% at large oncology centers in the US.24,28 Policies on screening modalities are also gradually shifting from a targeted approach to a universal approach.

A targeted screening approach for patients undergoing chemo-immunotherapy on the basis of HBV risk status is limited since chronic hepatitis may be asymptomatic, and sufficient information may not be elicited during initial patient encounters to adequately assess the risk of HBV infection.54,55 On the other hand, universal HBV screening for all patients newly diagnosed with cancer who require chemo-immunosuppressive therapy results in a more direct reduction in reactivation rates.24 In the US, hospital-enforced universal screening policies in some large cancer treatment centers provide evidence that increasing pre-therapy screening and prophylaxis for HBV can result in zero-to-minimal cases of HBV reactivation.28,53 Currently, the National Comprehensive Cancer Network (NCCN) recommends that all patients receiving an anti-CD20 antibody should be screened for HBV prior to exposure to the agent.56 Screening should be for both HBsAg and anti-HBc since HBV DNA undetected in serum can persist in tissues11,56,57 and the antigen may be absent in indolent cases of HBV.58 Patients who are found to be positive for either should be considered for HBV prophylaxis prior to chemo-immunosuppressive therapy.

According to clinical opinion in the oncologic literature, there is clear consensus on adopting screening to identify patients who are at high risk of HBV and also candidates for anti-CD20 monoclonal antibody. There are differences in opinion regarding the necessity to screen all patients who will receive chemotherapy irrespective of HBV risk status. Guidelines from the American Gastroenterological Association (AGA),26 the European Association for the Study of Liver Disease (EASL),59 the American Society of Clinical Oncology (ASCO),53 and the Asian-Pacific Association for the Study of the Liver (APASL)60 recommend that low and high risk patients receiving chemotherapy or immunotherapy should be considered for testing and prophylaxis. On the other hand, the NCCN57 and the American Association for the Study of Liver Diseases (AASLD)61 suggested excluding from screening, patients with low risk of HBV and candidates for cancer therapy associated with low risk of reactivation, because supporting evidence was insufficient. A tenable explanation for the disparity in screening approach may be consideration given to patients from regions with high HBV prevalence. At this time, clinicians should determine if screening for HBV is needed in each individual patient receiving chemotherapy. In the future, we hope that better data are available to help allocate resources for patients in need of HBV screening prior to chemotherapy.53

Improved coordination of primary care and specialist healthcare professional services is required to screen promptly all patients at risk of HBV infection irrespective of negative cancer status. Screening prescription by healthcare professionals to patients, prior to immunosuppressive therapy still needs to be enhanced.54,55,62 Improved screening rates to prevent HBV reactivation can be achieved with improved data management and alert systems integrated into existing electronic medical records.55,63 Between 2012 and 2013, a cancer center study showed the role of a best practice advisory (alert system) incorporated in the computerized physician order entry (CPOE) application in increasing HBV screening rates prior to therapy. At the end of the program, the study reported an improved screening rate for patients treated with biologic agents from < 50% to > 85%.63 Since prior HBV infection prior HBV infection is a baseline risk factor for HBV reactivation, prevention efforts need to maintain a clear distinction between identifying risk factors for HBV reactivation and for HBV infection.28,36 Notable risk factors for HBV infection include groups such as healthcare workers, injecting drug users, recipients of blood products or dialysis, household contacts of people with chronic HBV infection, incarcerated persons, people with multiple sex partners, men who have sex with men, and unvaccinated or partially vaccinated travelers to high endemic regions.36 Low and intermediate endemic countries require catch-up immunization targeted at these high risk groups. In addition, programs that mandate HBV vaccination for entry into schools, colleges, and work-places remain an effective strategy to reduce HBV infection in low-intermediate endemic regions.36

The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control (CDC) recommends universal vaccination of individuals, especially male adults, who test positive, since the risk of hepatitis B remains highest in this group.36 This recommendation is important because adult males have a higher incidence of NHL compared to women of the same age group.8,9,64 For children, universal vaccination at childbirth with follow-up remains appropriate for high endemic (>8%) regions. On a global scale, newborns who received a birth dose of HBV vaccine increased from 27% to 38% between 2006 and 2014. Birth cohorts who received three doses in 2008 and 2014 increased from 69% to 82%. Although these data indicate that HBV vaccination rates are rising, there is still room for improvement in high endemic areas.1,65 Since the last two decades, the CDC has recommended routine post-vaccination tests for anti-HBs and annual booster doses for sustained immunity among high risk groups and immunocompromised persons.66 Therefore, targeted and universal vaccination efforts should not wane, because the risk of exposure to HBV continues to persist.

Reactivation prophylaxis and therapy

HBV seropositive individuals who require chemotherapy or anti-CD20 antibody therapy should be started on antivirals in a timely manner. Globally, lamivudine has been the most utilized nucleos(t)ide analogue for the prevention of HBV reactivation during chemo-immunotherapy.33,6770 Prognosis of patients with lamivudine following HBV reactivation remains favorable, despite few cases of viral resistance.71 Newer nucleos(t)ide are now favored in reactivation management.7175 Newer nucleos(t)ide analogues, such as entecavir, adefovir, and tenofovir, have been used because of their lower viral resistance.27,57 In a notable study, Li and others compared entecavir with lamivudine as prophylaxis for hepatitis B reactivation in lymphoma patients undergoing chemotherapy. The entecavir group exhibited a significantly lower rate of HBV reactivation (0% vs 12.4%, p = 0.024) and a lower incidence of aborted chemotherapy compared to the lamivudine group (5.9 vs 20.2%, p = 0.042).74

The stage of NHL disease is a useful criterion when considering use of nucleos(t)ide analogues. Studies have shown that the efficacy of entecavir is higher than that of lamivudine, especially in advanced disease.72,76 In advanced diffuse large B-cell lymphoma (DLBCL), Huang and colleagues compared entecavir and lamivudine and demonstrated that there was a lower reactivation rate (6.6% vs 30%; difference, 23.4% [95% CI, 10.2% to 36.6%]; p = .001) and premature chemotherapy cessation (1.6% vs 18.3%; difference, 16.7% [95% CI, 6.4% to 27.0%]; p = .002) with entecavir compared to lamivudine.72 Importantly, despite the lower risk of viral resistance with tenofovir, adefovir, and entecavir compared to lamivudine,77 these newer agents on rare occasions were associated with mild renal dysfunction with long-term use.20,78,79 Therefore, dosage of these agents needs to be adjusted in renal impairment, and renal function should be assessed at least every 3 months.57,79

Another study that explored steroid-free chemotherapy in the prevention of HBV reactivation in NHL reported a lower incidence and severity of reactivation when compared to steroid-containing chemotherapy.80 Despite the overall survival rate, which was higher in the steroid-containing group, a limitation of this approach may be deciding between survival following rituximab-containing therapy and the risk of HBV reactivation. Finally, more studies are needed to understand the efficacy of antivirals when both rituximab and steroids are used.81

Therapeutic intervention for HBV reactivation in aggressive lymphomas/NHL is indicated in instances such as missed HBV status and failed or interrupted prophylactic therapy.27,8284 Failure of prophylactic lamivudine may result in withdrawal hepatitis, viral breakthrough, or mortality from liver failure.85,86 Predictors of lamivudine failure in a study include: elevated baseline HDV DNA titer (≥ 2,000 IU/mL) (hazard ratio [HR], 9.94; p = 0.0063) and the use of rituximab (HR, 3.19; p = 0.027) for viral breakthrough, while for withdrawal hepatitis, a high baseline HBV DNA titer (HR, 5.90; p = 0.007), liver cirrhosis (HR, 10.4; p = 0.002), and distant metastasis (HR, 5.14; P = 0.008) were independent risk factors.86 Therapeutic interventions also depend on the presence of secondary liver failure and prognosis of the lymphoma. Newer antivirals may be used where liver failure is absent.27,75 For patients with HBV reactivation resulting in liver failure, the AGA recommends liver transplantation.26,75 Favorable outcomes were recorded in patients who underwent liver transplantation and antiviral therapy, having established prior complete remission of disease and a favorable prognosis of the lymphoma type.75,87

Based on better outcomes from recent data, recent ASCO and NCCN guidelines on HBV reactivation recommend, when possible, that patients who are HBV positive (HBsAg-positive and/or anti-HBc positive) and require chemo-immunotherapy should be placed on prophylaxis with entecavir for the duration of treatment.53,61 Other agents, including tenofovir and lamivuidine, can also be used, but there may be more resistance to lamivudine therapy. Newer antiviral medications are readily favored considering the relatively high barrier to viral resistance compared to lamivudine for both prophylactic and therapeutic purposes. The literature suggests that prophylaxis against rituximab associated HBV-reactivation should be extended up to 12 months following oncologic therapy and should be combined with HBV viral load surveillance every 3 months.30,53,57 Although NCCN warns against lamivudine as a routine prophylactic agent due to risk of viral resistance, AASLD, EASL, ASIF, and APASL recommend lamivudine as a viable prophylactic agent based on its pharmaco-economic and safety profiles.5961,88 Specifically, the AASLD endorses lamivudine when the planned duration of chemotherapy is less than 12 months and entecavir or tenofovir for chemotherapy lasting beyond 12 months.20,61,89 In addition, the EASL advocates for use of baseline HBV DNA < 2,000 IU/mL for initiating lamivudine while values > 2,000 IU/mL are indications for prescribing entecavir or tenofovir.59 In addition, the APASL and ASIF recommend lamivudine for treatment-naïve patients with evident or impending hepatic derangement.60,88 We urge clinicians to follow HBV seropositive patients closely while using novel agents for NHL, to ensure that reactivation does not occur. Clinicians should also remember to screen patients for HBV who are receiving chemotherapy without rituximab, if they are at high risk for reactivation. If a patient is positive for HBV, then prophylaxis should be initiated. The literature remains unclear at this time whether universal screening for HBV should be done in all patients receiving chemotherapy.

There are groups of patients in whom routine antiviral therapy may not be indicated. These groups include patients who do not meet the criteria for reactivation (the rise in HBV DNA < 10-fold in patients with past or latent infection, ALT level < three times the upper limit of normal), younger patients in the immune-tolerant phase (normal ALT levels despite positive HBsAg and HBV DNA and minimal hepatic inflammation), and patients in the inactive carrier phase. In addition, patients are considered low risk with agents such as low dose corticosteroids or immunosuppressive agents (e.g., azathioprine and 6-mercaptopurine), and may be excluded from routine antiviral prophylaxis. Further research is needed to assess the risk in these patients.30,53,90

Lastly, critical consideration should be given to factors that may impact the potential outcomes of prophylactic and therapeutic interventions for HBV reactivation. These factors include cost of newer antivirals, liver transplant cost, medication adherence, development of mutant HBV, adverse effects of therapy, and a prolonged monitoring period.68,83,84,91 Further studies are needed to better understand these issues. Table 2 provides a summary of the modalities for preventing HBV reactivation.

Table 2.

Modalities for preventing HBV reactivation

Reactivation Prevention ModalityKey CharacteristicsReferences
Indication/AdvantagesDrawbacks
Pre-NHL therapy screening
 Targeted screeningScreen NHL patients receiving anti-CD20 antibody with + HBV risk statusMissed cases (asymptomatic HBV infection)53,61,62
 Universal screeningScreen all patients receiving anti-CD20 antibody irrespective of HBV risk statusFalse HBV positive cases Added cost to therapy26,59,60,63
 Best Practice Advisory (EHR alert system)Increase HBV screening ratesImplementation cost56,64
HBV Vaccination
 Catch-up vaccinationLow NHL endemic regions Reduced HBV reactivation ratesMissed cases36,54,66
 Universal vaccinationHigh endemic regions Reduced HBV reactivation ratesSurveillance cost1,36,54,66
Reactivation Prophylaxis
 EntecavirAgent of choice in advanced disease. Least viral resistanceExpensive Renal insufficiency (rare)61,72,73,74,78
 LamivudineMost used and studied agent. CheapestWithdrawal hepatitis Lamivudine failure (Viral resistance, viral breakthrough)31,32,33,34,55,68,71,85,89
 AdefovirLess viral resistanceExpensive Renal dysfunction (rare) Hypophosphatemia (rare)27,76,80,81
 TenofovirLeast viral resistanceExpensive Renal dysfunction (rare) Hypophosphatemia (rare)19,27,70,71
 Low dose/steroid free chemo-immunotherapyReduced incidence of reactivationPotentially adverse survival outcomes from undertreated NHL disease83,84
Reactivation Treatment
 LamivudineMost used agent globallyRisk of acquired viral resistance33,59,60,69,70,91
 Newer antivirals (Entecavir, Adefovir, Tenofovir)Lamivudine failure. Liver failure must be absentDepends on prognosis of lymphoma type27,53,61,68,77
 Liver transplantationIf liver failure is present with HBV reactivationDepends on cost, disease prognosis and post-transplant sequelae26,75

Conclusion

The immunosuppressive effect of NHL and from its therapy provides a pathway for HBV reactivation, especially in those patients treated with anti-CD20 antibody. This effect emphasizes chronic hepatitis B virus infection and reactivation as important public health issues that are preventable, especially among immunosuppressed populations. Because HBV seropositive individuals are often excluded from clinical trials of new agents, there is a paucity of data to measure the risk of morbidity and mortality from novel agent-induced HBV reactivation. Therefore, more aggressive post-market surveillance of new agents, well-designed best practice advisories, and timely case reports are needed to reduce the incidence of HBV reactivation. In addition, large prospective investigations coupled with well-utilized best practice advisories should be performed to understand the role of the more potent novel NHL therapies in HBV reactivation. Sustained HBV vaccination of children and especially adults can reduce the future risk of reactivation in patients with NHL, but this association requires further investigation.

Abbreviations

AASLD: 

American Association for the Study of Liver Diseases

ACIP: 

Advisory Committee on Immunization Practices

AGA: 

American Gastroenterological Association

ALT: 

alanine aminotransferase

anti-HBc: 

HBV core antibody

APASL: 

Asian-Pacific Association for the Study of the Liver

ASCO: 

American Society of Clinical Oncology

BTK: 

Bruton’s kinase

CDC: 

Centers for Disease Control and Prevention

CI: 

confidence interval

CLL: 

chronic lymphocytic leukemia

CPOE: 

computerized physician order entry

DLBCL: 

diffuse large B-cell lymphoma

EASL: 

European Association for the Study of Liver Disease

FDA: 

Food and Drug Administration

HBsAg: 

hepatitis B surface antigen

HBV: 

hepatitis B virus

HIV: 

human immunodeficiency virus

HR: 

hazard ratio

NCCN: 

National Comprehensive Cancer Network

NHL: 

non-Hodgkin’s lymphoma

OR: 

odds ratio

PI3Kδ: 

phosphatidylinositol 3-kinase delta inhibitors

RR: 

risk ratio

Declarations

Conflict of interest

None

Authors’ contributions

Conceived the topic of the review article (SD, LS), collected and reviewed pertinent articles (OOO, SD), wrote the manuscript and reviewed the final version (OOO, LS, SD), created the tables (OOO).

References

  1. Hepatitis B. vaccines. World Health Organization, 2009; p. 405-420.
  2. Wasley A, Kruszon-Moran D, Kuhnert W, Simard EP, Finelli L, McQuillan G. The Prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis 2010;202:192-201 View Article
  3. Backus LI, Belperio PS, Loomis TP, Han SH, Mole LA. Screening for and prevalence of hepatitis B virus infection among high-risk veterans under the care of the U.S. Department of Veterans Affairs: a case report. Ann Intern Med 2014;161:926-928 View Article
  4. Kim YM, Jeong SH, Kim JW, Lee SH, Hwang JH, Park YS. Chronic hepatitis B, non-Hodgkin’s lymphoma, and effect of prophylactic antiviral therapy. J Clin Virol 2011;51:241-245 View Article
  5. Kim JH, Bang YJ, Park BJ, Yoo T, Kim CW, Kim TY. Hepatitis B virus infection and B-cell non-Hodgkin’s lymphoma in a hepatitis B endemic area: a case-control study. Jpn J Cancer Res 2002;93:471-477 View Article
  6. Lim ST, Fei G, Quek R, Lim LC, Lee LH, Yap SP. The relationship of hepatitis B virus infection and non-Hodgkin’s lymphoma and its impact on clinical characteristics and prognosis. Eur J Haematol 2007;79:132-137 View Article
  7. Dalia S, Suleiman Y, Croy D, Sokol L. Association of lymphomagenesis and the reactivation of hepatitis B virus in non-Hodgkin lymphoma. Cancer Control 2015;22:360-365
  8. Fisher SG, Fisher RI. The epidemiology of non-Hodgkin’s lymphoma. Oncogene 2004;23:6524-6534 View Article
  9. Müller AM, Ihorst G, Mertelsmann R, Engelhardt M. Epidemiology of non-Hodgkin’s lymphoma (NHL): trends, geographic distribution, and etiology. Ann Hematol 2005;84:1-12 View Article
  10. Datta S, Chatterjee S, Policegoudra RS, Gogoi HK, Singh L. Hepatitis viruses and non-Hodgkin’s lymphoma: A review. World J Virol 2012;1:162-173 View Article
  11. Non-Hodgkin lymphoma - SEER stat fact sheets. Bethesda, MD:
  12. Dong HJ, Ni LN, Sheng GF, Song HL, Xu JZ, Ling Y. Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol 2013;57:209-214 View Article
  13. Evens AM, Jovanovic BD, Su YC, Raisch DW, Ganger D, Belknap SM. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol 2011;22:1170-1180 View Article
  14. Fan Y, Luo C, Luo L, Huang Z, Yu H. Retrospective analysis of hepatitis B virus reactivation after rituximab combination chemotherapy in patients with B-cell lymphoma. Chinese-German Journal of Clinical Oncology 2011;10:721-725 View Article
  15. Koo YX, Tan DS, Tan IB, Tao M, Lim ST. Hepatitis B virus reactivation in a patient with resolved hepatitis B virus infection receiving maintenance rituximab for malignant B-cell lymphoma. Ann Intern Med 2009;150:655-656 View Article
  16. Lunel-Fabiani F, Masson C, Ducancelle A. Systemic diseases and biotherapies: understanding, evaluating, and preventing the risk of hepatitis B reactivation. Joint Bone Spine 2014;81:478-484 View Article
  17. Mozessohn L, Chan KK, Feld JJ, Hicks LK. Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis. J Viral Hepat 2015;22:842-849 View Article
  18. Ozguroglu M, Bilici A, Turna H, Serdengecti S. Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin’s lymphoma. Med Oncol 2004;21:67-72 View Article
  19. Yeo W, Chan PK, Chan HL, Mo FK, Johnson PJ. Hepatitis B virus reactivation during cytotoxic chemotherapy-enhanced viral replication precedes overt hepatitis. J Med Virol 2001;65:473-477 View Article
  20. Phipps C, Chen Y, Tan D. Lymphoproliferative disease and hepatitis B reactivation: challenges in the era of rapidly evolving targeted therapy. Clin Lymphoma Myeloma Leuk 2016;16:5-11 View Article
  21. Yeo W, Chan HL. Hepatitis B virus reactivation associated with anti-neoplastic therapy. J Gastroenterol Hepatol 2013;28:31-37 View Article
  22. Hsu C, Tsou HH, Lin SJ, Wang MC, Yao M, Hwang WL. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology 2014;59:2092-2100 View Article
  23. Ludwig E. HBV reactivation in immunosuppressed patients: prevention or containment?. Hepatology 2014;59:2062-2064 View Article
  24. Di Bisceglie AM, Lok AS, Martin P, Terrault N, Perrillo RP, Hoofnagle JH. Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg?. Hepatology 2015;61:703-711 View Article
  25. Zhang A, Zhang M, Shen Y, Wang W, Zheng S. Hepatitis B virus reactivation is a risk factor for development of post-transplant lymphoproliferative disease after liver transplantation. Clin Transplant 2009;23:756-760 View Article
  26. Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:221-244
  27. Mastroianni CM, Lichtner M, Citton R, Del Borgo C, Rago A, Martini H. Current trends in management of hepatitis B virus reactivation in the biologic therapy era. World J Gastroenterol 2011;17:3881-3887 View Article
  28. Hwang JP, Fisch MJ, Lok AS, Zhang H, Vierling JM, Suarez-Almazor ME. Trends in hepatitis B virus screening at the onset of chemotherapy in a large US cancer center. BMC Cancer 2013;13:534 View Article
  29. Yavuz S, Paydas S, Disel U, Sahin B. Hepatitis B virus reactivation during fludarabine therapy in non-Hodgkin’s lymphoma. Leuk Lymphoma 2003;44:1249-1250 View Article
  30. Lee HM, Liapakis A, Lim JK. Diagnosis, management, and prevention of hepatitis B reactivation. Curr Hepatology Rep 2015;14:184-194 View Article
  31. Yeo W, Chan PK, Ho WM, Zee B, Lam KC, Lei KI. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol 2004;22:927-934 View Article
  32. Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003;125:1742-1749 View Article
  33. Li H, Zhang HM, Chen LF, Chen YQ, Chen L, Ren H. Prophylactic lamivudine to improve the outcome of HBsAg-positive lymphoma patients during chemotherapy: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2015;39:80-92 View Article
  34. Koo YX, Tan DS, Tan BH, Quek R, Tao M, Lim ST. Risk of hepatitis B virus reactivation in patients who are hepatitis B surface antigen negative/antibody to hepatitis B core antigen positive and the role of routine antiviral prophylaxis. J Clin Oncol 2009;27:2570-2571
  35. Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology 2008;47:844-853 View Article
  36. Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep 2006;55:1-33
  37. Mitka M. FDA: Increased HBV reactivation risk with ofatumumab or rituximab. JAMA 2013;310:1664 View Article
  38. Moreno C, Montillo M, Panayiotidis P, Dimou M, Bloor A, Dupuis J. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica 2015;100:511-516 View Article
  39. Cameron F, McCormack PL. Obinutuzumab: first global approval. Drugs 2014;74:147-154 View Article
  40. Kakkar AK, Balakrishnan S. Obinutuzumab for chronic lymphocytic leukemia: promise of the first treatment approved with breakthrough therapy designation. J Oncol Pharm Pract 2015;21:358-363 View Article
  41. Ogura M, Tobinai K, Hatake K, Uchida T, Suzuki T, Kobayashi Y. Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Cancer Sci 2013;104:105-110 View Article
  42. Richey EA, Lyons EA, Nebeker JR, Shankaran V, McKoy JM, Luu TH. Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs?. J Clin Oncol 2009;27:4398-4405 View Article
  43. Iannitto E, Minardi V, Calvaruso G, Mulè A, Ammatuna E, Di Trapani R. Hepatitis B virus reactivation and alemtuzumab therapy. Eur J Haematol 2005;74:254-258 View Article
  44. Nakano N, Kusumoto S, Tanaka Y, Ishida T, Takeuchi S, Takatsuka Y. Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab. Hepatol Res 2014;44:354-357 View Article
  45. Totani H, Kusumoto S, Ishida T, Masuda A, Yoshida T, Ito A. Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia–lymphoma patients with resolved HBV infection following systemic chemotherapy. Int J Hematol 2015;101:398-404 View Article
  46. Morrison VA. Immunosuppression associated with novel chemotherapy agents and monoclonal antibodies. Clin Infect Dis 2014;59:S360-S364 View Article
  47. Grover NS, Park SI. Novel targeted agents in hodgkin and non-Hodgkin lymphoma therapy. Pharmaceuticals 2015;8:607-636 View Article
  48. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014;370:1008-1018 View Article
  49. Flinn IW, Kahl BS, Leonard JP, Furman RR, Brown JR, Byrd JC. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 2014;123:3406-3413 View Article
  50. Cheson BD. CLL and NHL: the end of chemotherapy?. Blood 2014;123:3368-3370 View Article
  51. Merli M, Ferrario A, Maffioli M, Arcaini L, Passamonti F. Investigational therapies targeting lymphocyte antigens for the treatment of non-Hodgkin’s lymphoma. Expert Opin Investig Drugs 2015;24:897-912 View Article
  52. Siddiqi T, Rosen ST. Novel biologic agents for non-Hodgkin lymphoma and chronic lymphocytic leukemia-part 2: adoptive cellular immunotherapy, small-molecule inhibitors, and immunomodulation. Oncology 2015;29:299-308
  53. Hwang JP, Somerfield MR, Alston-Johnson DE, Cryer DR, Feld JJ, Kramer BS. Hepatitis B virus screening for patients with cancer before therapy: American Society of Clinical Oncology provisional clinical opinion update. J Clin Oncol 2015;33:2212-2220 View Article
  54. Liu CY, Chandrasekar PH, Masood A, Schiffer CA. Adherence to hepatitis B screening and prophylactic lamivudine for prevention of rituximab-associated hepatitis B reactivation. J Oncol Pharm Pract 2013;19:18-23 View Article
  55. Sun WC, Hsu PI, Yu HC, Lin KH, Tsay FW, Wang HM. The compliance of doctors with viral hepatitis B screening and antiviral prophylaxis in cancer patients receiving cytotoxic chemotherapy using a hospital-based screening reminder system. PLoS One 2015;10:e0116978 View Article
  56. Bréchot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Bréchot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: clinically significant or purely “occult”?. Hepatology 2001;34:194-203 View Article
  57. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines®) non-Hodgkin’s lymphomas (Version 4.2014). Available at https://www.nccn.org/about/nhl.pdf
  58. Law JK, Ho JK, Hoskins PJ, Erb SR, Steinbrecher UP, Yoshida EM. Fatal reactivation of hepatitis B post-chemotherapy for lymphoma in a hepatitis B surface antigen-negative, hepatitis B core antibody-positive patient: potential implications for future prophylaxis recommendations. Leuk Lymphoma 2005;46:1085-1089 View Article
  59. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-185 View Article
  60. Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008;2:263-283 View Article
  61. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661-662 View Article
  62. Visram A, Chan KK, McGee P, Boro J, Hicks LK, Feld JJ. Poor recognition of risk factors for hepatitis B by physicians prescribing immunosuppressive therapy: a call for universal rather than risk-based screening. PLoS One 2015;10:e0120749 View Article
  63. Sampedro B, Hernández-López C, Ferrandiz JR, Illaro A, Fábrega E, Cuadrado A. Computerized physician order entry-based system to prevent HBV reactivation in patients treated with biologic agents: the PRESCRIB project. Hepatology 2014;60:106-113 View Article
  64. Dorak MT, Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet 2012;3:268 View Article
  65. . Wkly Epidemiol Rec 2015;90:617-623
  66. . MMWR Recomm Rep 1993;42:1-18
  67. Hamaki T, Kami M, Kusumi E, Ueyama J, Miyakoshi S, Morinaga S. Prophylaxis of hepatitis B reactivation using lamivudine in a patient receiving rituximab. Am J Hematol 2001;68:292-294 View Article
  68. Kawai Y, Ikegaya S, Hata M, Kawahito M, Imamura S, Yoshida A. Successful lamivudine therapy for post-chemotherapeutic fulminant hepatitis B in a hepatitis B virus carrier with non-Hodgkin’s lymphoma: case report and review of the literature. Ann Hematol 2001;80:482-484 View Article
  69. Stroffolini T, Andriani A, Bibas M, Barlattani A. Successful treatment with lamivudine for reactivated hepatitis B infection following chemotherapy for non-Hodgkin’s lymphoma. Ann Hematol 2002;81:48-49 View Article
  70. He YF, Li YH, Wang FH, Jiang WQ, Xu RH, Sun XF. The effectiveness of lamivudine in preventing hepatitis B viral reactivation in rituximab-containing regimen for lymphoma. Ann Hematol 2008;87:481-485 View Article
  71. Tonziello G, Pisaturo M, Sica A, Ferrara MG, Sagnelli C, Pasquale G. Transient reactivation of occult hepatitis B virus infection despite lamivudine prophylaxis in a patient treated for non-Hodgkin lymphoma. Infection 2013;41:225-229 View Article
  72. Chen FW, Coyle L, Jones BE, Pattullo V. Entecavir versus lamivudine for hepatitis B prophylaxis in patients with haematological disease. Liver Int 2013;33:1203-1210 View Article
  73. Chen WC, Cheng JS, Chiang PH, Tsay FW, Chan HH, Chang HW. A comparison of entecavir and lamivudine for the prophylaxis of hepatitis B virus reactivation in solid tumor patients undergoing systemic cytotoxic chemotherapy. PLoS One 2015;10:e0131545 View Article
  74. Li HR, Huang JJ, Guo HQ, Zhang X, Xie Y, Zhu HL. Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy. J Viral Hepat 2011;18:877-883 View Article
  75. Sperl J, Frankova S, Kieslichova E, Oliverius M, Janousek L, Honsova E. Urgent liver transplantation for chemotherapy-induced HBV reactivation: a suitable option in patients recently treated for malignant lymphoma. Transplant Proc 2013;45:2834-2837 View Article
  76. Huang H, Li X, Zhu J, Ye S, Zhang H, Wang W. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA 2014;312:2521-2530 View Article
  77. Ho EY, Yau T, Rousseau F, Heathcote EJ, Lau GK. Preemptive adefovir versus lamivudine for prevention of hepatitis B reactivation in chronic hepatitis B patients undergoing chemotherapy. Hepatol Int 2015;9:224-230 View Article
  78. Jia HY, Ding F, Chen JY, Lian JS, Zhang YM, Zeng LY. Early kidney injury during long-term adefovir dipivoxil therapy for chronic hepatitis B. World J Gastroenterol 2015;21:3657-3662 View Article
  79. Tanaka M, Suzuki F, Seko Y, Hara T, Kawamura Y, Sezaki H. Renal dysfunction hypophosphatemia during long-term lamivudine plus adefovir dipivoxil therapy in patients with chronic hepatitis B. J Gastroenterol 2014;49:470-480 View Article
  80. Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology 2003;37:1320-1328 View Article
  81. Kusumoto S, Tanaka Y, Ueda R, Mizokami M. Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy. J Gastroenterol 2011;46:9-16 View Article
  82. Ceccarelli L, Salpini R, Sarmati L, Svicher V, Bertoli A, Sordillo P. Late hepatitis B virus reactivation after lamivudine prophylaxis interruption in an anti-HBs-positive and anti-HBc-negative patient treated with rituximab-containing therapy. J Infect 2012;65:180-183 View Article
  83. Masarone M, De Renzo A, La Mura V, Sasso FC, Romano M, Signoriello G. Management of the HBV reactivation in isolated HBcAb positive patients affected with Non Hodgkin Lymphoma. BMC Gastroenterol 2014;14:31 View Article
  84. Picardi M, Pane F, Quintarelli C, De Renzo A, Del Giudice A, De Divitiis B. Hepatitis B virus reactivation after fludarabine-based regimens for indolent non-Hodgkin’s lymphomas: high prevalence of acquired viral genomic mutations. Haematologica 2003;88:1296-1303
  85. Win LL, Powis J, Shah H, Feld JJ, Wong DK. Death from liver failure despite lamivudine prophylaxis during R-CHOP chemotherapy due to rapid emergence M204 mutations. Case Reports Hepatol 2013;2013:454897 View Article
  86. Kim IK, Kim BG, Kim W, Kim D, Kim YJ, Yoon JH. Clinical prediction of failure of lamivudine prophylaxis for hepatitis B virus-infected patients undergoing cytotoxic chemotherapy for malignancy. Antimicrob Agents Chemother 2012;56:5511-5519 View Article
  87. Benten D, Sterneck M, Panse J, Rogiers X, Lohse AW. Low recurrence of preexisting extrahepatic malignancies after liver transplantation. Liver Transpl 2008;14:789-798 View Article
  88. Carosi G, Rizzetto M, Alberti A, Cariti G, Colombo M, Craxì A. Treatment of chronic hepatitis B: update of the recommendations from the 2007 Italian Workshop. Dig Liver Dis 2011;43:259-265 View Article
  89. Lok AS, McMahon BJ, Brown RS, Wong JB, Ahmed AT, Farah W. Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta-analysis. Hepatology 2016;63:284-306 View Article
  90. Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med 2009;150:104-110 View Article
  91. Liu WC, Phiet PH, Chiang TY, Sun KT, Hung KH, Young KC. Five subgenotypes of hepatitis B virus genotype B with distinct geographic and virological characteristics. Virus Res 2007;129:212-223 View Article
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