Background

Hepatitis B virus (HBV) reactivation is a well-known risk during chemotherapy for hematological malignancies with reported rates ranging between 14% and 72%. However, there is a paucity of data regarding HBV infection management and reactivation risk in patients receiving systemic treatments for solid tumors.

Design

We conducted a PubMed search for publications from January 1990 until May 2016 related to HBV reactivation. The search terms were ‘hepatitis B reactivation’, cross-referenced with ‘chemotherapy’, then ‘hepatitis B’ cross-referenced with International Non-proprietary Name of each of the most used chemotherapy drugs in solid tumors.

Results

From these data, a grading of HBV reactivation risk and recommendations for management are given for most frequently used anticancer drugs in solid tumors.

Conclusion

Most drugs used for the treatment of solid tumors can induce hepatitis B reactivation in HBs antigen-positive patients. HBV screening can be recommended before systemic treatment initiation. Pre-emptive antiviral treatment can reduce the risk of HBV reactivation and prevent chemotherapy disruption.

introduction

Two billion people have been infected with the hepatitis B virus (HBV) worldwide [1] and more than 240 million have chronic liver infection [hepatitis B s antigen (HBsAg) positive] [2] bearing an increased risk of cirrhosis. The natural history of HBV infection (Figure 1) varies widely upon host factors such as integrity of immune system and age at primary infection, as well as viral factors including HBV genotype, viral mutations and viral load [3]. Primary infections spontaneously resolve in 95% of immuno-competent adults, but only in 10% of cases when the virus is contracted during the perinatal period. Therefore, viral replication may persist lifelong in a significant number of patients leading to chronic HBV infection (Figure 1) associated with different stages of liver injury and even when a ‘sero-virologic recovery’ is spontaneously achieved, intra-hepatic covalently closed circular DNA (cccDNA) may persist and be responsible of HBV reactivation. Furthermore, sensitive molecular biology techniques has evidenced low levels of HBV replication in the serum or the liver of subjects previously considered as resolved HBV infection (HBsAg-negative), the so-called ‘occult’ HBV infection [4].

Figure 1.

Natural history of hepatitis B virus infection. HBV, hepatitis B virus; HBsAg, hepatitis B s antigen; HBeAg, hepatitis B e antigen; anti-HBs, anti-hepatitis B s antigen antibodies; anti-HBc, anti-hepatitis c antigen antibodies; ALT, alanine aminotransaminase.

Figure 1.

Natural history of hepatitis B virus infection. HBV, hepatitis B virus; HBsAg, hepatitis B s antigen; HBeAg, hepatitis B e antigen; anti-HBs, anti-hepatitis B s antigen antibodies; anti-HBc, anti-hepatitis c antigen antibodies; ALT, alanine aminotransaminase.

Patients with persistent HBV infection (chronic or occult HBV infection) show various rates of viral replication which is partially controlled by host immune system (Figure 2). Exposure to any immunosuppressive factors may disturb viral control inducing HBV reactivation in these patients. HBV reactivation is defined as a reappearance or abrupt rise (over a 10-fold increase) of HBV DNA in the serum of patients with previous active, inactive or apparently resolved HBV infection [5]. Liver injury may develop and varies from asymptomatic increase in alanine aminotransferase (ALT) levels to acute liver failure. Hepatitis due to HBV reactivation is defined as threefold or greater increase in serum ALT to a level that exceeds 100 IU/l in patients with HBV reactivation and no other causes of liver injury. Considering the high prevalence of chronic HBV infection worldwide, oncologists are likely to face patients who suffer from both cancer and chronic HBV infection. HBV reactivation is a well-known risk during chemotherapy for hematological malignancies [6] and immunosuppressant therapy with reported rates ranging between 14% and 72% [7, 8]. However, there is a paucity of data regarding HBV infection management and reactivation risk in patients receiving systemic treatment for solid tumors. In this context, we aimed to review the existing data on chemotherapy-induced HBV reactivation, and discuss the issue of HBV infection during systemic treatment for solid tumors.

Figure 2.

Pathogenesis of hepatitis B virus reactivation induced by chemotherapy. The first stage is characterized by disruption of the immune system by chemotherapy and enhanced viral replication. The second stage consists in the restoration of the immune system upon chemotherapy withdrawal. The third stage is the return at baseline levels of liver function tests and HBV replication. HBV DNA, hepatitis B virus DNA; ALT, alanine aminotransferase; cccDNA, covalently closed circular DNA; CD8, CD8+ cytotoxic T cells; CD4, CD4+ helper T-cells; P, plasmocyte; Treg, regulatory T-cell; B, B-cell.

Figure 2.

Pathogenesis of hepatitis B virus reactivation induced by chemotherapy. The first stage is characterized by disruption of the immune system by chemotherapy and enhanced viral replication. The second stage consists in the restoration of the immune system upon chemotherapy withdrawal. The third stage is the return at baseline levels of liver function tests and HBV replication. HBV DNA, hepatitis B virus DNA; ALT, alanine aminotransferase; cccDNA, covalently closed circular DNA; CD8, CD8+ cytotoxic T cells; CD4, CD4+ helper T-cells; P, plasmocyte; Treg, regulatory T-cell; B, B-cell.

methods

We conducted a PubMed search for publications in English from January 1990 until May 2016 related to HBV reactivation. The search term was ‘hepatitis B reactivation’, cross-referenced with ‘chemotherapy’, then ‘hepatitis B’ cross-referenced with International Non-proprietary Name of each of all conventional chemotherapy agents, molecular-targeted agents and immunotherapy agents approved for the treatment of solid tumors. The results of the literature search are presented in Table 1. All relevant articles in the reference lists were also considered for review.

Table 1

Results of literature search

Class INN Total number of references retrieved References with abstract available 
Molecular-targeted therapies 
mTOR inhibitors Everolimus 17 17 
Temsirolimus 
MKIs Imatinib 15 14 
Sunitinib 
Sorafenib 84 78 
Erlotinib 
Other MKIsa 
MAbs and related agents Bevacizumab 12 12 
Cetuximab 
Panitumumab, Alfibercept 
Immunotherapy agents 
 Ipilimumab 
 Other immunotherapy agentsb 
Conventional chemotherapy agents 
Antimetabolites 5-fluorouracil 68 66 
 Gemcitabine 11 11 
 Capecitabine 
 Methotrexate 91 81 
Alkylating agents Oxaliplatin 
Cisplatin 65 64 
Carboplatin 
Cyclophosphamide 225 186 
Ifosfamide 
Topoisomerase inhibitors Doxorubicin 157 137 
 Epirubicin 20 20 
 Irinotecan 
 Etoposide 27 23 
 Topotecan 
Mitotic spindle targeting agents Paclitaxel 11 11 
 Docetaxel 
 Vinorelbine 
Class INN Total number of references retrieved References with abstract available 
Molecular-targeted therapies 
mTOR inhibitors Everolimus 17 17 
Temsirolimus 
MKIs Imatinib 15 14 
Sunitinib 
Sorafenib 84 78 
Erlotinib 
Other MKIsa 
MAbs and related agents Bevacizumab 12 12 
Cetuximab 
Panitumumab, Alfibercept 
Immunotherapy agents 
 Ipilimumab 
 Other immunotherapy agentsb 
Conventional chemotherapy agents 
Antimetabolites 5-fluorouracil 68 66 
 Gemcitabine 11 11 
 Capecitabine 
 Methotrexate 91 81 
Alkylating agents Oxaliplatin 
Cisplatin 65 64 
Carboplatin 
Cyclophosphamide 225 186 
Ifosfamide 
Topoisomerase inhibitors Doxorubicin 157 137 
 Epirubicin 20 20 
 Irinotecan 
 Etoposide 27 23 
 Topotecan 
Mitotic spindle targeting agents Paclitaxel 11 11 
 Docetaxel 
 Vinorelbine 

INN, International Nonproprietary Name; mTOR, mammalian target of rapamycin: MKI, multikinase inhibitors; MAbs, monoclonal antibodies.

aOther multikinase inhibitors: crizotinib, pazopanib, lenvatinib, cabozantinib, nintedanib, gefitinib, vemurafenib, dabrafenib, trametinib.

bOther immunotherapy agents: nivolumab, pembrolizumab.

The risk for anticancer treatment to induce HBV reactivation (as described in Table 2) was determined according to Grading of Recommendations Assessment, Development and Evaluation (GRADE, http://www.gradeworkinggroup.org/).

Table 2

Level of evidence [adapted from Grading of Recommendations Assessment, Development and Evaluation (GRADE) http://www.gradeworkinggroup.org/]

Code Quality of evidence Definition 
High 
  • Several high-quality studies with consistent results

  • In special cases: one large, high-quality multi-center trial

 
Moderate 
  • One high-quality study

  • Several studies with some limitations

 
Low 
  • One or more studies with severe limitations

 
Very low 
  • Expert opinion

  • No direct research evidence

  • One or more studies with very severe limitations

 
Code Quality of evidence Definition 
High 
  • Several high-quality studies with consistent results

  • In special cases: one large, high-quality multi-center trial

 
Moderate 
  • One high-quality study

  • Several studies with some limitations

 
Low 
  • One or more studies with severe limitations

 
Very low 
  • Expert opinion

  • No direct research evidence

  • One or more studies with very severe limitations

 

pathophysiology of HBV reactivation

Virus-specific T-cell response plays a major role in the resolution of HBV infection. Strong CD4+ helper and CD8 + cytotoxic T-cell responses have been evidenced in patients that clear HBV infection [9]. Cytotoxic CD8+ T cells destroy infected hepatocytes and contribute to viral clearance (Figure 2) [10]. Neutralizing antibodies are also important for protective immunity against HBV [11]. In spite of these, viral replication may persist indefinitely, leading to chronic or occult HBV infection.

The occurrence of HBV reactivation relies on the persistence of the cccDNA in the nuclei of hepatocytes [12]. In such cases, viral replication is strongly inhibited by host immune system and serum HBV DNA is low or undetectable (Figure 2). A high intra-hepatic cccDNA is a predictive factor for HBV reactivation in patients undergoing chemotherapy [13]. Schematically, HBV reactivation induced by conventional chemotherapy consists of three phases. In the initial phase, suppression of immune response (CD8+ cytotoxic T-cell response, anti-HBs antibody production) by the chemotherapy treatment leads to enhanced viral replication and widespread infection of hepatocytes, with an increase in the serum level of HBV DNA. Since HBV-related liver injury is mostly immune-mediated [14], no rise in ALT serum levels (>3 × baseline value) is observed. The second phase consists of restoration of host immune response upon chemotherapy discontinuation. Cytotoxic T cells clear infected hepatocytes expressing viral antigens (immune restoration syndrome) which may result in liver injury ranging from asymptomatic increase in ALT to acute liver failure and even death [5]. The rise in ALT serum levels is followed by a decrease in HBV DNA levels. In the third phase, both viral replication and ALT serum levels return to the basal levels (before chemotherapy). HBV reactivation related to chemotherapy protocols is presented in Figure 2.

potential risk of HBV reactivation induced by chemotherapy

Data on the risk of HBV reactivation related to individual anti-neoplastic drugs for solid tumors are scarce. A prospective study (626 patients) showed that HBV reactivation may occur in 19% (15/78) of HBsAg-positive patients undergoing different regimens of systemic chemotherapy [15]. The immunosuppressive agents most frequently associated with HBV reactivation were anthracyclines and vinca-alkaloids. Similar rates of HBV reactivation (20.5%) have been seen in HBsAg-positive patients undergoing transarterial chemo-lipiodolization (epirubicin/cisplatin; epirubicin or cisplatin alone) for hepatocellular carcinoma [16]. HBV reactivation may also occur in patients with occult HBV infection, but the risk seems to be lower. A recent prospective study including 27 HBsAg-negative patients with signs of ancient HBV infection (anti-HBc ± anti-HBs antibodies) found 2 (7.4%) cases of HBV reactivation (during cisplatin-based chemotherapy) [17]. The relevant evidences of HBV reactivation related with each anticancer agent for solid tumors are summarized in Table 3.

Table 3

Risk of HBV reactivation with the main antineoplastic agents used in solid tumors

Class of drug INN Effects on immune system and HBV replication Number of cases of HBV reactivation Type of solid tumor Outcome Risk of HBV reactivation HBV screening Antiviral prophylaxis Grading of evidence 
mTOR inhibitors Everolimus, temsirolimus 
  • Blockage of T- and B-cell proliferation [18]

  • Sirolimus promotes regulatory T cells expansion [19]

  • mTOR inhibition induces HBV replication [20]

 
Everolimus: 4 [2124
  • Renal cell carcinoma: 2

  • Breast cancer: 1

  • Pancreatic neuroendocrine tumor: 1

 
  • Death: 3 (entecavir or tenofovir therapy)

  • Recovery: 1 (tenofovir therapy)

 
Unknown, fatal outcome in 75% of reported cases All patients 
  • HBsAg+ /HBcAc+

  • HBsAg –/HBcAc +

 
Multikinase inhibitors See Table 1 
  • Inhibition of T-cell activation and proliferation [25]

  • Lymphopenia [26]

 
Imatinib:8 [2631
  • Chronic myelogenous leukemia: 6

  • GIST: 1

  • Desmoid tumor: 1

 
  • Death or LT: 3 (lamivudine therapy)

  • Recovery: 5 (entecavir therapy)

 
Unknown, fatal outcome in 38% of reported cases All patients 
  • HBsAg+ /HBcAc+

  • HBsAg –/HBcAc +

 
Anti-VEGF therapy Bevacizumab, aflibercept 
  • Inhibits immune cell trafficking [32]

 
No case reports No case reports No case reports Unknown No No 
Anti-EGFR monoclonal antibodies Panitumumab, cetuximab 
  • Promotes antigen- specific T-cell immunity [33]

 
No case reports No case reports No case reports Unknown No No 
Anti-CTLA-4 therapy Ipilimumab, 
  • Promotes immune response [34]

 
No case reports No case reports No case reports Unknown No No 
Antimetabolites 5-FU, Gem, Cap, Met 
  • Gem: impairs cell-mediated immunity [35, 36]

  • Methotrexate: reduces antibody production; suppresses T cells; inhibits pro- inflammatory cytokine production [37, 38]

 
  • R/5-FU: 6 [39, 40]

  • Gem: 1 [41]

  • Gem/Cis: 1 [42]

  • Gem/Eto: 2 [43]

  • Cap/Iri: 1 [44]

  • Met: at least 7 [4548]

 
  • Gastric adenocarcinoma: 6

  • Pleural carcinoma: 1

  • Pancreatic cancer: 1

  • Lung cancer: 2

  • Colorectal cancer: 1

  • Rheumatoid arthritis: 6

  • Bladder cancer: 1

 
  • R/5-FU:

    • recovery: 6 (lamivudine therapy)

  • Gem:

    • recovery: 4 (lamivudine therapy)

  • Cap:

    • death: 1

  • Met:

    • death: 4

    • recovery: 3

 
  • R/5-FU: 36% of HBsAg + patients

  • Gem, Cap: unknown

  • Met: unknown, fatal outcome in 50% of reported cases; reactivation even in HBsAg - patients

 
  • R/5-FU: all patients

  • Gem, Cap: patients with high risk of HBV infection

  • Met: all patients

 
  • HBsAg+ /HBcAc+

 
  • R/5- FU: A

  • Gem, Cap: C

  • Met: C

 
Alkylating agents Ox, cis, carb, cyclo 
  • Ox: activates immune system; decreases the number of regulatory T cells [49, 50]

  • Cyclo: induces lymphodepletion and B-cell defects; reduces serum antibody levels [51, 52]

 
  • Cis/Gem: 2 [40, 42]

  • 5-FU/Ox: 1 [40]

  • Cyclo: 11 [53]

  • Cyclo/Doxo: 20 [54, 55]

 
  • Pancreatic cancer: 1

  • Rectum cancer: 1

  • Lung cancer: 1

  • Immune-mediated diseases: 11

  • Breast cancer: 20

 
  • Ox, cis, carb:

    • death: 1

    • recovery: 2

  • Cyclo:

    • death: 1

    • recovery: 10

  • Cyclo/Doxo: - recover: 20

 
  • Ox, cis, carb: unknown

  • Cyclo: up to 41% of HBsAg + patients; one case of HBV reactivation despite tenofovir therapy

 
  • Ox, cis, carb: patients with high risk of HBV infection

  • Cyclo: all patients

 
  • HBsAg+ /HBcAc+

 
  • Ox, cis, carb: B

  • Cyclo: A

 
Anthracyclines Dox, Epi 
  • Depletion of T and B cells [56]

  • Directly stimulate HBV replication [57, 58]

 
  • Systemic Doxo: 36% of HBs + patients [59]

  • Doxo-based TACE: 30% of HBs + patients [60]

  • Epi/Doce: 40% of HBs + patients [61]

  • Doxo/Cyclo: 38% of HBs + patients [55]

 
  • Hepatocellular carcinoma: 30–36% of HBs + patients

  • Breast cancer: 38–40% of HBs + patients

 
  • early disruption of chemotherapy: more than 70% of patients

  • death: 2 [62]

 
30–40% of HBsAg + patients; a case of reactivation in HBsAg - patient All patients 
  • HBsAg+ /HBcAc+

  • HBsAg –/HBcAc +

 
Topoisomerase inhibitors Iri, Eto 
  • Etoposide: apoptosis if immune cells; neutropenia and lymphopenia

 
  • Eto/Gem: 2 [43]

  • Iri/Cap: 1 [44]

 
  • Lung cancer: 2

  • Colorectal cancer: 1

 
  • Eto/Gem:

    • recover: 2

  • Iri/Cap:

    • death: 1

 
  • Eto: 2 out of 3 HBsAg + patients in one clinical trial

  • Iri: unknown

 
  • Eto: all patients

  • Iri: patients with high risk of HBV infection

 
  • HBsAg +/HBcAc +

 
  • Eto: C

  • Iri: C

 
Mitotic spindle inhibitors Pacli, Doce, Vino 
  • Pacli: inhibits cytotoxic lymphocyte formation; decreases antibody serum level

 
  • Doce/Epi: 2 [61]

  • Pacli/Carbo/ Gem: 3

  • Vino: no case reports as monotherapy

 
  • Brest cancer: 2

  • Nasopharyngeal carcinoma: 3

 
  • Doce/Epi:

    • recover: 2 (lamivudine therapy)

  • Pacli/Carbo/ Gem:

    • recovery: 3

 
  • Doce/Epi: 2 out of 5 HBsAg + patients in one clinical trial

  • Pacli/Carbo/ Gem: 9% of patients in one clinical trial

  • Vino: associated with HBV reactivation in one prospective study [15]

 
Pacli, Doce, Vino: all patients 
  • HBsAg+ /HBcAc+

 
  • Pacli, Doce: C

  • Vino: A

 
Class of drug INN Effects on immune system and HBV replication Number of cases of HBV reactivation Type of solid tumor Outcome Risk of HBV reactivation HBV screening Antiviral prophylaxis Grading of evidence 
mTOR inhibitors Everolimus, temsirolimus 
  • Blockage of T- and B-cell proliferation [18]

  • Sirolimus promotes regulatory T cells expansion [19]

  • mTOR inhibition induces HBV replication [20]

 
Everolimus: 4 [2124
  • Renal cell carcinoma: 2

  • Breast cancer: 1

  • Pancreatic neuroendocrine tumor: 1

 
  • Death: 3 (entecavir or tenofovir therapy)

  • Recovery: 1 (tenofovir therapy)

 
Unknown, fatal outcome in 75% of reported cases All patients 
  • HBsAg+ /HBcAc+

  • HBsAg –/HBcAc +

 
Multikinase inhibitors See Table 1 
  • Inhibition of T-cell activation and proliferation [25]

  • Lymphopenia [26]

 
Imatinib:8 [2631
  • Chronic myelogenous leukemia: 6

  • GIST: 1

  • Desmoid tumor: 1

 
  • Death or LT: 3 (lamivudine therapy)

  • Recovery: 5 (entecavir therapy)

 
Unknown, fatal outcome in 38% of reported cases All patients 
  • HBsAg+ /HBcAc+

  • HBsAg –/HBcAc +

 
Anti-VEGF therapy Bevacizumab, aflibercept 
  • Inhibits immune cell trafficking [32]

 
No case reports No case reports No case reports Unknown No No 
Anti-EGFR monoclonal antibodies Panitumumab, cetuximab 
  • Promotes antigen- specific T-cell immunity [33]

 
No case reports No case reports No case reports Unknown No No 
Anti-CTLA-4 therapy Ipilimumab, 
  • Promotes immune response [34]

 
No case reports No case reports No case reports Unknown No No 
Antimetabolites 5-FU, Gem, Cap, Met 
  • Gem: impairs cell-mediated immunity [35, 36]

  • Methotrexate: reduces antibody production; suppresses T cells; inhibits pro- inflammatory cytokine production [37, 38]

 
  • R/5-FU: 6 [39, 40]

  • Gem: 1 [41]

  • Gem/Cis: 1 [42]

  • Gem/Eto: 2 [43]

  • Cap/Iri: 1 [44]

  • Met: at least 7 [4548]

 
  • Gastric adenocarcinoma: 6

  • Pleural carcinoma: 1

  • Pancreatic cancer: 1

  • Lung cancer: 2

  • Colorectal cancer: 1

  • Rheumatoid arthritis: 6

  • Bladder cancer: 1

 
  • R/5-FU:

    • recovery: 6 (lamivudine therapy)

  • Gem:

    • recovery: 4 (lamivudine therapy)

  • Cap:

    • death: 1

  • Met:

    • death: 4

    • recovery: 3

 
  • R/5-FU: 36% of HBsAg + patients

  • Gem, Cap: unknown

  • Met: unknown, fatal outcome in 50% of reported cases; reactivation even in HBsAg - patients

 
  • R/5-FU: all patients

  • Gem, Cap: patients with high risk of HBV infection

  • Met: all patients

 
  • HBsAg+ /HBcAc+

 
  • R/5- FU: A

  • Gem, Cap: C

  • Met: C

 
Alkylating agents Ox, cis, carb, cyclo 
  • Ox: activates immune system; decreases the number of regulatory T cells [49, 50]

  • Cyclo: induces lymphodepletion and B-cell defects; reduces serum antibody levels [51, 52]

 
  • Cis/Gem: 2 [40, 42]

  • 5-FU/Ox: 1 [40]

  • Cyclo: 11 [53]

  • Cyclo/Doxo: 20 [54, 55]

 
  • Pancreatic cancer: 1

  • Rectum cancer: 1

  • Lung cancer: 1

  • Immune-mediated diseases: 11

  • Breast cancer: 20

 
  • Ox, cis, carb:

    • death: 1

    • recovery: 2

  • Cyclo:

    • death: 1

    • recovery: 10

  • Cyclo/Doxo: - recover: 20

 
  • Ox, cis, carb: unknown

  • Cyclo: up to 41% of HBsAg + patients; one case of HBV reactivation despite tenofovir therapy

 
  • Ox, cis, carb: patients with high risk of HBV infection

  • Cyclo: all patients

 
  • HBsAg+ /HBcAc+

 
  • Ox, cis, carb: B

  • Cyclo: A

 
Anthracyclines Dox, Epi 
  • Depletion of T and B cells [56]

  • Directly stimulate HBV replication [57, 58]

 
  • Systemic Doxo: 36% of HBs + patients [59]

  • Doxo-based TACE: 30% of HBs + patients [60]

  • Epi/Doce: 40% of HBs + patients [61]

  • Doxo/Cyclo: 38% of HBs + patients [55]

 
  • Hepatocellular carcinoma: 30–36% of HBs + patients

  • Breast cancer: 38–40% of HBs + patients

 
  • early disruption of chemotherapy: more than 70% of patients

  • death: 2 [62]

 
30–40% of HBsAg + patients; a case of reactivation in HBsAg - patient All patients 
  • HBsAg+ /HBcAc+

  • HBsAg –/HBcAc +

 
Topoisomerase inhibitors Iri, Eto 
  • Etoposide: apoptosis if immune cells; neutropenia and lymphopenia

 
  • Eto/Gem: 2 [43]

  • Iri/Cap: 1 [44]

 
  • Lung cancer: 2

  • Colorectal cancer: 1

 
  • Eto/Gem:

    • recover: 2

  • Iri/Cap:

    • death: 1

 
  • Eto: 2 out of 3 HBsAg + patients in one clinical trial

  • Iri: unknown

 
  • Eto: all patients

  • Iri: patients with high risk of HBV infection

 
  • HBsAg +/HBcAc +

 
  • Eto: C

  • Iri: C

 
Mitotic spindle inhibitors Pacli, Doce, Vino 
  • Pacli: inhibits cytotoxic lymphocyte formation; decreases antibody serum level

 
  • Doce/Epi: 2 [61]

  • Pacli/Carbo/ Gem: 3

  • Vino: no case reports as monotherapy

 
  • Brest cancer: 2

  • Nasopharyngeal carcinoma: 3

 
  • Doce/Epi:

    • recover: 2 (lamivudine therapy)

  • Pacli/Carbo/ Gem:

    • recovery: 3

 
  • Doce/Epi: 2 out of 5 HBsAg + patients in one clinical trial

  • Pacli/Carbo/ Gem: 9% of patients in one clinical trial

  • Vino: associated with HBV reactivation in one prospective study [15]

 
Pacli, Doce, Vino: all patients 
  • HBsAg+ /HBcAc+

 
  • Pacli, Doce: C

  • Vino: A

 

INN, International Nonproprietary Name; HBV, hepatitis B virus; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; 5-FU, 5-fluorouracil; Gem, gemcitabine; Cap, capecitabine; Cis, cisplatin; Eto, etoposide; Iri, irinotecan; Ox, oxaliplatin; Carb, carboplatin; Cyclo, cyclophosphamide; Doxo, doxorubicin; Epi, epirubicin; TACE, transarterial chemoembolization; Pacli, paclitaxel; Doce, docetaxel; Vino, vinorelbine; R, radiotherapy; Met, methotrexate; HBsAg, hepatitis B s antigen.

conventional chemotherapy agents

platinum compounds

One case of HBV reactivation was reported in an HBsAg-positive patient under chemotherapy by cisplatin and gemcitabine for pancreatic cancer with liver metastases [63]. Liver function tests normalized upon chemotherapy withdrawal. Apart for one patient with occult HBV infection receiving FOLFOX6 [64], no other case of HBV reactivation has been published involving platinum compounds. This is not surprising, since oxaliplatin may induce activation of the immune system in experimental studies and decrease the number of regulatory T cells in the serum of patients with metastatic colorectal cancer [65]. Moreover, a retrospective study of 4400 patients undergoing chemotherapy revealed HBV reactivation in only two HBsAg-positive patients on platinum compounds-containing regimens (cisplatin/gemcitabine and 5-FU/oxaliplatin) [66].

cyclophosphamide

Cyclophosphamide is well known to induce lymphodepletion [67]. Long-term exposure to cyclophosphamide induces B-cell defects at multiple levels in patients with immune-mediated disease: B-cell activation, proliferation and differentiation; reduction in serum antibody levels [68]. Therefore, HBV reactivation occurring with cyclophosphamide treatment may be the consequence of B-cell depletion. A recent analysis of 138 cases of HBV reactivation during treatment of immune-mediated inflammatory diseases, collected from French physicians and literature review, revealed that cyclophosphamide was involved in 8% of cases (n = 11) [69]. Interestingly, reactivation occurred despite tenofovir pre-emptive therapy in one HBsAg-positive patient who received cyclophosphamide, but the median time from treatment initiation to HBV reactivation was only 8 weeks. In a retrospective study including 85 patients who received doxorubicin and cyclophosphamide adjuvant therapy for early breast cancer, HBV reactivation was reported in 38% of HBsAg-positive patients [70]. A similar rate of HBV reactivation (41%) was observed in 41 HBsAg-positive patients with breast cancer followed up during the course of doxorubicin and cyclophosphamide-based chemotherapy (cyclophosphamide/methotrexate/fluorouracil, doxorubicin/cyclophosphamide) [71]. The high rate of HBV reactivation was probably related to the association of two drugs with a major immunosuppressant effect.

irinotecan

No case report of HBV reactivation has been published in patients on irinotecan-based chemotherapy. Nevertheless, one case of potential HBV reactivation leading to death was observed in a phase II clinical trial (n = 36) evaluating the efficacy and safety of irinotecan plus capecitabine in patients with advanced colorectal cancer [72].

etoposide

Immunosuppression associated with etoposide use is probably related to the induction of neutropenia and lymphopenia. The main mechanism of cytotoxic effect of etoposide may be apoptosis of the immune cells [73]. In a phase II clinical trial (n = 46) evaluating gemcitabine/etoposide combination chemotherapy in the treatment of patients with advanced non-small-cell lung cancer, HBV reactivation has been documented in two out of three HBsAg-positive patients [54].

5-fluorouracil

5-Fluorouracil (5-FU) was not involved in HBV reactivation as single-agent chemotherapy. Nevertheless, a study evaluating hepatic toxicity of adjuvant chemo-radiotherapy including radiotherapy/5-FU for gastric adenocarcinoma reported hepatitis and evidence of HBV reactivation in 4 of the 11 HBsAg-positive patients [59]. Furthermore, 2 cases of HBV reactivation following radiotherapy/5-FU adjuvant treatment for gastric adenocarcinoma were also observed in a retrospective study of 4400 patients undergoing different chemotherapeutic regimen [66]. For capecitabine, one case of potential HBV reactivation leading to death has been observed in one patient using a combination of capecitabine and irinotecan for the management of advanced colorectal cancer [72].

gemcitabine

Gemcitabine has a relatively low myelotoxicity when used as a single agent [74]. However, in vitro studies showed that gemcitabine can impair cell-mediated immunity [75]. A case of HBV reactivation in an HBsAg-positive patient receiving gemcitabine for pleural carcinoma has been published [76]. Liver function tests returned to normal and HBV DNA decreased upon gemcitabine withdrawal. HBV reactivation has also been documented in a patient receiving a combination of cisplatin/gemcitabine for pancreatic cancer [63], and another two patients receiving gemcitabine/oral etoposide therapy for advanced lung cancer [54].

methotrexate

Methotrexate acts as an anti-inflammatory and immunosuppressive drug through different mechanisms such as reduction in antibody production, suppression of activation and adhesion molecules on the T cells, or inhibition of pro-inflammatory cytokine production [77, 78]. HBV reactivation is a well-defined event in HBsAg-positive patients undergoing methotrexate-based therapy [79, 80]. More recently, HBV reactivation has been documented even in HBsAg-negative patients (occult HBV infection) using low doses of methotrexate (10 mg/week) for rheumatoid arthritis [81, 82]. In one patient, a fatal hepatic failure developed, despite antiviral therapy with lamivudine.

taxanes

In vitro studies have shown that exposure of rat lymphocytes to paclitaxel inhibits cytotoxic lymphocyte formation [83]. Serum level of antibodies is also decreased upon paclitaxel administration. In accordance with these observation, a combination of low dose of paclitaxel (0.75–1 mg/kg) and ciclosporine (1 mg/kg) synergistically increases heart transplant survival in rats [83, 84]. Cases of HBV reactivation have been observed in clinical trials when paclitaxel was used in association with other chemotherapy drugs with immunosuppressant potential such as anthracyclines, carboplatin and gemcitabine [85, 86]. It is therefore difficult to ascertain the causality of paclitaxel in those cases, but HBV reactivation triggered by paclitaxel cannot be ruled out.

vinorelbine

No case of HBV reactivation has been reported in patients receiving single-agent vinorelbine. However, a prospective study showed that vinorelbine-containing chemotherapeutic regimens were associated with a higher risk of HBV reactivation in chronic HBsAg carriers [15].

anthracyclines

Doxorubicin induces apoptosis of resting peripheral human lymphocytes in vitro and depletion of mouse T and B cells in vivo [87]. Apart from their immunosuppressant effect, doxorubicine and epirubicin directly stimulate HBV replication in HBV-harboring hepatoblastoma cells in a dose-dependent manner [88, 89]. A prospective study showed an HBV reactivation rate of 36% in HBsAg-positive hepatocellular carcinoma patients undergoing systemic chemotherapy with cisplatin/interferon/doxorubicin/5-FU or doxorubicin alone [90]. HBV reactivation risk was not different between the two chemotherapeutic regimens. Similar rates of HBV reactivation (30%) were also reported during anthracycline-based transarterial chemotherapy for hepatocellular carcinoma and the risk was correlated treatment intensity [18].

In a phase III clinical trial evaluating the efficacy and safety of docetaxel/epirubicin chemotherapy for metastatic breast cancer, HBV reactivation was noticed in two of the five HBsAg-positive patients (40%) [85]. Furthermore, hepatitis attributable to HBV reactivation was reported in three out of eight (38%) retrospectively reviewed HBsAg-positive Chinese patients who received adjuvant chemotherapy with doxorubicin/cyclophosphamide for early breast cancer [70]. The resolution occurred upon chemotherapy discontinuation and treatment with antiviral lamivudine. Thus, HBV reactivation is a common event in HBsAg-positive patients undergoing anthracycline-containing chemotherapeutic regimens. Nevertheless, HBV-reactivation following cyclophosphamide/doxorubicin/5FU chemotherapy for breast cancer has been reported in one occult HBV infection patient (HBsAg-negative) [19].

molecular-targeted therapies and immunotherapy

mammalian target of rapamycin inhibitors

Everolimus and temsirolimus are drugs with anti-proliferative and potent antirejection properties mediated through the inhibition of the mammalian target of rapamycin (mTOR). mTOR inhibitors block T- and B-cell proliferation by inhibiting the response to growth factors [20]. It was also demonstrated that sirolimus (the active metabolite of temsirolimus) preferentially preserves the function of regulatory T cells which contributes to the immunosuppressive effect [21]. Furthermore, mTOR can have a negative feedback regulation of the HBsAg synthesis and mTOR inhibition could induce HBV replication [22].

Three cases of HBV reactivation have recently been reported in patients receiving everolimus. The first two cases were observed in patients with renal cell carcinoma [23, 24], one of which had fatal outcome, despite everolimus discontinuation and treatment with antiviral entecavir [23]. In the third case report, a fatal HBV reactivation occurred in a patient taking everolimus for metastatic breast cancer [25]. Moreover, in a phase III clinical trial evaluating the efficacy of everolimus for advanced pancreatic neuroendocrine tumors, fatal HBV reactivation developed in 1 out of 204 patients treated [26]. No case of HBV reactivation has been documented for temsirolimus.

multikinase inhibitors

At least eight cases of HBV reactivation have been reported in HBsAg-positive patients under imatinib for chronic myelogenous leukemia, GIST and desmoid tumor [2732]. Fulminant liver failure developed in three patients, despite drug withdrawal and initiation of antiviral treatment (lamivudine), leading to living donor liver transplantation (2 patients) [27, 31] or death (1 patient) [30]. The mechanism of imatinib-induced HBV reactivation is unclear. In vitro studies showed that imatinib can inhibit T-cell activation and proliferation [33]. Another possible explanation is that imatinib could induce lymphopenia [30].

monoclonal antibodies and immunotherapy

To date, no case of HBV reactivation was documented with those recent agents.

management of HBV reactivation

HBV screening

The benefit of HBV screening before chemotherapy initiation is scarcely documented in the scientific literature, and some discrepancies exist between recommendations published by different scientific societies. The European Association for the Study of the Liver recommends that all candidates for chemotherapy should be screened for HBsAg and anti-HBc antibody before initiation of treatment [34], whereas the American Association for the Study of Liver Diseases and the American Society of Clinical Oncology guidelines state that screening should be carried out only in patients with high risk of HBV infection [35]. Recent reports from Canada, United States, Australia and China showed that only 14%–19% of patients who receive chemotherapy are tested in clinical practice [3639]. A Canadian study evaluating cost-effectiveness of different HBV screening strategies before rituximab-based chemotherapy for lymphoma showed that universal screening reduces the rate of HBV reactivation by 10-fold and is less costly than screening only high-risk patients or screening no patients [40]. As the prevalence of chronic HBV infection is relatively low in Canada (2%) [41], the favorable cost-effectiveness of universal HBV screening was probably due to a high rate of HBV reactivation with rituximab-based chemotherapy. Oppositely, universal HBV screening was not cost-effective for patients with adjuvant chemotherapy for early breast cancer and palliative chemotherapy for non-small-cell lung cancer [42]. However, screening of high-risk population may be useful before initiation of chemotherapy for solid tumors, especially when a high risk of HBV reactivation is expected. Finally, the most recent meta-analysis of 26 studies [43] reported that reactivation (in chronic HBV, without prophylaxis) ranged from 4% to 68% (median, 25%). Prophylaxis reduced the risk for HBV reactivation [odds ratio (OR): 0.12, 95% confidence interval (CI) 0.06–0.22], HBV-related hepatitis (OR: 0.18, 95% CI 0.10–0.32) and chemotherapy interruption (OR: 0.10, 95% CI 0.04–0.27). The authors conclude that these results support HBV screening and antiviral prophylaxis before initiation of chemotherapy for solid tumors.

prevention of HBV reactivation

Clinical consequences of HBV reactivation may vary as a function of chemotherapy regimen and pre-existing liver injury. In clinical trials, HBV reactivation was associated with premature discontinuation of chemotherapy in more than 70% of patients with breast cancer receiving anthracycline-based chemotherapy [44, 71]. Serial monitoring of HBV DNA showed that reactivation is associated with aminotransferase increase in almost 60% of patients but liver function normalized with chemotherapy discontinuation and lamivudine treatment. However, case reports of HBV reactivation with fatal outcome have been reported during anthracycline-containing regimes (Table 3). Reactivation of HBV has a more unfavorable outcome in patients with hepatocellular carcinoma treated with transarterial or systemic anthracycline-based chemotherapy. Icteric hepatitis is present in half of patients developing HBV reactivation and mortality rate is at least 10%, despite lamivudine treatment [16, 90]. These differences may be explained by the lower hepatic reserve in this group of patients with pre-existing liver injury. Clinical trials evaluating outcome of HBV reactivation are not available for other chemotherapy agents. Nevertheless, a mortality rate of 38% and 75% of the isolated case reports is seen for tyrosine kinase inhibitors and mTOR inhibitors, respectively (Table 3).

The antiviral agent lamivudine has initially been used for the treatment of HBV reactivation in HBsAg-positive cancer patients [45, 46]. Nevertheless, fatal reactivations and disruption in the systemic treatment due to HBV reactivation occurred [15, 47]. Patients developing chemotherapy-induced HBV reactivation may have a mortality rate as high as 11%, despite lamivudine treatment. Therefore, prophylactic use of lamivudine in HBsAg-positive patients undergoing systemic treatment for solid tumors seems to be a more attractive strategy at least for chemotherapy regimens involved in HBV reactivation (Table 3). Indeed, a randomized controlled study showed that pre-emptive lamivudine use (initiated from the start of chemotherapy and continued for 1 year after the completion of chemotherapy) in patients receiving transarterial chemotherapy (epirubicin/cisplatin) for hepatocellular carcinoma reduces the rate of HBV reactivation (40.5% in the control group versus 2.8% in the pre-emptive group) [48]. Similarly, the efficacy of lamivudine to prevent HBV reactivation in HBsAg-positive breast cancer patients who undergo anthracycline-based chemotherapy was proven in one prospective randomized controlled study [49], one retrospective study [50] and two historic controlled studies [51, 52]. In another two studies, a lower rate of chemotherapy disruption was seen in pre-emptive lamivudine group [50, 52]. The lamivudine was initiated 1 week before the start of chemotherapy, and was continued for 8 weeks after discontinuation of chemotherapy. Lamivudine and adefovir have substantial resistance rates that increase over time and are not generally recommended for long-term therapy [34, 53]. The resistance may develop in up to 32% of lamivudine-treated patients after 1 year treatment [55]. Newer HBV antiviral drugs, such as entecavir and tenofovir, are able to suppress the replication of both lamivudine-resistant and wild-type HBV. Entecavir prophylaxis reduces the risk of HBV reactivation in patients with resolved HBV infection undergoing rituximab-based chemotherapy [56]. Furthermore, entecavir is more effective than lamivudine in preventing HBV reactivation in lymphoma patients during chemotherapy [57]. There are no studies evaluating tenofovir efficacy to prevent HBV reactivation during chemotherapy. Nevertheless, tenofovir is safe and more effective than adefovir to achieve complete HBV DNA suppression in patients with chronic hepatitis B [58]. Furthermore, a recent study showed that tenofovir did not induce resistance after 6 years of treatment [60]. Therefore, entecavir and tenofovir represent attractive therapeutic options for the prophylaxis of HBV reactivation in patients receiving systemic anticancer treatments (Table 4).

Table 4

Pre-emptive antiviral therapy for hepatitis B virus reactivation

Antiviral drug Commercial name Dose Duration of treatment Recommendation for use Comments References Grading of evidences 
Lamivudine Zeffix®, Epivir® 100 mg/day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Short duration chemotherapy

  • Viremia <2000 IU/ml

  • Inactive HBV infection

  • Antiviral naive

 
  • Reduces HBV reactivation risk

  • Prevents premature termination of chemotherapy

  • High rate of resistance

  • Therapeutic use do not change the outcome of HBV reactivation

 
  • Meta-analysis: 1 [96]

  • RCS: 2 [77, 78]

  • NRCS: 5 [80, 81, 97–99]

  • RS: 2 [79, 100]

  • LS: 2 [80, 101]

 
Adefovir Hepsera® 10 mg/day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Lamivudine resistance

  • Viremia <2000 IU/ml

  • Inactive HBV infection

 
Higher rate of resistance than entecavir and tenofovir No clinical studies for chemotherapy-related HBV reactivation 
Entecavir Baraclude® 0.5 mg/ day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Long duration chemotherapy

  • Viremia >2000 IU/ml

  • Active HBV infection

  • Lamivudine naïve

 
  • Strong antiviral effect

  • Low resistance rate

  • More effective than lamivudine in preventing HBV reactivation

 
RCS: 2 [84, 86
Tenofovir Viread® 245 mg/day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Long duration chemotherapy

  • Viremia >2000 IU/ml

  • Active HBV infection

  • Resistance to other antivirals

 
  • Strong antiviral effect

  • No resistance described

  • Improves outcome in patients with spontaneous HBV reactivation

 
No clinical studies for chemotherapy-related HBV reactivation 
Antiviral drug Commercial name Dose Duration of treatment Recommendation for use Comments References Grading of evidences 
Lamivudine Zeffix®, Epivir® 100 mg/day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Short duration chemotherapy

  • Viremia <2000 IU/ml

  • Inactive HBV infection

  • Antiviral naive

 
  • Reduces HBV reactivation risk

  • Prevents premature termination of chemotherapy

  • High rate of resistance

  • Therapeutic use do not change the outcome of HBV reactivation

 
  • Meta-analysis: 1 [96]

  • RCS: 2 [77, 78]

  • NRCS: 5 [80, 81, 97–99]

  • RS: 2 [79, 100]

  • LS: 2 [80, 101]

 
Adefovir Hepsera® 10 mg/day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Lamivudine resistance

  • Viremia <2000 IU/ml

  • Inactive HBV infection

 
Higher rate of resistance than entecavir and tenofovir No clinical studies for chemotherapy-related HBV reactivation 
Entecavir Baraclude® 0.5 mg/ day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Long duration chemotherapy

  • Viremia >2000 IU/ml

  • Active HBV infection

  • Lamivudine naïve

 
  • Strong antiviral effect

  • Low resistance rate

  • More effective than lamivudine in preventing HBV reactivation

 
RCS: 2 [84, 86
Tenofovir Viread® 245 mg/day 1 week before chemotherapy initiation–12 months after cessation of chemotherapy 
  • Long duration chemotherapy

  • Viremia >2000 IU/ml

  • Active HBV infection

  • Resistance to other antivirals

 
  • Strong antiviral effect

  • No resistance described

  • Improves outcome in patients with spontaneous HBV reactivation

 
No clinical studies for chemotherapy-related HBV reactivation 

HBV, hepatitis B virus; RCS, randomized controlled study; NRCS, non-randomized controlled study; RS, retrospective study; LS, longitudinal study.

To date, there are no sufficient evidences to recommend prophylactic HBV antiviral treatment before chemotherapy in patients with occult HBV infection. Nevertheless, pre-emptive HBV antivirals may be justified when chemotherapy regimens with high HBV reactivation risk (antracyclines or mTOR inhibitors) are used, or in HBsAg-negative/HBV DNA-positive patients.

treatment of HBV reactivation

Studies evaluating prophylactic versus therapeutic HBV antiviral drugs showed that the use of antiviral therapy once HBV reactivation has occurred is less effective in preventing liver failure and chemotherapy discontinuation [47, 61]. Clinical and biological signs of severe liver failure including encephalopathy, prolonged prothrombin time and jaundice may develop. Theoretically, liver transplantation should be considered, but the benefits must be weighed against the prognosis of underlying cancer. Huang et al. [62] identified the superiority of entecavir versus lamivudine in lymphoma population receiving chemotherapy treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, studies are needed to ascertain that a second-generation nucleus(t)ide analog, entecavir or tenofovir, is superior to a less expensive drug like lamivudine, and this probably depends on the baseline HBV DNA load.

conclusions

The issue of HBV reactivation in patients undergoing systemic treatment for solid tumors has been under-estimated in the medical literature. Nevertheless, the available data show that a number of routinely used anticancer agents can induce HBV reactivation in HBsAg-positive patients. The drugs for which the frequency of HBV reactivation appears to be highest are anthracyclines, vinca-alkaloids, methotrexate, cyclophosphamide, etoposide and everolimus. Life-threatening or severe hepatitis related to HBV reactivation have been reported. Chemotherapy withdrawal is sometimes required, which may affect the prognosis of cancer.

The evidence from existing studies suggests universal HBV screening before chemotherapy for solid tumors. Once HBsAg detected, prophylactic lamivudine administration may reduce the risk of HBV reactivation and prevent chemotherapy disruption. Finally, further prospective studies are required in order to strengthen the current recommendations.

funding

None declared.

disclosure

OM has acted as consultant for Amgen, Astra-Zeneca, Bayer, BMS, Lilly, Novartis, Pfizer, Roche and Servier. RC has acted as consultant for Amgen, Merck, Novartis, Roche and Sanofi-Aventis. SP has acted as consultant for: sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Vertex, Gilead Sciences, Roche, MSD, Novartis, Abbvie, Glaxo Smith Kline. PL has acted as consultant for Pfizer. All remaining authors have declared no conflicts of interest.

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