- Email: [email protected]
Passive transfer of anti-HBc after intravenous immunoglobulin administration in patients with cancer: a retrospective chart review
Articles
Passive transfer of anti-HBc after intravenous immunoglobulin administration in patients with cancer: a retrospective chart review Huifang Lu, Anna S Lok, Carla L Warneke, Sairah Ahmed, Harrys A Torres, Fernando Martinez, Maria E Suarez-Almazor, Jessica T Foreman, Alessandra Ferrajoli, Jessica P Hwang
Summary
Background Patients previously infected with hepatitis B virus (HBV; indicated by positivity for anti-HBc) can experience HBV reactivation during cancer chemotherapy. Intravenous immunoglobulin infusion, which is frequently used in supportive care, might facilitate passive transfer of anti-HBc. We aimed to estimate the probability of passive transfer of anti-HBc after intravenous immunoglobulin infusion in patients with cancer. Methods We reviewed institutional databases to identify adult patients who received outpatient chemotherapy between Jan 1, 2004, and Dec 31, 2011, at the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Eligible patients had received intravenous immunoglobulin therapy, had tested negative for both anti-HBc and HBsAg before infusion, and had been tested for anti-HBc after infusion. The primary endpoint was the proportion of patients who became positive for anti-HBc after intravenous immunoglobulin infusion. Findings 950 of 18 874 patients who underwent chemotherapy within the study time frame received intravenous immunoglobulin, of whom 870 had been tested for anti-HBc before infusion. 199 patients who were negative for antiHBc before receiving intravenous immunoglobulin were retested after infusion, of whom 29 (15% [95% CI 10–20]) became positive for anti-HBc. The probability of anti-HBc conversion at 1 week after intravenous immunoglobulin infusion was 34% (95% CI 22–48) and at 12 weeks was 4% (2–7). Interpretation Conversion of patients from anti-HBc negativity to anti-HBc positivity was common after intravenous immunoglobulin administration. However, the probability of a positive test decreased with time since infusion. Positive anti-HBc tests done shortly after intravenous immunoglobulin infusion should be interpreted with caution because they might indicate passive transfer instead of true infection. Funding None. Copyright © 2018 Elsevier Ltd. All rights reserved.
Introduction Intravenous immunoglobulin therapy is used for antibody deficiencies in patients with haematological malignancies, autoimmune conditions, neurological disorders, or infectious diseases.1–5 It results in the passive transfer of antibodies, which might include antiHBc.6–8 Patients with cancer anticipated to undergo therapies associated with a high risk of reactivation of hepatitis B virus (HBV), such as anti-CD20 monoclonal antibody therapy (eg, rituximab) or stem cell transplantation,9 are routinely screened for HBV with tests for HBsAg and anti-HBc, with negativity for HBsAg and positivity for anti-HBc indicating a past HBV infection and positivity for both HBsAg and anti-HBc indicating a chronic HBV infection. National oncology and hepatology associations9,10 recommend that patients with haematological malignancies who are negative for HBsAg but positive for anti-HBc receive anti-HBV prophylaxis before starting chemotherapies associated with a high risk of HBV reactivation. A positive test result for anti-HBc due to passive transfer of anti-HBc, www.thelancet.com/haematology Vol 5 October 2018
rather than a chronic or past HBV infection, is a falsepositive result and could lead to inappropriate use of anti-HBV prophylaxis.7,11 We aimed to estimate the falsepositive rate of anti-HBc testing and timing of anti-HBc passive transfer in patients with cancer receiving intravenous immunoglobulin therapy.
Lancet Haematol 2018; 5: e474–78 See Comment page e437 Department of General Internal Medicine (Prof H Lu MD, Prof M E Suarez-Almazor MD, J T Foreman BA, Prof J P Hwang MD), Department of Biostatistics (C L Warneke MS), Department of Stem Cell Transplantation (S Ahmed MD), Department of Infectious Diseases, Infection Control and Employee Health (H A Torres MD), Department of Laboratory Medicine (F Martinez MD), and Department of Leukemia (Prof A Ferrajoli MD), University of Texas MD Anderson Cancer Center, Houston, TX, USA; and Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA (Prof A S Lok MD) Correspondence to: Prof Jessica P Hwang, Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [email protected]
Methods
Study design and participants We performed a retrospective chart review of institutional databases to identify adult patients who received out patient chemotherapy for cancer between Jan 1, 2004, and Dec 31, 2011, at the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Study patients had received intravenous immunoglobulin therapy, tested negative for both anti-HBc and HBsAg before intravenous immunoglobulin infusion, and been tested for anti-HBc after infusion. We reviewed patient records for demo- graphic and clinical variables. This study was approved by the institutional review board at the University of Texas MD Anderson Cancer Center. e474
Articles
Research in context Evidence before this study We searched Ovid MEDLINE, PubMed, and Embase without language restrictions up to June 14, 2018, using Medical Subject Headings terms and keywords related to hepatitis B and intravenous immunoglobulin. Cited reference searching was completed in Scopus for highly relevant studies. Studies have shown that patients with cancer who receive intravenous immunoglobulin during anticancer or supportive care are at risk of passive transfer of antibodies, potentially including anti-HBc. These patients might also be at risk of reactivation of hepatitis B virus (HBV) due to highly immunosuppressive therapies such anti-CD20 antibodies and stem cell transplantation. The rate of, and risk factors for, passive transfer among patients with cancer receiving intravenous immunoglobulin is unknown. Added value of this study This retrospective study represents one of the largest cohorts of patients with cancer, developed over a 7 year study period, who have received anticancer and intravenous immunoglobulin therapies. We found that 29 (15% [95% CI 10–20]) of
18 874 patients with cancer receiving chemotherapy within study time frame
17 924 did not receive intravenous immunoglobulin
199 patients with cancer who tested negative for anti-HBc before intravenous immunoglobulin infusion were positive for anti-HBc after infusion. Conversion was highest in the first week after infusion (49%, 17/35), decreasing rapidly after 1 month. Implications of all the available evidence Patients with cancer who receive intravenous immunoglobulin might be at risk of passive transfer of anti-HBc. Our study supports testing for anti-HBc before intravenous immunoglobulin infusion in these patients to avoid falsepositive results due to passive transfer. Additionally, patients who are anticipated to receive anticancer therapy should be tested for HBsAg and anti-HBc before starting intravenous immunoglobulin therapy to identify their HBV infection status and clarify their risk of HBV reactivation. In patients known to have hypogammaglobulinaemia and previous HBV infection, anti-HBc tests might be falsely negative, and testing for HBV DNA might be considered as an alternative; however, HBV DNA would be undetectable in the serum of most patients with a past HBV infection.
immunoglobulin infusion, obtained from patient records. We also obtained information about subsequent HBV DNA testing and results and hepatitis flare (alanine aminotransferase concentration ≥100 U/L and more than three times that at baseline) after anticancer therapy.
Statistical analysis 950 received intravenous immunoglobulin
80 not tested for anti-HBc before first intravenous immunoglobulin
870 tested for anti-HBc before first intravenous immunoglobulin
52 positive for anti-HBc test before first intravenous immunoglobulin
818 negative for anti-HBc before first intravenous immunoglobulin
619 not tested for anti-HBc after intravenous immunoglobulin
199 tested for anti-HBc after intravenous immunoglobulin (study sample)
Figure 1: Diagram of study sample selection
Outcomes The primary endpoint was the proportion of patients who became positive for anti-HBc after intravenous e475
The proportion of patients who became positive for anti-HBc after intravenous immunoglobulin administration was reported with an exact binomial confidence interval. We used Fisher’s exact tests and Wilcoxon rank-sum tests to examine associations between anti-HBc passive transfer and demographic and clinical variables, including age at baseline anti-HBc test (defined as the most recent test before initiation of intravenous immunoglobulin therapy), sex, race or ethnicity, cancer type, receipt of rituximab or stem cell transplantation before intravenous immunoglobulin therapy, occurrence of hepatitis flare after chemotherapy, year of first intravenous immunoglobulin infusion, and time between intravenous immunoglobulin infusion and subsequent anti-HBc testing. Some patients had multiple infusions and anti-HBc tests, resulting in multiple observations per individual. To account for within-patient correlations, we used generalised estimating equations to fit a repeatedmeasures logistic regression model (PROC GENMOD) with a binomial distribution and logit link function to calculate the odds of a positive test based on the logtransformed number of days between intravenous immunoglobulin infusion and anti-HBc testing. We used the quasi-likelihood under the independence model criterion to choose the best correlation structure and found that an independent working correlation structure www.thelancet.com/haematology Vol 5 October 2018
Articles
best fit the data.12 The repeated-measures multiple logistic regression analysis considered age, ethnicity or race, sex, time since intranvenous immunoglobulin infusion, cancer type, rituximab therapy, and stem cell transplan tation as potential independent variables. A backward stepwise selection process was used to identify significant variables in the multivariable setting. All statistical tests were two-sided with an α value of 0·05. We did a sensitivity analysis, in which modelling was repeated with exclusion of participants whose baseline test was done more than 3 months before their first intravenous immunoglobulin infusion. Analyses were done with SAS for Windows, version 9.4.
Role of the funding source The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results 950 of 18 874 patients who underwent chemotherapy between Jan 1, 2004, and Dec 31, 2011, at the University of Texas MD Anderson Cancer Center received intravenous immunoglobulin therapy (figure 1). 870 patients had anti-HBc testing before intravenous immunoglobulin administration, of whom 52 had a reactive test and 818 had a non-reactive test. 619 patients with non-reactive baseline tests did not have a record of an anti-HBc test after receiving intravenous immunoglobulin therapy. The remaining 199 patients were negative for anti-HBc and HBsAg before infusion and were tested for anti-HBc after infusion; these patients constituted the study sample. The median time between baseline testing for antiHBc and intravenous immunoglobulin infusion in the study sample was 26 days (range 1–1739). Results of HBsAg tests done after intravenous immunoglobulin infusion were available for all but two patients in the study sample, and all test results were negative. Baseline characteristics of the entire study sample and conversion to anti-HBc status are summarised in the table. No patient received anti-HBV prophylaxis or treatment. Patients received a median of four (range 1–53) doses of intravenous immunoglobulin between baseline and the first reactive anti-HBc test or the last test for those who remained negative for anti-HBc after infusion. 29 (15% [95% CI 10–20%]) of 199 patients tested positive for anti-HBc after intravenous immunoglobulin infusion. The median time between infusion and testing was 6 days (range 1–60), with one patient retested on day 366. 17 (59%) of 29 patients were tested for HBV DNA after testing positive for anti-HBc, and all had undetectable HBV DNA. All 29 patients were tested for HBsAg after testing positive for anti-HBc, and all tests were negative. 18 (62% [95% CI 44–80]) of the 29 patients www.thelancet.com/haematology Vol 5 October 2018
Age at baseline anti-HBc test (years)
Conversion (n=29) No conversion (n=170) Total (n=199)
p value*
52 (20–73)
0·99
Race or ethnicity White
··
51 (20–79)
51 (20–79)
··
··
0·90
19 (66%)
111 (65%)
130 (65%)
··
Hispanic
6 (21%)
32 (19%)
38 (19%)
··
Black
4 (14%)
18 (11%)
22 (11%)
··
Asian
0
3 (2%)
3 (2%)
··
Other
0
6 (4%)
6 (3%)
Sex Female Male Cancer type Solid tumour (not HCC) Haematological malignancy Rituximab
··
··
··
9 (31%)
65 (38%)
74 (37%)
20 (69%)
105 (62%)
125 (63%)
··
··
··
·· ·· 1·00
1 (3%)
10 (6%)
11 (6%)
··
28 (97%)
160 (94%)
188 (94%)
··
··
··
··
No
15 (52%)
101 (59%)
116 (58%)
Yes
14 (48%)
69 (41%)
83 (42%)
Stem cell transplantation
·· 0·54
··
··
··
0·54 ·· ·· 0·77
Allogeneic
16 (55%)
95 (56%)
111 (56%)
··
Autologous
5 (17%)
37 (22%)
42 (21%)
··
None
8 (28%)
38 (22%)
46 (23%)
··
HCC=hepatocellular carcinoma. *p values are from Fisher’s exact test, with the exception of the test for the association between anti-HBc status and age, which was from a Wilcoxon rank-sum test.
Table: Baseline demographic and clinical characteristics of patients with and without conversion from anti-HBc negativity to anti-HBc positivity
who tested positive for anti-HBc after intravenous immunoglobulin infusion had hepatitis flare after chemotherapy compared with 115 (68% [61–75]) of 170 patients who tested negative (p=0·67). Ten (34%) of 29 patients were nonreactive on a subsequent anti-HBc test; 19 (66%) were not retested for anti-HBc. Year of first intravenous immunoglobulin admin istration ranged from 2004 to 2011; the median year was 2009 for patients with passive transfer and 2008 for those without. No significant associations were observed between passive transfer and age, race or ethnicity, sex, cancer type, rituximab use, or stem cell transplantation (table). All 361 available anti-HBc tests that were done after the first intravenous immunoglobulin admin istration were included in the repeated-measures analysis. Patients had a median of one (range 1–9) anti-HBc test after intravenous immunoglobulin infusion. 34 (9%) of 361 tests were reactive and 327 (91%) were nonreactive. 30 (88%) of the 34 reactive tests versus 39 (12%) of the 327 nonreactive tests were done within 4 weeks of intravenous immunoglobulin administration. During the first week after intravenous immunoglobulin admin istration, 35 patients were tested for anti-HBc, of whom 17 (49%) tested positive (one patient was tested twice and found to be positive both times). In multivariable analyses, the removal of variables that were not significantly associated with anti-HBc positivity e476
Articles
0·90 0·85 0·80 0·75 0·70 0·65
Probability
0·60 0·55 0·50 0·45 0·40 0·35 0·30 0·25 0·20 0·15 0·10 0·05 0
0
28
56
84
112
140
168
196
224
252
280
308
336
364
392
Time (days)
Figure 2: Probability of anti-HBc positivity according to time between intravenous immunoglobulin infusion and anti-HBc testing The red dotted lines are 95% CIs.
See Online for appendix
produced a reduced model that included only time between intravenous immunoglobulin infusion and antiHBc testing as significantly associated with anti-HBc positivity (odds ratio 0·38, 95% CI 0·29–0·50; appendix p 1). The probability of conversion to anti-HBc positivity decreased with increasing time between intravenous immunoglobulin administration and antiHBc testing (appendix p 2). The probability of a positive test result was 34% (95% CI 22–48) at 1 week after infusion, which decreased to 12% (7–18) at 4 weeks and 4% (2–7) at 12 weeks (figure 2). Results of the multivariable analyses were similar in a sensitivity analysis that excluded records for 63 patients whose baseline tests had been done more than 3 months before their first intravenous immunoglobulin infusion.
Discussion We found that conversion from an anti-HBc-negative status to an anti-HBc-positive status was common (we observed an overall conversion rate of 15% [29/199]) after intravenous immunoglobulin infusion among patients with cancer. We also found that the probability of anti-HBc positivity was higher for tests done within the first week than for tests done at 3 months after infusion. These findings, together with the observed loss of anti-HBc over time in patients who tested positive for anti-HBc after infusion, and the absence of conversion to HBsAg and HBV DNA positivity in the small subset of patients assessed for HBV infection, support our hypothesis that conversion to anti-HBc positivity after intravenous immunoglobulin administration is a result of passive transfer. A previous cross-sectional study6 reported a higher prevalence (46%, 37/80) of anti-HBc positivity after e477
intravenous immunoglobulin administration, which was probably related to frequent administrations of intra venous immunoglobulin (monthly for at least 6 months) and anti-HBc testing performed shortly after the last dose of intravenous immunoglobulin in that study. We did not detect differences in the number of anti-HBc tests or cumulative doses of intravenous immunoglobulin received between those who did and those who did not have anti-HBc positivity after intravenous immuno globulin infusion. Our results have several clinical implications. First, antiHBc testing should be done before starting intravenous immunoglobulin therapy in patients with cancer to ascertain whether subsequent positive results were caused by passive transfer. Second, given that the expected halflife of intravenous immunoglobulin is about 3–4 weeks,8 if anti-HBc testing is done soon after intravenous immunoglobulin infusion and the results are positive, we recommend retesting patients with an unknown HBV infection status at baseline at least 3–4 months after infusion to establish whether the result is secondary to passive transfer. If immediate clarification is needed, such as in a patient requiring immediate initiation of anticancer therapy or experiencing liver enzyme elevation, additional testing for HBsAg and HBV DNA and referral to hepatitis specialists should be considered. Given that anti-HBs in intravenous immunoglobulin might neutralise HBsAg, making testing for HBsAg less reliable, HBV DNA testing for confirmation of acute HBV infection in patients previously negative for anti-HBc who become positive for anti-HBc after intravenous immunoglobulin therapy is warranted. This study has limitations that primarily relate to the retrospective study design and the absence of a standardised protocol for anti-HBc testing in patients receiving intravenous immunoglobulin therapy as supportive care. We included patients who underwent baseline anti-HBc testing at varying times, some long before intravenous immunoglobulin administration; however, our results did not change when including in the analysis only patients who had baseline anti-HBc testing within months before receiving their first intravenous immunoglobulin infusion. The observed proportion (15%) of patients who converted to anti-HBc positivity in our study is probably an underestimate because few patients were retested for anti-HBc after intravenous immunoglobulin infusion and, in those that were, there was disparity in the time between intravenous immunoglobulin infusion and retesting. In the absence of a standardised protocol, anti-HBc retesting after intravenous immunoglobulin infusion was based on provider discretion, potentially introducing a source of bias that could increase the estimated conversion rate if patients who were retested had a greater conversion risk than did those who were not retested. Another limitation is that not all patients who became anti-HBc positive were tested for HBV DNA or liver enzymes to rule out www.thelancet.com/haematology Vol 5 October 2018
Articles
the possibility of an actual infection. Finally, our institution does not routinely test for anti-HBc in intravenous immunoglobulin products; thus, we cannot verify that the source of anti-HBc was the infused intravenous immunoglobulin. In conclusion, our results suggest that passive transfer of anti-HBc is common after intravenous immuno globulin infusion. This finding has important impli cations for patients with cancer who are receiving intravenous immunoglobulin therapy and might require immunosuppressive therapy. Therefore, anti-HBc testing should be considered before each intravenous immuno- globulin infusion in such patients. Contributors JPH and HL designed the study. JPH oversaw data collection, JTF collected data, and CLW performed the statistical analysis. JPH, HL, ASL, and CLW wrote the manuscript. All authors contributed to data interpretation and reviewed, edited, and approved the manuscript. Declaration of interests JPH reports grants from Gilead and Merck. ASL reports grants from Bristol-Myers Squibb and Gilead. MES-A is an advisory board member for Pfizer, Endo Pharmaceuticals, Bristol-Myers Squibb, and Eli Lilly. HAT reports grants from Gilead and Merck. All other authors declare no competing interests. Acknowledgments JPH was a recipient of a K07 career award from the National Cancer Institute (K07CA132955) and MES-A of a K24 career award from the National Institute for Musculoskeletal and Skin Disorders (K24 AR053593). This study was supported by the National Cancer Institute under award number P30CA016672, which supports the MD Anderson Cancer Center Clinical Trials Support Resource. We thank the following individuals at the University of Texas MD Anderson Cancer Center: Andrea Barbo for data collection, Laurissa Gann for literature review, and Stephanie Deming for editing. An abstract of this study was presented at the annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, on Oct 23, 2017.
www.thelancet.com/haematology Vol 5 October 2018
References 1 Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation. Cochrane Database Syst Rev 2008; 4: CD006501. 2 Ueda M, Berger M, Gale RP, Lazarus HM. Immunoglobulin therapy in hematologic neoplasms and after hematopoietic cell transplantation. Blood Rev 2018; 32: 106–15. 3 Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2012; 78: 1009–15. 4 Shehata N, Palda V, Bowen T, et al. The use of immunoglobulin therapy for patients with primary immune deficiency: an evidence-based practice guideline. Transfus Med Rev 2010; 24 (suppl 1): S28–50. 5 Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol 2003; 139: 1051–59. 6 Ramsay I, Gorton RL, Patel M, et al. Transmission of hepatitis B core antibody and galactomannan enzyme immunoassay positivity via immunoglobulin products: a comprehensive analysis. Clin Infect Dis 2016; 63: 57–63. 7 Benwell N, Boan P, Raby E, McGettigan B. False positive hepatitis B virus core and surface antibodies due to intravenous immunoglobulin. Intern Med J 2017; 47: 119–20. 8 Thibault V, Pinte L, Vergez J, Leger JM, Liou A. Too often forgotten: passive transfer of antibodies. Clin Infect Dis 2016; 63: 709–10. 9 Hwang JP, Somerfield MR, Alston-Johnson DE, et al. Hepatitis B virus screening for patients with cancer before therapy: American Society of Clinical Oncology provisional clinical opinion update. J Clin Oncol 2015; 33: 2212–20. 10 Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018; 67: 1560–99. 11 Arnold DM, Crowther MA, Meyer RM, et al. Misleading hepatitis B test results due to intravenous immunoglobulin administration: implications for a clinical trial of rituximab in immune thrombocytopenia. Transfusion 2010; 50: 2577–81. 12 Pan W. Akaike’s information criterion in generalized estimating equations. Biometrics 2001; 57: 120–25.
e478
Passive transfer of anti-HBc after intravenous immunoglobulin administration in patients with cancer: a retrospective chart review Huifang Lu, Anna S Lok, Carla L Warneke, Sairah Ahmed, Harrys A Torres, Fernando Martinez, Maria E Suarez-Almazor, Jessica T Foreman, Alessandra Ferrajoli, Jessica P Hwang
Summary
Background Patients previously infected with hepatitis B virus (HBV; indicated by positivity for anti-HBc) can experience HBV reactivation during cancer chemotherapy. Intravenous immunoglobulin infusion, which is frequently used in supportive care, might facilitate passive transfer of anti-HBc. We aimed to estimate the probability of passive transfer of anti-HBc after intravenous immunoglobulin infusion in patients with cancer. Methods We reviewed institutional databases to identify adult patients who received outpatient chemotherapy between Jan 1, 2004, and Dec 31, 2011, at the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Eligible patients had received intravenous immunoglobulin therapy, had tested negative for both anti-HBc and HBsAg before infusion, and had been tested for anti-HBc after infusion. The primary endpoint was the proportion of patients who became positive for anti-HBc after intravenous immunoglobulin infusion. Findings 950 of 18 874 patients who underwent chemotherapy within the study time frame received intravenous immunoglobulin, of whom 870 had been tested for anti-HBc before infusion. 199 patients who were negative for antiHBc before receiving intravenous immunoglobulin were retested after infusion, of whom 29 (15% [95% CI 10–20]) became positive for anti-HBc. The probability of anti-HBc conversion at 1 week after intravenous immunoglobulin infusion was 34% (95% CI 22–48) and at 12 weeks was 4% (2–7). Interpretation Conversion of patients from anti-HBc negativity to anti-HBc positivity was common after intravenous immunoglobulin administration. However, the probability of a positive test decreased with time since infusion. Positive anti-HBc tests done shortly after intravenous immunoglobulin infusion should be interpreted with caution because they might indicate passive transfer instead of true infection. Funding None. Copyright © 2018 Elsevier Ltd. All rights reserved.
Introduction Intravenous immunoglobulin therapy is used for antibody deficiencies in patients with haematological malignancies, autoimmune conditions, neurological disorders, or infectious diseases.1–5 It results in the passive transfer of antibodies, which might include antiHBc.6–8 Patients with cancer anticipated to undergo therapies associated with a high risk of reactivation of hepatitis B virus (HBV), such as anti-CD20 monoclonal antibody therapy (eg, rituximab) or stem cell transplantation,9 are routinely screened for HBV with tests for HBsAg and anti-HBc, with negativity for HBsAg and positivity for anti-HBc indicating a past HBV infection and positivity for both HBsAg and anti-HBc indicating a chronic HBV infection. National oncology and hepatology associations9,10 recommend that patients with haematological malignancies who are negative for HBsAg but positive for anti-HBc receive anti-HBV prophylaxis before starting chemotherapies associated with a high risk of HBV reactivation. A positive test result for anti-HBc due to passive transfer of anti-HBc, www.thelancet.com/haematology Vol 5 October 2018
rather than a chronic or past HBV infection, is a falsepositive result and could lead to inappropriate use of anti-HBV prophylaxis.7,11 We aimed to estimate the falsepositive rate of anti-HBc testing and timing of anti-HBc passive transfer in patients with cancer receiving intravenous immunoglobulin therapy.
Lancet Haematol 2018; 5: e474–78 See Comment page e437 Department of General Internal Medicine (Prof H Lu MD, Prof M E Suarez-Almazor MD, J T Foreman BA, Prof J P Hwang MD), Department of Biostatistics (C L Warneke MS), Department of Stem Cell Transplantation (S Ahmed MD), Department of Infectious Diseases, Infection Control and Employee Health (H A Torres MD), Department of Laboratory Medicine (F Martinez MD), and Department of Leukemia (Prof A Ferrajoli MD), University of Texas MD Anderson Cancer Center, Houston, TX, USA; and Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA (Prof A S Lok MD) Correspondence to: Prof Jessica P Hwang, Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA [email protected]
Methods
Study design and participants We performed a retrospective chart review of institutional databases to identify adult patients who received out patient chemotherapy for cancer between Jan 1, 2004, and Dec 31, 2011, at the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Study patients had received intravenous immunoglobulin therapy, tested negative for both anti-HBc and HBsAg before intravenous immunoglobulin infusion, and been tested for anti-HBc after infusion. We reviewed patient records for demo- graphic and clinical variables. This study was approved by the institutional review board at the University of Texas MD Anderson Cancer Center. e474
Articles
Research in context Evidence before this study We searched Ovid MEDLINE, PubMed, and Embase without language restrictions up to June 14, 2018, using Medical Subject Headings terms and keywords related to hepatitis B and intravenous immunoglobulin. Cited reference searching was completed in Scopus for highly relevant studies. Studies have shown that patients with cancer who receive intravenous immunoglobulin during anticancer or supportive care are at risk of passive transfer of antibodies, potentially including anti-HBc. These patients might also be at risk of reactivation of hepatitis B virus (HBV) due to highly immunosuppressive therapies such anti-CD20 antibodies and stem cell transplantation. The rate of, and risk factors for, passive transfer among patients with cancer receiving intravenous immunoglobulin is unknown. Added value of this study This retrospective study represents one of the largest cohorts of patients with cancer, developed over a 7 year study period, who have received anticancer and intravenous immunoglobulin therapies. We found that 29 (15% [95% CI 10–20]) of
18 874 patients with cancer receiving chemotherapy within study time frame
17 924 did not receive intravenous immunoglobulin
199 patients with cancer who tested negative for anti-HBc before intravenous immunoglobulin infusion were positive for anti-HBc after infusion. Conversion was highest in the first week after infusion (49%, 17/35), decreasing rapidly after 1 month. Implications of all the available evidence Patients with cancer who receive intravenous immunoglobulin might be at risk of passive transfer of anti-HBc. Our study supports testing for anti-HBc before intravenous immunoglobulin infusion in these patients to avoid falsepositive results due to passive transfer. Additionally, patients who are anticipated to receive anticancer therapy should be tested for HBsAg and anti-HBc before starting intravenous immunoglobulin therapy to identify their HBV infection status and clarify their risk of HBV reactivation. In patients known to have hypogammaglobulinaemia and previous HBV infection, anti-HBc tests might be falsely negative, and testing for HBV DNA might be considered as an alternative; however, HBV DNA would be undetectable in the serum of most patients with a past HBV infection.
immunoglobulin infusion, obtained from patient records. We also obtained information about subsequent HBV DNA testing and results and hepatitis flare (alanine aminotransferase concentration ≥100 U/L and more than three times that at baseline) after anticancer therapy.
Statistical analysis 950 received intravenous immunoglobulin
80 not tested for anti-HBc before first intravenous immunoglobulin
870 tested for anti-HBc before first intravenous immunoglobulin
52 positive for anti-HBc test before first intravenous immunoglobulin
818 negative for anti-HBc before first intravenous immunoglobulin
619 not tested for anti-HBc after intravenous immunoglobulin
199 tested for anti-HBc after intravenous immunoglobulin (study sample)
Figure 1: Diagram of study sample selection
Outcomes The primary endpoint was the proportion of patients who became positive for anti-HBc after intravenous e475
The proportion of patients who became positive for anti-HBc after intravenous immunoglobulin administration was reported with an exact binomial confidence interval. We used Fisher’s exact tests and Wilcoxon rank-sum tests to examine associations between anti-HBc passive transfer and demographic and clinical variables, including age at baseline anti-HBc test (defined as the most recent test before initiation of intravenous immunoglobulin therapy), sex, race or ethnicity, cancer type, receipt of rituximab or stem cell transplantation before intravenous immunoglobulin therapy, occurrence of hepatitis flare after chemotherapy, year of first intravenous immunoglobulin infusion, and time between intravenous immunoglobulin infusion and subsequent anti-HBc testing. Some patients had multiple infusions and anti-HBc tests, resulting in multiple observations per individual. To account for within-patient correlations, we used generalised estimating equations to fit a repeatedmeasures logistic regression model (PROC GENMOD) with a binomial distribution and logit link function to calculate the odds of a positive test based on the logtransformed number of days between intravenous immunoglobulin infusion and anti-HBc testing. We used the quasi-likelihood under the independence model criterion to choose the best correlation structure and found that an independent working correlation structure www.thelancet.com/haematology Vol 5 October 2018
Articles
best fit the data.12 The repeated-measures multiple logistic regression analysis considered age, ethnicity or race, sex, time since intranvenous immunoglobulin infusion, cancer type, rituximab therapy, and stem cell transplan tation as potential independent variables. A backward stepwise selection process was used to identify significant variables in the multivariable setting. All statistical tests were two-sided with an α value of 0·05. We did a sensitivity analysis, in which modelling was repeated with exclusion of participants whose baseline test was done more than 3 months before their first intravenous immunoglobulin infusion. Analyses were done with SAS for Windows, version 9.4.
Role of the funding source The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Results 950 of 18 874 patients who underwent chemotherapy between Jan 1, 2004, and Dec 31, 2011, at the University of Texas MD Anderson Cancer Center received intravenous immunoglobulin therapy (figure 1). 870 patients had anti-HBc testing before intravenous immunoglobulin administration, of whom 52 had a reactive test and 818 had a non-reactive test. 619 patients with non-reactive baseline tests did not have a record of an anti-HBc test after receiving intravenous immunoglobulin therapy. The remaining 199 patients were negative for anti-HBc and HBsAg before infusion and were tested for anti-HBc after infusion; these patients constituted the study sample. The median time between baseline testing for antiHBc and intravenous immunoglobulin infusion in the study sample was 26 days (range 1–1739). Results of HBsAg tests done after intravenous immunoglobulin infusion were available for all but two patients in the study sample, and all test results were negative. Baseline characteristics of the entire study sample and conversion to anti-HBc status are summarised in the table. No patient received anti-HBV prophylaxis or treatment. Patients received a median of four (range 1–53) doses of intravenous immunoglobulin between baseline and the first reactive anti-HBc test or the last test for those who remained negative for anti-HBc after infusion. 29 (15% [95% CI 10–20%]) of 199 patients tested positive for anti-HBc after intravenous immunoglobulin infusion. The median time between infusion and testing was 6 days (range 1–60), with one patient retested on day 366. 17 (59%) of 29 patients were tested for HBV DNA after testing positive for anti-HBc, and all had undetectable HBV DNA. All 29 patients were tested for HBsAg after testing positive for anti-HBc, and all tests were negative. 18 (62% [95% CI 44–80]) of the 29 patients www.thelancet.com/haematology Vol 5 October 2018
Age at baseline anti-HBc test (years)
Conversion (n=29) No conversion (n=170) Total (n=199)
p value*
52 (20–73)
0·99
Race or ethnicity White
··
51 (20–79)
51 (20–79)
··
··
0·90
19 (66%)
111 (65%)
130 (65%)
··
Hispanic
6 (21%)
32 (19%)
38 (19%)
··
Black
4 (14%)
18 (11%)
22 (11%)
··
Asian
0
3 (2%)
3 (2%)
··
Other
0
6 (4%)
6 (3%)
Sex Female Male Cancer type Solid tumour (not HCC) Haematological malignancy Rituximab
··
··
··
9 (31%)
65 (38%)
74 (37%)
20 (69%)
105 (62%)
125 (63%)
··
··
··
·· ·· 1·00
1 (3%)
10 (6%)
11 (6%)
··
28 (97%)
160 (94%)
188 (94%)
··
··
··
··
No
15 (52%)
101 (59%)
116 (58%)
Yes
14 (48%)
69 (41%)
83 (42%)
Stem cell transplantation
·· 0·54
··
··
··
0·54 ·· ·· 0·77
Allogeneic
16 (55%)
95 (56%)
111 (56%)
··
Autologous
5 (17%)
37 (22%)
42 (21%)
··
None
8 (28%)
38 (22%)
46 (23%)
··
HCC=hepatocellular carcinoma. *p values are from Fisher’s exact test, with the exception of the test for the association between anti-HBc status and age, which was from a Wilcoxon rank-sum test.
Table: Baseline demographic and clinical characteristics of patients with and without conversion from anti-HBc negativity to anti-HBc positivity
who tested positive for anti-HBc after intravenous immunoglobulin infusion had hepatitis flare after chemotherapy compared with 115 (68% [61–75]) of 170 patients who tested negative (p=0·67). Ten (34%) of 29 patients were nonreactive on a subsequent anti-HBc test; 19 (66%) were not retested for anti-HBc. Year of first intravenous immunoglobulin admin istration ranged from 2004 to 2011; the median year was 2009 for patients with passive transfer and 2008 for those without. No significant associations were observed between passive transfer and age, race or ethnicity, sex, cancer type, rituximab use, or stem cell transplantation (table). All 361 available anti-HBc tests that were done after the first intravenous immunoglobulin admin istration were included in the repeated-measures analysis. Patients had a median of one (range 1–9) anti-HBc test after intravenous immunoglobulin infusion. 34 (9%) of 361 tests were reactive and 327 (91%) were nonreactive. 30 (88%) of the 34 reactive tests versus 39 (12%) of the 327 nonreactive tests were done within 4 weeks of intravenous immunoglobulin administration. During the first week after intravenous immunoglobulin admin istration, 35 patients were tested for anti-HBc, of whom 17 (49%) tested positive (one patient was tested twice and found to be positive both times). In multivariable analyses, the removal of variables that were not significantly associated with anti-HBc positivity e476
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0·90 0·85 0·80 0·75 0·70 0·65
Probability
0·60 0·55 0·50 0·45 0·40 0·35 0·30 0·25 0·20 0·15 0·10 0·05 0
0
28
56
84
112
140
168
196
224
252
280
308
336
364
392
Time (days)
Figure 2: Probability of anti-HBc positivity according to time between intravenous immunoglobulin infusion and anti-HBc testing The red dotted lines are 95% CIs.
See Online for appendix
produced a reduced model that included only time between intravenous immunoglobulin infusion and antiHBc testing as significantly associated with anti-HBc positivity (odds ratio 0·38, 95% CI 0·29–0·50; appendix p 1). The probability of conversion to anti-HBc positivity decreased with increasing time between intravenous immunoglobulin administration and antiHBc testing (appendix p 2). The probability of a positive test result was 34% (95% CI 22–48) at 1 week after infusion, which decreased to 12% (7–18) at 4 weeks and 4% (2–7) at 12 weeks (figure 2). Results of the multivariable analyses were similar in a sensitivity analysis that excluded records for 63 patients whose baseline tests had been done more than 3 months before their first intravenous immunoglobulin infusion.
Discussion We found that conversion from an anti-HBc-negative status to an anti-HBc-positive status was common (we observed an overall conversion rate of 15% [29/199]) after intravenous immunoglobulin infusion among patients with cancer. We also found that the probability of anti-HBc positivity was higher for tests done within the first week than for tests done at 3 months after infusion. These findings, together with the observed loss of anti-HBc over time in patients who tested positive for anti-HBc after infusion, and the absence of conversion to HBsAg and HBV DNA positivity in the small subset of patients assessed for HBV infection, support our hypothesis that conversion to anti-HBc positivity after intravenous immunoglobulin administration is a result of passive transfer. A previous cross-sectional study6 reported a higher prevalence (46%, 37/80) of anti-HBc positivity after e477
intravenous immunoglobulin administration, which was probably related to frequent administrations of intra venous immunoglobulin (monthly for at least 6 months) and anti-HBc testing performed shortly after the last dose of intravenous immunoglobulin in that study. We did not detect differences in the number of anti-HBc tests or cumulative doses of intravenous immunoglobulin received between those who did and those who did not have anti-HBc positivity after intravenous immuno globulin infusion. Our results have several clinical implications. First, antiHBc testing should be done before starting intravenous immunoglobulin therapy in patients with cancer to ascertain whether subsequent positive results were caused by passive transfer. Second, given that the expected halflife of intravenous immunoglobulin is about 3–4 weeks,8 if anti-HBc testing is done soon after intravenous immunoglobulin infusion and the results are positive, we recommend retesting patients with an unknown HBV infection status at baseline at least 3–4 months after infusion to establish whether the result is secondary to passive transfer. If immediate clarification is needed, such as in a patient requiring immediate initiation of anticancer therapy or experiencing liver enzyme elevation, additional testing for HBsAg and HBV DNA and referral to hepatitis specialists should be considered. Given that anti-HBs in intravenous immunoglobulin might neutralise HBsAg, making testing for HBsAg less reliable, HBV DNA testing for confirmation of acute HBV infection in patients previously negative for anti-HBc who become positive for anti-HBc after intravenous immunoglobulin therapy is warranted. This study has limitations that primarily relate to the retrospective study design and the absence of a standardised protocol for anti-HBc testing in patients receiving intravenous immunoglobulin therapy as supportive care. We included patients who underwent baseline anti-HBc testing at varying times, some long before intravenous immunoglobulin administration; however, our results did not change when including in the analysis only patients who had baseline anti-HBc testing within months before receiving their first intravenous immunoglobulin infusion. The observed proportion (15%) of patients who converted to anti-HBc positivity in our study is probably an underestimate because few patients were retested for anti-HBc after intravenous immunoglobulin infusion and, in those that were, there was disparity in the time between intravenous immunoglobulin infusion and retesting. In the absence of a standardised protocol, anti-HBc retesting after intravenous immunoglobulin infusion was based on provider discretion, potentially introducing a source of bias that could increase the estimated conversion rate if patients who were retested had a greater conversion risk than did those who were not retested. Another limitation is that not all patients who became anti-HBc positive were tested for HBV DNA or liver enzymes to rule out www.thelancet.com/haematology Vol 5 October 2018
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the possibility of an actual infection. Finally, our institution does not routinely test for anti-HBc in intravenous immunoglobulin products; thus, we cannot verify that the source of anti-HBc was the infused intravenous immunoglobulin. In conclusion, our results suggest that passive transfer of anti-HBc is common after intravenous immuno globulin infusion. This finding has important impli cations for patients with cancer who are receiving intravenous immunoglobulin therapy and might require immunosuppressive therapy. Therefore, anti-HBc testing should be considered before each intravenous immuno- globulin infusion in such patients. Contributors JPH and HL designed the study. JPH oversaw data collection, JTF collected data, and CLW performed the statistical analysis. JPH, HL, ASL, and CLW wrote the manuscript. All authors contributed to data interpretation and reviewed, edited, and approved the manuscript. Declaration of interests JPH reports grants from Gilead and Merck. ASL reports grants from Bristol-Myers Squibb and Gilead. MES-A is an advisory board member for Pfizer, Endo Pharmaceuticals, Bristol-Myers Squibb, and Eli Lilly. HAT reports grants from Gilead and Merck. All other authors declare no competing interests. Acknowledgments JPH was a recipient of a K07 career award from the National Cancer Institute (K07CA132955) and MES-A of a K24 career award from the National Institute for Musculoskeletal and Skin Disorders (K24 AR053593). This study was supported by the National Cancer Institute under award number P30CA016672, which supports the MD Anderson Cancer Center Clinical Trials Support Resource. We thank the following individuals at the University of Texas MD Anderson Cancer Center: Andrea Barbo for data collection, Laurissa Gann for literature review, and Stephanie Deming for editing. An abstract of this study was presented at the annual meeting of the American Association for the Study of Liver Diseases, Washington, DC, on Oct 23, 2017.
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