Abstract
Background
Ibrutinib has been a first-line treatment for chronic lymphocytic leukemia since 2014. Case reports of hepatitis B virus (HBV) reactivation after ibrutinib initiation have been presented. The association between the risk of HBV reactivation and ibrutinib initiation remains unclear. This nationwide study aimed to estimate the incidence of HBV reactivation after ibrutinib initiation.
Method
This study included patients who received ibrutinib between 1 February 2014 and 31 October 2019. Possible reactivations were searched by (1) changes in HBV surface antigen or HBV DNA from no data or negative status to positive after ibrutinib initiation, (2) alanine aminotransferase levels that were at least 3 times the baseline value after ibrutinib initiation, and (3) new antiviral prescriptions against HBV after ibrutinib initiation. Individual chart reviews were conducted to identify HBV reactivation attributed to ibrutinib. The cumulative incidence of HBV reactivation was calculated.
Results
A total 4130 patients were eligible during the study period. Of these, patients with negative HBV core antibody (anti-HBcAb; n = 1670) and patients who were taking antivirals against HBV (n = 60) were excluded. There were 2219 patients without anti-HBcAb testing results. Among the remaining 181 patients with positive anti-HBcAb, 7 HBV reactivations were directly attributable to ibrutinib treatment after chart review, for a 3.9% cumulative incidence.
Conclusions
Our study revealed a low cumulative incidence of HBV reactivation after ibrutinib initiation among patients with previous anti-HBcAb positivity, indicating a moderate risk of HBV reactivation.
Keywords: HBV; HBV reactivation; ibrutinib; chronic lymphocytic leukemia
The Food and Drug Administration approved ibrutinib, a Bruton tyrosine kinase inhibitor, in 2013, and ibrutinib became a first-line treatment option for chronic lymphocytic leukemia (CLL) in 2014 [1]. It is also used for treatment of Mantel cell lymphoma, Waldenstrom macroglobulinemia, marginal zone lymphoma, and chronic graft-vs-host disease. Patients with active hepatitis B virus (HBV) infection were excluded from all the clinical trials for ibrutinib, and scant data were available for the risk of HBV reactivation after ibrutinib initiation. Some case reports and small retrospective studies presented the risk of HBV reactivation after ibrutinib administration, and 2 of these cases caused HBV-associated liver failure [2–7]. Hence, the risk of HBV reactivation after ibrutinib treatment remains unclear, and physicians demonstrate different approaches in prevention, especially regarding antiviral prophylaxis for patients receiving ibrutinib and with negative hepatitis B surface antigen (HBsAg) and positive hepatitis B core antibody (anti-HBcAb) [8]. Understanding the risk of HBV reactivation while receiving ibrutinib will guide physicians on the need for prophylactic antivirals to prevent HBV reactivation vs close clinical monitoring.
HBV reactivation is generally considered in patients with chronic HBV who have a 2-log increase in HBV DNA as compared with baseline and those with resolved HBV infection who have HBV DNA or HBsAg reappearance [9]. Our system-wide study aimed to evaluate the cumulative incidence of HBV reactivation risk among patients who received ibrutinib and were known to be positive with anti-HBcAb but not undergoing prophylaxis to prevent reactivation.
METHODS
This retrospective study was conducted at the Central Texas Veterans Health Care System, Temple, Texas, via the national Veterans Affairs (VA) pharmacy database. The institutional review board of our institution approved this study, which included all patients within the entire VA system who received ibrutinib between 1 February 2014 and 31 October 2019. The following patient data were extracted from the VA Corporate Data Warehouse: demographics; first and last ibrutinib dispense dates; HBV serology before and after ibrutinib initiation; concurrent anti-HBV medications, including but not limited to tenofovir, entecavir, tenofovir/emtricitabine, tenofovir/emtricitabine/efavirenz, and abacavir/dolutegravir/lamivudine; and liver function test results. In cases of multiple HBV serology, the result closest to ibrutinib initiation was used to determine the HBV status of the veteran. Veterans who had negative anti-HBcAb before ibrutinib initiation were excluded, as well as those who were taking medications that had antiviral activities for HBV right before ibrutinib initiation.
Possible HBV reactivations were searched according to 1 of the following criteria: (1) change of HBsAg or HBV DNA from no data or negative status to positive after starting ibrutinib or change of anti-HBcAb from no data to positive status after ibrutinib initiation; (2) alanine aminotransferase level that was at least 3 times the baseline value after starting ibrutinib; and (3) new prescription of tenofovir, tenofovir/emtricitabine, entecavir, or lamivudine after ibrutinib initiation. Once possible cases were found by these criteria, individual chart reviews were conducted to determine whether there was an actual HBV reactivation and whether it was due to ibrutinib. Actual HBV reactivation was identified by documentation of such incidence from the treating physicians and then verified by the study team by reviewing patients’ laboratory results based on the HBV reactivation criteria in the guidelines of the American Association for the Study of Liver Diseases (AASLD) [9]. The attribution of HBV reactivation to ibrutinib was determined by documentation from the treating physicians. Characteristics of patients with ibrutinib-induced HBV reactivation were collected, including serology before and after reactivation, reactivation outcome, and HCV status and treatment. Cumulative incidence was calculated by identifying HBV reactivation cases among patients at risk.
RESULTS
There were 4130 patients taking ibrutinib during the study period. Of these patients, 1670 demonstrating negative anti-HBcAb levels before ibrutinib initiation were excluded because they were not at risk for HBV reactivation (Figure 1). Of the remaining 2460 patients, 241 were positive for anti-HBcAb before ibrutinib initiation, and 2219 were without anti-HBcAb data before ibrutinib initiation. Among the 241 patients who were positive for anti-HBcAb before ibrutinib initiation, 60 receiving medications against HBV were excluded. Table 1 shows the demographics and characteristics of all 3 groups: anti-HBcAb positive, anti-HBcAb negative, and no anti-HBcAb testing.
Figure 1.
4130 patients taking ibrutinib during the study period. Of these patients, 1670 demonstrating negative anti-HBcAb levels before ibrutinib initiation were excluded. Of the remaining 2460 patients, 241 were positive for anti-HBcAb before ibrutinib initiation, and 2219 were without anti-HBcAb data before ibrutinib initiation. Among the 241 patients who were positive for anti-HBcAb before ibrutinib initiation, 60 receiving medications against HBV were excluded. 13 patients had confirmed HBV reactivation. Among 13 patients with HBV reactivation, 7 HBV reactivations were attributed to ibrutinib initiation. anti-HBcAb, hepatitis B core antibody; HBV, hepatitis B virus.
Table 1.
Demographics and Characteristics of 3 Groups of Veterans
| Patients, No. (%) or Mean; Median | |||
|---|---|---|---|
| At Risk With Anti-HBcAb (+) (n = 241) | With Anti-HBcAb (−) (n = 1670) | Without Anti-HBcAb Testing (n = 2219) | |
| Male | 237 (98) | 1647 (99) | 2183 (98) |
| Age at ibrutinib initiation, y | 71; 70 | 71; 71 | 74; 73 |
| Race | |||
| White | 150 (62) | 1301 (78) | 1901 (86) |
| African American | 83 (34) | 256 (15) | 178 (8) |
| Other | 8 (3) | 113 (7) | 140 (6) |
| Duration of ibrutinib treatment, d | 620; 480 | 583; 463 | 624; 510 |
| Rituximab before ibrutinib treatment | 148 (61) | 1031 (62) | 621 (28) |
| HBV reactivation due to ibrutinib | 7 | 0 | 0 |
Abbreviations: anti-HBcAb, hepatitis B core antibody; HBV, hepatitis B virus.
Sixteen patients met the search criteria for possible HBV reactivation after ibrutinib initiation. After individual chart review, 13 patients had confirmed HBV reactivation documented by the treating physicians and verified by the study team using the AASLD guideline criteria. The remaining 3 patients met the search criteria because of elevated alanine aminotransferase levels but did not have any evidence of HBV reactivation by serology or HBV DNA. Among 13 patients with HBV reactivation, 7 HBV reactivations were attributed to ibrutinib initiation. According to treating physicians’ documentation, 6 patients had HBV reactivation from chemotherapy that was prescribed before or simultaneous to ibrutinib: 5 cases were caused by rituximab, rituximab and venetoclax, venetoclax, acalabrutinib, and obinutuzumab; the last patient had HBV reactivation 6 months after rituximab discontinuation and 5 months after ibrutinib initiation. In this last case, the treating hepatologist attributed HBV reactivation to rituximab.
There was a 3.9% cumulative incidence of HBV reactivation directly attributable to ibrutinib initiation among patients at high risk (ie, anti-HBcAb positive). The cumulative incidence of HBV reactivation in patients receiving ibrutinib, regardless of association with ibrutinib, was 7.2%. Table 2 shows the characteristics of the 7 patients with HBV reactivation. None of the 7 patients recently received steroids or HCV treatment for chronic HCV, which could contribute to HBV reactivation. All patients who had ibrutinib-induced reactivation were male with a median age of 69 years. One patient did not have a surface antibody tested before starting ibrutinib; 2 had a negative surface antibody; and 4 had a positive surface antibody. The remaining 6 patients with HBV reactivation were African American, except for 1 patient. The most common indication for ibrutinib prescription was CLL. The time from ibrutinib initiation to HBV reactivation ranged from 3 to 32 months with a median of 22 months. Of 7 patients, 4 were still taking ibrutinib during HBV reactivation, whereas the other 3 had discontinued it. The time from the last ibrutinib exposure to HBV reactivation for these 3 patients ranged from 4 to 7 months. One patient's HBV reactivation was identified through annual hepatology follow-up because of an HBV reactivation history. The patient had previous rituximab-induced HBV reactivation and was treated with tenofovir with HBsAg loss and anti-HBsAb development. This patient discontinued tenofovir 4 years before the current ibrutinib-induced HBV reactivation. The patient did not have any clinical symptoms or abnormal liver function test results. Of 7 patients, 2 developed decompensated cirrhosis after HBV reactivation. Neither had HCV or known liver disease, as documented in the chart.
Table 2.
Characteristics of the 7 Patients with HBV Reactivation
| Time to Reactivation, mo | HBV Serology | ||||||
|---|---|---|---|---|---|---|---|
| Age, y | From Last Dose of Rituximab | From First Dose of Ibrutinib | Before Ibrutinib Administration | At Reactivation | ALT at Reactivation, IU/mL | HCV Status | Comments |
| 77 | >60 | 3 | HBV sAg (−) sAb (+) cAb (+) |
HBV sAg (+) eAg (+) HBV DNA >1.7M |
5 | HCV Ab (−) | HBV reactivation due to fludarabine/rituximab 6 y before the current reactivation. Treated with tenofovir with loss of sAg and development of sAb. Tenofovir stopped 4 y prior. Reactivation detected during annual hepatology follow-up. HBV controlled after entecavir |
| 69a | 23 | 22 | HBV sAg (−) sAb (+) cAb (+) |
HBV sAg (+) eAg (+) HBV DNA: 563 000 |
335 | HCV treatment with SVR 2 y prior | HBV controlled after entecavir administration |
| 59 | 25 | 21 | HBV sAg (−) sAb (−) cAb (+) |
HBV sAg (+) eAg (+) HBV DNA: 60.8M |
126 | HCV Ab (−) | No known prior liver disease but presented with ascites and cirrhosis. HBV controlled by entecavir |
| 75 | >60 | 24 | HBV sAg (−) cAb (+) |
HBV sAg (+) eAg (+) HBV DNA: 43.3M |
377 | HCV Ab (+) HCV viral load undetectable 2 y before HBV reactivation |
HBV controlled after entecavir administration |
| 67b | 27 | 8 | HBV sAg (−) sAb (−) cAb (+) |
HBV DNA: 7400 | 24 | HCV Ab (−) | Previously taking entecavir prophylaxis due to use of rituximab. Entecavir discontinued 2 y before current reactivation. Presented with ascites and cirrhosis. Died 3 mo after HBV reactivation due to chronic lymphocytic leukemia progression and decompensated cirrhosis. |
| 63 | None | 22 | HBV sAg (−) sAb (+) cAb (+) |
HBV DNA: 5430 | 351 | HCV treatment with SVR 4 y prior | HBV controlled after entecavir administration |
| 70 | >60 | 32 | HBV sAg (−) sAb (+) cAb (+) |
HBV sAg (+) eAg (+) HBV DNA: 175 847 |
1286 | HCV Ab (−) | HBV controlled after tenofovir administration |
All patients were African American and had chronic lymphocytic leukemia as their underlying disease, except where noted.
Abbreviations: Ab, antibody; ALT, alanine aminotransferase; cAb, core antibody; eAg, e antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; M, million; sAb, surface antibody; sAg, surface antigen; SVR, sustained virologic response.
aWaldenstrom macroglobulinemia.
bWhite.
DISCUSSION
This large retrospective study of a national cohort identified 7 cases of HBV reactivation that can be directly associated with ibrutinib initiation. The additional 6 cases that had HBV reactivation were not directly attributable to ibrutinib, because the patients were taking other more likely causative agents, such as rituximab, and other serious immunosuppressive chemotherapy agents. The HBV reactivation rate in patients taking ibrutinib was 3.9%, which indicates a moderate risk of HBV reactivation based on the American Gastroenterological Association (AGA) Institute guidelines [10]. Previous reports of similar assessments on reactivation also cited reactivation rates of 2.9% to 9.5% [2–4]. Our estimate is consistent with that in previously published smaller studies but toward the lower end of the range.
Among the 7 patients with HBV reactivation, ibrutinib was used to treat CLL in 6 patients and Waldenstrom macroglobulinemia in 1 patient. CLL is a disease that has a higher incidence in men, as well as in White Americans than African Americans or Asian Pacific Islanders in the United States [11]. However, of these 6 patients with underlying CLL and HBV reactivation, 5 were African American. Data collected at the VA indicated that veterans of African American race have a higher risk for HBV exposure when compared with those of White race [12]. Our data revealed a higher proportion of African Americans (34%) among patients with positive anti-HBcAb, as compared with only 15% of African Americans among patients with negative anti-HBcAb (Table 1). Yet, whether race or genetic factors play a role in HBV reactivation or whether this is merely random noise remains unclear due to the small reactivation rates in our study and should be further explored. As Table 2 shows, all patients developed HBV reactivation at least 23 months after the last rituximab dose, and 1 patient never received rituximab. Our study reported various times from ibrutinib initiation to HBV reactivation, ranging from 3 to 32 months with a median of 22 months. None of the 7 HBV reactivations were associated with HCV or HCV treatment.
Of the 7 patients, 2 presented with ascites and were assessed by gastroenterologists to have decompensated cirrhosis. Liver disease was not documented before HBV reactivation. One patient received entecavir prophylaxis because of the use of rituximab, and entecavir was discontinued 2 years before the current HBV reactivation. These patients may have underlying chronic liver disease due to other causes (eg, alcohol or fatty liver) that were not detected or documented, thus putting them at higher risk of cirrhosis. One of the 2 patients remains alive; the other patient died of CLL disease progression and decompensated cirrhosis 3 months after HBV reactivation.
During the study period, ibrutinib was still considered an alternative treatment for most patients with CLL. Most patients had previously received chemotherapy treatment before ibrutinib, which potentially clouded the picture of HBV reactivation. In particular, the AGA guidelines categorized rituximab as a high risk for HBV reactivation (>10%) [10], and the risk is up to 1 year or even longer after rituximab discontinuation. Some patients started taking ibrutinib within 1 year of the last dose of rituximab. Previous studies and ours revealed an unclear association of HBV reactivation during this period with rituximab or ibrutinib. In our current study, if an agent was a known high-risk factor for HBV reactivation according to AGA criteria (eg, rituximab), the treating physicians attributed reactivation to the high-risk agent rather than ibrutinib, as confirmed by the study team. All patients who developed ibrutinib-induced HBV reactivation in our study received the last rituximab dose at least 23 months before the reactivation. This indicates that HBV reactivation in our study was unlikely to be confounded by rituximab—thus, the direct attribution to ibrutinib. This could underestimate the cumulative risk of ibrutinib, but we used a more conservative attribution for this study to clearly understand the risks. However, even if all the cases of HBV reactivation attributed to other chemotherapies, including rituximab, were attributed to ibrutinib (n = 6), there would be 13 HBV reactivations from ibrutinib among 181 patients who had known anti-HBcAb positivity, for an overall reactivation risk of 7.2%, which was still considered a moderate risk by national societies.
One limitation of this study is its retrospective design. However, to date, all previous studies have been case reports or case series and categorized the risk to be small, similar to our study. The study also did not exclude patients with positive HBsAg. Furthermore, the study focused on patients who were at risk, which meant patients with anti-HBcAb positivity regardless of their HBsAg status; this is significant, considering the complexity and phases of HBV disease (eg, HBsAg conversions from positive to negative, or vice versa, during patients’ life spans) and the various numbers and types of HBV serology testing available in patients. Note that patients with positive HBsAg at the time of ibrutinib initiation were likely at higher risk of HBV reactivation. As such, these patients could have already been taking HBV antiviral medications and, if so, were excluded from the analysis.
Moreover, the study relied on treating physicians to determine whether the patient had HBV reactivation and whether it was caused by ibrutinib. This could cause variations in patient identification and classification. Yet, to decrease this variation, HBV reactivation was verified by the study team following the AASLD guidelines [9]. In addition, the study could miss silent cases of HBV reactivation in patients who never had elevated liver enzyme levels and had not undergone routine HBV DNA monitoring, which could underestimate the cumulative incidence of HBV reactivation.
Anti-HBV antiviral medication indications were not extracted during the study. Excluding patients taking anti-HBV antiviral medications could cause selection bias. These patients could be perceived to be at higher risk of HBV reactivation due to other factors influencing the physician's decision to prescribe prophylaxis preemptively, thereby making the study underestimate the cumulative incidence. These could also be patients at higher risk (ie, with HBsAg positivity) who started anti-HBV antiviral therapy as prescribed by treating physicians, as mentioned earlier. Additionally, the follow-up time after ibrutinib initiation and discontinuation varied due to the cutoff of our study period. HBV reactivation could develop months after ibrutinib discontinuation and beyond our study time. However, of 7 patients who had HBV reactivation, 3 developed reactivation 4 to 7 months after ibrutinib discontinuation. Finally, the study was conducted in the VA, and female patients are frequently underrepresented in our study population. The risk estimate may not apply to the general population.
In summary, we identified 7 cases of HBV reactivations that were directly caused by ibrutinib initiation among 181 patients at risk. The cumulative incidence of HBV reactivation after ibrutinib initiation in patients with positive anti-HBcAb was 3.9%, indicating a moderate risk.
Contributor Information
Ting-Yi Chen, Department of Medicine, Central Texas Veterans Health Care System, Temple, Texas, USA.
David A Jacob, Veterans Affairs Heart of Texas Health Care Network, VISN 17 PBM, Arlington, Texas, USA.
John D Coppin, Department of Research, Central Texas Veterans Health Care System, Temple, Texas, USA.
Chetan Jinadatha, Department of Medicine, Central Texas Veterans Health Care System, Temple, Texas, USA.
Notes
Acknowledgments. We thank Thanuri Navarathna for helping with the creation of the figures.
Disclaimer. The views represented here are those of the authors and do not represent the views of the Department of Veterans Affairs or the US government.
Patient consent statement. The design of the work has been approved by the Central Texas Veterans Health Care System institutional review board, and it conforms to standards currently applied in the United States. Additionally, our study was a retrospective review and did not include factors necessitating patient consent; hence, an informed consent waiver and Health Insurance Portability and Accountability Act waiver were approved by the institutional review board.
Financial support. This work was supported by the Central Texas Veterans Health Care System, Temple, TX. (Grant # n/a).
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