We found that the HBV screening prevalence among new patients receiving chemotherapy at a large US cancer center over the period 2004–2011 was only 16.2%. Of particular concern, the prevalence of HBV screening was low (<19%) even for patients with known HBV risk factors. Over 66% of patients with hematologic malignancies but less than 4% of those with solid tumors were screened. Predictors of HBV screening included having an HBV risk factor and planned rituximab therapy. Interestingly, race/ethnicity was associated with the likelihood of HBV screening for patients with hematologic malignancies but not with solid tumors. Importantly, HBV screening prevalence increased over time and higher rates were sustained after publication of national HBV screening recommendations. In this study of provider-driven screening, 8.3% of screened patients had a positive HBsAg or anti-HBc test result. The proportion of patients who tested positive for HBV infection increased by over 20% from period 1 to period 3, suggesting that increased screening may lead to increased identification of patients with HBV infection.
The finding that most patients with hematologic malignancies were screened for HBV infection whereas most patients with known HBV risk factors were not, together with the finding that most patients who received rituximab, a known risk factor for reactivation, were screened, suggests that oncologists are more aware of the risk factors for HBV reactivation than they are of the risk factors for HBV infection. This may have reflected the effect of the FDA letters, package inserts, and recommendations as well as publications in the oncology literature about HBV reactivation associated with rituximab treatment. These data indicate that future educational efforts on risk factors for HBV infection for oncology providers might increase HBV screening.
For patients with hematologic malignancies, the prevalence of HBV screening increased dramatically during period 1, which included the FDA letter. This increase may be related to the high risk (nearly 50%) of reactivation  and frequent reports of reactivation among patients with hematologic malignancies [17–19] and to the frequent reports of reactivation among patients receiving rituximab [20–24]. The further increase in screening prevalence during periods 2 and 3 was likely due to the emphasis in national recommendations on the risk of HBV reactivation in these patients.
For patients with solid tumors, odds of screening increased over all 3 time periods; however, the vast majority (96%) of patients were not screened. The low rate of HBV screening among patients with solid tumors is concerning because of previous reports of reactivation and related delays in chemotherapy and increases in mortality in patients with breast cancer [25–27], glioblastoma , germ cell tumors , and cancers of the lung, colon, and stomach [27, 29–31]. Indeed, the risk of reactivation among patients with solid tumors is estimated to be approximately 15% ; however, these data were derived in an HBV-endemic area. Therefore, studies are needed to define risks and to determine predictors of reactivation for US patients with solid tumors.
Most of the national recommendations [1, 2, 4–7] call for prechemotherapy HBV screening in patients with high risk of HBV infection. Although the overall screening prevalence among patients with HBV risk factors was low, the prevalence increased over time, and having an HBV risk factor predicted screening. However, since previous studies have shown that screening based on risk factors alone would miss up to 45% to 65% of patients who actually had HBV infection, [32, 33] future research is warranted to better understand the efficacy of risk-based screening.
Our study’s screening rate is lower than that in previous studies, which have described rates of adherence to cancer-related guidelines ranging from 27% to 97%, [34–41] although it is possible that our screening rates may have underestimated the actual rate since we could not verify HBV screening performed before registration at MD Anderson. Reasons for noncompliance with HBV screening guidelines may have included patient characteristics such as age [34, 38] and stage of disease , physician attitudes towards guidelines , and education about guidelines . One study  found that physicians’ lack of awareness of and lack of agreement with guidelines were potential barriers to adherence. A previous study by In et al.  reported a higher variation in surgical cancer care when guidelines were based on low levels of evidence or expert opinion. Future research providing high levels of evidence will be necessary to improve adherence to HBV screening.
We found that rituximab was a predictor of screening for all patients, especially those with solid tumors. Rituximab is a monoclonal antibody against CD20+ that causes severe B-cell depletion [46, 47] and facilitates uncontrolled replication of HBV. However, besides rituximab, many other chemotherapy drugs [25–28, 48–54] have been associated with HBV reactivation. Future studies focusing on mechanisms by which certain chemotherapy drugs may cause reactivation will help shape future evidence-based screening strategies.
Interestingly, whereas race/ethnicity did not predict HBV screening among patients with solid tumors, among patients with hematologic malignancies, Black patients had lower odds of screening than White patients. This is concerning because previous population-based studies have shown that the prevalence of HBV infection (current and past) is higher among Black than White adults (9.6% vs. 2.3%, P < 0.001) . Perhaps physicians are unaware of the higher HBV risk in Black patients. We were surprised that Asian race did not predict HBV screening even though the prevalence of chronic HBV infection in this group may be as high as 20% [55–57]. Failure to screen Asian patients may have reflected lack of awareness by physicians of HBV risk factors [58, 59]. In addition, we were surprised that patients with solid tumors who resided outside the US had lower odds of HBV screening, although it is possible that they were screened in their home countries.
We found substantial numbers of patients who had a negative HBsAg test result but a positive anti-HBc test result. Such patients may have occult HBV infection, as underscored by the high risk (78%) of HBV transmission in recipients transplanted with livers from donors with isolated anti-HBc positivity as compared to donors who were anti-HBc negative (0.05%) . It is possible that isolated anti-HBc may represent false-positive test result among populations with a low prevalence of HBV infection. However, reactivation has been reported in patients who are HBsAg negative but anti-HBc positive during chemotherapy particularly if the regimen includes rituximab [21, 24, 61]. The ASCO PCO  recommends anti-HBc testing in some populations—e.g., patients with hematologic malignancies—since the risk of reactivation has been reported to be 10% among patients with hematologic malignancies with isolated anti-HBc . The CDC recommends HBV screening using 3 HBV serology tests. We found that anti-HBs was rarely tested during our study period.
The strengths of our study include the large and heterogeneous patient population and the focus on actual rather than recalled HBV screening practice. Previous survey studies estimated 38%-80% of physicians screen patients before chemotherapy [11–13]; however, those results may inaccurately describe screening patterns since surveys record self-reporting of screening practice and not actual screening of individual patients. Our examination of physicians’ actual screening behavior at the level of individual patients avoided recall bias or subconscious attempts to report what should be done rather than what was actually done.
The main limitation of our study is its retrospective design and use of administrative databases, which prevented us from fully assessing HBV history and HBV risk factors. Patients may have received chemotherapy before their first chemotherapy administration at MD Anderson. Also, we excluded oral chemotherapy because we could not accurately access dispensing records outside of MD Anderson, but some oral chemotherapy could cause HBV. Patients’ race/ethnicity was self-described or assigned by referring clinics and may be incorrect. Another limitation is that we were not able to accurately determine prevalence of reactivation since not all patients who received chemotherapy were screened for HBV infection. This single-institution experience may not be generalizable to other settings, and our data cannot be generalized to patients who receive care in clinical trials as such patients were excluded. We did not explore socioeconomic factors such as income and educational level because this information is not part of our institutional Tumor Registry database. Most of our patients at MD Anderson have health insurance, and these plans are expected to pay for HBV screening tests. Finally, the last time period in our study was relatively short, limiting our ability to assess the full impact of the national recommendations. Nevertheless, our study provides valuable data from a large US academic cancer center with no changes in institutional policies regarding HBV screening during the study period.