Computerized physician order entry (CPOE) applications are widely used to prevent medical errors. In our center, a CPOE system has been in use since 2009 on both the inpatient and outpatient levels. A new and simple alert was introduced in the CPOE system to notify healthcare providers of the potential risk of viral reactivation when prescribing biological therapies, thereby facilitating the request for a serological profile (hepatitis B surface antigen [HBsAg], anti-HBc, and anti-HBs) in patients who have not had these tests. Between May 2012 and May 2013, a total of 1,076 patients undergoing biological treatment were included in the implementation of the CPOE in our hospital, resulting in the identification of 4 HBsAg-positive and 69 anti-HBc-positive/HBsAg-negative patients, two of them with positive viral loads. Since the implementation of this alert system, over 90% of patients who were prescribed a biological drug (BD) have undergone serological screening to detect hepatitis B virus (HBV) infection. The use of the alert system has increased the screening rate from less than 50% to 94% for HBsAg and from less than 30% to 85% for anti-HBc in patients for whom a BD is prescribed. Six patients received prophylactic antiviral therapy. No patient had HBV reactivation. Conclusion: This study demonstrates the feasibility of implementing a CPOE system that has allowed our hospital to increase the rate of HBV screening. Its use has facilitated the identification of patients at high risk for HBV reactivation and permitted physicians to prescribe prophylactic measures according to current guidelines. (Hepatology 2014;106–113)
Hepatitis B virus reactivation (HBVr) is well documented in patients with resolved infection and inactive HBV carriers receiving immunosuppressive therapy and/or antineoplastic chemotherapy, especially the drug rituximab.[1, 2] The clinical presentation of HBV reactivation is highly variable and may progress asymptomatically without liver function abnormalities but eventually leading to fulminating hepatitis and even death.
HBVr has become especially important in recent years with the advent of more potent chemotherapeutic agents for cancer, the use of biological medical products in multiple autoimmune diseases, and the possibility of prevention when appropriate therapy is instituted at the right time. The risk of reactivation is not uniform in all patients; it depends primarily on the time course of HBV infection, the type of disease, and the type of immunosuppressive therapy used, and it is particularly high in hepatitis B surface antigen (HBsAg)-positive patients receiving rituximab.[3, 4]
Because of this increased risk, various recommendations and guidelines have been proposed. Some guidelines advise screening for HBV serological markers in all patients about to receive immunosuppressive therapy, while others recommend screening of only those subjects who are considered to be at high risk for reactivation.[6, 7] The most recent guidelines by the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the Spanish Association for the Study of the Liver (AEEH) recommend screening for HBV (HBsAg and anti-HBc) in all patients about to start chemotherapy and immunosuppression. All three guidelines agree that HBV or HBV DNA viral loads should be determined in patients with positive HBsAg or anti-HBc.[8-10]
The PRESCRIB Project was prepared after reviewing our center's global screening results in the last quarter of 2011. The aim of the PRESCRIB project was to create a simple and useful tool to facilitate the screening of all patients who were to be treated with biological drugs (BDs) by medical specialists, to improve interdepartmental communication for the early detection of patients at risk for viral reactivation, and to facilitate early treatment of such cases. The PRESCRIB tool is based on an electronic prescription system (computerized physician order entry [CPOE]). To the authors' knowledge, this is the first published study to explore implementation of a CPOE system in the field of prevention of HBV reactivation.
The adoption of the CPOE system in our hospital resulted in the screening of almost all patients treated with BDs, regardless of the BD type, the department responsible for the patient, and the type of underlying disease. The use of this tool allowed the hospital to increase its HBsAg screening rate from below 50% before the implementation of the program to 94% during the universalization phase. The anti-HBc screening rate increased from 29% to 85%. It is important to emphasize that the rates of screening in the implementation phase probably were aided by educational efforts. However, we believe that the final remarkable result was achieved by combining an educational effort, which is insufficient by itself, with the development of a technology such as the CPOE.
Historically, CPOE use has improved patient safety, prevented medical errors,[15, 16] and facilitated communication between physicians and pharmacists. The PRESCRIB Project established an innovative strategy that further develops the CPOE capabilities introduced some years ago by our hospital pharmacy. This strategy involves a protocol of alerts for doctors who prescribe BDs, alerting them about the possibility of reactivation of hepatotropic viruses.
Some potential advantages of CPOE-like systems applied to the HBV screening have been suggested previously. Liu et al. noted that the implementation of CPOE in HBV screening for cancer patients who are to receive rituximab allowed the dispensing pharmacist to confirm this screening and to notify the treating physician if screening had not been performed. However, as suggested herein, the implementation of the CPOE requires staff and adequate training, which we aim to achieve; however, perhaps not all centers may be able to meet this requirement. Furthermore, as some authors have pointed out, the adoption of CPOE has been demonstrated to be slower and more problematic than anticipated, with adoption rates around 20% or less. Nevertheless, the advantages of CPOE remain compelling, as the PRESCRIB Project has demonstrated.
Previous studies have noted that some specialties, such as Oncology, tend to have lower overall rates of HBV screening.[14, 20] The results reported here for the PRESCRIB Project also show differences in screening rates by specialty. Indeed, Gastroenterology and Hematology have screening rates of over 80%, whereas in our hospital the initial screening rates at the Oncology Unit were below 50%. Although this problem was overcome by performing a targeted screening by the Hepatology Unit, it would likely be appropriate to pursue greater awareness in this group of specialists so as to encourage their involvement and ultimately achieve universal screening.[5, 14]
Compared to other publications,[21-23] prior to initiation of our project there was a high prevalence of HBsAg and anti-HBc screening, probably due to the higher percentage of prescriptions by Rheumatology and Hematology specialists in our center compared to other specialties including mainly Oncology specialists. This specialty has shown clearly lower screening rates.
The most frequently used BDs in our study were the tumor necrosis factor alpha (TNF-α) inhibitors infliximab and adalimumab and the anti-CD20 antibody rituximab. With these BDs, the risk of HBVr is variable and described elsewhere.[24-32] What is significant to note is that HBV reactivation may occur in patients with positive HBsAg, negative HBsAg, and positive anti-HBc, and even with the presence of anti-HBs.[33-35]
Anti-HBs antibody titers have been reported to have a protective effect in HBVr.[36, 37] Our data do not confirm these findings, as no reactivation has been detected at this time. Remarkably, one of the patients with positive anti-HBc antibody and positive DNA had an anti-HBs level of over 1,000 IU/mL.
CPOE has enabled our hospital to identify 73 patients with markers of HBV infection (HBsAg and anti-HBc). The 0.4% prevalence rate of positive HBsAg found in this study is slightly lower than the 0.7% rate that was previously documented in Spain.[38, 39] This probably reflects a decreasing trend, from the 1.2% rates reported in the 1980s to 0.7% in 2002 and 0.4% nowadays. Regarding the presence of positive anti-HBc with negative HBsAg, CPOE reported a prevalence of 8.2% (69 patients), which is lower than the value of 8.7% reported in 2002.[38, 39] The implementation in our country since 1992 of universal vaccination campaigns in children and newborns may be the reason for this downward trend, especially because immigration is very low in our hospital area.
If reactivation rates as generic and conservative as 25% for HBsAg-positive patients and 5% for positive anti-HBc and negative HBsAg are applied,[24, 31, 32, 39, 40] the use of CPOE would have avoided at least four HBVr cases in our hospital. In fact, in a recent publication on patients with rheumatic diseases it was demonstrated that knowing the patients' serology at the beginning of BD treatment could theoretically prevent up to 78% of reactivation episodes.
It is reasonable to wonder whether universal HBV screening by CPOE is cost-effective, especially under the current conditions of economic hardship. Only two studies have analyzed the cost-effectiveness of screening for HBV infection in patients who are about to receive chemotherapy or immunosuppression. A study of patients with solid tumors showed that such screening was not cost-effective in patients with metastatic disease, a result that was most likely associated with mortality. However, the use of the HBsAg tests in other cancer patients was indeed cost-effective. The cost-effectiveness of universal screening is clearer in the context of lymphomas, in which HBV screening by HBsAg in patients who are about to receive regimens including rituximab was shown to be cost-effective in any area, with a prevalence rate of HBsAg ≥0.2%; this includes the USA, Canada, Australia, and most European countries. However, it remains unclear whether inclusion of the anti-HBc marker is also a cost-effective practice in this situation. A future target of the CPOE use in HBV reactivation should be to achieve equal rates of HBsAg and anti-HBc screening (preferably 100% for both), because the rate of HBsAg screening is currently higher than anti-HBc screening, as shown in our study.
During development of the PRESCRIB Project, six patients received antiviral prophylaxis; four of them were HBsAg-positive, and two had positive anti-HBc and negative HBsAg but detectable viral load. The authors agree with the latest recommendations and guidelines on the management of this infection.[8-10]
In conclusion, the PRESCRIB Project has shown that it is feasible to use CPOE in our hospital to increase HBV screening for patients who are about to receive immunosuppressive drugs. The use of the PRESCRIB system has allowed physicians to identify patients at a higher risk for HBV reactivation and to provide prophylactic measures according to current guidelines. If it is accepted as a paradigm that HBV reactivation can be prevented with prophylactic oral antivirals, it is obvious that preventive screening should be a part of that strategy. Because a tool such as the CPOE can facilitate this preventive screening, it would be interesting to determine whether this experience can be extrapolated to other centers with CPOE systems and whether this is cost-effective for hospitals.