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Revista Española de Enfermedades Digestivas

versión impresa ISSN 1130-0108

Rev. esp. enferm. dig. vol.109 no.9 Madrid sep. 2017 



Cost-effectiveness of a hepatitis B virus screening strategy to prevent reactivation in patients with hematologic neoplasms

Coste-efectividad de una estrategia de cribado del virus de la hepatitis B para prevenir la reactivación en pacientes con neoplasia hematológica



Javier Crespo1, Rafael Esteban2, Covadonga Torres3, Itziar Oyagüez3, Miguel Ángel Casado3 and María Buti2

1Hospital Universitario Marqués de Valdecilla. Santander, Spain.
2Hospital Universitario Vall d'Hebrón. Barcelona, Spain.
3Pharmacoeconomics & Outcomes Research Iberia (PORIB). Madrid, Spain





Introduction: The effectiveness of a screening strategy for the detection of a hepatitis B virus (HBV) infection followed by prophylaxis in order to prevent HBV reactivation was assessed in patients with hematologic neoplasms.
Material and methods: A decision tree was developed to compare the cost and effectiveness (prevented reactivations) over an 18 month period of a screening strategy prior to chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) with a non-screening approach. HBsAg+ (hepatitis B surface antigen) and/or anti-HBc+ (antibodies to hepatitis B core antigen) and HBV-DNA+ patients received oral antiviral prophylaxis with tenofovir disoproxil (245 mg once daily) from chemotherapy baseline until one year after chemotherapy completion. Non-screened patients received tenofovir in case of a reactivation. Model probabilities were obtained from the literature. The total cost (€, 2015) included: antiviral prophylaxis, R-CHOP, screening tests (HBsAg, anti-HBc, HBV-DNA) and liver function tests. Drug therapy costs were estimated using ex-factory prices with mandatory deductions. The incremental cost-effectiveness ratio (ICER) was calculated in order to assess the cost-effectiveness of this intervention in terms of cost per reactivation averted versus no screening.
Results: In a hypothetical cohort of 1,000 patients, screening prevented 7.36 reactivations when compared to the non-screening approach (14.9 versus 22.3). Total cost/patient (including €8,282 for R-CHOP) was €8,584 for the screening strategy and €8,449 for the non-screening approach. The ICER for screening versus non-screening was €18,376/prevented reactivation.
Conclusion: HBV screening followed by oral antiviral prophylaxis yielded more health benefits than non-screening, reducing HBV reactivation in patients with hematologic neoplasms on chemotherapy.

Key words: Screening. Hepatitis B virus. Reactivation. Neoplasm. Cost-effectiveness.


Introducción: se analizó la efectividad de una estrategia de cribado de la infección por el virus de la hepatitis B (VHB) con consiguiente profilaxis en pacientes con neoplasia hematológica para evitar la reactivación del VHB.
Material y métodos: se utilizó un árbol de decisión para comparar costes y eficacia (reactivaciones evitadas), en 18 meses, de una estrategia con cribado previo a quimioterapia con R-CHOP (rituximab, ciclofosfamida, doxorrubicina, vincristina y prednisona) versus una estrategia sin cribado. Los pacientes HBsAg+ (antígeno de superficie de la hepatitis B) y/o antiHBc+ (anticuerpos del núcleo de la hepatitis B) y ADN-VHB+ recibieron profilaxis antiviral con tenofovir disoproxil desde el inicio de la quimioterapia hasta un año después de su finalización. Los pacientes sin cribado recibieron tenofovir en caso de reactivación. Las probabilidades del modelo se obtuvieron de la literatura. El coste total (€, 2015) incluyó: profilaxis antiviral, R-CHOP, pruebas de cribado (HBsAg, antiHBc y ADN-VHB) y función hepática. El coste farmacológico se calculó con el precio de venta al laboratorio aplicando la deducción obligatoria.
Resultados: en una cohorte hipotética de 1.000 pacientes, el cribado evitó 7,36 reactivaciones frente a la estrategia sin cribado (14,9 versus 22,3). El coste total/paciente (incluyendo 8.282 € de coste de R-CHOP) fue de 8.584 € para la estrategia con cribado y 8.449 € para la estrategia sin cribado. La relación coste-efectividad incremental del cribado versus la estrategia sin cribado fue de 18.376 €/reactivación evitada.
Conclusión: el cribado de la infección por el VHB permite implementar una profilaxis antiviral en pacientes con alto riesgo de reactivación, disminuyendo la frecuencia de dichas reactivaciones en pacientes con neoplasias hematológicas en tratamiento quimioterapia, con un coste incremental aceptable.

Palabras clave: Cribado. Hepatitis B. Reactivación. Neoplasia. Coste-efectividad.



Hepatitis B virus (HBV) infection represents a worldwide public health concern; there are approximately 240 million people with a chronic infection (1).

HBV reactivation is defined as any return or increase in HBV-DNA (> 1 log or > 20,000 IU/mL) in a patient with a current or prior HBV infection. HBV reactivation includes a wide range of clinical manifestations, from a mild, transient, silent hepatitis to fulminant and life-threatening forms. The notable heterogeneity of hepatitis B outcome depends on the interaction between the host's immune system and the virus's ability to evade immune mechanisms (2). HBV reactivation was first described over 35 years ago (3), with a higher risk for patients with hematologic malignancies as compared to other neoplasms. However, it has also been reported in patients receiving immunomodulators and/or biologics, immunosuppressants prior to solid organ transplantation and patients with hepatocarcinoma undergoing hepatic chemoembolization. Multiple reports have shown HBV reactivation in various clinical settings. This has become relevant during the last few years as a result of new drugs with a powerful immunosuppressive effect such as rituximab (4,5). In the meta-analysis of 21 studies reported by Kazt et al., 24-100% of patients with HBV reactivation developed acute hepatitis with a highly variable HBV-related mortality of 0-50% (6). As a consequence of HBV reactivation, chemotherapy or immunosuppressive therapy may be delayed or even discontinued and this may have an adverse clinical impact on overall survival (7). In the same meta-analysis, 10-19% of patients had their treatment withdrawn.

In transplanted patients, HBV reactivation increases mortality and graft loss risk. As shown by a meta-analysis of nine studies with 971 patients, the risk is higher when corticosteroids are administered and the risk level is at its highest with regimens combining corticosteroids and rituximab (8). This is particularly true for patients undergoing hematopoietic stem cell transplantation and patients receiving chemotherapy for lymphoma, especially of the non-Hodgkin type (5,7,9-14). In addition, survival in cancer patients recovering from HBV reactivation may be impaired by changes to the scheduled chemotherapy regimen (15).

Three randomized, controlled clinical trials have been performed (13,16,17) with lamivudine as a prophylaxis for Asian HBsAg+ patients scheduled to receive chemotherapy for lymphoma or hepatocarcinoma. The use of prophylaxis lamivudine was associated with a much lower incidence of HBV reactivations when compared to control subjects. In Spain, a multicenter study found that prophylactic tenofovir significantly reduced the incidence and severity of HBV reactivation in association with rituximab chemotherapy (18).

Since chronic infection is usually asymptomatic and commonly associated with normal ALT levels, infected individuals can only be reliably identified by testing for the hepatitis B surface antigen (HBsAg) and antibodies to the hepatitis B core antigen (anti-HBc). Therefore, it is advisable to analyze HBV infection markers before immunosuppressive therapy (1). However, a study performed in the USA found that only 14% of oncologists regularly screened patients (19). Similarly, only 14% of patients in a Toronto hospital were tested for HBsAg before chemotherapy (20).

Furthermore, some recent publications conclude that the evidence is insufficient to establish the benefits or risks of routine screening for a chronic HBV infection in cancer patients scheduled to receive immunosuppressive therapy (21). While preventive antiviral therapy has proven financially acceptable in HBsAg+ patients, information on the cost-effectiveness of HBV screening is scarce (15) and no data are available from Spain. Therefore, the aim of this study was to estimate HBV screening cost-effectiveness in patients with hematologic malignancies before rituximab-based chemotherapy from the perspective of the National Health System.



An excel-based model was designed that was structured like a decision tree in order to estimate the effectiveness and cost of two potential strategies, HBV screening and prophylaxis with tenofovir disoproxil fumarate (TDF) versus no screening. The study was performed in a hypothetical cohort of 1,000 patients with hematologic cancer before initiating chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The analysis was carried out from a National Health System perspective over an 18 month period (Fig. 1).



Effectiveness was assessed by considering the number of reactivations prevented by the screening versus the non-screening approach. The various probabilities of each strategy (reactivations, hepatitis and death) in each situation reflected the best scientific evidence available following a thorough review of the literature. The estimated prevalence of HBsAg+ was 1.3% and the prevalence of anti-HBc+ in HBsAg- patients was 11.1%. Table 1 details all the probabilities in the model with their respective references.



A numeric parameter known as the incremental cost-effectiveness ratio (ICER) was used to assess cost-effectiveness. Results are expressed as extra cost per incremental benefit unit achieved with the screening strategy versus the non-screening approach. The number of patients who needed to be screened to prevent reactivation was used as an efficacy variable. Therefore, the result should be interpreted as the additional cost that screening would represent in order to prevent one reactivation.

In the screening arm, HBsAg and anti-HBc testing was performed prior to chemotherapy. In patients with positive HBsAg and/or anti-HBc, DNA from the HBV (HBV-DNA) was assessed every other month in the absence of reactivation and every month if reactivation occurred. Patients at a high risk of reactivation (HBsAg+ and/or anti-HBc+ plus HBV-DNA+) received prophylaxis with TDF starting one week before chemotherapy onset until one year after chemotherapy finished.

In the non-screening arm, only delayed antiviral therapy (i.e., therapy at the time of reactivation diagnosis) was considered. From a chronological viewpoint, reactivation may occur after the initial dose of immunosuppressive and/or chemotherapeutic treatment or several months after immunosuppresive therapy was discontinued when the immune system had recovered its ability to detect the increased viral replication that occurred during the immunosuppressed stage. Based on the available evidence, it was assumed that HBV reactivation in patients with hematologic malignancy would peak at four months after R-CHOP onset (20,22,23).

Total cost estimates for each strategy included chemotherapy and antiviral drug costs, screening costs, liver function monitoring costs and costs related to clinical events (hepatitis and death). Drug costs were estimated according to ex-factory prices established in the "Catálogo de Medicamentos del Consejo General de Colegios Oficiales de Farmacéuticos" (24) and then applying the mandatory deduction as established by the Spanish Royal Decree 8/2010 (25). Antiviral therapy included the oral administration of TDF of one daily 245-mg tablet (26). R-CHOP chemotherapy cost was estimated for six 21-day cycles at a standard dose: rituximab, 375 mg/m2 on day 1 (27); cyclophosphamide, 750 mg/m2 on day 1 of every cycle (28); hydroxidaunorubicin: 50 mg/m2 on day 1 of every cycle (29); Oncovin®, 1.4 mg/m2 (max. 2 mg) on day 1 of every cycle (30); and prednisone, 100 mg on days 1 and 5 of every cycle (31). The body surface area considered was 1.7 m2 (32,33).

Liver function tests, including transaminase and bilirubin levels, were performed every two months. In the case of HBV reactivation, monthly monitoring was performed. Unitary costs for screening measurements and liver function monitoring were obtained from a national cost database (34). With regard to hepatitis management costs, the estimated costs of hepatitis B management in a study performed in various European countries including Spain were used. In addition, the average estimates from 2014 by the Spanish Ministry of Health, Social Services and Equality were used that corresponded to the minimum basic data set (MBDS) discharge registry from 2012 (35) for the following ICD-9 codes: 070 (viral hepatitis), 070.30 (viral hepatitis B without hepatic coma, acute or unspecified without hepatitis delta), 070.32 (chronic viral hepatitis B without hepatic coma without hepatitis delta), 573.3 (hepatitis, unspecified), 571.40 (chronic hepatitis, unspecified), and 571.49 (other chronic hepatitis) (36).

The cost of hepatic mortality was obtained from the literature (37) and updated according to the CPI inter-annual variation rate reported by the Statistics National Institute (38).

In order to assess the uncertainty of the results, several one-way sensitivity analyses (SA) were performed. New scenarios were set up and the following parameters were modified. The time to reactivation since R-CHOP chemotherapy onset was modified from four to five months (SA1).

The number of R-CHOP cycles considered was modified from six to eight cycles (a regimen also used in standard clinical practice) (SA2). With regard to the percentage of HBsAg- subjects, the prevalence was changed from 1.3% to 0.7% (prevalence in the general population) (SA3). The percentage of anti-HBc+ subjects was reduced by 25%, i.e., changing the prevalence from 11.10% to 8.32% (SA4). The probability of non-hepatic death in HBsAg+ patients with no reactivation in the screening arm was changed rendering it identical to the non-screening arm, i.e., changing the value from 0.0% to 7.8% (SA5).

All costs were expressed in euros (€) using values from 2015 (Table 2).




In a hypothetical cohort of 1,000 patients with a hematological neoplasm on R-CHOP therapy, a HBV screening strategy prior to chemotherapy onset would prevent a total of 7.36 reactivations as compared to the non-screening approach during an 18 month period (Table 3).



The total cost per patient was €8,584 in the screening strategy, with R-CHOP chemotherapy accounting for 97.6% of the cost. This total cost per patient was €8,449 for the non-screening approach, with drug costs accounting for 98.3% of the total (Table 3). In other words, the screening strategy represents an incremental cost of €135 per patient, i.e., an additional 1.6% versus non-screening. Furthermore, the contribution of clinical events (hepatitis, death) to the total cost of the screening strategy was 0.0%, whereas this contribution amounted to 0.6% in the non-screening arm.

The resulting ICER was €18,376 per prevented HBV reactivation in the screening versus the non-screening approach over a period of 18 months (Table 3).

One-way SA yielded the following results. With regard to the number of prevented reactivations, no changes occurred in the value obtained for the base case except for the analyses of modified percentages of HBsAg- subjects (SA3) and anti-HBc+ subjects (SA4). The 7.36 prevented reactivations in the base case were reduced to 4.28 and 7.19 for SA3 and SA4, respectively. With regards to the ICER (€18,376 per prevented reactivation with the screening versus non-screening approach in the base case), the values ranged from €16,078.07 for SA4 (modified percentage of anti-HBc+ subjects) to €27,155.06 for SA3 (modified percentage of HBsAg- subjects).



The PRESCRIB study assessed the cost-effectiveness of HBV screening in patients with hematologic malignancies prior to chemotherapy onset. This is one of the few studies that explored effectiveness of R-CHOP chemotherapy and the only study to assess cost-effectiveness in Spain. Furthermore, this is the first study to assess effectiveness as a function of prevented reactivation, a clinical parameter usually considered in routine clinical practice.

According to the results obtained, the cost of screening and the associated monitoring of liver function represents an additional cost of €135 per patient over a period of 18 months, with a prevented reactivation rate of 7.36 per 1,000 patients.

Therefore, we can conclude that antiviral prophylaxis after HBV screening reduces reactivation and mortality rates in patients with hematologic neoplasms on chemotherapy. Screening slightly increases overall cost as compared to the non-screening approach. However, screening reduces reactivations, which in turn may result in clinical events such as hepatitis, hepatocellular carcinoma, liver transplantation and hepatic death (39). There is also a factor that is difficult to quantify that has a negative impact on patients: the inability or delay in administering chemotherapy in patients with reactivation.

A recent study in Spain (18) compared the efficacy of TDF prophylaxis versus observation in anti-HBc+ and HBsAg- patients on rituximab therapy for hematologic malignancies. The results were in line with those obtained in the present study and showed that TDF administration prevented HBV reactivation.

Another study (15) assessed the cost-effectiveness of three screening strategies (all patients, only high-risk patients and no screening) in patients with lymphoma over a 12 month period. The study suggested that screening all patients was cost-effective as compared with the other strategies assessed, although the differences were small. However, this study only separated patient clinical profiles according to baseline HBsAg status.

The study by Day et al. (40) also involved a cost-effectiveness analysis in Australia that compared a screening approach to not screening in patients with solid tumors. They concluded that screening was cost-effective for selected patient subpopulations and/or by simplifying screening strategies.

It is interesting to note that the two previously reported cost-effectiveness studies used the same methodology and analyzed data using a decision tree-based model.

The limitations associated with the present study include the short time period of the analysis and the fact that the selection was conditioned by the available evidence of reactivation in this patient profile. A broader time period would allow the identification of significant differences in costs and results between the assessed alternative options, thus rendering the results more valid. In this respect, the natural history of the disease and how it may be modified by the assessed therapies are relevant factors that should be taken into account. Another aspect worth mentioning is that the model assumes that screening does not delay chemotherapy. However, it should be ensured that this is actually the case in routine clinical practice. Furthermore, the prophylactic strategy used (tenofovir) might not be appropriate for all patients and lamivudine could be used as an alternative. Finally, the difficulty in the interpretation of the above data is associated with a lack of a specific threshold of the cost per effectiveness unit achieved, in this case per reactivation prevented.

The public health care system has to cope with a shortage of resources and increasing demands for services. Thus, the healthcare and social benefits of implementing programs and strategies (such as new markers for reactivation [41]) with a prophylactic rather than therapeutic effect should be debated with regard to an adequate efficiency and additional advantages. However, these results show that HBV screening in a population with hematologic malignancies scheduled to receive rituximab-based chemotherapy will identify patients who will benefit from antiviral prophylaxis. This represents an added cost of €135 per patient over an 18 month period versus non-screening, and prevents 7.36 reactivations per 1,000 patients.



The authors thank Cándido Hernández from Gilead Sciences for his cooperation in the literature search for the identification of the most relevant papers.

The authors are also grateful to the reviewers of the Revista Española de Enfermedades Digestivas for their comments and proposals during the review process, which allowed an improvement of the quality of the manuscript.



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Itziar Oyagüez.
Pharmacoeoconomics & Outcomes Research Iberia (PORIB).
Paseo Joaquín Rodrigo 4o I.
28224 Pozuelo de Alarcón, Madrid. Spain

Received: 29-10-2016
Accepted: 11-04-2017