20 years ago, half a million citizens took to the streets of Prague to protest against the increasingly oppressive Communist Government. After a week of peaceful demonstrations and strikes, the 40-year regime ended and democracy returned to the Czech people. Today, the citizens are protesting once again—not against oppression, but against health-care copayments. The controversy is the latest chapter in the Czech health-care system’s unique 20-year transformation from an ineffective command-controlled system to one of the most successful and respected in the world. Since the introduction of fees for health-care services in January, 2008, the Czech Social Democratic Party has represented the large portion of the population that opposes this controversial change. For many, it is not the payment of 30 Czech crowns (US$1·60) for a visit to the doctor or for a prescription, the 60 crowns ($3·20) for each day of hospitalisation, nor the 90 crowns ($4·79) for an emergency room visit. It is the principle that health care has always been free. However, the latest attempt by the Social Democrats to abolish the fees was rejected by the Czech Senate.1 The June 18 ruling was well received by the Ministry of Health, which has defended the fees to ensure the financial stability of the health system. Because nearly 80% of health-care expenditure is financed by income-based payments, the Czech system is particularly vulnerable during an economic downturn: this year, the insurance system is projected to lose as much as 13 billion crowns ($692 million) in revenue. This loss could be as high as 20 billion crowns ($1·07 billion) without the health-care fees.2 Furthermore, preserving the fees might discourage the overuse of health-care resources, for which the country has an unusually high demand. In 2007, Czech citizens had an average of 14·6 outpatient contacts with medical personnel per person—the highest in Europe. Similarly, the numbers of acute-care admissions, inpatient admissions, and average lengths of hospital stays have all been higher than the European Union (EU) average since 2000.3 Yet financially, the Czech health-care system is remarkably efficient. Expenditure per capita is among the lowest in the world, at $1490 per person in 2006 (about 20% of 2006 US expenditure). Similarly, only 6·8% of the country’s total gross domestic product was spent on health care in 2006, a remarkably low proportion when compared internationally (figure).4 Figure Health expenditure and life expectancy for selected developed countries and Czech Republic, 1990 versus 2006 Despite the apparent contradiction between the health-care system’s high use and low expenditure, the health of the population has improved dramatically in the past 20 years. Life expectancies increased 5·4 years in men and 4·6 years in women, compared with average increases of 4·4 and 3·2 years, respectively, in richer countries.4 Over this period, the infant mortality rate has dropped to a quarter of what it was, to 3·14 deaths per 1000 livebirths—well below the EU average and among the lowest in the world.3 Mortality rates are typical of developed countries, with diseases of the circulatory system, cerebrovascular diseases, and cancers accounting for three-quarters of all deaths in 2007.7 Investments in prevention and containment have led to rates of communicable disease that are among the lowest in the EU. The prevalence of tuberculosis is low for the region, and similar patterns are seen for viral hepatitis, scarlet fever, and viral encephalitis.4,7 HIV has also been well contained throughout the country—there were only 147 new cases in 2008.8 Despite effective disease control, there is still great concern over the country’s high rates of obesity and tobacco use, especially in young people. Clearly, the Czech health-care system is not without its share of challenges. Besides the overuse of health-care resources and the ongoing controversy over copayments, the country has also faced human capital loss since the opening of EU borders, as many physicians have explored higher-paying opportunities in neighbouring countries. However, the accomplishments have certainly out weighed the difficulties. In 20 years, an effective health-care system has replaced that left by the country’s Communist rule. As one of the most successful overhauls of a health-care system in history continues, modern challenges must be properly dealt with in the next 20 years and beyond.

BACKGROUND Rituximab has been associated with hepatitis B virus reactivation (HBV-R). However, the characteristics and scope of this association remain largely undefined. METHODS We completed a comprehensive literature search of all published rituximab-associated HBV-R cases and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) MedWatch database. Literature and FDA cases were compared for completeness, and a meta-analysis was completed. RESULTS One hundred and eighty-three unique cases of rituximab-associated HBV-R were identified from the literature (n = 27 case reports, n = 156 case series). The time from last rituximab to reactivation was 3 months (range 0-12), although 29% occurred >6 months after last rituximab. Within FDA data (n = 118 cases), there was a strong signal for rituximab-associated HBV-R [proportional reporting ratio = 28.5, 95% confidence interval (CI) 23.9-34.1; Empiric Bayes Geometric Mean = 26.4, 95% CI 21.4-31.1]. However, the completeness of data in FDA reports was significantly inferior compared with literature cases (P < 0.0001). Among HBV core antibody (HBcAb(+)) series, the pooled effect of rituximab-based therapy showed a significantly increased risk of HBV-R compared with nonrituximab-treated patients (odds ratio 5.73, 95% CI 2.01-16.33; Z = 3.33, P = 0.0009) without heterogeneity (χ(2) = 2.12, P = 0.5473). CONCLUSIONS The FDA AERS provided strong HBV-R safety signals; however, literature-based cases provided a significantly more complete description. Furthermore, meta-analysis of HBcAb(+) series identified a more than fivefold increased rate of rituximab-associated HBV-R.

8096 Background: In 2004, based on 3 case reports, the FDA warned health care professionals of R-R HBV-reactivation (HBV-R). Since then, additional cases have been reported. However, the scope and characteristics of this association remain largely unknown. Methods: From 1997-2009, we identified 183 unique cases of R-R HBV-R: 169 from medical literature, 4 through institutional surveillance, while only 10 cases were reported to the FDA MedWatch system. Case reports were examined for quality/completeness and case series for incidence and mortality. Results: Of 169 R-R HBV-R cases reported in the literature, 26 were published as case reports and 143 as case series. Of the 26 case reports and 4 surveillance cases (n=30), 18 patients (pts) had + HBV core antibody (HBcAb+) and 12 HBV surface antigen (HBsAg+). The median number of rituximab doses prior to HBV-R was 6 (3-10). Median time from last rituximab dose to HBV-R was 4 months (0-21; 30% occurred >6 months). 60% of pts experienced fulminant liver failure, while the HBV-R mortality rate was 40%. Quality comparison and completeness of source data from the literature and surveillance reports were significantly superior to FDA reports (overall completeness ratio: 2.18, p=0.015). In terms of R-R HBV-R case series reports (n=143), 80 pts had HBcAb+ and 63 HBsAg+ (Table); 5 series included a control group. R-R therapy was associated with a significant increase in HBV-R (risk ratio 13.6, 95% CI 3.9, 72.2; p<0.0001), although the incidence and mortality varied greatly across studies. Conclusions: A paucity of R-R HBV-R safety reports have been reported to the FDA, of which are poor quality. Meta-analysis of the medical literature showed a significant increase in HBV-R with R-R therapy. However, incidence and mortality rates varied significantly across studies. Prospective examination of R-R HBV-R is warranted. Case series* Incidence of R-R HBV-R (vs. non R-R) Mortality rate# HBcAb+^ 8% (0.1%) 43% 45%, all R-R 40% 2.7% (0.8%) 0 24% (0) 20% 27%, all R-R NR 6% (0) 0 HBsAg + 16% (0) NR 65%, all R-R NR 80%, all R-R 17% Abbreviation: NR, not reported. * 89% cases from retrospective series. # From R-R HBV-R. ^ None with HBV prophylaxis. No significant financial relationships to disclose.

Abstract Abstract 1370 Poster Board I-392 Background: HBV is a major public health problem with infection that can lead to cirrhosis, liver failure, and death. Immunosuppressive therapy, such as steroids and/or chemotherapy, is known to cause a flare or “reactivation” of HBV (HBV-react). Rituximab was approved in 1997 for the treatment of B-cell lymphoma. In 2004, based on 3 case reports, the FDA warned healthcare professionals of rituximab-associated HBV-react. Since that time, multiple cases and retrospective series of rituximab-induced HBV-react have been reported in the literature. However, the characteristics and scope of this association still remains largely unknown. We evaluated the characteristics of patients with lymphoma who developed HBV-react after exposure to rituximab, and the quality of case reports available in the medical literature and at the FDA. Methods: Data sources included 2 observations at Northwestern Memorial Hospital, 83 reports from the medical literature, and 10 reports obtained from the FDA MedWatch database (n=97). Two reports of rituximab-related HBV-react not associated with lymphoma (vasculitis and gloumerulonephritis) were excluded. HBV-react was defined as ≥ 2-fold increase in serum HBV DNA with an increase in serum ALT compared with baseline. A completeness analysis was performed comparing cases submitted to the FDA MedWatch database vs. the medical literature and active surveillance. Results: Of 83 unique cases of HBV-react associated with rituximab reported in the literature, 28 were published as case reports, while 55 were included in case series. Of these 83 cases, 46 occurred in patients (pts) with anti-HBV core antibody (HBcAb+) in the absence of HBV surface antigen (HBsAg-), while 37 cases involved pts with chronic HBV hepatitis (i.e, HBsAg+). Among the 28 case reports and 2 Northwestern cases (n=30; HBcAb+ n=16, HBsAg+ n=14), the median age at HBV-react was 55 years (23M/9F). Histology of these cases were diffuse large B-cell lymphoma (n=19), indolent lymphoma (n=8), CLL (n=2), and mantle-cell lymphoma (n=1). In terms of concomitant treatment at time of HBV-react, 25 pts were receiving concurrent immunosuppressive therapy (chemotherapy +/- steroids n=22 and steroids n=3), while only 5 cases involved single-agent rituximab treatment. Each of these 5 latter pts had received chemotherapy prior to rituximab treatment (2, 3, 12, 24, and 34 months). The median number of rituximab doses received prior to HBV-react was 6 (range 3-10). The median time from last rituximab dose to HBV-react was 5 months (0-21 months); of note, 30% of cases occurred >6 months from last rituximab dose. In terms of outcome, 60% of pts experienced fulminant liver failure, while the remaining had HBV-related hepatitis. Furthermore, 40% (12/30) of pts died due to HBV-react. Quality comparison of source data of the literature and surveillance reports vs. the FDA is contained in Table 1. Overall completeness ratio for literature and observed reports vs. the FDA was 2.18. Of rituximab-related HBV-react occurrences (n=55) reported in 8 case series, five studies included a control group; there was a suggestion of increased risk of HBV-react with rituximab-based therapy, especially with concurrent steroids, although the absolute risk was not consistent (e.g., among HBcAb+ cases, reported rate of HBV-react: 2.7% to 23.8%). Conclusions: We have found 95 total cases of rituximab-associated HBV-react. A paucity of safety reports regarding rituximab-associated HBV-react have been reported to the FDA MedWatch. Furthermore, published cases in the medical literature and through active surveillance were superior in data quality compared with FDA reports. However, the absolute risks of rituximab-related HBV-react in HBsAg+ or HBcAb+ pts are still not known. Further examination of the relationship of HBV-react with single-agent rituximab and rituximab combined with immunosuppressive therapy, with and without steroids, using an active surveillance strategy is warranted. Disclosures: No relevant conflicts of interest to declare.

INTRODUCTION:Common manifestations of multiple myeloma include osteolytic lesions, cytopenias, hypercalcemia, and renal insufficiency. Patients may also exhibit heart failure which is often associated with either past therapy or cardiac amyloidosis. A less recognized mechanism is high-output heart failure. Diuretic therapy in this setting has little efficacy in treating the congested state. Furthermore, effective pharmacotherapy has not been established. We report two patients with multiple myeloma and high-output heart failure who failed diuretic therapy. The patients were given dexamethasone in conjunction with lenalidomide and thalidomide, respectively. Shortly thereafter, each patient demonstrated a significant improvement in symptoms. This is the first report of successful treatment of multiple myeloma-induced high-output failure via the utilization of these agents.CASE PRESENTATION:Two patients with multiple myeloma were evaluated for volume overload. The first was a 50-year-old man with refractory disease. Magnetic resonance imaging demonstrated diffuse marrow replacement throughout the pelvis. Cardiac catheterization conveyed elevated filling pressures and a cardiac output of 15 liters/minute. He quickly decompensated and required mechanical ventilation. The second patient was a 61-year-old man recently diagnosed with multiple myeloma and volume overload. Skeletal survey demonstrated numerous lytic lesions throughout the pelvis. His cardiac catheterization also conveyed elevated filling pressures and a cardiac output of 10 liters/minute. Neither patient responded to diuretic therapy and they were subsequently started on dexamethasone plus lenalidomide and thalidomide, respectively. The first patient's brisk diuresis allowed for extubation within 48 hours after the first dose. He had a net negative fluid balance of 15 liters over 10 days. The second patient also quickly diuresed and on repeat cardiac catheterization, his cardiac output had normalized to 4.7 liters/minute.CONCLUSION:Multiple myeloma can cause high-output failure. The mechanism is likely extensive bony involvement causing innumerable intramedullary arteriovenous fistulas. Diuretic therapy is not effective in treating this condition. Lenalidomide and thalidomide, both of which inhibit angiogenesis, seem to be viable treatment options. Based on the rapid and effective results seen in these two patients, a potential novel mechanism of 'pharmacologic fistula ligation' with these agents may be the most effective way to treat this presentation.