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Background: Haemophilia A (HA; Factor VIII deficiency) is a congenital X-linked bleeding disorder characterized by trauma-related or spontaneous bleeding events, most notably arising within the intraarticular space and resulting in chronic inflammation and degeneration of affected joints. Endogenous clotting factor activity relative to normal levels determines the severity of HA symptoms, as mild (> 5–40%), moderate (1–5%), or severe (< 1%). Within the current environment of rapid evolution in HA management, we seek to understand the interplay of condition severity and health-related quality of life (HRQoL) to characterise and differentiate unmet needs among people with HA (PwHA). Methods: A generalised linear regression model (GLM) was developed to explore the relationship between HA severity and EQ-5D-5 L index score from adult HA patients sampled in the "Cost of Haemophilia across Europe – a Socioeconomic Survey II" (CHESS II) cross-sectional, retrospective burden of illness study among adults with hereditary haemophilia A or B from eight European countries. HA patients of any severity with no active inhibitors during the 12 months prior to data capture and a completeEQ-5D-5 L response were included. A base GLM model was specified with covariates for demographic and clinical characteristics (age, body mass index, country, employment, HA severity, annual bleeding rate, problem joints, and chronic pain). Results: Of 381 evaluable patients, 221 (58.0%) had severe HA, 96 (25.2%) had moderate HA, and 64 (16.8%) had mild HA. Among the covariates included in the GLM model and after controlling for haemophilia-related outcomes, a significant association was observed between mild HA and higher EQ-5D-5 L index score (average marginal effects, 0.084; p = 0.016) relative to severe HA. Patient country of residence and magnitude of HA-related chronic pain were also associated with significant differences in index scores, with the latter showing a negative relationship with HRQoL outcomes. Conclusions: Condition severity and chronic pain are significant predictors of HRQoL in PwHA. Durable bleeding protection and effective management of chronic pain have the potential to address unmet treatment needs in this population. [ABSTRACT FROM AUTHOR]

Background: Haemophilia A carries a substantial healthcare burden, affecting health-related quality of life (HRQoL). The Cost of Haemophilia in Men: a Socioeconomic Survey II (CHESS II), a retrospective real-world study, characterised the burden of haemophilia and its impact on HRQoL and work productivity. The current analysis explored the impact of bleeding events on HRQoL and work productivity in Europe. This analysis focused on data collected from males aged 18 to 64 years with haemophilia A without inhibitors who were receiving replacement factor products or a monoclonal antibody and were not participating in a clinical trial at the time of study recruitment. Descriptive statistics were analysed using scores from EuroQoL's EQ-5D-5L index and EQ-VAS analogue scale and the Work Productivity and Activity Index Specific Health Problem (WPAI:SHP) percentage scores stratified by the number of annual bleeding events (ABs) 0, 1, 2, 3–4, or ≥ 5. Results: Of 918 males with haemophilia A in CHESS II, 318 met inclusion criteria and had data available for HRQoL measures; mean age (SD) was 33.8 (12.1) years and 96% were White. Mean (SD) ABs of 2.7 (2.9) occurred over the preceding 12 months: 20% had 3 or 4 ABs; 17% had ≥ 5 ABs. Mean EQ-5D-5L index scores for patients with 0, 1, 2, 3–4, or ≥ 5 ABs were 0.92, 0.76, 0.76, 0.71, and 0.56, respectively. Mean (SD) EQ-VAS scores were 86.9 (13.6), with 0 ABs versus 69.5 (19.1) for 3 or 4 ABs and 61.2 (17.2) for ≥ 5 ABs. Mean percentage of overall work productivity loss on the WPAI:SHP questionnaire ranged from 9.70 to 0 ABs to 47.65 for ≥ 5 ABs. Conclusions: In this European sample of adult men with haemophilia A, HRQoL and work productivity scores were lower among those reporting more AB events. Bleeding burden appears to affect HRQoL and productivity; however, this cross-sectional analysis limits the ability to draw firm conclusions on causality. [ABSTRACT FROM AUTHOR]

Introduction: Adequate prophylactic treatment and physical activity improve joint health and clinical outcomes for people with haemophilia A (HA). However, non‐clinical joint‐related burden of moderate (MHA) and severe (SHA) HA has not been well characterised. Aim: To quantify the joint health‐related humanistic and economic burden of MHA and SHA in Europe. Methods: A retrospective analysis of the cross‐sectional CHESS population studies using a patient‐centric measure of joint health (problem joints, PJs: chronic joint pain and/or limited range of movement due to compromised joint integrity with or without persistent bleeding) was conducted. Descriptive statistics summarised health‐related quality of life (HRQoL), work productivity/activity impairment and costs by number of PJs (0, 1 or ≥2) and HA severity. Results: A total of 1171 patients were included from CHESS‐II (n = 468) and CHESS‐PAEDs (n = 703). In both studies, 41 and 59% of patients had MHA and SHA, respectively. Prevalence of ≥2 PJs was similar with MHA and SHA (CHESS‐II: 23 and 26%; CHESS‐PAEDs: 4 and 3%, respectively). HRQoL was worse with an increasing number of PJs (CHESS‐II:.81 vs..66 with 0 and ≥2 PJs, respectively, for MHA;.79 vs..51 for SHA; CHESS‐PAEDs:.64 vs..26 and.72 vs..14). Total costs increased with increasing PJs regardless of severity in CHESS‐II (€2923 vs. €22,536 with 0 and ≥2 PJs, respectively, for MHA; €11,022 vs. €27,098 for SHA) and CHESS‐PAEDs (€6222 vs. €11,043 for MHA; €4457 vs. €14,039 for SHA). Conclusion: Presence of PJs was associated with a substantial humanistic and economic burden on patients with MHA or SHA across the lifespan. [ABSTRACT FROM AUTHOR]

Introduction: The "problem joint" (PJ) concept was developed to address patient‐centric needs for a more holistic assessment of joint morbidity for people with haemophilia (PwH). Aim: To quantify the humanistic burden of PJs in PwH to further support validation of the PJ outcome measure. Methods: Multivariable regression models evaluated the relationship between PJs and health‐related quality of life (HRQoL, EQ‐5D‐5L) and overall work productivity loss (WPL) using data from the 'Cost of HaEmophilia: a Socioeconomic Survey' population studies (adults: CHESS II, CHESS US+; children/adolescents: CHESS‐Paeds). Covariates included were haemophilia severity, age, comorbidities and education. Results: The CHESS II sample included 292 and 134 PwH for HRQoL and WPL analyses, mean age 38.6 years (39% ≥1 PJ, 61% none). CHESS US+ included 345 and 239 PwH for HRQoL and WPL, mean age 35 years (43% ≥1 PJ, 57% none). CHESS‐Paeds included 198 PwH aged 4–17 (HRQoL only), mean age 11.5 years (19% ≥1 PJ, 81% none). In CHESS II and CHESS US+, presence of PJs was associated with worse HRQoL (Both p <.001). Few CHESS‐Paeds participants had PJs, with no significant correlation with HRQoL. In CHESS II, upper body PJs were significantly correlated to WPL (p <.05). In CHESS US+, having ≥1 PJ or upper and lower body PJs were significantly correlated to WPL (vs. none; both p <.05). Conclusion: This study has shown a meaningful burden of PJs on PwH, which should be considered in clinical and health policy assessments of joint health. [ABSTRACT FROM AUTHOR]

Introduction: Gene therapy clinical trials measure steady‐state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. Aim: We evaluated the association between FEL and ABR in PwHB. Methods: This cross‐sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia‐treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. Results: The study included 407 PwHB and no inhibitors receiving on‐demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by.08 (p <.001). Predicted number of bleeding events according to FEL showed a significant non‐linear relationship between FEL and ABR (p <.05). Conclusion: This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US. [ABSTRACT FROM AUTHOR]

Background: Haemophilia bears substantial humanistic and economic burden on children and their caregivers. Characterising the differential impact of severe versus moderate paediatric haemophilia is important for clinical and health policy decisions. We analysed health-related quality of life (HRQoL), annual direct medical (excluding factor treatment costs), non-medical and societal costs among children and adolescents with moderate and severe haemophilia A or B without inhibitors from the European CHESS-PAEDs study. Information was reported by physicians and caregivers; patients aged ≥ 8 years self-reported their HRQoL. Descriptive statistics summarised demographic and clinical characteristics, costs, and HRQoL scores (EQ-5D-Y). Regression models estimated differences in HRQoL and costs for moderate versus severe haemophilia adjusting for age, body mass index z-score, country, number of comorbidities, and weight-adjusted annual clotting factor consumption.Results: The analytic sample comprised 794 patients with a mean age of 10.5 years; most had haemophilia A (79%) and 58% had severe haemophilia. Mean predicted direct medical costs in moderate patients were two-thirds of the predicted costs for severe disease (€3065 vs. €2047; p < 0.001; N = 794), while societal costs were more than half of the predicted costs for children with severe haemophilia (€6950 vs. €3666; p < 0.001; N = 220). Mean predicted HRQoL scores were 0.74 and 0.69 for moderate and severe disease, respectively (p < 0.05; N = 185).Conclusion: Children with haemophilia and their caregivers displayed a significant economic and humanistic burden. While severe patients showed the highest direct medical and societal costs, and worse HRQoL, the burden of moderate haemophilia on its own was substantial and far from negligible. [ABSTRACT FROM AUTHOR]

Background: Real-world studies of the burden of severe haemophilia B in the context of recent therapeutic advances such as extended half-life (EHL) factor IX (FIX) products are limited. We analysed data from the recent CHESS II study to better understand the clinical, humanistic, and economic burden of severe haemophilia B in Europe. Data from male adults with severe haemophilia B receiving prophylaxis were analysed from the retrospective cross-sectional CHESS II study conducted in Germany, France, Italy, Spain and the United Kingdom. Inhibitors were exclusionary. Patients and physicians completed questionnaires on bleeding, joint status, quality of life, and haemophilia-related direct and indirect costs (2019-2020). All outcomes were summarised using descriptive statistics.Results: A total of 75 CHESS II patients were eligible and included; 40 patients (53%) provided self-reported outcomes. Mean age was 36.2 years. Approximately half the patients were receiving EHL versus standard half-life (SHL) prophylaxis (44% vs 56%). Most patients reported mild or moderate chronic pain (76%) and had ≥ 2 bleeding events per year (70%), with a mean annualised bleed rate of 2.4. Mean annual total haemophilia-related direct medical cost per patient was €235,723, driven by FIX costs (€232,328 overall, n = 40; €186,528 for SHL, €290,620 for EHL). Mean annual indirect costs (€8,973) were driven by early retirement or work stoppage due to haemophilia. Mean quality of life (EQ-5D) score was 0.67.Conclusions: These data document a substantial, persistent real-world burden of severe haemophilia B in Europe. Unmet needs persist for these patients, their caregivers, and society. [ABSTRACT FROM AUTHOR]

Introduction: Few studies have examined the real‐world impact of haemophilia on daily activities and work productivity in people with severe haemophilia A (PWSHA). Aim: To determine clinical attributes and treatment characteristics associated with impairment in daily activities and work among PWSHA using the patient‐reported Work Productivity and Activity Impairment‐General Health Questionnaire (WPAI‐GH). Methods: PWSHA were asked to complete the WPAI‐GH as part of the Cost of Haemophilia in Europe: A Socioeconomic Survey (CHESS) study. Outcomes were determined for activity impairment (AI), absenteeism, presenteeism and overall work productivity loss (WPL). Descriptive statistics and regression analyses were used to evaluate the association between these outcomes and clinical and treatment attributes. Results: Overall, 376 participants completed the AI element of WPAI‐GH; 175 were employed and thus also reported on work impact. Mean ± standard deviation scores were as follows: AI = 34.2% ± 25.8%; absenteeism = 0.06% ±0.2%; presenteeism = 26.8% ± 22.4%; WPL = 28.6% ± 24.0%. Increased AI and WPL were associated with high haemophilia‐related morbidity, measured both as chronic pain (p <.001 for both) and joint synovitis (AI: p <0.001; WPL: p =.017). In descriptive and multivariate analyses, lifelong prophylaxis was associated with reduced AI (p <.001 and p =.031, respectively); high therapy adherence was associated with reduced AI (p =.001 and p =.012, respectively) and with reduced WPL (p <.001 and p =.012, respectively). Conclusion: The WPAI‐GH identified haemophilia‐related morbidity and treatment characteristics, including therapy regimen and adherence, as key attributes impacting functional impairment and work contributions of PWSHA. Early prophylactic intervention and greater adherence to therapy may lead to lower AI and WPL in PWSHA. [ABSTRACT FROM AUTHOR]

Aims: Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2-3 or 7-14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB. Materials and methods: With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including "bleed into joint", "bleed not into joint", "no bleed" and "death". Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings. Results: Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment accounts for >90% of the total HB treatment costs. Conclusions: This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm. [ABSTRACT FROM AUTHOR]

Background: Hemophilia B is a rare congenital bleeding disorder that has a significant negative impact on patients' functionality and health-related quality of life. The standard of care for severe hemophilia B in the United States is prophylactic factor IX replacement therapy, which incurs substantial costs for this lifelong condition. Accurate estimates of the burden of hemophilia B are important for population health management and policy decisions, but have only recently accounted for current management strategies. The 'Cost of Severe Hemophilia across the US: a Socioeconomic Survey' (CHESS US) is a cross-sectional database of medical record abstractions and physician-reported information, completed by hematologists and care providers. CHESS US+ is a complementary database of completed questionnaires from patients with hemophilia. Together, CHESS US and CHESS US+ provide contemporary, comprehensive information on the burden of severe hemophilia from the provider and patient perspectives. We used the CHESS US and CHESS US+ data to analyze the clinical, humanistic, and economic burden of hemophilia B for patients treated with factor IX prophylaxis between 2017 and 2019 in the US.Results: We conducted analysis to assess clinical burden and direct medical costs from 44 patient records in CHESS US, and of direct non-medical costs, indirect costs, and humanistic burden (using the EQ-5D-5L) from 57 patients in CHESS US+. The mean annual bleed rate was 1.73 (standard deviation, 1.39); approximately 9% of patients experienced a bleed-related hospitalization during the 12-month study period. Nearly all patients (85%) reported chronic pain, and the mean EQ-5D-5L utility value was 0.76 (0.24). The mean annual direct medical cost was $614,886, driven by factor IX treatment (mean annual cost, $611,971). Subgroup analyses showed mean annual costs of $397,491 and $788,491 for standard and extended half-life factor IX treatment, respectively. The mean annual non-medical direct costs and indirect costs of hemophilia B were $2,371 and $6,931.Conclusions: This analysis of patient records and patient-reported outcomes from CHESS US and CHESS US+ provides updated information on the considerable clinical, humanistic, and economic burden of hemophilia B in the US. Substantial unmet needs remain to improve patient care with sustainable population health strategies. [ABSTRACT FROM AUTHOR]

Background: Untreated hemophilia A patients may experience recurrent bleeding events leading to debilitating joint damages. While RCT and pharmacokinetic data support the value of Kovaltry [an unmodified full-length recombinant factor VIII (FVIII) product], real world evidence in children is lacking. This report describes a descriptive and multivariate analysis of the effectiveness of Kovaltry in children with hemophilia A in the real-world setting, using data from medical chart abstraction and cross-sectional surveys of physicians, patients, and caregivers.Results: Male patients aged < 18 years with moderate or severe hemophilia A, residing in five European countries and treated with FVIII were studied. The co-primary endpoints were the annualized bleeding rate (ABR) and the annual FVIII utilization rate. Twenty nine patients treated with Kovaltry were included, of whom 93% had severe disease and 75% were on continuous prophylactic treatment. The mean ABR was 2.66 ± 2.06, with rates decreasing with age. The children received on average 2.45 infusions per week, consistent across age groups (median 3; range 1-3). There were no reports of inhibitor development or adverse events in the study (AEs), and all patients were satisfied or very satisfied with the treatment. An exploratory multivariate analysis suggests no significant difference in ABR or units utilized between Kovaltry and some extended half life products in children with severe hemophilia A, though characteristics of these patient cohorts were markedly different.Conclusion: This analysis demonstrates the effectiveness and safety of Kovaltry in a pan-European pediatric population with severe hemophilia A. [ABSTRACT FROM AUTHOR]

Hemophilia B (HB) is a rare congenital disorder characterized by bleeding-related complications which are managed by prophylactic or post-bleeding event ("on-demand") replacement of clotting factor IX (FIX). The standard of care for severe HB is life-long prophylaxis with standard half-life (SHL) or extended half-life (EHL) products given every 2–3 or 7–14 days, respectively. FIX treatment costs in the US have been investigated, but the lifetime costs of HB treatment have not been well characterized, particularly related to the impact of joint health deterioration and associated health resource utilization. We developed a decision-analytic model to explore outcomes, costs and underlying cost drivers associated with FIX treatment options over the lifetime of an adult with severe or moderately severe HB. With participation from clinicians, health technology assessment specialists and patient advocates, a Markov model was constructed to estimate bleeding events and costs associated with health states including "bleed into joint", "bleed not into joint", "no bleed" and "death". Sub-models of joint health were based on 0, 1, or ≥2 areas of chronic joint damage. US third-party payer and societal perspectives were considered with a lifetime horizon; sensitivity analyses tested the robustness of primary findings. Total adult lifetime costs per patient with severe and moderately severe HB were $21,086,607 for SHL FIX prophylaxis, $22,987,483 for EHL FIX prophylaxis, and $20,971,826 for on-demand FIX treatment. For FIX prophylaxis, the cost of FIX treatment accounts for >90% of the total HB treatment costs. This decision analytic model demonstrated significant economic burden associated with the current HB treatment paradigm. [ABSTRACT FROM AUTHOR]

Introduction: The benefits of physical activity (PA) for people with haemophilia (PWH) may include improvements in joint, bone and muscle health. However, the factor VIII activity level required to avoid a bleeding episode associated with PA is unknown. Aim: To elicit the opinion of clinical experts on the minimum level and ideal factor VIII activity ('level') required to avoid a bleeding episode during participation in different types of PA for PWH. Methods: Based on the 2017 National Hemophilia Foundation PA descriptions, clinical experts estimated a minimally acceptable and an ideal factor level at which a bleed could be avoided. The uncertainty around estimates was quantified using an approach to construct a probability distribution to represent expert opinion. Results: Minimum and ideal factor level increased with higher risk PA, whether or not joint morbidity was present, as did the experts' uncertainty in their estimates (ie the range between lowest and highest estimates for minimum and ideal levels). Mean minimum levels ranged from 4% to 48% for low to high risk for people without joint morbidity, and from 7% to 47% for those with joint morbidity. For ideal factor levels, corresponding figures were 9%‐52% and 12%‐64%, respectively. Conclusion: To support a patient‐centric outcome, expert opinion indicates that the clinical norm of 0.01 IU/mL (1%) trough level is insufficient. It is anticipated that introducing a more targeted approach to meet the needs of patients who are increasingly physically active will benefit patients further in addition to recent treatment advances. [ABSTRACT FROM AUTHOR]

Background: Severe haemophilia is associated with major psychological and economic burden for patients, caregivers, and the wider health care system. This burden has been quantified and documented for a number of European countries in recent years. However, few studies have taken a standardised methodology across multiple countries simultaneously, and sought to amalgamate all three levels of burden for severe disease. The overall aim of the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS) study was to capture the annualised economic and psychosocial burden of severe haemophilia in five European countries. A cross-section of haemophilia specialists (surveyed between January and April 2015) provided demographic and clinical information and 12-month ambulatory and secondary care activity for patients via an online survey. In turn, patients provided corresponding direct and indirect non-medical cost information, including work loss and out-of-pocket expenses, as well as information on quality of life and adherence. The direct and indirect costs for the patient sample were calculated and extrapolated to population level.Results: Clinical reports for a total of 1,285 patients were received. Five hundred and fifty-two patients (43% of the sample) provided information on indirect costs and health-related quality of life via the PSC. The total annual cost of severe haemophilia across the five countries for 2014 was estimated at EUR 1.4 billion, or just under EUR 200,000 per patient. The highest per-patient costs were in Germany (mean EUR 319,024) and the lowest were in the United Kingdom (mean EUR 129,365), with a study average of EUR 199,541. As expected, consumption of clotting factor replacement therapy represented the vast majority of costs (up to 99%). Indirect costs are driven by patient and caregiver work loss.Conclusions: The results of the CHESS study reflect previous research findings suggesting that costs of factor replacement therapy account for the vast majority of the cost burden in severe haemophilia. However, the importance of the indirect impact of haemophilia on the patient and family should not be overlooked. The CHESS study highlights the benefits of observational study methodologies in capturing a 'snapshot' of information for patients with rare diseases. [ABSTRACT FROM AUTHOR]

Background: Hemophilia B (HB) is a rare disease caused by congenital Factor IX (FIX) deficiency. HB requires life-long management to prevent or manage bleeding and associated morbidity. Although HB affects only a small portion of the population, it is associated with high overall cost and imposes a significant financial burden on individuals, payers, and society in general. Due to variation in patient clinical characteristics and treatment choice, cost and healthcare resource utilization associated with disease management can vary significantly from patient to patient. Aims: To review published direct costs and healthcare resource utilization associated with the management of HB in the US. Methods: A systematic literature review was conducted by searching electronic databases (e.g. MEDLINE, Tufts CEA registry) to identify full-text studies (March 2009–March 2019). Additionally, a manual search for abstracts from relevant conferences was performed (from 2016). Studies were included in the review using pre-defined inclusion/exclusion criteria for population, study type, language (English), and location (US). Publications consisting of budget impact analysis, cost, burden of disease, healthcare resource utilization, and economics evaluations were included. Results: Of 693 titles and abstracts screened, a total of 17 studies evaluating cost and resource utilization in patients with HB in the US were included. Data sources for these studies included: medical records (n = 5), insurance claims databases (n = 10), and surveys (n = 2). Reported cost and resource use varied across studies depending on severity of the disease, treatment regimen, and product type: extended (EHL) or standard half-life (SHL). The cost of FIX replacement therapy constitutes the majority of costs in HB management. Among patients with severe or moderate HB, reported mean annual cost of FIX ranged from $187,070 to $925,864 with an average of $560,801. Annual cost of EHLs could exceed more than twice the cost of SHLs. For example, mean annual cost of EHL FIX was $921,291 vs $478,096 for SHL FIX. Rates of healthcare resource utilization were also substantial for patients with HB and include hospitalizations, emergency room visits, and physician visits. Conclusions: This systematic literature review found significant economic burden associated with HB in the US. The substantial costs and health resources utilized by patients highlight unmet needs remaining in HB. [ABSTRACT FROM AUTHOR]