Association of factor expression levels with annual bleeding rate in people with haemophilia B.

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.

Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment.

INTRODUCTION: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. AIM: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. METHODS: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post-treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. RESULTS: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). CONCLUSION: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.

Long-Term Health Outcomes of Huntington Disease and the Impact of Future Disease-Modifying Treatments: A Decision-Modeling Analysis.

Background and Objectives: Disease-modifying treatments (DMTs) such as gene therapy are currently under investigation as a potential treatment for Huntington disease (HD). Our objective was to estimate the long-term natural history of HD progression and explore the potential efficacy impacts and value of a hypothetical DMT using a decision-analytic modeling framework. Methods: We developed a health state transition model that separately analyzed 40-year-old individuals with prefunctional decline (PFD, HD Integrated Staging System [HD-ISS] stage <3, total functional score [TFC] 13), active functional decline Shoulson and Fahn category 1 (SF1, HD-ISS stage 3, TFC 13-11), and SF2 (HD-ISS stage 3, TFC 10-7). Three-year outcomes from the TRACK-HD longitudinal study were linearly extrapolated to estimate the long-term health outcomes and costs of each population. For PFD individuals, we used the HD-ISS to predict the onset of functional decline. HD costs and quality-adjusted life years (QALYs) were estimated over a lifetime horizon by applying health state-specific costs and utilities derived from a related HD burden-of-illness study. We then estimated the long-term health impacts of hypothetical DMTs that slowed or delayed onset of functional decline. We conducted sensitivity analyses to assess model uncertainties. Results: The expected life years for 40-year-old PFD, SF1, and SF2 populations were 20.46 (95% credible range [CR]: 19.05-22.30), 13.93 (10.82-19.08), and 10.99 (8.28-22.07), respectively. The expected QALYs for PFD, SF1, and SF2 populations were 15.93 (14.91-17.44), 8.29 (6.36-11.79), and 5.79 (4.14-12.91), respectively. The lifetime costs of HD were $508,200 ($310,300 to $803,700) for the PFD population, $1.15 million ($684,500 to $1.89 million) for SF1 individuals, and $1.07 million ($571,700 to $2.26 million) for SF2 individuals. Although hypothetical DMTs led to cost savings in the PFD population by delaying the cost burdens of functional decline, they increased costs in SF1 and SF2 populations by prolonging time spent in expensive progressive HD states. Discussion: Our novel HD-modeling framework estimates HD progression over a lifetime and the associated costs and QALYs. Our approach can be used for future cost-effectiveness models as positive DMT clinical trial evidence becomes available.

Humanistic Burden of Huntington Disease: Evidence From the Huntington Disease Burden of Illness Study.

Background and Objectives: Huntington disease (HD) is a rare, inherited, and highly complex neurodegenerative disorder with no currently approved disease-modifying treatments. We investigated the effect of HD on health-related quality of life and other patient-reported outcomes in the Huntington's Disease Burden of Illness (HDBOI) study. Methods: The HDBOI study is a retrospective, cross-sectional study conducted between September 2020 and May 2021 in France, Germany, Italy, Spain, the United Kingdom, and the United States. People with symptomatic onset HD (PwHD) were recruited by their HD-treating physicians and categorized as early (ES), mid (MS), or advanced stage (AS) HD. Physicians provided sociodemographic and clinical information from the participant's medical records in electronic case report forms (eCRF); participants or their proxies completed online Patient Public Involvement Engagement questionnaires (PPIE-P). Patient-reported outcomes included the 5-level EQ-5D version (EQ-5D-5L), Short-Form-(SF)-36 v2 (and SF-6-Dimension [SF-6D] utility), Huntington Quality of Life Instrument (H-QoL-I), and the Work Productivity and Activity Impairment Specific Health Problem. All outcomes were summarized using descriptive statistics, and differences between disease stages were assessed by Kruskal-Wallis tests. Results: A total of 2,094 PwHD were enrolled with completed eCRFs (100%) and PPIE-P forms (n = 482, 23%). Participants' mean age was 47.3 years; they were generally evenly distributed across countries, with the majority being ES (40%) followed by MS (33%) and LS (26%). The mean EQ-5D-5L (n = 336) utility score was 0.59 (SD, 0.27), with the highest mean utility scores [SD] in ES (0.72 [0.22]) followed by MS (0.62 [0.18]) and AS (0.37 [0.30]), p < 0.001. The mean SF-6D score (n = 482) was 0.57 (SD, 0.10), with mean values decreasing with advanced disease (ES, 0.61; MS, 0.56; AS, 0.50, p < 0.001). H-QoL-I mean scores (n = 482) also worsened with more advanced disease, from 0.58 for ES to 0.49 for MS and 0.37 for AS, p < 0.001. Impairment in daily activities and in work productivity also increased with more advanced disease. Overall proxy respondents reported on average worse outcomes than PwHD (self-reported) across all outcomes and disease stages suggesting a possible unawareness of deficits by PwHD. Discussion: The HDBOI study provides new insights into the characteristics and humanistic burden of PwHD and offers a meaningful contribution to this underserved research area.

Association of factor expression levels with health-related quality of life and direct medical costs for people with haemophilia B.

AIMS: Gene therapy trials aim to provide a functional cure for patients with haemophilia B (HB), and treatment impact is analyzed by factor IX expression levels (FELs). We investigated the relationship of FELs with health-related quality of life (HRQoL) and costs. MATERIALS AND METHODS: This was a retrospective cross-sectional analysis of the European (CHESS I-II) and US (CHESS-US) CHESS population studies. Physicians recruited consecutive patients and extracted information from the medical records; patients completed questionnaires between 2014 and 2015 (CHESS-I), 2018-2019 (CHESS-II) and 2019 (CHESS US). Patients with inhibitors were excluded. HRQoL was assessed using the EQ-5D-5L. Twelve-month haemophilia-related direct medical costs included office visits and hospitalizations based on country-level unit costs. A Tobit model was used to analyze FELs and HRQoL and generalized linear models for direct medical costs. RESULTS: A total of 191 men with HB completed the EQ-5D questionnaire; the mean age was 36.8 years, with a mean FEL of 10.1 IU/dL (median, 4.0). Mean EQ-5D was 0.77 (SD, 0.23). The Tobit model adjusting for age, body mass index and blood-borne viruses showed every 1% increase in FEL was associated with +0.006 points in the mean EQ-5D score (p = .003). Mean haemophilia-related direct medical costs excluding factor replacement therapy were €2,028/year (median, €919) in CHESS I-II (EU, n = 226), and $7,171/year (median, $586) in CHESS US (n = 181). Adjusted EU and US models showed every 1% increase in FEL was associated with a decrease in haemophilia-related direct medical costs of €108/year and $529/year, respectively. LIMITATIONS: Direct medical costs were based on physician extraction of encounters from medical records, potentially underestimating costs of care. The voluntary nature of participation may have introduced selection biases. CONCLUSIONS: We observed a significant association of increases in FEL with increased HRQoL and decreased costs in Europe and the United States among men with HB and no inhibitors.

Alma-Ata: Rebirth and Revision 6 Interventions to address maternal, newborn, and child survival: what difference can integrated primary health care strategies make?

Several recent reviews of maternal, newborn, and child health (MNCH) and mortality have emphasised that a large range of interventions are available with the potential to reduce deaths and disability. The emphasis within MNCH varies, with skilled care at facility levels recommended for saving maternal lives and scale-up of community and household care for improving newborn and child survival. Systematic review of new evidence on potentially useful interventions and delivery strategies identifies 37 key promotional, preventive, and treatment interventions and strategies for delivery in primary health care. Some are especially suitable for delivery through community support groups and health workers, whereas others can only be delivered by linking community-based strategies with functional first-level referral facilities. Case studies of MNCH indicators in Pakistan and Uganda show how primary health-care interventions can be used effectively. Inclusion of evidence-based interventions in MNCH programmes in primary health care at pragmatic coverage in these two countries could prevent 20-30% of all maternal deaths (up to 32% with capability for caesarean section at first-level facilities), 20-21% of newborn deaths, and 29-40% of all postneonatal deaths in children aged less than 5 years. Strengthening MNCH at the primary health-care level should be a priority for countries to reach their Millennium Development Goal targets for reducing maternal and child mortality.

Attitude toward organ donation: a survey in Pakistan.

This study was conducted to get an insight into the knowledge, attitude, and practices of the people of Pakistan regarding organ donation (OD), and to understand the various factors that influence these. Systematic sampling was used to generate a sample size of 357. Data collection was carried out via a questionnaire in the outpatient units of our hospital. All kinds of medical and surgical patients were interviewed. Knowledge of ODs that occur in Pakistan and the rest of the world was found to be 65.5 and 72.8%, respectively. The percentage of those willing to donate their organ/s was 59.9%. Knowledge of OD was significantly associated with education and socioeconomic status. Willingness to donate had a significant association with gender. It also had a moderate association with education and socioeconomic status. Awareness of OD and the knowledge that OD can save lives was also significantly associated with the willingness to donate.