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Aim: To evaluate all-cause and liver-associated healthcare resource utilization (HCRU) and costs among patients with alpha-1 antitrypsin deficiency (AATD) with liver disease (LD) and/or lung disease (LgD). Materials & methods: This was a retrospective analysis of linked administrative claims data from the IQVIA PharMetrics ® Plus and the IQVIA Ambulatory Electronic Medical Records (AEMR) databases from 1 July 2021 to 31 January 2022. Patients with AATD in the IQVIA PharMetrics Plus database were included with ≥1 inpatient or ≥2 outpatient medical claims ≥90 days apart with a diagnosis of AATD, or with records indicating a protease inhibitor (Pi)*ZZ/Pi*MZ genotype in the IQVIA AEMR database with linkage to IQVIA PharMetrics Plus. For a patient's identified continuous enrollment period, patient time was assigned to health states based on the initial encounter with an LD/LgD diagnosis. A unique index date was defined for each health state, and HCRU and costs were calculated per person-year (PPY). Results: Overall, 5136 adult and pediatric patients from the IQVIA PharMetrics Plus and IQVIA AEMR databases were analyzed. All-cause and liver-associated HCRU and costs were substantially higher following onset of LD/LgD. All-cause cost PPY ranged from US $11,877 in the absence of either LD/LgD to US $74,015 in the presence of both LD and LgD. Among liver transplant recipients in the AATD with LD health state, liver-associated total costs PPY were US $87,329 1-year pre-transplantation and US $461,752 1-year post-transplantation. In the AATD with LgD and AATD with LD and LgD health states, patients who received augmentation therapy were associated with higher all-cause total costs PPY and lower liver-associated total costs PPY than their counterparts who did not receive augmentation therapy. Conclusion: Patients with AATD had increased HCRU and healthcare costs in the presence of LD and/or LgD. HCRU and healthcare costs were highest in the AATD with LD and LgD health state.

Background: Alpha-1-Antitrypsin Deficiency (AATD) is an economically unexplored genetic disease., Methods: Direct and indirect costs (based on self-reported information on healthcare utilization) and health-related quality of life (HRQL, as assessed by SGRQ, CAT, and EQ-5D-3 L) were compared between 131 AATD patients (106 with, 25 without augmentation therapy (AT)) and 2,049 COPD patients without AATD participating in the COSYCONET COPD cohort. The medication costs of AT were excluded from all analyses to reveal differences associated with morbidity profiles. The association of AATD (with/without AT) with costs or HRQL was examined using generalized linear regression modelling (GLM) adjusting for age, sex, GOLD grade, BMI, smoking status, education and comorbidities., Results: Adjusted mean direct annual costs were €6,099 in AATD patients without AT, €7,117 in AATD patients with AT (excluding costs for AT), and €7,460 in COPD patients without AATD. AATD with AT was significantly associated with higher outpatient (+273%) but lower inpatient (-35%) and medication costs (-10%, disregarding AT) compared with COPD patients without AATD. There were no significant differences between groups regarding indirect costs and HRQL., Conclusion: Apart from AT costs, AATD patients tended to have lower, though not significant, overall costs and similar HRQL compared to COPD patients without AATD. AT was not associated with lower costs or higher HRQL., Trial Registration: NCT01245933.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is a genetic condition that can lead to the early onset of chronic obstructive pulmonary disease (COPD), a disorder that comprises elements of chronic bronchitis and emphysema. AATD is characterized by reduced levels of the AAT protease inhibitor, leading to unrestricted protease activity in the lung, which promotes destruction of lung tissue. In severe cases, patients with AATD have an increased mortality risk and, potentially, a poor quality of life due to more frequent COPD exacerbations and/or limitations on daily activity. However, the burden of AATD on members of the patient's immediate family who may serve as caregivers has not been described. Because the age range at which most patients are diagnosed with AATD may affect the economic status of an individual and/or of a family, it is likely that a diagnosis of AATD may have negative effects that extend beyond those on the diagnosed person to include immediate family members. Here, we review the literature to investigate the impact of the caregiver role of family members in disease states that affect an age group similar to AATD. Furthermore, we provide a case study showing the effect of AATD on immediate family members.

Introduction: Alpha-1 antitrypsin deficiency (AATD) is a relatively common, but under-recognized condition which manifests commonly with liver cirrhosis and emphysema. Specific therapy for lung-affected individuals with AATD is augmentation therapy, which consists of intravenous infusion of purified human plasma-derived alpha-1 antitrypsin (AAT). Augmentation therapy was first approved by the United States Food and Drug Administration (FDA) in 1987 for emphysema associated with severe AATD and today, six augmentation therapy preparations, all of which derive from pooled human plasma, have received FDA approval., Areas Covered: This paper reviews augmentation therapy for AATD, including the various available commercial preparations, their processing and biochemical differences, evidence regarding biochemical and clinical efficacy, patterns of clinical use, adverse effect profiles, cost-effectiveness and potential uses in conditions other than emphysema associated with AATD. Novel and emerging strategies for treating AATD are briefly discussed next, including alternative dosing and administration strategies, recombinant preparations, small molecule inhibitors of neutrophil elastase and of AAT polymerization, autophagy-enhancing drugs and gene therapy approaches., Expert Opinion: We conclude with a discussion of our approach to managing patients with AATD and use of augmentation therapy.

Background: α(1)-Antitrypsin deficiency (α-ATD) is a disorder inherited in an autosomal recessive pattern, with co-dominant alleles known as the protease inhibitor system (Pi). The main function of α(1)-antitrypsin (α-AT) is to protect the lungs against a powerful elastase released from neutrophil leucocytes. α-ATD typically presents with a serum α-AT level of <50 mg/dL. In severe α-ATD, phenotype PiZZ, protection of the lungs is compromised, leading to an accelerated decline in forced expiratory volume in 1 second (FEV(1)). As a result, a patient may develop pulmonary emphysema of the panacinar type at a young age (third to fourth decades of life), with cigarette smoking being the most significant additional risk factor. It has been shown that weekly or monthly infusion of human α-AT is effective in raising serum α-AT levels to desired levels (>80 mg/dL), with few, if any, adverse effects., Objective: The present study was designed to discern the number of years of life gained, and the expense per year of life gained, associated with use of α-AT augmentation therapy (α(1)-proteinase inhibitor [human]), relative to 'no therapeutic intervention' in persons with α-ATD., Methods: Monte Carlo simulation (MCS) was used to: (i) estimate the number of years of life gained; and (ii) estimate the health service expenditures per year of life gained for persons receiving, or not receiving, α-AT augmentation therapy. MCS afforded a decision-analytical framework parameterized with both stochastic (random) and deterministic (fixed) components, and yielded a fiscal risk-profile for each simulated cohort of interest (eight total: by sex, smoking status [non-smoker; or past use (smoker)]; and use of α-AT augmentation therapy). The stochastic components employed in the present inquiry were: (i) age-specific body weight, and height; (ii) age-specific mortality; and (iii) the probability distribution for receipt of a lung transplant, as a function of FEV(1). The deterministic components employed in the present inquiry were: (i) age in years for the simulated cohort; (ii) outlays for α-AT augmentation therapy; (iii) health service expenditures associated with receipt of a lung transplant; (iv) annual decline in FEV(1); (v) percent predicted FEV(1); (vi) initiation of α-AT augmentation therapy as a function of percent predicted FEV(1); (vii) need for a lung transplant as a function of percent predicted FEV(1); (viii) annual rate of lung infection; and (ix) mortality as a function of percent predicted FEV(1). Results are reported from a payer perspective ($US, year of costing 2010)., Results: Receipt of α-AT augmentation therapy was associated with a significant increase (p < 0.05) in years of life gained, with female smokers gaining an estimated mean 7.14 years (cost per year: $US248 361 [95% CI 104 531, 392 190]); female non-smokers gained an estimated mean 9.19 years (cost per year: $US160 502 [95% CI 37 056, 283 947)]); male smokers gained an estimated mean 5.93 years (cost per year: $US142 250 [95% CI 48 467, 236 032]); and male non-smokers gained an estimated mean 10.60 years (cost per year: $US59 234 [95% CI 20 719, 97 548])., Conclusion: Use of α-AT augmentation therapy was associated with an increase in years of life gained by sex and history of tobacco use, and at a cost per year of life gained comparable to that of other evidenced-based interventions.

The objective was to assess the cost-effectiveness of population screening for alpha-1 antitrypsin (AAT) deficiency. The design was a Markov-based decision analytic model. Hypothetical cohorts were analyzed from birth and followed over time until death using Monte Carlo simulation. The following strategies were compared: 1) screen all newborns, 2) screen all 10-year-old children, and 3) do not screen. Screenees found to have PI*ZZ AAT deficiency received the benefits of lower smoking rates and were offered augmentation therapy. In keeping with reported experience, most (96%) non-screened AAT deficient individuals remained undiagnosed and, therefore, missed these benefits. Under base conditions, screening all newborns cost nearly $422,000 per quality-adjusted life-year (QALY) gained; this estimate fell to $92,135 per QALY when the cost of screening was minimized to $6 in the model. Delaying screening until age 10 decreased the incremental cost-effectiveness ratio (ICER) to nearly $317,000. In sensitivity analysis, when the prevalence of PI*ZZ individuals increased from a baseline of 1.96 to 16 per 10,000, the ICER for newborn screening decreased below $100,000 per QALY. When the cost of screening and augmentation therapy were decreased simultaneously with increasing PI*ZZ prevalence, there were many scenarios in which the ICER decreased below $50,000. While population-based screening for AAT deficiency is not cost-effective under current conditions, cost-effectiveness criteria could be satisfied when case-finding in a high prevalence population is undertaken.

The biochemical and clinical efficacy of intravenous augmentation therapy in alpha(1)-antitrypsin deficiency is reviewed, adverse events experienced with this treatment are considered, and its cost effectiveness is discussed.

alpha(1)-Antitrypsin (AAT) deficiency is a common but under-recognised condition. Since its first description by Laurell and Eriksson in 1963, significant advances have been made in understanding the genetics, physiology and pathophysiology of this condition. The intravenous administration of purified AAT to AAT-deficient individuals has been shown to confer biochemical efficacy by raising the serum AAT level above an epidemiologically established 'protective threshold' while preserving the biochemical properties and functional capacity of the protease inhibitor. Although the lack of a large randomised controlled trial to date has precluded the definitive demonstration of clinical efficacy of intravenous AAT augmentation therapy, substantial evidence supporting its use in AAT-deficient individuals with moderate airflow obstruction has accumulated. For example, both large observational studies comparing rates of forced expiratory volume decline among recipients of augmentation therapy versus non-recipients have shown slower rates of decline among augmentation therapy recipients, especially those with moderately severe airflow obstruction. Also, some evidence suggests that use of augmentation therapy confers an anti-inflammatory effect. For example, a web-based survey suggested that recipients of augmentation therapy experienced fewer respiratory infections than non-recipients. Despite its high cost, intravenous AAT augmentation therapy remains the only US FDA-approved treatment option for patients with AAT deficiency. Research into new and evolving treatments is currently underway.

Study Objectives: To examine the sources of the direct medical costs of alpha(1)-antitrypsin (AAT) deficiency based on survey data from affected individuals., Background: Prior research has reported the total cost of AAT deficiency but has not examined the specific components of the direct medical costs of affected individuals., Methods: In order to detail the sources of the direct medical costs, we sent surveys to 688 respondents of a previous survey. We estimated the costs in three ways, which differed in the method of managing missing values. With method 1, the group mean value of cost per unit of utilization, multiplied by the occurrences of utilization, was used to replace the missing value. Two sensitivity analyses (ie, methods 2 and 3) were conducted to test the robustness of our estimate. With method 2, values of zero were entered for all missing values. With method 3, the missing values were replaced by the group mean value. The Wilcoxon test was used to test the cost differences between patients of different phenotypes. All cost data were expressed in 1998 US dollars., Results and Conclusions: Two hundred ninety-two individuals responded to the survey. The annual total health-care costs were high (mean range, $36,471 to $46,114 US dollars; median range, $12,485 to $37,100 US dollars [according to the method for managing missing data]) for AAT deficiency. The total costs for individuals with the PI*ZZ phenotype exceeded those for individuals with a non-PI*ZZ phenotype. The use of IV augmentation therapy accounted for more than half of all direct medical costs for the respondents. Besides the costs for therapy with alpha(1)-proteinase inhibitor (Prolastin; Bayer; West Haven, CT), other major cost sources were prescription drugs other than alpha(1)-proteinase inhibitor, hospitalization, health insurance, and physician visits.

Objective: Severe alpha(1)-Antitrypsin (AAT) deficiency (PiZZ) predisposes to the development of emphysema. Intravenous augmentation therapy with purified human AAT has been available since 1988. The dosage has varied from 60 mg/kg body weight once weekly to 250 mg/kg once monthly. We have found the dosage of 120 mg/kg every 2 weeks to be the most convenient for the patients. The treatment is very expensive. The objective of this investigation was to study whether tailored pharmacokinetic dosing of human AAT allows self-administration and reduces the total annual dose and cost of intravenous augmentation therapy., Methods: Five PiZZ individuals receiving purified human AAT at a dose of 120 mg/kg every 2 weeks were included in the study. Three patients had a percutaneous and one patient had a subcutaneous intravenous injection port system. After a 4-week interruption of the treatment an ordinary dose of 120 mg/kg human AAT was infused. Plasma AAT levels were determined preinfusion, postinfusion, and once daily for 10-14 days. The pharmacokinetic parameters of exogenous AAT were calculated for each patient. Based on these, individual dosage schemes were designed by computer simulation. The patients were treated with the new dose twice weekly for 4 weeks, and plasma AAT was determined immediately before the last two infusions., Results: At a dose of 1 or 2 g twice weekly the median annual consumption of human AAT was reduced from 286 to 156 g/patient. The trough plasma AAT level was maintained above 0.70 g/l, which is considered as protective. The three patients who had an implanted percutaneous venous port system learned to administer the treatment by themselves at home. The other two patients were treated at home by the district nurse., Conclusions: The results of our study indicate that tailored pharmacokinetic dosing of human AAT reduces the total annual dose and cost of IV augmentation therapy. In addition, this dosing facilitates self-administration of AAT and allows treatment at home.

A Markov-based decision model was created to assess the cost-effectiveness of augmentation therapy (Aug) for severe alpha1-antitrypsin deficiency, comparing strategies of: (1) no Aug, (2) Aug for life, and (3) Aug until FEV1 is below 35% predicted. A hypothetical cohort of 46-year-old patients with FEV1 49% predicted was followed over time using Monte Carlo simulation across five possible health states: (1) FEV1 50 to 79% predicted, (2) FEV1 35 to 49% predicted, (3) FEV1 below 35% predicted, (4) status-post-lung transplantation, and (5) dead. Treatment for life yielded 7.19 quality-adjusted life-years (QALYs) and cost 895,243 dollars. Treating until FEV1 is below 35% predicted cost 511,930 dollars and produced 6.64 QALYs. "No Aug" cost 92,091 dollars with 4.62 QALYs. The incremental cost-effectiveness ratio was 207,841 dollars/QALY for Aug until FEV1 is below 35% predicted and 312,511 dollars/QALY for the "Aug for life" strategy. In all sensitivity analyses, the incremental cost-effectiveness ratio for Aug for life exceeded 100,000 dollars. The cost of Aug needed to be reduced from 54,765 dollars to 4,900 dollars for the "Aug for life" strategy to be considered cost-effective. We conclude that, compared with other conventionally used health interventions, Aug is relatively less cost-effective. These results should encourage the development of more clinically and cost-effective therapies for alpha1-antitrypsin deficiency.

Background: For individuals with emphysema because of severe alpha(1)-antitrypsin deficiency, specific therapy called IV augmentation therapy has been available since 1989. Such therapy consists of IV infusion of pooled human plasma alpha(1)-antiprotease., Methods: To assess the direct medical costs of having alpha(1)-antitrypsin deficiency, the current study surveyed members of the Alpha One Foundation Registry for Individuals With alpha(1)-Antitrypsin Deficiency regarding their annual expenditures for treatment of this disease. Data regarding demographic features, alpha(1)-antitrypsin status, and health-resource utilization were collected from a self-administered questionnaire. Respondents were asked to provide total health-care expenditures, but costs by specific items of care (eg, drugs, physician visits, etc) were not available., Results: Mean annual cost estimates were higher for PI*ZZ-phenotype individuals ($30,948, n = 292) than for non-PI*ZZ-phenotype individuals ($20,673, n = 53; p = 0.049). Among PI*ZZ-phenotype individuals, self-reported costs of health-care services were further analyzed for those 288 individuals whose alpha(1)-antiprotease use status was reported. For the 185 current alpha(1)-antiprotease users, the mean annual cost was $40,123 (median, $36,000)., Conclusions: Annual health-care expenditures by individuals with alpha(1)-antitrypsin deficiency are very high, whether or not they are currently receiving augmentation therapy. Augmentation therapy adds substantial costs, especially for heavier individuals who are receiving weekly infusions.

Background: Significant challenges exist to investigating uncommon illnesses because too few patients are seen at any single clinical center to permit appropriate research studies. Recognizing this impediment to clinical research in alpha(1)-antitrypsin deficiency, the Alpha One Foundation, a patient-organized research foundation, has collaborated with clinician-scientists to organize a voluntary registry of individuals with alpha(1)-antitrypsin deficiency., Purpose: To facilitate clinical research in alpha(1)-antitrypsin deficiency by organizing a registry of affected individuals willing to be approached to participate in clinical studies., Methods: Elements of the Alpha One Foundation Research Network Registry include a Medical and Scientific Advisory Committee, composed of physician-investigators and patient advocates, designated clinical resource centers at medical institutions with expertise in the management of individuals with alpha(1)-antitrypsin deficiency, and a data coordinating center with responsibility for database management and analysis. Questionnaires requesting information about demographic features, alpha(1)-antitrypsin phenotype, smoking history, and health-care utilization were distributed to prospective registrants through the following channels: mailings from the Alpha One Foundation; mailings from the clinical resource centers; and distribution by home-care and pharmaceutical companies. Information from this questionnaire formed the basis of the initial registry database., Results: Between May 1997 and June 1999, 7,789 forms were distributed, and forms were returned by 712 unique registrants. Registrants have the following characteristics: mean (+/- SD) age, 49.3+/-13.2 years; women, 47.7%; white, 96.2%; PI*ZZ phenotype, 70.7%; ex-smokers, 73.3%; COPD patients, 87.2% (emphysema patients, 54.2%; chronic bronchitis patients, 33%); and self-reported liver disease, 6.4%. The mean number of physician visits reported by registrants in the preceding 12 months was 7.8+/-9.4, 59% reported currently receiving IV augmentation therapy, and 35% reported using supplemental oxygen at home. Examples of ongoing research studies using this unique database include: (1) a case-control study to evaluate occupational risk factors for obstructive lung disease in individuals with alpha(1)-antitrypsin deficiency and (2) a study to evaluate the health-care costs for affected individuals., Conclusions: A registry currently including 712 individuals with alpha(1)-antitrypsin deficiency has been organized through a collaboration between physician-investigators and a patient-organized research foundation. Use of the registry has already facilitated studies that were previously difficult because of the paucity of identifiable study subjects. The registry cohort promises to provide an important resource for future clinical and epidemiologic studies.

Study Objectives: Assess cost effectiveness for providing alpha(1)-antitrypsin (alpha(1)-AT) replacement therapy to individuals with severe COPD and alpha(1)-AT deficiency., Materials and Methods: The electronic databases MEDLINE and EMBASE were searched, and relevant bibliographies were reviewed. Effect size, defined as the absolute risk difference between treated and untreated groups, was taken from the highest level of supporting evidence. The cost for providing alpha(1)-AT replacement therapy was analyzed from a payer perspective and was based on Medicare reimbursement rates. Effect size and costs were varied. The year of life saved was discounted up to 7%., Results: The incremental cost per year of life saved for alpha(1)-AT replacement therapy (60 mg/kg/wk IV) in a 70-kg subject with severe alpha(1)-AT deficiency and an FEV(1) < 50% of predicted based on the National Institutes of Health (NIH) Registry mortality rate data is $13,971. The incremental cost depends substantially on the mortality rate reduction. When the effect size is altered from 10 to 70%, with the cost fixed at $52,000, the incremental cost per year of life saved ranges from $152,941 to $7,330. When effect size is 55% (as in the NIH Registry) but costs are increased almost 300%, from $52,000 to $150,000 per year, then the incremental cost per year of life saved increases from $13,971 to $40,301., Conclusion: No randomized, placebo-controlled trials are available to assess mortality rate reduction with alpha(1)-AT replacement therapy. The best currently available data are observational, from the NIH Registry. Based on these data, alpha(1)-AT replacement therapy is cost-effective in individuals who have severe alpha(1)-AT deficiency and severe COPD.

Systematic neonatal screening offers many advantages for the patients, its family and the community. The Genetic center of the University Hospital of Liège provides neonatal screening for the following diseases: phenylketonuria, congenital hypothyroidy, cystic fibrosis, alpha-1-antitrypsin, adrenal hyperplasia and biotinidase deficiency. On economical grounds, it is clear that the organisation of neonatal screening costs less to the community than the cost of the disease if diagnosis is made too late as to allow an alleviation, or even a total recovery, of the symptomatology.