Dataset Information

Utility Values Associated with Atypical Hemolytic Uremic Syndrome-Related Attributes: A Discrete Choice Experiment in Five Countries.

ABSTRACT:

Background

Atypical hemolytic uremic syndrome is a rare disease caused by complement dysregulation that can lead to progressive kidney damage or death if untreated. Owing to its rarity, the impact of atypical hemolytic uremic syndrome and available therapies (eculizumab and ravulizumab) on patients' health-related quality of life is difficult to describe, but such data are required for an economic evaluation.

Objective

The objective of this study was to estimate utility values for atypical hemolytic uremic syndrome-related attributes in five countries for an economic evaluation.

Methods

Using discrete choice experiment surveys, key atypical hemolytic uremic syndrome-related attributes (life expectancy, administration frequency, risk of meningitis, need for hospitalization, and risk of kidney impairment) were evaluated in adult general population samples from Australia, Canada, the Netherlands, Sweden, and the UK. Survey choice sets were constructed using a published orthogonal array. A mixed-effects logit model estimated preference strength for each attribute. Utilities were estimated using marginal substitution rates between overall survival and other attributes, weighted against average life expectancy.

Results

Across all countries (N = 2382), utility weights revealed a consistent pattern: participants were averse to the risk of kidney impairment (disutility/utility weight range: -0.185 to -0.158), risk of meningitis (-0.041 to -0.032), and the need for hospitalization (-0.063 to -0.048), but preferred 8-weekly vs 2-weekly infusions over 1 h (0.013-0.039).

Conclusions

Although all attributes played a role in determining treatment preferences, the largest drivers were life expectancy and risk of kidney impairment. Participants favored 8-weekly dosing (corresponding to ravulizumab administration frequency) vs 2-weekly dosing. The discrete choice experiment was designed such that estimated (dis)utility weights can be used in future cost-effectiveness models in atypical hemolytic uremic syndrome.

SUBMITTER: Williams K

PROVIDER: S-EPMC8298227 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome.MethodsWe sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.ResultsOf 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement.ConclusionsMutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.