Multi-target blood test for hepatocellular carcinoma early detection: a cross-sectional analysis of the prospective ALTUS study.

Background

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Aims

Globally, 350 million people are at risk for HCC. Ultrasound screening is recommended but is limited by poor early-stage sensitivity and low adherence. This study evaluated whether the multi-target HCC blood test (mt-HBT) demonstrates non-inferior sensitivity for early-stage HCC compared with ultrasound and assessed its specificity.

Methods

This prospective, multicenter study, conducted between July 2021 and June 2025 in the United States, evaluated the performance of the mt-HBT in a head-to-head comparison with standard-of-care ultrasound among adults with cirrhosis or chronic HBV infection who were eligible for routine HCC screening. All participants underwent computed tomography or magnetic resonance imaging as a reference standard. The co-primary outcomes were non-inferiority of mt-HBT to ultrasound for early-stage HCC sensitivity, with sequential testing of superiority, and mt-HBT specificity. A secondary outcome was overall (any-stage) mt-HBT sensitivity.

Results

Of 3089 participants, 2293 were evaluable with paired ultrasound and mt-HBT results. Thirty-seven HCCs were identified, with 27 classified as early stage by Milan criteria. Early-stage HCC sensitivities were 66.7% (95% CI, 47.8-81.4%) for mt-HBT and 22.2% (95% CI, 10.6-40.8%) for ultrasound, confirming mt-HBT non-inferiority within the prespecified 5% margin. The specificity for mt-HBT was 81.8% (95% CI, 80.1-83.4%), which did not meet the pre-specified co-primary outcome of 82%. Ultrasound specificity was 98.6% (95% CI, 98.0-99.0%). Any-stage HCC sensitivity was 73.0% (95% CI, 57.0-84.6%) for mt-HBT and 29.7% (95% CI, 17.5-45.8%) for ultrasound. No serious adverse events occurred during the blood collection process.

Conclusions

The mt-HBT had higher observed sensitivity than ultrasound for early-stage HCC, with a paired absolute difference of 44.4% (95% CI, 20.2-63.8); however, specificity did not meet the prespecified target. TRIAL REGISTRATION The trial is registered with ClinicalTrials.gov (NCT05064553) IMPACT AND IMPLICATIONS: HCC screening remains limited by the suboptimal sensitivity of ultrasound, particularly among patients with obesity and steatotic liver disease. In this prospective multicenter study, a multi-target HCC blood test demonstrated substantially higher sensitivity for early-stage HCC detection than ultrasound while maintaining favorable screening performance across diverse patient subgroups. These findings are important for clinicians, researchers, and patients because they support further evaluation of blood-based approaches to address known limitations of imaging-based screening.