Current hepatocellular carcinoma (HCC) surveillance strategies rely predominantly on ultrasound.¹ Yet, their clinical effectiveness is limited by operator and equipment dependence, impaired visualization in patients with obesity or non-viral liver disease, and poor adherence, with many at-risk patients not receiving recommended monitoring due to logistical, knowledge, and access barriers.¹ At the AASLD Annual Meeting 2025, Dr. Binu V. John from the Miami VA Medical Center in the United States (US), presented findings from the prospective Alternative to Ultrasound (ALTUS) study, demonstrating that the novel multi-target HCC blood test (mt-HBT) substantially outperformed ultrasound in early-stage HCC detection, highlighting the potential of blood-based surveillance in transforming clinical practice.¹

Blood-based molecular biomarkers mt-HBT offer a promising alternative to ultrasound-based surveillance in HCC detection, providing operator-independent assessment, reduced susceptibility to patient body habitus, and seamless integration into existing clinical workflows.¹ The mt-HBT combines methylated deoxyribonucleic acid (DNA) markers, serum alpha-fetoprotein (AFP), and patient sex to generate qualitative results and has demonstrated robust performance in prior case-control studies.¹

The ALTUS study was a prospective, multicenter study in a US surveillance population that evaluated the performance of mt-HBT in detecting early-stage HCC compared to standard ultrasound.¹ The study aimed to establish the non-inferiority of mt-HBT against ultrasound for sensitivity in early-stage HCC within a 5% margin, with potential for testing superiority, while ensuring specificity remained above 82% and the 95% confidence interval (CI) lower bound met clinical standards.¹ Overall sensitivity for all HCC stages was assessed as a secondary objective.¹

The ALTUS study enrolled adults with cirrhosis or chronic hepatitis B virus (HBV) infection undergoing routine HCC surveillance.¹ Participants underwent standard-of-care ultrasound surveillance alongside concurrent mt-HBT blood testing, with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) performed within 30 days as the diagnostic reference standard.¹ HCC diagnoses were established through centralized radiologic adjudication using Liver Imaging Reporting and Data System (LI-RADS) criteria or tumor-in-vein findings confirmed by two independent, blinded radiologists, or by histopathological confirmation.¹ Early-stage disease was defined according to the Milan Criteria, specifying a single lesion ≤5cm or up to three lesions, each ≤3cm, with no macrovascular invasion or extrahepatic metastases.¹

Among 3,089 enrolled participants, 2,467 were evaluable for effectiveness analyses, with a median age of 64 years and a predominance of cirrhosis driven by metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease, and chronic viral hepatitis.¹ Forty HCC cases were identified, of which 28 met Milan Criteria for early-stage disease.¹ In paired analyses, mt-HBT demonstrated an early-stage HCC sensitivity of 66.7% (95% CI: 47.8-81.4) vs. 22.2% (95% CI: 10.6-40.8) for ultrasound, representing a threefold improvement and meeting both non-inferiority and exploratory superiority criteria (p=0.002).¹ Overall HCC sensitivity reached 73.0% for mt-HBT, exceeding that of ultrasound alone (29.7%), AFP alone (27.0%), and ultrasound combined with AFP (51.4%).¹

Notably, test specificity achieved 81.8% (95% CI: 80.1-83.4), surpassing the 80% Delphi panel consensus threshold recommended for emerging HCC surveillance tools.¹ Performance advantages of mt-HBT were consistent across clinically relevant subgroups.¹ For very early tumors measuring <2cm, mt-HBT demonstrated a sensitivity of 63.6%, representing an approximately seven-fold improvement over ultrasound (9.1%) and substantially outperforming AFP (0%), underscoring its ability to detect lesions at a stage when curative interventions are most feasible.¹

In conclusion, the results from the prospective ALTUS study demonstrate that mt-HBT achieved substantially improved sensitivity for both early- and very early-stage HCC compared with standard-of-care ultrasound, while maintaining clinically acceptable specificity.¹ By addressing key limitations of imaging-based surveillance, this blood-based multi-target assay represents a viable alternative to ultrasound, with the potential to improve surveillance consistency and adherence, thereby enabling earlier detection and improved outcomes for patients at risk of HCC.¹