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FIB-4 fails to identify significant liver fibrosis in people with HIV: A large multinational screening study
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Hepatology May 1, 2026.
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Background and Aims:
Steatotic liver disease (SLD) and liver fibrosis are major comorbidities in people with HIV (PWH). Guidelines recommend stepwise screening using the Fibrosis-4 (FIB-4) index followed by transient elastography (TE), yet its accuracy and the extent of FIB-4 misclassification in PWH remain uncertain. We evaluated the diagnostic performance of FIB-4 against TE, quantified missed fibrosis, and assessed whether metabolic and HIV-specific factors improve risk prediction.
Approach and Results:
We conducted a multinational study of 4,917 PWH without viral hepatitis coinfection or hazardous alcohol intake undergoing TE screening across seven centers. SLD was defined by controlled attenuation parameter >275 dB/m and classified as metabolic dysfunction-associated SLD (MASLD) or metabolic dysfunction-associated alcohol-related liver disease (MetALD). Significant fibrosis (liver stiffness measurement [LSM] ≥8 kPa) was present in 12.6% of participants, advanced fibrosis (LSM ≥11 kPa) in 6.1%, and SLD in 21.7% (20.6% MASLD, 1.1% MetALD).
FIB-4 showed modest accuracy for significant fibrosis (AUROC 0.69, 95% CI 0.67–0.72) and misclassified 36% of fibrosis cases as low risk (FIB-4 <1.3).
Performance was poorer in MASLD than in non-MASLD (AUROC 0.60 vs 0.76; p<0.001). Participants with false-negative FIB-4 exhibited a more metabolic phenotype, including higher BMI and steatosis. Incorporating metabolic and HIV-specific factors improved discrimination and reclassification and enabled development of the FIB-HIV score, which outperformed FIB-4 (AUROC 0.78 vs 0.69; p<0.001).
Among the 4,917 participants, the mean age was 50.3 years, 26% were women, 33% reported light-to-moderate alcohol use, and 87.5% had an undetectable HIV viral load. Participants exhibited a high burden of metabolic comorbidities (Table 1).
Factors associated with significant liver fibrosis
Compared with PWH without significant fibrosis, individuals with significant fibrosis were older and more frequently male and Hispanic, more likely to have prior HCV or HBV infection, more likely to report injection drug use, and were less physically active. They also exhibited a more adverse metabolic profile and greater liver injury.
MASLD and MetALD were more common among individuals with fibrosis. HIV-specific factors associated with fibrosis included longer duration of HIV infection, nadir CD4 <300 cells/μL, and greater prior D-drug exposure. Compared with metabolically driven fibrosis, lean fibrosis occurred at younger age and more frequently in Hispanic individuals, and was associated with prior HCV or HBV infection, smoking, and light-to-moderate alcohol i
Conclusions:
In PWH, liver fibrosis is common and frequently missed by FIB-4, particularly in MASLD. TE-centered screening strategies augmented by metabolic and HIV-specific indicators may improve early fibrosis detection and risk stratification.
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