Current and Investigational Biomarkers of Liver Disease in HIV-HBV Co-infection.

Bridging the Gap: Screening for Nonalcoholic Fatty Liver Disease in the Primary Care Population

See Article on Page 331

Metabolic dysfunction-associated fatty liver disease: from basic research to clinical application.

(1) Background: Developing strategies to identify significant liver fibrosis in people with HIV (PWH) is crucial to prevent complications of non-alcoholic fatty liver disease (NAFLD). We aim to investigate if five simple serum biomarkers applied to PWH can optimize a care pathway to identify significant liver fibrosis defined by transient elastography (TE). (2) Methods: A two-tier fibrosis pathway was applied to three prospective cohorts of PWH undergoing TE with CAP. NAFLD was diagnosed as a controlled attenuation parameter ≥ 248 dB/m. Five simple fibrosis biomarkers (FIB-4 < 1.3, BARD score 0–1, NAFLD fibrosis score < −1.455, AST:ALT ratio < 0.8 and APRI < 0.5) were applied as first-tiers to exclude significant liver fibrosis. We determined the decrease in referral for TE that would have occurred based on biomarker assessment and the discordance between low simple fibrosis biomarkers and high TE (≥7.1 kPa), indicating significant liver fibrosis. (3) Results: Of the 1749 consecutive PWH, 15.1% had significant liver fibrosis by TE and 39.1% had NAFLD. The application of the fibrosis biomarkers as first tiers would have resulted in a decrease in TE referrals between 24.9% (BARD score) and 86.3% (APRI). The lowest discordance rate was with NAFLD fibrosis score (8.5%). After adjustments, BMI (odds ratio (OR) 1.12, 95% CI: 1.08–1.17) and triglycerides (OR 1.26, 95% CI: 1.11–1.44) were independent predictors of discordance for APRI < 0.5 and TE ≥ 7.1. The performance of the two-tier pathways was similar in PWH with and without NAFLD. (4) Conclusions: Implementing a two-tier pathway could save a substantial proportion up of TE examinations, reducing costs and helping resource optimization in HIV care. Patients with metabolic risk factors for NAFLD and low fibrosis biomarker may still be considered for TE referral.

Needle-free Nonalcoholic Fatty Liver Disease Prognostication: Moving One Step Closer

There has been an increased interest in the use of noninvasive tests (NITs) to identify advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NALFD). The aim of our study was to define the change in tests' characteristics (sensitivity and specificity) of different combinations of NITs to detect advanced fibrosis in NAFLD. We stratified NITs into first and second tiers and compared two different strategies of combining NITs to screen for advanced fibrosis in patients with NAFLD. One strategy was using NITs in parallel, and the other was using NITs sequentially. Within both of these strategies, there were two ways of interpreting the overall results. The first way was called "the AND rule," where a positive result required both individual test results to be positive. The second way was called "the OR rule," where a positive result required only one individual test to be positive. Accuracy of NITs was obtained from the literature search. Combined accuracy and likelihood ratio (LR) were calculated. Combination testing with parallel and sequential order testing under the AND Rule resulted in overall higher specificity and LR+ then using the NITs alone. Specificity ranged from 0.91 to 0.99, and LR+ from 9.3 to 68.6. The subsequent use of MRE was associated with LR+ between 36 and 69. Sensitivity was higher with parallel and sequential order testing under the OR Rule. LR+ ranged from 1.4 to 7.5, and sensitivity from 0.82 to 0.98. Screening for advanced fibrosis should be performed sequentially, with positive results confirmed by additional testing. Specificity and LR+ were highest when MRE was employed as the confirmatory test.

People with HIV (PWH) are at an elevated risk of developing severe COVID-19 outcomes because of compromised immunity and more comorbidities. However, existing literature suggests a lower rate of COVID-testing among PWH. This study aimed to explore the temporal trend of county-level COVID-19 testing rate and multi-level predictors of COVID-19 ever-testing among PWH in South Carolina (SC). Leveraging linked statewide HIV and COVID-19 datasets, we defined the study population as all adult (18 + years) PWH who were alive on March 2020 and living in SC. PWH with a COVID-19 testing record between March 2020 and October 2021 were defined as COVID-19 ever-testers. Logistic regression and generalized mixed models were used to investigate the association of PWH's demographic profile, HIV clinical characteristics (e.g., CD4 count, viral load), comorbidities, and social factors with COVID-19 testing among PWH. Among 15,660 adult PWH, 8,005 (51.12%) had ever tested for COVID-19 during the study period (March 2020-October 2021). PWH with older age, being male, and Hispanics were less likely to take COVID-19 testing, while men who have sex with men or injection drug users were more likely to take COVID-19 testing. PWH with higher recent viral load (10,000-100,000 copies/ml vs. <200 copies/ml: adjusted odds ratio [AOR]: 0.64, 95%CI: 0.55-0.75) and lower CD4 counts (> 350 cells/mm3 vs. <200 cells/mm3: AOR: 1.25, 95%CI: 1.09-1.45) had lower odds for COVID-19 testing. Additionally, PWH with lower comorbidity burden and those living in rural areas were less likely to be tested for COVID-19. Differences in COVID-19 test-seeking behaviors were observed among PWH in the current study, which could help provide empirical evidence to inform the prioritization of further disease monitoring and targeted intervention. More efforts on building effective surveillance and screening systems are needed to allow early case detection and curbing disease transmission among older, male, Hispanic, and immune-suppressed PWH, especially in rural areas.

Elastography for Detecting Hepatic Fibrosis: Options and Considerations

BackgroundWe aimed to investigate the prevalence of liver fibrosis and identify the associated risk factors among people with HIV (PWH) and metabolic dysfunction–associated steatotic liver disease (MASLD).MethodsAbdominal ultrasonography and transient elastography were performed to assess liver fibrosis and steatosis. Lean MASLD was defined as MASLD occurring in PWH with a body mass index (BMI) < 24 kg/m2. A cutoff of liver stiffness measurement ≥ 7.1 kPa was set for significant liver fibrosis. The prevalence, correlation factors, and risk factors were evaluated.ResultsAmong 361 PWH, 250 (69.25%) had a BMI < 24 kg/m2, and 141 (39.06%) were diagnosed with MASLD. The 141 PWH with MASLD were classified as 2 groups based on BMI: 58 (41.13%) as lean MASLD and 83 (58.87%) as overweight MASLD. Significant fibrosis was observed in 121 of the 361 PWH, including 75 of the 141 with MASLD, 28 of the 58 with lean MASLD, and 47 of the 83 with overweight MASLD. Among PWH with MASLD, independent risk factors for significant liver fibrosis included higher alanine aminotransferase levels and the presence of type 2 diabetes. Among PWH with lean MASLD, independent risk factors for significant liver fibrosis included elevated aspartate aminotransferase levels and the administration of non-nucleoside reverse transcriptase inhibitors.ConclusionsSignificant liver fibrosis is highly prevalent among PWH and MASLD. Multiple risk factors are associated with significant liver fibrosis among PWH. These findings underscore the importance of early identification and management of liver fibrosis in PWH.Clinical Trials RegistrationNCT04215926.

Reply to: Correspondence on “EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update”

Noninvasive Assessment of Liver Fibrosis and Portal Hypertension With Transient Elastography

Chasing after novel non-invasive markers to identify advanced fibrosis in NAFLD.

Accuracy of the Enhanced Liver Fibrosis Test vs FibroTest, Elastography, and Indirect Markers in Detection of Advanced Fibrosis in Patients With Alcoholic Liver Disease

Objective:Metabolic risk factors and nonalcoholic fatty liver disease (NAFLD) in people with HIV (PWH) have been increasing. Patients exhibiting the inflammatory subtype nonalcoholic steatohepatitis (NASH) are at increased risk of liver-related complications. Therefore, the aim was to investigate the prevalence of NASH with significant fibrosis in PWH using noninvasive tests (NITs).Design:In this prospectively enrolling cohort study, 282 PWH were explored for hepatic steatosis, fibrosis and steatohepatitis using vibration-controlled transient elastography (VCTE) and the Fibroscan-AST (FAST) score.Methods:On the basis of controlled attenuation parameter (CAP; dB/m) and liver stiffness measurement (LSM; kPa), patients were categorized according to the presence of steatosis (≥275 dB/m) and significant fibrosis (≥8.2 kPa). The FAST score was calculated according to established cut-offs.Results:The prevalence of hepatic steatosis in this cohort was 35.5% (n = 100) with 75 (75%) of these patients fulfilling the criteria of NAFLD. The prevalence of significant fibrosis (≥ F2) was 6.7% (n = 19). The FAST score identified a total of 32 (12.3%) patients with a cut-off greater than 0.35, of whom 28 (87.5%) PWH qualified as NASH. On multivariable analysis, waist circumference was a predictor of hepatic steatosis and type 2 diabetes was a predictor of significant fibrosis. Type 2 diabetes and ALT remained independent predictors of a FAST score greater than 0.35.Conclusion:NASH with significant fibrosis is highly prevalent among PWH. The FAST score may be helpful to identify patients at risk for significant liver disease.

People with HIV (PWH) are at heightened risk for type 2 diabetes (T2D) and insulin resistance (IR), even with effective antiretroviral therapy (ART). Adipose tissue dysfunction, including subcutaneous adipose tissue (SAT) fibrosis, is a key contributor to metabolic disease. However, the role of SAT fibrosis in IR among PWH remains poorly understood. We therefore investigated the relationship between SAT fibrosis and IR in PWH along with molecular signatures that might distinguish HIV-associated SAT fibrosis from that associated with obesity. We studied 112 participants, including 43 PWH and 69 people without HIV (PWoH) and excluding those with established T2D. Body composition was assessed by dual-energy X-ray absorptiometry (DXA), and SAT fibrosis was analyzed by quantifying hydroxyproline levels from biopsies. SAT transcriptional profiles were examined using a targeted fibrosis-related gene panel. Plasma levels of endotrophin, a marker of extracellular matrix remodeling, were also measured. PWH had significantly greater SAT fibrosis compared to PWoH, with the largest differences observed among participants without obesity. In this subgroup, SAT fibrosis was strongly associated with IR, despite the absence of elevated adiposity. Transcriptomic analysis identified a distinct fibrosis-associated gene expression pattern in PWH, marked by upregulation of COL14A1 and key immune-related genes (e.g. CCL4 , NLRP3 ). Pathway analysis further supported upregulated extracellular matrix remodeling and immune activation, along with downregulated thermogenesis, lipid metabolism, and insulin signaling in the SAT of non-obese PWH. Plasma endotrophin levels were significantly elevated in PWH and were independently associated with SAT fibrosis. Our findings identify SAT fibrosis as an obesity-independent driver of IR in PWH. Notably, SAT fibrosis predicts IR at normal body fat levels and can be noninvasively monitored through circulating endotrophin, offering a potential biomarker for early intervention. The distinct transcriptional signature of HIV-associated fibrosis reveals unique mechanisms that may underlie heightened metabolic risk in this population and highlight new therapeutic avenues targeting adipose tissue remodeling and metabolic dysfunction.