Society: AASLD

LIVE STREAM SESSION

BACKGROUND: Non-alcoholic steatohepatitis (NASH), a leading cause of liver-related morbidity and mortality, is highly prevalent in people living with HIV (PLWH).¹ Microbial translocation (MT) associated with hepatic inflammation and fibrosis may play a critical role in NASH pathogenesis.² Although HIV is associated with increased gut permeability and MT,³ few studies have evaluated the role of the gut-liver axis in NASH development in PLWH. We aimed to determine the associations of HIV and circulating biomarkers of MT on the FibroScan-AST (FAST)⁵ score, a non-invasive surrogate for NASH with advanced fibrosis, in a large US cohort of women with HIV (WWH) and women without HIV.
METHODS: Vibration controlled transient elastography (VCTE) was conducted from 2013-2018 among 1237 women without viral hepatitis (883 WWH, 354 without HIV). Serum and plasma MT biomarkers kynurenine to tryptophan (KT) ratio (a marker of MT), intestinal fatty acid binding protein (I-FABP, a marker of gut epithelial integrity), and the immune activation markers soluble(s) CD14 and sCD163 were tested within 6 months of the VCTE visit. We used linear regression models to evaluate the associations of HIV, demographic, and metabolic covariates with log-transformed FAST score. Next, we individually added KT ratio, I-FABP, and sCD14 and sCD163 to the models. Finally, we determined the mediating effect of MT using the difference method on the association of HIV with FAST.
RESULTS: Median age was 49 years. Most (74.5%) were Non-Hispanic Black and over half were obese (median BMI 30.5 kg/m²). Among WWH, median CD4 count was 651 cells/mm³ and 91% reported taking antiretroviral therapy. MT biomarker levels were higher in WWH (p< 0.001 for each). On multivariable regression, HIV infection was associated with a 49.2% higher FAST score (95%CI 29,73%), as were age (2.1% increase per year, 95%CI 1,3%), and heavy alcohol use (52% increase over no drinking, 95%CI 17,98%). Black race was associated with a 22% lower FAST score (95%CI -38,-2%). Higher levels of MT biomarker were each significantly associated with higher FAST score (Table 1). After adjustment for MT biomarkers, the association of HIV with FAST score was attenuated, and MT mediated 11-28% of the association of HIV with higher FAST (Figure 1).
CONCLUSION: Compared to women without HIV, WWH have higher circulating biomarkers of MT and higher FAST scores. MT biomarkers are strongly associated with higher FAST score and mediate the association of HIV with higher FAST score. Our findings suggest that MT is an important mechanism by which HIV increases the risk of NASH with advanced fibrosis. This study lays the groundwork for future efforts evaluating the relationship between MT, microbial composition, and NASH in PLWH.

Abbreviations: CI, 95% confidence interval, FAST, FibroScan- aspartate aminotransferase Score; KT, Kynurenine -Tryptophan; I-FABP, intestinal fatty acid binding protein; sCD14, soluble CD14; sCD163, soluble CD163<br /> MT biomarker levels were log transformed<br /> MT biomarkers underwent standardization defined as the log transformed variable divided by IQR to compare effect sizes over varying units<br /> FAST linear models were adjusted for HIV status, age, BMI, race, insulin resistance (HOMA IR), alcohol use, tobacco, and menopause state. Each MT biomarker was entered in the model separately.

Abbreviations: CI, 95% confidence interval, FAST, FibroScan- aspartate aminotransferase Score; KT, Kynurenine -Tryptophan; I-FABP, intestinal fatty acid binding protein; sCD14, soluble CD14; sCD163, soluble CD163
MT biomarker levels were log transformed
MT biomarkers underwent standardization defined as the log transformed variable divided by IQR to compare effect sizes over varying units
FAST linear models were adjusted for HIV status, age, BMI, race, insulin resistance (HOMA IR), alcohol use, tobacco, and menopause state. Each MT biomarker was entered in the model separately.

Figure 1: Path analysis showing multivariable adjusted effects of human immunodeficiency virus (HIV) infection status on steatohepatitis (as determined by FAST score). Standardized β coefficients for each MT mediator are shown, as well as percentages of the total effect attributable to microbial translocation (MT, as demonstrated by each biomarker), and non-MT pathways (other direct and indirect mechanisms of infection status). Models are adjusted for HIV status, CD4 count, and HIV viral load, age, BMI, race, insulin resistance (HOMA IR), alcohol use, tobacco, and menopause state.

Figure 1: Path analysis showing multivariable adjusted effects of human immunodeficiency virus (HIV) infection status on steatohepatitis (as determined by FAST score). Standardized β coefficients for each MT mediator are shown, as well as percentages of the total effect attributable to microbial translocation (MT, as demonstrated by each biomarker), and non-MT pathways (other direct and indirect mechanisms of infection status). Models are adjusted for HIV status, CD4 count, and HIV viral load, age, BMI, race, insulin resistance (HOMA IR), alcohol use, tobacco, and menopause state.

Mark Kuniholm

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