Biological Mediators Predict Liver Fibrosis Progression Over Time in an HIV Mono‐Infected Cohort
Authors: Stewart Tiffanie , Campa Adrianna , Sales‐Martinez Sabrina , Boyer Jacqueline Hernandez , Wu Wensong , Liuzzi Juan , Baum Marianna 
Published: November 2023

Background

Antiretroviral therapy (ART) has drastically reduced mortality due to HIV; however, the aging of people living with HIV (PLWH) has been marked by significant morbidity and mortality due to non‐AIDS defining illnesses. While co‐infection with HIV and Hepatitis C (HCV) is a major contributor to liver disease progression, PLWH have faster progression of liver fibrosis than those who are not HIV infected. The mechanism of liver fibrogenesis involves increased oxidative stress and transforming growth factor‐beta1 (TGF‐β1), hepatocyte apoptosis, and microbial endotoxin. The aim of this study was to investigate whether these biological mediators of liver fibrosis predict development of liver fibrosis over 2 years in HIV mono‐infected participants.

Methods

A subset of the Miami Adults Studies on HIV (MASH) cohort in Miami, FL (n=65) was chosen for longitudinal analysis. Participants were grouped into categories of liver fibrosis at baseline according to their FIB‐4 score (a cut‐off of <1.45, excludes advanced fibrosis (stages 4–6 of the Ishak scale); a cut‐off of >3.25 has a positive value to predict advanced fibrosis). Oxidative stress (malondialdehyde [MDA], % oxidized glutathione [%GSSH]), hepatocyte apoptosis (Cytokeratin 18 [CK‐18]), TGF‐β1, and the microbial endotoxin lipopolysaccharide (LPS) were measured in plasma using commercially available kits. Multivariate linear regressions were used to find associations cross‐sectionally. Logistic regression and General Estimating Equations (GEE) were used for longitudinal analyses for over 2 years. Mixed model analysis used repeated measures to describe the associations between biological factors and FIB‐4 index with time as an interaction. All models were adjusted for covariates that are known to influence liver fibrosis.

Results

In this subset of 65 participants of the MASH cohort, 13.8% of HIV mono‐infected participants progressed at least one FIB‐4 stage from baseline to 2 years. High %GSSH (≥ 24% at baseline) was associated with 4.342 times higher odds of progressing in liver fibrosis category over time, after adjusting for covariates (aOR 4.342 [95% CI 1.026 – 18.144]; P= 0.046). LPS showed a trend of increasing the odds of liver fibrosis progression (OR 1.098 [95% CI 0.794 – 5.741]; P= 0.097]. As a continuous variable, CK‐18 protein was significantly associated with an increase in the odds of progressing FIB‐4 category over 2 years (OR 1.008, [95% CI 1.001 – 1.015]; P=0.021), and showed a trend in progressing at least one category of liver fibrosis over two years when using a cut off value (OR 4.311 [95% CI 0.881 – 21.089]; P = 0.071). There were no significant associations in this subset between FIB‐4 and MDA, and TGF‐β1.

Conclusions

Identifying biomarkers associated with the progression of liver fibrosis in HIV mono‐infection is important as these serve as potential targets for future therapies and/or prevention of liver disease progression. Establishing cut off values for some biological mediators of liver fibrosis, such as oxidative stress and LPS, may be useful. Larger studies are warranted to investigate mediators of fibrosis in PLWH.

Support or Funding Information

Funded by: NIDA, NIAAA