Stratifying the risk of NAFLD in patients with HIV under combination antiretroviral therapy (cART)

Abstract

Background: De novo steatosis is the main criteria for non-alcoholic fatty liver disease (NAFLD), which is becoming a clinically relevant comorbidity in HIV-infected patients. This may be due to the HIV virus itself, as well as long-term toxicities deriving from antiretroviral therapy. Therefore, HIV infected patients require prevention and monitoring regarding NAFLD.

Methods: This study investigated the differential role of body mass index (BMI) and combination antiretroviral treatment (cART) drugs on NAFLD progression. This single center prospective longitudinal observational study enrolled HIV monoinfected individuals between August 2013 to December 2018 with yearly visits. Each visit included liver stiffness and steatosis [defined as controlled attenuation parameter (CAP)>237 dB/m] assessment by annually transient elastography using an M- or XL-probe of FibroScan, and calculation of the novel FibroScan-AST (FAST) score. Risk factors for denovo/progressed steatosis and tripling of FAST-score increase were investigated using Cox regression model with time-dependent covariates.

Findings: 319 monoinfected HIV positive patients with at least two visits were included into the study, of which 301 patients had at least two valid CAP measurements. 51·5%(155) patients did not have steatosis at first assessment, of which 45%(69) developed steatosis during follow-up. A BMI>23 kg/m² (OR: 4·238, 95% CI: 2·078-8·938; p < 0·0001), tenofovir-alafenamid (TAF) (OR: 5·073, 95% CI: 2·362-10·899); p < 0·0001) and integrase strand transfer inhibitors (INSTI) (OR: 2·354, 95% CI: 1·370-4·048; p = 0·002), as well as type 2 diabetes mellitus (OR: 7·605, 95% CI: 2·315-24·981; p < 0·0001) were independent predictors of de novo steatosis in multivariable analysis. Tenofovir disoproxilfumarate (TDF) was associated with a lower risk for weight gain and steatosis progression/onset using CAP value (HR: 0·28, 95% CI: 0·12-0·64; p = 0·003) and FAST scores (HR: 0·31, 95% CI: 0·101-0·945; p = 0·04).

Interpretation: Steatosis can develop despite non-obese BMI in patients with HIV monoinfection under cART, especially in male patients with BMI over 23 kg/m². While TAF and INSTI increase the risk of progression of steatosis, TDF was found to be independently associated with a lower risk of a clinically significant weight gain and thereby, might slow down development and progression of steatosis.

Funding: There was no additional funding received for this project. All funders mentioned in the 'declaration of interests' section had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Keywords: APRI, AST to platelet ratio index; ART, antiretroviral treatment; AST, aspartate aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; Cap; DAA, direct-acting antiviral; FAST, FibroScan-AST; FIB4, fibrosis-4; HCV, chronic hepatitis C; Hiv; INSTI, integrase strand transfer inhibitors; NAFLD, Non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; Nafld; PLHIV, people living with HIV; PrEP, pre-exposure prophylaxis; Steatosis; TAF, tenofovir-alafenamid; TDF, Tenofovir disoproxilfumarate; TE, transient elastography; cART.

Fig. 1

Panel A. Proportion of non-steatosis and different stages of steatosis in each visit; Panel B. River diagram of patients with non-steatosis and different stages of steatosis in first and last visit. Panel C. Percentages of patients with non-steatosis and different stages of steatosis in first and last visit. Comparison of numbers change between two visits were using Chi-square test; ***, P < 0·0001; Stages of steatosis Panel A-C: S0 < 238 dB/m, S1: 238–259 dB/m, S2: 260–291 dB/m, S3: >292 dB/m; Panel D. Plot of association of weight gain and CAP changes. P values were calculating using Pearson correlation; Panel E. Plot of association of BMI changes and CAP changes. P values were calculating using Pearson correlation; Panel F. Forrest plot of hazard ratio in multi-variate time-dependent Cox regression of 5 percent weight gain; Panel G. Forrest plot of hazard ratio in multi-variate time-dependent Cox regression of 10 percent weight gain; Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; FAST, FibroScan-AST; FIB-4, Fibrosis-4; HR, hazard ratio; LDL, low-density lipoprotein; TDF, tenofovir disoproxil fumarate.

Fig. 2

Panel A. Forrest plot of hazard ratio in multi-variate time-dependent Cox regression of de novo steatosis or steatosis progression. Panel B. Forrest plot of odds ratio in multi-variate logistic regression of de novo steatosis in patients without steatosis at baseline; Panel C. Decision tree of de novo steatosis risk among the patients without steatosis at baseline, and mean risk of de novo steatosis with 95% CI among internal validation using 1000-time bootstrapping; Abbreviations: CI, confidence interval.

Fig. 3

Panel A. Venn diagram of number of patients treated with INSTI, TDF and/or TAF. Panel B. Forrest plot of hazard ratio in multi-variate time-dependent Cox regression of de novo steatosis. Panel C. Cumulative incidence of CAP progression in HIV patients compared between patients treated with TAF or not. P value was calculated by log rank test; Panel D. Cumulative incidence of CAP progression in HIV patients compared between patients treated with INSTI or not. P value was calculated by log rank test. Abbreviation: BMI, body mass index; TDF, tenofovir disoproxil fumarate; INSTI, integrase strand transfer inhibitors; TAF, tenofovir-alafenamid.

Fig. 4

Panel A. Density curve of FAST score at inclusion and last visit. Comparison between two visits were using paired t-test. ***, P < 0·0001; Panel B. Density curve of FAST score at inclusion and last visit in patients with TDF, TAF and INSTI. Comparison between two visits were using paired t-test. *, P < 0·05; NS, not significant; Panel C. Forrest plot of hazard ratio in multi-variate time-dependent Cox regression of tripling FAST score increase. Abbreviation: ALT, alanine aminotransferase; FAST, FibroScan-AST; HR, hazard ratio; TAF, tenofovir-alafenamid; TDF, tenofovir disoproxil fumarate; INSTI, integrase strand transfer inhibitors.