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/m 2 (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/m 2 . 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.

Discordant Liver Fibrosis Predictors in Virologically Suppressed People Living with HIV without Hepatitis Virus Infection

“…Strikingly, a higher risk of increased liver fibrosis was associated to longer cumulative TAF exposure according to APRI and FIB-4 scores and to a longer cumulative RAL exposure among those with liver stiffness ≥F2 at TE. These data are in line with previously published data, which showed that both drugs were associated with a significant weight gain after initiation of therapy and with development and progression of liver steatosis [ 62 ]. The accumulation of fat can cause liver inflammation, hepatic cell death and steatohepatitis, leading to faster progression of liver fibrosis over time in the absence of an effective intervention for harm reduction.…”

Two-Tier Care Pathways for Liver Fibrosis Associated to Non-Alcoholic Fatty Liver Disease in HIV Mono-Infected Patients

“…However, the prevalence of significant liver fibrosis in PWH without NAFLD was still 9.2%, pointing out that HIV mono-infected patients can develop significant liver fibrosis in the absence of NAFLD. These liver fibrosis cases may be due to risk factors for liver disease other than the metabolic ones and that are unique to HIV infection, including chronic inflammation and exposure to ART [20,51]. Indeed, patients with significant liver fibrosis and without NAFLD had a lower CD4 cell count and a higher proportion of exposure to didanosine, while metabolic comorbidities and high BMI were less frequent.…”

Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients – a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown

“…Of these, the most studied and the most aggressive type of cellular toxicity is represented by the mitochondrial toxicity (197) induced by NRTIs, NNRTIs, PIs and by some INSTI representatives (198,199). This may occur shortly after ART starting and may be perpetuated depending on various risk factors (197,(199)(200)(201).…”

“…Both mitochondrial dysfunction and the metabolic changes play a decisive role in the development of HALS ( 194 , 202 ) and favor liver steatosis and NAFLD development ( 194 ) as can be seen in the Figure 2 . The degree of liver toxicity becomes apparent after 6-8 months of NRTI treatment ( 203 ) and differs depending on the type of NRTI and its persistence within the cell ( 200 , 201 ). MetS also develops as a consequence of ART-mitochondrial toxicity ( 202 , 204 ) and of visceral adipose tissue imbalance induced by hepatokines/adipokines disequilibrium ( 205 ).…”