Prevalence and Predictors of Hepatic Steatosis in Persons Living With HIV

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver conditions associated with fat accumulation that ranges from benign, non-progressive liver fat accumulation to severe liver injury, cirrhosis, and liver failure. NAFLD is the most common liver disease in US adults and the second leading cause for liver transplantation in the US. The natural history of NAFLD in the general population has been well described, with those with non-alcoholic fatty liver (NAFL, or simple steatosis) destined to have rare incidence of hepatic events compared to those with non-alcoholic steatohepatitis (NASH), who are at high risk for future development of cirrhosis, liver cancer and liver failure. The NASH Clinical Research Network (NASH CRN) was established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2002, through the mechanism of RFA-DK-01-025, to further the understanding of diagnosis, mechanisms, progression and therapies of NASH. The NASH CRN effort has resulted in numerous seminal studies in the field. However, NASH CRN studies have systematically excluded persons living with HIV (PLWH), as NAFLD in these persons was thought to be different from that in the general population due to HIV, ART, concomitant medications, and co-infections. This has resulted in major knowledge gaps regarding NAFLD in the setting of HIV. This ancillary study of NAFLD and NASH in Adults with HIV (HIV NASH CRN), HNC 001 goal is to examine the prevalence of hepatic steatosis and NAFLD in a large, multicenter, and multiethnic cohort of PLWH (Steatosis in HIV Study)

NAFLD is the most prevalent of all liver disorders and is the most common cause of chronic aminotransferase elevations in the United States. NAFLD also represents a major health threat worldwide, with a substantial impact on healthcare expenditures in the US and Europe. With the availability of highly effective ART, chronic liver disease has become a leading cause of non-AIDS related morbidity and mortality in PLWH. NAFLD is projected to become the leading cause of liver disease in the aging HIV population. The reported prevalence of NAFLD in PLWH without viral hepatitis co-infection ranges from 15-54% when assessed by imaging modalities and vibration-controlled transient elastography (VCTE), and is up to 73% in studies including liver biopsy, exceeding the reported prevalence of NAFLD in the general population. These prevalence figures vary as different modalities [computed tomography (CT), ultrasound, or Controlled attenuation parameter (CAP)] and criteria to define NAFLD were used. Further, current reports of NAFLD prevalence in PLWH are largely limited to single centers with small numbers of participants, inclusion of patients with concurrent HCV or limiting the study population to single sex or military personnel and their dependents. Systematic characterization of NAFLD in PLWH requires a large, representative, multi-ethnic, multi-centric cohort, which is currently lacking.

While obesity, insulin resistance and other components of the metabolic syndrome have been reported in some studies to increase the risk for NAFLD in PLWH, they are not universally observed in all PLWH, as studies of men with HIV report lower incidence of hepatic steatosis and lower BMI compared to controls. The impact of HIV and ART on NAFLD risk has also been much debated, with some studies supporting a role for the duration of infection and ART agents used, and others showing no associations. Recent reports suggest a potential decrease in NAFLD/NASH frequency and severity with light to moderate alcohol consumption in the general population. While PLWH commonly report alcohol use, the effects of non-heavy alcohol consumption on NAFLD and NASH risk and severity have not been studied in this population. Similarly, while coffee consumption has reported benefits on NAFLD in the general population, this effect has not been explored in PLWH. Several genetic variants have been found to modulate the risk and severity of NAFLD in the general population (Primary NAFLD), such as PNPLA3, TM6SF2, FADS1, GCKR, MBOAT7, and HSD17B13. To date, only a few studies evaluated genetic variation as a risk for NAFLD and its severity in PLWH. Emerging studies suggest an important role for gut microbiome as well as circulating gut derived metabolites in modulating the severity of Primary NAFLD but similar studies are lacking in PLWH.

OBJECTIVES

• To determine the prevalence of hepatic steatosis and NAFLD in a large, multicenter, and multiethnic cohort of PLWH.
• To enroll at least 1250 PLWH into a cross-sectional study. The presence of hepatic steatosis and NAFLD and advanced fibrosis will be defined based on clinical, diagnostic, and VCTE criteria. Core data collection will include clinical, demographic, behavioral, anthropometric and laboratory information.
• To evaluate the prevalence of alcoholic liver disease versus NAFLD and assess the effects of varying amounts of alcohol and other beverage consumption on the risk and severity of hepatic steatosis.
• To evaluate the relationship between host (age, sex/gender, race/ethnicity, obesity, genetic variants, gut microbiome, etc.), HIV disease (HIV-1 RNA level, CD4+ T cell count, HIV duration) and HIV treatment with ART (type and duration), and environmental (alcohol, coffee and other beverages, diet, physical activity, sleep, food insecurity) factors and the prevalence of hepatic steatosis and NAFLD in PLWH.
• To establish a robust specimen bank comprised of serum, plasma, genomic DNA as well as PBMC and stool at select sites.