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Associate Professor of Medicine
McGill University Health Centre
Division of Gastroenterology and Hepatology and Division of Infectious Diseases
Research Institute of McGill University Health Centre
Montreal, Quebec, Canada
Giada Sebastiani, MD, has disclosed that she has received funds for research support from Merck and Theratec; consulting fees from Allergan, Intercept, Gilead Sciences, Merck, Novartis, Novo Nordisk, and Pfizer; and fees for non-CME/CE services from AbbVie, Gilead Sciences, Merck, Novartis, Novo Nordisk, and Pfizer.
More than 50% of people with HIV (PWH) in the United States are now 50 years of age or older. Despite improved life expectancy and decrease in mortality related to HIV/AIDS, mortality related to liver disease has increased 10-fold in the post-antiretroviral (ART) era. PWH are at high risk for nonalcoholic fatty liver disease (NAFLD), defined as liver fat accumulation exceeding 5% of hepatocytes (in the absence of other causes of liver disease such as excessive alcohol consumption and viral hepatitis).
NAFLD is actually an umbrella term encompassing 2 pathologic and clinical entities: nonalcoholic fatty liver (or simple liver steatosis without hepatocyte injury) and nonalcoholic steatohepatitis (NASH) characterized by liver steatosis with hepatocyte injury (inflammation, ballooning injury, Mallory hyalin, or necrosis). NASH is a progressive liver disease, eventually leading to liver scarring (fibrosis), cirrhosis, and end-stage complications. NAFLD affects approximately 25% of the adult population worldwide and is strongly associated with features of the metabolic syndrome, namely, type 2 diabetes, obesity, dyslipidemia, and hypertension.
Metabolic Factors, HIV Factors
NAFLD prevalence is higher in PWH, ranging from 35% to 65%. This increased burden is likely driven by a multifactorial and complex pathogenesis underlying NAFLD in the specific context of HIV infection. Metabolic factors, such as obesity, insulin resistance, dyslipidemia, and hypertension, are very frequent in PWH.
Moreover, the progression of liver disease in aging PWH is complicated by the additional risk posed by HIV-related factors. These factors include chronic HIV-associated inflammation and persistent immune activation, as mirrored by detectable HIV-1 RNA and low CD4+ cell count. Additional HIV-related factors in the pathogenesis of NAFLD include prolonged ART use and past exposure to some dideoxynucleoside analogues (d-drugs like didanosine and stavudine), potentially leading to hepatotoxicity and lipodystrophy. The guidelines from the European AIDS Clinical Society (EACS) also suggest that lipid-neutral ART regimens should be considered in PWH at risk of or with NAFLD. Another ART-related issue potentially affecting NAFLD is the weight gain related to regimens based on some integrase inhibitors.
Of importance, NAFLD is not only more frequent in PWH than in the general HIV-uninfected population but also more severe: A meta-analysis reported a prevalence of significant liver fibrosis at 22% in PWH, at least twice that in the general population. Longitudinal studies showed a more rapid progression of liver pathology to severe hepatic steatosis in PWH compared with PWH coinfected with hepatitis C virus. NAFLD in PWH is also a significant predictor of frailty and cardiometabolic conditions, such as hypertension and type 2 diabetes.
Who Is at Risk?
Given the prevalence and consequences of NAFLD, in which of our PWH should we look for NAFLD and how can we identify it?
The diagnosis of NAFLD is difficult in clinical settings, as up to 80% of patients may have normal liver transaminases. If it is true that most patients with NAFLD have normal liver transaminases, on the other hand, persistent elevated alanine aminotransferase in absence of other causes of liver disease is strongly suggestive of NASH. In the practice of HIV medicine, chronic elevation of liver transaminases is detected in 15% to 20% of PWH, and histological studies reported that 65% of these cases have NASH on liver biopsy.
However, liver enzymes may not be the whole story. Available studies report that, in PWH, BMI and glycemic indices are the most common predictors of NAFLD and associated liver fibrosis. In fact, more than 80% of PWH with NAFLD have at least metabolic comorbidities or elevated liver transaminases. Accordingly, guidelines from the EACS recommend assessing for NAFLD and associated liver fibrosis in all PWH with either elevated liver transaminases, obesity, metabolic syndrome, or past exposure to d-drugs like didanosine and stavudine. The initial diagnostic assessment should be carried out with noninvasive tests, including ultrasound and the simple fibrosis biomarker FIB-4, based on liver transaminases and platelet count.
In your practice, do you screen your PWH at risk for NAFLD? Answer the polling question and join the conversation by posting in the discussion section.