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NAFLD Is Increasingly Affecting Patients With HIV
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April 20, 2021
Zahra Qamar, MD; Steven F. Solga, MD; and Lisa A. Spacek, MD, PhD, FIDSA
Contagion, Contagion, April 2021
The prevalence of this disease in this patient population is much higher than in the general public.
https://www.contagionlive.com/view/nafld-increasingly-affecting-patients-with-hiv
• European AIDS Clinical Society recommends screening all PWH with metabolic syndrome for NAFLD by ultrasound, evaluation of liver enzymes, and serum fibrosis biomarkers
• In a meta-analysis of PWH, the prevalence of NAFLD, biopsy-proven NASH, and fibrosis were 35%, 42% and 22% respectively, which is significantly higher than that of the general population
• In diagnosing, MRI and transient elastography have the best performing characteristic
• Managing NAFLD consists of treating liver disease as well as its associated metabolic comorbidities such as obesity, hyperlipidemia, and diabetes
• Chronic liver disease is the second most common cause of non-AIDS-related mortality in PWH
Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and encompasses a spectrum of disorders, including simple hepatic steatosis (fatty liver), nonalcoholic steatohepatitis (NASH), and cirrhosis. NAFLD is defined by the presence of 5% or greater hepatic steatosis in patients without risk factors of heavy alcohol consumption, viral hepatitis, treatment with steatogenic medications, or genetic causes of hepatic fat deposition.1 NASH is a histological diagnosis characterized by inflammation, ballooning of hepatocytes and fibrosis or nonalcoholic fatty liver that is not associated with hepatocellular damage. Worldwide, the prevalence of NAFLD in the general population is rising and estimated to be 25%.2 This mirrors the rising prevalence of obesity, type 2 diabetes (T2DM), and metabolic syndrome. The disease is most prevalent in the Middle East and South America, whereas it is lowest in Africa. Patients with NAFLD experience increased morbidity and mortality, which are most commonly attributed to cardiovascular disease when compared with matched controls.3 In the United States, NAFLD is the third most common cause of hepatocellular carcinoma, with up to 13% of cases occurring in absence of cirrhosis.4
With longer life expectancy and declining AIDS-associated mortality, non-AIDS-related comorbidities have emerged as diagnostic and treatment problems in persons with HIV (PWH). Chronic liver disease is the second most common cause of non-AIDS-related mortality in PWH.5 Results of a US study of 47,062 PWH from 2006 to 2016 showed that 22% had some form of liver disease. The increased prevalence of liver disease is multifactorial and attributable to NAFLD, alcohol use, and viral hepatitis.6 In a meta-analysis of PWH, the prevalence of NAFLD, biopsy-proven NASH, and fibrosis were 35%, 42% and 22% respectively, which is significantly higher than that of the general population.7
General Pathogenesis and Risk Factors
Insulin resistance (IR) is a key factor in pathogenesis of hepatic steatosis. Dietary factors, including high consumption of fats and sugars, have been linked to NAFLD development.8 IR causes triglycerides to mobilize from the adipose tissue to the liver, whereas IR-associated hyperinsulinemia promotes hepatic de novo lipogenesis.9 Hepatic steatosis is a benign condition that can progress to NASH in certain individuals, and NASH can progress to cirrhosis and liver cancer. Mitochondrial dysfunction plays an important role in dysregulation of the liver’s lipid environment. Enhanced mitochondrial fatty acid oxidation induces production of reactive oxygen species, which results in oxidative stress and development of NASH.10
Pathogenesis and Risk Factors Specific to HIV Infection
There are multiple complex mechanisms by which HIV infection increases the risk of NAFLD. These are incompletely understood and include comorbid risk factors, direct viral effects, and adverse effects of antiretroviral therapy (ART).
Components of metabolic syndrome are more common among PWH. T2DM is 4 times more prevalent in PWH, and dyslipidemia and hypertension are also more common.11-13 Results of a US outpatient study revealed that nearly half of patients were obese at the time of starting ART, and in the next 2 years, 20% moved up to a higher BMI category.14 Achhra et al showed that weight gain in the first year after initiation of ART was associated with increased risk of cardiovascular disease and diabetes.15 NAFLD, which is called lean NAFLD when it affects patients with a BMI of less than 25 kg/m2, occurs in 1 in 4 lean PWH. Lean patients with NAFLD had more metabolic derangements, such as higher triglyceride and ALT levels and lower HDL levels, than lean patients without NAFLD. They had longer duration of HIV infection and higher CD4 lymphocyte counts, and they were more likely to maintain viral suppression. This clinical phenotype may be related to genetic factors, change in gut microbiota, dysfunctional adipose tissue, and improved ability to adapt to an excess intake of calories. However, the exact mechanism is not completely understood.16
Direct viral effects also may contribute to NAFLD. Depletion of CD4+ lymphocytes in the gut causes disruption of the gut epithelial barrier, facilitating microbial translocation into the portal and systemic translocation. This promotes liver fibrosis by activation of hepatic Kupffer cells and induction of proinflammatory cytokines, including tumor necrosis factor, interleukin (IL)-1, and IL-6.17,18 HIV-induced mitochondrial dysfunction results in production of reactive oxygen species, which causes oxidative stress that is known to increase fat accumulation in hepatocytes.19
Finally, certain ARTs may contribute to the pathogenesis of NAFLD. Older nucleoside reverse transcriptase inhibitors, (eg, stavudine, zidovudine, and didanosine) inhibit mitochondrial RNA and have been associated with liver fibrosis. Although these drugs are no longer recommended, associated adverse effects may be irreversible.7,20 Protease inhibitors increase central adiposity, decrease hepatic clearance of very-low-density lipoproteins, increase hepatic triglyceride production, and potentially contribute to NAFLD.21,22 ART in the current era, particularly integrase strand transfer inhibitors, is associated with weight gain with metabolic consequences that are not yet known.23
Diagnosis
The American Association for the Study of Liver Diseases does not recommend screening high-risk groups for NAFLD. However, the European AIDS Clinical Society recommends screening all PWH with metabolic syndrome for NAFLD by ultrasound, evaluation of liver enzymes, and serum fibrosis biomarkers.1,24
The severity of NAFLD is assessed by stratifying the degree of steatosis. Simple hepatic steatosis is generally benign, whereas NASH can progress to cirrhosis, liver failure, and liver cancer. Vodkin et al compared 66 biopsy-proven cases of NAFLD in patients who were infected with HIV versus those who were HIV-negative. They found that those with HIV-associated NAFLD were more likely to have definite steatohepatitis (36.4% vs 62.7%, P=0.027) and had higher scores for noninvasive markers of advanced disease.25 Noninvasive tests have varying degrees of performance in assessing NAFLD in people living with HIV (PLWH).22 Of the imaging modalities, MRI and transient elastography have the best performing characteristics. APRI score (AST: platelet count) and FIB-4 (fibrosis-4 score) can be considered when evaluating patients who are HIV-positive with NAFLD.26 Although liver biopsy is the gold standard for diagnosing and staging NAFLD, it is invasive, prone to sampling errors, and has risk for complications.
Management
Managing NAFLD consists of treating liver disease as well as its associated metabolic comorbidities such as obesity, hyperlipidemia, and diabetes. First-line therapy in NAFLD/NASH consists of lifestyle changes focusing on physical activity and diet. Weight loss of 10% is associated with resolution of steatosis and improvement of fibrosis in most individuals.27 Liver-specific dietary recommendations, such as diet composition, are generally lacking or controversial. Patients with NAFLD must avoid routine or heavy alcohol consumption, and many practitioners recommend complete abstinence, especially for patients with advanced NAFLD.
Bariatric surgery improves comorbid diseases and improves long-term outcomes in obese individuals. A systematic review of studies focusing on pre- and postoperative liver enzymes and histology revealed that bariatric surgery is associated with significant reduction in liver enzymes and histological features of NAFLD, including steatosis, fibrosis, and inflammation. However, further studies are needed before recommending bariatric surgery as a treatment for NAFLD.28
Although there are currently no FDA-approved treatments for NAFLD, multiple agents are under investigation. Pioglitazone has been shown to improve liver histology in patients with and without T2DM and biopsy-proven NASH.29 This effect was also seen among patients with HIV/hepatitis C (HCV) coinfection.30 In individuals with and without HIV, vitamin E use improves steatosis and steatohepatitis but does not improve hepatic fibrosis.31,32
Tesamorelin is an FDA-approved growth hormone (GH)-releasing hormone analog that restores endogenous pulsatile GH secretion and reduces visceral fat in individuals in PWH. A randomized-controlled trial (RCT) of PWH showed that tesamorelin significantly reduced hepatic fat fraction and prevented the progression of fibrosis but did not improve existing fibrosis.33
Obeticholic acid, a farnesoid X receptor agonist, plays a central role in the regulation of bile acids and metabolism. Interim analysis of an RCT revealed that it improved fibrosis and markers of NASH disease activity.34 However, due to safety concerns, it is currently not approved for treatment of NASH.
Maraviroc, a chemokine receptor 5 (CCR5) antagonist, may reduce the incidence of NAFLD as an add-on therapy for individuals with NAFLD and well-controlled HIV infection.35 Cenicriviroc, a chemokine 2 and 5 receptor inhibitor, may also prove to be an effective treatment for NASH.36 Other investigational drugs undergoing evaluation include elafibranor, a peroxisome proliferator-activator, and resmetirom, a thyroid hormone receptor β-agonist.37,38
Conclusion
Addressing NAFLD is an important issue for PWH. Because these individuals are living longer, they are at increased risk of developing chronic diseases such as obesity, T2DM, and NAFLD. PWH with features of metabolic syndrome should be evaluated for NAFLD. As both NAFLD and HIV may lead to increased risk of cardiovascular disease, managing dyslipidemia, hypertension, T2DM, and obesity may improve patients’ longevity and quality of life.39
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