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Increased Prevalence of Hepatic Steatosis in Young Adults With Lifelong HIV
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In this study, we demonstrated that hepatic steatosis is highly prevalent (33%) in PWH who have been infected since birth or early childhood. Categorical cut offs for grade 1 (CAP ≥ 248 dB/m) and grade 2 (CAP ≥ 268 dB/m) steatosis revealed a significantly higher prevalence of hepatic steatosis in PWH compared to matched HIV-negative controls. These results are of concern, particularly as they were observed in young adult patients without diabetes or HCV, known risk factors for NAFLD.....We found metabolic parameters to be the largest contributors to hepatic steatosis, in particular waist circumference. However, future studies with larger sample sizes and longitudinal follow-up are needed to further elucidate the role of HIV and HIV-related risk factors in NAFLD and to assess the predictive abilities of transient elastography for future progression of liver disease in this setting.....PWH participants were 61% female, 72% virally suppressed (HIV RNA <40 copies/mL), with a mean age of 28 years, mean CD4 T-cell count 605 cells/μL, and had an average of 19 years of ART exposure......PWH participants had significantly higher levels of several metabolic and inflammatory laboratory indices (Table 2). Compared to controls, PWH had lower HDL cholesterol and higher levels of triglyceride, glucose, HOMA IR, CRP, and D-dimer, as well as higher waist circumference and waist-to-hip ratio. PWH also had significantly lower CD4 T-cell and CD4/CD8 ratios compared to control subjects.
Using linear regression analyses, BMI (r = 0.4, P value = .0008), waist circumference (r = 0.54, P value = .0001), waist-hip ratio (r = 0.35, P value = .004), cholesterol (r = 0.25, P value = .04), triglycerides (r = 0.25, P value > .05), and HOMA IR (r = 0.35, P value = .005) were significantly positively associated with CAP score, whereas age, sex, social history, diastolic blood pressure, HDL cholesterol, glucose, AST, ALT, CRP, and D-dimer were not. These associations largely persisted when repeated in a subanalysis of only PWH.
Forty-six PWH since birth or early childhood (ie, perinatal or transfusion acquired) and 20 age-, race-, and sex-matched HIV-negative controls were prospectively recruited as part of a convenience sample from a natural history study exploring the physical and psychological impact of lifelong HIV infection (Clinical Trials.gov NCT number 01656564).
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Increased Prevalence of Hepatic Steatosis in Young Adults With Lifelong HIV
The Journal of Infectious Diseases 10 March 2019 - Julia A. Aepfelbacher,1 Julia Balmaceda,1 Julia Purdy,2 Aviva Mattingly,1 Kirsten Zambell,3 Karyn Hawkins,4 Cheryl Chairez,1 Kara Anne Curl,1 Nicola Dee,1
and Colleen Hadigan1
1National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and Departments of 2Critical Care Medicine, 3Nutrition, and 4Nursing, National Institutes of Health Clinical Center, Bethesda, Maryland
Abstract
Little is known about the effects of lifelong human immunodeficiency virus (HIV) or antiretroviral therapy on hepatic steatosis and fibrosis. Using transient elastography, we evaluated 46 young adults with lifelong HIV and 20 matched HIV-negative controls. Steatosis was present in 33% of persons with HIV and only 10% of controls (P = .04). Hepatic fibrosis scores were not elevated and did not differ between groups. Metabolic parameters, particularly increased waist circumference, and not HIV-specific factors, were significantly associated with steatosis. While this finding should be examined in larger cohorts, modifiable metabolic disturbances may be important targets to optimize liver health in this population.
DISCUSSION
In this study, we demonstrated that hepatic steatosis is highly prevalent (33%) in PWH who have been infected since birth or early childhood. Categorical cut offs for grade 1 (CAP ≥ 248 dB/m) and grade 2 (CAP ≥ 268 dB/m) steatosis revealed a significantly higher prevalence of hepatic steatosis in PWH compared to matched HIV-negative controls. These results are of concern, particularly as they were observed in young adult patients without diabetes or HCV, known risk factors for NAFLD.
While the prevalence of hepatic steatosis in cohorts of adults with HIV infection varies, ranging from 29% to 43% [2], our results are consistent with large-scale studies utilizing transient elastrography. Pembroke et al [10] demonstrated a prevalence of hepatic steatosis of 36% (n = 541, CAP ≥ 248 dB/m) in a large Canadian cohort of adults with HIV infection. A study of 326 subjects in Spain reported a 37% prevalence (≥238 dB/m) [11], and, more recently, Perazzo et al [5] reported a similar prevalence of 35% (≥248 dB/m) in Brazil. Despite a younger average age, our cohort exhibited a prevalence on par with those of older, largely male populations. In contrast, our observed fibrosis prevalence of 7% (kPa ≥ 7.1) was lower than previously reported values, which range from 13% to 34%, a difference that could be attributed to the relatively young age of our cohort.
In the general population, there are well-established risk factors for NAFLD, including insulin resistance, central adiposity, and dyslipidemia, factors that parallel rising levels of obesity, diabetes mellitus 2, and metabolic syndrome [3]; however, less is known about the pathophysiology of NAFLD in HIV. Previous research indicates that combination ART, altered lipid metabolism, chronic immune activation, low CD4/CD8 T-cell ratio, and inflammation place HIV populations at increased risk for liver disease [12]. In a 2017 meta-analysis of NAFLD in individuals with HIV without HCV, hepatic steatosis was most closely related to metabolic parameters, including BMI, waist circumference, hypertension, dyslipidemia, and elevated fasting glucose [2]. Recently, both Pembroke et al [10] and Macias et al [11] found that upon multivariate analysis BMI remained the sole independent predictor of hepatic steatosis. Our results reinforce previously observed relationships between metabolic parameters and hepatic steatosis. We found hepatic steatosis was increased in those with HIV, and positively associated with BMI, waist circumference, cholesterol, and HOMA IR. Waist circumference emerged as the only independent risk factor for hepatic steatosis in this population. While modifiable, many of these risk factors disproportionately affect PWH due to the confluence of social, economic, and HIV-specific factors. For example, increased waist circumference may represent central adiposity associated with lipodystrophy and antiretroviral-specific effects on body fat distribution.
Simple hepatic steatosis is highly prevalent among young HIV populations, which is worrisome because hepatic steatosis may progress to more severe forms of liver disease. With rising rates of obesity and diabetes globally, and a disproportionate burden of NAFLD in PWH, early and effective detection of high-risk patients and subsequent preventative strategies are needed.
To our knowledge, this is the first study to evaluate the hepatic consequences of lifelong HIV in young adults using transient elastography and to use a well-matched HIV-negative comparison group. However, our study may have several limitations. Due to the relatively small sample size, we may not have been able to detect the role of HIV-specific factors, including ART regimen and duration, viral suppression, and CD4 count in hepatic steatosis; however, in larger adult studies, the relationship between HIV-specific factors and hepatic steatosis also remains unclear. Two studies in high-resource settings [10, 11] found no relationship between ART duration and hepatic steatosis prevalence. A recent study in Germany found that ART and control of HIV seem to play an indirect role in the development of hepatic steatosis through return to health effects [13]. Prior research linked exposure to thymidine analogues to hepatic steatosis [5], but in current US cohorts the use of these agents is increasingly rare. None of our cohort were using a thymidine analogue during the study. An additional potential limitation is the cross-sectional design of our study that did not allow for the determination of a temporal relationship between hepatic steatosis and/or the possible development of liver fibrosis and cirrhosis. Lastly, we excluded individuals who were living with HCV and diabetes in order to isolate HIV-specific risk factors, which may limit the generalizability of our study to the broader population of PWH.
In conclusion, hepatic steatosis was common in our cohort of PWH since birth or early childhood, with prevalence on a par with that of older populations with HIV infection. We found metabolic parameters to be the largest contributors to hepatic steatosis, in particular waist circumference. However, future studies with larger sample sizes and longitudinal follow-up are needed to further elucidate the role of HIV and HIV-related risk factors in NAFLD and to assess the predictive abilities of transient elastography for future progression of liver disease in this setting.
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