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Non-Viral Liver Disease in HIV+ - Increased Prevalence of Liver Fibrosis in PLWH
Increased Prevalence of Liver Fibrosis in People Living With Human Immunodeficiency Virus Without Viral Hepatitis Compared to Population Controls
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Download the PDF here
Download the PDF here
15 December 2020
Forty-one (12%) of PWH without viral hepatitis had elevated LSM assessed by transient elastography compared to 154 (7%) population controls. Our results are comparable with previous studies, where the prevalence of liver fibrosis has been reported to range from 8% to 18% in adult PWH without viral hepatitis when assessed by transient elastography [6, 18, 30-36]. The proportion of PWH with mild, moderate, and severe fibrosis was higher compared to population controls (P < .01) (Figure 2). Compared to PWH without elevated LSM, PWH with elevated LSM were older (62 vs 56 years; P < .01), with higher waist circumference (102 vs 93 cm; P < .01), BMI (26 vs 24 kg/m2; P = .02), and AST (31 vs 28 IU/L; P = .02). They were more frequently diabetic (23% vs 5%; P < .01), overweight and obese (56% vs 39%; P = .02), and more frequently had metabolic syndrome (62% vs 40%; P = .02) and hepatic steatosis (27% vs 6%; P < .01)......Transient elastography was performed and elevated liver stiffness measurement (LSM) defined as 7.6 kPa as a proxy for significant liver fibrosis. In conclusion, HIV infection was independently associated with higher odds of elevated LSM, and the proportion of individuals with elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, and previous exposure to ddI were independently associated with elevated LSM, suggesting that liver fibrosis may be induced by a combination of hepatotoxic drugs, aging, and steatosis. Future studies on the pathogenesis of liver fibrosis in PWH without viral hepatitis are warranted......In this cross-sectional study of 342 unselected PWH aged 50-70 years without viral hepatitis, we show that elevated LSM, a surrogate marker of liver fibrosis, was more prevalent in PWH compared to population controls. Interestingly, a positive HIV status in individuals without viral hepatitis was independently associated with higher odds of elevated LSM. Moreover, age, higher BMI, and plasma ALT were associated with elevated LSM, as well as previous exposure to ddI. ......positive HIV status may induce a pathway of synergistic effects leading to accelerated fibrogenesis....... ......Age was associated with significant liver fibrosis, and the association between HIV infection and liver fibrosis increased with age, although this may partly be explained by the fact that older PWH tended to have been treated with more hepatotoxic agents no longer used. In the general population, the pathogenesis of nonalcoholic steatohepatitis (NASH) and liver fibrosis is described as a "multiple-parallel hit" model [40].......environmental factors (eg, diet, sedentary lifestyle), metabolic factors (eg, obesity, insulin resistance), and genetic factors (eg, PNAPL3) contribute to lipid accumulation of the hepatocyte [41], production of proinflammatory cytokines (eg, tumor necrosis factor alpha [TNF-α], interleukin 6 [IL-6]).....Thus, the immune profile of PWH is similar to the aging and immunosenescent immune profiles as in NASH and may contribute to both increased inflammation and increased fibrogenesis in the liver. Interestingly, ALT and AST levels were higher in PWH compared to uninfected controls and have been linked to liver fibrosis by several study groups including ours [6, 44].
In this study, we aimed to estimate the prevalence of and factors associated with liver fibrosis in PWH without viral hepatitis compared to HIV-uninfected controls, and to estimate if positive HIV status was independently associated with liver fibrosis. We hypothesized that PWH had a higher prevalence of liver fibrosis compared to the general population and that a positive HIV status was independently associated with liver fibrosis. In PWH, the prevalence of liver fibrosis has been reported to be 15% in unselected PWH [6]. This is higher than in the general population where the prevalence has been reported to be 2%-9% [7, 8], and PWH seem to be at higher risk of liver fibrosis. Possible explanations may be adverse lifestyle behavior, microbial translocation [9, 10], immune activation or immunosenescence [11, 12], ART-induced liver toxicities [13-16], and nonalcoholic fatty liver disease (NAFLD) [17]. However, studies that assess the prevalence and risk of liver fibrosis among unselected PWH without viral hepatitis and with an uninfected comparator group are few [18, 19]. The study was initiated in 1989 and comprises 2 cohorts with inhabitants aged 55 years and older (RS-I, RS-II), and 1 cohort with inhabitants aged 45 years and older (RS-III). For this study, participants aged 50-70 years enrolled from March 2011 to November 2014 from RS-II and RS-III were used as a comparator group. The comparator group was assumed to be HIV uninfected, as the prevalence of PWH in the Netherlands in 2017 was 0.1% [22]. Individuals with HBV infection and/or HCV infection were excluded from the analyses.
A total of 342 PWH from the COCOMO Study, and 2190 controls from the Rotterdam Study were included for this study (Figure 1). Clinical and demographic characteristics are shown in Table 1 and HIV-specific characteristics in Table 2.
Elevated LSM in PWH and Population Controls
Forty-one (12%) of PWH without viral hepatitis had elevated LSM assessed by transient elastography compared to 154 (7%) population controls (P < .01). The proportion of PWH with mild, moderate, and severe fibrosis was higher compared to population controls (P < .01) (Figure 2). The proportion of PWH with CT-defined moderate-to-severe hepatic steatosis was 24 (8%), while the proportion of population controls with ultrasound-defined steatosis was 776 (35%). In sensitivity analyses, individuals with elevated ALT were excluded, and the proportion of individuals with elevated LSM remained higher in PWH with normal ALT compared to population controls (11% vs 7%; P < .01). Compared to PWH without elevated LSM, PWH with elevated LSM were older (62 vs 56 years; P < .01), with higher waist circumference (102 vs 93 cm; P < .01), BMI (26 vs 24 kg/m2; P = .02), and AST (31 vs 28 IU/L; P = .02). They were more frequently diabetic (23% vs 5%; P < .01), overweight and obese (56% vs 39%; P = .02), and more frequently had metabolic syndrome (62% vs 40%; P = .02) and hepatic steatosis (27% vs 6%; P < .01).
HIV Infection and Elevated LSM
HIV infection was associated with higher odds of elevated LSM (aOR, 1.84 [95% CI, 1.17-2.88]; P < .001). The association between HIV infection and elevated LSM increased with age (Figure 3); individuals aged 57-63 years had higher odds of elevated LSM (aOR, 4.35 [95% CI, 1.27-14.88]; P = .02) when compared to individuals aged 50-52 years, and the odds were even higher in individuals aged 63-79 years (aOR, 8.67 [95% CI, 2.56-29.35]; P < .01).
Factors Associated With Elevated LSM in PWH
In univariate regression analysis, higher age, BMI, waist circumference, ALT, and triglycerides and presence of diabetes and steatosis were all associated with higher odds of elevated LSM in PWH, whereas higher total cholesterol was associated with lower odds of elevated LSM (Table 2). CD4 T-cell count >350 cells/μL was associated with lower odds of elevated LSM, while previous exposure (but not cumulative exposure time) to ddI was associated with higher odds of elevated LSM (OR, 2.57 [95% CI, 1.29-5.12]; P < .01) in univariate analyses. Neither duration of HIV infection, route of HIV transmission, plasma HIV RNA, nor previous or cumulative exposure to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, thymidine analogues, stavudine, or zidovudine was associated with elevated LSM and thus were not tested in multivariate analysis.
In multivariate analyses, higher age, ALT, and BMI were independently associated with elevated LSM in PWH (Figure 4). The effect of previous exposure to ddI remained statistically significant in multivariate analyses (aOR, 2.26 [95% CI, 1.01-5.06]; P = .04) in the total population of PWH. To test whether this was an independent effect of ddI exposure or an effect of longer duration of HIV infection, we tested the effect of ddI in a subgroup of PWH with comparable duration of HIV infection (≥20 years). In this population, 62 PWH were previously exposed to ddI and 95 PWH were not exposed to ddI (median duration of HIV infection, 25 vs 27 years; P = .13). Although statistically nonsignificant, the effect of ddI exposure remained associated with higher odds of elevated LSM in univariate analysis and after adjustment for sex and age (OR, 2.26 [95% CI, .92-5.53] and aOR, 2.26 [95% CI, .90-5.63], respectively; both P = .08).
Hepatic Fibrosis Associates With Multiple Cardiometabolic Disease Risk Factors: The Framingham Heart Study - (02/10/21)
Notably, hepatic fibrosis remained significantly associated with obesity-related traits, hypertension, low HDL cholesterol, and, most strongly, with diabetes, with 2.5 times increased odds, even after accounting for CAP, which suggests an association between hepatic fibrosis and cardiometabolic disease in addition too the association with hepatic steatosis. Hepatic fibrosis is associated with obesity traits, diabetes, hypertension, and low HDL cholesterol and occurs in approximately 10% of adults in an unselected, community-based sample. Our findings may have implications for screening strategies and also highlight the importance of evaluating for cardiometabolic disease in patients with hepatic fibrosis. Other noninvasive imaging modalities, such as magnetic resonance elastography, are more accurate compared with VCTE(48); however, we choose to perform VCTE because of the lower cost and point-of-care availability. Our study is cross-sectional; we cannot rule out residual confounding or establish causal relations. We examined multiple associations and did not account for multiple testing, and so some of our associations may be falsely positive.
Editorial - NAFLD and Cardiometabolic Risk Factors: The Liver Fibrosis Trajectory Through the Lens of Biological Interactions
06 December 2020
NAFLD often co-occurs with one or more cardiometabolic risk factors(1) that are shared with NAFLD-associated fibrosis, suggesting that multiple etiologic pathways are involved in the disease biology.(2) As hepatic steatosis and cardiometabolic traits shape one another,(1)this interrelationship drives multiple burdens of predisposing conditions, making it difficult to discriminate the extent and determinants of progression to severe liver disease. As a result, the role of steatosis in predisposing an individual to liver fibrosis in the context of multiple and concomitant risk factors has not been adequately studied.
The investigators showed that fibrosis-as measured by vibration-controlled transient elastography-is positively associated with multiple cardiovascular (CV) risk factors, including obesity, type 2 diabetes (T2D), and hypertension, and is negatively associated with high-density lipoprotein and total cholesterol. Based on these findings, the authors concluded that the association between fibrosis and cardiometabolic traits is independent of hepatic steatosis measured by the controlled attenuation parameter.(3) However, as Long et al. pointed out, lack of longitudinal data was one of the limitations of their study. This point is undoubtedly relevant because, since its launch in 1948, the FHS has become a multigenerational and paradigmatic study as a part of which CV and metabolic disease patterns are analyzed.
The elucidation of liver fibrosis risk factors via population-based epidemiological studies has deepened the knowledge of NAFLD and NASH-fibrosis pathogenesis. Thus, robust epidemiological studies are essential for obtaining quantitative data physicians can use when formulating best-practice recommendations that ultimately control the disease's progression. The research dilemma with NAFLD/NASH cross-sectional data is that they only provide a snapshot of NASH fibrosis. As a result, a "cause and effect" relationship cannot be established, and the natural history of fibrosis cannot be appraised.
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