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Increased Prevalence of Liver Fibrosis in People Living With Human Immunodeficiency Virus Without Viral Hepatitis Compared to Population Controls
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The Journal of Infectious Diseases 1 August 2021
The prevalence of elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, previous exposure to didanosine, and positive HIV status were independently associated with higher odds of elevated LSM.....The prevalence of elevated LSM was higher in PWH than in uninfected controls (12% vs 7%; P < .01). Human immunodeficiency virus (HIV) infection was independently associated with elevated LSM.
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.
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]. In short, 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]), activation of Kupffer cells, and secretion of inflammatory cytokines (eg, TNF-α, interleukin 1β [IL-1β]). Kupffer cells and recruited innate immune cells may induce inflammation in the liver, and IL-1β secretion in particular plays a crucial role in the progression of NAFLD/NASH. Eventually, hepatic stellate cells are activated by, for example, proinflammatory cytokines and IL-1β, resulting in fibrogenesis in the liver parenchyma. In PWH, increased levels of proinflammatory cytokines (including TNF-α, IL-6, and IL-1β) have been demonstrated as well as reduced production of naive CD4 T cells, increased numbers of late differentiated CD4+ and CD8+ T cells, and shortened telomere length [42, 43]. 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......the effect of hepatic steatosis on liver fibrosis in PWH seemed stronger than in population controls, and suggests that a positive HIV status may induce a pathway of synergistic effects leading to accelerated fibrogenesis.......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]. Prospective studies are needed to explore these age-specific differences in more detail and to characterize specific phenotypes of PWH at risk of liver fibrosis.
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.
HIV infection is a chronic disease and the population of PWH is aging. Consequently, the number of age-related comorbidities has increased, and by 2030 >80% of PWH are predicted to have at least 1 age-related comorbidity [2]. Liver disease is the second leading cause of death among PWH with high mortality rates among PWH coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) [3]. However, the spectrum of liver disease among PWH likely will change due to the ability to suppress HBV replication with ART, direct-acting antiviral therapy for HCV infection, and the World Health Organization’s 2030 HCV elimination plan [4, 5]. 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].
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).
Abstract
Background
Liver fibrosis is associated with poor liver-related outcomes and mortality. People with human immunodeficiency virus (PWH) may be at increased risk. We aimed to estimate the prevalence and factors associated with liver fibrosis in PWH compared to population controls.
Methods
This was a cross-sectional cohort study comparing 342 PWH with 2190 population controls aged 50-70 years.
Transient elastography was performed and elevated liver stiffness measurement (LSM) defined as 7.6 kPa as a proxy for significant liver fibrosis. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were computed by logistic regression.
The Copenhagen Co-Morbidity in HIV Infection (COCOMO) Study is an observational, prospective cohort study of PWH aged 20 years and above in the area of Copenhagen, Denmark [20].
Results
The prevalence of elevated LSM was higher in PWH than in uninfected controls (12% vs 7%; P < .01). Human immunodeficiency virus (HIV) infection was independently associated with elevated LSM. In multivariate analysis, elevated LSM was associated with HIV (aOR, 1.84 [95% CI, 1.17-2.88]; P < .01); higher age (per decade: aOR, 3.34 [95% CI, 1.81-6.18]; P < .01); alanine aminotransferase (ALT) (per 10 IU/L: aOR, 1.25 [95% CI, 1.05-1.49]; P < .01); body mass index (BMI) (per 1 kg/m2: aOR, 1.17 [95% CI, 1.05-1.29]; P < .01), and previous exposure to didanosine (per year: aOR, 2.26 [95% CI, 1.01-5.06]; P = .04).
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).
Conclusions
The prevalence of elevated LSM was higher in PWH compared to population controls. Higher age, BMI, ALT, previous exposure to didanosine, and positive HIV status were independently associated with higher odds of elevated LSM.
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