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Belly Fat Predicts Fibrosis - Clinical Predictors of Liver Fibrosis Presence and Progression in Human Immunodeficiency Virus-Associated Nonalcoholic Fatty Liver Disease
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Clinical Infectious Diseases 15 June 2021- Lindsay T. Fourman et al.
".....Over 12 months, fibrosis progressed in 38% (n = 9) of placebo-treated participants with HIV-associated NAFLD......We previously conducted a randomized, double-blind trial in which participants were assigned to receive the growth hormone-releasing hormone (GHRH) analogue tesamorelin 2 mg daily or identical placebo for 12 months [11]. This trial demonstrated that tesamorelin significantly reduced liver fat (primary endpoint) and prevented fibrosis progression (secondary endpoint) among PLWH...In this longitudinal study of HIV-associated NAFLD, high rates of hepatic fibrosis and progression were observed. Visceral adiposity was identified as a novel predictor of worsening fibrosis. In contrast, baseline histologic characteristics did not relate to fibrosis progression."
Abstract
Background
Nonalcoholic fatty liver disease (NAFLD) affects more than one-third of people living with human immunodeficiency virus (HIV). Nonetheless, its natural history is poorly understood, including which patients are most likely to have a progressive disease course.
Methods
We leveraged a randomized trial of the growth hormone-releasing hormone analogue tesamorelin to treat NAFLD in HIV. Sixty-one participants with HIV-associated NAFLD were randomized to tesamorelin or placebo for 12 months with serial biopsies.
Study subjects (mean age, 53 ± 7 years; 81% male) had long-standing HIV infection (mean, 16 ± 9 years) that was well controlled. All participants were on stable ART with 62% receiving an integrase inhibitor-based regimen.
A total of 24 participants with HIV-associated NAFLD randomized to placebo had paired liver biopsy specimens available at baseline and 12 months. Clinical characteristics in this subset were comparable to the overall study group.
Among our overall sample with HIV-associated NAFLD, 43% had evidence of hepatic fibrosis at baseline with the following distribution by stage: stage 1, 36%; stage 2, 40%; stage 3, 24% (Figure 1A).
Study Design
We previously conducted a randomized, double-blind trial in which participants were assigned to receive the growth hormone-releasing hormone (GHRH) analogue tesamorelin 2 mg daily or identical placebo for 12 months [11]. This trial demonstrated that tesamorelin significantly reduced liver fat (primary endpoint) and prevented fibrosis progression (secondary endpoint) among PLWH [11]. In the current study, we examined the natural history of NAFLD using this study population. We assessed clinical correlates of fibrosis in the overall study sample by leveraging baseline biopsy specimens before treatment. We also identified clinical predictors of fibrosis progression by utilizing serial biopsy specimens among the subset of participants assigned to placebo. The data presented here have not been reported elsewhere.
We enrolled 61 men and women 18-70 years old who had documented HIV infection as well as hepatic steatosis defined by liver fat fraction ≥ 5% on proton magnetic resonance spectroscopy (1H-MRS). Recruitment through clinics, community health centers, and general local advertisements targeted individuals with HIV infection and known NAFLD.
Results
In all participants with baseline biopsies (n = 58), 43% had hepatic fibrosis. Individuals with fibrosis had higher NAFLD Activity Score (NAS) (mean ± standard deviation [SD], 3.6 ± 2.0 vs 2.0 ± 0.8; P < .0001) and visceral fat content (mean ± SD, 284 ± 91 cm2 vs 212 ± 95 cm2; P = .005), but no difference in hepatic fat or body mass index. Among placebo-treated participants with paired biopsies (n = 24), 38% had hepatic fibrosis progression over 12 months. For each 25 cm2 higher visceral fat at baseline, odds of fibrosis progression increased by 37% (odds ratio, 1.37 [95% confidence interval, 1.03-2.07]). There was no difference in baseline NAS between fibrosis progressors and nonprogressors, though NAS rose over time in the progressor group (mean ± SD, 1.1 ± 0.8 vs -0.5 ± 0.6; P < .0001).
Fibrosis also was positively associated with the noninvasive parameters alanine aminotransferase (mean, 41 ± 30 U/L vs 23 ± 8 U/L; P = .002), aspartate aminotransferase (mean, 44 ± 27 U/L vs 23 ± 10 U/L; P = .0003), and FIB-4 (mean, 1.88 ± 0.98 vs 1.12 ± 0.44; P = .0003). Notably, while VAT was higher among individuals with fibrosis (mean, 284 ± 91 cm2 vs 212 ± 95 cm2; P = .005), there were no differences between groups in BMI, waist circumference, or SAT (Figure 2).
Beyond a high prevalence of fibrosis, we also showed for the first time that individuals with HIV-associated NAFLD may experience rapid fibrosis progression. In this regard, over a 12-month period, 38% of placebo-treated participants experienced worsening of hepatic fibrosis, whereas only 13% experienced improvement.
Conclusions
In this longitudinal study of HIV-associated NAFLD, high rates of hepatic fibrosis and progression were observed. Visceral adiposity was identified as a novel predictor of worsening fibrosis. In contrast, baseline histologic characteristics did not relate to fibrosis progression.
In an era of rising rates of obesity and hepatitis C virus (HCV) cure, nonalcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease among people living with human immunodeficiency virus (PLWH) [1]. More than one-third of individuals are affected with risk factors that include elevated body mass index (BMI), metabolic comorbidities, and high CD4+ T-cell count [1].
Introduction
The spectrum of NAFLD is broad, ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) to fibrosis. Importantly, among patients with NAFLD in the general population, the severity of fibrosis is the strongest predictor of all-cause and liver-specific mortality [2, 3]. Thus, understanding the clinical predictors of fibrosis presence and progression in human immunodeficiency virus (HIV) is imperative so that individuals with the most aggressive hepatic disease can be appropriately monitored and targeted for intervention.
Individuals with HIV/HCV coinfection have been shown to have faster progression of fibrosis as well as a higher frequency of hepatic decompensation compared to HCV-monoinfected patients [4, 5]. While these findings raise concern that the course of NAFLD in HIV may also be accelerated, its natural history among this patient population has not been previously well-defined. In this regard, studies focused on hepatic fibrosis in the setting of HIV monoinfection have most often examined a heterogeneous sample not specifically selected for NAFLD [6-9]. Furthermore, these analyses have only rarely included long-term follow-up or utilized liver biopsies that would allow for comprehensive assessment of other histologic changes [10]. While these previous studies have consistently demonstrated high rates of hepatic fibrosis in association with metabolic risk factors [6-10], the subset of patients with HIV-associated NAFLD at highest risk for disease-related morbidity remains elusive.
In the current analysis, we leveraged phenotypic data including liver biopsy samples from a recent randomized placebo-controlled trial to characterize the longitudinal course of NAFLD in HIV. This previous study demonstrated that a strategy to reduce visceral fat prevented fibrosis progression among individuals with HIV-associated NAFLD [11]. In this current analysis, we investigated for the first time the relationship of visceral fat and other clinical characteristics with liver fibrosis, particularly with respect to the natural history of fibrosis progression among placebo-treated participants undergoing serial liver biopsies. Given the high frequency of NAFLD in HIV, accurately predicting which patients will have the most severe course of disease is critically needed to optimize screening, prevention, and treatment strategies for this population.
Discussion excerpts
In the current study, we demonstrated that individuals with the most profound visceral fat accumulation were at the highest risk of fibrosis presence and progression. Furthermore, we identified high visceral fat content as a novel clinical predictor of accelerated hepatic disease.
In summary, we showed high rates of hepatic fibrosis presence and progression among individuals with HIV-associated NAFLD over a 12-month period. Moreover, we identified high visceral adiposity as a novel predictor of a more aggressive course of hepatic fibrosis. Meanwhile, although worsening of fibrosis was associated with a rise in NAS, no association was observed between baseline NAS and fibrosis progression. Given the accelerated nature of NAFLD in HIV as well as the limited utility of available indices to prognosticate an individual patient's trajectory, new biomarkers and metrics to identify those who require more intensive monitoring and therapy are critically needed. Furthermore, since assessment of visceral adiposity is not routinely available in the clinical setting, use of novel clinical methodologies to quantify visceral fat should be explored. Only by accurately risk-stratifying patients with HIV-associated NAFLD can we individualize and optimize care for this heterogeneous group of patients.
PLWH are prone to visceral adiposity due to a confluence of direct viral effects, ART toxicity, and lifestyle factors [19-21]. Importantly, pathologic gains in visceral fat have been observed even with the newest integrase inhibitor-based regimens, which were once regarded as metabolically neutral [22]. Previously, we have shown that visceral fat is higher in HIV than non-HIV among individuals with normal or overweight BMI [23]. Moreover, in the current cohort, VAT only loosely correlated with BMI, reinforcing the premise that BMI may not be an accurate gauge of visceral adiposity in this group. The dissociation of visceral fat from BMI in HIV parallels the discordant relationships of these parameters with hepatic fibrosis that we observed. Our findings suggest that detailed measures of body composition, but not BMI alone, may be useful to prognosticate disease course in patients with HIV-associated NAFLD.
In addition to its clinical utility, the emergence of visceral fat accumulation as a novel predictor of hepatic fibrosis progression may provide key insights into the pathogenesis of NAFLD in HIV. Visceral fat synthesizes and secretes cytokines that are directly delivered to the liver by the portal circulation. Accordingly, hepatic fibrosis may occur in response to this systemic proinflammatory state [17, 24]. Visceral fat may also be a key source of circulating profibrotic mediators, which in turn may directly drive end organ scarring [25].
Taken together, this evidence suggests that therapies to reduce visceral fat may be effective to prevent progression of steatohepatitis and fibrosis in the context of HIV-associated NAFLD. Notably, in the randomized trial on which the current study is based, we found that the GHRH analogue tesamorelin, which is known to reduce visceral fat, also prevented hepatic fibrosis progression among participants with HIV-associated NAFLD [11].
Among study participants with HIV-associated NAFLD, we found a striking 43% to have evidence of hepatic fibrosis on initial biopsy. In studies of NAFLD among the general population, liver fibrosis is the strongest clinical predictor of morbidity and mortality [2, 3]. Thus, a high prevalence of NAFLD [1], coupled with a high proportion of fibrosis in those with NAFLD, suggests that a large patient population of PLWH is susceptible to liver-related complications. Few studies have assessed the prevalence of hepatic fibrosis in PLWH exclusively selected for NAFLD. In 1 study of fatty liver conducted in China, the frequency of fibrosis diagnosed by transient elastography was 27% in PLWH vs 5% in matched controls [14]. The higher prevalence of fibrosis that we observed in the current analysis may relate to racial or methodologic differences between studies. An additional US-based report found the frequency of fibrosis in HIV-associated NAFLD to be 61% with a similar rate observed among the general population [15]. Notably, in this previous study, liver biopsies were obtained for clinical purposes, and thus participants may have had more advanced disease than in the current report.
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