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VAT & Fatty Liver/Fibrosis – "Clinical Predictors of Liver Fibrosis Presence and Progression in HIV-Associated NAFLD"
 
  "Visceral adiposity was identified as a novel clinical predictor of worsening fibrosis" Summary:
 
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In this longitudinal study of HIV-associated NAFLD, we observed high rates of hepatic fibrosis presence and progression. We identified visceral adiposity as a novel predictor of fibrosis progression.
 
CROI: Clinical Predictors of Liver Fibrosis Presence and Progression in HIV-Associated Nonalcoholic Fatty Liver Disease (03/23/20)
 
Over one-third of individuals are affected with risk factors that include elevated BMI, metabolic comorbidities, and high CD4+ T cell count [1]. The spectrum of NAFLD is broad, ranging from simple steatosis to 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.
 
CROI: NAFLD AND LIVER FIBROSIS PREDICT HIGH CARDIOVASCULAR RISK IN HIV-MONOINFECTED PATIENT (04/02/20)
 
CROI: BENEFITS OF RILPIVIRINE FOR LIVER FIBROSIS IN HIV/HCV COINFECTED SUBJECTS (03/23/20)
 
Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease - (02/28/20)
 
GP perceptions of liver disease; HIV & Fatty Liver/NASH NASH Diagnosis and Management in General Practice - (01/09/20)
 
CROI: FATTY LIVER DISEASE: A GROWING CONCERN - (04/12/17) a plenary talk by noted fatty liver expert Rohit Loomba from UCSD
 
CROI: Changes in Liver Fibrosis and Steatosis in HIV Mono-Infected patients over 24 months - 50% have fatty liver at average age of 46 - (03/28/17)
 
CROI: LIVER STEATOSIS AND FIBROSIS IN AT-RISK EUROPEAN HIV-MONOINFECTED PATIENTS - 64% with steatosis among those who had elevated LFTs and/or metabolic syndrome and/or lipodystrophy - (03/28/17)
 
IAC: Two-fold higher chance of liver steatosis with HIV in big Brazilian study - (07/31/18)
 
Accepted manuscript
 
Clinical Predictors of Liver Fibrosis Presence and Progression in HIV-Associated NAFLD
 
09 April 2020 Clinical Infectious Diseases - Lindsay T. Fourman *1, Takara L. Stanley *1, Isabel Zheng 1, Chelsea S. Pan 1, Meghan N. Feldpausch 1, Julia Purdy 2, Julia Aepfelbacher 2, Colleen Buckless 3, Andrew Tsao 3, Kathleen E. Corey 4, Raymond T. Chung 4, Martin Torriani 3,
David E. Kleiner 5, Colleen M. Hadigan 2, Steven K. Grinspoon 1
1 Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
2 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
3 Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
4 Liver Center, Gastroenterology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
5 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
 
Abstract
 
Background

 
Nonalcoholic fatty disease (NAFLD) affects over one-third of people living with HIV. Nonetheless, the natural history of HIV-associated NAFLD 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. Participants underwent liver biopsy at baseline and 12 months with histologic evaluation performed by an expert pathologist blinded to treatment.
 
Results
 
In all participants with baseline biopsies (n=58), 43% had hepatic fibrosis. Individuals with fibrosis had higher NAFLD Activity Score (NAS) (3.6±2.0 vs. 2.0±0.8, P<0.0001) and visceral fat content (284±91 cm2 vs. 212±95 cm2, P=0.005), but no difference in hepatic fat or BMI. 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, the odds of fibrosis progression increased by 37% (OR 1.37, 95% CI 1.03, 2.07). There was no difference in baseline NAS score between fibrosis progressors and non-progressors, though NAS score rose over time in the progressor group (1.1±0.8 vs. -0.5±0.6, P<0.0001).
 
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 clinical predictor of worsening fibrosis. In contrast, baseline histologic characteristics were not found to relate to fibrosis changes over time. Further studies are needed to identify additional biomarkers of accelerated disease.
 
Introduction
 
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 HIV (PLWH) [1]. Over one-third of individuals are affected with risk factors that include elevated BMI, metabolic comorbidities, and high CD4+ T cell count [1]. The spectrum of NAFLD is broad, ranging from simple steatosis to 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 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.
 
Results
 
Participant Characteristics
 
A total of 58 participants with HIV-associated NAFLD had liver biopsy specimens available at baseline. Clinical characteristics of the overall sample were summarized in Supplementary Table 1. Study subjects (53 ± 7 years, 81% male) had long-standing HIV infection (16 ± 9 years) that was well controlled. All participants were on stable ART with 62% receiving an integrase inhibitor-based regimen. Baseline liver fat content was 13.8% 8.6%, whereas NAS score was 2.7 ± 1.6. A total of 59% of participants were obese. BMI was strongly correlated with SAT (r = 0.86, P < 0.0001), and more weakly associated with VAT (r = 0.29, P = 0.02) (Supplementary Figure 1).
 
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 (Supplementary Table 1).
 
Clinical Correlates of Baseline Hepatic Fibrosis (Overall Sample)
 
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). Clinical correlates of baseline hepatic fibrosis are shown in Table 1. Individuals with and without fibrosis were of comparable age and sex. While fibrosis tended to be more common among white subjects, racial differences between groups were not statistically significant. In contrast, there was no association of fibrosis with CD4+ T cell count, HIV viral load, C-reactive protein (CRP), or interleukin-6 (IL-6).
 
With regard to hepatic and metabolic indices, individuals with hepatic fibrosis had higher NAS score (3.6 ± 2.0 vs. 2.0 ± 0.8, P < 0.0001) with elevations in both lobular inflammation (1.5 ± 0.8 vs. 0.9 ± 0.2, P = 0.0004) and hepatocellular ballooning (0.7 ± 0.8 vs. 0.0 ± 0.2, P < 0.0001). In contrast, liver fat content was not found to differ between groups. Fibrosis also was positively associated with the non-invasive parameters alanine aminotransferase (ALT, 41 ± 30 U/L vs. 23 ± 8 U/L, P = 0.002), aspartate aminotransferase (AST, 44 ± 27 U/L vs. 23 ± 10 U/L, P = 0.0003), and FIB-4 (1.88 ± 0.98 vs. 1.12 ± 0.44, P = 0.0003). Notably, while VAT was higher among individuals with fibrosis (284 ± 91 cm2 vs. 212 ± 95 cm2, P = 0.005), there were no differences between groups in BMI, waist circumference, or SAT (Figure 2).
 
Clinical Predictors of Hepatic Fibrosis Progression (Placebo Group)
 
Over 12 months, fibrosis progressed in 38% (n = 9) of placebo-treated participants with HIV-associated NAFLD. Meanwhile, 50% (n = 12) of subjects had no change in fibrosis, whereas 13% (n = 3) experienced fibrosis regression (Figure 1B). Among all placebo-treated participants, the mean rate of fibrosis progression was 0.2 ± 0.8 stages per year. A total of 56% (n = 5) of participants with fibrosis progression had no evidence of fibrosis at baseline.
 
Baseline VAT was higher among those with fibrosis progression than without progression (306 ± 119 cm2 vs. 212 ± 89 cm2, P = 0.04). An analogous relationship was also observed in a sub-analysis of those without any baseline fibrosis (308 ± 120 cm2 vs. 184 ± 79 cm2, P = 0.03). In multivariable regression modeling, each 25 cm2 higher VAT at baseline was associated with a 37% increased odds of fibrosis progression upon adjusting for baseline NAS score, liver fat content, and BMI (OR 1.37, 95% CI 1.03, 2.07; P = 0.03). In contrast, baseline NAS score, hepatic fat, and BMI were themselves not found to be associated with fibrosis progression in our cohort (Table 2). Likewise, baseline hepatic fibrosis, SAT, and waist circumference also did not differ in progressors versus non-progressors. Lastly, comparisons of demographic and HIV-related characteristics were not found to be significant between groups (Supplemental Table 2).
 
Changes in Clinical Indices with Hepatic Fibrosis Progression (Placebo Group)
 
We next examined changes in clinical indices that accompanied fibrosis progression among our placebo-treated participants with HIV-associated NAFLD (Table 3). Though baseline NAS score did not predict worsening of fibrosis, NAS score did significantly increase among fibrosis progressors versus non-progressors over the 12-month study period (1.1 ± 0.8 vs. -0.5 ± 0.6, P < 0.0001) (Figure 3A). This change reflected a rise in both lobular inflammation (0.4 ± 0.5 vs. -0.2 ± 0.4, P = 0.003) and hepatocellular ballooning (0.4 ± 0.5 vs. -0.2 ± 0.6, P = 0.01). In contrast, the baseline difference in visceral fat between fibrosis progressors and non-progressors remained constant over time (Figure 3B). CRP (4.0 ± 5.4 mg/L vs. -0.2 ± 2.4 mg/L, P = 0.02) and hemoglobin A1c (HbA1c, 0.3% ± 0.4% vs. -0.1% ± 0.3%, P =0.02) also were noted to increase in association with fibrosis progression. No other changes in clinical parameters were found to be significantly associated with worsening of hepatic fibrosis among our study cohort.
 
Discussion
 
In this study, we demonstrated a high prevalence and progression rate of biopsy-proven liver fibrosis among a modern cohort of PLWH with well-defined NAFLD. Furthermore, we identified high visceral fat content as a novel clinical predictor of accelerated hepatic disease. Baseline histologic indices including NAS score were not found to be associated with worsening fibrosis, though fibrosis progression was itself accompanied by a concurrent rise in NAS score among our study sample. These findings may have important implications for the risk stratification of patients with HIV-associated NAFLD, and underscore the critical need for additional measures to prognosticate disease severity.
 
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, suggest 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 one study of fatty liver conducted in China, the frequency of fibrosis diagnosed by transient elastography was 27% in PLWH versus 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 U.S.-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. Our reliance on liver biopsy specimens that were obtained routinely per protocol provides a window into the natural history of HIV-associated NAFLD that has rarely been afforded by other studies.
 
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. Notably, among the subset of participants with fibrosis progression, fewer than half had evidence of fibrosis at baseline; as such, absence of fibrosis at a single time point did not preclude an aggressive disease course. To our knowledge, prior studies have not evaluated changes in liver histology over time in individuals with well-defined HIV-associated NAFLD. In a systematic review of NASH in the general population, a comparable proportion of subjects were found to have progression of fibrosis on repeat biopsy, but the duration of follow-up was longer than in the current analysis [16]. When standardized by time, the mean rate of fibrosis progression in the general population with NASH was 0.03 stages/year, as compared to 0.2 stages/year in the current cohort with HIV-associated NAFLD [16].
 
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. In contrast, we did not find an association of hepatic fibrosis presence or progression with BMI, waist circumference, subcutaneous fat, or hepatic fat. Indeed, the association between baseline visceral fat and fibrosis progression persisted upon adjusting for BMI, hepatic fat, and NAS score. Our findings of a relationship between visceral fat and fibrosis at baseline are consistent with cross-sectional studies in the general population [17, 18]. Meanwhile, our longitudinal analysis extends the data suggested by these previous reports, demonstrating that higher baseline visceral fat content predicts worsening of fibrosis over one year.
 
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 pro-inflammatory state [17, 24]. Visceral fat may also be a key source of circulating pro-fibrotic mediators, which in turn may directly drive end organ scarring [25]. In two studies of individuals without HIV infection undergoing weight loss surgery, greater macrophage infiltration in visceral but not subcutaneous fat was directly associated with a higher number of hepatic fibroinflammatory lesions and an increased stage of liver fibrosis [26, 27]. Further, in C57BL/6J mice on a high fat diet, surgical removal of visceral epididymal white adipose tissue significantly reduced progression of steatohepatitis compared to sham surgery [28]. 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].
 
Importantly, unlike visceral fat, we did not find baseline liver histology to be associated with disease course in this sample with HIV-associated NAFLD. Specifically, we showed that individuals with hepatic fibrosis at baseline had higher baseline NAS score. Moreover, those with worsening of fibrosis had a greater rise in NAS score over the course of the study period. However, baseline NAS score was not found to distinguish hepatic fibrosis progressors from non-progressors over the ensuing 12 months. This finding counters some reports in the general population, which have shown that the presence of NASH strongly predicts hepatic fibrosis progression [16, 29]. In addition, other indices of inflammation and markers of metabolic status including CRP and HbA1c were not useful in this study to predict fibrosis progression. Further studies are needed to assess the relative value of unique HIV parameters, such as excess visceral adiposity identified in this study, versus histologic indices to predict disease course in HIV-associated NAFLD. Our findings also highlight potential differences in NAFLD pathophysiology in PLWH versus the general population.
 
To our knowledge, this study comprises the first longitudinal assessment of a well-defined sample with HIV-associated NAFLD, and the first to assess serial liver biopsies to determine natural history in this group. Importantly, participants in this analysis were virologically suppressed on modern ART, and thus our findings are likely to be generalizable to contemporary PLWH. As another strength of this analysis, we evaluated hepatic fibrosis by liver biopsy rather than by non-invasive methods. In addition to serving as the gold standard for fibrosis measurement [30], the use of liver biopsy allowed us to relate other histologic indices to fibrosis presence and progression in cross-sectional and longitudinal analyses. Notably, since biopsies were obtained at a fixed interval on all study subjects per protocol, our findings were unlikely to have been influenced by ascertainment bias. As a limitation of this analysis, our sample size was relatively small. As such, we may have had limited power to detect certain differences between groups or to adjust our analyses in multivariable models; the absence of an association between a variable of interest and fibrosis presence or progression should not be interpreted as definitive evidence against such a relationship. Moreover, the overall number of women in this cohort did not allow us to investigate sex-specific differences in fibrosis progression. Biopsy length is an important factor in the diagnostic accuracy of histopathology [31]. All samples used in this study were deemed adequate for analysis by the study pathologist (D.E.K.), and sample lengths did not differ between individuals with versus without fibrosis at baseline. In addition, based on the randomized longitudinal design of this study within HIV, a non-HIV comparator group was not included, though we were able to draw inferences with respect to the general population from existing literature.
 
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, while worsening of fibrosis was associated with a rise in NAS score, no association was observed between baseline NAS score 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.
 
Funding
 
This work was supported by the National Institutes of Health [1KL2TR002542-01 to L.T.F.]; the National Institute of Allergy and Infectious Diseases [U01AI115711]; the Nutrition Obesity Research Center at Harvard [P30DK040561]; the National Center for Advancing Translational Science [1UL1TR002541-01]; and the Intramural Research Program of the NIH, National Cancer Institute. Study drug for the trial was supplied by Theratechnologies, Inc., although treatment data were not the focus of the current manuscript.

 
 
 
 
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