Clinical Predictors of Liver Fibrosis Presence and Progression in Human Immunodeficiency Virus–Associated Nonalcoholic Fatty Liver Disease

Fourman, Lindsay T; Stanley, Takara L.; Zheng, Isabel; Pan, Chelsea S; Feldpausch, Meghan N.; Purdy, Julia B.; Aepfelbacher, Julia; Buckless, Colleen; Tsao, Andrew; Corey, Kathleen E.; Chung, Raymond T.; Torriani, Martin; Kleiner, David E.; Hadigan, Colleen; Grinspoon, Steven

doi:10.1093/cid/ciaa382

Cited by 17 publications

(13 citation statements)

References 30 publications

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“…On initial biopsies, 43% had evidence of hepatic fibrosis, and within 1 year 38% experienced worsening of hepatic fibrosis on repeat biopsies regardless of baseline presence of fibrosis. The rate of fibrosis progression in HIV-associated NAFLD was accelerated compared to the rate found in a systematic review for NASH in the general population [61 ▪▪ ]. In this study, visceral fat was found to be a significant predictor of fibrosis presence and progression.…”

Section: Unique Mechanisms Of Fibrosis In Hivcontrasting

confidence: 40%

“…Notably, Fourman and colleagues recently found that HIV-associated NAFLD was not only associated with a high prevalence of fibrosis but also rapid fibrosis progression [61 ▪▪ ]. On initial biopsies, 43% had evidence of hepatic fibrosis, and within 1 year 38% experienced worsening of hepatic fibrosis on repeat biopsies regardless of baseline presence of fibrosis.…”

Section: Unique Mechanisms Of Fibrosis In Hivmentioning

confidence: 99%

“…2) [62]. Visceral fat is proinflammatory and profibrotic [61 ▪▪ ], and lipolysis of peripheral adipose tissue can increase the hepatic influx of free fatty acids, leading to steatohepatitis [36]. In addition to the fibrogenic pathways previously described, LPS from HIV-associated microbial translocation may also contribute to NAFLD development through increases in insulin resistance, liver triglyceride content, and adipose tissue inflammation [63].…”

Section: Unique Mechanisms Of Fibrosis In Hivmentioning

confidence: 99%

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Causes and outcomes of hepatic fibrosis in persons living with HIV

Yen

Sherman

2022

Current Opinion in HIV and AIDS

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Purpose of reviewThe epidemiology of liver disease in people living with HIV has evolved since the arrival of effective hepatitis C virus (HCV) treatment. Nonalcoholic fatty liver disease (NAFLD) in HIV patients is highly prevalent while hepatitis D, hepatitis E, and occult hepatitis B remain underappreciated. We discuss mechanisms of fibrosis in HIV and review clinical outcomes of HIV-associated liver diseases. Recent findingsHIV-HCV co-infection is receding as a cause of progressive liver disease, but fibrosis biomarkers after HCV treatment remain elevated. Antiretroviral therapy (ART) with anti-hepatitis B virus (HBV) activity promotes stable liver disease, but oversimplifying ART regimens in unrecognized suppressed HBV may lead to activation of HBV. A high prevalence of fibrosis and rapid progression of fibrosis are seen in HIVassociated NAFLD, with visceral fat as a major risk factor. Newer ART such as integrase strand inhibitors may have limited intrinsic hepatoxicity but do increase weight, which may secondarily lead to hepatic steatosis. Promising therapies for HIV-associated NAFLD include tesamorelin and CCR5 blockade agents. SummaryOur understanding of the natural history and pathogenesis of liver diseases in HIV has advanced and adapted to the changing landscape of liver disease in this population. Future research should evaluate long-term clinical and histological outcomes, prevention strategies, and treatment options to improve morbidity and mortality in HIV-related liver diseases.

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Section: Unique Mechanisms Of Fibrosis In Hivcontrasting

confidence: 40%

Section: Unique Mechanisms Of Fibrosis In Hivmentioning

confidence: 99%

Section: Unique Mechanisms Of Fibrosis In Hivmentioning

confidence: 99%

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Causes and outcomes of hepatic fibrosis in persons living with HIV

Yen

Sherman

2022

Current Opinion in HIV and AIDS

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“…Additionally, study participants comprised a modern cohort of PLWH, and the results derive from a 1-year randomized controlled trial with a placebo comparator. Given that the HIV population is at high risk of NAFLD and increased fibrosis progression rates ( 1 , 2 , 36 ), there is a critical need for dedicated studies among this patient group. Our findings also may yield insights for other populations with NAFLD and thus provide a strong rationale for additional studies.…”

Section: Discussionmentioning

confidence: 99%

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Fourman¹,

Billingsley²,

Agyapong³

et al. 2020

JCI Insight

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Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone–releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.

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“…NAFLD also is a leading comorbidity in people living with HIV (PLWH) 1 , which may relate to the high prevalence of weight gain and abdominal fat accumulation described among this group 2 , 3 . Notably, compared to the general population, NAFLD has a more aggressive clinical course with a high frequency of nonalcoholic steatohepatitis (NASH) and fibrosis, and an accelerated rate of fibrosis progression among PLWH 4 , 5 . Despite the critical need, there are no approved therapies for NAFLD in HIV or the general population 6 .…”

Section: Introductionmentioning

confidence: 99%

Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach

Fourman

Stanley

Billingsley

et al. 2021

Sci Rep

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NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log2-fold change − 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, − 0.35 ± 0.56 vs. − 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, − 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831

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Clinical Predictors of Liver Fibrosis Presence and Progression in Human Immunodeficiency Virus–Associated Nonalcoholic Fatty Liver Disease

Cited by 17 publications

References 30 publications

Causes and outcomes of hepatic fibrosis in persons living with HIV

Causes and outcomes of hepatic fibrosis in persons living with HIV

Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach

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