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Macrophage Activation and the Tumor Necrosis Factor Cascade in Hepatitis C Disease Progression Among HIV-Infected Women Participating in the Women's Interagency HIV Study

French, Audrey L. MD*,†; Martin, Jonathan W. DO*,†; Evans, Charlesnika T. PhD‡,§; Peters, Marion MD; Kessaye, Seble G. MD; Nowicki, Marek PhD#; Kuniholm, Mark PhD**; Golub, Elizabeth PhD††; Augenbraun, Michael MD‡‡; Desai, Seema N. PhD for the WIHS

JAIDS Journal of Acquired Immune Deficiency Syndromes: December 1, 2017 - Volume 76 - Issue 4 - p 438–444
doi: 10.1097/QAI.0000000000001524
Translational Research

Background: HIV/hepatitis C–coinfected persons experience more rapid liver disease progression than hepatitis C virus (HCV) monoinfected persons, even in the setting of potent antiretroviral therapy.

Methods: We sought to articulate the role of macrophage activation and inflammation in liver disease progression by measuring serial soluble markers in HIV/HCV-coinfected women. We compared markers measured during retrospectively defined periods of rapid liver disease progression to periods where little or no liver disease progression occurred. Liver disease progression was defined by liver biopsy, liver-related death or the serum markers AST-to-platelet ratio index and FIB-4. Soluble CD14, sCD163, lipopolysaccharide (LPS), tumor necrosis factor (TNF) receptor II, interleukin-6, and chemokine ligand 2 (CCL 2) were measured at 3 time points over 5 years.

Results: One hundred six time intervals were included in the analysis: including 31 from liver disease progressors and 75 from nonprogressors. LPS, sCD14, interleukin-6, and CCL2 levels did not differ in slope or quantity over time between rapid liver disease progressors and nonprogressors. TNFRII and sCD163 were significantly higher in liver disease progressors at (P = 0.002 and <0.0001 respectively) and preceding (P = 0.01 and 0.003 respectively) the liver fibrosis outcome in unadjusted models, with similar values when adjusted for HIV RNA and CD4 count.

Conclusions: In women with HIV/HCV coinfection, higher sCD163 levels, a marker of macrophage activation, and TNFRII levels, implying activation of the TNF-α system, were associated with liver disease progression. Our results provide an addition to the growing body of evidence regarding the relationship between macrophage activation, inflammation, and liver disease progression in HIV/HCV coinfection.

*CORE Center/Stroger (Cook County) Hospital, Chicago, IL;

Rush University Medical Center, Chicago, IL;

Hines VA Medical Center, Chicago, IL;

§Northwestern University Medical Center, Chicago, IL;

University of California, San Francisco, CA;

Georgetown University Medical Center, Washington, DC;

#Mendez National Institute of Transplantation Foundation, Los Angeles, CA;

**Department of Epidemiology & Population Health, University at Albany, State University of New York, Rensselaer, NY;

††Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; and

‡‡Department of Medicine, State University of New York Downstate, Brooklyn, NY.

Correspondence to: Audrey L. French, MD, Division of Infectious Diseases, Stroger Hospital of Cook County, 1900 W Polk, Chicago, IL 60612 (e-mail:

The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH).

Data were presented in part at Conference on Retroviruses and Opportunistic Infectious 2015; February 23–26, 2015; Seattle, WA.

The authors have no funding or conflicts of interest to disclose.

Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH).

WIHS (Principal Investigators): U01-AI-103408; Bronx WIHS (Kathryn Anastos), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (Seble Kassaye), U01-AI-034994; Connie Wofsy Women's HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I—WIHS IV).

Received March 23, 2017

Accepted August 02, 2017

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Hepatitis C virus (HCV) infection is highly prevalent in HIV-infected persons and a significant cause of morbidity and mortality.1–3 Liver disease progression is accelerated in persons coinfected with HIV/HCV compared with those monoinfected with HCV.4–6 This accelerated disease progression occurs even among those on antiretroviral therapy.7,8 The mechanism for accelerated liver disease progression is not completely understood and is likely multifactorial.

Microbial translocation is increased in HIV infection and our group, and others have found that markers of microbial translocation are associated with rapid liver disease progression in HIV/HCV-coinfected patients.9,10 Hepatic macrophage activation by endotoxin is postulated to be a mechanism by which microbial translocation contributes to hepatic fibrosis in hepatitis C infection. We sought to characterize the role of macrophage activation and inflammation by comparing soluble marker levels over time in HIV/HCV-coinfected women with varied trajectories of liver disease progression.

Despite the availability of highly effective HCV antiviral therapies, many persons in the United States and other countries do not have access to these drugs because of limited resources and high cost.11–13 Therefore, understanding the mechanisms of and markers for accelerated liver disease progression in HIV/HCV coinfection remains important to identify patients most at risk of liver disease outcomes who can be targeted for earlier therapy. Also, because the deleterious effects of microbial translocation, theoretically, may be mitigated by lifestyle changes, such as diet, probiotics, or abstinence from alcohol,14–16 understanding how microbial translocation affects liver disease remains relevant.

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This is a nested study of HIV/HCV-infected women participating in the Women's Interagency HIV Study (WIHS). The WIHS is a longitudinal study of HIV-infected and at-risk uninfected women which of that enrolled 2054 HIV-infected women and 569 uninfected women at 6 sites: Chicago, San Francisco Bay Area, Brooklyn and Bronx/Manhattan, New York, Washington, DC, and Los Angeles from October 1994 to November 1995. From October 2001 to September 2002, an additional 737 HIV-infected women and 406 uninfected women were enrolled. Informed consent was obtained from all participants in accordance with the US Department of Health and Human Services (DHHS) guidelines, the institutional review boards of participating institutions, and the Helsinki Declaration of 1975, revised in 2000. Women are seen semiannually for interview, physical examination, and collection of blood and genital specimens. The WIHS cohort was designed to reflect the demographics of the HIV epidemic among the US women. Details of cohort recruitment, retention, and demographics are published elsewhere.17,18

Study subjects were HIV/HCV-coinfected women with the available data and specimens required for the study. Hepatitis C infection was defined as hepatitis C antibody and HCV RNA positivity. Soluble markers of microbial translocation and monocyte/macrophage activation [lipopolysaccharide (LPS), soluble CD163, and CD14], markers of inflammation/immune activation [interleukin-6, IL-6, and tumor necrosis factor receptor II (TNFRII)], and a profibrogenic chemokine, chemokine ligand 2 (CCL2) were measured from banked specimens, frozen uninterrupted at −80°C since collection.

We retrospectively defined intervals of time during which women experienced rapid liver disease progression and intervals during which there was no or minimal liver disease progression and compared serial soluble markers from these intervals. Liver disease progression intervals with available longitudinal specimens were first identified using the definitions below. After the liver disease progression intervals were identified, nonprogression intervals from the same calendar time were identified in approximately a 2:1 ratio. We chose a 5-year span in consultation with academic hepatologists as a reasonable definition of rapid disease progression.

Liver disease was defined by liver biopsy, death related to complications of decompensated liver disease, or by the noninvasive markers, APRI [aspartate aminotransferase (AST)-to-platelet ratio index: AST/upper limit of normal/platelet count (109/L) × 100] and FIB-4 [age × AST (U/L)/(platelets (109/L) × alanine aminotransferase (U/L)]1/2).19,20 Liver death was ascertained by review of death certificates, reviewed by 2 clinicians to come to a consensus cause of death. Death was ascribed to liver disease if cirrhosis or decompensated liver disease was the primary cause of death or the main underlying cause with a nonspecific primary cause (eg, when sepsis was the primary cause and cirrhosis the first underlying cause, or gastrointestinal bleed with esophageal varices and cirrhosis).3,21,22 In the case of liver death, the soluble markers were measured on a specimen collected during a routine study visit approximately 1 year before liver death to assure that liver disease was present but avoid measuring markers that may reflect premortem infectious or inflammatory conditions.

Soluble markers were measured at 3 time points for each interval studied; time points were approximately 2.5 years apart. Time 1 (T1) for all women was a point when there was no or minimal fibrosis by liver biopsy or noninvasive markers (APRI <0.5 and FIB-4 <1.45) at TI or a visit within 6 months of T1 and no clinical evidence of end-stage liver disease by self-report. For liver disease progressors, T3 was a point 5 years later where there was a liver biopsy with cirrhosis or bridging fibrosis, liver death within approximately 1 year or both APRI and FIB-4 consistent with cirrhosis (APRI >1.5 and FIB-4 >3.25, respectively). For nonprogressors, T3 was a point where there was no clinical evidence of end-stage liver disease and biopsy or both markers were consistent with no or minimal fibrosis (APRI <0.5 and FIB-4 <1.45). T2 was equidistant between T1 and T3, approximately 2.5 years from each, with a range of 2–3 years.

To avoid confounders, the study included time intervals from HIV/HCV-coinfected women who were hepatitis B surface antigen negative, had no hepatitis C therapy during the time interval, and had no hazardous drinking (defined by the National Institute of Alcohol Abuse and Alcoholism criteria of ≥7 drinks/wk) during the time interval.

APRI and FIB-4 are the most commonly used noninvasive markers in the WIHS because data are available at most WIHS visits to calculate these scores. Both have been found to be correlated with liver fibrosis and predict liver disease outcomes in HIV-infected persons and in WIHS23. APRI >1.5 has an area under the receiver operating curve of 0.76 for biopsy-proven significant fibrosis (METAVIR F2-4) and 0.82 for cirrhosis in a large meta-analysis including HIV-infected and uninfected HCV-infected patients23 and a range of 0.71–0.82 for significant fibrosis and 0.81–0.92 and cirrhosis in large series.24 The negative predictive values of APRI <0.5 for lack of significant fibrosis has been found to be 80%–91% in populations with a prevalence of fibrosis similar to WIHS.18,25 Several reviews have found that the accuracy of APRI for cirrhosis was the same or better for studies of HIV/HCV-coinfected persons compared with HCV monoinfected persons.18,20,26,27 FIB-4 >3.25 has been found to correlate with severe fibrosis (METAVIR F3-4) with area under the receiver operating curve 0.72–0.85, and FIB-4 <1.45 has been found to have a negative predictive value for significant fibrosis of 95% in one large study of HIV/HCV-coinfected persons28 with similar values (0.81–0.92) in more recent studies.22,29,30

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Laboratory Methods

Plasma LPS levels were quantified in duplicate by dilution of plasma specimens to 10% with endotoxin-free water using a Limulus Amebocyte Assay (Lonza Group Ltd., Basel, Switzerland). Background was subtracted and LPS levels were calculated by following the manufacturer's recommended protocol. Commercially available enzyme-linked immunosorbent assays were used to measure soluble CD14 (R & D Systems, Minneapolis, MN), sCD163 (Trillium Diagnostics, Bangor, ME), TNFRII (R&D Systems), IL-6 (R& D Systems), and CCL2 (R&D Systems). All assays were performed according to the manufacturer's instructions. Laboratory investigators were blinded to the liver disease progression status of participants.

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Statistical Methods

Demographic and clinical characteristics were assessed at periods (T1-3), which were contemporaneous with measures of the soluble plasma markers. At the initial study visit (T1), age, median CD4+ T-lymphocyte count (CD4 count), median HIV RNA level, antiretroviral therapy use, and alcohol, injection drug or cocaine use ever and in the past 6 months (by self-report) were assessed. Over the duration of the study period, we calculated median CD4 count and median HIV RNA level, use of highly active antiretroviral therapy (HAART), and alcohol use (by self-report) at each visit. The unadjusted association between progression and categorical covariates were assessed using Fisher exact tests, and continuous variables were compared using the Wilcoxon rank-sum test. Unadjusted associations between progression and each plasma marker were also assessed at T1, T2, and T3 using Wilcoxon rank-sum tests. Because HIV RNA levels have been associated with inflammatory and activation markers, the association between progression status and each plasma marker was calculated controlling for the level of HIV RNA. Similarly, the associations were calculated controlling for the CD4 count. Because of a suspected relationship between the chemoattractant protein CCL2 and fibrosis, we further investigated the relationship between CCL2 and FIB-4 values using Wilcoxon rank-sum test. Repeated measures analysis using Proc General Linear Model with the link function identity were fit to assess associations and slopes for each serum marker by progression status and time controlling for log HIV RNA level. P values from repeated measures analysis are reported for demonstrating differences in slopes between progressors and nonprogressors for each plasma marker. All analyses were performed in SAS software, version 9.3 (SAS Institute Inc., Cary NC). Graphs were produced using STATA 14 (StataCorp LLC, College Station, TX).

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A total of 106 time intervals from 106 women were included in the analysis; 31 of them were categorized as progressors and 75 were categorized as nonprogressors. Reflecting the WIHS as a whole, the majority of study patients were African American. The median age at T1 was 41.0 in nonprogressors and 42.3 in progressors. The groups were similar in terms of race, age, HIV RNA, CD4 count, nadir CD4, and HAART use (Table 1) as well as illicit drug use. By design, alcohol use was low in both groups. Median CD4+ T-lymphocyte count was 462 in liver disease progressors and 498 in nonprogressors, although only about 40% were on HAART at T1. In addition, HAART use, mean CD4 count, and HIV RNA values were very similar between progressors and nonprogressors over the course of the study (data not shown). Progressors did have a higher mean FIB4 score at baseline than nonprogressors, which was statistically significant. APRI was similar between progressors and nonprogressors at baseline.



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Association of Soluble Marker Levels With Liver Disease Progression

The 6 soluble markers were measured in the liver disease progressors and nonprogressors at 3 time points. There were no significant differences in the level of soluble markers at T1 between progressors and nonprogressors. The median time between T1 and T3 was 4.89 years in progressors and 4.84 years in nonprogressors. LPS, sCD14, IL-6, and CCL-2 levels did not differ in slope or quantity over time between women who had rapid liver disease progression and nonprogressors (Table 2 and Fig. 1). TNFRII levels were significantly higher in progressors at T2, (4372.5 vs 3100.6 pg/mL for nonprogressors, P = 0.01) and T3 (4215.9 vs 3007.1 pg/mL for nonprogressors P = 0.002) in unadjusted and analyses adjusted for HIV RNA (P = 0.003 and 0.0003, respectively) and CD4 count (P = 0.007 and 0.002, respectively) (Table 2). Similarly, sCD163 showed a significant difference between progressors and nonprogressors with higher levels in progressors at T2 (4321.6 vs 3006 ng/mL for nonprogressors P = 0.008) and T3 (P < 0.0001) in unadjusted analyses, with similar values in analyses adjusted for HIV RNA and CD4 count. Progressors had a steeper slope of change over time in sCD163 (742 over 5 years vs −38.4 ng/mL) compared with nonprogressors in unadjusted models and models adjusted for HIV RNA level (P = 0.01 and 0.02, respectively); however, TNFRII showed no significant difference in slope between progressors and nonprogressors (P = 0.17) (Fig. 1). We performed an additional analysis to determine whether CCL2 was correlated with fibrosis by FIB-4. There was a significant relationship between this chemoattractant protein and FIB-4 >3.25 (consistent with fibrosis): mean CCL2 235.6 pg/mL (sd 101.9) in those with FIB-4 >3.25 and 141.1 pg/mL (sd 101.9) in those with FIB-4 ≤3.25 (P = 0.03).





In addition, GLM models confirmed that progression of liver disease and HIV viral load were associated with higher levels of TNFRII (P < 0.0001 for both) and soluble CD163 (P < 0.0001 and P = 0.02, respectively). IL-6 levels increased over time (P = 0.001) and with increasing HIV viral load (P = 0.002) for both progressors and nonprogressors. Although not associated with liver disease progression, sCD14, as expected, increased with increasing HIV RNA level (P < 0.0001) as did CCL-2 (P = 0.0002).

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In this longitudinal study of HIV/HCV-coinfected women, we demonstrated that liver disease progressors had significantly higher levels of sCD163 and TNFRII than nonprogressors and that elevated levels of these soluble markers preceded the defined fibrosis outcome.

Soluble CD163, a marker of macrophage activation, was higher in progressors and this difference was apparent at T2, before the fibrosis outcome. CD163 is a cell-surface glycoprotein receptor that is highly expressed on most tissue macrophages, including hepatic Kupffer cells. CD163 is cleaved from the cell surface in response to LPS, and sCD163 is thus considered a marker of translocation of microbial products across the gastrointestinal mucosa.31 Cleavage of CD163 from Kupffer cells triggers the release of proinflammatory proteins,32,33 thus promoting fibrosis formation by stellate cells.34,35 Several investigators have found sCD163 to be a marker of hepatic fibrosis in cross-sectional studies, and some have proposed using sCD163 levels alone or in combination with HOMA-IR and platelet count as noninvasive markers of HCV-induced hepatic fibrosis.29,36 Our findings support the use of sCD163 as a marker of liver disease progression and support a central role of macrophage activation in hepatitis C disease progression.

We found that TNFRII was elevated in liver disease progressors at and before the liver fibrosis end point. TNFRII is part of the tumor necrosis factor cascade that is involved in the immune response to infection and typically signals cell survival.37 Expressed on various cell types, including monocytes/macrophages, the receptor is induced by a number of mediators, such as LPS and TNF-alpha. Soluble TNFRII is produced by cleavage of the cell surface receptor and can be used as a surrogate marker for activation of the TNF-α system. In HIV disease, sTNFR-II levels have been shown to be elevated and associated with poor clinical outcomes.38,39 Significantly elevated levels of sTNFR-II were reported in HCV-infected patients with cirrhosis and hepatocellular carcinoma compared with controls and may reflect the degree of hepatic inflammation.40,41 A recent study showed that HCV-induced endothelial inflammatory response depends on the functional expression of TNFR-II.42 Exactly how the TNF cascade affects HCV disease progression and what triggers of activation of the TNF-cascade in HIV/HCV coinfection are not fully articulated.

We found that classic markers of microbial translocation, LPS and sCD14, were not higher in women with more rapid liver disease progression. This is in contrast to an early cross-sectional study that showed that elevated LPS was independently associated with cirrhosis10 as well as several studies examining sCD14 levels (including our own), which reported that elevated levels of sCD14 were associated with an increased risk of liver disease progression in patients with and without HIV.9,10,43,44 The difference in outcomes is perhaps due to difference in study design, population, or the end points defining liver disease progression, or related to the low proportion of patients in the current study that reported hazardous alcohol consumption. Our earlier study included women with heavy alcohol use, and there are some data that alcohol use itself without significant liver disease, increases sCD14 levels in HIV-infected persons.39,45

CCL2 (also known as monocyte chemoattractant protein 1 or MCP-1) is an inflammatory cytokine that is a principal chemoattractant for inflammatory monocytes and has been implicated in hepatic cell ischemia and inflammatory liver injury.46,47 We had hypothesized that CCL2 may be on the pathogenetic pathway of HCV-associated liver disease progression in HIV and that levels of CCL2 may be associated with fibrosis progression. Although in our primary analysis we found that CCL2 levels were not significantly different in progressors and nonprogressors, an additional analysis revealed that CCL2 was correlated with FIB-4 >3.25 (which is consistent with cirrhosis). This implies that soluble CCL2 should continue to be explored as a marker of hepatic injury in chronic viral liver disease and supports the central role of inflammatory monocytes in hepatic injury in HIV/HCV-infected persons.48

Our findings should be considered in light of the limitations of our study. For many patients, we used noninvasive markers of fibrosis stage to define our progressors and nonprogressors. Although we used levels of APRI and FIB-4 at the extremes that have been found to correlate highly with minimal or severe fibrosis, these measures are not the gold standard and may not accurately reflect liver histology. We dichotomized women as either liver disease progressors or nonprogressors for the time points studied; liver disease progression, in vivo, is a continuum, women who we labeled nonprogressors may have experienced some liver disease progression during the 5-year study period. Although all our subjects had minimal or no liver fibrosis at T1 by our definitions, liver disease progressors had significantly higher median FIB-4 levels at T1 than nonprogressors, implying some difference in stage of liver disease at baseline. However, given that the trajectory of progression was markedly different between the 2 groups, the correlations between progression and trends in soluble markers should be valid despite this difference at baseline. An obvious limitation is sample size; although the significant associations we found should be robust, we do not have power to assert the lack of association. Also, because of sample size, we were unable to adjust for all variables that could potentially affect inflammation or liver disease progression.

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In women with HIV/HCV, coinfection sCD163 levels, a marker of macrophage activation, were associated with liver disease progression. In addition, TNFRII levels correlated with liver disease progression. Our results provide an addition to the growing body of evidence regarding the relationship between macrophage activation, inflammation, and liver disease progression in women with HIV/HCV coinfection.

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HIV; hepatitis C; hepatic fibrosis; macrophage activation; tumor necrosis factor receptor; inflammation; microbial translocation

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