Host Response to Translocated Microbial Products Predicts Outcomes of Patients With HBV or HCV Infection

Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Gastroenterology (Impact Factor: 16.72). 07/2011; 141(4):1220-30, 1230.e1-3. DOI: 10.1053/j.gastro.2011.06.063
Source: PubMed


Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes.
In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment.
Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively).
LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection.

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    • "Soluble CD14 (sCD14) and IL-18 are two biomarkers of innate immune activation associated with viral disease. sCD14 is often considered as a marker of monocyte activation in response to lipopolysaccharide [12], and as a marker of microbial translocation [13], [14]. However, elevated levels of sCD14 have also been observed in patients with non-alcoholic steatohepatitis [15], and common variable immunodeficiency [16], [17], suggesting other possible origins for sCD14 in plasma, one of which may be the liver [18]–[20]. "
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    ABSTRACT: Soluble CD14 (sCD14) and IL-18 are markers and mediators of the innate immune response, and their plasma levels candidate biomarkers of HCV treatment effects and outcome. Here, we retrospectively studied sCD14 and IL-18 over the course of interferon-based treatment of HCV genotype 1 infection, with the aim to investigate the impact of direct-acting antivirals (DAAs) on the dynamics and relationships between these biomarkers and treatment effects and outcome. Two cohorts were followed longitudinally; one treated with standard dual therapy of pegylated IFNα and ribavirin, and one cohort receiving triple therapy including Telaprevir. sCD14 and IL-18 were measured before and during treatment and analyzed in relation to treatment effects. The initial analysis confirmed two patterns previously observed in patients with HCV/HIV-1 co-infection: Baseline levels of sCD14 were significantly lower in patients that went on to clear HCV infection in response to IFNα and ribavirin, and sCD14 levels were strongly induced during the course of this treatment. Interestingly, baseline levels of sCD14 and IL-18 in combination predicted treatment outcome in dual therapy better than either marker alone. Notably, these associations were weaker with the addition of Telaprevir to the treatment regimen, suggesting that the relationships between innate immune activation and outcome were altered and diminished by inclusion of a DAA in the treatment. In triple therapy, the dynamic increase of sCD14 in response to treatment was higher in patients clearing the virus, suggesting that the innate response to interferon is still significantly associated with outcome in patients treated with DAA-containing regimens. These results support the notion that levels of innate immune activation before and during treatment are associated with interferon-based treatment outcome. Furthermore, the addition of Telaprevir significantly alters the dynamics and relationships between innate immune biomarkers and treatment effects and outcome.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "In particular, Fib-4 > 1.45 is accepted for F0-F1, but does not perform well in intermediate stages; however a Fib-4 value > 3.25 (a more reliable measure for intermediate fibrosis stages) was observed only in 3 patients, and, therefore, this more strigent definition of the endpoint could not be used in this analysis. Conversely, previous literature reports on HIV/HCV co-infected patients [5,9], including data from our group [12], described in detail the effects of MT in liver disease as assessed by histology and/or elastography measures. Given that hepatic stellate cells and Kupffer cells are the main target through which LPS promotes fibrogenesis [19], direct measures of liver disease may more faithfully mirror the effects of MT on hepatic tissues. "
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    ABSTRACT: We evaluated whether immune activation (IA) and microbial translocation (MT) might play a role in accelerating liver disease progression in HIV-HBV/HCV co-infected patients. ART-naive HIV/viral hepatitis co-infected patients from Icona with a CD4 cell count >200/mul and with a known date of prior HIV neg/pos tests and >=1 plasma sample stored were included in the study. Plasma MT (LPS, sCD14) and IA (IL-6,TNFalpha) were measured using ELISA while activated CD8 + CD38 + HLA-DR + were measured by flow cytometry, with one measurement being performed for all patients and two measurements for a smaller group of subjects. The association between these biomarkers and the time to i) a single ALT >200 IU/l and ii) a Fib-4 >1.45 was also investigated. A standard survival analysis with robust standard errors was used for all evaluations. Follow-up was censored at patients' last clinical follow-up. We studied 127 HIV-infected hepatitis viruses co-infected patients (118 HCV, 9 HBV). Overall median (IQR) CD4, VL, age were 596/mul (208-1303), 3.8 log10cp/mL (3-4.3), 34 years (22-56). While heightened TNF-[unknown] was associated with a 13-fold increased risk of Fib-4 > 1.45 (RH 13.05, 95%CI 2.43-70; p = 0.003), markers of MT did not show an association with liver illness. Interestingly, higher sCD14 was associated with a decreased risk of Fib-4 > 1.45, independently of other biomarkers considered (RH 0.20, 95%CI 0.04-0,9; p = 0.04). In HIV/hepatitis virus co-infected ART-naive patients, higher TNF-alpha plasma levels were associated with a 13-fold increase in the risk of progression to a Fib-4 >1.45, suggesting that the pro-inflammatory status in HIV infection might hasten the course of HCV. In view of the fact that sCD14 may hinder the interaction between LPS and the phagocyte membrane CD14, we herewith propose a model which aims to demonstrate that high sCD14 levels might contribute to shelter liver function through the down-regulation of the inflammatory cascade.
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    • "Sensing of microbial products by hepatocytes, hepatic stellate cells, and Kupffer cells within the liver activates proinflammatory and profibrotic pathways (Duffield et al., 2005; Rivera et al., 2001; Seki et al., 2007; Su, 2002). Through mechanisms yet to be defined, HIV reduces the number of Kupffer cells and impairs hepatic function, thereby reducing the capacity of the liver to mitigate the consequences of microbial translocation (Balagopal et al., 2008, 2009; French et al., 2013; Sandler et al., 2011a). The combined loss of mucosal immune surveillance and hepatic impairment allows proinflammatory microbial products to access the peripheral circulation and the organ systems it supplies. "
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    ABSTRACT: Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.
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