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.
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.
1. Lewden C, Salmon D, Morlat P, et al. Causes of death among human immunodeficiency virus(HIV
)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. In J Epidemiol. 2005;34:121–130.
2. Weber R, Sabin C, Friis-Muller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the data collection on adverse events of anti-HIV
drugs study group. Arch Intern Med. 2006;166:1632–1641.
3. French AL, Gawel S, Hershow R, et al. Trends in mortality and causes of death for women with HIV
in the US: a ten year study. J Acquir Immune Defic Syndr. 2009;51:399–406.
4. Lo Re V, Kallan M, Tate J, et al. Hepatic decompensation of antiretroviral-treated patients co-infected with HIV
and hepatitis C
virus compared with hepatitis C
virus monoinfected patients: a cohort study. Ann Intern Med. 2014;160:369–379.
5. Chen T, Ding E, Seage Lii G, et al. Meta-analysis: increased mortality associated with hepatitis C
-infected persons is unrelated to HIV
disease progression. Clin Infect Dis. 2009;49:1605–1615.
6. Fierer D, Dieterich D, Fiel M, et al. Rapid progression to decompensated cirrhosis, liver transplant, and death in HIV
-infected men after primary hepatitis C
infection. Clin Infect Dis. 2013;56:1038–1043.
7. de Ledinghen V, Barreiro P, Foucher J, et al. Liver fibrosis on account of chronic hepatitis C
is more severe in HIV
-positive than HIV
-negative patients despite antiretroviral therapy. J Viral Hepat. 2008;15:427–433.
8. Thein H, Yi Q, Dore G, et al. Natural history of hepatitis C
virus infection in HIV
-infected individuals and the impact of HIV
in the era of highly active antiretroviral therapy: a meta-analysis. AIDS. 2008;22; 1979–1991.
9. French AL, Evans C, Agniel D, et al. Microbial translocation
and liver disease progression in women coinfected with HIV
and hepatitis C
virus. J Infect Dis. 2013;208:670–689.
10. Balogopal A, Philip F, Asemborski J, et al. HIV
-related microbial translocation
and progression of hepatitis C
. Gastroenterology. 2008;135:226–233.
11. Chhatwal J, Kanwal F, Roberts M, et al. Cost-effectiveness and budget impact of hepatitis C
virus treatment with sofosbuvir and ledipasvir in the United States. Ann Intern Med. 2015:162;397–406.
12. Najafzadeh M, Andersson K, Shrank W, et al. Cost-effectiveness of novel regimens for the treatment of hepatitis C
virus. Ann Intern Med. 2015:162;407–419.
13. Rein D, Wittenborn J, Smith B, et al. The cost-effectiveness, health benefits, and financial costs of new antiviral treatments for hepatitis C
virus. Clin Infect Dis. 2015;61:157–168.
14. D'Ettorre G, Ceccarelli G, Giustini N, et al. Probiotics reduce inflammation
in antiretroviral treated, HIV
-infected individuals: results of the Probio-HIV
Clinical Trial. PLoS One. 2015;10:e0132700.
15. Weber AR, Sattar A, Funderburg NT, et al. Alcohol and dietary factors associated with gut integrity and inflammation
-infected adults. HIV
16. Kelly CJ, Colgan SP, Frank DN. Of microbes and meals: the health consequences of dietary endotoxemia. Nutr Clin Pract. 2012;27:215–225.
17. Barkan SE, Melnick SL, Preston-Martin S, et al. The Women's interagency HIV
study. Epidemiology. 1998;9:117–125.
18. Hessol NA, Schneider M, Greenblatt RM, et al. Retention of women enrolled in a prospective study of HIV
infection: impact of race, unstable housing and use of HIV
therapy. Am J Epidemiol. 2001;154:563–573.
19. Sterling R, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV
/HCV coinfection. Hepatology. 2006;43:1317–1325.
20. Kim BK, Kim DY, Park JY, et al. Validation of FIB-4 and comparison with other simple noninvasive indices for predicting liver fibrosis and cirrhosis in hepatitis B virus-infected patients. Liver Int. 2010;30:546–553.
21. Sarkar M, Aouzierat B, Bacchetti P, et al. Association of IFNl3 and IFNL4 polymorphisms with liver-related mortality in a multiracial cohort of HIV
/HCV co-infected women. J Viral Hepat. 2015;22:1055–1060.
22. Bambha K, Pierce C, Cox C, et al. Assessing mortality with hepatitis C
virus and HIV
using indirect markers of fibrosis. AIDS. 2012;26:599–607.
23. Shaheen AA, Myers RP. Diagnostic accuracy of the aspartate aminotransferase to platelet ratio index for the prediction of hepatitis C
related fibrosis: a systematic review. Hepatology. 2007;46:912–921.
24. Stauber RE, Lackner C. Noninvasive diagnosis of hepatic fibrosis
in chronic hepatitis C
. World J Gastroenterol. 2007;13:4287–4294.
25. Carvalho-Filho RJ, Schiavon LL, Narciso-Schaivon JL, et al. Optimized cutoffs improve performance of aspartate aminotransferase to platelet ratio index for predicting significant liver fibrosis in HIV
/HCV co-infection. Liver Inter. 2008;1478:486–492.
26. Nunes D, Fleming C, Offner G, et al. HIV
infection does not affect the performance of noninvasive markers of fibrosis for the diagnosis of hepatitis C
related liver disease. J Acquir Immune Defic Syndr. 2005;40:538–544.
27. Merli M, Castagna A, Salpietro S, et al. Diagnostic accuracy of APRI, FIB-4 and Forns for the detection of liver cirrhosis in HIV
/HCV-coinfected patients. New Microbiol. 2016;39:110–113.
28. Vallet-Pichard A, Mallet V, Nalpas B, et al. FIB-4; an inexpensive and accurate marker of fibrosis in HCV infection: comparison with liver biopsy and fibrotest. Hepatology. 2007;46:32–36.
29. Tanwar S, Trembling PM, Hogan BJ, et al. Biomarkers of hepatic fibrosis
in chronic hepatitis C
: a comparison of 10 biomarkers using 2 different assays for hyaluronic acid. J Clin Gastroenterol. 2017;51:268–277.
30. Amorin TG, Staub GJ, Lazzorato C, et al. Validation and comparison of simple noninvasive models for the prediction of liver fibrosis in hepatitis C
. Ann Hepatol. 2012;11:855–861.
31. Fabriek BO, van Bruggen R, Deng DM, et al. The macrophage scavenger receptor CD163 function as an innate immune sensor for bacteria. Blood. 2009;113:887–892.
32. Etzerodt A, Moestrup SK. CD163 and inflammation
: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal. 2013;18:2352–2363.
33. Etzerodt A, Maniecki MB, Moller K, et al. Tumor necrosis factor alpha-converting enzyme (TACE/ADAM17) mediates ectodomain shedding of the scavenger receptor CD163. J Luekoc Biol. 2010;88:1201–1205.
34. Kazankov K, Barrera F, Holger JM, et al. Soluble CD163, a macrophage activation
marker, is independently associated with fibrosis in patients with chronic viral hepatitis B and C. Hepatology. 2014;60:521–530.
35. Ramanchandran P, Iredale JP. Macrophages: central regulators of hepatic fibrinogenesis and fibrosis resolution. J Hepatol. 2012;56:1417–1419.
36. Kuniholm MH, Hanna DB, Landay AL, et al. Soluble CD163 is associated with noninvasive measures of liver fibrosis in hepatitis C
virus- and hepatitis C
virus/human immunodeficiency virus-infected women. Hepatology. 2015;61:734–735.
37. Faustman DL, Davis M. TNF receptor 2 and disease: autoimmunity and regenerative medicine. Front Immunol. 2013;4:478.
38. Morlat P, Periera E, Clayette P, et al. Early evolution of plasma soluble TNF-alpha p75 receptor as a marker of progression in treated HIV
-infected persons. AIDS Res Hum Retroviruses. 2008;24:1383–1389.
39. Tenorio AR, Zheng Y, Bosch RJ, et al. Soluble markers of inflammation
and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis. 2014;210:1248–1259.
40. Kakuma S, Okumura A, Ishikawa T, et al. Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha receptors in type C chronic liver disease. Clin Exp Immunol. 1997;109:458–463.
41. Kallinowski B, Haseroth K, Marinos G, et al. Induction of tumour necrosis factor receptor type p55 and p75 in patients with chronic hepatitis C
virus infection. Clin Exp Immunol. 1998;111:269–277.
42. Pircher J, Czermak T, Merkel M, et al. Hepatitis C
virus induced endothelial inflammatory response depends on the function expression of TNF alpha receptor subtype 2. PLoS One. 2014;9:e113351.
43. Pinzone MR, Celesia BM, Di Rosa M, et al. Microbial translocation
in chronic liver diseases. Int J Microbiol. 2012;2012:694629.
44. Monnig MA, Kahler CW, Cioe PA, et al. Alcohol use predicts elevation in inflammatory marker soluble CD14 in men living with HIV
. AIDS Care. 2016;28:1434–1440.
45. Carrico AW, Hunt PW, Emenyonu NI, et al. Unhealthy alcohol use is associated with monocyte activation prior to starting anti-retroviral therapy. Alcohol Clin Exp Res. 2015;39:2422–2426.
46. Zhang J, Xu P, Song P, et al. CCL2–CCR2 signaling promotes hepatic ischemia/reperfusion injury. J Surg Res. 2016;202:352–362.
47. Ramachandran P, Iredale JP. Liver fibrosis: a bidirectional model of fibrogenesis and resolution. QJM. 2012;105:813–817.
48. Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66:1300–1312.