Advertisement

Screening for Hepatocellular Carcinoma in HIV-Infected Patients: Current Evidence and Controversies

  • N. Merchante
  • M. Rodríguez-Fernández
  • J. A. PinedaEmail author
Co-infections and Comorbidity (S Naggie, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Co-infections and Comorbidity
  2. Topical Collection on Co-infections and Comorbidity

Abstract

Purpose of Review

This review aims to summarize evidence regarding hepatocellular carcinoma (HCC) screening in the specific context of HIV infection and discuss areas of uncertainty.

Recent Findings

It has not been definitely established if HCC incidence in HIV/HCV-coinfected patients with cirrhosis is above the 1.5%/year threshold that makes screening cost-effective. Outside cirrhosis or HBV infection, available data do not support surveillance. The performance of currently recommended ultrasound (US) screening strategy is poor in HIV-infected patients, as rates of early-stage HCC detection are low. Magnetic resonance imaging–based surveillance strategies or liquid biopsy are innovative approaches that should be specifically tested in this setting.

Summary

HIV-infected patients with cirrhosis are at risk of HCC. US surveillance identifies patients with early-stage HCC who will benefit of curative therapies, although the quality of the evidence supporting screening remains limited. The HIV population should be a priority group to assess and validate new surveillance strategies.

Keywords

Hepatitis C virus Cirrhosis Hepatocellular carcinoma HIV Screening Surveillance 

Notes

Compliance with Ethical Standards

Conflict of Interest

No potential conflicts of interest relevant to this article were reported.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 1.
    Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, et al. Global Burden of Disease Liver Cancer Collaboration. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: Results from the global burden of disease study 2015. JAMA Oncol. 2017;3(12):1683–91.  https://doi.org/10.1001/jamaoncol.2017.3055.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    World Health Organization. Projections of mortality and causes of death, 2016 to 2060 (http://www.who.int/healthinfo/global_burden_disease/projections/en/).
  3. 3.
    De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5 a population based study. Lancet Oncol. 2014;15(1):23–34.  https://doi.org/10.1016/S1470-2045(13)70546-1.CrossRefPubMedGoogle Scholar
  4. 4.
    Bruix J. Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53(3):1020–2.  https://doi.org/10.1002/hep.24199.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236.  https://doi.org/10.1016/j.jhep.2018.03.019.CrossRefGoogle Scholar
  6. 6.
    Merchante N, Merino E, López-Aldeguer J, Jover F, Delgado-Fernádez M, Galindo MJ, et al. Increasing incidence of hepatocellular carcinoma in HIV-infected patients in Spain. Clin Infect Dis. 2013;56(1):143–50.  https://doi.org/10.1093/cid/cis777.CrossRefPubMedGoogle Scholar
  7. 7.
    Rosenthal E, Roussillon C, Salmon-Céron D, Georget A, Hénard S, Huleux T, et al. Liver-related deaths in HIV-infected patients between 1995 and 2010 in France: the Mortavic 2010 study in collaboration with the Agence Nationale de Recherche sur le SIDA (ANRS) EN 20 Mortalité 2010 survey. HIV Med. 2015;16(4):230–9.  https://doi.org/10.1111/hiv.12204.CrossRefPubMedGoogle Scholar
  8. 8.
    Sahasrabuddhe VV, Shiels MS, McGlynn KA, Engels EA. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States. Cancer. 2012;118(24):6226–33.  https://doi.org/10.1002/cncr.27694.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Merchante N, Merino E, Rodríguez-Arrondo F, Tural C, Muñoz J, Delgado-Fernández M, et al. HIV/hepatitis C virus coinfected who achieved sustained virological response are still at risk of developing hepatocellular carcinoma. AIDS. 2014;28(1):41–7.  https://doi.org/10.1097/QAD.0000000000000005.CrossRefPubMedGoogle Scholar
  10. 10.
    •• Merchante N, Rodríguez-Arrondo F, Revollo B, Merino E, Ibarra S, Galindo MJ, et al. Hepatocellular carcinoma after sustained virological response with interferon-free regimens in HIV/HCV-coinfected patients. AIDS. 2018;32(11):1423–30.  https://doi.org/10.1097/QAD.0000000000001809This retrospective study from the Spanish multicentre cohort GEHEP-002 shows that the frequency of HCC emergence after SVR has not increased after widespread use of DAA in HIV/HCV-coinfected patients.CrossRefPubMedGoogle Scholar
  11. 11.
    •• Merchante N, Rivero-Juárez A, Téllez F, Merino D, Ríos-Villegas MJ, Villalobos M, et al. Sustained virological response to direct-acting antiviral regimens reduces the risk of hepatocellular carcinoma in HIV/HCV-coinfected patients with cirrhosis. J Antimicrob Chemother. 2018;73(9):2435–43.  https://doi.org/10.1093/jac/dky234This Spanish multicentre prospective cohort work demonstrates that SVR with all-oral DAA regimens reduces the risk of HCC in HIV/HCV-coinfected patients with compensated cirrhosis.CrossRefPubMedGoogle Scholar
  12. 12.
    Yu ML, Lin SM, ChuangWL DCY, Wang JH, Lu SN, et al. a sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: a nationwide, multicentre study in Taiwan. Antivir Ther. 2006;11(8):985–94.PubMedGoogle Scholar
  13. 13.
    Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med. 2005;142(2):105–14.  https://doi.org/10.7326/0003-4819-142-2-200501180-00009.CrossRefPubMedGoogle Scholar
  14. 14.
    Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, De Santo JL, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52(3):833–44.  https://doi.org/10.1002/hep.23744.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Okanoue T, Itoh Y, Minami M, Sakamoto S, Yasui K, Sakamoto M, et al. Interferon therapy lowers the rate of progression to hepatocellular carcinoma in chronic hepatitis C but not significantly in an advanced stage: a retrospective study in 1148 patients. Viral hepatitis therapy study group. J Hepatol. 1999;30(4):653–9.CrossRefGoogle Scholar
  16. 16.
    Braks RE, Ganne-Carrie N, Fontaine H, Paries J, Grando-Lemaire V, Beaugrand M, et al. Effect of sustained virological response on long-term clinical outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by interferon alfa and ribavirin. World J Gastroenterol. 2007;13(42):5648–53.  https://doi.org/10.3748/wjg.v13.i42.5648.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Singal AK, Singh A, Jaganmohan S, Guturu P, Mummadi R, Kuo YF, et al. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis. Clin Gastroenterol Hepatol. 2010;8(2):192–9.  https://doi.org/10.1016/j.cgh.2009.10.026.CrossRefPubMedGoogle Scholar
  18. 18.
    van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584–93.  https://doi.org/10.1001/jama.2012.144878.CrossRefPubMedGoogle Scholar
  19. 19.
    Sherman M. Surveillance for hepatocellular carcinoma. Best Pract Res Clin Gastroenterol. 2014;28(5):783–93.  https://doi.org/10.1016/j.bpg.2014.08.008.CrossRefPubMedGoogle Scholar
  20. 20.
    Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and study design issues. Semin Oncol. 2010;37(3):202–15.  https://doi.org/10.1053/j.seminoncol.2010.05.006.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(7):417–22.  https://doi.org/10.1007/s00432-004-0552-0.CrossRefPubMedGoogle Scholar
  22. 22.
    Poustchi H, Farrell GC, Strasser SI, Lee AU, McCaughan GW, George J. Feasibility of conducting a randomized control trial for liver cancer screening: is a randomized controlled trial for liver cancer screening feasible or still needed? Hepatology. 2011;54(6):1998–2004.  https://doi.org/10.1002/hep.24581.CrossRefPubMedGoogle Scholar
  23. 23.
    •• Yang JD, Mannalithara A, Piscitello AJ, Kisiel JB, Gores GJ, Roberts LR, et al. Impact of surveillance for hepatocellular carcinoma on survival in patients with compensated cirrhosis. Hepatology. 2018;68(1):78–88.  https://doi.org/10.1002/hep.29594This work, based on a 100,000 individual subjects’ cohort, describes that HCC surveillance decreases all-cause and tumor-specific mortality in patients with compensated cirrhosis regardless of liver transplantation availability.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med. 2014;11(4):e1001624.  https://doi.org/10.1371/journal.pmed.1001624.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723–50.  https://doi.org/10.1002/hep.29913.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Moon AM, Weiss NS, Beste LA, Su F, Ho SB, Jin GY, et al. No association between screening for hepatocellular carcinoma and reduced cancer-related mortality in patients with cirrhosis. Gastroenterology. 2018;155(4):1128–39.  https://doi.org/10.1053/j.gastro.2018.06.079.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Verma A, Konerman MA, Zhao B. Impact of a structured hepatocellular carcinoma surveillance program in patients with cirrhosis: frequency, evaluation and subsequent clinical outcomes of patients with abnormal imaging findings. Presented at: AASLD: The Liver Meeting 2017, October 20–24, 2017, Washington, DC.Google Scholar
  28. 28.
    Atiq O, Tiro J, Yopp AC, Muffler A, Marrero JA, Parikh ND, et al. An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis. Hepatology. 2017;65(4):1196–205.  https://doi.org/10.1002/hep.28895.CrossRefPubMedGoogle Scholar
  29. 29.
    Sarasin FP, Giostra E, Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child–Pugh class a cirrhosis. Am J Med. 1996;101(4):422–34.  https://doi.org/10.1016/S0002-9343(96)00197-0.CrossRefPubMedGoogle Scholar
  30. 30.
    Giordano TP, Kramer JR, Souchek J, Richardson P, El-Serag HB. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without the hepatitis C virus: a cohort study, 1992–2001. Arch Intern Med. 2004;164(21):2349–54.CrossRefGoogle Scholar
  31. 31.
    Montes Ramírez ML, Miró JM, Quereda C, Jou A, von Wichmann MÁ, Berenguer J, et al. Incidence of hepatocellular carcinoma in HIV-infected patients with cirrhosis: a prospective study. J Acquir Immune Defic Syndr. 2014;65(1):82–6.  https://doi.org/10.1097/QAI.0b013e3182a685dc.CrossRefPubMedGoogle Scholar
  32. 32.
    Kramer JR, Kowalkowski MA, Duan Z, Chiao EY. The effect of HIV viral control on the incidence of hepatocellular carcinoma in veterans with hepatitis C and HIV coinfection. J Acquir Immune Defic Syndr. 2015;68(4):456–62.  https://doi.org/10.1097/QAI.0000000000000494.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Corma-Gómez A, Macías J, Téllez F, Freyre-Carrillo C, Morano L, Rivero-Juárez A, et al. Liver stiffness at the time of sustained virological response predicts the clinical outcome in HIV/HCV-coinfected patients with advanced fibrosis treated with direct-acting antivirals. Clin Infect Dis 2019. ciz1140.  https://doi.org/10.1093/cid/ciz1140.
  34. 34.
    Guía de práctica clínica sobre los tumores no definitorios de SIDA e infección por el VIH. Panel de expertos de GESIDA. Actualización Marzo 2019. Available at: http://gesida-seimc.org/wp-content/uploads/2019/05/gesida_DC_TumoresNoDefinitorios_Marzo_2019_14_05_19.pdf
  35. 35.
    •• Papatheodoridis G, Dalekos G, Sypsa V, Yurdaydin C, Buti M, Goulis J, et al. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy. J Hepatol. 2016;64(4):800–6.  https://doi.org/10.1016/j.jhep.2015.11.035This nine center cohort work shows that PAGE-B represents a simple and reliable score for prediction of the 5-year HCC risk in Caucasian chronic hepatitis B patients.CrossRefPubMedGoogle Scholar
  36. 36.
    Kim JH, Kim YD, Lee M, Jun BG, Kim TS, Suk KT, et al. Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy. J Hepatol. 2018;69(5):1066–73.  https://doi.org/10.1016/j.jhep.2018.07.018.CrossRefPubMedGoogle Scholar
  37. 37.
    •• Wandeler G, Mauron E, Atkinson A, Dufour JF, Kraus D, Reiss P, et al. Incidence of hepatocellular carcinoma in HIV/HBV-coinfected patients on tenofovir therapy: relevance for screening strategies. J Hepatol 2019. S0168–8278(19)30226–0.  https://doi.org/10.1016/j.jhep.2019.03.032. This European large-scale multicentre prospective cohort study describes that the incidence of HCC in HIV/HBV-coinfected individuals remained below the HCC screening threshold in patients without cirrhosis who started TDF aged <46 years.CrossRefGoogle Scholar
  38. 38.
    Lok AS, Seeff LB, Morgan TR, di Bisceglie AM, Sterling RK, Curto TM, et al. HALT-C trial group. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009;136(1):138–48.  https://doi.org/10.1053/j.gastro.2008.09.014.CrossRefPubMedGoogle Scholar
  39. 39.
    Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14.  https://doi.org/10.1016/S0140-6736(18)30010-2.CrossRefPubMedGoogle Scholar
  40. 40.
    Santos J, Valencia E. GeSIDA expert panel. Consensus statement on the clinical management of non-AIDS defining malignancies. Enferm Infecc Microbiol Clin. 2014;32(8):515–22.  https://doi.org/10.1016/j.eimc.2014.04.008.CrossRefPubMedGoogle Scholar
  41. 41.
    Forner A, Reig M, Varela M, Burrel M, Feliu J, Briceño J, et al. Diagnosis and treatment of hepatocellular carcinoma. Update consensus document from the AEEH, SEOM, SERAM, SERVEI and SETH. Med Clin. 2016;146(11):511. e1–e22.  https://doi.org/10.1016/j.medcli.2016.01.028.CrossRefGoogle Scholar
  42. 42.
    Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, et al. Meta-analysis surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther. 2009;30(1):37–47.  https://doi.org/10.1111/j.1365-2036.2009.04014.x.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Singal AG, Conjeevaram HS, Volk ML, Fu S, Fontana RJ, Askari F, et al. Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis. Cancer Epidemiol Biomark Prev. 2012;21(5):793–9.  https://doi.org/10.1158/1055-9965.EPI-11-1005.CrossRefGoogle Scholar
  44. 44.
    Singal AG, Nehra M, Adams-Huet B, Yopp AC, Tiro JA, Marrero JA, et al. Detection of hepatocellular carcinoma at advanced stages among patients in the HALT-C trial: where did surveillance fail? Am J Gastroenterol. 2013;108(3):425–32.  https://doi.org/10.1038/ajg.2012.449.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Fetzer DT, Rodgers SK, Harris AC, Kono Y, Wasnik AP, Kamaya A, et al. Screening and surveillance of hepatocellular carcinoma: an introduction to ultrasound liver imaging reporting and data system. Radiol Clin N Am. 2017;55(6):1197–209.  https://doi.org/10.1016/j.rcl.2017.06.012.CrossRefPubMedGoogle Scholar
  46. 46.
    Santi V, Trevisani F, Gramenzi A, Grignaschi A, Mirici-Cappa F, Del Poggio P, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol. 2010;53(2):291–7.  https://doi.org/10.1016/j.jhep.2010.03.010.CrossRefPubMedGoogle Scholar
  47. 47.
    Trinchet JC, Chaffaut C, Bourcier V, Degos F, Henrion J, Fontaine H, et al. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities. Hepatology. 2011;54(6):1987–97.  https://doi.org/10.1002/hep.24545.CrossRefPubMedGoogle Scholar
  48. 48.
    García-Samaniego J, Rodríguez M, Berenguer J, Rodríguez-Rosado R, Carbó J, Asensi V, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol. 2001;96(1):179–83.  https://doi.org/10.1111/j.1572-0241.2001.03374.x.CrossRefPubMedGoogle Scholar
  49. 49.
    Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB. Hepatitis C infection and the increasing incidence of hepatocellular carcinoma: a population-based study. Gastroenterology. 2004;127(5):1372–80.  https://doi.org/10.1053/j.gastro.2004.07.020.CrossRefPubMedGoogle Scholar
  50. 50.
    Puoti M, Bruno R, Soriano V, Donato F, Gaeta GB, Quinzan GP, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS. 2004;18(17):2285–93.CrossRefGoogle Scholar
  51. 51.
    •• Merchante N, Figueruela B, Rodríguez-Fernández M, Rodríguez-Arrondo F, Revollo B, Ibarra S, et al. Low performance of ultrasound surveillance for the diagnosis of hepatocellular carcinoma in HIV-infected patients. AIDS. 2019;33(2):269–78.  https://doi.org/10.1097/QAD.0000000000002065This retrospective study from the Spanish multicenter cohort GEHEP-002 demonstrates that the performance of ultrasound surveillance of HCC in HIV-infected patients is very poor and worse than that shown outside HIV infection.CrossRefPubMedGoogle Scholar
  52. 52.
    Rodríguez de Lope C, Reig M, Matilla A, Ferrer MT, Dueñas E, Mínguez B, et al. Clinical characteristics of hepatocellular carcinoma in Spain. Comparison with the 2008-2009 Period and analysis of the causes of diagnosis out of screening programs. Analysis of 686 cases in 73 centers. Med Clin (Barc) 2017. 149(2):61–71.  https://doi.org/10.1016/j.medcli.2016.12.048.CrossRefGoogle Scholar
  53. 53.
    •• Simmons O, Fetzer DT, Yokoo T, Marrero JA, Yopp A, Kono Y, et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment Pharmacol Ther. 2017;45(1):169–77.  https://doi.org/10.1111/apt.13841This retrospective cohort study asserts that alternative surveillance modalities are needed in subgroups prone to inadequate ultrasounds including obese patients or those with Child–Pugh B or C cirrhosis, among others, in order to avoid surveillance failure.CrossRefPubMedGoogle Scholar
  54. 54.
    Patel P, Hanson DL, Sullivan PS, Novak RM, Moorman AC, Tong TC, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992–2003. Ann Intern Med. 2008;148(10):728–36.  https://doi.org/10.7326/0003-4819-148-10-200805200-00005.CrossRefPubMedGoogle Scholar
  55. 55.
    Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr. 2009;52(5):611–22.  https://doi.org/10.1097/QAI.0b013e3181b327ca.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Clifford GM, Rickenbach M, Polesel J, Dal Maso L, Steffen I, Ledergerber B, et al. Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma. AIDS. 2008;22(16):2135–41.  https://doi.org/10.1097/QAD.0b013e32831103ad.CrossRefPubMedGoogle Scholar
  57. 57.
    Kanwal F, Singal AG. Surveillance for hepatocellular carcinoma: current best practice and future direction. Gastroenterology. 2019;157(1):54–64.  https://doi.org/10.1053/j.gastro.2019.02.049.CrossRefPubMedGoogle Scholar
  58. 58.
    Pocha C, Dieperink E, McMaken KA, Knott A, Thuras P, Ho SB. Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography—a randomised study. Aliment Pharmacol Ther. 2013;38(3):303–12.  https://doi.org/10.1111/apt.12370.CrossRefPubMedGoogle Scholar
  59. 59.
    •• Kim SY, An J, Lim YS, Han S, Lee JY, Byun JH, et al. MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma. JAMA Oncol. 2017;3(4):456–63.  https://doi.org/10.1001/jamaoncol.2016.3147This prospective surveillance study describes that in cirrhotic patients with high risk of HCC, MRI screening resulted in a higher HCC detection rate (and at very early stage) and lower false-positive findings compared with US.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Goossens N, Singal AG, King LY, Andersson KL, Fuchs BC, Besa C, et al. Cost-effectiveness of risk score-stratified hepatocellular carcinoma screening in patients with cirrhosis. Clin Transl Gastroenterol. 2017;8(6):e101.  https://doi.org/10.1038/ctg.2017.26.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Marrero JA, Feng Z, Wang Y, Nguyen MH, Befeler AS, Roberts LR, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology. 2009;137(1):110–8.  https://doi.org/10.1053/j.gastro.2009.04.005.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, et al. Des-γ-carboxy prothrombin and α-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology. 2010;138(2):493–502.  https://doi.org/10.1053/j.gastro.2009.10.031.CrossRefPubMedGoogle Scholar
  63. 63.
    Zhang B, Yang B. Combined alpha fetoprotein testing and ultrasonography as a screening test for primary liver cancer. J Med Screen. 1999;6(2):108–10.  https://doi.org/10.1136/jms.6.2.108.CrossRefPubMedGoogle Scholar
  64. 64.
    Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 2003;125(1):89–97.  https://doi.org/10.1016/s0016-5085(03)00689-9.CrossRefPubMedGoogle Scholar
  65. 65.
    Shen Q, Fan J, Yang XR, Tan Y, Zhao W, Xu Y, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol. 2012;13(8):817–26.  https://doi.org/10.1016/S1470-2045(12)70233-4.CrossRefPubMedGoogle Scholar
  66. 66.
    Berhane S, Toyoda H, Tada T, Kumada T, Kagebayashi C, Satomura S, et al. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol. 2016;14(6):875–86.e6.  https://doi.org/10.1016/j.cgh.2015.12.042.CrossRefPubMedGoogle Scholar
  67. 67.
    Baumert TF, Berg T, Lim JK, Nelson DR. Status of direct-acting antiviral therapy for hepatitis C virus infection and remaining challenges. Gastroenterology. 2019;156(2):431–45.  https://doi.org/10.1053/j.gastro.2018.10.024.CrossRefPubMedGoogle Scholar
  68. 68.
    •• Backus LI, Belperio PS, Shaohumian TA, Mole LA. Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease. Hepatology. 2019;69(2):487–97.  https://doi.org/10.1002/hep.29408This work, based on an observational cohort analysis, concludes that hepatitis C virus–infected patients who achieve SVR after direct-acting antiviral treatment had significantly lower all-cause mortality and lower incident HCC rates than those who did not achieve SVR.CrossRefPubMedGoogle Scholar
  69. 69.
    •• Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology. 2017;153(4):996–1005.e1.  https://doi.org/10.1053/j.gastro.2017.06.012This retrospective cohort study shows that among DAA-treated patients, SVR was associated with a reduction in the risk of HCC, although in patients with SVR, the absolute risk of HCC remained high in patients with established cirrhosis.CrossRefPubMedGoogle Scholar
  70. 70.
    •• Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol 2017; pii: S0168–8278(17)32273–0. Epub ahead of print.  https://doi.org/10.1016/j.jhep.2017.08.030. This study, based on 62,354 patients who initiated antiviral treatment in the Veterans Affairs national healthcare system, demonstrates that DAA-induced SVR is associated with a 71% reduction in HCC risk and concludes that treatment with DAAs is not associated with increased HCC risk compared with treatment with IFN.CrossRefGoogle Scholar
  71. 71.
    •• Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol. 2017;67(6):1204–12.  https://doi.org/10.1016/j.jhep.2017.07.025This meta-analysis asserts that there is no evidence for differential HCC occurrence or recurrence risk following SVR from DAA and IFN-based therapy.CrossRefPubMedGoogle Scholar
  72. 72.
    Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450–62.  https://doi.org/10.1056/NEJMra1713263.CrossRefPubMedGoogle Scholar
  73. 73.
    Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156(2):477–91.e1.  https://doi.org/10.1053/j.gastro.2018.08.065.CrossRefPubMedGoogle Scholar
  74. 74.
    Ioannou GN, Beste LA, Green PK, Singal AG, Tapper EB, Waljee AK, et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology. 2019;157(5):1264–78.CrossRefGoogle Scholar
  75. 75.
    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84.  https://doi.org/10.1002/hep.28431.CrossRefPubMedGoogle Scholar
  76. 76.
    Guaraldi G, Squillace N, Stentarelli C, Orlando G, D'Amico R, Ligabue G, et al. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis. 2008;47(2):250–7.  https://doi.org/10.1086/589294.CrossRefPubMedGoogle Scholar
  77. 77.
    Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: a meta-analysis of the risk factors. Hepatology. 2010;52(1):71–8.  https://doi.org/10.1002/hep.23619.CrossRefPubMedGoogle Scholar
  78. 78.
    Macías J, González J, Tural C, Ortega-González E, Pulido F, Rubio R, et al. Prevalence and factors associated with liver steatosis as measured by transient elastography with controlled attenuation parameter in HIV-infected patients. AIDS. 2014;28(9):1279–87.  https://doi.org/10.1097/QAD.0000000000000248.CrossRefPubMedGoogle Scholar
  79. 79.
    Vuille-Lessard É, Lebouché B, Lennox L, Routy JP, Costiniuk CT, Pexos C, et al. Nonalcoholic fatty liver disease diagnosed by transient elastography with controlled attenuation parameter in unselected HIV monoinfected patients. AIDS. 2016;30(17):2635–43.  https://doi.org/10.1097/QAD.0000000000001241.CrossRefPubMedGoogle Scholar
  80. 80.
    Macias J, Rivero-Juarez A, Neukam K, Tellez F, Merino D, Frias M, et al. Impact of genetic polymorphisms associated with nonalcoholic fatty liver disease on HIV-infected individuals. AIDS. 2015;29(15):1927–35.  https://doi.org/10.1097/QAD.0000000000000799.CrossRefPubMedGoogle Scholar
  81. 81.
    Núñez-Torres R, Macías J, Rivero-Juarez A, Neukam K, Merino D, Téllez F, et al. Fat mass and obesity-associated gene variations are related to fatty liver disease in HIV-infected patients. HIV Med. 2017;18(8):546–54.  https://doi.org/10.1111/hiv.12489.CrossRefPubMedGoogle Scholar
  82. 82.
    Macías J, Berenguer J, Japón MA, Girón-González JA, Rivero A, López-Cortés LF, et al. Hepatic steatosis and steatohepatitis in human immunodeficiency virus/hepatitis C virus-coinfected patients. Hepatology. 2012;56(4):1261–70.  https://doi.org/10.1002/hep.25791.CrossRefPubMedGoogle Scholar
  83. 83.
    Macías J, Mancebo M, Merino D, Téllez F, Montes-Ramírez ML, Pulido F, et al. Changes in liver steatosis after switching from efavirenz to raltegravir among human immunodeficiency virus-infected patients with nonalcoholic fatty liver disease. Clin Infect Dis. 2017;65(6):1012–9.  https://doi.org/10.1093/cid/cix467.CrossRefPubMedGoogle Scholar
  84. 84.
    Macías J, Real LM, Rivero-Juárez A, Merchante N, Camacho A, Neukam K, et al. Changes in liver steatosis evaluated by transient elastography with the controlled attenuation parameter in HIV-infected patients. HIV Med. 2016;17(10):766–73.  https://doi.org/10.1111/hiv.12384.CrossRefPubMedGoogle Scholar
  85. 85.
    Macías J, Pineda JA, Real LM. Non-alcoholic fatty liver disease in HIV infection. AIDS Rev. 2017;19(1):35–46.PubMedGoogle Scholar
  86. 86.
    •• Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155(6):1828–37.  https://doi.org/10.1053/j.gastro.2018.08.024This retrospective cohort study describes that the risk of HCC was higher in NAFLD patients than that observed in general clinical population, emerging most of them in NAFLD cirrhotic patients.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62(6):1723–30.  https://doi.org/10.1002/hep.28123.CrossRefPubMedGoogle Scholar
  88. 88.
    Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE study. Liver Int. 2015;35(9):2155–66.  https://doi.org/10.1111/liv.12818.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Wong RJ, Cheung R, Ahmed A. Nonalcoholic steatohepatitis is the most rapidly growing indication for liver transplantation in patients with hepatocellular carcinoma in the U.S. Hepatology. 2014;59(6):2188–95.  https://doi.org/10.1002/hep.26986.CrossRefPubMedGoogle Scholar
  90. 90.
    Yasui K, Hashimoto E, Komorizono Y, Koike K, Arii S, Imai Y, et al. Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2011;9(5):428–33.  https://doi.org/10.1016/j.cgh.2011.01.023.CrossRefPubMedGoogle Scholar
  91. 91.
    Mittal S, El-Serag HB, Sada YH, Kanwal F, Duan Z, Temple S, et al. Hepatocellular carcinoma in the absence of cirrhosis in United States veterans is associated with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2016;14(1):124–31.  https://doi.org/10.1016/j.cgh.2015.07.019.CrossRefPubMedGoogle Scholar
  92. 92.
    Piscaglia F, Svegliati-Baroni G, Barchetti A, Pecorelli A, Marinelli S, Tiribelli C, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: a multicenter prospective study. Hepatology. 2016;63(3):827–38.  https://doi.org/10.1002/hep.28368.CrossRefPubMedGoogle Scholar
  93. 93.
    Davila JA, Henderson L, Kramer JR, Kanwal F, Richardson PA, Duan Z, et al. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med. 2011;154(2):85–93.  https://doi.org/10.7326/0003-4819-154-2-201101180-00006.CrossRefPubMedGoogle Scholar
  94. 94.
    Singal AG, Yopp A, Skinner C, Packer M, Lee WM, Tiro JA. Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review. J Gen Intern Med. 2012;27(7):861–7.  https://doi.org/10.1007/s11606-011-1952-x.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Singal AG, Li X, Tiro J, Kandunoori P, Adams-Huet B, Nehra MS, et al. Racial, social, and clinical determinants of hepatocellular carcinoma surveillance. Am J Med. 2015;128(1):90.e1–7.  https://doi.org/10.1016/j.amjmed.2014.07.027.CrossRefGoogle Scholar
  96. 96.
    Dalton-Fitzgerald E, Tiro J, Kandunoori P, Halm EA, Yopp A, Singal AG. Practice patterns and attitudes of primary care providers and barriers to surveillance of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015;13(4):791–8.  https://doi.org/10.1016/j.cgh.2014.06.031.CrossRefPubMedGoogle Scholar
  97. 97.
    Simmons OL, Feng Y, Parikh ND, Singal AG. Primary care provider practice patterns and barriers to hepatocellular carcinoma surveillance. Clin Gastroenterol Hepatol. 2019;17(4):766–73.  https://doi.org/10.1016/j.cgh.2018.07.029.CrossRefPubMedGoogle Scholar
  98. 98.
    Farvardin S, Patel J, Khambaty M, Yerokun OA, Mok H, Tiro JA, et al. Patient-reported barriers are associated with lower hepatocellular carcinoma surveillance rates in patients with cirrhosis. Hepatology. 2017;65(3):875–84.  https://doi.org/10.1002/hep.28770.CrossRefPubMedGoogle Scholar
  99. 99.
    Goldberg DS, Taddei TH, Serper M, Mehta R, Dieperink E, Aytaman A, et al. Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis. Hepatology. 2017;65(3):864–74.  https://doi.org/10.1002/hep.28765.CrossRefPubMedGoogle Scholar
  100. 100.
    Beste LA, Ioannou GN, Yang Y, Chang MF, Ross D, Dominitz JA, et al. Improved surveillance for hepatocellular carcinoma with a primary care-oriented clinical reminder. Clin Gastroenterol Hepatol. 2015;13(1):172–9.  https://doi.org/10.1016/j.cgh.2014.04.033.CrossRefPubMedGoogle Scholar
  101. 101.
    •• Singal AG, Tiro JA, Marrero JA, McCallister K, Mejias C, Adamson B, et al. Mailed outreach program increases ultrasound screening of patients with cirrhosis for hepatocellular carcinoma. Gastroenterology. 2017;152(3):608–15.  https://doi.org/10.1053/j.gastro.2016.10.042This prospective study of patients with documented or suspected cirrhosis at a large safety-net health system found outreach strategies to double the percentage of patients with cirrhosis who underwent ultrasound screening for HCC. However, adding patient navigation to telephone reminders provided no significant additional benefit.CrossRefPubMedGoogle Scholar
  102. 102.
    Palmirotta R, Lovero D, Cafforio P, Felici C, Mannavola F, Pellè E, et al. Liquid biopsy of cancer: a multimodal diagnostic tool in clinical oncology. Ther Adv Med Oncol. 2018;10:1758835918794630.  https://doi.org/10.1177/1758835918794630.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    •• Kisiel JB, Dukek BA, VSR Kanipakam R, Ghoz HM, Yab TC, Berger CK, et al. Hepatocellular carcinoma detection by plasma methylated DNA: discovery, phase I pilot, and phase II clinical validation. Hepatology. 2019;69(3):1180–92.  https://doi.org/10.1002/hep.30244This work, conducted in 4 sequential case–control experiments, identified some methylated DNA markers that proved to accurately detect HCC by plasma testing.CrossRefPubMedGoogle Scholar
  104. 104.
    Zhang Q, Lou Y, Yang J, Wang J, Feng J, Zhao Y, et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut. 2019;68(11):2019–31.CrossRefGoogle Scholar
  105. 105.
    Lupberger J, Croonenborghs T, Roca Suarez AA, Van Renne N, Jühling F, Oudot MA, et al. Combined analysis of metabolomes, proteomes, and transcriptomes of hepatitis C virus-infected cells and liver to identify pathways associated with disease development. Gastroenterology. 2019;157(2):537–51.CrossRefGoogle Scholar
  106. 106.
    Hamdane N, Jühling F, Crouchet E, El Saghire H, Thumann C, Oudot MA, et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology. 2019;156(8):2313–29.CrossRefGoogle Scholar
  107. 107.
    Liu XN, Cui DN, Li YF, Liu YH, Liu G, Liu L. Multiple “omics” data-based biomarker screening for hepatocellular carcinoma diagnosis. World J Gastroenterol. 2019;25(30):4199–212.CrossRefGoogle Scholar
  108. 108.
    Luo P, Yin P, Hua R, Tan Y, Li Z, Qiu G, et al. A large-scale, multicenter serum metabolite biomarker identification study for the early detection of hepatocellular carcinoma. Hepatology. 2018;67(2):662–75.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • N. Merchante
    • 1
  • M. Rodríguez-Fernández
    • 1
  • J. A. Pineda
    • 1
    Email author
  1. 1.Unit of Infectious Diseases and MicrobiologyHospital Universitario de ValmeSevilleSpain

Personalised recommendations