Hepatocellular carcinoma in Hepatitis B and Human Immunodeficiency Virus coinfection in Africa: a focus on surveillance

Abstract

Human immunodeficiency virus (HIV) and hepatitis-B virus (HBV) infections are weighty public health challenges, especially in the African continent. The direct carcinogenic effect of HBV means that it remains a potent cause of early-onset hepatocellular carcinoma (HCC) in Sub-Saharan Africa (SSA), where it causes significant morbidity and mortality. The presence of HIV infection in HBV-infected patients poses a complicating factor, as coinfection has been shown to hasten the progression of liver disease to cirrhosis and HCC, and often resulting in early-age hepatocarcinogenesis with consequent late diagnosis and lower survival. In this review, we discuss this unique conundrum, the epidemiology of HIV-HBV coinfection in SSA, its effect on liver disease and development of HCC, as well as practices and barriers to HCC surveillance in this distinct population. We propose a way forward to curb this considerable health burden focusing on reduction of disease stigma, the need for easy-to-measure biomarkers, and implementation of large prospective studies in this population.

Keywords

HBV / HIV / coinfection / hepatocellular carcinoma / surveillance / Sub-Saharan Africa

References

[1] Akinyemiju T,Ahmed M.Global Burden of Disease Liver Cancer CollaborationThe 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 Oncol2017;3:1683-91 PMCID:PMC5824275

[2] Perz JF,Farrington LA,Bell BP.The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide.J Hepatol2006;45:529-38

[3] WHO. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Available from: https://www.who.int/publications/i/item/9789240027077 [Last accessed on 12 Oct 2022]

[4] Joshi D,Dieterich D,Agarwal K.Increasing burden of liver disease in patients with HIV infection.The Lancet2011;377:1198-209

[5] Puoti M,Soriano V.HIV HCC Cooperative Italian-Spanish GroupHepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.AIDS2004;18:2285-93

[6] Saud LRC,Maccali C.Hepatocellular carcinoma in patients coinfected with hepatitis B or C and HIV: more aggressive tumor behavior?.Eur J Gastroenterol Hepatol2021;33:583-8 PMCID:PMC9446514

[7] El-Kassas M.Hepatocellular carcinoma in Africa: challenges and opportunities.Front Med (Lausanne)2022;9:899420 PMCID:PMC9263092

[8] Mbaga DS,Kengne-Ndé C.Hepatitis B, C and D virus infections and risk of hepatocellular carcinoma in Africa: a meta-analysis including sensitivity analyses for studies comparable for confounders.PLoS One2022;17:e0262903 PMCID:PMC8782350

[9] Tanon A,Ekouevi DK.IeDEA West Africa CollaborationThe spectrum of cancers in West Africa: associations with human immunodeficiency virus.PLoS One2012;7:e48108 PMCID:PMC3483170

[10] Maponga TG,Vermeulen H.Hepatitis B virus-associated hepatocellular carcinoma in South Africa in the era of HIV.BMC Gastroenterol2020;20:226 PMCID:PMC7359588

[11] Singal AG,Tiro J.Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis.PLoS Med2014;11:e1001624 PMCID:PMC3972088

[12] Rodríguez de Lope C,Matilla A.; en representación del Grupo de Estudio de Cáncer Hepático (GECH). 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;149:61-71

[13] Alter MJ.Epidemiology of viral hepatitis and HIV co-infection.J Hepatol2006;44:S6-9

[14] Leumi S,Amougou MA,Nyaga UF.Global Burden of Hepatitis B Infection in People Living With Human Immunodeficiency Virus: A Systematic Review and Meta-analysis.Clin Infect Dis2020;71:2799-806

[15] Statista.. HIV prevalence country ranking 2018. Available from: https://www.statista.com/statistics/270209/countries-with-the-highest-global-hiv-prevalence/ [Last accessed on 12 Oct 2022]

[16] World Health Organization. Global hepatitis report, 2017. Available from: https://www.who.int/publications/i/item/9789241565455 [Last accessed on 7 Jun 2022]

[17] Deressa T,Fonseca K.The burden of hepatitis B virus (HBV) infection, genotypes and drug resistance mutations in human immunodeficiency virus-positive patients in Northwest Ethiopia.PLoS One2017;12:e0190149 PMCID:PMC5744989

[18] Ocama P,Apica B.Hepatitis B and HIV co-infection is still treated using lamivudine-only antiretroviral therapy combination in Uganda.Afr Health Sci2015;15:328-33. PMCID:PMC4480502

[19] Kilonzo SB,Kashasha F.Liver fibrosis and hepatitis B coinfection among art naïve HIV-infected patients at a tertiary level hospital in northwestern Tanzania: a cross-sectional study.J Trop Med2017;2017:5629130 PMCID:PMC5554579

[20] Yousif M,Hussein W.Genotyping and virological characteristics of hepatitis B virus in HIV-infected individuals in Sudan.Int J Infect Dis2014;29:125-32

[21] Magoro T,Mavhandu L.Serologic and genotypic characterization of hepatitis B virus in HIV-1 infected patients from South West and Littoral Regions of Cameroon.Virol J2016;13:178 PMCID:PMC5073451

[22] Stabinski L,Barnhart M,Hamm TE.Prevalence of HIV and hepatitis B virus co-infection in sub-Saharan Africa and the potential impact and program feasibility of hepatitis B surface antigen screening in resource-limited settings.J Acquir Immune Defic Syndr2015;68 Suppl 3:S274-85

[23] Kenfack-Momo R,Takuissu GR.Epidemiology of hepatitis B virus and/or hepatitis C virus infections among people living with human immunodeficiency virus in Africa: a systematic review and meta-analysis.PLoS One2022;17:e0269250 PMCID:PMC9154112

[24] Spearman CW,Ally R.Hepatitis B in sub-Saharan Africa: strategies to achieve the 2030 elimination targets.2017;2:900-9

[25] Weber R,Friis-Møller N.Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study.Arch Intern Med2006;166:1632-41

[26] Yang JD,Gores GJ,Plymoth A.A global view of hepatocellular carcinoma: trends, risk, prevention and management.Nat Rev Gastroenterol Hepatol2019;16:589-604 PMCID:PMC6813818

[27] Tuyama AC,Saiman Y.Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis.Hepatology2010;52:612-22 PMCID:PMC2917256

[28] Debes JD,Boonstra A.Mechanisms of accelerated liver fibrosis progression during HIV infection.J Clin Transl Hepatol2016;4:328-35 PMCID:PMC5225153

[29] Thornton AC,Bhagani S.UK Collaborative HIV cohort (UK CHIC) steering committeeHepatitis B, hepatitis C, and mortality among HIV-positive individuals.AIDS2017;31:2525-32 PMCID:PMC5690308

[30] Thio CL,Skolasky R.HIV-1, hepatitis B virus, and risk of liver-related mortality in the multicenter cohort study (MACS).The Lancet2002;360:1921-6

[31] Colin JF,Loriot MA.Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men.Hepatology1999;29:1306-10

[32] Pinato DJ,Sharma R.Hepatocellular carcinoma: an evolving challenge in viral hepatitis and HIV coinfection.AIDS2017;31:603-11

[33] Singh KP,Audsley J,Sasadeusz J.HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment.AIDS2017;31:2035-52 PMCID:PMC5661989

[34] Kabarambi A,Abaasa A,Orrell C.Determinants and reasons for switching anti-retroviral regimen among HIV-infected youth in a large township of South Africa (2002-2019).AIDS Res Ther2022;19:32 PMCID:PMC9237968

[35] Hernández-ramírez RU,Dubrow R.Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population-based, registry-linkage study.The Lancet HIV2017;4:e495-504 PMCID:PMC5669995

[36] 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults.MMWR Recomm Rep1992;41(RR-17):1-19

[37] Epeldegui M,Martínez-Maza O.HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma.Immunol Res2010;48:72-83 PMCID:PMC3640300

[38] Martínez-Maza O.B-cell activation and lymphoma in patients with HIV.Curr Opin Oncol2002;14:528-32

[39] Althoff KN,Humes E.The shifting age distribution of people with HIV using antiretroviral therapy in the United States.AIDS2022;36:459-71 PMCID:PMC8795488

[40] Anugwom CM,Akbar SMF.Hepatitis B-related hepatocellular carcinoma: surveillance strategy directed by immune-epidemiology.Hepatoma Res2021;7:23 PMCID:PMC8057710

[41] Venkataramani M,Colombani P,Agwu AL.Hepatocellular carcinoma in a teenager with perinatally acquired HIV Infection without hepatitis B or C coinfection: a case report.AIDS Patient Care STDS2010;24:693-6 PMCID:PMC2994537

[42] Giordano TP,Souchek J,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 Med2004;164:2349-54

[43] Jaquet A,Ekouevi DK.IeDEA West Africa CollaborationCancer and HIV infection in referral hospitals from four West African countries.Cancer Epidemiol2015;39:1060-5 PMCID:PMC4679441

[44] Kramer JR,Duan Z.The effect of HIV viral control on the incidence of hepatocellular carcinoma in veterans with hepatitis C and HIV coinfection.J Acquir Immune Defic Syndr2015;68:456-62 PMCID:PMC4334674

[45] Ochoa-Callejero L,Rubio-Mediavilla S,Martínez A.Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model.PLoS One2013;8:e53992 PMCID:PMC3541191

[46] García-Samaniego J.Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C.Am J Gastroenterol2001;96:179-83.

[47] Berretta M,Cacopardo B.Hepatocellular carcinoma in HIV-infected patients: check early, treat hard.Oncologist2011;16:1258-69 PMCID:PMC3228175

[48] Ryom L,De Wit S.D:A:D Study GroupUse of antiretroviral therapy and risk of end-stage liver disease and hepatocellular carcinoma in HIV-positive persons.AIDS2016;30:1731-43

[49] Yang R,Ke H,Gao S.Combination antiretroviral therapy is associated with reduction in liver fibrosis scores in patients with HIV and HBV co-infection.AIDS Res Ther2021;18:98 PMCID:PMC8684625

[50] Boyd A,Miailhes P.Liver fibrosis regression and progression during controlled hepatitis B virus infection among HIV-HBV patients treated with tenofovir disoproxil fumarate in France: a prospective cohort study.J Int AIDS Soc2017;20:21426 PMCID:PMC5467614

[51] Li KW,Liang S.Higher prevalence of cancer related mutations 1762T/1764A and PreS deletions in hepatitis B virus (HBV) isolated from HBV/HIV co-infected compared to HBV-mono-infected Chinese adults.Virus Res2017;227:88-95

[52] Audsley J,Yuen L.HBV mutations in untreated HIV-HBV co-infection using genomic length sequencing.Virology2010;405:539-47 PMCID:PMC2935930

[53] Stella L,Gasbarrini A,Ponziani FR.Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment.World J Gastroenterol2022;28:2251-81 PMCID:PMC9185215

[54] Chidambaranathan-reghupaty S,Sarkar D.Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification.Adv Cancer Res2021;149:1-61 PMCID:PMC8796122

[55] Rossotti R,Mazzarelli C.Similar survival but higher and delayed hepatocellular carcinoma recurrence in HIV-positive compared to negative cirrhotics undergoing liver transplantation.Dig Liver Dis2022:S1590-8658(22)00500

[56] Cunha L,Bhatt N.Hepatocellular carcinoma: Clinical-pathological features and HIV infection in Mozambican patients.Cancer Treat Res Commun2019;19:100129 PMCID:PMC6504939

[57] Okeke E,Mullen B.The impact of HIV on hepatocellular cancer survival in Nigeria.Trop Med Int Health2021;26:335-42

[58] Tassachew Y,Belyhun Y.Prevalence of HIV and Its Co-infection with hepatitis B/C virus among chronic liver disease patients in Ethiopia.Hepat Med2022;14:67-77 PMCID:PMC9113656

[59] Jaquet A,Tanon A.Etiology of hepatocellular carcinoma in West Africa, a case-control study.Int J Cancer2018;143:869-77 PMCID:PMC6041181

[60] Shiels MS.Evolving epidemiology of HIV-associated malignancies.Curr Opin HIV AIDS2017;12:6-11 PMCID:PMC5240042

[61] Marrero JA,Sirlin CB.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.Hepatology2018;68:723-50

[62] Méndez-Sánchez N,Alves de Mattos A.Latin American association for the study of the liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma.Ann Hepatol2014;13(Suppl 1):S4-40

[63] Corrigendum to EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol2019;70:817

[64] Beauchamp E,Walmsley S,Cooper C.Canadian Co-infection Cohort Study (CTN222)Missed opportunities for hepatocellular carcinoma screening in an HIV/hepatitis C virus-coinfected cohort.Clin Infect Dis2013;57:1339-42

[65] Lim C,Gervais A.Standardized care management ensures similar survival rates in HIV-positive and HIV-negative patients with hepatocellular carcinoma.J Acquir Immune Defic Syndr2012;61:581-7

[66] Patel N.Surveillance for hepatocellular carcinoma in people of African ancestry with HIV and Hepatitis B.Int J STD AIDS2022;33:202-4

[67] Willemse S,Sogni P.Hepatocellular Carcinoma Screening Project Working Group for the Collaboration of Observational HIV on behalf of Epidemiological Research Europe (COHERE) In EuroCoordLow compliance with hepatocellular carcinoma screening guidelines in hepatitis B/C virus co-infected HIV patients with cirrhosis.J Viral Hepat2019;26:1224-8 PMCID:PMC6851829

[68] Hearn B,Bichoupan K.Low adherence of HIV providers to practice guidelines for hepatocellular carcinoma screening in HIV/hepatitis B coinfection.Clin Infect Dis2015;61:1742-8 PMCID:PMC4809983

[69] Yang JD,Aziz AOA.Characteristics, management, and outcomes of patients with hepatocellular carcinoma in Africa: a multicountry observational study from the Africa Liver Cancer Consortium.2017;2:103-11

[70] Kedar Mukthinuthalapati VVP,Ndlovu N.Hepatocellular Carcinoma in Sub-Saharan Africa.JCO Glob Oncol2021;7:756-66 PMCID:PMC8457845

[71] Kew MC.Hepatic iron overload and hepatocellular carcinoma.Liver Cancer2014;3:31-40 PMCID:PMC3995380

[72] Okeke E,Roberts L.Epidemiology of liver cancer in Africa: current and future trends.Semin Liver Dis2020;40:111-23

[73] Ocama P,Kagimu M,Wabinga H.Hepatitis B virus and HIV infection among patients with primary hepatocellular carcinoma in Kampala, Uganda.Afr Health Sci2011;11 Suppl 1:S20-3 PMCID:PMC3220119

[74] Gomaa A,Saleh S.Changing presenting features of hepatocellular carcinoma in Egyptian patients. 7th International Liver Cancer Association (ILCA) Annual Conference 2013, September 13-15; Washington, DC, USA: Abstract P-077.

[75] Riebensahm C,Muula G.IeDEA-Southern AfricaScreening for hepatocellular carcinoma among adults with HIV/HBV co-infection in Zambia: a pilot study.Int J Infect Dis2022;116:391-6

[76] Tzartzeva K,Rich NE.Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.Gastroenterology2018;154:1706-1718.e1 PMCID:PMC5927818

[77] Stewart KA,Kambala S.Trends in ultrasound use in low and middle income countries: a systematic review.Int J MCH AIDS2020;9:103-20 PMCID:PMC7031872

[78] Berhane S,Tada T.Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients.Clin Gastroenterol Hepatol2016;14:875-886.e6

[79] Kisiel JB,V S R Kanipakam R.Hepatocellular carcinoma detection by plasma methylated dna: discovery, phase I pilot, and phase II clinical validation.Hepatology2019;69:1180-92 PMCID:PMC6429916

[80] Chalasani NP,Bhattacharya A.A novel blood-based panel of methylated DNA and protein markers for detection of early-stage hepatocellular carcinoma.Clin Gastroenterol Hepatol2021;19:2597-2605.e4

[81] Qu C,Wang P.Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy.Proc Natl Acad Sci U S A2019;116:6308-12 PMCID:PMC6442629

[82] Pontisso P,Benvegnù L.Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma.Br J Cancer2004;90:833-7 PMCID:PMC2410161

[83] Mokrane FZ,Vavasseur A.Radiomics machine-learning signature for diagnosis of hepatocellular carcinoma in cirrhotic patients with indeterminate liver nodules.Eur Radiol2020;30:558-70

[84] Zhang W,Tian J.A narrative review of near-infrared fluorescence imaging in hepatectomy for hepatocellular carcinoma.Ann Transl Med2021;9:171 PMCID:PMC7867918

[85] Quadri NS,Rodin H.Promoting hepatitis b awareness: evaluating an educational approach through health care workers in Tanzania.Ann Glob Health2021;87:22 PMCID:PMC7908926

[86] Quadri NS.The Waiting Room Project: An Approach to Community Health Education in Hepatitis B.Am J Trop Med Hyg2020;103:537 PMCID:PMC7356481

[87] Yang JD,Afihene MY.Africa Network for Gastrointestinal and Liver DiseasesHepatocellular carcinoma occurs at an earlier age in Africans, particularly in association with chronic hepatitis B.Am J Gastroenterol2015;110:1629-31

[88] Sultan A,Wondifraw Z,Bane A.Single center analysis of therapy and outcomes of hepatocellular carcinoma in Sub-Saharan Africa.Expert Rev Gastroenterol Hepatol2020;14:1007-11 PMCID:PMC7544626