HIV. Epidemiological profiles of viral hepatitis in Italy: effect of migration. Massimo Puoti. AO Ospedale Niguarda Ca Granda, Milano

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1 Massimo Puoti Dept of Infectious Diseases, AO Ospedale Niguarda Ca Granda, Milano Issa El Hamad 1 st Dept of Infectious Diseases, AO Spedali Civili Brescia Chiara Pezzoli Dept of Infectious Diseases University of Brescia Brescia Epidemiological profiles of viral hepatitis in Italy: effect of migration HIV

2 ASL di Brescia D.G. Dr. Carmelo Scarcella D.S. A. Dr. Francesco Vassallo Centro di Salute Internazionale Ambulatorio di Medicina del Disagio Responsabile Dr. Issa El Hamad 1 Divisione Malattie Infettive AO Spedali Civili Brescia Dirigenti Medici Dr.ssa S. Rossi ASL di Brescia Dr.ssa C. Scolari ASL di Brescia Dirigenti e consulenti Dr. Salvatore Casari Clinica Malattie Infettive Università di Brescia Dr. Silvio Caligaris Clinica Malattie Infettive Università di Brescia Dr. Massimo Puoti Clinica Malattie Infettive Università di Brescia

3 Epidemiological profiles of hepatitis in Italy efect of migration: HIV & Hepatitis coinfections Impact of immigration on HIV epidemiology in Italy Hepatitis B and HIV coinfection Special issues in HIV management in immigrants and relationship with concurrent liver diseases HBV genotypes in HIV HBV coinfection Impact of late presentation of HIV infection in HBV coinfected immigrants

4 Epidemiological profiles of hepatitis in Italy efect of migration: HIV & Hepatitis coinfections Impact of immigration on HIV epidemiology in Italy Hepatitis B and HIV coinfection Special issues in HIV management in immigrants and relationship with concurrent liver diseases HBV genotypes in HIV HBV coinfection Impact of late presentation of HIV infection in HBV coinfected immigrants

5 Proportion of immigrant in all cases of AIDS in Italy by year of diagnosis 7.9 % of all cases in Italy

6 Proportion of new diagnosis of HIV infection immigrants vs italians (immigrants : 9% in 1992 vs. 29% in 2010) (Valle d Aosta, Piemonte, Liguria, Lombardia, Friuli Venezia-Giulia, Veneto, Bolzano, Trento, Emilia- Romagna, Lazio, Puglia, Marche, Calabria, Pescara, Sassari e Catania) COA, Notiziario ISS 2010

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8 Diagnosis of HIV is later in immigrants Proportion of AIDS cases whose HIV infection was previously unknown at the moment of diagnosis ( ) Potential causes of late diagnosis: Infection acquired in the native country(akinsete OO et al, AIDS Patient Care STDs, 2007) Culture and language(sobrino-vegas P et al. Current HIV Research, 2009) No targeted information campaign Low perception of risk and of the importance of diagnosis Other priorities (job, home, permesso di soggiorno...) Stigmatization Institutional barriers Political and legal issues 8 Source: Not Ist Super Sanità, 2010; 23(4 suppl. 1)

9 Incidence of new diagnoses of AIDS per population in Italy in

10 Illegal immigrants show an earlier diagnosis of AIDS when screening programs are activated The PRISHMA project: HIV test offered to a illegal immigrants Acceptability : 97,5% (3.976/4.078) Feasibility : 73,6% (3.003/4.078) screening proposal and test in 2 different sites Screened 3003: 29 positive 1% (60% acquired HIV in Italy) Where screening is offered early diagnosis of HIV infection in illegal immigrants Late presenters (CD4 < 350/µL): Italians Legal Immigrants Illegal immigrants Very late presenters (CD4 < 200/µL): Italians Legal Immigrants Ilegal immigrants AIDS presenters: Italians Legal immigrants Illegal immigrants 580 (47,1%) 114 (42,7%) 110 (50,0%) 828 (67,2%) 172 (64,4%) 164 (74,5%) NO SI p OR (IC 95%) (89,1%) 246 (92,1%) 211 (95,9%) 652 (52,9%) 153 (57,3%) 110 (50,0%) 404 (32,8%) 95 (35,6%) 56 (25,5%) 134 (10,9%) 21 (7,9%) 9 (4,1%) 0,108 0,234 0,390 0,018 0,085 0, ,194 (0,914-1,559) 0,890 (0,668-1,185) 1 1,132 (0,858-1,494) 0,700 (0,505-0,969) 1 0,699 (0,433-1,131) 0,350 (0,175-0,697) 10

11 Immigrants are one third of HIV patients on follow up in Brescia from 2000 Year of HIV Dx 2000 First visit no more than 1 year after HIV positive test ART naive at first visit N (%) N (%) All HIV (100) Italians (71,7) Status : - Legal immigrants -Illegal immigrants 267 (54,8) 220 (45,2) Country of birth - Africa 268 (55) Immigrants 487 (28,3) -South America - Eastern Europe 110 (22,6) 50 (11,9) - Asia 30 (6,2) - ND 21 (4,3) 11

12 Patients ethnicity and nationality of antiretroviral naives HIV+in Icona foundation Study

13 Epidemiological profiles of hepatitis in Italy efect of migration: HIV & Hepatitis coinfections Immigrants are a growing subgroup of HIV infected patients: HIV screening in high risk behaviour and in those coming from high endemicity areas is mandatory

14 Epidemiological profiles of hepatitis in Italy efect of migration: HIV & Hepatitis coinfections Impact of immigration on HIV epidemiology in Italy Hepatitis B and HIV coinfection Special issues in HIV management in immigrants and relationship with concurrent liver diseases HBV genotypes in HIV HBV coinfection Impact of late presentation of HIV infection in HBV coinfected immigrants

15 The global geographic distribution and annual mortality of chronic hepatitis B virus infection and HIV infection. HBV HIV Persons infected: n % of world population 350 million 6% 2-4 million % 40 million 1% Deaths in 2008 n % of infected % 3 million 7.5% Alter MJ J Hepatology 2006 Centers for Disease Control and Prevention. Hepatitis B slide set. Available at: ttp:// 5. UNAIDS/WHO. HIV prevalence in adults, end Available at: y04global_en.ppt#1.

16 Burden of Chronic Hepatitis B in HIV-infected Persons Varies by Risk Group and Geography % HBV in HIV-infected persons Western Europe and US Alter et al, J Viral Hep 2007; Zhou et al J Gastro Hepatol 2007; Nyinenda et al J Infect 2008; Drop-Ndiaye J Med Virol 2008; Lee et al J Forma Med Assoc 2008.

17 HIV-HBV co-infected Nigerian PEPFAR cohort 1564 HIV-infected persons from Jos, Nigeria Initiated HAART 10/04-6/ (16.7%) HBsAg+ Median CD4 126 cells/ml Lower in co-infected (107 versus 130 cells/ml, p=0.001) HBV DNA levels are low N (%) HBV DNA < 20,000 IU/ml HBeAg+ 90 (35) 12% HBeAg 171 (65) 65% Idoko et al, CID 2009 :

18 HBV DNA levels low in majority of HIV-HBV coinfected individuals in ACTG A5175 and A5208 HBsAg negative N=1914 HBeAg negative N=57 HBeAg positive N=55 Age, years* CD4, cells/ml* HIV RNA, log cp/ml* ALT (U/L) AST (U/L) HBV DNA (IU/mL)* HBV DNA <2000 IU/mL 68% 6% HBV DNA <20,000 IU/mL 77% 10% *median values Thio et al, CROI 2010

19 Prevalence of HBV Co-infection in persons living with HIV in EuroSIDA cohort Among 9803 subjects in the EuroSIDA Cohort: 5883 had a HBsAg test available at time of enrollment 530 (9%) were positive North:HBsAg +:9.7 % Argentina HBV+: 17.8% Central HBs Ag+ 9.2% East HBsAg+: 6% South HBsAg+ 9.1% Konopnicki D et al.; AIDS

20 Tested for anti HCV & HBsAg 85% Caucasian 81% Non Caucasian

21 Epidemiological profiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Immigrants are a growing subgroup of HIV infected patients: HIV screening in high risk behaviour and in those coming from high endemicity areas is mandatory Hepatitis B coinfection is common in HIV+ immigrants (7.83%) as in italian natives (6.33%); HCV is less common in immigrants (9.87% vs. 37.6%)

22 Epidemiological prophiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Impact of immigration on HIV epidemiology in Italy Hepatitis B and HIV coinfection Special issues in HIV management in immigrants and relationship with concurrent liver diseases HBV genotypes in HIV-HBV coinfection Impact of late presentation of HIV infection in HBV coinfected immigrants

23 HIV-1 subtyping is mandatory in immigrants Worldwide distribution of HIV-1 subtype 23

24 Trends in HIV-1 subtype in new HIV-1 diagnosis in Brescia, Italy and prevalence of HIV-2 in immigrants % patients Cochran Armitage test for trend P<0.001 Sottotipo C: P=0.006 Sottotipo F1: P<0.001 Sottotipo G: P=0.009 CRF 02_AG: P< Anno A1 C CRF02_AG F1 G Altri Torti C. et al. Epidemiol Infect 2010; 138: Prevalence of HIV-2 in HIV infected immigrants in Brescia : 01/ / 2007 : N of immigrants observed during the study period: 220/2941 = 7.5% N of immigrants screened for HIV-2 = 141 Prevalence of HIV-2= 14/141 = 9.9% 24

25 Implication of high prevalence of non B HIV-1 subtype and HIV-2 in immigrants Need for HIV subtyping: Correct meausurement of HIV RNA [1,2]; Identification of more aggressive subtypes ( ie subtype D) need for closer monitoring off and on therapy] [3-4]; HIV-2: NNRTI uneffective fosamprenavir, enfuvirtide null or partial efficacy [2, 5-7]; Correct interpretation of resistance testing [8-9] Rodes B et al. J Clin Microbiol, 2007; 45(1): Easterbrook PJ et al J Int AIDS Soc, 2010; 13(1): Bousheri et al. JAIDS, 2009; 52(5): Rodes B. et al. Clin Infect Dis, 2005; 41: e19-e Van der Ende ME AIDS, 2003; 17(suppl 3): S55-S Poveda E et al. AIDS Res Hum Retroviruses, 2004; 20(3): Geretti AM. Curr Opin Infect Dis, 2006; 19(1): Kantor R. et al. PLOS Medicine, Holguin A et al. AIDS Rev Apr-Jun;8(2):

26 Ethnicity and hepatitis: association with co-factors of liver disease progression and treatment efficacy or toxicity Association Pathogenesis Interactions with Hepatitis viruses coinfection African ethnicity Renal Disease African ethnicity - metabolic syndrome Asian ethnicity - diabetes African ethnicity and bone African ethnicity IFN responsiveness Asian ethnicity - IFN responsiveness 26 Genetic susceptibility(hivan, hoat1 ), predisposing conditions (diabetes and hypertension) Greater BMI, lower lipid alteration and lipodystrophy, higher insulin resistance and hypertension Higher BMD with lower bone reabsorption; lower vitamin D Lower responsiveness to IFN and higher prevalence of IL28b SNP <> C/C Higher prevalence of IL28b SNP C/C Higher rates of TDF renal toxicity More rapid evolution of liver diseases ( HCV > HBV) lower IFN responsiveness More rapid evolution of HCV Controversial effect on Tenofovir bone toxicity Lower efficacy of anti HCV therapy Higher efficacy of anti HCV therapy

27 Ethnicity and pharmacogenomics : impact on efficacy and toxicity of antiretrovirals.. and anti HCV DAA???? CYP2B6 G516T, polymorphism in black ethnicity Lower metabolism and Higher toxicity of Efavirenz Confirmed HLA B 5701 prevalence lower in black ethnicity Lower incidence of reaction to Abacavir but the test is 100% predictive Confirmed CYP2D6 genetic variant in black ethnicity Rapid metabolization of Lopinavir need for TDM of Lopinavir when uneffective Confirmed HLA DRB1*0101, HLA-B*3505, HLA-Cw8 UGT1A1, SLC01B1 Nevirapine rash +/- hepatitis Efavirenz rash (>risk in Black, Hispanic, Asian etnicity) Hyperbilirubinemia ATV e IDV(>risk in Asian etnicity) LPVr levels (> risk in black etnicity) HLA association confirmed in small studies, different ethnicities Confirmed mtdna haplogroups T, L1c d4t Neuropathy Not confirmed CFTR/ SPINK Pancreatitis Confirmed in HIV seroneg MDR Hyperbilirubinemia ATV (< risk in black etnicity) Not confirmed Resistin Metabolic Syndrome Not confirmed APOE4, Mannose binding lectin (MBL)-2 27 HIV associated cognitive disorders Not confirmed

28 Epidemiological profiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Immigrants are a growing subgroup of HIV infected patients: HIV screening in high risk behaviour and in those coming from high endemicity areas is mandatory Hepatitis B coinfection is common in HIV+ immigrants (7.83%) as in italian natives (6.33%); HCV is less common in immigrants (9.87% vs. 37.6%) HIV is different in immigrants: Need for subtyping Different toxicities & interaction with liver disease pathogenesis Different pharmacogenomics

29 Epidemiological profiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Impact of immigration on HIV epidemiology in Italy Hepatitis B and HIV coinfection Special issues in HIV management in immigrants and relationship with concurrent liver diseases HBV genotypes in HIV-HBV coinfection Impact of late presentation of HIV infection in HBV coinfected immigrants

30 Geographical distribution of the prevalence of HBV genotypes Hadzyiannis S J J Hepatology in press

31 Regional distribution of hepatitis B virus genotypes in HIV-HBV co-infected patients from EuroSIDA 170 of 1179 HIV-HBV in cohort genotyped Genotype A 72.9%; Genotype D 17.1% 12% gta IDU vs 54% non-a Genotype A Common in North and Central regions Associated with MSM Higher median HBV DNA despite similar numbers with HBV therapy Soriano, V. et al. J. Antimicrob. Chemother : ;

32 Impact of HBV genotypes on natural history of Hepatitis B in HIV- Geographic area Asociation Evidence A1 Subsaharian Africa HCC in young males w/o cirrhosis 2c A2 North Europe HCC and Cirrhosis in aged 2c B1 Japan HCC and Cirhosis in aged 2c B2-6 Far East HCC and cirrhosis in age younger than B1 2c C1-4 Far East Later anti HBe seroconversion &HCC and cirrhosis risk > B 1b, 2a D1-4 South and Easastern Europe, Mediterranean basin Anti Hbe+; Cirrhosis and HCC in aged 2c F1 Alaska, South and Central America HCC and Cirrhosis in younger ages in Alaska 2b Level 1: Strong evidence: 1a Longitudinal cohort studies vs HBsAg- controls 1b Longitudinal uncontrolled population cohort studies Level 2: Intermediate evidence: 2a Longitudinal clinical cohort studies; 2b Population and clinical cohorts nested case control studies ; 2c: Cross sectional case control clinical studies Level 3 : Weak Evidence. Observational studies or case series

33 Genotype G associated with more fibrosis in French HIV-HBV cohort Genotype A (70%), genotype G (11.8%), genotype D (13.7%) 104 /308 HIV-HBV co-infected patients with liver biopsy F0-F1: 36 F2: 43 F3: 15 F4: 12 13/13 with genotype G >F1 >F1 not different based on treatment regimen Associations with >F1 OR 95% CI Genotype G inf Efavirenz HIV >9.5 years Lacombe et al AIDS :419

34 Additional HBV genotype studies In 40 Taiwanese HIV-HBV patients, HBV genotype B had higher HBV DNA and more rapid development of LMV-R (Hsieh TH et al AVT (8): Two other studies demonstrate genotype A associated with HIV- HBV MSM In Japanese cohort, 20/32 (62.5%) of MSM or bisexuals were genotype A compared to 1/9 (11%) of heterosexuals and 1.9% of HBV monoinfected (Shibayama et al J Med Virol :24) Spanish study of 23 HIV-HBV subjects (Perez-Olmeda. AIDS Res Hum Retro 19:657) Genotype A Genotype D MSM, % IDU, % 33 67

35 Epidemiological profiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Immigrants are a growing subgroup of HIV infected patients: HIV screening in high risk behaviour and in those coming from high endemicity areas is mandatory Hepatitis B coinfection is common in HIV+ immigrants (7.83%) as in italian natives (6.33%); HCV is less common in immigrants (9.87% vs. 37.6%) HIV is different in immigrants: Need for subtyping Different toxicities & interaction with liver disease pathogenesis Different phatrmacogenomics HBV is different in immigrants: peculiarities of HBV subtypes

36 Epidemiological profiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Impact of immigration on HIV epidemiology in Italy Hepatitis B and HIV coinfection Special issues in HIV management in immigrants and relationship with concurrent liver diseases HBV genotypes in HIV-HBV coinfection Impact of late presentation of HIV infection in HBV coinfected immigrants

37 Diagnosis of HIV is later in immigrants Proportion of AIDS cases whose HIV infection was previously unknown at the moment of diagnosis ( ) Potential causes of late diagnosis: Infection acquired in the native country(akinsete OO et al, AIDS Patient Care STDs, 2007) Culture and language(sobrino-vegas P et al. Current HIV Research, 2009) No targeted information campaign Low perception of risk and of the importance of diagnosis Other priorities (job, home, permesso di soggiorno...) Stigmatization Institutional barriers Political and legal issues 37 Source: Not Ist Super Sanità, 2010; 23(4 suppl. 1)

38 Hepatitis Flares in HIV-HBV coinfected patients starting anti HBV active HAART (TICO trial substudy) TICO Trial substudy: 36 antiretroviral naïve HIV/HBV in Thailand randomized to receive: TDF vs LAM vs TDF + LAM as part of an Efavirenz based HAART 8 (22%) cases with Hepatic Flares ( ALT > 5 x VN or > 200 within 12 weeks) 1 died for LF (3%) Predictors of flares: High HBVDNA High ALT Low CD4 Pathogenesis of flares: Immune Restoration Diseases by cytokines substudy: T cell and NK activation markers in cases IP-10 and scd30 & markers of IFNγ induction (IL-18) and activity (MCP-1) Crane et al Hepatology 2009 JID 2009

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40 Epidemiological profiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Immigrants are a growing subgroup of HIV infected patients: HIV screening in high risk behaviour and in those coming from high endemicity areas is mandatory Hepatitis B coinfection is common in HIV+ immigrants (7.83%) as in italian natives (6.33%); HCV is less common in immigrants (9.87% vs. 37.6%) HIV is different in immigrants: Need for subtyping Different toxicities & interaction with liver disease pathogenesis Different phatrmacogenomics HBV is different in immigrants: peculiarities of HBV subtypes Late presentation in HIV HBV coinfected higher risk of decompensation in cirrhotics after immune restoration

41 Epidemiological profiles of hepatitis in Italy effect of migration: HIV & Hepatitis coinfections Immigrants are a growing subgroup of HIV infected patients: HIV screening in high risk behaviour and in those coming from high endemicity areas is mandatory Hepatitis B coinfection is common in HIV+ immigrants (7.83%) as in italian natives (6.33%); HCV is less common in immigrants (9.87% vs. 37.6%) HIV is different in immigrants: Need for subtyping Different toxicities & interaction with liver disease pathogenesis Different phatrmacogenomics HBV is different in immigrants: peculiarities of HBV subtypes Late presentation in HIV HBV coinfected higher risk of decompensation in cirrhotics after immune restoration

42 ASL di Brescia D.G. Dr. Carmelo Scarcella D.S. A. Dr. Francesco Vassallo Centro di Salute Internazionale Ambulatorio di Medicina del Disagio Responsabile Dr. Issa El Hamad 1 Divisione Malattie Infettive AO Spedali Civili Brescia Dirigenti Medici Dr.ssa S. Rossi ASL di Brescia Dr.ssa C. Scolari ASL di Brescia Dirigenti e consulenti Dr. Salvatore Casari Clinica Malattie Infettive Università di Brescia Dr. Silvio Caligaris - Clinica Malattie Infettive Università di Brescia Dr. Massimo Puoti - Clinica Malattie Infettive Università di Brescia

43 Dipartimento Malattie Infettive AO Spedali Civili di Brescia Malattie Infettive 1 Divisione direttore Dr. Alfreedo Scalzini Clinica di Malattie Infettive e Tropicali direttore Prof. Giampiero Carosi

44 Icona Foundation Study GOVERNING BODY- M. Moroni (Chair), G. Angarano, A. Antinori, G. Carosi, R. Cauda, A. d Arminio Monforte, G. Di Perri, M. Galli, R. Iardino, G. Ippolito, A. Lazzarin, C.F. Perno, P.L. Viale, F Von Schlosser. SCIENTIFIC SECRETARY- A d Arminio Monforte STEERING COMMITTEE A. Ammassari, M Andreoni, A. Antinori, C. Balotta, P. Bonfanti, S Bonora, M Borderi, M.R. Capobianchi, A. Castagna, F. Ceccherini-Silberstein, A. Cozzi-Lepri, A. d Arminio Monforte, A. De Luca, M Gargiulo, C. Gervasoni, E. Girardi, M Lichtner, S. Lo Caputo, G Madeddu, F Maggiolo, S Marcotullio, L Monno, R. Murri, C. Mussini, M. Puoti, C. Torti STATISTICAL AND MONITORING TEAM A Cozzi-Lepri, I Fanti, T Formenti PARTICIPATING PHYSICIANS AND CENTERS Italy M. Montroni, A. Giacometti, A Costantini, A. Riva (Ancona); U. Tirelli, F. Martellotta (Aviano-PN); G. Angarano, L Monno, N. Ladisa, (Bari); F. Suter, F. Maggiolo (Bergamo); PL: Viale, G. Verucchi, B Piergentili, (Bologna); G. Carosi, G. Cristini, C. Torti, C. Minardi, D. Bertelli (Brescia); T. Quirino, C Abeli (Busto Arsizio); P.E. Manconi, P. Piano (Cagliari); J Vecchiet, K Falasca (Chieti); G Carnevale, S Lorenzotti (Cremona); L. Sighinolfi, D. Segala (Ferrara); F. Leoncini, F. Mazzotta, M. Pozzi, S. Lo Caputo (Firenze); G. Cassola, G Viscoli, A. Alessandrini, R. Piscopo, G Mazzarello (Genova); C. Mastroianni, V. Belvisi (Latina); P. Bonfanti, C Molteni (Lecco); A. Chiodera, P. Castelli (Macerata); M Galli, A. Lazzarin, G. Rizzardini, M. Puoti, A. d Arminio Monforte, AL Ridolfo, A Foschi, A Castagna, S Salpietro, S. Merli, L Carenzi, M.C. Moioli, P Cicconi, T Formenti (Milano); R. Esposito, C. Mussini (Modena); A Gori, V Pastore (Monza), N. Abrescia, A. Chirianni, M. De Marco, (Napoli); C. Ferrari, R Borghi (Parma); F Baldelli, B Belfiori (Perugia); G. Parruti, F Sozio (Pescara); G. Magnani, M.A. Ursitti (Reggio Emilia); M. Arlotti, P. Ortolani (Rimini); R. Cauda, M Andreoni, A. Antinori, G. Antonucci, P. Narciso, V Tozzi, V. Vullo, A. De Luca, M. Zaccarelli, L Gallo, R. Acinapura, P. De Longis, L Ceccarelli, R Libertone, M.P. Trotta, A Miccoli, (Roma); AM Cattelan (Rovigo); M.S. Mura, G Madeddu (Sassari); P. Caramello, G. Di Perri, G.C. Orofino, M Sciandra (Torino); E. Raise, F. Ebo (Venezia); G. Pellizzer, D. Buonfrate (Vicenza). The Icona Foundation Study is supported by unrestricted educational grants of Abbott, Bristol-Myers Squibb Gilead