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HIV and hepatitis B co-infection  : interactions and issues

HIV and hepatitis B co-infection  : interactions and issues. Dr Karine Lacombe SMIT St Antoine, AP-HP – PARIS UPMC – Inserm UMR-S707. 9th Advanced HIV course 8th September 2011. Same routes of transmission:

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HIV and hepatitis B co-infection  : interactions and issues

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  1. HIV and hepatitis B co-infection : interactions and issues Dr Karine Lacombe SMIT St Antoine, AP-HP – PARIS UPMC – Inserm UMR-S707 9th Advanced HIV course 8th September 2011

  2. Same routes of transmission: • 90% of HIV-infected patients with markers of prior HBV infection + 5-15% w/ chronic infection1 • HIV (33M) + HBV (400M) = 2-4M HIV-HBV2 • Routes of transmission and age at transmission differ: • Zones with low HBV endemicity (<2%) • Europe, North America • IDU, sex • P(HIV-HBV)= 5 – 10% • Zones with high HBV prevalence (>8%) • Africa, Asia • perinatal, young age (injections, scarification) • p(HIV-HBV) = 15% • Global prevalence HIV prevalence, 2008 1Alter M. J Hepatol 2006. 2WHO Report, 2008.

  3. HBV prevalence increased in HIV infected patients5 • 7,28% in patients from a tertiary care center from Delhi, compared to 1,4% in healthy controls 1UNAIDS Report 2010, 2Goldstein SC, et al. Int J Epidemiol 2005, 4World Health Report 2004 5Gupta S. BMC Infect Dis 2010

  4. ?

  5. 2 different viral pathogens with complex interactions… …And complex issues for the clinicians and stakeholders to tackle with.

  6. Main issues… Prevention / Transmission Screening / Diagnosic Treatment Morbidity Mortality

  7. 1st issue, morbidity and mortality:Impact of HIV on HBV • After an acute infection with HBV : • About 25% of the patients evolvetowards chronicity1,2 • In HIV negative patients, chronicity rate for acquisition atadultageis < 5%3 • Duringchronic course of HBV infection • Rare spontaneousHBeSeroconversion: 12% in 5 years4 • Common episodes of hepaticflares • Immune restoration • Hepatitisreactivationat ART discontiuation • Viral breakthrough 1Bodsworth, et al. J Infect Dis 1991. 2 Gatanaga, Eur J Clin Microbiol Infect Dis 2000. 3Hyams, et al. Clin Infect Dis 1991.4Gilson, et al. AIDS 1997.

  8.  Life expectancy +  opportunistic infections • non AIDS related deaths (of which 25% are liver related) • (Mocroft A, et al. AIDS 2002)  Liver related deaths (Thio CL, et al. Lancet 2002) Liver related deaths in French survey « Mortalité 2005 » = 2nd cause of death in HIV patients non related to AIDS in France Lewden C, et al. JAIDS 2008 RR (death if co-infection) = 3.58 [2.09 – 6.16] (Konopnicki, AIDS 2005) RR(death if chronic HBV) = 3.7 [2.4 – 5.9] (D:A:D, Arch Intern Med 2006) RR(death if HBV compared to HCV)=2,16 [1,0-4,6] (Oluwaseun F, CROI 2011)

  9. 1st issue, morbidity and mortality:Impact of HBV on HIV • Stilldebated in terms of mortality • Europeanstudy on > 12,000 patients • 36% excessrisk / HBV (OR=1.36 [1.12 – 1.64]1 • Might trigger an additive effect to that of HIV on immune activation • Role of chronic Hep B on incidence of hepatoxicityat ART initiation2 • Above all if TB treatment3 1Nikolopoulos G, CID 2009. 2Sulkowski MS. J Hepatol 2008. 2Hoffmann CJ, et al. AIDS. 2007

  10. 1st issue, morbidity and mortality :Impact of multiple infections • Multiple hepatic virus co-infection • Routes of transmission common to HCV and HDV • 29.9% of HIV-HBV alsoinfectedwith HCV in Eurosida1 • 7.8% of HIV-HBV-HDV and HIV-HBV-HCV-HDV in French HIV-HBV Cohort2 •  HCV and HDV viral replication3 •  progression to cirrhosis and ESLD4,5 1Konopnicki D, AIDS 2005. 2Lacombe K, AIDS 2005. 3Boyd A, J Viral Hepat 2009. 4lacombe K, AIDS 2007. 5Sheng WH, CID 2007.

  11. 2nd issue: Screening and diagnosisScreening procedures • Frequency of periodic screening • When HIV diagnosed and everyotheryear if antiHBcAb-antiHBsAb negative1, according to riskfactors if immunizationfails • Test for HCV ab, HDV Ab and HAV Ab • If HAV neg, immunization +++ • If antiHBcAbneg + antiHbsAbneg • immunization • If isolatedantiHBcAb • Fear of occult HBV infection2,3 • Screen for HBV-DNA • If suspicion of acute HBV • Screen for antiHBcimmunoglobulin M 1EACS Guidelines 2011 2Perez-Rodriguez MK, World J Gastroenterol 2009. 3N’Dri Yoman, Antivi Ther 2010

  12. 2nd issue: Screening and diagnosisDiagnostic and follow-up tools • Clinical: comorbidities (metabolic syndrome, alcohol, drugs, multiple viral hepatitis) • Biological: standard lab tests, viral hepatitisserologies (HCV, HDV, HAV, HEV), other causes of hepatitis • HBV: full serology, HBV-DNA • Livergrading and staging: • Liverbiopsy: still important1 • Biochemical tests: interesting2 • Elastometry: recentlyevaluated in HIV-HBV co-infection3, but performance must bequestionned if macronodularfibrosis. 1Don CR, Hepatol 2009. 2Bottero J, JHepatol 2009. 3Miailhes P, J Viral Hepat 2010.

  13. 2nd issue: Screening and diagnosisTools for follow-up • Follow-up and prevention of ESLD1: • Crucial because of higher and faster risk of onset of ESLD • Physical exam + doppler US + FP • Cirrhotic and pre-cirrhotic : every 3 to 6 months • Others: every year • Risk of HCC without cirrhosis when HBV+ • Crucial need to be pro active2 1EACS guidelines 2011. 2Zech CJ, Dig Dis 2009.

  14. 3rd issue: treatmentHIV-HBV interactions • Absolutenecessity to use drugswith dual activity • Risk of severehepatitisat ART initiation because of immune restoration to HBV1 • Evengreaterrisk of severehepatitisattreatment discontinuation2 • Risk of viral breakthrough if use of drugs with low genetic barrier (lamivudine, telbivudine, adefovir) 1Manegold C, et al. Clin Infect Dis 2001. 2Bonacini M. et al. Gastroenterol 2002

  15. 3rd issue: treatmentHBV drugs in the HIV context (1) • IFN – PegIFN: • efficacyquestioned in the context of HIV1,2,3 • Lamivudine: • Oldest oral antiHBVdrug • Viral breakthrough in 90% of patients after 4 years4 • Adefovir: • Slow decline of HBV-DNA withemergence of ADV-R strains • New ADV-R strainsselected in HIV-infected patients4 • Telbivudine: • Mild HIV suppression without HIV resistance5 • No in vitro antiHIVactivity 1Di Martino V, Gastroenterol 2002. 2Ingiliz M, Antivir Ther 2008. 3Johnson M, HIV Clin Trials 2007.4Benhamou Y, Hepatol 1999. 5Low E, AIDS 2009

  16. 3rd issue: treatmentHBV drugs in the HIV context (2) • Entecavir: • Decreasedefficacy in case of priorexposure to 3TC1 • Selection of HIIV resistance in monotherapy2 • Useless in HBV intensification strategy3 • Tenofovir: • StrongantiHIV and antiHBV activity4 • No known pattern of resistance5 • Long termtolerancequestioned (bone, kidneys) • Emergence of low-replicative patients 1Product package. 2McMahon MA, NEJM 2007. 3Luetkemeyer AF, JAIDS 2011. 4de Vries-Sluijs TE. Gastroenterol 2010

  17. 3rd issue: treatmentAssessingtreatment indications EACS Guidelines 2011

  18. 3rd issue: treatmentTimely initiation of treatment

  19. 3rd issue: treatmentWhat to do if no HBV-DNA ? «  SALY Guidelines 2010 » - RESAPSI (African Doctors Association) ALT >2N normal Repeatafter 1-2 monts CD4<500 CD4>=500 if >2N, treat treatment Reevaluateafter 6 months

  20. 3rd issue: treatmentWhatdrugsshouldbeused ? TDF 3TC or FTC LPV/r EFV * If ALT ≥ 3 N, do not use EFV. 2IN +LPV/r * If ALT < 3N, 2NUCs + EFV * Preferedchoice TDF + 3TC + EFV * If persistencehypertransaminasemiaat M6 or clinicalsigns (icterus), refer to specialized center • Do not prescribenevirapine • TDF ( + 3TC/FTC)shouldbemaintained in case of switch to 2nd line therapy

  21. 3rd issue: treatmentImpact of antivirals on HBV genetics? • pol mutations selected by exposure to Nucleos(t)ides (3TC, FTC, ADV, ETV, LdT) • Double stranded DNA with overlapping reading frames: pol mutations  S mutations • S mutations selected as consequence of pol mutations + selective pressure of host origin • associated with decrease of HBs antigenicity1 and vaccine escape2 • false negative with ELISA test Lee WM.N Engl J Med. 1997  Is HIV-coinfection a threat for emergence of vaccine escape mutants (because of Rxhistorywith 3TC) and drug-resistantstrains (because of long-termexposure to NRTI?3 1Torresi J, J clinc virol 2002. 2Kamili S, Hepatol 2009. 3special issue Antivir Ther 2010

  22. 4st issue: PreventionImmunization • Lack of immunization efficacy in the context of severe immunosuppression1 • Crucial to immunize early during childhood • Implementation of community vaccine programme with WHO guidance (2002) in many resource limited countries2 • New strategy with double dose x4 vaccine3 1Collier AC, et al.Ann Intern Med 1988. 2 WHO website 3Launay O. NEMJ 2011

  23. 4st issue: PreventionHBV-PMTCT • Control of HBV replication • Risk of transmission = 90% if HBeAg+ ; 30% if antiHBe Ac+1,2 • Decline to 26-54% if HBIg alone • Decline to 25-26% if infant immunization alone • Decline to 5-11% if HBIg + immunization • Risk of transmission decreased when HBV-DNA replication is controled2: 56% to 0% according to HBV-DNA level3 • In the field: • HBIg very expensive • Mothers do not return on time for infants immunization • Efficacy +++ of nucleos(t)ides as PMTCT agents during at least the last trimester of pregnancy (trials going on) 1Beasly RP, Hwang LY, et al. Lancet 1983. 2Lo KJ, Tsai YT, et al. Hepatogastroenterol 1985. 3Yuan J, Lin J. et al. J Viral Hepat 2006.

  24. CONCLUSION: challenges and future issues • What to use in patients withabsolutely no indication for HIV treatment but necessity of HBV treatment ? • Tolerance of TDF on the long term ? • What options in patients with TDF contra-indications and priorexposure to 3TC? • What options in patients with on goingreplicationwhile on TDF and no TDF mutations? • How to increaseawareness on the necessity of HBV-PMTCT in resource-limited countries ?

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