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HCV in HIV patients, Cure and Beyond

HCV in HIV patients, Cure and Beyond. K. Lacombe 1 , M. Lemoine 2 , G. Raguin 3 , A. Fontanet 4 , F. Zoulim 5. 1 Université Pierre et Marie Curie, Paris VI – AP-HP, hôpital St Antoine – Inserm UMR-S707 2 Medical Research Council, The Gambia Unit, Banjul, The Gambia .

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HCV in HIV patients, Cure and Beyond

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  1. HCV in HIV patients,Cure and Beyond K. Lacombe1, M. Lemoine2, G. Raguin3, A. Fontanet4, F. Zoulim5 1Université Pierre et Marie Curie, Paris VI – AP-HP, hôpital St Antoine – Inserm UMR-S707 2Medical Research Council, The Gambia Unit, Banjul, The Gambia. 3GIP ESTHER, Paris – France 4Pasteur Institute, Paris - France 5Université Lyon 2 - HCL, hôpital de la Croix Rousse - Inserm U1052, Lyon - France

  2. HIV AND HCV:AN INTRICATE HISTORY 1

  3. Evidence fromdatabasesfrom the bench and from the bedside Deleterious and synergicticeffect of HIV and HCV 2

  4. 4-5 M co-infected patients, depending on location and routes of transmission 1UNAIDS Global Report 2012. 2Hanafiah, Hepatology 2012. 3Perz, J Hepatol 2006 4

  5. Decreasingprevalence in Western countries Ex: Cohorts of the Spanish AIDS Research Network1,2 • Success of harmreduction (opiate substitution, needle exchange) • Decrease in the HIV prevalence > HCV prevalence in IVDUs 1Perez Cachafeiro, Clin Infect Dis 2012. 2Serrano-Villar, CROI 2013 5

  6. Alarmingincrease of HCV and HIV prevalence in Eastern Europe Trends in HIV and HCV amonginjectingdrugusers in Eastern Europe , 2005 - 2010 HCV prevalence Euro Surveill. 2011;16(48):pii=20031. 6

  7. Africa and Asia, the hidden epidemics1,2 • Dakar area – UDSEN study3 • est.sizeIVDUs: 1324 • P(HIV): 5,2% • P (HCV): 23,3% 1Madhava V. Lancet 2002. 2Nelson P, Lancet 2011. 3Ba I, ICASA 2012 7

  8. Evidence fromdatabasesfrom the bench and from the bedside Deleterious and synergicticseffect of HIV and HCV 2

  9. Enhancedfibrosis progression • Hepaticstellatecellsinfected by HIV through CCR5 receptorsleading to the promotion of myofibroblasticdifferenciation and ultimatelyacceleratingfibrosing process1 • Activation of reactiveoxygenspecies by HCV and HIV in HSC  triggers a cascade of proteinesactivationincreased expression of profibrogenicgenes and decreased expression of antifibrogenic genes2 • Increasedapoptosis of HCV-infectedhepatocytesthrough HIV-mediated TRAIL (TNF RelatedApoptosisInducing Ligand) upregulation3 1Tuyama AC, Hepatology 2010. 2 Lin W, J Infect Dis 2013. 3Babu CK, PlosOne 2009. 9

  10. Influence of impaired CD4+ T-cells on NK cell anti-fibroticactivity1 • NK-cell anti fibroticactivitymediated by Il-2 upregulated by CD4-T cells • HIV-HCV infection  impairedsecretion of Il2 due to CD4-T celldysfunction •  results in impaired NK cell anti-fibroticactivity 1Glässner, J Hepatol 2013 10

  11. Evidence fromdatabasesfrom the benchfrom the bedside Deleterious and synergicticseffect of HIV and HCV 2

  12. Liver-relateddeath: top 4 in the causes of death in HIV patients1 1Weber R. 19th IAC, Washington, USA, 2012. Abst THAB03104 12

  13. Liver-relateddeath: 1st cause of death in HIV-HCV patients1 43 % 12 % 8 % 5 % 4 % 4 % 4 % 2 % 6 % 7 % Decompensatedcirrhosis HCC Post-transplantation Cirrhotic Patients: > 50% deathsrelated to HCV Non cirrhotic patients : 60% deaths non related to HCV nor HIV 1HSogni P. Conference on French HIV-HCV Consensus Guidelines, 2012 13

  14. Overall, ESLD and deathremainhigher in HIV-HCV patientsIncART era1 Cum. I X 1,5 1Lo Re V, WEAB0102, IAC 2012, Washington DC - USA 14

  15. HCV INFECTION: A CURABLE DISEASE 15

  16. ? 95-100% SVR IFN = Interferon-α PEG-INF = Peg-Interferon-α RBV = Ribavirin W = weeks PEG = PEG-IFN-α 2014 90 2011 80 70 60 2002 50 % of patients with sustained virological response (SVR) 40 30 1999 20 10 PEG-IFN +RBV +new PI Telaprevir OrBoceprevir INF-freeregimens 12 weeks 0 IFN 24 W IFN 48 W IFN +RBV 24 W IFN +RBV 48 W PEG-IFN +RBV 48 W 16

  17. Evidence for cure arguments fromvirologyarguments fromimmunology arguments fromgenetics arguments fromtherapeutics 17

  18. Absence of virus integration in humangenome Host cell Host cell Host cell HCV RNA HCV HBV HIV Nucleus Nucleus Nucleus proviral DNA cccDNA Host DNA Long termreduction of viral replication Life long suppression of viral replication Definitive viral suppression = possible SVR 1Thomas XV. PlosOne 2012. 18

  19. No persistance of mutations in the viral genome • Extendedfollow-up of G1 HCV mono-infected patients included in telaprevir phase II trials1 • Absence of detectable mutations in 89% of patients whohadfailedafter a median 25 months of f/u fromtreatment discontinuation •  HCV is not HIV: no archived mutations 1Zeuzem S, AASLD 2010. Abst 227. 19

  20. Evidence for cure arguments fromvirology arguments fromimmunology arguments fromgeneticsarguments fromtherapeuticfield 17

  21. cARTmay restore an anti-HCV T-cell response1 T cell ELISpot responses to hepatitis C virus (HCV) core peptides before and on successful combination antiretroviral therapy   Argument for early introduction of cART ? 1Rohrbach J. Gut 2010 21

  22. Il28B polymorphism, a geneticdeterminant of treatment response1 1Thompson AJ, Gastroenterol 2012. 2Lawitz E, EASL 2013 22

  23. Evidence for cure arguments fromvirologyarguments fromimmunology arguments fromgeneticsarguments fromtherapeuticfield 17

  24. A viral genome with multiple therapeutic targets Bartenschlager, Nature Rev 2013 24

  25. New drugs in HIV patients: efficient in naive / relapsers… SVR12 withsimeprevir (TMC435)3 SVR12 with telaprevir1 2nd generation NS3/4 inhibitors EVR withfaldaprevir (BI201335)3 SVR12 with boceprevir2 1st generation NS3/4 inhibitors 25 1Sulkowski M. Ann Intern Med 2013. 2Sulkowski, AASLD2012. 3Dieterich D. CROI 2013. 4Dieterich D. CROI 2013

  26. New drugs in HIV patients: … and also in partial / nullresponders EVR in pretreated patients (TELAPREVIH)1 EVR in pretreated patients (BOCEPREVIH)2 88% response rate at W16 (EVR) 63% response rate at W16 (EVR) 1Cotte L. CROI 2013. 2Poizot-Martin I. CROI 2013. 26

  27. New drugs in HIV patients: … albeitmildlytolerated RASH 34% w/ TVR, none w/ BOC ANEMIA 41% w/BOC, 18% w/ TVR Severe (> 50% BSA) Mild (≤ 25% BSA) Moderate (25% to 50% BSA)  Use of RBV decreasebefore EPO AdaptedfromClinicalCareOptions 27

  28. Present and future trials in HIV patients1 1Clinicaltrials.gov: last accessed 22/06/2013 28

  29. Encouragingresultswith new compounds • New viral targets: other viral proteinstargeted in the HCV replication cycle: • NS4B (thatcanbeinhibited by silibilin) • p7 • Host-cellfactors • CYPA inhibitors (alisporivir) • miR-122 (miravirsen) • Monoclonal antibodies (undirect antiviral properties): SIMTUZUMAB (GS-6624), BAVITUXIMAB 29

  30. Cure, but what stands beyond ? FUTURE CHALLENGES 30

  31. Avoiding new infectionsOpimizingtreatmentstrategiesOvercomingbarriers to care 31

  32. Acute hepatitis C in MSM: how to curb the epidemics? 1 Eurosida for Eurocoord PREVENTION (STI+++) Information ++ To reduce rate of re-infection2 SCREENING +++ Define best screening algorithm3,4 TREATMENT Define best treatment strategy5,6 1Rockstroh, JIAS 2012. 2MartinT, IAS 2013. 3Thomson, AIDS 2009. 4Linas, ClinInfect Dis 2012. 5Boesecke C, CROI 2012. 6Fierer, CROI 2013. 4Boesecke, AASLD 2012 32

  33. Hepatitis C and IV drug use: increasingeffectiveness of harmreduction programs Whoshouldbetreated ?1: « breaking the taboosisrequired in the fightagainsthepatitis C among PWID »2 • Cost-effectivenessstudy : • - In IVDUs population with 20 – 40% HCV prevalence : more cost-effective to treatIVDUs • - in IVDUs population withat least 60% HCV prevalence : more cost-effective to treat ex / no IVDUsbecause of high rate of re-infections in IVDUs • Emphasis on harmreduction programmes in populations withhigh HCV prevalence and treatment to beconsideredat a patient land not mass level 1Martin, Hepatology 2012. 2Brugmann, Hepatology 2012 33

  34. Hepatitis C and nosocomial transmission, a persistant risk factor in RLS In Egypt, HCV transmission associatedwithmedical procedures1 1Kandell AM. BMC Infect Dis, 2012 34

  35. Treatment as prevention concept in HCV 1 1Durier N. Plos One 2012 35

  36. The vaccine issue • Immunization = mostcost-effective way of prevention of transmitteddiseases • HCV vaccine research > 20 years but no vaccine availableyet • lack of animal models • ability of HCV to escape host immunity • geneticvariability of host defenses • Severalongoing trials with vaccine candidates for the prevention of HCV infection1 1Fauvelle C, MicrobiolPathogenesis 2013 36

  37. Avoiding new infectionsOpimizingtreatmentstrategiesOvercomingbarriers to care 31

  38. Course of treatment: with or without IFN? • Drawbacks of IFN-basedregimen: tolerability and suboptimalresponse in patients w/priorfailurewith IFN • Challenges: combiningdrugswithdifferenttargets of action = highestpotency / barrier to resistance and best safety profile1 • Remaining questions: efficacy in cirrhotics, priornullresponders, difficult to treatgenotypes (G3) ?2 • HIV patients: - PHOTON study (SOF + RBV in G1) - Abbott M12-240 (antipolymerase + PI + anti- NS5A + RTV), end of 2013 1Liang TJ, NEJM 2013. 2Dusheiko J, Lancet 2013. 38

  39. Drug-drug interactions withARVs 39

  40. Cost-effectiveness: whoshouldbetreated and how and when? • Cost-effectivenessstudyperformed in France1 • F0-F1  delayingtreatmentuntil F2 (1000-1200€ / QALY gained / patients • F2  delayingtreatmentuntil F3 or arrival of DAAs • Sensitivity: in F2 patients, mightreconsider if latearrival of DAAs, lower SVR withDAAswhentreatedat F3, alcohol abuse 1Deuffic-Durban S, EASL 2013 40

  41. Is liver monitoring indicated in SVR patients ? Liverrelateddeaths Overall deaths Non liver- non AIDS- relateddeaths Non liver- relateddeaths  Clearbenefit of SVR 1Berenguer J, Clin Infect Dis 2012 41

  42. Is liver monitoring indicated in SVR patients ?  But risk of HCC stillpresent: regularliverassessment +++ 1Aleman. Clin Infect Dis 2013 42

  43. ESLD: facilitateaccess to liver transplantation Patients survival post trplststratified by HIV status1 • Differences in patients survivalonly due to presence of HIV • in patients with HIV, riskfactors for death = olderage of donor, HCV+ graft, low BMI, kidneytrsplt • if none of thosefactors: equalsurvival 1Terrault N, Am J Transplant. 2012 43

  44. Avoiding new infectionsOpimizingtreatmentstrategiesOvercomingbarriers to care 31

  45. Multiple barriersat multiple steps of the continuum of care Adaptedfrom G. Matthews 45

  46. Overcoming patients and providers barriers • Treatmentefficacyisidenticalwether patients are comingfrom a middle or lowincome country2 • Intrication of individual and social factors (stigma, discrimination, housingproblems, geographicalaccess, criminalisation, compartmentalized nature of health care systems1 1Ford N, Bull World HealthOrgan 2012. 2Harris M, Harmreduction 2013. 46

  47. Overcoming providers barriers Rapid Testing1 - Point-of-care tests - Salivary rapid testing • Easier assessment of the infection • and the liver disease2 • Dry-blood spots (HCV viral load • quantification/genotyping) • - Portable Fibroscan (Echosens) • - Portable sonography • Mostlyunavailable in RLS • = advocacy a priority 47 1Yaari A, J Viral Methods 2006. 2Tuaillon E, Hepatology 2010

  48. Overcoming the costsbarrier  History of HIV http://www.medicinespatentpool.org 48

  49. Costs in RLS: lessonsfrom HIV/AIDS experience • In 2000: ART: $10,000-15,000/patient/year • Today < $100/year • In 2000, only0.1% received ARV in Africa • Today, almost 68% ofwomenand 47% ofmen in needs in low/midlleincome countries 49

  50. Treatment for All isansweringtothecivilsociety‘sdemand International conference on HIV/AIDS, Washington 2012 50

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