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Www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 HCV in HIV patients, Cure and Beyond K. Lacombe 1, M. Lemoine 2, G. Raguin 3, A. Fontanet.

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Presentation on theme: "Www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 HCV in HIV patients, Cure and Beyond K. Lacombe 1, M. Lemoine 2, G. Raguin 3, A. Fontanet."— Presentation transcript:

1 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 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. 3 GIP ESTHER, Paris – France 4 Pasteur Institute, Paris - France 5 Université Lyon 2 - HCL, hôpital de la Croix Rousse - Inserm U1052, Lyon - France

2 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 HIV AND HCV: AN INTRICATE HISTORY 1

3 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Evidence from databases from the bench and from the bedside 2 Deleterious and synergictic effect of HIV and HCV

4 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 HIV 1 HCV 2,3 Prevalence34M 0,8% 185M 2,35% Incidence2,5M4M Mortality1,7M350 000 1 UNAIDS Global Report 2012. 2 Hanafiah, Hepatology 2012. 3 Perz, J Hepatol 2006 4-5 M co-infected patients, depending on location and routes of transmission 4

5 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Decreasing prevalence in Western countries Ex: Cohorts of the Spanish AIDS Research Network 1,2 1 Perez Cachafeiro, Clin Infect Dis 2012. 2 Serrano-Villar, CROI 2013 5  Success of harm reduction (opiate substitution, needle exchange)  Decrease in the HIV prevalence > HCV prevalence in IVDUs

6 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Alarming increase of HCV and HIV prevalence in Eastern Europe 6 Trends in HIV and HCV among injecting drug users in Eastern Europe, 2005 - 2010 Euro Surveill. 2011;16(48):pii=20031. HCV prevalence

7 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Africa and Asia, the hidden epidemics 1,2 1 Madhava V. Lancet 2002. 2 Nelson P, Lancet 2011. 3 Ba I, ICASA 2012 7 Dakar area – UDSEN study 3 -est.size IVDUs: 1324 - P(HIV): 5,2% - P (HCV): 23,3%

8 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Evidence from databases from the bench and from the bedside 2 Deleterious and synergictics effect of HIV and HCV

9 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Enhanced fibrosis progression  Hepatic stellate cells infected by HIV through CCR5 receptors leading to the promotion of myofibroblastic differenciation and ultimately accelerating fibrosing process 1  Activation of reactive oxygen species by HCV and HIV in HSC  triggers a cascade of proteinesactivation  increased expression of profibrogenic genes and decreased expression of antifibrogenic genes 2 1Tuyama AC, Hepatology 2010. 2 Lin W, J Infect Dis 2013. 3 Babu CK, PlosOne 2009.  Increased apoptosis of HCV-infected hepatocytes through HIV-mediated TRAIL (TNF Related Apoptosis Inducing Ligand) upregulation 3 9

10 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Influence of impaired CD4+ T-cells on NK cell anti-fibrotic activity 1 1 Glässner, J Hepatol 2013 10  NK-cell anti fibrotic activity mediated by Il-2 upregulated by CD4-T cells  HIV-HCV infection  impaired secretion of Il2 due to CD4-T cell dysfunction  results in impaired NK cell anti-fibrotic activity

11 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Evidence from databases from the bench from the bedside 2 Deleterious and synergictics effect of HIV and HCV

12 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Liver-related death: top 4 in the causes of death in HIV patients 1 1 Weber R. 19th IAC, Washington, USA, 2012. Abst THAB03104 12

13 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Liver-related death: 1st cause of death in HIV-HCV patients 1 43 % 12 % 8 % 5 % 4 % 2 % 6 % 7 % Decompensated cirrhosis HCC Post-transplantation Cirrhotic Patients: > 50% deaths related to HCV Non cirrhotic patients : 60% deaths non related to HCV nor HIV Cirrhotic Patients: > 50% deaths related to HCV Non cirrhotic patients : 60% deaths non related to HCV nor HIV 1 HSogni P. Conference on French HIV-HCV Consensus Guidelines, 2012 13

14 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Overall, ESLD and death remain higher in HIV-HCV patientsIn cART era 1 1 Lo Re V, WEAB0102, IAC 2012, Washington DC - USA 14 Cum. I X 1,5

15 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 HCV INFECTION: A CURABLE DISEASE 15

16 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 % of patients with sustained virological response (SVR) IFN 24 W 70 50 30 20 10 60 40 IFN 48 W IFN +RBV 24 W IFN +RBV 48 W PEG-IFN +RBV 48 W 0 80 90 IFN = Interferon-α PEG-INF = Peg-Interferon-α RBV = Ribavirin W = weeks PEG = PEG-IFN-α 2002 2011 1999 2014 PEG-IFN +RBV +new PI Telaprevir Or Boceprevir INF-free regimens 12 weeks ? 95-100% SVR 16

17 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Evidence for cure arguments from virology arguments from immunology arguments from genetics arguments from therapeutics 17

18 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Absence of virus integration in human genome Host cell Nucleus cccDNA Host DNA proviral DNA HCV RNA Long term reduction of viral replication Life long suppression of viral replication Definitive viral suppression = possible SVR HBVHIV HCV 1 Thomas XV. PlosOne 2012. 18

19 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 No persistance of mutations in the viral genome  Extended follow-up of G1 HCV mono-infected patients included in telaprevir phase II trials 1  Absence of detectable mutations in 89% of patients who had failed after a median 25 months of f/u from treatment discontinuation  HCV is not HIV: no archived mutations 1 Zeuzem S, AASLD 2010. Abst 227. 19

20 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Evidence for cure arguments from virology arguments from immunology arguments from genetics arguments from therapeutic field 17

21 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 cART may restore an anti-HCV T-cell response 1  T cell ELISpot responses to hepatitis C virus (HCV) core peptides before and on successful combination antiretroviral therapy  1 Rohrbach J. Gut 2010 21  Argument for early introduction of cART ?

22 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Il28B polymorphism, a genetic determinant of treatment response 1 1 Thompson AJ, Gastroenterol 2012. 2 Lawitz E, EASL 2013 SVR Peg-IFN – RBV 1 SVR NS3-4A + PR 2 SVR New DAA (SOF) 3 CC69%90% - TVR 82% - BOC 98% CT - TT33% – 27%71% - 73% TVR 71% - 69% BOC 88% 22

23 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Evidence for cure arguments from virology arguments from immunology arguments from genetics arguments from therapeutic field 17

24 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 A viral genome with multiple therapeutic targets Bartenschlager, Nature Rev 2013 24

25 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 New drugs in HIV patients: efficient in naive / relapsers… SVR12 with telaprevir 1 SVR12 with boceprevir 2 1st generation NS3/4 inhibitors 2nd generation NS3/4 inhibitors SVR12 with simeprevir (TMC435) 3 EVR with faldaprevir (BI201335) 3 1 Sulkowski M. Ann Intern Med 2013. 2 Sulkowski, AASLD2012. 3 Dieterich D. CROI 2013. 4 Dieterich D. CROI 2013 25

26 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 New drugs in HIV patients: … and also in partial / null responders EVR in pretreated patients (TELAPREVIH) 1 1 Cotte L. CROI 2013. 2 Poizot-Martin I. CROI 2013. EVR in pretreated patients (BOCEPREVIH) 2 26 63% response rate at W16 (EVR) 88% response rate at W16 (EVR)

27 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 New drugs in HIV patients: … albeit mildly tolerated Adapted from ClinicalCareOptions RASH 34% w/ TVR, none w/ BOC ANEMIA 41% w/BOC, 18% w/ TVR Mild (≤ 25% BSA) Moderate (25% to 50% BSA) Severe (> 50% BSA)  Use of RBV decrease before EPO 27

28 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Present and future trials in HIV patients 1 1 Clinicaltrials.gov: last accessed 22/06/2013 GENODRUGDURATION NCT01667731G1, G2, G3SOF + RBV12 – 24 Ws NCT01565889G1SOF + PEG + RBV12 NCT01471574G1Dacla + PEG + RBV24 NCT01878799G1SOF + GS855812 NCT01725542G1, G4Dacla + asuna + PEG + RBV 24 28

29 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Encouraging results with new compounds  New viral targets: other viral proteins targeted in the HCV replication cycle: o NS4B (that can be inhibited by silibilin) o p7  Host-cell factors o CYPA inhibitors (alisporivir) o miR-122 (miravirsen) o Monoclonal antibodies (undirect antiviral properties): SIMTUZUMAB (GS-6624), BAVITUXIMAB 29

30 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 FUTURE CHALLENGES 30 Cure, but what stands beyond ?

31 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Avoiding new infections Opimizing treatment strategies Overcoming barriers to care 31

32 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Acute hepatitis C in MSM: how to curb the epidemics? 1 Rockstroh, JIAS 2012. 2 MartinT, IAS 2013. 3 Thomson, AIDS 2009. 4 Linas, Clin Infect Dis 2012. 5 Boesecke C, CROI 2012. 6 Fierer, CROI 2013. 4 Boesecke, AASLD 2012 1 Eurosida for Eurocoord 32 PREVENTION (STI+++) Information ++ To reduce rate of re-infection 2 SCREENING +++ Define best screening algorithm 3,4 TREATMENT Define best treatment strategy 5,6

33 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Hepatitis C and IV drug use: increasing effectiveness of harm reduction programs Who should be treated ? 1 : « breaking the taboos is required in the fight against hepatitis C among PWID » 2 1 Martin, Hepatology 2012. 2 Brugmann, Hepatology 2012 33  Cost-effectiveness study : - In IVDUs population with 20 – 40% HCV prevalence : more cost-effective to treat IVDUs - in IVDUs population with at least 60% HCV prevalence : more cost- effective to treat ex / no IVDUs because of high rate of re-infections in IVDUs  Emphasis on harm reduction programmes in populations with high HCV prevalence and treatment to be considered at a patient land not mass level

34 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Hepatitis C and nosocomial transmission, a persistant risk factor in RLS 1 Kandell AM. BMC Infect Dis, 2012 34 In Egypt, HCV transmission associated with medical procedures 1 Risk factorsOR95% CI Hospital exposure - IV - administred fluids 13,75,6 – 33,5 - hospital admission 7,84,3 – 14,3 - invasive procedure 4,72,8 – 7,9 Outpatient care -abcess drainage33,44,2 – 267,9 - injections with re-used syringes23,14,7 - 153

35 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Treatment as prevention concept in HCV 1 Durier N. Plos One 2012 1 35

36 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 The vaccine issue  Several ongoing trials with vaccine candidates for the prevention of HCV infection 1 1 Fauvelle C, Microbiol Pathogenesis 2013  Immunization = most cost-effective way of prevention of transmitted diseases  HCV vaccine research > 20 years but no vaccine available yet  lack of animal models  ability of HCV to escape host immunity  genetic variability of host defenses 36

37 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Avoiding new infections Opimizing treatment strategies Overcoming barriers to care 31

38 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Course of treatment: with or without IFN? Drawbacks of IFN-based regimen: tolerability and suboptimal response in patients w/prior failure with IFN Challenges: combining drugs with different targets of action = highest potency / barrier to resistance and best safety profile 1 Remaining questions: efficacy in cirrhotics, prior null responders, difficult to treat genotypes (G3) ? 2 HIV patients: - PHOTON study (SOF + RBV in G1) - Abbott M12-240 (antipolymerase + PI + anti- NS5A + RTV), end of 2013 1 Liang TJ, NEJM 2013. 2 Dusheiko J, Lancet 2013. 38

39 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Drug-drug interactions with ARVs TVRBOCNew DAAs NRTI All (except those contra-indicated with PR: AZT, DDI, D4T) ? NNRTI efavirenz+1pill x 3 /day Increased neuro effects of EFV ? rilpivirine? PI atazanavir? lopinavir? darunavir? fosamprenavir? AI raltegravir? 39

40 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Cost-effectiveness: who should be treated and how and when? Cost-effectiveness study performed in France 1 F0-F1  delaying treatment until F2 (1000-1200€ / QALY gained / patients F2  delaying treatment until F3 or arrival of DAAs Sensitivity: in F2 patients, might reconsider if late arrival of DAAs, lower SVR with DAAs when treated at F3, alcohol abuse 1 Deuffic-Durban S, EASL 2013 40

41 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Is liver monitoring indicated in SVR patients ? 1 Berenguer J, Clin Infect Dis 2012 Overall deaths Liver related deaths Non liver- related deaths Non liver- non AIDS- related deaths  Clear benefit of SVR 41

42 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Is liver monitoring indicated in SVR patients ?  But risk of HCC still present: regular liver assessment +++ 1 Aleman. Clin Infect Dis 2013 42

43 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 ESLD: facilitate access to liver transplantation Patients survival post trplst stratified by HIV status 1 1 Terrault N, Am J Transplant. 2012  Differences in patients survival only due to presence of HIV  in patients with HIV, risk factors for death = older age of donor, HCV+ graft, low BMI, kidney trsplt  if none of those factors: equal survival 43

44 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Avoiding new infections Opimizing treatment strategies Overcoming barriers to care 31

45 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Multiple barriers at multiple steps of the continuum of care Adapted from G. Matthews 45

46 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Overcoming patients and providers barriers Treatment efficacy is identical wether patients are coming from a middle or low income country 2 Intrication of individual and social factors (stigma, discrimination, housing problems, geographical access, criminalisation, compartmentalized nature of health care systems 1 1 Ford N, Bull World Health Organ 2012. 2 Harris M, Harm reduction 2013. 46

47 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Overcoming providers barriers Easier assessment of the infection and the liver disease 2 -Dry-blood spots (HCV viral load quantification/genotyping) - Portable Fibroscan (Echosens) - Portable sonography Rapid Testing 1 - Point-of-care tests - Salivary rapid testing 1 Yaari A, J Viral Methods 2006. 2 Tuaillon E, Hepatology 2010 47  Mostly unavailable in RLS = advocacy a priority

48 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Overcoming the costs barrier http://www.medicinespatentpool.org 48  History of HIV

49 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Costs in RLS: lessons from HIV/AIDS experience In 2000: ART: $10,000-15,000/patient/year Today < $100/year  In 2000, only 0.1% received ARV in Africa  Today, almost 68% of women and 47% of men in needs in low/midlle income countries 49

50 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Treatment for All is answering to the civil society‘s demand International conference on HIV/AIDS, Washington 2012 50

51 www.ias2013.org Kuala Lumpur, Malaysia, 30 June - 3 July 2013 ACKNOWLEDGMENTS Pierre-Marie Girard, Jürgen Rockstroh, Sanjay Baghani, Patrick Ingiliz, Alexandra Calmy, Christoph Boesecke, Nicolas Durier, Isabelle Andrieux-Meyer, Serge Eholié, Anders Boyd, Maria Winnock, Dominique Salmon, Philippe Sogni, Yasdan Yasdanpanah, Sylvie Deuffic-Burban, Ralph Chami, Bogdana Coudsy, Gail Matthews, Amir Guidoum, Niklas Luhmann, Audrey Coilly.


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