HCV in HIV patients, Cure and Beyond K. Lacombe1, M. Lemoine2, G. Raguin3, A. Fontanet4, F. Zoulim5 Mister chairmen, dear colleagues and friends, it is a great honor for me to deliver the last plenary lecture of this IAS conference on the topic of hepatitis C in HIV patients. Clinicians, patients and stakeholders are facing one of the major shifts in the paradigm of HCV care and management with the advent of very potent anti HCV drugs, that makes HCV cure a reachable goal at a mass level. However, numerous issues are liying between cure and us, and this talk will address those challenges and try to provide some answers through the eye of latest published data on the subject.  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

HIV AND HCV: AN INTRICATE HISTORY HIV and hepatitis C share an intricate history from an epidemiological point of view, but also from a pathogenesis perspective  1

Evidence from databases from the bench and from the bedside Deleterious and synergictic effect of HIV and HCV Evidence from databases from the bench and from the bedside Both viruses share the same routes of transmission through blood exchange, mainly by means of IV drug use and unsafe medical procedures. 2

4-5 M co-infected patients, depending on location HIV1 HCV2,3 Prevalence 34M 0,8% 185M 2,35% Incidence 2,5M 4M Mortality 1,7M 350 000 This translates in about 4 to 5 millions of co-infected patients. Depending on geographical origin and routes of transmission,10 to 90% of HIV patients have encountered hepatitis C virus. However, global prevalence data hide very disparate figures. 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

Decreasing prevalence in Western countries Ex: Cohorts of the Spanish AIDS Research Network1,2 Indeed, in western countries such as Spain, harm reduction programmes based on needle exchange and opiate substitution have been successfully implemented for years. The decrease in the number of active IV drug users has been accompanied by a decrease in the number of new HIC-HCV co-infected patients, particularly driven by the decrease in HIV prevalence in IVDUs. Success of harm reduction (opiate substitution, needle exchange) Decrease in the HIV prevalence > HCV prevalence in IVDUs 1Perez Cachafeiro, Clin Infect Dis 2012. 2Serrano-Villar, CROI 2013 5

Alarming increase of HCV and HIV prevalence in Eastern Europe Trends in HIV and HCV among injecting drug users in Eastern Europe , 2005 - 2010 This is in total contrast with what is currently evidenced in regions like Eastern Europe where the HCV and HIV epidemics are thriving, mostly fuelled by unsafe injection practices. The graph on the right reports indeed the increasing trends in newly acquired HCV infections in young IVDUs between 2005 and 2010 HCV prevalence Euro Surveill. 2011;16(48):pii=20031. 6

Africa and Asia, the hidden epidemics1,2 Dakar area – UDSEN study3 est.size IVDUs: 1324 P(HIV): 5,2% P (HCV): 23,3% In Asia and Africa, HCV infection has emerged as a hidden epidemics and starts to be evidenced in difficult to reach communities such as those of IV drug users. As an example, a recent survey conducted in Dakar has estimated the size of the IVDUs around 1324 persons, of which 23.3% are infected with HCV. In Asia, chronic hepatitis C prevalence has been evaluated to be over 60% in main countries from central to South-Eastern Asia, here again driven by IV drug use. 1Madhava V. Lancet 2002. 2Nelson P, Lancet 2011. 3Ba I, ICASA 2012 7

Evidence from databases from the bench and from the bedside Deleterious and synergictics effect of HIV and HCV Evidence from databases from the bench and from the bedside 2

Enhanced fibrosis progression Hepatic stellate cells infected by HIV through CCR5 receptors leading to the promotion of myofibroblastic differenciation and ultimately accelerating fibrosing process1 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 genes2 Fibrosis progression is the result of several complex cellular and cytokines dysregulation.  Tuyama and colleagues have nicely demonstrated in 2010 that hepatic stellate cells can be infected by HIV through CCR5 receptors, leading to the promotion of myrofibroblastic differenciation, ultimately accelerating the fibrosis process.  3 years later, Lin has reported the role of the production of reactive oxygen species, again by both HCV and HIV, in HSC and hepatocytes, resulting in a cascade of proteines activation that translates into the increased expression of profibrogenic genes and decreased expression of antifibronegic genes.  Finally a third mechanism of enhanced hepatocytes apoptosis has been demonstrated by Babu, through the TRAIL upregulation caused by HIV. Indeed, HIV renders cells more susceptible to liver injury when infected by HCV, by inducing a signalling cascade leading to hepatocytes apoptosis.  Increased apoptosis of HCV-infected hepatocytes through HIV-mediated TRAIL (TNF Related Apoptosis Inducing Ligand) upregulation3 1Tuyama AC, Hepatology 2010. 2 Lin W, J Infect Dis 2013. 3Babu CK, PlosOne 2009. 9

Influence of impaired CD4+ T-cells on NK cell anti-fibrotic activity 1 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 There is also an immunological pathway recently investigated by Glassner and colleagues, who demonstrated that in HIV infected patients,  the well known impaired functioning of CD4+ T cells is associated with a lack of Natural Killer cell anti-fibrotic activity, reflected by the decrease in the expression of Interleukin 2.  This lack of healthy NK cells may contribute to accelerated liver fibrosis progression in HIV/HCV patients. 1Glässner, J Hepatol 2013 10

Evidence from databases from the bench from the bedside Deleterious and synergictics effect of HIV and HCV Evidence from databases from the bench from the bedside 2

Liver-related death: top 4 in the causes of death in HIV patients1 Thanks to an increasing quality in the management of chronic hepatitis, liver-related death has recently fallen from the 3rd to  the 4th place in the causes of death in HIV infected patients. 1Weber R. 19th IAC, Washington, USA, 2012. Abst THAB03104 12

Liver-related death: 1st cause of death in HIV-HCV patients1 Decompensated cirrhosis HCC Post-transplantation 43 % 12 % 8 % 5 % 4 % 2 % 6 % 7 % However, in HIV-HCV patients, liver related death remains the 1st cause of death,  led by decompensated cirrhosis. Cirrhotic Patients: > 50% deaths related to HCV Non cirrhotic patients : 60% deaths non related to HCV nor HIV 1HSogni P. Conference on French HIV-HCV Consensus Guidelines, 2012 13

Overall, ESLD and death remain higher in HIV-HCV patientsIn cART era1 Cum. I X 1,5 And when compared to HCV mono-infected patients, the cumulative risk of hepatic decompensation and death remains significantly higher  with a 1.5-fold increase in co-infected patients, as shown in this large cohort study from the US. 1Lo Re V, WEAB0102, IAC 2012, Washington DC - USA 14

HCV INFECTION: A CURABLE DISEASE Those data provided from the bench, databases and bedside all converge towards the evidence that cure should be the ultimate goal of HCV management. We are fortunately entering an era where this goal is definitely reachable. 15

% of patients with sustained virological response (SVR) IFN 24 W 70 50 30 20 10 60 40 48 W +RBV PEG-IFN 80 90 IFN = Interferon-α PEG-INF = Peg-Interferon-α RBV = Ribavirin W = weeks PEG = PEG-IFN-α 2002 2011 1999 2014 INF-free regimens 12 weeks ? 95-100% SVR PEG-IFN +RBV +new PI Telaprevir Or Boceprevir Indeed, the efficacy of Hep C treatment has greatly improved over the last decade. From 1992 to 2010, a sustained virological response was obtained with PegINF and RBV in around 50 to 60% of HCV infected patients, but only in a mere 40% of co-infected patients.  Since 2011, SVR has stared to increase  and with the advent of new direct antiviral agents, cure may be obtained in most patients. 16 16

Evidence for cure. arguments from virology. arguments from immunology Evidence for cure arguments from virology arguments from immunology arguments from genetics arguments from therapeutics But let us detail why cure must be an evidence, first from a virology perspective. 17

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 Definitive viral suppression = possible SVR HBV HIV HCV Unlike HBV and HIV, where viral genome is integrated either in the nucleus for HBV (as cccDNA) or directly in the host DNA (as proviral DNA), HCV RNA is not integrated in the host cell, thus explaining why aiming at a definitive viral suppression is perfectly feasible if potent antiviral drugs are used. 1Thomas XV. PlosOne 2012. 18

No persistance of mutations in the viral genome Extended follow-up of G1 HCV mono-infected patients included in telaprevir phase II trials1 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 A 2nd evidence supporting the fact that there is no integration of HCV and thus cure is reachable, is that there is no archiving of resistant viral strains. Indeed, in the extended follow-up of G1 mono-infected patients treated with telaprevir phase II trials, no mutation conferring resistance to anti-HCV proteas inhibitors has been detected after a mean 25 months of follow-up in 89% of patients having experienced virological failure. And this is obviously different from we know in HIV where the integration of HIV DNA in the host genome results in the accumulation of resistance over time in patients failing therapy. 1Zeuzem S, AASLD 2010. Abst 227. 19

Evidence for cure. arguments from virology. arguments from immunology Evidence for cure arguments from virology arguments from immunology arguments from genetics arguments from therapeutic field But let us detail why cure must be an evidence, first from a virology perspective. 17

cART may 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 ? For example, treating patients with potent ARV regimens leads to the restoration of of anti-HCV T-Cell immune response, as demonstrated in this work by Rohrbach and colleagues, where a significant increase in the proportion of individuals with detectable ELISpot responses to HCV core peptides was seen during successful cART. This means that treating HIV has a direct impact on HCV –associated disease, and this is a indirect argument to start HIV treatment early in the co-infected patients. 1Rohrbach J. Gut 2010 21

Il28B polymorphism, a genetic determinant of treatment response1 SVR Peg-IFN – RBV1 NS3-4A + PR2 New DAA (SOF)3 CC 69% 90% - TVR 82% - BOC 98% CT - TT 33% – 27% 71% - 73% TVR 71% - 69% BOC 88% Of course, we cannot address the question of genetic determinants of anti HCV response without mentioning the role of Il28B genotype in the response to interferon-based therapy. Sustained virological response to PegIFN has been clearly associated with the CC allele of Il28B gene, 69% of SVR in CC patients wersus less than 30 in CT and TT patients. This trends persists with protase inhibitors and even with newer drugs such as sofosbuvir, although less obvious because the overall response rate is so high with the new molecules. 1Thompson AJ, Gastroenterol 2012. 2Lawitz E, EASL 2013 22

Evidence for cure. arguments from virology. arguments from immunology Evidence for cure arguments from virology arguments from immunology arguments from genetics arguments from therapeutic field But let us detail why cure must be an evidence, first from a virology perspective. 17

A viral genome with multiple therapeutic targets Bartenschlager, Nature Rev 2013 Multiple steps along the viral replication cycle have been identified as potential targets for antiviral drugs.  Boceprevir and telaprevir are the 1st marketed drugs and ihnibit the NS3-NS4A protease of the viral genome.  Other molecules are targeting other steps such as the replicase NS5A (daclatasvir)  or the NS5B enzyme involved in viral RNA synthesis, itself devided in nucleoside analogs (such as deleobuvir) ou non nucleoside analogs (such mericitabine). 24

New drugs in HIV patients: efficient in naive / relapsers… 2nd generation NS3/4 inhibitors SVR12 with simeprevir (TMC435)3 EVR with faldaprevir (BI201335)3 SVR12 with telaprevir1 SVR12 with boceprevir2 1st generation protease inhibitors have been evaluated in HIV patients naive of HCV trearment with a increased success rate of 30% compared to peg-IFN ribavine based-therapy.  Results of trials with 2nd generation protease inhibitors are also very encouraging in naive patients and relapsers, with 80% of SVR with simeprevir and almost 90% of early virological response with faldaprevir. 1st generation NS3/4 inhibitors 25 1Sulkowski M. Ann Intern Med 2013. 2Sulkowski, AASLD2012. 3Dieterich D. CROI 2013. 4Dieterich D. CROI 2013

EVR in pretreated patients EVR in pretreated patients New drugs in HIV patients: … and also in partial / null responders EVR in pretreated patients (TELAPREVIH)1 EVR in pretreated patients (BOCEPREVIH)2 In pretreated patients including those with a prior null response to peg-Riba, encouraging early results have also being obtained with 1st generation protease inhibitors in those two ANRS trials, with an early virological response up to 88% with telaprevir and 63% with boceprevir. We now need to wait until the end of treatment and see if this is maintained 12 weeks after treatment interruption. 88% response rate at W16 (EVR) 63% response rate at W16 (EVR) 1Cotte L. CROI 2013. 2Poizot-Martin I. CROI 2013. 26

New drugs in HIV patients: … albeit mildly tolerated RASH 34% w/ TVR, none w/ BOC ANEMIA 41% w/BOC, 18% w/ TVR However, tolerance is a main challenge with these new drugs, especially telaprevir and boceprevir, with a fairly high risk of rash and anemia: 34% risk of rash with telaprevir, 48% risk of anemia with boceprevir, notwistanding the fact that they are quite difficult to take because of food constraints and high pill burden. Severe (> 50% BSA) Mild (≤ 25% BSA) Moderate (25% to 50% BSA)  Use of RBV decrease before EPO Adapted from ClinicalCareOptions 27

Present and future trials in HIV patients1 GENO DRUG DURATION NCT01667731 G1, G2, G3 SOF + RBV 12 – 24 Ws NCT01565889 G1 SOF + PEG + RBV 12 NCT01471574 Dacla + PEG + RBV 24 NCT01878799 SOF + GS8558 NCT01725542 G1, G4 Dacla + asuna + PEG + RBV Fortunately, aside from simeprevir and faldaprevir, several new drugs with shorter duration of administration are currenttly being tested in HIV patients, such as sofosbuvir, daclatasvir, asuaprevir, ledipasvir, I have listed ome of the trials here. 1Clinicaltrials.gov: last accessed 22/06/2013 28

Encouraging results with new compounds New viral targets: other viral proteins targeted in the HCV replication cycle: NS4B (that can be inhibited by silibilin) p7 Host-cell factors CYPA inhibitors (alisporivir) miR-122 (miravirsen) Monoclonal antibodies (undirect antiviral properties): SIMTUZUMAB (GS-6624), BAVITUXIMAB Further away in the HCV replication cycle, new viral targets are being studies such as anti NS4B and molecules that target the P7 protein. New inhibiting pathways involving host-cell factors are also being explored and are very promising, such as cyclophilin inhibitor and miR 122, and monoclonal antibodies such as simtuzumab or bavituximab. 29

FUTURE CHALLENGES Cure, but what stands beyond ? 30 As you have seen in the previous slides, cure is definitely at the corner of the street. However, many challenges are still laying in front of us. 30

Avoiding new infections Opimizing treatment strategies Overcoming barriers to care The first challenge we have to tackle with is how avoiding new infections. 31

Acute hepatitis C in MSM: how to curb the epidemics? 1 Eurosida for Eurocoord From 2004 and later, an epidemics of acute HCV infection has been identified in HIV infected men who have sex with men in the Western countries, translating into a regular increase of the number of cases over time in the Eurosida cohort. Acute HCV should be considered as an STI in MSM and should be cared of as such. This implies  the implementation of prevention strategies, particularly to reduce the rate of infection(see pres. Thomas Martin yesterday),  the definition of screening strategies (and somes papers listed here have tried to define the best screening strategies, based on regular screening and transaminases and HCV-RNA),  and the choice of the best treatment strategy, either bi or tri-therapy but in any case at an early stage of acute infection 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, Clin Infect Dis 2012. 5Boesecke C, CROI 2012. 6Fierer, CROI 2013. 4Boesecke, AASLD 2012 32

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 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 The second population at risk of acquiring HCV is the group of drug users. The role of HCV treatment as a mean for preventing HCV infection is being extensively debatted and as quoted from Brugmann: Breaking the taboos is required in the fight against hepatitis C among people using drugs ». A nice work published recently has shown that the choice of who to treat from a cost effective point of view is linked to the HCV prevalence within the group. For example, with a 20% or 40% prevalence, active IDUs should be treated, whereas in a 60% pevalence context, only ex or non IDUs should be treated because of high rates of re-infections in active IVDUs. Emphasis should therefore be put on harm reduction programmes for IDUs and treatment considered at the patient level and not mass level. Emphasis on harm reduction programmes in populations with high HCV prevalence and treatment to be considered at a patient land not mass level 1Martin, Hepatology 2012. 2Brugmann, Hepatology 2012 33

Hepatitis C and nosocomial transmission, a persistant risk factor in RLS In Egypt, HCV transmission associated with medical procedures1 Risk factors OR 95% CI Hospital exposure - IV - administred fluids 13,7 5,6 – 33,5 - hospital admission 7,8 4,3 – 14,3 - invasive procedure 4,7 2,8 – 7,9 Outpatient care -abcess drainage 33,4 4,2 – 267,9 - injections with re-used syringes 23,1 4,7 - 153 Avoiding new HCV infections is also tightly linked to the increase in the quality and effectiveness of universal rules for preventing nosocomial transmission, because nosocomial acquisition of HCV is still one of the predominant risk factors for HCV infection in resources limited settings. In this original work from Egypt, many factors associated with hospital exposure and outpatients care have been indeed linked with a higher risk of HCV infection. 1Kandell AM. BMC Infect Dis, 2012 34

Treatment as prevention concept in HCV 1 All this leads to the question of HCV treatment as a mean of preventing HCV transmission and modeling studies are starting to show that treating infected IVDUs may have an impact in the chronic HCV global prevalence. In this model built with data from Vietnam, it has been estimated that a realistic 25% of treatment coverage might decrease the prevalence of HCV from 60 to 45%. But if we try to tend to a 75% coverage, which is probably unrealistic given what we know fom the feasibility of HCV treatment at a mass level in western countries, the prevalence may further decrease to 30% 1Durier N. Plos One 2012 35

The vaccine issue 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 Finally, in the challenge of preventing HCV infection, vaccination has been explored but despite more than twenty years of research, there is still no HCV vaccine available. The lack of suitable small animal models to study HCV infection, together with both the ability of the virus to escape host immunity and genetic variability of host defenses, remain major challenges for vaccine development. Several trials with vaccine candidates are currently ongoing. Several ongoing trials with vaccine candidates for the prevention of HCV infection1 1Fauvelle C, Microbiol Pathogenesis 2013 36

Avoiding new infections Opimizing treatment strategies Overcoming barriers to care The first challenge we have to tackle with is how avoiding new infections. 31

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 profile1 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 A way of optimizing treatment would be to increase tolerance and rate of response without IFN. Drawbacks of IFN-based regimens are indeed its low tolerability and subtimal response in patients who previously failed IFN-based regimens. The challenge is to find the right drugs combination that targets different phases of HCV cycle and provide the highest potency (even in difficult to treatpatients such as genotype 3, prior null repsonders or cirrhotics) and genetic barrier along with the best safety profile. HIV patients are engaged in the race for IFN-free regimens through two trials, the PHOTON study driven by Gilead and a study with the 4-drugs regimen from Abbott 1Liang TJ, NEJM 2013. 2Dusheiko J, Lancet 2013. 38

Drug-drug interactions with ARVs TVR BOC New 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 Another challenge in optimizing the course of treatment at the present time is the management of drug drug interactions. Indeed, as shown in this table, associating antiretroviral drugs with boceprevir or telaprevir may be a bit tricky, but this may not be the case anymore in the near future because most drugs that are under development do not seem to exhibit strong drug drug interactions with ARVs. 39

Cost-effectiveness: who should be treated and how and when? Cost-effectiveness study performed in France1 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 Another question that emerges when adressing the issue of treatment optimization is one pertaining to who should be treated and when. In HCV mono-infected patients, it has been demonestrated in this cost-effectiveness study performed in France that the F2 fibrosis is the threshold at which treatment should be delayed until F3 or new DAA arrival. In the sensitivity analysis, treating F2 patients could be considered in case of late arrival of DAA or alcohol abuse, or if response rate for F3 patients is finnaly lower than expected. Such important data are urgently needed in HIV patients. 1Deuffic-Durban S, EASL 2013 40

Is liver monitoring indicated in SVR patients ? Overall deaths Liver related deaths Non liver- related deaths Non liver- non AIDS- related deaths Now, if we think that most patients will get cured of HCV, can we stop liver assessment and think that those patients have rejoined the HCV-negative population? We know from cohort studies that there is an obvious benefit to get cured from HCV, and this study led colleagues from Spain has clearly shown that there is a real decrease in the rates of overall death, liver and non liver-related deaths, as well as non liver non AIDS related deaths.  Clear benefit of SVR 1Berenguer J, Clin Infect Dis 2012 41

Is liver monitoring indicated in SVR patients ? However, does that mean that patients are not at risk of liver problem anymore ? Not at all, espacially if they were cirrhotic, because the risk of HCC, although decreased, is not equal to zero. That means that patients should still be engaged in regular medical follow-up.  But risk of HCC still present: regular liver assessment +++ 1Aleman. Clin Infect Dis 2013 42

ESLD: facilitate access to liver transplantation Patients survival post trplst stratified by HIV status1 Finally, one of the last challenges is the management of end stage liver diseases in HIV patients, particularly regarding liver transplantation. Presently, there is a difference in post transplant survival between HIV neg and HIV pos patients that have been attributed to the older age of donor, HCV positivy of graft, low BMI and concomitant kidney transplantation. If none of this factor is present, then this recent work published by Terrault and colleagues ahev shown that survival is equal wether the patient is HIV infected or not, which is very reasuuring for the future. 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 1Terrault N, Am J Transplant. 2012 43

Avoiding new infections Opimizing treatment strategies Overcoming barriers to care The first challenge we have to tackle with is how avoiding new infections. 31

Multiple barriers at multiple steps of the continuum of care Those barriers are multiple, including poor screening, poor liver assessment, stigmatisation, patient and providers lack of knowledge and denial, andhigh cost of drugs. However, we have to date the means to overcome those barriers. Adapted from G. Matthews 45

Overcoming patients and providers barriers Treatment efficacy is identical wether patients are coming from a middle or low income country2 Intrication of individual and social factors (stigma, discrimination, housing problems, geographical access, criminalisation, compartmentalized nature of health care systems1 First I would like to remind you that, as Nathan Ford has clearly shown last year, treatment efficacy in mildle and low income countries is not questionable, so if patients are not cured it is because they do not get treatment. Not getting treatment is due to a complex intrication of individual, political and social factors such as stigman, disctrimination, housing problems, geographical access, criminalisation)… doesn’ it remind you of what we have lived with HIV ?... 1Ford N, Bull World Health Organ 2012. 2Harris M, Harm reduction 2013. 46

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 Some of the providers barriers could be easily overcome because we have innovative tools to screen for HCV such as reliable point of care tests, and to assess viral replication using dried blood spots and liver damage with portative elastometry and sonography devices. Mostly unavailable in RLS = advocacy a priority 47 1Yaari A, J Viral Methods 2006. 2Tuaillon E, Hepatology 2010

Overcoming the costs barrier 48 If access to care is a matter of costs,  we have the possibility through advocacy to negociate prices with the pharmaceutical industry,  or to push the industries to register their drugs as generic prices, for example through the Health Impact Fund.  On the other hand, with short course of interferon-free regimens, optimisation of chemical synthesis and cheaper sourcing of raw materials, the price of a full course of treatment may fall as low as 200 dollars per person.  History of HIV http://www.medicinespatentpool.org

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 We should indeed look back at the HIV experience which demonstrated that it is feasible to provude access to all at lower price. 49

Treatment for All is answering to the civil society‘s demand International conference on HIV/AIDS, Washington 2012 We shoudl indeed get quickly to the point  because we have no choice but to provide the right reply to the civil society demand 50

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.