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HCV: Simplifying adapting diagnosis and therapy

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1 HCV: Simplifying adapting diagnosis and therapy
Dr. Isabelle Andrieux-Meyer MSF Access Campaign IAS Kuala Lumpur, Sunday 30th June .

2 Market opportunity How can we take advantage of the new diagnostics & treatment opportunities to create access to HCV diagnostics and treatment for people living in resource limited settings? MSF has performed an independent HCV landscape analysis to map current and future trends in disease burden, product development, and market evolution for diagnostics, and medicines used in HCV care.

3 HCV: Simplifying adapting diagnosis and therapy
Epidemiological data HCV diagnosis landscape HCV treatment landscape

4 Epidemiological burden of HIV/HCV coinfection
Worldwide between 150 and 170 million people live with hepatitis C infection. (WHO 2012) The majority of them are not aware of their infection. ( Lavanchy Liver Intl 2009) Between 4 and 5 million people living with HIV are currently co-infected with HCV .( Easterbrook Sem Liv Dis 2012) While HIV can be controlled by antiretroviral therapy, co-infected people die from HCV related complications, like liver cirrhosis or liver cancer.( Nelson Lancet 2011). Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS. ( Branch CID 2012) World Health Organisation, Fact sheet No.164,July Available at: Lavanchy D. The global burden of hepatitis C. Liver International,2009; 29:74-81). Easterbrook P, et al. Challenges and priorities in the management of HIV/HBV and HIV/HCV coinfection in resource-limited settings. Sem Liv Dis 2012:32(2): Nelson P, et al. Global epidemiology of viral hepatitis among people who inject drugs: results of global systematic reviews. Lancet 2011; 378: ).Branch AD, et al. Mortality in HCV-infected patients with a diagnosis of AIDS in the era of combination anti-retroviral therapy. Clin Inf dis 2012; 55: ).

5 New HCV /HIV epidemiological data. Center for Disease Analysis 2013 (1)
Center for Disease Analysis, unpublished data.  With permission.Center for Disease Analysis searched studies for HIV/HCV co-infection rate in the HIV population in each countries.  Studies were not available in all countries.  A regional co-infection average was developed for each World Bank region and applied to all countries in that region using each country’s HIV population as reported by Confidential information. With authors permission.

6 New HCV /HIV epidemiological data. Center for Disease Analysis 2013 (2)

7 HIV / AIDS TREATMENT PROGRAMMES
MSF currently provides HIV treatment to 250,000 people in 23 countries.

8 MSF Access Campaign

9 HCV: Simplifying adapting diagnosis and therapy
Epidemiological data HCV diagnosis landscape HCV treatment landscape

10 Access to HCV testing: game -changer
Globally, 59% of the world’s population has no access to hepatitis C diagnosis. These findings correlate with the wealth of the country: Dx using serology is available in 53% of lower middle income countries, and 11% of low income countries ( WHA report 2010). MSF RDT (rapid diagnostic test) procurement: HCV Scan (EY laboratories) HCV Spot (MP Medicals) Average price 1-4 EUR per test. New line OraQuick  (Orasura, USA): Best and most up to date performance but 10-12x more expensive than other RDTs.( MSF HCV landscape analysis 2013) => Limited evidence on the accuracy of HCV RDS in HIV/HCV coinfection. ( Shivkumar Ann Intern Med 2012)( Smith J Itl Dis 2011) [i] Viral hepatitis: global policy. London: World Hepatitis Alliance; Available from: MSF HCV landscape analysis 2013 available at: . Shivkumar S, et al. Accuracy of rapid and point of care screening tests for hepatitis A: a systematic review and meta-analysis. Ann Intern Med 2012; 157: Smith BD, et al. Evaluation of three rapid screening assays for detection of antibodies to hepatitis C virus. J Infect Dis 2011; 204(6): ). 10

11 HCV confirmation test: Detection of HCV RNA
Anti-HCV antibodies indicate exposure to the virus, but cannot determine if infection is present or if the infection has cleared spontaneously. All persons with positive anti-HCV antibody test must undergo additional testing for the presence of the HCV itself to determine whether current infection is present and whether there is an indication for treatment HCV PCR is the most common method to detect viral RNA. It is also used to quantify the virus for treatment monitoring purpose. Usually: Abbott, Roche, Siemens quantitative VL. HCV PCR is hardly accessible and costs >=100 USD per test. We need affordable : POC HCV Viral load : pipeline Wave 80, Alere, Cepheid, IQuum, Daktari. Flexible PCR platforms ( Multitest: HBV-HIV-HCV) like Sacace generic open platform test, or Qiagen. ( MSF HCV landscape analysis)

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13 Genotyping & Fibrosis evaluation
The required length of peg-IFN-ribavirin treatment, the current standard of care, and the expected outcome from treatment, is dependent on the HCV genotype. Tests, using a range of different technologies: Abbott , Roche, Siemens tests Sacace: generic open platform test (real time PCR) Pipeline point-of-care test: Wave80 New oral drugs will allow for simplification , if we have access to pan-genotypic treatment then genotyping may not be needed Liver fibrosis can be assessed at field level using Transient elastography: Fibroscan®, or serum biomarkers like APRI.(Lin ZH. Hepatol 2011) Lin ZH, et AL. Performance of the aspartate aminotransferase-to-platelets ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatol 2011; 53:

14 HCV: Simplifying adapting diagnosis and therapy
Epidemiological data HCV diagnosis landscape HCV treatment landscape

15 PegIFN-Ribavirin Treatment Outcomes in LMICs very similar to high income settings
PegIFN, peginterferon; RBV, ribavirin; TVR, telaprevir. The lessons learned from the phase II telaprevir studies are shown on this slide. First, the optimal duration of telaprevir therapy was found to be 12 weeks, and it appeared that the optimal duration of the peginterferon and ribavirin backbone was 48 weeks. Second, ribavirin was found to be critically important to decrease breakthrough and relapse rates. Finally, activity was demonstrated in null responders, breakthrough patients, and relapsers. Ford et al , Bull WHO 2012 15

16 Sustained virological response (SVR) in patients co-infected with HCV and HIV by disease, patient and treatment covariates. Davies A, Singh KP, Shubber Z, duCros P, et al. (2013) Treatment Outcomes of Treatment-Naïve Hepatitis C Patients Co-Infected with HIV: A Systematic Review and Meta-Analysis of Observational Cohorts. PLoS ONE 8(2): e doi: /journal.pone HCV genotypes 1 or 4 (pooled SVR 24.5%) vs genotypes 2 or 3 (pooled SVR 59.8%) Davies A, et al. PLoS ONE 2013.

17 CHANGING HCV TREATMENT LANDSCAPE
Dore GJ Med J Aust, (10): Dore GJ Med J Aust, 2012. 17

18 Novel drugs against HCV: DAA, HTA and their combinations
DAA combinations R7128 + ITMN-191 DAA: Nuc- Polymerase inhibitors PSI PSI-938 Phase I IDX IDX-320 GS GS-9256 BI RG7348 BI BI Telaprevir + VX-222 Phase II MK-0608 HTA: Cyclophilin Inhibitors TMC SCY635 BMS BMS Phase III BMS PSI-7792 R7128 PSI-7977 DEBIO-025 (Novartis) Approved IDX-184 PF AZD07295 ABT-072 Boceprevir GS-9190 BMS Telaprevir ABT-333 ANA-598 BMS ABT TMC435 VX-222 BI201335 DAA: NS5A inhibitor MK5172 BI201127 BMS650032 MK7009 (vaniprevir) VX-985 ITMN-191/R7227 DAA: Non Nuc- Polymerase inhibitors ACH1625 ABT-450 BMS791325 IDX-320 DAA: Protease inhibitors DAA = direct-acting antiviral HTA = host-targeting antiviral; Nuc = nucleos(t)ide NOT EXHAUSTIVE

19 HCV pipeline drugs (1) Several pharmaceutical companies are in a position to develop their own FDC. We need phase III trial results to confirm the positive preliminary results: Gilead: SOFOSBUVIR based ( SOF-GS 5885-RBV) Sofosbuvir: FDA registration submitted April 10th 2013 for GT1 ( IFN sparing) and for GT2 and 3 all oral. Sofosbuvir-Ledipasvir: Plan to submit 2014 Abbott: ABT 450/r + ABT ABT RBV BMS: Daclatasvir- Asunaprevir based Boerhinger- Ingelheim: BI OD + BI /-RBV Janssen: Simeprevir

20 Sofosbuvir ( ex- GS 7677) Gilead. Nucleoside/nucleotide polymerase inhibitor. 400 mg once daily Phase III Potent, high genetic barrier to resistance Pan genotype: GT 1,2,3,4,5,6. Simple, good safety and tolerability profile: common adverse events: fatigue, headache, nausea, insomnia, dizziness, no need of food intake, no significant drug interaction, no rash, less anemia. Under study in HIV-HCV co-infected people. The initial indication in GT1,4,5,6 will be SOF + peg IFN/RBV for 12 to 24 weeks. In GT 2 and 3 : SOF with or without RBV.

21 Sofosbuvir in GT1 treatment naive
Study name Combination Outcomes ATOMIC 1 SOF+pIFN + RBV 12 or 24 weeks SVR 90% NEUTRINO 2 SOF + pIFN + RBV SVR 12: 89% ELECTRON 3 SOF+ Ledipasvir + RBV SVR 12 : 100% ( 34/34) ION-14 SOF+ Ledipasvir +/-RBV ongoing xxxxx5 SOF+ Daclatasvir +/-RBV SVR 100% ELECTRON6 SOF +RBV 12 weeks SVR4:88% QUANTUM7 12 vs 24 weeks 12 weeks: SVR: 59% (10/17) SPARE8 SOF +RBV (weight based or 600mg RBV) SVR12: 90% 1. [1]Kowdley K, Lawitz E, Crespo I, et al. GS 7977+Peg/RBV in HCV genotype1: The ATOMICTrial. An end to response-guided therapy? 47th Annual Meeting of the European Association for the Study of the Liver.April ; Barcelona, Spain. Available from: (accessed November ). [1] Gilead. Presse Relase. Gilead Announces Sustained Virologic Response Rates from Two Phase 3 Studies of Sofosbuvir for Hepatitis C . Published Feruary 19, Accessed February 19,2013. [1]Gane E et al. ELECTRON: 100% suppression of viral load through 4 weeks’ post-treatment for sofosbuvir + ledipasvir (GS-5885) + ribavirin for 12 weeks in treatment-naive and -experienced hepatitis C virus GT 1 patients.20th Conference on Retroviruses and Opportunistic Infections. DATE, 2013; Atlanta, USA (Abstract 41LB . [1]Press Release Gilead. Gilead Announces 100 Percent Sustained Virologic Response Rate (SVR4) for an Interferon-Free Regimen of Sofosbuvir (GS-7977), GS-5885 and Ribavirin in Treatment-Na ïve Genotype 1 Hepatitis C Infected Patients - Phase 3 Study with a Fixed-Dose Combination Tablet of Sofosbuvir and GS-5885 Now Underway - November 10, Available at: 5. [1]Sulkowski M, Gardiner D, Lawitz E, et al. Potent viral suppression with all-oral combination of daclastavir(NS5A inhibitor) and GS-7977 (NS5B inhibitor) , +/- ribavirin, in treatment-naïve patients with chronic HCV GT1,2 and 3 ( Abstract 1422). 47th Annual Meeting of the European Association for the Study of the Liver.April 18-22, 2012: Barcelona, Spain. Available from: _24858/program.aspx.(Accessed November12, 2012).6. Gane EJ, Stedman C, Anderson J, etal. 100% rapid virologicresponse for PSI-7977+ribavirin in genotype 1 nullresponders (ELECTRON): earlyviraldeclinesimilar to thatobserved in genotype 1 and genotype2/3 treatment-naïve patients (Abstract 54LB). 19th Conference on Retroviruses and Opportunistic Infections.March ; Seattle, USA. Available from: AccessedNovember 12, 2012).7. Gilead Sciences (Press release). Gilead announces early sustainedvirologic response rates for GS-7977 plus ribavirin in genotype 1 treatment naïve hepatitis C patients. Interim results reported from ELECTRON and QUANTUM studies April 18. Available from: ) Accessed on 2012 November 12).8. Osinusi A et al. High efficacy of sofosbuvir with weight-based ribavirin for 24 weeks in difficult-to-treat patients. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, abstract 157LB, 2013

22 Update Sofosbuvir EASL 2013 phase III
Study Population Treatment groups SVR12 rates Neutrino 910 GT 1/4/5/6 treatment-naïve   GT4:28 cases GT5:1case GT6:6 cases Sofosbuvir + RBV + Peg-IFN for 12 weeks 90% (295/327) GT 1a: 92% GT 1b: 82% Cirrhotic: 81% Fission910 GT 2/3 treatment naive SOF + RBV for 12 weeks Or Peg IFN+RBV for 24 weeks 67% ( 107/253) GT2:97% GT3:56% 67% ( 162/243) Positron 910 GT2/3 , IFN intolerant, ineligible or unwilling SOF+RBV for 12 weeks Or Placebo for 12 wks 78% ( 161/207) 0% (0/71) Fusion 910 GT2/3 treatment experienced SOF+RBV for 16 weeks 50% ( 50/100) GT2: 86% GT3: 30% GT3 non cirrhotics:37% GT3 cirrhotic: 19% 73% (69/95) GT2: 94% GT3: 62% GT3 non cirrhotic: 63%, cirrhotic: 61% 9:Gilead press release. Data from phase 3 studies of Gilead’s Sofosbuvir for hepatitis C to be presented at 48th annual EASL meeting: findings published online today in the new England Journal of medicine. Available at: . 10: Lawitz E, Mangia E, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. NEJM. April 23,2013. Available at:

23 GS 5885= Ledipasvir Gilead. NS5a Inhibitor
In combination with Sofosbuvir and RBV for 12 weeks: SVR12 100% in GT1. Fixed dose combination In treatment experienced people: same protocol: SVR12: 100% SOF Ledipasvir registration expected 2014. Under study in HIV-HCV co-infected people.

24 Daclatasvir (DCV) BMS. NS5a Inhibitor. 60mg once daily Phase III
Potent, high genetic barrier to resistance Genotype: 1,2 ,3,4. Simple, AE: fatigue, headache, nausea. No safety signal. No data yet in HIV-HCV co-infected SVR: GT1 DCV +SOF +/-RBV 12 weeks: SVR12: 95% GT2 &3: DCV +SOF +/-RBV 12 weeks: SVR12: % GT1 DCV +Asunaprevir +/-BMS or 24 weeks: SVR12: 94% Studied with SOF, but collaboration stopped. Limited data in liver advanced diseases, in HIV-HCV co-infected people and in treatment experienced people.

25 ABT-450/ritonavir Abbott. Protease Inhibitor.
In Combination with ABT-267 +/-ABT-333 +/-RBV: 100/100 mg , 200/100mg twice daily Phase III GT 1, under study in GT2 and GT3. Potent, low genetic barrier to resistance Genotype: 1. Under study in 2 and 3,no results yet. Simple, hyperbilirubinemia, fatigue, headache, pain, vomiting, some drug interaction expected, no safety signal. SVR : GT1 naïve: SVR12: 87-97% GT1 null responders: 87-93% No data yet in HIV-HCV co-infected people , in treatment experienced people and in case of liver advanced disease.

26 SIMEPREVIR Janssen/Medivir/ Tibotec. Protease inhibitor. Phase III
GT1and 4 AE: flu-like symptoms, rash, neutropenia, transient elevation of bilirubin. Can be interesting for treatment GT1 experienced people , or GT4 in addition to peg IFN RBV. Under study with Daclatasvir and Sofosbuvir.

27 Transformative Current Care The Future Lab Requirements Treatment
Pre-treatment: Serology, VL, genotype, staging (ultrasound or markers), potential prognostic markers Monitoring: 5 VL; CBC, Cr, ALT weeks 1,2,4 and monthly; TSH, T4 q3 month Treatment (24-)48 weeks weekly injections, daily pills High rates of side effects Efficacy: about 50% Costs: Minimum $2500 Lab Requirements Pre-treatment: Serology, VL, genotype(?) Monitoring: 3 VL, Monthly Creat/Hg/ALT Treatment 12-16 weeks 2 pills daily Efficacy: % Costs: oral regimen should be < 500 USD per diagnostic +treatment package

28 Key programmatic components for provision of HCV treatment
An adequate clinic infrastructure Laboratory and diagnostic services Drug Supply Human Resources (doctors ,nurses and psychosocial support) Referral system Monitoring and Evaluation Civil society participation

29 Conclusion More data are needed for people living with HIV-HCV co-infection, and advanced liver disease. Simplified diagnosis procedures and 2nd generation DAA treatment regimen will substantially increase impact and feasibility of treatment , and treatment as prevention ( Gane E, NEJM 2013, Poordad F, NEJM 2013) Enhanced efficacy (likely >90% all genotypes) Once/twice-daily oral-only dosing Reduced toxicity High barrier to resistance Shortened treatment duration (~12 weeks) May lead to: Higher uptake/adherence/completion Integration, decentralization and scaling –up of HIV-HCV services, including vulnerable groups like injection drug users. If the package of diagnosis and treatment can be largely available at affordable cost : < 500 usd. Gane, E. J., et al. Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. NEJM 2013;368(1): Poordad, F., et al. Exploratory Study of Oral Combination Antiviral Therapy for Hepatitis C. NEJM 2013;368(1): 45-53

30 MSF new report: /content/diagnosis- and-treatment -hepatitis-c- technical-landscape

31 Acknowledgments MSF viral hepatitis team: MSF hepatitis access team:
D.Donchuk, H.Bygrave, Marcio Fonseca da Silveira, M.Serafini, P.Du Cros, S.Balkan. MSF hepatitis access team: J.Cohn, T.Roberts, M.Balasegaram,R.Malpani, B.Milani, A.Rehman, K.Athersuch, N.Ernoult, L.Menghaney, P.Cawthorne, J.Rius. Questions:


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