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HCV: Simplifying adapting diagnosis and therapy

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

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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)

  5. New HCV /HIV epidemiological data. Center for Disease Analysis 2013 (1)

  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)

  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)

  12. 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)

  13. HCV: Simplifying adapting diagnosis and therapy • Epidemiological data • HCV diagnosis landscape • HCV treatment landscape

  14. PegIFN-Ribavirin Treatment Outcomes in LMICs very similar to high income settings Ford et al , Bull WHO 2012

  15. Sustained virological response (SVR) in patients co-infected with HCV and HIV by disease, patient and treatment covariates. • 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. Novel drugs against HCV:DAA, HTA and their combinations NOT EXHAUSTIVE DAA combinations R7128 + ITMN-191 DAA: Nuc-Polymerase inhibitors Phase I PSI-7977 + PSI-938 BI-207127 GS-9190 + GS-9256 IDX-184 + IDX-320 RG7348 BI-201335 + BI-207127 Phase II Telaprevir + VX-222 MK-0608 HTA: Cyclophilin Inhibitors TMC-649128 BMS-790052 + BMS-650032 SCY635 Phase III R7128 BMS-790052 + PSI-7792 PSI-7977 Approved DEBIO-025 (Novartis) IDX-184 PF-868554 AZD07295 ABT-072 Boceprevir GS-9190 BMS-790052 ABT-333 Telaprevir ANA-598 BMS-824393 ABT-837093 VX-222 TMC435 BI201335 BI201127 MK5172 DAA: NS5A inhibitor BMS650032 MK7009 (vaniprevir) ITMN-191/R7227 DAA: Non Nuc-Polymerase inhibitors VX-985 ACH1625 BMS791325 ABT-450 IDX-320 DAA: Proteaseinhibitors DAA = direct-acting antiviral HTA = host-targeting antiviral; Nuc = nucleos(t)ide

  18. 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-267 + ABT-333 + RBV BMS: Daclatasvir- Asunaprevir based Boerhinger- Ingelheim: BI 201335 OD + BI 207127 +/-RBV Janssen: Simeprevir

  19. 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.

  20. Sofosbuvir in GT1 treatment naive

  21. Update Sofosbuvir EASL 2013 phase III

  22. 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.

  23. 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: 88-100% • GT1 DCV +Asunaprevir +/-BMS 791325 12 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.

  24. 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.

  25. 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.

  26. Transformative Current Care The Future • Lab Requirements • Pre-treatment: Serology, VL, genotype(?) • Monitoring: 3 VL, Monthly Creat/Hg/ALT • Treatment • 12-16 weeks 2 pills daily • Efficacy: 90-100% • Costs: oral regimen should be < 500 USD per diagnostic +treatment package • Lab Requirements • 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

  27. 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

  28. 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.

  29. MSF new report: http://www.msfaccess.org /content/diagnosis- and-treatment -hepatitis-c- technical-landscape

  30. Acknowledgments • MSF viral hepatitis 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: • isabelle.andrieux-meyer@geneva.msf.org

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