Prof. Gamal Esmat How to Treat HCV in a Resource-Limited Setting the Success Story in Egypt

How to Treat HCV in a Resource-Limited Setting The Success Story in Egypt.

Prof. Gamal Esmat Prof. Hepatology &Ex. Vice President of Cairo University, Egypt Member of WHO Strategic Committee for Viral Hepatitis www.gamalesmat.com H EGYPT

▪ Estimated ~ 170 million globally

Population: 96 Million >10% ~2-5% HCV-Ab prevalence:~7% ~1-2% G4 about 90%

World Health Organization. Hepatitis C: global prevalence: update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16. Global prevalence &genotype distribution Trends in Percentage of population age 15-59 testing positive HCV Ab, Egypt 1996-2008-2015 Grafiektitel 1996 2008 2015

25,8 22,9 20,1 16,6 14,2 11,8 12 10 9

total Women Men HCV therapy: past, present and future Frequent Suppression of curability of Simeprevir + HCV with DAA diverse sofosbuvir Ribavirin combination populations without IFN Daclatasvir+ (PI + NI) sofosbuvir (GT1b) Ledipasvir + sofosbuvir Daclatasvir Proof Telaprevir Paritaprevir/RTV/ (Japan and Interferon of concept for and ombitasvir + Europe) DAA (PI) boceprevir dasabuvir ± RBV

1990 2000 2005 2010 2011 2012 2013 2014 2015+

Simeprevir or sofosbuvir Curability of Pegylated with IFN (GT1) HCV without interferons interferon First approved IFN-free therapy: Sofosbuvir + RBV (GT2,3) Simeprevir + sofosbuvir (off label use in US and EU) Evolution of HCV treatment and SVR rates 1989 2011 2013 2014/15 95–100 100 All genotypes Genotype 1 Genotype 2/genotype 3 85–97 80–90 76–82 80 61–79 66–79

60 31–44 42–46 40 33–36 18–39

6–19 11–19 10–22

SVR (%) SVR 20

0 24 48 78 IFN monotherapy (weeks) IFN + ribavirin PegIFN PegIFN +PegIFN ribavirin + ribavirin SMV + BOC/TVR or SOF SOF+ + DAA PegIFN + RBVRBV comb os

Davis GL, et al. N Engl J Med 1989; 321:1501–1506; Poynard T, et al. N Engl J Med 1995; 332:1457–1462; McHutchison JG, et al. N Engl J Med 1998; 339:1485–1492; Poynard T, et al. Lancet 1998; 352: 1426–1432; Zeuzem S, et al. N Engl J Med 2000; 343:1666–1672; Linsay KL, et al. Hepatology 2001; 34:395–403; Pockros PJ, et al. Am J Gastroenterol 2004; 99:1298–1305; Manns MP, et al. Lancet 2001; 358:958–965; Fried MW, et al. N Engl J Med 2002; 347:975–982; Poordad F, et al. N Engl J Med 2011; 364:1195–1206; Jacobson IM, et al. N Engl J Med 2011; 364:2405–2416; Simeprevir prescribing information, November 2013; Lawitz E, et al. N Engl J Med 2013; 368:1878–1887; Zeuzem S, et al. Hepatology 2013; 58(Suppl 1):733A; AbbVie press release 2014 [Accessed 25-02-14]; Gilead press release 2013 [Accessed 25-02-14]; Sulkowski MS, et al. N Engl J Med 2014; 370:211–221. We now have highly efficacious DAAs that target different stages in the HCV lifecycle

Summary of New England Journal of Medicine studies on IFN-free therapy Receptor binding in GT 1 patients published in 2014 and endocytosis Transport 96% and release

Fusion and uncoating Virion assembly

(+) RNA ER lumen Translation and LD NS5A inhibitors polyprotein LD processing

LD Membranous web RNA replication ER lumen

Non-NA NS5B inhibitors 3680/ NS3 protease NA NS5B inhibitors 3826 inhibitors SVR DAA: direct-acting antiviral agent; ER: endoplasmic reticulum; Lindenbach BD, Rice CM. Nature 2005;436(Suppl):933–8; GT: genotype; IFN: interferon; LD: luminal domain; NA: nucleos(t)ide analogue; Liang J, Ghany MG. N Engl J Med 2014;370:2043–7. NS: non-structural protein; SVR: sustained virological response Percentage of women and men with an active hepatitis C infection by age, Egypt 2015

30 27,8 25 23,7

20 17,6 16,1 15 women 12,4 men 10 10,8 10,4

7,1 6,9 7,3 5 4,7 5,3 3,1 3,2 1,5 1,9 0 0,60,9 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 Percentage of HCV infection with Anti Schistosomiasis treatment (2008-2015)

35 35 31,3 30 30 24,8 25 23,8 25

20 20 16,9 2008 15,5 2008 15 15 2015 2015 10,7 11,2 10,9 10 10 5,4 4,4 5 5 3,3 2,1

0 0 Had anti No Do not know, Had anti No Do not know, Schisto missing Schisto missing treatment treatment Females Males

Opening of 23 national treatment centres, 2007-2013

Total number of patients treated with PEG-IFN (2007-2013): 350,000 Annual number of new patients treated: 45,000 Annual budget from the Ministry of Health: 90 million $

 The course for 3 months will cost 900 $ instead of 84 000 $ in USA.

 Manufactured outside Egypt but with different color(FDA approved) and written on it(to be sold only in Egypt).

 Renewal of the agreement every year. A large number of patients were ineligible for treatment

IFN-based therapy era

x Intolerant to IFN x Intolerant to RBV x Autoimmune conditions x Hepatic dysfunction or decompensated cirrhosis Treatable HCV x Severe heart disease patients x Pregnant Chronic HCV- x Mental health risk infected patients

Roche. PEGASYS (peginterferon alfa-2a) SmPC, October 2017 RBV: ribavirin …and more patients are now eligible for treatment

DAA therapy era

• Cirrhotic • Co-morbidities • Renal impairment • Psychiatric • Drug user Treatable HCV patients • Transplant • Decompensated cirrhotic Chronic HCV- infected patients The number of treated patients in Egypt has increased dramatically with the introduction of DAAs

750,000

500,000

250,000 Number Number of patients treated 0 2008 2010 2012 2014 2016 Year

Polaris Observatory. Hepatitis C. Available at: http://polarisobservatory.org/polaris_view/graphs.htm (accessed November 2017) IFN-free regimens

Paritaprevir/r Ombitasvir NS5A inhibitors ‘…asvirs’

Sofosbuvir Daclatasvir Protease inhibitors Sofosbuvir Ledipasvir ‘…previrs’ Polymerase Simeprevir Sofosbuvir inhibitors ‘…buvirs’ Non-Nucs Nucleos(t)ide

Sofosbuvir + RBV

EASL Recommendations 2015, DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.025. Accessed April 2015. Our aim to maintain a disease Control (by reaching international prevalence disease rates with 2% infection rate compared with the current 7% infection rate).

To reach for disease Elemination (disease rate <1%)

Waked,……,Esmat.et.al .Ar.J.G.2014 Elimination of HCV in Egypt Overcoming the Barriers

Decrease incidence Ideal drug Mass treatment Elimination of HCV in Egypt Overcoming the Barriers

Decrease incidence Ideal drug Mass treatment Decrease incidence

• Blood safety. • Avoid unneeded injection. • Auto destructive syringes. • Infection control. • Media awareness. • Case detection and treatment by Ideal drug. Can treatment impact HCV spread?

• Treatment can ba a method of prevention if: • Applied early in the course of infection. R0 of the untreated HCV epidemic in the Egyptian community is 3.50 (95% CI 2.95-4.03). • Efficacy >80% • Patients contributing most to HCV spread, the so-called «surperinjectors», are targeted preferentially (for treatment, and prevention!)

(Breban et al. Lancet Global Health, 2014) National Plan of Action: conclusions

• Increase policymakers’ commitment to supporting the policy change necessary to prevent viral hepatitis transmission. • Educate healthcare workers to prevent transmission of viral hepatitis in Egypt. • Increase public awareness of viral hepatitis prevention. • Promote safe injection practices in the community. • Annual treatment of 200-350.000 patients by DAA.in 46 centers in 2015 aiming to reach 100 centers by the end of 2016

Egyptian National Plan of Action for the Preventton , Care & Treatment of Viral Hepatitis 2014–2018 Elimination of HCV in Egypt Overcoming the Barriers

Decrease incidence Ideal drug Mass treatment DAAs Battle

Negotiation Phase Brands(1% of its USA price)

National Victory Phase Generics(15% of the brands)

25 Victory Phase

Egyptian Generics

26 The cost of 3 months treatment(sofo+dacla) per patient Brand vs Generic( 1$=17 EP)

12.000 EP 10.545 10.000

8.000 Reduced by 85,5 %

6.000

4.000

2.000 EP 1.527 0 SOF-DAC/RBV

600.000 Patients in 2016 Money Saved Over 12 Months(600.000 Patients)

600,000 patients 15% 5,359,200,000 EP

Availability of the generic drugs in a reduced price encourage people to take medication from private sector (300.000 patients) Number of treated patients through the Egyptian national treatment program with DAAs till the end of 2017

1,344,496 Patients

40694 3% 201694 15%

293217 Govermental support 22% 808891 60% HIO Cash Military & Police hospitals

Availability of the generic drugs in a reduced price encourage people to take medication from private sector (300.000 patients) NCCVH registry

Treatment outcome for the different Protocols (Real Life)

97% 96% 100% 90% 93% 90% 78% 80% 70% 60% 50%

Percent 40% 30% 20% 10% 0% SOF/IFN/RBV SOF/RBV SOF/SIM SOF/DAC SOF/DAC/RBV

A. Elsharkawy, R. Fouad, W. El Akel, M. El Raziky, M. Hassany, G. Shiha, M. Said, I. Motawea, T. El Demerdash, S. Seif, A. Gaballah, Y. El Shazly, M. A. M. Makhlouf, I. Waked, A. O. Abdelaziz, A. Yosry, M. El Serafy, M. Thursz, W. Doss, G. Esmat . Sofosbuvir-based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt. Aliment Pharmacol Ther 2017; 45: 681–687

Decrease incidence Ideal drug Mass treatment Online Regestiration A web-based online registration system website (www.nccvh.org.eg) once the first DAA was registered in Egypt. This portal was designed for registration of patients with HCV and scheduling appointments at the treatment centres. Inputs from patients’ registry include their national ID, residence and a simple question for validation. Patients registered online for appointments till 1/6/2017

1 6 4 3 9 2 8 >150 Treatment centers affiliated to HCV National Treatment Program(NCCVH&HIO) in Egypt

In 2007, the NCCVH established its first specialized centres for treatment of viral hepatitis within MOHP healthcare facilities. Centres were planned to be geographically distributed in the most populous areas. Training the healthcare professionals (hepatologists, infectious disease specialists, physicians ) to deliver an efficient counseling, care and treatment programme for patients with chronic HCV in accordance with the updated national guidelines.

El-Akel W, .., Esmat, Doss . National treatment programme of hepatitis C in Egypt: hepatitis C virus model of care. J Viral Hepat. 2017;00:1-6. doi:10.1111/jvh.12668. Nile River in Cairo Mass Treatment

To reach 2% Infection Rates in 2025 and less than 1% in 2030:

Treatment with 90% curing rate or higher should be applied. Number of yearly cured cases should exceed from 65,000 case in 2014 to 150,000 case in 2015(>300.000), then to 275,000 case in 2016(>600.000), then to 350.000 from 2018. 28/07/2016 NO waiting lists Timeline for treatment protocols

أنظمة العالج المتبعة في الوحدات التابعة اللجنة القومية

Dec-14 Jan-15 Feb-15 Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 Sep-15 Oct-15 Nov-15 Dec-15 Jan-16 Feb-16 Mar-16 Apr-16 May-16 Jun-16 Jul-16 Sof/IFN/RBV SOF/RBV SOF/SIM SOF/DAC SOF/DAC/RBV

Generic DAA Where Egypt was (<2014)

HCV-infected Diagnosed IFN SVR patients patients

50% 6,000,000 20% 30% (3%)

Waked I, et al. Arab J Gastroenterol 2014;15:45–52; National Registry, data on file IFN: interferon; SVR: sustained virological response Where Egypt is now (2017)

HCV-infected Diagnosed DAA SVR patients patients

90–95% 6,000,000 20% 90–95% (16%)

Waked I, et al. Arab J Gastroenterol 2014;15:45–52; National Registry, data on file DAA: direct-acting antiviral agent Targeted screening for HCV in Egypt

• Families of HCV patients • Healthcare providers • Prisoners • Students admitted to universities • Patients attending intervention procedures in hospitals • Before ID or driving license • Government employees • Everyone

Esmat G, personal opinion ID: identification document Screening Program

• Launched in January 2017 • Screened 3,300,000 till August 2017 • Stakeholders – MOH (preventive sector, NCCVH) – Ministry of Administrative development – National Bank – NGO Media&NGOs Screening Program Launched in January 2017 Screened 3,300,000 till August 2017

1,500,000 3,300,000 6 categories screened subjects 1,800,000 •Inpatients Field screening •Health care workers •Prisoners •First year students •Upper Egypt •Submitted for travel •All age groups •Blood banks Donors ELISA test Saliva rapid test Screening results till Aug 2017 3,300,000

HCV Ab +ve; 290400 HCV Ab -ve; HCV RNA - 3009600 ve 14%

HCV RNA +ve 86%

249744 patients need to be treated Current national treatment program centers

Total number 172 units NCCVH 71 units MOH 101 units Where Egypt could go! (>2017)

HCV-infected DiagnosedDiagnosed DAADAA SVRSVR patients patientspatients

6,000,000 90–95% 90–95% 90–95%

Waked I, et al. Arab J Gastroenterol 2014;15:45–52; National Registry, data on file Slides with courtosy of Prof. H. Wedemeyer Elimination of HCV in Egypt

Curing of 3,750,000 patients should be considered to reach 2% infection rates.

Curing of 5,000,000 patients to reach less than 1% infection rate, during selected period of time.

Waked,……,Esmat.et.al .Ar.J.G.2014 HCV treatment in 2013 and strategies to reduce the burden of HCV by 2030

2030 Total infected 2013 a) Increase b) Increase efficacy efficacy and 7.000.000 6.000.000 only treatment 6.000.000 5.000.000 Treated (annual) 65,000 65,000 325,000 4.045.000 4.000.000 Treatment rate 1.1% 1.1% 7.1% 3.000.000 Average SVR 48% 90% (2014) 90% 2.000.000 -95% Newly diagnosed 1.000.000 125,000 125,000 340,500 280.000 (annual) 0 Common treatment age 15–59 15–59 15–74 2013 2030a 2030b Treated stages ≥ F2 ≥ F2 ≥ F0 Compensated Decompensated cirrhosis cirrhosis HCC 800.000 138.000 630.000 150.000 20.000 16.000 16.000 110.000 600.000 507.000 15.000 100.000 400.000 -87% 10.000 -85% -88% 50.000 17.000 5.000 2.400 200.000 76.000 0 0 0 2013 2030a 2030b 2013 2030a 2030b 2013 2030a 2030b

Waked I, et al. Arab J Gastroenterol 2014;15:45–52 World Hepatitis Day in Egypt 28July 2015

• Egypt was chosen to host World Hepatitis Day 2015 as the country has demonstrated a high level of commitment by tackling hepatitis comprehensively in their plan of action for prevention, care and treatment. • The Ministry of Health has set up 32 specialized centres and introduced a new hepatitis C drug last year, which is the first highly- effective and approved direct-acting antiviral drug for the nationwide treatment of hepatitis C infection. This medication is safer than previous medications and has been shown to cure more than 90% of those completing treatment, in combination with other drugs. In a global first, the drug has been made available to Egyptian patients for US$ 900, which is 1% of its international price. So far, 128 000 people have started the new treatment. Number of deaths/year from selected conditions, Global Burden of Disease Study 2010 and 2013

Endorsement of success

. Endorsement of success From Land Of History

We will Make HCV a History THANK YOU please visit

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