genotyping & fibrosis evaluation

HCV: Simplifying adapting diagnosis and therapy

Dr. Isabelle Andrieux-MeyerMSF Access CampaignIAS Kuala Lumpur, Sunday 30th June .

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.


Epidemiological data HCV diagnosis landscape HCV treatment landscape

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)

New HCV /HIV epidemiological data. Center for Disease Analysis

2013 (1)

New HCV /HIV epidemiological data. Center for Disease Analysis

2013 (2)

HIV / AIDS TREATMENT PROGRAMMES

MSF currently provides HIV treatment to 250,000 people in 23 countries.

MSF Access Campaign

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)

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)

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)

PegIFN-Ribavirin Treatment Outcomes in LMICs very similar to high income settings

Ford et al , Bull WHO 2012

Sustained virological response (SVR) in patients co-infected with HCV and HIV by disease, patient and treatment covariates.

Davies A, et al. PLoS ONE 2013.

• HCV genotypes 1 or 4 (pooled SVR 24.5%) vs genotypes 2 or 3 (pooled SVR 59.8%)

CHANGING HCV TREATMENT LANDSCAPE

Dore GJ Med J Aust, 2012.

Novel drugs against HCV:DAA, HTA and their combinations

IDX-320

Phase I

Phase II

Phase III

Approved

DAA:Nuc-

Polymerase inhibitors

DAA:Non Nuc-

Polymerase inhibitors

DAA:Proteaseinhibitors

DAA:NS5A

inhibitor

HTA:Cyclophilin Inhibitors

DAA combinations

AZD07295

BMS-790052

BMS-824393

Telaprevir + VX-222

BMS-790052 + BMS-650032

R7128 +ITMN-191

GS-9190 +GS-9256

Boceprevir

TMC435

ABT-450

MK5172

MK7009 (vaniprevir)

Telaprevir

BMS650032

BI201335

ACH1625

ITMN-191/R7227

GS-9190

ANA-598

VX-222

BI201127

ABT-837093

IDX-184

R7128PSI-7977

BI-207127

DAA = direct-acting antiviralHTA = host-targeting antiviral; Nuc = nucleos(t)ide

SCY635

DEBIO-025(Novartis)

NOT EXHAUSTIVE

BMS-790052 + PSI-7792

BI-201335 +BI-207127

IDX-184 + IDX-320

PSI-7977 + PSI-938

VX-985

PF-868554

MK-0608RG7348

TMC-649128

BMS791325

ABT-072

ABT-333

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

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.

Sofosbuvir in GT1 treatment naiveStudy name Combination OutcomesATOMIC 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

12 or 24 weeksSVR 100%

ELECTRON6

SOF +RBV 12 weeksSVR4:88%

QUANTUM7

SOF +RBV 12 vs 24 weeks12 weeks: SVR: 59% (10/17)

SPARE8 SOF +RBV (weight based or 600mg RBV)

12 weeksSVR12: 90%

Update Sofosbuvir EASL 2013 phase IIIStudy Population Treatment groups SVR12 rates

Neutrino 910

GT 1/4/5/6treatment-naïve GT4:28 casesGT5:1caseGT6:6 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 weeksOr Placebo for 12 wks

78% ( 161/207)0% (0/71)

Fusion 910 GT2/3 treatment experienced

SOF+RBV for 12 weeksOr

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%

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.

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.

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.

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.

TransformativeCurrent Care 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

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

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

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.

MSF new report:http://www.msfaccess.org

/content/diagnosis-and-treatment-hepatitis-c-

technical-landscape

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: [email protected]

genotyping & fibrosis evaluation

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