XI Workshop SEIEVAIl Sistema Epidemiologico Integrato dell’Epatite Virale Acuta (SEIEVA) a 30 anni 

dal suo avvio: riflessioni sullo stato dell’arte e prospettive futureISS ‐ Giovedì 17 dicembre 2015

HCV, un problema di Salute Globale

Stefano Vella

TOLERABIL ITY

EFFICACY

IFN

IFN/RBV

PEG‐IFN/RBV

PEG‐IFN/RBV/TVRPEG‐IFN/RBV/BOC

PEG‐IFN/RBV/SMV

PEG‐IFN/RBV/SOF

48 WEEKS

24‐48 WEEKS

24 WEEKS

12 WEEKS

Dore GJ & Feld J. CID 2015

20 years

3 years

• Several highly effective IFN-free DAA regimens for different genotypes

• No impact of HIV on HCV treatment outcomes

• HCV resistance testing of limited clinical relevance

• Some treatment individualization required (e.g. cirrhosis)

• Decompensated cirrhosis reversible, but not always

• Shorter duration (6-8 wks) pangenotypic regimens in development

HCV: recent developments in IFN-free therapy

0

10

20

30

40

50

60

70

80

90

100

SOF/LDV PTV/OBV/DSV/RBV ASV/BCV/DCV GZR/EBR SOF/SMV

Naïve (12 wks)

Exp (12 wks)

Naïve (8 wks)

IFN-free DAA therapy: GT1 regimens

SVR12%

Zeuzem, NEJM 2014; Afdhal, NEJM 2014; Kowdley, NEJM 2014; Feld, NEJM 2014; Poordad, AASLD 2014; Zeuzum, ILC 2015; Kwo, ILC 2015

0

10

20

30

40

50

60

70

80

90

100

SOF/LDV PTV/OBV/DSV/RBV SOF/DCV* GZR/EBR

HCVHIV/HCV

IFN-free DAA therapy: HCV vs HIV/HCV

SVR12%

Afdhal, NEJM2014; Naggie, CROI2015; Feld, NEJM2014; Rockstroh, WAC2014; Wyles, CROI2015; Zeuzem, ILC2015; Rockstroh, ILC2015; Poordad, ILC2015

GT1, treatment naïve, F0-4; 12 weeks duration

*HCV mono in post-transplant

0

10

20

30

40

50

60

70

80

90

100

SOF/RBV SOF/DCV SOF/GS-5816

SVR12%

68/70 20/21

Lawitz E, et al. NEJM 2013; Everson G et al. ILC 2014; Wyles D et al. CROI 2015; Poordad F et al. ILC 2015

17/18

Treatment naïve and exp., 12 wks

IFN-free DAA therapy: GT2 regimens

0

10

20

30

40

50

60

70

80

90

100

SOF/RBV SOF/DCV SOF/GS-5816

TN

TE

103/183 50/54 50/53

IFN-free DAA therapy: GT3 regimens

Lawitz E, NEJM 2013; Nelson DR, Hepatology 2015; Everson G, ILC2014; Pianko S, AASLD 2014

91/101 44/51

Treatment naïve and exp., 12 wks

SVR12%

grazoprevir/elbasvir: Integrated Analysis for Patients with Cirrhosis

*Death (coronary artery disease)mFAS (modified full analysis set) excludes patients who discontinued treatment for reasons unrelated to study medication

88,991,4 93,9

100

No RBV +RBV No RBV +RBV12 Weeks 16 or 18

Weeks

Treatment Experienced

97,8 96,1 100 100

0

25

50

75

100

Patie

nts,

(%)

LTFU/EarlyDiscon. 1* 1* 0 0

SVR12 (mFAS†) 98.5% (135/137)

97% (73/75)

100% (56/56)

100%(6/6)

BreakthroughRelapse

11

11

00

00

135138

7376

5656

66

4854

7481

4649

4949

2* 1* 0 092.3% 92.5% 93.9% 100.0%(48/52) (74/80) (46/49) (49/49)

0 0 0 00 0 2 04 6 1 0

Jacobson I, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-22.

GRAZOPREVIR/ELBASVIR for Treatment-naive Patients with HCV/HIV Co-infection and HCV GT1, 4 or 6

SVR24: Full Analysis Set

93,1% 93,1% 93,2% 92.9%

0%

25%

50%

75%

100%

All Patients GT1a GT1b GT4

Patie

nts,

%

All GT GT1a GT1b GT4Relapse, n (%) 5 (2.4) 4 (2.8) 0 (0) 1 (3.6)Other Failure Criteria, n (%) 10 (4.6) 6 (4.2) 3 (6.8) 1 (3.6)

Reinfection, n 2 1 1 0LTFU or discontinuedunrelated to VF, n

8 5 2 1

203/218

134/144

41/44

26/28

Rockstroh J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 210.

Open-label, Single-arm, Multicenter Study Across Europe, United States and Australia Treatment-naive Patients with HCV GT1, 4 Or 6 HCV/HIV Co-infection

Future DAA combinations (2016-17)

Elbasvir(MK 8742)

2nd generationNS5A inh

Pangenotypic (± Gt3)

Grazoprevir(MK 5172)

2nd generationprotease inh.

Fixed dose combination of two or three DAAs

ABT 450/RProtease inh.

Daclatasvir

NS5A inh.

BeclabuvirPolymerase 

Inh.Pangenotypic

MK 3682 (IDX 21437)Polymerase 

Inh.

Sovaprevir(ACH-1625

Protease inh.

ACH-3102

NS5A inh.

ACH‐3422Polymerase 

Inh.Pangenotypic (?)

‐ Ultra‐short therapy (4‐6 wks)‐ >95% SVR for all pts.‐Pangenotypic‐One‐pill regimen, no RBV

GS 5816

2nd generationNS5A inh.

Pangenotypic

Sofosbuvir

Nucleotidepolymerase inh.

The development of interferon-free

HCV therapy is one of the major

advances in clinical medicine in

recent decades

Key Attributes

• Extremely high efficacy (>95%)

• Well tolerated

• Once daily dosing

• Pangenotypic

• Short duration (6-8 weeks)

HCV treatment: in pursuit of “perfectovir”

Key Attributes

• Extremely high efficacy (>95%)

• Well tolerated

• Once daily dosing

• Pangenotypic

• Short duration (6-8 weeks)

• Affordable

HCV treatment: in pursuit of “perfectovir”

Sofosbuvir Medicaid restrictions in US

Barua S, et al. Ann Intern Med 2015

Liver disease stage

Sofosbuvir Medicaid restrictions in US

Barua S, et al. Ann Intern Med 2015

Illicit drug use

Prevalenza dell’infezione da HCV nel mondo

* Estimated number of chronically infected individuals (2010)

• Lavanchy D. Clin Microbiol Infect 2011; 17:107–115;CDC: http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter‐3‐infectious‐diseases‐related‐to‐travel/hepatitis‐c.htm.

Prevalence of HCV >10%5–10%2–5%

<1%No data

Africa28 M*

Americas14 M*

Europe18 M*

130–170 million people world wide are infected with HCV

Middle East16 M*

1–2%

China30 M

S. Korea 0.8 M

Japan3 M

N. Korea0.2 M

Australia0.2 M

India18 M

Indonesia9 M

Prevalenza dell’infezione da HCV in Europa

Central Europe > 2.9 million

Western Europe > 10 million

East Europe > 6.2 million

HIV/AIDS as a model of Global Health: 

the battle towards universalaccess to antiretroviral drugs

AIDS: A heavy toll so far…

Crisismanagement

StrategicResponse

75 million people infected with HIV

35 million people living with HIV

39 million AIDS‐related deaths

HIV/AIDS: dramatic impact on life expectancy

World AIDS ConferenceDURBAN, 2000

At the country‐level, the HIV response is already having a dramatic impact on life expectancy

• Pharmaceutical industry competition  

• Discounting, risk‐sharing arrangements, volume taxation

• Compulsory licenses

• Advocacy/Activism

• Voluntary licenses (Gilead + Generic companies in 113 LMICs)

HCV treatment: drug price reform

• IFN‐free therapy is enormous advance on IFN‐containing therapy 

• Even advanced liver disease may be partially reversible

• Cost of  starting treatment only at later stages: ongoing monitoring and care for residual liver disease after HCV eradication, potentially for decades 

• Hopefully, drug price curve will continue downwards

• Potential for HCV treatment as prevention (at least in some settings)

CONCLUSION: interferon-free therapy access for all

Incidence and Predictors of Hepatocellular Carcinoma Following SVR

Incidence of HCC with SVR 3.27/1000 PY (0.327% PY) and with no SVR 13.2/1000 PY (1.32% PY) [HR 0.358]

Age, DM, cirrhosis and G3 risk factors post SVR

VA Study Cohort

10,638 without HCC and 100 with HCC

10,865 without HCC and 425 with HCC

22,197 with HCV RNA tests available to determine SVR12

10,817 with SVR 11,380 without SVR

HCC Incidence Following SVR: By Cirrhosis

010%20%30%40%50%60%70%80%90%

100%

Cum

ulat

ive

inci

denc

eof

HC

C

0 1 2 3 4 5 6 7 8

Years After SVR

Cirrhosis

No Cirrhosis

El-Serag H, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 90.

• IFN‐free therapy is enormous advance on IFN‐containing therapy 

• Even advanced liver disease may be partially reversible

• Cost of  starting treatment only at later stages: ongoing monitoring and care for residual liver disease and progression after HCV eradication, potentially for decades 

• Hopefully, drug price curve will continue downwards

• Potential for HCV treatment as prevention (at least in some settings)

CONCLUSION: interferon-free therapy access for all