Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV)

Fuad AM HasanDepartment Of Medicine

Faculty of MedicineKuwait University

Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV)

Fuad AM HasanDepartment Of Medicine

Faculty of MedicineKuwait University

Current And Future Treatment of HCV:

The Count Down To The Demise of Hepatology

Fuad AM HasanDepartment Of Medicine

Faculty of MedicineKuwait University

True or False

• Hepatitis C is incurable. Treatment only suppresses the virus

• Interferon and ribavirin therapy are associated with minor adverse events

• HCV genotype is a major determinant of response to interferon based therapy.

• Boceprevir and telaprevir are effective against all genotypes.

• Sofosbuvir in combination with IFN and ribavirin cures around 90% of HCV infected patients

Outline

• HCV structure and life cycle• HCV genotypes• Standard treatment of HCV (2001-2011)• Standard treatment of HCV genotype 1 (2011-

2013)• Current treatment of HCV genotypes 1-6• The future

HCV Polyprotein Processing and Viral Protein Function

McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12

HCV Life Cycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and uncoating

Transportand release

(+) RNATranslation and

polyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotide

Nonnucleoside

Block replication complex formation, assemblyNS5A inhibitors

RNA replication

HCV Genotypes

The Prevalence of HCV Genotype 4 in Kuwait

71

>90 100*

62

0

20

40

60

80

100

Kuwait Egyptian Syrian Saudi

Kuwait

Egyptian

Syrian

Saudi

Hasan et al. Hepatogastroenterology 2002 *Eastern province of Syria

Seroprevalence of HCV in Kuwait

kuwaiti blood donors

Non Kuwaiti blood donors

T2 diadetes: kuwaiti

T2 diadetes: Egyptian

Civil service applicants*

0

2

4

6

8

10

12

14

16

18

20

Ameen R et al. Transfusion. 2005 ;45:1973-80.Chehada W et al. J infect Public Health 2011 ;4:200-6*Al Khalidi J et al. Unpublished data

Treatment of HCV 2001-2011

Pegylated Interferon plus Ribavirin combination was the standard treatment of HCV regardless of

genotype until 2011

Sustained Virologic Responses By Genotype

45

80

68*

0

20

40

60

80

100

% o

f p

atie

nts

G1 G2/3 G4

*Hasan F, et al. Am J Gastroenterol 2004;99:1733-1737

Interferon Plus Ribavirin TherapyLimitations

20-60 % do not respond

Numerous side effects

Factors that affect outcome

Treatment regimen

PEG-IFNRibavirinDAA

Host factors

Age, gender, race obesity, co-morbiditiesGenetic factors (IL28B and ITPA)

Disease features

Fibrosis, steatosis, co-infection (HBV, HIV)

Viral factors

Genotype / SubtypeQuasispecies / ResistanceViral load

Factors That Influence Response to Interferon Based Therapy

Most Important Factors that Influence Treatment Outcome

HCV Genotype

IL 28 B Polymorphism

Degree of Fibrosis

HCV RNA level

Side Effects of PegIFN/Ribavirin

“Interferon Man”

Fever

Myalgias

Hair loss

Depression

Anemia

Rash

Many others !

Was it the Interferon Man ?

Contraindications of Pegylated Interferon and Ribavirin

• De-compensated cirrhosis• Coronary artery disease, heart failure, serious

dysrythmia • Proliferative diabetic retinopathy• Kidney transplant patients• Renal impairment (ribavirin)

2011: Telaprevir and Boceprevir for HCV Genotype 1

Sustained Virologic Response: Telaprevir plus Peg Interferon Plus Ribavirin PR

T12/PR

683/903

PR48

166/361n/N =

74–79*

INCIVO (telaprevir) EU SmPC

*p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCESVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used

SVR rates with boceprevir plus PR versus PR alone

38

63 66

0

20

40

60

80

100

SV

R (

%)

BOC RGT

233/368

BOC44/PR48

242/366

PR48

137/363n/N =

VICTRELIS (boceprevir) EU SmPC

* *

*p<0.001 for both boceprevir arms versus PR48SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward

Adverse Events with Telapravir and Bocepravir

TelaprevirTelaprevir plus P/R P/R

Pruritis 45-50% 28%

Nausea 40-43% 31%

Rash 56% 34%

Anemia 37-39% 19%

Diarrhea 28-32% 17%

Anorectal discomfort 11% 3%

BoceprevirAnemia 50% 30%

Dysgeusia 35-43% 16%

Neutropenia 25% 19%

Nausea 46% 42%

Contraindicated Drugs and Other Precautions for Telaprevir

*These interactions have been studied; †Impaired renal/hepatic function; ‡No clinical data are available regarding the treatment of organ transplant patients with TRADENAME in combination with peg-IFN/RBV. Therefore, the use of TRADENAME in organ transplant patients is not recommended; §Normal renal/hepatic function.

Contraindicated Not recommended Use with caution

Potential for increased toxicity from concomitant

medication

Alfuzosin (UroXatral)

Amiodarone (Cordarone, Pacerone)

Dihydroergotamine (D.H.E. 45 and Migranal)

Ergonvine (Ergonovine Maleate)

Ergotamine (Ergomar)

Flecainide (Tambocor)

Lovastatin (Altocor, Altoprev, Mevacor)

Methylergonavine (Methergine)

Midazolam oral*(Versed)

Pimozide (Orap)

Propafenone (Rythmol)

Quinidine (Quinaglute Dura-Tabs,

Quinidex Extentabs, Cardioquin, Quinora)

Sildenafil for PAH(Revatio)

Simvastatin

(Zocor)

Triazolam (Halcion)

Budesonide inhaled(Pulmicort Flexhaler, Pulmicort Respules)

Colchicine†

(Colcrys)

Cyclosporine*‡ (Atopica, Gengraf, Neoral,

Sandimmune,

Fluticasone inhaled(Flovent)

Salmeterol (Serevent)

Sirolimus‡ (Rapamune)

Tacrolimus*‡

(Prograf )

Tadalafil for PAH(Adcirca)

Voriconazole(Vfend)

 

Alprazolam*(Niravam, Xanax)

Amlodipine* (Norvasc)

Atorvastatin* (Lipitor)

Bosentan (Tracleer)

Clarithromycin (Biaxin)

Colchicine§ (Colcrys)

Desipramine (Norpramin)

Digoxin* (Lanoxin)

Diltiazem(Cardizem, Dilacor,

Tiazac)

Erthromycin(E.S.P., Eryzole, Pediazole,

Sulfimycin)

Felodopine (Plendil)

Itraconazole (Sporanox)

Ketoconazole* (Feoris, Nizoral)

Lidocaine (Xylocaine)

Midazolam IV* (Versed)

Nicardipine (Cardene)

Nifedipine(Adalat, Afeditab CR, Nifediac, Nifedical,

Procardia)

Nisoldipine (Sular)

Posaconazole (Noxafil)

Sildenafil for ED (Viagra)

Tadalafil for ED (Cialis)

Telithromycin (Ketek)

Tenofovir* (Viread)

Trazadone (Desyrel, Oleptro)

Vardenafil (Levitra, Staxyn)

Verapamil (Calan, Covera, Isoptin,

Verelan)

Warfarin (Coumadin, Jantoven,

Marfarin)

Important Safety Information

December 2013Simeprevir and Sofosbuvir

Efficacy With Simeprevir + P/R in Tx-Naive GT1 Patients: Phase III Trials

• SMV + P/R for 12 wks followed by 12-36 wks of P/R (placebo control)

Jacobson I, et al. EASL 2013. Abstract 1425.

18/31

n/N =5/17

188/229

60/113

82

5358

29

100

80

60

40

20

0No Cirrhosis Cirrhosis

n/N =419/521

133/264

138/165

36/83

49/84

23/44

228/267

70/133

100

80

60

40

20

0

SVR

(%)

Simeprevir + P/R Placebo + P/R

80

50

84

43

5852

85

53

Overall GT1aWithout

Q80K

GT1a WithQ80K

GT1b

Simeprevir Is Well Tolerated

Bilirubin Hemoglobin

Mea

n (µ

mol

/L)

Mea

n (µ

mol

/L)

Wks Wks

Mild unconjugated hyperbilirubinemia → transporter No anemia signal beyond P/R Rash up to 25% (mild)

Manns M, et al. EASL 2013. Abstract 1413.

SMV + P/RP/R

SMV + P/RP/R

30

20

10

00 24 8 12 16 20 24 36 48

200

180

120

1000 2 4 8 12 16 20 24 36 48

160

140

Efficacy With Sofosbuvir + P/R in Tx-Naive GT1/4/5/6 Patients: Phase III Trials

• Single-arm study of sofosbuvir + P/R for 12 wks

SVR1

2 (%

)

92

80

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

SVR12 According to Fibrosis Level

SVR1

2 (%

)

8996

100100

80

60

40

20

0GT1 GT4 GT5/6

261/292 27/28 7/7

SVR12 According to GT

n/N =

Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

Efficacy of Sofosbuvir in GT2

1. Gane E, et al. EASL 2013. Abstract 5.2. Jacobson I, et al. N Engl J Med. 2013;368:1867-1877.

SVR1

2 (%

)

No Cirrhosis Cirrhosis

58/59 44/54 10/11 8/13n/N =

100

80

60

40

20

0

98

82

91

62

12 wks of SOF + RBV PegIFN/RBVTreatment Naive[1]

6/1025/26 7/923/23

No Cirrhosis Cirrhosis

GT2

n/N =

100

80

60

40

20

0

96

60

78

16 wks of SOF + RBV100

Treatment Experienced[2]

FDA Approved Indications for Sofosbuvir

Treatment Duration

HCV genotype 1 &4 Sofosbuvir+Peg-IFN+RBV 12 wks

HCV genotype 2 Sofosbuvir + RBV 12 wks

HCV genotype 3 Sofosbuvir + RBV 24 wks

HCV plus HCCDecompensated Cirrhosis

Sofosbuvir + RBV 48 wks or Tx

DO NOT USE TELAPREVIR OR BOCEPREVIR

The FutureInterferon Free Regimens

IFN-Free Therapy for Tx-Naive GT1 HCV

1. Kowdley K, et al. EASL 2013. Abstract 3. 2. Lawitz E, et al. AASLD 2013. Abstract 215. 3. Everson GT, et al. AASLD 2013. Abstract LB-1. 4. Lawitz E, et al. AASLD 2013. Abstract 76.

AI443-014[3]

Daclatasvir + Asunaprevir +BMS-791325

for 12 wks

77

100

80

60

40

20

0

10096

89

25 27 13

MK-5172 + MK-8742 20 mg + RBVMK-5172 + MK-8742 50 mg + RBV

MK-5172 + MK-8742 50 mg

C-WORTHY12-wk regimens[4]

100

80

60

40

20

0

92100

80

60

40

20

0

9595100

20 21 19

SOF/LDV FDC 8 wksSOF/LDV + RBV 8 wksSOF/LDV FDC 12 wks

LONESTAR[2]

100

80

60

40

20

0

96 90

79 80

12 wks

AVIATOR[1]

ABT-450/RTV + ABT-333 + ABT-267 + RBV

SVR1

2/24

(%)

24 wks

n =

Is the demise of Hepatology imminent ?

• HCV cure rate approaching 95%• HBV incidence declining rapidly due to vaccination• Treatment of HBV and HCV using direct acting

antivirals is safe, simple and can be handled by internists.

• Alcoholic liver disease and NASH can be handled by internists

• Only end stage liver disease and liver transplant patients need specialty care ?