Current status and benefits of therapy for chronic hepatitis c virus hcv
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Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV). Fuad AM Hasan Department Of Medicine Faculty of Medicine Kuwait University. Current Status and Benefits of Therapy for Chronic Hepatitis C Virus (HCV). Fuad AM Hasan Department Of Medicine Faculty of Medicine

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

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

Fuad AM Hasan

Department Of Medicine

Faculty of Medicine

Kuwait University


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

Fuad AM Hasan

Department Of Medicine

Faculty of Medicine

Kuwait University


Current And Future Treatment of HCV:The Count Down To The Demise of Hepatology

Fuad AM Hasan

Department Of Medicine

Faculty of Medicine

Kuwait 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

Receptor bindingand endocytosis

Transportand release

Fusion and uncoating

LD

LD

Translation andpolyprotein processing

ER lumen

Virionassembly

(+) RNA

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

Nucleoside/nucleotide

Nonnucleoside

Membranousweb

RNA replication

ER lumen

NS5A inhibitors

Block replication complex formation, assembly

RNA replication

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


HCV Genotypes


The Prevalence of HCV Genotype 4 in Kuwait

Hasan et al. Hepatogastroenterology2002

* Eastern province of Syria


Seroprevalence of HCV in Kuwait

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

*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 Influence Response to Interferon Based Therapy

Treatment regimen

PEG-IFN

Ribavirin

DAA

Host factors

Age, gender, race obesity, co-morbidities

Genetic factors

(IL28B and ITPA)

Factors that affect outcome

Disease features

Fibrosis, steatosis,

co-infection (HBV, HIV)

Viral factors

Genotype / Subtype

Quasispecies / Resistance

Viral load


Most Important Factors that Influence Treatment Outcome

HCV Genotype

IL 28 B Polymorphism

Degree of Fibrosis

HCV RNA level


Side Effects of PegIFN/Ribavirin

Fever

Myalgias

Hair loss

Depression

Anemia

Rash

“Interferon Man”

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

74–79*

PR48

166/361

T12/PR

683/903

n/N =

*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

INCIVO (telaprevir) EU SmPC


SVR rates with boceprevir plus PR versus PR alone

*

*

PR48

137/363

BOC RGT

233/368

BOC44/PR48

242/366

n/N =

*p<0.001 for both boceprevir arms versus PR48

SVR 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

VICTRELIS (boceprevir) EU SmPC


Adverse Events with Telapravir and Bocepravir


Important Safety Information

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.


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)

Simeprevir + P/R

Placebo + P/R

100

100

82

85

84

80

80

80

58

58

53

60

60

53

52

50

43

SVR (%)

40

40

29

20

20

419/521

133/264

138/165

36/83

49/84

23/44

228/267

70/133

188/229

60/113

18/31

5/17

n/N =

n/N =

0

0

Overall

GT1aWithoutQ80K

GT1a WithQ80K

GT1b

No Cirrhosis

Cirrhosis

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


Simeprevir Is Well Tolerated

Bilirubin

Hemoglobin

200

30

180

20

SMV + P/RP/R

SMV + P/RP/R

160

Mean (µmol/L)

Mean (µmol/L)

140

10

120

100

0

0

2

4

8

12

16

20

24

36

48

0

2

4

8

12

16

20

24

36

48

Wks

Wks

  • Mild unconjugatedhyperbilirubinemia→ transporter

  • No anemia signal beyond P/R

  • Rash up to 25% (mild)

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


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

SVR12 According to GT

SVR12 According to Fibrosis Level

100

96

100

100

92

89

80

80

80

60

60

SVR12 (%)

SVR12 (%)

40

40

20

20

n/N =

261/292

27/28

7/7

252/273

43/54

0

0

GT1

GT4

GT5/6

No Cirrhosis

Cirrhosis

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


Efficacy of Sofosbuvir in GT2

Treatment Naive[1]

Treatment Experienced[2]

12 wks of SOF + RBV

PegIFN/RBV

16 wks of SOF + RBV

100

98

96

100

100

91

82

78

80

80

62

60

60

60

SVR12 (%)

40

40

20

20

n/N =

25/26

23/23

6/10

7/9

n/N =

58/59

44/54

10/11

8/13

0

0

No Cirrhosis

Cirrhosis

No Cirrhosis

Cirrhosis

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

GT2


FDA Approved Indications for Sofosbuvir


DO NOT USE TELAPREVIR OR BOCEPREVIR


The FutureInterferon Free Regimens


IFN-Free Therapy for Tx-Naive GT1 HCV

C-WORTHY12-wk regimens[4]

AVIATOR[1]

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

LONESTAR[2]

AI443-014[3]

Daclatasvir + Asunaprevir +

BMS-791325for 12 wks

SOF/LDV FDC 8 wks

MK-5172 + MK-8742 20 mg + RBV

SOF/LDV + RBV 8 wks

MK-5172 + MK-8742 50 mg + RBV

24 wks

SOF/LDV FDC 12 wks

12 wks

MK-5172 + MK-8742 50 mg

100

100

95

95

100

96

96

100

100

100

92

90

89

80

80

80

80

60

60

60

60

SVR12/24 (%)

40

40

40

40

20

20

20

20

n =

77

21

19

20

80

27

13

79

25

0

0

0

0

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.


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 ?


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