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

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 hcv1

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

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

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

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

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

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

HCV Genotypes


The prevalence of hcv genotype 4 in kuwait

The Prevalence of HCV Genotype 4 in Kuwait

Hasan et al. Hepatogastroenterology2002

* Eastern province of Syria


Seroprevalence of hcv in kuwait

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

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

Sustained Virologic Responses By Genotype

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


Interferon plus ribavirin therapy limitations

Interferon Plus Ribavirin TherapyLimitations

20-60 % do not respond

Numerous side effects


Factors that influence response to interferon based therapy

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

Most Important Factors that Influence Treatment Outcome

HCV Genotype

IL 28 B Polymorphism

Degree of Fibrosis

HCV RNA level


Side effects of pegifn ribavirin

Side Effects of PegIFN/Ribavirin

Fever

Myalgias

Hair loss

Depression

Anemia

Rash

“Interferon Man”

Many others !


Was it the interferon man

Was it the Interferon Man ?


Contraindications of pegylated interferon and ribavirin

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

2011: Telaprevir and Boceprevir for HCV Genotype 1


Sustained virologic response telaprevir plus peg interferon plus ribavirin pr

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

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

Adverse Events with Telapravir and Bocepravir


Contraindicated drugs and other precautions for telaprevir

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 2013 simeprevir and sofosbuvir

December 2013Simeprevir and Sofosbuvir


Efficacy with simeprevir p r in tx naive gt1 patients phase iii trials

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

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

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

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

FDA Approved Indications for Sofosbuvir


Do not use telaprevir or boceprevir

DO NOT USE TELAPREVIR OR BOCEPREVIR


The future interferon free regimens

The FutureInterferon Free Regimens


Ifn free therapy for tx naive gt1 hcv

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

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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