powerpoint presentation...smv 80+ pegifn/ rbv/ smv 24-48 wks pegifn/ rbv/ sof 12-24 • ns5b uridine...

10/4/2014

1

HCV ECHO®WESTERN STATES

Original presentation by: Date prepared:

Interferon-Free Hepatitis C Regimens: New Therapies, New Recommendations- A Guide for PharmacistsPaulina Deming, PharmDAssociate ProfessorCollege of PharmacyProject ECHOUniversity of New Mexico Health Sciences Center

October 6, 2014

Paulina Demoing

July 19, 2014

HCV ECHO® WESTERN STATES

Conflict of Interest Disclosure Statement

No conflicts

OBJECTIVES

1. Discuss the current standards of care for chronic HCV infections

2. List adverse reactions associated with new treatments for HCV and describe how to manage them

3. Describe how to use an interferon-free treatment regiment

4. Manage drug interactions that are common in patients with HCV and comorbid conditions

• According to the AASLD/IDSA guidelines, boceprevirand telaprevir are no longer recommended for the retreatment of HCV G1 prior non-responders because of which of the following reasons?

A. Less effective

B. Longer duration of therapy

C. Poorly tolerated

D. All of the above

Self-Assessment Questions

• Which of the following best describes the role of interferon in HCV therapy?

A. It is no longer needed, all new therapies are interferon-free

B. It remains a mainstay of therapy in combination with ribavirin

C. It remains an option for HCV therapy, although at decreased duration and in combination with new therapies


• Which of the following best describes the drug interactions expected with new therapies?

A. Simeprevir has drug-drug interactions with statins which can be managed by reducing the dose of the statin

B. Sofosbuvir has substantial clinically relevant drug interactions limiting its use with comorbid conditions

C. Both sofosbuvir and simeprevir have substantial drug-drug interactions limiting their use in HIV-HCV coinfection


10/4/2014

2

• New HCV treatment guidelines and outcomes in previously treated patients

• Outcomes and drug interaction concerns in patients co-infected with HIV

• Managing HCV drug interactions in patients with dyslipidemia and asthma and in patients post-transplant

• Emerging therapies

Outline Estimated 170 Million Persons With HCV Infection Worldwide

World Health Organization. Wkly Epid Rec .1999;74:425-427. World Health Organization. Hepatitis C: Global Prevalence:

Update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. WasleyA, et al. Semin Liver Dis. 2000;20:1-16.

Europe

8.9 million

(1.03%)Americas

13.1 million

(1.7%)

Africa

31.9 million

(5.3%)

Western

Pacific

62.2 million

(3.9%)

Eastern

Mediterranean

21.3 million

(4.6%)

Southeast Asia

32.3 million

(2.15%)

Estimated 36,000 persons living with HCV

> 3000 cases reported each year to NMDOH

> 4000 cases in 2012

Highest rate of chronic liver disease/cirrhosis deaths in the nation

Hepatitis C in New Mexico

Hepatitis C Rates

Per 100,000 Population

0 - 60

61 - 97

98 - 117

118 - 214

215 - 345

Hepatitis C Rates by County, 2012 Hepatitis C Prevalence (NHANES Estimate)

Armstrong GL, et al. Ann Intern Med. 2006;144:705-14.;Chak E, et al. Liver Int. 2011;31:1090-1101

3.2 Million HCV Antibody positive

Possibly up to 7.1 Million HCV Antibody positive in US

10/4/2014

3

• Prevalence among persons born 1945–1965: 3.25%

– 5 x higher than among adults born in other years

Prevalence of HCV in US By Year of Birth:

NHANES Data

Armstrong GL, et al. Ann Internal Med. 2006;144:705-714. Smith BD, et al. AASLD 2011

New screening guidelinesRationale for Recommendations:• 45%-85% of infected

persons are undiagnosed• Limitations of current

risk-based strategies • 75% of chronic infections

are in persons born from 1945-1965

Hepatitis C: Progression of Disease

25-30 yearsNormal Liver

Chronic Hepatitis

HCCESLDDeath

HCV Infection

20-25 years

Cirrhosis

Time

Figure 2

• Disease progression is variable and non-linear

• Modifiable factors are important in disease progression and should be addressed

– Weight loss

– Diabetes control

– Alcohol and marijuana

– Vaccination for HAV, HBV

Progression of HCV Disease

• 40-74% of patients will develop > 1 of the following1

– Mixed cryoglobulinemia Vasculitis Peripheral neuropathy Myalgias and/or arthralgias

– Insulin resistance and diabetes Risk increased by 70% compared to non-infected controls2

(OR 1.7) Linked to insulin resistance without overt diabetes

– Central nervous system effects Impaired cognition Fatigue

Extra Hepatic Manifestations of HCV

1. Best Practice Rsrch Clin Gastroenterol. 2012;26:401-412.

2. Hepatol. 2008;49(5):831.

• High prevalence (15%) of HCV in patients with B-cell lymphoproliferative disorders

• Two-fold increased risk of non-Hodgkin’s lymphoma (NHL)

• HCV patients with mixed cryoglobulinemiahave 35-fold increased risk of NHL

HCV and Lymphomas

Gastroenterology. 2003;125(6):1723.

10/4/2014

4

• HCV infections reached a peak in late 1980s

– 1989: 291,000 per year

– 2006: 20,000 per year

Forecasting Morbidity and Mortality of HCV Patients in U.S

Rein, DB et al. Dig Liver Dis. 2011;43:66-72

• Chronically infected cohort

– Long incubation period

– Many undiagnosed/ unaware of infection

– Patients infected in 1960s-1980s approaching era of HCV related morbidity

Forecasted Annual Incident Cases of Decompensated Cirrhosis (DCC), Hepatocellular Carcinoma (HCC), Liver Transplants, and Deaths Associated

with Persons with Chronic Hepatitis C Infection and No Liver Cirrhosis in the United States in 2005

Rein, DB et al. Dig Liver Dis. 2011;43:66-72.

The Evolution of Highly Effective Treatment

Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.

INCIVEK [PI]. Cambridge, MA: Vertex Pharmaceuticals; 2012. VICTRELIS [PI]. Whitehouse Station, NJ: Merck & Co; 2011. OLYSIO [PI]. Titusville, NJ: Janssen Therapeutics; 2013. SOVALDI [PI]. Foster City, CA; Gilead Sciences, Inc. 2013.

IFN

6 mos

PegIFN/

RBV

12 mos

IFN

12 mos

IFN/RBV

12 mos

PegIFN

12 mos

2001

1998

2011

StandardIFN

RBV

PegIFN

1991

BOC and TPV

PegIFN/

RBV/

BOC or TPV

6-12 mos

IFN/RBV

6 mos

6

16

34

42 39

55

70+

0

20

40

60

80

1002013

SOF

89+

SMV

80+

PegIFN/

RBV/

SMV

24-48

wks

PegIFN/

RBV/

SOF

12-24

wks

• NS5B uridine (pyrimidine) nucleotide inhibitor of HCV polymerase effective indicated for genotypes 1-4 as part of combination therapy

• 89-96% cure rates in genotypes 1-4

• Duration of therapy varies– 12 weeks HCV G1 and G2

– 24 weeks required for HCV G3

• High barrier to resistance

• Once daily, 400 mg oral tablet

• Few drug interactions

• Well tolerated, safe

Sofosbuvir

Sofosbuvir Phase 3 Studies

Study Population Total Patients Cirrhotics

NEUTRINO GT 1,4,5,6 Treatment Naïve 327 54 (17%)

FISSION GT 2 & 3 Treatment Naïve 499 100 (20%)

FUSION GT 2 & 3 Treatment Experienced 201 68 (34%)

POSITRON

GT 2 & 3

IFN Intolerant, Ineligible or

Unwilling

278 44 (15%)

Total 1,302 266 (20%)

Lawitz et al, Jacobson et al, Nelson et al, Gane et al. EASL 2013. Amsterdam, The Netherlands.

• Drug interaction potential:

– Low

– Expected with potent P-glycoprotein drugs (ex: rifampin, phenytoin, carbamazepine)

What to Expect When Using Sofosbuvir

• Most common reported side effects:

– Headache

– Fatigue

• Laboratory abnormalities:

– Hemoglobin decline when combined with ribavirin

10/4/2014

5

• Once daily oral HCV NS3/4A protease inhibitor

• Indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen

• Effective in HCV genotype 1 infected subjects

• Screening patients with HCV genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended– Alternative therapy should be considered for patients infected with

HCV genotype 1a containing the Q80K polymorphism

Simeprevir Treatment Duration and Expected Outcomes

SMV, PegIFN, & RBV

PegIFN & RBV Total txtduration

Expected SVR

Naïve and prior relapsers, including cirrhotics

First 12 weeks Addl 12 wks 24 wks Treatment Naïve and Prior Relapsers: ~80%

Prior partial and null responders including cirrhotics

First 12 wks Addl 36 wks 48 wks Prior Partial Responders:~ 65%

Prior Null Responders: ~53%

• Laboratory Abnormalities

– Hyperbilirubinemia

– Anemia

What to Expect When Using Simeprevir

• Side Effects

– Photosensitivity

– Rash

– Pruritus

– Nausea

– Myalgia

– Dyspnea

• Clarithromycin, Telithromycin

• Herbals– St. John’s Wort

– Milk thistle

• Most antiretrovirals

Simeprevir Major Drug Interactions

• Anticonvulsants– Carbamazepine

– Phenytoin

• Rifamycins

• Azoles

New Recommendations for Management of Hepatitis C

http://www.hcvguidelines.org/

Current HCV Treatment Recommendations

AASLD/IDSA HCV Guidance

Population Recommended IFN Ineligible** Alternative

GT 1 TN* SOF + PegIFN + RBV (12 wks)SOF + RBV (24 wks)SOF + SMV (12 wks)

SMV + PegIFN + RBV (24 wks)

TE SOF + SMV (12 wks) SOF + RBV (24 wks)SOF + PegIFN + RBV (12 wks)SMV + PegIFN + RBV (24 wks)

PegIFN + RBV + PI Failure

SOF (12 wks) + PegIFN + RBV (12-24 wks)

SOF + RBV (24 wks)

GT 2 TN* SOF + RBV (12 wks)

TE SOF + RBV (12 wks) SOF + PegIFN + RBV (12 wks)

GT 3 TN* SOF + RBV (24 wks) SOF + PegIFN + RBV (12 wks)

TE SOF + RBV (24 wks) SOF + PegIFN + RBV (12 wks)

GT 4 TN* SOF + PegIFN + RBV (12 wks)SOF + RBV (24 wks)SMV x 12 weeks + PegIFN + RBV x 24-48 weeks

TE SOF + PegIFN + RBV (12 wks) SOF + RBV (24 wks)

GT 5 TN* SOF + PegIFN + RBV (12 wks) SOF + RBV (24 wks) PegIFN + RBV (48 wks)


GT 6 TN* SOF + PegIFN + RBV (12 wks) SOF + RBV (24 wks) PegIFN + RBV (48 wks)


*Treatment-naive patients with compensated cirrhosis, including those with hepatocellular carcinoma, should receive the same treatment as recommended

for patients without cirrhosis.

**Recommended or Alternative regimens for IFN ineligible patients.

AASLD/IDSA/IAS–USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed July 11, 2014


10/4/2014

6

• In Previous Non-Responders– PEG/RBV with or without

telaprevir or boceprevir

– Monotherapy with PEG, RBV, or a direct acting antiviral agent

• Rationale: relatively worse efficacy, long duration of therapy, poor tolerability

What’s Not Recommended


• Pegylated interferon (PEG) and ribavirin (RBV) no longer mainstay of treatment

– Less efficacious

– More adverse effects

NEUTRINO: Sofosbuvir + P/R for 12 Weeks in Treatment-Naive GT 1/4/5/6 HCV

• Open-label, single-arm study of sofosbuvir 400 mg QD + P/R for 12 weeks in treatment-naive patients with GT1/4/5/6 HCV

– 17% cirrhosis; 89% GT1; 9% GT4; < 1% GT5; 2% GT6

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

Overall

SV

R1

2 (

%)

8996

100100

80

60

40

20

0GT1 GT4 GT5,6

261/292 27/28 7/7n/N =

90

295/327

92

80

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

0

20

40

60

80

100

Overall GT 2 GT 3

SOF + RBV 12 Weeks

Peg-IFN + RBV 24 WeeksSV

R12 (

%)

67 67

97

78

5663

170/

253

162/

243

68/

70

52/

67102/

183

110/

176

Jacobson et al. N Engl J Med 2013, 368: 1867-1877, Lawitz et al., N Engl J Med 2013, 368: 1878-1887.

GT2 and GT 3: SVR by Genotype

FISSION Study (Treatment Naive)

HCV GT 3 Treatment Naïve and Treatment Experienced Patients Receiving SOF + RBV for 24 Weeks:Virologic Response and SVR12

VALENCE

212/250 12/13

95

87/92

87

85/98

92

62

29/470

20

40

60

80

10085

213/250

Overall Naïve,Non-cirrhotic

Experienced,Non-cirrhotic

Naïve,Cirrhotic

Experienced,Cirrhotic

SVR

12 (

%)

Non-cirrhotic

Cirrhotic

Overall

Zeuzem S, et al. N Engl J Med 2014;370:1993–2001.

• Sofosbuvir (SOF) 400 mg daily plus simeprevir (SIM) 150 mg daily with or without weight-based ribavirin (RBV) for 12 weeks

• Weight based ribavirin: 1000 mg if patient weight <75 kg to 1200 mg if patient weight >75 kg

Recommendations for Therapy of HCV G1 Patients with Prior PEG/RBV Non-Response


100 100 100

88

9792

100

94

10096

0

20

40

60

80

100

F0-F1 F2

SVR

12,

%

OLYSIO/SOF + RBV OLYSIO/SOF + RBVOLYSIO/SOF OLYSIO/SOF OLYSIO/SOF±RBV

24 weeks 12 weeks Overall

COSMOS Cohort 1: SVR12 by METAVIR Score (Excluding Non-VF*)

8/8 11/12 3/3 10/10 11/11 15/16 7/8 6/6 29/30 42/44

*Excluding patients who discontinued for non-virologic reasons

36Prepared by Janssen Scientific Affairs, LLC

10/4/2014

7

COSMOS Cohort 2: SVR12 – Primary endpoint (ITT population)

ITT, intent-to-treat; Non-VF, Non-virologic failure; RBV, ribavirin; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end

7% 7% 7%

0

20

40

60

80

100

OLYSIO/SOF±RBV

Pro

po

rtio

n o

f p

atie

nts

, %

OLYSIO/SOF + RBV OLYSIO/SOF + RBVOLYSIO/SOF OLYSIO/SOF

24 weeks 12 weeks Overall

SVR12 Non-VF Relapse

93% 100% 93%93% 94%

2/30 1/142/27 3/872/87

28/30 16/16 13/1425/27 82/87

3%2%

Non-VF, patients who did not achieve SVR12 for reasons other than virologic failure

37

• Sofosbuvir 400 mg daily for 12 weeks plus daily weight based ribavirin plus weekly pegylatedinterferon for 12-24 weeks

– Assumes patient is interferon eligible

Alternative Regimen for Previous Non-Responders to PEG/RBV (with or without previous protease inhibitor)


NEUTRINO & FISSION• Sofosbuvir plus PEG/RBV in

treatment naïve patients

• Overall SVR 89% in HCV G1– Lower in patients with

cirrhosis 80% vs no cirrhosis 92%

• SVR response in treatment experienced patients was estimated by FDA

Rationale for Recommendation

Lawitz E, et al. N Engl J Med. 2013;368(20):1878-1887.

• Daily simeprevir 150 mg for 12 weeks plus weight-based ribavirin and weekly pegylated interferon for 48 weeks

• Patients with cirrhosis must have well compensated liver disease to receive simeprevir

Alternative Regimen for Previous Non-Responders to PEG/RBV (with or without previous protease inhibitor)

Zeuzem S. et al. Gastroenterology. 2013a.


• Sofosbuvir 400 mg daily plus weight-based ribavirin for 12 weeks

– Patients with cirrhosis may benefit for a treatment duration of 16 weeks

Recommendations for HCV G2 PEG/RBV Non-Responders


42Zeuzem S, et al. AASLD 2013. Washington, DC. #1085

Sofosbuvir + Ribavirin for 12 weeks of treatment

100% of patients had HCV RNA < LLOQ at Week 4

Relapse after completion of therapy accounted for all virologic failures

Rationale for Recommendations: VALENCE Virologic Response and SVR12

HCV GT2 Treatment-Naïve and –Experienced

93

68/73 212/250

Overall

97 100 91 88

Naïve,Non-cirrhotic

Experienced,Non-cirrhotic

29/30 2/2 7/830/33

SV

R12 (

%)

Naïve,Cirrhotic

Experienced,Cirrhotic

0

20

40

60

80

100

Overall

Non-cirrhotic

Cirrhotic

10/4/2014

8

FUSION & POSITRON

Jacobson IM, et al. N Engl J Med. 2013;368(20):1867-1877

Rationale for Recommendation to Consider Longer Duration of Treatment

• 78% SVR rate with 16 weeks of treatment as compared to 60% with 12 weeks of treatment

• Daily sofosbuvir 400 mg and weight based ribavirin and pegylated interferon for 12 weeks

Alternative Regimen for HCV G2 Prior PEG/RBV Non-Responders


Rationale for Recommendation to Use Sofosbuvir+ PegIFN + Ribavirin:

LONESTAR-2 Virologic Response

HCV GT 2 Treatment-Experienced Patients

Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4

96 100 93

0102030405060708090

100

SV

R1

2 (%

)

Overall

Non-cirrhotic

Cirrhotic

22/23 9/9 13/14*

LLOQ, lower limit of quantification

* 1 cirrhotic patient prematurely discontinued therapy without HCV RNA <LLOQ and did not achieve SVR

• Daily sofosbuvir 400 mg and weight based ribavirin for 24 weeks

Recommendations for HCV G3 PEG/RBV Non-Responders


FUSION & POSITRON

Rationale for Recommendation for Longer Duration of Treatment for HCV G3

• SVR rate for 12 weeks of treatment: 30%

– 19% SVR if cirrhosis

– 37% SVR without cirrhosis

• SVR rate for 16 weeks of treatment: 62%

– 61% SVR if cirrhosis

– 63% SVR without cirrhosis

Jacobson IM, et al. N Engl J Med. 2013;368(20):1867-1877 48Zeuzem S, et al. AASLD 2013. Washington, DC. #1085

Rationale for Extending Duration of Therapy:

VALENCE Virologic Response and SVR12

HCV GT3 Treatment-Naïve and –Experienced

Sofosbuvir and ribavirin for 24 week duration of therapy

1 patient experienced virologic breakthrough – PK documented non-adherence

Relapse after completion of therapy accounted for all other virologic failures

Non-cirrhotic

212/250 12/13

94

86/92

Naïve,

Non-cirrhotic

87

87/100

Experienced,

Non-cirrhotic

92

Naïve,

Cirrhotic

60

27/45

Experienced,

Cirrhotic

0

20

40

60

80

10085

Overall

212/250

Overall

Cirrhotic

SV

R12 (

%)

10/4/2014

9

• Daily sofosbuvir 400 mg and weight based ribavirin and pegylated interferon for 12 weeks

Alternative Regimen for HCV G3 PEG/RBV Non-Responders


Rationale for Adding PegIFN: LONESTAR-2 Virologic Response

HCV GT 3 Treatment-Experienced Patients

SOF + PegIFN + RBV x 12 weeks

Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4

83 83 83

0102030405060708090

100

SV

R1

2 (%

)

Overall

Non-cirrhotic

Cirrhotic

20/24 10/12* 10/12*

*1 patient relapsed and 1 patient was lost to follow-up in each subgroup/12†

• For HCV G1 prior nonresponders, the use of boceprevir or telaprevir as a retreatment strategy with pegylated interferon and ribavirin is not recommended

– Less effective

– Longer duration of therapy

– Poor tolerability

• Pegylated interferon and ribavirin are no longer the mainstay of treatment

Key Points for Retreatment

• Clinical Scenario: 46 yo female with chronic HCV, hypertension and hyperlipidemia

• What drug interactions can be expected and how should they be handled?

Concerns for Concurrent Use of Statins and Boceprevir and Telaprevir

Boceprevir Telaprevir

Atorvastatin Use lowest effective doseMax daily dose of 40 mg

Avoid coadministration

Fluvastatin, pitavastatin, rosuvastatin

Contraindicated in active liver disease- DDI unlikely

Contraindicated in active liver disease- DDI possible

Lovastatin Contraindicated Contraindicated

Pravastatin Caution is warranted Caution is warranted

Simvastatin Contraindicated Contraindicated

Victrelis® Prescribing Information, Merck and Co. Inc. September 2013

Incivek® Prescribing Information, Vertex Pharmaceuticals Inc. October 2013

Drug Interactions with Simeprevir

Drug Effect Recommendation

Calcium Channel Blockers:Amlodipine, diltiazem,felodipine, nicardipine, nifedipine, nisoldipine, verapamil

Increase concentration of calcium channel blockers

Use caution

Atorvastatin Increase concentration of atorvastatin

Use lowest possible dose, do not exceed 40 mg

Rosuvastatin Increase concentration of rosuvastatin

Start at 5 mg daily, do not exceed 10 mg daily

Simvastatin Increase concentration of simvastatin

Use lowest possible dose

Pitavastatin, Pravastatin, Lovastatin

Expected to increase concentration of eachstatin

Use lowest possible dose

Olysio ® [package insert]. Titusville, NJ: Janssen Therapeutics; 2013.

10/4/2014

10

• No drug interactions expected with statins, calcium channel blockers, or oral steroids

Sofosbuvir

Sovaldi ® [package insert]. Foster City, CA: Gilead Sciences, Inc; 2013.

• Clinical Scenario: 44 yo male coinfected with HIV and HCV.

• What kind of response rates can this patient expect?

• What drug interactions can be expected and how should they be handled?

AASLD/IDSA Recommendations for Treatment

HCV Genotype Recommended Treatment

HCV 1 SOF + PEG/RBV x 12 weeksSOF + RBV x 24 weeksSOF + SMV +RBV x 12 weeks

HCV 2 SOF + RBV x 12 weeks

HCV 3 SOF + RBV x 24 weeks

HCV 4 SOF + PEG/RBV x 12 weeks

HCV 5 SOF + PEG/RBV x 12 weeks

No differences in drug therapy for HIV-HCV coinfection


96100

76

0

20

40

60

80

100

Week 4 EOT SVR12

GT 1

HC

V R

NA

< 2

5 I

U/m

L (%

)

110/114 87/114

96 9688

0

20

40

60

80

100

Week 4 EOT SVR12

GT 2

HC

V R

NA

< 2

5 I

U/m

L (%

)

25/26 23/2622/23

Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212

No HCV resistance (S282T) was observed in virologic failures via deep sequencing

Two patients had HCV breakthrough; both had documented non-adherence to SOF

Two patients had transient HIV breakthrough; both had documented non-adherence to ART

100 98

67

0

20

40

60

80

100

Week 4 EOT SVR12

GT 3

HC

V R

NA

< 2

5 I

U/m

L (%

)

41/41 28/42

SOF + RBV x24 weeks SOF + RBV x12 weeks SOF + RBV x12 weeks

All-Oral Therapy of SOF + RBV in Treatment-Naive HIV/HCV Coinfection

PHOTON-1 Virologic Response

100/100 39/40

Osinusi A, et al. JAMA. 2013;310(8):804-811.Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212. Zeuzem S, et al. AASLD 2013. Washington, DC. #1085. Lawitz E, et al. N Engl J Med. 2013 May 16;368(20):1878-87.

Similar response rates in HIV/HCV coinfected patients compared

to HCV monoinfected patients

GT 1SOF + RBV

24 weeks

GT 2SOF + RBV

12 weeks

GT 3SOF + RBV

12 weeks

All-Oral Therapy of SOF + RBV

Comparison of HCV Monoinfected to HIV/HCV Coinfected

GT 3SOF + RBV

24 weeks

SVR

12

(%

)

6876

0

20

40

60

80

100

SPARE PHOTON-1

SVR

12

(%

)

9388

0

20

40

60

80

100

VALENCE PHOTON-1

SVR

12

(%

) 5667

0

20

40

60

80

100

FISSION PHOTON-1

SVR

12

(%

)

85

0

20

40

60

80

100

VALENCE

Similar response rates in HIV/HCV co-infected patients compared

to HCV mono-infected patients

91 91

0

20

40

60

80

100

NEUTRINO(HCV Mono-infected)

Study 1910(HIV/HCV Co-infected)

SVR

12

(%

)

Rationale for Recommendations: SOF + PegIFN + RBV x 12 Weeks

Comparison of HCV Mono-infected to HIV/HCV Co-infected

Lawitz E, et al. APASL 2013. Singapore. Oral #LB-02 Rodriguez-Torres M, et al. IDWeek 2013; San Francisco, CA. Poster #714

10/4/2014

11

HIV Drug Interactions with Simeprevir


Cobicistat-containingproduct (elvitegravir/ cobicstat/ emtricitabine/ tenofovir)

Increases simeprevir Co-administration not recommended

Darunavir/ ritonavir Increases simeprevirIncreases darunavir

Co-administration not recommended

Ritonavir Increases simeprevir Co-administration not recommended

Efavirenz Decreases simeprevir Co-administration not recommended


HIV Drug Interactions with Simeprevir


Other ritonavir-boosted or unboosted HIV PIs(atazanavir, fosamprenavir, lopinavir, indinavir, nelfinavir, saquinavir, tipranavir)

Increases or decreases simeprevir


NNRTI: delaviridine, etravirine, or nevirapine

Increases or decreases simeprevir



• Raltegravir

• Rilvirine

• Tenofovir

HIV Drugs without Clinically Significant Drug Interactions with Simeprevir


HIV Drugs Interactions with Sofosbuvir

Known Interaction

• Tipranavir/ritonavir– Reduces concentration of

sofosbuvir and its active metabolite

– Do not coadminister

No Clinically Significant Interactions

• Darunavir/ritonavir

• Efavirenz

• Emtricitabine

• Raltegrevir

• Rilviripine

• Tenofovir disoproxilfumarate


• SOF + RBV resulted in high SVR12 rates in HCV treatment-naïve, HIV-infected patients with GT 1, 2, and 3 coinfection

– Similar to those observed in patients with HCV monoinfection

• SOF + RBV was effectively co-administered with multiple antiretroviral regimens including inhibitors of HIV-1 protease, reverse transcriptase (non-nucleoside/nucleoside) and integrase inhibitor

• Simeprevir use limited to HIV regimens with raltegrevir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricatabine, lamivudine, abacavir

Key Points in HIV-HCV Coinfection

Sulkowski MS, et al. AASLD 2013. Washington, DC. Oral #212

AASLD/IDSA HCV Guidelines Available at: www.hcvguidelines.org/full-report/unique-patient-populations-hivhcv-coinfection-box-recommendations-hivhcv-coinfected

• Clinical Scenario: 48 yo male with cirrhosis s/p liver transplant, previously treated with pegylatedinterferon and ribavirin, prior non-responder, now planning retreatment of HCV

• What drug interactions can be expected?

10/4/2014

12

Challenges of Boceprevir and Telaprevir in Post-Transplant Setting

Cyclosporine Tacrolimus

Telaprevir Increase Cmax by 32%Increase AUC by 4.6x

Increase Cmax by 9.35xIncrease AUC by 70.3x

Boceprevir Increase Cmax by 101%Increase AUC by 168%

Increase Cmax by 10xIncrease AUC by 17x

• Require frequent monitoring of immunosuppressive agent

• Require (substantial) dose reductions and/or decreased frequency of dosing

Victrelis Prescribing Information, Merck and Co. Inc. September 2013

Incivek Prescribing Information, Vertex Pharmaceuticals Inc. October 2013

Drug Interactions with Simeprevir and Immunosuppressive Agents

Drug Effect Recommendations

Cyclosporine Increases cyclosporine No dose adjustmentMonitor cyclosporine levels

Tacrolimus Decreases tacrolimus No dose adjustmentMonitor tacrolimus levels

Sirolimus Either decrease or increase sirolimus

Monitor sirolimus levels


• Cyclosporine and tacrolimus

– No interaction and no dose adjustment needed

Using Sofosbuvir in Patients on Immunosuppressive Agents


• http://www.hcvguidelines.org/

• http://www.hep-druginteractions.org/

Tools for Managing HCV Therapies and Drug Interactions

• Clinical Scenario: 38 yo female with chronic HCV with no evidence of cirrhosis

• Should this patient be treated now or wait for newer therapies?

The Holy Grail of HCV Therapy: Interferon Free

http://www.hep-druginteractions.org/

http://www.hep-druginteractions.org/

10/4/2014

13

Future HCV Direct Acting Agents (DAAs)

Faldaprevir

Daclatasvir

Danoprevir

Asunaprevir Mericitabine

Vaniprevir

Ledipasvir

ABT-267

ABT-333

ABT-450/r

NS5ANS3 NS4A NS5B

IDX-719

BMS-791325

Protease Inhibitors Polymerase InhibitorsNS5A Inhibitors

Deleobuvir

GS-9451

VX-222

Tegobuvir

GS-9669

• INVESTIGATIONAL – Not yet FDA-approved

Simeprevir Sofosbuvir74

Ledipasvir (LDV, GS-5885): NS5A Inhibitor

NS5A is essential for RNA replication

and post-replication assembly and

secretion

LDV has picomolar potency against

genotype 1a and 1b HCV

Effective against signature NS5B-resistant mutant S282T

Once-daily oral dosing

Dosed in >3000 patients

No clinically significant drug-drug interactions with sofosbuvir

N

NN

O

N

O

O

N

N

H

ON

O

O

H

N

H

H HF F

Lawitz EJ et al, J Hepatol 2012; 57: 24–31; Gane EJ, et al. CROI 2013; Atlanta, GA. Oral #41LB

75

Ledipasvir/Sofosbuvir: A Single Tablet Regimen (STR)

LDV

NS5A

inhibitor

SOF - NS5B

nucleotide

polymerase

inhibitor

LDV

NS5A

inhibitor

SOF - NS5B

nucleotide

polymerase

inhibitor

Ledipasvir

– Picomolar potency against HCV GT 1a and 1b1

– Effective against NS5B RAV S282T2

– Once-daily, oral, 90 mg

Sofosbuvir

‒ Potent antiviral activity against HCV GT 1–6

‒ Effective against NS5A RAVs3

‒ High barrier to resistance

‒ Once-daily, oral, 400-mg tablet

Ledipasvir/Sofosbuvir STR

– Once-daily, oral fixed-dose (90/400 mg) combination tablet, RBV-free

– Minimal DDIs, no food effect

– >2000 patients treated

Priority Review and Breakthrough Status Granted

PDUFA: Oct 10, 20141. Lawitz E, et al. EASL 2011, poster 1219; 2. Cheng G, et al. EASL 2012, poster 1172; 3. SOVALDI® [PI]. Gilead Sciences, Inc. Foster City, CA December 2013

LDV/SOF + RBV

LDV/SOF

LDV/SOF + RBV

LDV/SOF

Wk 0 Wk 12 Wk 24

LDV/SOF

LDV/SOF + RBV

Wk 8

ION-1 treatment naïve: N = 865

ION-2 treatment experienced: N = 440

ION-3 treatment naïve: N = 647

N=1952 total patients

ION-1

ION-2

ION-3

LDV/SOF Phase 3 Program (ION-1, ION-2, ION-3)

LDV/SOF Phase 3 Program

0

20

40

60

80

100

ION-1GT 1 treatment-naïve

including cirrhotics

ION-3GT 1 treatment-naïve

non-cirrhotic

ION-2 GT 1 treatment-experienced

including cirrhotics and PI failures

99 97 98 99 94 93 95 94 96 99 99

LDV/SOF LDV/SOF+RBV

12 Weeks 24 Weeks 12 Weeks 24 Weeks12 Weeks

Efficacy Summary

ION Phase 3 Program (ION-1, ION-2, ION-3)

SVR

12

(%

)

Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print] Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]

8 Weeks

107/111

102/109

108/109

110/111

211/217

211/214

212/217

215/217

202/215

201/216

206/216

Error bars represent 95% confidence intervals.

• 97% (1886/1952) overall SVR rate

Retreatment of Relapsers to SOF+RBV with LDV/SOF STR for 12 Weeks

14/14 14/14 14/14 14/14 14/14 14/14

100 100 100

0

20

40

60

80

100

Week 4 EOT SVR12

% o

f p

atie

nts

with

HC

V

RN

A <

LL

OQ

14/14 14/14 14/14

SYNERGY Trial (NIAID, LDV/SOF)

Osinusi A, EASL, 2014, O11

IFN and RBV free regimen of LDV/SOF resulted in 100% SVR12 rates in patients who had previously failed SOF+RBV 24 week therapy

10/4/2014

14

LDV/SOF ± RBV in Difficult-to-Treat HCV Populations

ELECTRON-2 (LDV/SOF±RBV)

Gane E, EASL, 2014, O6

Wk 0 Wk 12 Wk 24

SVR12

LDV/SOFGT 1; n=20

CTP class B cirrhotics

LDV/SOF + RBVGT 1; n=19

Prior SOF exposure

LDV/SOF + RBV, n=26

LDV/SOF, n=25GT 3; n=51

Treatment naïve,

including cirrhosis

Random

ized

• Prior treatment history of SOF relapsers included SOF + RBV ± DAA

• Cirrhosis was present in all CTP class B and 16% of GT 3 patients

SVR12 Results with LDV/SOF±RBV for 12 Weeks

100

65 64

100

0

20

40

60

80

100

GT1 Retreatment GT1 CPT Class B GT3 Naïve GT3 Naïve

SV

R1

2 (

%)

LDV/SOF + RBV LDV/SOF LDV/SOF LDV/SOF + RBV

13/20 16/25 26/2619/19

The regimens were safe and well tolerated

Gane E, EASL, 2014, O6

ELECTRON-2 (LDV/SOF±RBV)

LDV/SOF STR for 12 weeks in HCV GT 1 Treatment-naïve Co-infected with HIV

100 100 100 100 100 100100 100 100 100

0

20

40

60

80

100

Week 4 Week 8 EOT SVR4 SVR8 SVR12

% o

f patien

ts w

ith

HC

V R

NA

<

LL

OQ

ARV Untreated ARV Treated

13/13

37/37

13/13

37/37

13/13

30/30

12/12

22/22

10/10

10/10

ERADICATE Study (NIAID, LDV/SOF)

Osinusi A, EASL, 2014, O14 Source: Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.

Hepatitis C Cascade of Care in United States

100%

50%

35%

9% 6%

• Chronic HCV infections pose substantial healthcare burden in the US and in NM

• All oral, interferon free regimens are available and emerging therapies will provide additional interferon free treatment options

• Newer treatments improve cure rates even among previously difficult to treat patients

• Rapidly evolving field of HCV therapy

– Treatment duration approaching 12 weeks

– Complexity of treatment will likely further decrease

• Access to treatment remains a challenge

Final Thoughts

powerpoint presentation...smv 80+ pegifn/ rbv/ smv 24-48 wks pegifn/ rbv/ sof 12-24 • ns5b uridine...

Documents