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Hepatitis C Treatment QuestionsJenny Chan 10/16/14 PharmD Candidate c/o 2015Providence Everett Ambulatory Care

Image from: http://www.emcdda.europa.eu/userfiles/image/pods/hcv/hcvVirus380x285.jpg

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Back to the Basics• Most common blood-borne pathogen.• In the U.S. approx. 3.2 million people

chronically infected. • Nearly 85% of acutely infected patients go

on to develop chronic infections.• Chronic infections will eventually progress

to cirrhosis in 20-30 years. • Characteristics of HCV• Single stranded RNA virus without a proofreading polymerase • Fast viral replication (est. serum half-life 2-3 hours)

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Back to the Basics• 6 major genotypes (1-6, subdivided into a

and b)•Most common genotype: 1a/1b followed by genotypes 2 and 3. • Genotypes 4, 5, 6 more uncommon. • Genotype determines treatment success. • Genotype 1 is more difficult to treat.

• High risk groups• Injection drug users• Prisoners • Homeless people

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Is a HCV vaccine possible?• Currently, HCV is not vaccine

preventable. • The high mutation rate and

variable surface make vaccine development a challenge.

• However, Inovio is currently developing a synthetic multi-antigen DNA immunotherapy targeting HCV genotypes 1a and 1b and antigens NS3/4A. INO-800 HCV is in Phase I clinical trials and results expected in 2015.

INO-8000 HCV. http://www.inovio.com/products/infectious-disease-vaccines/hepatitis/ino8000HCV/Study protocol: http://clinicaltrials.gov/show/NCT02027116Image: http://www.inovio.com/technology/electroporation-delivery/electroporation-devices/intramuscular-delivery/

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Current Treatment Guidelines Genotype 1Treatment-Naïve Patients

Interferon Eligible • Daily sofosbuvir (400

mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is recommended for IFN-eligible persons with HCV genotype 1 infection, regardless of subtype.

Not Eligible for Interferon• Daily sofosbuvir (400

mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg] for 12 weeks is recommended

• RBV: ribavirin

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Contraindications to Interferon Therapy• Intolerance to IFN• Autoimmune hepatitis or other autoimmune

disorders• Hypersensitivity to PEG or any of its components• Decompensated hepatic disease• Major uncontrolled depressive illness• A baseline neutrophil count below 1500/uL, a

baseline platelet count below 90,000/uL or baseline hemoglobin below 10 g/dL

• A history of preexisting cardiac disease

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Current Treatment Guidelines Genotype 1Treatment-Experienced Patients

No Previous HCV PI• Daily sofosbuvir (400

mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for retreatment of HCV genotype 1 infection, regardless of subtype or IFN eligibility.

Previous HCV PI• Daily sofosbuvir (400

mg) for 12 weeks plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) and weekly PEG for 12 to 24 weeks is recommended for retreatment of HCV genotype 1 infection, regardless of subtype

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Current Treatment Guidelines Genotype 2Treatment-Naïve Patients

Treatment Naïve• Daily sofosbuvir (400

mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for treatment-naive patients with HCV genotype 2 infection.

Treatment Experienced

• Daily sofosbuvir (400 mg) for 12 weeks and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 to 24 weeks is an alternative for retreatment of IFN-eligible persons with HCV genotype 1 infection, regardless of subtype.

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Who Should Receive Treatment?• Treatment is recommended for patients with chronic HCV

infection and highest priority given to those patients with advanced fibrosis, compensated cirrhosis, liver transplant patients and patients with severe extrahepatic disease.

• Treatment not recommended for the following:• Patients with limited life expectancy (<12 months) due to non-liver

issues• Patients in whom HCV therapy would not improve symptoms or

prognosis • Cost of treatment• Solvaldi (sofosbuvir): $1000/pill, or $84,000 for a typical 12 week

course plus cost of other medications• Harvoni (sofosbuvir/ledipasvir): $1125/pill, or $94,500 for a 12-

week course. Approved 10/10/14 for standalone use.

Harvoni, a Hepatitis C Drug From Gilead, Wins F.D.A. Approval. Oct 10, 2014. http://www.nytimes.com/2014/10/11/business/harvoni-a-hepatitis-c-drug-from-gilead-wins-fda-approval.html

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Efficacy of Sofosbuvir: Phase III Studies

Study Design Genotype SVR4

SVR12

FISSION SOF 400 mg/RBV 12 wk (n = 253) OR PEG/RBV (n = 243)

2, 3; naïve 74 67 (G2 97; G3 56)67

NEUTRINO SOF 400 mg/RBV/PEG 12 wk (n = 327)

1, 4, 5, 6; naïve (98% G1 or 4)

92 90 (G1a 92; G1b 82; G4 96)

POSITRON SOF 400 mg/RBV (n = 207) OR Placebo (n = 71) 12 weeks

2, 3; naïve (IFN not an option)83 78 (G2 93; G3 61)

FUSION SOF 400 mg/RBV 2, 3; previous treatment failure

   

  12 weeks (n=103) OR   56 50 (G2 86; G3 30)  16 weeks (n = 98)   77 73 (G2 94; G3 62)

Figure modified from Table 2: Phase III studies of sofosbuvir. Stedman C. Sofosbuvir, a NS5B polymerase inhibitor in the treatment of hepatitis C: a review of its clinical potential. Therap Adv Gastroenterol. May 2014; 7(3): 131-40. doi: 10.1177/1756283X1515825.

Sustained Virologic Response (SVR): defined as serum HCV below 25 copies/mL 12 weeks after treatment cessation.

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HIV and HCV Co-Infection• ~30-40% of HIV infected people are coinfected

with HCV and this proportion is even higher in IVDU

• HIV infection results in more rapid progression to liver cirrhosis, ESLD, and hepatocellular carcinoma but the effects of HCV infection on HIV are unclear.

• Multivariate Cox-regression model used on ERCHIVES• Among 8,039 HIV infected US veterans, 65% had HCV

coinfection.• All-cause mortality rate 74.1 per 1000 person-years (PY)

with HIV/HCV coinfection compared to 39.8 per PY with HIV monoinfection.• HCV treatment, higher CD4 count, and higher BMI are

predictors of decreased mortality.

Erqou S, Mohanty A, Murtaza Kasi P, Butt A. Predictors of Mortality among United States Veterans with Human Immunodeficiency Virus and Hepatitis C Virus Coinfection. ISRN Gastroenterol [Internet]. 2014 April 7 [cited 2014 Oct 11].DOI: 10.1155/2014/764540

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HIV and HCV Coinfection Treatment Trials• TURQUOISE-1• Randomized open-label trial• Hep C genotype 1 patients with well-controlled HIV on

antiretroviral regimens that included raltegravir or PI atazanavir.

• Duration:12 and 24 weeks• Triple Regimen

• ABT-450 (ritonavir/ombitasvir)• Dasabuvir• Weight-based RBV

• Results• 12-week tx group: SVR 12 weeks after tx cessation was 93.5%• 24-week tx group: SVR 4 weeks after tx cessation was 97%

Oral Hepatitis C Drugs Helping Patients Coinfected with HIV. July 25,2014. http://www.medscape.com/viewarticle/828945#vp_1.

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HIV/HCV Coinfection Treatment Trials• PHOTON-2• Open-label nonrandomized and uncontrolled trial• Hep C genotype 1-4 patients on a backbone HIV

regimen that consisted of tenofovir plus emtricitabine• Regimen• Sofosbuvir 400 mg a day plus weight-based RBV

• Duration: • Treatment naïve GT 1, 3, 4: 24 weeks• Treatment naïve GT 2: 12 weeks• Treatment experienced GT 2,3: 24 weeks

• Results• Over 80% SVR at 12 weeks after tx cessation in all genotypes

Oral Hepatitis C Drugs Helping Patients Coinfected with HIV. July 25,2014. http://www.medscape.com/viewarticle/828945#vp_1.

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Pregnancy Considerations• HCV prevalence in pregnant women is low (1-2%) in most

western countries but much higher in developing countries.

• Acute infection during pregnancy is rare. Most common scenario is chronic infection.

• Risks of HCV infection• Premature rupture of membrane and caesarean delivery• Increased risk of gestational diabetes in mothers with excessive

weight gain. • May exacerbate chronic hepatitis and worsen liver function in

women with liver cirrhosis• Vertical transmission• Mother-to-child HCV transmission rate is low (3-5%). • Transmission rate increases up to 19.4% if the mother is HIV(+).

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Pregnancy Considerations • Should pregnant women be treated?• Which drug is NOT recommended for use in

pregnant women or women who may become pregnant?

• For how long should pregnancy be avoided after using one of the agents above?

• Other options?

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Treatment in Children• Spontaneous clearance of HCV has been reported

in up to 25-30% of HCV-infected children. • Children 2 years or older are eligible for treatment

but not all children should be treated. • Treat only those at high risk of progression?

• Pediatric HCV infection is associated with minimal or mild liver disease. Hepatocellular carcinoma is rare in children with HCV infection.

Tosone G, Enrico Maraolo A, Mascolo S, Palmiero G, Tambaro O, Orlando R. Vertical hepatitis C virus transmission: Main questions and answers. World J Hepat [Internet]. 2014 Aug 27 [cited 2014 Oct 11]. 6(8): 538-48. doi: 10.4254/wjh.v6.i8.538

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Use of Statins in HCV Patients

• Statins may provide additional benefit to treatment of HCV.

• Phase 2 Randomized controlled trial (n=45)• Fluvastatin or simvastatin has some antiviral activity

against HCV as monotherapy. • The addition of fluvastatin or simvastatin to

PEG-IFN/RBV for 48 weeks in HCV genotype 1 treatment-naïve patients showed a trend towards improving SVR (not statistically significant). • 13 patients (statin) vs 5 patients (placebo) achieved

SVR• Statin therapy was well-tolerated. No reports of unusual

muscle pain. Bader T, Hughes LD, Fazili J, Frost B, Dunnam M, Gonterman A, Madhoun M, Aston CE. A randomized controlled trialAdding fluvastatin to peginterferon and ribavirin for naïve genotype 1 hepatitis C patients. J Viral Hept [Internet]. 2013 Mar 6 [cited 2014 Oct 15]. 20)9):622-7. DOI: 10.1111/jvh.12085.

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Use of Statins in HCV Patients• Statins may have a protective effect on hepatocellular

carcinoma (HCC) in HCV patients. • Population-based cohort study (n= 260,864)• HCV patients enrolled in a Taiwanese database from

1999-2010• Statin used defined as >28 cumulative daily doses.• 13.4% of this population used statins• 10.7% of this population were diagnosed with HCC• Adjusted HR 0.53; 95% CI, 0.49 to 0.58) after

controlling for confounders (age, sex, urbanization, income, liver cirrhosis, and diabetes)

Tsan Y, Lee C Ho W, Lin M, Wang J, Chen P. Statins and the Risk of Hepatocellular Carcinoma in Patients With Hepatitis C Virus Infection. JCO [Internet] 2013 Mar 18 [cited 2014 Oct 15]. 31(12): 1514-21. DOI: 10.1200/JCO.2012.44.6831.

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Statins and DDIs in HCV PatientsStatin PI Magnitude of

interaction (fold)

Recommendation

Lovastatin, Simvastatin

All Up to 30 Should not be co-administered

Atorvastatin Teleprevir 8 Should not be co-administered

Pitavastatin All 0.7-1 Start at standard dosePravastatin All 0.7-1 Start at standard doseRosuvastatin All 1-3 Avoid if possible. Start at

5 mg. Max daily dose= 10 mg

Fluvastatin All No data Coadministration probably safe. Start at standard dose.

All = All ritonavir- or cobicistat-boosted HIV + PIs or other ARV and boceprevir and telaprevir.

Chauvin B, Drouot S, Barrail-Tran A, Taburet A. Drug-Drug Interactions Between HMG-CoA Reductase Inhibitors(Statins) and Antiviral Protease Inhibitors. Clin PHarmacokinet [Internet]. 2013 May 24 [cited 2014 Oct 15]. 52:815-31. DOI: 10.1007/s40262-013-0075-4

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New Hep C Drugs in the Pipeline

Phase 2Drug Category

Drug Name

Protease Inhibitors

ACH-2684Danoprevir Sovaprevir

NS5A Inhibitors ACH-3102NS5A Inhibitor/PI

Daclatasvir/SimeprevirIDX719/SimeprevirACH-3102/Sovaprevir

NS5A Inhibitor/ Polymerase Inhibitor

GS-5816/Sofosbuvir

PI/Polymerase Inh.

Simeprevir/TMC647055/Ritonavir

Phase 3Drug Category Drug NamePI/NS5A Inh/Poly Inh

ABT-450/r, Ombitasvir/Dasabuvir

NS5A Inhibitor/PI/ Polymerase Inhibitor

Daclatasvir/Asunaprevir/BMS-791325

PI/NS5A inhibitor MK-5172/MK-8742NS5A Inh./Poly Inh.

Daclatasvir/Sofosbuvir

Hepatitis C Treatments in Current Clinical Development. Updated Sept 17, 2014. http://hcvadvocate.org/hepatitis/hepc/Quick_Ref_Guide.pdf

Red: Submitted to the FDA. Expected approval Dec 2014

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New Hep C Drugs in the Pipeline

Phase 2Drug Name Drug

CategoryResminostat HDAC InhibitorCF102 A3AR

Agonist/Anti-Liver Cancer

GI-5005 Therapeutic Vaccine

Miravirsen microRNAOral Interferon Oral InterferonSCY-635 Cyclophilin

Inhibitor TG4040 Therapeutic

Vaccine

Phase 3Drug Name Drug

CategoryAlinia ThiazolidesDoxorubicin Anti-Liver

CancerLivatag (Doxorubicin/Transdrug)

Anti-Liver Cancer

Hepatitis C Treatments in Current Clinical Development. Updated Sept 17, 2014. http://hcvadvocate.org/hepatitis/hepc/Quick_Ref_Guide.pdf

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References• Deming P. Chapter 26. Viral Hepatitis. In: DiPiro JT, Talbert RL, Yee

GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com.offcampus.lib.washington.edu/content.aspx?bookid=689&Sectionid=48811468. Accessed October 11, 2014.

• AASLD/IDSA/IAS–USA. Recommendations for Testing, Managing and Treating Hepatitis C. Updated Aug 11, 2014. Available from: http://www.hcvguidelines.org. Accessed Oct 8, 2014.