Hepatitis C May Nguyen, PharmD, CGP PHAS 3311 Spring 2015

Required Reading Pharmacology for the Primary Care Provider

Unit 14, Chapter 67, 68, 69

Lippincotts Illustrated Reviews Unit VII, Chapter 38

Hepatic Viruses

Hepatic Viruses A, B, C, D and E

Hepatitis D (uncommon in US) transmission (parenteral) requires co-infection with hepatitis B to replicate can lead to chronic infection

Hepatitis E (uncommon in US) is spread by fecal-oral route typically self

limited (chronic infection rare)

Hepatitis B and C are the most common causes of chronic hepatitis, cirrhosis and hepatocellular carcinoma Lauer G, et al. N Engl J Med 2001;345(1):41-52.

www.cdc.gov/hepatitis

Hepatitis Vaccines Vaccines only available for types A and B No vaccine for Hepatitis D but can be prevented by Hepatitis B

vaccine (since co-infection required for replication)

Vaccine Recommendations Immunity Administration* Hepatitis A (inactivated)

All children at age 1 Risk populations in community or travel Illegal drug use Occupational risk Sexual risks Chronic liver disease Frequent blood infusions Transplant

100% after second dose lasting up to 20 years or longer

2 doses given 6-18 months apart

Hepatitis B (recombinant)

All infants, beginning at birth Risk populations Similar to Hepatitis A above Also HIV, DM

~ 95% after 3rd dose lasting at least 20 years

3 doses - 2nd and 3rd doses at 1 and 6 months

www.cdc.gov/vaccines/pubs/pinkbook/hepa.htmll www.cdc.gov/vaccines/pubs/hepb/html

*Combination vaccines available but dosing age and schedule may vary

HAV available in us since 1995 Inactivated Vaccines Scientists produce inactivated vaccines by killing the disease-causing microbe with chemicals, heat, or

radiation. Such vaccines are more stable and safer than live vaccines: The dead microbes cant mutate back to their disease-causing state. Inactivated vaccines usually dont require refrigeration, and they can be easily stored and transported in a freeze-dried form, which makes them accessible to people in developing countries.

Most inactivated vaccines, however, stimulate a weaker immune system response than do live vaccines. So it would likely take several additional doses, or booster shots, to maintain a persons immunity. This could be a drawback in areas where people dont have regular access to health care and cant get booster shots on time.

HBV available since 1986 Can also be given to pregnant and immunocompromised HBV vaccine - The recommendation to vaccinate patients with diabetes was added in October 2011. It was based on findings that lapses in infection control procedures during blood glucose monitoring have led to HBV transmission. Unvaccinated adults 60 years or younger with diabetes may be vaccinated at the discretion of the treating clinician after assessing their risk and the likelihood of an adequate immune response to vaccination.

Recombinant vector vaccines similar to DNA vaccines, but they use an attenuated virus or bacterium to introduce microbial DNA to cells of the body. Vector refers to the virus or bacterium used as the carrier.

In nature, viruses latch on to cells and inject their genetic material into them. In the lab, scientists have taken advantage of this process. They have figured out how to take the roomy genomes of certain harmless or attenuated viruses and insert portions of the genetic material from other microbes into them. The carrier viruses then ferry that microbial DNA to cells. Recombinant vector vaccines closely mimic a natural infection and therefore do a good job of stimulating the immune system.

Recombinant vaccine is produced by inserting a plasmid containing the gene for HBsAg into common bakers yeast (Saccharomyces cerevisiae). Yeast cells then produce HBsAg, which is harvested and purified. The recombinant vaccine contains more than 95% HBsAg protein (5 to 40 mcg/mL); yeast-derived proteins may constitute up to 5% of the final product, but no yeast DNA is detectable in the vaccine. HBV infection cannot result from use of the recombinant vaccine, since no potentially infectious viral DNA or complete viral particles are produced in the recombinant system. Vaccine HBsAg is adsorbed to aluminum hydroxide.

Hepatitis C

Hepatitis C - Epidemiology

Acute infection (only 20-30% experience symptoms) 75 85% develop chronic infection 60 70% will develope chronic liver disease 5 20% will go on to develop cirrhosis over a period of 2030 yrs 1 5% will die from cancer or cirrhosis

Most common blood-borne viral infection in the US Chronic infection ~130 to 140 million people worldwide Leading cause of chronic hepatitis, cirrhosis, and liver cancer and

primary indication for liver transplantation

www.cdc.gov/hepatits/HCV

Hepatitis C Screening One-time testing for HCV is recommended in the following

Behaviors (may require more frequent testing) History of illicit drug use (especially IV), sexual risks

Exposures HD, tattoos, health care workers with needlestick or

mucosal HCV blood exposure, children born to HCV-infected mothers,Blood transfusion or organ transplant prior to 1992 and history of incarceration

Comorbid medical conditions HIV, chronic liver disease or hepatitis

Baby- Boomers born between 1945 and 1965

www.cdc.gov/hepatits/HCV

Among persons in the United States who are chronically infected with HCV, an estimated 45% to 85% are unaware of their infection.3 This presents a challenge for appropriate identification of HCV cases and highlights the importance of recognizing risk factors for infection. The single most important risk factor for HCV infection is injection drug use, which accounts for more than 60% of acute infections

The most recent surveys of active IVDUs indicate that approximately one-third of young (1830 years) IVDUs are HCV infected. Older and former IVDUs typically have a much higher prevalence (~7090%) of HCV infection, which is generally attributable to needle sharing during the 1970s and 1980s, before the risks of blood-borne viruses were widely known.15

When to Treat? The decision to treat hepatitis C is dependent on many

factors that are outside the scope of this lecture. Depends on virus genotype, patient factors (compliance),

viral load, antigen levels and progression of disease.

In general, treatment recommended for persons with Complications (cirrhosis, fibrosis, transplant, etc) or high risk

for complications (HBV, HIV, DM, etc) High risk for HCV transmission to others

www.cdc.gov/hepatits/HCV

Hepatitis C Treatment Goals of therapy

Improve survival Achieve a sustained virologic response (SVR) Defined as undetectable HCV RNA 6 months post-treatment

Prevent complications (ex. cirrhosis, HCC, liver transplant)

Treatment considerations Hepatitis C genotype Patient factors Concomitant diseases, compliance, pregnancy, insurance and

access to healthcare, prior treatment experience Drug factors SVR rates, daily pill burden, side effects, drug interactions

www.cdc.gov/hepatits/HCV

Historical HCV Treatment Options Prior to 2011

Peg-interferon and ribavirin (PEG-IFN/RBV) regimens for all genotypes Associated with low SVR rates and significant side effects Genotype 1= 45-50% Most common genotype Genotype 2 = 70-80% 2nd most common genotype Genotype 3 = 70-80% Genotype 4 = 45-70% Genotype 5 = 45-70% Genotype 6 = 45-70%

2011- 2014 Direct-acting antivirals (DAA) - Protease inhibitors Boceprevir Telaprevir

Given with PEG-IFN/RBV regimens for genotype 1 Increased SVR rate for genotype 1 up to 50-80% Boceprevir and telaprevir no longer recommended for treatment of HCV due to

pill burden, side effects, many drug interactions and low barrier to resistant Replaced by newer, more effective medications

www.cdc.gov/hepatits/HCV

HCV is classified into genotypes, with type 1 being the most prevalent in the United States (~72%), followed by type 2 and type 3; other types make up about 1%

Both agents were approved in 2011 for treatment in combination with IFN and RBV for HCV genotype 1 infection. BOC and TVR inhibit the viral NS3/4A protease, which is responsible for cleaving HCV viral protein into mature proteins.

The cumbersome administration of these agents is one drawback to their use. Each requires multiple pills to be taken several times a day:

Boceprevir 800 mg orally three times daily (available in 200 mg tablets) Telaprevir 1125 mg orally twice daily (available in 375 mg tablets) In addition, telaprevir should be administered with at least 20 g of fat for optimal absorption. The first-generation protease inhibitors are associated with substantial adverse effects, in particular

anemia and, for telaprevir, rash. In clinical trials, 10 to 12 percent of patients discontinued therapy due to adverse effects, and 36 to 45 percent developed significant anemia (

A Quick Review of PEG-IFN/RBV Regimens

Interferon and Ribavirin (MOA) Mechanism of Action (MOA)

Not specific to Hepatitis C (broad spectrum agents)

Interferon alfa Cytokine involved in host antiviral immune response Interferes with viral replication Inhibits viral protein translation Induces immune response

Ribavirin Nucleoside analogue Inhibits replication of RNA and DNA viruses Not effective for monotherapy

Hepatitis C Treatment Prior to 2011

Treatment typically consists of combination therapy PEG-INF+RBV Duration 12 to 48 weeks depending on genotype and PEG-INF+RBV no longer recommended first line

Hoofnagle J. N Engl J Med 2006;355:2444-2451.

Interferon vs Peg-Interferon Pegylation is a process where by polyethylene glycol

molecules to a drug to change the PK profile

Interferon-alpha is typically given SQ three times a week Peg-interferon-alpha is given SQ once a week PEG-IFN formulations Pegylated interferon alfa-2a (Pegasys) Dose: 180 mcg SC once weekly

Pegylated interferon alfa-2b (Peg-Intron) Dose: 1.5 mcg/kg weekly

Ribavirin for Hepatitis C

Ribavirin needs renal adjustment

Contraindications to PEG-IFN/RBV

Lauer G, et al. N Engl J Med 2001;345(1):41-52.

Common ADRS with PEG-IFN/RBV

PEG-IFN: Commonly associated with psychiatric, fatigue, flu-like side effects Ribavirin: Commonly associated with GI, rash, fatigue, anemia side effects

www.pharmacytoday.org Lauer G, et al. N Engl J Med 2001;345(1):41-52.

New Hepatitis C Therapy: Direct-Acting Antivirals (DAA)

New HCV Treatment Options Simeprevir (Olysio)

FDA approved November 22, 2013

Sofosbuvir (Sovaldi) FDA approved December 6, 2013

Ledipasvir/Sofosbuvir (Harvoni) FDA approved October 10, 2014

Paritaprevir/Ombitasvir/Ritonavir + Dasabuvir (Viekira Pak)

FDA Approved December 19, 2014

Current Drug Targets NS3/4A Protease Required for post-translational

processing and replication of HCV

NS5A protein Plays a role in HCV replication and

assembly

NS5B RNA-Dependent Polymerase Involved in post-translational

processing necessary HCV replication Enzymes structure is highly

conserved across all HCV genotypes, giving agents that inhibit NS5B efficacy against all six genotypes

Duguam M, Oshea R. CCJM 2014;81(3):159-172

Direct- Acting Antivirals (DAA) NS3/4A Protease Inhibitors

2nd Generation treatment for genotype 1 only Simeprevir Paritaprevir

NS5A Protein Inhibitors treatment for genotype 1 only

Ledipasvir Ombitasvir

NS5B RNA-Dependent Polymerase Inhibitors Nucleoside/ nucleotide analogues (NPIs) Sofosbuvir treatment for genotype 1-6

Non-nucleoside analogues (NNPIs) Dasabuvir treatment for genotype 1 only

Other

Ritonavir (Not a DAA) No Hepatitic C activity Given with paritaprevir for boosting effect

Treatment Nave Regimens Genotype Regimen Treatment Duration

1a Ledipasvir/sofosbuvir (Harvoni) 12 weeks Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (Viekira Pak) + RBV

12 weeks without cirrhosis 24 weeks with cirrhosis

Sofosbuvir (Sovaldi)/Simeprevir (Olysio)

12 weeks without cirrhosis 24 weeks with cirrhosis

1b Ledipasvir/sofosbuvir (Harvoni) 12 weeks Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (Viekira Pak) + RBV (cirrhosis patients only)

12 weeks

Sofosbuvir (Sovaldi)/Simeprevir (Olysio) 12 weeks without cirrhosis 24 weeks with cirrhosis

2 Sofosbuvir + RBV 12 weeks without cirrhosis 16 weeks with cirrhosis

Shorter treatment duration and better SVR compared to PEG-IFN/RBV regimens!

http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection

Genotype Regimen Treatment Duration 3 Sofosbuvir + RBV 24 weeks

Sofosbuvir + RBV + PEG-IFN 12 weeks

4 Ledipasvir/sofosbuvir (Harvoni) 12 weeks Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (Viekira Pak) + RBV

12 weeks

Sofosbuvir (Sovaldi)/Simeprevir (Olysio) 24 weeks Sofosbuvir (Sovaldi)/Simeprevir (Olysio) + RBV 12 weeks Sofosbuvir + RBV + PEG-IFN 12 weeks

5 Sofosbuvir + RBV + PEG-IFN 12 weeks PEG-IFN + RBV 48 weeks

6 Ledipasvir/sofosbuvir (Harvoni) 12 weeks Sofosbuvir + RBV + PEG-IFN 12 weeks

Treatment Nave Regimens

These genotypes are less common Genotype 3 more difficult to treat with new regimens with sofosbuvir

Treatment Experienced Regimens Experienced patients

Failed PEG-IFN + RBV Treatment options similar to nave patients

Failed PEG-IFN + RBV + NS3/4A Protease Inhibitors (simprevir, telaprevir, bocepravir) Treatment with ledipasvir-sofosbuvir RBV preferred Duration 12 (no cirrhosis) or 24 (cirrhosis) weeks

Failed sofosbuvir-containing regimen If genotype 1,4,6 Retreatment with ledipasvir-sofosbuvir RBV for 12-24 weeks

If genotype 2, 3, 5 Retreatment with sofosbuvir + RBV PEG-IFN for 12-24 weeks

www.hcvguidelines.org

A Quick Pharmacology Review of New Hepatitis C Treatment Regimens

http://www.hepatitisc.uw.edu/page/treatment/drugs

Simeprevir (Olysio) MOA 2nd generation HCV NS3/4A protease inhibitor Dose 150 mg capsulle once daily (oral) with food

Dose adjustments

No renal or hepatic dose adjustment Not recommended in severe liver disease (Child Pugh Class C)

ADRs Photosensitivity, rash (within 4 weeks of tmt), nausea, hyperbilirubinemia (mild, within 2 weeks), headache, insomnia, fatigue

Pregnancy C

Drug Interactions

Many since metabolized via CYP3A enzymes Levels with inducers (rifampin, St. John's Wort, anticonvulsants) Levels with inhibitors (clarithromycin, ritonavir) Not recommended with many HIV meds: cobicistat, efavirenz,

etravirine, delavirdine, nevirapine, or any HIV protease inhibitor (ritonavir-boosted or unboosted)

Clinical Pearls

Approved for genotype 1 only Recommended in combination with sofusbuvir Low barrier to resistance Not recommended experienced pts who failed other HCV protease inhibitors

SVR Treatment nave: >90% in combination with sofusbuvir

Simeprevir: 99% protein bound Hepatic metabolism via CYP3A Inhibits 3A4, P-glycoprotein AUC 60-70% w/ food

Sofosbuvir (Sovaldi) MOA Nucleotide analogues NS5B polymerase inhibitor Dose 400 mg tablet once daily (not effected by food)

Dose adjustments

No renal or hepatic dose adjustment

ADRs Headache, insomnia, fatigue, diarrhea

Pregnancy B

Drug Interactions

Fewer interactions than other DAAs Interactions with strong inducers of intestinal P-gp Levels with anticonvulsants (carbamazepine, phenytoin, etc), rifampins, St.

Johns wort, tipranavir-ritonavir

Clinical Pearls

Indicated for all 6 major genotypes regardless of prior treatment experience Recommended in combination with simeprevir OR in fixed combination with ledipasvir (Harvoni) OR ribavirin High barrier to resistance Lepipasvir/sofosbuvir recommended for pts with treatment failure (including PIs) Can be given to HIV, advance liver disease

SVR Treatment nave > 90% in combination with sofusbuvir > 90% in combination with ledipasvir > 90% in combination with RBV

Ledipasavir/Sofosbuvir (Harvoni) MOA NS5A Inhibitor / NS5B polymerase inhibitor Dose 90mg/400mg fixed dose combination tablet once daily (not effected by food)

Dose adjustments

No renal or hepatic dose adjustment

ADRs Headache, fatigue

Pregnancy B

Drug Interactions

Fewer interactions than other DAAs Interactions with strong inducers of intestinal P-gp Levels with anticonvulsants (carbamazepine, phenytoin, etc), rifampins, St.

Johns wort, tipranavir-ritonavir

Clinical Pearls

Recommended for 1,4, and 6 genotypes regardless of prior tmt experience High barrier to resistance (primarily due to sofosbuvir) Lepipasvir/sofosbuvir recommended for pts with treatment failure (including PIs) Can be given to HIV, advance liver disease One pill a day regimen!

SVR Treatment nave > 90%

MOA NS5 Inhibitor /NS3/4A protease inhibitor / Booster + Non-nucleoside NS5B polymerase inhibitor

Dose Ombitasvir 25 mg/Paritaprevir 150 mg/ ritonavir 100 mg Two tablets once daily in the morning (with food) AND Dasabuvir 250 mg tablet twice daily

Dose adjustments

No renal or hepatic dose adjustment Not recommended in severe liver disease (Child Puch Class C)

ADRs Hypersensitivity reaction, pruritus, nausea, fatigue, elevated hepatic enzymes

Pregnancy B

Drug Interactions

Many! Especially because of potent ritonavir inhibition of CYP3A4 (please see next slide for details)

Clinical Pearls

Indicated for genotype 1 and 4 Often in combination with weight based RBV given twice daily High pill burden compared to other regimens Low barrier to resistance Can be used in HIV (but not al HAART regimens)

SVR Treatment nave: >90%

VIEKIRA Pak

Paritaprevir: metabolized by 3A4 (major) Ritonavir boosts concentration Ombitasvir: non-hepatic metabolism Dasabuvir: metabolized via CYP2C8 (major) and 3A (minor)

The concomitant use of ombitasvir-paritaprevir-ritonavir and dasabuvir with ethinyl estradiol-containing medications can result in significant elevations in hepatic aminotransferase levels; accordingly patients should discontinue any ethinyl estradiol-containing medications prior to starting ombitasvir-paritaprevir-ritonavir and dasabuvir.

http://www.hepatitisc.uw.edu/go/treatment-infection/treatment-genotype-1/core-concept/all

Assessment

AL is a 48 year old HIV positive patient with chronic HCV infection with genotype 1a. He will be receiving therapy with direct-acting HCV antivirals at your clinic for the first time. He has no severe renal or liver impairment at this time and has been stable on HAART for many years. Current home meds: efavirenz, tenofovir and emtricitabine Which of the following hepatitis C regimens is BEST for this patient? A. Ledipasvir/sofosbuvir (Harvoni)

B. Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir (Viekira Pak) + RBV C. Sofosbuvir (Sovaldi) / Simeprevir (Olysio) D. Boceprevir + PEG-IFN + RBV