Hepatitis B: Objectives. Hepatitis C: Objectives. Hepatitis B: Natural History. Hepatitis B is a DNA virus and is NOT curable.

1/25/15

Rebekah Hamner, MA, MSN, APRN, AGCNS Austin Hepatitis Center

Dr. Imtiaz Alam

Two “Silent Epidemics” - Chronic

Hepatitis B and Hepatitis C: A Primer

for Primary Care Practitioners

Hepatitis B: Objectives

1. Identify

●  when to initiate treatment

●  3 first line medications

●  common side effects of hepatitis B treatments

(25 min)

2. Identify

●  recommended monitoring of patients who are

pregnant

●  when treatment initiation may be considered in

this population. (10 min)

Hepatitis C: Objectives

1. Identify the

-treatment regimen

-monitoring for patients with hepatitis C

genotypes 1, 2, 3. (35 min)

2. Identify common side effects of hepatitis C

treatments (5 min)

3. Identify drug interactions with treatment

regimens for hepatitis C genotypes 1, 2, 3. (5

min)

4. Q & A (10 min)

Disclosures

Add disclosure details here if there is any development. 1.  Abbvie, Viekira Pak

2.  Quest Diagnostics

Hepatitis B

is a

DNA virus

and is NOT curable.

Hepatitis B: Natural History

●  800,000-1.4 million C-HBV in US ●  240 million worldwide ●  Survives 7 days outside the body

●  High prevalence areas >/= 8%, Most of Africa, Asia ●  Progression to chronic HBV

●  greatest risk if infected as a child ●  90% if infant

●  25-50% if in childhood

●  Die prematurely due to cirrhosis or liver cancer ●  If infected at birth or childhood 25% ●  If infected after childhood

Hepatitis B: Natural History

●  no transmission

●  breastfeeding, kissing, coughing, sneezing, ●  different clinical presentation

●  asymptomatic → “Silent Killer” ●  hepatic decompensation ●  HBV is a reportable condition

●  HBV infection rates down 82% since 1991 ●  routine vaccination

http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#overview

Hepatitis B: Natural History

●  different immunological PHASES, + HBsAntigen ●  IMMUNE-ACTIVE

●  high viral levels, elevated ALT → treat ●  IMMUNE TOLERANT

●  high viral levels, normal ALT, little/no biopsy activity ●  INACTIVE CARRIER

●  low or undetected viral levels, normal ALT ●  LATENT

●  detected viral level, no HBsAg HBV DNA virial count < 2000 IU = low AST < 19 for females, 30 for males = normal

http://www.uptodate.com/contents/overview-of-the-management-of-hepatitis-b-and-case-examples#H1

Hepatitis B: Who/when to Screen

●  Foreign-born persons from countries of high HBV endemicity ●  Before beginning immunosuppressive therapy (anti-TNF meds,

chemo)

●  may begin preemptive antiviral therapy ●  Hemodialysis patients

●  Pregnant women

●  ALT/AST elevation of unknown etiology

●  Persons with known or suspected exposure to HBV including: ●  infants born to HBV-infected mothers

●  household contacts of HBV-infected persons ●  needle sharing, needlestick

●  sex contacts

●  persons with known occupational or other exposures to infectious blood or body fluids

●  HIV-positive persons ●  MSM- Men who have sex with men

http://www.cdc.gov/hepatitis/HBV/PDFs/ChronicHepBTestingFlwUp.pdf

http://commons.wikimedia.org/wiki/File:Hepatitis_B_virus_v2.svg

Hepatitis B: Screening

→

If:

+  HB surface antigen (x 6 mo) = chronic infection +  HB surface antibody = + immunity

+  HB core antibody AND HB surface antibody ●  there are gray areas!!

●  If all are negative:

●  give vaccination series, 3-dose series, 0, 1, 6 months ●  If + HB surface antigen ….

http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#overview

Hepatitis B: Work up

treatment / cirrhosis status / infectivity / HCC screening ●  CMP - AST/ALT ->19 for Females, >30 for Males ●  CBC - platelets

●  Hep A, Hep C, HIV

●  AFP, AFP-L3, DCP- every 6 months for hepatocellular cancer (HCC) screening

●  Hepatitis B e antigen (HBeAg) ●  Hepatitis B e antibody (HBeAb) ●  hepatitis B virus DNA PCR quantitative ●  Fibrosure (F1-F2-F3-F4)

●  Fibroscan (F1-F2-F3-F4), may replace biopsy ●  Abdominal ultrasound - every 6 months for HCC screen

Hepatitis B: Work up not included

-Hep D -Liver biopsy

●  useful in certain cases

●  HBV DNA > 2,000 and ALT normal ●  used less and less

●  limitations

●  25-30% sampling error ●  different interpretations ●  invasive

●  expensive

personal photo: Rebekah Hamner

http://www.fibroscanlosangeles.com/

Hepatitis B: Treatment Goals

●  Suppress the virus….NOT A CURE ●  AST/ALT normalization

●  Prevent progression of the disease to ●  cirrhosis

●  liver failure

●  hepatocellular carcinoma (HCC)

● Pts with HBV have an increased risk of HCC

even if

●  NO cirrhosis present ●  on therapy ●  Liver regeneration

●  Prevent transmission of the disease to newborns

Hepatitis B: Treatment

Initiation

Hepatitis B: Treatment Options

At least 5 years, probably for LIFE

●  tenofevir disproxil (Viread)

●  entecavir (Baraclude)

●  telbivudine (Tyzeka)

Limited time

●  PEG-interferon (Pegasys)

… or a combination

Hepatitis B: Treatment Options

tenofevir disproxil (Viread) 300 mg po once daily ●  potent antiviral activity, 76% at 1 year ●  suppresses lamivudine, telbivudine or entecavir

resistant

●  low to no level of resistance ●  is used off label in pregnancy ●  with or without food ●  copay card -watch kidney function -not for nursing mothers -expensive, no generic -HBV rebound if D’C med

SE: rash, nausea, diarrhea, headache, depression, weakness http://www.viread.com/en/learn_about_viread.aspx http://www.uptodate.com/contents/overview-of-the-management-of-hepatitis-b-and-case-examples#H33 http://www.aasld.org/sites/default/files/guideline_documents/ChronicHepatitisB2009.pdf

Hepatitis B: Treatment Options

entecavir (Baraclude) 0.5 mg or 1 mg po once daily ●  potent antiviral activity

●  suppresses lamivudine resistant

●  may consider use with decompensated cirrhosis ●  less association with renal impairment ●  low level of resistance

●  now generic ●  copay card -not for nursing mothers -expensive

-HBV rebound if D’C med -2 hrs before/after meal

SE: transient elevated ALT, rash, nausea, diarrhea, headache, insomnia

http://www.uptodate.com/contents/overview-of-the-management-of-hepatitis-b-and-case-examples#H1 http://packageinserts.bms.com/pi/pi_baraclude.pdf

Hepatitis B: Treatment Options

telbivudine (Tyzeka) 600 mg po once daily ●  less potent antiviral activity ●  suppresses lamivudine resistant ●  can develop resistance ●  copay card

http://www.uptodate.com/contents/overview-of-the-management-of-hepatitis-b-and-case-examples#H1

http://www.pharma.us.novartis.com/product/pi/pdf/tyzeka.pdf

-watch kidneys -not for nursing mothers -expensive

-2 hrs before/after meal -HBV rebound if D’C med

SE: fatigue, increased CK, nausea, diarrhea, headache, cough, rash

Hepatitis B: Treatment Options

PEG-interferon-alpha 2 a (Pegasys), 180 mcg injection weekly x 48 weeks

●  potential for loss of HBV DNA (17~30%) ●  better for genotype A and B

-many side effects, some can be lasting

-do not use in patients with psychiatric illness -do not use in pregnancy

SE: flu-like symptoms, extreme fatigue, nausea, diarrhea, headache, rash

http://www.uptodate.com/contents/overview-of-the-management-of-hepatitis-b-and-case-examples#H1 http://emedicine.medscape.com/article/177632-treatment#aw2aab6b6b2aa

Hepatitis B: Treatment Summary

●  Can take many months to suppress virus ●  In most cases treatment is for LIFE ●  Occasionally, on therapy will see…

Seroconversion of

Hepatitis B surface antigen (HBsAg) to Hepatitis B surface antibody (HBsAb)

-Continue meds for at least 1 year more before considering stopping therapy

Hepatitis B: Transmission in Pregnancy

●  most common mode of transmission

worldwide

●  higher chance for mother to baby

transmission if:

●  high viral load, > 10,000,000 IU

●  + HBe antigen

●  treat in 3rd trimester if HBV DNA >

10,000,000 IU

●  breast feeding if +HBV NOT contraindicated

●  breast feeding if on HBV medication IS

contraindicated

http://emedicine.medscape.com/article/177632-treatment#aw2aab6b6b4aa

Hepatitis B: Treatment in Pregnancy

Goals:

●  Monitor HBV DNA viral count and ALT ●  Suppress maternal viremia

●  Prevent mother to baby HBV transmission THIS IS OFF LABEL

●  tenofevir disproxil (Viread) 300 mg po once daily ●  entecavir (Baraclude) 0.5 mg or 1 mg po once daily ●  telbivudine (Tyzeka) 600 mg po once daily ● PEG-interferon-alpha 2 a (Pegasys), 180 mcg injection

weekly x 48 weeks

Hepatitis B: Treatment in Pregnancy

tenofevir disproxil (Viread) 300 mg po once daily category B

OFF LABEL USE

Huang H, Wu Q, Wang Q. Tenofovir disoproxil: effective and

safe in prevention of mother-to-child transmission of hepatitis

B virus. Program and abstracts of the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); November 7-11, 2014; Boston, Massachusetts. Abstract 1851.

-was administered during entire pregnancy

Hepatitis B: Treatment in Pregnancy

telbivudine (Tyzeka) 600 mg po once daily category B

OFF LABEL USE

Sheng Q, Ding Y, Bai H, et al. Efficacy and safety of telbivudine in preventing mother-to-infant HBV transmission in HBV-infected pregnant women in immune tolerant phase. Program and abstracts of the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); November 7-11, 2014; Boston, Massachusetts. Abstract 1864 “Telbivudine treatment effectively and safely prevented mother-to-infant transmission of HBV from chronically infected mothers with a high degree of viremia late in pregnancy.”

Hepatitis C: Objectives

1. Identify the

-treatment regimen

-monitoring for patients with hepatitis C

genotypes 1, 2, 3. (35 min)

2. Identify common side effects of hepatitis C

treatments (5 min)

3. Identify drug interactions with treatment

regimens for hepatitis C genotypes 1, 2, 3. (5

min)

4. Q & A (10 min)

Hepatitis C

is an

RNA virus

and it IS curable.

Hepatitis C: Natural History

●  It’s curable!! ●  3.2 million in US ●  130-150 million worldwide ●  Survives 14 days outside the body ●  4x as prevalent as HIV or HBV

●  In 2007 C-HCV surpasses HIV in mortality trends ●  The majority (73.4%) of registered deaths related to HCV

occurred in adults aged 45 to 64 years, BABY BOOMERS

Hepatitis C: Natural History

Rule of 20s

Hepatitis C: Prevalence

In specific US populations: By population, and NOT S/Sx. ●  more males than females

●  75% in the homeless clinic in Austin, whereas in US 52% ●  injection drug users

●  incarcerated

●  5% vertical transmission rate

●  sharing household items such as razors and toothbrushes ●  3-5% chance of contracting HCV if in a mutually monogamous

relationship with someone who is HCV +

> 25% chance of contracting HCV if you have multiple partners

●  those born between 1945 and 1965

●  The #1 risk factor that we are told to focus on now is age. Right now anyone who is 48-66 years of age must be tested

http://www.cdc.gov/hepatitis/C/cFAQ.htm#statistics

Point of Care Testing for HCV with

OraQuick

• FDA approved June 25, 2011

• Hepatitis C antibody test

• Fingerstick

• Results in 20 minutes

• If + f/u w/ laboratory testing

• Accuracy

• Sensitivity- 99.7%

• Specificity- 99.9%

This is the only point of care HCV antibody test I know of.

+

Your patient screened positive

Does he/she have chronic hep C?

-We don’t know yet.

Is Hepatitis C Curable?

-Yes!!

Remember: Screen, Treat, Cure!!

Hepatitis C: ROS

● MANY have

no signs or symptoms May have:

● Fatigue

● Polyarthralgia and polymyalgia ● Fever

● Nausea or anorexia ● RUQ tenderness

PS: The CDC has great posters for your office.

Hepatitis C: Lab Work up

● CMP, CBC, *fibrosis marker, pt/INR ● ALT: 7-55 u/L → men 30, women 19 !!! ● Fibroscan, Abd U/S,

●  HCV antibody

● 1000s to 1,000,000s to 10,000,000s IU ● no stratification of meaning

●  Fibrosis

● Genotype: 1a, 1b, 2, 3, 4, 5, 6

*fibrosis markers: FibroSure, FibroSpect, ELF, HepaScore, and others

Patterns of ALT Levels in Patients

with Chronic Hepatitis C

Hepatitis C: Treatment Goals

●  CURE

●  Prevent progression of the disease to ●  cirrhosis

●  liver failure

●  hepatocellular carcinoma (HCC) ●  Potential reversal of fibrosis cirrhosis…

yes ...cirrhosis!! ●  eradicate HCV by 2036!!!

Hepatitis C: Treatment

● Treatment efficacy & options vary

depending on:

● Genotype- 1a, 1b, 2, 3, or 4

● Prior treatment status- naïve, relapser,

partial/null responder

● Cirrhotic or not

● Coinfection: HIV, HBV

● Obesity

● Other meds pt is taking

Hepatitis C: Treatment in Pregnancy

●  Not recommended

●  Ribavirin is category X in pregnancy ●  Advise 2 forms of contraceptives while on

therapy, and for 6 months post therapy, if EITHER partner is taking ribavirin!!!!!!

Hepatitis C: Treatment History

●  1990’s: Interferon (IFN) - injection, ribavirin (RBV).

●  2011-2013: Direct acting antivirals (DAA): telaprevir (Incivek), boceprevir (Victrelis) = Already obsolete. Just two years in and Incivek and Victrelis are:

-no longer the standard of therapy. -not used.

Where direct acting antivirals (DAAs) are working.

http://hepatitiscresearchandnewsupdates.blogspot.com/2013/01/interferon-free-therapy-with-direct.html

Hepatitis C: Treatment

Treatment medications and duration are dictated by: ●  genotype

●  1a, 1b, 2, 3, 4 ●  prior treatment response

●  null partial relapse ●  cirrhosis status

●  non-cirrhotic → shorter duration, probably 12 weeks ●  cirrhotic → longer duration, 24 weeks

●  insurance ●  Express Scripts ●  CVS

●  other medications the patient is taking ●  http://hep-druginteractions.org/ ●  Hep iChart

Hepatitis C: Newer Treatments

2013- simeprevir (Olysio) 150 mg daily, PO

Only Genotype 1

*few side effects -photosensitivity *contains sulfonamide moiety

*Some restrictions for genotype 1a if w/ IFN + RBV *Low genetic barrier to resistance

*NOT for monotherapy

-give with interferon + ribavirin or sofosbuvir Interactions: Remember categories.

Abx: ~mycin Antifungals: ~azole HIV meds Statins Anticonvulsants Antiarrhythmics Steroids Antimycobacterials Herbals: St. John’s wort, milk thistle This is not a complete list.

https://www.olysio.com/shared/product/olysio/prescribing-information.pdf

Hepatitis C: Newer Treatments

2013 sofosbuvir (Sovaldi) 400 mg daily, PO

Genotype 1, 2, 3, 4, HIV coinfection

*High genetic barrier to resistance *few drug interactions *few side effects (HA), fatigue *NOT for monotherapy

-give with interferon + ribavirin or simeprevir Interactions: Remember categories.

HIV meds Anticonvulsants Antimycobacterials Herbals: St. John’s wort This is not a complete list.

https://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf

Hepatitis C: Newer Treatments

2014 sofosbuvir + ledipasvir (Harvoni) 400 mg/ 90 mg, PO

Genotype 1, (off-label in genotype 3, 4)

*High genetic barrier to resistance * relatively few drug interactions *few side effects (HA), fatigue, nausea *one pill once a day

Interactions: Remember categories. same as Sovaldi

PPI/H2B: take equivalent to omeprazole 20 mg at EXACTLY

the same time

Antacids: take 4 hours before or after

There are other potential DD interactions that req monitoring.

http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf

Hepatitis C: Newer Treatments

ombitasvir + paritaprevir boosted with ritonavir + dasabuvir (Viekira pak) +/ - weight based dosing ribavirin

Genotype 1 (off-label genotype 4)

*take w/ food *blister packs

*non-overlapping resistance profiles Interactions: Fewer clear-cut categories.

Estrogen Herbals: St. John’s wort HIV meds Statins Asthma/COPD: Serevent, Advair, fluticasone

Anticonvulsants

gemfibrozil, rifampin, Halcion, Tramadol, furosemide, amlodipine

Treatment according to genotype

following American Association for

the Study of Liver Diseases

guidelines.

Starting with genotype 2.

Hepatitis C: Genotype 2 Treatment

Sovaldi + Ribavirin 1000/1200 mg x 12 weeks

Summary of sustained virologic responses (SVR) in research: ●  naive, non-cirrhotic SVR 97% (VALENCE)

●  naive, cirrhotic SVR 83% (FISSION); 94% (POSITRON), 100% (VALENCE), consider extending to 16 weeks ●  prior failure, non-cirrhotic SVR 90-91% (FUSSION,

VALENCE)

●  prior failure, cirrhotic SVR 78% (FUSSION), consider adding interferon for SVR 93% (LONESTAR 2)

Hepatitis C: Genotype 3 Treatment

1.  Sovaldi + Ribavirin 1000/1200 mg x 24 weeks ●  naive, non-cirrhotic SVR 93% (VALENCE)

●  naive, cirrhotic SVR 92% (VALENCE), consider extending to 16 weeks

●  prior failure, non-cirrhotic SVR 85%(VALENCE) ●  prior failure add interferon, x 12 weeks for SVR 82%

(VALENCE)

2. Harvoni + Ribavirin 1000/1200 mg x 12 weeks ●  naive, non-cirrhotic SVR 100% (VALENCE) ●  naive, cirrhotic SVR 100% (VALENCE)

Hepatitis C: Genotype 1 Treatment

There are 10 treatment options depending on: ●  genotype

●  subtype

●  prior treatment status ●  cirrhosis status

The following is just to give you an idea of where we are in regards to SVR response based on some of the above factors. It is not a complete treatment guide.

Hepatitis C: Genotype 1a Treatment

1.  naive, non-cirrhotic

a. Harvoni x 12 weeks SVR 96% (ION-3) to 98% SVR (ION-1) b. *Harvoni x 8 weeks [If Baseline HCV RNA <6 million IU/mL] 93% SVR (ION-3)

c. Sovaldi + Olysio x 12 weeks SVR 95% (COSMOS [Pooled Analysis] – F0-3)

d. Viekira Pak + RBV [with food] x 12 weeks SVR 96% (Sapphire I) to 97% SVR12 [Pearl IV]

Hepatitis C: Genotype 1a Treatment

a. Harvoni x 12 weeks SVR 94% (ION-1)

b. Sovaldi and Olysio x 24 weeks SVR 100% (COSMOS [Pooled Analysis] F4 )

Hepatitis C: Cost

Many paths to cure -  insurance -  assistance programs -  grants

-  donations -  free meds

Ultimately, everyone deserves a chance for a cure.

Hepatitis C: Treatment Summary

●  Many fewer side effects

●  Shorter duration of therapy, in most cases ●  Counsel no alcohol

●  Still need to watch out for: -drug to drug interactions -side effects

●  We need to advocate for screening and patient treatment.

References

FibroScan Los Angeles. (2013). Retrieved from http://www.fibroscanlosangeles.com/

Highlights of prescribing information. (2014, August). Retrieved from http://packageinserts.bms.com/pi/pi_baraclude.pdf

Highlights of prescribing information. (2013, January.). Retrieved from http://www.pharma.us.novartis.com/product/pi/pdf/tyzeka.pdf

Highlights of prescribing information. (2014). Retrieved from

https://www.olysio.com/shared/product/olysio/prescribing-information.pdf

Highlights of prescribing information. (2014, October). Retrieved from

http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf

Highlights of prescribing information. (2014, November). Retrieved from

https://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf

Highlights of prescribing information. (2014, February). Retrieved from http://www.rxabbvie.com/pdf/viekirapak_pi.pdf

Hepatitis B information for health professionals [Fact sheet]. (2015, March 6). Retrieved March 9, 2015, from Centers for Disease Control and

Prevention website: http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#overview

Hepatitis C fact sheet number 164. (2014, April). Retrieved March 9, 2015, from http://www.who.int/mediacentre/factsheets/fs164/en/

References

Hepatitis C Information for the public. (2014, December 9). Retrieved from http://www.cdc.gov/ hepatitis/C/cFAQ.htm#statistics

Huang H, Wu Q, Wang Q. Tenofovir disoproxil: effective and safe in prevention of mother-to-child transmission of hepatitis B virus. Program and abstracts of the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); November 7-11, 2014; Boston, Massachusetts. Abstract 1851.

Know more hepatitis. (2015, January 15). Retrieved from http://www.cdc.gov/knowmorehepatitis/media/Posters.htm

Lok, A. S. (2013, February 7). Hepatitis B viris. Retrieved March 9, 2015, from http://www.uptodate.com/contents/overview-of-the-management-of-hepatitis-b-and-case-examples#H1

Lok, A. S., & McMahon, B. J. (n.d.). Chronic hepatitis B: Update 2009. Retrieved from http://www.aasld.org/sites/default/files/guideline_documents/ChronicHepatitisB2009.pdf

Pyrsopoulos, N. (2015, January 11). Hepatitis B treatment and management (B. Anand, Ed.). Retrieved March 9, 2015, from http://emedicine.medscape.com/article/177632-treatment#aw2aab6b6b2aa

Recommendations for routine testing and follow-up for chronic hepatitis B virus (HBV) infection.(n.d.). Retrieved March 9, 2015, from

http://www.cdc.gov/hepatitis/HBV/PDFs/ ChronicHepBTestingFlwUp.pdf

Sheng Q, Ding Y, Bai H, et al. Efficacy and safety of telbivudine in preventing mother-to-infant HBV transmission in HBV-infected pregnant women in immune tolerant phase. Program and abstracts of the 65th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); November 7-11, 2014; Boston, Massachusetts. Abstract 1864

References

Tran, J., & Saab, S. (2008, August 28). Hepatitis B: Indications for therapy initiation. Retrieved March 9, 2015, from http://www.medscape.org/viewarticle/579594

Vickers, T. (2007, November 14). File: Hepatitis B virus v2.svg. Retrieved March 9, 2015, from http://commons.wikimedia.org/wiki/ File:Hepatitis_B_virus_v2.svg

Viread. (2014, December). Retrieved March 9, 2015, from http://www.viread.com/en/ learn_about_viread.aspx

When and in whom to initiate HCV therapy. (2015, January 26). Retrieved March 9, 2015, from http://www.hcvguidelines.org/node/72

Yapalil, S., Talaat, N., & Lok, A. S. (2014). Management of hepatitis B. Retrieved from http://www.medscape.com/viewarticle/ 818901_4

Thank you.