1. Hepatitis C Sarah Weninger Viral Hepatitis Prevention Coordinator
Division of Disease Control
Phone: or

2. Presentation Outline Transmission Risk Groups
Burden of disease in North Dakota
Diagnosing Hepatitis C

3. What is hepatitis? Hepatitis = inflammation of the liver viruses,
bacteria,
parasites
toxins,
drugs,
alcohol
autoimmunity
Hepatitis = inflammation of the liver
The word "hepatitis" means inflammation of the liver. Toxins, certain drugs, some diseases, heavy alcohol use, bacterial and viral infections can all cause hepatitis. Hepatitis is also the name of a family of viral infections that affect the liver; the most common types in the United States are hepatitis A, hepatitis B, and hepatitis C.
Hepatitis A is an acute liver disease caused by the hepatitis A virus (HAV), lasting from a few weeks to several months. It does not lead to chronic infection. Transmission: Ingestion of fecal matter, even in microscopic amounts, from close person-to-person contact or ingestion of contaminated food or drinks.
Vaccination: Hepatitis A vaccination is recommended for all children starting at age 1 year, travelers to certain countries, and others at risk.
Hepatitis B is a liver disease caused by the hepatitis B virus (HBV). It ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term (chronic) illness that can lead to liver disease or liver cancer. Transmission: Contact with infectious blood, semen, and other body fluids from having sex with an infected person, sharing contaminated needles to inject drugs, or from an infected mother to her newborn.
Vaccination: Hepatitis B vaccination is recommended for all infants, older children and adolescents who were not vaccinated previously, and adults at risk for HBV infection.
Hepatitis C is a liver disease caused by the hepatitis C virus (HCV). HCV infection sometimes results in an acute illness, but most often becomes a chronic condition that can lead to cirrhosis of the liver and liver cancer. Transmission: Contact with the blood of an infected person, primarily through sharing contaminated needles to inject drugs. Vaccination: There is no vaccine for hepatitis C.
Hepatitis D is a serious liver disease caused by the hepatitis D virus (HDV) and relies on HBV to replicate. It is uncommon in the United States. Transmission: Contact with infectious blood, similar to how HBV is spread. Vaccination: There is no vaccine for hepatitis D.
Hepatitis E is a serious liver disease caused by the hepatitis E virus (HEV) that usually results in an acute infection. It does not lead to a chronic infection. While rare in the United States, hepatitis E is common in many parts of the world. Transmission: Ingestion of fecal matter, even in microscopic amounts; outbreaks are usually associated with contaminated water supply in countries with poor sanitation.Vaccination: There is currently no FDA-approved vaccine for hepatitis E.

4. How is hepatitis C virus spread?
Bloodborne Virus
When blood from an infected person enters the body of a person who is not infected
The rate of new HBV infections has declined by approximately 80% since 1991, when a national strategy to eliminate HBV infection was implemented in the United States. The decline has been greatest among children born since 1991, when routine vaccination of children was first recommended.
An estimated 800,000–1.4 million persons in the United States have chronic HBV infection. Chronic infection is an even greater problem globally, affecting approximately 350 million persons. An estimated 620,000 persons worldwide die from HBV-related liver disease each year.

5. How is hepatitis C virus spread?
HCV is transmitted primarily through large or repeated percutaneous exposures to infectious blood
Injection drug use (currently the most common means of HCV transmission in the United States)
Receipt of donated blood, blood products, and organs
Needlestick injuries in health care settings
Birth to an HCV-infected mother
HCV can also be spread infrequently through sex with an HCV-infected person (an inefficient means of transmission)
Sharing personal items contaminated with infectious blood, such as razors or toothbrushes
Other health care procedures that involve invasive procedures, such as injections

6. Who is at-risk for Hepatitis C?
Risk groups:
Current or Former Injection-drug users
Recipients of clotting factors made
before 1987
Hemodialysis patients
Recipients of blood and/or solid organs donated before 1992
People with undiagnosed liver problems
Infants born to HCV-infected mothers
HIV infected individuals or those having sex with an HIV-infected individual

7. Hepatitis C Average incubation period – 6-9 weeks Acute illness
Range: 2 weeks – 6 months
Acute illness
80% of people are
asymptomatic
Chronic infection occurs
in 55-85% of infected
people
HCV infection is leading
indication for liver
transplant in the U.S.
Cirrhosis - scarring of the liver and poor liver function as a result of chronic liver disease

8. What are the symptoms of acute hepatitis?
*New infections may be asymptomatic
Nausea
Vomiting
Diarrhea
Dark urine
Fever
Joint pain
Light colored stools
Jaundice
Elevated liver enzymes (ALT, AST, Bilirubin)
Fatigue
Abdominal pain (upper right quadrant)
Loss of appetite
ALT – Alanine aminotransferase (Also known as: Serum glutamic-pyruvic transaminase SGPT) – The ALT test detects liver injury. ALT values are usually compared to the levels of other enzymes, such as alkaline phosphatase (ALP) and aspartate aminotransferase (AST), to help determine which form of liver disease is present. ALT is often used to monitor the treatment of persons who have liver disease, to see if the treatment is working, and may be ordered either by itself or along with other tests. NOTE: A standard reference range is not available for this test. Because reference values are dependent on many factors, including patient age, gender, sample population, and test method, numeric test results have different meanings in different labs. Your lab report should include the specific reference range for your test. Very high levels of ALT (more than 10 times the highest normal level) are usually due to acute hepatitis, often due to a virus infection. In acute hepatitis, ALT levels usually stay high for about 1–2 months, but can take as long as 3–6 months to come back to normal. ALT levels are usually not as high in chronic hepatitis, often less than 4 times the highest normal level: in this case, ALT levels often vary between normal and slightly increased, so doctors typically will order the test frequently to see if there is a pattern.
AST – Aspartate aminotransferase - AST is an enzyme found mostly in the heart and liver, and to a lesser extent in other muscles. When liver or muscle cells are injured, they release AST into the blood. When liver damage is due to alcohol, AST often increases much more than ALT (this is a pattern seen with few other liver diseases). AST is also increased after heart attacks and with muscle injury, usually to a much greater degree than is ALT.
Bilirubin - To screen for or monitor liver disorders; Bilirubin is an orange-yellow pigment found in bile. Red blood cells (RBCs) normally degrade after 120 days in the circulation. At this time, a component of the RBCs, hemoglobin (the red-colored pigment of red blood cells that carries oxygen to tissues), breaks down into unconjugated bilirubin. Unconjugated bilirubin is carried to the liver, where sugars are attached to it to make it water soluble, producing conjugated bilirubin. This conjugated bilirubin is passed to the bile by the liver and is further broken down by bacteria in the small intestines and eventually excreted in the feces. The breakdown products of bilirubin give feces its characteristic brown color. If bilirubin levels increase in the blood, the appearance of jaundice becomes more evident. Normally, almost all bilirubin in the blood is unconjugated. When bilirubin levels are high, a condition called jaundice occurs, and further testing is needed to determine the cause. In adults or older children, bilirubin is measured to diagnose and/or monitor liver diseases, such as cirrhosis, hepatitis, or gallstones.
Alkalkine phosphatase – ALP – normally ordered as part of a routine liver panel or when a person has symptoms of a liver or bone disorder

9. Natural History of HCV infection
100 People
Time
15% - 45%
Resolve (15)
55%-85%
Chronic (85)
80%
20%
Stable (68)
Cirrhosis (17)
75%
25%
Combination therapy with pegylated interferon and ribavirin is the treatment of choice, resulting in sustained virologic response (defined as undetectable HCV RNA in the patient's blood 24 weeks after the end of treatment) rates of 40%–80% (up to 50% for patients infected with genotype 1, the most common genotype found in the United States, and up to 80% for patients infected with genotypes 2 or 3). Combination therapy using interferon and ribavirin is FDA-approved for use in children ages 3–17 years. Treatment success rates are now being improved with the addition of polymerase and protease inhibitors to standard pegylated interferon/ribavirin combination therapy.
Stable (13)
Mortality (4)
Leading Indication for Liver Transplant
Adapted from Alter HJ

10. Hepatitis C Prevention
Avoid blood exposure:
New syringe, cooker, cotton etc.
every time for injection
Use barriers and lubricants
Cover open cuts/wounds
Use universal precautions
Don’t share personal items that may contain blood (toothbrush/razor)
Ensure instruments used for tattooing, piercing, acupuncture are new or sterilized

11. Supporting a Healthy Liver
Drink water
Do not drink alcohol
Get vaccinated against hepatitis A and B
Eat a healthy diet with adequate protein
Exercise
Reduce stress
Minimize contact with other toxins
Check with health provider before starting new medications

12. Burden of Disease

13. Diagnosing Hepatitis C

14. Who should be tested for hepatitis C?
Persons born from 1945 through 1965
Persons who have ever injected illegal drugs, including those who injected only
Recipients of clotting factor concentrates made before 1987
Recipients of blood transfusions or solid organ transplants before July 1992
Patients who have ever received long-term hemodialysis treatment
Persons with known exposures to HCV, such as
health care workers after needlesticks involving HCV-positive blood
recipients of blood or organs from a donor who later tested HCV- positive
All persons with HIV infection
Patients with signs or symptoms of liver disease (e.g., abnormal liver enzyme tests)
Children born to HCV-positive mothers (to avoid detecting maternal antibody, these children should not be tested before age 18 months)

15. Types of Tests Used to Diagnose Hepatitis C
Screening tests for antibody to HCV (anti-HCV)
enzyme immunoassay (EIA)
enhanced chemiluminescence immunoassay (CIA)
Qualitative tests to detect presence or absence of virus (HCV RNA polymerase chain reaction [PCR])
Quantitative tests to detect amount (titer) of virus (HCV RNA PCR)
Genotyping

16. Hepatitis C Antibody Tests
Window Period of 2 to 26 weeks
Determine if the patient was ever infected with the virus or if they are currently infected with HCV
Hepatitis C Antibodies will remain in the body for life even if people clear the virus
When the body is exposed to a virus, the immune system produces anitbodies against the virus. Antibodies are proteins that attach to foreign invaders, marking them for destruction by the immune system. The window period refers to the time it would take for screening tests to detected these antibodies. The window period is 2 to 26 weeks.

17. Hepatitis C Viral Load Tests
Measures the amount of HCV RNA in the blood.
Confirms active infection.
Determines treatment options and effectiveness of medications.
Most often used are HCV RNA by polymerase chain reaction (PCR) and transcription mediated amplication (TMA)
HCV RNA is the genetic material of the virus. The presence of viral RNA indicates that the virus is actively replicating (reproducing and infecting new cells). Viral load tests are often performed after a positive screen to an antibody test. Can have qualitative and quantitative viral load tests. Quantitative tests are used to assess if treatment is successful.
The three types of RNA tests include Polymerase Chain Reaction, Branched Chain DNA (bDNA) and Transcription mediated amplification (TMA). PCR detects HCV RNA in the blood and is very sensitive. (5 to 10 IU/mL). BDNA is easier and cheaper but only measures viral loads greater than 50 IU/mL. TMA allows for the amplification and detection of nucleic acids (components of genetic material) in blood serum.

18. HCV Genotypes Six Major Genotypes: 1, 2, 3, 4, 5, 6
Within the Genotypes there are divisions called subtypes, ex. 1a and 1b and quasispecies
Genotype 1 is the most common in the U.S.
1,2,3= Worldwide; 4=MiddleEast and Africa; 5=South Africa; 6=SouthEast Asia; quasispecies are a set of related genotypes that exist in an environment with a high mutation rate. As the HCV replicates it also mutates. A single individual with Hepatitis C may have a large number of different species. The rapid mutation rate make it hard for the immune system to clear the virus, which is why so many individuals develop chronic disease. The variability of the virus make it difficult to find medications to be effective against all types of HCV and hard to develop a vaccine that will protect against all HCV strains.

19. Liver Enzyme/Function Tests
When the liver is damaged, certain liver enzymes and proteins build up and can be measured with blood tests
Most common liver function test (LFT) with HCV is the alanine aminotransferase, or ALT level test
Other LFTS include aspartate amiontransferase (AST) and bilirubin levels
It is argued that those individuals with normal ALT levels do not need treatment, but 20-30% of individuals but normal ALT levels do show disease progression. AST= elevated in those with liver or muscle damage, not as specific as ALT
High levels of AP and GGT may indicate obstructed bile flow
Low levels of serum albumin in assocated with cirrhosis
High bilirubin levels may lead to jaundice, dark urine and pale-colored stool

20. ALT Levels
Some individuals with HCV have elevated ALT while others have normal levels
Persistently elevated ALT levels may be reason for a biopsy to check for liver damage
ALT levels used to monitor treatment
When liver cells are damaged, enzymes called aminotransferases may leak in to the blood. Normal ALT level for the adult male is 0-48 IU/L. Many with acute or chronic HCV infection have elevated ALT levels

21. Liver Cancer
Hepatocellular carcinoma (HCC) is a type of liver cancer associated with advanced hepatitis C
Alpha fetoprotein (AFP) is elevated in more than half of individuals with HCC, may be a biological tumor marker
Risk Factors include presence of cirrhosis, older age, male gender, AFP levels, alcohol use and coinfection with HBV

22. Hepatitis C Treatment
Goal: To achieve a sustained virologic response (SVR) and delay or stop progress to more serious liver damage
Not all Hepatitis C infected individuals are eligible for treatment

23. Simeprevir is indicated in combination with peginterferon and ribavirin for the treatment of adult patients with chronic hepatitis C genotype 1 infection and compensated liver disease, including those with cirrhosis; the indications for use include patients that are treatment naive and treatment experienced.

24. Sofosbuvir
Sofosbuvir is indicated for treatment of patients with HCV monoinfection and HCV/HIV-1 coinfection:
Genotype 1 or 4: sofosbuvir plus peginterferon-alfa plus ribavirin for a duration of 12 weeks
Genotype 2: sofosbuvir plus ribavirin for a duration of 12 weeks
Genotype 3: sofosbuvir plus ribavirin for a duration of 24 weeks
Sofosbuvir for patients with chronic HCV monoinfection:
Genotype 1 and not eligible for interferon: sofosbuvir plus ribavirin for a duration of 24 weeks can be considered
Hepatocellular carcinoma awaiting liver transplantation: sofosbuvir plus ribavirin for a duration of up to 48 weeks or until liver transplantation, whichever occurs first, to prevent post-transplant HCV reinfection

25. Simeprevir (Olysio) Summary
Approval Status: FDA approved December 6, 2013
Indication for HCV Monoinfection - GT 1: Simeprevir (12 weeks) + peginterferon + ribavirin (12 or 36 weeks) - Poor response to Simeprevir + Peginteferon + Ribavirin with GT1a and NS3 Q80K polymorphism at baseline
Class & Mechanism - NS3/4A protease inhibitor - Activity against GT 1,2,4,5,6 (strongest activity against GT 1a, 1b)
Simeprevir Dosing mg PO once daily with food - In combination with peginterferon + ribavirin (triple therapy)
Adverse Effects (AE) attributable to Simeprevir - Rash (including a photosensitivity reaction), pruritus, and nausea
Wholesaler Acquisition Cost in United States tablet bottle = $22,120; estimated 12-week cost = $66,360

26. Simeprevir + Sofosbuvir +/- Ribavirin for HCV GT 1 COSMOS Trial: Key Points
High Rates of SVR even in difficult to treat groups, including patients compensated cirrhosis and prior nonresponse to therapy
Rapid virologic response (RVR) did not predict SVR 12
Addition of ribavirin did not clearly improve SVR rates
Extending treatment to 24 weeks did not clearly improve SVR rates, except possibly in patients with prior relapse and advanced fibrosis
Patients with baseline G80K (Gln80Lys) had high SVR rates, including those with compensated cirrhosis
Ribavirin did not significantly impact SVR in patients with baseline G80K
Regimen well tolerated: fatigue, headache, and nausea were most common side effect
Phase 3 studies underway with simeprevir + sofosbuvir in OPTIMIST program
Source: Lawitz E, et al. Lancet. 2014;July 28 [Epub ahead of print]

27. Standard of Care Pegylated Interferon and Ribavirin
Pegylated interferon is taken by injection
Strengths the immune system
Ribavirin is a pill
Not effective against the hepatitis C virus alone
Slows the growth of the virus when used together with pegylated interferon

28. Combination Therapy Therapy is taken from 24 or 48 weeks
Reduces the amount of hepatitis C virus in your body
Prevents further liver damage
In clinical studies, approximately 5 out of 10 people achieve SVR

29. Therapy Notes Dosing schedule must be strictly followed
Pregnancy should be avoided
Side Effects include: flu-like symptoms, tiredness, upset stomach, redness at injection site, skin problems, hair loss, trouble sleeping, blood sugar problems
More serious side effects include: mental health problems, blood, lung, heart and eye problems, weakness numbness, liver problems
Flu-Like Symptoms: fever, chills, muscle aches, joint pain, headaches

30. What topics should be discussed with patients who have HCV infection?
HCV-positive persons should be advised to avoid alcohol because it can accelerate cirrhosis and end-stage liver disease.
Patients should be informed about the low but present risk for transmission with sex partners.
Sharing personal items that might have blood on them, such as toothbrushes or razors, can pose a risk to others.
Cuts and sores on the skin should be covered to keep from spreading infectious blood or secretions.
Donating blood, organs, tissue, or semen can spread HCV to others.
HCV is not spread by sneezing, hugging, holding hands, coughing, sharing eating utensils or drinking glasses, or through food or water.
Patients may benefit from a joining support group.

31. Questions? Sarah Weninger Viral Hepatitis Prevention Coordinator
Division of Disease Control
Phone: or
Questions?