Prospective Cohort Study: To Provide Evidence & Guidance in Hepatitis C Virus Screening, Comparing the New Birth Cohort Recommendations From the CDC, Versus Classical Traditional Strategies With Established Risk Factors

A. SPECIFIC AIMS (limit one page)

1. Compare yield of risk based versus risk based and birth cohort screening for hepatitis C
virus as a function of number invited to screen. The control group will receive the
routine care as delivered normally by local medical practice. This will be conducted in
the Salt Lake Area.

2. Determine cost in each arm of hepatitis C virus screening strategy.

3. Assess patient history for unknown risk factors for infection with HCV.

4. Create a registry of HCV positive and HCV negative patients to follow in future studies
to determine long term outcomes.

Outcome Measures:

1. Rate of positive screening for HCV in each group as a function of number invited to
screen.

2. Rate of persistent HCV infection in screen-positive patients based on confirmatory
testing.

3. Determine percentage Utah population that test positive for HCV as compared to national
average.

4. Listing of risk factors for each patient and analysis of risk factor tools to discover
new risk factors and causes.

B. BACKGROUND AND SIGNIFICANCE (Limit two pages)

There has been much published in regards to recommendations to screen patients for HCV. Much
of the attention is due to new treatments. Specific antiviral treatments to genotype 1 of HCV
have received much attention. The reported sustained viral response in HCV genotype 1 with
these new agents have been impressive but currently at great expense(12). With these new
advances it has become paramount to identify patients early to avoid great morbidity and
early mortality.

There are also disparate recommendations on screening for HCV between the Centers for Disease
Control and Prevention and the United States Preventive Task Force. The American Association
for the Study of Liver Diseases has sided with the CDC. The CDC has a new birth cohort
recommendation in addition to risk factor screening versus the USPTF recommendation to do
screening based upon risk factors only.

Given conflicting guidelines, tailored evidence to provide guidance to Intermountain
clinicians would be useful; especially as the Intermountain population may differ from the
U.S. population in risk making application of national guidelines more uncertain. This study
will delineate the most effective screening approach for the population served, identify the
rates of false positive tests, and delineate the costs of the screening strategies as
recommended.

Currently only one percent of patients in the birth cohort of 1945-1965 and cared for by
Intermountain Healthcare providers have been screened. Ambulatory practitioners are not
effectively screening patients or may not believe these patients to be at sufficient risk to
merit screening. It is unclear whether screening based on risk factors alone, or screening
based upon risk factors and birth cohort recommendations most effectively manages the burden
of chronic HCV infection for patients managed by Intermountain Healthcare providers.

A well-designed prospective cohort study is needed to understand the risks and benefits of
different HCV screening strategies on diagnostic yield and clinical outcomes (9).

We hypothesize that screening based on established risk factors will detect HCV 2.7 % of the
population tested. We believe that adding the proposed birth cohort in addition to risk
factors for screening will not increase the number of those we identify with chronic HCV.

Once we have generated a registry of patients through this Initial study we believe this
group could be followed inexpensively for clinical endpoints for many years to come. We would
have a group of newly diagnosed chronically infected patients with HCV, identified by the CDC
and USPTF guidelines. We then could ensure evidence base HCV treatment and follow endpoints
of chronic liver disease and its complications. We would then be able to know if screening
for hepatitis C virus is beneficial to the patient we care for and cost effective.

We have 885,000 patients of intermountain healthcare born between 1945 and 1965. Only one
percent of them have been screened for HCV. In those screened 11% had positive HCV tests. The
national average is 2.7 percent. This is not based upon any clear screening program. We
appear to be screening for hepatitis C well below the national average. The state of Utah
Epidemilogist's data indicate that 1% of Utahns have hepatitis C.

If we tested per CDC recommendation we would expect to diagnose 20,000 additional patients
with HCV. If each individual were screened and those who tested positively received liver
biopsy and treatment we could expect this to cost the system close to 3 billion dollars.

In summary, it is likely that many people with chronic HCV have not been identified and
treated. In this study, we will determine the effectiveness of each screening strategies.
This will inform clinicians about how to screen know how to screen for chronic HCV based on
evidence and not recommendations. Further as we follow the newly diagnosed patients we will
determine if our screening was effective following our evidence based management. We will
also be able to measure costs as opposed to just calculations based on quality of life year.

C. EXPERIMENTAL DESIGN AND METHODS (Limit five pages)

We have identified 9 internal medicine offices in the Salt Lake area. We will divide the
clinics into three groups (three clinics per each group). We are currently performing a
prestratification of the groups to make sure there isn't an age, sex, or racial divergency.
Group 1 would be our control group. The providers at these facilities will perform any
hepatitis C virus screening as they would normally. Group 2 would provide risk factor
screening per USPTF guide lines. Group 3 would use the CDC's recent birth cohort
recommendations in addition to risk factor screening. The only exclusion criteria is if the
patient has a test positive for hepatitis C virus or they give a positive history regarding
infection.

We would like to identify 2000 patients for each strategy in 3 months. We would do this by
asking office manager and physicians of clinics to let their office staff give a screening
strategy form to each patient and ask them to be a part of this study. We will create sheets
the patients can complete while they are waiting for their appointment. The clinical staff
would then be asked to interpret and order the appropriate testing.

We will place the strategy on a one sided sheet of paper that can be given to all internal
medicine patients between the age of 18 and 75.

I have enlisted the help of Dr. Greg Elliott, Scott Stevens, and Scott Woller and others in
an steering committee to offer expert advice and guidance.

Strategies:

1. Screen for hepatitis C as per regular practice as is occurring in their clinics
currently.

1. Form would ask them if they ever had been tested for Hepatitis C.

2. The rest of screening would be left to the provider's discretion.

2. Screen for hepatitis C as per conventional risk factors:

a. A sheet with these risk factors will be provided i. Those with a history of illicit
injection drug use or intranasal cocaine use, even if only used once ii. Those who
received clotting factors made before 1987 iii. Those who received blood/organs before
July 1992 iv. Those who have been informed that they received blood from a donor who
later tested positive for HCV v. Those who were ever on chronic hemodialysis vi. Those
with evidence of liver disease (persistently elevated alanine aminotransferase [ALT]
level) vii. Those infected with HIV viii. Children born to HCV-infected mothers. ix.
Those with a needle stick injury or mucosal exposure to HCV-positive blood x. Those who
are a current sexual partner of an HCV-infected person xi. Incarcerated individuals xii.
Healthcare, emergency, and public safety workers after needle stick/mucosal exposure to
HCV-positive blood xiii. Children born to HCV-positive women xiv. Are spouses or
household contacts of HCV-infected patients

Those with these risk factors will be tested for HCV, HBV, and HIV

Investigative factors:

- Recipients of transplanted tissue after 1992

- Those with a history of tattooing, body piercing

- Those with a history of sexually transmitted diseases or multiple sex partners

- Long-term steady sexual partners of HCV-positive persons

Any exposure you are concerned about:______________________________.

3. Screen for hepatitis C by conventional risk factors and new CDC birth cohort
recommendations.

1. Anyone born in the United States between 1945 and 1965

2. Those with a history of illicit injection drug use or intranasal cocaine use, even
if only used once

3. Those who received clotting factors made before 1987

4. Those who received blood/organs before July 1992

5. Those who have been informed that they received blood from a donor who later tested
positive for HCV

6. Those who were ever on chronic hemodialysis

7. Those with evidence of liver disease (persistently elevated alanine
aminotransferase [ALT] level)

8. Those infected with HIV

9. Children born to HCV-infected mothers.

10. Those with a needle stick injury or mucosal exposure to HCV-positive blood

11. Those who are a current sexual partner of an HCV-infected person

12. Incarcerated individuals

13. Healthcare, emergency, and public safety workers after needle stick/mucosal
exposure to HCV-positive blood

14. Children born to HCV-positive women

15. Are spouses or household contacts of HCV-infected patients

Investigative risk factors:

- Recipients of transplanted tissue after 1992

- Those with a history of tattooing, body piercing

- Those with a history of sexually transmitted diseases or multiple sex partners

- Long-term steady sexual partners of HCV-positive persons

Any exposure you are concerned about:______________________________.

Guidance for initial positive HCV screen:

All patients will be tested for HCV, HBV, and HIV if they have the above risk factors.

If patients are found to be Hepatitis C positive by EIA, a HCV RNA quantity (viral load)
would be performed. If the HCV RNA is negative and EIA is +, will order a HCV RIBA. (not
PCR); if RIBA is negative this indicates a false positive EIA test.

Those patients with positive results would be notified by their primary physicians. We would
provide a decision tree for work up and treatment of a newly found infection. Patients can be
referred to gastroenterologists, hepatologists, and primary care providers who treat chronic
hepatitis C virus infection.

F. IMPACT (Limit one page)

Hepatitis C virus is the leading cause of chronic liver disease in the United States, and is
the leading reason for liver transplantation. Recent advances, in treatment , have made
Hepatitis C virus chronic infection curable for many patients. It is important to identify,
treat, and attempt to cure these patients, many of whom don't know they are affected.

Recommendations have been made to try and accomplish this. There needs to be evidence to
guide our screening and therapy. With this study we could provide evidence to Intermountain,
Utah, and I believe the greater medical community. In a few months we could have data that is
publishable having compared the screening recommendations for HCV. We would know which if any
of the screening strategies are superior in identifying chronic HCV.

We would do a follow up study, hopefully with additional funding from an outside group,
having identified new carriers of chronic Hepatitis C. We would provide current evidence
based antiviral treatments that are available based on genotype. This would allow us to see
the comparative progression of liver disease with its subsequent complications in the three
screened groups. We could follow these groups for up to 20 years and have evidence that would
guide screening and treatment for HCV.

Inclusion Criteria:

- anyone between the ages of 18 and 75 years old.

Exclusion Criteria:

- anyone who gives a history of chronic Hepatitis C virus infection or who has had a
positive lab result in the past.