DRAFT FOR PUBLIC COMMENT

1 April 23, 2012
Recommendations for the Identification of Hepatitis C Virus (HCV) Chronic Infection
Among Persons Born during 1945 through 1965

Disclaimer:

This information is distributed solely for the purpose of pre-dissemination public comment under applicable information quality guidelines. It has not been formally disseminated by the Centers for Disease Control and Prevention. It does not represent and should not be construed to represent any agency determination or policy."DRAFT FOR PUBLIC COMMENT

2 Contents

SUMMARY .................................................................................................................................... 4

INTRODUCTION .......................................................................................................................... 4

BACKGROUND ............................................................................................................................ 5

RATIONALE FOR AUGMENTING HCV TESTING .................................................................. 6

METHODS ................................................................................................................................... 12
Research Questions ................................................................................................................... 15

Prevalence Data ..................................................................................................................... 16

Patient

- important Outcomes .................................................................................................. 16

RESULTS ..................................................................................................................................... 17

Review of HCV Infection Prevalence Data .............................................................................. 17

Patient -Important Outcomes ..................................................................................................... 17

All -Cause Mortality ............................................................................................................... 18
Hepatocellular Carcinoma .................................................................................................... 18
Failure to Achieve Sustained Virologic Response ................................................................. 18

Treatment

- Related Serious Adverse Events ........................................................................... 19
Quality of Life ........................................................................................................................ 19

HCV Transmission ................................................................................................................. 19

Alcohol Use

............................................................................................................................ 20

Determination of the Recommendations ...................................................................................... 20 Resource Implications ................................................................................................................... 21

RECOMMENDATIONS .......................................................................................................... 23

PUBLIC HEALTH TESTING CRITERIA .................................................................................. 23

TESTING METHODS

.................................................................................................................. 24

PREVENTION MESSAGES

........................................................................................................ 26

LINKAGE TO CARE AND TREATMENT ................................................................................ 26

FUTURE DIRECTIONS .............................................................................................................. 27

REFERENCES ............................................................................................................................. 28

APPENDICES .............................................................................................................................. 36 Appendix A. Acronyms Used in this Document .......................................................................... 37 Appendix B. Conflicts of Interest ................................................................................................. 39DRAFT FOR PUBLIC COMMENT

3 Appendix C. Analytic Framework ................................................................................................ 45 Appendix D. Search Strategy for HCV Prevalence ...................................................................... 46 Appendix E. Flow Chart for HCV Prevalence .............................................................................. 47 Appendix F. Search Strategy for Patient -Important Outcomes .................................................... 48

A ppendix G. Flow Chart for All- Cause Mortality ........................................................................ 50 Appendix H. Flow Chart for Hepatocellular Carcinoma .............................................................. 51 Appendix I. Meta-Analysis of the Effects of Treatment Response on Incidents of Hepatocellular Carcinoma ..................................................................................................................................... 52 Appendix J. Summar y of Findings Tables .................................................................................... 53

Authors .......................................................................................................................................... 58DRAFT FOR PUBLIC COMMENT

4 Recommendations for the Identification of Hepatitis C Virus (HCV) Chronic Infection
Among Persons Born from 1945 through 1965

S UMMARY Hepatitis C virus (HCV) causes substantial morbidity and mortality in the United States. Many of the 2.7-3.9 million persons living with HCV are unaware they are infected and do not receive

care or potentially lifesaving treatment. To ensure that persons at greatest risk for hepatocellular carcinoma and other HCV-related liver disease are tested for HCV and linked to needed care and treatment if infected , the Centers for Disease Control and Prevention ( CDC ) is expanding its 1998 guidelines( 1 ) to recommend test ing of persons born during 1945 through 1965, a population with a disproportionately high prevalence of HCV infection and related disease. Persons in this birth cohort account for three

- fourths of all HCV infections in the United Stat es ( 2 ) and 73% of HCV -associated mortality( 3 ). With t he advent of new therapies tha t can halt disease progression and provide a virologic cure (sustained viral clearance 24 weeks following completion of treatment ) for many patients living with hepatitis C, testing and linkage

to care of infected persons born 1945-1965 is expected to reduce HCV -related morbidity and mortality. CDC developed these recommendations with the assistance of a work group representing diverse perspectives . The recommendations are informed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology ( 4 ), an approach that provides guidance and tools to define the research questions, conduct the systematic review, assess the overall quality of the evidence, and determine the direction and strength of the recommendations. This report, which is intended to augment CDC’s 1998 Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV

Related Chronic Disease , will serv e as a resource for health-care professionals, public health officials, and organizations involved in the development, implementation, and evaluation of prevention and clinical services.

INTRODUCTION In the United States, an estimated 2.7- 3.9 million perso ns (1.0%-1.5%) are living with hepatitis C infection ( 5 ), and approximately 20,000 persons are newly infected each year. Although effective treatments are available to eradicate hepatitis C virus ( HCV ) infection

, most persons with HCV do not know they are infected therefore they do not receive needed care and cannot be evaluated for treatment. HCV t esting is a critical first step toward improving health outcomes for persons infected with HCV.

Since 1998, routine HC V testing has been recommended for persons most likely to be infected with HCV . This determination is made on the basis of a known epidemiologic relationship between a risk factor and acquiring HCV infection, the prevalence of a risk behavior or characteristic in the population, the prevalence of infection among those with a risk behavior or characteristic, and the presence of a recognized exposure to HCV

. These r ecommendations were developed by the Hepatitis C Virus (HCV) Birth Cohort Testing Work Group, which included experts from CDC and other federal agencies, professionalDRAFT FOR PUBLIC COMMENT

5 associations, community and advocacy groups, and medical associations. The Work Group employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology ( 4

, 6-13 ) to inform recommendation development. The GRADE approach provides guidance and tools to define the research questions, conduct the systematic review, assess the overall quality of the evidence, and determine the direction and strength of the recommendation s. Following this evidence review

, CDC ’s Division of Viral Hepatitis (DVH) developed this report, which was then peer

- reviewed by external experts and was posted for public comment.

These birth

- year

- based recommendations are intended to augment the 1998 HCV testing guidelines. CDC currently is conducting systematic reviews of risk

- based and medical indication -based screening and testing guidelines and will publish updated, comprehensive recommendations for the identification and prevention of HCV infection when this process is completed. Moving forward, these comprehensive recommendations will be reviewed every 5 years and updated to include advances in the published evidence.

BACKGROUND HCV causes acute infection , which may be characterized by mild to severe illness but is usually asymptomatic

. In approximately 75%-85% of persons, HCV persists as a chronic infection

, plac ing infected persons at risk for hepatocellular carcinoma (HCC) , cirrhosis, and extrahep atic complications that develop over the decades following onset of infection ( 14 ).

Because HCV is a bloodborne infection, r isks for HCV transmission primarily are associated with exposures to contaminated blood or blood products ( 1 ). In 1998, the highest prevalence of antibody to HCV (anti- HCV) was found among persons with substantial or repeated direct percutaneous exposures, such as persons who inject drugs, persons who received blood from infected donors, and persons with hemophilia (60%- 90%); moderate rates were found among those with repeated direct or unapparent percutaneous exposures involving smaller amounts of blood, such as hemodialysis patients (10%-30%). Persons with un apparent percutaneous or mucosal exposu res , including those with high -risk sexual behaviors, s exual and household contacts of persons with chronic HCV infection (1%- 10%), and persons with sporadic percutaneous exposures (e.g., health

- care workers [1%-2% ]) had lower rates. The lowest rates of anti- HCV occurred among persons reporting no high- risk characteristics (e.g., volunteer blood donors [0.3% ])

.
Prior to 1965, t he estimated annual incidence of HCV infection (then known as Non ANon B hepatitis) was low (18 cases per 100,000 persons). How ever, due to increasing injection drug use (IDU) and increased use of blood and blood products for transfusion, the incidence of HCV infection increased steadily into the 1980s and remained high (130 cases per 100,000 population), representing an average o f 230,000 infections per year during that decade ( 15 ). In 1988 , HCV was identified , and by 1992, sensitive multiantigen serologic assays for testing the blood supply had been developed and licensed. From 1992 – 2004, the number of reported cases of new HC V infection decreased 78.4% ( 16 ), a decline attributed largely to a decrease in cases among persons who inject drugs (PWID ).( 17 ) S af er injection practices among PWID contributed to some of this decline, but the downward trend was most likely related to HCV infection saturation of the injection drug

- using population.( 17 ) A small er proportion of theDRAFT FOR PUBLIC COMMENT

6 overall decline in HCV infection incidence was attributed to effective screening of blood donors to prevent HCV transmission. Most of the declines in HCV incidence occurred in the 1990s. Si nce 2004, HCV incidence has remained stable ( 17 ). In 2009, the estimated number of newly acquired ( i.e., acute) infections in the United States was 16,000 ( 16

, 18 ). Among American Red Cross Blood Service systems in the United States, prevalence among first time blood donors has decreased by 53% from 0.35% in 1999 to 0.16% in 2008.( 19 ) The overall prevalence of anti -HCV in the general population of the United States can be estimated by analyzing the National Health and Nutrition Examination Survey (NHANES) data

, a representative sample of the civilian non -institutionalized population. NHANES data indicate that HCV infection prevalence did not change from 1988 through 2002 (1.6%-1.8 %) , consistent with the finding that the incidence of infection declined and then remained stable during this time period ( 5
, 15

, 17

, 20 ). The anti- HCV p revalence estimate has been lower in recent years, at 1.3% 1 during 2005-2008 ( 21 ) , representing an estimated 3. 6 1 million anti -HCV positive persons (95% CI= xx -xx 1 ); of these persons, 2.8 1 million (95% CI= xx -xx 1 ) are chronically infected. NHANES data underestimate the actual national prevalence, because these surveys do not include samples of incarcerated or homeless persons, populations known to have high prevalence of HCV infection. Although there are no systematic surveys comparable to NHANES that sample these po pulations, their inclusion would likely increase the estimated number of infected persons by about 500,000( 22 ).

RATIONALE FOR AUGMENTING HCV TEST ING RECOMMENDATIONS
In 1998, recommendations for identifying HCV- infected persons were iss ued as part of a comprehensive strategy for the prevention and control of HCV infection and HCV- related chronic disease (1)

. HCV testing was recommended for patien ts at high risk of HCV infection, including persons who 1) had ever injected drugs, 2) were ever on chronic hemodialysis, 3) received blood transfusions or organ transplants prior to July 1992, or 4) received clotting factor concentrates produced prior to 1987. S creening also was recommended for persons who had a recognized exposure (healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures and children born to HCV-infected mothers) and persons with laborato ry evidence of liver disease (persistently elevated alanine aminotransferase levels). In 1999, HCV testing was recommended additionally for persons infected with human immunodeficiency virus (HIV). ( 23 )

Limited Effectiveness of Current Testing Strategies

C urrent risk

- based test ing strategies have met limited success, as evidenced by the substantial number of HCV- infected persons who remain unaware of their infection ( 24 ). Estimates of the proportion of U.S. adults who are chronically infected yet unaware of their HCV infection status range from 45%-85% ( 25-28 ) depending on setting, risk level in the population, and site- specific testing practices. Even among high -risk populations for whom routine test ing is recommended, testing for HCV seromarkers is variable ( 25

, 26 ) , and a sizeable percentage o f
t hese persons remain unaware of their infection status ( 29 ). Inadequate health insurance
coverage and limited access to regular health care pose barriers to HCV test ing and

1 These estimates will be revised when updated surveillance data become available.DRAFT FOR PUBLIC COMMENT

7 diagnosis( 28 ); however, even among the well insured, risk

- based testing practices have not been successful in identifying most HCV -infected persons ( 27 ).

A more significant barrier to the suc cess of the risk -based approach to HCV test ing occurs at the provider level. Many providers lack knowledge about hepatitis serology and
treatment ; s tudies have shown that providers’ level of knowledge regarding HCV infection prevalence, natural history, available tests, and testing procedures is low ( 30-33 ). Although upto -date professional guidelines on HCV test ing are available from the American Academy of Family Physicians (AAFP) ( 34 ) and the American Association for the Study of Liver Disease (AASLD) ( 14

, 35 ), 41.7% of primary care physicians reported they were unfamiliar with them ( 36 ). P hysician s’ reluctance t o assess risk factors also contributes to low testing rates ; f ewer than half of all U.S. physicians ask their patients sensitive questions related to high -risk behaviors (e.g., IDU ) ( 31 ). In addition, accuracy of patient recall of risk behaviors, including drug use and

sexua l encounters, decreases over time ( 37 ).

Increasing Morbidity and Mortality

HCV -associated disease is the leading indication for liver transplantation and a leading cause of HCC in the United States ( 24

, 38-40 ). HCC and cirrhosis have been increasing among persons infected with HCV ( 41

, 42 ), and these outcomes are projected to rise substantially in the coming decades ( 43

, 44 )

. Annual HCV- related mortality in the United States now outpaces that of HIV. A CDC review of death certificate data found that the hepatitis C mortality rate increased significantly from 1999-2007 (a nnual mortality rate change : +0.18 deaths/100,000 per year) . In 2007, HCV caused 15,106 deaths, whereas the number of deaths from HIV declined to 12,734 ( 3 ) . Of the HCV -related deaths, 73.4% occurred among persons aged 45- 64 years. Incidence of HCC is increasing significantly in the United States representing the fastest growing cause of cancer

- related mortality , and infection with HCV accounts for more than 50% of incident HCC ( 45 ).

Data fo r observed HCV disease progression over a 20-year period indicate that 20% ofinfected persons will progress from fibrosis to cirrhosis and as many as 5% will die from HCVrelated liver disease. ( 46 ) Mo deling studies have forecasted substantial increases in morbidity and mortality among HCV -infected persons as they progress into their third, fourth, and fifth decades living with the disease ( 47

, 48 ). O ver the next 40

- 50 years , these models project that 1.76 million (6 0.7 %) persons with untreated HCV infection ( 44 ) will develop cirrhosis, with a peak prevalence of 1 million cases occurring from the mid-2020s through the mid-2030s ( 44 ) ; approximately 400,000 will develop HCC ( 44 ). Of pe rsons with hepatitis C who do not receive needed care and treatment , approximately 1 mill ion will die from related complications ( 44

, 49 ).

Benefits of HCV Diagnosis and Care
Clinical preventive services , regular medical monitoring, and behavioral changes can improve health outcomes for persons with HCV infection. Because co -infection with HIV and consumption of alcohol (51) hasten the progression of HCV (50) , professional practice guidelines for hepati tis C management issued by AASLD (14) include counseling to decrease or eliminate alcohol consumption and hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccination for susceptible persons (14). Additional guidance from AASLD includes: 1)DRAFT FOR PUBLIC COMMENT

8 counseli ng and education to reduce interactions between herbal supplements, over-the-counter, and prescription medications ( 14

, 50 ) and 2) counseling to encourage weight loss for persons who are overweight to reduce the likelihood of insulin resistance and disease progression (14, 52). Excess weight has been linked to increased disease progression among HCV

- infected person s ( 51 ). As HCV

- associated liver disease progresses, the likelihood of sustaining a treatment response decreases ( 52

, 53 ); t herefore

, early clinical evaluation and linkage to care are critical interventions.

Benefits of HCV Treatment

AASLD recommendations, endorsed by the Infectious Disease Society of America (IDSA) and American Gastroenterological Association (AGA), propose antiviral trea tment for persons with histological signs of bridging fibrosis, septal fibrosis , or cirrhosis. In May 2011, the first generation of new direct

- acting antiviral agents (DAAs) , the HCV NS3/4A protease inhibitors t elaprevir and b oceprevir, were licensed for c linical use in the United States

. Compared with conventional pegylated interferon and weight-based ribavirin therapy alone, the addition of one of these two protease inhibitors to the standard treatment regimen in clinical trials increase d sustained virol ogic response (SVR) rates from 44 % to 7 5% and 38% to 63%, respectively , in persons with HCV genotype 1 (the most common genotype in the United States) ( 54

, 55 ). Persons who achieve an SVR after treatment have a substantial reduction in risk for all

cause mortality (54%) ( 56 ) and substantially lower rates of liver

- related death and decompensated cirrhosis ( 57
, 58 ). Given the recent introduction of these new treatment regimens, the long- term effects of treatment in every day clinical practice remain to be established, and the benefits may be different in community settings . In addition to the new FDA

- approved medications, there are currently 22 new HCV treatments (protease and polymerase inhibitors) in Phase II or P hase III clinical trials , ( 59 ) and treatment recommendations are expected to change as new medications are available for use in the United States

.

CONSIDERATION OF A NEW HCV TESTING STRATEGY

Given the limited effectiveness of the current risk

- based HCV testing recommendations

, CDC has evaluated alternative public health strategies for increasing the proportion of infected persons who know their HCV infection stat us. Several analyses of nationally representative data have found a disproportionately high prevalence of HCV infection among persons who were born between the mid -1940s and the mid-1960s. In an analysis of 1988-1994 National Health and Nutrition Examinati on Survey (NHANES) data, 65% of persons with HCV infection were 30- 49 years of age ( 20 ), roughly corresponding to this birth cohort. In an analysis of NHANES data from 1999-2002, a similarly high proportion of all persons with HCV antibody had been born from 1945 through 1964 (Figure 1) ( 5 )

. A recent analysis of 1999- 2008 NHANES data found that the prevalence of HCV among persons in the 1945-1965 birth cohort was 3.25% (95%CI, 2.80 to 3.76); persons born during these years accoun ted for over three fourths (76.5%) of the total anti

- HCV prevalence in the United States ( 2 ). Given the disproportionately higher
pr evalence among persons born during these years, CDC evaluated multiple birth cohort s within these years for targeted HCV testing

.DRAFT FOR PUBLIC COMMENT

9 Selection of a Target Birth Cohort

To select a target birth cohort for an expanded testing strategy, CDC examined the prevalen ce, proportion of burden, race/ethnicity and sex stratifications for seven birth cohorts of differing intervals ( Figure 1 ) . The 1945 -1965, 1950-1970, and 1945-1970 cohorts captured the population with the most anti

- HCV prevalence, whereas the 1950-1965 and 1950-1960 cohorts included persons born in years with the highest HCV prevalence. The 1945 -1949 and 1966-1970 birth cohorts represent the tails of the prevalence curve and were examined separately to consider how wide the birth cohort should extend. The weighted, unadjusted anti- HCV prevalence and estimates of the size of the chronically infected population within each proposed birth cohort were determined (Table 1).

Figure 1. Prevalence of hepatitis C virus antibodies by age group (A) and year of birth (B).DRAFT FOR PUBLIC COMMENT

10 Table 1. Prevalence r ates and burden of hepatitis C virus ( HCV ) infection, by s even b irth cohorts Proposed b irth cohort Anti

- HCV
p revalence*

(weighted, unadjusted) Current U.S.
p opulation (in millions) † Number of

a nti

- HCV

positive
p ersons (in

millions) Number of chronically

i nfected
p ersons (in millions) § Proportion of i nfected
p opulation i dentified

1945

- 1965 3.27% 78.8 2.58 1.94 75.9%

1950

- 1970 3.22% 86.1 2.77 2.08 78.4%

1945

- 1970 2.98% 98.8 2.94 2.21 84.7%

1950

- 1965 3.65% 66.1 2.41 1.81 6 7.9%

1950

- 1960 4.04% 44.2 1.79 1.34 52.3%

1945

- 1949 1.65% 12.7 0.21 0.16 7.1%

1966

- 1970 1.77% 20.0 0.35 0.26 9.7%

*Unpublished data from National Health and Nutrition Examination Survey (NHANES) 1999

- 2008 data. Prevalence not adjusted by age or other covariates

. † Source: U.S. Census Bureau. Current Population Reports: Population Projections of the U.S. by Age, Sex, Race, and Hispanic Origin: 1995 to 2050, P25

- 1130.

§ 75% of anti

- HCV positive persons are estimated to be chronically infected

.

On th e basis of prevalence rates and burden, the 1945-1965 birth cohort was selected as the target population. Because this cohort included the 1950-1965 and the 1950-1960 cohorts, these were eliminated from further consideration. T he three remaining cohorts ( 1945-1965, 1950-1970, and 1945-1970) each represented a substantial proportion of the population and a substantial proportion of the infected population. Further, only minimal difference s in the anti

HCV prevalence, number of anti-HCV positive persons, and number of chronically infected persons were observed. The three cohorts were additionally stratified by rac e/ ethnic ity and gender (Table 2) . The differences in the male to female ratio were insignificant and do not drive the selection decision . However, the difference in prevalence by race/ethnicity between the birth cohorts is substantial. Both the 1950-1970 and 1945-1970 cohorts have a lower prevalence of HCV

- infected non-Hispanic black populations than the 1945-1965 cohort. Because non

- Hispanic black populations have a greater prevalence of HCV infection than their white counterparts, a testing strategy based on the 1945-1965 cohort was selected to enable this health disparity to be addressed . Of the 210,000 anti-HCV positive persons in the 1945-1949 cohort, approximately 71,000 (35 %) are African American.DRAFT FOR PUBLIC COMMENT

11 When examining testing strategies using the 1945-1970 birth cohort versus the 1945- 1965 birth cohort, the health impact (identifying ~260,000 chronic cases) did not justify the increased costs ($8 00 million) associated with the 1945 -1970 birth cohort. Also, the cost per chronic case identified for the 1945-1965 compared with the 1945-1970 birth cohort ($2,874 vs. $3,161) and the number needed to screen to avert a single HCV-related death in the 1945-1965 birth cohort compared with the 1945-1970 birth cohort (607 vs. 679) were lower in both instances . Data collected through CDC consumer testing also supported use of the 1945-1965 birth cohort. Such testing demonstrated that the 1945-1965 birth cohort is a recognized sub

population understood as the “baby boomers; ” familiarity with this sub -population and the term used to describe it likely will facilitate adoption of the recommendation. Based on these
assessments , CDC selected the 1945-1965 birth cohort as the target population.

The confluence of the high incidence of HCV infection in the relatively remote past, the high prevalence of chronic infection , and a long period of subclinical infection ( 2

, 60 ) contribut e to a large proportion of persons who remain unaware of their HCV infection status. Taken together, these factors create a unique and challenging public health situation: an age wave of persons progressing through time who are at increasing risk for severe liver disease that is preventable by appropriate testing, care and treatment.

HCV Infection Prevalence in the 1945-1965 Birth Cohort
Although the prevalence of anti- HCV in the U.S. population is an estimated 1.6% ( 5 ), it is about two times higher among persons born from 1945 through 1965 (3.2 5 %). Among persons born outside the cohort , prevalence is substa ntially lower (0. 88 %)

. The high prevalence amongDRAFT FOR PUBLIC COMMENT

12 persons in this birth cohort reflects the substantial number of new infections that occurred throughout the 1970s and 1980s and the high likelihood of HCV persisting chronic ally. Males in this cohort had almost twice the prevalence as their female counterparts; H CV infection prevalence was highest among non-Hispanic black males (8.12%), followed by non- Hispanic white males (4.05%) and Mexican

- American males (3.41%).
Complicating health outcomes among HCV- infe cted persons born during 1945-1965 are a lack of health insurance ( 31.5%) and use of alcohol

. Of all anti -HCV positive persons in the 1945-1965 birth cohort who self-reported alcohol use, 57.8 % reported drinking an average of
two or more alcoholic drinks p er day.

METHODS

In April 2011, the HCV Birth Cohort Test ing Work Group convened to explore the practicality of developing a recommendation for one- time HC V testing for persons unaware of their infection status

. While the epidemiologic data exist to support the consideration of a birth
year testing strategy , a formal review of the literature was needed to examine the effect that this testing would have on diagnosing persons unaware of their HCV infection status, as well as the potential benefits and harms that this strategy would have on persons tested

. The HCV Birth Cohort Testing Work Group consisted of 1) a steering committee in the CDC Division of Viral Hepatitis (DVH) , which led and conducted the evidence reviews; 2) an internal (to DVH) work group (consisting of representatives from DVH’s La boratory Branch and from the DVH Prevention and Epidemiology and Surveillance Branches ), which was tasked with reviewing and providing input on the evidence compiled by the steering committee through biweekly meet ings ; and 3) an external (to CDC) work group that provided input on materials compiled by the steering committee thr ough regular teleconferences, an evidence grading methodology training workshop, and a consultation. The external work group members were identified by their involvement in hepatitis - and recommendation

- specific activities (e.g., publications, hepatitis C advocacy group representation, self-identified HCV infection, and relevant federal agency appointments) and included members from a wide r ange of disciplines, organizations, and geographic regions, including

• federal organizations (Agency for Healthcare Research and Quality, National Cancer Institute, Food and Drug Administration, Veteran’s Affairs, Health Resources and Services Administratio n, Substance Abuse and Mental Health Services Administration, and National Institute of Diabetes Digestive and Kidney Diseases ),

• professional associations (e.g., the Amer ican Medical Association and the American Academy of Family Physicians),

• community and advocacy groups (e.g., the Adult Viral Hepatitis Prevention Coordinator program and the National Viral Hepatitis Roundtable ), and

• medical specialty associations (e.g., AASLD and AGA ).

Several subject matter experts (e.g., hepatologists, economists, and g uideline methodologists) also served as members of the external group. All HCV Birth Cohort Testing Work Group participants were required to disclose conflict s of interest (if any) and were notifiedDRAFT FOR PUBLIC COMMENT

13 of the restrictions regarding lobbying during the recommendation development process (Appendix B: Conflicts of Interest). No members’ activities were restricted based on the information disclosed.

Comprehensive systematic reviews of the literature were conducted, analyzed, and assessed in two stages to examin e the availability and quality of the evidence regarding HCV infection prevalence and the effects of one- time HCV testing for persons unaware of their status

. H CV Birth Cohort Testing Work Group members communicated through regular teleconferences, an in -persons GRADE methodology workshop, and a consultation. Initial evidence from the systematic review of the prevalence data was shared during the teleconferences and the birth years, 1945-1965, were selected. Following that selection, the systematic review focused on the effects of testing persons born during 1945 through 19 65 for HCV infection, which were presented at the consultation.

In August 2011, CDC convened a 2- day consultation with H CV Birth Cohort Testing Work Group members to review and evaluate the quality of the evidence of effectiveness of the proposed strategy of one- time testing of all members of the 1945 -1965 birth cohort, consider benefits versus harms of patient -important outcomes (Appendix J: Summary of Findings Tables), weigh the variability between the values and preferences of HCV testing among potential patients , and consider resource implications. During the consultation, presentations were given to review the rationale for these recommendations, population- level data on the prevalenc e of HCV infection among persons born from 1945 through 1965, and the results of the systematic reviews conducted to determine the benefits and harms of the patient -important outcomes. For each patient -important outcome, a summary of findings table with an analysis of the quality of the evidence was presented to c onsultation attendees for discussion (Appendix J : Summary of Findings Tables). At the conclusion of the consultation, work group members provided input on the quality of the evidence and strength of the recommendations. Following the consultation, the DVH Steering Committee and Internal CDC Work Group reviewed all of the information and reached a decision regarding the strength of the recommendations. A t that time, a recommendations statement and qualifying remarks were developed in accordance with GRADE methodology.

External feedback from the public was solicited through conference presentations, meetings with national stakeholders, peer review, and public comment 2

. External HCV Birth Cohort Testing Work Group members were asked to comment on the recommendations statement and remarks during the public comment process. Feedback was reviewed by the CDC Steering Committee and the draft was modified accordingly. Throughout the development process, CDC also sought input from participants at national conferences, including AASLD’s 2011 Single Topic Conference, the 2010 Annual Meeting of the American Public Health Association, the 2010 AASLD Conference, and the 2011 Guidelines International Network Conference.

GRADE Methodology

2 This document will be made available for public comment af ter clearance and this section will be revised to include specific dates of that process.DRAFT FOR PUBLIC COMMENT

14 These recommendations were developed using GRADE methodology ( 4

, 6-13 ) . The GRADE
met hodology has been adopted by over 60 organizations, including CDC federal advisory committees (i.e., the Advisory Committee on Immunization Practices [ ACIP ] [63] and Healthcare Infection Control Practices Advisory Committee [ HICPAC ]), the World Health Orga nization (WHO), the Infectious Disease Society of America ( IDSA ), AGA, and the Cochrane Collaboration (www.gradeworkinggroup.org). GRADE provides guidance and tools to define research questions, develop an analytic framework, conduct systematic reviews, as sess the overall quality of the evidence, and determine the direction and strength of the recommendations.

Research questions were formulated to guide the development of the recommendation using a population, intervention, comparator, and outcome (PICO) format. The research questions were developed to support a two-stage approach to the evidence review: 1) to determine the baseline risk of HCV infection and 2) to measure the effects of an intervention (i.e., patientassociated benefits and harms ).

Per the GRADE process, the H CV Birth Cohort Testing Work Group designed an analytic framework (Appendix C: Analytic Framework)

, which was used to examine patient

- important
outcomes associated with each step of the testing effort, from the identification of the t arget population to the treatment of persons found to be infected with HCV.

To measure the benefits and harms of HCV screening and treatment, patient- important outcomes were compiled. These outcomes were ranked, each according to its relevance to the

rec ommendation (a rating of 1-3 being of low importance; 4- 6 being important but not critical to decision making; and 7- 9 as critical to decision making). Literature reviews were conducted on outcomes identified as important or critical to decision making. Work group members had three opportunities to rank the outcomes: 1) when the outcomes were first identified, 2) after the evidence was presented, and 3) during the discussion of the benefits and harms, allowing the work group to weigh the relative importanc e of the outcomes based on the evidence presented and the benefits and harms.

The quality of the evidence for each patient -important outcome was assessed collectively by individual outcome, not by individual studies, in the GRADE profiler software (GRADEpr o 3.6). The quality of the evidence was categorized as being “h igh, ” “moderate, ” “l ow,” or “v ery low” depending on the established criteria for downgrading or upgrading the quality. Studies

were downgraded if they met at least one of the following five c riteria: 1) risk of bias; 2) inconsistency or heterogeneity; 3 ) i ndirectness; 4) imprecision; or 5) publication bias. Conversely, studies were upgraded if they met any of three criteria: 1) l arge effect size; 2) doseresponse; or 3) plausible confounders (i.e ., when biases from a study may be working to underestimate an apparent intervention effect) (Appendix J: Summary of Findings Tables). Outcomes were re -ranked for importance after consideration of evidence by the work group members

. The following four factors were considered when determining the relevance and strength of a GRADE

- based recommendation: 1) quality of evidence, 2) balance between benefits and harms

, 3) values and preferences , and 4) resource implications . During the consultation, the H CV Birth Cohort Testing Work Group considered each of these factors in light of the evidence presented. A statement based on the direction and strength of the recommendation wasDRAFT FOR PUBLIC COMMENT

15 developed using the GRADE criteria ; statements were either “ for ” or “against” an i ntervention and were either strong (designated by a “should” statement) or conditional (designated by a “may consider” statement).



### Research **Questions**

To facilitate a succinct

, systematic review of the evidence, the HC V Birth Cohort Testing Work Group dev eloped several review questions (Box 1) to be considered when examin ing prevalence data and patient -important outcomes (Appendix C: Analytic Framework) ; review questions were aligned with the analytic framework and were formed in accordance with PICO. The division of these questions into two topics, prevalence data and patient -important outcomes, reflects the two

- stage approach that was used to 1) define the testing strategy and birth years of interest, and 2) to examine the effects of testing persons born during 1945 through 1965 for HCV infection. Because the patient -important outcomes questions encompass a multitude of outcomes, they are formed without listing one specific outcome; they present only the population, intervention, and comparator.

Box 1 . Re search questions

Literature Review
The DVH steering committee evaluated current HCV test ing guidelines ( 1

, 14

, 61-65 ), reviewed existing scientific evidence, and conducted systematic

- reviews and meta

- analyses to synthesize the evidence available on the review questions. This evidence was compiled and presented to the Hepatitis C Virus Birth Cohort Test ing Work Group throughout the development
process.

The systematic review process for these recommendations was separated into two stages : 1) a review of HCV infection prevalence to determine the effect of a birth

- year testing strategy, and 2) a review of the patient-important outcomes to understand the effect of a testing intervention for persons born from 1945-1965. Search strategies varied for each stage; however, following the initial collection of results from the search, titles and abstracts were reviewed by two persons. If disagreement on the inclusion of an article occurred , an independent third

Prevalence Data

1. What is the effect of a birth

- year bas ed testing strategy versus the standard of care (i.e.,
risk

- based testing) among persons for HCV infection?

Patient

- Important Outcomes

1. Should HCV testing followed by antiviral treatment versus no testing (or failed treatment) be conducted among persons born from 1945 through 1965?

2. Should HCV testing versus no testing be used in average risk adults born from 1945 through 1965?DRAFT FOR PUBLIC COMMENT

16 reviewer decided whether the article would be included . For the titles and abstracts that met the inclusion criter ia, the full article was retrieved and reviewed. Information from the full articles was extracted for the GRADE profiles to conduct the meta

- analyses.

Prevalence Data During the first stage of the review, the effect of a birth

- year

- based screening strate gy for persons infected with HCV was considered. The goal of the review was to determine if prior literature addressed a birth

- year -based strategy or provided additional support for the prevalence estimates (see Selection of a Target Birth Cohort). T he DV H steering committee reviewed all literature regarding the effect of a birth

- year

- based testing strategy for HCV infection that had been published after CDC’s 1998 recommendation . To be selected for review, articles had to have been published from 1995 through 2011, describe results of U.S. -based studies, and include participants within the birth cohort. Case studies were excluded , as well as studies of persons coinfected with HBV or HIV. Seven databases were searched for primary research, including grey literature and conference abstracts: Pubmed/Medline, Embase, Sociological Abstracts, Cochrane (e.g., Database of Systematic Reviews, Central Register of Controlled Trials, and Economic Evaluation Database), CINAHL, Database of Abstracts of Reviews of Effec ts, and the New York Academy of Me dicine (Appendix D: Search Strategy for HCV Prevalence Review)

.

Patient -important Outcomes A literature search for the effect of patient -important outcomes on persons tested and treated for HCV was conducted in PubMed. A search of previously published systematic reviews and meta

- analyses was conducted initially and used to address the patient -important outcomes when available and of high quality . When systematic reviews or meta

- analyses were

un available, primary studies w ere sought and added to the results (Appendix F : Search Strategy for Review of Patient -Important Outcomes). When possible, data from primary studies were entered into systematic review software (Review Manager, 2008) to produce meta

- analyses for estimation of effect sizes. Otherwise, effect size data were extracted directly from published
meta

- analyses.
The selection criteria for the primary literature search included intervention studies (i.e., controlled trials , cohort studies, and case -control studies) conducted world-wide, published during 1995 through 2011 in English . Case studies were excluded, along with studies of transplant recipients and persons co

- infected with HBV or HIV. To be selected, studies needed to present data inclusive of persons born during 1945 through 1965. Because protease inhibitors (PIs) have only recently been licensed, evidence was insufficient on their long- term effect on the patient -important outcomes. Therefore, only studies providing treatment regimens with Pegylated Inte rferon (with and without Ribavirin) or Interferon ( with or without Ribavirin ) were examined.

Separate, targeted literature reviews were conducted for those outcomes given ratings of 4 or higher by the group; these outcomes included

• all

- cause mortality;

• HC C;

• sustained viral response (SVR) (a marker of virologic cure);DRAFT FOR PUBLIC COMMENT

17 • serious adverse events (i.e., treatment

- related side effects ) ; and

• quality of life;

• HCV transmission; and

• brief alcohol interventions.

A systematic, targeted review was conducted to examine potential harmful and beneficial patient -important outcomes associated with HCV testing and treatment. A similar review also was conducted to examine reduction or cessation of alcohol use associated with strategic brief interventions provided to persons ide ntified as HCV

- infected. Only those outcomes considered critical to decision making (i.e., all

- cause mortality, HCC, SVR, treatment

- related serious adverse effects, quality of life, HCV transmission, and alcohol use) were graded on their quality and used to inform the strength of the recommendations.

RESULTS

Review of HCV Infection Prevalence D ata

O f the 10,619 articles that met the search criteria for the HCV infection prevalence review , 31 papers provid ed data on HCV infection prevalence by birth year (Appendix E: Flow Chart for HCV Prevalence ). Three of those papers ( 5
, 20

, 66 ) examined nationally representative data from NHANES . Compared with the other 28 articles, the quality of the nationally representative, population- based NHANES data was much higher ; for this reason, NHANES data from 1999 through 2008 were used to determin e the most efficacious birth years
to target when testing persons for HCV infection. The NHANES analysis revealed a 3. 25 % prevalence of anti -HCV among persons born during 1945 through 1965 (95%CI, 2.80-3.76). Persons in the bi rth cohort are five times more likely than pe rsons outside of the birth cohort to be anti -HCV positive ( 2 )

. Infected p ersons in the 1945-1965 birth cohort represent 76.5 % of all adults living with HCV infection in the United States.

Prevalence data for the 1945 -1965 birth cohort were presented to the HC V Birth Cohort Testing Work Group early in the development process. The results were reviewed again during a discussion of patient- important outcomes at the consultation.

Patient

- Important Outcomes Of the patient

- important outcomes determined to be either important or critical for decision making (see GRADE Methodology), evidence was foun d in the literature on all

- cause mortality, HCC, SVR, serious adverse events, quality of life, and alcohol use. However, f or several other important or critical outcomes (i.e., HCV transmission, insurability, reassurance of testing negative, false reassura nce of testing negative, and worry or anxiety caused by testing true positive), no studies examining their importance and relevance to a birth cohort recommendation could be identified.

At the consultation, the Hepatitis C Virus Birth Cohort Test ing Work Group re -ranked the patient -important outcomes based on the findings from the literature and determined that while evidence about HCV transmission was not available, it remained critical to decision-making andDRAFT FOR PUBLIC COMMENT

18 would still be considered as evidence

. The relative importance of the outcomes associated with insurability, reassurance of testing negative, false reassurance of testing negative, and worry or anxiety caused by testing true positive were re -ranked based on the evidence and the benefits and harms (App endix J: Summary of Findings Tables). While these outcomes were not presented in the evidence table, they were considered when determining the balance of benefits and harms.

All -Cause Mortality Previously published systematic reviews and meta- analyses di d not provide all

- cause mortality information relevant to this population, so a systematic review was carried out (Appendix F. Search Strategy for Patient

- Important Outcomes) . A total of 22 published articles examined all -cause mortality among persons tes ted and treated for HCV infection (Appendix G : Flow Chart for All

- Cause Mortality) . H owever, a review of the full articles and meta

- analysis of the extracted data revealed weaknesses in most of these studies resulting from insufficient sampl e sizes, unrepresentative study populations, and other sources of confounding. However, one study was found to be both directly applicable to the target population and of high quality on the basis of representation of the U.S. -based study population, sample size, and ri gor (57). These factors improved the Work Group ’s confidence in the estimate of the effect. This study, which included a sample size of 16,868 HCV -infected persons identified through the U.S. Department of Veterans Affairs ( VA), found that treatment- rela ted SVR reduced the risk of mortality among persons diagnosed with HCV infection (RR=0.46; 95% CI=0.41-0.51). However, this study only compares persons who responded to therapy with persons who did not respond to therapy and does not address a screened population or an untreated population. Therefore , the confidence in the estimate of effect was deemed to be low , and no upgrading of the quality of evidence was performed despite a large estimate d treatment effect . (Appendix J : Summary of Findings Tables)

Hepatocellular Carcinoma A systematic review was conducted to examine HCC as a patient

- important outcome

. A total of 37 observational studies (n=29,575) examin ed the incidence of HCC among persons achieving an SVR versus those who did not respond to treatm ent ( Appendix H : Flow Chart for HCC; Appendix I : Meta

- Analysis of the Effects of Treatment Response on Incidents of HCC) ( 67-103 ). Data from these studies revealed that treatment

- related SVR reduced the risk of HCC (0.29; 95% CI=0.24, 0.35). Minimal heterogeneity was reported (I 2 =25%) , mainly attributed to the few occurrences of HCC and small sample sizes in the studi es

. No other criteria were fully met to justify downgrading the quality of the evidence for this outcome. Instead, the quality of the evidence was upgraded to Moderate because of the substantial risk

- ratio effect (Appendix J : Summary of Findings Tables ).

Failure to Achieve Sustained Viro logic Response A previously published Cochrane systematic review , which included randomized, controlled trials conducted from 1995 through March 2009, examined the outcome of SVR among persons randomized to receive either interferon monotherapy or interferon plus ribavirin ( 104 ). A n additional systematic review of the evidence was not conducted because of the high quality of the initial review. For the Cochrane review, SVR failure was defined as detectable HCV RNA at least 6 months after treatment. Sixty randomized, controlled t rials (n=9,146) featuring treatment -naïve patients

, patients who had received treatment but relapse d, and nonresponders to therapy were analyzed. Treatment consisting of interferon with out ribavirin significantly increased the failure of SVR among patients (r isk ratio= 0.75 ; 95 % CI=0.71, 0.79) ;DRAFT FOR PUBLIC COMMENT

19 treatment with both interferon and ribavirin is more likely to result in SVR, and therefore is considered more protective. Although S VR was initially judged by the HCV Birth Cohort Testing Work Group to be directly associated with patient -important outcomes (e.g., reduced viral transmission ), further deliberation resulted in SVR being defined as an intermediary
outcome that is predictive of reduced morbidity and mortality, particularly from HCC. Thus, downgrading SVR from high to moderate quality evidence was justified given the indirectness of the outcome (Appendix J: Summary of Findings Tables).

Treatment

- Related Serious Adverse Events Treatment for HCV infection can result in serious adverse events (SAEs) , including nausea, anemia, and suicidal thoughts. The Cochrane systematic review, which examined the effect of treatment for HCV infection on development of SVR, also examined 11 RCTs to determine the association between SAEs and the course of HCV treatment ( 104 ). This review fo und that compared with monotherapy, combination therapy did not increase risk of SAE s. Because th e treatment

- related SAEs are derived from high quality, randomized controlled trials and the estimates of those effects are precisely quantifiable, the quality of evidence was judged to be high (Appendix J: Summary of Findings Tables ). Since the standard of care changed to include the new direct acting antivirals when they were approved for use in the United States market in June, 2011 there has not been sufficient time to collect data for a systemati c review of their SAEs since the clinical trials . In the Telaprevir phase III clinical trial the most common adverse events included gastrointestinal disorders, pruritus, rash and anemia, and 11% of those receiving Telaprevir discontinued therapy due to the adverse events compared with 1% of those receiving pegylated interferon and ribavirin alone( 54 ). In the Boceprevir phase III clinical trial the most common adverse events included fatigue, headache, nausea and anemia. There were no differences in discontinuation rates between study arms (55 – Poordad, unlinked) . The harms of these new treatments may be different in community se ttings.

Quality of Life One systematic review was identified that examined the effect of HCV testing and treatment on patients’ quality of life (QoL) ( 105 ). This study included seven observational studies. While a nalysis of the se studies did not yield an effect size, the mean QoL associated with the SVR in the intervention group was 6.6 points higher than the control group. On the basis of study design and the limited e vidence available regarding QoL, the quality of the evidence for this outcome was rated as low (Appendix J: Summary of Findings Tables).

HCV T ransmission Searches were conducted for previously published systematic reviews, meta

- analyses, and individual ar ticles that addressed HCV transmission. No intervention studies examining the effect of HCV testing on the patient

- important outcome of HCV transmission were identified

. However, HCV transmission was found to be of relatively high importance when determi ning the strength of the recommendations, despite the absence of related intervention studies (Appendix J : Summary of Findings Tables)

. Future research is needed to address this crit ical gap in knowledge.DRAFT FOR PUBLIC COMMENT

20 Alcohol Use A search was conducted for systematic r eviews, meta -analyses, and individual articles on the effect of an alcohol- use -reduction intervention among persons found to be infected with HCV. Due to a paucity of available evidence, the search was broadened to include reviews focused on alcohol interventions for persons tested for HCV, not just those found positive. R ecently, a meta -analysis of 22 randomized, controlled trials (n=7,619) examined the effects of HCV test ing followed by a brief alcohol intervention (i.e., an assessment of the drinking behaviors of patients and provision of brief, one- on -one counseling to those patients determined to drink alcohol excessively) on drinking behaviors versus testing alone ( 106 ) . The mean reduction of drinking (g rams /week) in the intervention groups was 38.42% lo wer (95% CI = 30.91, 65.44) than in the control groups after follow-up at ≥1 year. The quality of th is evidence was initially rated as high , because it was derived from RCTs without major risk of bias. However, because the body of evidence was not specific ally derived from persons with HCV infection , the quality of evidence was down graded to moderate due to indirectness (Appendix J : Summary of Findings Tables).

Determination of the R ecommendations Four factors must be considered when determining the releva nce and strength of a GRADE

- based recommendation: quality of evidence, balance between benefits and harms

, values and preferences , and resource implications. During the consultation, the Hepatitis C Virus Birth Cohort Testing Work Group considered each of these factors in light of the evidence presented

. Determining the Quality of the Evidence across Outcomes Critical for Decision Making The GRADE methodology follows the principle that the overall quality of evidence should be determined based on the lowes t quality of evidence of any outcome deemed critical for decision making. For the proposed HCV testing recommendation, critical factors included all

cause mortality, HCC, SVR, and SAE s ( 107 ) . However, rating the overall quality of evidence must take two factors into consideration: 1) the desirable effects of testing and treatment (the low quality evidence of mortality reduction and the moderate quality evidence of reducing HCC) and 2) the harms of testing and treatment (the high quality evidence of adverse events associated with HCV eradication) (Table 3. Quality of the Evidence across Outcomes Critical for Decision Making). Thus, if the reduction in HCC alone is a sufficiently significant desirable outcome to support testing and treatment (moderate quality evidence), and no uncertainty exists reg arding the effect of the undesirable consequences ( i.e., high quality evidence of SAEs ), then the overall quality of evidence supporting testing and treatment in this cohort is determined to be moderate.
Table 3. Quality of the e vidence c ritical for d eci sion making, by outcome

Outcome Ranking Quality of Evidence

Undesirable Outcome

SAEs Critical for decision making High

Failure to Achieve SVR Critical for decision making ModerateDRAFT FOR PUBLIC COMMENT

21 Desirable Outcome

HCC Critical for decision making Moderate

All

- ca use Mortality Critical for decision making Low

Benefits versus Harms Upon review of both published and anecdotal evidence, t he benefits of test ing and
treat ing persons with HCV infection were determined to be greater than the harms . Published evidence wa s predominantly drawn from the summary of findings tables , as well as additional literature shared by the H CV Birth Cohort Testing Work Group. To supplement that information , anecdotal evidence on the benefits and harms associated with several factors was considered , including the recei pt of a false positive test result , the need to wait or return for test results

, access to treatment, and the effect of HCV -infection notification for insurance and employment.

While certain harms (i.e., worry or anxiety whi le waiting for test results, complications due to insurability, and occurrence of SAEs during treatment ) can be uncomfortable for patient s, the benefits associated with effective treatment include SVR which is associated with reduc tions in liver

- related mo rbidity and all

- cause mortality. Based on this understanding, the benefits associated with HCV treatment were judged to be greater than the harms. Addition al factors support this judgment. For instance, concerns about receipt of inaccurate HCV test resul ts can be assuaged by the accuracy of HCV RNA testing, and the time and resources needed to screen, provide a brief alcohol intervention, and refer patients to care is outweighed by the efficacy of these interventions in reducing alcohol use.

Values and P references HCV testing is widely accepted among various populations ( 108

, 109 ). No evidence exists to sup port the assumption that persons born during 1945-1965 would have different attitudes about HCV testing

.

Resource Implications Only two U.S.

- based studies specifically examined the cost effectiveness and resource implications of birth

- year

- based HCV test ing linked to HCV care and treatment; both studies found the interventions to be cost effective.( 49

, 110 ) These studies, which evaluated slightly different definitions of “birth cohort,” compared birth

- cohort testing and treatment with the status quo of risk- and medical -indication based testing recommendations; both studies demonstrated nearly identical cost -effectiveness results. The first study, which defined the birth cohort as persons born from 1945 through 1965, estimated a cost per quality- adjusted life year ( QALY ) gained of $35,700 based on a 12- week response -guided course of Telaprevir added to the st andard treatment regimen (i.e., pegylated interferon with ribavirin); cost per QALY was an estimated $15,700 when assuming treatment with the standard regimen alone ( 49 ). The second study defined the birth cohort as persons born from 1946 through 1970 and estimated a cost per QALY gained of $39,963 for patients treated with Telaprevir in addition to pegylated interferon with ribavirin ( 110 ).DRAFT FOR PUBLIC COMMENT

22 These cost

- effectiveness studies had different a ssumptions about the timing of HCV testing and treatment. The study that examined the 1945-1965 birth cohort included all possible costs and benefits in a single year ( 49 ) , whereas the study that examined the 1946-1970 birth cohort assumed 20% of the eligible population would be screened and treated each year for 5
years. ( 2

, 49 ) Per person testing costs would be approximately $54 including antibody testing, nucleic acid testing of antibody positives, and post-test counseling ( 44 ).

In addition to reductions in morbidity and mortality (Table 4), the increase in testing and treatment of persons born from 1945 through 1965 would increase testing and treatment costs compared with current risk

- based testing and treatment strategies . C osts can be determined using three different scenarios: risk -based testing with pegylated interferon and ribavirin (PR) therapy; birth cohort testing with PR therapy; an d birth cohort testing with PR therapy and a new direct acting anti vi ral (DAA), the current standard of care. Testing the 1945-1965 birth cohort and treating with PR+DAA is expected to cost $15.2 billion more than r isk -based testing followed by PR alone, b ut this approach averts an estimated $2.5 billion in medical costs ( 49 ) (Table 5)

. Table 4. Testing and c linical o utcomes , by hepatitis C virus ( HC V) t esting s trategy Outcome Risk

- based testing + pegylated interferon with ribavirin ( PR ) Birth c ohort t esting + PR with a direct acting agent ( DAA ) Differential

Antibody tests administered 14,793,816 60,404,514 45,610,698 more tests conducted Positive results delivered to patient 262,260 1,070,840 808,580 more cases identified Patients treated 135,089 551,800 416,711 more patients treated Patients who achieved a sustained viral response 53,160 310,855 257,695 more patients achieved SVRs

Ever devel oped compensated cirrhosis 994,291 791,053 203,238 cirrhosis cases averted

Ever developed decompensated cirrhosis (DCC) 360,388 286,699 73,689 DCC cases averted

Ever developed hepatocellular carcinoma (HCC) 230,784 183,595 47,189 HCC cases averted

Ever received a transplant 75,752 60,268 15,484 transplants averted

HCV

- related d eaths 591,172 470,293 120,879 deaths avertedDRAFT FOR PUBLIC COMMENT

23 Table 5. Cost of hepatitis C virus ( HCV ) t esting and t reatment (in millions) *

Risk

- based t esting + PR Birth c ohort t esting + PR Bi rth c ohort t esting + PR+DAA Testing c osts $754 $3,078 $3,078 Treatment c osts $1,508 $6,162 $20,662 Total m edical c osts $ 2,262 $ 9,240 $ 23,740 *Rein D, Smith, B.D., Wittenborn, J.S., Lesesne, S.B. The Cost

- Effectiveness of Birth Cohort Hepatitis C Antibo dy Screening in U.S. Primary Care Settings. Annals of Internal Medicine. 2012;156(4):263

- 70.

C olorectal screening rates were reviewed t o estimate the testing costs associated with

one- time HCV testing for persons in the 1945-1965 birth cohort. Both interventions focus on screening at a single time point in time (i.e., at age 50 for colorectal screening ) ; therefore, data from colorectal screening programs are useful for estimat ing the rate of adoption of a recommendation for one -time prevention services

. In an analysis of 2005 National Health Interview Survey data (a nationally representative household survey), 19.8% of women and 23.7% of men reported receiving colorectal screening in the previous 3 years (the time since implementation of the United States Preventive Services Task Force [USPSTF] screening recommendation).( 111 ) These percentages were obtained after years of updated colorectal screening recommendations and implementation of extensive education al campaigns , so they likely are higher than those expected to follow adoption of HCV testing recommendations. However, if the birth cohort recommendation was adopted at the same level, approximately 5.6 million women and 6.7 million men would be tested for HCV within the first 3 years of implementation at a cost of $664 million; more than 400,000 HCV infected persons would be identified

.

RECOMMENDATIONS The following recommendations for HCV testing are intended to augment theRecommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCVRelated Chronic Disease issu ed by CDC in 1998 ( 1 ).

In addition to testing adults of all ages at risk for HCV infection, CDC recommends that:

• Adults born from 1945 through 1965 should receive one

- time testing for HCV without prior ascertainment of HCV risk factor status (Stron g Recommendation, Moderate Quality of Evidence), and

• A ll persons with identified HCV infection should receive a brief alcohol screening and intervention as appropriate, followed by referral to appropriate care and treatment services for HCV infection and r elated conditions as indicated (Strong Recommendation, Moderate Quality of Evidence)

.

PUBLIC HEALTH TEST ING CRITERIADRAFT FOR PUBLIC COMMENT

24 A strategy for t esting persons in the 1945-1965 birth cohort for HCV infection is consistent with established general public health screen ing criteria ( 112 ) as evidenced by the following factors: 1) HCV infection is a serious health problem affecting a large number of people with significant negative health outcomes that can be diagnosed be fore symptoms appear; 2) testing for HCV infection is readily available, minimally invasive , and reliable; 3) benefits include limiting disease progression and facilitating early access to treatments that can save significant life years; and 4) testing is cost effective. Such test ing would help identify unrecognized infections and help HCV

- infected persons receive beneficial care and therapy prior
to onset of severe HCV

- related disease ( 112 ).

TESTING MET HODS

Hepatitis C Antibody Testing Laboratory testing methods for HCV included in these recommendations were established by CDC ’s Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus in 2003 ( 113 ). No new methods are introduced in these recommendations. HCV testing should be initiated with an FDA-approved serologic test for antibody to HCV (anti

HCV ). These assays are highly sensitive. A person who tests anti-HCV negative does not have HCV infection and has not been infected in the past. Except for persons who have ongoing or recent risks for HCV exposure (e.g., IDU), no further testing is needed ( 1 ). Positive or indeterminate test results should be followed by supp lemental testing to confirm anti

- HC V (e.g., an immumoblot assay ) or presence of HCV RNA by nucleic acid test ( NAT ). FDA -approved HCV antibody tests also have a high level of specificity, and a person whose anti-HCV test is confirmed positive should be presumed to either 1 ) have active ( i.e., current) HCV infection or 2) have had HCV infection in the past that has subsequently resolved (i.e., cleared). Anti- HCV test ing cannot distinguish between active HCV infection and past, cleared HCV infection; this distinction requires that persons who initially test anti -HCV positive be tested by an HCV NAT

. Hepatitis C Nucleic Acid Testing One of the following FDA -approved HCV NAT s, commonly known as “HCV RNA tests,” should be used to identify active HCV infection among persons who have tested antiHCV positive : 1) quantitative NATs (i.e., for viral load) or 2 ) qualitative NATs

. Pe rson s who test anti -HCV positive and are also positive by HCV NAT should be considered to have active HCV infection ; these persons need further medical evaluation and care. A person who is anti- HCV positive but who tests negative by HCV NAT is considered to have past, cleared HCV infection ( 114 ). In the absence of ongoing risk, these persons do not require further testing. A ll specimens with an anti

- HCV antibody test result of “indeterminate” also should be tested by NAT ( 113 ). Persons with a positive NAT aft er an indeterminate anti

- HCV test result should be considered actively infected; these persons require further medical evaluation and care ( 113 ).

Provision of HCV Test Results
Negative Test Results Persons with negative anti -HCV test results should be informed of their test results and reassured that they are not infected unless they were recently at risk for infection. Repeat test ingDRAFT FOR PUBLIC COMMENT

25 can be considered for persons with ongoing risk behaviors. If persons reveal other health

- related

concerns , they should be evaluated or medically referred as indicated.

Indeterminate Test Results Persons whose HCV test results are indeterminate should be advised that the result is inconclusive. These persons should be provided appropriate follow- up testing or referral for further testing and should be instructed about how to reduce the risk of possible transmission until they are retested and their in fection status is known (see Prevention Messages).

Positive Test Results Persons who test positive for both HCV antibody and HCV RNA should be told that they are infected and need further medical evaluation for liver disease, ongoing monitoring, and possi ble treatment. At the time positive test results are co mmunicated to patients , providers should evaluate their level of alcohol use and provide a brief alcohol intervention to those found to use alcohol excessively or engage in binge drink ing. Persons w ith HCV infection also should be provided information (either through face- to -face sessions, video , or written materials) about 1) HCV infection, 2) risk factors for disease progression, and 3 ) preventive self

- care and
treatment options, also addressing how to prevent transmission of HCV to others. HCV

- infected patients also should know about the resources available to them within their communities

, including providers of medical evaluation and social support.

Post

- test Counseling Messages Persons found to be infected with HCV also can benefit from t he following types of counseling messages

.

• C ontact a health care provider or specialist (hepatologist, gastroenterologist, infectious disease) for

o m edical evaluation of the presence or development of chronic liver disease ;

o advice on possible treatment decisions and strategies ; and

o advice on how to monitor the health of your liver, even if treatment is not recommended

.

• To protect the liver from further harm,

o consider vaccination against hepatitis A and B if l iver disease is present ;

o r educe or discontinue alcohol consumption;

o avoid taking new medicines, including over-the-counter and herbal agents ( 14), without checking with your health care provider ; and

o obtain HIV risk assessm ent and testing.

• For p erson s who are overweight and/or obese (BMI> 30kg/m2) ( 51),

o c onsider weight management or losing weight and

o f ollow a healthy diet an d stay physical ly active

.

• To minimize the risk of transmission to others

,
o do not donate blood, body organs, tissue, or semen andDRAFT FOR PUBLIC COMMENT

26 o d o not share appliances that may come into contact with blood, such as toothbrushes, dental appliances, razors, and nail clip pers

.

PREVENTION MESSAGES

HCV -specific information and secondary prevention messages (e.g., alcohol reduction messages) should be provided to patients infected with , and at risk for acquiring HCV. Prevention messages can help reduce the risk for HCV trans mission to others (for specific prevention messages, refer to CDC’s Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Diseas e [1]). This information may be provided at time of testing or when results ar e delivered. For persons who access testing for HCV infection, general information should be available regarding HCV, along with information about the antibody test for HCV and NAT. Persons also should be informed of how they will be receiving their HCV t est result.

L INKAGE TO CARE AND TREATMENT

M any persons identified as HCV -infected do not receive recommended medical evaluation and care after the diagnosis of HCV infection ( 33 ) ; this gap in linkage to care can be attributed to several factors, including being uninsured or underinsured, failure to provide a referral or failure to follow up on a referral, drug or alcohol use issues, and other barriers,. The lack of such care, or significant delays before care is received , has a negative impact on the health outcomes of infected persons. Although routine testing of persons born 1945-1965 is expected to lead to more HCV- infected persons being identified earlier in t he course of disease, to improve health outcomes, persons testing positive for HCV must be provided with appropriate

care an d treatment. Linking patients to care and treatment is a critical component of the strategy
to reduce the burden of disease.

A lternative strategies are needed for HCV -infected persons who are experiencing barriers
to care . These persons may benefit from the replication of effective linkage

- to

- care models and from the development of other evidence-based interventions. A ctive linkage

- to

- care programs provided in a culturally sensitive manner ( 115-117 ) (e.g., the use of case managers to schedule appointments, bring infected patients to doctors’ appointments, and follow-up with patients ) have been found to be more effective ( 115 ) than passive referral methods ( e. g. , providing patients with information about the disease and a list of resources or referrals to medical care)

. Such linkage creates opportunities for patients to receive information, vaccinations, prevention counseling messages, and to more fully engage in care ( 118 ). Once patients receive care, case management can provide active link age ( 119-121 ) to social services ( 116

, 122 ) , referral to substance abuse services ( 123-126 ), and assistance with transpo rtation and housing ( 117

, 120 ). Recommendations for the medical management of HCV infection and disease ar e updated regularly by AASLD. As noted above, s ignificant advances are being made in the care, management , and treatment of HCV infection at the time of publication of this recommendation

. Although primary care clinicians can readily provide much of the ca re necessary for initial evaluation and management of persons with HCV infection, antiviral treatment is complex, and collaboration between primary providers and specialists is critical for optimal care. CDC isDRAFT FOR PUBLIC COMMENT

27 working with academic and clinical partners and with other federal and state agencies to replicate best practices and develop new models for collaborative care ( 127 ).

FUTURE DIRECTIONS

CDC is planning a n ational education campaign called Know More Hepatitis
, which targets primary care providers as well as persons born within the birth cohort. For this campaign

, CDC will employ various communication and social media strategies to raise awareness among healt h-care professionals about high rates of chronic viral hepatitis infection among their patients, the need for testing, and the benefits of early identification and appropriate medical management. These communication strategies are designed to complement the more targeted technical training and education being undertaken by CDC and its academic and medical partners. Reaching out directly to health -care professionals helps build the knowledge and capacity of the provider community to respond to patients who will be reached by the public education campaign, which encourages patients to be aware of their risk and to get tested. CDC also plans to work with national, regional and local medical societies and health

- care organizations to educate their members about chronic viral hepatitis infection, as well as to promote CDC resources, including professional clinical tools, training modules, guidelines, and patient education materials. The Know More Hepatitis campaign also includes a multi

- media public education component designed to encourage testing for hepatitis C among the age cohort as called for within these guidelines.
CDC will conduct demonstration studies to guide implementation efforts for these recommendations; conduct surveillance to monitor implementatio n, adoption, and impact; and evaluate and grade new evidence as it becomes available. CDC will soon begin conducting systematic reviews of other testing and prevention recommendations that were included in the 1998 HCV test ing recommendations ( 1 ). Additionally, CDC will be reviewing evidence related to the potential benefits and harms of testing persons who were determined to be of “uncertain need ” in the 1998 recommendations (i.e., those with risks that have not been well defined, such

as intranasal drug use or a history of multiple sex partners). Upon completion of these reviews, recommendations will be revised as necessary. The revised guidelines , which will incorporate the present birth -cohort- based recommendations as well as risk

- based strategies , will provide updated, comprehensive recommendations for the identification and management of HCV infection in the United States

.DRAFT FOR PUBLIC COMMENT

28 

### REFERENCES

1. Recommendations for prevention and control of hepatitis C virus (HCV) infection a nd HCV

related chronic disease. Centers for Disease Control and Prevention. Morbidity and mortality weekly report Recommendations and reports. 1998;47(RR

- 19):1

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- Rohrberg D, Mezger J, Walton M, Bruce RD, Altice FL. Impact of enhanced services on virologic outcomes in a directly administered antiretroviral therapy trial for HIV

- infected drug users. J Acquir Immune Defic Syndr. 2006 Dec 1;43 Suppl 1:S48

- 53. 127. Arora S, Thornton K, Murata G, Deming P, Kalishman S, Dion D, et al. Outcomes of treatment for hepatitis C virus infection by primary care providers. N Engl J Med. 2011 Jun 9;364(23):2199

- 207.DRAFT FOR PUBLIC COMMENT

36 

### APPENDICESDRAFT FOR PUBLIC COMMENT

37 

### Appendix A. **Acronyms Used in this Document**

AAFP Americ an Academy of Family Physicians

AASLD American Association for the Study of Liver Disease

AGA American Gastroenterological Association

BAI Brief alcohol intervention

CDC Centers for Disease Control and Prevention

DAA Direct acting antivirals

DVH Division o f Viral Hepatitis

GRADE Grading of Recommendations Assessment, Development, and Evaluation

HAV Hepatitis A virus

HBV Hepatitis B virus

HCC Hepatocel l ular carcinoma

HCV Hepatitis C virus

HIV Human immunodeficiency virus

HRQOL Health

- Related Quality of Lif e

ICER Incremental Cost Effectiveness Ratio

IDSA Infectious Diseases Society of America

IDU Injection drug use

NAT Nucleic acid test

NHANES National Health and Nutrition Evaluation Survey

NIH National Institutes of Health

NVHR National Viral Hepatitis Roun dtable

OMB Office of Management and Budget

PCI Positive case identification

PICO Population, Intervention, Comparator, OutcomeDRAFT FOR PUBLIC COMMENT

38 PWID Persons who inject drugs

QALY Quality

- adjusted life year

RNA Ribonucleic a cid

SAE Serious adverse events

STI Sexually transm itted infection

SVR Sustained virologic response

WHO World Health OrganizationDRAFT FOR PUBLIC COMMENT

39 

### Appendix B. Conflicts of Interest External Work Group Members

Miriam Alter, PhD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Sanjeev Arora, MD, FACP, FACG For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Consultancy: Served on Advisory Board of Vertex Pharmaceuticals in 2009 Grants/Grants Pending: Grants from Vertex Pharmaceuticals, Roche/ Genentech, Gilead, Zyrnogenetics, Bristol Myers, Pharmasett, and Abbott paid to institution for clinical trials Lectures/ Speakers Bureaus: Scherring Corp., served on September Bureau for Roche Pharmaceuticals until mid

- 2009

Bruce Bacon, MD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Doug Camp os - Outcalt, MD, MPA For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Alfred DeMaria, Jr., MD For the Work Under Consideration: No financial co nflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Janet Durfee, MSN, RN, APRN For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Yngve Falck

- Ytter, MD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Colleen Flanigan For the Work Under Consideration: Support for Travel: CDC Foundation Other Relevant Financial Activities: No financial conflict of interest reported

Marc Ghany, MD For the Work Under Consideration: No financial conflict of interest reported Other Relevant F inancial Activities: No financial conflict of interest reported

Robert Gish, MDDRAFT FOR PUBLIC COMMENT

40 For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Board Membership: Hepahope Consultancy: Performed as a co nsultant to Abbott, Anadys Pharmaceuticals, Inc., Bayer AG, Bristol-Myers Squibb Company, Durect, Hepahope, Hoffman-LaRoche Ltd., Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Human Genome Sciences, Merck, Metabasis Therapeutics, OSI/Astellas P armasset, Schering -Plough Corporation, Three Rivers Pharma, VitalTherapies, and ZymoGenetics; payments directed to an SPF fund for research and education Lectures/ Speakers Bureaus: Speakers bureau activities for Bayer, Bristol -Myers Squibb Company, F. Hof fman -LaRoche Ltd., Gilead Sciences, Inc., GlaxoSmithKline, Onyx, Merck/Schering -Plough Corporation, Three Rivers, Salix, SciClone Pharmaceuticals focused on HBV, HCV, and liver cancer, specifically epidemiology, diagnosis, and treatment, with additional program presentations for HBV and management of complications of cirrhosis; has a speakers contract to do promotional talks for BMS, Roche, Schering-Plough, Gilead Sciences, Bayer and Onyx; payments are directed to an SPF fund for research and education Gran ts/ Grants Pending: Support from Bayer-Onyx, Bristol-Myers Squibb Company, Genentech/ F. Hoffman -LaRoche, Ltd., Gilead Sciences, Genentech, Pharmasset, Zymogenetics; payments directed to an institutional fund under contract to CPMC Stock/ Stock Options: Ma jor Stock Shareholder for Hepahope

Fasiha Kanwal, MD, MSHS For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Emmett Keeffe, MD, MACP For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Consultancy: Vertex Travel/ Accommodations: Vertex

Kathleen Koechlin, PhD, MPH, BSN, RN For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Cameron Lewis For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Jake Liang, MDDRAFT FOR PUBLIC COMMENT

41 For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Robert Lubran, MPA, MS For the Work Under Considerati on: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Iris Mabry

- Hernandez, MD, MPH For the Work Under Consideration: No financial conflict of interest reported Other Relevant F inancial Activities: No financial conflict of interest reported

Katherine McGlynn, PhD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Barb ara McGovern, MD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Employment: Editor at UpToDate Other: Editor at Infectious Diseases Society of America

Rachel McLean, MPH For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Michael Ninburg For the Work Under Consideration: No financial conflict of interest reported Other Relevan t Financial Activities: Consultancy: Vertex, Abbott, Genentech, GlaxoSmithKline, Merck, Hoffman LaRoche, Tibotec, Beoringer Ingelheim Grants/ Grants Pending: Grants from Vertex, Merck, Genentech, Hoffman La Roche, Schering Plough, Gilead, Novartis, and Human Genome Sciences paid to institution Payment for the Development of Educational Presentations: Vertex, Hoffmann La Roche, and Schering Plough, paid to institution

Phillip Reichert, MPH For the Work Under Consideration: No financial conflict of inter est reported Other Relevant Financial Activities: No financial conflict of interest reported

Vinod Rustgi, MD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Consultancy: Merck, Vertex Grants/ Grants Pending: Grants from BMS, Gilead, Anadys, Boehringer- Ingelheim

Abbott paid to institution Lectures/ Speakers Bureaus:DRAFT FOR PUBLIC COMMENT

42 Merck, Vertex, Genentech, Gilead, Onyx

Lorren Sandt For the Work Under Consideration: No financial conflict of interes t reported Other Relevant Financial Activities: Consultancy: Abbott, for community advisory board and paid to institution Grants/ Grants Pending : Unrestricted educational grants from Vertex, Merck, and Genentech paid to institution; Conference grant from Gilead paid to institution Travel/ Accommodations: Money for travel from BMS, Vertex, Boehringer Ingelheim, Merck, Genentech/Roche and Tibotec for community advisory boards and paid to institution

Gloria Searson For the Work Under Consideration: No fin ancial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Anne Spaulding, PhD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Consultancy: Georgia Correctional Healthcare; clinical consultant for hepatitis and HIV care Grants/ Grants Pending: Grant support from DHHS, CDC, HRSA, and indirectly from NIH paid to institution Lectures/ Speakers Bureaus: Hepatitis Foundation Internati onal, Albany Medical College

Donna Sweet, MD, AAHIVS, MACP For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Grants/ Grants Pending: Pfizer, BMS Pharmaceuticals Lectures/ Speakers Bureaus : Abbott, BMS, Boehringer Ingelheim, Tibotec, Gilead

Andrew Talal, MD, MPH For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Board Membership: Merck & Co., Genentech/Roche, Boehringer Ingelheim, Pfizer, Bayer/ Onyx, Vertex Consultancy: Merck & Co., Genentech Grants/ Grants Pending: Merck & Co., Vertex, Boehringer -Ingelheim, and Genentech/Roche, Pfizer, Bayer/Onyx paid to institution Lectures/ Speakers Bureaus: Vertex and Genentech/ Roche Payment for Development of Educational Presentations: Merck & Co., MedscapeDRAFT FOR PUBLIC COMMENT

43 Litjen Tan, PhD, MS For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Chris Taylor For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Grants/ Grants Pending: Vertex, Gilead, OraSure, Merck & Co., Janssen, BMS paid to institution Travel/ Accommodations: Ver tex, OraSure

Lisa Townshend

- Bulson, MSN, FNP For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: Expert Testimony: CDC Cooperative Agreement with ANTHC, paid to institution

Tam Van For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Kathleen Whitaker, PhD For the Work Under Consideration: No financial conflict of interest report ed Other Relevant Financial Activities: No financial conflict of interest reported

Richard Wild, MD, JD, MBA, FACEP For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflic t of interest reported

John Wong, MD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

CDC Work Group Members

Geoff Beckett, PA, MPH For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Scott Holmberg, MD, MPH For the Work Under Consideration: No financial conflict of interest report ed Other Relevant Financial Activities: No financial conflict of interest reported

Deborah Holtzman, PhD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of intere st reported

Rebecca Morgan, MPH For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reportedDRAFT FOR PUBLIC COMMENT

44 Dan Riedford, JD For the Work Under Consideration: No fina ncial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Bryce Smith, PhD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Philip Spradling, MD For the Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

Chong

- Gee Teo, MD, PhD For th e Work Under Consideration: No financial conflict of interest reported Other Relevant Financial Activities: No financial conflict of interest reported

John Ward, MD For the Work Under Consideration: No financial conflict of interest reported Other Re levant Financial Activities: No financial conflict of interest reportedDRAFT FOR PUBLIC COMMENT

45 

### Appendix **C . Analytic Framework** DRAFT FOR PUBLIC COMMENT

46 

### Appendix **D**

**. Search Strategy**  **for HCV Prevalence**DRAFT FOR PUBLIC COMMENT

47 

### Appendix **E**

**. Flow Chart**  **for HCV Prevalence**DRAFT FOR PUBLIC COMMENT

48 

### Appendix **F . Search Stra**  **tegy for Patient**

**- Importan**  **t Outcomes** DRAFT FOR PUBLIC COMMENT

49DRAFT FOR PUBLIC COMMENT

50 Appendix G. 

### Flow Chart **for All** 

**- Cause Mortality** DRAFT FOR PUBLIC COMMENT

51 

### Append **ix H** 

**. Flow Chart**  **for Hepatocellular Carcinoma** DRAFT FOR PUBLIC COMMENT

52 

### Appendix **I . Meta** 

**- Analysis of**  **the E**  **ffects of Treatment Response**  **on Incidents of Hepatocellular Carcinoma** DRAFT FOR PUBLIC COMMENT

53 

### Appendi **x J.**  **Summary of Findings Tables**DRAFT FOR PUBLIC COMMENT

54DRAFT FOR PUBLIC COMMENT

55 1 Intervention with goal to achieve SVR

2 Over 70% relative risk reduction

3 Comparison of mortality in patients achieving SVR vs. no SVR

4 Although adjustment for cirrhosis severity (e.g., CP or MELD score) would be ideal, Backus et al. adjusted for presence of cirrhosis in general and albumin, bilirubin, and platelet count which are valid substitutes for severity of underlying liver disease. Not downgraded.

5 The results are for genotype 1 (72% of cohort). Genotype 2: HR 0.64 (CI 0.46, 0.88); genotype 3: 0.51 (CI 0.35, 0.73)

6 Study included the years from 2001 to 2009. The median follow-up period was 3.8 years after final outcome (SVR/NVR) was established. The interquartile range was 2.5 to 5.2 years.

7 Total number of participants: 5,978; distribution between participants and controls not given

8 CI not provided. Effect was reported as significant. Minimally clinically important difference estimated to be 4.2 (range, 3- 5). Effect size results: 0.3; no CI given; according to Cohen, small effect sizes are in the 0.2 and less range; moderate 0.5; large 0.8 and larger

range.

9 SVR considered as viral cure (eliminating infection). Not downgraded for indirectness.

10 From meta -analysis of RCTs of PEG-interferon alpha 2a vs. 2b

11 Severe adverse effects that lead to treatment discontinuations include (but are not limited to): 99% will experience at least one of the following: cytopenias (anemia, neutropenia, thrombocytopenia); flu-like symptoms, neuro-psychiatric disturbances (depression, irritability, insomnia, anxiety, psychosis etc.), teratogenicity, rash, etc.

12 Assumption: almost no patients with chronic, established HCV will spontaneously clear the virus without treatment.DRAFT FOR PUBLIC COMMENT

56DRAFT FOR PUBLIC COMMENT

57DRAFT FOR PUBLIC COMMENT

58 

### Authors Bryce D. Smith, PhD, Division of Viral Hepatitis, CDC, Atlanta, GA ; Rebecca L. Morgan,
MPH , Division of Viral Hepatitis, CDC, Atlanta, GA ; Geoff Beckett, PA -C, MPH, Division of Viral Hepatitis, CDC, Atlanta, GA ; Yngve Falck

- Ytter, MD
, Case Western Reserve University, Cleveland Heights, OH ; Chong -Gee Teo, MD, PhD , Division of Viral Hepatitis, CDC, Atlanta,
GA ; Amy Jewett, MPH, Division of Viral Hepatitis, CDC, Atlanta, GA; Brittney B aack, MPH

, Division of Viral Hepatitis, CDC, Atlanta, GA ; Deborah Holtzman, PhD, Division of Viral Hepatitis , CDC, Atlanta, GA ; David B. Rein , PhD, NORC at the University of Chicago, Atlanta,
GA ; Nita Patel, PhD, Division of Viral Hepatitis, CDC, Atlanta, GA; John W. Ward , MD, Division of Viral Hepatitis, CDC, Atlanta, GA; Miriam Alter, PhD, University of Texas Medical Branch, Galveston, TX.



### Contributors

DVH Steering Committee

Geoff A. Beckett, PA -C , MPH, Division of Viral Hepatitis, CDC, Atlanta, GA; Rebecca L. Morgan, MPH, Division of Viral Hepatitis, CDC, Atlanta, GA; Bryce D. Smith, PhD, Division of Viral He patitis, CDC, Atlanta, GA; John W. Ward, MD, Division of Viral Hepatitis, CDC, Atlanta, GA.

DVH Internal Work Group

Geoff Beckett, PA, MPH, Division of Viral Hepatitis, CDC, Atlanta, GA; Scott Holmberg, MD, MPH, Division of Viral Hepatitis, CDC, Atlanta, G A; Deborah Holtzman, PhD, Division of Viral Hepatitis, CDC, Atlanta, GA; Rebecca L. Morgan, MPH, Division of Viral Hepatitis, CDC, Atlanta, GA; Dan Riedford, JD, Division of Viral Hepatitis, CDC, Atlanta, GA; Bryce Smith, PhD, Division of Viral Hepatitis, CDC, Atlanta, GA; Phil Spradling, MD, Division of Viral Hepatitis, CDC, Atlanta, GA; Chong- Gee Teo , MD, PhD, Division of Viral Hepatitis, CDC, Atlanta, GA; John Ward, MD, Division of Viral Hepatitis, CDC, Atlanta, GA.

Hepatitis C Virus Birth Cohort Testing Work Group

Miriam Alter, PhD, University of Texas Medical Branch, Galveston, TX; Sanjeev Arora, MD, FACP, FACG, University of New Mexico, Albuquerque, NM; Bruce Bacon, MD, Saint Louis University School of Medicine, St. Louis, MO; Doug Campos- Outcalt, MD, MPA, University of Arizona College of Medicine, Phoenix, AZ; Alfred DeMaria, Jr., MD, Council of State and Territorial Epidemiologists and Massachusetts Department of Public Health, Jamaica Plain, MA; Janet Durfee, MSN, RN, APRN, Veterans Health Administration, Washington, D.C.; Colleen Flanigan, New York State Department of Health, Albany, NY; Marc Ghany, MD, National Institutes of Health, Bethesda, MD; Robert Gish, MD, University of California, San Diego, La Jolla, California; Fasiha Kanwal, MD, MSHS, St. Louis VA Medical Center, St. Louis, MO;DRAFT FOR PUBLIC COMMENT

59 Emmett Keeffe, MD, MACP, Stanford University Medical Center, Stanford, CA; Kathleen Koechlin, PhD, MPH, BSN, RN, Ohio Department of Health, Columbus, OH; Cameron Lewis, Arizona Department of Health Services, Phoeni x, AZ; Jake Liang, MD, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD; Robert Lubran, MPA, MS,Substance Abuse and Mental Health Services Administration, Rockville, MD; Iris MabryHernandez, MD, MPH, U.S. Department of Health and Human Services, Rockville, MD; Katherine McGlynn, PhD, National Cancer Institute, NIH, Bethesda, MD; Barbara McGovern, MD, Lemuel Shattuck Hospital, Jamaica Plain, MA; Rachel McLean, MPH, California Department of Public Health, Sacramento, CA; Michael Ninburg, Hepatitis Education Project, Seattle, WA; Monica Parker, PhD, Association of Public Health Laboratories, Silver Spring, MD; Phillip Reichert, MPH, Florida Department of Health, Tallahassee, FL; Vinod Rustgi, MD, American Gastroenterological Association, Fairfax, VA; Lorren Sandt, Caring Ambassadors Program, Oregon City, OR; Gloria Searson, ICSW, COPE, Inc., New York, NY; Averell Sherker, MD, FRCP(C), National Institutes of Health, Bethesda, MD; Anne Spaulding, PhD, Emory University School of Public Health, Atlanta, GA; Donna Sweet, MD, AAHIVS, MACP, University of Kansas School of Medicine, Wichita, Wichita, KS; Andrew Talal, MD, MPH, Weill Cornell Medical College, New York, NY; Litjen Tan, PhD, MS, American Medical Association, Chicago, IL; C hris Taylor, National Alliance of State and Territorial AIDS Directors, Washington, D.C.; Lisa Townshend-Bulson, MSN, FNP, Alaska Native Tribal Health Consortium, Anchorage, AK; Tam Van, Association of Public Health Laboratories, Silver Spring, MD; Kathlee n Whitaker, PhD, Food and Drug Administration, Silver Spring, MD; Richard Wild, MD, JD, MBA, FACEP, Centers for Medicare and Medicaid Services, Atlanta, GA; John Wong, MD, Tufts Medical Center, Boston, MA.

Additional Consultation Attendees

Faruque Ahmed, C DC, Atlanta, GA ; Brittney Baack, Division of Viral Hepatitis, CDC; John Douglas, MD, CDC, Atlanta, GA; Alycia Downs, Division of Viral Hepatitis, CDC, Atlanta, GA; Jeff Efird, MPA, Division of Viral Hepatitis, CDC, Atlanta, GA; Amy Jewett, CDC, Atlanta, GA ; Cynthia Jorgensen, DrPH, Division of Viral Hepatitis, CDC, Atlanta, GA; Amanda Lewis, MPH, CHES, Division of Viral Hepatitis, CDC, Atlanta, GA; Nita Patel, DrPH, Division of Viral Hepatitis, CDC, Atlanta, GA; Meredith Reilly, Department of Health and Human Services Office of the Assistant Secretary for Health, Washington, D.C.; Rachel Wilson, Division of Viral Hepat itis, CDC, Atlanta, GA.

Senior Methodologist

Yngve Falck

- Ytter , MD, Case Western Reserve University, Cleveland Heights, OH

.

Peer ReviewersDRAFT FOR PUBLIC COMMENT

60 Hol ly Hagan, PhD, New York University College of Nursing, New York, NY; Ray Kim, MD, Mayo Clinic, Rochester, MN; Linda Kinsinger, MD, MPH, Veterans Health Administration, Washington, D.C.; Anna Lok, MD, FRCP, University of Michigan, Ann Arbor, MI.

Acknowledge ments

Ashia Boyce, Georgetown University, Washington, D.C. ; Thein Lwin, MPH , Georgia State University, Atlanta, GA ; Marc Pitasi, MPH Candidate, Emory University, Atlanta, GA; Aida Risman , Emory University, Atlanta, GA ; Becky Satterthwaite, Public Health Li brary and Information Center, CDC, Atlanta, GA ; Rachel Wilson, Division of Viral Hepatitis, CDC, Atlanta, GA