Born Identification

[Johanne]

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Since 1998, routine HCV testing has been recommended by CDC for persons most likely to be infected with HCV (8) (Box). These recommendations were made on the basis of a known epidemiologic association between a risk factor and acquiring HCV infection. However, many persons with HCV infection do not recall or report having any of these specific risk factors.

In 1998, recommendations for identifying HCV-infected persons were issued as part of a comprehensive strategy for the prevention and control of HCV infection and HCV-related chronic disease (8). HCV testing was recommended for persons at high risk for HCV transmission, including persons who 1) had ever injected drugs, 2) were ever on chronic hemodialysis, 3) received blood transfusions or organ transplants before July 1992, or 4) received clotting factor concentrates produced before 1987 (Box). Screening also was recommended for persons who had a recognized exposure (i.e., health-care, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures and children born to HCV-infected mothers) and persons with laboratory evidence of liver inflammation (i.e., persistently elevated alanine aminotransferase levels). In 1999, HCV testing also was recommended for persons infected with HIV (25).

AASLD recommends considering antiviral treatment for HCV-infected persons with histological signs of bridging fibrosis, septal fibrosis, or cirrhosis (18). In 2011, the first generation of direct-acting antiviral agents (DAAs), the HCV NS3/4A protease inhibitors telaprevir and boceprevir, were licensed in the United States for treatment of HCV genotype 1(the most common genotype in the United States). Compared with conventional pegylated interferon and weight-based ribavirin therapy (PR) alone, the addition of one of these two protease inhibitors in clinical trials increased rates of sustained virologic response (SVR) (i.e., viral clearance following completion of treatment) from 44% to 75% and 38% to 63%, respectively, in persons with HCV (50,51). In a study of veterans with multiple co-morbidities, achieving an SVR after treatment was associated with a substantial reduction in risk for all-cause mortality of >50% (52) and substantially lower rates of liver-related death and decompensated cirrhosis (i.e., cirrhosis with the diagnosis of at least one of the following: ascites, variceal bleeding, encephalopathy, or impaired hepatitis synthetic function) (18). Because of the recent introduction of these treatment regimens, the long-term effects of DAA treatment in clinical practice have yet to be established, and the benefits might be different in community settings. In addition to the new Food and Drug Adminstration (FDA)-approved medications, approximately 20 HCV treatments (protease and polymerase inhibitors) are undergoing Phase II or Phase III clinical trials (53); treatment recommendations are expected to change as new medications become available for use in the United States.

To select a target birth cohort for an expanded testing strategy, CDC considered various birth cohorts with increased HCV prevalence (Table 1). For each proposed cohort, CDC determined the weighted, unadjusted anti-HCV prevalence and the size of the population.

CDC employed the GRADE methodology to inform the guideline development process. In April 2011, CDC convened the HCV Birth Cohort Testing Work Group to explore the practicality of developing a recommendation for one-time HCV testing for persons unaware of their infection status. Epidemiologic data exist to support the consideration of a birth year testing strategy; however, the GRADE process dictated that a formal review of the literature be conducted 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 Work Group consisted of 1) a steering committee within CDC's DVH, which led and conducted the evidence reviews; 2) representatives from DVH's Laboratory, Prevention, and Epidemiology and Surveillance Branches, who were tasked with reviewing and providing input on the evidence compiled by the steering committee through biweekly meetings; and 3) external (to CDC) representatives, who provided input on materials compiled by the steering committee through teleconferences, an evidence grading methodology training workshop, and a consultation. External representatives were selected on the basis of expertise with viral hepatitis; members included representatives from hepatitis C-related community-based organizations, persons living with HCV infection, hepatologists, economists, infectious disease specialists, and guideline methodologists. A wide range of disciplines, organizations, and geographic regions was represented, to include

Several subject matter experts (e.g., hepatologists, economists, infectious disease specialists, and guideline methodologists) also served as members of the external group. Work Group participants were required to disclose conflicts of interest and were notified of the restrictions regarding lobbying during the recommendation development process (Appendix A). No members' activities were restricted based on the information disclosed.

In August 2011, CDC convened a 2-day consultation with Work Group members to 1) review and evaluate the quality of the evidence for the proposed birth cohort-based strategy, 2) consider benefits versus harms of patient-important outcomes, 3) weigh the variability between the values and preferences of HCV testing among potential patients, and 4) consider resource implications. During the consultation, a summary of findings table addressing each patient-important outcome was presented to consultation attendees for discussion (Appendix B). Work Group members later provided input on the quality of the evidence and strength of the recommendations. Following the consultation, the DVH Steering Committee and other DVH representatives reviewed the information and reached a decision regarding the strength of the recommendations. At that time, a recommendations statement and qualifying remarks were developed in accordance with GRADE methodology.

Feedback from the public was solicited through conference presentations, meetings with national stakeholders, and public comment. Further, the proposed guidelines were peer-reviewed by external experts in viral hepatitis. A Federal Register notice was released on May 18, 2012, announcing the availability of the draft recommendations for public comment through June 8, 2012. In addition, external Work Group members were asked to comment on the recommendations statement and remarks during the public comment process. Feedback from the public comment period was reviewed by the DVH 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, the 2011 Guidelines International Network Conference, and Digestive Disease Week 2012.

Research questions were formulated to guide the development of the recommendations using a population, intervention, comparator, and outcome (PICO) format (9). The research questions were developed to support a two-stage approach to the evidence review: 1) determine the baseline prevalence of HCV infection and 2) measure the effects of an intervention (i.e., patient-important 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 (GRADEpro 3.6). The quality of the evidence was categorized as being "high," "moderate," "low," or "very low" depending on the established criteria for rating the quality up or down. The quality of evidence for each of the outcomes was rated down if it met at least one of the following five criteria: 1) risk of bias; 2) inconsistency or heterogeneity; 3) indirectness (addressing a different population than the one under consideration); 4) imprecision; or 5) publication bias. Conversely, the quality of the evidence was rated up if it met any of three criteria: 1) large effect size; 2) dose-response; or 3) plausible residual confounders (i.e., when biases from a study might be affecting the estimated apparent intervention effect) (Appendix B). Outcomes were reranked for importance after consideration of evidence by the Work Group members.

The following four factors are 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 Work Group considered each of these factors in light of the evidence presented. A statement based on the direction and strength of the recommendation was developed using the GRADE criteria; statements were either "for" or "against" an intervention and were either strong (designated by a "should" statement) or conditional (designated by a "may consider" statement).

A literature search for the effect of HCV testing and treatment on patient-important outcomes was conducted (Appendix E). 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 unavailable, primary studies were sought and added to the results. 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.

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