In 2004, the USPSTF issued its recommendations on screening for hepatitis C virus (HCV) infection (1). On the basis of its review of the evidence, the Task Force recommended against routine screening for HCV infection in asymptomatic adults who are not at increased risk (a grade D recommendation) and found insufficient evidence to recommend for or against routine screening for HCV infection in high-risk adults (a grade I recommendation). The scientific community appears to agree that the USPSTF adequately reviewed the scientific evidence for hepatitis C screening. There also seems to be agreement that the available screening tests are accurate and that current antiviral therapy leads to loss of detectable viremia, although it has not yet been shown to improve morbidity or mortality. There appears to be some controversy, however, about the translation of the evidence into the USPSTF finding of insufficient evidence to recommend for or against routine screening for HCV infection in high-risk adults. Before we discuss this recommendation specifically, it is important to review what a grade I recommendation really means and how the USPSTF may arrive at this letter grade.

The USPSTF uses an explicit analytic framework to define the scope of the evidence review for each topic it considers. The scope includes specifying the population at risk, the accuracy of screening tests, the efficacy of interventions (treatments) in improving health outcomes, and the harms caused by screening and by the interventions. Before arriving at a recommendation, the USPSTF takes into account the strength of the overall evidence and the balance between the magnitudes of benefits and harms (or the net benefit). When there is adequate evidence to determine the magnitude of the net benefit of delivering a preventive service, the USPSTF assigns 1 of 4 letter grades, A, B, C, or D, which indicate that the net benefit is substantial, moderate, small, or none, respectively. When there is inadequate evidence to determine the net benefit, the USPSTF assigns an I letter grade. The I letter grade simply reflects the lack of adequate evidence to make a recommendation; it is neither a recommendation for nor a recommendation against providing the service on a routine basis. A preventive service could receive an I letter grade for several reasons: Studies may be lacking, existing studies may be of poor quality, or good-quality studies may have conflicting results. Therefore, an I recommendation is a call for additional research that would provide the appropriate evidence base for the USPSTF to make either a positive or negative recommendation.

The USPSTF reviewed and evaluated the evidence base for HCV screening. This review found no direct evidence—that is, no controlled trial of the efficacy of screening in improving health outcomes—to evaluate the benefit of screening for HCV in either the general or the high-risk population (1). Therefore, the USPSTF evaluation focused on the chain of evidence that could be linked to answer the questions necessary to build a case for screening. The USPSTF review identified risk factors associated with an increased risk for HCV infection but found no prospective studies to determine the predictive accuracy of assessing these factors (2). The USPSTF found good evidence that existing tests—enzyme immunoassay and polymerase chain reaction—are accurate and have high sensitivity and specificity. These tests will have higher positive predictive value when used to screen persons at increased risk for HCV infection than when used to screen those at average risk.

To determine the magnitude of health benefit of screening for HCV infection, it is important to consider the natural history of HCV. Unlike HIV infection (in which nearly 100% of infected persons will develop AIDS and die as a result), the natural history of HCV infection is unclear. Only a minority of persons with chronic HCV infection (10% to 20%) develop cirrhosis after 20 to 30 years; there is currently no way to predict who will develop cirrhosis and who will not. Liver biopsy is commonly done as a part of diagnostic work-up and will cause major complications in 1% to 2% of patients. The evidence shows that only 30% to 40% of infected individuals referred for treatment are actually eligible to receive it and that 54% to 60% respond with sustained reduced viremia, although it is not known how long this lasts. In addition, the evidence shows that 50% to 60% of patients experience adverse effects as a result of treatment, and these adverse effects lead to many patients—up to 22% of those receiving combination therapy with pegylated interferon (2)—withdrawing from therapy.

It is not known whether current treatment will prevent severe liver disease such as cirrhosis or reduce progression to severe liver disease in HCV-infected persons. It is also not known whether counseling HCV-positive patients to change behavior decreases transmission of infection or improves intermediate or clinical outcomes. No evidence shows that counseling against alcohol use slows the progression to liver disease. There is also no evidence of the magnitude of harms associated with screening, such as psychological harms including anxiety, "labeling," or impact on partner relationships. Because of these gaps in the chain of evidence needed to demonstrate improved health outcomes from screening for HCV infection in high-risk persons, the USPSTF gave a grade I recommendation to HCV screening for this group.

The USPSTF believes that the I recommendation, directed to the primary care clinician, reflects the lack of adequate evidence to make either a positive or a negative recommendation about screening for HCV infection. There may be other reasons to advocate for HCV testing—for example, disease surveillance, research, or disease management in a particular patient—and these may form the basis for other expert panels or organizations that may review the same evidence and arrive at a different recommendation. This does not change the fact that there is insufficient evidence to recommend screening on the basis of proven health benefits for the individual patient.

Practicing primary care clinicians have limited time and resources to deliver preventive services. The USPSTF believes that services with adequate evidence of substantial to moderate net health benefit (those with A and B recommendations) ought to receive the highest priority for delivery in the primary care setting. Once clinicians are able to deliver these services, they can decide how to prioritize services that have received C and I letter grades and, in rare cases, even those that have received grade D recommendations. This strategy would be expected to yield the greatest benefit to the health of individuals and the population with the most prudent use of time and resources. This USPSTF recommendation may not alter the practice of clinicians who already assess risk factors and screen high-risk patients for HCV infection. However, it is important to recognize that high-risk people are screened for HCV infection in the hope that treatment may improve health outcomes without causing substantial harms, not because of a proven, long-term net health benefit.

Finally, as mentioned earlier, a grade I recommendation reflects the need for more research. Hepatitis C virus infection is an important public health problem, and better treatment options and prevention strategies clearly are needed. The I letter grade should be viewed as representing the USPSTF conclusions based on the evidence available at this time. The USPSTF continually updates its recommendations, especially when there is new evidence of benefit, and looks forward to the time when its recommendation on screening for HCV infection can be reconsidered on the basis of new research.

Replication and iteration are hallmarks of science. Differences of opinion among independent experts regarding interpretation of current evidence are not unusual. An essential theme underlying all USPSTF recommendations is a commitment to evaluating the quality of scientific studies and synthesizing the results in a systematic and transparent fashion so that clinicians and patients can make informed decisions.