Editorials
editor's note: Screening for and treating hepatitis C virus infection is a controversy affecting millions of Americans. The following two editorials highlight some of the issues involved in this public health challenge.
Integrating Risk History Screening and HCV Testing into Clinical and Public Health Settings
See related article on page 655.
Chronic hepatitis C virus (HCV) infection affects an estimated 3 million persons in the United States, most of them younger than 50 years.1 Most of these infections are asymptomatic until advanced liver disease develops. HCV infection is one of the leading causes of chronic liver disease morbidity and mortality and the most common indication for liver transplantation. Specific populations at increased risk for infection have been defined, and reliable diagnostic tests exist. Treatment is available that eradicates the virus and eliminates or reduces liver inflammation and fibrosis in some patients. Counseling can be offered to all patients with HCV infection to modify or prevent the adverse effects of cofactors, such as alcohol consumption, on disease progression.
Various groups of experts generally agree on these characterizations of HCV infection.2-6 There is disagreement, however, on how this evidence should be translated into preventive interventions. Especially controversial are recommendations for identifying incidents of HCV infection by testing persons who are at high risk, for example, those who received blood transfusions before more sensitive testing of donors was implemented or those who injected illicit drugs. The details of this controversy have been published.7,8
One group of experts, the U.S. Preventive Services Task Force (USPSTF),9 found insufficient evidence to recommend for or against routine testing for HCV infection in high-risk asymptomatic adults because it found no studies that proved, directly or indirectly, that testing for HCV infection leads to a reduction in cases of HCV-related chronic disease and deaths. Other groups of experts, including the Centers for Disease Control and Prevention2; National Institutes of Health3; Veterans Health Administration4; and independent infectious-disease, hepatology, and public health organizations,5 have recommended or endorsed that testing be offered routinely to persons at high risk for HCV infection so that infected persons have the opportunity to seek medical evaluation to determine the severity of their disease, to consider treatment, and to make lifestyle changes that could reduce the likelihood of progression of their silent disease.
Different conclusions were reached by these groups of experts, not because their reviews or evaluations of the evidence varied, but because their definitions of "benefit" differed.7,8 As the USPSTF indicated, no data show that treatment of persons with HCV infection will prevent disease progression to HCV-related cirrhosis, liver cancer, and death, or that counseling against alcohol use will slow progression to liver disease. However, as the other groups of experts indicated, the expectation that current benefits will translate into long-term ones is supported by data that current antiviral therapies produce positive effects in a large subgroup of patients. These effects include virus elimination and normalization of liver enzyme levels that are maintained for at least 10 years. The magnitude of the combined adverse effects of alcohol use and HCV infection, and the potential to modify these effects, also cannot be ignored. Chronic HCV infection requires many years of follow-up to determine whether treatment or other interventions increase life expectancy or quality, and it seems inappropriate to wait several decades to measure the impact of early identification of HCV infection, particularly when most persons with chronic HCV infection are asymptomatic despite the presence of active disease. Symptoms do not develop reliably in these persons until cirrhosis is present, which is too late for therapy to have a major impact on survival.
Because practicing primary care physicians have limited time and resources to deliver a spectrum of preventive services, the USPSTF feels the highest priority should be given to services with evidence of substantial to moderate net health benefit.8 No amount of debate is going to change the fact that experts disagree on how benefit should be defined or what to do while waiting for direct evidence that testing will reduce HCV-related complications. Even if there were agreement on the issue of benefit, there would remain differences in opinion on the feasibility of ascertaining risk factor histories during patient visits. Most HCV-positive persons can be identified by asking about their histories of injection drug use and blood transfusion (occurring before 1992).10 Regardless, choosing between competing priorities is problematic in all areas of health care. As "experts," we need to take some responsibility, in collaboration with clinical practice groups, for exploring innovative methods to implement our recommendations. For example, the Veterans Health Administration4 is developing an automated system, based on patients' computerized medical record information, that will prompt physicians about several interventions, including which patients to test for HCV infection (M.O. Rigsby, personal communication, 2004). Such a system likely could be adapted to other large health care organizations to identify high-risk characteristics common to multiple diseases, such as smoking, obesity, and illicit drug use, and to provide reminders about appropriate immunizations. Similar algorithms might be developed for use by individual patients using computer-assisted technology. Based on the information provided, a computerized risk-assessment summary with corresponding recommended preventive services could be produced for each patient during the same visit.
There clearly is a need for further research on the long-term effectiveness of antiviral therapy and counseling to reduce HCV-related liver damage. However, the sheer number of relatively young persons with chronic HCV infection who may develop complications as they age emphasizes the need to identify strategies to efficiently integrate risk history screening and HCV testing into current clinical and public health prevention activities.
The author thanks Leonard B. Seeff, M.D., Bruce R. Bacon, M.D., David L. Thomas, M.D., Michael O. Rigsby, M.D., Adrian M. Di Bisceglie, M.D., and Susan Goldstein, M.D., for assistance in the preparation of the manuscript.
The Author
Miriam J. Alter, Ph.D., is associate director for epidemiologic science in the Centers for Disease Control and Prevention's Division of Viral Hepatitis in Atlanta.
Address correspondence to Miriam J. Alter, Ph.D., Division of Viral Hepatitis, Mailstop D-66, Centers for Disease Control and Prevention, Atlanta, GA 30333 (e-mail: mja2@cdc.gov). Reprints are not available from the author.
REFERENCES
1. Alter MJ, Kruszon-Moran D, Nainan OV, McQuillan GM, Gao F, Moyer LA, et al. The prevalence of hepatitis C infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-62.
2. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998;47(RR-19):1-39.
3. National Institutes of Health. National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002-June 10-12, 2002. Hepatology 2002;36(suppl 1):S3-20.
4. Veterans Health Administration. Treatment recommendations for patients with chronic hepatitis C. September 2003. Accessed online June 1, 2005, at: http://www.hepatitis.va.gov/vahep?page=tp03-01-04-01.
5. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C [published correction appears in Hepatology 2004;40:269]. Hepatology 2004;39:1147-71.
6. Chou R, Clark EC, Helfand M. Screening for hepatitis C virus infection: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2004;140:465-79.
7. Alter MJ, Seeff LB, Bacon BR, Thomas DL, Rigsby MO, Di Bisceglie AM. Testing for hepatitis C virus infection should be routine for persons at increased risk for infection. Ann Intern Med 2004;141:715-7.
8. Calonge N, Randhawa G. The meaning of the U.S. Preventive Services Task Force grade I recommendation: screening for hepatitis C virus infection. Ann Intern Med 2004;141:718-9.
9. U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: recommendation statement. Ann Intern Med 2004;140:462-4.
10. Gunn RA, Murray PJ, Brennan CH, Callahan DB, Alter MJ, Margolis HS. Evaluation of screening criteria to identify persons with hepatitis C virus infection among sexually transmitted disease clinic clients: results from the San Diego Viral Hepatitis Integration Project. Sex Transm Dis 2003;30:340-4.
Screening for HCV Infection: Understanding the USPSTF Recommendation
The U.S. Preventive Services Task Force (USPSTF), a nonfederal, independent panel of scientists with notable experience in primary care and evidence-based medicine, is convened and supported by the Agency for Healthcare Research and Quality and charged by Congress to develop evidence-based recommendations for the health care community. These recommendations generally are aimed at primary care physicians, who deliver a range of preventive services to asymptomatic persons in a typical ambulatory practice setting.
In 2004, the USPSTF issued two recommendations1 on screening for hepatitis C virus (HCV) infection: a recommendation against routine screening for HCV infection in asymptomatic adults who are not at increased risk (grade D recommendation), and a finding of insufficient evidence to recommend for or against routine screening for HCV infection in adults at high risk (grade I recommendation). The latter recommendation has elicited some controversy, and it may be useful to clarify the reasoning behind the recommendation.
The USPSTF examines the evidence for the impact of screening and associated interventions on both favorable and adverse health outcomes, then weighs the benefits and harms to arrive at a net health benefit at the population level to assist the physician who makes decisions at the individual level. Recommendations with A, B, C, and D grades reflect net health benefits that are (respectively) substantial, moderate, small, and none. Grade I reflects substantial gaps in available evidence such that the USPSTF is unable to assess the net health benefit; therefore, it is a call for further research to clarify the net health benefit.2
When the natural history of a disease is known and
the relationship of intermediate outcome measures (e.g., biochemical marker
levels, disease stage, viral titers) and health outcome measures (e.g.,
morbidity and mortality rates) is well established, improvement in intermediate
outcomes is a valid surrogate measure for improvement in health outcomes.
However, the natural history of HCV infection is not well described in the
literature. The great majority of persons infected with HCV apparently do not
progress to cirrhosis, with only 10 to 20 percent of infected persons
developing cirrhosis after 20 to
30 years of infection.3,4 Currently, no method can reliably predict which
patients will progress to cirrhosis. In the absence of the ability to target
therapy to patients who need it, treating all HCV-infected persons would be
worthwhile only if the treatment has proven benefit in reducing or preventing
disease progression to cirrhosis or cancer, and if the treatment has minimal or
no adverse effects. In addition, the maximal potential public health benefit
would be reduced if all HCV-infected patients do not receive or respond to
treatment. Factors influencing treatment eligibility and response rates include
severity of liver damage, active alcohol abuse, illicit drug use, and other
serious physical or psychologic comorbidities.
A review3 of the available evidence on HCV infection shows that only 30 to 40 percent of infected persons who are referred for treatment are eligible to receive it, and that only 54 to 60 percent of treated patients have sustained reduced viremia. The duration of this response beyond the length of the current studies (i.e., a few years) is not known. Most importantly, the efficacy of treatment in reducing or preventing disease progression to cirrhosis has not been established. Adverse effects are experienced by 50 to 60 percent of treated patients; these effects are severe enough for up to 22 percent of patients who receive combination therapy with pegylated interferon and ribavirin to discontinue treatment.3 Additional harms are associated with the diagnostic work-up (e.g., complications from liver biopsy) and screening (e.g., psychologic harms such as anxiety, negative effects on partner relationships). The magnitude of harms of screening is unclear.
It is not known whether counseling HCV-infected persons to change their behavior decreases rates of disease transmission or if it leads to improved health outcomes. There is no evidence showing that vaccination against hepatitis A virus or counseling against alcohol use in HCV-infected persons leads to reduced rates of cirrhosis. Although there may be other reasons to advocate HCV testing (e.g., disease surveillance, research, disease management in individual patients), it does not alter the fact that on the basis of proven health benefit to individual patients, the evidence to support screening is insufficient.
Primary care physicians have limited time and resources to deliver preventive services. The USPSTF believes that services with adequate evidence for substantial to moderate net health benefit (grades A and B) should receive the highest priority for delivery. After delivering these services, physicians can decide how to prioritize other interventions. This strategy would be expected to yield the greatest health benefit to individual patients and to the entire population while making the most prudent use of time and resources.
The authors of this editorial are responsible for its contents. No statement in this editorial should be construed as an offical position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
The Authors
Gurvaneet S. Randhawa, M.D., M.P.H., is senior service fellow in the Center for Outcomes and Evidence at the Agency for Healthcare Research and Quality, Rockville, Md.
Ned Calonge, M.D., M.P.H., is chief medical officer and state epidemiologist at the Colorado Department of Public Health and Environment, Denver.
Address correspondence to Ned Calonge, M.D., M.P.H., Colorado Department of Public Health and Environment, 4300 Cherry Creek Dr. South, Denver, CO 80246. Reprints are not available from the authors.
REFERENCES
1. U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: recommendation statement. Ann Intern Med 2004;140:462-4.
2. Calonge N, Randhawa G. The meaning of the U.S. Preventive Services Task Force grade I recommendation: screening for hepatitis C infection. Ann Intern Med 2004;141:718-9.
3. Chou R, Clark EC, Helfand M. Screening for hepatitis C virus infection: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2004;140:465-79.
4. Freeman AJ, Dore GJ, Law MG, Thorpe M, Von Overbeck J, Lloyd AR, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology 2001;34(4 pt 1):809-16.
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Academy of Family Physicians. |
