Final Evidence Review
Final Evidence Review for Hepatitis C: Screening
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
A Systematic Review to Update the 2004 U.S. Preventive Services Task Force Recommendation
Release Date: November 2012
By: Roger Chou, MD; Erika Barth Cottrell, PhD, MPP; Ngoc Wasson, MPH; Basmah Rahman, MPH; and Jeanne-Marie Guise, MD, MPH
The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.
This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
This article was first published in Annals of Internal Medicine on November 27, 2012 (Ann Intern Med 2012; http://www.annals.org).
Background: Identification of hepatitis C virus (HCV)–infected persons through screening could lead to interventions that improve clinical outcomes.
Purpose: To review evidence about potential benefits and harms of HCV screening in asymptomatic adults without known liver enzyme abnormalities.
Data Sources: English-language publications identified from MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists.
Study Selection: Randomized trials and cohort, case–control, and cross-sectional studies that assessed yield or clinical outcomes of screening; studies reporting harms from HCV screening; and large series reporting harms of diagnostic liver biopsies.
Data Extraction: Multiple investigators abstracted and checked study details and quality by using predefined criteria.
Data Synthesis: No study evaluated clinical outcomes associated with screening compared with no screening or of different risk- or prevalence-based strategies. Three cross-sectional studies in higher prevalence populations found screening strategies that targeted multiple risk factors were associated with sensitivities greater than 90% and numbers needed to screen to identify 1 case of HCV infection of less than 20. Data on direct harms of screening were sparse. A large study of percutaneous liver biopsies (n = 2740) in HCV-infected patients with compensated cirrhosis reported no deaths and a 1.1% rate of serious adverse events (primarily bleeding and severe pain).
Limitations: Modeling studies were not examined. High or unreported proportions of potentially eligible patients in the observational studies were not included in calculations of screening yield because of unknown HCV status.
Conclusion: Although screening tests can accurately identify adults with chronic HCV infection, targeted screening strategies based on the presence of risk factors misses some patients with HCV infection. Well-designed prospective studies are needed to better understand the effects of different HCV screening strategies on diagnostic yield and clinical outcomes.
Primary Funding Source: Agency for Healthcare Research and Quality.
The prevalence of anti–hepatitis C virus (HCV) antibody in the United States is about 1.6%1. Approximately 78% of affected patients have viremia, indicating chronic infection. About two thirds of patients with HCV infection were born between 1945 and 1964, with the highest prevalence (4.3%) in people 40 to 49 years of age in 1999–20021. There were 16,000 new cases of HCV infection in 20092.
In 2007, HCV infection was associated with an estimated 15,000 deaths in the United States3. Liver disease related to HCV is the most common indication for liver transplantation among U.S. adults4, 5 and is a leading cause of hepatocellular carcinoma6.
The virus is primarily acquired via percutaneous exposures to infected blood, such as injection drug use7-13. Transfusions before 1992 and high-risk sexual behaviors are also associated with increased risk, although the efficiency of sexual transmission appears to be relatively low7, 8, 14, 15.
The natural course of HCV infection varies. Studies of community cohorts estimate cirrhosis in 7% of people after 20 years of infection, with rates about twice as high in clinical and referral cohorts16, 17. Studies with longer follow-up suggest that disease progression accelerates after 20 years18.
Screening for HCV infection could identify persons at earlier stages of disease, before they develop serious or irreversible liver damage, and lead to treatments to improve clinical outcomes or reduce transmission risk. Up to three quarters of HCV-infected persons are unaware of their status19.
In 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against HCV screening in adults not at increased risk (D recommendation) and found insufficient evidence to recommend for or against screening in high-risk adults (I recommendation)20. Although the USPSTF found that screening tests are accurate and that antiviral treatments improve viremia21, the recommendations were based on the lower prevalence of HCV infection in persons without risk factors; the relatively low rate of long-term progression, potentially resulting in overtreatment; and lack of evidence that screening improves important health outcomes or reduces transmission risk. Other groups recommend screening in higher-risk patients22-24. The Centers for Disease Control and Prevention (CDC) also recently recommended screening all persons born between 1945 and 196525.
The purpose of this report is to review the evidence on HCV screening in asymptomatic adults without known liver enzyme abnormalities26. This review cuses on research gaps identified in the 2004 USPSTF review21 and will be used together with a separate review on antiviral treatments27 by the USPSTF to update its HCV screening recommendations.
We developed a review protocol and analytic framework that included the following key questions:
1. Does screening for HCV infection in nonpregnant adults without known abnormal liver enzymes reduce mortality and morbidity due to HCV infection, affect quality of life, or reduce incidence of HCV infection?
2. What is the effectiveness of different risk- or prevalence-based methods for screening for HCV infection on clinical outcomes?
3. What is the sensitivity and number needed to screen to identify 1 case of HCV infection of different risk- or prevalence-based methods for screening for HCV infection?
4. What are the harms associated with screening for HCV infection, including diagnostic liver biopsies?
Detailed methods and data for the review, including search strategies, detailed inclusion criteria, data abstraction tables, and tables with quality ratings of individual studies, are available in the full report, which includes the analytic framework and additional key questions26. The protocol was developed using a standardized process with input from experts and the public. The analytic framework focuses on direct evidence that HCV screening improves important health outcomes compared with not screening, as well as the chain of indirect evidence (diagnostic accuracy of screening, clinical utility and harms of subsequent testing in HCV-infected persons, and benefits and harms of treatments) linking screening with improved health outcomes. Key questions related to risk modification of mother-to-infant transmission are presented in the full report26 and in a separate article28. We did not re-review the diagnostic accuracy of HCV antibody testing, which the 2004 USPSTF review found to be high21.
Data Sources and Searches
A research librarian searched Ovid MEDLINE (1947 to May 2012), Embase, the Cochrane Library Database, Scopus, and PsycINFO; clinical trial registries (including ClinicalTrials.gov); and grants databases. We supplemented electronic searches by reviewing reference lists of retrieved articles.
At least 2 reviewers independently evaluated each study to determine inclusion eligibility. Papers were selected for full review if they were relevant to a key question and met the predefined inclusion criteria. For screening, we included randomized trials, cohort studies, case–control studies, and cross-sectional studies that compared different screening strategies in asymptomatic adults without known liver enzyme abnormalities and reported clinical outcomes or sufficient information to compute the sensitivity and number needed to screen to identify 1 HCV-infected person. We also included large studies (sample size >1000 participants) reporting harms associated with diagnostic liver biopsy published since 2004 and uncontrolled or controlled studies reporting direct harms associated with screening.
Clinical outcomes were mortality, end-stage liver disease, cirrhosis, hepatocellular carcinoma, need for transplantation, quality of life, HCV transmission, harms associated with screening (such as anxiety, labeling, and effects on quality of life), and harms associated with liver biopsy (including death, bleeding, and severe pain).
We restricted inclusion to English-language articles and excluded studies published only as abstracts. We excluded studies of posttransplant patients, HIV-infected patients, patients undergoing hemodialysis, and persons with occupational exposures, in whom screening and treatment considerations may differ from those in the general population29-33.
Data Extraction and Quality Rating
One investigator abstracted details about the study design, patient population, setting, interventions, analysis, follow-up, and results. A second investigator reviewed data for accuracy. Two investigators independently applied predefined criteria34-36 to assess the quality of each study as good, fair, or poor. Discrepancies were resolved through a consensus process.
For studies reporting the diagnostic yield of different screening strategies, we computed the number needed to screen to identify 1 case of HCV infection by dividing the number of screening tests performed by the number of HCV cases identified. The proportion screened was the number of patients screened upon application of a particular screening strategy, divided by the total number of patients assessed.
We assessed the overall strength of each body of evidence as “high,” “moderate,” “low,” or “insufficient” in accordance with the AHRQ “Methods Guide for Effectiveness and Comparative Effectiveness Reviews”37, based on the quality of studies, consistency between studies, precision of estimates, and directness of evidence.
Role of the Funding Source
This research was funded by AHRQ's Effective Health Care Program. Investigators worked with AHRQ staff to develop and refine the scope, analytic framework, and key questions. AHRQ staff had no role in study selection, quality assessment, synthesis, or development of conclusions. AHRQ staff provided project oversight, distributed the draft report for peer review, and reviewed the draft report and manuscript. The investigators are solely responsible for the content of the manuscript and the decision to submit for publication.
The Appendix Figure shows the results of the search and study selection process. No study compared clinical outcomes between individuals screened and not screened for HCV infection or between individuals screened by using different risk- or prevalence-based strategies.
Yield of Risk-Based Screening Methods
Four cross-sectional studies (samples sizes ranging from 985 to 3367) provided data to calculate the diagnostic accuracy and yield of alternative HCV screening criteria (Table 1)38-41. Two studies evaluated patients attending sexually transmitted disease clinics38, 41 and 2 evaluated patients attending urban primary care clinics39, 40. Three studies evaluated higher-prevalence populations (HCV prevalence, 4.6% to 8.3%)38-40 and 1 a lower-prevalence population (HCV prevalence, 1.0%)41. One study of patients in primary care and gastroenterology clinics (n = 429) also evaluated alternative screening criteria but used a case–control design42. All of the studies applied and evaluated alternative screening criteria retrospectively. Other limitations of the studies were that high proportions of potentially eligible patients were not included in analyses because of unknown HCV status or that the study did not report the proportion with unknown HCV status. Although the studies used different criteria for targeted screening, several factors (a personal history of injection drug use, sexual intercourse with an injection drug user, and pre-1992 blood transfusion) were consistently used across studies to identify higher-risk individuals.
One cross-sectional study of a lower-prevalence population in a Dutch sexually transmitted disease clinic (n = 985; HCV seroprevalence, 1%) found that screening based on presence of 1 or more positive items on a 20-item questionnaire was associated with a sensitivity of 90% for identifying persons with HCV infection and a number needed to screen to identify 1 case of HCV infection of 2.4 (Table 2)41.
Three cross-sectional studies in higher-prevalence populations found that screening strategies targeting multiple risk factors were associated with sensitivities of more than 90% and numbers needed to screen of 9.3 to 18 (Table 2)38-40. One cross-sectional study in a sexually transmitted disease clinic (n = 3367; HCV seroprevalence, 4.9%) found that screening patients with 1 of 5 risk factors (injection drug user, sex partners of injection drug user, received a pre-1992 blood transfusion, bacterial sexually transmitted disease in last 5 years, or age ≥30 years) would have resulted in testing 63% of clinic attendees, with a sensitivity of 97% for identifying HCV infection and a number needed to screen of 1338. One study of patients in an inner-city primary care clinic (n = 1000; HCV seroprevalence, 8.3%) found that screening patients with positive findings in at least 1 of 3 domains (medical history, exposure history, or social history) would have resulted in screening 71% of the population, with a sensitivity of 92% and a number needed to screen of 9.339. A study of U.S. veterans (n = 2263; HCV seroprevalence, 4.6%) found that screening patients according to presence of 1 or more of 5 risk factors (Vietnam-era veteran, tattoo/body piercing, blood transfusion before 1992, abnormal liver enzyme levels, past or present injection drug use) would have resulted in screening of 78% of the population compared with screening based on presence of these or 6 additional risk factors (multiple sexual contacts, intemperate alcohol use, intranasal cocaine use, blood exposure [mucous membranes], unexplained liver disease, hemodialysis), with a sensitivity of 97% and number needed to screen of 1840.
More narrowly targeted screening strategies evaluated in these studies were associated with specificities of more than 95% and numbers needed to screen of less than 2, but missed up to two thirds of infected patients38-40. Two studies found screening only injection drug users would have resulted in testing of 3.0% or 5.8% of the population, with sensitivities of 41% and 60%, and numbers needed to screen of 1.6 and 1.9, respectively38, 40. One study found screening patients with positive findings in 3 different domains (medical, exposure, or social history) would have resulted in testing of 5.6% of the population, with a sensitivity of 34% and number needed to screen of 2.039.
A case–control study (222 cases) found screening based on presence of 4 or more of 7 risk factors (self-reported history of sex with a prostitute, history of exposure to potentially infected blood transfusion, rejections as a blood donor, refused life insurance, witnessed use of injecting drugs, sexual intercourse with an injection drug user, or self-reported hepatitis B virus infection) would have identified 24% of HCV-infected persons, with a specificity of nearly 100% (203 of 204)42. Screening patients with 1 or more risk factors would have identified 94% of infected persons, with a specificity of 35%.
The 2004 USPSTF review21 included a post hoc analysis of National Hepatitis Screening Survey data that found that screening using 1 of 3 different risk factor models would have identified 53% to 69% of HCV-infected persons43.
Potential Harms Associated with Screening
Three studies (n = 15 to 161) found diagnosis of HCV infection associated with some negative effects on psychological status, strain on spousal relationships, or binge drinking, but these studies had important shortcomings, including no control group of HCV-infected persons unaware of their status, reliance on retrospective recall, and poorly defined outcomes44-46. A small, fair-quality cross-sectional study (n = 34) included in the 2004 USPSTF review found that HCV-infected intravenous drug users aware of their status reported worse quality of life than those unaware47.
One study of percutaneous liver biopsies (n = 2740) in HCV-infected patients with compensated cirrhosis and at least moderate fibrosis reported a 1.1% rate of serious adverse events, most commonly bleeding or severe pain, with no deaths48. Two other small studies (n = 126 and n = 166) included in the 2004 USPSTF review reported no episodes of bleeding, perforation, or death after percutaneous liver biopsy in HCV-infected persons49, 50.
In patients undergoing liver biopsy for various indications, large series (n = 1398 to 61,184) published since 2004 reported periprocedural mortality rates of 0% to 0.2% and major complications (primarily bleeding) in 0.3% to 1.0%51-55, consistent with studies included in the 2004 USPSTF review56-62).
The evidence reviewed in this report is summarized in Table 3. As in the 2004 USPSTF review21, we found no direct evidence on effects of HCV screening versus no screening on clinical outcomes, or on the comparison of clinical effects of alternative screening strategies. Retrospective studies found that screening strategies targeting multiple risk factors were associated with sensitivities exceeding 90% and numbers needed to screen to identify 1 case of HCV infection of less than 2038-41. More narrowly targeted alternative screening strategies (such as screening only persons with a history of injection drug use) were associated with numbers needed to screen of less than 2, but they missed up to two thirds of infected patients.
Although direct harms of screening appear minimal, harms such as labeling, anxiety, and stigmatization remain poorly studied and difficult to quantify63-65. Harms of biopsy include a risk for death of less than 0.2% and serious complications (primarily bleeding and severe pain) in about 1%48, 51-55. As detailed in our full report, noninvasive tests have fair to good accuracy for diagnosing fibrosis and good to excellent accuracy for diagnosing cirrhosis compared with liver biopsy26. Although clinical practice has evolved toward less routine use of liver biopsy before antiviral therapy and the proportion of HCV-infected patients undergoing liver biopsy has decreased overall, no study reported the proportion of screen-detected patients who undergo biopsy. Thus, it is difficult to determine the magnitude of harms associated with liver biopsy subsequent to screening.
In the absence of direct evidence on clinical outcomes associated with screening, an indirect chain of evidence showing the availability of accurate diagnostic tests and effective treatments could link screening with improvements in clinical outcomes. The 2004 USPSTF review found HCV antibody testing to be highly accurate21. Much of the benefits from screening are likely to be based on the effectiveness of antiviral treatments, including newly approved direct-acting antiviral agents, which are addressed in a separate review27. Therefore, screening recommendations should be based on the evidence for screening and treatment in totality27. Studies showing that screening or subsequent interventions are associated with decreased transmission risk could also significantly affect estimates of potential benefits, but these are not yet available26.
Our study has limitations. We excluded non–English-language articles, which could result in language bias, although we identified no non–English-language studies that would have met inclusion criteria. We could not formally assess for publication bias because of small numbers of studies. We also excluded modeling studies, which might be informative for understanding benefits and harms of screening, given the challenges in conducting the large, long-term studies needed to assess clinical outcomes associated with screening. Available evidence regarding screening yield is derived from a few retrospective studies. High or unreported proportions of potentially eligible patients in these observational studies were not included in calculations of screening yield because of unknown HCV status.
The CDC recently recommended that all persons born between 1945 and 1965 be screened for HCV infection, in addition to persons with risk factors for HCV infection25. The CDC based its recommendation on the prevalence of patients with HCV infection in this birth cohort (accounting for about three quarters of patients with HCV infection in the United States), the high proportion of patients with undiagnosed HCV infection, projected disease burden after several decades of infection, and estimated benefits from antiviral treatments. Although cost-effectiveness analyses suggest that the birth cohort screening approach is highly cost-effective, no clinical data are yet available13. The CDC's birth cohort approach was not evaluated in the studies included in our review on the yield of alternative screening strategies. Clinical studies that prospectively evaluate the accuracy, yield, and outcomes of alternative HCV screening strategies, including the birth cohort approach, are needed.
Copyright and Source Information
Source: Agency for Healthcare Research and Quality.
Acknowledgment: The authors thank Robin Paynter, MLIS; Rose Campbell, MLIS; Christina Bougatsos, MPH; Ian Blazina, MPH; Tracy Dana, MLS; Jessica Griffin, MS; AHRQ Task Order Officer Christine Chang, MD, MPH; and USPSTF Medical Officer Iris Mabry-Hernandez, MD, MPH.
Grant Support: By the Agency for Healthcare Research and Quality (contract number 290-2007-10057-I, task order 8), Rockville, Maryland.
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1085.
Requests for Single Reprints: Roger Chou, MD, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, email@example.com.
- Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-14. [PMID: 16702586]
- National Center for HIV/AIDS, Viral Hepatitis, STD & TB Prevention. Disease burden from viral hepatitis A, B, and C in the United States. Updated 13 September 2011, 31 May 2012. Accessed at www.cdc.gov/hepatitis/pdfs/disease_burden.pdf on 30 August 2012.
- Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med. 2012;156:271-8. [PMID: 22351712]
- Busch MP. Insights into the epidemiology, natural history and pathogenesis of hepatitis C virus infection from studies of infected donors and blood product recipients. Transfus Clin Biol. 2001;8(3):200-6. [PMID: 11499958]
- Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;36:S30-4. [PMID: 12407574]
- El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 2004;127:S27-34. [PMID: 15508094]
- Alter H. Discovery of non-A, non-B hepatitis and identification of its etiology. Am J Med. 1999;107:16S-20S. [PMID: 10653450]
- Kaur S, Rybicki L, Bacon BR, Gollan JL, Rustgi VK, Carey WD. Performance characteristics and results of a large-scale screening program for viral hepatitis and risk factors associated with exposure to viral hepatitis B and C: results of the National Hepatitis Screening Survey. National Hepatitis Surveillance Group. Hepatology. 1996;24:979-86. [PMID: 8903363]
- Yawn BP, Gazzuola L, Wollan PC, Kim WR. Development and maintenance of a community-based hepatitis C registry. Am J Manag Care. 2002;8:253-61. [PMID: 11915975]
- Austin GE, Jensen B, Leete J, De L'Aune W, Bhatnagar J, Racine M, et al. Prevalence of hepatitis C virus seropositivity among hospitalized US veterans. Am J Med Sci. 2000;319:353-9. [PMID: 10875289]
- Cheung RC. Epidemiology of hepatitis C virus infection in American veterans. Am J Gastroenterol. 2000;95:740-7. [PMID: 10710068]
- Garfein RS, Vlahov D, Galai N, Doherty MC, Nelson KE. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodeficiency, and human T-lymphotropic viruses. Am J Public Health. 1996;86:655-61. [PMID: 8629715]
- Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, et al. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156:263-70. [PMID: 22056542]
- Bellentani S, Pozzato G, Saccoccio G, Crovatto M, Crocè LS, Mazzoran L, et al. Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut. 1999;44:874-80. [PMID: 10323892]
- Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. The Retrovirus Epidemiology Donor Study. N Engl J Med. 1996;334:1685-90. [PMID: 8637512]
- Thein HH, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48:418-31. [PMID: 18563841]
- 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;34:809-16. [PMID: 11584380]
- Wiese M, Grüngreiff K, Güthoff W, Lafrenz M, Oesen U, Porst H; East German Hepatitis C Study Group. Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany—a 25-year multicenter study. J Hepatol. 2005;43:590-8. [PMID: 16237783]
- Hagan H, Campbell J, Thiede H, Strathdee S, Ouellet L, Kapadia F, et al. Self-reported hepatitis C virus antibody status and risk behavior in young injectors. Public Health Rep. 2006;121:710-9. [PMID: 17278406]
- U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: recommendation statement. Ann Intern Med. 2004;140:462-4. [PMID: 15023712]
- Chou R, Clark EC, Helfand M; U.S. Preventive Services Task Force. 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. [PMID: 15023713]
- Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74. [PMID: 19330875]
- Dienstag JL, McHutchison JG. American Gastroenterological Association medical position statement on the management of hepatitis C. Hepatology. 2006;130:225-30. [PMID: 16401485]
- Hepatitis C virus infection. American Academy of Pediatrics. Committee on Infectious Diseases. Pediatrics. 1998;101:481-5. [PMID: 9499195]
- Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945 to 1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012. [PMID: 22910836]
- Chou R, Cottrell EB, Wasson N, Rahman B, Guise JM. Screening for hepatitis C virus infection in adults: a comparative effectiveness review (Prepared by Oregon Evidence-based Practice Center under Contract No. 290-2007-10057-I.). 2012. Accessed at www.effectivehealthcare.ahrq.gov.
- Chou R, Hartung D, Rahman B, Wasson N, Cottrell EB, Fu R. Comparative effectiveness of treatment for hepatitis C virus infection in adults: a systematic review. Ann Intern Med. 2013. [Forthcoming]
- Cottrell EB, Chou R, Wasson N, Rahman B, Guise JM. Reducing risk for mother-to-infant transmission of hepatitis C: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013. [Forthcoming]
- Furusyo N, Hayashi J, Kanamoto-Tanaka Y, Ariyama I, Etoh Y, Shigematsu M, et al. Liver damage in hemodialysis patients with hepatitis C virus viremia: a prospective 10-year study. Dig Dis Sci. 2000;45:2221-8. [PMID: 11215743]
- Kliem V, van den Hoff U, Brunkhorst R, Tillmann HL, Flik J, Manns MP, et al. The long-term course of hepatitis C after kidney transplantation. Transplantation. 1996;62:1417-21. [PMID: 8958266]
- Rostaing L, Rumeau JL, Cisterne JM, Izopet J, Chabannier MH, Durand D. Liver histology in renal transplant patients after more than 10 years of hepatitis C virus infection. Transplant Proc. 1996;28:2836-7. [PMID: 8908089]
- Soto B, Sánchez-Quijano A, Rodrigo L, del Olmo JA, García-Bengoechea M, Hernández-Quero J, et al. Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol. 1997;26:1-5. [PMID: 9147999]
- Sánchez-Quijano A, Andreu J, Gavilán F, Luque F, Abad MA, Soto B, et al. Influence of human immunodeficiency virus type 1 infection on the natural course of chronic parenterally acquired hepatitis C. Eur J Clin Microbiol Infect Dis. 1995;14:949-53. [PMID: 8654444]
- Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52:377-84. [PMID: 9764259]
- Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, et al; Methods Work Group, Third U.S. Preventive Services Task Force. Current methods of the U.S. Preventive Services Task Force: a review of the process. Am J Prev Med. 2001;20:21-35. [PMID: 11306229]
- Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-36. [PMID: 22007046]
- Agency for Healthcare Research and Quality. Methods guide for effectiveness and comparative effectiveness reviews. AHRQ publication no. 10(12)-EHC063-EF. April 2012. Accessed at www.effectivehealthcare.ahrq.gov/ehc/products/60/318/MethodsGuide_Prepublication-Draft_20120523.pdf on 19 June 2012.
- 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. [PMID: 12671556]
- McGinn T, O'Connor-Moore N, Alfandre D, Gardenier D, Wisnivesky J. Validation of a hepatitis C screening tool in primary care. Arch Intern Med. 2008;168:2009-13. [PMID: 18852403]
- Zuniga IA, Chen JJ, Lane DS, Allmer J, Jimenez-Lucho VE. Analysis of a hepatitis C screening programme for US veterans. Epidemiol Infect. 2006;134:249-57. [PMID: 16490127]
- Zuure F, Davidovich U, Kok G, Depla AC, Hoebe C, van den Hoek A, et al. Evaluation of a risk assessment questionnaire to assist hepatitis C screening in the general population. Euro Surveill. 2010;15:19539. [PMID: 20429995]
- Nguyen MT, Herrine SK, Laine CA, Ruth K, Weinberg DS. Description of a new hepatitis C risk assessment tool. Arch Intern Med. 2005;165:2013-8. [PMID: 16186472]
- Lapane KL, Jakiche AF, Sugano D, Weng CS, Carey WD. Hepatitis C infection risk analysis: who should be screened? Comparison of multiple screening strategies based on the National Hepatitis Surveillance Program. Am J Gastroenterol. 1998;93:591-6. [PMID: 9576453]
- Anderson EM, Mandeville RP, Hutchinson SJ, Cameron SO, Mills PR, Fox R, et al. Evaluation of a general practice based hepatitis C virus screening intervention. Scott Med J. 2009;54:3-7. [PMID: 19728405]
- Fabris P, Tositti G, Giordani MT, Baldo V, Grasso A, Pignattari E, et al. Assessing patients' understanding of hepatitis C virus infection and its impact on their lifestyle. Aliment Pharmacol Ther. 2006;23:1161-70. [PMID: 16611277]
- Trepka MJ, Zhang G, Leguen F, Obiaja K, Malow RM, De La Rosa M. Benefits and adverse effects of hepatitis C screening: early results of a screening program. J Public Health Manag Pract. 2007;13:263-9. [PMID: 17435493]
- Rodger AJ, Jolley D, Thompson SC, Lanigan A, Crofts N. The impact of diagnosis of hepatitis C virus on quality of life. Hepatology.1999;30:1299-301. [PMID: 10534353]
- Seeff LB, Everson GT, Morgan TR, Curto TM, Lee WM, Ghany MG, et al; HALT–C Trial Group. Complication rate of percutaneous liver biopsies among persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8:877-83. [PMID: 20362695]
- Saadeh S, Cammell G, Carey WD, Younossi Z, Barnes D, Easley K. The role of liver biopsy in chronic hepatitis C. Hepatology. 2001;33:196-200. [PMID: 11124836]
- Farrell RJ, Smiddy PF, Pilkington RM, Tobin AA, Mooney EE, Temperley IJ, et al. Guided versus blind liver biopsy for chronic hepatitis C: clinical benefits and costs. J Hepatol. 1999;30:580-7. [PMID: 10207798]
- Atwell TD, Smith RL, Hesley GK, Callstrom MR, Schleck CD, Harmsen WS, et al. Incidence of bleeding after 15,181 percutaneous biopsies and the role of aspirin. AJR Am J Roentgenol. 2010;194:784-9. [PMID: 20173160]
- Huang JF, Hsieh MY, Dai CY, Hou NJ, Lee LP, Lin ZY, et al. The incidence and risks of liver biopsy in non-cirrhotic patients: An evaluation of 3806 biopsies [Letter]. Gut. 2007;56:736-7. [PMID: 17440193]
- Myers RP, Fong A, Shaheen AA. Utilization rates, complications and costs of percutaneous liver biopsy: a population-based study including 4275 biopsies. Liver Int. 2008;28:705-12. [PMID: 18433397]
- van der Poorten D, Kwok A, Lam T, Ridley L, Jones DB, Ngu MC, et al. Twenty-year audit of percutaneous liver biopsy in a major Australian teaching hospital. Intern Med J. 2006;36:692-9. [PMID: 17040353]
- West J, Card TR. Reduced mortality rates following elective percutaneous liver biopsies. Hepatology. 2010;139:1230-7. [PMID: 20547160]
- Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology. 000;32:477-81. [PMID: 10960438]
- Froehlich F, Lamy O, Fried M, Gonvers JJ. Practice and complications of liver biopsy. Results of a nationwide survey in Switzerland. Dig Dis Sci. 1993;38:1480-4. [PMID: 8344104]
- Garcia-Tsao G, Boyer JL. Outpatient liver biopsy: how safe is it? [Editorial]. Ann Intern Med. 1993;118:150-3. [PMID: 8416312]
- Gilmore IT, Burroughs A, Murray-Lyon IM, Williams R, Jenkins D, Hopkins A. Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: an audit by the British Society of Gastroenterology and the Royal College of Physicians of London. Gut. 1995;36:437-41. [PMID: 7698705]
- Janes CH, Lindor KD. Outcome of patients hospitalized for complications after outpatient liver biopsy. Ann Intern Med. 1993;118:96-8. [PMID: 8416324]
- McGill DB, Rakela J, Zinsmeister AR, Ott BJ. A 21-year experience with major hemorrhage after percutaneous liver biopsy. Hepatology. 1990;99:1396-400. [PMID: 2101588]
- Vautier G, Scott B, Jenkins D. Liver biopsy: blind or guided? [Editorial]. BMJ. 1994;309:1455-6. [PMID: 7804036]
- Stewart BJ, Mikocka-Walus AA, Harley H, Andrews JM. Help-seeking and coping with the psychosocial burden of chronic hepatitis C: a qualitative study of patient, hepatologist, and counsellor perspectives. Int J Nurs Stud. 2012;49:560-9. [PMID: 22154094]
- Zickmund S, Ho EY, Masuda M, Ippolito L, LaBrecque DR. “They treated me like a leper”. Stigmatization and the quality of life of patients with hepatitis C. J Gen Intern Med. 2003;18:835-44. [PMID: 14521647]
- Conrad S, Garrett LE, Cooksley WG, Dunne MP, MacDonald GA. Living with chronic hepatitis C means ‘you just haven't got a normal life any more'. Chronic Illn. 2006;2:121-31. [PMID: 17175655].
Table 1. Studies of Alternative Screening Strategies
|Study, Year, Country (Reference)||Study Design||Sample Size, n||Setting, Population Characteristics||HCV Screening Strategies||Quality|
|Gunn et al, 2003, USA38||Cross-sectional||3367||STD clinic
Age ≥30 y: 4.6%
Female: Not reported
Self-reported injection drug use: 5.7%
|A: Screen all
B: Ever injected drugs (self-report)
C: Ever injected drugs or blood transfusions before 1992 (self-report)
D: Same as C, or sex partner used injection drugs (self-report)
E: Same as D (self-report or identified by clinic staff)
F: Same as E, plus bacterial sexually transmitted disease in last 5 y
G: Same as F, plus age ≥30 y
|McGinn et al, 2008, USA39||Cross-sectional||1000||Urban primary care clinic
Age: Mean, 50 y
|A: Screen all
B: Positive findings in ≥1 of 3 domains
C: Positive findings in ≥2 domains
D: Positive findings in 3 domains
|Nguyen et al, 2005, USA42||Case–control||429 (225 HCV-positive, 204 HCV-negative)||Gastroenterology and primary care clinics
Born 1940–1949: 20%
Born 1950–1959: 38%
Back 1960–1969: 18%
Reports seeing use of injecting drugs: 34%
|A: Screen all
B: ≥1 risk factor, based on 7-item instrument (self-report history of sex with a prostitute, history of exposure to potentially infected blood during transfusion, rejection as a blood donor, refused life insurance, witnessing use of injecting drugs, sexual intercourse with an injecting drug user, self-report of HBV infection)
C: ≥2 risk factors
D: ≥3 risk factors
E: ≥4 risk factors
|Zuniga et al, 2006, USA40||Cross-sectional||2263||Urban primary care clinics
Age 40–54 y: 31%
Vietnam-era veteran: 50%
Blood transfusion before 1992: 17%
Any injection drug use: 4.5%
Abnormal liver function test results: 9.1%
|A: Any of 11 risk factors (Vietnam-era veteran, multiple sexual contacts, tattoo/body piercing, intemperate alcohol use, blood transfusion before 1992, intranasal cocaine use, blood exposure [mucous membranes], abnormal liver enzyme levels, injection drug use [past or present], unexplained liver disease, hemodialysis)
B: Any of 5 risk factors (Vietnam-era veteran, tattoo/body piercing, blood transfusion before 1992, abnormal liver enzyme levels, injection drug use)
C: Self-reported injection drug use (past or present)
|Zuure et al, 2010, the Netherlands41||Cross-sectional||884||STD clinics
Population characteristics not reported
|A: Screen all
B: ≥1 risk factor, based on 20-item questionnaire*
HBV = hepatitis B virus; HCV = hepatitis C virus; STD = sexually transmitted disease.
* Injection drug use, born in HCV-endemic country, blood transfusion before 1992, HCV-infected mother, mother is/was injection drug user, living with HCV-infected individual, living with injection drug user, needle exposure to high-risk person, needle exposure in HCV-endemic country, hemophilia patient, hemodialysis patient, organ recipient, received blood products in medium-/high-risk country, exposure of healthcare workers to blood/tissue in medium-/high-risk country, surgical/dental procedure in medium-/high-risk country, ritual intervention (circumcision, scarification) in medium-/high-risk country, tattoo in medium-/high-risk country, body piercing in medium-/high-risk country, HIV-positive status, noninjection drug use ≥3 times/wk for ≥3 mo.
Table 2. Screening Strategies: Effects of Applying Alternative Screening Criteria on Proportion Screened, Sensitivity, Specificity, and Number Needed to Screen to Identify 1 Case of Hepatitis C Virus Infection
|Study, Year, Country (Reference)||HCV Prevalence, % (n/n)||Screening Strategy||Proportion Screened,
|Specificity, % (n/n)||Number Needed to
Screen to Identify
1 Case of HCV
Infection, n (n/n)*
|Gunn et al, 2003, USA38||4.9 (165/3367)||A: Screened all
B: Injection drug use (self-report)
C: Injection drug use or blood transfusions (self-report)
D: Injection drug use, blood transfusions, or sex partner was an injection drug user (self-report)
E: Same as D (self-report or identified by clinic staff)
F: Same as E, plus bacterial sexually transmitted disease in last 5 y
G: Same as F, plus age ≥30 y
|A: 100 (3356/3356)
B: 5.8 (193/3356)
C: 7.5 (253/3356)
D: 10 (347/3356)
E: 12 (413/3356)
F: 34 (1145/335)
G: 63 (2127/3356)
|A: 100 (165/165)
B: 60 (99/165)
C: 64 (105/165)
D: 67 (110/165)
E: 70 (116/165)
F: 81 (134/165)
G: 97 (160/165)
|A: 0 (0/3191)
B: 97 (3097/3191)
C: 95 (3043/3191)
D: 93 (2954/3191)
E: 91 (2894/3191)
F: 68 (2180/3191)
G: 38 (1224/3191)
|A: 20 (3356/165)
B: 1.9 (193/99)
C: 2.4 (253/105)
D: 3.2 (347/110)
E: 3.6 (413/116)
F: 8.5 (1145/134)
G: 13 (2127/160)
|McGinn et al, 2008, USA39||8.3 (83/1000)||A: Screen all
B: Positive findings in ≥1 of 3 domains
C: Positive findings in ≥2 domains
D: Positive findings in 3 domains
|A: 100 (1000/1000)
B: 71 (709/1000)
C: 23 (228/1000)
D: 5.6 (56/1000)
|A: 100 (83/83)
B: 92 (76/83)
C: 65 (54/83)
D: 34 (28/83)
|A: 0 (0/917)
B: 31 (284/917)
C: 81 (743/917)
D: 97 (889/917)
|A: 12 (1000/83)
B: 9.3 (709/76)
C: 4.2 (228/54)
D: 2.0 (56/28)
|Nguyen et al, 2005, USA42]||Case–control design:
n = 225
HCV-positive, 204 HCV-negative
|A: Screen all
B: ≥1 risk factor, based on 7-item instrument
C: ≥2 risk factors
D: ≥3 risk factors
E: ≥4 risk factors
|A: 100 (429/429)
B: 78 (335/429)
C: 48 (207/429)
D: 28 (118/429)
E: 13 (56/429)
|A: 100 (225/225)
B: 94 (212/225)
C: 79 (178/225)
D: 51 (115/225)
E: 24 (55/225)
|A: 0 (0/204)
B: 35 (81/204)
C: 86 (175/204)
D: 99 (201/204)
E: 100 (203/204)
|Not applicable (case–control design)|
|Zuniga et al, 2006, USA40||4.6 (103/2263)||A: Any of 11 risk factors
B: Any of 5 risk factors
C: Self-reported injection drug use (past or present)
|A: 100 (2263/2263)
B: 78 (1776/2263)
C: 3.0 (68/2263)*
|A: 100 (103/103)
B: 97 (100/103)
C: 41 (42/103)
|A: 0 (0/2160)
B: 22 (484/2160)
C: 99 (2134/2160)
|A: 22 (2263/103)
B: 18 (1776/100)
C: 1.6 (68/42)
|Zuure et al, 2010, the Netherlands41||1.0 (98/985)||A: Screen all
B: ≥1 risk factor, based on 20-item questionnaire
|A: 100 (985/985)
B: 21 (207/985)
|A: 100 (98/98)
B: 90 (88/98)
|A: 0 (0/887)
B: 87 (768/887)
|A: 10 (985/98)
B: 2.4 (207/88)
HCV = hepatitis C virus.
*Number of screening tests performed/number of HCV cases identified.
Table 3. Summary of Evidence
|Strength of Evidence of Findings From 2012 AHRQ Report*†||Studies Identified, n
|Overall Quality||Consistency (High, Moderate, Low)||Directness (Direct or Indirect)||Precision (High, Moderate, Low)||Summary of Findings|
|Does screening for HCV infection in nonpregnant adults without known abnormal liver enzymes reduce mortality and morbidity due to HCV, affect quality of life, or reduce transmission of HCV?|
|No evidence||No studies||No studies||No studies||No studies||No studies||No study compared clinical outcomes between individuals screened and not screened for HCV infection.|
|What is the effectiveness of different risk- or prevalence-based methods for screening for HCV infection on clinical outcomes?|
|No evidence||No studies||No studies||No studies||No studies||No studies||No study compared clinical outcomes associated with different risk- or prevalence-based strategies for targeted HCV screening.|
|What is the sensitivity and number needed to screen to identify 1 case of HCV infection of different risk- or prevalence-based methods for screening for HCV infection?|
|Overall strength of evidence: low||5 studies (4 cross-sectional, 1 case–control)
|Poor||High||Direct||High||Five studies found screening strategies that targeted multiple risk factors were associated with sensitivities of >90% and numbers needed to screen to identify 1 case of HCV infection of <20. More narrowly targeted screening strategies were associated with numbers needed to screen of <2, but with the tradeoff of missing up to two thirds of infected patients.|
|What are the harms associated with screening for HCV infection, including diagnostic liver biopsies?|
|Screening: overall strength of evidence: low
Liver biopsies: overall strength of evidence: moderate
|Screening: 5 (1 cross-sectional, 3 intervention series, and 1 controlled trial)
Liver biopsies: 6
Intervention series: 88,587
Liver biopsies: fair
|Screening: unable to assess (assessed different outcomes)
Liver biopsies: moderate
Liver biopsies: direct
Liver biopsies: moderate
|Screening: Five studies of patients with diagnosis of HCV infection suggested potential negative psychological and social effects, but results are difficult to interpret because of small sample sizes and methodologic shortcomings, including no unscreened comparison group.
Liver biopsies: One study (n = 2740) of patients with chronic HCV infection and compensated cirrhosis reported serious adverse events in 1.1%, including 0.6% serious bleeding episodes and 0.3% severe pain, with no deaths. Five large (n = 1398–61,184) intervention series of percutaneous liver biopsy for a variety of conditions reported periprocedural mortality in <0.2% and serious complications in 0.3%–1.0%.
Appendix Figure. Summary of evidence search and selection.
The study flow diagram summarizes the search and selection of articles addressing the following key questions: 1. Does screening for hepatitis C virus (HCV) infection in nonpregnant adults without known abnormal liver enzymes reduce mortality and morbidity due to HCV, affect quality of life, or reduce transmission of HCV? 2. What is the effectiveness of different risk- or prevalence-based methods for screening for HCV infection on clinical outcomes? 3. What is the sensitivity and number needed to screen to identify 1 case of HCV infection of different risk- or prevalence-based methods for screening for HCV infection? 4. What are the harms associated with screening for HCV infection, including diagnostic liver biopsies? Reproduced from reference.26
* Includes hand searches and gray literature searches.
† The total number of studies included in the full report, which addresses additional key questions, is 166.
Internet Citation: Final Evidence Review: Hepatitis C: Screening. U.S. Preventive Services Task Force. November 2012.