Screening for Hepatitis C Virus Infection Prepared for: Agency for Healthcare Research and Quality (AHRQ)

 Introduction to the epidemiology of and screening for hepatitis C virus (HCV) infection  Systematic review methods  The clinical questions addressed by the comparative effectiveness review  Results of studies and evidence-based conclusions about the benefits and adverse effects of screening for HCV infection  Updated recommendations from the U.S. Preventive Services Task Force and the Centers for Disease Control and Prevention for screening for HCV infection  What to discuss with patients and their caregivers Outline of Material Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 The hepatitis C virus (HCV) is the most common chronic blood-borne pathogen in the United States.  About 78 percent of individuals who test positive for anti-HCV antibody have detectable hepatitis C virus in their blood, indicating chronic infection.  The Centers for Disease Control and Prevention estimated that there were 16,000 new cases of acute HCV infection in the United States in  HCV infection was associated with an estimated 15,000 deaths in Background: Prevalence of Hepatitis C Virus Infection Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 The strongest risk factor for infection with the hepatitis C virus (HCV) is injection drug use.  Transfusions received before 1992 are also a risk factor for HCV infection.  Blood transfusions are no longer an important source of infection because of the implementation of effective screening programs for donated blood.  People born between 1945 and 1965 are at particular risk.  About 75 percent of patients with HCV infection were born between the years 1945 and 1965, with the highest prevalence (4.3%) in people 40 to 49 years of age in 1999 – Background: Risk Factors for Hepatitis C Virus Infection Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Infection with the hepatitis C virus (HCV) is a leading cause of complications from chronic liver disease including cirrhosis, hepatic failure, hepatocellular cancer, and death.  Although the incidence of HCV infection has been declining over the last two decades, the rates of cirrhosis, hepatic failure, and hepatocellular cancer are expected to rise in the next 10 to 20 years.  This rise is expected because of the long lag time between infection with HCV and the development of complications. Background: Clinical Consequences of Hepatitis C Virus Infection Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Screening for hepatitis C virus (HCV) infection in asymptomatic adults without a history of liver disease or liver enzyme abnormalities may identify infected patients early, before they develop serious liver damage.  Data from the Centers for Disease Control and Prevention suggest that out of every 100 people infected with HCV:  About 75 to 85 will develop chronic HCV infection  About 5 – 20 will develop cirrhosis over 20 – 30 years, with the rates increasing after 30 years  HCV antibody testing with subsequent polymerase chain reaction testing was found to be accurate for identifying patients with HCV infection. Background: Importance of Screening for Hepatitis C Virus Infection Centers for Disease Control and Prevention. Available at Accessed August 9, Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at U.S. Preventive Services Task Force. Ann Intern Med. 2004;140(6): PMID:

 The authors of this review aimed to evaluate the evidence regarding:  The effects of screening for hepatitis C virus (HCV) infection on clinical outcomes in asymptomatic adults  The relative effectiveness of various screening strategies for HCV infection  The potential harms of screening for HCV infection  The effects of counseling interventions on clinical and intermediate outcomes in patients with HCV infection  The effects of labor-and-delivery practices and breastfeeding on mother-to-child transmission of HCV infection  This review has also been used by the U.S. Preventive Services Task Force to update its recommendations on HCV screening. Background: Objectives of This Systematic Review Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others.  A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment.  The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients.  The Research Summaries and the full report, with references for included and excluded studies, are available at Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Key Question 1a. Does screening for hepatitis C virus (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?  Key Question 1b. Does screening for HCV infection during pregnancy reduce vertical transmission of HCV or improve mortality or morbidity for the mother or child? Clinical Questions Addressed by This Comparative Effectiveness Review (1 of 4) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

Clinical Questions Addressed by This Comparative Effectiveness Review (2 of 4)  Key Question 2a. What is the effectiveness of different risk-based or prevalence-based methods for screening for HCV infection in improving clinical outcomes?  Key Question 2b. What is the sensitivity and number needed to screen to identify one case of HCV infection of different risk-based or prevalence-based methods for screening for HCV infection?  Key Question 3. What are the harms associated with screening for HCV infection, including adverse effects such as anxiety, labeling, and impact on relationships? Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Key Question 4a. What are the comparative effectiveness and comparative diagnostic accuracy of various tests and strategies for the workup to guide treatment decisions in patients who test positive for HCV infection?  Key Question 4b. What proportion of patients with screen-detected HCV infection receives treatment?  Key Question 5. What are the harms associated with the workup for guiding treatment decisions? Clinical Questions Addressed by This Comparative Effectiveness Review (3 of 4) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Key Question 6a. How effective is counseling or immunization of patients with hepatitis C virus (HCV) infection at improving health outcomes or reducing the spread of HCV?  Key Question 6b. Does becoming aware of a positive serostatus for HCV infection decrease high-risk behaviors?  Key Question 6c. How effective is counseling or immunization of patients with HCV infection at improving intermediate outcomes, including change in high-risk behaviors?  Key Question 7. Do any interventions decrease or increase the risk of vertical transmission of HCV during delivery or in the perinatal period? Clinical Questions Addressed by This Comparative Effectiveness Review (4 of 4) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 The strength of evidence was classified into four broad categories: Rating the Strength of Evidence From the Comparative Effectiveness Review Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 There was no direct evidence of clinical benefits and limited evidence on harms associated with screening for hepatitis C virus infection, when compared with no screening or between different screening approaches, in nonpregnant and pregnant adults. Strength of Evidence: Insufficient Evidence for the Clinical Benefits and Harms of HCV Screening in Nonpregnant and Pregnant Asymptomatic Adults Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Targeted screening strategies based on multiple risk factors were associated with sensitivities of more than 90 percent and with numbers needed to screen to identify one case of hepatitis C virus infection of less than 20. Strength of Evidence: Low  The more narrowly targeted screening strategies were associated with numbers needed to screen of less than two but with the trade-off of missing up to two-thirds of infected patients. Strength of Evidence: Low Sensitivity of Different Strategies for Hepatitis C Virus Screening Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 Biopsy-related adverse effects appeared to be small, with a risk of death of less than 0.2 percent and a risk of serious complications (primarily bleeding and severe pain) of about 1 percent. Strength of Evidence: Moderate Evidence for the Clinical Benefits and Adverse Effects Associated With Detection of Hepatitis C Virus Infection Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 From 15 to 33 percent of patients with screen-detected chronic hepatitis C virus (HCV) infection received treatment; however, this varied according to the population assessed and the treatment eligibility criteria used. Strength of Evidence: Moderate  Treatment of HCV genotype 1 infection with triple and dual antiviral therapy regimens resulted in sustained virologic response (SVR) rates of 66 to 80 percent and 43 to 52 percent, respectively.* Strength of Evidence: Moderate  Evidence from cohort studies and meta-analyses suggested that achieving an SVR after antiviral therapy was associated with a lower risk of all-cause mortality, hepatocellular carcinoma, and cirrhosis when compared with not achieving an SVR. Strength of Evidence: Moderate Evidence for the Clinical Benefits and Adverse Effects Associated With Treatment of HCV Infection (1 of 2) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76. Available at *For information on the effectiveness of antiviral regimens in patients infected with HCV of other genotypes, please refer to the complementary review on treatment of HCV infection referenced below.

 Dual and triple antiviral therapy regimens for hepatitis C virus (HCV) infection have been shown to be associated with adverse effects such as fatigue, headache, flu-like symptoms, hematologic events, and rash. Strength of Evidence: Moderate Evidence for the Clinical Benefits and Adverse Effects Associated With Treatment of HCV Infection (2 of 2) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76. Available at

 Knowledge of hepatitis C virus (HCV) serostatus may reduce alcohol use in the short term, but the evidence indicates that any such behavior is not lasting. Strength of Evidence: Low  Evidence on the effects of counseling or immunizations for the hepatitis A and B viruses on health outcomes, reduction in the spread of HCV, or decrease in high-risk behaviors was limited. Strength of Evidence: Insufficient Impact of Awareness of HCV Serostatus and Counseling on Health Outcomes and Reduction in the Spread of HCV Infection or High-Risk Behaviors in HCV-Positive Patients Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 The risk of vertical transmission of hepatitis C virus (HCV) infection did not differ significantly between cesarean (elective or emergent) delivery and vaginal delivery. Strength of Evidence: Moderate  Prolonged labor (>6 hours based on one study) after membrane rupture was associated with increased risk of vertical transmission of HCV infection. Strength of Evidence: Low  No significant association was found between breastfeeding and risk of transmitting HCV infection. Strength of Evidence: Moderate Risk of Vertical Transmission of Hepatitis C Virus During Delivery or the Perinatal Period Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 New oral antiviral agents, some of which do not require interferon in the treatment regimen, are under development and have obtained fast-track status for review in the next few years by the U.S. Food and Drug Administration.  Preliminary studies suggest that these agents may be more tolerable than currently available therapies.  Clinical practice has evolved toward less routine use of biopsy. However, this comparative effectiveness review found no studies reporting the proportion of patients who undergo biopsy before treatment.  Noninvasive diagnostic tests are being developed for the diagnosis of fibrosis and cirrhosis and for guiding treatment decisions in HCV- positive patients (see the full report). Additional Information Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 The USPSTF recommends screening for hepatitis C virus (HCV) infection in adults at high risk, including those with any history of intravenous drug use or blood transfusions before  The USPSTF recommends that clinicians offer screening for HCV infection in adults born between 1945 and Grade B Recommendation* U.S. Preventive Services Task Force 2013 Recommendations for HCV Infection Screening U.S. Preventative Services Task Force. Available at Accessed June 26, * The USPSTF recommends this service. There is moderate certainty that the net benefit is moderate.

In addition to the 1998 guidelines for testing for chronic HCV infection, the Centers for Disease Control and Prevention published the following recommendation in August  People who should be tested once in their lifetime for hepatitis C virus (HCV) infection without ascertaining their risk factors include:  Adults born in the years 1945 through 1965 The Centers for Disease Control and Prevention 2012 Testing Recommendation for Chronic HCV Infection The Centers for Disease Control and Prevention. Available at Accessed August 9, 2013.

 No direct evidence comparing clinical outcomes in patients screened with those not screened was available.  However, several studies provided indirect evidence regarding the potential benefits of screening.  Screening tests (hepatitis C virus [HCV] antibody testing with subsequent polymerase chain reaction testing) can accurately identify adults with chronic HCV infection.  Targeted screening strategies resulted in numbers needed to screen to identify one case of HCV infection of less than 20; however, they missed a significant number of infected patients.  In HCV-positive patients, treatment with antiviral regimens resulted in sustained virologic response rates of 43 – 80 percent, which was associated with a reduction in hepatocellular carcinoma and mortality. Conclusions (1 of 2) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at Chou R, Hartung D, Rahman B, et al. AHRQ Comparative Effectiveness Review No. 76. Available at U.S. Preventive Services Task Force. Ann Intern Med. 2004;140(6): PMID:

 The evidence was insufficient to determine the effectiveness of counseling in patients who were positive for hepatitis C virus or the effectiveness of immunizations for the hepatitis A and B viruses on clinical outcomes.  Limited evidence suggests that for some patients, knowledge of hepatitis C status may be associated with reduction in high-risk behaviors such as alcohol use in the short term.  Additional research is needed to understand effective interventions for preventing vertical transmission. Conclusions (2 of 2) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 The patient’s risk status for hepatitis C virus (HCV) infection  That HCV infection is potentially curable  „„The U.S. Preventive Services Task Force recommendations about screening for HCV infection  The available diagnostic tests for HCV infection and their accuracy  The potential emotional and social impact of being screened for HCV infection What To Discuss With Your Patients and Their Caregivers (1 of 2) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at

 The potential benefits and harms of diagnostic tests for hepatitis C virus (HCV) infection  If the patient tests positive for HCV infection, the possibility that he/she might be referred to a liver specialist  For HCV-positive patients:  The available tests and workup strategies to guide treatment decisions and the accuracy of the various tests  The importance of monitoring for fibrosis, cirrhosis, and hepatocellular carcinoma  The impact of various interventions in preventing vertical transmission of HCV during delivery or in the perinatal period What To Discuss With Your Patients and Their Caregivers (2 of 2) Chou R, Barth Cottrell EB, Wasson N, et al. AHRQ Comparative Effectiveness Review No. 69. Available at