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Chou R, Clark E, Helfand M. Screening for Hepatitis C Virus Infection [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2004 Mar. (Systematic Evidence Reviews, No. 24.)

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Screening for Hepatitis C Virus Infection [Internet].

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1Introduction

In this systematic review, we focus on whether it is useful to test for anti-hepatitis C virus (anti-HCV) antibody (Ab) in asymptomatic adults who have no history of liver disease or known liver function test abnormalities. The review is intended for use by the US Preventive Services Task Force (USPTF), which will make recommendations regarding screening in the general adult population or high-risk subpopulations.

Published Guidelines

The USPTF has not previously made recommendations regarding HCV screening. Published guidelines from other major panels are presented in Table 1.

Table 1. Current HCV screening recommendations.

Table 1

Current HCV screening recommendations.

Burden of Suffering

HCV is a single-stranded, positive-sense RNA virus of the family Flaviviridae. After its characterization in 1989, studies identified HCV as the major cause of post-transfusion and community-acquired non-A, non-B hepatitis (NANBH).16 There are six HCV genotypes and more than 50 (as many as 90) subtypes.7 These genotypes can differ by up to 50% of their nucleotide sequences, and the virus has a high propensity to mutate. These characteristics may help explain some of the difficulties in developing effective vaccines and treatments.

HCV is the most common chronic bloodborne pathogen in the United States.8 In a large population-based study, 1.8% of a large household-based sample was positive for anti-HCV antibody (2.3% in adults 20 years or older), which would translate into an estimated 3.9 million infected persons in the U.S.9 Of these, 74% had viremia, indicating chronic infection (an estimated 2.7 million). Because sampling was based on households, some groups with a higher prevalence of infection (such as the homeless or incarcerated) were not included. Studies in other specific populations and settings have reported a higher prevalence of anti-HCV antibodies, with the highest rates consistently in intravenous drug users.1013

The incidence of HCV infection has fallen since the 1990s. The yearly incidence of HCV infection was estimated to average 230,000 cases per year in the 1980s, but by 2001 had declined to 25,000 cases per year.14 The reduction in incidence is a result of mostly unknown factors, though a decrease in incidence among injection drug users, which could be partially related to safer needle-using practices, may explain some of this change.8

A high proportion of infected adults are thought to be unaware of their status. No reliable data are available for the proportion of patients in the United States with HCV who know they are infected; estimates range from 5 to 50%.1517 In a French population-based study, 24% (17/72) were aware that they were seropositive for HCV infection.18

HCV infection is a leading cause of complications from chronic liver disease in the United States. Approximately 40% of cases of chronic liver disease are HCV-related, and HCV infection is associated with an estimated 8,000–10,000 deaths each year.8 HCV-related end-stage liver disease is now the most common indication for liver transplantation among American adults, accounting for over 30% of cases, and there was a 5-fold increase in the number of patients with HCV who underwent liver transplantation between 1990 and 2000.19, 20 Data from the Healthcare Cost and Utilization Project database indicated that in 1998, 140,000 discharges listed an HCV diagnosis, accounting for approximately 2% of all discharges in the database, and were associated with an estimated total hospital charge in excess of $1 billion, a substantial increase from only a few years earlier.20, 21 Although the incidence of HCV infection has declined, the morbidity, mortality, and costs associated with chronic HCV infection are expected to increase 2–4-fold in the next 2 decades because of the delay between acute infection and presentation with serious liver disease.2224

Despite the above data, there is uncertainty about the degree of excess mortality associated with chronic HCV infection. In a widely-publicized prospective cohort study of people who received transfusions, in 568 patients with acute NANBH (about 80% presumed to have HCV infection) there was no difference in 20-year overall mortality compared to controls (54% in patients with NANBH versus 57% in controls), even though there was an increase in cause-specific mortality from liver disease (3.3% vs. 1.1–2.0%, p=0.03).25, 26 Similar findings were reported when 222 patients from this study with confirmed HCV infection were followed for an additional 5 years (67% mortality [4.1% from liver disease] in patients with chronic HCV versus 65% [1.3% from liver disease] in controls).27 Because patients were older (average age 49) when enrolled in this study and had a high mortality rate (which could have been related to the condition for which they received the transfusion), the results may have been affected by confounding from co-morbid conditions. In two other longitudinal cohort studies that evaluated patients who acquired illness as younger adults, there was a non-significant trend towards worse survival in patients with anti-HCV antibodies. In one study, 11-year mortality in patients with HCV infection was 12.7% (117/924) versus 9% (43/475) (p=0.08) in matched controls.28 Risk factors for decreased survival in patients with HCV infection compared to patients without HCV infection were older age, male gender, and alcohol consumption. In the other study, mortality was 41% (7/17) after at least 45 years in seropositive patients versus 26% (2,226/8,551) in controls (relative risk [RR] 1.48; 95% confidence interval [CI], 0.8–2.6).29 On the other hand, most other longitudinal studies of patients who acquired infection as younger adults or children from transfusion of blood products have reported few deaths after around 20 years of infection; longer duration of follow-up in these populations may be necessary.3033

Chronic HCV infection can also cause morbidity in the absence of cirrhosis or other serious complications. HCV infection without cirrhosis is associated with significantly worse quality of life measures and symptoms (primarily fatigue) compared to the general population, though confounding factors such as intravenous drug use and other co-morbid conditions have not been well-controlled in studies.32, 34, 35 One study in women with a low prevalence of intravenous drug use, however, found high levels of psychological distress and impaired quality of life in women with anti-HCV antibodies that did not correlate to the presence or absence of chronic infection.36 In some adults with chronic HCV infection who are unaware of their status, the term “asymptomatic” may not be appropriate, as preliminary data suggest that some quality of life measures are lower than in age-matched controls.37

Definitions

This section summarizes terminology describing the tests used to identify patients with HCV infection, the results of these tests (Table 2), and the response to treatment. The Centers for Disease Control and Prevention has recently published detailed guidelines for laboratory testing and how to report results of anti-HCV and supplemental testing.38

Table 2. HCV screening test results and usual interpretation.

Table 2

HCV screening test results and usual interpretation.

Enzyme-linked immunoassay (ELISA) or enzyme immunoassay (EIA): ELISA (also referred to as EIA) detects antibodies against recombinant HCV antigens. “First generation” ELISA tests used a single antigen; later-generation tests added additional antigens.3941 Both second and third-generation tests are in standard use. Because of concerns about false-positive tests, particularly in low-prevalence populations (such as blood donors or asymptomatic adults), the CDC has recommended confirming positive ELISA results with a supplemental test (recombinant immunoblot assay or polymerase chain reaction), unless the signal-to-cut-off ratio is above a pre-determined threshold that has been shown to confirm positive >95% of the time.38

ELISA are the least expensive diagnostic test for HCV infection, with an average charge of about $60.00.42

Recombinant immunoblot assay (RIBA): RIBA is a supplemental test that also detects antibodies against HCV antigens. In these assays, multiple HCV antigens are individually displayed on a nitrocellulose strip as bands. Positive RIBA results have at least two reactive bands; indeterminate results have one reactive band. Because positive RIBA results require reactivity to more than one HCV antigen, they are considered more specific (but not more sensitive) than ELISA for past HCV infection, and are used to confirm positive ELISA results in low-prevalence populations.42 However, RIBA is not an independent gold standard for ELISA because the two tests use similar antigens to detect anti-HCV antibodies.

Currently available third-generation RIBA are thought to be more specific than earlier-generation tests because they produce fewer indeterminate results.43 The interpretation of indeterminate RIBA results remains uncertain.38, 44, 45 The relative proportion of RIBA-positive, indeterminate, and negative tests in ELISA-positive patients varies according to the population studied.

RIBA is typically 2–3 times more expensive than ELISA and usual charges are about $140.00.42

Reverse transcription polymerase chain reaction (RT-PCR or PCR): PCR is a laboratory method used to detect circulating HCV RNA in blood. PCR can be quantitative or qualitative, and under optimal conditions qualitative PCR can detect 100 international units (IU)/mL or less of circulating virus.42, 46 Because the absence of viremia in anti-HCV-antibody positive patients is associated with little or no risk for HCV infectivity47 or complications related to chronic HCV infection, sustained PCR-detected viremia has become the gold standard for chronic HCV infection.29, 33, 4850 In patients who are PCR-positive, the degree of viremia correlates poorly with degree of liver damage,5054 though it may help predict the likelihood of response to treatment.55

Strict quality control is necessary for PCR testing to be reliable. False negative test results can occur because some patients with active infection have intermittent viremia, and a small portion of patients with chronic HCV infection can become non-viremic, particularly with the development of liver cancer.56 57, 58 For this reason, repeat PCR resting is suggested in high-risk patients who are anti-HCV antibody-positive but negative on initial PCR. False-positive PCR tests may also occur due to contamination of samples (11% in one early quality control study) but appear to be much less frequent since standardization of assay techniques.57

PCR testing is associated with charges of about $130.00 for a qualitative test and $200.00 for a quantitative test.42

“False-positive” ELISA: Patients who are ELISA-positive but RIBA-negative or RIBA- and PCR-negative are usually considered “false-positives”; i.e., no evidence of past or current HCV infection. False positive ELISA results may occur in patients with autoimmune diseases and in neonates born to mothers with chronic HCV infection, who frequently pass on antibodies to their neonates but usually do not pass the virus.42, 46

“False-negative” ELISA: Patients who are ELISA-negative but PCR-positive are usually considered “false-negatives.” False-negatives are probably most common very early after infection (6–8 weeks for third-generation-ELISA to become positive versus 2–3 weeks for PCR) or in patients who have an impaired immune system.42

“Cleared” or “resolved” HCV infection: Patients who are ELISA- and RIBA-positive but PCR-negative on repeated testing are generally considered to have “cleared” or “resolved” HCV infection. This is usually not considered a “false-positive” finding because the positive RIBA test provides “specific” evidence of past exposure to HCV.59 Patients who are ELISA-positive, RIBA-indeterminate (or not performed), and PCR-negative may be either false-positives or have cleared their HCV infection. The proportion of positive tests that are false-positive is higher in low prevalence settings.60, 61

“Chronic” or “active” HCV infection: Patients who are persistently PCR-positive are said to have chronic HCV infection. Chronic infection may present with or without symptoms, abnormal transaminase levels, or abnormal biopsy findings. In this review, the term “asymptomatic chronic HCV infection” refers to patients who report no symptoms of HCV infection. Like symptomatic patients, asymptomatic patients may or may not have abnormal biopsies or transaminases.

Liver biopsy results: The Histologic Activity Index (HAI) is used to grade histologic findings. The Knodell score and the METAVIR scoring system are common methods used to report the HAI.62, 63 The Knodell score is a semiquantitative scoring system in which fibrosis and portal, periportal, and lobular necrotic and inflammatory components are assessed separately and their coding values added. Total maximum scores vary depending on exactly how the scores are totaled.64 The METAVIR system reports both the inflammatory and the fibrosis scores using separate standardized scores for activity and fibrosis.63

Early responders (ER): Patients with HCV infection who receive treatment and clear their viremia (become undetectable by PCR) or have a significant response (usually defined as a 2-log drop in HCV RNA level) in the first few months of treatment are referred to as early responders. People who are not early responders (usually measured at 12 weeks of therapy) have a low chance of successful treatment and may not benefit from further therapy.46 Normalization of transaminases (biochemical response) was reported in earlier trials of HCV treatment, but has been replaced by assessments of virologic status, which are thought to be more accurate predictors of successful treatment.

End of treatment responders (ETR): Patients with HCV infection who receive treatment, clear their viremia, and maintain this response until the end of treatment are referred to as end of treatment responders. Presence of HCV RNA at the end of treatment is highly predictive of relapse when therapy is stopped.46

Sustained responders (SR) or sustained virologic responders (SVR): Patients with HCV infection who receive treatment, clear their viremia, and maintain this response 6 to 12 months after the completion of treatment are referred to as sustained responders or sustained virologic responders (SVR).

Non-responders (NR): Patients with HCV infection who do not clear their viremia during treatment.

Relapsers: Patients with HCV infection who initially respond virologically to treatment but later suffer a recurrence of viremia.

Natural History

In this section, we review modes of acquisition of HCV, clinical presentations of chronic HCV infection, and risk factors associated with more rapid or frequent progression to cirrhosis and other long-term complications. We also review the literature regarding the natural history of chronic HCV, and when available we highlight data that appear more applicable to patients likely to be identified by screening.

HCV is acquired primarily by large or repeated percutaneous exposures to blood. In approximately 1/3 of patients, acute HCV infection causes symptomatic illness (primarily jaundice, nausea, right upper quadrant pain, or fatigue) after a mean incubation period of 7 weeks.65 In other patients, acute HCV infection is anicteric and not associated with symptoms or transaminase elevations. HCV viremia is detectable in the blood within 2 weeks of acute infection.65 In large population-based cross-sectional studies and good-quality cohort studies, 16%–45% of patients cleared acute HCV infection, as defined by sustained absence of HCV RNA in serum and normalization of transaminase levels.8, 9, 18, 32, 33, 66 Chronic HCV infection is thought to be present in the other 55–84% of patients.

The natural course of chronic HCV infection varies widely. A proportion of patients with chronic HCV infection have only mild liver disease even after decades of infection or never develop histologic evidence of liver disease.67 In other patients, inflammation and fibrosis of the liver may progress to cirrhosis, which can lead to end stage liver disease (ESLD) or hepatocellular carcinoma (HCC).8, 68, 69 Once cirrhosis develops, patients have a much higher risk of death, and some may benefit from liver transplantation.

The strongest predictors of a progressive course of chronic HCV infection appear to be older age at acquisition,51, 70 co-morbid medical conditions (such as heavy alcohol use,7076 HIV,77, 78 and other chronic liver disease79, 80), and duration of infection. The mode of acquisition, viral load, transaminase level, and viral genotype have not been established as consistent predictors of disease progression, though some cross-sectional and longitudinal studies8185 have found associations.

Race and gender may also have some effect on the natural history of chronic HCV infection, though data are preliminary. African Americans have generally been under-represented in studies on the natural history of HCV infection, despite a higher prevalence of infection. One recent cross-sectional study, however, found less advanced liver disease in African Americans with chronic HCV infection compared to non-African Americans, despite a longer estimated duration of infection.86 A systematic review of 57 studies on the natural history of HCV infection found that male gender was associated with more rapid disease progression.70

Estimating the proportion of patients in the general population with HCV infection who will progress to cirrhosis has been difficult because the time of acquisition is rarely recognized, particularly in asymptomatic patients, and a long duration (decades) is required to track patients to important endpoints.87 Factors affecting the rate of cirrhosis in a particular population include the prevalence of co-morbid conditions, the age at acquisition, the proportion receiving treatment, and whether the population was referred or community-based.70 Most data on the natural history of HCV infection has been in referral populations, but community-based cohort studies appear to be more representative of the general population.

A systematic review of studies of HCV natural history included 57 of 145 identified studies, and divided them into four broad categories: liver clinic series (number of studies=33), posttransfusion cohorts (n=5), blood donor series (n=10), and community-based cohorts (n=9).70 Estimates of the prevalence of cirrhosis after 20 years of chronic HCV were 22% (95% CI, 18–26%) for liver clinic series, 24% (11%–37%) for posttransfusion cohorts, 4% (1%–7%) for blood donor series, and 7% (4%–10%) for community-based cohorts. After accounting for age of acquisition, gender effects, and alcohol intake, estimates of cirrhosis were still substantially higher in liver clinic series, and were thought to be an effect of selection bias. The authors concluded that in the general population of patients who acquire HCV infection in young adulthood, less than 10% are estimated to develop cirrhosis within 20 years.

The systematic review included both cross-sectional and cohort community-based studies, and included studies that may not have accurately estimated the duration of infection. We reviewed in detail six retrospective cohort studies that identified HCV patients near the time they were first infected after a known exposure, and determined their outcome 10–45 years later (Table 3).28, 29, 32, 33, 66, 88 Three of these studies28, 29, 33 were not included in the systematic review. We excluded retrospective cohorts27, 89 in which patients were initially identified based on presentation with acute symptoms, in order to focus on more representative populations with both symptomatic and asymptomatic acute infection. We also did not review in detail two retrospective cohort studies of children who acquired HCV, since the natural history may be different in this population (cirrhosis 0% and 0.3% after 17–20 years).30, 31 Most of the included studies evaluated patients who acquired HCV infection via exposure to infected blood products;28, 29, 32, 33, 66 one screened acknowledged injection drug users for chronic HCV infection.88 In two studies,33, 66 about 10% of viremic patients received treatment for HCV infection; no patients were reported to have received treatment in the other studies. Two studies32, 33 evaluated Irish women infected by contaminated anti-D immune globulin in 1977 and 1978 but treated in different centers; histopathologic findings in these populations were reported in two other studies.90, 91 All of these studies were characterized by patients who contracted HCV infection while young and relatively healthy.

Table 3. Long-term outcomes of chronic HCV infection in community-based cohorts including asymptomatic patients.

Table 3

Long-term outcomes of chronic HCV infection in community-based cohorts including asymptomatic patients.

Cirrhosis was found in 0%33 to 10%28 of patients after at least 10 years of HCV infection (Table 3). Approximately 90% of patients had mild or moderate hepatitis, with fewer than 5% having higher grade histologic lesions without cirrhosis.32, 33, 66, 88, 90, 91 In the study of intravenous drug users (currently the most common mode of acquisition), 2.4% (40/1667) had evidence of ESLD after a median of 15 years of infection; 1% (2/210) without ESLD had cirrhosis on biopsy.88 One longitudinal study91 that performed sequential biopsies found little evidence for progression of disease 2 years after initial biopsy, and another33 reported that 22% (10/44) of patients had improvement in inflammation on sequential biopsies 4 years apart, suggesting that chronic HCV could remain undetected for at least several years.

The retrospective cohort studies described above included both symptomatic and asymptomatic patients with HCV. We identified no cohort studies specifically of asymptomatic patients, a subgroup of HCV patients likely to be identified only by screening. A recent community-based, cross-sectional Italian study found 116 anti-HCV positive (85 viremic) patients in a population of 4,820 screened; 5% (4/78) of viremic patients had cirrhosis (fibrosis score F4) on liver biopy and 38% (20/78) had more than minimal fibrosis (F2–F4).92 Other representative cross-sectional (i.e., uncertain duration of infection) studies of asymptomatic patients in the US and Europe reported prevalences of cirrhosis ranging from 0–9%.3, 49, 85, 9397

We did not identify studies evaluating whether patients with untreated asymptomatic chronic HCV infection progress to symptomatic illness over time. Symptoms that could be related to HCV infection (primarily fatigue and arthralgias) were reported in over 80% of viremic women in one community-based study,32 but another study in a similar population found symptoms reported more frequently in non-viremic rather than viremic patients.33 We also did not identify studies evaluating how long patients unaware of their HCV status would remain undetected without screening.

In summary, it appears that few (10% or less) patients who acquire chronic HCV as young adults will progress to cirrhosis after 10–20 years of follow-up. There are no cohort studies specifically of patients with asymptomatic HCV infection, but cross-sectional studies have also found low rates of cirrhosis. The majority of patients now acquire HCV infection via injection drug use, but most data on natural history are from patients who became infected from contaminated blood products. The most important predictors of progressive HCV infection appear to be older age at acquisition; longer duration of infection; and presence of co-morbid conditions such as alcohol use, HIV, or other liver disease.

Analytic Framework and Key Questions

The analytic framework in Figure 1 indicates the strategy we used to evaluate screening for HCV infection in adults without known or suspected liver disease or liver function test abnormalities. We defined universal screening to mean that everyone is tested, regardless of symptoms or risk factors; selective screening means that only those who meet specific criteria are tested. The key questions, which guided our literature review, were determined in conjunction with liaisons from the USPSTF.

Figure 1. Screening for Hepatitis C: Analytic framework and key questions.

Figure

Figure 1. Screening for Hepatitis C: Analytic framework and key questions.

The analytic framework shows the target populations, interventions, and intermediate and health outcome measures we examined. We narrowed the scope of the literature review after a preliminary search. We excluded children from the review because of the low prevalence of anti-HCV antibodies (0.2–0.4% in 6–19 years old)9 and the unclear safety and efficacy of treatment in this population.98 We also excluded pregnant women because of unclear safety of treatment and insufficient evidence regarding ability to lower vertical transmission rates (estimated at around 5% in mothers without HIV).99102 We excluded other specific populations such as post-transplant patients, HIV patients, and hemodialysis patients. In these patients, screening test characteristics and natural history of HCV infection may differ from what is observed in the general population.78, 103106 In addition, these populations have generally been excluded from large trials of treatment and data regarding clinical outcomes are lacking. Patients with occupational exposures were also excluded because of clear consensus regarding screening after percutaneous exposures.8

Our review evaluated the screening strategy in which a later-generation HCV ELISA is the initial test, with confirmatory RIBA. These are the screening tests that are currently in standard use for the diagnosis of current or resolved HCV infection.38 PCR testing, transaminase testing, and liver biopsy was considered the standard work-up to determine presence of chronic HCV infection and eligibility for treatment in patients who tested positive for anti-HCV antibodies.

For treatment of chronic HCV infection, we focused on evidence regarding efficacy and safety of pegylated interferon with ribavirin, the treatment regimen found in good-quality clinical trials and systematic reviews to have the highest efficacy. Because of the short duration that this treatment regimen has been available for evaluation, we also reviewed evidence regarding the effect of other interferon-based treatment regimens on long-term clinical outcomes. Ribavirin alone, amantadine, and corticosteroids were not included as they have not been found to be efficacious.8, 68, 69

For outcomes, we were particularly interested in reviewing any literature regarding the benefit of early antiviral treatment of chronic HCV in asymptomatic patients. Clinical outcomes that we evaluated were mortality, end-stage liver disease, cirrhosis, and hepatocellular cancer. Quality of life outcomes were also evaluated. Intermediate outcomes were loss of detectable viremia, improvement in histologic findings, and normalization of transaminase levels. We also reviewed adverse outcomes from screening and treatment including side effects from treatment, adverse events from liver biopsy, and effects of diagnosing chronic HCV infection on quality of life.

Other reasons for screening for HCV infection might be to prevent spread of the disease or to identify those who might benefit from hepatitis A or B vaccination, alcohol cessation counseling, or other interventions. We performed an additional literature search and review to identify potential benefits from screening from these types of interventions in patients with chronic HCV.

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