BRUCE R. BACON, MD, James F. King, M.D. Endowed Chair in Gastroenterology; Professor of Internal Medicine; and Director, Division of Gastroenterology
and Hepatology, St Louis University School of Medicine, St Louis, Mo.
EMMET B. KEEFFE, MD, Professor of Medicine, Stanford University School of Medicine; and Chief of Hepatology and Co-Director, Liver Transplant
Program, Stanford University Medical Center, Palo Alto, Calif.
VICTOR J. NAVARRO, MD, Clinical Associate Professor of Medicine, Jefferson Medical College; and Medical Director, Liver Transplant Program, Division
of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, Pa.
In the asymptomatic patient with hepatitis C, the only clue to disease may be fluctuating transaminitis. The immune response
triggered by the virus includes the activation of antibody-producing B lymphocytes and polymorphonuclear leukocytes. Early
and aggressive treatment can help prevent progression to end-stage liver disease. (ILLUSTRATION: KEVIN SOMERVILLE)
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Infection with hepatitis C virus (HCV) is the most common blood-borne infection in the United States and the leading cause
of death from liver disease.1-3 Although treatment has improved greatly over the past 5 years with the use of antiviral combination therapy (peginterferon
plus ribavirin), diagnosis remains elusive and inconsistent in the absence of HCV-specific blood screening.
Symptoms accompanying HCV infection are rare (reported in only 10%-20% of cases) and nonspecific (fatigue, abdominal pain,
nausea, or aching muscles or joints), and ALT levels remain normal in 30% to 40% of cases.1 Thus, chronic HCV infection, which accounts for up to 85% of those exposed to the virus, can only be reliably detected by
specific laboratory studies.1,2,4 Potentially fatal consequences of chronic HCV infection include progressive liver fibrosis leading to cirrhosis, end-stage
liver disease, and hepatocellular carcinoma.1
The primary care physician's only hope of intervening early enough in the course of HCV infection to delay or prevent serious
sequelae is to carefully elicit risk factors and screen accordingly. Otherwise, the diagnosis of HCV infection will continue
to be made either fortuitously, based on elevated ALT levels (present in 60%-70%), or inopportunely, once advanced liver disease
has developed and current medications are less effective or ineffective.2 Obtaining a history of high-risk behaviors associated with contracting HCV and other blood-borne pathogens as part of the
complete medical history and on new intake questionnaires is critical for timely diagnosis. Careful questioning has been shown
to elicit an HCV risk factor in 90% of cases.5
DETECTION While the diagnosis of HCV infection can only be made definitively with anti-HCV and/or HCV RNA screening, the recent recommendations
of the United States Preventive Services Task Force (USPSTF) cast doubt on whether such screening of high-risk patients improves
long-term health outcomes.6 The grade I recommendation published in November 2004 in Annals of Internal Medicine states that "the USPSTF found insufficient evidence to recommend for or against routine screening for HCV infection in adults
at high risk for infection."
The consultants for this article take issue with the USPSTF recommendation and strongly urge routine screening of all high-risk
patients. Their professional opinion is shared by representatives from the CDC, the National Institute of Diabetes and Digestive
and Kidney Diseases, the National Institutes of Health (NIH), the American Association for the Study of Liver Diseases (AASLD),
the Infectious Diseases Society of America, the Veterans Health Administration, and the Hepatitis Council of the American
Liver Foundation—all of whom jointly issued a compelling rebuttal to the conservative USPSTF grade (see "The HCV screening
controversy").7
Figure 1. Cases of HCV by selected risk factors, United States, 1982-2001
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Persons for whom screening is recommended HCV transmission occurs primarily through exposure to infected blood, with the most important risk factor being injection-drug
use (see Figure 1). Although some demographics are associated with a higher prevalence of infection (such as age 30-49), such
characteristics never justify screening in the absence of a risk factor.4 Wide agreement exists that a patient fitting any one of the criteria below is at high risk for contracting HCV infection
and should receive blood screening:1,2,8- Persons who have injected illicit drugs (even 1-time experimental users who do not consider themselves to be drug users).
- Persons with conditions associated with a high prevalence of HCV infection, including
- Persons with HIV infection. (Since HIV and HCV are characterized by similar modes of acquisition, an important interaction
occurs between them, making HCV more aggressive in the context of HIV coinfection.)8
- Persons with hemophilia who received clotting factor concentrates before 1987.2,8
- Persons who ever received hemodialysis.
- Persons with unexplained elevated ALT levels, defined as above the upper limits of normal and documented to be elevated for
at least 6 months.2 (Even minor ALT elevations can be clues to liver disease and thus warrant evaluation for HCV infection, in addition to screening
for both hepatitis A and B, assessment for metabolic syndrome, and inquiries about alcohol use. The 3 most common differential
diagnoses for mildly elevated ALT levels are chronic hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease.)
- Persons with subtle CBC abnormalities. (Thrombocytopenia and leukopenia may indicate advanced liver disease from HCV infection,
in particular.)
- Persons with extrahepatic manifestations of HCV infection, found in 5% to 20% of cases (cryoglobulinemia, membranoproliferative
glomerulonephritis, porphyria cutanea tarda).
- Persons with evidence of advanced liver disease (cirrhosis, enlarged spleen, jaundice, swelling of the abdomen or legs, internal
bleeding, spider angiomas).
- Prior recipients of transfusions or organ transplants, including
- Persons notified that they had received blood from a donor who later tested positive for HCV infection.
- Persons who received a transfusion of blood or blood products before July 1992.
- Persons who received an organ transplant before July 1992.
- Children born to HCV-infected mothers. (The child should be aged 1 year or older at the time of screening.)2,8
- Health care, emergency medical, and public safety workers after a needle stick injury or mucosal exposure to HCV-positive
blood.2,8
- Current sexual partners of HCV-infected persons. (Although the prevalence of infection is very low, a negative test result
provides reassurance to the individual.)1,8
Risk factors for which the screening need is uncertain Although the following risk factors are not widely regarded as definitive prompters of screening, some guidelines recommend
routine screening in their presence, and the consultants for this article contend that, at the very least, they warrant careful
consideration in the decision to screen for HCV, as well as for other health reasons.
Intranasal drug use The NIH recommends screening persons who share instruments for intranasal drug use, although the CDC considers the need
to screen uncertain.1,2 It is thought that intranasal drug use could result in the sharing of straws contaminated with blood from irritated nasal
membranes.
Multiple sex partners Again the NIH and CDC are at odds; the former recommends routine screening of persons with multiple sex partners, whereas
the latter deems the screening need to be uncertain. Case-control studies have shown an unexplained association between having
multiple sex partners and contracting HCV infection.2,9,10 Perhaps it is the sex itself (aggressive or unusual behavior leading to trauma), unacknowledged percutaneous factors, or
the presence of sexually transmitted diseases promoting HCV transmission by influencing viral load or modifying mucosal barriers.
Despite considerable inconsistencies among studies, HCV does seem to be spread inefficiently through sexual transmission in
the presence of high-risk sexual behavior.
Receipt of injection in the developing world Medical equipment in some developing countries may be inadequately sterilized.
Body piercings/tattoos Although some studies suggest that body piercings and tattoos act as modes of transmission for HCV, the AASLD guidelines
note that discrepancies in study design make it difficult to draw definitive conclusions or to recommend routine testing based
on these percutaneous exposures.8
Eliciting risk factors Although probing for risk factors in patient interviews and on new intake forms is crucial to detection of HCV infection,
patients will not necessarily be eager to admit to behavior that may have put them at risk. Sensitivity and careful probing
are required. When inquiring about injecting-drug use, you might ask, "Have you ever used illegal drugs—even once as an experiment?"
or "Have you ever been exposed to needles?" Whatever the style of questioning, it needs to facilitate open dialogue in sensitive
areas.
WORKUP Aside from making a physical assessment for evidence of hepatic dysfunction (cirrhosis, enlarged spleen, spider angiomas,
jaundice, edema, swelling of the abdomen, and encephalopathy), physicians should order laboratory tests for high-risk patients
to determine whether viral antibodies are present and, if so, whether the virus is active. Recommended screening thus begins
with an anti-HCV test; a positive result is confirmed by HCV RNA testing. The anti-HCV test and the confirmatory HCV RNA test,
in addition to a full hepatic panel, are the only tests necessary for primary care physicians to order if they plan to refer
patients who are diagnosed with HCV infection.
Currently, no test determines the time of origin of the HCV infection; however, this information is useful, because of the
insidious nature of the infection. A patient who contracted HCV infection 20 years ago is more likely to have advanced liver
disease than one who contracted it a few years ago. Cirrhosis develops in about 10% to 15% of HCV-infected patients over a
20- to 30-year period.1 The patient interview provides an opportunity to approximate the time of infection.
Anti-HCV: The gold-standard initial screenAn enzyme-linked immunosorbent assay (ELISA), also known as enzyme immunoassay (EIA), is the gold standard for initial HCV
screening. Both false-positive and false-negative results are rare, since the test is highly sensitive (97% or greater after
6 months) and highly specific (99% in immunocompetent patients) for HCV antibody.1 A negative anti-HCV assay necessitates no further testing—unless immunosuppression from HIV infection or chronic hemodialysis
is known or suspected. In such cases, the physician would proceed as if the anti-HCV test result were positive.8
A positive anti-HCV assay merely indicates past or present infection; it does not differentiate between acute, chronic, or
resolved infection. Even patients who have spontaneously recovered from exposure (15%-25% of acute cases) will continue to
retain the antibody.4 Therefore, the HCV RNA test should be ordered for all patients who test positive for the HCV antibody. If the infection is
no longer active, the HCV RNA test will be negative, ALT levels should be normal, and no further workup is necessary.
The only case in which the ELISA may not be considered for the initial screen is in that of a recently infected patient (such
as a health care worker who just incurred a needle stick with contaminated blood). The HCV antibody may require up to 8 weeks
to be detectible, whereas HCV RNA can be detected in just 1 to 2 weeks.11 Thus, when the exposure to HCV is recent, HCV RNA is the preferred screening test. The detection of HCV RNA in the blood
for at least 6 months demonstrates a chronic rather than acute infection.8
HCV RNA testing: Qualitative or quantitative?
As mentioned, a positive anti-HCV screen warrants HCV RNA testing with reverse transcriptase polymerase chain reaction (RT-PCR)
test. There are 2 types of HCV RNA screening tests to choose between—qualitative and quantitative—and both are FDA approved.
Qualitative tests are more sensitive, but quantitative tests provide more details about the virus—and the sensitivity of some
of the newer ones is approaching that of qualitative assays. The choice is dictated by whether the physician will ultimately
refer or treat patients with confirmed infection. With both types of assay, a positive result indicates the need for either
further testing or referral to a gastroenterologist or hepatologist.
Qualitative assays are sufficient for physicians who will refer. These "yes/no" tests are highly sensitive and clearly indicate whether or
not active virus is present by detecting the presence of circulating HCV RNA; they yield no further details on the characteristics
of the virus.
According to the CDC, 80% of patients with acute or chronic HCV infection will test positive for HCV RNA; the tests have improved
over the past few years, however, so this number may be even higher now.2 The AASLD guidelines state that a person with a positive anti-HCV test and a negative qualitative HCV RNA test has most likely
recovered.8 Other possible interpretations are that the test results are false-negative (20%) or, rarely, that the patient has intermittent
or low-level viremia.2 When either a false-negative or false-positive result is suspected, supplemental testing with the recombinant immunoblot
assay (RIBA) is suggested.8 It should be noted that confirmatory qualitative testing may be superfluous in patients with evidence of liver disease and
obvious risk factors for HCV infection.1
Quantitative assays are valuable for physicians who intend to treat, since they assess both viral activity and load. The size of the viral load
may predict the efficacy of therapy. For example, a patient with an HCV level of more than 1 million IU/mL of the virus is
less likely to respond to treatment than one with fewer. Because the quantitative test is less sensitive than the qualitative
assay, the latter can be done if a false-negative quantitative result is suspected. Finally, quantitative tests are useful
in determining efficacy of treatment, evaluated by sustained virologic response. For example, a 100-fold reduction in virus
level after 3 months of treatment indicates a good response and higher likelihood of ultimate eradication.
It is important to obtain the actual HCV RNA level from the laboratory rather than a report that the level exceeds an upper
limit of detection. To avoid confusion, treating physicians should also request that the laboratory use the same quantitative
assay each time the patient is tested—dynamic ranges differ among assays—and that they express values in international units.
RIBA: Limited utility The supplemental RIBA—once used routinely to confirm a positive anti-HCV test—is seldom used anymore. Because it tests for
antibodies to specific antigens of the virus, RIBA can be used for clarification when a patient tests positive for anti-HCV
and negative for HCV RNA.8 Except for this possible use, however, the test has little, if any, practical diagnostic value. A positive RIBA test result,
followed by 2 or more negative qualitative assays, suggests that HCV infection has resolved; no further testing is recommended.
A negative RIBA test result indicates that the anti-HCV positive result by ELISA was false-positive and signals the end of
testing.
Other tests Further testing may range from a simple hepatic function panel to liver biopsy. Here are the circumstances in which they should
be ordered.
Hepatic function panel When HCV antibody is present on initial screening, a hepatic function panel should be ordered. Indicators of potential hepatic
dysfunction or advanced disease associated with chronic HCV infection are elevated ALT, AST, and bilirubin levels, as well
as a low albumin level, prolonged prothrombin time, thrombocytopenia, and leukopenia. Normal liver tests, however, do not
preclude the presence of disease due to HCV, since the hepatic enzymes of HCV patients tend to fluctuate in and out of the
normal range. In fact, ALT levels remain normal in 30% to 40% of chronically infected patients.2,4
Ultrasound Some treating physicians opt for an ultrasound as a baseline test to assess the status of the liver, since it will show
hepatic contour abnormalities, abdominal fluid, and other changes suggesting cirrhosis. This is most critical when clues of
advanced liver disease are present. However, some specialists say that imaging with ultrasound or a CT scan should be reserved
for cancer screening following histologic diagnosis of cirrhosis or advanced fibrosis.
Testing for hepatitis A and B This should be part of baseline testing for HCV, along with vaccination if there is no prior exposure. Testing should be
done for anti-HAV total, anti-HBs, and anti-HBc total. If these test results are negative, the patient should receive hepatitis
A and B immunization.
Genotyping Since establishment of the HCV genotype helps predict response to therapy, it is valuable to the treating physician. Six
major genotypes with many more subtypes have been identified, and 2 genotype tests are available for clinical use: the Trugene
HCV 59NC Genotyping Kit and the line-probe assay Inno-LiPA HCV II.1,8 Genotyping need only be conducted once because genotype does not mutate during the disease course.
Genotype 1, which accounts for 70% to 75% of all HCV infection in this country, has a lower response to combination therapy
(sustained virologic response in only 42% to 52% compared with 76% to 88% for genotypes 2 and 3).1,8 Therefore, identification of genotype 1 HCV infection would prompt liver biopsy to determine whether histologic changes are
minimal enough to support treatment deferment until more effective and tolerable medications are approved. Although new treatments
are not expected for at least 5 years, the course of HCV is slow, and a patient without signs of advanced or impending liver
disease can likely wait without serious repercussions.
Liver biopsy Once a standard guide to HCV management and treatment, the liver biopsy is now being questioned by some as a necessary prelude
to treatment.8 Since newer treatments have led to better responses, it is argued that biopsy may be extraneous in some cases—particularly
in persons with HCV genotypes 2 and 3, which tend to respond well to treatment.
In genotype 1 treatment, however, liver biopsy continues to have a strong role in evaluating inflammation and fibrosis. It
remains the only method of precisely gauging the severity of HCV damage and showing the contributions of iron, steatosis,
and concurrent alcoholic liver disease on the progression of chronic HCV infection toward cirrhosis.1 Although the information that biopsy yields is valuable to the referring physician, the specialist will arrange this test,
if necessary.
COUNSELING AND FOLLOW-UP Patients positive for HCV infection should be educated about lifestyle modifications to prevent further liver damage, namely
avoidance of alcohol (see "What you need to know about hepatitis C"). Even moderate alcohol intake (10 g/d) is associated with enhanced disease progression.2 Milk thistle, while not hepatoprotective, is benign. If its use confers a placebo effect, the physician can safely support
it.
Patients should also be counseled on methods to reduce the risk of transmission and on the importance of treatment. Physicians
who will refer can inform patients that specialist consultation is needed to learn more about the prognosis, to determine
whether liver biopsy is needed, and to ascertain whether therapy is an option.
Reducing transmission risks Patients should be admonished not to share toothbrushes, razors, or any other personal care item that may contain particles
of blood, and to keep open wounds and sores covered at all times. Barrier contraception is recommended for those who are not
in a monogamous relationship and for those currently taking ribavirin (and for 6 months following discontinuation), since
the drug is teratogenic. Aside from possible birth control to avoid the teratogenic effects of ribavirin, monogamous couples
do not need to change their sexual practices. Contracting HCV through sexual intercourse in a monogamous relationship is rare
(estimated 2%-3% seroprevalence among partners).1,5 However, the partner has the right to be screened for reassurance if desired.
Follow-up of high-risk patients with negative test results Frequency of screening must be tailored to the individual. Patients who had discontinued high-risk behavior for at least 6
months prior to testing should be reassured that negative anti-HCV results are definitive and that repeat testing is unnecessary
unless high-risk behavior resumes. Anti-HCV-negative patients who are still actively engaged in high-risk behavior should
first receive attentive counseling to abort the behavior. Patients who continue to inject drugs should be cautioned to avoid
reusing or sharing syringes, needles, water, and cotton or other paraphernalia; to clean the injection site with a new alcohol
swab; and to dispose of syringes and needles safely.8 Guidelines for follow-up in such cases do not exist, but if the behavior continues, screening every 6 to 12 months is considered
reasonable. Again, intervening to stop the risky behavior is paramount.
Follow-up of referred patients The gastroenterologist or hepatologist should guide the HCV-positive patient through treatment, including managing side effects,
counseling, and checking treatment response. Side effects with the standard regimen of peginterferon plus ribavirin are common,
substantial, and difficult to manage. According to the CDC, "interferon dosage must be reduced in 10% to 40% of patients and
discontinued in 5% to 15% because of serious side effects."2 About 80% of patients experience flulike symptoms for the first few weeks of treatment; depression, bone marrow suppression,
and ribavirin-induced hemolytic anemia are common.
Although drug interactions are rare, primary care physicians should be wary of prescribing medications that may exacerbate
side effects. In addition, they should alert the specialist to patient characteristics that would preclude treatment with
peginterferon (serious depression, major cytopenias, hyperthyroidism, renal transplantation, and evidence of autoimmune disease
if sudden, severe anemia develops) and ribavirin (preexisting anemia, bone marrow suppression, or renal failure—and note that
ribavirin treatment is potentially life-threatening in the presence of ischemic heart disease or cerebrovascular disease).
Primary care examinations of the patient's overall health and well-being at 6- to 12-month intervals are reasonable, depending
on disease severity. ALT levels may be normal for up to 1 year in patients with histologically confirmed chronic hepatitis.
A single normal ALT reading thus cannot be used to exclude ongoing hepatic injury.
Key information to extract during follow-up care includes whether the patient was diagnosed with cirrhosis and is thus at
risk for hepatic decompensation or the development of hepatocellular carcinoma. In addition,
- Is the patient a candidate for pharmacologic therapy?
- Is the patient currently on a treatment plan?
- Has the patient been experiencing side effects or difficulty adhering to the plan?
Any significant change in health status should be reported to the specialist.
This consensus article was written by Stacy DiLoreto in consultation with Drs Bacon, Keeffe, and Navarro.
Dr Bacon discloses that he is a consultant to Schering-Plough and a clinical research investigator for Roche Pharmaceuticals.
Dr Keeffe discloses that he receives grant support and is on the advisory board and speakers' bureau for Roche, and that he
is on the speakers' bureau for Schering-Plough and InterMune.
Dr Navarro discloses that he receives grant support from Roche.
REFERENCES 1. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002—June 10-12,
2002. Hepatology. 2002;36;S3-S20.
2. Centers for Disease Control and Prevention (CDC) Division of Viral Hepatitis. Hepatitis C: what clinicians and other health
professionals need to know. Available at: http://www.cdc.gov/hepatitis. Accessed January 18, 2005.
3. Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;36:S30-S34.
4. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Recomm Rep. 1998;47:1-39. Available at: ftp://ftp.cdc.gov/pub/Publications/mmwr/rr/rr4719.pdf.
5. Alter MJ. Prevention of spread of hepatitis C. Hepatology. 2002;36: S93-S98.
6. US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: recommendation statement. Ann Intern Med. 2004;140: 462-464.
7. Alter MJ, Seeff LB, Bacon BR, et al. Testing for hepatitis C virus infection should be routine for persons at increased
risk for infection. Ann Intern Med. 2004;141:715-717.
8. Strader DB, Wright T, Thomas DL, et al. AASLD practice guideline: diagnosis, management, and treatment of hepatitis C.
Hepatology. 2004;39:1147-1171.
9. Puro V, Petrosillo N, Ippolito G, et al. Risk of hepatitis C seroconversion after occupational exposures in health care
workers. Italian Study Group on Occupational Risk of HIV and Other Bloodborne Infections. Am J Infect Control. 1995;23:273-277.
10. Terrault NA. Sexual activity as a risk factor for hepatitis C. Hepatology. 2002;36:S99-S105.
11. Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36:S21-S29.
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The HCV screening controversy The United States Preventive Services Task Force (USPSTF) recently issued a grade I recommendation regarding routine HCV screening
for asymptomatic patients.1 According to the statement, "The USPSTF found insufficient evidence to recommend for or against routine screening for HCV
infection in adults at high risk for infection." The USPSTF reserves a grade I recommendation for services for which efficacy
data are lacking, of poor quality, or conflicting, or for which the balance of benefits and harms is inscrutable. In the case
of HCV screening, studies of the long-term effects of newer treatments (peginterferon plus ribavirin), such as their ability
to prevent sequelae like cirrhosis and subsequent mortality, have yet to be completed. Furthermore, the organization contends
that potential harms of screening and treatment (labeling, adverse treatment effects, and unnecessary biopsies) versus the
alleged benefits need clarification.
Prominent figures in the major US infectious disease and liver organizations collectively decried the statement in a well-referenced
rebuttal calling for routine screening of all persons at increased risk for HCV infection.2 According to the rebuttal, the recommendation to screen high-risk asymptomatic patients—first presented by the CDC in 1998—remains
applicable.2,3
Supporters of routine screening acknowledge the lack of conclusive HCV mortality data, attributing it to the novelty of effective
pharmacologic treatment and the prolonged follow-up (more than 20-30 years) needed to acquire these data. However, they furnish
compelling evidence of a therapeutic effect:
- Virus eradication in 40% to 50% of patients with genotype 1 and 75% to 85% of those infected with genotypes 2 and 3
- Normalization of serum ALT levels
- Improved liver histology.
Defenders of the USPSTF recommendation say that the I grade is not a recommendation against screening but merely "a call for
additional research that would provide the appropriate evidence base for the USPSTF to make either a positive or negative
recommendation."4 The rebuttal authors question the sense of waiting for definitive data to prove mortality benefit, when strong indications
show the utility of screening and subsequent treatment.
1. US Preventive Services Task Force. Screening for hepatitis C virus infection in adults: recommendation statement. Ann Intern Med. 2004; 140:462-464.
2. Alter MJ, Seeff LB, Bacon BR, et al. Testing for hepatitis C virus infection should be routine for persons at increased
risk for infection. Ann Intern Med. 2004;141:715-717.
3. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR.
1998;47:1-33.
4. Calonge N, Randhawa G. The meaning of the US Preventive Services Task Force grade I recommendation: screening for hepatitis
C virus infection. Ann Intern Med. 2004;141:718-719.
