Management of Hepatitis C. 1997 March 24-26;15(3):1-41.
1. What is the Natural History of
2. What is the Most Appropriate
Approach To Diagnose and Monitor Patients?
3. What is the Most Effective
Therapy for Hepatitis C?
4. Which Patients With Hepatitis
C Should Be Treated?
5. What Recommendations Can
Be Made To Patients To Prevent Transmission of Hepatitis C?
6. What Are the Most Important
Areas for Future Research?
To provide health care providers, patients, and the general public with a
responsible assessment of current available methods to diagnose, treat, and
manage hepatitis C.
A non-Federal, nonadvocate, 12-member panel representing the fields of general
internal medicine, hepatology, gastroenterology, infectious diseases, medical
ethics, transfusion medicine, epidemiology, biostatistics, and the public.
In addition, 25 experts from these same fields presented data to the panel
and a conference audience of 1,600.
The literature was searched through Medline and an extensive bibliography
of references was provided to the panel and the conference audience. Experts
prepared abstracts with relevant citations from the literature. Scientific
evidence was given precedence over clinical anecdotal experience.
The panel, answering predefined questions, developed their conclusions based
on the scientific evidence presented in open forum and the scientific literature.
The panel composed a draft statement that was read in its entirety and circulated
to the experts and the audience for comment. Thereafter, the panel resolved
conflicting recommendations and released a revised statement at the end of
the conference. The panel finalized the revisions within a few weeks after
Hepatitis C is a common infection with variable course that can lead to chronic
hepatitis, cirrhosis, and hepatocellular carcinoma. The course of illness
may be adversely affected by various factors, especially alcohol consumption.
Therefore, more than one drink per day is strongly discouraged in patients
with hepatitis C, and abstinence from alcohol is recommended. Initial therapy
with interferon alfa (or equivalent) should be 3 million units three times
per week for 12 months. Patients not responding to therapy after 3 months
should not receive further treatment with interferon alone, but should be
considered for combination therapy of interferon and ribavirin or for enrollment
in investigational studies. Individuals infected with the hepatitis C virus
should not donate blood, organs, tissues, or semen. Safe sexual practices,
including the use of latex condoms, is strongly encouraged for individuals
with multiple sexual partners. Expansion of needle exchange programs should
be considered in an effort to reduce the rate of transmission of hepatitis
C among injection drug users.
The hepatitis C virus (HCV) is one of six viruses
(A, B, C, D, E, and G) that together account for the majority of cases of
viral hepatitis.According to the National Health and Nutrition Examination
Survey of 1988-94 and other population-based surveys, estimates of the incidence
and prevalence of HCV infection have been made. Nearly 4 million Americans
are infected with hepatitis C. The infection is more common in minority
populations (3.2 percent of African-Americans and 2.1 percent of
Mexican-Americans) than in non-Hispanic whites (1.5 percent). The incidence
of hepatitis C infection appears to be declining since its peak in 1989.
Currently, approximately 30,000 acute new infections are estimated to occur
each year, about 25-30 percent of which are diagnosed. Hepatitis C accounts
for 20 percent of all cases of acute hepatitis. Currently, hepatitis C is
responsible for an estimated 8,000-10,000 deaths annually, and without effective
intervention that number is postulated to triple in the next 10-20 years.
Hepatitis C is now the leading reason for liver transplantation in the United
The switch from commercial to volunteer blood donors and the development
of a diagnostic blood test for hepatitis B in the early 1970s led to screening
of blood donors and reduced from 30 to 10 percent the incidence of hepatitis
following multiple transfusions. The remainder of these transfusion-associated
cases were termed "non-A, non-B" hepatitis. In 1989, Michael Houghton and
his colleagues ushered in a new era for the discovery of infectious agents
when they used molecular biologic techniques to clone hepatitis C, the agent
responsible for 80-90 percent of non-A, non-B hepatitis. This was a scientific
tour de force because the technique was successful in identifying an agent
that had not been visualized, grown in culture, or immunologically defined.
Following the introduction of sensitive and effective blood tests for the
detection of hepatitis C, the risk of transfusion-related hepatitis is now
in the range of 1 in 100,000 units transfused.
Hepatitis C is transmitted primarily by the parenteral route, and sources
of infection include injection drug use, needle-stick accidents, and transfusions
of blood or blood products. Since 1990 and the introduction of tests for
anti-HCV, new cases of posttransfusion hepatitis C have virtually disappeared.
Hepatitis C virus is not easily cleared by the host's immunologic defenses.
Thus, a persistent infection develops in perhaps as many as 85 percent of
patients with acute hepatitis C. This inability to clear the virus by the
infected host sets the stage for the development of chronic liver disease.
The range of disease states following hepatitis C infection is broad. Lastly,
in contrast to hepatitis A and B, there is no effective vaccine to prevent
acquisition of hepatitis C infection.
For the reasons listed above, the National Institute of Diabetes and Digestive
and Kidney Diseases and the Office of Medical Applications of Research of
the National Institutes of Health, along with cosponsors the National Institute
of Allergy and Infectious Diseases, National Heart, Lung, and Blood Institute,
National Institute on Drug Abuse, and Centers for Disease Control and Prevention,
sponsored a Consensus Development Conference on March 24-26, 1997. Following
1-1/2 days of testimony by experts in the relevant fields and discussion
from the audience, a consensus panel representing general internal medicine,
hepatology, gastroenterology, infectious diseases, medical ethics, transfusion
medicine, epidemiology, biostatistics, and the public considered the evidence
and formulated a consensus statement to address the following six predefined
What is the natural history of hepatitis C?
What is the most appropriate approach to diagnose and monitor patients?
What is the most effective therapy for hepatitis C?
Which patients with hepatitis C should be treated?
What recommendations to patients can be made to prevent transmission of hepatitis
What are the most important areas for future research?
The hepatitis C virus is an RNA virus of the Flaviviridae family. Individual
isolates consist of closely related yet heterogeneous populations of viral
genomes (quasispecies). Probably as a consequence of this genetic diversity,
HCV has the ability to escape the host's immune surveillance, leading to
a high rate of chronic infection. Comparing the genomic nucleotide sequences
from different HCV isolates enables classification of viruses into several
genotypes and many more subtypes. The extensive genetic heterogeneity of
HCV has important diagnostic and clinical implications, perhaps explaining
variations in clinical course, difficulties in vaccine development, and lack
of response to therapy.
Data on the natural history of hepatitis C are limited, because the onset
of infection is often unrecognized and the early course of the disease is
indolent and protracted in many individuals. Prospective cohort studies are
few, are typically small, include relatively few subjects whose date of infection
can be well documented (e.g., blood transfusion recipients and victims of
accidental needle sticks), and have relatively short followup. The natural
history of this disease appears to differ according to geography, alcohol
use, virus characteristics (e.g., genotype, viral load), coinfection with
other viruses, and other unexplained factors.
After initial exposure, HCV RNA can be detected
in blood in 1-3 weeks.Within an average of 50 days (range: 15-150 days),
virtually all patients develop liver cell injury, as shown by elevation of
serum alanine aminotransferase (ALT). The majority of patients are asymptomatic
and anicteric. Only 25-35 percent develop malaise, weakness, or anorexia,
and some become icteric. Fulminant liver failure following HCV infection
has been reported but is a rare occurrence. Antibodies to HCV (anti-HCV)
almost invariably become detectable during the course of illness. Anti-HCV
can be detected in 50-70 percent of patients at the onset of symptoms and
in approximately 90 percent of patients 3 months after onset of infection.
HCV infection is self-limited in only 15 percent of cases. Recovery is
characterized by disappearance of HCV RNA from blood and return of liver
enzymes to normal.
About 85 percent of HCV-infected individuals fail to clear the virus by 6
months and develop chronic hepatitis with persistent, although sometimes
intermittent, viremia. This capacity to produce chronic hepatitis is one
of the most striking features of HCV infection. The majority of patients
with chronic infection have abnormalities in ALT levels that can fluctuate
widely. About one-third of patients have persistently normal serum ALT levels.
Antibodies to HCV or circulating viral RNA can be demonstrated in virtually
Chronic hepatitis C is typically an insidious process, progressing, if at
all, at a slow rate without symptoms or physical signs in the majority of
patients during the first two decades after infection. A small proportion
of patients with chronic hepatitis C -- perhaps less than 20 percent -- develop
nonspecific symptoms, including mild intermittent fatigue and malaise. Symptoms
first appear in many patients with chronic hepatitis C at the time of development
of advanced liver disease.
In chronic hepatitis, inflammatory cells infiltrate the portal tracts and
may also collect in small clusters in the parenchyma. The latter instance
is usually accompanied by focal liver cell necrosis. The margin of the parenchyma
and portal tracts may become inflamed, with liver cell necrosis at this site
(interface hepatitis). If and when the disease progresses, the inflammation
and liver cell death may lead to fibrosis. Mild fibrosis is confined to the
portal tracts and immediately adjacent parenchyma. More severe fibrosis leads
to bridging between portal tracts and between portal tracts and hepatic veins.
Such fibrosis can progress to cirrhosis, defined as a state of diffuse fibrosis
in which fibrous septae separate clusters of liver cells into nodules. The
extent of fibrosis determines the stage of disease and can be reliably assessed.
Severe fibrosis and necroinflammatory changes predict progression to cirrhosis.
Once cirrhosis is established, complications can ensue that are secondary
to liver failure and/or to portal hypertension, such as jaundice, ascites,
variceal hemorrhage, and encephalopathy. The development of any of these
complications marks the transition from a compensated to a decompensated
The rate of progression is highly variable. Long-term studies suggest that
most patients with progressive liver disease who develop cirrhosis have
detectable ALT elevations; these can, however, be intermittent. The relationship
is inconsistent between ALT levels and disease severity as judged histologically.
Although patients with HCV infection and normal ALT levels have been referred
to as "healthy" HCV carriers, liver biopsies can show histological evidence
of chronic hepatitis in many of these patients.
Chronic hepatitis C infection leads to cirrhosis in at least 20 percent of
patients within 2 decades of the onset of infection. Cirrhosis and end-stage
liver disease may occasionally develop rapidly, especially among patients
with concomitant alcohol use.
Chronic infection by HCV is associated with an increased risk of liver cancer.
The prevailing concept is that hepatocellular carcinoma (HCC) occurs against
a background of inflammation and regeneration associated with chronic hepatitis
over the course of approximately 3 or more decades. Most cases of HCV-related
HCC occur in the presence of cirrhosis.
The risk that a person with chronic hepatitis C will develop HCC appears
to be 1-5 percent after 20 years, with striking variations in rates in different
geographic areas of the world. Once cirrhosis is established, the rate of
development of HCC increases to 1-4 percent per year. Among patients with
cirrhosis due to hepatitis C, HCC develops more commonly in men than in women
and in older than in younger patients.
Patients with chronic hepatitis C occasionally present
with extrahepatic manifestations or syndromes considered to be of immunologic
origin, including arthritis, keratoconjunctivitis sicca, lichen planus,
glomerulonephritis, and essential mixed cryoglobulinemia. Cryoglobulins
may be detected in the serum of about one-third of patients with HCV, but
the clinical features of essential mixed cryoglobulinemia develop in only
about 1-2 percent of patients. Chronic hepatitis C may be a major underlying
cause of porphyria cutanea tarda.
After an average followup of 18 years, a prospective study of patients who
received blood transfusions showed no difference in overall mortality between
HCV-infected cases and noninfected controls. Liver-related mortality, although
rare, was twice as high in the cases (3.2 percent vs. 1.5 percent). A recent
European study showed that survival among hepatitis C patients with compensated
cirrhosis was 91 percent after 5 years and 79 percent after 10 years. Among
patients developing decompensated cirrhosis, however, 5-year survival was
only 50 percent.
A variety of tests are available for hepatitis C diagnosis. Tests that detect
antibody against the virus include the enzyme immunoassays (EIAs), which
contain HCV antigens from the core and nonstructural genes, and the recombinant
immunoblot assays (RIBAs), which contain the same HCV antigens as EIA in
an immunoblot format. In addition, several polymerase chain reaction (PCR)-based
assays for HCV RNA have been developed to detect the RNA virus directly.
Liver biopsy can determine the extent of liver injury due to HCV. Although
some histologic findings are characteristic of HCV infection, such as portal
lymphoid aggregates, steatosis, and bile duct injury, these alone are not
sufficiently specific to establish a diagnosis of hepatitis C. There are
currently no reliable, readily available tests for detection of HCV antigens
in the liver.
The EIA tests are reproducible and inexpensive and have been automated. They
are suitable for screening low- and high-prevalence populations and as an
initial test for patients with clinical liver disease. The RIBA test is most
frequently used as a supplemental assay. Qualitative HCV RNA detection by
reverse transcription (RT)-PCR is generally accepted as the most sensitive
test, and a standardized assay has been developed. However, significant
variability of results among laboratories has been reported in proficiency
surveys. Clinicians should be aware of the proficiency record of laboratories
performing HCV RNA testing to ensure test accuracy for their patients.
Using carefully standardized research PCR tests for HCV RNA as a reference
standard, the sensitivity of the second-generation enzyme immunoassay, EIA-2,
is 92-95 percent. Its specificity has not been precisely established. Studies
performed to date indicate that 25-60 percent of blood donors with no risk
factors for hepatitis C who are positive by the EIA-2 test are also positive
by the PCR test for HCV RNA. Of low-risk donors who are both EIA-2 and
RIBA-positive, 70-75 percent are positive for HCV RNA. Positive predictive
values are much higher in patients with hepatitis C risk factors, elevated
ALT levels, or clinical liver disease.
Practitioners frequently encounter patients suspected
of having HCV infection.In low-risk populations, such as blood donors
who report no risk factors for HCV (e.g., parenteral drug use, history of
transfusion, multiple sexual partners), a negative EIA test is sufficient
to rule out infection. However, low-risk individuals with positive EIA tests
should undergo supplementary RIBA testing. If the RIBA is negative, the anti-HCV
EIA result is likely to have been a false positive, and the patient is unlikely
to have hepatitis C. If the RIBA is positive, the patient can be assumed
to have or to have had hepatitis C. These patients can benefit by testing
for HCV RNA by PCR, the result of which will indicate whether the patient
has ongoing viremia or not. A single positive assay for HCV RNA by PCR confirms
HCV infection; unfortunately, a single negative assay does not prove that
the patient is not viremic or has recovered from hepatitis C. Followup testing
for ALT levels and perhaps repeating the HCV RNA in the future may be needed.
If the results of the RIBA are "indeterminate," followup testing is indicated
to demonstrate whether HCV RNA is present. It is hoped that further advances
in anti-HCV testing will eventually decrease the percentage of false-positive
EIA and indeterminate RIBA results.
Individuals with even mildly elevated ALT levels, with or without risk factors
for hepatitis C, should be tested for anti-HCV by EIA and, if positive, the
results confirmed by either supplemental RIBA or qualitative HCV RNA by PCR.
Obviously anti-HCV testing is very helpful in all patients with clinical
In patients presenting with biochemical or clinical evidence of liver disease
(e.g., repeatedly elevated ALT levels), a positive EIA test is sufficient
to diagnose hepatitis C infection, especially if risk factors are present.
A qualitative HCV RNA test can be used for confirmation. If the patient is
being considered for antiviral therapy, liver biopsy is of value to assess
Testing for serum ALT levels is the most inexpensive and noninvasive means
of assessing disease activity. However, a single determination of ALT levels
is not always accurate in reflecting the severity of the underlying liver
disease. In most studies, there is only a weak association between ALT levels
and severity of the histopathological findings on liver biopsy. Serial
determinations of ALT levels over time may provide a better means of assessing
liver injury, but the accuracy of this approach has not really been shown.
Nevertheless, the resolution of elevated ALT levels with antiviral therapy
does appear to be an important indicator of disease response, and serial
determinations of ALT levels can be recommended as the general means of
monitoring patients with this disease.
Testing for HCV RNA by PCR can be very helpful in initial diagnosis, but
repeat testing over time is generally not helpful in management of untreated
patients; almost all remain viremic, and a negative result may merely reflect
a transient fall of viral titer below the level of detection rather than
permanent clearance. On the other hand, repeat testing for HCV RNA during
antiviral therapy can be helpful, because loss of HCV RNA with treatment
is a strong predictor of a sustained beneficial response.
Testing for HCV RNA level (or viral load) by a quantitative assay, either
quantitative PCR (qPCR) or the branched DNA signal amplification assay (bDNA),
can provide accurate information on viral titer. In many studies, the likelihood
of a response to interferon alfa has correlated with a low level of HCV RNA
present before treatment. However, there is no level of HCV RNA that absolutely
precludes the possibility of a response and there is little or no correlation
between disease severity or disease progression and level or titer of HCV
RNA. Furthermore, current assays are not as sensitive as the standard,
qualitative PCR test and suffer from lack of standardization. Thus, sequential
testing for HCV RNA levels is not clinically helpful in management of patients.
At least 6 genotypes and more than 30 subtypes of HCV RNA have been identified.
HCV genotype may be an independent predictor of response to interferon alfa
therapy. In many studies, patients with genotypes 2 and 3 are more likely
to have a sustained treatment response than those with genotypes 1a or 1b.
Methods of genotyping include PCR-based techniques and, more recently, less
expensive serotyping (antibody) assays. However, both genotyping and serotyping
should be considered research tools and not part of a diagnostic or therapeutic
algorithm in clinical practice.
Liver biopsy is considered the gold standard for
assessment of patients with chronic hepatitis.When combined with serial
determinations of ALT levels, liver biopsy is very helpful in judging the
severity or activity of the liver disease and the stage or degree of fibrosis.
Liver biopsy is recommended before treatment to assess the grade and stage
of disease and to exclude other forms of liver disease or complications (such
as concurrent alcoholic liver disease, medication-induced liver injury, and
iron overload). However, liver biopsy is expensive and is associated with
some morbidity. Therefore, serial ALT and qualitative HCV RNA testing are
recommended for monitoring patients under treatment.
Although several different forms of interferon have been evaluated in the
treatment of patients with chronic hepatitis C, the bulk of available evidence
pertains to the alpha interferons (interferon alfa). The efficacy of interferon
alfa therapy currently is defined biochemically as normalization of serum
ALT and virologically as loss of serum HCV RNA. Serum ALT and HCV RNA are
measured at two time points: at the end of treatment (End-of-Treatment Response
[ETR]) and 6 months posttreatment (Sustained Response [SR]). Based on these
markers, randomized clinical trials have demonstrated that treatment with
interferon alfa benefits some patients with chronic hepatitis C. In terms
of biochemical response, treatment with interferon alfa at a dosage of 3
million units administered subcutaneously three times weekly for 6 months
has produced a biochemical ETR of 40-50 percent and a biochemical SR of 15-20
percent. In terms of virological response, the 6-month course of treatment
has produced an ETR of 30-40 percent and an SR of 10-20 percent. The biochemical
and virological improvement has been accompanied by histological improvement.
Increasing the duration of treatment to 12 months is not associated with
higher biochemical or virological ETR, but the biochemical SR is increased
to 20-30 percent. For patients who do not achieve a biochemical or virological
ETR (nonresponders), retreatment with a standard dose of interferon alfa
is rarely effective. Further therapy with newer interferons and/or higher
dosages may achieve a virological SR of only 10 percent. For patients who
achieve a biochemical ETR with 6 months of treatment, but who relapse during
followup, retreatment for 12 months has been associated with a biochemical
ETR rate of 75-85 percent and an SR rate of 30-40 percent. The benefit of
treatment of longer duration is still being evaluated. It should be recognized
that although interferon treatment may be associated with favorable effects
on biochemical and virological markers, its effects on important clinical
outcomes such as quality of life and disease progression remain undetermined.
Three months after beginning an initial course of
therapy, patients who are unlikely to respond to that dosage and frequency
can be identified by persistent elevation of serum ALT levels and presence
of HCV RNA in the serum.In this situation, therapy should be discontinued
because the likelihood of future response is extremely low. If either HCV
RNA is negative or ALT levels are normal (or both), therapy should be continued
for 12 months. Nonresponders should be encouraged to participate in clinical
trials directed toward this difficult-to-treat group.
Most of the clinical trials in chronic hepatitis C have evaluated interferon
alfa-2b. Other trials have used interferon alfa-2a, interferon alfa-n1, consensus
interferon, interferon beta, and interferon alfa-n3. All forms of interferon
appear to have similar efficacy in chronic hepatitis C.
Because most patients do not experience sustained response, attempts have
been made to identify individuals who are more likely to respond to therapy.
The important factors associated with a favorable response to treatment include
HCV genotype 2 or 3, low serum HCV RNA level (less than 1,000,000 copies/ml),
and absence of cirrhosis.
Flulike symptoms (fever, chills, malaise, headache, arthralgia, myalgia,
tachycardia) occur early in the majority of patients who receive interferon,
but generally diminish with continued therapy. Later side effects include
fatigue, alopecia, bone marrow suppression, and neuropsychiatric effects
such as apathy, cognitive changes, irritability, and depression. Relapse
of drug and/or alcohol abuse may occur. Nocturnal administration of interferon
reduces the frequency of side effects, and the flulike syndrome is ameliorated
by pretreatment with acetaminophen. A reduction in interferon dosage is required
in 10-40 percent of patients because of side effects, and treatment must
be discontinued in 5-10 percent. Higher dosages tend to be associated with
higher rates of side effects.
Severe side effects are observed in less than 2 percent of patients. These
include autoimmune disease (thyroid disease being most common), depression
with suicidal risk, seizure disorder, acute cardiac and renal failure,
retinopathy, interstitial pulmonary fibrosis, hearing impairment, and sepsis.
Rare deaths have occurred due to liver failure or sepsis, principally in
patients with cirrhosis.
An important side effect of interferon in hepatitis C is a paradoxical worsening
of liver disease with therapy. This exacerbation of hepatitis is probably
an autoimmune reaction, and it can be severe. Indeed, fatal occurrences have
been reported. Thus, patients with hepatitis C whose serum ALT levels increase
on therapy should be followed more carefully, and if levels rise to greater
than twice the baseline, interferon should be promptly discontinued.
It is appropriate that a percutaneous liver
biopsy be obtained before initiating therapy with interferon in order to
assess the degree of necroinflammatory activity, the extent of fibrosis,
and the presence of any other cause of liver injury.Laboratory tests
that should be obtained before starting therapy include liver chemistries
(serum ALT, bilirubin, albumin, prothrombin time), complete blood count (CBC)
with differential and platelet count, antinuclear antibodies, thyroid stimulating
hormone, serum HCV RNA, and glucose. Monitoring during therapy should be
done at 2- to 4-week intervals with serum ALT and CBC. Both serum ALT and
serum HCV RNA testing should be done after 3 months to assess whether the
patient is responding to therapy. This should be repeated at the end of therapy
to document end-of-treatment response. Followup testing, with serum ALT and
serum HCV RNA, should be done 6 months after therapy is stopped to determine
whether there has been a sustained response. Followup liver biopsy is not
Disappointing results with interferon have prompted interest in new treatment
approaches to chronic hepatitis C. Early work with corticosteroids, ursodiol,
and thymosin has produced scant or no evidence of sustained benefit. High
concentrations of iron in liver tissue may blunt the response to interferon.
This has sparked interest in iron reduction therapy, through phlebotomy or
chelation, in an attempt to enhance the response to interferon. Thus far,
studies of iron reduction have been inconclusive.
The adjunctive drug of most promise, at present, is ribavirin, an oral antiviral
agent that, when used alone, reduces serum ALT levels in approximately 50
percent of patients. However, ribavirin by itself does not lower serum HCV
RNA levels, and relapses occur in virtually all patients when therapy is
stopped. Of greater promise are recent reports that the combination of interferon
alfa and ribavirin leads to higher sustained virological response rates (40-50
percent) than interferon alfa alone in 6-month clinical trials. Ribavirin
has not been licensed or approved for use in hepatitis C by the Food and
Drug Administration. Large-scale trials of the combination in hepatitis C
are now under way. Combination therapy with ribavirin and interferon has
also shown promise in the retreatment of those who relapse. Hemolytic anemia
has been the major side effect of ribavirin, necessitating a dosage reduction
in more than 10 percent of patients.
All patients with chronic hepatitis C are potential candidates for specific
therapy. However, given the current status of therapies for hepatitis C,
treatment is clearly recommended only in a selected group of patients. In
others, treatment decisions are less clear and should be made on an individual
basis or in the context of clinical trials.
Treatment is recommended for the group of patients with chronic hepatitis
C who are at the greatest risk for progression to cirrhosis. These patients
are characterized by persistently elevated ALT, positive HCV RNA, and a liver
biopsy with either portal or bridging fibrosis and at least moderate degrees
of inflammation and necrosis.
Indication for therapy is less obvious in other groups of patients. One such
group consists of patients with persistent ALT elevations, but with less
severe histological changes -- that is, no fibrosis and minimal necroinflammatory
changes. In these patients, progression to cirrhosis is likely to be slow,
if at all; therefore, observation and serial measurements of ALT and liver
biopsy every 3-5 years is an acceptable alternative to treatment with interferon.
Another such group consists of patients with compensated cirrhosis (without
jaundice, ascites, variceal hemorrhage, or encephalopathy), in whom current
data do not definitively show that interferon therapy will prolong survival
or delay development of hepatocellular carcinoma. Similarly, firm recommendations
on treatment with interferon cannot be made for patients below age 18 or
over age 60 because of incomplete data. In all these groups of patients,
treatment decisions should be made jointly between patient and physician,
after full discussion of risks and benefits. However, where possible, treatment
in these instances should be undertaken in the context of clinical trials,
so that data become available for future decisionmaking.
Patients with decompensated cirrhosis should not be treated with currently
available therapy for hepatitis C and should be considered for liver
transplantation. Therapeutic trials for hepatitis C in these patients should
be performed only in the setting of clinical trials carried out in collaboration
with liver transplant centers.
Data suggest a benefit from interferon treatment with higher clearance of
HCV RNA in patients with acute hepatitis C. In light of these findings,
interferon treatment of patients with acute hepatitis C could be recommended.
Current studies suggest that treatment of patients with persistently normal
ALT is not beneficial and may actually induce liver enzyme abnormalities.
Therefore, these patients should not receive therapy outside of
placebo-controlled clinical trials.
Nonspecific symptoms such as fatigue are difficult to interpret and should
not influence treatment decisions. However, patients with clinical evidence
of essential mixed cryoglobulinemia could benefit from long-term therapy
Because severity of disease or progression to cirrhosis has not been conclusively
related to the mode of acquisition of hepatitis C or to particular risk groups,
therapy should not be denied on the basis of these factors. However, treatment
of patients who are drinking significant amounts of alcohol or who are actively
using illicit drugs should be delayed until these habits are discontinued
for at least 6 months. Such patients are at risk for the potential toxic
effects of alcohol and other drugs and also present problems with compliance.
Treatment for addiction should be provided prior to treatment for hepatitis
Patients with chronic hepatitis C and concurrent HIV infection may have an
accelerated course of disease. Therefore, patients who have stable HIV infection
with good clinical and functional status should be considered for treatment,
according to guidelines outlined in this statement.
Even though high HCV RNA levels or genotype 1 predict a less favorable response
to therapy, treatment should not be withheld on the basis of these parameters.
Contraindications to treatment with interferon that must be carefully considered
are history of major depressive illness, cytopenias, hyperthyroidism, renal
transplant, and convincing evidence of autoimmune disease.
The large reservoir of individuals infected with HCV globally provides a
source of transmission to others at risk. Prior to the identification of
HCV, the majority of non-A, non-B hepatitis cases were associated with blood
transfusion, injection drug use, health care, employment, or sexual or household
exposure to a contact with hepatitis. HCV is now rarely transmitted by
transfusion because of screening tests that exclude infectious donors.
Direct percutaneous exposure is the most efficient
method for transmitting HCV.In drug users, HCV infection is acquired
rapidly after beginning injection drug use, with 50-80 percent of new users
becoming positive for antibody to HCV within 6-12 months. Injection drug
use accounts for half of all new infections annually and perhaps greater
than 50 percent of chronic infections. In addition, it is thought that the
majority of the rest of the cases can be explained by transfusion prior to
1990, occupational exposures to blood, hemodialysis, high-risk sexual activity
(multiple partners, history of sexually transmitted diseases), and noninjection
illegal drug use (intranasal cocaine). Percutaneous exposures such as body
piercing and tattooing are potential sources of transmission if contaminated
equipment or supplies are used, although their role in transmission of HCV
in the United States has not been confirmed. It is now considered that the
route of transmission is unknown in less than 10 percent of newly acquired
cases of hepatitis C.
Data regarding transmissibility by sexual contact have been conflicting.
Based on studies in sexually transmitted disease clinics, sexual transmission
appears to occur; however, even with multiple sexual partners the risk is
low. The risk appears to be increased by coinfection with HIV or other sexually
transmitted diseases. Although transmission in long-term monogamous relationships
may occur, the risk is thought to be minimal.
There is some evidence for occupational and nosocomial transmission of HCV
infection. Health care workers have a higher prevalence than the general
population, although many may have acquired it from other sources. However,
inadvertent needle stick injuries and lack of application of universal
precautions may be contributing factors. The risk of infection from needle
sticks in hepatitis C is intermediate between that of HIV and hepatitis B.
HCV transmission between patients in dialysis centers may be related to poor
infection control practices. Although transmission from health care workers
to patients has been documented, such transmission is thought to be rare.
Perinatal transmission between mother and baby has been documented, although
the risk is estimated at no more than 6 percent. The risk is increased if
the mother is coinfected with HIV. Although data are limited, there is no
evidence that breast-feeding transmits HCV from mother to baby.
Continued monitoring of the epidemiology of acute and chronic hepatitis C
is necessary. Additional studies of the specific mode of transmission in
minority groups, low socioeconomic groups, institutionalized individuals,
and injection and intranasal drug users are needed, as well as more information
on sexual, household, occupational, nosocomial, and perinatal transmission.
Large-scale, long-term studies are needed to better define the natural history
of hepatitis C and especially to identify factors associated with disease
progression to cirrhosis. Studies of the natural history are needed in special
groups, such as minorities, children, those over 60, HCV-infected patients
with normal ALT, HCV-infected patients coinfected with HIV, and injection
drug users. Information is also needed about the role of ultrasound and alpha
fetoprotein monitoring for early detection of hepatocellular carcinoma in
patients with chronic hepatitis C.
Studies are needed on the recovery from and persistence of viral infection
as well as the pathogenesis and mechanism of liver cell injury by HCV. Is
damage due to cytopathic effects of the virus on the liver cell, or is it
immunologically mediated? What is the mechanism of hepatic fibrosis? Can
fibrosis be separated from inflammation/necrosis of the liver? Such studies
would be greatly facilitated by development of suitable animal and cell culture
models. The mechanism of development of hepatocellular carcinoma in patients
with hepatitis C needs elucidation.
Given the large number of persons who are already infected with HCV, there
is an urgent need for effective antiviral therapeutics capable of inhibiting
virus replication and stopping or delaying the progression of liver disease.
A major bottleneck to the drug discovery process is the absence of a readily
available cell culture system that is fully permissive for viral replication.
Thus, development of such systems should be a high priority. An improved
understanding of the molecular virology of HCV is also critically important
to antiviral drug development. These studies should include the development
of infectious molecular clones, which would allow analyses of structure-function
relations among HCV nonstructural proteins that participate in the viral
Alcohol ingestion clearly worsens the course of hepatitis C, but the reasons
for this interaction are unknown. Studies of the interaction between HCV
and obesity, diabetes mellitus, iron, and medications are also needed.
Unresolved questions remain regarding the diagnostic tests for hepatitis
C. What is the prevalence of significant liver disease among RIBA-positive,
HCV RNA-negative individuals? What should be the gold standard for HCV RNA
assays? What is the frequency of intermittent viremia in untreated patients?
What are the criteria for selecting patients for, or withdrawing patients
from, treatment? How can the reliability of HCV RNA tests be improved? How
can the dynamic range and intra-assay variability of the HCV RNA test be
Future clinical trials should expand the range of outcomes studied to include
quality of life from the patient's point of view, as well as costs and survival.
In addition, those trials should include minorities, patients over age 60,
patients under age 18, HIV-coinfected patients, and liver transplant patients.
We need to identify effective, nontoxic therapeutic agents. Clinical trials
are also needed to identify optimal treatment regimens for those who do not
respond to interferon therapy, or who relapse following interferon therapy.
Prospective studies are needed to identify and test prospectively the factors
that predict response to therapy. In addition, studies are needed of possible
drug interactions, especially between the antiretroviral drugs used to treat
HIV infection and those drugs used to treat hepatitis C.
Although continued education of risk groups and screening of blood, organs,
tissue, and semen remain vitally important, the key to prevention is development
of an effective and safe vaccine for hepatitis C. This will require a better
understanding of the molecular determinants of both cellular and humoral
immunity to HCV, the nature of antigenic variation as related to viral
quasispecies diversity, and the mechanism(s) by which HCV regularly eludes
the host immune system and establishes persistent infection.
Strategies should be developed to educate at-risk groups concerning transmission
of disease, as well as provide access to diagnosis and treatment. It would
be helpful also to evaluate the role of intranasal cocaine use as a possible
route of infection.
Individuals who have a history of transfusions of blood or blood products
prior to 1990, who are on chronic hemodialysis, who have a history of injection
drug use, who have had multiple sexual partners, who are the spouses or close
household contacts of hepatitis C patients, and who share instruments for
intranasal cocaine use should be tested for hepatitis C.
Hepatitis C is a common infection with variable course that can lead to chronic
hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. The course
of illness may be adversely affected by various factors, especially alcohol
consumption. Therefore, more than one drink per day is strongly discouraged
in patients with hepatitis C, and abstinence from alcohol is recommended.
Those addicted to alcohol or drugs should be helped to obtain treatment for
their addiction so that they might qualify for anti-HCV therapy.
Because of assay variability, qualitative and quantitative PCR testing for
HCV RNA must be interpreted cautiously. Rigorous proficiency testing is
recommended for clinical laboratories performing this assay. The branched
DNA signal amplification assay for viral level has been standardized, but
may fail to detect low titers of HCV RNA. Sequential measurement of HCV RNA
levels (viral load) has not, to date, proven useful in managing patients
with hepatitis C.
Liver biopsy is indicated when histologic findings will assist decisionmaking
regarding patient management. In patients who are not treated with antiviral
therapy initially, liver biopsy can be considered to assess disease progression.
HCV genotyping and tests for HCV RNA levels (viral load) may provide useful
prognostic information, especially regarding response to therapy, but at
present must be considered research tools.
Currently available therapy for chronic hepatitis
C is indicated for patients who have persistently abnormal ALT (greater than
6 months),a positive HCV RNA, and liver biopsy demonstrating either portal
or bridging fibrosis and at least moderate degrees of inflammation and necrosis.
Patients with milder histological disease, compensated cirrhosis, or who
are under age 18 or over 60 should be managed on an individual basis or in
the context of clinical trials. Patients with decompensated cirrhosis should
not be treated with interferon but should be considered for liver
transplantation. Patients with persistently normal ALT and minimal histologic
abnormalities should not be treated outside clinical trials. Contraindications
to treatment of patients with interferon that must be considered are a history
of major depressive illness, cytopenia, active alcohol use or illicit drug
use, hyperthyroidism, renal transplantation, or autoimmune disease. Therapy
should not be limited by mode of acquisition, risk group, HIV status, HCV
RNA level, or genotype.
Nonresponders to interferon therapy can be identified early by assessing
the serum ALT level and presence of serum HCV RNA after 3 months of therapy.
If the ALT level remains abnormal and the serum HCV RNA remains detectable,
interferon therapy should be stopped, because further treatment is unlikely
to produce a response. Nonresponders should not be retreated with the same
regimen, but should be considered for combination therapy or enrollment in
investigational protocols using different dosages or agents.
Patients who have an end-of-treatment response to a 6-month course of interferon
alfa, but then relapse, should receive retreatment with a 12-month course
of interferon alfa or be considered for combination therapy with interferon
plus ribavirin or other regimens, preferably in a clinical trial.
Hepatitis A and B vaccination is recommended for all HCV-positive patients.
Patient support groups should be encouraged, especially for those undergoing
therapy, those who fail therapy, and also those recovering from addiction.
The following recommendations are made to avoid transmission of hepatitis
In health care settings, adherence to universal (standard) precautions for
the protection of medical personnel and patients is essential.
HCV-positive individuals should refrain from donating blood, organs, tissues,
or semen. In some situations, the use of organs and tissues from HCV-positive
individuals may be considered. For example, in emergency situations the use
of a donor organ in which the HCV status is either positive or unknown may
be considered in a HCV-negative recipient after full disclosure and informed
consent. Strategies should be developed to identify prospective blood donors
with any prior history of injection drug use. Such individuals must be deferred
from donating blood.
Safer sexual practices should be strongly encouraged in persons with multiple
sexual partners, including the use of latex condoms. In monogamous long-term
relationships, transmission is rare. Although HCV-positive individuals and
their partners should be informed of the potential for transmission, there
are insufficient data to recommend changes in current sexual practice in
persons with a steady partner. It is recommended that sexual partners of
infected patients should be tested for antibody to HCV.
In households with an HCV-positive member, sharing razors and toothbrushes
should be avoided. Covering open wounds is recommended. Injection needles
should be carefully disposed of using universal precaution techniques. It
is not necessary to avoid close contact with family members or to avoid sharing
meals or utensils. There is no evidence to justify exclusion of HCV-positive
children or adults from participation in social, educational, and employment
Pregnancy is not contraindicated in HCV-infected individuals. Perinatal
transmission from mother to baby occurs in less than 6 percent of instances.
There is no evidence that breast-feeding transmits HCV from mother to baby;
therefore, it is considered safe. Babies born to HCV-positive mothers should
be tested for anti-HCV at 1 year.
Needle exchange and other safer injection drug use programs may be of benefit
in reducing parenterally transmitted diseases. Expansion of such programs
should be considered in an effort to reduce the rate of transmission of hepatitis
It is important that clear and evidenced-based information be provided to
both patients and physicians regarding the natural history, means of prevention,
management, and therapy of hepatitis C.