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Hepatitis C
Synonyms and related keywords:
hepatitis C virus, HCV, non-A non-B hepatitis, acute hepatitis, hepatitis,
virus infection, viral infection, virus, chronic liver disease, hepatocellular
carcinoma,
cirrhosis, liver transplant, liver transplantation, orthotopic liver transplantation,
OLT, quasispecies, interferon, IFN
Author: Vinod K Dhawan, MD, Chief, Program Director, Division of Infectious
Diseases, Professor, Department of Internal Medicine, King/Drew Medical Center,
Charles R Drew University; Professor, Department of Clinical Medicine, UCLA
Vinod K Dhawan, MD, is a member of the following medical societies:
American College of Physicians,
American Society for Microbiology, American Society of Tropical Medicine
and Hygiene, Infectious Diseases Society of America, and Royal College of Physicians and Surgeons of Canada
Editor(s):
George Y Wu, MD, PhD, Chief, Division of Gastroenterology-Hepatology,
Herman Lopata Chair in Hepatitis Research; Professor, Department of Medicine,
University of Connecticut Health Center; Francisco Talavera, PharmD, PhD,
Senior Pharmacy Editor, Pharmacy, eMedicine; Oscar S Brann, MD, Program
Director of Gastroenterology Fellowship, Associate Clinical Professor UCSD School
of Medicine, Department of Internal Medicine, Naval Medical Center San Diego;
Alex J Mechaber, MD, FACP, Associate Director of Generalist Primary Care
Clerkship, Assistant Professor, Department of Internal Medicine, Division of
General Internal Medicine, University of Miami School of Medicine; and Julian
Katz, MD, Professor, Department of Internal Medicine, Division of Gastroenterology,
MCP Hahnemann University
INTRODUCTION
Background:
The prevalence of hepatitis C virus (HCV) infection is increasing worldwide.
The World Health Organization estimates that more than 170 million individuals
throughout the world are infected with HCV. An estimated 1.8% of the population
in the United States is positive for HCV antibodies; this rate corresponds to
an estimated 3.9 million persons with HCV infection nationwide. Infection due
to HCV accounts for 20% of all cases of acute hepatitis, an estimated 30,000
new acute infections, and 8,000-10,000 deaths each year in the United States.
Medical care costs associated with the treatment of HCV infection in the United
States are estimated to be more than $600 million per year. Most patients infected
with HCV have chronic liver disease, which may progress to cirrhosis and hepatocellular
carcinoma. Chronic infection with HCV is one of the most important causes of
chronic liver disease (see Image 1). Currently, chronic hepatitis C is the most common indication
for orthotopic liver transplantation in the United States.
HCV is a spherical, enveloped, single-stranded RNA virus belonging to family
Flaviviridae. In persons who are infected, HCV may produce approximately a trillion
new viral particles each day in a steady state of viral replication. The RNA-dependent
RNA polymerase, an enzyme critical in HCV replication, lacks proofreading capabilities
and thus generates a large number of mutant viruses known as quasispecies. Viral
quasispecies represent minor molecular variations with only 1-2% nucleotide
heterogeneity. These quasispecies pose a major challenge with respect to immune-mediated
control of HCV and may explain the variable clinical course and the difficulties
in vaccine development.
Six major HCV genotypes and numerous subtypes have been identified based on
molecular relatedness. Molecular differences between genotypes are relatively
large, and they have a difference of at least 30% at the nucleotide level. Genotypes
1, 2, and 3 have a worldwide distribution, while genotypes 4, 5, and 6 are localized
to specific geographic locations. Genotype 1 is the most common genotype in
the United States. HCV genotype 1, particularly 1b, does not respond to therapy
as well as genotypes 2 and 3. Genotype 1 also may be associated with more severe
liver disease and a higher risk of hepatocellular carcinoma. Genotype 4 is the
most prevalent genotype in Egypt, genotype 5 is found in South Africa, and genotype
6 is found in Southeast Asia.
HCV encodes a single polyprotein of 3011 amino acids that is processed into
10 structural and regulatory proteins (see Image 2). Structural components include the core and 2 envelope
proteins, E1 and E2. Two regions of the E2 protein have an extremely high rate
of mutation; these are designated hypervariable regions 1 and 2. Envelop protein
E2 contains the binding site for CD-81, a receptor expressed on hepatocytes
and B lymphocytes. HCV also encodes a virus-specific helicase, protease, and
polymerase, all of which are critical in viral replication. These enzymes are
attractive targets for antiviral therapy. Similarly, the untranslated regions
at both ends of the viral RNA, 5'-UTR and 3'-UTR, are highly conserved. These
sites are involved in critical stages of viral replication and may be logical
targets for therapy.
Currently, HCV is predominantly transmitted by means of percutaneous exposure
to infected blood. In developed countries, most new HCV infections are related
to intravenous drug abuse. The screening of blood donors for HCV antibody since
1990 has decreased the risk of transfusion-associated HCV to less than 1 case
in 103,000 transfused units. The risk may be even lower with the use of more
sensitive assays with the polymerase chain reaction (PCR) to screen blood. These
newer assays have decreased the window after infection, during which the virus
may escape detection, to approximately 3 weeks.
HCV also may be transmitted by means of acupuncture, tattooing, and sharing
razors. Needlestick injuries in the health care setting result in a 3% risk
of HCV transmission. However, the prevalence of hepatitis C among health care
workers is similar to that of the general population. Nosocomial patient-to-patient
transmission may occur by means of a contaminated colonoscope; dialysis; or
surgery, including organ transplantation before 1992. Uncommon routes of transmission
of HCV, ie, those that affect no more than 5% of the individuals at risk, include
high-risk sexual activity and maternal-fetal transmission. Co-infection with
human immunodeficiency virus type 1 (HIV-1) appears to increase the risk of
both sexual and maternal-fetal transmission of HCV. Casual household contact
and contact with the saliva of those infected are inefficient modes of transmission.
No risk factors are identified in approximately 10% of cases.
Pathophysiology:
The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral
clearance is associated with the development and persistence of strong virus-specific
responses by cytotoxic T lymphocytes and helper T cells. In most persons infected
with HCV, viremia persists, and this is accompanied by variable degrees of hepatic
inflammation and fibrosis. Findings from more recent studies suggest that 50%
or more of the hepatocytes may be infected with HCV.
Immunodeficiency associated with HIV infection accelerates the course of hepatitis
C. In one Spanish series, as many as 25% of patients infected with HIV had cirrhosis
within 15 years of infection with HCV, compared with only 6.5% of those who
were HIV negative. Co-infection with the hepatitis B virus (HBV) also has been
associated with increased severity of chronic hepatitis C and accelerated progression
to cirrhosis. In addition, HBV co-infection seems to enhance the development
of hepatocellular carcinoma.
Frequency:
- In the US: HCV infections account for approximately 30,000 new infections
and 8,000-10,000 deaths each year in the United States. Of the new infections,
60% occur in persons who use intravenous drugs; fewer than 20% are acquired
through sexual exposure; and 10% are due to other causes, including occupational
or perinatal exposure and hemodialysis. The overall prevalence of anti-HCV
antibodies in the United States is 1.8% of the population. Approximately 74%
of individuals are positive for HCV RNA; this rate indicates that an estimated
3.9 million persons are infected with HCV and 2.7 million persons in the United
States have chronic infection. Three fourths of these individuals are infected
with HCV genotype 1.
- Internationally: More than 170 million individuals throughout the
world are infected with HCV. The prevalence rates in healthy blood donors
are 0.01-0.02% in the United Kingdom and northern Europe, 1-1.5% in southern
Europe, and 6.5% in parts of equatorial Africa. Prevalence rates as high as
20% are reported in Egypt; these rates are attributed to the use of parenteral
antischistosomal therapy.
Mortality/Morbidity: Hepatitis C is the major cause of chronic hepatitis
in the United States. HCV infections account for 20% of all cases of acute hepatitis.
It accounts for more than 40% of all referrals to active liver clinics.
- Severe progression of hepatitis C to cirrhosis occurs in approximately 20%
of patients who have chronic infection. The rate and chance of progression
varies with certain factors, including sex, alcohol use, concomitant hepatitis,
age, and several other factors.
- Hepatocellular carcinoma develops in 1-4% of patients with cirrhosis each
year. HCV is largely responsible for the recent increase in the incidence
of hepatocellular carcinoma in the United States.
- In the United States, the number of deaths due to HCV-related complications
has increased from fewer than 10,000 in 1992 to just fewer than 15,000 in
1999. This number is expected to increase in the future because of the current
large pool of patients with chronic infections.
Race: In the United States, hepatitis C is more common among minority
populations such as black persons and Hispanic persons than in other populations.
Furthermore, genotype 1 is more prevalent in black persons in the United States
than in other racial groups.
Sex: Females infected with HCV have somewhat better outcome than their
male counterparts.
Age: In the United States, 65% of persons with HCV infection are aged
30-49 years. Those who acquire the infection at a younger age have a somewhat
better prognosis than those who are infected later in life.
CLINICAL
History: The natural history of hepatitis C evolves over decades (see Image 3).
- Clinical manifestations after acute infection occur in only 20-30% of patients,
usually within 7-8 weeks after exposure to HCV.
- Chronic subclinical infection with persistent HCV viremia is the most frequent
outcome and occurs in 70-80% of patients.
Symptoms frequently are absent until the liver disease is advanced.
Spontaneous clearance of viremia in chronic infection is rare.
- Cirrhosis develops in 15-20% of individuals with chronic infections.
Its development may take as long as 30 years.
Once cirrhosis occurs, the risk of hepatocellular carcinoma is approximately
1-4% per year.
A more rapid disease progression is observed among individuals infected with
HIV or HBV, those with alcoholism, males, and those who acquire the infection
at an older age.
Compared with other patients infected with HCV, the incidence of cirrhosis
in patients with alcoholism is increased 15-fold, and the incidence in those
with HIV co-infection is increased 5-fold.
- Superinfection with hepatitis A virus in persons who are infected with HCV
may result in severe acute or even fulminant hepatitis.
- Symptoms of hepatitis C include malaise, weakness, anorexia, and fatigue.
Physical:
Latently infected patients may have no abnormal findings upon examination.
Others who have hepatitis, cirrhosis, or hepatocellular carcinoma may present
with the following:
- Jaundice
- Yellowish discoloration of the eyes and urine
- Hepatomegaly (eg, hepatocellular carcinoma)
- Findings of portal hypertension (eg, ascites, spider angiomata)
Causes:
Hepatitis C is caused by a spherical, enveloped, single-stranded RNA virus
belonging to the family Flaviviridae.
Differentials:
Alcoholic Hepatitis
Amebic Hepatic Abscesses
Autoimmune Hepatitis
Hepatitis A
Hepatitis B
Hepatitis D
Hepatitis E
Hepatitis, Viral
Other Problems to be Considered:
Drug-induced (ie, toxic) hepatitis
Work Up
Lab Studies:
Hepatitis C antibody test
- Anti-HCV serologic screening involves an enzyme immunoassay (EIA), including
EIA-2 and EIA-3. Serologic assays for antibodies to HCV, ie, anti-HCV antibodies,
are 97% specific. However, these assays cannot be used to distinguish an acute
infection from a chronic infection.
- In 3 successive versions of EIA, sensitivity has increased progressively.
With older tests, some HCV infections may have been missed 6-9 months after
infection. The most recent third-generation EIA involves core protein and
nonstructural proteins 3, 4, and 5; these can be used to detect antibodies
within 4-10 weeks after the onset of infection.
- False-negative results for the presence of HCV antibody can occur in persons
with compromised immune systems, such as those with HIV-1 infection, patients
with renal failure, and those with HCV-associated essential mixed cryoglobulinemia.
- False-positive EIA results can occur in persons without risk factors and
in those without signs of liver disease, such as blood donors or health care
workers.
Recombinant immunoblot assay
- Recombinant immunoblot assay (RIBA-2) is used to confirm HCV infection.
- A positive immunoblot assay result is defined as the detection of antibodies
against 2 or more antigens, and an indeterminate assay result is defined as
the detection of antibodies against a single antigen.
- RIBA-2 is useful to confirm positive EIA results in low-risk populations.
HCV-RNA detection with polymerase chain reaction
- HCV-RNA assays with PCR can be used to detect infection within 1-3 weeks
of exposure.
- Compared with other tests, qualitative HCV-RNA tests based on the PCR technique
have a lower limit of detection of fewer than 100 copies of HCV RNA per milliliter.
- HCV-RNA PCR tests are useful in confirming viremia, assessing the treatment
response, and examining patients with suspected false-negative results with
antibody testing.
- HCV-RNA PCR assays are more than 90% sensitive and specific.
Viral load tests
- The viral load detected with quantitative assays can be used to predict
the outcome of anti-HCV therapy but not the likelihood of disease progression.
- Three commercial tests to quantify the degree of viremia are currently available.
They are described as follows:
Branched-chain DNA assay (Quantiplex HCV RNA, version
2.0)
Reverse-transcription PCR (Cobas Amplicor HCV monitor,
version 2.0)
Reverse-transcription PCR (HCV SuperQuant)
Because viral RNA is unstable , serum samples should be frozen within 3 hours
after they are obtained.
A single testing system should be used for serial monitoring of the viral load
in each patient because the results may be test-dependent to some extent.
- Serum alanine aminotransferase test
The serum alanine aminotransferase (ALT) level may
be elevated in patients with acute hepatitis C, and the ALT level is useful
for helping monitor the effectiveness of therapy for HCV infection.
Because ALT levels may be normal or may fluctuate,
a single normal value does not rule out active infection, progressive liver
disease, or even cirrhosis. Similarly, the normalization of ALT levels with
therapy is not a proof of cure.
Viral genotyping is essential in the treatment of
patients infected with HCV. The genotype helps predict the outcome of therapy
and helps determine the duration of therapy.
Currently, the only clinically relevant distinction
is between genotype 1 and genotypes 2 and 3. Patients with genotype 1 infection
usually are treated for 12 months, compared with a shorter period (eg, 6 mo)
in patients with the other genotypes.
- A diagnostic algorithm for the evaluation of hepatitis C is shown in Image 4.
- Pretreatment tests should include the following:
Anti-HCV antibody EIA
Genotyping
Quantitative HCV RNA assay: Reverse transcriptase
PCR is more sensitive than bDNA testing
Determinations of ALT and aspartate aminotransferase
(AST), bilirubin, and albumin levels
Screening for co-infection with HIV
- Patients should be closely monitored for treatment toxicity. Tests to help
monitor drug toxicity include the following:
CBC count with differential and platelet counts
Renal function testing
Determination of glucose level
Determination of the activated partial thromboplastin
time, prothrombin time, (including International Normalized Ratio), and baseline
thyroid-stimulating hormone
Imaging Studies:
- Ultrasonography of the liver and biliary passages helps exclude other diagnostic
possibilities.
Procedures:
Liver biopsy before the initiation of treatment
is not considered mandatory. However, liver biopsy is important for helping
determine the activity of HCV-related liver disease.
Histologic evaluation of a liver biopsy sample and
histologic staging remain the only reliable methods of predicting the prognosis
and likelihood of disease progression. A scoring system for prognostic assessment
takes into account the 2 cardinal features of liver injury, namely, inflammation
and fibrosis.
Biopsy findings also may help rule out other concurrent
causes of liver disease. Therefore, biopsy generally is recommended in the initial
examination of persons with chronic HCV infection. However, some recommend biopsy
only if the treatment does not result in sustained remission.
Histologic Findings:
Liver biopsy findings reveal lymphocytic infiltration, portal or bridging fibrosis,
and moderate degrees of inflammation and necrosis. Regenerative nodules are
noted in patients with cirrhosis. Findings of hepatocellular carcinoma may be
present in some patients.
Treatment:
Medical Care:
- The goals of treatment of chronic HCV infection include the following:
Eradicate HCV.
Delay fibrosis and progression to cirrhosis.
Prevent hepatic decompensation and obviate liver
transplantation.
Prevent hepatocellular carcinoma
- The virologic response to treatment is categorized in several ways, as follows:
The end-of-treatment response (ETR) refers to the
absence of viremia at completion of therapy; ie, the serum HCV-RNA value is
below the level of detection.
A sustained virologic response (SVR) indicates the
persistent absence of serum HCV RNA for 6 months or longer after therapy.
Relapse is defined as an undetectable serum HCV-RNA
level at the completion of therapy, with subsequent viremia.
A nonresponse is defined as a failure to eliminate
HCV RNA from the serum during therapy.
- The treatment of hepatitis C has evolved over the years (see Image 5). It is discussed as follows:
Recombinant interferon (IFN) alfa 2b was the first
drug approved by the US Food and Drug Administration (FDA) for use in the treatment
of hepatitis C.
Approximately 40% of patients treated with 3 million
U of IFN alfa 3 times a week had an initial response that was characterized
by normalization of liver function test results and a loss of detectable HCV
RNA.
Relapse occurs in most patients after therapy.
A sustained viral response occurs in only 6% in
patients treated for 6 months and in 16% of those treated for 1 year with IFN
alfa alone.
Combination therapy with IFN alfa and the nucleoside
analog ribavirin has improved the SVR rate to 41%.
Patients with HCV genotype 1 have a much less favorable
response to therapy and are treated for 12 months with IFN and ribavirin, compared
with patients infected with genotypes 2 and 3, in whom a 6-month course of therapy
is sufficient.
Fried et al noted that 5 million U of IFN alfa 2b
daily for 24 weeks more rapidly decreased the HCV-RNA level and increased the
initial and ETR rates when compared with a regimen of 3 million U of IFN alfa
2b 3 times a week in patients with chronic hepatitis C.
Jaeckel et al recently reported findings from a
landmark study of treatment of acute hepatitis C infection, as follows:
- Treatment with IFN alfa 2b was reported to prevent chronic infection in
98% of a group of 44 German patients with acute hepatitis C.
- The study patients received 5 million U of IFN alfa 2b subcutaneously daily
for 4 weeks and then 3 times per week for another 20 weeks. Therapy was well
tolerated in all patients but one.
- This report is likely to alter the approach to treatment in patients acutely
infected with HCV.
- Antiviral therapy of chronic hepatitis C currently is recommended for patients
with elevated serum ALT levels who meet the following parameters:
They must be older than 18 years
.
They must have positive findings with HCV EIA and
HCV-RNA tests.
Liver biopsy findings must be consistent with a
diagnosis of chronic hepatitis, although the diagnosis is not required.
They must not have active autoimmune disease.
No hepatic encephalopathy, variceal bleeding, ascites,
or other clinical signs of decompensation are present.
- Pretreatment laboratory tests should be performed
- The following preparations of IFN currently are available for treatment
of hepatitis C:
IFN alfa 2b (Intron-A; Schering-Plough, Kenilworth,
NJ) is a recombinant IFN preparation.
IFN alfa 2a (Roferon; Hoffmann-La Roche, Basel,
Switzerland) is a recombinant IFN preparation, differing from IFN alfa 2b by
only a single amino acid residue.
IFN alfacon-1 (Infergens; Amgen, Thousand Oaks,
Calif) or consensus IFN (CIFN) is a genetically engineered compound synthesized
by combining the most common amino acid sequences from all 12 naturally occurring
IFNs.
- It has greater cytokine-induction, antiviral, antiproliferative, natural
killer cell, and gene-induction activities than both IFN alfa 2a and IFN alfa
2b on an equal-mass basis.
- However, initial studies of the recommended CIFN dose of 9 mcg in IFN-naive
patients with chronic hepatitis C have resulted in viral response rates similar
to those of standard IFN-alfa monotherapy.
Regarding pegylated IFNs, recent developments in IFN technology have led to
the development of long-lasting IFNs.
Polyethylene glycol (PEG) molecules are added to IFN.
These new pegylated IFNs have better sustained absorption, a slower rate of
clearance, and a longer half-life than those of unmodified IFN.
They permit more convenient once-weekly dosing. The FDA has approved pegylated
IFNs for use in the treatment of chronic hepatitis C
Pegylated IFNs have significantly improved the quality of life for patients
who have a good response to therapy.
Two pegylated IFN preparations currently are available.
- PEG-IFN alfa 2b (PEG-Intron; Schering-Plough) consists of IFN alfa 2b attached
to a single 12-kD PEG chain. PEG-IFN alfa 2b is excreted by the kidneys.
- PEG-IFN alfa 2a (PEGASYS; Hoffmann-La Roche) consists of IFN alfa 2a attached
to a 40-kD branched PEG molecule. PEG-IFN alfa 2a is metabolized predominantly
by the liver.
- Several reports have documented the improved sustained viral response with
pegylated IFNs.
In a study of patients with chronic hepatitis C,
Zeuzem and colleagues found that pegylated IFN alfa 2a at 180 mcg subcutaneously
administered once per week was associated with a higher rate of virologic response
than IFN alfa 2a at 6 million U subcutaneously administered 3 times per week
for 12 weeks followed by 3 million U 3 times per week for 36 weeks.
- Findings were 69% versus 28% (P = .001) at week 48 of therapy and
39% versus 19% (P = .001) at week 72 of therapy.
- Drug discontinuation in these treatment-naive patients and the frequencies
of dose reduction were similar in the 2 treatment groups.
Heathcote and colleagues reported on the use of
pegylated IFN alfa 2a in a controlled trial of patients with cirrhosis.
- The SVR rate was 30% after 48 weeks of therapy with 180 mcg, compared with
8% for patients treated with standard IFN alfa.
- Adverse effects did not significantly increase with the pegylated product.
In a dose escalation study of patients with chronic
hepatitis C, Reddy et al report that SVR rates for PEG-IFN alfa 2a once weekly
were 10% with 45 mcg, 30% with 90 mcg, 36% with 180 mcg, and 29% with 270 mcg,
compared with 3% with 3 million U of IFN alfa 2a administered 3 times weekly.
The types and frequencies of adverse events and abnormal laboratory test results
were similar among all groups.
The 180-mcg PEG-IFN alfa 2a dose appeared to be the optimal dose on the basis
of the SVR and associated adverse-effect profile.
Lindsay and colleagues recently reported findings
from an international, randomized, controlled, parallel-group, double-blind
study.
- They compared PEG-IFN alfa 2b (PEG-Intron) to IFN alfa 2b in the initial
treatment of compensated chronic hepatitis C in a large cohort of 1219 patients.
- PEG-IFN alfa 2b maintained (at dose of 0.5 mcg/kg) or surpassed (at doses
of 1 mcg/kg and 1.5 mcg/kg) the clinical efficacy of IFN alfa 2b (at the standard
3-times-weekly dose) while preserving its safety profile.
Manns et al recently published a report of an international
clinical trial in which they compared PEG-IFN alfa 2b plus ribavirin with IFN
alfa 2b plus ribavirin in 1530 patients with chronic hepatitis C.
- Patients were assigned randomly to 3 groups as follows: (1) IFN alfa 2b,
at 3 million U subcutaneously administered 3 times per week plus ribavirin
at 1000-1200 mg/d orally administered; (2) PEG-IFN alfa 2b at 1.5 mcg/kg each
week plus ribavirin 800 mg/d; and (3) PEG-IFN alfa 2b at 1.5 mcg/kg per week
for 4 weeks then 0.5 mcg/kg per week plus ribavirin at 1000-1200 mg/d for
48 weeks.
- The SVR rate (see Image 6) was significantly higher in the higher-dose PEG-IFN
group (274 of 511 patients [54%]) than in the lower-dose PEG-IFN (244 of 514
patients, [47%] P = .01) or IFN (235 of 505 patients, [47%] P
= .01) groups.
- Among patients with HCV genotype 1 infection, the corresponding SVR rates
were 42% (145 of 348 patients), 34% (118 of 349 patients), and 33% (114 of
343 patients).
- The rate for patients with genotype 2 and 3 infections was approximately
80% for all treatment groups.
- Adverse-effect profiles were similar among the treatment groups.
- Secondary analyses identified body weight as an important predictor of SVR.
In this study, when the dose was optimized for the patient's body weight,
with a dose of more than 10.6 mg/kg of ribavirin daily, the SVR with IFN regimens
was 61% for all genotypes, 48% for genotype 1, and 88% for genotypes 2 and
3.
IFN therapy may cause a variety of adverse effects,
as follows:
- Influenzalike symptoms occur in more than 60% of patients.
- Other adverse effects include chronic fatigue and depression and mood dysfunction
and depression.
- Short courses of IFN are relatively well tolerated. Increasing the duration
of therapy from 6 months to 12 months increases the incidence of adverse effects.
- IFN therapy also may cause insomnia, rash and pruritus, anorexia, neutropenia,
thrombocytopenia, and thyroid dysfunction.
Ribavirin therapy may cause the following:
- Patients may develop hemolytic anemia.
- Teratogenicity is a possibility. One should confirm negative pregnancy test
results before initiating therapy. All patients, male and female, should be
counseled about the risks and advised to use birth control.
- Patients may develop cough and dyspnea.
- Rash and pruritus has been described.
- Insomnia is an adverse effect of ribavirin therapy.
- Anorexia also is an adverse effect of ribavirin therapy.
- In clinical trials, as many as 20% of patients receiving combination therapy
were unable to tolerate the regimen.
- Psychiatric illness or substance abuse should be addressed prior to treatment
for HCV infection.
- The treatment of preexisting mood disorders before initiation of therapy
for HCV infection is essential to increase the likelihood that the patient
will comply with therapy.
- Interleukin-10 (IL-10) is a cytokine that down-regulates the proinflammatory
response.
IL-10 has a modulatory effect on hepatic fibrogenesis.
In a preliminary report, Nelson et al treated 24
patients with chronic hepatitis C in whom the disease had not previously responded
to IFN-based therapy.
IL-10 had a salutary effect on hepatic inflammation
and fibrosis.
Further studies are necessary to evaluate the therapeutic
potential of IL-10 in patients with chronic hepatitis C.
- Between 30% and 50% of persons infected with HIV are co-infected with HCV.
Co-infection is highest among those who use injection
drugs, with a rate of approximately 90%.
The rate of co-infection among homosexual men is
approximately 10%.
Co-infection with HIV both accelerates the clinical
progression of hepatitis C and increases the risk of perinatal HCV transmission
from 5% (range, 3-8%) to 17% (range, 7-36%).
- Highly active antiretroviral therapy (HAART) is a combination therapy used
in patients with HIV disease. HAART-associated immune recovery may increase
HCV replication.
This recovery may represent an immune reconstitution
phenomenon.
HAART-associated hepatotoxicity may complicate the
treatment of HCV infection.
- Patients co-infected with HIV and HCV should be closely monitored during
treatment for possible drug interactions.
After IFN alfa 2b and ribavirin combination therapy
is initiated, the CBC count and hemoglobin level should be checked regularly.
If warranted, the use of epoetin and granulocyte
colony-stimulating factor may be considered.
- At week 24 of treatment, the patient should be evaluated for IFN-associated
thyroid dysfunction.
HCV-RNA levels should be monitored.
If the HCV-RNA level is undetectable , therapy should
be continued for an additional 24 weeks regardless of the genotype.
HCV RNA is rechecked 6 months after treatment. If
HCV RNA is detectable and the patient has mild liver disease, therapy may be
stopped.
If HCV RNA is detectable and the patient has advanced
fibrosis, maintenance IFN therapy may be considered.
Surgical Care:
Consultation with a surgeon may be necessary for patients in whom liver transplantation
or hepatic resection for hepatoma is considered.
Consultations:
- An infectious diseases specialist should be consulted, as indicated.
- A gastroenterologist should be consulted, as indicated.
Diet:
No special diet is recommended.
(There is a diet written for people with Hep C, Cirrhosis, etc. located at:
Hepatitis Diet
Activity:
No special restrictions are needed unless the patient has advanced liver disease
with portal hypertension.
Medication:
Combination therapy with IFN alfa and the nucleoside analog ribavirin is the
current standard of care in patients infected with HCV. Patients with HCV genotype
1 have a much less favorable response to therapy and are treated for 12 months,
compared with patients infected with genotypes 2 and 3, in whom a 6-month course
of therapy is sufficient. If viremia is present after 6 months, additional therapy
has a negligible incremental benefit and treatment should be stopped in all
patients regardless of the viral genotype. With HIV co-infection, all patients
with a response to therapy at the end of 6 months should receive an additional
6 months of combination therapy regardless of the genotype. Patients with acute
hepatitis C infection should be treated for 6 months.
Drug Category: Antivirals
Shorten the clinical course, prevent complications, prevent latent and/or subsequent
recurrences, decrease transmission, and eliminate established latency.
| Drug Name |
Interferon alfa 2b (Intron-A) -- Recombinant IFN preparation. |
| Adult Dose |
3 million U SC 3 times/wk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity; decompensated liver disease; significant
preexisting psychiatric disease; ongoing or recent alcohol use; platelet
count <,70,000/mm3 |
| Interactions |
Theophylline may increase toxicity by reducing clearance; cimetidine may
increase antitumor effects; zidovudine and vinblastine may increase toxicity |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis,
aggressive behavior, hallucinations, violent behavior, suicidal ideation,
suicide attempt, suicide, homicidal ideation [rare]), even without previous
history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia;
neutropenia; thrombocytopenia |
| Drug Name |
Interferon alfa 2a (Roferon) -- Recombinant IFN preparation. |
| Adult Dose |
3 million U SC 3 times/wk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity; decompensated liver disease; significant
preexisting psychiatric disease; ongoing or recent alcohol use; platelet
count <,70,000/mm3 |
| Interactions |
Theophylline may increase toxicity by reducing clearance; cimetidine may
increase antitumor effects; zidovudine and vinblastine may increase toxicity |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis,
aggressive behavior, hallucinations, violent behavior, suicidal ideation,
suicide attempt, suicide, homicidal ideation [rare]), even without previous
history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia;
neutropenia; thrombocytopenia |
| Drug Name |
Interferon alfacon-1 (Infergens) -- CIFN is a genetically engineered compound
synthesized by combining the most common amino acid sequences from all 12
naturally occurring IFNs. |
| Adult Dose |
9 mcg SC 3 times/wk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity; decompensated liver disease; significant
preexisting psychiatric disease; ongoing or recent alcohol use; platelet
count <,70,000/mm3 |
| Interactions |
Theophylline may increase toxicity by reducing clearance; cimetidine may
increase antitumor effects; zidovudine and vinblastine may increase toxicity |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis,
aggressive behavior, hallucinations, violent behavior, suicidal ideation,
suicide attempt, suicide, homicidal ideation [rare]), even without previous
history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia;
neutropenia; thrombocytopenia |
| Drug Name |
Peginterferon alfa 2b (PEG-Intron) -- Consists of IFN alfa 2b attached
to a single 12-kD PEG chain. Excreted by the kidneys. Pegylated IFNs have
sustained absorption, a slower rate of clearance, and a longer half-life
than unmodified IFN. Permit a more convenient once-weekly dosing. Has significantly
improved quality of life for patients. |
| Adult Dose |
1.5 mcg/kg SC qwk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity; decompensated liver disease; significant
preexisting psychiatric disease; ongoing or recent alcohol use; platelet
count <,70,000/mm3 |
| Interactions |
Theophylline may increase toxicity by reducing clearance; cimetidine may
increase antitumor effects; zidovudine and vinblastine may increase toxicity |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis,
aggressive behavior, hallucinations, violent behavior, suicidal ideation,
suicide attempt, suicide, homicidal ideation [rare]), even without previous
history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia;
neutropenia; thrombocytopenia; thyroid dysfunction; retinal abnormalities |
| Drug Name |
Peginterferon alfa 2a (Pegasys) -- Consists of IFN alfa 2a attached to
a 40-kD branched PEG molecule. Predominantly metabolized by the liver. |
| Adult Dose |
180 mcg SC qwk |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity; decompensated liver disease; significant
preexisting psychiatric disease; ongoing or recent alcohol use; platelet
count <,70,000/mm3 |
| Interactions |
Theophylline may increase toxicity by reducing clearance; cimetidine may
increase the antitumor effects; zidovudine and vinblastine may increase
toxicity |
| Pregnancy |
D - Unsafe in pregnancy |
| Precautions |
Insomnia; mental dysfunction (eg, mood dysfunction, depression, psychosis,
aggressive behavior, hallucinations, violent behavior, suicidal ideation,
suicide attempt, suicide, homicidal ideation [rare]), even without previous
history of psychiatric illness; flulike symptoms; rash and pruritus; anorexia;
neutropenia; thrombocytopenia; thyroid dysfunction; retinal abnormalities |
| Drug Name |
Ribavirin (Rebetol) -- Antiviral nucleoside analog. Chemical name is D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide.
Given alone, has little effect on the course of hepatitis C. When with IFN,
significantly augments rate of sustained virologic response. |
| Adult Dose |
10.6 mg/kg PO qd or divided bid |
| Pediatric Dose |
Not established |
| Contraindications |
Documented hypersensitivity; pregnancy |
| Interactions |
Decreases effects of zidovudine |
| Pregnancy |
X - Contraindicated in pregnancy |
| Precautions |
Hemolytic anemia (vulnerable individuals, eg, those with significant cardiovascular
disease or underlying anemia should not take ribavirin); teratogenicity
(confirm negative pregnancy test before therapy; both male and female patients
should be counseled about risks and advised to use birth control); cough
and dyspnea; rash and pruritus; insomnia; anorexia |
Follow-Up
Further Inpatient Care:
- Severely ill patients with hepatitis due to HCV infection should be transferred
to an intensive care unit for close observation and aggressive treatment.
Further Outpatient Care:
- Patients should be monitored closely for adverse effects and responses to
therapy.
Transfer:
- Patients should be transferred to referral centers for liver transplantation,
if indicated.
Deterrence/Prevention:
- Currently, no products are available to prevent hepatitis C infection.
- The development of immunoprophylaxis for this disease is proving to be difficult;
an effective neutralizing immune response has not been demonstrated after
HCV infection.
- Patients with hepatitis C should be advised to abstain from alcohol use.
- Patients with hepatitis C should be advised to use barrier protection during
sexual intercourse.
- Screening high-risk patients and initiating appropriate treatment may curtail
the incidence of cirrhosis and hepatocellular carcinoma.
Complications:
- Chronic infection develops in 70-80% of patients infected with HCV.
- Cirrhosis develops within 20 years of disease onset in 20% of those with
chronic infection.
- Hepatocellular carcinoma develops in 1-4% of patients with cirrhosis each
year. Hepatocellular carcinoma may develop on an average of 30 years after
the onset of infection. It is more common in the presence of alcoholism, cirrhosis,
and HBV co-infection.
- HCV is a well-recognized cause of a variety of manifestations. Among the
most commonly reported are the following:
Cryoglobulinemia: Cryoglobulins are found in as
many as half the persons with HCV infection. HCV is the chief cause of essential
mixed cryoglobulinemia, ie, type II cryoglobulinemia; as many as 90% of affected
persons have HCV viremia. Cryoprecipitates usually contain large amounts of
HCV antigens and antibodies. Approximately 10-15% of affected patients have
symptoms such as weakness, arthralgias, and purpura; these often are related
to vasculitis.
Membranoproliferative glomerulonephritis
Idiopathic thrombocytopenic purpura
Lichen planus
Keratoconjunctivitis sicca
Raynaud syndrome
Sjögren syndrome
Porphyria cutanea tarda
Necrotizing cutaneous vasculitis
Non-Hodgkin lymphoma
- The precise pathogenesis of these extrahepatic complications has not been
determined, although most are the clinical expression of autoimmune phenomena.
Prognosis:
- Infection with HCV is self-limiting in only a small minority of those infected.
Chronic infection develops in 70-80% of patients infected with HCV.
- Cirrhosis develops within 20 years of disease onset in 20% of those with
chronic infection.
- Hepatocellular carcinoma develops in 1-4% of patients with cirrhosis each
year after an average of 30 years. Hepatocellular carcinoma is more common
in the presence of alcoholism, cirrhosis, and HBV co-infection.
- With the currently recommended therapy for chronic hepatitis C, which includes
PEG IFN and ribavirin, cure rates are as high as 60%.
Patient Education:
- Patients with hepatitis C should be advised to abstain from alcohol use.
- Optimally, patients should use barrier protection during sexual intercourse.
- Patients with hepatitis C should not donate blood or organs.
MISCELLANEOUS
Medical/Legal Pitfalls:
- Failure to recommend appropriate therapy for hepatitis C may cause legal
problems.
- Failure to monitor for adverse effects of therapy, especially depression
due to IFN use, may cause legal problems.
- In pregnant patients, ribavirin may have teratogenic effects.
- Patients with acute infection appear to have an excellent chance of responding
to 6 months of standard therapy. Patients stuck by a needle used on a person
who is infected should have an HCV PCR performed immediately and then every
2 months for 6 months. If the viral infection is diagnosed, therapy can be
instituted.
Special Concerns:
- Patients should be closely monitored for adverse effects of therapy.
Recommend that patients or their spouses not become pregnant while either is
on therapy.
PICTURES
Picture 1. Hepatitis C. Causes of chronic liver disease.
Courtesy of the US Centers for Disease Control and Prevention, Atlanta, Ga.
Click to view larger image
Picture 2. Hepatitis C viral genome.
Courtesy of Hepatitis Resource Network.
Click to view larger image
Picture 3. Natural history of hepatitis C virus infection.
Click to view larger image
Picture 4. Diagnostic algorithm for hepatitis C virus infection.
Click to view larger image
Picture 5. Evolution of the treatment for hepatitis C virus infection.
Click to view larger image
Picture 6. Pegylated interferon alfa 2b plus ribavirin therapy for chronic
hepatitis C.
From Manns et al: Lancet 2001 Sep 22; 358(9286): 958-65.
Click to view larger image
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