The hepatitis C virus (HCV) is one of the most important causes of chronic

liver disease in the United States. It accounts for about 15 percent of acute
viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of
cirrhosis, end-stage liver disease, and liver cancer. Of the U.S. population,
1.6 percent, or an estimated 4.1 million Americans, have antibody to HCV
(anti-HCV), indicating ongoing or previous infection with the virus.
Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the
.United States

A distinct and major characteristic of hepatitis C is its tendency to cause

chronic liver disease in which the liver injury persists for a prolonged period
if not for life. About 75 percent of patients with acute hepatitis C ultimately
.develop chronic infection

Chronic hepatitis C varies greatly in its course and outcome. At one end of
the spectrum are infected persons who have no signs or symptoms of liver
disease and have completely normal levels of serum enzymes, the usual
blood test results that indicate liver disease. Liver biopsy usually shows
some degree of injury to the liver, but the extent is usually mild, and the
overall prognosis may be good. At the other end of the spectrum are patients
with severe hepatitis C who have symptoms, high levels of the virus (HCV
RNA) in serum, and elevated serum enzymes, and who ultimately develop
cirrhosis and end-stage liver disease. In the middle of the spectrum are many
patients who have few or no symptoms, mild to moderate elevations in liver
.enzymes, and an uncertain prognosis

Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer.
Researchers estimate that at least 20 percent of patients with chronic
hepatitis C develop cirrhosis, a process that takes at least 10 to 20 years.
Liver failure from chronic hepatitis C is one of the most common reasons for
 liver transplants in the United States. After 20 to 40 years, a small
percentage of patients develop liver cancer. Hepatitis C is the
cause of about half of cases of primary liver cancer in the
developed world. Men, alcoholics, patients with cirrhosis,
people over age 40, and those infected for 20 to 40 years
.are at higher risk of developing HCV-related liver cancer

Risk Factors and Transmission

HCV is spread primarily by contact with infected blood and

blood products. Blood transfusions and the use of shared,
unsterilized, or poorly sterilized needles, syringes and
injection equipment or paraphernalia have been the main
routes of the spread of HCV in the United States. With the
introduction in 1991 of routine blood screening for HCV
antibody and improvements in the test in mid-1992,
transfusion-related hepatitis C has virtually disappeared. At
present, injection drug use is the most common risk factor
for contracting the infection. However, some patients who
acquire hepatitis C do not have a recognized risk factor or
.known exposure to infected blood or to drug use

The most common risk factors for acquiring hepatitis C are

injecting drugs, including having used injection drugs•

only once many years ago

having a blood transfusion before June 1992, when•

sensitive tests for anti-HCV were introduced for blood
screening
 receiving clotting factor concentrates (such as anti-•
hemophilic factor) before 1987, when effective means
to inactive HCV were introduced

hemodialysis for kidney failure•

birth to an HCV-infected mother•

suffering a needle-stick accident from a person with•

hepatitis C

Other risk factors that have a slightly increased risk for

hepatitis C are

having sex with someone with hepatitis C or having•

multiple sex partners

intranasal use of cocaine using shared equipment or•

paraphernalia

Maternal-Infant Transmission

Maternal-infant transmission is not common. In most studies,

less than 5 percent of infants born to HCV-infected mothers
become infected. The disease in newborns is usually mild
and free of symptoms. The risk of maternal-infant spread
rises with the amount of virus in the mother’s blood, if the
mother also has human immunodeficiency virus (HIV)
infection, or if there are complications of delivery such as
early rupture of membranes and fetal monitoring. Breast-
.feeding has not been linked to the spread of HCV
 Sexual Transmission

Sexual transmission of hepatitis C between monogamous

partners appears to be uncommon. Surveys of spouses and
monogamous sexual partners of patients with hepatitis C
show that fewer than 5 percent are infected with HCV, and
many of these have other risk factors for this infection.
Spread of hepatitis C to a spouse or partner in stable,
monogamous relationships occurs in less than 1 percent of
partners per year. For these reasons, changes in sexual
practices are not recommended for monogamous patients.
Testing sexual partners for anti-HCV can help with patient
counseling. People with multiple sex partners should be
advised to follow safe sex practices, which should protect
against hepatitis C as well as hepatitis B, HIV, and other
.sexually transmitted diseases

Sporadic Transmission

Sporadic transmission, when the source of infection is

unknown, is the basis for about 10 percent of acute hepatitis
C cases and for 30 percent of chronic hepatitis C cases.
These cases are usually referred to as sporadic or
community-acquired infections. These infections may have
come from exposure to the virus from cuts, wounds, or
.medical injections or procedures
 Unsafe Injection Practices

In many areas of the world, unsafe injection practices in the

delivery of health care are an important and common cause
of hepatitis C (and hepatitis B as well). Use of inadequately
sterilized equipment, reuse of needles and syringes, and
inadvertent contamination of medical infusions are
unfortunately well-documented causes of transmission of
hepatitis C. Careful attention to universal precautions and
injection techniques should prevent this type of spread. In
the United States, multiple-use vials are a frequent culprit in
.leading to medical-care linked spread of hepatitis C

Signs and symptoms

:Acute
Acute hepatitis C refers to the first 6 months after infection
with HCV. Between 60% to 70% of people infected develop
no symptoms during the acute phase. In the minority of
patients who experience acute phase symptoms, they are
generally mild and nonspecific, and rarely lead to a specific
diagnosis of hepatitis C. Symptoms of acute hepatitis C
infection include decreased appetite, fatigue, abdominal
.pain, jaundice, itching, and flu-like symptoms

The hepatitis C virus is usually detectable in the blood within

one to three weeks after infection by PCR, and antibodies to
the virus are generally detectable within 3 to 15 weeks.
 Spontaneous viral clearance rates are highly variable and
between 10–60% of persons infected with HCV clear the
virus from their bodies during the acute phase as shown by
normalization in liver enzymes (alanine transaminase (ALT) &
aspartate transaminase (AST)), and plasma HCV-RNA
clearance (this is known as spontaneous viral clearance).
However, persistent infections are common[ and most
patients develop chronic hepatitis C, i.e., infection lasting
.more than 6 months

Previous practice was to not treat acute infections to see if

the person would spontaneously clear; recent studies have
shown that treatment during the acute phase of genotype 1
infections has a greater than 90% success rate with half the
.treatment time required for chronic infections

Chronic
Chronic hepatitis C is defined as infection with the hepatitis
C virus persisting for more than six months. Clinically, it is
often asymptomatic (without symptoms) and it is mostly
.discovered accidentally

The natural course of chronic hepatitis C varies considerably

from one person to another. Although almost all people
infected with HCV have evidence of inflammation on liver
biopsy the rate of progression of liver scarring (fibrosis)
shows significant variability among individuals. Accurate
 estimates of the risk over time are difficult to establish
because of the limited time that tests for this virus have
.been available

Recent data suggest that among untreated patients, roughly

one-third progress to liver cirrhosis in less than 20 years.
Another third progress to cirrhosis within 30 years. The
remainder of patients appear to progress so slowly that they
are unlikely to develop cirrhosis within their lifetimes. In
contrast the NIH consensus guidelines state that the risk of
progression to cirrhosis over a 20-year period is 3-20
.percent

Factors that have been reported to influence the rate of HCV

disease progression include age (increasing age associated
with more rapid progression), gender (males have more
rapid disease progression than females), alcohol
consumption (associated with an increased rate of disease
progression), HIV coinfection (associated with a markedly
increased rate of disease progression), and fatty liver (the
presence of fat in liver cells has been associated with an
.(increased rate of disease progression

Symptoms specifically suggestive of liver disease are

typically absent until substantial scarring of the liver has
occurred. However, hepatitis C is a systemic disease and
patients may experience a wide spectrum of clinical
manifestations ranging from an absence of symptoms to a
more symptomatic illness prior to the development of
 advanced liver disease. Generalized signs and symptoms
associated with chronic hepatitis C include fatigue, flu-like
symptoms, joint pains, itching, sleep disturbances, appetite
.changes, nausea, and depression

Once chronic hepatitis C has progressed to cirrhosis, signs

and symptoms may appear that are generally caused by
either decreased liver function or increased pressure in the
liver circulation, a condition known as portal hypertension.
Possible signs and symptoms of liver cirrhosis include ascites
(accumulation of fluid in the abdomen), bruising and
bleeding tendency, varices (enlarged veins, especially in the
stomach and esophagus), jaundice, and a syndrome of
cognitive impairment known as hepatic encephalopathy.
Hepatic encephalopathy is due to the accumulation of
ammonia and other substances normally cleared by a
.healthy liver

Liver enzyme tests show variable elevation of ALT and AST.

Periodically they might show normal results. Usually
prothrombin and albumin results are normal, but may
become abnormal, once cirrhosis has developed. The level of
elevation of liver tests do not correlate well with the amount
of liver injury on biopsy. Viral genotype and viral load also do
not correlate with the amount of liver injury. Liver biopsy is
the best test to determine the amount of scarring and
inflammation. Radiographic studies such as ultrasound or CT
scan do not always show liver injury until it is fairly
 advanced. However, non-invasive tests (blood sample) are
coming, with FibroTest and ActiTest, respectively estimating
liver fibrosis and necrotico-inflammatory. These tests are
validated and recommended in Europe (FDA procedures
(initiated in USA

Chronic hepatitis C, more than other forms of hepatitis, can

be associated with extrahepatic manifestations associated
with the presence of HCV such as porphyria cutanea tarda,
cryoglobulinemia (a form of small-vessel vasculitis)[11] and
glomerulonephritis (inflammation of the kidney), specifically
membranoproliferative glomerulonephritis (MPGN). Hepatitis
C is also rarely associated with sicca syndrome (an
autoimmune disorder), thrombocytopenia, lichen planus,
diabetes mellitus and with B-cell lymphoproliferative
.disorders
 Diagnosis
The diagnosis of "hepatitis C" is rarely made during the
acute phase of the disease because the majority of people
infected experience no symptoms during this phase of the
disease. Those who do experience acute phase symptoms
are rarely ill enough to seek medical attention. The diagnosis
of chronic phase hepatitis C is also challenging due to the
absence or lack of specificity of symptoms until advanced
liver disease develops, which may not occur until decades
.into the disease

Chronic hepatitis C may be suspected on the basis of the

medical history (particularly if there is any history of IV drug
abuse or inhaled substance usage such as cocaine), a history
of piercings or tattoos, unexplained symptoms, or abnormal
liver enzymes or liver function tests found during routine
blood testing. Occasionally, hepatitis C is diagnosed as a
result of targeted screening such as blood donation (blood
donors are screened for numerous blood-borne diseases
.including hepatitis C) or contact tracing

Hepatitis C testing begins with serological blood tests used

to detect antibodies to HCV. Anti-HCV antibodies can be
detected in 80% of patients within 15 weeks after exposure,
in >90% within 5 months after exposure, and in >97% by 6
months after exposure. Overall, HCV antibody tests have a
strong positive predictive value for exposure to the hepatitis
C virus, but may miss patients who have not yet developed
 antibodies (seroconversion), or have an insufficient level of
antibodies to detect. Rarely, people infected with HCV never
develop antibodies to the virus and therefore, never test
positive using HCV antibody screening. Because of this
possibility, RNA testing (see nucleic acid testing methods
below) should be considered when antibody testing is
negative but suspicion of hepatitis C is high (e.g. because of
elevated transaminases in someone with risk factors for
.(hepatitis C

Anti-HCV antibodies indicate exposure to the virus, but

cannot determine if ongoing infection is present. All persons
with positive anti-HCV antibody tests must undergo
additional testing for the presence of the hepatitis C virus
itself to determine whether current infection is present. The
presence of the virus is tested for using molecular nucleic
acid testing methods such as polymerase chain reaction
(PCR), transcription mediated amplification (TMA), or
branched DNA (b-DNA). All HCV nucleic acid molecular tests
have the capacity to detect not only whether the virus is
present, but also to measure the amount of virus present in
the blood (the HCV viral load). The HCV viral load is an
important factor in determining the probability of response
to interferon-based therapy, but does not indicate disease
.severity nor the likelihood of disease progression

In people with confirmed HCV infection, genotype testing is

generally recommended. HCV genotype testing is used to
 determine the required length and potential response to
.interferon-based therapy

Serologic Tests

Enzyme Immunoassay
Persons suspected to have hepatitis C should be tested for
anti-HCV as an initial screening test. Anti-HCV is detected by
enzyme immunoassay (EIA). The third-generation test (EIA-3)
used today is more sensitive and specific than previous
ones. As with all enzyme immunoassays, however, false-
positive results are occasionally a problem with the EIA-3.
.Additional or confirmatory testing is often helpful

The best approach to confirm the diagnosis of hepatitis C is

to test for HCV RNA using a sensitive assay such as
polymerase chain reaction (PCR) or transcription-mediated
amplification (TMA). The presence of HCV RNA in serum
.indicates an active infection

Testing for HCV RNA is also helpful in patients in whom EIA

tests for anti-HCV are unreliable. For instance,
immunocompromised patients may test negative for anti-
HCV despite having HCV infection because they may not
produce enough antibodies for detection with EIA. Likewise,
patients with acute hepatitis may test negative for anti-HCV
when first tested. Antibody is present in almost all patients
by 1 month after onset of acute illness; thus, patients with
acute hepatitis who initially test negative may need follow-
 up testing. In these situations, HCV RNA is usually present
.and confirms the diagnosis

Recombinant Immunoblot Assay

Immunoblot assays can be used to confirm anti-HCV
reactivity. These tests are also called “Western blots”; serum
is incubated on nitrocellulose strips on which four
recombinant viral proteins are blotted. Color changes
indicate that antibodies are adhering to the proteins. An
immunoblot is considered positive if two or more proteins
react and is considered indeterminate if only one positive
band is detected. In some clinical situations, confirmatory
testing by immunoblotting is helpful, such as for the person
with anti-HCV detected by EIA who tests negative for HCV
RNA. The EIA anti-HCV reactivity could represent a false-
positive reaction, recovery from hepatitis C, or continued
virus infection with levels of virus too low to be detected (the
last occurs only rarely when sensitive PCR or TMA assays are
used). If the immunoblot test for anti-HCV is positive, the
patient has most likely recovered from hepatitis C and has
persistent antibody. If the immunoblot test is negative, the
.EIA result was probably a false positive

Immunoblot tests are routine in blood banks when an anti-

HCV-positive sample is found by EIA. Immunoblot assays are
highly specific and valuable in verifying anti-HCV reactivity.
Indeterminate tests require further follow-up testing,
 including attempts to confirm the specificity by repeat
.testing for HCV RNA

Direct Assays for HCV RNA

PCR and TMA amplification can detect low levels of HCV RNA
in serum. Testing for HCV RNA is a reliable way of
demonstrating that hepatitis C infection is present and is the
most specific test for infection. Testing for HCV RNA is
particularly useful when aminotransferase levels are normal
or only slightly elevated, when anti-HCV is not present, or
when several causes of liver disease are possible. This
method also helps diagnose hepatitis C in people who are
immunosuppressed, have recently had an organ transplant,
or have chronic renal failure. Currently available PCR assays
will detect HCV RNA in serum down to a lower limit of 50 to
100 copies per milliliter (mL), which is equivalent to 25 to 50
international units (IU). A slightly more sensitive TMA test
has recently become available. Almost all patients with
.chronic hepatitis C will test positive by these assays

Quantification of HCV RNA in Serum

Several methods are available for measuring the

concentration or level of virus in serum, which is an indirect
assessment of viral load. These methods include a
quantitative PCR and a branched DNA (bDNA) test.
Unfortunately, these assays are not well standardized, and
different methods from different laboratories can provide
 different results on the same specimen. In addition, serum
levels of HCV RNA can vary spontaneously by 3- to 10-fold
over time. Nevertheless, when performed carefully,
quantitative assays provide important insights into the
nature of hepatitis C. Most patients with chronic hepatitis C
have levels of HCV RNA (viral load) between 100,000 (105)
and 10,000,000 (107) copies per mL. Expressed as IU, these
.averages are 50,000 to 5 million IU

Viral levels as measured by HCV RNA do not correlate with

the severity of the hepatitis or with a poor prognosis (as in
HIV infection); but viral load does correlate with the
likelihood of a response to antiviral therapy. Rates of
response to a course of peginterferon and ribavirin are
higher in patients with low levels of HCV RNA. There are
several definitions of a “low level” of HCV RNA, but the usual
.definition is below 800,000 IU (~ 2 million copies) per mL

In addition, monitoring HCV RNA levels during the early

phases of treatment may provide early information on the
likelihood of a response. Yet because of the shortcomings of
the current assays for HCV RNA level, these tests are not
.always reliable guides to therapy

Genotyping and Serotyping of HCV

There are six known genotypes and more than 50 subtypes
of hepatitis C. The genotype is helpful in defining the
epidemiology of hepatitis C. More important, knowing the
 genotype or serotype (genotype-specific antibodies) of HCV
is helpful in making recommendations and counseling
regarding therapy. Patients with genotypes 2 and 3 are two
to three times more likely to respond to interferon-based
therapy than patients with genotype 1. Furthermore, when
using combination therapy, the recommended dose and
duration of treatment depend on the genotype. For patients
with genotypes 2 and 3, a 24-week course of combination
treatment using peginterferon and 800 milligrams (mg) of
ribavirin daily is adequate, whereas for patients with
genotype 1, a 48-week course and full dose of ribavirin
(1,000 to 1,200 mg daily) is recommended. For these
reasons, testing for HCV genotype is clinically important.
Once the genotype is identified, it need not be tested again;
.genotypes do not change during the course of infection

Normal Serum ALT Levels

Up to 40 percent of patients with chronic hepatitis C have
normal serum alanine aminotransferase (ALT) levels, even
when tested on multiple occasions. In this and other
situations in which the diagnosis of chronic hepatitis C may
be questioned, the diagnosis should be confirmed by testing
for HCV RNA. The presence of HCV RNA indicates that the
.patient has ongoing viral infection despite normal ALT levels

:Treatment

IFN therapy with and without ribavirin

Although the short courses of standard IFN monotherapy first
introduced in the 1980s by Hoofnagle et al (1986), Davis et
al (1989), and Di Bisceglie et al (1989) led to sustained
improvement in liver disease and loss of virus in less than
10% of patients, these therapies were the first to cure
chronic viral hepatitis.13,2,14 A major advance in the treatment
of chronic hepatitis C was the addition of the oral nucleoside
analogue ribavirin to the IFN regimen. As reported in the
landmark 1998 studies by McHutchison et al and Poynard et
al, IFN alfa-2b and ribavirin combination therapy for 6-12
months resulted in sustained eradication rates of 30-40%.15
However, patients with HCV genotype 1 who were treated
for 12 months had a much less favorable response to
therapy with IFN and ribavirin compared with patients
infected with genotypes 2 and 3, in whom a 6-month course
.of therapy was sufficient

IFN monotherapy appears to play a role in the treatment of

acute HCV infection. In 2001, Jaeckel et al reported that
treatment with IFN alfa-2b prevented chronic infection in
98% of a group of 44 German patients with acute hepatitis
C.16 In this study, patients received 5 million U/d of IFN alfa-
2b subcutaneously for 4 weeks and then 3 times per week
for another 20 weeks; the IFN alfa-2b was well tolerated in
all patients but one. Because spontaneous resolution is
common, no definitive timing of therapy can be
recommended; however, waiting 2-4 months after the onset
.of illness seems reasonable

The 2 most frequently used recombinant IFN preparations in

clinical trials are IFN alfa-2b (Intron-A; Schering-Plough,
Kenilworth, NJ) and IFN alfa-2a (Roferon; Hoffmann-La Roche,
Basel, Switzerland), which differ from each other by only a
single amino acid residue. IFN alfacon-1 (Infergens; Amgen,
Thousand Oaks, Calif), or consensus IFN, 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
consensus IFN dose of 9 mcg in IFN-naive patients with
chronic hepatitis C, such as that by Tong et al from 1997,
have resulted in viral response rates similar to those of
standard IFN-alfa monotherapy.17

PEG-IFN monotherapy

Developments in IFN technology have led to the

development of long-lasting IFNs in which PEG molecules are
added to IFN. These new PEG-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 PEG-IFNs for the
.treatment of chronic hepatitis C
 The 2 PEG-IFN preparations currently available are (1) PEG-
Intron (Schering-Plough), which consists of IFN alfa-2b
attached to a single 12-kd PEG chain and is metabolized
predominantly by the liver, and (2) Pegasys (Hoffmann-La
Roche), which consists of IFN alfa-2a attached to a 40-kd
branched PEG molecule. Note that pegylated alfa-2b is
.excreted by the kidneys

Several reports have documented the improved SVR with

PEG-IFN monotherapy. In a 2000 randomized study of
patients with chronic hepatitis C, Zeuzem et al found that
PEG-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.18 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

In 2000, Heathcote and colleagues reported on the use of

PEG-IFN alfa-2a in a controlled trial of subjects with
cirrhosis.19 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
 PEG-IFN therapy with ribavirin

As previously described with IFN alfa monotherapy, the

addition of ribavirin to PEG-IFN has heralded a new era in the
treatment of chronic HCV, resulting in 3 landmark trials:
Manns et al from 2001, Fried et al from 2002, and
Hadziyannis et al from 2004.20,11,21

In 2001, Manns et al compared PEG-IFN alfa-2b plus ribavirin

with IFN alfa-2b plus ribavirin in 1530 subjects with chronic
hepatitis C.20 Subjects were randomly assigned to 3 groups,
as follows: (1) IFN alfa-2b at 3 million U subcutaneously 3
times per week plus ribavirin at 1000-1200 mg/d orally, (2)
PEG-IFN alfa-2b at 1.5 mcg/kg/wk plus ribavirin at 800 mg/d,
and (3) PEG-IFN alfa-2b at 1.5 mcg/kg/wk for 4 weeks and
then 0.5 mcg/kg/wk plus ribavirin at 1000-1200 mg/d for 48
.weeks

The SVR rate (see Media file 6) was significantly higher in the
higher-dose PEG-IFN group (274 [54%] of 511 subjects) than
in the lower-dose PEG-IFN (244 [47%] of 514 subjects; P = .
01) or IFN (235 [47%] of 505 subjects; 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 rates for patients with genotype 2 and 3 infections were
approximately 80% for all treatment groups. Adverse-effect
profiles were similar among the treatment groups.
Secondary analyses identified body weight and HCV RNA
viral load less than 1 million copies per milliliter as important
predictors of SVR. 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

In 2002, Fried at al compared the efficacy and safety of PEG-

IFN alfa-2a plus ribavirin to IFN alfa-2b plus ribavirin and
PEG-IFN alfa-2a monotherapy in a multicenter, randomized,
controlled trial.11 A total of 1121 subjects were randomly
assigned to treatment and received at least one dose of
study medication, consisting of 180 mcg of PEG-IFN alfa-2a
once weekly plus daily ribavirin (1000 or 1200 mg,
depending on body weight), weekly PEG-IFN alfa-2a plus
daily placebo, or 3 million U of IFN alfa-2b thrice weekly plus
.daily ribavirin for 48 weeks

This study showed that a significantly higher proportion of

subjects who received PEG-IFN alfa-2a plus ribavirin had an
SVR compared with subjects who received IFN alfa-2b plus
ribavirin (56% vs 44%, P <.001) or PEG-IFN alfa-2a alone
(56% vs 29%, P <.001). The SVR rates for patients with HCV
genotype 1 were 46%, 36%, and 21%, respectively, for the 3
regimens. Among patients with HCV genotype 1 and high
baseline levels of HCV RNA, the SVR rates were 41%, 33%,
and 13%, respectively. The overall safety profiles of the 3
treatment regimens were similar; the prevalence of
 influenzalike symptoms and depression was lower in the
groups receiving PEG-IFN alfa-2a than in the group receiving
IFN alfa-2b plus ribavirin. Overall, once-weekly PEG-IFN alfa-
2a plus ribavirin was tolerated as well as IFN alfa-2b plus
ribavirin and produced significant improvements in the SVR
rate compared with IFN alfa-2b plus ribavirin or PEG-IFN alfa-
.2a alone

In 2004, Hadziyannis et al reported the efficacy and safety of

24 or 48 weeks of treatment with PEG-IFN alpha-2a plus a
low or standard dose of ribavirin in a randomized, double-
blinded trial.21 The 1311 subjects were randomized to PEG-
IFN alfa-2a at 180 mcg/wk for 24 or 48 weeks plus a low
dose (800 mg/d) or standard weight-based dose (1000 or
1200 mg/d) of ribavirin. An SVR was defined as undetectable
HCV RNA at the end of treatment and during 12-24 weeks of
.follow-up

Their study showed that in subjects infected with HCV

genotype 1, 48 weeks of treatment was statistically superior
to 24 weeks and that standard-dose ribavirin was
statistically superior to low-dose ribavirin. In subjects with
HCV genotype 1, absolute differences in SVR rates between
48 and 24 weeks of treatment were 11.2% (95% confidence
interval [CI], 3.6-18.9%) and 11.9% (CI, 4.7-18.9%),
respectively, between standard- and low-dose ribavirin. SVR
rates for PEG-IFN alfa-2a and standard-dose ribavirin for 48
weeks were 63% (CI, 59-68%) overall and 52% (CI, 46-58%)
 in subjects with HCV genotype 1. In subjects with HCV
genotypes 2 or 3, the SVR rates in the 4 treatment groups
.were not statistically significantly different

In conclusion, treatment with PEG-IFN alfa-2a and ribavirin

may be individualized by genotype. Patients with HCV
genotype 1 require treatment for 48 weeks and a standard
dose of ribavirin; those with HCV genotype 2 or 3 seem to be
.adequately treated with a low dose of ribavirin for 24 weeks

Currently, no studies have compared PEG-IFN alfa-2b plus

ribavirin versus PEG-IFN alfa-2a plus ribavirin. According to
the 2002 US National Institutes of Health consensus
statement on the management of hepatitis C, standard of
care for the treatment of hepatitis C is PEG-IFN with ribavirin
for 48 weeks in patients with genotype 1 and is 24 weeks for
.patients with genotype 2 or 3

Adverse effects are common with IFN and ribavirin

combination therapy, with approximately 75% of patients
:experiencing one or more of the following

Interferon - Hematological complications (ie,•

neutropenia, thrombocytopenia), neuropsychiatric
complications (ie, memory and concentration
disturbances, visual disturbances, headaches,
depression, irritability), flulike symptoms, metabolic
complications (ie, hypothyroidism, hyperthyroidism,
low-grade fever), gastrointestinal complications (ie,
nausea, vomiting, weight loss), dermatological
 complications (ie, alopecia), and pulmonary
(complications (ie, interstitial fibrosis

Ribavirin - Hematological complications (ie, hemolytic•

anemia), reproductive complications (ie, birth defects),
(and metabolic complications (ie, gout

Growth factors, such as granulocyte-stimulating factor and

erythropoietin, are frequently used to counteract the
adverse hematological effects of IFN and ribavirin,
respectively. Despite the encouraging results reported by
Afdhal et al in 2004 and Van Thiel et al in 1995, cost-
effectiveness data supporting their routine use as a means
.of avoiding IFN and ribavirin dose reductions are insufficient

In patients who are at risk of depression or who develop

depression during treatment, any antidepressant is better
than none. Because available evidence suggests that all
antidepressants will have an effect, Schaefer et al reported
in 2002 that treatment must be individualized on the basis of
adverse effect profile, drug-to-drug interactions, and general
.(considerations (eg, speed of onset, efficacy

Telaprevir, PEG-IFN, and ribavirin

Despite the advent of new treatment strategies with addition

of ribavirin to PEG-IFN, the current available therapies for
chronic HCV infection are effective in fewer than 50% of
patients with HCV genotype 1. The PROVE1 study
demonstrated that addition of telaprevir, a protease inhibitor
specific for HCV nonstructural 3/4A serine protease, to the
current treatment regimen improved virologic response to
HCV. In early studies, there was a rapid reduction of chronic
.HCV RNA levels

McHutchison et al and the PROVE1 study team evaluated the

addition of either telaprevir (1250 mg on day 1, then 750 mg
q8h) or matched placebo to the treatment regimen of
weekly PEG-IFN alfa-2a and daily ribavirin.25 The groups that
received telaprevir showed significantly improved sustained
virologic response rates (as defined by an undetectable HCV
RNA level 24 wk after the end of therapy) in patients with
genotype 1 HCV (P = 0.002). However, the telaprevir groups
had a higher rate of discontinued treatment (21%) compared
with the placebo group (11%) because of adverse effects,
.particularly rash