Viral Hepatitis

Clinical Correlation

Hepatitis C
 Hepatitis C Virus: Morphology and Characteristics

Hepatitis C Virus
• Nucleic Acid: 9.6 kb ssRNA

• Classification: Flaviviridae,
Hepacivirus

40-60 nm • Genotypes: 1 to 6

• Enveloped

• In vitro model: primary

hepatocyte and T cell cultures;
replicon system
• In vivo replication: in cytoplasm,
hepatocyte and lymphocyte;
human and other primates
 Hepatitis C Virus

capsid envelop protease/helic RNA- RNA polymerase

e ase dependent
protein
c22 33c c-100

5’ 3’

c E1 E2 NS NS NS NS
ore 2 3 4 5

hypervariable
region
 Hepatitis C Life Cycle

CD81?

www.rockefeller.edu/pubinfo/hepc.jpg
 Prevalence

HCV - Epidemiology

Prevalence

Worldwide 170 million ( 3%)

 Current Likelihood of Transmission

HCV - Epidemiology

Current Likelihood of Transmission

Transfusion ~ 1 in 1,000,000
Maternal-Infant
• Mother HIV-negative ~ 5%
• Mother HIV-positive 15 - 20%

Heterosexual partner ~1 in 1,000 per yr

Needlestick injury
• HCV-positive source ~ 5%
• HCV status unknown ~ 1%

Terrault NA, Hepatology 2002 ;36(Suppl 1):S99

Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106
 Relative Risk Factors for Hepatitis C
Transmission
High Risk Injection drug use Blood or blood
product transfusion
or transplantation
prior to 1992
Moderate Risk High-risk sexual Vertical transmission
activity* from mother to baby

Low risk Occupational Sexual activity

exposure between long-term
spouses/sexual
partners
Very low/No risk Casual contact Household contact

*Sexual transmission of HCV is not clearly understood. However, certain high risk sexual
behaviors have been associated with HCV transmission such as anal sex, sex with trauma, sex in
the presence of a sexually transmitted disease (STD), and sex without a condom.
 Hepatitis C - Clinical
Features
Incubation period: Average 6-7 wks
Range 2-26 wks
Clinical illness (jaundice): 30-40% (20-30%)
Chronic hepatitis: 70%
Persistent infection: 85-100%
Immunity: No protective
antibody
response identified
 Outcome Following Hepatitis C Infection

HCV - Natural History

Outcome Following Hepatitis C Infection

Acute hepatitis C
55 - 85%
Chronic infection
70%
Chronic hepatitis
1 - 4%/yr
20% HCC
Cirrhosis
Decompensation
Time 4 - 5%/yr
(yr)
10 20 30
Clinical Symptoms and Signs

• Many patients with chronic hepatitis C have no symptoms

of liver disease. If symptoms are present, they are usually
mild, nonspecific, and intermittent. They may include
• fatigue
• mild right-upper-quadrant discomfort or tenderness
• nausea
• poor appetite
• muscle and joint pains
• Similarly, the physical exam is likely to be normal or
show only mild enlargement of the liver or tenderness.
Clinical Features of Cirrhosis

Once a patient develops cirrhosis or if the patient has severe disease,

symptoms and signs are more prominent.
In addition to fatigue, the patient may complain of muscle weakness,
poor appetite, nausea, weight loss, itching, dark urine, fluid retention,
and abdominal swelling.
Physical findings of cirrhosis may include
• enlarged liver
• enlarged spleen
• jaundice
• muscle wasting
• excoriations ascites
• ankle swelling
Extrahepatic Manifestations

• Complications that do not involve the liver develop in 1 to 2 percent of people

with hepatitis C; the most common is cryoglobulinemia, which is marked by
• skin rashes, such as purpura, vasculitis, or urticaria
• joint and muscle aches
• kidney disease
• neuropathy
• cryoglobulins, rheumatoid factor, and low-complement levels in serum
• Other complications of chronic hepatitis C are
• glomerulonephritis
• porphyria cutanea tarda
• Diseases that are less well documented to be related to hepatitis C are
• seronegative arthritis
• keratoconjunctivitis sicca (Sjögren's syndrome)
• non-Hodgkin's type, B-cell lymphomas
• fibromyalgia
 Diagnosis of Hepatitis C

• The use of serological and virological tests has become essential

in the management of hepatitis C virus (HCV) infection in order
to diagnose infection, guide treatment decisions and assess the
virological response to antiviral therapy.

• Virological tools include serological assays for anti-HCV

antibody detection and serological determination of the HCV
genotype, and molecular assays that detect and quantify HCV
RNA and determine the HCV genotype.
Serologic Tests Used to Diagnose Hepatitis C
Enzyme Immunoassay Enzyme Immunoassay
Recombinant Immunoblot Assay
PCR Amplification
Biochemical Indicators of Hepatitis C Virus Infection
Quantification of HCV RNA in Serum
Genotyping and Serotyping of HCV
Normal Serum ALT Levels
Liver Biopsy
Immunostaining
 VIROLOGICAL TOOLS
Serological assays

Anti-HCV antibody detection

The detection of anti-HCV antibodies in plasma or serum is
based on the use of third-generation EIAs, that detect mixtures
of antibodies directed against various HCV epitopes.

The presence of anti-HCV antibodies is revealed by anti-

antibodies labeled with an enzyme that catalyzes the
transformation of a substrate into a colored compound. The
optical density (OD) ratio of the reaction (sample OD/internal
control OD) is proportional to the amount of antibodies in the
serum or plasma sample
Anti-HCV antibody detection(cont)

The specificity of third-generation EIAs for anti-HCV is greater than 99%

– Recombinant Immunoblot Assay used to confirm anti-HCV reactivity,

too. 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.

– 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.
Anti-HCV antibody detection(cont)

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 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 without virus. If the immunoblot test is
negative, the EIA result was probably a false positive.
 Acute hepatitis C infection

HCV - Diagnosis

1000
Acute HCV Infection
HCV RNA positive
800
Anti-HCV
600
ALT
(IU/L)
400
Symptoms

200

Normal
0 ALT
0 2 4 6 8 10 12 24 1 2 3 4 5 6 7
Weeks Months
Time After Exposure
Hoofnagle JH, Hepatology 1997; 26:15S
 Hepatitis C: Typical Serologic Course

HCV
antibody
Symptoms
Person is sick,
but test for
Hep C is
Titer

negative

ALT
(liver
functio
n test)
Normal
0 1 2 3 4 5 6 1 2 3 4
Months Years
Time after
Exposure
 VIROLOGICAL TOOLS
Serological assays
Serological determination of the HCV genotype

The HCV genotype can be determined by seeking for antibodies directed

to genotype-specific HCV epitopes with a competitive EIA.

The currently available assay (Murex HCV serotyping 1-6 HC02, Abbott
Laboratories, North Chicago, Illinois) identifies the type (1 to 6), but does
not discriminate among the subtypes, and provides interpretable results in
approximately 90% of chronically infected immunocompetent patients.

Mixed serological reactivities can be observed that could be related to

mixed infection although cross-reactivity or recovery from one genotype
infection and persistence of viremia with another genotype cannot be ruled
out.
 VIROLOGICAL TOOLS
Detection and quantification of HCV RNA
• PCR amplification can detect low levels of HCV RNA in
serum.

Testing for HCV RNA by PCR is particularly useful when

• aminotransferases are normal or only slightly elevated,
• anti-HCV is not present,
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.
 VIROLOGICAL TOOLS
Detection and quantification of HCV RNA

Qualitative, non-quantitative HCV RNA detection

Qualitative detection assays are based on the principle of target
amplification using either “classic” polymerase chain reaction (PCR),
“real-time” PCR or TMA.

HCV RNA is extracted and reverse transcribed into a double stranded

complementary DNA (cDNA), which is subsequently processed into a
cyclic enzymatic reaction leading to the generation of a large number of
detectable copies.

Double-stranded DNA copies of HCV genome are synthesized in PCR-

based assays, whereas single-stranded RNA copies are generated in TMA.
 VIROLOGICAL TOOLS
Detection and quantification of HCV RNA

Qualitative, non-quantitative HCV RNA detection

HCV RNA quantification In “real-time” PCR, each round of
amplification leads to the emission of a fluorescent signal and
the number of signals per cycle is proportional to the amount
of HCV RNA in the starting sample.

Qualitative detection assays must detect 50 HCV RNA IU/ml

or less, and have equal sensitivity for the detection of all HCV
genotypes.
HCV RNA quantification
HCV RNA can be quantified by means of target amplification techniques
(competitive PCR or real-time PCR) or signal amplification techniques
(branched DNA (bDNA) assay)

Table shows the respective dynamic ranges of quantification of the

currently available assays, i.e. the HCV RNA intervals within which
quantification is accurate in the corresponding assay.

HCV RNA levels falling above the upper limit of quantification of the assay
are underestimated and the samples must be retested after 1/10 to 1/100
dilution in order to achieve accurate quantification.

The most promising approach for the future is fully automated real-time
PCR assays, which are faster, more sensitive than classical target
amplification techniques and are not prone to carryover contamination.
Assay Manufacturer Technique Lower limit of Dynamic range of
detection quantification
(qualitative (quantitative assay)
assay)
Amplicor® HCV v2.0 Roche Molecular Systems Manual RT-PCR 50 IU/ml NA

Cobas® Amplicor® HCV Roche Molecular Systems Semi-automated RT-PCR 50 IU/ml NA

v2.0

Versant® HCV RNA Bayer HealthCare Manual TMA 10 IU/ml NA

Qualitative Assay

Amplicor HCV Monitor® Roche Molecular Systems Manual RT-PCR 600 IU/ml 600-500,000 IU/ml
v2.0

Cobas® Amplicor HCV Roche Molecular Systems Semi-automated RT-PCR 600 IU/ml 600-500,000 IU/ml
Monitor v2.0
RT : Abbott
LCx HCV RNA Quantitative
reverse transcriptaseSemi-automated RT-PCR
Diagnostic 25 IU/ml 25-2,630,000 IU/ml
Assay PCR : polymerase chain reaction
TMA
Versant® HCV RNA:3.0
transcription-mediated
Bayer HealthCare amplification
Semi-automated bDNA 615 IU/ml 615-7,700,000 IU/ml
Assay
bDNA : “branched DNA“
Cobas® TaqMan HCV Test NA : not
Roche applicable
Molecular Systems Semi-automated real-time 15 IU/ml 43-69,000,000 IU/ml
*for 0.2 ml or 0.5 ml of plasma analyzed,PCR respectively
Abbott RealTime Abbott Diagnostic Semi-automated real-time 30 IU/ml or 12 IU/ml* 12-100,000,000 IU/ml
PCR
• 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.

• 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.
 VIROLOGICAL TOOLS
Molecular determination of the HCV genotype (genotyping)

• In clinical practice, HCV genotype can be determined by

various commercial kits, using direct sequence analysis of
the 5' noncoding region or reverse hybridization analysis
using genotype-specific probes located in the 5' noncoding
region.

• The type is used for therapeutic decision-making.

• An assay based on direct sequencing of the NS5B region is

currently in development
 Guide to the interpretation of hepatitis C
testing
Antibody to HCV RNA Usual interpretation Other possible
HCV interpretation
Negative Negative No infection
Positive Positive HCV present

Positive Negative Resolved infection 1. False-positive (<1%)

Negative Positive Infection present (usually in
immunocompromised
patients or patients
undergoing hemodialysis)
2. Treated, HCV below
detectable limits
(verify with qualitative HCV
RNA PCR)
1. Early infection
2. False-positive or
contaminated test
system
Algorithm for laboratory investigation of suspected HCV infection
Test for anti-HCV
by EIA or ELISA

Negative Positive

Not infected. No further tests unless: HCV RNA quantitative assay

• Acute exposure by PCR or bDNA
• Hemodialysis
• Immunocompromised
Negative Positive

HCV RNA qualitative assay by

PCR Genotype

Negative = resolved infection Positive = infected

 Liver Biopsy
• Liver biopsy is not necessary for diagnosis but is considered the most accurate
means to estimate the necroinflammatory activity and the extent of fibrosis
together with recognition of architectural disturbances.

• Liver biopsy is also helpful in ruling out other causes of liver disease, such as
alcoholic liver injury or iron overload.

• Immunostaining using polyclonal or monoclonal antibodies to detect HCV

antigens in the liver has been reported to be useful. However, these tests are not
commercially available, and, even in the hands of research investigators,
immunostaining detects HCV antigens in liver tissue in only 60 to 70 percent of
patients with chronic hepatitis C--largely in those with high levels of HCV in
serum.

• This test also requires special handling of liver tissue and thus is not
appropriate fo routine clinical use.
 Liver Biopsy
• HCV causes the following changes in liver tissue:
• Necrosis and inflammation around the portal areas, so-called "piecemeal necrosis" or
"interface hepatitis."

Necrosis of hepatocytes and focal inflammation in the liver parenchyma.

• Inflammatory cells in the portal areas ("portal inflammation").

• Fibrosis, with early stages being confined to the portal tracts, intermediate stages
being expansion of the portal tracts and bridging between portal areas or to the central
area, and late stages being frank cirrhosis characterized by architectural disruption of
the liver with fibrosis and regeneration.

• Grading and staging of hepatitis by assigning scores for severity are helpful in
managing patients with chronic hepatitis.

• The degree of inflammation and necrosis can be assessed as none, minimal, mild,
moderate, or severe. The degree of fibrosis can be similarly assessed. Scoring
systems are particularly helpful in clinical studies on chronic hepatitis.
 Histologic grading and staging in hepatitis C
Scale Necro- Fibrosis Total score
inflammation
Histology 0–18 0–4 0–22
Activity
Index
(HAI)12
Ishak 0–18 0–6 0–24
modified
HAI13
METAVIR14 0–3 0–4 0–7
 Is liver biopsy mandatory in children with chronic
hepatitis C?
• On the basis of the studies available so far, chronic hepatitis C in children
seems to be a milder disease with a more favourable natural course when
compared to hepatitis C virus (HCV) infection in adults.

• Several histological studies have confirmed that in children chronic HCV

infection is morphologically benign in the majority of cases, progression of
fibrosis is relatively slow and cirrhosis is extremely rare.

• Liver histology investigation of a child with chronic hepatitis C has few

chances to highlight severe lesions.
• the presence of bridging

• Fibrosis or cirrhosis reduces the expected response rate to antiviral

therapy.
 Noninvasive Tests
• Recently, x-ray and imaging studies have been developed
that may be able to separate different degrees of fibrosis in
the liver.

• The most promising technique is “elastrography,”(fibro

scan) in which sound or magnetic waves are passed
through the liver and the speed with which they return is
measured, which provides an index of the elasticity and
stiffness of the liver.
 Noninvasive Tests
• Liver stiffness is used as an indirect measure of liver fibrosis.

• Most importantly, measuring the relative stiffness of the liver over

time may provide a noninvasive way to monitor the development of
fibrosis and help guide recommendations for when therapy should
be recommended.

• Ultrasound elastrography is currently under evaluation for its

reliability in measuring the degree of fibrosis in the liver in patients
with hepatitis C. Ultimately, elastrography may be able to replace
liver biopsy as a way of monitoring the progression of disease in
chronic hepatitis C.
 Noninvasive Tests
• The “danger signals” that suggest the presence of advanced fibrosis include an
aspartate aminotransferase (AST) that is higher than ALT (reversal of the
ALT/AST ratio),
• a high gamma glutamyl transpeptidase or alkaline phosphatase,
• a decrease in platelet count (which is perhaps the earliest change),
• elevations in serum globulins,
• and, of course, abnormal bilirubin, albumin, or prothrombin time.
• Physical findings of a firm liver, or enlarged spleen or prominent spider
angionata or palmar erythema, are also danger signals.
• While none of these findings are completely reliable, their presence should
raise the suspicion of significant fibrosis and lead to evaluation for treatment
sooner rather than later.
 Biochemical Indicators of Hepatitis C Virus Infection
• In chronic hepatitis C, increases in the alanine and aspartate aminotransferases
range from 0 to 20 times (but usually less than 5 times) the upper limit of
normal.

• Alanine aminotransferase levels are usually higher than aspartate

aminotransferase levels, but that finding may be reversed in patients who have
cirrhosis.

• Alkaline phosphatase and gamma glutamyl transpeptidase are usually normal.

If elevated, they may indicate cirrhosis.

• Rheumatoid factor and low platelet and white blood cell counts are frequent in
patients with cirrhosis, providing clues to the presence of advanced disease.

• The enzymes lactate dehydrogenase and creatine kinase are usually normal.

• Albumin levels and prothrombin time are normal until late-stage disease.
 DIAGNOSIS OF HCV INFECTION
Acute hepatitis C

• Patients with a suspicion of acute hepatitis C should be tested for both anti-
HCV antibodies by EIA and HCV RNA with a sensitive technique, i.e. an
HCV RNA assay with a lower limit of detection of 50 IU/ml or less

• The presence of HCV RNA in the absence of anti-HCV antibodies is strongly

indicative of acute HCV infection, which will be confirmed by
seroconversion (i.e. the appearance of anti-HCV antibodies) a few days to
weeks later.

• Acutely infected patients can also have both HCV RNA and anti-HCV
antibodies at the time of diagnosis. It is difficult, in this case, to distinguish
acute hepatitis C from an acute exacerbation of chronic hepatitis C or an
acute hepatitis of another cause in a patient with chronic hepatitis C
 DIAGNOSIS OF HCV INFECTION
Acute hepatitis C
• Acute hepatitis C is very unlikely if both anti-HCV antibodies and HCV RNA
are absent.

• It is also unlikely if anti-HCV antibodies are present without HCV RNA.

These patients should however be retested after a few weeks because HCV
RNA can be temporarily undetectable, due to transient, partial control of viral
replication by the immune response before replication escapes and chronic
infection establishes

• Apart from such cases, the presence of anti-HCV antibodies in the absence of
HCV RNA is generally seen in patients who have recovered from a past HCV
infection.

• Nevertheless, this pattern cannot be differentiated from a false positive EIA

result, the exact prevalence of which is unknown.
 DIAGNOSIS OF HCV INFECTION
Chronic hepatitis C
• In patients with clinical or biological signs of chronic liver disease, chronic
hepatitis C is certain when both anti-HCV antibodies and HCV RNA (sought
for with a sensitive technique, detecting 50 IU/ml or less) are present.

• Detectable HCV replication in the absence of anti-HCV antibodies is

exceptional with the current third-generation EIAs, almost exclusively
observed in profoundly immunodepressed patients, hemodialysis patients or
agammaglobulinemic subjects.

• Indeed, neither anti-HCV antibodies nor the HCV RNA load correlate with
the severity of liver inflammation or fibrosis nor with their progression. Thus,
they cannot be used to predict the natural course of infection or the onset of
extrahepatic manifestations.
 Differential Diagnosis
The major conditions that can be confused clinically with chronic
hepatitis C include
• autoimmune hepatitis
• chronic hepatitis B and D
• alcoholic hepatitis
• nonalcoholic steatohepatitis (fatty liver)
• sclerosing cholangitis
• Wilson disease
• alpha-1-antitrypsin-deficiency-related liver disease
• drug-induced liver disease
 What is the most effective therapy
for hepatitis C?
• Combination therapy results in better treatment responses than monotherapy,
but the highest response rates have been achieved with pegylated interferon in
combination with ribavirin.

• Genotype determinations influence treatment decisions.

• Currently the best indicator of effective treatment is an SVR,

Defined by the absence of detectable HCV RNA in the serum as
shown by a qualitative HCV RNA assay with lower limit of detection
of 50 IU/mL or less at 24 weeks after the end of treatment.
 What is the most effective therapy
for hepatitis C?
• Three large pivotal trials have examined the efficacy of pegylated
interferon plus ribavirin in the treatment of chronic HCV infection. These
trials excluded patients with decompensated cirrhosis and comorbid
conditions.

• Factors associated with successful therapy included

• genotypes other than 1,
• lower baseline viral levels,
• less fibrosis or inflammation on liver biopsy,
• and lower body weight or body surface area.
• Among patients with genotypes 2 or 3, SVRs with standard interferon and
ribavirin were comparable to those with pegylated interferon and ribavirin,
 What is the most effective therapy
for hepatitis C?
• 24 weeks of treatment and an 800 mg dose of ribavirin appears to
be sufficient for persons with genotypes 2 and 3, while patients
with genotype 1 need 48 weeks of treatment and standard doses of
ribavirin.
• Early viral response (EVR), defined as a minimum 2 log decrease
in viral load during the first 12 weeks of treatment, is predictive of
SVR and should be a routine part of monitoring patients.

• Patients who fail to achieve an EVR at week 12 of treatment have

only a small chance of achieving an SVR even if therapy is
continued for a full year. Treatment need not be extended
beyond 12 weeks in these patients.
 Effective therapy for hepatitis C
• The absence of detectable serum HCV RNA has been associated with
resolution of liver injury, reduction in hepatic fibrosis, and a low likelihood of
a relapse of the HCV infection.

• Selected patients who fail to achieve an SVR may benefit from re-treatment
with pegylated interferon-based regimens.

• Decisions regarding re-treatment should be based on

(1) previous type of response,
(2) the previous therapy and the difference in potency of the new
therapy,
(3) the severity of the underlying liver disease,
(4) viral genotype and other predictive factors for response,
(5) tolerance of previous therapy and adherence.
 Before Starting Therapy
• Do a liver biopsy to confirm the diagnosis of HCV, assess the grade and
stage of disease, and rule out other diagnoses. In situations where a liver
biopsy is contraindicated, such as clotting disorders, combination
therapy can be given without a pretreatment liver biopsy.

• Test for serum HCV RNA to document that viremia is present.

• Test for HCV genotype (or serotype) to help determine the duration of
therapy and dose of ribavirin.

• Measure blood counts and aminotransferase levels to establish a

baseline for these values.

• Counsel the patient about the relative risks and benefits of treatment.
Side effects should be thoroughly discussed.
 Which patients with hepatitis C should be treated?
• All patients with chronic hepatitis C are potential
candidates for antiviral therapy.
• Treatment is recommended for patients with an increased
risk of developing cirrhosis.
These patients are characterized by
• detectable HCV RNA levels higher than 50 IU/mL,
• a liver biopsy with portal or bridging fibrosis,
• and at least moderate inflammation and necrosis.
• The majority also have persistently elevated ALT values
 Which patients with hepatitis C should b treated?
• All patients with chronic hepatitis C should be vaccinated against hepatitis A,
and seronegative persons with risk factors for hepatitis B virus (HBV) should
be vaccinated against hepatitis B.

• Approximately 30 percent of patients with chronic HCV infection have normal

ALT levels, and another 40 percent have ALT levels less than two times the
upper limit of normal.

• Although most of these patients have mild disease, histologically, some may
progress to advanced fibrosis and cirrhosis.

• Experts differ on whether to biopsy and treat these patients. 23 Numerous

factors must be considered in recommending
 Which patients with hepatitis C should b treated?
• Treatment, including favorable genotype, presence of hepatic
fibrosis, patient motivation, symptoms, severity of comorbid
illness, and the patient’s age.

• When patients with normal or minimally elevated ALT levels

are treated with monotherapy, their SVR rates are similar to
those of patients with higher ALT levels.

• Studies of pegylated interferon with ribavirin have not been

completed in patients with normal ALT levels.
During Therapy

• Measure blood counts and aminotransferase levels at weeks 1, 2,

and 4 and at 4- to 8-week intervals thereafter.

• Adjust the dose of ribavirin downward (by 200 mg at a time) if

significant anemia occurs (hemoglobin less than 10 g/dL or
hematocrit < 30 percent) and stop ribavirin if severe anemia
occurs (hemoglobin < 8.5 g/dl or hematocrit < 26 percent).
• Adjust the dose of peginterferon downward if there are intolerable side
effects such as severe fatigue, depression, or irritability or marked decreases
in white blood cell counts (absolute neutrophil count below 500 cells/mm3)
or platelet counts (decrease below 30,000 cells/mm3). When using
peginterferon alfa-2a, the dose can be reduced from 180 to 135 and then to
90 mcg per week. When using peginterferon alfa-2b, the dose can be
reduced from 1.5 to 1.0 and then to 0.5 mcg per kg per week.

• In patients with genotype 1, measure HCV RNA levels immediately before

therapy and again (by the same method) at week 12. Therapy can be stopped
early if HCV RNA levels have not decreased by at least two log10 units, as
studies have shown that genotype 1 patients without this amount of decrease
in HCV RNA are unlikely to have a sustained response (likelihood is < 1
percent). In situations where HCV RNA levels are not obtainable, repeat
testing for HCV RNA by PCR (or TMA) should be done at 24 weeks and
therapy stopped if HCV RNA is still present, as a sustained response is
unlikely.
• Reinforce the need to practice strict birth control during therapy
and for 6 months thereafter.

• Measure thyroid-stimulating hormone levels every 3 to 6 months

during therapy.

• Patients with genotypes 2 or 3 can stop therapy at 24 weeks.

Patients with genotype 1 who are HCV RNA negative at 24
weeks should continue therapy to a full 48 weeks.

• At the end of therapy, test HCV RNA by PCR to assess whether

there is an end-of-treatment response.
• After Therapy

• Measure aminotransferase levels every 2 months

for 6 months.

• Six months after stopping therapy, test for HCV

RNA by PCR (or TMA). If HCV RNA is still
negative, the chance for a long-term “cure” is
excellent; relapses have rarely been reported after
this point.
 Hepati tis C Prev entio n
Hepatitis C Prevention

• Screening of blood, organ, tissue donors

• Blood and body fluid precautions
• Education
– High-risk behavior modification
– Same risk factors as hepatitis B
– Blood > sex > Perinatal

• No vaccine
• IG does not protect
 Prognostic Tests

Prognostic Tests

• Genotyping – genotype 1 and 4 have a worse prognosis overall and respond

poorly to interferon therapy. A number of commercial and in-house assays are
available.
– Genotypic methods – DNA sequencing, PCR-hybridization e.g. INNO-LIPA.
– Serotyping – particularly useful when the patient does not have detectable RNA.
• Viral Load – patients with high viral load are thought to have a poorer
prognosis. Viral load is also used for monitoring response to IFN therapy. A
number of commercial and in-house tests are available.
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