Hcv

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 e protein c22

protease/helic ase 33c

RNA- RNA polymerase dependent c-100

5’

3’ c E1 ore

E2

hypervariable region

NS 2

NS 3

NS 4

NS 5

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 • Mother HIV-positive

Heterosexual partner

~ 5% 15 - 20%

~1 in 1,000 per yr

Needlestick injury

• HCV-positive source • HCV status unknown

Terrault NA, Hepatology 2002 ;36(Suppl 1):S99 Roberts EA, Yeung L. Hepatology 2002 ;36(Suppl 1):S106

~ 5% ~ 1%

Relative Risk Factors for Hepatitis C Transmission High Risk

Moderate Risk

Low risk

Very low/No risk

Injection drug use

Blood or blood product transfusion or transplantation prior to 1992

High-risk sexual activity*

Vertical transmission from mother to baby

Occupational exposure

Sexual activity between long-term spouses/sexual partners

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: Clinical illness (jaundice): Chronic hepatitis: Persistent infection: Immunity:

Average 6-7 wks Range 2-26 wks 30-40% (20-30%) 70% 85-100% 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 20%

1 - 4%/yr

HCC

Cirrhosis Time (yr)

4 - 5%/yr 10

20

Decompensation 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 antiantibodies 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 falsepositive 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

Acute HCV Infection

1000

HCV RNA positive 800

Anti-HCV ALT

600

(IU/L)

Symptoms

400 200 0

0

2

4

6

8

Weeks

10

12

24

1

2

3

Time After Exposure

Hoofnagle JH, Hepatology 1997; 26:15S

4

5

Months

6

Normal ALT

7

Hepatitis C: Typical Serologic Course

HCV antibody

Symptoms

Titer

Person is sick, but test for Hep C is negative ALT (liver functio n test)

Normal 0

1

2

3 4 Months

5

6

Time after Exposure

1

2 3 Years

4

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 PCRbased 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 detection (qualitative assay)

Dynamic range of quantification (quantitative assay)

Amplicor® HCV v2.0

Roche Molecular Systems

Manual RT-PCR

50 IU/ml

NA

Cobas® Amplicor® HCV v2.0

Roche Molecular Systems

Semi-automated RT-PCR

50 IU/ml

NA

Versant® HCV RNA Qualitative Assay

Bayer HealthCare

Manual TMA

10 IU/ml

NA

Amplicor HCV Monitor® v2.0

Roche Molecular Systems

Manual RT-PCR

600 IU/ml

600-500,000 IU/ml

Cobas® Amplicor HCV Monitor v2.0

Roche Molecular Systems

Semi-automated RT-PCR

600 IU/ml

600-500,000 IU/ml

25 IU/ml

25-2,630,000 IU/ml

615 IU/ml

615-7,700,000 IU/ml

15 IU/ml

43-69,000,000 IU/ml

30 IU/ml or 12 IU/ml*

12-100,000,000 IU/ml

RT : Abbott reverse transcriptaseSemi-automated RT-PCR Diagnostic PCR : polymerase chain reaction Versant® HCV RNA:3.0 Bayer HealthCare Semi-automated bDNA TMA transcription-mediated amplification Assay bDNA : “branched DNA“ : not applicable Cobas® TaqMan HCV Test NA Roche Molecular Systems Semi-automated real-time *for 0.2 ml or 0.5 ml of plasma analyzed,PCR respectively LCx HCV RNA Quantitative Assay

Abbott RealTime

Abbott Diagnostic

Semi-automated real-time 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

HCV RNA

Usual interpretation

Other possible interpretation

Negative

Negative

No infection

Positive

Positive

HCV present

Positive

Negative

Resolved infection

1. False-positive (<1%) 2. Treated, HCV below detectable limits (verify with qualitative HCV RNA PCR)

Negative

Positive

Infection present (usually in immunocompromised patients or patients undergoing hemodialysis)

1. 2.

Early infection False-positive or contaminated test system

Algorithm for laboratory investigation of suspected HCV infection Test for anti-HCV by EIA or ELISA

Negative

Positive HCV RNA quantitative assay by PCR or bDNA

Not infected. No further tests unless: • Acute exposure • Hemodialysis • Immunocompromised

Negative HCV RNA qualitative assay by PCR Negative = resolved infection

Positive = infected

Positive Genotype

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

Necroinflammation

Histology 0–18 Activity Index (HAI)12 Ishak 0–18 modified HAI13 METAVIR14 0–3

Fibrosis

Total score

0–4

0–22

0–6

0–24

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 antiHCV 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 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.

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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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