Hepatitis C is a major global public health problem. HCV infection is one of the main causes of cirrhosis and HCC. HCV-related end stage liver disease is the leading reason for liver transplantation in the USA.
Acute HCV infection
The incubation period for acute hepatitis C averages 6 to 10 weeks.41
Most persons (~80%) who develop acute hepatitis C have no symptoms.56
The onset of disease is usually insidious, with anorexia, vague abdominal discomfort, nausea and vomiting, fever and fatigue, progressing to jaundice in about 25% of patients, less frequently than hepatitis B.5, 41, 55, 94
Rapid, fulminant liver failure associated with HCV infection is a rare event.39
Severity ranges from inapparent cases in approximately 75% of infections to rare fulminating, fatal cases.41 Chronic liver disease with fluctuating or persistently elevated liver enzymes is common, occurring after >60% of HCV infections in adults.41, 52
Of those with chronic liver disease, 5%-20% may develop cirrhosis.
About 5% of infected persons may die from the consequences of long term infection (liver cancer or cirrhosis).94
The course of acute hepatitis C is variable, although elevations in serum ALT levels, often in a fluctuating pattern, are its most characteristic feature. Normalization of ALT levels might occur and suggests full recovery, but this is frequently followed by ALT elevations that indicate progression to chronic disease.39, 94
After acute infection, 15%-25% of persons resolve their infection without sequelae.94 Spontaneous elimination of the virus is rare.
Chronic HCV infection
Chronic hepatitis can be defined as a continuing disease without improvement for at least six months.
Chronic hepatitis is not a single disease, but rather a complex clinico-pathological syndrome with multiple causes, varying stages of necro-inflammatory and sclerosing liver damage, different prognoses and responses to treatment.3
Most persons (60%-80%) who have chronic hepatitis C have no symptoms.56
Chronic HCV infection develops in 75%-85% of persons, with persistent or fluctuating ALT elevations indicating active liver disease developing in 60%-70% of chronically infected persons. No clinical or epidemiologic features among patients with acute infection have been found to be predictive of either persistent infection or chronic liver disease.94
An important clinical feature of infection with HCV is the high rate of chronic hepatitis and slowly progressive lifelong infection, which may lead to cirrhosis and liver failure in about 10%-20% of persons with chronic hepatitis C.41, 94, 101
HCV-associated cirrhosis leads to liver failure and death in about 20%-25% of cirrhotic cases. HCV-associated cirrhosis now represents a leading indication for liver transplantation.39
Development of HCC is rare in patients with chronic hepatitis C who do not have cirrhosis.5
Chronic infection is often not symptomatic, until evidence of liver failure becomes clinically apparent. The rate of progression to cirrhosis is usually slow, with 20 or more years elapsing between infection and the development of serious complications.5, 41, 52
The period of communicability spans from one or more weeks before onset of the first symptoms and may persist in most persons indefinitely.
Based on infectivity studies in chimpanzees, the titre of HCV in the blood appears to be relatively low. Peaks in virus concentration appear to correlate with peaks in ALT activity.
Susceptibility is general. The degree of immunity following infection is not known. Repeated infections with HCV have been demonstrated in an experimental chimpanzee model.74
HCV infection does not cause fulminant hepatic failure, but, occurring in the setting of another chronic liver disease such as chronic HBV infection, may precipitate liver failure.41
Persons who have chronic liver disease are at increased risk for fulminant hepatitis A.94
Most of the serious liver disease associated with HCV is a consequence of the chronic, persistent nature of the infection.39
Even in the asymptomatic carrier, a decrease in quality of life has been reported.
Click here for: HCV and hepatocellular carcinoma (HCC)
Click here for: Extrahepatic manifestations of HCV infection
Click here for: Course of acute infection progressing to chronicity
Click here for: Schemes of potential clinical sequela of HCV infection
Click here for: Atypical forms of chronic hepatitis C
Diagnosis of hepatitis is made by biochemical assessment of liver function. Initial laboratory evaluation should include: total and direct bilirubin, ALT, AST, alkaline phosphatase, prothrombin time, total protein, albumin, globulin, complete blood count, and coagulation studies.
Hepatitis C diagnosis depends on demonstration of anti-HCV detected by an EIA. Anti-HCV is generally not detectable in patients with initial signs or symptoms of hepatitis C. Anti-HCV develop in acute infection generally between 2 and 8 weeks after evidence of liver injury. Some persons may not test positive for 6-9 months after onset of illness. Hepatitis C viremia may be detected by RT-PCR within days after infection.39, 41, 52, 55
Tests are not yet available to distinguish acute from chronic HCV infection: Positive anti-HCV IgM levels are found in 50-93% of patients with acute hepatitis C and in 50-70% of patients with chronic hepatitis C. Therefore, anti-HCV IgM cannot be used as a reliable marker of acute HCV infection.41, 69
Most sera containing anti-HCV antibodies are also HCV PCR-positive, indicating that these antibodies are markers of ongoing infection and do not correlate with resolution or clearance of infection. The ability of serum antibodies to recognize all HCV quasispecies is restricted, and neutralizing anti-HCV antibodies have not yet been identified.41, 52, 97
Target amplification techniques using either polymerase chain reaction (PCR) or transcription-mediated amplification (TMA) have been developed as qualitative tests for detecting HCV RNA, whereas both target amplification (PCR) and signal amplification techniques (branched DNA) may be used to measure HCV RNA levels.65 Because of assay variability, rigorous quality assurance and control should be introduced in clinical laboratories performing these assays, and proficiency testing should be recommended.94 For these purposes, the First International Standard for Nucleic Acid Amplification Technology (NAT) Assays for HCV RNA have been established.78
An EIA test for HCV core-antigen detection has been established and appears to be suitable for large-scale screening of blood donations, whilst its use in clinical monitoring remains to be determined.51, 62, 67
Children should not be tested for anti-HCV before 12 months of age as anti-HCV from the mother may last until this age.94 Diagnosis relies on determination of ALT levels and presence of HCV RNA in baby blood after the second month of life. 77
An early diagnosis in the course of the disease can:
• increase the chances of successful treatment
• increase impact of essential lifestyle changes
• limit cross-infection
*EIA result Suggested action anti-HCV positive HCV infection in a patient with a positive EIA test should be confirmed by a qualitative HCV RNA assay. However confirmation may be unnecessary in a patient who has evidence of liver disease and obvious risk factors for HCV. The immunoblot assay is still useful as a supplemental assay for persons screened in nonclinical settings and in persons with a positive EIA who test negative for HCV RNA. anti-HCV negative A negative EIA test is sufficient to exclude a diagnosis of chronic HCV infection in immune-competent patients, if the test is performed within 4-6 weeks of infection. Rarely, patients on haemodialysis and patients with immune deficiencies may have false-negative EIAs. In these patients, an assay for HCV RNA is necessary for diagnosis of chronic infection.
HCV infection in a patient with a positive EIA test should be confirmed by a qualitative HCV RNA assay. However confirmation may be unnecessary in a patient who has evidence of liver disease and obvious risk factors for HCV. The immunoblot assay is still useful as a supplemental assay for persons screened in nonclinical settings and in persons with a positive EIA who test negative for HCV RNA.
A negative EIA test is sufficient to exclude a diagnosis of chronic HCV infection in immune-competent patients, if the test is performed within 4-6 weeks of infection.
Rarely, patients on haemodialysis and patients with immune deficiencies may have false-negative EIAs. In these patients, an assay for HCV RNA is necessary for diagnosis of chronic infection.
Different antibodies appear in serum at different intervals from the time of initial inoculation. Anti-core antibodies directed to the nucleocapsid protein are generally the first to appear and can be detected by the time ALT is peaking.3
Infected individuals generally develop antibodies reactive with the core (C) protein as well as several nonstructural protein antigens of HCV within days to weeks after onset of clinical symptoms. However, protective antibodies have not been identified yet.39, 52, 74
The serology of HCV infection does not follow the classical pattern of IgM response observed in other viral infections because it may be absent, late or persistent after HCV infection and does not correlate with the histologic activity.3
If antibodies reactive with the hypervariable region of E2 possess virus neutralizing activity, the virus escapes this neutralizing activity by selecting out new amino acids within this hypervariable domain.39, 52
HCV specific CD4+ T cells have been identified in the peripheral blood of chronically infected patients.39
Reinfection is common after rechallenge of previously infected chimpanzees, although manifestations of HCV infection are generally reduced in secondary infections. Reinfections with both homologous and heterologous HCV strains indicate that poor immunity is not only related to antigenic variation among different strains of HCV.52, 74 Chimpanzees differ though from humans in that they make a weak (if any) humoral immune response to the structural proteins.39
However, HCV persists despite the induction of a broad humoral and cell-mediated immune response. One mechanism of HCV persistence occurs via the generation of immune-escape mutants.39
HCV readily causes a persistent infection, although some individuals spontaneously control infection. 'Successful' immune responses appear to be multi-specific and sustained-including a major role for CD4(+)T cells. Some antiviral CD8(+)T cells show reduced capacity to secrete antiviral cytokines either temporarily ('stunning') or in the long term ('stunting'). The co-ordination of multiple immune effector functions may be required to gain control of HCV.29, 47
Prior to donor screening for anti-HCV (1992), HCV was the most common cause of post-transfusion hepatitis worldwide, accounting for about 90% of this disease in the USA.52
Studies carried out in the 1970s suggested that about 7% of transfusion recipients developed NANB hepatitis, and that up to 1% of blood units might contain the responsible virus.52 The introduction of anti-HCV screening has reduced the transmission by up to almost 100%.52, 84, 95
Currently in the USA, HCV accounts for about 20% of acute viral hepatitis cases, of which less than 5% are associated with blood transfusion. The prevalence of anti-HCV is highest in injecting drug users and haemophilia patients (up to 98%)33, 54, 65, 76, 85, 105, highly variable in haemodialysis patients (<10%-90%)12, 15, 42, 59, 66, 81, 83, low in heterosexuals with multiple sexual partners, homosexual men, healthcare workers and family contacts of HCV infected persons (1%-5%), and lowest in volunteer blood donors (0.3%-0.5%). In the general population it varies (0.2%-18%).52, 102
HCV infection has no recognized seasonal distribution.74
WHO estimates that about 3% of the world’s population has been infected with HCV and that some 170 million are chronic carriers at risk of developing liver cirrhosis and/or liver cancer. These chronic carriers represent a reservoir sufficiently large for HCV to persist.
Click here for: Global prevalence of hepatitis C
HCV infects hepatocytes. It is still unclear whether the liver damage associated with HCV infection is the result of a direct cytopathic effect or is caused by a host immune-mediated cytolytic response. Both processes are probably involved in causing hepatic damage.39, 41, 52, 74, 97, 103
Factors that may affect the natural history of HCV infection: Various cofactors such as presence of HBV and alcohol intake appear to promote disease progression. Chronic HBV / HCV co-infection (HBsAg and anti-HCV positive) is uncommon globally, although it may be emerging in China. Co-infected patients have a higher risk of hepatocellular carcinoma than those who are only infected with one virus. However, it is unclear whether this high risk reflects a combined effect of the two viruses in the absence of interaction or some synergistic effect. The serological profile of anti-HBc alone / anti HCV positive is common. Some evidence suggests that presence of anti-HBc alone might increase the risk of hepatocellular carcinoma among patients with chronic HCV infection 14, 24, 39 Intake of more than 50 g alcohol / day accelerates progression to cirrhosis with a threefold risk increase.35, 99 Consistently normal ALT levels are associated with slower fibrosis progression. Limited evidence suggests that steatohepatitis may affect fibrosis progression. Steatohepatitis, rather than obesity, seems to be the important co-factor. However, one intervention study from Brisbane, Australia, suggests that reducing weight reduces fibrosis progression.8, 37, 40, 70
The influence of HIV infection depends upon CD4 count with a confounding effect of immune reconstitution following successful HAART. The relative risk for the development of cirrhosis among HIV and HCV co-infected patients is around two.26, 80 Preliminary evidence suggests that smoking may influence the development of HCC.
Factors that probably do not affect the natural history of HCV infection: Most studies suggest that in general, viral load or genotypes do not influence disease severity or progression.
Experiments carried out with chimpanzees have shown that the administration of powerful immunosuppressants before and after virus inoculation prevents the development of acute hepatitis despite viremia in the animal and viral expression in the liver. Removal of the immunosuppressant triggered an immune response which resulted in the onset of acute hepatitis followed by virus elimination.39
Transmission occurs by percutaneous exposure to contaminated blood and plasma derivatives. Contaminated needles and syringes are most important vehicles of spread, especially among injecting drug users.5, 41, 52, 101
Because the virus possesses a lipid-containing envelope, exposure of virus to bile and secretion from the liver through the biliary tract to the gut would result in rapid loss of virus infectivity.52
Uncommon but occasional is the transmission at birth from mother to child. About 5 out of every 100 infants born to HCV infected women become infected at the time of birth. Unfortunately, no treatment can prevent this from happening.5, 94, 106 Perinatal transmission explains only a small proportion of chronic HCV infections. This contrasts with HBV infection, in which most adult chronic carriers acquired infection in the newborn period.41, 52, 101
The risk of mother to infant transmission of HCV increases dramatically if the mother is co-infected with HIV possibly due to an increase in HCV titre as a result of immunosuppression.5, 39, 52, 101, 106
The risk of mother-baby transmission correlates with the titre of maternal HCV viremia.5
For women found to be HCV positive, there are no recommendations against pregnancy or breast-feeding, nor is a special method recommended to deliver the baby.103 However, invasive fetal monitoring (eg. using scalp electrodes) should be avoided.5 HCV-positive mothers should consider abstaining from breast-feeding if their nipples are cracked or bleeding.94
There is no such thing as safe blood since there is still the risk of having antibody-negative and PCR-negative blood units that can transmit disease. The advice is to use blood products only in the most necessary cases.3, 86, 95
Click here for: Risk factors associated with hepatitis C in the USA
The major risk factor for HCV infection is parenteral exposure, primarily through blood products and needle sharing among injecting drug users.5 Screening for HCV (introduced in 1990) among blood donors has reduced the risk of acquiring HCV from blood products by half to two thirds to a rate of 3 to 6 cases per 1000 recipients.41, 74
In the past, recipients of blood products were at high risk (for HCV infection). Over the last 25 years, testing blood donations for HCV has became a universal requirement. Testing procedures have made major progress in sensitivity in the last 15-20 years. However 48% of countries reported that they were not testing 100% of blood donations for HCV (WHO Global Database on Blood Safety, unpublished data). In the many countries where pretransfusion screening of blood donations for HCV is systematically performed, the residual risk of HCV transmission is minimal. Moreover, plasma derived medicinal products (including antihaemophilic factors) are undergoing additional viral inactivation and removal procedures resulting in greatly reduced or eliminated transmission of HCV by these products.
However, the risk is still present in many developing countries. Contaminated and inadequately sterilized syringes and needles have resulted in outbreaks of hepatitis C among patients in clinics and physicians’ offices. Occasionally, outbreaks have been traced to tattoo parlors and acupuncturists. Rarely, transmission to patients from HCV positive health care workers or to health care workers from HCV positive patients have been documented. It is clear from the various studies that the risk of occupational risk of HCV transmission does exist and rigorously applied universal infection precautions are the mainstay against nosocomial HCV infection.57, 87
A low frequency of HCV infection (0.004 to 0.0004% per unit transfused) continues to accompany blood transfusion due to the presence of infectious donors who are not detected by currently available antibody screening tests.95, 103 Before any screening test was available, the risk of contracting the virus was 1 in 200 units transfused.56
Groups at risk of contracting an HCV infection :
• recipients of previously unscreened blood, blood products and organs (blood transfusion or solid organ transplant before 1992, coagulation factor concentrates before 1987)
• patients and employees in hemodialysis centers (nosocomial infections)
• injecting drug users sharing contaminated needles and/or injection materials
• people exposed to unsterile medical or dental equipment
• occupational exposure to blood
• people administrating or receiving acupuncture and/or tattooing with unsterile medical devices
• health care workers
• sexual, household and perinatal transmission are possible.39
• infants born to infected mothers
A number of cases, 10% to 40%, have no identifiable risk factor.10
The mechanisms by which HCV may lead to HCC are still unsolved. Unlike HBV, HCV does not integrate into the host genome, and HCV does not seem to encode a transforming protein. HCV itself may therefore not be directly oncogenic. The feature that links HCV with cancer may rather be the repeated cycles of hepatocyte destruction and regeneration over many years. These repetitive-destruction- regenerative cycles may cause neoplastic changes, which then progress to carcinoma.21, 39, 41, 52, 97, 101
Specific diagnosis requires liver biopsy.52 The clinical usefulness of liver biopsy is to establish the diagnosis, to identify or exclude other lesions, to obtain a grading of necro-inflammatory activity, to stage the progression of the disease (clinical follow-up), and to assess the effects of treatment.25
The yearly incidence of HCC in people with cirrhosis is 3-5%.
No unique histopathologic findings that allow specific histopathologic diagnosis are associated with HCV infection.41
Hepatitis C may be associated with autoimmune diseases such as Sjögren’s syndrome and sialadenitis, idiopathic pulmonary fibrosis, polyarteritis nodosa, porphyria cutanea tarda, and a variant of autoimmune hepatitis associated with the presence of anti-kidney and liver microsomal autoantibodies.39, 41, 52, 53
Antiviral treatment should be considered for hepatitis C patients manifesting extrahepatic complications.53
IMG Fig 87-1 41
Fig 87-1 41
From: Hsu HH and Greenberg HB. Hepatitis C. In: Hoeprich PD, Jordan MC, and Ronald AR, eds. Infectious Diseases. A treatise of infectious processes, 5th ed. JB Lippincott Co, Philadelphia, 1994:820-825,41 with permission.
Typical course of acute HCV infection progressing to chronicity. HCV RNA, as detected by polymerase chain reaction (PCR), becomes positive within days of inoculation. Clinical disease develops after an incubation period ranging from 6-10 weeks. Symptoms, when present, are generally mild. Antibodies to HCV (anti-HCV) develop a mean of 12 weeks after infection and persist. The serum alanine aminotransferase (ALT) level remains elevated but can fluctuate widely. Treatment with interferon in this patient led to a complete response during therapy with normalization of ALT and loss of HCV RNA, but the patient relapsed upon discontinuation of treatment.41
The clinical latent period between acquisition of HCV infection and the development of end-stage cirrhosis and HCC may be longer than 20 years.
IMG Fig. 4
Fig. 4 39
From: Houghton M. Hepatitis C viruses. In: Fields BN, Knipe DM, and Howley PM, eds. Fields Virology, 3rd ed. Philadelphia, Lippincott - Raven, 1996:1035-1058,39 with permission.
Summary of potential clinical sequelae of HCV infection.39
Fig. 1 55
From: Marcellin P. Hepatitis C: the clinical spectrum of the disease. Journal of Hepatology, 1999, 31(Suppl.1):9-16,55 with permission ().
Spectrum of HCV infection.55
Patients with chronic hepatitis C may have no elevations in serum aminotransferases, although some of these may show signs of hepatitis by liver biopsy. Since no symptoms are often shown, these patients are detected when they donate blood.
Treatment of patients with chronic hepatitis C with normal aminotransferase levels is not generally recommended, but this issus is the subject of ongoing clinical research.
Atypical serologic patterns
Some patients with chronic hepatitis C test negative for anti-HCV. Detection of HCV RNA by PCR can establish the diagnosis. If the diagnosis is still elusive, and other diseases like autoimmune hepatitis, drug-induced liver injury, sclerosing cholangitis, Wilson’s disease, and a-1-antitrypsin deficiency are excluded, a course of corticosteroids before the use of anti-viral therapy should be tried. If there is no response to corticosteroids, interferon therapy may be considered under careful monitoring in a tertiary specialist referral centre.31
Decompensated liver disease
Only patients with early or mildly decompensated cirrhosis should be treated. The treatment of decompensated cirrhosis should be evaluated by a specialist. The best possibility for a sustained improvement in health for advanced cases is liver transplantation.5, 31
Only limited experience of therapy of chronic hepatitis C in immunosuppressed patients is available. Although preliminary reports suggest that interferon-a/ribavirin can suppress viral replication and improve serum aminotransferase levels in immunosuppressed patients, the safety and relative benefit of interferon-a/ribavirin therapy in this setting is still unclear, and should be considered experimental and carried out in the context of prospective clinical trials .31
interferon therapy for patients with essential mixed cryoglobulinemia and associated hepatitis C improves symptoms, but once interferon is discontinued, symptoms recur. A long-term maintenance interferon therapy may be warrented, the efficacy of which is currently under investigation.31
From: Marcellin P. Hepatitis C: the clinical spectrum of the disease. Journal of Hepatology, 1999, 31(Suppl.1):9-16,55 with permission.
Time course of HCV markers for chronic hepatitis C.55
Anti-HCV (antibody) - EIA ( enzyme immunoassay) - recombinant immunoblot assay (e.g. RIBA™) Verify if necessary positive EIA with HCV RNA detection Indicates past or present infection, but does not differentiate between acute, chronic or past infection. Sensitivity >95%. Detects anti-HCV in 80% of patients within 5-6 weeks of onset of hepatitis. Late seroconversion can occur. High false-positive rate for EIA in low prevalence populations and in those with auto-immune disorders. HCV RNA (virus) Qualitative tests · PCR - Amplicor HCV™ · Transcription-mediated amplification“ (TMA) - Versant HCV Quantitative tests · PCR - Amplicor HCV Monitor™ · branched DNA signal amplification - Quantiplex™ HCV RNA (bDNA) - Versant HCV RNA Quantitative Assay · other tests - SuperQuant, LCx, real-time PCR… Detect presence or absence of virus. Detects virus 1-3 weeks after exposure. Detection of HCV RNA during course of infection may be intermittent. A single negative PCR is not conclusive. Determines *titre of HCV. Used to monitor patients on antiviral therapy. False positive and false negative results can occur from improper handling, storage, and contamination of test samples. Less sensitive than qualitative PCR. Should preferably not be used to confirm or exclude the diagnosis of HCV or to monitor treatment end point. HCV core antigen EIA · Trak-C Detects presence or absence of virus. Detects virus 1-3 weeks after exposure. Under evaluation for the monitoring of patients on antiviral therapy Not licensed. Appears to be suitable for large-scale screening of blood donations, its use in clinical monitoring remains to determined Groups isolates of HCV into 6 genotypes based on genetic differences. With new therapies, length of treatment varies based on genotype. Genotype 1 and possibly 4 is/are associated with a lower response to antiviral therapy.
- EIA ( enzyme immunoassay)
- recombinant immunoblot assay (e.g. RIBA™)
Verify if necessary positive EIA with HCV RNA detection
Indicates past or present infection, but does not differentiate between acute, chronic or past infection.
Detects anti-HCV in 80% of patients within 5-6 weeks of onset of hepatitis. Late seroconversion can occur. High false-positive rate for EIA in low prevalence populations and in those with auto-immune disorders.
HCV RNA (virus)
- Amplicor HCV™
· Transcription-mediated amplification“ (TMA)
- Versant HCV
- Amplicor HCV Monitor™
· branched DNA signal amplification
- Quantiplex™ HCV RNA (bDNA)
- Versant HCV RNA Quantitative Assay
· other tests
- SuperQuant, LCx, real-time PCR…
Detect presence or absence of virus. Detects virus 1-3 weeks after exposure. Detection of HCV RNA during course of infection may be intermittent. A single negative PCR is not conclusive.
Determines *titre of HCV. Used to monitor patients on antiviral therapy.
False positive and false negative results can occur from improper handling, storage, and contamination of test samples.
Less sensitive than qualitative PCR. Should preferably not be used to confirm or exclude the diagnosis of HCV or to monitor treatment end point.
HCV core antigen EIA
Detects presence or absence of virus. Detects virus 1-3 weeks after exposure. Under evaluation for the monitoring of patients on antiviral therapy
Appears to be suitable for large-scale screening of blood donations, its use in clinical monitoring remains to determined
Groups isolates of HCV into 6 genotypes based on genetic differences.
With new therapies, length of treatment varies based on genotype.
Genotype 1 and possibly 4 is/are associated with a lower response to antiviral therapy.
The EIA test is done first. If positive, it should be confirmed e.g. by the same assay but on a second, different sample and if necessary by HCV RNA. If the EIA test is negative or borderline positive, the patient is unlikely to be infected with HCV.39, 93
The high sensitivity of diagnostic assays should be verified in different parts of the world. Account should be taken of the possibility that different genotypes may change their distribution, due to the large population movements in the modern age.
HCV RNA assays provide a direct measure of viral load:
PCR-based assays, the branched-DNA (bDNA) assays and other are used to determine qualitatively or quantitively HCV RNA. They are used in blood screening, to follow disease progression and to monitor therapeutic response, e.g. to interferon-a/ribavirin, in HCV-infected people.65, 93
Genotyping and quantitative HCV RNA tests are recommended prior to the treatment of patients.5
Qualitative HCV RNA testing, which is not performed routinely, should be restricted to the following situations:69
- etiological diagnosis of seronegative acute hepatitis of unknown cause
- etiological diagnosis of seronegative chronic hepatitis of unknown cause
- patients with weakly positive EIA results, particularly in immuno-suppressed patients
- chronic hepatitis C with repeatedly normal ALT levels
- diagnosis of HCV infection in babies born to HCV-infected mothers
- monitoring of anti-viral therapy
- diagnosis performed within the “window period” (1-3 weeks after infection)
Virological tests do not provide information on severity or prognosis of HCV-related disease.69
From: Pawlotsky J-M. Diagnostic tests for hepatitis C. Journal of Hepatology, 1999, 31(Suppl.1):71-79,69 with permission.
Principles of target amplification techniques for the detection of hepatitis C virus (HCV) RNA. HCV particles are lyzed and the released RNA is reverse transcribed (RT) into a double-stranded (ds) complementary DNA (cDNA). Double-stranded cDNAs are then processed into a cyclic enzymatic reaction, leading to the production of a large number of copies: polymerase chain reaction (PCR) produces ds-DNA molecules, whereas transcription-mediated amplification (TMA) produces single-stranded (ss) molecules.69
From: Pawlotsky J-M. Diagnostic tests for hepatitis C. Journal of Hepatology, 1999, 31(Suppl.1):71-79,69 with permission.
Principles of branched DNA-based single amplification for the detection and quantification of hepatitis C virus (HCV) RNA. HCV particles are lyzed and the released RNA is hybridized onto the wells of a microtiter plate. Hybridized RNAs are then labeled by means of branched DNA (bDNA) molecules, which achieve signal amplification.69
Three generations of “ELISA” tests
Detection of antibody to a single epitope by ELISA (EIA) was the first test developed in 1990.48 It had poor sensitivity and was not helpful early after infection since the antibody appears four to six months after infection. Second and third generation ELISA and RIBA™ tests have increased sensitivity and narrowed the window period between infection and viral detection:
Third-generation EIAs detect the same antibodies with better sensitivity, plus antibodies directed to NS5.69 With the current third-generation assays, the window period between HCV infection and the detection of anti-HCV antibodies is, on average, of 7-8 weeks. As a consequence, the residual risk of HCV transmission by anti-HCV-negative blood products in 1999 in France has been estimated to 4.9/million donations.69, 95
Existing assays do not differentiate between:
- false positive EIA results
- patients having recovered from acute infection
- patients with chronic HCV infection and HCV RNA levels below the detection limit
Generally, the performance of currently available screening assays requires only one test for the diagnosis of HCV infection in clinical virology laboratories.69
From: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_c/slide_21.htm, Centers for Disease Control and Prevention, Atlanta, GA, USA.
Recent studies have demonstrated that injecting-drug use currently accounts for 60% of HCV transmission in the United States.10 Although the role of sexual activity in transmission of HCV remains unclear, less than or equal to 20% of persons with HCV infection report sexual exposures (i.e., exposure to an infected sexual partner or to multiple partners) in the absence of percutaneous risk factors. Other known exposures (occupational, hemodialysis, household, perinatal) together account for approximately 10% of infections. Thus, a potential risk factor can be identified for approximately 90% of persons with HCV infection. In the remaining 10%, no recognized source of infection can be identified, although most persons in this category are associated with low socioeconomic level. Although low socioeconomic level has been associated with several infectious diseases and might be a surrogate for high-risk exposures, its nonspecific nature makes targeting prevention measures difficult.10