Elecsys Hepatitis testing Powerful tools for patient oriented decision making
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1 Elecsys Hepatitis testing Powerful tools for patient oriented decision making
2 cobas modular platform Flexible configurations for tailor made solutions With the cobas modular platform (cobas 4000 and 6000 analyzer series and cobas 8000 modular analyzer series) Roche has developed a platform concept based on a common architecture that delivers tailor-made solutions for diverse workload and testing requirements. The cobas modular platform is designed to reduce the complexity of laboratory operation and provide efficient and compatible solutions for network cooperation. Flexible and intelligent solutions Multiple configurations with tailor-made solutions for higher efficiency and productivity Consolidation of clinical chemistry and immunochemistry with more than 200 parameters for cost and workflow improvements Future sustainability through easy adaptation to changing throughput and parameter needs Consistency of interaction with hardware, software and reagents for less training and more staff flexibility Consistency of patient results due to a universal reagent concept cobas 8000 modular analyzer series Large volume 38 configurations <c 502> <e 602> <c 701> <c 702> cobas 6000 analyzer series Mid volume 7 configurations <c 501> <e 601> cobas 4000 analyzer series Low volume 3 configurations <c 311> <e 411>
3 Introduction to hepatitis The liver The liver is located on the right hand side of the abdominal cavity, below the lungs. It is the largest solid organ in the body and has four main functions: Metabolism of nutrients to produce energy Storage of excess nutrients Synthesis of essential molecules Metabolism of hormones, drugs and toxins Vein Liver Artery Gall bladder These functions are all vital to life. Hepatitis Hepatitis literally means inflammation of the liver and can have a number of causes. The most common cause is infection with one of a group of viruses, most frequently hepatitis A virus (HAV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Rarer causes include infection with other viruses, such as hepatitis delta virus, Epstein-Barr virus, rubella and yellow fever virus, bacterial infections, and drug- or poison-induced hepatitis. 1 In addition, hepatitis can result from autoimmune, 2 or metabolic conditions. 3 If the cause is viral, the body mounts an immune response to attack the virus. As it is necessary for these viruses to enter liver cells, called hepatocytes, to replicate and produce more virus, the immune system attacks the liver tissue resulting in liver damage. 4 Symptoms Hepatitis can be an acute (lasting less than six months) or chronic (lasting longer than six months) condition. 4 Many cases of acute hepatitis are asymptomatic, so patients often do not know that they have been infected. Patients with symptomatic acute hepatitis exhibit similar symptoms regardless of the causative virus. During the initial stages of infection these include fever, tiredness, weakness, nausea and vomiting, aching limbs and muscles, painful and enlarged liver (characterized as pain in the upper right quadrant of the torso), as well as flu-like symptoms. 5 The patient may then develop jaundice, which is characterized by a yellowing to the eyes and skin, dark-colored urine, and pale stools. Jaundice is caused by an inability of the liver to process bilirubin (the yellow-colored component of bile), which builds up in the blood stream as a result. 4 Patients with chronic hepatitis frequently exhibit no symptoms, but the condition can progress to very severe disease such as cirrhosis (where damage to the liver leads to replacement of normal tissue with scar and fibrous tissue), hepatocellular carcinoma (HCC) and end-stage liver failure. 6,7 Figure 1: Structure of the liver Drugs Autoantibodies Alcohol Wilson s Disease Toxins Figure 2: Agents that can cause hepatitis Viruses HAV HBV HCV HDV HEV HSV CMV EBV Rubella virus Coxsackie virus Yellow Fever virus Varicella Zoster virus Echo virus Diagnosis The diagnosis of hepatitis is made by biochemical measurements of liver function, including serum and urine bilirubin levels, total protein and serum albumin levels, and activity of alanine aminotransferase (ALT), aspartate aminotransferase and alkaline phosphatase enzymes. However, specific tests must be carried out to determine the cause of the hepatitis. These include detection of components of the virus particles, viral DNA/RNA, and antibodies to the virus in patient serum samples. 4
4 Hepatitis A Virology Hepatitis A virus (HAV) was first described in It is a member of the Picornaviridae family, which includes viruses that cause the common cold. It is a small, nm non-enveloped virus with a 7.5 kb single-stranded, positive-sense RNA genome 9,10,11 (Figure 3). Core protein 1 Core protein 3 Core protein 4 Core protein 2 Single-stranded RNA genome Figure 3: Structure of hepatitis A virus 152 strains of HAV have been identified. These have been Viral envelope Viral core into seven genotypes (I VII), with >85% nucleotide classified sequence identity between the strains in each genotype.11 Genotypes I and III have also been sub-classified into A and B subgroups. The HAV strains in genotypes I, II III and VII were isolated from human cases, while the strains from genotypes IV, V, and VI were identified from simian species.11 Prevalence Globally, HAV is a leading cause of infectious jaundice;12 there 13 RNA stangenome are 1.4 million HAV infections each year.single-stranded In areas where dards of sanitation are low, such as parts of Africa, Asia and Latin America, the seroprevalence is close to 100% in children DNA polymerase Hepatitis B core antigen (HBcAg) Disease progression Hepatitis A virus has only been linked with acute hepatitis disease. Onset of symptoms is typically abrupt, often in less than 24 hours. These are usually non-specific and a high fever is common in around 50% of cases. Diarrhea, nausea and vomiting are common in children, however increasingly severe symptoms are observed in adults. Patients usually seek medical advice at the onset of jaundice, around 10 days after the onset of symptoms, and in many cases the fever has normalized at this time.9,10,12 Symptoms slowly resolve over a period of several weeks10 and patients make a complete recovery in 3 6 months.9 Relapses are possible in the weeks to months following symptom resolution (multiple relapses are common in children), but the prognosis is good for a full recovery.9,10,12 Although HAV infection does not progress to chronic hepatitis disease, it can occasionally lead to severe complications.9,10,12 These include cholestasis (jaundice that persists for several months, followed by full recovery), extra-hepatic symptoms such as rashes and arthritis, acute liver failure, and fulminant hepatitis (exclusively in patients over 50 years of age). It is also suggested that HAV infection could be a trigger for autoimmune hepatitis development.12 Hepatitis B surface antigen (HBsAg) Core protein 4 Core protein 2 Partially double-stranded DNA Estimated child immunity rate. Darker shades indicate a higher exposure rate. HBsAg = HBV DNA = Figure 4: Seroprevalence of hepatitis A virus in children and adults 14 Marker of Marker of immunological virus replication response H Core protein Hepatitis B e antigen (HBeAg) secreted during active infection Envelope Core under 5 years of age.10,13 Conversely, the overall seroprevalence is much lower in the USA and Western Europe (can be as low at 10% in some regions) and is predominantly found in adults.10,13 See Figure 4 below. Transmission of HAV is usually by the fecal-oral route, which can result in outbreaks that affect entire communities.9,10,12,13 Symptoms develop after an incubation period of days, although HAV particles are secreted in feces for 1 2 weeks prior to the appearance of symptoms;10,12 risk of transmission is thought to be greatest during this period.12 Estimated adult susceptibility rate. Darker shades indicate a greater proportion of at-risk adults.
5 Anti-HAV IgM Anti-HAV (IgG + IgM) HAV (feces) Relative concentration Beginning of icterus Acute phase days Convalescence phase days Immunity years Anti-HAV IgM ( ) Anti-HAV (IgG + IgM) HAV (feces) Figure 5: Course of markers during hepatitis A infection Time after infection Diagnosis Diagnosis of HAV infection is achieved by measuring HAV-specific antibodies in patient blood samples. HAV-specific immunoglobulin M (IgM) is produced at the start of infection and the amount in the blood increases over the next 4 6 weeks then drops to undetectable levels over the following 3 6 months. At this time, blood liver enzyme activity returns to normal in the majority of patients (summarized in Figure 5). HAV-specific IgM is replaced by HAV-specific immunoglobulin G (IgG) that confers long-term protection against re-infection with HAV. 9,10,12 Two tests are used for the specific diagnosis of HAV infection: those that detect HAV-specific IgM (anti-hav IgM) and total HAV-specific antibodies (anti-hav) in the blood. A positive result from anti-hav alone cannot differentiate between acute and past infections; a positive anti-hav IgM result is needed to confirm the presence of acute infection. Anti-HAV can be used to determine immune status after vaccination. 9,10,12 An algorithm used for the diagnosis of HAV infection is shown in Figure 6. + Acute HAV infection Test for HAV infection anti-hav - IgM + Past HAV infection anti-hav No HAV infection Treatment and prevention Currently, there are no specific anti-viral therapies for HAV and general anti-virals have limited effect. Patients are recommended to eat a balanced diet, rest and avoid alcoholic beverages that may further harm the liver. Patients with HAV rarely suffer severe sequelae, so only require hospital treatment if dehydration results from severe anorexia or vomiting. 10,12 Prevention of HAV infection is possible by using passive immunization with human anti-hav IgG or vaccines. 12 Several vaccines are available, comprising inactivated virus or live-attenuated virus, and have been predicted to confer protection for over 20 years. 12,15,16 In regions with intermediate infection prevalence toddlers are vaccinated to reduce the burden of adult disease (which is typically symptomatic) and in the USA children are routinely vaccinated around the age of one year. 15 International travelers or workers in regions of high prevalence, such as Asia, Africa, Latin America, Eastern Europe, and the Middle East should be immunized before travel if they have not previously been exposed or immunized. 15 Vaccines can also be used post-exposure if administered rapidly following exposure. 15 HBV? HCV? Figure 6: An algorithm for diagnosis of HAV infection
6 Hepatitis B Virology Hepatitis B virus (HBV) or Dane particle was identified in the 1970s 17 after earlier work that discovered Australia antigen, now known as HBV surface antigen.18 It is an enveloped virus with a partially double-stranded circular DNA genome, and classified as a member of the Hepadnaviridae family. 6,19 This is illustrated in Figure 7. Hepatitis B e antigen (HBeAg) secreted during active infection DNA polymerase Envelope Core Hepatitis B surface antigen (HBsAg) There is also a regional variation in the prevalence of HBV;22,23 this is shown in Table 1. Genotypes B and C are predominantly found in Asia, whereas genotypes A and D predominate in Europe and the USA. HBV genotype Region A Asia, Africa, Europe, North America B Asia C Asia, Oceania D Europe, Africa, Asia E Africa F Central and South America G Europe, South Africa H Central and North America Table 1: Regional variation in HBV genotype prevalence 22,23 Hepatitis B core antigen (HBcAg) Partially double-stranded DNA Figure 7: Structure of hepatitis B virus Eight genotypes have been described, labeled A to H, that vary by >8% over=the whole genome. HBsAg = HBV DNA Marker of immunological Marker of virus replication Prevalence response Approximately two billion people worldwide are infected with HBV; 350 million of these are chronic carriers.20 The prevalence in Africa and Asia is much higher than the USA, however there are still around 5,000 HBV-related deaths per year in the USA.6 Overall, 45% of the global population lives in areas of high seroprevalence for HBV, but there is a marked variation in prevalence in different locations20 (shown in Figure 8). Low (HBsAg prevalence <2%) Intermediate (HBsAg prevalence 2%-7%) Figure 8: Global prevalence of HBV infection 21 High (HBsAg prevalence 8% Transmission of HBV is via exposure to blood, organs, or other bodily fluids from an infected individual. HBV cannot cross the skin, so transmission must occur through a break in the skin or needle puncture.6,19,20 Worldwide, transfer of HBV from mother to child is the predominant mode of transmission; however in areas of low prevalence, such as the USA and Western Europe, intravenous drug use, occupational exposure, and unprotected sexual intercourse are the major transmission routes.6,20,24 Blood transfusions and organ transplants are no longer considered a major risk in developed countries due to the introduction of rigorous screening programs in the last 20 years.6,20 Unlike hepatitis C virus (HCV), HBV replicates very quickly, so there is a significant chance of transmission from an isolated occupational exposure, such as a needle-stick injury. This means that health care workers should be considered at high risk.6 Disease progression HBV can cause both acute and chronic disease, and chronic infection is difficult to eliminate as the viral DNA can integrate into the host genome.24 In an acute infection, the incubation period is 1 6 months after infection; during this time, the virus is spreading through the liver tissue. The host immune system then attacks the virus to resolve the infection. As the virus is replicating in the hepatocytes, the immune attack causes damage to the liver tissue, which releases alanine aminotransferase (ALT) into the circulation. The strength of the immune response to HBV infection varies between individuals, so while around 65% of acute HBV infections are asymptomatic, the remainder produces non-specific symptoms and jaundice during the resolution phase of infection.19 A very small number of acute HBV patients (0.1 1%) progress to fulminant hepatitis and liver failure requiring a transplant.19
7 The progression from acute to chronic HBV infection varies depending on the host age at infection. 24,25 Roughly 90% of infected newborns, 20 30% of infants between 1 and 2 years, 6% of children between 5 and 15 years, and 1 5% of adult patients progress to chronic HBV infection. 25 The four stages of chronic HBV infection are summarized in Figure 9. In the immune tolerant phase, there are very few damaged hepatocytes as the immune response to the invading HBV is not very strong. This means that ALT levels are normal, but HBV DNA, HBsAg and HBeAg can all be detected in patient serum samples. 19,25,26 The infection can resolve within 20 years without therapy, but only in around 15% of cases. 6 HBV DNA ALT HBsAg Immune tolerant HBeAg+ Immune reactive Immune control HBeAg Immune escape The immune reactive or clearance phase commences years after the immune tolerant phase. 6 The host immune system actively attacks the liver tissue to clear the HBV infection and the damaged hepatocytes release large amounts of ALT into the circulation. HBV DNA (>10 6 copies/ml), HBsAg, and HBeAg are all present in patient samples. 19,25,26 This phase of the disease is known as HBeAg-positive chronic hepatitis B. In this stage of chronic HBV infection, 12 20% of patients progress to serious liver damage within 5 years. 6 Treatment? Treatment Observe Treatment HBeAg + chronic hepatitis B Figure 9: The four stages of chronic HBV infection 26 There are four stages of chronic HBV infection. Each stage is characterized by the levels of serum markers. These are HBV DNA, ALT, HBV surface antigen (HBsAg), and HBV e antigen (HBeAg). HBsAg is a protein that forms part of the outer surface of the HBV particle and is one of the first markers to appear in serum after infection, along with HBV DNA. HBeAg is derived from the pre-core protein and is regarded as a marker of viral replication and infectivity. Antibodies specific to a third viral protein, HBV core antigen (HBcAg) can also be detected in blood during HBV infection. 6 The changes to the marker concentrations that are observed in acute and chronic HBV infection are shown in the figure below. Concentration ALT in acute infection ALT in chronic infection Clinical symptoms appear HBsAg HBeAg IgM-anti-HBc HBV-DNA Inactive carrier status Acute hepatitis B Months after hepatitis B virus infection Figure 10: Course of markers during HBV infection 25 HBeAg chronic hepatitis B Transition from acute to chronic hepatitis B Anti-HBs HBeAg clearance and development of HBe-specific antibodies (known as HBeAg seroconversion) occur in the immune control phase. This happens spontaneously in 10 20% of patients., 6 while others will achieve this phase through therapy. HBV DNA (<10 4 copies/ml) and HBsAg levels are low and liver function markers, such as ALT, return to baseline levels Patients who achieve sustained immune control are known as inactive carriers and this is considered a good clinical outcome. These patients can, however, undergo immune escape and reactivation and progress to active HBeAg-negative disease which is associated with disease progression to cirrhosis or liver cancer Patients progress to HBeAg-negative disease. This is caused by a mutation in the viral genome that prevents or reduces HBeAg production HBV DNA and ALT levels are increased, but fluctuate. HBeAg-negative chronic HBV infection has a longer duration than HBeAg-positive disease and liver damage is often greater. 19,25,26 Long-term complications of HBV infection can be very severe. They include cirrhosis, liver failure (also called liver decompensation), and liver cancer, known as hepatocellular carcinoma (HCC) % of HBV-infected patients will develop one or more of these complications. 20 Progression to cirrhosis occurs in 2 6% of HBeAgpositive HBV-infected patients and 8 9% of HBeAg-negative HBVinfected patients. 6 Risk of progression to liver failure is 15 20% over 5 years and is higher in patients with active infection than inactive carriers. 25 The annual rate of HCC development is 2.5 3% in patients with cirrhosis and 0.5 1% in patients without cirrhosis. 6 There is some evidence to suggest that the genotype of HBV may have some influence on the final outcome of the infection. Genotype B is associated with higher HBeAg loss, genotype C is highly linked to development of HCC. Genotype F HBV is linked with very high mortality rates. 28
8 Diagnosis Diagnosis of the presence and stage of HBV infection is achieved by measuring the serum markers discussed above. In acute infection (see Figure 11), HBsAg can be detected first, 1 6 weeks before physical symptoms are observed. Antibodies to HBcAg (anti-hbc) can be detected from 1 2 weeks later and for up to 6 months after HBsAg clearance (resolution of acute infection). HBeAg and HBV DNA are present early in infection and can be detected until approximately three months after onset of infection, which corresponds to a peak in ALT levels. Antibodies to HBsAg (anti-hbs) can be detected 1 2 months later. Detection of anti-hbs and anti-hbc IgG is indicative of a past, resolved infection; presence of anti-hbs alone indicates that the patient has immunity due to HBV vaccination. 25 HBsAg Anti-HBs IgM anti-hbc Total anti-hbc Titer HBsAg IgM anti-hbc Total anti-hbc Acute (6 months) Chronic (years) HBeAg Anti-HBe Years Weeks after exposure Figure 12: Typical serological course of a hepatitis B virus infection with progression to chronic hepatitis B. HBeAg Symptoms Anti-HBe Table 2 shows how test results for all of the serum markers correspond to the phase of HBV infection. Titer Weeks after exposure Figure 11: Typical serological course of an acute hepatitis B virus infection with recovery. Current guidelines suggest that the following groups should be routinely screened for HBV infection: individuals living in high or intermediate HBV prevalence areas; individuals who have regular contact with HBV-infected people; intravenous drug users; people with multiple sexual partners; individuals in prison; individuals already infected with HCV, HIV, or who have elevated liver enzyme levels; renal dialysis patients; pregnant women; and immunosuppressed patients. 27 Persistence of HBeAg for longer than 10 weeks and HBsAg for longer than 6 months in serum suggests a progression to chronic infection 25 (see Figure 12). HBsAg Anti-HBs HBeAg Anti-HBe Anti-HBc IgM Anti-HBc IgG HBV DNA Positive Negative Positive Negative Positive Positive or High Early phase acute HBV negative Negative Negative Negative Positive Positive Positive or Low Window phase acute HBV negative Positive Negative Positive Negative Negative Positive High HBeAg-positive CHB Phase Positive Negative Negative Positive Negative Positive Moderate HBeAg-negative CHB Positive Negative Negative Positive Negative Positive Low/ Inactive carrier absent Negative Positive or Negative Positive Negative Positive Absent Immune due to resolution of disease negative Negative Positive Negative Negative Negative Negative Negative Immune due to vaccination Table 2: Interpretation of assay results for hepatitis B 6
9 Treatment and prevention The main aim of therapy for chronic hepatitis B infection is to suppress the amount of virus present in the circulation, reduce liver damage, and prevent progression to cirrhosis and HCC. Treatment options for chronic hepatitis B are nucleos(t)ide analogs (NAs), which act by suppressing viral replication, or finite therapy with pegylated interferon alfa (PEG-IFN-a). The latter has a dual mode of action, both antiviral and immunomodulatory effects, which can result in a sustained post-treatment response. An advantage of pegylated interferon is its ability to induce clearance of HBsAg from serum this is considered by treatment guidelines to be the closest outcome to cure. All major international treatment guidelines include pegylated interferon as a first-line treatment option. 27,29,30 However, this is successful in around only 1 in 3 patients. Table 3 shows the advantages and disadvantages of the two types of therapy. 29 Advantages Disadvantages Pegylated interferon Finite duration Absence of resistance Higher rates of HBc and HBs seroconversion Moderate antiviral effect Poor tolerance Subcutaneous injections Nucleos(t)ide analogues Potent antiviral effect Good tolerance Oral administration Indefinite duration Risk of resistance Lower rates of HBc and HBs seroconversion Identify responders (PPV) at week 12 of therapy HBeAg-positive patients HBsAg <20,000 IU/mL 36,42 HBeAg-negative patients >10% decline in HBsAg 34 (Week 24 of therapy for genotype D) 43 Identify non-responders (NPV) at week 12 of therapy HBeAg-positive patients HBsAg >20,000 IU/mL 36,42 HBeAg-negative patients (genotype D) No decline in HBsAg and <2 log 10 decline in HBV DNA 44 Table 4: Practical application of response-guided therapy during PEG-IFN-a treatment using HBsAg levels. Transmission of HBV can be controlled in several ways. Good hygiene, safe sexual practices, effective sterilization and single-use medical instruments, and continued screening of blood products can help to block routes of HBV infection. 27,45 In addition, safe and effective vaccines to prevent HBV infection have been available for over 20 years. These vaccines contain HBsAg, as it is known that anti-hbs is present in the blood of individuals who have fully resolved HBV infection. Vaccination consists of three injections given one month apart, with a booster 6 12 months later if required. Anti-HBs titers are tested to assess effectiveness and titers greater than 10 miu/ml are considered protective. However, the standard three-dose vaccine fails to stimulate an immune response in 5 10% of adults. 46 Vaccination is recommended for individuals that have regular contact with a HBV-infected person, newborns of HBV-infected mothers, dialysis patients, and individuals at risk from occupational exposure. 27 The use of DNA vaccines in a therapeutic setting is also being investigated. 46 Table 3: Advantages and disadvantages of pegylated interferon and nucleos(t)ide analogues in treatment of chronic hepatitis B infection The same serum markers used to diagnose chronic hepatitis B infection can also be used to monitor the effectiveness of therapy. Guidelines from the European Association for the Study of the Liver (EASL) suggest that low HBV DNA and high ALT levels pre-treatment are predictors of a favorable outcome to therapy, as are significant decreases in HBeAg and HBV DNA levels at weeks 12 and 24, respectively. 29 A number of studies have shown that the degree and timescale of reductions in HBsAg levels during PEG-IFN-a-based therapy may predict sustained response in both HBeAg-positive and HBeAg-negative CHB and may also predict response to treatment with some NAs. 37,38 Practical application of response-guided therapy during PEG-IFN-a treatment using HBsAg levels are shown in table 4. There is also evidence that HBsAg levels, particularly in combination with HBV DNA levels, can be used to identify patients who are in the inactive carrier phase of HBV infection as compared with patients with active disease, and so distinguish those patients who do not require therapy from those who would benefit from treatment
10 Hepatitis C Virology Hepatitis C virus (HCV) was first identified in It is a member of the Flaviviridae family and has a single-stranded, positive-sense RNA genome 7,48 (Figure 13). The classification of HCV subtypes is very complex. Currently over 50 subtypes have been identified and these have been classified into six genotypes that vary by 31 33% at the nucleotide level. 49 There are multiple subtypes within each genotype that vary by 20 25%. 49 Replication of HCV RNA is prone to errors, meaning that the genome mutates producing new strains. Because of this, the virus exists in the blood as a quasispecies, i.e., several slightly different versions of the same virus, with a difference of 1 5% in their genome. 7,48 Core Figure 13: Structure of hepatitis C virus Envelope Single-stranded RNA genome Prevalence Worldwide, % of people are thought to be infected with HCV, with the highest prevalence being found in Africa, the Eastern Mediterranean and Asian regions 50,51 (Figure 14). There is a regional difference in the predominant virus genotype as shown Table >10% % <1% 5 10% 1 2.4% unknown Figure 14: Prevalence of hepatitis C virus 51 HCV genotype 1a Region found Worldwide Susceptible groups 1b Europe, North America Older patients, blood transfusions 2 Mediterranean, Middle East Older patients 3 Mainly Europe Intravenous drug users 4 Middle East Patients undergoing medical treatment 5 South Africa Unknown 6 Hong Kong, Vietnam, Australia Intravenous drug users Table 5: Regional variation in the predominant hepatitis C virus genotype Transmission of HCV is by percutaneous exposure to blood products or organs from an infected person. This can occur via one large exposure, such as a blood transfusion or organ transplant, or from repeated small exposures, such as injection of drugs using unsterilized or shared needles. In developed regions such as Western Europe and North America, where blood donor screening programs have operated for many years, the major mode of HCV transmission is through intravenous drug use. This is associated with a greater risk of progression to chronic disease than for hepatitis B virus (HBV) or human immunodeficiency virus (HIV) in this population. In less developed countries, the major routes of transmission are through medical treatment with unsterilized equipment or unscreened blood. Occupational exposures, such as accidental needle-stick injury, and mucosal exposure, such as birth to an infected mother or sex with an infected partner, are considered a much lower risk for HCV than they are for HBV. 48,50 Disease progression Infection with HCV can lead to acute and chronic hepatitis disease. Approximately 70 85% of HCV infections progress to chronic disease, although this varies according to patient gender, age, race and immune status. 7,48 In acute infection, the average incubation period is seven weeks. Approximately 80% of patients exhibit no symptoms; in the remainder, non-specific symptoms and jaundice (as seen in hepatitis A virus [HAV] and HBV infection) are observed around this time. Symptoms last for several weeks before spontaneous resolution, which occurs in 15 30% of patients. Those infected with genotype 3 HCV are more likely to make a full recovery than patients infected with genotype 1. 7,48 Patients who develop chronic (rather than acute) HCV infection are much less likely to exhibit symptoms, but can develop the same long-term complications that are observed with HBV: cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). The outcome of chronic hepatitis C is difficult to anticipate for each patient, as there is a subset of patients who appear to be at greater risk of more rapid disease progression. This is thought to be due to genetic or environmental factors that are not initially apparent. 7,48,52
11 Diagnosis Hepatitis C virus infection can be detected by measuring the amount of HCV RNA, alanine aminotransferase (ALT) and HCVspecific immunoglobulins (anti-hcv) in patient serum samples. This can also indicate if the infection is acute or chronic. 7,48 In acute infection, HCV RNA levels increase in the first few weeks after infection to a maximum as symptoms appear. Serum ALT also peaks at this time, up to 10-fold greater than baseline. Levels of both markers return to baseline at the same time as symptoms subside. Anti-HCV can be detected from the onset of symptoms onwards. 7,48 This is summarized in Figure 15. ALT [U/L] 1, HCV RNA ALT Symptoms ALT normal Weeks Years Time after exposure Figure 15: Course of markers during acute HCV infection 7 Anti-HCV 5 6 In chronic HCV infection, HCV RNA can be detected years after infection. In the initial stages, HCV RNA and ALT levels are similar to those in the early part of acute infection. However, anti- HCV rises to higher levels during chronic infection and there are marked fluctuations of HCV RNA and ALT levels, so patients should receive regular follow-up for up to a year after symptoms appear to have resolved 7,48 (Figure 16). ALT [U/L] 1, HCV RNA ALT Symptoms ALT normal Weeks Years Time after exposure Figure 16: Course of markers during chronic HCV infection 7 Anti-HCV HCV RNA [IU/mL] HCV RNA [IU/mL] Patients are initially screened using an assay that detects anti- HCV. If this gives a positive result, follow-up tests are carried out to confirm the anti-hcv result and to measure HCV RNA. Table 6 shows how these test results should be interpreted in clinical practice. 48 Screening assay for anti-hcv Nucleotide tests for HCV RNA Confirmation test for anti-hcv Interpretation Negative Not applicable Not applicable Never infected Positive Not done Not done Unknown screening test result must be confirmed Positive Positive Positive/not done Active HCV infection Positive Negative Not done Unknown negative HCV RNA result alone confirms status; screening test result must be confirmed Positive Negative Positive Past infection; RNA test should be repeated to rule out active infection Positive Not done Positive Past infection; follow up with RNA/liver enzyme tests to determine status Positive Not done/negative negative Never infected Table 6: Interpretation of assay results for hepatitis C Current guidelines suggest that the following individuals should be screened for HCV: intravenous drug users; people associated with high prevalence populations; people who received a blood transfusion or organ transplant before 1992; children born to HCV-infected mothers; workers who have been exposed, e.g., via needle-stick injury; and people who have a HCV-infected sexual partner. 53 Treatment and prevention The goal of treatment for chronic hepatitis C is to prevent complications by eradicating the infection. The virus is considered to be eradicated when the patient achieves a sustained virologic response (SVR). This means that HCV RNA is undetectable at the end of treatment and is still undetectable 24 weeks later. 53 Patients who achieve SVR also usually show a dramatic decrease in HCV RNA levels at week 12 of treatment; this is called early virologic response (EVR). Currently, the standard of care for chronic HCV infection is the combination of pegylated-interferon (PEG-IFN) and ribavirin. Treatment schedules can be guided by how the patient responds to therapy and is shown in table
12 Several new direct anti-viral agents are in development for treatment of chronic hepatitis C and are likely to be licensed for therapy in the coming years. Initially they will be used with pegylated interferon and ribavirin in triple therapy. Genotype 1 (4, 5, 6) Genotype 2, 3 Measure baseline viral load Start 48 weeks PEG-IFN+ribavirin Measure EVR at treatment week 12 If viral load is at least 100-fold less than baseline, continue treatment until 48 weeks, provided HCV RNA is undetectable at treatment week 24 If viral load is less than 100-fold less than baseline, stop treatment Table 7: Response-guided therapy in HCV 55 Start 24 weeks of PEG- IFN+ribavirin As a high response rate is observed with genotype 2 and 3 infections, measurement of HCV RNA at treatment week 12 is not required Currently no vaccine is available for HCV due to the genetic diversity of the virus. However, DNA vaccines are being investigated. It is thought that the T-cell response to HCV is reduced in chronic hepatitis C so the vaccines in development have been designed to stimulate the T-cell response to clear the infection. 56
13 Summary Virus Hepatitis A virus Hepatitis B virus Hepatitis C virus Prevalence 1.4 million infections annually 2 billion infected worldwide % infected worldwide worldwide Transmission Fecal-oral route Body fluid transfer Infected blood or organ transfer Acute/chronic disease Acute only Acute and chronic Acute and chronic Diagnostic tests anti-hav anti-hav IgM HAV RNA HBsAg HBsAg confirmatory HBsAg quant HBeAg anti-hbs anti-hbe anti-hbc anti-hbc IgM HBV DNA Anti-HCV HCV RNA Treatment Balanced nutrition Avoid alcohol Hospitalization if dehydrated Nucleotide/nucleoside analogues Pegylated interferon Pegylated interferon and ribavarin Prevention Passive immunization Vaccination Improved hygiene Passive immunization with hepatitis B-specific immunoglobulin (can also be administered soon after exposure to HBV in individuals who are not immune to provide immediate, short-term protection) Screening of blood products Vaccination Screening of blood products No vaccine available
14 Glossary Acute describes an illness of short duration Anti-viral a drug that acts by reducing viral replication Autoimmune hepatitis liver disease caused by a cell-mediated response to the body s own liver Carcinoma a cancer that begins in epithelial cells, such as the skin or tissues that line or cover body organs e.g., breast, colon, liver, lungs Chronic describes an illness of long duration Cirrhosis scarring of the liver tissue Diagnosis the process of identifying an illness DNA deoxyribonucleic acid, a double-stranded nucleic acid molecule that contains the genetic code in most organisms Inflammation tissue reaction to damage, characterized by heat, redness, swelling and pain Jaundice yellowing of the skin and whites of the eyes due to the presence of excess bilirubin in the blood Liver failure/decompensation a situation when the liver has become too damaged to function correctly Metabolism the chemical reactions that occur in the body that are necessary to maintain life Passive immunization treatment with antibodies directed towards an invading pathogen Pathogen a disease-producing agent, such as a virus or bacterium RNA ribonucleic acid, a single-stranded nucleic acid molecule that is involved in the synthesis of proteins in cells and contains the genetic code of some viruses Fulminant hepatitis liver disease characterized by rapid and severe loss of liver function Seroprevalence the frequency of individuals in a population that have immunity to a particular pathogen Genotype the genetic makeup of an organism or, in this case, virus Strain a genetic variant or subtype of an organism Genome all of the genetic information of an organism Hepatitis inflammation of the liver Symptom a perceived change in some function, sensation, or appearance that is experienced by a patient, which indicates the presence of a disease or disorder. Examples include headache, cough, or rash Hepatocytes the predominant cell type in the liver where most of the functions of the liver take place Immune response the mechanism by which the body recognizes and protects itself from pathogens Transmission the act of passing on a disease to another individual Vaccine a treatment which stimulates the immune system to protect against infection by a particular pathogen Infection invasion of the body by a pathogen, such as a virus Virus a small (ultramicroscopic) infectious agent that replicates within the cells of host organisms and causes disease
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16 References 1 Melnick, J.L. (1995). History and epidemiology of hepatitis A virus. J Infect Dis; 171(Suppl 1): S Czaja, A.J., Manns, M.P. (2010). Advances in the diagnosis, pathogenesis and management of autoimmune hepatitis. Gastroenterology; 139: Scott, J., et al.(1978). Wilson s disease, presenting as chronic active hepatitis. Gastroenterology; 74: Thomson, A.B.R., Shaffer, E.A. (eds). First principles of gastroenterology: the basis of disease and an approach to management. Chapter 13 The liver, pp Ryder, S.D., Beckingham, I.J. (2001). Acute hepatitis. BMJ; 322: Elgouhari, H.M., et al. (2008). Hepatitis B infection: understanding its epidemiology, course and diagnosis. Cleve Clin J Med; 75: Hoofnagle, J.H. (2002). Course and outcome of hepatitis C. Hepatology; 36: S Feinstone, S.M., Kapikian, A.Z., Purceli, R.H. (1973). Hepatitis A: detection by immune electron microscopy of a virus like antigen associated with acute illness. Science;182: Lemon, S.M. (1997). Type A viral hepatitis: epidemiology, diagnosis, and prevention. Clin Chem; 43: Koff, R.S. (1998). Hepatitis A. Lancet; 351: Costa-Mattioli, M., et al. (2003). Genetic variability of hepatitis A virus. J Gen Virol; 84: Hollinger, F.B., Emerson, S.U. Hepatitis A virus. In: Field s Virology, Knipe, D.M., Howley, P.M. (Eds), 5th Edition, Lippincourt Williams and Wilkins, Philadelphia, pp Hepatitis A. WHO report WHO/CDS/CSR/EDC/ csr/disease/hepatitis/hepatitisa_whocdscsredc2000_7.pdf 14 The global prevalence of hepatitis A virus infection and susceptibility: a systematic review. WHO report WHO/IVB/ hq/2010/who_ivb_10.01_eng.pdf 15 Nothdurft, H.D. (2008). Hepatitis A vaccines. Exp Rev Vaccines; 7: Clemens, R., et al. (1995). Clinical experience with an inactivated hepatitis A vaccine. J Infect Dis; 171(Suppl 1): S Dane, D.S., Cameron, C.H., Briggs, M. (1970). Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet; 1: Blumberg, B.S., et al. (1965). 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