Hepatitis B virus (HBV) is one of the most important causes of chronic liver disease in the world. An estimated 2 billion individuals have current or past infection, and 300 to 400 million individuals, including 1.25 million people in the United States, are chronically infected. Between 25% and 40% of individuals with chronic hepatitis B die from cirrhosis or liver cancer, and more than 300,000 cases of HBV-related cancer occur each year. This makes hepatitis B the second most important carcinogen after tobacco.
Immigration patterns play an important role in the demographics of chronic hepatitis B in the United States. Although hepatitis B is not highly prevalent in the United States, individuals from areas where hepatitis B is highly prevalent have been immigrating to the United States, particularly during the past 10-15 years. This has resulted in a population of HBV-infected individuals in the United States from various backgrounds.
cccDNA, covalently closed circular DNA; dsDNA, double-strand DNA; ER, endoplasmic reticulum; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBcAg, hepatitis B core antigen; mRNA, messenger RNA. This slide illustrates the lifecycle of HBV in the hepatocyte. The infectious HBV virion is taken up into the liver cell and the viral polymerase converts pregenomic RNA into partially double-stranded DNA. This is then moved to the nucleus and covalently closed circular DNA is formed. Messenger RNA is formed from the covalently closed circular DNA and moved to the cytoplasm where it is packaged. A minor strand and then a partially double-stranded DNA is formed using both the polymerase and reverse transcriptase to make a complete viral particle. Precore/core protein is used and e antigen is formed in parallel to the core/precore protein. Surface antigen is also formed from the messenger RNA. This concludes complete viral packaging and release of complete virions or subviral particles of e-antigen as well as some core antigen and surface antigen, which serve as decoys to the immune system and probably modulate the immune system directly. Hepatitis B virus is not cytopathic, except in rare situations, such as liver transplantation, where the patient has high levels of immune suppression.
HBsAg, hepatitis B surface antigen; MHC, major histocompatibility complex; TNF- , tumor necrosis factor alfa. The other part of this picture is the immune response to the HBV-infected hepatocyte expressing viral antigens. CD8+ T cells attach to the hepatocyte where major histocompatibility complex expression class I binds to antigen-presented molecules on the liver cell surface. Cytokines, such as tumor necrosis factor-alfa and interferon-gamma, stimulate a Th1 response interacting with antigen-presenting cells, both CD8+ cells and CD4+ cells, directly causing cell lysis. These immune response cytokines regulate inflammatory responses, which can result in the progression of liver disease and the worsening of fibrosis to cirrhosis. This immune and inflammatory response, either alone or in combination with advanced fibrosis and cirrhosis, can result in liver cancer.
The prevalence of HBV among individuals who have immigrated to the United States from areas of high HBV prevalence was recently investigated in a study by Guan and colleagues. From 2001-2004, the overall prevalence of HBV in Asian Americans in 5 large US cities was 10.4%, which is higher than that expected for the general US population. This finding highlights the impact of immigration on HBV demographics in the United States. For more information, please go online to: http://www.clinicaloptions.com/Hepatitis/Conference Coverage/Boston 2004/Capsules/1269.aspx
HBV is associated with clinical consequences in both the acute and chronic phases of infection. Acute HBV infection can cause fatal fulminant liver failure, which is a rare but present risk. The bigger burden of disease is caused by chronic infection. Progressive liver disease can culminate in cirrhosis, liver failure, and hepatocellular carcinoma (HCC). Extrahepatic manifestations of hepatitis B are rare but can include polyarteritis nodosum and glomerular nephritis.
Efforts to reduce the burden of chronic hepatitis B disease have focused on 2 major strategies: vaccination and prevention of complications. The HBV vaccine is safe and effective and has significantly reduced the incidence of new infections. For patients already infected with chronic hepatitis B, several strategies are used to prevent liver-related complications. These strategies include lifestyle modifications—in particular, limiting alcohol intake and controlling weight—administering anti-HBV therapies if appropriate, and performing surveillance for HCC.
Vaccination is the best strategy for reducing the burden of chronic hepatitis B worldwide. The impact of vaccination, along with other prevention strategies, is evidenced by the decreasing incidence of acute hepatitis B in the United States during the past 20 years. Incidence of new infections began to decline in the mid-1980s, partly as a result of safer injection and sexual practices prompted by the HIV epidemic. Screening of pregnant women for hepatitis B began in the late 1980s, followed by the introduction of vaccinations for infants and then adolescents in the early to mid-1990s.
The HBV vaccine was licensed 20 years ago. Vaccines were initially derived from plasma, although recombinant vaccines are currently used. The 3-dose series is associated with high efficacy and an excellent safety record. Since 1982, vaccination has been recommended for adolescents and adults at high risk. In 1991, a comprehensive strategy was developed to eliminate hepatitis B transmission. The program initially focused on infants and later expanded to include adolescents. Currently, HBV vaccination is recommended for all unvaccinated persons 18 years of age and younger and for adults at high risk of infection.
Acute HBV infection has declined significantly in the past decade, reflecting the effects of routine vaccination. Vaccination rates are high among infants and young children but lower among adolescents and adults. Indeed, while HBV incidence has declined slowly in adults, it has increased among some subgroups, indicating a missed opportunity for vaccination among these groups. The risk of serious complications of chronic hepatitis B is also declining, a trend that is likely due to vaccination efforts.
The impact of vaccination on the incidence of childhood HCC in HBV-endemic areas is evident in this study by Chang and colleagues, which compared incidence of liver cancer in Taiwanese children before and after the implementation of a vaccination program in 1984. In the decade before the vaccine program, the overall incidence of HCC in children aged 6-9 years was 0.52 cases per 100,000 persons. The incidence decreased significantly to 0.13 cases per 100,000 persons in the after-program cohort. Updated data show a continuation of this trend, indicating that prevention of HBV infection can influence the important endpoints of chronic disease such as liver cancer.
HBV vaccination is still associated with several challenges. First, a small proportion of individuals fails to respond effectively to the vaccine. Ongoing strategies are attempting to maximize the likelihood of response in these individuals. Second, questions remain regarding the durability of the vaccine response and the need for booster vaccinations. Third, given the slight trend of increasing incidence of HBV infection among certain adult subgroups, some high-risk adults are apparently not receiving the needed vaccination.
The reduced vaccine response noted in some individuals has been extensively studied, and both patient- and vaccine-related factors appear to be involved. The most important patient-related factors include older age, male sex, history of smoking and obesity, and issues related to immune deficiency that can influence the likelihood of achieving an effective vaccine response. Although vaccine-related factors are less important, altering the dose, schedule, and route of vaccination and using adjuvants may enhance responses in patients who fail to respond to the first series of vaccines.
Studies investigating the durability of the vaccine response have documented 15-18 years of immunity in different populations. Even in individuals who test antibody negative, immunity appears to be preserved with responses demonstrated after booster doses, and in vitro studies have showed preserved T-cell responses in peripheral blood mononuclear cells. For these reasons, booster vaccinations are not currently recommended for individuals demonstrating initial responses to the vaccine.
McMahon and colleagues recently published a study outlining factors in HBV vaccination durability. Fifteen years after vaccination, 28% of individuals had anti-HBs antibody titers greater than 100 IU/L, whereas 38% had titers greater than 10 IU/L, and the remainder had lower levels. Low initial antibody response, younger age at vaccination, and female sex were all predictive of a decline in HBV antibody titers over the 15-year period. For more information, please go online to: http://www.clinicaloptions.com/Hepatitis/Journal Options/Articles/McMahon-AIM-2005-03/Capsule.aspx
Effective HBV vaccination in adults requires properly identifying high-risk individuals. Data indicate that individuals who present with acute hepatitis B generally have risk factors that would have supported prior vaccination. Fifty-six percent of patients with acute hepatitis B have had a sexually transmitted disease or been incarcerated. Eighty-nine percent have a history of injection drug use. Thirty-five percent are men having sex with men, and 70% are individuals with multiple sexual partners. These statistics highlight the overlapping risks between injection drug use and high-risk sexual activities that increase the risk for HBV infection and suggest the need for vaccination.
In summary, the HBV vaccine is highly effective and has resulted in a declining incidence of HBV infection. Vaccination rates among infants and children are high, and the implementation of infant vaccination programs is leading to declining incidence in countries endemic for HBV. This has been borne out in the reduced rates of serious liver complications, including liver cancer. In the United States, adults and adolescents at risk should be offered vaccination; this will reduce the number of missed opportunities for preventing infection. Finally, as a result of the development of a vaccine, HBV-related HCC is now a vaccine-preventable cancer.
The risk of developing chronic HBV infection is closely related to the age at time of infection. Among neonates infected with hepatitis B, 90% develop chronic infection and only 10% develop acute infection and then recover. By contrast, 95% or more of adults infected with hepatitis B develop acute infection and recover, and only 5% or fewer develop chronic infection.
The age at time of infection influences the epidemiology of HBV infection worldwide. In areas where HBV is endemic, such as Asia and sub-Saharan Africa, individuals are generally exposed to the virus at the time of birth, perinatally, or early in childhood. The rate of chronicity is therefore high, which perpetuates the burden of chronic HBV infection in the population. In areas of low HBV endemicity, such as North America, individuals are typically exposed to the virus as adults through sexual contact or percutaneous exposure. Because these individuals are likely to clear the virus spontaneously, the risk of chronicity is low and the burden of chronic liver disease related to cirrhosis and liver cancer is also low.
Understanding the natural history of chronic hepatitis B is critical to managing infected patients and making treatment decisions. Upon developing chronic HBV infection, individuals are HBsAg positive and have detectable HBeAg. In the initial “immune tolerant” phase, alanine aminotransferase (ALT) levels are normal and HBV DNA levels are typically high. Patients are often asymptomatic and liver biopsies indicate minimal inflammation. Duration of the immune tolerant phase varies and can last for several decades. It is typically long-lasting in individuals infected as infants or children but short-lived in those infected during adulthood. Patients then enter the immune active phase, in which ALT levels become abnormal, HBV DNA levels fluctuate and are often elevated, and biopsy would indicate inflammation and necrosis of the liver. Fibrosis can eventually develop, which may culminate in the development of cirrhosis. Individuals in the immune active phase are at the greatest risk for liver disease progression and are the target group for treatment. A prolonged immune active phase is associated with an increased risk for fibrosis and, ultimately, cirrhosis. During the immune active phase, patients may seroconvert, becoming anti-HBe positive. This milestone, which can occur spontaneously or with treatment, typically signals progression from the immune active phase to the nonreplicative phase. In this third phase, anti-HBe is present, ALT levels have returned to normal, and HBV DNA levels are low. Liver biopsy would reveal minimal necroinflammation, although residual fibrosis or cirrhosis may still be present. Patients in the nonreplicative phase may spontaneously lose HBsAg and thereby move into the final phase of resolved infection. Depending on the length of time spent in each phase, individuals may present to their physicians with either mild or active liver disease, and some patients may already have cirrhosis. Understanding where each patient falls in the natural history helps clinicians make optimal treatment decisions and anticipate future events.
Although seroconversion from HBeAg-positive to anti-HBe status typically signals a transition from the immune active to the nonreplicative phase, this does not always occur. Spontaneous seroconversion from HBeAg-positive to anti-HBe status is typically sustained. Hsu and colleagues found that 67% of individuals who spontaneously seroconvert remain anti-HBe positive. These patients experience reductions in ALT levels and declines in HBV DNA levels. However, in 33% of patients, ALT levels remain elevated, in most cases because of the evolution to HBeAg-negative chronic hepatitis B disease, which results from mutations in the precore or core promoter regions of the HBV genome. These patients are HBeAg negative and anti-HBe positive, yet have abnormal ALT levels and elevated HBV DNA levels, and are at risk for liver injury.
Most patients presenting to clinicians in practice fall into 1 of 4 groups. All of these individuals have chronic HBV infection as indicated by the presence of HBsAg. Those in the immune tolerant phase are HBeAg positive, have normal ALT levels, high levels of HBV DNA, and mild or normal histology. Current treatment strategies are not focused on these patients. Two groups have active disease: those with HBeAg-positive chronic hepatitis B and those with HBeAg-negative chronic hepatitis B with promoter mutations. Both groups exhibit abnormal ALT levels, elevated HBV DNA levels, and necroinflammation with varying degrees of fibrosis. Because these patients are at the greatest risk for disease progression and liver disease complications, they are the target groups for treatment. Finally, patients with inactive chronic HBV infection carry HBsAg but lack HBeAg. They are anti-HBe positive but exhibit normal ALT levels, low HBV DNA levels, and may have residual fibrosis on histology.
Resolution of HBV infection is marked by the loss of HBsAg and the acquisition of anti-HBs. Natural clearance occurs in approximately 0.5% of HBsAg carriers each year. The primary determinant of HBsAg loss is the duration of infection. Patients diagnosed before they are 20 years of age are more likely to lose HBsAg than those infected at an older age. McMahon and colleagues found that half of individuals who clear surface antigen and develop anti-HBs still maintain low but detectable serum HBV titers.
For patients with chronic hepatitis B, the annual risk of developing cirrhosis varies from 5% for HBeAg-positive patients to 1% to 2% for HBeAg-negative, seroconverted patients. Individuals with cirrhosis have a 3% risk of developing liver decompensation and a 2% risk of developing HCC. Although patients with cirrhosis are at greatest risk for developing HCC, patients who are noncirrhotic but chronically infected have some risk of developing HCC. This should be considered in developing an HCC surveillance strategy. The longer an individual is in the immune active phase, the greater the risk of complications such as cirrhosis, decompensation, and cancer. Other factors associated with progressive disease are heavy alcohol use and the presence of immune suppression, specifically coinfection with HIV.
In the initial evaluation of a patient with HBV infection, a detailed history and physical exam are extremely important. The history should focus on the likely mode of acquisition in order to estimate the duration of infection and predict the risk of complications. For example, patients with HBV infection and a family history of HCC are at greater risk for developing HCC and therefore require special surveillance. The physical exam focuses on determining disease stage and the possible presence of cirrhosis or decompensated liver disease. Use of alcohol should be discussed as it can influence disease progression and should be avoided in patients with chronic hepatitis B. Investigations should focus on assessing liver disease activity, serologic and virologic markers of disease, and screening tests for HCC.
It is important to identify where each patient lies in the natural history of HBV infection. This categorization is made based on the presence or absence of HBeAg, the HBV DNA level, ALT level, and liver histology. These assessments help define each patient’s profile and determine the best treatment strategy.
Although a liver biopsy is not required to establish a diagnosis of chronic hepatitis B, it has several uses in the diagnostic process and can help guide treatment decisions. Biopsy analysis can reveal the degree of necroinflammation and the extent of fibrosis, which may be important in deciding whether to treat a patient and how to proceed with future screenings for complications. Biopsy analysis can clarify diagnosis when ALT and HBV DNA levels are discordant or borderline elevated. Additionally, histology is important for assessing patients at risk for other causes of liver test abnormalities such as metabolic fatty liver disease and alcohol-related liver disease.
Patients in the immune active phase of disease represent the target group for treatment, as they are at greatest risk for disease progression. These patients have abnormal liver tests and elevated HBV DNA levels. They may be HBeAg positive or HBeAg negative, depending on the presence of promoter variances. HBeAg-positive patients tend to have HBV DNA levels greater than 10 5 copies/mL, whereas HBeAg-negative patients may have slightly lower levels of at least 10 4 copies/mL. Biopsies may be helpful in characterizing patients with borderline HBV DNA levels and abnormal ALT levels. Based upon the liver tests and the HBV DNA levels, a treatment decision can be made.
Treatment endpoints differ between the 2 distinct chronic hepatitis B patient populations. For HBeAg-positive patients, HBeAg loss and seroconversion to anti-HBe are primary goals of therapy. Seroconversion is accompanied by a decline in ALT levels to normal and an HBV DNA decline to low levels. Achievement of seroconversion typically helps define the duration of therapy. For HBeAg-negative patients, seroconversion is not an endpoint. In general, patients with HBeAg-negative chronic hepatitis B require longer therapy than HBeAg-positive patients to achieve improvements in ALT levels and histology although there is significant overlap in treatment duration between the 2 groups.
The most important goal of therapy is a reduction in the rate of liver-related complications. Treatment progress is measured by the attainment of important endpoints including sustained HBV DNA suppression, HBeAg seroconversion, and improved liver histology. These can result in the important endpoint of reduced rates of liver complications.
This slide set summarizes some of the most important information on the epidemiology, diagnosis, and treatment of hepatitis C.
Nearly 4 million persons in the United States are infected with hepatitis C virus (HCV). Approximately 35,000 new cases are diagnosed each year. A major issue is that most cases—approximately 85%—become chronic resulting in hepatitis C accounting for the leading cause of chronic liver disease, cirrhosis, and liver cancer in the United States, as well as the number one indication for liver transplantation.
As previously mentioned, the majority of individuals exposed to HCV will develop chronic infection; however, 15% of patients exposed to HCV are somehow capable of spontaneously resolving this infection. Research is currently ongoing to better understand how these people can resolve their infection, and this may shed some light on how to better treat hepatitis C in the future.
This next slide looks at the biochemical and virologic response of patients exposed to HCV. In the green line you can see acute elevation in liver transaminases within the first couple of weeks after exposure to the virus, indicating acute HCV infection. Notice in the red bar I have indicated presence or absence of HCV RNA. During the acute phase of HCV infection, if you test for HCV, sometimes the virus will be detectable, but at other times the virus is undetectable. Because of this intermittent viremia, virologic assays are not the best assays to screen for acute hepatitis C. Over the next couple of weeks of infection, liver transaminases decline and then go into an undulating pattern over the next 1-1.5 years, when the serum alanine aminotransferase (ALT) can fall into the normal range for either brief or prolonged periods of time, only to elevate again. This shows that individuals with chronic hepatitis C can have both elevated liver enzymes and normal liver enzymes, and sometimes they can have persistently normal liver enzymes for long periods of time. However, these individuals will test positive for antibodies to hepatitis C and, if they have chronic infection, will be viremic. The blue line indicates an individual who had spontaneous resolution from hepatitis C. Again, you see acute elevation of liver transaminases during the acute phase, intermittent viremia in the first couple of weeks after the infection, and then the liver transaminases coming down and remaining persistently normal. It is important to recognize that individuals who have been exposed to HCV but develop spontaneous resolution will also develop antibodies to hepatitis C. This is the type of individual who may go and donate blood to a blood bank and have a positive antibody for hepatitis C or be noted as having a positive antibody on life or health insurance physical exams. However, they have persistently normal liver enzymes, and when tested for HCV RNA, they are virus undetectable.
The next slide illustrates the natural history of HCV infection. As previously mentioned, a small percentage of individuals will go on to spontaneous resolution—about 15%—whereas 85% develop chronic disease. Of this 85% who develop chronic disease, about 80%, (68% of all infected individuals), will have stable chronic hepatitis without significant progression over the next 20 years. By contrast, 20% of those who develop chronic disease (17% of all infected individuals) will develop cirrhosis over the next 20-25 years. Of these cirrhotic patients, many will continue to progress slowly, and about 25% will rapidly develop hepatocellular carcinoma (HCC) or liver failure. Thus, liver cancer and liver failure occur in approximately 4% of patients who are exposed to HCV over a 20- to 25-year period.
Who are the patients at risk to develop chronic HCV infection and develop this progressive liver disease? They are individuals who were exposed to blood products before the development of hepatitis C testing, individuals who intermittently used or continual to use intravenous drugs or inhale cocaine, and individuals with chronic renal failure on dialysis. These individuals have a high risk of HCV exposure either through blood products used to treat the complications of chronic renal failure or because of contamination in dialysis units. Incarcerated individuals, many of whom have used drugs in the past, have a high prevalence for HCV infection. Occupational exposure to blood products is a potential mode of exposure, and individuals who receive organ or tissue grafts from HCV-positive donors through transplant are also exposed to the virus. Finally, individuals who have participated in body piercing and tattooing may be exposed through these activities.
The next slide looks at the prevalence of hepatitis C antibodies in patients in the United States broken down by race and sex. Overall, 1.8% of the US population has antibodies to hepatitis C. In blacks, the prevalence exceeds 3.5%, and is approximately twice as high as in whites. Hepatitis C antibodies are also twice more common in males than in females.
This next slide looks at the age distribution of patients with hepatitis C. You can see that the peak age for HCV infection is 30-49 years. Prevalence is very low in children younger than 11 years and in individuals older than 70 years of age. In the United States, the prevalence among 30 to 49 year olds is anywhere from 3.5% to 4.0%. If these individuals are not identified and treated, they will continue to progress as they get older, developing more severe liver disease and flooding our hospitals with end-stage liver disease. For example, the patients that currently represent the most common indication for liver transplantation—end-stage hepatitis C—are between 50 and 69 years of age. If the 30- to 49-year-old patients, who have a much higher prevalence of infection, are not identified and treated now, they will develop more progressive liver disease over the next 10-20 years and many will require liver transplantation. In this scenario, this group of individuals will completely outstrip our ability to care for them. Therefore, it is estimated that the risk of death from hepatitis C in the future will increase dramatically.
This first slide looks at the tests that are used to identify patients with hepatitis C and assess disease severity and response to therapy. The first, aspartate aminotransferase and ALT tests, are not really liver function tests although many physicians refer to them as such. Rather, they measure liver transaminases, which are indicative of inflammation or irritation to the liver. The true tests to measure liver function include bilirubin, albumin, and prothrombin time or international normalized ratio. When the liver has dysfunction, these tests start to show abnormalities. Unfortunately, that does not occur until patients develop cirrhosis. Therefore, the majority of patients with chronic hepatitis C show normal liver function based upon these liver function tests. One of the most sensitive tests of advanced liver disease is the platelet count. A large number of studies have now demonstrated that thrombocytopenia—platelet counts below the lower limit of normal—is indicative of cirrhosis in individuals who do not have some sort of primary platelet or bone marrow disorder. Identifying thrombocytopenia is an easy way to identify patients with cirrhosis, and clearly liver histology represents the gold standard of determining the severity of disease and histologically can identify cirrhosis and the degree of scarring or fibrosis is present in the liver. One test we monitor to determine treatment response is serum ALT. If treatment is working effectively, we expect that the ALT levels will drop back down into the normal range on therapy. We also monitor the level of HCV RNA, and the goal is to have virus levels become undetectable during treatment. Hepatitis C virus genotype determines how long we need to treat patients, and liver histology can be used as a marker to show that the liver has improved after therapy.
It is critical when evaluating patients with hepatitis C to measure HCV RNA levels. The roles of diagnostic testing are to identify patients with viral hepatitis infection, to measure previous exposure to the HCV, to differentiate active from inactive infection and resolved infection, and to assess response to therapy both during and after treatment.
This next slide lists the 2 types of virologic tests available: serologic tests and virologic tests. Serologic tests measure circulating antibodies within the blood stream of patients exposed to HCV. Serologic tests are highly sensitive, but the specificity varies depending on the patient population being evaluated. Antibodies develop very early in the infection—typically 2-6 months after exposure—depending on levels of immune suppression. Individuals who are immunosuppressed, such as HIV patients and patients with chronic renal failure, may take many months to develop antibodies against hepatitis C after exposure. Serologic tests are generally used for screening because they are cheaper and are very sensitive. Virologic tests measure virus levels, and they are both highly sensitive and highly specific. Again, there can be intermittent viremia early after infection so a true, persistently positive virus test for individuals recently exposed to HCV will be present approximately 2-6 weeks after exposure. Again, virologic tests are used to confirm active infection after the screening test is positive.
This slide illustrates the basis of antibody production in an individual after exposure to HCV. As you can see, the schematic illustrates the virus infecting the liver cell. The virus then produces large quantities of its own proteins or antigens, which are then expressed on the cell surface of the infected hepatocyte. The immune system recognizes this expression and reacts by producing antibodies, which then bind to the infected cell. That is one way in which the immune system attempts to rid the system of infected cells. However, as we know, this is not very successful without treatment. It is important to recognize that the hepatitis C antibodies circulating in response to this process are not protective antibodies. Instead, they are simply markers of previous exposure. If an individual is hepatitis C antibody positive but virus negative, and then participates in risky behaviors, he or she still has the potential to become infected with hepatitis C.
This next slide shows the mechanism of detecting hepatitis C antibodies in the laboratory. The schematic shows a microtiter well plate that is impregnated with hepatitis C antigens, graphically represented as triangles. The patient’s serum is added to the plate, and any circulating HCV antibodies will bind to the hepatitis C antigens. In the next step, tagged antibodies are added to the plate and, upon interaction with HCV antibodies, a chemical reaction will occur. These enzyme-linked immunosorbent assay (ELISA) antibody tests are highly sensitive at detecting circulating antibodies against hepatitis C. However, these tests are so sensitive that false-positive reactions may occur. There is a potential for cross-reactivity against nonspecific circulating antibodies. Given this risk, the positive predictive value of the test depends upon the HCV infection risk of the population under investigation. A positive anti-HCV test is 95% accurate in patients with risk factors for hepatitis C and elevated serum ALT. However, in healthy patients with no risk factors and normal ALT levels, a positive anti-HCV test is really only 50% accurate. Most false positives are seen in people at low risk for hepatitis C. This might be the type of individual mentioned previously who goes to the blood bank to donate blood and then later gets a letter stating that they have tested positive via ELISA for hepatitis C. In fact, for many of these individuals, an additional test will show that they are HCV negative.
As stated, the primary limitation of antibody testing is the potential for false positives. False positives can occur in individuals with high levels of circulating autoantibodies, particularly those individuals with autoimmune disorders or individuals who were previously exposed to HCV but had spontaneous resolution. These individuals will continue to have circulating antibodies and a positive anti-HCV test but negative HCV RNA tests. It is important to recognize that the ELISA anti-HCV screening test does not accurately detect HCV in certain populations, such as patients in whom the antibodies are poorly produced. False negatives occur in chronically immunosuppressed individuals, including transplant recipients, chronic renal failure patients on dialysis, or HIV-positive patients.
In the past, the recombinant immunoblot assay (RIBA) test was used frequently to confirm anti-HCV. In this test a cellulose strip is impregnated with several HCV antigens, and then the patient sera is placed on the strip to create an antigen-antibody reaction, rather than the antibody-antibody reaction used with the ELISA test. This is a supplemental assay that is much more specific, but not more sensitive, than anti-HCV tests. It was used in the past to confirm infection in patients that tested positive but did not have risk factors or elevated ALT. False-positive reactions are rare but can still occur, particularly in patients previously exposed to HCV who had spontaneous resolution. These patients still have circulating hepatitis C antibodies that will react with the RIBA assay. So, the RIBA assay has some limitations to it, and now that excellent virologic tests are widely available, the need for the RIBA test in the diagnosis of HCV has diminished. However, one potential continued use for this assay is to confirm that an individual has had spontaneous resolution of their HCV infection.
The first indication for using HCV RNA assays is to confirm HCV infection. This is particularly helpful for ruling out false positives in antibody-positive patients with persistently normal serum ALT and a lack of risk factors and in persons with antinuclear antibodies and for making certain the virus is present before initiating treatment. HCV RNA assays are also used to evaluate the effectiveness of treatment, to predict the likelihood of response before initiating therapy, and to confirm response (virus negativity) after therapy is completed.
There are 3 basic types of virologic assays available commercially. The most common and widely used is the polymerase chain reaction (PCR) assay. This assay amplifies virus from the serum, reproducing and creating millions of copies within the test tube. This allows for easy detection and quantification; both qualitative and quantitative PCR assays are available. A newer assay, which is similar to PCR but amplifies the target in a different way, is the transcription-mediated amplification (TMA) assay. Currently this test is only qualitative, meaning it provides only a positive or negative result. In the future it may be quantitative as well. Finally, there is the quantitative branched DNA assay, which is very accurate for measuring virus levels. It functions by attaching a probe to the virus and then amplifying the probe. The assay is highly reproducible. The primary limitation is that the assay has a limit of detection below which virus cannot be detected. It is therefore typically combined with a PCR or TMA assay to confirm results in individuals who measure undetectable via bDNA testing.
It is important to realize that HCV RNA assays have some inherent variability. The assays are only able to measure virus within a sensitivity of plus or minus 1 half-log unit. What does this mean? It means, as illustrated in this graph, that the assays are unable to differentiate an individual with 1 x 10 6 copies/mL of HCV RNA from an individual with 1 x 10 5 copies/mL of HCV RNA. One must keep this in mind when measuring HCV. If the virus appears to be changing by approximately 5-fold, it may just be because of this inherent variability in the assay, and not an actual change. Thus, changes in assay must be greater than 10-fold in order to be clinically meaningful.
In general, HCV RNA is extremely constant over time in the absence of treatment. This is very different, for example, from HIV, where the level of virus correlates with the severity of disease. The graph on this slide shows 5 representative patients. As you can see, the virus level is somewhat variable, but within the range of the assay. If we were to look at the mean virus levels across this 4-year follow-up period, we would see no significant change in virus level. Because HCV levels remain very stable in the absence of treatment, it is not necessary to continually measure HCV RNA to determine if the level is changing.
This figure looks at levels of HCV in individuals with variable degrees of liver fibrosis. You can see that the level of HCV RNA is very constant across the spectrum of liver disease severity.
The same is seen for level of inflammation present on liver biopsy. Again, there is no correlation between the level of HCV RNA and the degree of inflammation.
There are 3 major types of HCV in the United States. The most common is genotype 1, which represents approximately 72% of HCV-infected patients in the United States. The prevalence of genotypes 2 and 3 is fairly equally split and represents the majority of the remaining approximate 25%. In this large study published in 2004, genotype 2 represented 17% and genotype 3 represented 10% of HCV-infected patients in the United States. There are other HCV genotypes, including genotypes 4, 5, and 6, which are almost exclusively found in individuals originating from areas of the world where these particular genotypes are endemic. For example, genotype 4 is almost completely restricted to individuals who immigrate to the United States from Egypt and the Middle East, genotype 5 is predominantly from South Africa, and genotype 6 is generally from Southeast Asia.
This slide illustrates how HCV RNA is genotyped with an InnoLiPA , or line probe, assay. After the virus is amplified through PCR, it is then placed on a cellulose strip where various types of hepatitis C antigens have been impregnated. The HCV anneals to the specific genotype, providing a positive reaction and identifying the genotype species.
The final way to assess liver disease severity in hepatitis C is with liver biopsy. This is the only test able to accurately assess severity of inflammation and degree of fibrosis. The baseline degree of inflammation and fibrosis are able to determine risk of cirrhosis development in the future, the need for therapy, and the need for ongoing therapy if initial treatment has failed. For example, an individual who failed interferon therapy and has mild liver disease and no apparent cirrhosis based on liver biopsy, has little urgency to undergo retreatment with new or more aggressive therapies. In contrast, an individual with more scarring and bridging fibrosis on biopsy may request such treatments. The biopsy is very useful for managing patients in these scenarios.
Many physicians want to know if a liver biopsy is necessary before initiating treatment. I think this depends upon the patient and the physician. If a patient wants treatment regardless of the biopsy findings, then there is really no reason to perform a biopsy. If the patient does not want treatment, or if treatment is contraindicated regardless of biopsy results, there is really no reason to do the biopsy because it will not help you to manage this type of patient. If lab results or radiologic studies do not suggest cirrhosis, a biopsy may also not be necessary. Finally, if a patient starts treatment without having a biopsy and then experiences a sustained virologic response, there is no reason to perform a posttreatment biopsy. Because they are now cured of hepatitis C, the results will have no impact on your course of action. Where is a biopsy helpful? It is helpful if it affects a patient’s choice to receive treatment. For instance, if the patient would prefer not to receive treatment but would accept treatment upon learning of advance fibrosis, then the biopsy becomes very helpful. If lab results or radiologic studies suggest cirrhosis, a biopsy may help confirm these findings. If a patient was treated without a liver biopsy but failed to achieve a sustained virologic response, performing the liver biopsy posttreatment could help decide the next course of action.
Recently we have heard about some noninvasive tests that may replace liver biopsy. These tests are helpful sometimes, but not always. These data were presented several years ago for one of these noninvasive tests, the FibroTest. This figure shows the stage of fibrosis according to liver biopsy vs stage according to FibroTest. In individuals without scarring (stage 0 fibrosis) fibrosis, their FibroTest results fall into a wide range, such that a result of 0.3 could represent mild fibrosis or no fibrosis. Of more importance, higher levels on the FibroTest—between 0.50 and 0.75—do not differentiate individuals with moderate or severe fibrosis from patients with cirrhosis. In my own practice, I do not find the noninvasive serum markers of fibrosis very helpful because there is too much overlap in these tests. For patients who cannot make a decision regarding course of treatment, the FibroTest often will not help to answer that question. For these patients, a liver biopsy is necessary.
Let us look at a particular group of patients with hepatitis C—those with persistently normal serum ALT. Persistently normal serum ALT used to be thought of as an indicator of mild disease and no liver damage. That may not be the case. As shown in this slide, patients with persistently normal ALT can fall into 3 different patterns: 1) the group that is always normal, 2) the group that has the single spikes of elevations in serum ALT, and 3) the group that temporarily becomes abnormal and then drops down into the normal range. It is fairly obvious from this graph that it could be easy to miss individuals with single elevations or prolonged elevations if serum ALT is not tested frequently enough. In general, the more you test a patient with a normal ALT, the more you will find that it is not normal all the time.
If you examine the histology in patients with normal ALT, as we did in this study published from our center several years ago, you can find that there is no correlation between race and ALT. There is also no correlation between level of HCV RNA and ALT. In addition, fibrosis score seems to be more closely related to ALT than does level of inflammation.
In this study we looked at patients with normal ALT vs elevated ALT, and you can see that patients with persistently normal ALT tended to have a higher percentage of milder liver disease and no fibrosis. However, 12% of patients had advanced bridging severe fibrosis and/or cirrhosis. For patients with elevated ALT, the fibrosis distribution was more even. In general, patients with normal ALT always have some degree of liver impairment on liver biopsy, but they do tend to have milder fibrosis.
If you ask patients with hepatitis C how they feel, about 56% of them say they are asymptomatic, about 37% say they have symptoms, and about 7% have complications of cirrhosis. Of those who have symptoms, the most common symptom is simply fatigue—80% of symptomatic patients complain of fatigue. The symptoms can be very, very subtle indeed.
What happens to these minimally symptomatic individuals as we follow them over time? The majority of individuals will develop progressive fibrosis and eventually cirrhosis from hepatitis C. The liver biopsy helps predict the risk of developing cirrhosis over a 20-year period in patients with hepatitis C. For individuals who do not have any evidence of fibrosis on their initial biopsy, the risk of developing cirrhosis over the next 20 years is only about 25% to 30%. On the other hand, once a patient has fibrosis, he or she will develop progressive fibrosis and eventually cirrhosis, it will just take time. According to this study, 100% of individuals with portal fibrosis develop cirrhosis, but it takes 18-20 years. However, individuals with high levels of fibrosis on initial biopsy will develop cirrhosis sooner, in only about 8-10 years. That initial biopsy can be very helpful in providing feedback to the patient on why they should embark on therapy even though they are asymptomatic or minimally symptomatic.
This next study by Marc Ghany shows the usefulness of measuring the degree of inflammation on liver biopsy. If you look at just the necrosis score from the liver biopsy and the degree of inflammation, which was mild, the rate of fibrosis progression over the next 5 years was low. The rate of fibrosis increased stepwise with the degree of inflammation, as can be seen in this slide.
Another factor that affects fibrosis progression is alcohol use; individuals with hepatitis C who drink alcohol on a regular basis have a higher mean fibrosis score according to time of infection compared with individuals who do not drink alcohol. The impact of consuming alcohol continues to increase stepwise over the decades.
Another factor that affects fibrosis progression in patients with hepatitis C is age of initial exposure to HCV. Patients who are initially exposed to HCV when they are older than 40 years of age generally have a higher degree of fibrosis regardless of how long they have had the disease, compared with individuals who are infected at a younger age.
Clearly, the degree of fibrosis increases stepwise over time although the inflammation on the biopsy is rather constant, as seen in this slide. On average, patients who have higher inflammation scores tend to progress faster than those who have lower inflammation scores, as we saw in the previous study.
This slide shows the affects of alcohol consumption on the risk of developing cirrhosis in individuals with hepatitis C. Those individuals who consume alcohol on a regular basis have a much higher rate of cirrhosis than those who do not consume alcohol for each decade of having HCV infection.
Another factor that can affect fibrosis progression in HCV-infected patients is degree of steatosis. Individuals with more fat on liver biopsy tend to have more fibrosis and, as a result, develop cirrhosis at a faster rate. Individuals with lower degrees of fat have less fibrosis on liver biopsy. One of the important things you can do for your hepatitis C patients who do not want therapy is encourage weight loss. The more the patient weighs, the higher the likelihood that the patient will have fatty liver. That fat is going to contribute to more severe hepatitis C.
Survival in HCV-infected patients depends upon whether they have stable or decompensated cirrhosis. Individuals with stable cirrhosis who have never developed a complication of their cirrhosis have a good 10-year survival of about 80%. By contrast, individuals who have decompensated cirrhosis have a 10-year survival of approximately 30%. The rate at which individuals develop decompensated liver disease is approximately 3% to 5% per year, cumulatively, and this continues to increase as patients with cirrhosis are followed over 10 years. The rate at which individuals develop HCC is on the average about 1% to 3% per year, cumulatively. Thus, after 10 years, the risk of patients with cirrhosis developing liver cancer is approximately 12% to 14%.
The incidence of HCC in the United States is clearly increasing, across a several groups, including both men and women, and both blacks and whites. This is predominantly due to the hepatitis C epidemic and hepatitis C causing liver cancer in the setting of cirrhosis.
The schematic in this slide looks collectively at these natural history data. Some patients with mild hepatitis C will have mild hepatitis C for their entire life—30-50 years—and never develop scarring in their liver, and hepatitis C does not significantly impact their life expectancy. This likely applies to about 15% to 30% of patients. Another 20% to 30% of patients develop rapidly progressing hepatitis C with cirrhosis, decompensated cirrhosis, and liver cancer within 20-25 years of exposure. The remaining 50% to 65% of patients develop fibrosis progression to cirrhosis, but at variable rates—some individuals will develop cirrhosis after 25 years, some after 30 years, some after 40 years, and so on.
The next slide in this section looks at the future of hepatitis C. In the blue bars you see the prevalence of hepatitis C starting from back in 1960 and projecting forward to the year 2020 and beyond. As you can see, we have already reached the peak of the hepatitis C identification epidemic. This peak prevalence was in 2000 or 2001 with a peak prevalence of just over 2% of the general population. As I mentioned earlier in this talk, the prevalence is now down to approximately 1.8%. This rate is projected to decline slowly over time because the incidence of new infections is low and patients with chronic disease and cirrhosis unfortunately develop mortality and die from this disease. The green bars indicate the number of individuals who have had HCV infection for the last 20 years. As we project forward into the years 2010-2015, the number of patients infected for 20 or more years continues to increase. These are the patients who will develop cirrhosis, decompensated cirrhosis, or liver cancer in the future and will require liver transplantation. In terms of the epidemic of end-stage liver disease, we are just starting to see an exponential rise that will not peak until the next decade. At that time, caring for all of these patients will come at a significant cost to society. Again, this stresses the importance of identifying and treating patients with hepatitis C early in the course of their disease, before it becomes severe.
How do we identify patients with hepatitis C? There are a couple of ways. First, we find patients with elevated serum liver transaminases either during routine physical examination or routine blood testing after starting certain medications. Patients may also test positive for anti-HCV during volunteer blood donations or for life or health insurance physicals. However, one of the most important ways that physicians can identify patients with hepatitis C is to inquire about previous risk behaviors and screen patients who disclose these behaviors.
Hepatitis C is associated with many extrahepatic manifestations, including nonspecific antibody production, essential mixed cryoglobulinemia, glomerular nephritis, porphyria cutanea tarda (PCT), leukoclastic vasculitis, non-Hodgkin’s lymphoma, autoimmune thyroiditis, diabetes, and Sjögren’s syndrome.
Many individuals with hepatitis C have circulating autoantibodies and are sometimes incorrectly diagnosed with other disorders. For example, 70% of patients with hepatitis C have circulating rheumatoid factor. Approximately one third have cryoglobulins, and anywhere from 13% to 21% have low-titer or high-titer antinuclear antibodies (ANA). A slightly lower percentage have smooth muscle antibodies—about 5% have antibodies to liver or kidney microsomes—and about 7% have antithyroid antibodies. These antibodies are all significantly higher than we see in the control population without hepatitis C.
It is important to realize that there is no specific relationship between the presence of these autoantibodies and the severity of HCV infection or the genotype of hepatitis C. There is a correlation between rheumatoid factor titer and cryoglobulinemia, but not symptomatic cryoglobulinemia. An important point to realize is that circulating autoantibodies from true autoimmune disorders can result in false-positive hepatitis C reactions, as we mentioned earlier.
Cryoglobulinemia is classified into 3 types. Type 2 cryoglobulinemia is found almost exclusively in individuals with hepatitis C and is associated with polyclonal IgG, monoclonal IgM, and rheumatoid factor.
Why do individuals with hepatitis C develop so many autoantibodies? The schematic in this slide illustrates one of the proposed mechanisms. Because hepatitis C is a rapidly reproducing virus that is constantly changing because of the high mutation frequency, it is able to evade the immune response. Because the immune system wants to constantly attack this virus, there is a constant immune stimulation, causing clonal expansion of B cells. Under genetic and environmental factors which are poorly defined, the immune system produces polyclonal IgG, monoclonal IgM, and rheumatoid factor. These antibodies bind to HCV causing large aggregates called cryoglobulins, which trap hepatitis C in dependent areas and blood vessels causing the symptoms of cryoglobulinemia.
This slide illustrates the dermatitis of cryoglobulinemia—a patchy discoloration in the lower extremities resulting from deposition of cryoglobulins in small capillaries. Ulcerations may develop, and these areas can be very pruritic.
Approximately 20% of individuals with cryoglobulinemia will have elevated liver transaminases. Almost all patients will be positive for anti-HCV and about 80% for HCV. The 20% who do not test positive for virus test this way because the virus is trapped by the cryoglobulins. When the blood sample is spun down, most of the virus comes down into the sediment with the cryoglobulins resulting in a lack of virus in the serum. If HCV RNA were to be measured in the precipitate of those patients, HCV RNA would be detected. Virtually all patients with type 2 mixed cryoglobulinemia have hepatitis C as the underlying cause, compared with individuals without type 2 cryoglobulinemia in whom hepatitis C is uncommon.
Cryoglobulinemia can cause several manifestations. In addition to the dermatitis, it can also cause vasculitis and myalgias. Clearly some fibromyalgia patients have myalgias from hepatitis C and cryoglobulinemia. Cryoglobulinemia can also cause arthralgias. Many of these patients are rheumatoid factor and/or ANA positive. Cryoglobulinemia can also cause membranal proliferative glomerular nephritis, neuropathy, and in some cases, chronic fatigue syndrome.
Another extrahepatic manifestation of hepatitis C is sialadenitis, or inflammation of the salivary glands. Sialadenitis is caused by inflammation or migration of lymphocytes into the salivary glands. It can mimic primary Sjögren’s syndrome, but there are several factors that differentiate it from Sjogren’s. Hepatitis C-induced sialadenitis is negative for the antibodies that are positive in Sjögren’s syndrome: Sjogren’s-specific antibody A and B. On biopsy of the salivary glands, it is evident that the way the lymphocytes infiltrate the salivary gland is different between the 2 disorders. In hepatitis C, the infiltration is milder: it is pericapillary and involves mostly CD8 cells. In primary Sjögren’s syndrome, the lymphocyte involvement is severe, periductal, and involves mostly CD4 cells. In HCV-induced sialadenitis, patients experience dry mouth, which is often why they will seek clinical attention. Patients with primary Sjögren’s syndrome also have dry mouth, but in contrast to HCV sialadenitis, they will have also have xerophthalmia.
Another extrahepatic manifestation of hepatitis C is B-cell lymphoma. In 8 case series that evaluated more than 1700 patients, you can see that individuals with B-cell lymphoma had a prevalence of hepatitis C of approximately 25% overall. In the control population of other cancers the incidence of hepatitis C was much lower and similar to what we see in the general population. Clearly this constant immune proliferation and clonal expansion of B cells driven by hepatitis C can at times transfer or progress to B-cell lymphoma.
Diabetes has recently been recognized to be associated with hepatitis C. In this study prevalence of diabetes mellitus and insulin resistance was much higher in patients with hepatitis C than in healthy individuals from the National Health and Nutrition Examination Survey study when adjusted for age, race, and sex.
This next slide shows that individuals with hepatitis C who develop diabetes and insulin resistance tend to do so as they develop progressive, stage 3 or 4 fibrosis and cirrhosis. We see a lower incidence of diabetes in our patients with mild hepatitis C than we see in our patients with more advanced hepatitis C and advanced fibrosis and cirrhosis.
Another extrahepatic manifestation that is well recognized now by dermatologists is PCT, a genetic disease of bilirubin metabolism. Individuals who develop the skin manifestations of PCT usually have an underlying liver disease. In the past this liver disease was attributed to alcohol, but it now seems clear that one of the primary drivers for PCT is hepatitis C. In this series of 2 case series and 3 uncontrolled series including more than 250 patients, prevalence of hepatitis C was about 70% in patients with PCT.
Lichen planus is another dermatologic disorder commonly seen in individuals with hepatitis C. Lichen planus is seen in less than 1% of the general population. In total, HCV infection will be seen in 10% to 30% of patients with lichen planus. Lichen planus is characterized by pruritic papules that look like flat-topped, raised lesions on the skin. The lesions can occur anywhere on the body but are most commonly seen in the oral mucosa. Histologically, the affected skin is densely packed with T lymphocytes, which is another manifestation of hepatitis C.
The 2 studies shown in this slide illustrate the effectiveness of the 2 peginterferons approved for treatment of hepatitis C—peginterferon alfa-2a and peginterferon alfa-2b. Approximately 80% of individuals with genotype 2 or 3 HCV achieve a sustained virologic response with peginterferon combined with ribavirin, meaning 80% are cured of hepatitis C. Unfortunately, genotype 1 is more resistant to treatment, yet 40% to 45% of patients with genotype 1 achieve a sustained virologic response after treatment with peginterferon and ribavirin.
In summary, chronic HCV infection leads to cirrhosis and liver failure in a large number of individuals. It is important for primary care physicians to recognize that chronic hepatitis C is a common driver of non-liver disorders and that effective treatment of chronic hepatitis C can prevent fibrosis and disease progression and reduce complications of hepatitis C including cirrhosis and liver cancer.
Screening for liver cancer is critically important for patients with hepatitis B although there is a lack of consensus on some aspects of screening. All patients with cirrhosis should be screened, as cirrhosis is associated with an increased risk of HCC. However, HBV-infected individuals without cirrhosis are also at risk for HCC. There is some debate regarding the optimal age of initiating liver cancer screening. Although hepatitis-related HCC can develop at any age, the risk increases with longer duration of infection. Data from countries where infection occurs during infancy and childhood indicate that patients older than 35 years of age are at higher risk for HCC than patients younger than 35 years of age. In practice, most screening is initiated between the ages of 35 and 40 years.
The use of alfa-fetoprotein (AFP) for HCC screening has been studied extensively. Up to one third of patients with liver cancer have normal AFP levels. Therefore, using only AFP screening would miss many cases of HCC. False-positive results are also an issue, as AFP may be elevated in cirrhotic patients without HCC. However, AFP levels above 1000 ng/mL are diagnostic of HCC with few exceptions. Persistently rising AFP levels are also highly suggestive of HCC, but this pattern is not commonly seen.
Although there are many recommendations for liver cancer screening, the most common practices include a combination of AFP and ultrasound every 6-12 months in high-risk individuals, as defined by cirrhosis or family history. Medium-risk individuals, including those aged 30-40 years and those with active disease, should receive AFP with an ultrasound every year. A high or rising AFP along with a negative ultrasound may still indicate cancer, and consideration should be given to alternative imaging studies in these patients.
In another study evaluating the efficacy of lamivudine, Liaw and colleagues treated 651 patients with cirrhosis with lamivudine (n = 436) or placebo (n = 215) for just more than 3 years. They evaluated the disease progression in terms of the development of decompensated liver disease and liver cancer. Treatment with lamivudine was associated with a significantly lower risk of disease progression. These data support the treatment of individuals with chronic HBV infection in order to prevent the serious complications of advanced disease.
Global Burden of HBV
2 billion current or past infections
300-400 million with chronic HBV disease
1.25 million in the US
25%-40% of persons with chronic HBV disease die from cirrhosis or HCC
Over 300,000 cases/year of HBV-related HCC
HBV is second most important carcinogen behind tobacco
World Health Organization. Fact sheet. Available at: http://www.who.int. Accessed January 31, 2006. Centers for Disease Control. Fact sheet. Available at: http://www.cdc.gov. Accessed January 31, 2006. Lai CL, et al. Lancet . 2003;362:2089-2094.
Prevalence of Chronic Hepatitis B HBsAg Prevalence > 8% - High 2-8% - Intermediate < 2% - Low Immigration numbers summed by continent from 1996-2002 ~ 2 million Asians ~ 400,000 South Americans ~ 350,000 Africans ~ 930, 000 Europeans 350- 400 million chronically infected with Hepatitis B 260-300 million in Asia 1.25 million in the US HBV infection during Adolescence/adulthood for Caucasians 530,000 annual cases of HCC, 82% virus related 316,000 HBV related 118,000 HCV related
Philippines Ranks Among the Highest in HCC-related Deaths Age-adjusted Mortality Rates due to HCC (per 100,000) El-Serag & Rudolph. Gastroenterology 2007
Life Cycle of HBV in the Hepatocyte Adapted from Lai CL, et al. J Med Virol. 2000; Infectious HBV virion Viral polymerase converts pregenomic RNA to partially ds DNA Partially dsDNA Subviral particles Hepatocyte mRNA Cytoplasm Nucleus Precore/core HBeAg ER HBcAg HBsAg cccDNA Minus strand DNA Encapsulated pregenomic mRNA Complete viral packaging and release of complete virions or subviral particles of e-Ag and core and surface antigen serves as decoy to the immune system and modulates the immune system directly
HBV-Triggered Immune Response Ganem D, et al. N Engl J Med. 2004;350:1118-1129. MHC class II CD4+ T cell HBV peptides HBV MHC class I MHC class I TNF-α Interferon-gamma Down- regulations of viral replication HBV DNA HBsAg HBV peptides CD8+ T cell Antigen- presenting cell CD8+ T cell Infected hepatocyte HBV cores HBV RNA HBV antigens Immune and inflammatory response
Features C ( n=9 ) Ba ( n=11) Aa ( n=11 ) Mutations in the core promoter Mutations in the ATG initiator codon in the precore region T1809 10/11 (91%)* 0/9 (0%) 0/11(0%) < .0001 T1812 11/11 (100%)* 0/9 (0%) 0/11 (0%) < .0001 Mutations in the precore region T1858 1/11 (9%)* 9/9 (100%) 11/11 (100%) < .0001 T1862 11/11(100%)* 0/9 (0%) 0/11 (0%) < .0001 H1888 7/11 (86%)* 0/9 (0%) 0/11 (0%) < .0001 T1762/A1764 3/11 (27%)* 8/9 (89%) 10/11 (91%) < .005 HBeAg 5/11 (45%) 7/11 (64%) 5/9 (56%) Age (yr) 52.8 ±17.2 55.8 ±12.7 52.7 ±16.3 Characteristics of HBV genotypes among HCC patients N.S. N.S. N.S. Sollano, Quino, Mizokami, APASL 2005 A1896 0/11 (0%) 0/9 (0%) 1/11 (9%)
HBV/C Should Be Classified into 5 Subtypes Sollano, Quino, Muzokawi APASL, 2005 Subtype Ce (C2) Subtype Cs (C1) Subtype Cf (C5) Subtype Cp (C3) Subtype Ca (C4) HBV Genotype C 100 96 100 100 100 100 76 100 100 100 97 88 N-China Korea Japan S-China Vietnam Myanmar Philippine Vietnam Polynesia Micronesia Australian Aborigine
Model of Natural History of Chronic Hepatitis B D eath Hepatocellular carcinoma Decompensated cirrhosis Cirrhosis Chronic hepatitis Inactive disease Reactivation
Hepatitis B Disease Progression Acute Infection Chronic Infection Cirrhosis Death 5%-10% of chronic HBV-infected individuals 1 Liver Failure (Decompensation) >30% of CHB individuals 1
>90% of infected children progress to chronic disease
<5% of infected immunocompetent adults progress to chronic disease 1
24% of patients decompensate within 5 years of developing cirrhosis 2 Liver Cancer (HCC) Liver Transplantation
Torresi J, Locarnini. Gastroenterology 2000.
Fattovich G et al. Hepatology 1995
In 2007… Immune Tolerance Immune Clearance Inactive carrier Reactivation HBV DNA ALT HBeAg POSITIVE Anti- HBe NEGATIVE HBeAg NEGATIVE Anti- HBe POSITIVE Hepatitis B as a DYNAMIC DISEASE VARIABLE natural history FLUCTUATIONS in disease activity
Primary Goal of Hepatitis B Therapy: Preventing Cirrhosis, HCC, and Death
Durable Suppression of HBV Replication
HBV Seroprevalence Among Asian Americans Guan R, et al. AASLD 2004. Abstract 1269.
5 large US cities (2001-2004)
43 yrs (12-80)
11% 14% 10% 11% 15% 11% 10.4% 0% 4% 8% 12% 16% Philadelphia San Francisco Boston Chicago NY(1) NY(2) Overall Proportion of Individuals HBsAg+
Reflects effects of routine infant and childhood vaccination
Vaccination rates high in this population but decline to ~ 60% in adolescents
Slowest rate of decline in adults
Some adult subgroups showing increase in incidence (men ≥ 19 yrs, women ≥ 40 yrs)
Decline in risk of serious complications of chronic HBV
Reduced rates of childhood HCC in countries of high endemnicity
Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.
Annual Incidence of Liver Cancer in Children Aged 6-15 Years Chang MH, et al. N Engl J Med. 1997;336:1855-1859. *P < .001 for comparison between birth cohort. Vaccination program in effect since July 1984 Age at Diagnosis Before Program Cohort (1974-1984), Incidence per 100,000 After Program Cohort (1984-1986), Incidence per 100,000 6 0.46 0.00 7 0.53 0.15 8 0.48 0.31 9 0.61 0.00 Total 0.52 0.13*
Vaccine is highly effective – HBV incidence is declining
Infants and children vaccination rates high
In countries endemic for HBV, infant vaccination has reduced rates of liver complications
Missed opportunities among adults
If sexually active, IDU at risk
HBV-related HCC is vaccine-preventable cancer
Outcomes of Acute HBV Infection Recover Subclinical Hepatitis Fulminant Hepatitis Acute Hepatitis ACUTE INFECTION Chronic Infection DEATH < 1% 0.1-2.7% 5-20% Juszczyk J. Vaccine. 2000;18(suppl 1):S23-S25. Risk is Related to Age at Infection Outcome Neonates, % Children, % Adults, % Chronic carrier 90 20 < 5 Recover 10 80 > 95
Clinical-Epidemiologic Correlations Available at: http://www.who.int/mediacentre/factsheets/fs204/en/ . Accessed February 6, 2006. Designed by Jules Dienstag, MD HBV Endemicity Location Age of Infection Mode of Transmission Chronicity HCC Risk High 10-15% Asia Sub-Sahara Africa Birth Toddler Perinatal Horizontal Likely High Low < 2% N. America W. Europe Scandinavia Early Adulthood Percutaneous Sexual Rare Low
Natural History of Chronic HBV Infection 0 10 20 30 40 50 60 70 Years Serology HBeAg Anti-HBe ALT level HBV DNA level (viremia) Disease Chronic active hepatitis Cirrhosis/HCC Immune tolerant (phase I) Immune Active (phase II) Non-Replicative (phase III) Chronicity Stage Minimal inflammation Resolved Normal to cirrhosis/HCC HBsAg Anti-HBs
Possible Outcomes of HBeAg+ Chronic HBV Infection 24% HBeAg-negative CHB with detectable HBV DNA 5% Undetermined causes 67% Sustained remission Spontaneous seroconversion (n = 283) 33% ALT elevation (> 2 x ULN) 4% HBeAg reversion Hsu YS, et al. Hepatology. 2002;35:1522-1527.
Possible Outcomes of HBeAg+ Chronic HBV Infection Lai CL, et al. Lancet. 2003:362:2089-2094. Lok AS, et al. Gastroenterology. 2001;120:1828-1853. Patient Populations in Chronic Hepatitis B Marker Immune Tolerant HBeAg+ CHB Inactive HBsAg Carrier HBeAg – CHB (Precore Mutant) HBsAg + + + + HBeAg + + – – Anti-HBe – – + + ALT Normal Normal HBV DNA (copies/mL) > 10 5 > 10 5 < 10 3 > 10 4 Histology Normal/Mild Active Normal Active
Clarify diagnosis when ALT and HBV DNA levels are discordant
Exclude other coexistent causes of liver disease (eg, fatty liver or alcoholic liver disease)
Guide decision regarding initiation of treatment
Ferrell L, et al. in McSween, et al, editors. Pathology of the liver, 4th ed. London:Churchill Livingstone; 2002:313-362. Buckley A ,et al. Can J Gastroenterol 2000;14:481-82. Park A , et al. Minerva Gastroenterol Dietol. 2004;50:289-303.
Mitchell L. Shiffman, MD Professor of Medicine Chief, Hepatology Section Medical Director, Liver Transplant Program Virginia Commonwealth University Health System Richmond, Virginia Hepatitis C: Epidemiology, Diagnosis and Treatment
Hepatitis C Virus Infection Magnitude of the Problem
Nearly 4 million persons in United States infected
Approximately 35,000 new cases yearly
85% of new cases become chronic
Leading cause of
Chronic liver disease
Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.
Hepatitis C Virus Fate of Acute Infection 15% Chronic 85% Spontaneous resolution Alter MJ, et al. N Eng J Med. 1999;341:556-562.
Hepatitis C Virus Response to Acute Infection 0 50 100 150 200 0 6 12 18 24 Month ALT (IU/l) Resolution Chronic HCV RNA +/- + - Illustration by Mitchell L. Shiffman, MD.
Hepatitis C Virus Infection Population at Risk
Transfusion of blood products before 1992
Intravenous drug use
Nasal inhalation of cocaine
Chronic renal failure on dialysis
Occupational exposure to blood products
Transplantation of an organ/tissue graft from an HCV-positive donor
Body piercing and potentially tattoo
Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed February 1, 2006.
Hepatitis C Virus Infection Prevalence Sex B, Blacks; F, female; H, Hispanic; M, male; W, Whites. 0 1.0 2.0 3.0 4.0 All W B H M F Race Anti-HCV Positive (%) Alter MJ, et al. N Eng J Med. 1999;341:556-562. 1.8%
Hepatitis C Virus Infection Prevalence by Age 0 1.0 2.0 3.0 4.0 5.0 < 11 11-19 20-29 30-39 40-49 50-59 60-69 ≥ 70 Age Group Anti-HCV Positive (%) Alter MJ, et al. N Eng J Med. 1999;341:556-562.
Management of Chronic HCV Tests Utilized LFTs Disease Severity Response to Therapy AST/ALT Bilirubin Albumin Pro-time (INR) Platelet count Liver histology ALT HCV RNA HCV genotype Liver histology
Chronic HCV With Normal Serum ALT ALT Patterns and Flares ULN 0 20 40 60 80 100 120 0 3 6 9 12 15 18 21 24 Month ALT (IU/l) Single elevations Periodic elevations Always normal Illustration by Mitchell L. Shiffman, MD.
Chronic HCV Infection Normal Serum ALT Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601. Normal ALT Elevated ALT n = 37 n = 58
Chronic HCV Infection Normal vs Elevated Serum ALT Normal ALT Elevated ALT Portal 26% No fibrosis 23% Mild 39% Cirrhosis 6% Bridging 6% Portal 20% No fibrosis 16% Mild 33% Cirrhosis 18% Bridging 13% Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.
Chronic HCV Infection Symptoms Asymptomatic Symptomatic Cirrhosis 0 20 40 60 80 100 Fatigue Percentage of Patients 37% 7% 56% Unpublished data from MCV Hepatitis Program, 1995.
Chronic HCV Infection Progression to Cirrhosis 0 20 40 60 80 100 0 5 10 15 20 Time (Years) Bridging Portal None Approximate Percentage of Patients With Cirrhosis Yano M, et al. Hepatology. 1996;23:1334-1340. Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis
Fibrosis Progression of HCV Effect of Inflammation Ghany MG, et al. Gastroenterol. 2003;124:97-104. Change in Fibrosis Score According to Necrosis Score at Baseline Piecemeal Necrosis Score at Baseline 0-1 3-2 > 4 Number of patients 30 66 27 Mean change in fibrosis score per year .05 .19 .37
HCV Fibrosis Progression Effect of Alcohol Poynard T, et al. Lancet. 1997;349:825-832. Alcohol intake > 50 g/day* < 50 g/day *50 g is equal to approximately 3.5 drinks < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years) 4.0 3.0 2.0 1.0 0 Fibrosis Score
HCV Fibrosis Progression Effect of Age < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years) Fibrosis Score 4.0 3.0 2.0 1.0 0 Poynard T, et al. Lancet. 1997;349:825-832. Age at time of infection > 40 years < 40 years
HCV Fibrosis Progression Effect of Histology Poynard T, et al. Lancet. 1997;349:825-832. < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years) Fibrosis Inflammation Grade or Stage 4.0 3.0 2.0 1.0 0
HCV and Alcohol Risk of Cirrhosis Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men. 0 20 40 60 80 100 10 20 30 40 Years Following Exposure Cirrhosis (%) HCV HCV + alcohol Wiley TE, et al. Hepatology. 1998:28:805-809.
Fibrosis Progression in HCV Effect of Steatosis 2% 4% 7% 18% 6% 18% 30% 33% 0 20 40 60 80 100 < 5% 5%-10% 11%-30% > 30% Percentage of Steatosis at Initial Biopsy Cumulative Probability of Fibrosis Progression (%) Year 4 Year 6 Fartoux L, et al. Hepatology. 2005;41:82-87. Cumulative Probability of Fibrosis According to Level of Steatosis
HCV in Patients With Cirrhosis Survival and Rate of Decompensation Fattovich G, et al. Gastroenterology. 1997;112:463-472. 0 20 40 60 80 100 Survival (%) Stable Decompensation 10-Year Cumulative Survival 0 10 20 30 40 50 0 2 4 6 8 10 Years Percentage of Patients Decompensation HCC Cumulative Probability
Hepatocellular Carcinoma Incidence in the United States 0 2 4 6 8 10 12 1976-1980 1991-1995 Cases/100,000 Black male White male Black female White female El-Serag HB, et al. N Engl J Med. 1999;340:745-750.
Chronic Hepatitis C Infection Progression to Cirrhosis 0 10 20 30 40 50 HCC Cirrhosis C Cirrhosis A Severe Moderate Mild Years Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43. 20%-33% 15%-33%
Hepatitis C Virus Infection The Burden of Disease Armstrong GL, et al. Hepatology. 2000;31:777-782. 0 1.0 2.0 3.0 1960 1980 2000 2020 Year All patients Infection for > 20 years Anti-HCV Positive (%)
Hepatitis C Virus Infection Identification of Patients
Found to have elevated serum ALT during
Routine physical examination
Routine blood testing after starting certain medications
Test positive for anti-HCV during
Volunteer blood donation
Health or life insurance applications
Inquires about previous risk behaviors
Chronic Hepatitis C Virus Extrahepatic Manifestations
Chronic HCV infection leads to cirrhosis and liver failure in a large number of persons
Primary care physicians must recognize that chronic HCV is common in specific nonliver disorders
Effective treatment of chronic HCV can prevent fibrosis progression and reduce complications of HCV
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