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Hepatitis C: Epidemiology, Diagnosis and Treatment

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1 Hepatitis C: Epidemiology, Diagnosis and Treatment
Mitchell L. Shiffman, MD Professor of Medicine Chief, Hepatology Section Medical Director, Liver Transplant Program Virginia Commonwealth University Health System Richmond, Virginia This slide set summarizes some of the most important information on the epidemiology, diagnosis, and treatment of hepatitis C.

2 Hepatitis C: Epidemiology
Now let us move on to talk about the epidemiology of hepatitis C.

3 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 Cirrhosis Liver cancer Liver transplantation 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. Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: Accessed February 1, 2006.

4 Hepatitis C Virus Fate of Acute Infection
Spontaneous resolution 15% 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. Chronic 85% Alter MJ, et al. N Eng J Med. 1999;341:

5 Hepatitis C Virus Response to Acute Infection
200 HCV RNA +/- + - 150 Resolution ALT (IU/l) 100 Chronic 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 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. 50 6 12 18 24 Month Illustration by Mitchell L. Shiffman, MD.

6 Hepatitis C Virus Infection Natural History
Acute HCV Resolved 15% (15%) Chronic HCV 85% (85%) Stable 80% (68%) Cirrhosis 20% (17%) 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 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. Slowly progressive 75% (13%) HCC Liver failure 25% (4%) HCC, hepatocellular carcinoma

7 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 Incarceration Occupational exposure to blood products Transplantation of an organ/tissue graft from an HCV-positive donor Body piercing and potentially tattoo 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. Centers for Disease Control and Prevention. Hepatitis C fact sheet. Available at: Accessed February 1, 2006.

8 Hepatitis C Virus Infection Prevalence
4.0 3.0 Anti-HCV Positive (%) 2.0 1.8% 1.0 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. All W B H M F Sex Race B, Blacks; F, female; H, Hispanic; M, male; W, Whites. Alter MJ, et al. N Eng J Med. 1999;341:

9 Hepatitis C Virus Infection Prevalence by Age
5.0 4.0 3.0 Anti-HCV Positive (%) 2.0 This next slide looks at the age distribution of patients with hepatitis C. You can see that the peak age for HCV infection is 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 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. 1.0 < 11 11-19 20-29 30-39 40-49 50-59 60-69 ≥ 70 Age Group Alter MJ, et al. N Eng J Med. 1999;341:

10 Hepatitis C: Diagnosis and Management
Now let us move on to our next section on diagnosis and management.

11 Management of Chronic HCV Tests Utilized
Disease Severity Response to Therapy AST/ALT Bilirubin Albumin Pro-time (INR) Platelet count Liver histology ALT HCV RNA HCV genotype LFTs 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.

12 Viral Hepatitis Role of Diagnostic Testing
Identify patients with viral hepatitis infection Previous exposure to hepatitis virus Active infection Inactive infection Resolved infection Assess response to therapy Prior to onset of treatment During and following treatment 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.

13 Hepatitis C Virus Diagnostic Testing
Diagnostic Test Type Specifications Serologic Virologic Mode of detection Antibodies Virus Sensitivity > 95% > 98% Specificity Variable Detection postexposure 2-6 months 2-6 weeks Use Screening Confirmation 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.

14 Hepatitis C Virus Host Production of HCV Antibodies
HCV infects cell HCV proteins expressed on surface of hepatocytes Antibodies to HCV proteins produced by host HCV antibodies DO NOT convey immunity 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. Y Y Y Y Y Y Y Y Illustration by Mitchell L. Shiffman, MD.

15 Testing for Hepatitis C Virus Anti-HCV Antibodies
ELISA screening test Sensitivity: 97% Detects circulating HCV antibodies False positive reactions may occur Cross-reacting circulating antibodies Nonspecific binding of anti-HCV antibodies Positive predictive value 95% with risk factors and elevated ALT 50% without risk factors and normal ALT 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. Illustration by Mitchell L. Shiffman, MD.

16 HCV Antibody Testing Limitations
False positives Autoimmune disorders Spontaneous resolution of viral infection False negatives Chronically immune suppressed Transplant recipients Chronic renal failure on dialysis HIV positive 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.

17 Testing for Hepatitis C Virus Recombinant Immunoblot Assay
Supplemental assay Detects circulating antibodies to 4 HCV proteins Antigen-antibody reaction More specific than anti-HCV enzyme immunoassay False positive reaction can still occur Largely replaced by HCV RNA testing 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. Control Positive ≥ 2 bands Indeterminate 1 band Illustration by Mitchell L. Shiffman, MD.

18 Testing for Hepatitis C Virus Indications for HCV RNA
Confirm HCV infection Persistently normal serum ALT No risk factors HCV antibody positive Antinuclear antibodies Prior to initiating therapy Assess effectiveness of treatment Predict likelihood of response before and during therapy Confirm response after therapy completed 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.

19 Testing for Hepatitis C Virus Virologic Assays
PCR TMA b-DNA Polymerase chain reaction Transcription mediated amplification Branched chain DNA Amplifies target Amplifies probe Qualitative Quantitative 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.

20 Quantitative HCV RNA Assays Inherent Variability
Normal variation of 1 log unit in HCV RNA assays Differences of < 1 log between samples of probably NOT significant HCV RNA titer best reported in log units 100,000,000 10,000,000 1,000,000 100,000 HCV RNA (IU/mL) 10,000 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 106 copies/mL of HCV RNA from an individual with 1 x 105 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. 1000 100 10 1 I II III IV V Sample Nolte FS, et al. J Clin Microbiol. 2001;39:

21 Serum HCV RNA Level Stability Over Time
8 Patient 6 1 2 Log HCV RNA (IU/mL) 4 3 4 2 5 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. Limit of detection Baseline 1 2 3 4 Time (Years) Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

22 HCV RNA and Liver Histology Fibrosis
Serum HCV RNA does not correlate with level of fibrosis 8 Genotype 6 1 Log HCV RNA (copies/mL) 2 4 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. 3 2 4 No Fibrosis Portal Fibrosis Bridging Fibrosis Cirrhosis Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

23 HCV RNA and Liver Histology Inflammation
Serum HCV RNA does not correlate with level of inflammation 8 Genotype 6 1 (copies/mL) 2 Log HCV RNA 4 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. 3 4 2 2 4 6 8 10 12 Inflammation Score Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

24 Hepatitis C Virus Genotypes in the USA
17% Type 3 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. 10% Type 1 72% All others 1% McHutchinson JG, et al. N Engl J Med. 1998;339:

25 Determination of HCV Genotype INNOLiPA Assay
Best pretreatment predictor of response Determines duration of therapy All patients should have genotype determined prior to initiating therapy 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. Illustration by Mitchell L. Shiffman, MD.

26 Hepatitis C Virus Infection Liver Biopsy
Only test that can accurately assess Severity of inflammation Degree of fibrosis Determines the following Risk for developing cirrhosis in future Need for therapy Need for ongoing therapy when initial treatment has failed 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.

27 Management of Chronic HCV Is Liver Biopsy Necessary?
NO Patient wants treatment even if no fibrosis Patient does not want treatment or treatment contraindicated even if advanced fibrosis Labs and radiographic studies do not suggest cirrhosis Patient achieves SVR YES Patient would only accept treatment if advanced fibrosis Labs or radiographic studies suggest cirrhosis may be present Patient fails to achieve SVR and no recent biopsy available 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.

28 Assessment of Liver Histology Noninvasive Serum Tests
1.0 1.0 0.8 0.8 0.6 0.6 FIBROTEST ACTITEST 0.4 0.4 0.2 0.2 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. 1 2 3 4 1 2 3 Fibrosis Stage Activity Grade Poynard T, et al. Hepatology. 2003;38:

29 Chronic HCV With Normal Serum ALT ALT Patterns and Flares
120 Single elevations 100 Periodic elevations Always normal 80 ALT (IU/l) 60 ULN 40 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. 20 3 6 9 12 15 18 21 24 Month Illustration by Mitchell L. Shiffman, MD.

30 Chronic HCV Infection Normal Serum ALT
Normal ALT Elevated ALT n = 37 n = 58 Race White, % Black, % 48 29 52 71 Serum ALT, IU/L 46.6 ± 5.2 76.7 ± 6.0 Log HCV RNA, copies/mL 5.42 ± 0.13 5.50 ± 0.07 Histology score Inflammation Fibrosis 4.2 ± 0.1 0.7 ± 0.2 5.3 ± 0.1 1.6 ± 0.2 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. Shiffman ML, et al. J Infect Dis. 2000;182:

31 Chronic HCV Infection Normal vs Elevated Serum ALT
Portal Bridging 26% 13% Bridging Cirrhosis Portal 6% 18% 20% No Cirrhosis fibrosis 6% 23% No 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. fibrosis Mild 16% Mild 33% 39% Normal ALT Elevated ALT Shiffman ML, et al. J Infect Dis. 2000;182:

32 Chronic HCV Infection Symptoms
Symptomatic 100 37% Cirrhosis 80 7% 60 Percentage of Patients 40 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. 20 56% Asymptomatic Fatigue Unpublished data from MCV Hepatitis Program, 1995.

33 Chronic HCV Infection Progression to Cirrhosis
Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis Approximate Percentage of Patients With Cirrhosis 100 80 Bridging 60 Portal 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 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. 40 None 20 5 10 15 20 Time (Years) Yano M, et al. Hepatology. 1996;23:

34 Fibrosis Progression of HCV Effect of Inflammation
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 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. Ghany MG, et al. Gastroenterol. 2003;124:

35 HCV Fibrosis Progression Effect of Alcohol
4.0 3.0 Alcohol intake Fibrosis Score 2.0 > 50 g/day* < 50 g/day 1.0 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. < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years) *50 g is equal to approximately 3.5 drinks Poynard T, et al. Lancet. 1997;349:

36 HCV Fibrosis Progression Effect of Age
4.0 3.0 Age at time of infection Fibrosis Score 2.0 > 40 years < 40 years 1.0 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. < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years) Poynard T, et al. Lancet. 1997;349:

37 HCV Fibrosis Progression Effect of Histology
4.0 3.0 Fibrosis Grade or Stage 2.0 Inflammation 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. 1.0 < 10 11-20 21-30 31-40 > 40 Duration of Infection (Years) Poynard T, et al. Lancet. 1997;349:

38 HCV and Alcohol Risk of Cirrhosis
100 80 60 HCV Cirrhosis (%) HCV + alcohol 40 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. 20 10 20 30 40 Years Following Exposure Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men. Wiley TE, et al. Hepatology. 1998:28:

39 Fibrosis Progression in HCV Effect of Steatosis
Cumulative Probability of Fibrosis According to Level of Steatosis 100 80 60 Cumulative Probability of Fibrosis Progression (%) Year 4 Year 6 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. 40 33% 30% 20 18% 18% 6% 7% 2% 4% < 5% 5%-10% 11%-30% > 30% Percentage of Steatosis at Initial Biopsy Fartoux L, et al. Hepatology. 2005;41:82-87.

40 HCV in Patients With Cirrhosis Survival and Rate of Decompensation
10-Year Cumulative Survival Cumulative Probability 50 100 Decompensation Stable Decompensation 40 80 HCC 30 60 Percentage of Patients Survival (%) 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%. 20 40 10 20 2 4 6 8 10 Years Fattovich G, et al. Gastroenterology. 1997;112:

41 Hepatocellular Carcinoma Incidence in the United States
12 10 8 Black male White male 6 Cases/100,000 Black female 4 White female 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. 2 El-Serag HB, et al. N Engl J Med. 1999;340:

42 Chronic Hepatitis C Infection Progression to Cirrhosis
Mild 15%-33% Moderate Severe Cirrhosis A 20%-33% 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 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. Cirrhosis C HCC 10 20 30 40 50 Years Shiffman ML. Viral Hepatitis Rev. 1999;5:27-43.

43 Hepatitis C Virus Infection The Burden of Disease
3.0 All patients 2.0 Infection for Anti-HCV Positive (%) > 20 years 1.0 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 , 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. 1960 1980 2000 2020 Year Armstrong GL, et al. Hepatology. 2000;31:

44 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 Physician Inquires about previous risk behaviors 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.

45 Hepatitis C: Extrahepatic Manifestations
The final part of this program deals with another way that individuals with hepatitis C come to medical attention—through extrahepatic manifestations of the disease.

46 Chronic Hepatitis C Virus Extrahepatic Manifestations
Nonspecific antibodies Essential mixed cryoglobulinemia Glomerulonephritis Porphyria cutanea tarda Leukocytoclastic vasculitis Mooren’s corneal ulcer Non-Hodgkin’s lymphoma Autoimmune thyroiditis Diabetes mellitus Sjögren’s syndrome 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.

47 Chronic Hepatitis C Virus Autoantibodies
HCV, % Control, % Rheumatoid factor 70 8 Cryoglobulins 36 < 1 ANA > 1:40 > 1:180 21 13 10 2 Antismooth muscle 7 Anti–liver-kidney microsome 5 Antithyroid 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. Pawlotsky JM, et al. Hepatology. 1994;19:

48 Chronic Hepatitis C Virus Autoantibodies (cont’d)
No relationship between presence of autoantibodies and Severity of chronic HCV HCV genotype Correlation between rheumatoid factor titer and Cryoglobulinemia But not symptomatic cryoglobulinemia Circulating autoantibodies from autoimmune disorders may result in False positive anti-HCV 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.

49 Cryoglobulinemia Classification
Immunoglobulin Classification I Monoclonal No rheumatoid factor Primary II Polyclonal IgG Monoclonal IgM Rheumatoid factor Secondary mixed HCV infection III Polyclonal IgM Infections Autoimmune disorders Lymphoproliferative diseases 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. Cacoub P, et al. Curr Opin Rheumatol. 2002;14:29-35.

50 Immune Manifestations of HCV Pathogenesis
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. Illustration by Mitchell L. Shiffman, MD

51 HCV and Cryoglobulinemia Dermatitis
Occurs in dependent areas Deposition of cryoglobulins in small capillaries Ulcerations may develop Pruritic 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.

52 Extrahepatic Effects of HCV Cryoglobulinemia
100 80 60 Elevated ALT Percentage of Patients Anti-HCV 40 HCV RNA 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. 20 Cryoglobulinemia Controls Misiani R, et al. Ann Int Med. 1992;117:

53 HCV and Cryoglobulinemia Manifestations
Dermatitis (dependent areas) Vasculitis Myalgias (fibromyalgia?) Arthralgias (RA and/or ANA positive) Membranoproliferative glomerulonephritis Neuropathy Chronic fatigue syndrome (?) 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.

54 Extrahepatic Effects of HCV Lymphocytic Sialadenitis
Characteristic HCV Sialadenitis Primary Sjögren’s Syndrome SS-A, SS-B Negative Positive Lymphocytic capillaritis Mild Pericapillary Mostly CD8 cells Severe Periductal Mostly CD4 cells Sicca syndrome: Xerophthalmia Xerostomia Absent 8%-36% Present 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.

55 Extrahepatic Effects of HCV B-Cell Lymphoma
Ferri (1994) 8 case series 1754 pts evaluated Mazzaro (1996) Silvestri (1996) Izumi (1996) McColl (1996) Zignego (1997) 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. DeRosa (1997) Zuckerman (1997) 30 20 10 10 20 30 B Cell Lymphoma Controls

56 Chronic HCV and Diabetes Mellitus Case Prevalence
N = 179 with chronic HCV Prevalence of diabetes mellitus and insulin resistance noted Compared with expected rate based on NHANES III study after adjusting for Age Sex Race Prevalence of DM or insulin resistance higher in those with chronic HCV 20 Observed Expected 16 12 Number of Cases 8 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. 4 Females Males Zein CO, et al. Am J Gastroenterol. 2005;100:48-55.

57 Chronic HCV and Diabetes Mellitus Relationship to Fibrosis Stage
40 30 Percentage of Patients 20 10 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. 1 2 3 4 Histologic Stage Zein CO, et al. Am J Gastroenterol. 2005;100:48-55.

58 Extrahepatic Effects of HCV Porphyria Cutanea Tarda
Fargion (1992) De Castro (1993) Criber (1995) 2 case series 3 uncontrolled series 280 patients Alcohol: 36%-77% 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. Stolzel (1995) Kondo (1997) 100 80 60 40 20 5 10 15 20 PCT Control

59 Extrahepatic Effects of HCV Lichen Planus
Occurs in < 1% of the general population 10%-30% of patients with chronic HCV Appearance Flat topped, violaceous, pruritic papules Throughout body Oral mucosa Histology Dense infiltration of dermis with T lymphocytes 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. Nagao Y, et al. J Gastroenterol Hepatol. 2004;19:

60 Hepatitis C: Treatment
In the final portion of this program we will discuss the treatment of hepatitis C. Why is it so important to have covered so much information on recognizing hepatitis C and detailing how hepatitis C progresses, causes cirrhosis, and causes liver cancer? It is important because there are highly effective treatments for hepatitis C.

61 Treatment of Chronic HCV Peginterferon and Ribavirin
100 80 60 Sustained Virologic Response (%) PegIFN-2a/RBV 40 PegIFN-2b/RBV 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. 20 1 2-3 Genotype Fried MW, et al. N Eng J Med. 2002;347: Manns MP, et al. Lancet 2001;358:

62 Treatment of Chronic HCV Effect on Survival
Interferon treatment reduces risk of death, transplantation, and complications of cirrhosis Risk Factors for Survival (Multivariate Cox Regression Analysis) Survival Outcome Risk Ratio 95% Confidence Interval Interferon therapy vs no therapy Death and liver transplantation 0.5* Death, liver transplantation, and complications Development of HCC 0.7 Several studies have shown that individuals who achieve a sustained virologic response after treatment with peginterferon and ribavirin will have improved survival and reduced risk of liver cancer. Individuals who were treated with interferon had approximately half the risk of dying or requiring liver transplantation compared with individuals who received no treatment. Likewise, the risk of developing complications from cirrhosis is approximately halved for individuals who receive treatment. *P < .05. Niederau C, et al. Hepatology. 1998;28:

63 Treatment of Chronic HCV Effect on Development of HCC
Interferon treatment reduces the risk of developing hepatocellular carcinoma among patients with chronic HCV (P = .002) Hepatocellular carcinoma incidence Untreated controls: 38% (24%-58%) Interferon-treated patients: 4% (1%-15%) HCC risk ratio: ( ; P = .01) If you examine patients with cirrhosis who achieve a sustained virologic response after interferon therapy, the risk of developing liver cancer is significantly reduced. Compared with untreated controls where the risk of developing cancer was 38% over long-term follow-up, the risk was reduced to 4% in patients treated with interferon, a highly significant risk reduction. Nishiguchi S, et al. Lancet. 1995;346:

64 The Many Faces of HCV Infection Summary
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 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.

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