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Hepatitis C

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Hepatitis C

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    1. Hepatitis C

    2. Characteristics

    3. Hepatitis C: A Global Health Problem Key Point: According to CDC estimates, approximately 3-4 million people in the US are currently infected with the hepatitis C virus (see map). There are, however, a few distinct geographic regions where infection is especially common. In Egypt, for example, HCV infection occurs in 10% to 30% of the general population. Likewise, the prevalence of infection is greater than 10% in certain parts of Asia and high rates of infection have been found in certain geographic regions of Japan, Taiwan, and Italy. As noted below, however, there are a number of countries where data are not available.1 Reference: 1. 1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28. 3. Edlin, et al. Five Million Infected with the Hepatitis C Virus: A Corrected Estimate. Presented at AASLD, 2005. Oral presentation 44. 4. Fontanet, A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html Hepatitis C: A Global Health Problem Key Point: According to CDC estimates, approximately 3-4 million people in the US are currently infected with the hepatitis C virus (see map). There are, however, a few distinct geographic regions where infection is especially common. In Egypt, for example, HCV infection occurs in 10% to 30% of the general population. Likewise, the prevalence of infection is greater than 10% in certain parts of Asia and high rates of infection have been found in certain geographic regions of Japan, Taiwan, and Italy. As noted below, however, there are a number of countries where data are not available.1 Reference: 1. 1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28. 3. Edlin, et al. Five Million Infected with the Hepatitis C Virus: A Corrected Estimate. Presented at AASLD, 2005. Oral presentation 44. 4. Fontanet, A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html

    4. HCV, HBV, HIV: Prevalence vs Undiagnosed Cases HCV, HBV, and HIV: Prevalence vs Undiagnosed Cases Estimates of the number of undiagnosed cases relative to the total number of infected individuals are higher for HCV and HBV (65%–70%) than for other viral infections, such as HIV (25%) References American Liver Foundation. Hepatitis C Factsheet. Available at: www.liverfoundation.org. Accessed May 11, 2007. NIAID. HIV Infection and AIDS: An Overview. 2005. Available at: www.niaid.nih.gov. Accessed May 14, 2007. Lok A, McMahon B. Chronic hepatitis C. Hepatology. 2004;39:1-5. Thompson MJ, Taylor VM, Jackson JC, et al. Hepatitis B knowledge and practices among Chinese American women in Seattle, Washington. J Cancer Education. 2002;17:222-226.HCV, HBV, and HIV: Prevalence vs Undiagnosed Cases Estimates of the number of undiagnosed cases relative to the total number of infected individuals are higher for HCV and HBV (65%–70%) than for other viral infections, such as HIV (25%) References American Liver Foundation. Hepatitis C Factsheet. Available at: www.liverfoundation.org. Accessed May 11, 2007. NIAID. HIV Infection and AIDS: An Overview. 2005. Available at: www.niaid.nih.gov. Accessed May 14, 2007. Lok A, McMahon B. Chronic hepatitis C. Hepatology. 2004;39:1-5. Thompson MJ, Taylor VM, Jackson JC, et al. Hepatitis B knowledge and practices among Chinese American women in Seattle, Washington. J Cancer Education. 2002;17:222-226.

    5. Statistics 170 Million infected worldwide 2.7-3 Million active infection nationwide High medical costs - $600 Million 30K New infections/year 10K Deaths/year Most important causes of Liver Disease OLT

    6. HCV Genotypes Hepatitis C virus RNA virus–high mutation rates Evolved different genotypes 6 known genotypes Genotype 1 (75%) Genotype 2 (10%) Genotype 3 (10%) The above 3 are the most common in the United States Little difference in mode of transmission or natural history of infection among different genotypes HCV Genotypes The hepatitis C virus (HCV) is an RNA virus with a high mutation rate and has evolved different genotypes There are 6 known genotypes with the 3 presented on the slide being the most common in the US There is little difference in the mode of transmission or natural history of infection among the genotypes, but there is a large difference in response to interferon alfa-based treatment regimens among genotypes Therefore, it is generally recommended that the genotype be determined before starting medical therapy Reference Flamm SL. Chronic hepatitis C virus infection. JAMA. 2003;289:2413-2417.HCV Genotypes The hepatitis C virus (HCV) is an RNA virus with a high mutation rate and has evolved different genotypes There are 6 known genotypes with the 3 presented on the slide being the most common in the US There is little difference in the mode of transmission or natural history of infection among the genotypes, but there is a large difference in response to interferon alfa-based treatment regimens among genotypes Therefore, it is generally recommended that the genotype be determined before starting medical therapy Reference Flamm SL. Chronic hepatitis C virus infection. JAMA. 2003;289:2413-2417.

    7. Prevalence of HCV in Select Populations Prevalence of HCV in Select Populations The prevalence of individual populations in the United States is presented above References Centers for Disease Control. Prevention and control of infections with hepatitis viruses in correctional settings: recommendations and reports. Morb Mortal Wkly Rep. 2003;52(RR-1):1-33. Edlin B. Prevention and treatment of hepatitis C in injection drug users. Hepatology. 2002;36 (5 suppl 1):S210-S219. National Household Survey on Drug Abuse. The NHSDA report: injection drug use. March 14, 2003. Poles M, Dieterich D. Hepatitis C virus/human immunodeficiency virus coinfection: clinical management issues. Clin Infect Dis. 2000;31:154-161. LaBrecque D, Sandt L. Alcohol and hepatitis C. In: Hepatitis C Choices. Vancouver, WA. Hepatitis C Caring Ambassadors Program. 2002:7-15. Alter M, Kruszon-Moran D, Nainan O, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562. Nyamathi A, Dixon E, Robbins W, et al. Risk factors for hepatitis C virus infection among homeless adults. J Gen Intern Med. 2002;17:134-143. Bräu N, Bini E, Shahidi A, et al. Prevalence of hepatitis C and coinfection with HIV among United States veterans in the New York City metropolitan area. Am J Gastroenterol. 2002;97:2071-2078. Jonas M. Children with hepatitis C. Hepatology. 2002;36(5 suppl 1):S173-S178. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714.Prevalence of HCV in Select Populations The prevalence of individual populations in the United States is presented above References Centers for Disease Control. Prevention and control of infections with hepatitis viruses in correctional settings: recommendations and reports. Morb Mortal Wkly Rep. 2003;52(RR-1):1-33. Edlin B. Prevention and treatment of hepatitis C in injection drug users. Hepatology. 2002;36 (5 suppl 1):S210-S219. National Household Survey on Drug Abuse. The NHSDA report: injection drug use. March 14, 2003. Poles M, Dieterich D. Hepatitis C virus/human immunodeficiency virus coinfection: clinical management issues. Clin Infect Dis. 2000;31:154-161. LaBrecque D, Sandt L. Alcohol and hepatitis C. In: Hepatitis C Choices. Vancouver, WA. Hepatitis C Caring Ambassadors Program. 2002:7-15. Alter M, Kruszon-Moran D, Nainan O, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562. Nyamathi A, Dixon E, Robbins W, et al. Risk factors for hepatitis C virus infection among homeless adults. J Gen Intern Med. 2002;17:134-143. Bräu N, Bini E, Shahidi A, et al. Prevalence of hepatitis C and coinfection with HIV among United States veterans in the New York City metropolitan area. Am J Gastroenterol. 2002;97:2071-2078. Jonas M. Children with hepatitis C. Hepatology. 2002;36(5 suppl 1):S173-S178. Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714.

    8. Prevalence of HCV in Racial/Ethnic Populations Prevalence of HCV in Racial/Ethnic Populations The prevalence of anti-HCV antibodies was statistically significantly different between non-Hispanic black persons and non-Hispanic white persons (but not between Mexican American persons and non-Hispanic white persons) The rates of HCV RNA positivity were similar among non-Hispanic white persons (77.3%) and non-Hispanic black persons (79.7%) References Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714. US Census Bureau. Available at: www.census.gov. Accessed March 21, 2007.Prevalence of HCV in Racial/Ethnic Populations The prevalence of anti-HCV antibodies was statistically significantly different between non-Hispanic black persons and non-Hispanic white persons (but not between Mexican American persons and non-Hispanic white persons) The rates of HCV RNA positivity were similar among non-Hispanic white persons (77.3%) and non-Hispanic black persons (79.7%) References Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714. US Census Bureau. Available at: www.census.gov. Accessed March 21, 2007.

    9. Hepatitis C Virus Infection Prevalence by Age 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 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.

    11. HCV replication and infection Click on video frame to start animation sequence. Animation start – the outer layer of the HCV virion has two types of envelope proteins. Inside is a capsid, composed of core protein, that contains a single strand of positive-sense ribonucleic acid (RNA). Viral entry: endocytosis – the virion enters the host cell (hepatocyte) by binding to receptors on the cell membrane (not shown in animation for simplicity) and undergoing receptor-mediated endocytosis. Uncoating – the viral RNA is released into the cytoplasm of the host cell. Translation: protein synthesis – the RNA binds to a ribosome on the endoplasmic reticulum via an internal ribosome entry site (IRES), and is translated into a polyprotein precursor that is further processed into structural and non-structural viral proteins. Polyprotein processing – host signal peptidase is responsible for cleavage between C/E1, El/E2, E2/p7 and p7/NS2, while viral NS2 protease cleaves the NS2/3 junction (not shown in animation for simplicity). NS3/4A protease then acts on the rest of the polyprotein cleavage sites downstream. RNA replication – the replicase complex transcribes the original positive-stranded RNA of the virus to form a complementary negative-stranded RNA intermediate. This, in turn, serves as a template for the synthesis of new positive-stranded RNA. Assembly/packaging – structural proteins and new viral RNA assemble to form progeny HCV virions that are subsequently released from the host cell (Release). References 1. Liu C. Clin Liver Dis 2006;10:773-91. 2. Lindenbach BD, Rice CM. Nature 2005;436:933-938.Click on video frame to start animation sequence. Animation start – the outer layer of the HCV virion has two types of envelope proteins. Inside is a capsid, composed of core protein, that contains a single strand of positive-sense ribonucleic acid (RNA). Viral entry: endocytosis – the virion enters the host cell (hepatocyte) by binding to receptors on the cell membrane (not shown in animation for simplicity) and undergoing receptor-mediated endocytosis. Uncoating – the viral RNA is released into the cytoplasm of the host cell. Translation: protein synthesis – the RNA binds to a ribosome on the endoplasmic reticulum via an internal ribosome entry site (IRES), and is translated into a polyprotein precursor that is further processed into structural and non-structural viral proteins. Polyprotein processing – host signal peptidase is responsible for cleavage between C/E1, El/E2, E2/p7 and p7/NS2, while viral NS2 protease cleaves the NS2/3 junction (not shown in animation for simplicity). NS3/4A protease then acts on the rest of the polyprotein cleavage sites downstream. RNA replication – the replicase complex transcribes the original positive-stranded RNA of the virus to form a complementary negative-stranded RNA intermediate. This, in turn, serves as a template for the synthesis of new positive-stranded RNA. Assembly/packaging – structural proteins and new viral RNA assemble to form progeny HCV virions that are subsequently released from the host cell (Release). References 1. Liu C. Clin Liver Dis 2006;10:773-91. 2. Lindenbach BD, Rice CM. Nature 2005;436:933-938.

    12. Hepatitis C Virus Fate of Acute Infection 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. 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.

    13. Natural History 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. 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.

    14. Hepatitis C Virus Infection Natural History 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. 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.

    15. Hepatitis C Virus Infection Population at Risk Ever injected illegal drugs / intranasal cocaine use Tattoo and Body piercing Received clotting factors made before 1987 Received blood/organs before July 1992 Ever on chronic hemodialysis Evidence of liver disease Incarceration Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood Children born to HCV-positive women

    16. Testing Strategies for HCV

    17. Hepatitis C Virus Diagnostic Testing 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 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.

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

    19. Physical Exam Non Specific (Malaise / Weakness) Chronic liver disease Palmar Erythema Temporal Wasting Gynecomastia Spider Angiomas Caput Medussa Dupuytren’s contracture Clubbing Asterixis Icterus Enlarged Parotid Testicular atrophy HSM

    20. Extrahepatic Manifestations Autoimmune / Rheumatological Mixed Cryoglobulinemia, Sjögren and Arthritis Hematological NHL Endocrinological Thyroid and DM Dermatological PTC and Lichen Planus

    21. Laboratory Evaluation CBC BMP LFT’s TFT’s HIV Viral Hepatitis Genotype Viral Load Liver Biopsy A1C Hemochromatosis (Fe Studies) A1-AT Wilson’s Dz Autoimmune ANA, RF, AMA

    22. 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. 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.

    23. Liver Biopsy (Metavir)

    24. Who to treat?

    25. Who to treat? Age 18 Liver Enzyme elevation Liver Biopsy (Stage dependant ?) Compensated Liver Disease (Tbili, INR, Alb, Plt, HE, Ascites) Hematologic parameters (Hb, WBC, Cr) Controlled depression

    26. Who NOT to treat? Major/Uncontrolled depressive disorder Renal/Lung/Heart Transplant Autoimmune Hepatitis Uncontrolled hyperthyroidism Pregnant – Unwilling to go contraception Age under 3 Hypersensitivity Severe Disease: HTN, CHF, CAD, DM, COPD

    27. Goals of Treatment Sustained Virological Response Prevent the progression of Cirrhosis Reduce Risk of HCC

    28. Factors Associated With SVR Pretreatment or fixed Genotype HCV RNA level Histology Race HIV coinfection Steatosis / IR? Body weight Adherence Dynamic factors Rapid virologic response (HCV RNA negative at Wk 4) Early virologic response Partial (HCV RNA decline of > 2 logs at Wk 12) Complete (HCV RNA negative at Wk 12) SVR, sustained virologic response. This slide lists a number of factors that have been associated with SVR. On the left are pretreatment or fixed factors, and on the right are the dynamic factors associated with outcomes. HCV genotype has been known for some time to play an important role in determining the likelihood of SVR, with genotype 1 leading to the most unfavorable results. Similarly, HCV RNA levels and the presence of advanced fibrosis are negative predictors of SVR. In the United States, one of the most important predictors is now known to be race, as has been demonstrated in several studies. The Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep C) study showed that SVR rates in blacks treated with the exact same regimens are reduced by approximately 50% vs whites. In addition, HIV coinfection, steatosis, high body weight, and adherence are all negative predictors of SVR. We also recognize that the best predictor of SVR is actually the rate at which the virus disappears during the course of treatment. Therefore, we will examine the importance of RVR—defined as achieving undetectable HCV RNA at Week 4—and early virologic response (EVR)—defined as either achieving undetectable HCV RNA by Week 12 (complete EVR), or achieving an HCV RNA decline > 2 logs by Week 12 (partial EVR).SVR, sustained virologic response. This slide lists a number of factors that have been associated with SVR. On the left are pretreatment or fixed factors, and on the right are the dynamic factors associated with outcomes. HCV genotype has been known for some time to play an important role in determining the likelihood of SVR, with genotype 1 leading to the most unfavorable results. Similarly, HCV RNA levels and the presence of advanced fibrosis are negative predictors of SVR. In the United States, one of the most important predictors is now known to be race, as has been demonstrated in several studies. The Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep C) study showed that SVR rates in blacks treated with the exact same regimens are reduced by approximately 50% vs whites. In addition, HIV coinfection, steatosis, high body weight, and adherence are all negative predictors of SVR. We also recognize that the best predictor of SVR is actually the rate at which the virus disappears during the course of treatment. Therefore, we will examine the importance of RVR—defined as achieving undetectable HCV RNA at Week 4—and early virologic response (EVR)—defined as either achieving undetectable HCV RNA by Week 12 (complete EVR), or achieving an HCV RNA decline > 2 logs by Week 12 (partial EVR).

    29. SVR in Patients Who Achieved an RVR RVR, rapid virologic response; SVR sustained virologic response. Interestingly, patients who achieved RVR, regardless of genotype, had nearly equivalent chances of achieving SVR (genotype 1: 88%; genotype 2: 86%; genotype 3: 86%; and genotype 4: 100%). Therefore, achieving an RVR appears to be a great equalizer across genotypes. RVR, rapid virologic response; SVR sustained virologic response. Interestingly, patients who achieved RVR, regardless of genotype, had nearly equivalent chances of achieving SVR (genotype 1: 88%; genotype 2: 86%; genotype 3: 86%; and genotype 4: 100%). Therefore, achieving an RVR appears to be a great equalizer across genotypes.

    30. Calculating a Cure: Pretreatment Characteristics Likelihood of SVR depends on interactions of multiple factors Can individual probabilities of SVR be estimated? Data from 2 registration trials of pegIFN-2a + RBV used to identify important factors related to SVR Modeling used to vary important baseline characteristics PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. When evaluating an individual patient, we must recognize that they may have an aggregate of several of these characteristics that make them more or less likely to respond to treatment. In a retrospective study, we examined the interactions of multiple baseline factors and asked whether individual probabilities of SVR could be estimated based upon all these interactions. In this study, data from 2 large registration trials of peginterferon alfa-2a and ribavirin were used to identify important factors related to SVR.PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. When evaluating an individual patient, we must recognize that they may have an aggregate of several of these characteristics that make them more or less likely to respond to treatment. In a retrospective study, we examined the interactions of multiple baseline factors and asked whether individual probabilities of SVR could be estimated based upon all these interactions. In this study, data from 2 large registration trials of peginterferon alfa-2a and ribavirin were used to identify important factors related to SVR.

    31. Everyone Is Special ALT, alanine aminotransferase; SVR, sustained virologic response. We showed that the probability of achieving SVR based on the interaction of baseline characteristics can in fact be modeled. Thus, at one end of the spectrum, the probability that patients with the least favorable treatment characteristics—for example, patients who are older or who have cirrhosis, a very high body mass index (BMI), and high levels of HCV RNA—will achieve SVR is low at 7%. By contrast, the probability that young patients with no fibrosis, ideal BMIs, and low levels of HCV RNA will achieve SVR is more than 90%. Most patients have some favorable prognostic factors and some negative prognostic factors, and thus their likelihood of achieving SVR falls somewhere between these 2 extremes. Nevertheless, these data demonstrate the importance of understanding a patient’s baseline characteristics so that they can be appropriately counseled. In addition, these results raise the question of whether alterations in the current dosing regimens could help overcome some of these treatment-resistant characteristics.ALT, alanine aminotransferase; SVR, sustained virologic response. We showed that the probability of achieving SVR based on the interaction of baseline characteristics can in fact be modeled. Thus, at one end of the spectrum, the probability that patients with the least favorable treatment characteristics—for example, patients who are older or who have cirrhosis, a very high body mass index (BMI), and high levels of HCV RNA—will achieve SVR is low at 7%. By contrast, the probability that young patients with no fibrosis, ideal BMIs, and low levels of HCV RNA will achieve SVR is more than 90%. Most patients have some favorable prognostic factors and some negative prognostic factors, and thus their likelihood of achieving SVR falls somewhere between these 2 extremes. Nevertheless, these data demonstrate the importance of understanding a patient’s baseline characteristics so that they can be appropriately counseled. In addition, these results raise the question of whether alterations in the current dosing regimens could help overcome some of these treatment-resistant characteristics.

    32. Genotype 1/4

    33. Genotype 2/3

    34. Current Therapy of Hepatitis C Based on HCV genotype Genotype 1

    35. Definition: Viral Responses Sustained Virological Response (SVR) End of Treatment Response (ETR) Non-Responders (NR) Breakthrough and Null responders Relapser (R) Rapid Virological Response (RVR) – 4wk Early Virologcal Response (EVR) – 12wk cEVR pEVR

    36. Definition: Viral Responses

    37. Efficacy of current HCV combination therapy by genotype Therapy using pegylated IFN-alfa combined with ribavirin leads to SVR in 42–52% of patients infected with HCV genotype 1,1–3 the genotype accounting for about 75% of cases in the United States.4 Click for slide to build. For patients with HCV genotype 2 or 3 infection, SVR rates are 76–93%.1–3,5 An SVR is defined as the loss of detectable HCV RNA during treatment and its continued absence for at least 6 months after stopping treatment. Current HCV combination therapy is associated with adverse effects such as anemia, myalgia, fatigue, gastrointestinal symptoms, depression, anxiety, irritability, insomnia and impaired concentration.1–3,5 In studies, patients infected with HCV genotype 1 required treatment for 48 weeks; those with genotypes 2 or 3 needed treatment for 24 weeks.1,5 In trials consisting of 48 weeks of treatment with pegylated interferon and ribavirin, up to 16% of patients were withdrawn from therapy due to adverse events or laboratory abnormalities, and between 9% and 42%* underwent dose modification.1–3 *11–25% (Fried et al, 2002), 28–38% (Hadziyannis et al, 2004), 9–42% (Manns et al, 2001) References 1. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346-355. 2. Fried MW, et al. N Engl J Med 2002;347:975-982. 3. Manns MP, et al. Lancet 2001;358:958-965. 4. Hoofnagle JH, Seef LB. N Engl J Med 2006;355:2444-2451. 5. Zeuzem S, et al. J Hepatol 2004;40:993-999. Therapy using pegylated IFN-alfa combined with ribavirin leads to SVR in 42–52% of patients infected with HCV genotype 1,1–3 the genotype accounting for about 75% of cases in the United States.4 Click for slide to build. For patients with HCV genotype 2 or 3 infection, SVR rates are 76–93%.1–3,5 An SVR is defined as the loss of detectable HCV RNA during treatment and its continued absence for at least 6 months after stopping treatment. Current HCV combination therapy is associated with adverse effects such as anemia, myalgia, fatigue, gastrointestinal symptoms, depression, anxiety, irritability, insomnia and impaired concentration.1–3,5 In studies, patients infected with HCV genotype 1 required treatment for 48 weeks; those with genotypes 2 or 3 needed treatment for 24 weeks.1,5 In trials consisting of 48 weeks of treatment with pegylated interferon and ribavirin, up to 16% of patients were withdrawn from therapy due to adverse events or laboratory abnormalities, and between 9% and 42%* underwent dose modification.1–3 *11–25% (Fried et al, 2002), 28–38% (Hadziyannis et al, 2004), 9–42% (Manns et al, 2001) References 1. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346-355. 2. Fried MW, et al. N Engl J Med 2002;347:975-982. 3. Manns MP, et al. Lancet 2001;358:958-965. 4. Hoofnagle JH, Seef LB. N Engl J Med 2006;355:2444-2451. 5. Zeuzem S, et al. J Hepatol 2004;40:993-999.

    38. Current Therapy of Hep C

    39. Rapid Virologic Response (RVR)

    40. Slow-to-Respond Patients: Extending Therapy

    41. SVR rate 72 wks treatment in G1 pts with pEVR PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day HCV RNA positive at Wk 12 but HCV RNA negative at Wk 24 (N = 101 slow responders) Continued treatment through 48 vs 72 wks Baseline characteristics 48% black 78% high HCV RNA 26% F3/4 fibrosis 34% BMI > 30 18% high fasting glucose EOT, end of treatment; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. On the other hand, not achieving RVR had a clear impact on SVR rates. In this study, focusing specifically on patients who did not achieve RVR, those treated with peginterferon plus low-dose ribavirin for only 24 weeks had an SVR rate of only 16% vs 44% in those receiving peginterferon plus the standard dose of ribavirin for a full 48 weeks. EOT, end of treatment; PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response. On the other hand, not achieving RVR had a clear impact on SVR rates. In this study, focusing specifically on patients who did not achieve RVR, those treated with peginterferon plus low-dose ribavirin for only 24 weeks had an SVR rate of only 16% vs 44% in those receiving peginterferon plus the standard dose of ribavirin for a full 48 weeks.

    42. SVR rate 72 wks treatment in G1 pts with pEVR

    43. ACCELERATE Trial: SVR G2/3 Pts With and Without an RVR RVR, rapid virologic response; SVR sustained virologic response. The likelihood of achieving SVR is not only high for HCV genotype 1 patients who achieve RVR but also for genotype 2 or 3 patients. The ACCELERATE trial treated genotype 2/3 patients for either 16 or 24 weeks and examined the impact of achieving RVR on SVR. Patients who achieved RVR had an 82% likelihood of achieving SVR when treated for 16 weeks, compared with a 90% likelihood of achieving SVR when treated for 24 weeks. By contrast, only 27% of patients who did not achieve RVR achieved SVR when treated for 16 weeks vs 49% when treated for 24 weeks. Therefore, the importance of RVR should not be overlooked, even in genotype 2/3 patients. RVR, rapid virologic response; SVR sustained virologic response. The likelihood of achieving SVR is not only high for HCV genotype 1 patients who achieve RVR but also for genotype 2 or 3 patients. The ACCELERATE trial treated genotype 2/3 patients for either 16 or 24 weeks and examined the impact of achieving RVR on SVR. Patients who achieved RVR had an 82% likelihood of achieving SVR when treated for 16 weeks, compared with a 90% likelihood of achieving SVR when treated for 24 weeks. By contrast, only 27% of patients who did not achieve RVR achieved SVR when treated for 16 weeks vs 49% when treated for 24 weeks. Therefore, the importance of RVR should not be overlooked, even in genotype 2/3 patients.

    44. Influence of Cumulative RBV: Wks 1-12 on SVR in G1 RBV, ribavirin; SVR, sustained virologic response. Reddy and colleagues performed a retrospective analysis of the influence of cumulative ribavirin exposure during the early and latter parts of therapy in patients with genotype 1 HCV. The investigators determined that the patients who were most adherent to treatment and therefore had the greatest cumulative ribavirin exposure—in this case, more than 97%—had the greatest chance of achieving SVR (66%). However, a cumulative ribavirin exposure decrease during the first 12 weeks of treatment led to a commensurate decrease in the likelihood of achieving SVR. In fact, when cumulative ribavirin exposure was decreased to 60% to79%, SVR rates dropped to 45%, and discontinuation of ribavirin leading to a cumulative exposure of less than 60% decreased SVR rates to 0%. Therefore, these data reinforce the importance of ribavirin and suggest that lowering the dose of ribavirin if required because of adverse effects is better than complete discontinuation.RBV, ribavirin; SVR, sustained virologic response. Reddy and colleagues performed a retrospective analysis of the influence of cumulative ribavirin exposure during the early and latter parts of therapy in patients with genotype 1 HCV. The investigators determined that the patients who were most adherent to treatment and therefore had the greatest cumulative ribavirin exposure—in this case, more than 97%—had the greatest chance of achieving SVR (66%). However, a cumulative ribavirin exposure decrease during the first 12 weeks of treatment led to a commensurate decrease in the likelihood of achieving SVR. In fact, when cumulative ribavirin exposure was decreased to 60% to79%, SVR rates dropped to 45%, and discontinuation of ribavirin leading to a cumulative exposure of less than 60% decreased SVR rates to 0%. Therefore, these data reinforce the importance of ribavirin and suggest that lowering the dose of ribavirin if required because of adverse effects is better than complete discontinuation.

    45. Discontinuing RBV on G1 Patients Responding to Therapy PegIFN, peginterferon; RBV, ribavirin. The importance of ribavirin was tested prospectively by Bronowicki and colleagues in a study of genotype 1 HCV–infected patients who were treated with peginterferon alfa-2a and ribavirin 800 mg/day. At Week 24, those patients who had undetectable HCV RNA were randomized to either continue the current dosing with peginterferon plus ribavirin or to stop ribavirin and continue peginterferon alone for the full 48 weeks. The purpose of this study was to test the hypothesis that patients achieving HCV RNA undetectability at Week 24 could stop ribavirin and still have the same chance of achieving SVR. PegIFN, peginterferon; RBV, ribavirin. The importance of ribavirin was tested prospectively by Bronowicki and colleagues in a study of genotype 1 HCV–infected patients who were treated with peginterferon alfa-2a and ribavirin 800 mg/day. At Week 24, those patients who had undetectable HCV RNA were randomized to either continue the current dosing with peginterferon plus ribavirin or to stop ribavirin and continue peginterferon alone for the full 48 weeks. The purpose of this study was to test the hypothesis that patients achieving HCV RNA undetectability at Week 24 could stop ribavirin and still have the same chance of achieving SVR.

    46. Discontinuing RBV oif n Patients Responding to Therapy: SVR PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. However, as alluded to in the retrospective analyses, SVR rates were significantly greater for patients who remained on combination therapy for the full 48 weeks of treatment vs those who stopped ribavirin at Week 24: 68% vs 53%, respectively (P = .004).PegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response. However, as alluded to in the retrospective analyses, SVR rates were significantly greater for patients who remained on combination therapy for the full 48 weeks of treatment vs those who stopped ribavirin at Week 24: 68% vs 53%, respectively (P = .004).

    47. Complication / Side Effect PEG-Interferon alfa 2 a/b Flu-like symptoms Depression / Mood instability Cytopenias (WBC / Plt) Thyroid (hypo / hyper) Alopecia Nausea / Vomiting /Abdominal pain Ribavirin Hemolytic anemia Rash

    48. Non-Responder / Relapser New Molecules (STAT-C) Clinical Trials Retreatment with different PEG molecule Infergen (Consensus IFN)? Induction Therapy?

    49. Future Therapies Viral Entry Inhibitors HC Ig. and Monoclonal Ab. HCV RNA Translation Inh. Post Translational Processing Inh. NS3-4A Serine Proteinase Inh. HCV Replication Inhibitors NS5B Polymerase Inh, Cyclophilin B Inh, NS5A Inh, Helicase Inh Virus Assembly and Release Inh

    50. Targets for New Treatments

    51. Randomized, placebo-controlled, phase II trial PROVE 1: Telaprevir + PegIFN/RBV in Naive HCV GT1 EOT, end of treatment; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; QD, once daily; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx   EOT, end of treatment; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; QD, once daily; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx  

    52. PROVE 1: Response Rates (ITT) ITT, intent to treat; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; TVR, telaprevir.   Checked numbers which were correct but added in n/N info and description for clarification For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx ITT, intent to treat; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; TVR, telaprevir.   Checked numbers which were correct but added in n/N info and description for clarification For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx

    53. PROVE 1: AEs Associated With TVR Gastrointestinal events, skin events (rash, pruritus), and anemia more frequent in TVR treatment arms Moderate and severe rash more frequent in TVR-based treatment arms Incidence and severity of other AEs similar to peginterferon alfa-2a and ribavirin alone Cumulative discontinuation due to AEs by Week 12 TVR treatment arms: 18% Peginterferon alfa-2a and ribavirin only: 4% Hemoglobin levels lower in TVR arms for first 12 weeks AEs, adverse events; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; TVR, telaprevir.   For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx AEs, adverse events; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; TVR, telaprevir.   For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx

    54. PROVE 2: TVR + PegIFN ± RBV in HCV G1 Naive Patients PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; RVR, rapid virologic response; TVR, telaprevir.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/58.aspx PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; RVR, rapid virologic response; TVR, telaprevir.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/58.aspx

    55. PROVE 2: Response Rates (ITT) ITT, intent to treat; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; TVR, telaprevir. Changed PROVE2 slides to match PROVE 1 . They have to be table format as we cannot represent the PROVE 1 as bar chart For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx ITT, intent to treat; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; TVR, telaprevir. Changed PROVE2 slides to match PROVE 1 . They have to be table format as we cannot represent the PROVE 1 as bar chart For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/4.aspx

    56. PROVE 2: Adverse Events Skin events (rash, pruritus) more frequent in TVR treatment arms Rash most common reason for treatment discontinuation in TVR/pegIFN/RBV treatment arms: 7% (12 of 163) Macropapular rash which resolved after treatment discontinuation (median time to discontinuation: ~ 9 weeks) Cumulative discontinuation due to AEs by Week 12 Both pegIFN/RBV/placebo 48 weeks and TVR/pegIFN 12 weeks: 10% TVR/pegIFN/RBV 12 weeks: 12% TVR/pegIFN/RBV 12 weeks ? pegIFN/RBV 12 weeks: 16% All treatment arms experienced comparable mean decreases in hemoglobin levels in the first 12 weeks No incremental effect on neutrophil or platelet counts in TVR treatment arms AEs, adverse events; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; TVR, telaprevir.       For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/58.aspx AEs, adverse events; PROVE, Investigation of HCV Protease Inhibition for Viral Evaluation; RBV, ribavirin; TVR, telaprevir.       For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/58.aspx

    57. SPRINT-1: Boceprevir + PegIFN/RBV in Naive HCV G1 RBV, ribavirin; SPRINT-1, Serine Protease Inhibitor Therapy; TID, 3 times daily.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/995.aspx RBV, ribavirin; SPRINT-1, Serine Protease Inhibitor Therapy; TID, 3 times daily.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/995.aspx

    58. SPRINT-1: Undetectable HCV: Wks 4 / 12 of Boceprevir Therapy RBV, ribavirin; SPRINT-1, Serine Protease Inhibitor Therapy.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/995.aspx RBV, ribavirin; SPRINT-1, Serine Protease Inhibitor Therapy.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/995.aspx

    59. SPRINT-1: Highest WHO Grade Anemia 28 Weeks of Treatment Epoetin-alfa treatment PegIFN/RBV lead-in arm ? pegIFN/RBV + boceprevir: 48% PegIFN/RBV + boceprevir: 45% PegIFN/RBV: 25% RBV, ribavirin; SPRINT-1, Serine Protease Inhibitor Therapy.       For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/995.aspx   RBV, ribavirin; SPRINT-1, Serine Protease Inhibitor Therapy.       For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/995.aspx  

    60. STEALTH C-1: NTZ + PegIFN ± RBV in G4 HCV Patients Nitazoxanide (NTZ): broad-spectrum activity against parasites, anaerobic bacteria and viruses BID, twice daily; NTZ, nitazoxanide; RBV, ribavirin; STEALTH-C, Studies to Evaluate Alinia for the Treatment of Hepatitis C.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/68.aspx BID, twice daily; NTZ, nitazoxanide; RBV, ribavirin; STEALTH-C, Studies to Evaluate Alinia for the Treatment of Hepatitis C.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/68.aspx

    61. STEALTH C-1: NTZ + PegIFN ± RBV in G4 HCV Patients 77 patients completed NTZ lead in Week-12 HCV RNA reduction: 0.26 log10 IU/mL (P = .0032) RVR (IFN-naive patients) PegIFN + RBV: 38% PegIFN + RBV + NTZ: 64% (P = .048)* No increase in AEs noted in NTZ arms vs SOC AEs, adverse events; NTZ, nitazoxanide; RBV, ribavirin; SOC, standard of care; STEALTH-C, Studies to Evaluate Alinia for the Treatment of Hepatitis C.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/68.aspx AEs, adverse events; NTZ, nitazoxanide; RBV, ribavirin; SOC, standard of care; STEALTH-C, Studies to Evaluate Alinia for the Treatment of Hepatitis C.     For more information, go online to: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/Investigational%20HCV/Capsules/68.aspx

    62. STAT-C: Specifically Targeted Antiviral Therapy for Hepatitis C Reference Slide courtesy of Nelson D. Adapted from 2007 Roche HCV Symposium, AASLD 2007. Boston, MA.STAT-C: Specifically Targeted Antiviral Therapy for Hepatitis C Reference Slide courtesy of Nelson D. Adapted from 2007 Roche HCV Symposium, AASLD 2007. Boston, MA.

    63. Graveyard for HCV Compounds is Filling Up Quickly! Reference Courtesy of Nelson D. Adapted from 2008 Roche HCV Symposium. Graveyard for HCV Compounds is Filling Up Quickly! Reference Courtesy of Nelson D. Adapted from 2008 Roche HCV Symposium.

    64. Hepatitis C Future There is a national strategy for hepatitis C prevention - and yes, this was developed by CDC almost 4 years ago. It wasn't really well vetted for a number of reasons that were kind of the expediency of the time. But, what goes around this national strategy are things about communication, issues around how we put prevention programs at the local level - and that includes not just health departments, but clinical care settings, how advocacy groups are involved and patient support groups are involved. It defines issues around surveillance and evaluation and it defines issues of the need for additional research. We don't have all of the answers. But this doesn't exist for hepatitis A or for hepatitis B, or for all of these being put together as a single entity. There is a national strategy for hepatitis C prevention - and yes, this was developed by CDC almost 4 years ago. It wasn't really well vetted for a number of reasons that were kind of the expediency of the time. But, what goes around this national strategy are things about communication, issues around how we put prevention programs at the local level - and that includes not just health departments, but clinical care settings, how advocacy groups are involved and patient support groups are involved. It defines issues around surveillance and evaluation and it defines issues of the need for additional research. We don't have all of the answers. But this doesn't exist for hepatitis A or for hepatitis B, or for all of these being put together as a single entity.

    65. HCV Prevention and Detection Prevention Community Education Awareness Risk Factors • Complications Detection Testing high risk populations

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