This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hepatitis C affects an estimated 4 million people in the U.S., with 30,000 new cases diagnosed annually (1-3). The hepatitis C virus (HCV) ranks second behind alcoholism among the causes of liver disease and is the leading reason for liver transplants (4-6). Health experts say the number of deaths from HCV may soon surpass the number attributed to AIDS (Mayo Clinic, Dec. 12, 1998). In fact, hepatitis C might be the most common cause of primary liver cancer in the developed world. In Italy, Spain, and Japan, at least half of liver cancers could be related to HCV (7). Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer (8). About 20 percent of patients develop cirrhosis within 10 to 20 years of the onset of infection (9). Men, alcoholics, patients with cirrhosis, people over age 40, and those infected for 20 to 40 years are more likely to develop HCV-related liver cancer (7). Unfortunately, hepatitis C, like the AIDS virus, mutates frequently, hindering the development of a vaccine (20-21). Therefore, the focus of research over the last 15 years has been to develop treatments that promote a sustained response (a response is considered to be sustained if HCV RNA remains undetectable for 6 months or more after therapy stops). In the United States, three different regimens have been approved as therapy for hepatitis C, monotherapy with alfa interferon, combination therapy with alfa interferon and ribavirin (14-16) and pegylated alfa-2b with ribavirin. Interferon, a protein produced by the body that interferes with viral growth, is administered by subcutaneous injection. Ribavirin is a broad-spectrum antiviral agent that is administered orally (19). With interferon monotherapy, 30 to 35 percent of patients become HCV RNA negative with treatment, but almost half of these relapse when treatment stops. The sustained virologic response rate, therefore, averages only 7 to 15 percent (18). Combination therapy with interferon and ribavirin, however, leads to loss of HCV RNA on treatment in 50 to 55 percent of patients and a sustained loss in 35 percent (14-17). Although the combination therapy consistently yields higher rates of sustained response than monotherapy, it is more expensive and is associated with more side effects. In most situations, the combination therapy is still preferable and at present, interferon monotherapy is reserved for patients who have contraindications to the use of ribavirin. Despite these developments, about 60 percent of treated patients remain unresponsive. Few options exist for patients who either do not respond to therapy or who respond and later relapse. Patients who relapse after a course of interferon monotherapy may respond to a 24-week course of combination therapy, particularly if they became and remained HCV RNA negative during the period of monotherapy (15). Another approach is the use of long-term or continual interferon, which is feasible only if the interferon is well tolerated and has a clear-cut effect on serum aminotransferases and liver histology, despite lack of clearance of HCV RNA. New medications and approaches to treatment are needed. Most promising for the immediate future are newer forms of 'long-acting' interferons, which are alfa interferons that are modified by polyethylene glycol (PEG) so that they can be given once a week and yet provide a sustained level of interferon. These 'pegylated' formulations may avoid the peaks and troughs of interferon levels and interferon side effects that occur when it is given three times a week. Pegylated interferons are now being evaluated in prospective controlled trials. Other promising approaches are the use of other cytokines and the development of newer antivirals, such as RNA polymerase, helicase, or protease inhibitors. The purpose of the study is to conduct a randomized, controlled trial in patients with chronic hepatitis C to determine if four years of Peginterferon alfa-2a therapy in previous interferon nonresponders can safely prevent progression from fibrosis to cirrhosis and, in cirrhotics, reduce the risk of liver decompensation, cancer development, and the need for liver transplantation (12-13). In addition, this study will evaluate the effects of long-term therapy on quality of life in such patients with advanced fibrosis or cirrhosis. References 1. Di Bisceglie AM. Hepatitis C. Lancet, 1998;351:351-5. 2. Cheung RC. Epidemiology of hepatitis C virus infection in American veterans. Am J Gastroenterol, 2000;95:740-7. 3. Lemon SM, Layden TJ, Seeff L, Suzaki H, Nishioka K, Mishiro R, et al. The 20th United States-Japan Joint Hepatitis Panel Meeting. Hepatology, 2000;31:800-6. 4. Dhar R, Omaran L. Bacon BR, Solomon H, Di Biseglie AM. Liver transplantation in patients with chronic hepatitis C and alcoholism. Dig Dis Sci, 1999;44:2003-7. 5. Charlton M. Seaberg E, Wiesner R, Everhart J, Zetterman R, Lake JK, Hoofnagle J. Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology, 1998;28:823-30. 6. Di Bisceglie AM. Liver transplantation for hepatitis C: The promise and the challenges. Hepatology, 1995;22:660-2. 7. Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology, 1997;26:34S-38S. 8. Marcellin P. Hepatitis C: The clinical spectrum of the disease. J Hepatol, 1999;31:9-16. 9. Alberti A, Chemallo L, Benvegnu L. Natural history of hepatitis C. J Hepatol, 1999;31:17-24. 10. Butterworth RF. Complications of cirrhosis III. Hepatic encephalopathy. J Hepatol, 2000;32:171-80. 11. Bosch J, Carcia-Pagan JC. Complications of cirrhosis I. Portal hypertension. J Hepatol, 2000;32:141-56. 12. Blendis L, Wong F, Sherman M. Interferon therapy prevents hepatocellular carcinoma in some persons with chronic HCV: The role of fibrosis. Gastroenterology, 2000;118:446-8. 13. Baffis V, Shrier I, Sherker AH, Szilagyi A. Use of interferon for prevention of hepatocellular carcinoma in cirrhotic patients with hepatitis B or hepatitis C virus infection. Ann Intern Med, 1999;131:696-701. 14. Hoofnagle JH. Management of hepatitis C: Current and future perspectives. J Hepatol, 1999;31:264-8. 15. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SD, Trepo C, Shiffman ML, Zeuzem R, Craxi A, Ling MH, Albrecht J. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis & Intervetion Therapy Group. N Engl J Med, 1998;339:1493-9. 16. Di Bisceglie AM, Conjeevarem HS, Fried MW, Sallie R, Park Y, Yurd C, Swain M, Ckeiner DE, Mahoney K, Hoofnagle JH. Ribavirin as therapy for chronic hepatitis C. A randomized double-blind placebo-controlled trial. Ann Intern Med, 1995;123:897-903. 17. Hoofnagle JH, Di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med, 1997;336:347-56. 18. Carithers RL Jr, Emerson SS. Therapy of hepatitis C: Meta-analysis of interferon alfa-2b trials. Hepatology, 1997;26:83S-88S. 19. Dusheiko G, Main J, Thomas H, Reichard O, Lee C, Dhillon A, Rassa Fryden A, Reesink H, Bassendine M, Norkrans G, Cuypers T, Lelie N, Watson J, Weegink C, Sillikens P, Weiland O. Ribavirin treatment for patients with chronic hepatitis C: Results of a placebo-controlled study. J Hepatol, 1996;25:591-8. 20. Shouval D. Vaccines for prevention of viral hepatitis. Haemophilia, 1998;4:587-94. 21. Lamonaca V, Missale G, Urbani R, Pilli M, Boni C, Mon C, Sette A, Southwood R, Bertoni R, Valli A, Fiaccardori F, Ferraci C. Conserved hepatitis C virus sequences are highly immunogenic CD4(+) T cells: Implications for vaccine development. Hepatology, 1999;30:1088-98.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
2M01RR000827-31
Application #
7374244
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2006-04-01
Project End
2006-11-30
Budget Start
2006-04-01
Budget End
2006-11-30
Support Year
31
Fiscal Year
2006
Total Cost
$43,095
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Juraschek, Stephen P; Appel, Lawrence J; Miller 3rd, Edgar R (2017) Metoprolol Increases Uric Acid and Risk of Gout in African Americans With Chronic Kidney Disease Attributed to Hypertension. Am J Hypertens 30:871-875
Chen, Teresa K; Tin, Adrienne; Peralta, Carmen A et al. (2017) APOL1 Risk Variants, Incident Proteinuria, and Subsequent eGFR Decline in Blacks with Hypertension-Attributed CKD. Clin J Am Soc Nephrol 12:1771-1777

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