Treatment of chronic hepatitis B and hepatitis C with interferon alfa-2b – includes patient information sheets
Peter J. Molloy
Hepatitis B and C account for the vast majority of cases of chronic viral hepatitis. The diagnosis of chronic hepatitis B requires persistent elevations of the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels for more than six months, as well as the presence of hepatitis B surface antigen (HBsAg) in the serum. The diagnosis is supported by the histologic finding of chronic hepatitis on liver biopsy. If available, a hepatitis B virus DNA assay should be obtained to verify the presence of replicating virus in the serum and to quantify the intensity of the infection.
The diagnosis of chronic hepatitis C requires fluctuating ALT levels, the presence of detectable hepatitis C antibody by enzyme-linked immunosorbent assay or recombinant immunoblast assay or the finding of hepatitis C virus RNA (polymerase chain reaction) in the serum. The diagnosis is supported by histologic evidence of chronic hepatitis on liver biopsy. An algorithm for the management of chronic hepatitis C is presented in Figure 1.
Sequelae of Chronic Hepatitis
Both types of chronic viral hepatitis can progress to cirrhosis with or without hepatocellular carcinoma, but they do so at different rates and over different time periods. In a span of five to 20 years, cirrhosis develops in approximately 20 percent of patients with chronic hepatitis B. Compared with the general population, the incidence of hepatocellular carcinoma increases 200- to 300-fold in patients with chronic hepatitis B. Cirrhosis develops over a 20- to 40-year period in 50 percent or more of patients with hepatitis C. Chronic hepatitis C carries a risk of hepatocellular carcinoma that is at least equal to, if not greater than, the risk associated with hepatitis B.
Hepatitis B virus is a large, incomplete, double-stranded DNA virus. It replicates more like a retrovirus than other large DNA viruses do, because it uses reverse transcriptase rather than DNA polymerase. Hepatitis C virus is a small, singlestranded RNA virus.
Both hepatitis B virus and hepatitis C virus infect tissues other than the liver, including the pancreas and bone marrow.[4,5] The presence of extrahepatic sites of viral infection and replication explains the rare occurrence of bone marrow aplasia (aplastic anemia) in some patients with evidence of recent acute viral hepatitis.
Interferon Alfa-2b for Chronic Hepatitis
Interferon alfa-2b (Intron A) has been shown to reduce the rates of cirrhosis and hepatic cancer due to both hepatitis B and C viruses. In hepatitis B infection, interferon alfa-2b probably works by enhancing the endogenous immune response to infected cells. Specifically, the number of cytotoxic T cells programmed to identify and destroy infected liver cells are expanded and activated by this agent. As a result of these actions, the serum ALT level of patients successfully treated with interferon alfa-2b increases. The ALT level may remain elevated for three or four months before it begins to decline to a normal level. Patients with far-advanced liver disease due to the hepatitis B virus are not candidates for interferon alfa-2b therapy, because the increase in the ALT level can precipitate overt hepatic failure or initiate a sequence of events terminating in multiorgan failure or death.
In hepatitis C disease, the beneficial effects of interferon alfa-2b are thought to occur because of this agent’s antiproliferative and antiviral actions, rather than its immune-modulating action. As a result, ALT levels fall, rather than increase, with effective therapy. Thus, hepatic decompensation is not a concern.
The excitement produced by the introduction of interferon alfa-2b into clinical practice was soon quieted by the disappointing response rates to this agent in terms of viral clearance and disease activity. The hepatitis B virus response rate is defined as the seroconversion of hepatitis B early antigen (HBeAg) to hepatitis B early antibody (HBeAb).
Fewer than 40 percent of patients with hepatitis B respond to interferon alfa-2b therapy.[7,8] The initial response rate in patients with hepatitis C is between 40 and 50 percent, with a 50 percent relapse rate when therapy is discontinued.[9-11] Many untoward consequences occur in both responders and nonresponders.[12,13]
PREDICTORS OF POOR RESPONSE
Factors associated with a reduced likelihood of achieving a response to interferon alfa-2b therapy have been identified for both chronic hepatitis B and hepatitis C.
For chronic hepatitis B, the predictors of a poor response to interferon alfa-2b include the following: male gender; acquisition of hepatitis B congenitally or before the age of two years; advanced histologic disease; the presence of human immunodeficiency virus (HIV) infection; increased iron stores in the liver; a low serum ALT level, and a high viral titer (greater than 150 [mu]g per mL).
For chronic hepatitis C, the factors associated with a reduced likelihood of achieving a response to interferon alfa-2b therapy include the following: advanced histologic disease; high-titer hepatitis C virus RNA carriage (more than 106 virions per mL); a high serum ALT level; type 1B viral genotype, and increased iron stores in the liver.
INTERFERON ALFA-2B FOR CHRONIC HEPATITIS B
A recent meta-analysis of 15 randomized controlled studies of the use of interferon alfa-2b in the treatment of chronic hepatitis B found that only 7.8 percent of the treated patients became HBsAg negative, compared with 1.9 percent of the study subjects who were given placebo. Although small, this response rate was four times greater than that in the placebo-treated control subjects. Thirty-three percent of the treated subjects became HBeAg negative, compared with 12 percent of the placebotreated control subjects. More importantly, 37 percent of the study subjects treated with interferon alfa-2b became negative for hepatitis B virus DNA, compared with 17 percent of the placebo-treated control subjects. Based on these results, it was concluded that interferon alfa-2b is effective at terminating hepatitis B virus replication in one-third of treated cases.
Investigators at the National Institutes of Health (NIH) detailed the long-term clinical and serologic consequences of a response to interferon alfa-2b in patients with liver disease associated with chronic hepatitis B. In the NIH report, a response was defined as a loss of hepatitis B virus DNA and HBeAg and an ALT level of less than or equal to two times the upper limit of normal. The patients in this multicenter study were followed for a mean of 4.5 years. Eighty-seven percent of the interferon alfa-2b responders continued to be HBeAg negative and hepatitis B virus DNA negative, and 57 percent of the responders became HBsAg negative. Of the interferon alfa-2b responders, 13 percent experienced a disease relapse, usually in the first year of follow-up. However, one patient relapsed after six years of follow-up. The NIH investigators concluded that remission of hepatitis B in patients who respond to interferon alfa-2b is long-lasting in the majority of cases. Moreover, most responders lose HBsAg over a period of at least several years.
INTERFERON ALFA-2B FOR CHRONIC HEPATITIS C
The first two studies that reported on the use of interferon alfa-2b to treat chronic hepatitis C used similar doses.[9,10] In the larger study, 166 adults with hepatitis C received no treatment or 1 million units or 3 million units of interferon alfa-2b subcutaneously three times weekly for six months. Of the patients who received the higher dose of interferon alfa-2b,38 percent exhibited normalization of the ALT level, compared with 4 percent of those who received placebo. The ALT level declined by 50 percent or more in an additional 7 percent of patients who received the higher dose of interferon alfa-2b. Unfortunately, 51 percent of the responsive patients relapsed when interferon alfa-2b was discontinued. It was concluded that interferon alfa-2b is an effective therapy for controlling disease activity in patients with chronic hepatitis C.
More recently, an open-label randomized study compared the results of administration of 1 million, 3 million and 6 million units of interferon alfa-2b three times a week for 24 weeks in 336 patients with chronic hepatitis C manifested by an elevated ALT level and an abnormal liver biopsy. The response rate increased with the dose of interferon alfa-2b, from a rate of 17 percent with 1 million units, to a rate of 45 percent with 3 million units, to a rate of 62 percent with 6 million units. More importantly, the sustained response rate increased from 4 percent to 7 percent to 15 percent as the dose of interferon alfa-2b increased from 1 million units to 3 million units to 6 million units, respectively. Based on these results, it was concluded that a dose of 6 million units three times weekly is more effective than either 1 or 3 million units. The dose of 6 million units was also noted to be as tolerable as the lower doses.
Japanese investigators have used even larger doses of interferon alfa-2b (up to 10 million units per day) to achieve results two or three times better than those reported by investigators in the Western world.
CURRENT TREATMENT MODALITIES
Multiple protocols are currently being applied for chronic hepatitis B and C. Most current protocols favor higher doses of interferon alfa-2b administered for longer periods. The most widely used protocol for chronic hepatitis C uses 3 million units administered three times weekly for 18 to 24 months. The dose is adjusted based on the patient s tolerance for the drug and the patient’s white blood cell and platelet counts.
COST-EFFECTIVENESS OF INTERFERON ALFA-2B
Interferon alfa-2b therapy is expensive, with the cost varying according to the dose and the duration of therapy. The average wholesale price for one dose of 3 million units is $31.50. A recent study supported the cost-effectiveness of interferon alfa-2b therapy in patients with chronic hepatitis B, based on an increase in life expectancy and quality-adjusted life years leading to a decrease in projected lifetime cost. Similar data have documented a significant reduction in the cost of health care and an increased life expectancy with interferon alfa-2b therapy in patients who have chronic hepatitis C, particularly young patients without fibrosis.
Use of Phlebotomy
A recent advance in the treatment of hepatitis C disease has been the addition of phlebotomy to interferon alfa-2b therapy. Phlebotomy is performed in an effort to reduce the rate of viral replication to a level where drug therapy has the potential to terminate viral replication. This treatment concept was developed from an earlier observation that patients who responded to interferon alfa-2b administered at standard doses had lower hepatic iron levels than nonresponders.
Based on this initial investigation, two different groups[21,22] have treated nonresponders with a combination of iron reduction therapy, consisting of repetitive phlebotomies, and standard interferon alfa-2b therapy. Both groups reported that individual patients responded to this combined therapy. One of the groups noted that patients with chronic hepatitis C who respond to the combination therapy rarely relapse.
Much remains to be learned about how interferon alfa-2b can be used to treat viral hepatitis most effectively. The ideal dose and duration of therapy have yet to be determined. However, interferon alfa-2b should be used to treat chronic viral hepatitis, since no other effective therapy exists and this agent is effective in many patients.
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REFERENCES[1.] Resnick RH, Koff R. Hepatitis C-related hepatocellular carcinoma. Arch Intern Med 1993;153:1672-7. [2.] Gearlich WH, Heermann KH. Functions of hepatitis B virus protein and virus assembly In: Hollinger FB, Lemon SM, Margolis H, eds. Viral hepatitis and liver disease: proceedings of the 1990 International Symposium on Viral Hepatitis and Liver Disease: contemporary issues and future prospects. Baltimore: Williams & Wilkins, 1991:121-34. [3.] Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244: 359-62. [4.] Yoffe B, Burns DK, Bhatt HS, Combes B. Extrahepatic hepatitis B virus DNA sequences in patients with acute hepatitis B infection. Hepatology 1990;12:187-92. [5.] Qian C, Camps J, Maluenda MD, Civeira MP, Prieto J. Replication of hepatitic C virus in peripheral blood mononuclear cells. Effect of alpha-interferon therapy. J Hepatol 1992;16:380-3. [6.] Tzakis AG, Arditi M, Whitington PF, Yanaga K, Esquivel C, Andrews WA, et al. Aplastic anemia complicating orthotopic liver transplantation for non-A, non-B hepatitis. N Engl J Med 1988;319:393-6. [7.] Perrillo RR Interferon therapy for chronic type B hepatitis: the promise comes of age. Gastroenterology 1989;96:532-35. [8.] Wong DK, Cheung AM, O’Rourkel K, Maylor CD, Detsky AS, Helcote J. Effect of alpha-interferon treatment in patients with hepatitis B e Ag-posihve chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119:312-23. [9.] Hoofnagle JH, Mullen KD, Jones DB, Rustgi V, Di Biscoglie A, Peters M, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon. A preliminary report. N Engl J Med 1986;315:1575-8. [10.] Davis GL, Balart LA, Schiff ER, Lindsay K, Bodenheimer HC Jr, Perrillo RP, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med 1989;321:1501-6. [11.] Dusheiko G, Dibisceglie A, Bowyer S, Sachs E, Ritchie M, Schoub B, et al. Recombinant leukocyte interferon treatment of chronic hepatitis B. Hepatology 1985;5:556-60. [12.] Perrillo RP. Treatment of chronic hepatitis B with interferon: experience in Western countries. Semin Liver Dis 1989;9:240-8. [13.] Davis GL, Lindsay K, Albrecht J, Bodenheimer HC, Balot LA, Perillo RP, et al. Clinical predictors of response to recombinant interferon-a treatment in patients with chronic non-A, non-B hepatitis (hepatitic). Hepatitis Interventional Group. J Viral Hepatitis 1994;1:55-63. [14.] Wong DK, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993;119:312-23. [15.] Korenman J, Baker B, Waggoner J, Everhart JE, Di Bisceglie AM, Hoofaagle JH. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med 1991;114:629-34. [16.] Rakela J, Tong M, Schiffman M, et al. An open label randomized parallel evaluation of one, three and six million units of interferon alpha 2b in the six month treatment of patients with chronic non-A, non-B hepatitis [Abstract]. Gastroenterology 1993;104:976a. [17.] Iino S, Hino K, Kuroki T, Suzuki H, Yamamoto S. Treatment of chronic hepatitis C with high-dose interferon alpha-2b. A multicenter study Dig Dis Sci 1993;38:612-8. [18.] Wong JB, Koff RS, Tme F, Pauker SG. Cost-effectiveness of interferon-alpha 2b treatment for hepatitis B e antigen-positive chronic hepatitis B. Ann Intern Med 1995;122:664-75. [19.] Bennett WG, Inoue Y, Beck JR, Pauker SG, Davis GL. Justification of a single 6-month course of interferon (IFN) for histologically mild chronic hepatitis C [Abstract]. Hepatology 1995;. [20.] Van Thiel DH, Friedlander L, Fagiuoli S, Wright Hl, Irish W, Gavaler JS. Response to interferon alpha therapy is influenced by the iron content of the liver. J Hepatol 1994;20:410-5. [21.] Bacon BR, Rebholz AK, Fried M, et al. Beneficial effect of iron reduction therapy in patients with chronic hepatitis C who fail to respond to Interferon Alpha. Hepatology 1993;18:150A. [22.] Caraceni P, Fagiuoli S, Van Thiel DH. Iron reduction therapy: simply camouflage, or a real weapon? [Editorial] Am J Gastroenterol 1994;89:970-3.
The Authors PETER J MOLLOY, M.D. is codirector of the gastroenterology fellowship program at Western Pennsylvania Hospital, Pittsburgh.
MAHER AZZOUZ, M.D. is senior gastroenterology fellow at Western Pennsylvania Hospital.
DAVID H. VAN THIEL, M.D. is currently director of transplantation at the University of Kentucky Chandler Medical Center, Lexington. He formerly was senior consultant in liver disease at Western Pennsylvania Hospital.
Address correspondence to Peter J. Molloy, M.D., Mellon Pavilion, Suite M-58, 4815 Liberty Ave., Pittsburgh, PA 15244.
COPYRIGHT 1996 American Academy of Family Physicians
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