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Management of hepatitis C in the hemophilia patient
Management of Hepatitis C in the Hemophilia Patient Michael W. Fried, MD
Patients with hemophilia who received clotting factor concentrates before the availability of heattreated factors in the mid-1980s were almost universally infected with hepatitis C virus (HCV). Until recently, the clinical impact of chronic hepatitis C was largely overshadowed by human immunodeficiency virus (HIV) infection in this risk group. With recent advances in treating HIV infection, there is greater emphasis on the morbidity and mortality associated with chronic hepatitis C in the hemophilic population. A recent study from the United Kingdom demonstrated that mortality from chronic liver disease in hemophilic patients was 16.7 times greater than in the general population, and death resulting from liver cancer, 5.6 times greater. Before the advent of protease inhibitors, which can alter the natural history of HIV infection, co-infection with HIV appeared to accelerate the course of chronic hepatitis C. Levels of HCV RNA were dramatically increased after HIV seroconversion, and liver failure was found in 9% of patients, exclusively among those co-infected with HIV. HCV genotypes generally reflect the predominant genotype of the donor population, but multiple genotypes may be present. Liver biopsy may be performed safely via the percutaneous or transjugular route in hemophilic patients with chronic hepatitis C, although there is an increased cost because of the expense of factor replacement. Response to interferon in this population has been similar to that expected in the general population. Large trials are underway to evaluate the role of combination therapy with interferon and ribavirin for the treatment of patients with hemophilia and hepatitis C. Am J Med. 1999;107(6B):85S– 89S. © 1999 by Excerpta Medica, Inc.
From the Department of Medicine, Clinical Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Requests for reprints should be addressed to Michael W. Fried, MD, Department of Medicine, Clinical Hepatology, University of North Carolina at Chapel Hill, CB 7080, Burnett-Womack Building, Room 708, Chapel Hill, North Carolina 27599-7080. © 1999 by Excerpta Medica, Inc. All rights reserved.
T
he importance of heat inactivation of blood products was not fully appreciated until the mid-1980s. Hemophilia patients who received factors before then were exposed to active, infectious viruses and were almost universally infected with HCV and HIV. The clinical impact of hepatitis C has been largely overshadowed by that of human immunodeficiency virus (HIV) infection in this group; however, recent advances in the treatment of HIV have increased the life expectancy and quality of life of HIV-infected patients, leading to a greater focus on the morbidity and mortality of hepatitis C in patients with hemophilia. Several inherited disorders of coagulation are treated with clotting factors, thereby placing several groups of patients at risk for HCV infection from such concentrates. Hemophilia A, or factor VIII deficiency, is the most common, representing 85% of hemophilia patients. The abnormal factor VIII gene is located on the X chromosome, and the disease occurs in approximately 1 in 5,000 males. There is no racial or ethnic predilection. Hemophilia B, or factor IX deficiency, includes 10% to 15% of all hemophilic patients. Von Willebrand’s disease is an autosomal dominant trait characterized by prolonged bleeding time and is thought to be one of the most common congenital bleeding disorders. Abnormal von Willebrand factor is responsible for defective platelet adherence to damaged endothelium.
PREVALENCE OF VIRAL HEPATITIS IN HEMOPHILIA PATIENTS Kumar et al1 determined the serologic markers for viral liver diseases in 41 patients with inherited coagulation disorders. Twenty-four percent of these patients were positive for hepatitis A, similar to the background expected in the United States. The carrier rate of hepatitis B is greater than expected in population-matched controls, with 7% positive for surface antigen (HBsAg), and 56% positive for core antibody (HBcAb). Of these 41 patients, fully 90% were anti–HCV antibody positive.1 Eyster et al2 studied blood-borne viral diseases in a large cohort of patients (n ⫽ 223) with hemophilia, of which 70% were anti-HCV positive, and 44% were positive for HIV (Figure 1). Virtually all of the HIV(⫹) pa0002-9343/99/$20.00 85S PII S0002-9343(99)00391-5
A Symposium: Hepatitis C in the Hemophilia Patient/Fried
Figure 1. Prevalence of hepatitis C virus and human immunodeficiency virus. (Reprinted with permission from J Acquir Immune Defic Syndr Hum Retrovirol.2)
Figure 2. Increasing prevalence of HCV infection with severity of hemophilia (A) and type of transfusion product (B). FFP or CRYO ⫽ fresh frozen plasma or cryoprecipitate; NHT CONC. ⫽ non– heat treated factor concentrates. (Reprinted with permission from J Acquir Immune Defic Syndr Hum Retrovirol.2)
tients were co-infected with HCV, but some HCV(⫹) patients were not infected with HIV. In addition, there was a fortunate group of patients who were not infected with either HIV or HCV. The prevalence of hepatitis C in patients with clotting disorders is related to the severity of the clotting disorder. Patients with milder disease required fewer factor concentrates than individuals with more severe hemophilia (Figure 2A). Similarly, virtually all patients who received non– heat-treated factor concentrates were seropositive for anti-HCV antibody (Figure 2B). Infection with HCV was not as common in patients who received fresh frozen plasma or cryoprecipitate. 86S
December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
CLINICAL BEHAVIOR OF HCV INFECTION IN HEMOPHILIA PATIENTS The natural history of hepatitis C has been investigated for patients with coagulation disorders. In their study, Eyster et al2 followed patients for 10 to 25 years. Of the 44% of patients who were co-infected with HCV and HIV, 8 of 91 (9%) developed clinical liver failure, including ascites, bleeding esophageal varices, or death from liver disease. In contrast, none of the 54 HCV(⫹)/HIV(⫺) patients developed overt liver disease. For co-infected patients, the risk of developing liver failure was approximately half that of developing acquired immune deficiency syndrome (AIDS). Volume 107 (6B)
A Symposium: Hepatitis C in the Hemophilia Patient/Fried
HCV RNA levels are significantly higher in hemophilia patients co-infected with HCV and HIV.3,4 For example, Eyster et al2 found HCV RNA levels from stored sera of HCV(⫹)/HIV(⫹) patients and from HCV(⫹)/HIV(⫺) patients increased in both groups over the 15 years of follow-up. However, the increase was only threefold for the HIV(⫺) patients compared with 56-fold in the coinfected patients. Furthermore, HCV RNA levels were inversely correlated with CD4 counts. These results indicate that HCV replication is enhanced by HIV infection as immune deficiency progresses. With widespread use of protease inhibitors today, the effect of HIV/HCV co-infection may now be different, because these highly active antiretroviral agents can alter the natural history of HIV infection.
HEPATOCELLULAR CARCINOMA IN HEMOPHILIA PATIENTS WITH HEPATITIS C A study in the United Kingdom compared death rates from hepatocellular carcinoma (HCC) and liver disease in hemophilia patients with the expected national death rates. A review of the National Hemophilia Register revealed 4,865 patients at risk for HCV infection from factor transfusions between 1965 and 1985, with follow-up ending in 1993. Examination of death certificates showed a sixfold increase in deaths from HCC and a 17-fold increase in deaths resulting from chronic liver disease over the expected death rates.5 These data were further analyzed to determine the effect of age at first viral exposure on the cumulative risk of death from HCC or end-stage liver disease. The risk of death is comparatively increased for patients initially exposed to blood products when they were older than 45 years of age. In addition, co-infection with HIV significantly increases the cumulative death risk from HCC or liver disease for those patients first exposed between 25 and 44 years of age.5 The risk of developing HCC was also studied in a cohort of 385 Italian patients with at least 10 years of exposure to blood products. These patients were followed for 4 years with annual alpha-fetoprotein and ultrasound screening. Six of the 385 developed HCC, a rate markedly above the 7 per 100,000 expected in the general population. In all six cases, aggressive screening showed that the tumors were multifocal and not amenable to treatment. In addition, all patients had clinical evidence of cirrhosis. Further study of the hemophilia patients who developed HCC compared with those who did not identified several risk factors. For example, there was a 31-fold increase in risk of HCC for those patients entering the study with baseline alpha-fetoprotein values ⬎11 ng/mL. Additionally, initial infection at age ⬎45 years was associated with
an 18-fold increased risk of developing HCC. This study confirmed the high incidence of HCC in hemophilia patients with hepatitis C.6
LIVER BIOPSY FOR HEMOPHILIA PATIENTS WITH HCV INFECTION The previously mentioned studies of hepatitis C in patients with hemophilia relied on clinical end points: hepatocellular carcinoma, ascites, or other manifestations of hepatic decompensation. As we know from many studies of the natural history of hepatitis C infection, for most patients with varying degrees of inflammation or even well-compensated cirrhosis, only liver biopsy will definitively reveal the extent of disease. Liver biopsy is also the only way to determine whether treatment has produced histologic improvements or, conversely, to detect disease progression for patients who choose not to be treated or fail to respond to treatment. For obvious reasons, liver biopsy in patients with disorders of coagulation raises complex and sometimes emotional issues. In general, hematologists may be reluctant to have liver biopsies performed on their patients with hemophilia. This is not universal, however, and at some medical centers, liver biopsy for hemophilia patients with hepatitis C is routine. The cost of factor replacement after liver biopsy is an important and possibly limiting consideration. Factor replacement may range from $3,000 to $7,500, depending on the severity of hemophilia and the quantity of factor concentrates necessary to achieve 100% replacement. Hospital and monitoring fees represent additional expenses that increase the ultimate cost of liver biopsy. One strategy that may facilitate acceptance of liver biopsy in hepatitis C patients with coagulation disorders is to plan to perform the liver biopsy at the same time the patient is undergoing another procedure that will require factor replacement (e.g., dental extractions, or joint replacements or other orthopedic procedures). Such “piggybacking” would allow the patient to experience the benefit of two procedures while incurring the costs of factor replacement only once. Several studies have examined the safety of liver biopsy for patients with hemophilia. Wong et al7 included 28 patients with hemophilia A or B or von Willebrand’s disease. Patients with factor VIII inhibitor were excluded because of the difficulty of factor VIII replacement for such patients. Patients with either abnormal or normal alanine aminotransferase (ALT) levels were included; only 64% were viremic (HCV RNA positive). Immediately before liver biopsy, factor VIII or IX levels were measured, and clotting factors were administered to replace levels up to 100%. Factor replacement continued every 12 to 36 hours after liver biopsy to maintain at least 50% of factor levels. Pathologic review of these biopsies revealed generally mild histology. Most patients (63%) had portal inflammation, but bridging fibrosis or cirrhosis was
December 27, 1999
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Figure 3. Distribution of HCV genotypes in hemophilia patients. (Reprinted with permission from Blood.11)
not observed. Another study of liver biopsies from 50 hemophilia patients with HCV infection confirmed these findings. Generally mild histologic changes were noted, with very little inflammation or fibrosis observed.8 No major complications of liver biopsy were reported in either of these studies. Nevertheless, bleeding complications after liver biopsy in patients with hemophilia have been reported, so decisions concerning this procedure in this population must be individualized.9,10
HCV GENOTYPES IN PATIENTS WITH HEMOPHILIA HCV genotypes generally reflect the predominant genotype of the donor population (e.g., genotype 1 in the United States). Because patients with hemophilia may be exposed to several thousand donors from a single factor infusion, multiple genotypes may be present. For example, among 96 patients with hemophilia from the United Kingdom, approximately 50% were infected with HCV genotype 1 (Figure 3). However, some unusual genotypes were noted that were typical of geographic regions other than the United Kingdom, including genotypes 4 and 5, most common in the Middle East and South Africa, respectively. These unusual genotypes probably reflect the background of some of the donors to the factor concentrates. Additionally, 7% of the patients studied had mixed genotypes, which is unusual among volunteer blood donors in the UK.11 Another study from the United Kingdom noted that HCV genotypes may change before and during interferon-␣ therapy in up to 40% of patients with hemophilia. Interferon-treated patients were more likely to change genotypes than those who did not receive interferon. No consistent genotype emerged as a result of interferon treatment, however.12 A recent study has also suggested that genotypes may change over 88S
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time, in the absence of interferon therapy, in hemophilic patients with chronic hepatitis C.13
INTERFERON THERAPY FOR HEPATITIS C IN HEMOPHILIA PATIENTS Interferon therapy for chronic hepatitis C in patients with hemophilia is currently being studied in randomized trials. In one multicenter trial from Italy, 107 HIV-negative patients with HCV and hemophilia were randomized to observation or 3 MIU interferon-␣ three times a week for one year. HCV RNA was measured both by bDNA and reverse transcription polymerase chain reaction (RT-PCR) assays. HCV genotype 1A was predominant in this population. Liver biopsies were not performed, but 5% of patients showed clinical evidence of cirrhosis. After 48 weeks of therapy, 27% of patients had normal ALT levels and no detectable HCV RNA. Twelve months after therapy was completed, sustained response was observed in 13% of patients. No untreated patient cleared HCV RNA.14 Interferon is known to stimulate the development of autoimmune phenomena. This is of obvious clinical concern regarding hemophilia patients, as the development of factor VIII antibodies represents a significant management issue. To determine whether interferon therapy promotes the development of factor VIII antibodies, investigators followed 35 patients with hemophilia A.15 Factor VIII antibodies developed in 10% of patients (2 of 21) who were treated with interferon for 20 months and 21% of untreated patients (3 of 14), indicating that interferon does not stimulate the development of factor VIII antibodies. A randomized clinical trial now under way at multiple institutions has been designed to compare the impact of ribavirin and interferon-␣/ribavirin combination therapy with interferon monotherapy at 3 MIU three times per week. Nonresponders to interferon alone after 3 Volume 107 (6B)
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months cross over to combination therapy. In order to evaluate sustained response, patients will be followed for 6 months after the completion of therapy. Preliminary results of this trial will be available in the near future. 3.
LIVER TRANSPLANTATION Patients with end-stage liver disease may be candidates for liver transplantation. A review of transplantation databases in the United Kingdom identified 26 hemophilia patients who underwent liver transplantation between 1982 and 1996. In 69% of these, hepatitis C was the cause of liver failure. Six of the 26 (23%) were co-infected with HIV. Perioperative bleeding complicated 15% of the cases. By 9 months after transplantation, hepatitis C had recurred in 30% of those patients transplanted for HCV infection. Survival after liver transplantation was quite good, especially for patients who were not co-infected with HIV, as 90% were alive 1 year and 83% alive 3 years after transplant. In comparison, survival was 67% at 1 year, and 23% at 3 years for patients co-infected with HIV.16 Additionally, hemophilia was cured in all patients who survived for 1 year: A serendipitous “side effect” of liver transplantation in hemophilic patients is that hepatic grafts produce clotting factors within 24 hours of transplantation.
4.
5.
6.
7.
8.
9.
SUMMARY 10.
Patients with hemophilia constitute a high-risk group for the acquisition of HCV infection. As HIV therapies improve, the focus of physicians caring for patients with inherited coagulation disorders is shifting from HIV infection to recognition of the increased morbidity and mortality associated with hepatitis C. Screening these patients is of critical importance, as infected patients should be identified, followed, and aggressively treated. It is clear that HIV co-infection accelerates the progression to endstage liver disease. The natural history studies are limited by a paucity of data on histology and hepatic synthetic function in hemophilia patients. Initial studies of interferon therapy in hemophilia patients infected with HCV demonstrate response rates similar to those seen in hepatitis C patients in general. The role of combination therapy with interferon-␣ and ribavirin in these patients is currently under investigation.
11.
12.
13.
14.
15.
REFERENCES 1. Kumar A, Kulkarni R, Murray DL, et al. Serologic markers of viral hepatitis A,B,C, and D in patients with hemophilia. J Med Virol. 1993;41:205–209. 2. Eyster ME, Diamondstone LS, Lien JM, et al. Natural history
16.
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of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr Hum Retrovirol. 1993;6:602– 610. Eyster ME, Fried MW, DiBisceglie AM, Goedert JJ. Increasing HCV RNA levels in hemophiliacs: relationship to HIV infection and liver disease. Blood. 1994;84:1020 –1023. Sherman KE, O’Brien J, Gutierrez AG, et al. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993;31:2679 –2682. Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in hemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Hemophilia Center Directors’ Organization. Lancet. 1997; 350:1425–1431. Tradati F, Colombo M, Mannucci PM, et al. A prospective multicenter study of hepatocellular carcinoma in Italian hemophiliacs with chronic hepatitis C. The Study Group of the Association of Italian Hemophilia Centers. Blood. 1998;91: 1173–1177. Wong VS, Baglin T, Beacham E, et al. The role for liver biopsy in haemophiliacs infected with the hepatitis C virus. Br J Haematol. 1997;97:343–347. Ahmed MM, Mutimer DJ, Elias E, et al. A combined management protocol for patients with coagulation disorders infected with hepatitis C virus. Br J Haematol. 1996;95:383– 388. Lee CA. Investigation of chronic hepatitis C infection in individuals with haemophilia. Br J Haematol. 1997;96:425– 426. Telfer P. Liver biopsy for haemophilic patients with chronic HCV infection. Br J Haematol. 1997;99:239 –240. Preston FE, Jarvis LM, Makris M, et al. Heterogeneity of hepatitis C virus genotypes in hemophilia: relationship with chronic liver disease. Blood. 1995;85:1259 –1262. Eyster ME, Sherman KE, Goedert JJ, Katsoulidou A, Hatzakis A. Prevalence and changes in hepatitis C virus genotypes among multitransfused persons with hemophilia: The Multicenter Hemophilia Cohort Study. J Infect Dis. 1999; 179:1062–1069. Devereux H, Telfer P, Brown D, Morris A, Dusheiko G, Emery V, Lee C. Longitudinal genotype analysis and quantification of hepatitis C virus in haemophilic patients receiving interferon-alpha therapy. J Viral Hepat. 1996;3:43– 48. Rumi MG, Santagostino E, Morfini M, et al. A multicenter controlled, randomized, open trial of interferon alpha 2b treatment of anti-human immunodeficiency virus negative hemophilic patients with chronic hepatitis C. Hepatitis Study Group of the Association of Italian Hemophilia Centers. Blood. 1997;89:3529 –3533. Mauser-Bunschoten EP, Damen M, Reesink HW, et al. Formation of antibodies to factor VIII in patients with hemophilia A who are treated with interferon for chronic hepatitis C. Ann Intern Med. 1996;125:297–299. Gordon FH, Mistry PK, Sabin CA, et al. Outcome of orthotopic liver transplantation in patients with hemophilia. Gut. 1998;42:744 –749.
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Patients with hemophilia who received clotting factor concentrates before the availability of heattreated factors in the mid-1980s were almost universally infected with hepatitis C virus (HCV). Until recently, the clinical impact of chronic hepatitis C was largely overshadowed by human immunodeficiency virus (HIV) infection in this risk group. With recent advances in treating HIV infection, there is greater emphasis on the morbidity and mortality associated with chronic hepatitis C in the hemophilic population. A recent study from the United Kingdom demonstrated that mortality from chronic liver disease in hemophilic patients was 16.7 times greater than in the general population, and death resulting from liver cancer, 5.6 times greater. Before the advent of protease inhibitors, which can alter the natural history of HIV infection, co-infection with HIV appeared to accelerate the course of chronic hepatitis C. Levels of HCV RNA were dramatically increased after HIV seroconversion, and liver failure was found in 9% of patients, exclusively among those co-infected with HIV. HCV genotypes generally reflect the predominant genotype of the donor population, but multiple genotypes may be present. Liver biopsy may be performed safely via the percutaneous or transjugular route in hemophilic patients with chronic hepatitis C, although there is an increased cost because of the expense of factor replacement. Response to interferon in this population has been similar to that expected in the general population. Large trials are underway to evaluate the role of combination therapy with interferon and ribavirin for the treatment of patients with hemophilia and hepatitis C. Am J Med. 1999;107(6B):85S– 89S. © 1999 by Excerpta Medica, Inc.
From the Department of Medicine, Clinical Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Requests for reprints should be addressed to Michael W. Fried, MD, Department of Medicine, Clinical Hepatology, University of North Carolina at Chapel Hill, CB 7080, Burnett-Womack Building, Room 708, Chapel Hill, North Carolina 27599-7080. © 1999 by Excerpta Medica, Inc. All rights reserved.
T
he importance of heat inactivation of blood products was not fully appreciated until the mid-1980s. Hemophilia patients who received factors before then were exposed to active, infectious viruses and were almost universally infected with HCV and HIV. The clinical impact of hepatitis C has been largely overshadowed by that of human immunodeficiency virus (HIV) infection in this group; however, recent advances in the treatment of HIV have increased the life expectancy and quality of life of HIV-infected patients, leading to a greater focus on the morbidity and mortality of hepatitis C in patients with hemophilia. Several inherited disorders of coagulation are treated with clotting factors, thereby placing several groups of patients at risk for HCV infection from such concentrates. Hemophilia A, or factor VIII deficiency, is the most common, representing 85% of hemophilia patients. The abnormal factor VIII gene is located on the X chromosome, and the disease occurs in approximately 1 in 5,000 males. There is no racial or ethnic predilection. Hemophilia B, or factor IX deficiency, includes 10% to 15% of all hemophilic patients. Von Willebrand’s disease is an autosomal dominant trait characterized by prolonged bleeding time and is thought to be one of the most common congenital bleeding disorders. Abnormal von Willebrand factor is responsible for defective platelet adherence to damaged endothelium.
PREVALENCE OF VIRAL HEPATITIS IN HEMOPHILIA PATIENTS Kumar et al1 determined the serologic markers for viral liver diseases in 41 patients with inherited coagulation disorders. Twenty-four percent of these patients were positive for hepatitis A, similar to the background expected in the United States. The carrier rate of hepatitis B is greater than expected in population-matched controls, with 7% positive for surface antigen (HBsAg), and 56% positive for core antibody (HBcAb). Of these 41 patients, fully 90% were anti–HCV antibody positive.1 Eyster et al2 studied blood-borne viral diseases in a large cohort of patients (n ⫽ 223) with hemophilia, of which 70% were anti-HCV positive, and 44% were positive for HIV (Figure 1). Virtually all of the HIV(⫹) pa0002-9343/99/$20.00 85S PII S0002-9343(99)00391-5
A Symposium: Hepatitis C in the Hemophilia Patient/Fried
Figure 1. Prevalence of hepatitis C virus and human immunodeficiency virus. (Reprinted with permission from J Acquir Immune Defic Syndr Hum Retrovirol.2)
Figure 2. Increasing prevalence of HCV infection with severity of hemophilia (A) and type of transfusion product (B). FFP or CRYO ⫽ fresh frozen plasma or cryoprecipitate; NHT CONC. ⫽ non– heat treated factor concentrates. (Reprinted with permission from J Acquir Immune Defic Syndr Hum Retrovirol.2)
tients were co-infected with HCV, but some HCV(⫹) patients were not infected with HIV. In addition, there was a fortunate group of patients who were not infected with either HIV or HCV. The prevalence of hepatitis C in patients with clotting disorders is related to the severity of the clotting disorder. Patients with milder disease required fewer factor concentrates than individuals with more severe hemophilia (Figure 2A). Similarly, virtually all patients who received non– heat-treated factor concentrates were seropositive for anti-HCV antibody (Figure 2B). Infection with HCV was not as common in patients who received fresh frozen plasma or cryoprecipitate. 86S
December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
CLINICAL BEHAVIOR OF HCV INFECTION IN HEMOPHILIA PATIENTS The natural history of hepatitis C has been investigated for patients with coagulation disorders. In their study, Eyster et al2 followed patients for 10 to 25 years. Of the 44% of patients who were co-infected with HCV and HIV, 8 of 91 (9%) developed clinical liver failure, including ascites, bleeding esophageal varices, or death from liver disease. In contrast, none of the 54 HCV(⫹)/HIV(⫺) patients developed overt liver disease. For co-infected patients, the risk of developing liver failure was approximately half that of developing acquired immune deficiency syndrome (AIDS). Volume 107 (6B)
A Symposium: Hepatitis C in the Hemophilia Patient/Fried
HCV RNA levels are significantly higher in hemophilia patients co-infected with HCV and HIV.3,4 For example, Eyster et al2 found HCV RNA levels from stored sera of HCV(⫹)/HIV(⫹) patients and from HCV(⫹)/HIV(⫺) patients increased in both groups over the 15 years of follow-up. However, the increase was only threefold for the HIV(⫺) patients compared with 56-fold in the coinfected patients. Furthermore, HCV RNA levels were inversely correlated with CD4 counts. These results indicate that HCV replication is enhanced by HIV infection as immune deficiency progresses. With widespread use of protease inhibitors today, the effect of HIV/HCV co-infection may now be different, because these highly active antiretroviral agents can alter the natural history of HIV infection.
HEPATOCELLULAR CARCINOMA IN HEMOPHILIA PATIENTS WITH HEPATITIS C A study in the United Kingdom compared death rates from hepatocellular carcinoma (HCC) and liver disease in hemophilia patients with the expected national death rates. A review of the National Hemophilia Register revealed 4,865 patients at risk for HCV infection from factor transfusions between 1965 and 1985, with follow-up ending in 1993. Examination of death certificates showed a sixfold increase in deaths from HCC and a 17-fold increase in deaths resulting from chronic liver disease over the expected death rates.5 These data were further analyzed to determine the effect of age at first viral exposure on the cumulative risk of death from HCC or end-stage liver disease. The risk of death is comparatively increased for patients initially exposed to blood products when they were older than 45 years of age. In addition, co-infection with HIV significantly increases the cumulative death risk from HCC or liver disease for those patients first exposed between 25 and 44 years of age.5 The risk of developing HCC was also studied in a cohort of 385 Italian patients with at least 10 years of exposure to blood products. These patients were followed for 4 years with annual alpha-fetoprotein and ultrasound screening. Six of the 385 developed HCC, a rate markedly above the 7 per 100,000 expected in the general population. In all six cases, aggressive screening showed that the tumors were multifocal and not amenable to treatment. In addition, all patients had clinical evidence of cirrhosis. Further study of the hemophilia patients who developed HCC compared with those who did not identified several risk factors. For example, there was a 31-fold increase in risk of HCC for those patients entering the study with baseline alpha-fetoprotein values ⬎11 ng/mL. Additionally, initial infection at age ⬎45 years was associated with
an 18-fold increased risk of developing HCC. This study confirmed the high incidence of HCC in hemophilia patients with hepatitis C.6
LIVER BIOPSY FOR HEMOPHILIA PATIENTS WITH HCV INFECTION The previously mentioned studies of hepatitis C in patients with hemophilia relied on clinical end points: hepatocellular carcinoma, ascites, or other manifestations of hepatic decompensation. As we know from many studies of the natural history of hepatitis C infection, for most patients with varying degrees of inflammation or even well-compensated cirrhosis, only liver biopsy will definitively reveal the extent of disease. Liver biopsy is also the only way to determine whether treatment has produced histologic improvements or, conversely, to detect disease progression for patients who choose not to be treated or fail to respond to treatment. For obvious reasons, liver biopsy in patients with disorders of coagulation raises complex and sometimes emotional issues. In general, hematologists may be reluctant to have liver biopsies performed on their patients with hemophilia. This is not universal, however, and at some medical centers, liver biopsy for hemophilia patients with hepatitis C is routine. The cost of factor replacement after liver biopsy is an important and possibly limiting consideration. Factor replacement may range from $3,000 to $7,500, depending on the severity of hemophilia and the quantity of factor concentrates necessary to achieve 100% replacement. Hospital and monitoring fees represent additional expenses that increase the ultimate cost of liver biopsy. One strategy that may facilitate acceptance of liver biopsy in hepatitis C patients with coagulation disorders is to plan to perform the liver biopsy at the same time the patient is undergoing another procedure that will require factor replacement (e.g., dental extractions, or joint replacements or other orthopedic procedures). Such “piggybacking” would allow the patient to experience the benefit of two procedures while incurring the costs of factor replacement only once. Several studies have examined the safety of liver biopsy for patients with hemophilia. Wong et al7 included 28 patients with hemophilia A or B or von Willebrand’s disease. Patients with factor VIII inhibitor were excluded because of the difficulty of factor VIII replacement for such patients. Patients with either abnormal or normal alanine aminotransferase (ALT) levels were included; only 64% were viremic (HCV RNA positive). Immediately before liver biopsy, factor VIII or IX levels were measured, and clotting factors were administered to replace levels up to 100%. Factor replacement continued every 12 to 36 hours after liver biopsy to maintain at least 50% of factor levels. Pathologic review of these biopsies revealed generally mild histology. Most patients (63%) had portal inflammation, but bridging fibrosis or cirrhosis was
December 27, 1999
THE AMERICAN JOURNAL OF MEDICINE威
Volume 107 (6B)
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A Symposium: Hepatitis C in the Hemophilia Patient/Fried
Figure 3. Distribution of HCV genotypes in hemophilia patients. (Reprinted with permission from Blood.11)
not observed. Another study of liver biopsies from 50 hemophilia patients with HCV infection confirmed these findings. Generally mild histologic changes were noted, with very little inflammation or fibrosis observed.8 No major complications of liver biopsy were reported in either of these studies. Nevertheless, bleeding complications after liver biopsy in patients with hemophilia have been reported, so decisions concerning this procedure in this population must be individualized.9,10
HCV GENOTYPES IN PATIENTS WITH HEMOPHILIA HCV genotypes generally reflect the predominant genotype of the donor population (e.g., genotype 1 in the United States). Because patients with hemophilia may be exposed to several thousand donors from a single factor infusion, multiple genotypes may be present. For example, among 96 patients with hemophilia from the United Kingdom, approximately 50% were infected with HCV genotype 1 (Figure 3). However, some unusual genotypes were noted that were typical of geographic regions other than the United Kingdom, including genotypes 4 and 5, most common in the Middle East and South Africa, respectively. These unusual genotypes probably reflect the background of some of the donors to the factor concentrates. Additionally, 7% of the patients studied had mixed genotypes, which is unusual among volunteer blood donors in the UK.11 Another study from the United Kingdom noted that HCV genotypes may change before and during interferon-␣ therapy in up to 40% of patients with hemophilia. Interferon-treated patients were more likely to change genotypes than those who did not receive interferon. No consistent genotype emerged as a result of interferon treatment, however.12 A recent study has also suggested that genotypes may change over 88S
December 27, 1999 THE AMERICAN JOURNAL OF MEDICINE威
time, in the absence of interferon therapy, in hemophilic patients with chronic hepatitis C.13
INTERFERON THERAPY FOR HEPATITIS C IN HEMOPHILIA PATIENTS Interferon therapy for chronic hepatitis C in patients with hemophilia is currently being studied in randomized trials. In one multicenter trial from Italy, 107 HIV-negative patients with HCV and hemophilia were randomized to observation or 3 MIU interferon-␣ three times a week for one year. HCV RNA was measured both by bDNA and reverse transcription polymerase chain reaction (RT-PCR) assays. HCV genotype 1A was predominant in this population. Liver biopsies were not performed, but 5% of patients showed clinical evidence of cirrhosis. After 48 weeks of therapy, 27% of patients had normal ALT levels and no detectable HCV RNA. Twelve months after therapy was completed, sustained response was observed in 13% of patients. No untreated patient cleared HCV RNA.14 Interferon is known to stimulate the development of autoimmune phenomena. This is of obvious clinical concern regarding hemophilia patients, as the development of factor VIII antibodies represents a significant management issue. To determine whether interferon therapy promotes the development of factor VIII antibodies, investigators followed 35 patients with hemophilia A.15 Factor VIII antibodies developed in 10% of patients (2 of 21) who were treated with interferon for 20 months and 21% of untreated patients (3 of 14), indicating that interferon does not stimulate the development of factor VIII antibodies. A randomized clinical trial now under way at multiple institutions has been designed to compare the impact of ribavirin and interferon-␣/ribavirin combination therapy with interferon monotherapy at 3 MIU three times per week. Nonresponders to interferon alone after 3 Volume 107 (6B)
A Symposium: Hepatitis C in the Hemophilia Patient/Fried
months cross over to combination therapy. In order to evaluate sustained response, patients will be followed for 6 months after the completion of therapy. Preliminary results of this trial will be available in the near future. 3.
LIVER TRANSPLANTATION Patients with end-stage liver disease may be candidates for liver transplantation. A review of transplantation databases in the United Kingdom identified 26 hemophilia patients who underwent liver transplantation between 1982 and 1996. In 69% of these, hepatitis C was the cause of liver failure. Six of the 26 (23%) were co-infected with HIV. Perioperative bleeding complicated 15% of the cases. By 9 months after transplantation, hepatitis C had recurred in 30% of those patients transplanted for HCV infection. Survival after liver transplantation was quite good, especially for patients who were not co-infected with HIV, as 90% were alive 1 year and 83% alive 3 years after transplant. In comparison, survival was 67% at 1 year, and 23% at 3 years for patients co-infected with HIV.16 Additionally, hemophilia was cured in all patients who survived for 1 year: A serendipitous “side effect” of liver transplantation in hemophilic patients is that hepatic grafts produce clotting factors within 24 hours of transplantation.
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SUMMARY 10.
Patients with hemophilia constitute a high-risk group for the acquisition of HCV infection. As HIV therapies improve, the focus of physicians caring for patients with inherited coagulation disorders is shifting from HIV infection to recognition of the increased morbidity and mortality associated with hepatitis C. Screening these patients is of critical importance, as infected patients should be identified, followed, and aggressively treated. It is clear that HIV co-infection accelerates the progression to endstage liver disease. The natural history studies are limited by a paucity of data on histology and hepatic synthetic function in hemophilia patients. Initial studies of interferon therapy in hemophilia patients infected with HCV demonstrate response rates similar to those seen in hepatitis C patients in general. The role of combination therapy with interferon-␣ and ribavirin in these patients is currently under investigation.
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of hepatitis C virus infection in multitransfused hemophiliacs: effect of coinfection with human immunodeficiency virus. The Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr Hum Retrovirol. 1993;6:602– 610. Eyster ME, Fried MW, DiBisceglie AM, Goedert JJ. Increasing HCV RNA levels in hemophiliacs: relationship to HIV infection and liver disease. Blood. 1994;84:1020 –1023. Sherman KE, O’Brien J, Gutierrez AG, et al. Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections. J Clin Microbiol. 1993;31:2679 –2682. Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in hemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Hemophilia Center Directors’ Organization. Lancet. 1997; 350:1425–1431. Tradati F, Colombo M, Mannucci PM, et al. A prospective multicenter study of hepatocellular carcinoma in Italian hemophiliacs with chronic hepatitis C. The Study Group of the Association of Italian Hemophilia Centers. Blood. 1998;91: 1173–1177. Wong VS, Baglin T, Beacham E, et al. The role for liver biopsy in haemophiliacs infected with the hepatitis C virus. Br J Haematol. 1997;97:343–347. Ahmed MM, Mutimer DJ, Elias E, et al. A combined management protocol for patients with coagulation disorders infected with hepatitis C virus. Br J Haematol. 1996;95:383– 388. Lee CA. Investigation of chronic hepatitis C infection in individuals with haemophilia. Br J Haematol. 1997;96:425– 426. Telfer P. Liver biopsy for haemophilic patients with chronic HCV infection. Br J Haematol. 1997;99:239 –240. Preston FE, Jarvis LM, Makris M, et al. Heterogeneity of hepatitis C virus genotypes in hemophilia: relationship with chronic liver disease. Blood. 1995;85:1259 –1262. Eyster ME, Sherman KE, Goedert JJ, Katsoulidou A, Hatzakis A. Prevalence and changes in hepatitis C virus genotypes among multitransfused persons with hemophilia: The Multicenter Hemophilia Cohort Study. J Infect Dis. 1999; 179:1062–1069. Devereux H, Telfer P, Brown D, Morris A, Dusheiko G, Emery V, Lee C. Longitudinal genotype analysis and quantification of hepatitis C virus in haemophilic patients receiving interferon-alpha therapy. J Viral Hepat. 1996;3:43– 48. Rumi MG, Santagostino E, Morfini M, et al. A multicenter controlled, randomized, open trial of interferon alpha 2b treatment of anti-human immunodeficiency virus negative hemophilic patients with chronic hepatitis C. Hepatitis Study Group of the Association of Italian Hemophilia Centers. Blood. 1997;89:3529 –3533. Mauser-Bunschoten EP, Damen M, Reesink HW, et al. Formation of antibodies to factor VIII in patients with hemophilia A who are treated with interferon for chronic hepatitis C. Ann Intern Med. 1996;125:297–299. Gordon FH, Mistry PK, Sabin CA, et al. Outcome of orthotopic liver transplantation in patients with hemophilia. Gut. 1998;42:744 –749.
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