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Viral Causes of Secondary Immune Thrombocytopenic Purpura

Published Online: August 20th 2011 US Hematology, 2007;1(1):62-4 DOI: https://dx.doi.org/10.17925/ohr.2007.01.01.62
Authors: Eric M Cheung, Howard A Liebman
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Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a decreased number of platelets and mucocutaneous bleeding. ITP may be primary (idiopathic) or secondary to an underlying disorder. Secondary disorders are increasingly being recognized as important and significant contributors to immune thrombocytopenia. Disorders associated with ITP include lymphoproliferative disorders, autoimmune and collagen vascular diseases, and chronic infections. The two predominant viral causes of secondary ITP are the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV). It is important to understand the various underlying mechanisms of these disease entities and to recognize that treatment strategies may differ from those for other types of immune thrombocytopenia.

Hepatitis C Virus Infection
Epidemiology

In general, studies report a positive HCV serology in 10–36% of patients with chronic ITP.1–6 According to a large series, HCV-positive patients with chronic ITP are characteristically older (54.9±8 versus 40.3±8 years; p=0.001) and more frequently Asian than HCV-negative patients, with an equal distribution between the sexes.4

Pathophysiology

Multiple pathogenic mechanisms have been elucidated in thrombocytopenia related to chronic HCV infection. In patients with advanced liver disease, thrombocytopenia may result from the sequestration of platelets in spleens enlarged from portal hypertension and the inadequate production of thrombopoietin.7,8 Another mechanism includes the binding to and possible infection of platelets and megakaryocytes by HCV, thereby leading to the phagocytosis of platelets.9,10 Finally, HCV-infected patients may experience an alteration in the regulation of their immune systems, triggering the production of autoantibodies against platelet glycoproteins.11 A compelling argument for this hypothesis is the higher prevalence of thrombocytopenia and antiplatelet antibodies in patients with hepatitis C-induced liver disease than in patients infected with hepatitis B.12

Clinical Manifestations

HCV-infected thrombocytopenic patients do not always manifest in a predictable manner. Japanese and American studies were conflicting as to whether the platelet counts in HCV-positive patients were lower or higher than those in HCV-negative patients.2,4 Although the signs and symptoms of thrombocytopenia are less frequent in HCV-positive ITP, major bleeding is more frequent (25 versus 10%; p=0.0059). Serum cryoglobulins and anticardiolipin antibodies are present more frequently in HCV-positive ITP patients (90 and 62%, respectively) and rare in HCV-negative ITP patients (7 and 15%, respectively; p≤0.001) compared with HCV-positive ITP. Cryoglobulins are associated with the development of vasculitis and the combination of cryoglobulinemic vasculitis and thrombocytopenia, which may explain the increased incidence of bleeding in HCV-infected patients. However, in French and Chinese studies the characteristics of ITP in HCV-positive patients did not differ from those of HCV-negative patients.5,6

Treatment

Although HCV-positive patients respond with improved platelet counts to treatment with intravenous immunoglobulin (IVIg), anti-RhD Ig, and splenectomy,2,5 they respond variably to corticosteroid therapy.2,11,13,14 In addition, caution must be exercised when administering corticosteroids. In one study, six of seven patients (85%) treated with prednisone doubled their hepatic transaminase levels and had increases in their HCV viral loads, two patients developed elevated serum bilirubin levels, and one patient developed overt jaundice.15 Treatment with interferon-α (IFN-α) may increase platelet counts, especially among HCV patients who completely respond to IFN-α treatment.3,15,16 In one study, responders to IFN-α, as opposed to non-responders, experienced decreases in the levels of HCV quantitative ribonucleic acid, hepatic transaminases, and cryoglobulins.15

HIV Infection
Epidemiology

An association between AIDS and thrombocytopenia was noted before the discovery of HIV.17–20 Prior to the advent of highly active antiretroviral therapy (HAART), the rate of thrombocytopenia (platelet count <150x109/l) was estimated to be between 5 and 30%.21–27 This estimation is likely to be lower because of the frequent and early use of HAART. Recent data from the Women’s Interagency HIV Study documented a reduction in the incidence of anemia and neutropenia in HIV-infected women on HAART therapy, and one could assume a similar reduction in the incidence of thrombocytopenia.28,29
Thrombocytopenia is more prevalent in patients with a clinical diagnosis of AIDS, CD4 lymphocyte count of <200/mcl, and history of intravenous drug abuse.22–27,30,31 Compared with HIV-infected homosexuals, HIV-infected injection drug users have an increased incidence and severity of thrombocytopenia, which may be the result of a higher incidence of co-infection with hepatitis C and underlying liver disease.23–25,30–34

Pathophysiology

Multiple mechanisms contribute to the development of thrombocytopenia in the HIV-infected patient, including immune complex disease leading to accelerated platelet clearance,19,35–38 the presence of antiplatelet glycoprotein antibodies,37,39–41 and anti-HIV antibodies that cross-react with platelet membrane glycoproteins (antigenic mimicry).42–45 Additional evidence exists for defective platelet production and direct infection of megakaryocytes, resulting in megakaryocytic apoptosis.46–56
HIV-associated thrombocytopenia of early HIV infection often resembles classic ITP in which thrombocytopenia results primarily from peripheral destruction, whereas patients with immunological AIDS (CD4 lymphocytes <200/mcl) have thrombocytopenia attributable to decreased platelet production and ineffective hematopoiesis.46–48

Clinical Manifestations

Thrombocytopenia in HIV patients can precede the development of overt AIDS by several years, manifesting in a form clinically indistinguishable from classic ITP.57 The clinical presentation of HIV-related ITP is often mild, with only a minority of patients having platelet counts of <50x109/l.25–27 Major bleeding is rare and only a few cases of fatal hemorrhage have been reported.59 Severe thrombocytopenia in patients with advanced HIV infection is frequently associated with additional cytopenias.21–23

HIV-related thrombocytopenia is responsive to therapies frequently used in the management of classic ITP. Prednisone therapy produces a major hematological response in the platelet count (100×109/l) of over half the patients treated, although only a minority of patients will maintain platelets above 50×109/l after corticosteroid therapy is discontinued.20,60 There has been no evidence of a deleterious effect of short-term prednisone treatment on HIV-infected, immune-suppressed patients.
IVIg and anti-RhD are equally effective in acutely elevating platelet counts in severely affected patients. Surgical splenectomy, as opposed to splenic irradiation, is safe and effective in HIV patients with refractory thrombocytopenia.17,18,20,31,47,48,62–64
HIV-related hematological disorders correlate with the degree of HIV viral replication as measured by plasma viral load.65 Effective antiretroviral therapies result in improvements in HIV-related cytopenias, including thrombocytopenia.65–71 Zidovudine monotherapy may increase the platelet count in 60–70% of HIV–thrombocytopenic patients.66–68 Other antiretroviral drugs, when given as monotherapy, have been shown to improve hematological parameters to a lesser degree.72,73 HAART, in both de novo and zidovudine-refractory thrombocytopenic patients, can induce sustained platelet responses in association with viral suppression.65,69,70 Responses to zidovudine and HAART may be limited in HIV-infected injection drug users, possibly reflecting the influence of concurrent liver disease and HCV infection.74,30,71 Several trials have shown a benefit of IFN-α in HIV-infected patients with either elevated serum alanine aminotransferase or HCV-infected patients.3,4,74,15,75

Conclusion

Thrombocytopenia is an important finding in patients infected with either HCV or HIV. Platelet destruction in viral infection-associated ITP occurs via various mechanisms, including accelerated platelet clearance as a result of immune complex disease in HIV-infected patients; cross-reactivity of anti-platelet glycoprotein antibodies and viral antibodies in both HIV and HCV-infected patients; and splenic sequestration of platelets secondary to portal hypertension, decreased production of thrombopoietin, and a dysregulated immune system in HCV-infected patients.
All patients presenting with chronic thrombocytopenia with risk factors (multiple sex partners, IV drug abuse, or blood transfusion recipients)76 or from a population sector with a high prevalence of infection should be screened for the presence of HCV and HIV, as these patients will require different treatment strategies from patients with other forms of autoimmune thrombocytopenia.
The use of antiviral therapy in HCV and antiretroviral therapy in HIV lowers the incidence of thrombocytopenia in populations with these infections. In both HIV- and HCV-positive patients, there is often a response to IVIg, anti-RhD Ig, and splenectomy. Although HIV patients will typically respond, at least transiently, to corticosteroid therapy, HCV patients should avoid corticosteroid therapy for as long as possible, because it can increase the viral load and worsen liver damage. In HCV-positive patients without clinically evident liver disease, treatment with IFN-α combination therapy should be considered. ■

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References

  1. Pivetti S, Novarino A, Merico F, et al., High prevalence of autoimmune phenomena in hepatitis C virus antibody positive patients with lymphoproliferative and connective tissue disorders, Br J Haematol, 1996;95:204–11.
  2. Sakuraya M, Murakami H, Uchiumi H, et al., Steroid-refractory chronic idiopathic thrombocytopenic purpura associated with hepatitis C virus infection, Eur J Haematol, 2002;68:49–53.
  3. Garcia-Suarez J, Burgaleta C, Hernanz N, et al., HCV-associated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy, Br J Haematol, 2000;110:98–103.
  4. Rajan SK, Espina BM, Liebman HA, Hepatitis C virus-related thrombocytopenia: Clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura, Br J Haematol, 2005;129:818–24.
  5. Zhang L, Li H, Zhao H, Ji L, Yang R, Hepatitis C virus-related adult chronic idiopathic thrombocytopenic purpura: Experience from a single Chinese center, Eur J Haematol, 2003;70:196–7.
  6. Pawlotsky JM, Bouvier M, Fromont P, et al., Hepatitis C virus infection and autoimmune thrombocytopenic purpura, J Hepatol, 1995;23:635–9.
  7. Yabu K, Kiyosawa K, Ako S, et al., Type C chronic hepatitis associated with thrombocytopenia in two patients, J Gastroenterol Hepatol, 1994;9:99–104.
  8. Adinolfi LE, Giordano MG, Andreana A, et al., Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis, Br J Haematol, 2001;113:590–95.
  9. Hamaia S, Li C, Allain JP, The dynamics of hepatitis C virus binding to platelets and 2 mononuclear cell lines, Blood, 2001;98:2293–2300.
  10. Bordin G, Ballare M, Zigrossi P, et al., A laboratory and thrombokinetic study of HCV-associated thrombocytopenia: A direct role of HCV in bone marrow exhaustion, Clin Exp Rheumatol, 1995;13(Suppl. 13):S39–43.
  11. Pockros PJ, Duchini A, McMillan R, et al., Immune thrombocytopenic purpura in patients with chronic hepatitis C virus infection, Am J Gastroenterol, 2002;97:2040–45.
  12. Nagamine T, Ohtuka T, Takehara K, et al., Thrombocytopenia associated with hepatitis C viral infection, J Hepatol, 1996;24: 135–40.
  13. Hernandez F, Blanquer A, Linares M, et al., Autoimmune thrombocytopenia associated with hepatitis C virus infection, Acta Haematol, 1998;99:217–20.
  14. Ramos-Casals M, Garcia-Carrasco M, Lopez-Medrano F, et al., Severe autoimmune cytopenias in treatment-naive hepatitis C virus infection: Clinical description of 35 cases, Medicine (Baltimore), 2003;82:87–96.
  15. Rajan S, Liebman HA, Treatment of hepatitis C related thrombocytopenia with interferon alpha, Am J Hematol, 2001;68:202–9.
  16. Iga D, Tomimatsu M, Endo H, et al., Improvement of thrombocytopenia with disappearance of HCV RNA in patients treated by interferon-alpha therapy: Possible etiology of HCVassociated immune thrombocytopenia, Eur J Haematol, 2005;75:417–23.
  17. Morris L, Distenfeld A, Amorosi E, Karpatkin S, Autoimmune thrombocytopenic purpura in homosexual men, Ann Intern Med, 1982;96:714–17.
  18. Ratnoff OD, Menitove JE, Aster RH, Lederman MM, Coincident classic hemophilia and idiopathic thrombocytopenic purpura in patients under treatment with concentrates of antihemophilic factor (factor VIII), N Engl J Med, 1983;308:439–42.
  19. Walsh CM, Nardi MA, Karpatkin S, On the mechanism of thrombocytopenic purpura in sexually active homosexual men, N Engl J Med, 1984;311:635–9.
  20. Walsh C, Krigel R, Lennette E, Karpatkin S, Thrombocytopenia in homosexual patients. Prognosis, response to therapy, and prevalence of antibody to the retrovirus associated with the acquired immunodeficiency syndrome, Ann Intern Med, 1985;103:542–5.
  21. Murphy MF, Metcalfe P,Waters AH, et al., Incidence and mechanism of neutropenia and thrombocytopenia in patients with human immunodeficiency virus infection, Br J Haematol, 1987;66:337–40.
  22. Kaslow RA, Phair JP, Friedman HB, et al., Infection with the human immunodeficiency virus: clinical manifestations and their relationship to immune deficiency. A report from the Multicenter AIDS Cohort Study, Ann Intern Med, 1987;107:474–80.
  23. Rossi G, Gorla R, Stellini R, et al., Prevalence, clinical, and laboratory features of thrombocytopenia among HIV-infected individuals, AIDS Res Hum Retroviruses, 1990;6:261–9.
  24. Peltier JY, Lambin P, Doinel C, et al., Frequency and prognostic importance of thrombocytopenia in symptom-free HIV-infected individuals: A 5-year prospective study, Aids, 1991;5:381–4.
  25. Mientjes GH, van Ameijden EJ, Mulder JW, et al., Prevalence of thrombocytopenia in HIV-infected and non-HIV infected drug users and homosexual men, Br J Haematol, 1992;82:615-619.
  26. Sloand EM, Klein HG, Banks SM, et al., Epidemiology of thrombocytopenia in HIV infection, Eur J Haematol, 1992;48: 168–72.
  27. Sullivan PS, Hanson DL, Chu SY, et al., Surveillance for thrombocytopenia in persons infected with HIV: Results from the multistate Adult and Adolescent Spectrum of Disease Project, J Acquir Immune Defic Syndr Hum Retrovirol, 1997;14:374–9.
  28. Berhane K, Karim R, Cohen MH, et al., Impact of highly active antiretroviral therapy on anemia and relationship between anemia and survival in a large cohort of HIV-infected women:Women’s Interagency HIV Study, J Acquir Immune Defic Syndr, 2004;37: 1245–52.
  29. Levine AM, Karim R, Mack W, et al., Neutropenia in human immunodeficiency virus infection: Data from the women’s interagency HIV study, Arch Intern Med, 2006;166:405–10.
  30. Burbano X, Miguez MJ, Lecusay R, et al., Thrombocytopenia in HIVinfected drug users in the HAART era, Platelets, 2001;12:456–61.
  31. Landonio G, Galli M, Nosari A, et al., HIV-related severe thrombocytopenia in intravenous drug users: prevalence, response to therapy in a medium-term follow-up, and pathogenetic evaluation, Aids, 1990;4:29–34.
  32. Ciernik IF, Cone RW, Fehr J,Weber R, Impaired liver function and retroviral activity are risk factors contributing to HIV-associated thrombocytopenia: Swiss HIV Cohort Study, Aids, 1999;13:1913–20.
  33. Quan CM, Krajden M, Grigoriew GA, Salit IE, Hepatitis C virus infection in patients infected with the human immunodeficiency virus, Clin Infect Dis, 1993;17:117–19.
  34. Quaranta JF, Delaney SR, Alleman S, et al., Prevalence of antibody to hepatitis C virus (HCV) in HIV-1-infected patients (nice SEROCO cohort), J Med Virol, 1994;42:29–32.
  35. Karpatkin S, Nardi M, Lennette ET, et al., Anti-human immunodeficiency virus type 1 antibody complexes on platelets of seropositive thrombocytopenic homosexuals and narcotic addicts, Proc Natl Acad Sci USA, 1988;85:9763–7.
  36. Karpatkin S, Nardi M, Autoimmune anti-HIV-1gp120 antibody with antiidiotype-like activity in sera and immune complexes of HIV-1-related immunologic thrombocytopenia, J Clin Invest, 1992;89:356–64.
  37. Karpatkin S, Nardi MA, Hymes KB, Sequestration of anti-platelet GPIIIa antibody in rheumatoid factor immune complexes of human immunodeficiency virus 1 thrombocytopenic patients, Proc Natl Acad Sci U S A, 1995;92:2263–7.
  38. Samuel H, Nardi M, Karpatkin M, et al., Differentiation of autoimmune thrombocytopenia from thrombocytopenia associated with immune complex disease: systemic lupus erythematosus, hepatitis-cirrhosis, and HIV-1 infection by platelet and serum immunological measurements, Br J Haematol, 1999;105:1086–91.
  39. Bettaieb A, Oksenhendler E, Fromont P, et al., Immunochemical analysis of platelet autoantibodies in HIV-related thrombocytopenic purpura: a study of 68 patients, Br J Haematol, 1989;73:241–7.
  40. Nardi MA, Liu LX, Karpatkin S, GPIIIa-(49-66) is a major pathophysiologically relevant antigenic determinant for antiplatelet GPIIIa of HIV-1-related immunologic thrombocytopenia, Proc Natl Acad Sci U S A, 1997;94:7589–94.
  41. Zandman-Goddard G, Shoenfeld Y, HIV and autoimmunity, Autoimmun Rev, 2002;1:329–37.
  42. Bettaieb A, Fromont P, Louache F, et al., Presence of cross-reactive antibody between human immunodeficiency virus (HIV) and platelet glycoproteins in HIV-related immune thrombocytopenic purpura, Blood, 1992;80:162–9.
  43. Hohmann AW, Booth K, Peters V, et al., Common epitope on HIV p24 and human platelets, Lancet, 1993;342:1274–5.
  44. Nardi M, Tomlinson S, Greco MA, Karpatkin S, Complementindependent, peroxide-induced antibody lysis of platelets in HIV-1- related immune thrombocytopenia, Cell, 2001;106:551–61.
  45. Li Z, Nardi MA, Karpatkin S, Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia, Blood, 2005;106:572–6.
  46. Ballem PJ, Belzberg A, Devine DV, et al., Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection, N Engl J Med, 1992;327:1779–84.
  47. Landonio G, Nosari A, Spinelli F, et al., HIV-related thrombocytopenia: four different clinical subsets, Haematologica, 1992;77:398–401.
  48. Najean Y, Rain JD, The mechanism of thrombocytopenia in patients with HIV infection, J Lab Clin Med, 1994;123:415–20.
  49. Zucker-Franklin D, Termin CS, Cooper MC, Structural changes in the megakaryocytes of patients infected with the human immune deficiency virus (HIV-1), Am J Pathol, 1989;134:1295–1303.
  50. Zucker-Franklin D, Seremetis S, Zheng ZY, Internalization of human immunodeficiency virus type I and other retroviruses by megakaryocytes and platelets, Blood, 1990;75:1920–23.
  51. Sakaguchi M, Sato T, Groopman JE, Human immunodeficiency virus infection of megakaryocytic cells, Blood, 1991;77:481–5.
  52. Kunzi MS, Groopman JE, Identification of a novel human immunodeficiency virus strain cytopathic to megakaryocytic cells, Blood, 1993;81:3336–42.
  53. Sato T, Sekine H, Kakuda H, et al., HIV infection of megakaryocytic cell lines, Leuk Lymphoma, 2000;36:397–404.
  54. Sundell IB, Koka PS, Thrombocytopenia in HIV infection: impairment of platelet formation and loss correlates with increased c-Mpl and ligand thrombopoietin expression, Curr HIV Res, 2006;4:107–16.
  55. Zucker-Franklin D, Cao YZ, Megakaryocytes of human immunodeficiency virus-infected individuals express viral RNA, Proc Natl Acad Sci U S A, 1989;86:5595-5599.
  56. Kowalska MA, Ratajczak J, Hoxie J, et al., Megakaryocyte precursors, megakaryocytes and platelets express the HIV coreceptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets, Br J Haematol, 1999;104:220–29.
  57. Karpatkin S, Autoimmune thrombocytopenias, Autoimmunity, 2004;37:363–8.
  58. Ragni MV, Bontempo FA, Myers DJ, et al., Hemorrhagic sequelae of immune thrombocytopenic purpura in human immunodeficiency virus-infected hemophiliacs, Blood, 1990;75:1267–72.
  59. Finazzi G, Mannucci PM, Lazzarin A, et al., Low incidence of bleeding from HIV-related thrombocytopenia in drug addicts and hemophiliacs: Implications for therapeutic strategies, Eur J Haematol, 1990;45:82–5.
  60. Oksenhendler E, Bierling P, Farcet JP, et al., Response to therapy in 37 patients with HIV-related thrombocytopenic purpura, Br J Haematol, 1987;66:491–5.
  61. Scaradavou A,Woo B,Woloski BM, et al., Intravenous anti-D treatment of immune thrombocytopenic purpura: Experience in 272 patients, Blood, 1997;89:2689–2700.
  62. Leissinger CA, Andes WA, Role of splenectomy in the management of hemophilic patients with human immunodeficiency virus-associated immunopathic thrombocytopenic purpura, Am J Hematol, 1992;40:207–9.
  63. Oksenhendler E, Bierling P, Chevret S, et al., Splenectomy is safe and effective in human immunodeficiency virus-related immune thrombocytopenia, Blood, 1993;82:29–32.
  64. Marroni M, Sinnone MS, Landonio G, et al., Splenic irradiation versus splenectomy for severe, refractory HIV-related thrombocytopenia: Effects on platelet counts and immunological status, Aids, 2000;14:1664–7.
  65. Servais J, Nkoghe D, Schmit JC, et al., HIV-associated hematologic disorders are correlated with plasma viral load and improve under highly active antiretroviral therapy, J Acquir Immune Defic Syndr, 2001;28:221–5.
  66. Landonio G, Cinque P, Nosari A, et al., Comparison of two dose regimens of zidovudine in an open, randomized, multicentre study for severe HIV-related thrombocytopenia, Aids, 1993;7:209–12.
  67. Oksenhendler E, Bierling P, Ferchal F, et al., Zidovudine for thrombocytopenic purpura related to human immunodeficiency virus (HIV) infection, Ann Intern Med, 1989;110:365–8.
  68. Cinque P, Landonio G, Lazzarin A, et al., Long-term treatment with zidovudine in patients with human immunodeficiency virus (HIV)- associated thrombocytopenia: Modes of response and correlation with markers of HIV replication, Eur J Haematol, 1993;50:17–21.
  69. Aboulafia DM, Bundow D,Waide S, et al., Initial observations on the efficacy of highly active antiretroviral therapy in the treatment of HIV-associated autoimmune thrombocytopenia, Am J Med Sci, 2000;320:117–23.
  70. Carbonara S, Fiorentino G, Serio G, et al., Response of severe HIVassociated thrombocytopenia to highly active antiretroviral therapy including protease inhibitors, J Infect, 2001;42:251–6.
  71. Miguez MJ, Burbano X, Archer H, Shor-Posner G, Limited impact of highly active antiretroviral therapy in thrombocytopenia, J Acquir Immune Defic Syndr, 2002;30:260–61.
  72. Schacter LP, Rozencweig M, Beltangady M, et al., Effects of therapy with didanosine on hematologic parameters in patients with advanced human immunodeficiency virus disease, Blood, 1992;80:2969–76.
  73. Nasti G, Errante D, Tirelli U, Successful treatment of HIV-1-related, zidovudine resistant, thrombocytopenia with didanosine, Am J Hematol, 1997;55:118–19.
  74. Marroni M, Gresele P, Landonio G, et al., Interferon-alpha is effective in the treatment of HIV-1-related, severe, zidovudineresistant thrombocytopenia. A prospective, placebo-controlled, double-blind trial, Ann Intern Med, 1994;121:423–9.
  75. Northfelt DW, Charlebois ED, Mirda MI, et al., Continuous lowdose interferon-alpha therapy for HIV-related immune thrombocytopenic purpura, J Acquir Immune Defic Syndr Hum Retrovirol, 1995;8:45–50.
  76. NIH Consensus Statement on Management of Hepatitis C: 2002. NIH Consens State Sci Statements, 2002;19:1–46.

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