Hematopoietic hormones are being used increasingly in clinical practice, most often to maintain the dose intensity of conventional chemotherapy schedules, decrease the risk of neutropenic fever, and reduce the period of neutropenia or anemia following high-dose chemotherapy plus bone marrow transplantation and chemotherapy protocols for leukemia. Hematopoietic growth factors are also frequently employed in the setting of active infections, including AIDS, either to ameliorate the myelosuppressive toxicities of various antibiotics and chemotherapy regimens or to augment the host immune response.[2,3] Clinicians use these drugs to control the number and function of host defense cells but are uncertain as to the specific settings in which they are most useful.[4,5]
This review briefly outlines the bone marrow defects that occur during various stages of HIV infection, as well as some pathophysiologic mechanisms that may contribute to alterations in hematopoiesis. The expanding literature on the use of hematopoietic growth factors in the treatment of AIDS is then discussed, with particular focus on the three colony-stimulating factors (CSFs) most commonly used clinically: recombinant human erythropoietin (rHuEPO [Epogen, Procrit]), granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim [Leukine, Prokine]), and granulocyte-colony stimulating factor (G-CSF, filgramostim [Neupogen]).
The immunopathogenesis of HIV infection is extremely complex. A variety of viral and immune mechanisms contribute to the progressive deterioration of immunologic function and to the progression of HIV disease to AIDS. By weakening the hosts immune system, the virus indirectly contributes to his or her likelihood of contracting opportunistic infections and malignancies, which are the clinical hallmarks of this devastating illness.
Cytopenias occur in 10% to 20% of individuals with early HIV disease and in 75% to 90% of those with advanced disease. Ineffective hematopoiesis and premature destruction of circulating blood cells (due to autoimmunity and a menagerie of viral, bacterial, fungal, and protozoan infections) are additional contributing factors. Opportunistic malignancies and the myelosuppressive effects of antiviral, antimicrobial, and chemotherapeutic agents further compromise the hosts ability to maintain adequate blood counts. The precise mechanisms that result in ineffective hematopoiesis are poorly defined and usually multifactorial (Table 1).
Histologic Marrow Alterations With HIV Infection
In 50% to 60% of patients with AIDS, bone marrow is hypercellular, due to absolute hyperplasia in one or more of the nonlymphoid cell lines.[8,9] In general, the myeloid-to-erythroid ratio tends to be close to normal or shows a relative myeloid hyperplasia. Lymphoid aggregates, plasmacytosis, and dysplasia are often noted, although their reported frequencies vary considerably in different reviews. This variation is due, in large part, to the failure of these retrospective studies to take into account such confounding clinical variables as the stage of HIV disease, coexisting infection, and drug therapies. Approximately 5% of patients have hypocellular bone marrow, typically in the setting of advanced HIV infection.
A dysplasia of at least one cell line occurs in approximately 70% of patients with AIDS. The most common bone marrow features are dysplastic granulocytic maturation and vacuolization of granulocytic precursors. Roughly one-half of patients have erythrocytic dysplasia and one-third have megakaryocytic dysplasia. Although the dysplasia is morphologically similar to that seen in primary myelodysplastic syndromes and is often associated with reticuloendothelial iron blockade and megaloblastic hematopoiesis, cytogenetic abnormalities and leukemic transformation rarely occur. In general, the degree and frequency of dysplastic changes increase with concurrent opportunistic infections.
Less certain is the relationship between peripheral blood cytopenias and the degree of marrow cellularity.[13,14] For example, the majority of patients with isolated thrombocytopenia have normal or increased marrow megakaryocytes with variable dysplastic features, as well as clinical findings suggestive of autoimmune idiopathic thrombocytopenia. They may also have elevated levels of platelet-bound immunoglobulin and circulating immune complexes capable of binding platelets, and these abnormalities, more than a relative decrease in megakaryocyte production, contribute to the development of thrombocytopenia.
Hematopoietic Alterations Due to Infection, Medications, or Tumor
Viral InfectionsSeveral viruses may affect bone marrow function and diminish blood counts. The increased prevalence and pathogenicity of cytomegalovirus (CMV) infection in the immunocompromised host is particularly important. Like HIV, CMV may cause histiocytic erythrophagocytosis and autoimmune destruction of blood cells, but neither virus produces distinctive histopathologic changes in bone marrow. Hematopoietic cells infected with CMV are less responsive to CSFs and may serve as reservoirs of latent viral infection. Furthermore, CMV (and possibly HIV) can infect bone marrow stromal cells, potentially diminishing their ability to produce cytokines and growth factors.
Parvovirus is a remediable cause of severe chronic anemia in patients with HIV infection.[20,21] Failure of erythrocyte production results from direct viral infection and lysis of erythroid progenitor cells. Although usually a self-limited illness, in the absence of an adequate antibody response, B19 parvovirus infection can persist. It may also rarely inhibit myeloid and megakaryocytic progenitors, resulting in neutropenia and thrombocytopenia.
Pathognomonic histopathologic findings of parvovirus infection consist of giant pronormoblasts in the bone marrow together with an absence of erythroid progenitors. The diagnosis can be confirmed by in situ hybridization, using sequence-specific parvovirus DNA probes.
Exposure to human herpesvirus-6 during infancy typically results in a mild, self-limited exanthem. The virus has a tropism for CD4+ lymphocytes and monocytes, where it may remain dormant for decades. With immunosuppression, it may reactivate and affect the ability of marrow precursor cells to respond to hematopoietic stimulants, resulting in further suppression of T-cell function.
The various hepatitis viruses may also downregulate hematopoiesis, although the mechanism by which they do so is less well understood.
Other opportunistic infections that can involve the bone marrow include fungi and mycobacteria. Cryptococcus neoformans, Histoplasma capsulatum, and Mycobacterium avium intracellulare (MAI) are the pathogens most likely to affect hematopoiesis.[7,8,12] In contrast, extrapulmonary pneumocystosis rarely involves bone marrow in the current era of effective systemic therapies to prevent Pneumocystis carinii pneumonia.[25,26]
Occasionally, the host marrow may reveal disseminated fungal or mycobacterial involvement long before other signs of infection are apparent. Histologic clues suggesting fungal or mycobacterial infection include a marrow diffusely infiltrated with lymphoid and plasma cells that have loose macrophage aggregates and clusters. Less frequently seen are pseudogranuloma cells and granulomata.[7,24]
Successful detection of these organisms requires the use of special stains, sensitive culture techniques, and patience. Weeks may pass before a fastidious pathogen is identified.
Examining the buffy coat may also demonstrate Histoplasma, Candida, or other phagocytized pathogens within the cytoplasm of neutrophils and monocytes. Many microbiology laboratories now employ lysis centrifugation techniques whereby white blood cells are lysed and intracellular pathogens are more rapidly released into culture media, reducing the time to obtain a positive culture.
Anti-infective DrugsDrugs used to prevent and treat the infectious complications of AIDS are also hematotoxic. Of these, zidovudine (AZT [Retrovir]), cidofovir, pentamidine, trimethoprim-sulfamethoxazole, pyrimethamine (Daraprim), sulfadiazine, dapsone (Dapsone), amphotericin B, and, especially, ganciclovir (Cytovene), are the most problematic.
Myelosuppression is the most common dose-limiting toxicity of ganciclovir therapy (both oral and intravenous forms) in immunocompromised hosts. Dose-limiting neutropenia (minimal absolute neutrophil count [ANC] less than 500 cells/mm3) occurred in 24% of AIDS patients receiving chronic oral ganciclovir for CMV retinitis, and anemia (minimal hemoglobin value less than 8.0 g/dL) developed in 15%; when ganciclovir was given intravenously, 37% of patients developed neutropenia and 24% became anemic.
The hematologic side effects of many of these anti-infective drugs are amplified when they are used in varying combinations. Substituting less hematotoxic alternatives for the offending agent(s) can sometimes be accomplished without compromising treatment benefits.
Neoplasms are a common consequence of altered immunity. Non-Hodgkins lymphoma (NHL) will eventually develop in 10% to 15% of HIV-infected patients. This percentage will likely increase as strategies to eliminate HIV viral replication and prevent and treat opportunistic infections improve. In this setting, lymphomatous bone marrow involvement is characterized by peripheral blood pancytopenia. Obtaining a bone marrow aspirate and biopsy as part of the staging evaluation provides insight into the myeloid reserve, and possibly, the need for prophylactic intrathecal central nervous system therapy prior to beginning systemic chemotherapy. Although not tested prospectively, retrospective studies suggest that patients at greatest risk for meningeal relapse are those with bone marrow involvement, sites of disease that are at close proximity to the meninges, or small noncleaved histology.
Kaposis sarcoma has occurred in as many as 20% to 40% of HIV-infected adult homosexuals. However, the frequency of this complication in the United States is decreasing. Kaposis sarcoma rarely involves the bone marrow, although the drugs used to treat it are myelosuppressive. Interferon-alfa (Intron A, Roferon-A), vindesine (Eldisine), doxorubicin, etoposide (VePesid), and paclitaxel (Taxol) are associated with considerable hematologic toxicity, particularly if they are combined with other myelosuppressive drugs. Vincristine, bleomycin (Blenoxane), and the newly available liposomal anthracyclines (Doxil and DaunoXome)[32,33] are generally less hematotoxic.
1. Goodnough LT, Anderson KC, Kurtz S, et al: Indications and guidelines for the use of hematopoietic growth factors. Transfusion 33:944-959, 1993.
2. Hermans P: Clinical use of haematological growth factors in patients with human immunodeficiency virus (HIV-1) infection. Biomed Pharmacother 48:69-72, 1994.
3. Miles S: The use of hematopoietic growth factors in treating HIV infection. Curr Opin Hematol 2:227-233, 1995.
4. American Society of Clinical Oncology: Recommendations for the use of hematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. J Clin Oncol 12:2471-2508, 1994.
5. Bennett CL, Smith TJ, Weeks JL, et al: Use of hematopoietic colony stimulating factors: The American Society of Clinical Oncology survey. J Clin Oncol 14:2511-2520, 1996.
6. Ho DD, Neumann AU, Perelson AS, et al: Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373:123, 1995.
7. Aboulafia DM, Mitsuyasu RT: Hematologic abnormalities in AIDS. Hematol Oncol Clin North Am 5:195-214, 1991.
8. Namiki TS, Boone DC, Meyer PR: A comparison of bone marrow findings in patients with acquired immunodeficiency syndromes (AIDS) and AIDS-related conditions. Hematol Oncol 5:99-106, 1987.
9. Mir N, Costello C, Luckit J, et al: HIV-disease and bone marrow changes: a study of 60 cases. Eur J Haematol 42:339-343, 1989.
10. Israel DS, Plaisance KI: Neutropenia in patients infected with human immunodeficiency virus. Clin Pharm 10:268-279, 1991.
11. Goasguen JE, Bennett JM: Classification and morphologic features of the myelodysplastic syndromes. Semin Oncol 19:4-13, 1992.
12. Schneider DR, Picker LJ: Myelodysplasia in the acquired immune deficiency syndrome. Am J Clin Pathol 84:144-152, 1985.
13. Zon L, Groopman JE: Hematologic manifestations of the human immunodeficiency virus (HIV). Semin Hematol 25:208-218, 1988.
14. Saba HI, Spiers ASD, Greene IN, et al: Hematologic effects of human immunodeficiency virus infection. Cancer Control 2:104-112, 1995.
15. 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 327:1779-1784, 1992.
16. Sloand EM, Klein HG, Banks SM, et al: Epidemiology of thrombocytopenia in HIV infection. Eur J Haematol 48:168-172, 1992.
17. Doweiko JP, Groopman JE: Hematological consequences of HIV infection, in Bolognesi D, Broder S (eds): Textbook of AIDS Medicine, pp 617-628. Baltimore, Williams and Wilkins, 1994.
18. Maciejewski JP, Brauning EE, Donahue RE, et al: Infection of hematologic progenitor cells by human cytomegalovirus. Blood 80:170-178, 1992.
19. Lagneaux L, Delforge A, Snoeck R, et al: Imbalance in production of cytokines by bone marrow stromal cells following cytomegalovirus infection. J Infect Diseases 174:913-918, 1996.
20. Frickhofen N, Abkowitz JL, Safford M, et al: Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): A treatable cause of anemia. Ann Intern Med 113:926-933, 1990.
21. Chernak E, Dubin G, Henry D, et al: Infection due to parvovirus B19 in patients infected with human immunodeficiency virus. Clin Infect Dis 20:170-173, 1995.
22. Pont J, Puchhammer-Stockl E, Chott A, et al: Recurrent granulocytic aplasia as clinical presentation of a persistent parvovirus B19 infection. Br J Haematol 80:160-165, 1992.
23. Flamand L, Gosselin J, Stefanescu I, et al: Immunosuppressive effects of human herpesvirus 6 on T-cell function: Suppression of interleukin-2 synthesis and cell proliferation. Blood 85:1263-1271, 1995.
24. Castella A, Croxson TS, Mildvan D, et al: The bone marrow in AIDS: A histologic, hematologic, and microbiologic study. Am J Clin Pathol 84:425-432, 1985.
25. Raviglione ML, Garner GR, Mullen MP: Pneumocystic carinii in bone marrow (letter). Ann Intern Med 109:253,1988.
26. Bundow DL, Aboulafia DM: Skin involvement with Pneumocystis despite dapsone prophylaxis: A rare cause of skin nodules in a patient with AIDS. Am J Med Sci 313(3):182-186, 1997.
27. Drew WL, Ives D, Lalezari JP, et al: Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis in patients with AIDS. N Engl J Med 333:615-620, 1995.
28. Biggar RJ, Rabkin CS: The epidemiology of AIDS-related neoplasia. Hematol Oncol Clin North Am 10: 997-1007, 1996.
29. Kaplan L, Northfield D: Neoplasia and HIV infection, in Crowe S, Hoy J, Mills J (eds): Management of the HIV Patient, pp 366-383. New York, Cambridge University Press, 1996.
30. Aboulafia DM, Mitsuyatsu RT: Lymphomas and other cancers associated with acquired immunodeficiency syndrome, in Devita VT, Hellman S, Rosenberg SA (eds): AIDS, 4th ed, pp 319-330. Philadelphia, Lippincott-Raven, 1996.
31. Gompels MM, Hill A, Jenkins P, et al: Kaposis sarcoma in HIV infection treated with vincristine and bleomycin. AIDS 6:1175-1180, 1992.
32. Northfelt DW, Dezube B, Miller B, et al: Randomized trial of Doxil vs Adriamycin, bleomycin, vincristine (ABV) in the treatment of severe AIDS-related Kaposis sarcoma (AIDS-KS). Blood 81(10; suppl 1):382a, 1995.
33. Gill PS, Wernz J, Scadden DT, et al: Randomized phase III trial of liposomal daunorubicin vs doxorubicin, bleomycin and vincristine in AIDS-related Kaposis sarcoma. J Clin Oncol 14:2353-2364, 1996.
34. Moses AV, Williams S, Heneveld ML: Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. Blood 87:919-925, 1996.
35. Davis BR, Zauli G: Effects of human immunodeficiency virus infection on hematopoiesis. Ballieres Clinical Hematology 8:113-130, 1995.
36. Re MC, Zauli G, Furlini G, et al: The impaired number of circulating granulocyte/ macrophage progenitors (CFU-GM) in human immunodeficiency virus-type 1 infected subjects correlates with an active HIV-1 replication. Arch Virol 129:53-64, 1993.
37. Schwartz GN, Kessler SW, Rothwell SW, et al: Inhibitory effect of HIV-1-infected stromal cell layers on the production of myeloid progenitor cells in human long-term bone marrow cultures. Exp Hematol 22:1288-1296, 1994.
38. Calenda V, Sebahoun G, Chermann JC: Modulation of normal human erythropoietic progenitor cells in long-term liquid culture after HIV-1 infection. AIDS Res Hum Retrovirus 8:61-67, 1992.
39. Stenberg HN, Crumpacker CS, Chatis PA: In vitro suppression of normal human bone marrow progenitor cells by human immunodeficiency virus. J Virol 65:1765-1769, 1991.
40. Sigiura K, Oyaizu N, Pahwa R, et al: Effects of human immunodeficiency virus-1 envelope glycoprotein on in vitro hematopoiesis of umbilical cord blood. Blood 80:1463-1469, 1992.
41. Stanley SK, Kessler SW, Justement JS, et al: CD34+ bone marrow cells are infected with HIV in a subset of seropositive individuals. J Immunol 149:689-697, 1992.
42. Zauli G, Re MC, Visani G, et al: Evidence for a human immunodeficiency virus type 1-mediated suppression of uninfected hematopoietic (CD34+) cells in AIDS patients. J Infect Dis 166:710-716, 1992.
43. De Luca A, Teofili L, Antinori A, et al. Hematopoietic CD34+ progenitor cells are not infected by HIV-1 in vivo but show impaired clonogenesis. Br J Haematol 85:20-24, 1993.
44. Kaushal S, LaRussa S, Lartner S, et al: Exposure of human CD34+ cells to human immunodeficiency virus type I does not influence their expansion and proliferation of hematopoietic progenitors in vitro. Blood 88:130-137, 1996.
45. Wickramasinghe SN, Beatty C, Shiels S, et al: Ultrastructure of the bone marrow in HIV infection: Evidence of dyshemopoiesis and stromal cell damage. Clin Lab Haematol 14:213-229, 1992.
46. Steinberg HN, Anderson J, Crumpacker CS, et al: HIV infection of the BS-l human stromal cell line: Effects on murine hematopoiesis. Virology 193:524-527, 1993.
47. Schwartz GN, Kessler SW, Rothwell SW, et al: Inhibitory effect of HIV-1-infected stromal cell layers in the production of myeloid progenitor cells in human long-term bone marrow cultures. Exp Hematol 22:1288-1296, 1994.
48. Mauss S, Steinmetz HT, Jablowski H: Lack of induction of granulocyte colony-stimulating factor in human immunodeficiency virus-seropositive individuals (letter). Blood 88:1897-1898, 1996.
49. Sakaguchi M, Sato T, Groopman JE: Human immunodeficiency virus infection of megakaryocyte cells. Blood 77:481-485, 1991.
50. Zucker-Franklin D, Seremetis S, Zheng ZY: Internalization of human immunodeficiency virus type I and other retroviruses by megakaryocytes and platelets. Blood 75:1920-1923, 1990.
51. Meltzer MS, Skillman DR, Gomatos PJ, et al: Role of mononuclear phagocytes in the pathogenesis of human immunodeficiency virus infection. Ann Rev Imunol 8:169-194, 1990.
52. Zauli G, Davis BR, Re MC, et al: Tat protein stimulates production of transforming growth factor-beta 1 by marrow macrophages: A potential mechanism for human immunodeficiency virus-l-induced hematopoietic suppression. Blood 80:3036-3043, 1992.
53. Baumler CB, Bohler T, Herr I, et al: Activation of the CD95 (APO-I/Fas) system in T-cells from human immunodeficiency virus type-l-infected children. Blood 88:1741-1746, 1996.
54. Marandin A, Katz A, Oksenhendler E, et al: Loss of primitive hematopoietic progenitors in patients with human immunodeficiency virus infection. Blood 88:4568-4578, 1996.
55. Esser R, Glienke W, von Briesen H, et al: Differential replication of pro-inflammatory and hematopoietic cytokines in human macrophages after infection with human immunodeficiency virus. Blood 88:3474-3481, 1996.
56. van der Lelie J, Lang JM, et al: Autoimmunity against blood cells in human immunodeficiency virus (HIV) infection. Br J Hematol 67:109-114, 1987.
57. Harbol AW, Liesveld JL, Simpson Haidaris PJ, et al: Mechanism of cytopenia in human immunodeficiency virus infection. Blood Rev 8:241-251, 1994.
58. Scadden DT: Hematologic disorders and growth factor support in HIV infection. Hematol Oncol Clin North Am 10: 1149-1161, 1996.
59. Zauli G, Vitale M, Re MC, et al: In vitro exposure to human immunodeficiency virus type I induces apoptotic cell death of the factor-dependent TF-I hematopoietic cell line. Blood 83:167-175, 1994.
60. McGinniss MH, Macher AM, Rook AH, et al: Red cell autoantibodies in patients with acquired immune deficiency syndrome. Transfusion 26:405-409, 1986.
61. Rarick MU, Espina B, Mocharnuk R, et al: Thrombotic thrombocytopenic purpura in patients with human immunodeficiency virus infection: A report of three cases and review of the literature. Am J Hematol 40:103, 1992.
62. Volberding PA, Lagakos SW, Koch MA, et al: Zidovudine in asymptomatic human immunodeficiency virus infection: A controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter: The AIDS Clinical Trial Group of the National Institute of Allergy and Infectious Diseases. N Engl J Med 322:941-949, 1990.
63. Richman DD, Fischl MA, Grieco MH, et al: The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. N Engl J Med 317:192-197, 1987.
64. Calabresi P, Falcone A, St Clair MH, et al: Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity. Blood 76:2210-2215, 1990.
65. Carpenter CC, Fischl MA, Hammer SM, et al: Antiretroviral therapy for HIV infection in 1997: Updated recommendations of the International AIDS Society-USA panel. JAMA 276(24):146-154, 1996.
66. Popovsky MA, Benson K, Glassman H, et al: Transfusion practices in human immunodeficiency virus-infected patients. Transfusion 35:612-616, 1995.
67. Jacobson MA, Peiperl L, Volberding PA, et al: Red cell transfusion therapy for anemia in patients with AIDS and ARC: Incidence, associated factors, and outcome. Transfusion 30:133-137, 1990.
68. Kravcik S, Toye BW, Fyke K, et al: Impact of Mycobacterium avium complex prophylaxis on the incidence of mycobacterial infections and transfusion-requiring anemia in an HIV-positive population. J AIDS Hum Retroviruses 13:27-32, 1996.
69. Blumberg N, Triulzi DJ, Heal JM: Transfusion-induced immunomodulation and its clinical consequences. Transfus Med Rev 4:24-35, 1990.
70. Henry DH, Beall GN, Benson CA: Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy: Overview of four clinical trials. Ann Intern Med 117:739-748, 1992.
71. Aboulafia DM: Clinical implications of human T-cell leukemia virus type-I/II associated diseases. AIDS Reader 5:118-129, 1995.
72. Jensen LS, Anderson AJ, Christiansen PM, et al: Postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery. Br J Surg 79:513-516, 1992.
73. Mezrow CK, Bergstein 1, Tarrier PI: Postoperative infections following autologous and homologous blood transfusions. Transfusion 32:27-30, 1992.
74. Blumberg N, Agarwal MM, Chuang C: Relation between recurrence of cancer of the colon and blood transfusion Br Med J (Clin Res Ed) 290:1037-1039, 1985.
75. Busch MP, Hop WC, Hoynck van Papendrecht MA, et al: Blood transfusions and prognosis in colorectal cancer. N Engl J Med 328:1372-1376, 1993.
76. Busch MP, Lee TH, Heitman J: Allogenic leukocytes but not therapeutic blood elements induce reactivation and dissemination of latent human immunodeficiency virus type 1 infection: Implications for transfusion support of infected patients. Blood 80:2128-2135, 1992.
77. Sloand E, Kumar P, Klein HG, et al: Transfusion of blood components to persons infected with human immunodeficiency virus type 1: Relationship to opportunistic infection. Transfusion 34:48-53, 1994.
78. Vamvakas E, Kaplan HS: Early transfusion and length of survival in acquired immunodeficiency syndrome: Experience with a population receiving medical care at a public hospital. Transfusion 33:111-118, 1993.
79. Fischl M, Galpin JE, Levine JD, et al: Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 322:1488-1493, 1990.
80. Shrivastava D, Rao TK, Sinert R, et al: The efficacy of erythropoietin in human immunodeficiency virus-infected end-stage renal disease patients treated by maintenance hemodialysis. Am J Kidney Dis 25:904-909, 1995.
81. Phair JP, Abels RI, McNeill MV, et al: Recombinant human erythropoietin treatment: Investigational new drug protocol for the anemia of the acquired immune deficiency syndrome: Overall results. Arch Intern Med 153:2669-2675, 1993.
82. Henry DH, Jemsek JG, Levin AS, et al: Recombinant human erythropoietin and the treatment of anemia in patients with AIDS or advanced ARC not receiving ZDV (letter). J Acquir Immun Defic Syndr 5:847-848, 1992.
83. Glaspy JA, Chap L: The clinical application of recombinant erythropoietin in the HIV-infected patient. Hematol Oncol Clin North Am 8:945-959, 1994.
84. Miles SA, Mitsuyasu RT, Moreno J, et al: Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine. Blood 77:2109-2117, 1991.
85. Miles SA, Mitsuyasu RT, Lee K, et al: Recombinant human granulocyte colony-stimulating factor increases circulating burst forming unit-erythron and red blood cell production in patients with severe human immunodeficiency virus infection. Blood 75:2137-2142, 1990.
86. Bozzette SA, Parker R, Hay J: A cost analysis of approved antiretroviral strategies in persons with advanced human immunodeficiency virus disease and zidovudine intolerance. J Acquir Immun Defic Syndr 7:355-362, 1994.
87. Northfelt DW: Hematologic aspects of HIV infection: in Cohen PT, Sande MA, Volbeeding PA (eds): The AIDS Knowledge Base: A Textbook on HIV Disease from the University of California San Francisco and the San Francisco General Hospital, pp 5.16-1-5,16-17. Boston, Little Brown, 1995.
88. Hoxie JA: Hematologic manifestations of AIDS, in Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, (eds): Hematology: Basic Principles and Practice, 2nd ed, pp 2171-2191. New York, Churchill Livingstone, 1995.
89. Brody GP, Buckley M, Sathe YS, et al: Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:326-339, 1986.
90. Farber BF, Lesser M, Kaplan MH, et al: Clinical significance of neutropenia in patients with human immunodeficiency virus infection. Infect Control Hosp Epidemiol 12:429-434, 1991.
91. Shaunak S, Bartlett JA: Zidovudine-induced neutropenia: Are we too cautious? Lancet 2:91-92, 1989.
92. Northfelt DW, Polsky B: Bacteremia in persons with HIV infection, in Volberding P, Jacobson MA (eds): AIDS Clinical Review, pp 59-79. New York, Marcel Dekker, 1991.
93. Northfelt D, Hamblet J, Aragon T, et al: Outcome of febrile neutropenia in patients with AIDS-related non-Hodgkins lymphoma. Blood 76(suppl 1):491.
94. Calaffa WT, Graham NMM, Vahov D: Bacterial pneumia in adult populations with human immunodeficiency virus (HIV) infection. Am J Epidemiol 138:1-14, 1993.
95. Keiser P, Higgs E, Scanton J: Neutropenia is associated with bacteremia in patients with the human immunodeficiency virus. Am J Med Sci 312:118-122, 1996.
96. Moore RD, Keruly JC, Chaisson RE: Neutropenia and bacterial infection in acquired immune deficiency syndrome. Arch Intern Med 155:1965-1970, 1995.
97. Jacobson MA, Cohen PT, Liu RC, et al: Risk of hospitalization for serious bacterial infections (SBI) associated with neutropenia severity in patients with HIV(abstract). International Conference on AIDS, 11(1):231, July 7-12, 1996.
98. Groopman JE, Mitsuyasu RT, DeLeo MJ, et al: Effect of recombinant human granulocyte-macrophage colony-stimulating factor on myelopoiesis in the acquired immune deficiency syndrome. N Engl J Med 317:593-598, 1987.
99. Hardy WD: Combined ganciclovir and recombinant granulocyte-macrophage colony-stimulating factor in the treatment of cytomegalovirus retinitis in AIDS patients. J Acquir Immune Defic Syndr 4:S22-28, 1991.
100. Kaplan LD, Kahn JO, Crowe S, et al: Clinical and virological effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients receiving chemotherapy for human-immunodeficiency virus-associated non-Hodgkins lymphoma: Results of a randomized trial. J Clin Oncol 9:929-940, 1991.
101. Sparano JA, Wiernick PH, Hu X, et al: Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine, and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkins lymphoma. J Clin Oncol 14:3026-3035, 1996.
102. Gill PS, Levine AM, Krailo M, et al: AIDS-related malignant lymphomas: Results of prospective treatment trials. J Clin Oncol 5:1322-1328, 1987.
103. Kaplan L, Straus D, Testa M, et al: Low-dose compared with standard-dose M-BACOD chemotherapy for non-Hodgkins lymphoma associated with human immunodeficiency virus infection. N Engl J Med 336(23):1641-1648, 1997.
104. Kimura S, Matsuda J, Ikematsu S, et al: Efficacy of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with AIDS. AIDS 4:1251-1255, 1990.
105. Garavelli PL, Berti P: Efficacy of recombinant granulocyte colony-stimulating factor in the long-term treatment of AIDS-related neutropenia (letter). AIDS 7:589-590, 1993.
106. Clumeck N, Wit SD, Hermans P, et al: Recombinant granulocyte colony-stimulating factor (rG-CSF) in HIV patients with zidovudine related neutropenia. J Nutr Sci Vitaminol (Tokyo) spec no. 353-356, 1992.
107. Alvarado-Diez R, Feregrino-Goyos M, Eid-Lidt G, et al: AIDS neutropenia management with colonies stimulating factors (GMCSF and GCSF) (abstract). International Conference on AIDS, 10:189, 1994.
108. Jacobson MA, Stanley HD, Heard SE: Ganciclovir with recombinant methionyl human granulocyte colony-stimulating factor for treatment of cytomegalovirus disease in AIDS patients (letter). AIDS 6:515-517, 1992.
109. Pluda JM, Yarchoan R, Smith PD, et al: Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection. Blood 76:463-472, 1990.
110. Hermans P, Franchioly P, Clumek N: Double blind, randomized comparison of the safety profile of granulocyte-macrophage colony stimulating factor (GM-CSF) in advanced HIV-infected patients with neutropenia (abstract 697). 33rd International Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1993.
111. Hermans P: Clinical use of haematological growth factors in patients with human immunodeficiency virus (HIV-1) infection. Biomed Pharmacother 48:69-72, 1994.
112. Krown SE, Paredes J, Bundow D, et al: Interferon-alpha, zidovudine, and granulocyte-macrophage colony-stimulating factor: A phase I AIDS Clinical Trial Group study in patients with Kaposis sarcoma associated with AIDS. J Clin Oncol 10: 1344-1351, 1992.
113. Koyanagi Y, OBrien WA, Zhao JQ, et al: Cytokines alter production of HIV-1 from primary mononuclear phagocytes. Science 241:1673-1675, 1988.
114. Schuitemaker H, Koostra NA, van Oers MH, et al: Induction of monocyte proliferation and HIV expression by IL-3 does not interfere with anti-viral activity of zidovudine. Blood 76:1490-1493, 1990.
115. Hammer SM, Gillis JM, Groopman JE, et al: In vitro modification of human immunodeficiency virus infection by granulocyte-macrophage-colony-stimulating factor and gamma interferon. Proc Natl Acad Sci USA 83:8734-8738, 1986.
116. Perno CF, Cooney DA, Gao WY, et al: Effect of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages. Blood 80:995-1003, 1992.
117. Scadden DT, Bering HA, Levine JD, et al: Granulocyte-macrophage colony-stimulating factor initiates the neutropenia of combined interferon alpha and zidovudine treatment of acquired immunodeficiency syndrome-associated Kaposis sarcoma. J Clin Oncol 9:802-808, 1991.
118. Perno CF, Yarchoan R, Cooney DA, et al: Replication of human immunodeficiency virus on monocutes: Granulocyte/macrophage colony-stimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3´-azido-2´3´-dideoxythymidine (AZT) and other dideoxynucleoside cogeners of thymidine. J Exp Med 169;933-951, 1989.
119. Jacobson MA, ODonell JJ: Approaches to the treatment of cytomegalovirus retinitis: ganciclovir and foscarnet. J Acquir Immune Defic Syndr 4:Sl l-15, 1991.
120. Balbiano R, Degioanni M, Valle M, et al: Prevention of severe neutropenia in AIDS patients with intermittant, low-dose G-CSF (filgrastim) (abstract PB0323). International Conference on AIDS, 10(1):223, August 7-12, 1994.
121. Baldwin GC, Gasson JC, Quan SG, et al: Granulocyte-macrophage colony-stimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proc Natl Acad Sci USA 85:273-276, 1988.
122. Torres R, Villarreal C, Robles M, et al: Comparative study between two treatment schemes for Cryptococcus neoformans meningitis in AIDS patients: Granulocytic and macrophages colonies stimulator factor (GM-CSF) plus amphotericine-B vs amphotericine alone: Preliminary report (abstract). Int Conf AIDS 9:367, 1993.
123. Kovacs JA, Vogel S, Albert JM, et al: Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 335:1350-1356, 1996.
124. Bernstein ZP, Porter MM, Gould M, et al: Prolonged administration of low-dose interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion of innate immune effectors without significant clinical toxicity. Blood 86:3287-3294, 1995.
125. Scaddon DT, Levine JD, Bresnahan J, et al: In vivo effects of interleukin-3 in HIV type 1 -infected patients with cytopenia. AIDS Res Hum Retroviruses 11: 731-740, 1995.
126. Miles SA, Lee K. Hutlin L, et al: Potential use of human stem cell factor as adjunctive therapy for human immunodeficiency virus-related cytopenias. Blood 78:3200-3208, 1991.
127. Vanden Driessche T, Chuah MKL, Morgan RA: Gene therapy in AIDS, in Curran J, Essex M, Fauci AS (eds): AIDS:Biology, Diagnosis, Treatment and Prevention. 4th ed, pp 519-529. New York, Lippincott-Raven, 1996.