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Use of Recombinant Interferons and Hematopoietic Growth Factors in Patients Infected with Human Immunodeficiency Virus Ronald T. Mitsuyasu

From the Division of Hematology-Oncology, and the UCLA AIDS Clinical Research Center, UCLA School of Medicine, Los Angeles, California

AIDS is a multisystem disease caused by the human immunodeficiency virus (HIV). After primary infection of CD4+ T lymphocytes, continued replication of HIV within T cells and macrophages leads to the deterioration of the immune system. Because the CD4+ T cell population coordinates much of the immune response, patients with AIDS demonstrate a wide variety of immunologic defects. These defects involve T lymphocytes, affecting both their number and function, as well as B lymphocytes, resulting in both abnormalities in antibody response and polyclonal activation of B cells. Abnormalities of macrophage function have also been documented in HIV-infected patients. Since its recognition nearly 10 years ago, considerable progress has been made in the treatment of HIV infection and its associated opportunistic infections and malignancies. In large measure these advances have involved the development of new

This article is part of a series of papers in the present issue of Reviews on the evolving use of biologicals in the treatment and prevention of infectious diseases. The papers were presented at a symposium held during the Interscience Conference on Antimicrobial Agents and Chemotherapy in October 1990 in Atlanta. The symposium was supported by an educational grant from Amgen Inc., Thousand Oaks, California. Grant support: U.S. Public Health Service (AI 27660) and the State of California University-Wide Task Force on AIDS (90RCC 86 LA). Reprints and correspondence: Dr. Ronald T. Mitsuyasu, Division of Hematology-Oncology, UCLA Medical Center, Room 60-054 CHS, Los Angeles, California 90024-1793. Reviews of Infectious Diseases 1991;13:979-84 © 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1305-0047$02.00

antiretroviral and antimicrobial agents. Genetic engineering has also made recombinant cytokines available. Cytokines are soluble protein factors produced by cells that have powerful biologic effects on the hematopoietic and immune systems (humoral and cellular). The production of some cytokines in patients with HIV infection may be deficient. In an attempt to augment immune function, researchers have included a number of recombinant cytokines in clinical trials. These include interleukin-2, the interferons, and the hematopoietic growth factors. Interleukin-2 modulates T cell immunity. Type I interferons (ex and constitute a family of inducible cellular glycoproteins that regulate lymphocyte and natural killer cell activities and suppress HIV expression. Type II interferon ('Y) regulates monocyte and macrophage activities. Hematopoietic growth factors, which include erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), among others, have also attracted considerable attention. These growth factors have proven clinically active in ameliorating HIV-related neutropenia or in offsetting the dose-limiting cytopenias caused by a number of drugs used to treat the infections and malignancies associated with AIDS. This paper will focus on the role of interferons and hematopoietic growth factors.

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Interferons Interferon-a. In the early 1980s, recombinant interferon-a was first investigated as a potential treatment for AIDS-related Kaposi's sarcoma (KS) because of its antiviral effects, tumor

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The recombinant cytokines are increasingly important therapeutic agents for patients with AIDS. Recombinant interferon-a has demonstrated antitumor and antiretroviral activities in patients with Kaposi's sarcoma. Limited studies with Interferon-d suggest that it also has antitumor effects in patients with Kaposi's sarcoma, but interferon-v appears to be ineffective in controlling this tumor. The hematopoietic growth factors, including erythropoietin, granulocyte colonystimulating factor (G-CSF) , and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been evaluated in several populations of human immunodeficiency virus (HIV)-infected individuals. The combination of G-CSF and recombinant human erythropoietin completely reversed the zidovudine-induced neutropenia of AIDS patients but was only partially effective in reversing anemia. In several clinical trials, GM-CSF induced marked increases in leukocyte counts and improved neutrophil function in some AIDS patients. In severelyimmunocompromised patients with disease caused by HIV who were receiving therapy with either G-CSF or GM-CSF, opportunistic infections continued to occur despite increases in circulating white blood cell counts. Recombinant cytokines may be used in the future in AIDS patients as adjunctive treatment with myelosuppressive antibiotics and chemotherapeutic drugs, as a possible means of enhancing host defense, or as agents of immune reconstitution.

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(perhaps through the induction of endonucleases and protein kinase), and an inhibition of virion assembly and release. Three studies that summarized the antiretroviral effects of interferon-a in different patient populations have been reported [11-13]; these patient populations included AIDS patients with KS, AIDS patients who did not have KS, and asymptomatic HIV-seropositive patients, respectively. In a study reported by Lane et al. [11], patients with AIDSrelated KS received 35 x lQ6 U of interferon alfa-2b on a daily basis. As expected, responders had a higher mean CD4+ T cell count (399 cells/rum") than did nonresponders (154 cells/ram'). The antiretroviral effect of interferon-a became apparent when patients who were antigenemic at the start of therapy were analyzed for changes in their levels of p24 antigen. Of the six responding patients with elevated blood levels of antigen at the start of therapy, five patients' serum p24 antigen levels substantially decreased (at least 75 %) after 12 weeks. In contrast, none of the nonresponding patients' serum p24 antigen levels substantially decreased. In a separate but concurrent placebo-controlled trial of zidovudine in KS patients, none of the p24 antigen levels of patients who received placebo for 12 weeks significantly decreased, despite the fact that their mean T cell count (364 cells/rum') was equivalent to that of the responders in the first study [11]. In a study of AIDS patients who did not have KS by Friedland et al. [12], patients were randomly assigned to one of three groups: those receiving placebo, those receiving 3 x 106 U of interferon alfa-2a per day, or those receiving 36 X 106 U of interferon alfa-2a per day. The patients of the populations studied were severely ill as reflected by low median CD4+ T cell counts. Furthermore, before treatment, no substantial differences in p24 antigen levels were seen. The 20 patients receiving placebo had a mean CD4+ T cell count of 62 cells/rum>; of these, three of 12 antigenemic patients had a reduction in p24 antigen levels. In 22 patients with mean CD4+ T cell counts of 56 cells/mm! who were receiving lowdose interferon-a, two of 11 antigenemic patients had reductions in p24 antigen levels. Of 25 patients with mean CD4+ T cell counts of 47 cells/rum' who were in the high-dose interferon-a group, two of 14 had reductions in p24 antigen levels. Thus, there did not appear to be any differences between serum p24 antigen levels of patients who received interferon-a treatment and those who did not; in addition, there were no significant differences in the overall survival rates among the patients of the three groups. Lane et al. [13] recently reported the results of a doubleblind study in which HIV-positive asymptomatic patients with mean CD4+ T cell counts of rv600 cells/mm' at enrollment received either placebo or therapy with interferon alfa-2b, given initially at 35 X 106 Did. All patients had positive viral cultures or were p24 antigenemic upon their enrollment into the study. In the treatment group, cultures for seven (64 %) of 11 patients became negative after they had completed at least 12 weeks of therapy. In contrast, cultures for only two

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antiproliferative activity, and immunomodulating capabilities. Interferon-a has subsequently become the first licensed cytokine approved specifically for the treatment of KS. In the first study to demonstrate the activity of interferon-a against KS in 1983, Krown et al. [1] treated patients with KS with interferon that was subcutaneously administered at relatively high dosages, ranging from 36 x 106 to 54 x IQ6 Did. Of the 36 patients enrolled in this study, eight had a complete response and five had a partial response for an overall objective rate of response of 38 %. However, in a subsequent study [2], only one of 39 patients had a major tumor response to low dosages of interferon alfa-2a (3 X 106 Did). A number of studies in which a variety of doses and administration schedules of interferon-a, both recombinant and lymphoblastoid, were used have subsequently been reported; the data from these indicate an overall objective response rate of rv 25 % [3-5]. Retrospective analysis of prognostic factors suggested that neither the dose of interferon nor the stage of the tumor at the time of treatment had a substantial impact on the outcome of treatment [6]. Several other prognostic factors, however, were significant. These included lack of prior opportunistic infections, lack oflymphoma-like symptoms (i.e., fever, night sweats, and weight loss), and relatively high baseline counts of CD4+ T cells. Intact cellular immunity (skin test reactivity and proliferative response to mitogens and alloantigens) and low or normal endogenous interferon levels (which often become elevated as disease progresses) were also found to be significantly associated with tumor response [7]. These findings suggest that in AIDS patients, there may be a close correlation between the antitumor effect of interferon-a and its immune effects. It is also of interest to note that whereas AIDS patients have evidence of immune activation as measured by increased levels of soluble markers such as {32microglobulin and neopterin, cells from these patients are defective in producing interferon-a and interferon-v in response to appropriate antigenic and infectious stimuli [8-10]. There are a number of dose-limiting, flulike symptoms associated with interferon therapy. These include myalgia, fever, rigors, asthenia, and anorexia. Other objectively measured adverse effects include neutropenia, thrombocytopenia, elevation in levels of transaminase, and neurologic toxicities such as mild confusion and paresthesias. All of the adverse effects are reversible once therapy with the drug is discontinued. Antiretroviral activity ofinterferon-a. One important property of interferon-a is its antiretroviral activity. The mechanism by which interferon-a exerts its antiretroviral effects depends on the infected cell type. For example, in infected T lymphocytes, interferon-a appears to act at a late stage in viral replication, during virion assembly and release. In monocytes and macrophages there may be multiple mechanisms by which interferon-a exerts its antiretroviral effects. These include an early effect of interferon before the level of reverse transcription, a later effect at the posttranscriptional levels

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Interferons and Growth Factors in AIDS

Hematopoietic Growth Factors The use of a number of therapeutic agents to treat HIV infection and its related diseases results in cytopenia, which is the major dose-limiting toxicity. Recombinant hematopoietic growth factors, which can correct the cytopenias associated

with other therapies, have the significant potential for altering the course of HIV disease. For example, in placebocontrolled clinical trials of recombinant human erythropoietin in patients with AIDS-related anemia or anemia secondary to zidovudine therapy, erythropoietin was found to correct the anemia and decrease the transfusion requirements of these patients [16]. The human recombinant colony-stimulating factors, which were named for the type of colonies they stimulated from patient bone marrow in semisolid culture medium, may also play an important therapeutic role. These factors include G-CSF and GM-CSF, both of which have been the subject of several clinical studies. G-CSF. The use of combination myeloid lineage-specific growth factors offers the possibility of stimulating the development of multiple lineages of blood cells. In addition, because G-CSF may influence the development of the earliest red blood cell precursors (i.e., burst-forming unit-erythroid [BFU-E]) [17], the combined use of G-CSF and erythropoietin has a particularly compelling rationale and was one of the first combinations examined in a clinical trial in patients with HIV infection. In a phase 1111 clinical trial [18], neutropenic and anemic patients with AIDS or HIV infection received subcutaneous injections of G-CSF (3.6p.g/[kg·d]) until a targeted white blood cell count of >5,000 cells/rum' for 14 days was achieved. Subcutaneous injections of erythropoietin (beginning at a dosage of 150 U/[kg'd]) were added to the therapeutic regimen until hemoglobin levels increased to 15 giL. At that point, successive groups of eight patients were also treated with zidovudine (either 1,000 or 1,500 mg/d). Patients were observed for hematologic toxicity to zidovudine as well as for opportunistic infections and malignancies. The results of the study showed that all 22 enrolled patients responded to G-CSF therapy; responses were usually seen within 3 days. The median dosage of G-CSF required to achieve the target neutrophil count was 3.6 p.g/[kg·d]. In addition, erythropoietin increased hemoglobin levels in 20 of the 22 evaluable patients. The two treatment failures occurred in patients who had previously received ganciclovir. The median dose of erythropoietin necessary for a response was 238 U/kg. Upon reinitiation ofzidovudine therapy, none of the patients could tolerate a dosage of >1,500 mg/d because of toxicities such as thrombocytopenia and/or gastrointestinal disorders. Of the 20 evaluable patients, 16 received 1,000 mg ofzidovudine per day and four received 1,500 mg ofzidovudine per day. While G-CSF prevented zidovudine-induced neutropenia in all evaluable patients, erythropoietin was only partially effective in reversing the anemia in these patients. Six patients had to discontinue treatment because of persistent anemia once zidovudine therapy was reinitiated. No pretreatment factors were found that predicted this apparent resistance to erythropoietin; however, the eight patients who were resistant to erythropoietin therapy had relatively lower levels of BFU-E

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(13 %) of 16 patients in the placebo group became negative after the same amount of time. These differences were highly significant (P = .008) and suggest that interferon-ex has a substantial antiretroviral effect. Although this study was not designed to look at clinical efficacy parameters, long-term follow-up (mean, 24 months) was reported [13]. Although five patients in the placebo group developed an opportunistic infection and three of them died, none of the patients in the treatment group had developed opportunistic infections or had died of related problems as of the time of the published report. Antiretroviral activity of interferon-S. One of the first studies of interferon-S in AIDS patients consisted of 39 patients with AIDS-related KS who were treated with either 90 x 106 or 180 x 106 U of interferon-S per day [14]. Thirty-five patients had at least one poor prognostic variable, as indicated by high p24 antigen levels, low CD4 + T cell counts «200/mm 3) , elevated levels of 112-microglobulin, or a history of opportunistic infection or of chemotherapy. Results of this study showed that for KS patients the antiretroviral effect of interferon-S is similar or slightly less pronounced than that of interferon-ex [14]. A total of 15% of patients from both treatment arms had complete or partial responses. As was the case with interferon-a, patients with higher CD4+ T cell counts were more likely to respond to treatment. Significantly, eight (42 %) of 19 patients with elevated baseline levels of p24 antigen had a marked reduction in serum p24 antigen levels. However, this response and the antitumor effect were seen only in patients whose 112microglobulin levels were normal before treatment or who were able to increase their 112-microglobulin levels in response to treatment with interferon. This indicates that the ability to respond immunologically to interferon may be necessary to mediate the antitumor effect of interferon. Interferon-y, Interferon-y has a number of effects on the immune system. In the mid-1980s, several phase I studies involving patients with AIDS and opportunistic infection or KS were performed. Therapeutic dosages of interferon-v ranged from 10 to 10,000 p.g/m2, one to three times per week. In each of the studies, patients had evidence of monocyte and macrophage activation, although there was essentially no clinical response [15]. Substantial flulike symptoms were also seen in the treated patients. Nonetheless, since interferon-y activates monocytes and macrophages, this agent may be useful for controlling opportunistic pathogens. At present, a number of studies are being conducted to evaluate interferon-y as a possible adjunct to standard antimicrobial therapy for several opportunistic infections.

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at enrollment (50% ± 23 % of normal) and seemed to have a higher BFU-E sensitivity to the suppressive effects ofzidovudine in vitro. The combination of G-CSF and erythropoietin did not adversely affect HIV replication; zidovudine continued to decrease plasma and serum p24 antigen levels. However, despite the alleviation of neutropenia by G-CSF, opportunistic infections continued to occur [18]. CD4+ T cell counts were unchanged, and no changes in the CD4+/CD8+ T cell ratios were detected in the patients. In this study, toxicities related to the use of G-CSF were limited to transient bruising and inflammation at the sites of injection. Flulike symptoms were not reported. Palpable splenomegaly was detected in 16 patients. The only adverse effect associated with the administration of erythropoietin was the development of transient and mild local skin irritation at the injection site, and this was observed in seven patients. GM-CSF. The first study that demonstrated the benefit of GM-CSF in patients with AIDS was reported by Groopman et a1. in 1987 [19]. In this study, three to four patients per dose level received GM-CSF by continuous infusion for 14 days at dosages ranging from 0.5 to 8.0 ILg/[kg·d]. Results of the study showed that in these patients granulocyte counts increased in response to GM-CSF in a dose-responsive manner. As shown in figure 1, at a dosage of 4.0 ILg/[kg'd], the increase in the leukocyte count was reflected primarily in mature neutrophils, neutrophilic bands forms, monocytes, and eosinophils. A study using long-term administration of GM-CSF has shown that the leukocyte count can be kept in a normal or targeted range without evidence of marrow exhaustion [20] . The dosage of GM -CSF that is needed to main-

tain leukocyte counts in the normal range in patients with AIDS is relatively low compared with that needed for patients with cancer who are undergoing cytotoxic chemotherapy. This may reflect a heightened sensitivity to the hematopoietic stimulatory effects of this drug. The adverse effects of GM-CSF are similar to the flulike symptoms associated with interferon [19]. These include myalgia, fatigue, and, in some patients, fever. In addition, local erythema may be seen in many patients, especially in those who are receiving higher dosages [19]. Erythema is transient, however, and tends to dissipate as therapy with the drug is continued. This may reflect the inhibitory effect of neutrophil migration that is associated with the use of GM-CSF [19]. A potential drawback to the use of GM-CSF and other macrophage-stimulating agents is the concern that macrophage activation in Hlv-infected individuals may promote HIV replication. Data reported by Koyanagi et a1. [21] support this concern and show that these agents can produce a three- to fourfuld increase in HIV replication in vitro when monocytes infected with a monocytotropic strain of HIV are exposed to increasing concentrations ofthe macrophage-stimulating agents . On the other hand, agents such as G-CSF, which has little effect on monocyte and macrophage functions, appear to have little effect on HIV replication in vitro (figure 2). In phase IIll clinical trials of GM -CSF, however, there have been no consistent or persistent changes in measurable parameters of HIV replication when GM-CSF was given as a single agent [19, 20]. Indeed, in vitro studies have shown that GM-CSF can increase the uptake and phosphorylation of several thymidine and uridine nucleoside analogues in HIVinfected T cells and monocytes, results suggesting that the therapeutic index of nucleoside analogues such as zidovudine may be enhanced in patients treated with GM-CSF [22]. Several studies in which combinations of zidovudine and GM CSF were investigated have been completed [23, 24]. Another potential use of GM-CSF is the enhancement of leukocyte function , which may increase host defenses against infections. Most patients with HIV disease have normal neutrophil function; however, in patients who have defects, normal activity can be restored with administration ofGM-CSF [25]. A number of studies have been initiated in which GM-CSF is used as adjunctive therapy with a variety of drugs that have marked myelosuppressive effects. These agents include zidovudine ; ganciclovir; ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine); interferon-a; CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone); and mBACOD (bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone) [26]. It is believed that the use of hematopoietic growth factors, in conjunction with these myelosuppressive agents, will allow increased dose intensity and result in prolonged or more-effective therapeutic effects. To date, however, there is insufficient evidence to indicate that increased dose intensity will lead to a more-effective response in patients who receive these myelosuppressive agents.

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Figure 1. The total leukocyte countanddifferential bloodcell count of a patient with AIDS who was treated with recombinant human GM-CSF. A dosageof 1.0 x 1()4 UI[kg'd] was administered by bolus intravenous infusionover 60 minuteson day 1 and was followed by continuous infusion from day 3 to day 17. The total leukocyte count is represented by the uppermost line. Shaded areas represent relativecomponentsof the total leukocytecount at each time point. Modified and reprinted with permission from [19] .

RID 1991;13 (September-October)

RID 1991;13 (September-October)

Interferons and Growth Factors in AIDS

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pressive effects of antibiotics and chemotherapy. The effects of these agents on HIV replication are still controversial and may vary depending on the state of disease, concomitant medications or illnesses, and the cell culture system that is used for assessment. Many studies are in progress involving several different disease states to determine if amelioration of neutropenias by the use of colony-stimulating factors (i.e., G-CSF and GMCSF) translates into improved control of infections or tumors in addition to improved survival. The role of these cytokines as immune enhancers will need to be explored further in conjunction with other effective antiretroviral therapy and with other treatments for opportunistic infections. The next few years offer researchers many opportunities to use these powerful agents to control the adverse consequences of HIV infection and other life-threatening diseases. References

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Figure 2. Kinetics of HIV production in infected mononuclear phagocyte cultures treated with GM-CSF, macrophage colonystimulating factor (M-CSF), and interleukin-3 (IL-3). G-CSF, bovine serum albumin (BSA), and medium alone are shown in nanograms of p24 antigen per milliliter, which is based on p24 antigen standards. One representative experiment is shown. Primary human mononuclear phagocytes were prepared and incubated for 3 days. On day 3, these cells were removed with use of OKT3 monoclonal antibody and rabbit complement. On day 4, these cells were infected with HIV JR-FL that was isolated at a level of 500 ng of HIV type 1 p24 antigen per 5 x 106 cells grown in culture in the presence of hexadimethrine bromide. On day 5, cells were removed from the plates and seeded into 96-well plates at a density of 3 x 1()4 cells/well. Growth factors (GM-CSF, 100 pM; M-CSF, 1 nM; IL-3, 100 pM; and G-CSF, 100 pM) were added to cells in duplicate wells. BSA (0.001 %) and medium alone were used as controls. Medium with growth factors was changed every 3 or 4 days, and virus was assayed on days 4, 7, and 14 after infection. Reprinted with permission [21].

Conclusion The recombinant cytokines are generally well tolerated in patients with HIV disease. Recombinant interferon-a plays a clear role in the therapy for patients with KS and may have significant antiretroviral effects. The recombinant hematopoietic growth factors G-CSF, GM-CSF, and erythropoietin can correct neutropenia and anemia that are associated with HIV infection and may prove useful in ameliorating the myelosup-

1. Krown SE, Real FX, Cunningham-Rundles S, Myskowski PL, Koziner B, Fein S, Mittelman A, Oettgen HF, Safai B. Preliminary observations on the effect of recombinant leukocyte A interferon in homosexual men with Kaposi's sarcoma. N Engl J Med 1983;308:1071-6 2. Krown SE, Real FX, Vadhan-Raj S, Cunningham-Rundles S, Krim M, Wong G, Oettgen HE Kaposi's sarcoma and acquired immunodeficiency syndrome. Treatment with recombinant interferon alpha and analysis of prognostic factors. Cancer 1986;57(Suppl 8):1662-5 3. Volberding PA, Mitsuyasu RT, Golando JP, Spiegel RJ. Treatment of Kaposi's sarcoma with interferon alfa-2b (Intron A). Cancer 1987; 59(Suppl 3):620-5 4. Evans LM, Itri LM, Campion M, Wyler-Plaut R, Krown SE, Groopman JE, Goldsweig H, Volberding PA, West S, Mitsuyasu RT. Interferon alfa-2a in the treatment of AIDS-related Kaposi's sarcoma. J BioI Response Mod (in press) 5. Gelmann EP, Preble ar, Steis R, Lane HC, Rook AH, Wesley M, Jacob J, Fauci A, Masur H, Longo D. Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immunodeficiency syndrome. Am J Med 1985;78:737-41 6. Krown SE. Type I interferons (alpha and beta) in HIV disease. Biotherapy 1990;2:137-47 7. Vadhan-Raj S, Wong G, Gnecco C, Cunningham-Rundles S, Krim M, Real FX, Oettgen HF, Krown SE. Immunological variables as predictors of prognosis in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome. Cancer Res 1986;46:417-25 8. Lopez C, Fitzgerald PA, Siegal FP. Severe acquired immune deficiency syndrome in male homosexuals: diminished capacity to make interferon-a in vitro associated with severe opportunistic infections. J Infect Dis 1983;148:962-6 9. Hersh EM, Gutterman JV, Spector S, Friedman H, Greenberg SB, Reuben JM, LaPushin R, Matza M, Mansell pw. Impaired in vitro interferon, blastogenic, and natural killer cell responses to viral stimulation in acquired immune deficiency syndrome. Cancer Res 1985;45:406-10 10. Murray HW, Rubin BY, Masur H, Roberts RB. Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med 1984;310:883-9 11. Lane HCC, KovacsJA, Feinberg J, Herpin B, Davey V, Walker R, Deyton L, Metcalf JA, Baseler M, Salzman N. Antiretroviral effects of interferon-alpha in AIDS-associated Kaposi's sarcoma. Lancet 1988; 2:1218-22 12. Friedland GH, Klein RS, Saltzman BR, Vileno JL, Landesman S, Hol-

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man S, Hirsch MS, Schooley RT, Flynn T, Byington R, Crumpacker C, Hussey S, Handsfield HH, Collier AC, Nadler P, Pizzuti D, Soo W, Wlodkowski T. Scheer R. A randomized placebo-controlled trial of recombinant human interferon alpha 2a in patients with AIDS. J Acquir Immune Defic Syndr 1988;1:111-8 Lane HC, Davey V, KovacsJA, Feinberg J, Metcalf JA, Herpin B, Walker R, Deyton L, Dayton RTJr, Falloon J, Polis MA, Salzman NP, Baseler M, Masur H, Fauci AS. Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med 1990;112:05-11 Miles SA, Wang HJ, Cortes E, Carden J, Marcus S, Mitsuyasu RT. Betainterferon therapy in patients with poor-prognosis Kaposi's sarcoma related to the acquired immunodeficiency syndrome (AIDS). A phase II trial with preliminary evidence of antiviral activity and low incidence of opportunistic infections. Ann Intern Med 1990;112:582-9 Murray HW. Interferon gamma therapy in AIDS for mononuclear phagocyte activation. Biotherapy 1990;2:149-58 Fischl M, Galpin JE, Levine JD, Groopman JE, Henry DH, Kennedy P, Miles S, Robbins W, Starrett B, Zalusky R, Abels RI, Tsai HC, Rudnicks SA. Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 1990;322:1488-93 Miles SA, Mitsuyasu RT, Lee K, Moreno J, Alton K, Egrie JC, Souza L, Glaspy JA. 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 1990;75:2137-42 Miles SA, Mitsuyasu RT, Moreno J, Baldwin G, Alton NK, Souza L, Glaspy JA. Combined therapy with recombinant G-CSF and erythropoietin decreases hematologic toxicity from zidovudine. Blood 1991;77:2109-17 Groopman JE, Mitsuyasu RT, DeLeo MJ, Oette DH, Golde DW. Effect of recombinant human granulocyte-macrophage colony-stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Engl J Med 1987;317:593-8

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20. Mitsuyasu R, Levine J, Miles SA, DeLeo M, Oette D, Golde D, Groopman 1. Effectsof long term subcutaneous (SC) administration of recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with HIV-related leukopenia [abstract]. Blood 1988; 72(Suppl 1):356a 21. Koyanagi Y, O'Brien WA, Zhao JQ Golde DW, Gasson JC, Chen IS. Cytokines alter production of HIV-l from primary mononuclear phagocytes. Science 1988;241:1673-5 22. Perno CF, Yarchoan R, Cooney DA, Hartman NR, Webb DS, Hao Z, Mitsuya H, Johns DG, Broder S. Replication of human immunodeficiency virus in monocytes. Granulocyte/macrophage colonystimulating factor (GM-CSF) potentiates viral production yet enhances the antiviral effect mediated by 3'-azido-2:3' -dideozythymidine (AZT) and other dideoxynucleoside congeners of thymidine. J Exp Med 1989;169:933-51 23. Fischl MA, Uttamchandani R, Gagnon S, Thompson L, Santiago S. Phase I study of interferon alpha-2b (Intron), zidovudine, and rGM-CSF in patients with AIDS-associated Kaposi's sarcoma [abstract no. T.B.P. 331]. In: Abstracts of the 5th International Conference on AIDS. Ottawa: International Development Research Centre, 1989:342 24. Scadden D, Bering H, Levine J, Allen D, Bresnahan J, Epstein C, Evans L, Groopman 1. Combined AZT/interferon-alpha/GM-CSF for AIDSassociated Kaposi's sarcoma (KS) [abstract]. Blood 1989;74(Suppl 1):127a 25. Baldwin GC, Gasson JC, Quan SG, Fleischmann J, Weisbart R, Oette D, Mitsuyasu RT, Golde DW. Granulocyte-macrophage colonystimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proc Natl Acad Sci USA 1988;85:2763-6 26. Mitsuyasu R. Hematopoietic growth factors in the treatment of patients with HIV infection. Biotherapy 1990;2:173-81

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