D. T. S c a d d e n

The Use of GM-CSF in AIDS Introduction Summary: Hematopoietic growth factors may mitigate the cytopenias that frequently complicate HIV disease or its treatment. Clinical and in vitro studies have indicated the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO) to overcome the myelosuppression of HIV or many of the drug therapies used in the care of HIV-infected individuals. In addition, neutrophil or monocyte functional abnormalities observed in AIDS patients may be improved by the use of GM-CSF. Issues which may distinguish the use of hematopoietic growth factors in AIDS as compared with in other clinical settings include: 1) interaction of the growth factor with other cytokines which are aberrantly expressed, 2) direct effects of the growth factor on the replicative activity of HIV, and 3) potential interactions of the growth factor with other concurrently administered medications. This review focuses on the potential roles and limitations of growth factor use in AIDS and reviews the clinical studies using GM-CSF in HIV-infected individuals.

Zusammenfassung:Anwendung von GM-CSF bei AIDS. Zytopenien, die h~iufig als Komplikation der HIV-Infektion und ihrer Therapie auftreten, lassen sich durch hfimatopoietische Wachstumsfaktoren abschw/ichen. Nach klinischen und In vitro-Studien haben GM-CSF (Granulozyten und Makrophagenkoloniestimulierender Faktor), G-CSF (Granulozytenkoloniestimulierender Faktor) und EPO (Erythropoietin) die Ffihigkeit, die durch HIV oder viele der in der Behandlung HIV-Infizierter eingesetzten Medikamente hervorgerufene Myelosuppression aufzufangen. AuBerdem kann GM-CSF funktionelle Anomalien der neutrophilen Granulozyten oder Monozyten, die bei AIDS-Kranken beobachtet werden, bessern. In der Anwendung h/imatopoietischer Wachstumsfaktoren bei AIDS-Patienten und anderen klinischen Umst~inden bestehen folgende Unterschiede: 1. Interaktion der Wachstumsfaktoren mit anderen aberrant exprimierten Zytokinen; 2. Direkte Wirkungen der Wachstumsfaktoren auf die Replikationsaktivit/it von HIV; 3. M6gliche Interaktionen mit anderen Begleitmedikationen. In der folgenden Ubersicht sollen die M6glichkeiten und Grenzen im Einsatz h/imatopoietischer Wachstumsfaktoren bei AIDS umrissen und klinische Studien mit GM-CSF bei HIV-Infizierten zusammengefagt dargestellt werden.

The use of hematopoietic growth factors in HIV disease is theoretically appealing because of the cytopenias, blood cell dysfunction and chronic myelosuppressive therapies that frequently accompany HIV [1]. Low blood cell counts complicate the clinical care of AIDS patients by restricting the use of drug therapies for HIV or its complications. Growth factors may mitigate the problem of reduced blood cell counts. The pathophysiology of cytopenia in HIV disease may be complex and particular attention should be paid to suppression of hematopoiesis secondary to mycobacterial, fungal, cytomegalovirus (CMV) or, rarely, parvovirus infection. Also infiltration of the bone marrow by neoplasms such as non-Hodgkin's lymphoma may occur. In the absence of secondary causes of low blood cell counts, multifactorial disturbances of he~atopoiesis may be present. These include direct interaction of HIV with blood cell progenitors [2-7], indirect effects of the virus on the bone marrow microenvironment [8, 9] or alterations in immune function leading to enhanced destruction of blood cells [10-13]. Dysplastic morphologic features common in the bone marrows of HIV-infected persons [14, 15] have suggested a possible direct effect of HIV on early blood cells. However, whether HIV infects blood cell progenitors in vivo remains highly controversial. Differentiated cells such as megakaryocytes [16, 17] and cells of monocytemacrophage lineage [4, 18] are permissive of HIV infection. Erythroid and granulocytic cells have not been documented to be HIV positive. If early bone marrow progenitors are infected it appears to occur with low frequency and does not impair the ability of these cells to respond to growth factors in vitro [3, 6, 12]; a phenomenon borne out by subsequent clinical experience. Microenvironmental changes within the bone marrow have been postulated. This may be due to the dysregulated expression of cytokines critical for maintaining normal hematopoiesis by T cells, macrophages or mesenchymally derived cells [9] infected by HIV. However, in vitro experimental data in this area are controversial with a number of reports indicating a lack of effect of HIV on cytokine expression in mononuclear cell populations [19, 20]. In contrast, there are several reports of abnormal cytokine levels in the serum of HIV-infected individuals including erythropoietin (EPO) [21], interleukin-6 [22], D. T. Scadden, M. D., Div. of Hematology/Oncology,Dept. of Medicine,

New England Deaconess Hospital, Harvard Medical School, Boston, MA, USA. Correspondence to: D. T. Scadden, M. D., 110 Francis Street, Suite 4A, Boston, MA, USA.

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D. T. Scadden: GM-CSF in AIDS transforming growth factor-beta [23] and tumor necrosis factor-alpha (TNF) [24]. How these alterations affect hematopoiesis in these patients is not clear, nor is it apparent that they alter the responsiveness to exogenously administered growth factors. To date no unexpected hematological responses have distinguished growth factor use in this population. However, as the clinical use of growth factors is refined and earlier acting growth factors are developed, altered clinical responses may become apparent. In addition to alterations in cell numbers, the function of mature blood elements may be impaired in HIV disease. Abnormal granulocyte intracellular killing and phagocytosis [25], macrophage defects and impaired Fc-mediated clearance [26] have been reported. It is not yet known whether the abnormalities in mature cell function are associated with an increased clinical susceptibility to encapsulated organisms or intracellular microbial infection. Abnormal Fc clearance may paradoxically play a role in maintaining blood counts in HIV-infected patients, many of whom have antibody coating of blood cells; decreased clearance of these cells by a dysfunctional reticuloendothelial system (RES) [26] may improve cell survival. Stimulation of RES function by growth factors may theoretically induce undesirable effects on cell clearance or may enhance uptake of HIV using antibody dependent mechanisms [27]. The potential for growth factors to improve host defense against opportunistic infection or HIV [28] may offset these issues, however. Unique Aspects of Growth Factor Use in AIDS

A potentially important consideration for the use of growth factors in AIDS is the evidence for a direct interaction between growth factors and HIV replication. The data are controversial and appear to be dependent upon the viral strain and the cell culture system used [29, 30, 31]. However, stimulation of HIV replication by GM-CSF and, to a lesser extent, macrophage colonystimulating factor and IL-3, has been documented in adherent mononuclear cell systems. Similar results have been reported with interleukin-6 and TNF [32, 33]. Notably, G-CSF has not been shown to induce HIV replication [30]. The in vivo data regarding growth factor effects on HIV are conflicting. Studies employing GM-CSF alone [34] or in conjunction with ganciclovir [35] did not observe consistent effects on serum HIV p24 antigen levels. In contrast, a study alternating GM-CSF and zidovudine [36] and a trial employing GM-CSF in AIDS lymphoma chemotherapy [37] reported evidence for enhanced p24 expression with GM-CSF use. In the lymphoma trial, patients receiving GM-CSF had a more rapid rise in serum HIV p24 antigen levels following chemotherapy than controls. However, when chemotherapy was completed the serum p24 antigen levels relative to baseline were not significantly different in the two groups. The phenomenon S 104

of HIV stimulation by GM-CSF remains ill-defined and no adverse clinical events have been associated with the change in p24 antigen levels. However, this is a potential area of concern with growth factor use in AIDS. Another area in which growth factor use in AIDS may differ from other settings is in the interaction with other drugs. Unlike patients who receive hematopoietic growth factors following cancer chemotherapy or bone marrow transplantation, HIV-infected patients are likely to receive these factors while continuing to receive myelosuppressive drugs. Growth factors are added to chronically administered regimens for HIV or its complications in an effort to mitigate otherwise doselimiting cytopenias. Therefore, interactions between growth factors and anti-infective or neoplastic medications need to be considered and laboratory data suggests that some of these interactions may be substantial. Indeed some interactions may provide therapeutic opportunities. In mononuclear cell systems, the anti-HIV effect of zidovudine has been potentiated by tenfold or greater in the presence of GM-CSF. GM-CSF apparently increases intracellular concentrations of zidovudine and may augment zidovudine phosphorylation [31, 38, 39]; this has not been accompanied by increased cellular toxicity [39, 40]. Similar effects have been reported with interleukin-3 [39], though not all hematopoietic growth factors have this property. In addition, the effect of GM-CSF is not generalizable to all nucleoside analogues: dideoxyinosine (ddI) and dideoxycytidine (ddC) are not similarly affected [31]. Taking therapeutic advantage of the pharmacodynamic effects of GM-CSF on zidovudine may be an area of future investigation. Clinical Experience with GM-CSF in AIDS

GM-CSF, Epo and G-CSF have been tested in HIV infection and IL-3 is currently in clinical trial. GM-CSF was demonstrated to improve the white blood cell count and absolute neutrophil count in neutropenic patients with AIDS [34]. A subsequent study using subcutaneous GM-CSF for longer periods of time in patients who were neutropenic while on zidovudine demonstrated the ability of GM-CSF to improve the absolute neutrophil count at doses 1-5 ~tg/kg/d [41]. Flu-like symptoms, local erythema at the site of injection and eosinophilia were common. In addition, five of 17 patients developed thrombocytopenia. Whether the thrombocytopenia was a result of zidovudine myelosuppression unmasked due to GM-CSF overcoming otherwise dose-limiting neutropenia, a direct effect of GM-CSF on thrombopoiesis or an improved RES clearance of platelets is unknown. GM-CSF also was shown to mitigate the neutropenia induced by combined zidovudine and interferon-a (IFN) in the treatment of AIDS patients with Kaposi's sarcoma [42]. It was able to overcome this major dose-limiting toxicity of the combined therapy without evidence for tachyphylaxis or anti-GM-CSF antibody generation with up to 15 months of daily GM-CSF therapy. GM-CSF may

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D. T. Scadden: G M - C S F in A I D S

offer an alternative to dose reduction of zidovudine/IFN in this setting. In AIDS associated non-Hodgkin's lymphoma, GM-CSF was given in a randomized fashion to patients receiving CHOP chemotherapy [37]. There was improvement in the period of neutropenia, number of days of fever and antibiotics and reduced delay of chemotherapy due to neutropenia in the GM-CSF treated group. CMV disease is a complication of HIV infection that is increasing in frequency in the U.S. and commonly causes loss of vision due to retinitis. Ganciclovir is a frequently used therapy for CMV retinitis in the U.S. and is highly myelosuppressive in the AIDS population. A recently completed, randomized trial compared ganciclovir with ganciclovir plus GM-CSF for AIDS patients with CMV retinitis. Preliminary results indicated a reduction in the period of neutropenia and an improved dose delivery of ganciciovir in the GM-CSF treated cohort [35]. Data on preservation of vision await further analysis. Although the ganciclovir trial data are encouraging, whether GM-CSF is capable of improving survival or quality of life parameters for patients with Kaposi's sarcoma, zidovudine induced neutropenia or nonHodgkin's lymphoma awaits further clinical testing. Among AIDS patients treated with GM-CSF who had a documented abnormality of neutrophil function, improvements of intracellular killing and phagocytosis with the use of GM-CSF have been observed [25]. The clinical trial in which this was noted was not designed to test the clinical effects of these changes. However, these data support the potential for GM-CSF in this role. Future Directions for GM-CSF in AIDS

Clinical trials of GM-CSF in HIV-infected patients have to date focused primarily on an adjunctive role for this growth factor for patients who become neutropenic on other medications and measured parameters of safety or hematologic effect. More recent trials and trials in preparation are designed to test the capacity of GM-CSF

to affect more clinically significant end points such as quality of life, survival or infectious events. An area of possible future development for GM-CSF, outside of abrogating cytopenias, is to manipulate the interactions of GM-CSF with HIV and anti-HIV drugs to therapeutic advantage. It may be possible to translate the in vitro noted enhancement of zidovudine antiviral potency in the presence of GM-CSF into clinical benefit. Further, might it be possible to use the HIV stimulatory effects of GM-CSF to augment the sensitivity of the virus to other antiretroviral drugs in much the same way that GM-CSF is being used in experimental anti-leukemic therapy? Addressing these issues is only now becoming possible as better assays for measuring in vivo HIV replicative activity are being developed. The capacity of GM-CSF to enhance mature cell function, such as intracellular killing of bacterial or fungal organisms by granulocytes or monocyte macrophages, may offer a further clinical application in AIDS. The observed reversal of impaired neutrophil function in patients receiving GM-CSF supports the possible clinical application of growth factors to augment host response. It may be possible to exploit GM-CSF's effects on mature cells [43-46] to improve the outcome of patients infected with mycobacterial or fungal organisms. Finally, progressive HIV disease is associated with the inexorable loss of CD4+ lymphocytes. Although it is unlikely, that GM-CSF directly participates in lymphopoiesis, the use of early acting growth factors and combinations of growth factors to achieve changes in lymphocyte numbers is a direction for future investigation. At present, GM-CSF and other hematopoietic growth factors are envisioned in a primarily adjunctive role, supportingblood counts during periods of myelosuppressive drug therapy. Growth factors acting in HIV disease to augment therapeutic properties of drugs, to enhance host defense against opportunistic pathogens or to restore lymphocyte populations are exciting areas for future research.

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Infection 20 (1992) Suppl. 2 © MMV Medizin Verlag GmbH Mtinchen, Mfinchen 1992

The use of GM-CSF in AIDS.

Hematopoietic growth factors may mitigate the cytopenias that frequently complicate HIV disease or its treatment. Clinical and in vitro studies have i...
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