Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine

Abstract

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G- CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.

Antiviral therapy: current concepts and practices.

“…The same investigators also identified two patients with defective bacterial killing mechanisms (one in phagocytosis and one in intracellular killing), but these, too, appeared to be corrected by GM-CSF (14). Subsequent studies have shown both G-CSF and GM-CSF to be very effective in correcting the neutropenias seen with zidovudine therapy alone (311) or combined with interferon, and the two CSFs have allowed treatment to continue in patients otherwise unable to tolerate it because of bone marrow toxicity (92,408). This has been true of patients with advanced (408) as well as early (92) HIV disease.…”

Biological response modifiers and infectious diseases: Actual and potential therapeutic agents

“…Patients with AIDS may undergo primary bone marrow failure or myelosuppression due to antiviral or supportive anti-infection therapy. G-CSF has demonstrated marked improvements in neutrophil counts in patients with anemia and neutropenia also receiving erythropoietin and zidovudine [41]. Such therapy allowed further treatment with zidovudine after zidovudine-induced myelosuppression was corrected.…”

The utilization of humanized mouse models for the study of human retroviral infections

“…After the intravenous or intraorgan infection with HIV-1, only human cells were infected and from these, only CD4+ T and myelomonocytic cells. Initial HIV-1 infections of SCID-hu Thy/Liv animals resulted in a near-eradication of CD4+/CD8+ DP thymocytes and a decrease in the CD4+ SP T cell population of the human implanted tissue [ 77 , 87 , 88 ], a depletion shown to be reduced upon treatment with several anti-HIV compounds [ 89 - 93 ] (Table 3 ).…”