Page 2550 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 157 Hematologic Manifestations of HIV/AIDS 2273

The most common causes of neutropenia in HIV infected patients Sargramostim or GM-CSF (Leukine) and filgrastim or G-CSF
are medication-related myelosuppression. In a study of 87 consecu- (Neupogen), are the primary pharmacologic agents used in the treat-
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tive HIV-infected patients with neutrophil counts of <2 × 10 /L, only ment of severe neutropenia in HIV-infected patients and have been
three patients were not receiving medications associated with a risk shown in clinical studies to be safe and effective. A long-term study
of neutropenia and 66% were receiving three or more myelosuppres- of 105 HIV-infected patients randomized to receive weekly injections
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sive medications. Neutropenia is a common complication reported of GM-CSF (125 µg/m ) or placebo while receiving zidovudine
with many of the drugs used to treat opportunistic infections such antiretroviral therapy reported after 6 months of treatment that
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as Pneumocystis carinii, toxoplasmosis or CMV infection. These GM-CSF treated patients were more likely to have a HIV plasma
medications are listed in Table 157.4. Although neutropenia resulting RNA level below level of detection and less zidovudine resistance
from HIV-related myelosuppression often improves with HAART, mutations. A study of 123 HIV-infected leukopenic patients treated
antiretroviral-associated neutropenia can be observed with higher with GM-CSF treated for 12 weeks were compared with 121
doses of zidovudine. Zidovudine-associated neutropenia resolves with untreated leukopenic patients showed the total leukocyte count
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dose reduction or discontinuation of the medication. In a study of including neutrophils and monocytes increased by 65% at week 12
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62 HIV-infected patients with neutrophil counts of 1 × 10 /L or less, when compared with baseline values (p < .001). In the untreated
cancer chemotherapy, zidovudine, trimethoprine-sulfamethoxazole leukopenic HIV-infected patients, the total leukocyte count decreased
and ganciclovir were the medications most commonly responsible for by 24% below baseline values at week 12 (p < .001). Common side
neutropenia. In the same report, medication-related neutropenia effects of treatment with GM-CSF include fever, fatigue, myalgias,
associated with infection was most often seen in the patients receiving bone pain and headache.
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cancer chemotherapy. Rare cases of agranulocytosis have been A randomized study of 258 HIV-infected patients with CD4
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reported with the use of the antiretroviral drugs, abacvir and lymphocyte counts below 0.2 × 10 /L and neutrophil counts of <1
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indinavir. × 10 /L were randomized to one of two dose regimens of G-CSF
Neutropenia is often observed in patients with bone marrow (1 µg/kg/day or 300 µg three times a week) versus no treatment.
involvement by opportunistic infections such as Mycobacterium Patients in the control group who developed severe neutropenia (<0.5
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avium or CMV. Bone marrow involvement with HIV-associated × 10 /L) were then randomized to one of the treatment regimens.
malignancies and their subsequent treatment can also result in sig- The intention-to-treat analysis found the incidence of severe neutro-
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nificant and prolonged neutropenia. However, malignancy treatment- penia (<0.5 × 10 /L) was 1.7% in the treated group versus 22% in
related neutropenia in clinical trials appears to be less severe in the untreated controls. The incidence of bacterial infections was 31%
patients receiving simultaneous HAART. lower in the treated group, with fewer severe bacterial infections
and significantly few hospital days (45% reduction) for bacterial
infections.
Abnormalities of Neutrophil and Monocyte Function The use of G-CSF has been associated with a reduction in severe
neutropenia in patients treated for CMV infection with ganciclovir
A number of acquired functional defects have been described in both (Cytovene), but the evidence is unclear as to whether it offers a clear
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neutrophils and monocytes from patients with HIV infection. Many clinical benefit. However, in general it has been shown to be safe
of these defects are observed in patients with advanced disease with and effective in raising leukocyte counts when administered to
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high levels of plasma viral RNA and CD4 lymphopenia. Impaired patients with HIV infection receiving antiretroviral therapy. 7,19
chemotaxis and reduced expression of leukocyte adhesion molecules G-CSF is indicated for drug-induced, cancer-related and HIV-related
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necessary for migration of neutrophils to sites of infection have been neutropenia with an ANC of less than 0.5 × 10 /L cell/mcl. The
reported. Decreased opsonization of antibody coated bacteria because initial dose is 1–10 µg/kg/day and should be titrated by 1 µg/kg/day
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of Fc receptor dysfunction and decreased superoxide production to obtain a neutrophil count of 1.0 × 10 /L. Most patients will
necessary for optimal intracellular killing of bacterial and fungal respond to a dose of 1 µg/kg/day. G-CSF usage should be carefully
organisms have been observed in both neutrophils and macrophages monitored and the dose reduced or stopped when the neutrophil
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from HIV-infected patients. Defective intracellular killing of myco- count exceeds 1.0 × 10 /L.
bacterial and fungal organisms may also be caused in part by defective
production of IFN-γ.
THROMBOCYTOPENIA IN HIV INFECTION
Management of Neutropenia in HIV-Infected Patients Thrombocytopenia, alone or in association with anemia and/or
leucopenia, is frequently seen in approximately 40% of HIV-infected
Impact of HAART and Use of Granulocyte- patients in the course of their disease. Thrombocytopenia has been
Macrophage–Colony Stimulating Factor and reported to be the first sign of HIV infection in up to 10% of infected
individuals. The most common cause of thrombocytopenia in HIV
Granulocyte-Colony Stimulating Factor infection is HIV-related autoimmune thrombocytopenia, which is
clinically indistinguishable from classic immune thrombocytopenia
Treatment of neutropenia should be guided by the underlying cause. (ITP).
This may require treatment of active infection or removal of medica- An association between AIDS and ITP was described before HIV
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tions associated with the development of neutropenia. The use of had been isolated and characterized. HIV infects CD4 lymphocytes,
HAART has clearly been shown to reduce the risk of developing monocytes, and macrophages, and some experimental evidence also
leukopenia and neutropenia and significantly increasing the neutro- documents infection of megakaryocytes. Although a number of dif-
phil counts in treated patients. The Women’s Interagency HIV Study ferent mechanisms have been reported by which HIV infection can
of 1729 HIV-infected women found that the use of HAART, without produce thrombocytopenia, the ability of effective antiretroviral
zidovudine, was associated with protection against developing neu- therapy to improve platelet counts demonstrates a clear relationship
tropenia. In addition, HAART, even incorporating zidovudine, was between viral replication, the expression of viral related proteins, and
associated with resolution of neutropenia in women with advanced the host response to platelets.
HIV disease. Another study of 66 HIV-infected patients treated with
HAART reported statistically significant increases in total leukocyte
and neutrophil counts after 6 months of treatment. These studies Epidemiology
support the use of effective HAART as the initial approach to the
management of mild to moderate leukopenia and neutropenia in Thrombocytopenia was first associated with AIDS before the
HIV infected patients. discovery of HIV. Before the use of HAART, HIV-associated