Page 2549 - Hematology_ Basic Principles and Practice ( PDFDrive )

2272 Part XIII Consultative Hematology

degree of enzyme deficiency, patients may not have had a previous response to erythropoietin, as observed in anemia of acute and chronic
documented episode of hemolysis. G6PD deficiency–associated inflammation, is common in HIV-infected patients with anemia.
hemolysis can occur in HIV infected patients who are taking dapsone However, erythropoietin (Epogen; Procrit) therapy should be consid-
or trimethoprim and sulfamethoxazole combinations for pneumocys- ered for refractory anemia in symptomatic patients with a hemoglobin
tis prophylaxis or treatment. In some patients, the degree of hemolysis level of <11 g/dL in men and <10 g/dL in women. The primary goal
does not result in significant anemia because RBC destruction is well should be to maintain quality of life and functional status. Many
compensated by effective RBC production and patients can continue patients may be asymptomatic with lower hemoglobin (9–10 g/dL)
on treatment. However, patients with the Mediterranean form of and physicians should use erythropoietic agents only for symptomatic
G6PD may develop severe hemolysis, and treatment with such medi- patients with these lower hemoglobin levels. The initial adult dose is
cations is contraindicated. 40,000 units subcutaneously per week, which has been shown to be
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Extrinsic causes of RBC hemolysis observed in patients with HIV equivalent to treatment three times a week at 100 to 200 U/kg. Also
infection include microangiopathic hemolytic disorders such as darbepoetin alfa given at a dose of 3.0 µg/kg every 2 weeks has been
thrombotic thrombocytopenic purpura (TTP, discussed in the section shown to be as equally effective. Onset of action as characterized by
on thrombocytopenia), vasculitis, or disseminated intravascular an increase in the reticulocyte count is within 1 to 2 weeks, with
coagulation. Patients will have associated thrombocytopenia and increased hemoglobin noted in 2 to 6 weeks. The baseline level of
demonstrate RBC fragmentation on the peripheral blood smear. endogenous serum erythropoietin has been shown to be predictive of
Autoimmune hemolytic anemia rarely occurs in HIV-infected indi- response to the therapeutic use of erythropoietin. A baseline erythro-
viduals, although a positive antiglobulin (Coombs) test is not uncom- poietin level of greater than 500 IU/L is associated with a significantly
mon. Patients with documented autoimmune hemolysis may respond lower response to treatment. Response to erythropoietin therapy also
to treatment with corticosteroids, rituximab, or splenectomy. The risk depends on the severity of anemia, presence of active infection and
of HIV progression with the use of corticosteroids and rituximab does available iron stores. If hemoglobin fails to increase more than 1 g/dL
not appear to be an issue in patients receiving HAART. after 4 weeks of therapy, the dose may be increased to 60,000 units
weekly. After an additional 4 weeks, if hemoglobin does not increase
Impact of Anemia on HIV Disease Progression by at least 1 g/dL from baseline, therapy should be discontinued.
When combined with the use of HAART, erythropoietin treatment
and Survival may result in a more rapid improvement in hemoglobin, but has not
been shown to improve survival or statistically reduce the total number
Anemia has been shown to be an independent risk factor for clinical of transfusions. This may be because of the marginal contribution that
progression of HIV disease. In a patient in whom HAART is to be erythropoietin supplementation may have in the background of the
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initiated, anemia, CD4 cell count <0.2 × 10 /L, HIV viral load, and significant improvement in immune status and bone marrow function
a pretreatment diagnosis of clinical AIDS are well established risk provided by effective antiretroviral therapy. 15
factors for rapid disease progression. A moderate anemia of 8 to 14 g/
dL in men or 8 to 12 g/dL in women is associated with a relative
hazard of disease progression or death of 2.2 (95% confidence interval LEUKOPENIA AND NEUTROPENIA: INCIDENCE
[CI], 1.6–2.9), p < .0001), whereas a more severe anemia of less than AND PATHOGENESIS
8 g/dL has a relative hazard of 7.1 (95% CI, 2.5–20.1, p < .0002).
Anemia has a significant impact on overall survival in HIV-infected Leukopenia is common in patients with advanced HIV infection
patients. A Baltimore study of 2348 HIV-infected patients found that occurring in up to 85% of patients with clinical AIDS. In such
a hemoglobin of 6.5 to 8 g/dL was predictive of a threefold risk of death patients, low WBC counts are frequently a result of both decreased
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and a hemoglobin of <6.5 g/L was predictive of a fourfold increased lymphocytes and neutrophils. Neutropenia (<1.5 × 10 /L) is reported
risk of death. A European study of 6725 HIV-infected patients found in 5% to 10% of HIV-infected patients with the highest prevalence
the hemoglobin level at baseline was an independent prognostic factor in patients with advanced HIV infection (AIDS). In a 7.5-year lon-
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for survival along with the CD4 lymphocyte count and HIV plasma gitudinal study of 1729 women with HIV infection an absolute
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viral load. For each 1 g/dL decrease in hemoglobin level, the relative neutrophil count (ANC) of less than 1 × 10 /L was documented in
hazard of death was 1.39 (95% CI, 1.34–1.43; p < .0001). Additional 31%. HIV-related risk factors for the development of neutropenia
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cohort studies from the United States including the Multistate Adult include a high plasma HIV viral RNA and a low CD4 lymphocyte
and Adolescent Spectrum of HIV Surveillance Project and the Women’s count. In turn, the use of HAART is associated with a lower risk of
Interagency HIV Study have also confirmed that anemia is an indepen- developing neutropenia. Decreases in the neutrophil count are often
dent risk factor for mortality in HIV infected individuals. transient, self-limiting, and rarely of clinical significance, but a neu-
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trophil count of less than 0.5 × 10 /L of prolonged duration does
Management of Anemia and the Use of Erythropoietin pose a significant risk of infection. In a study of 87 consecutive
HIV-infected patients who developed neutrophil counts of less than
in HIV-Infected Patients 1 × 10 /L, the median duration of neutropenia was 13 days and nadir
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neutrophil count was 0.66 × 10 /L. Infection occurred in only 6 (8%)
Treatment of anemia should be directed toward correcting the of 71 evaluable patients, of whom 4 patients had neutrophil counts
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underlying cause whenever possible. The use of blood transfusion less than 0.5 × 10 /L. Ten (12%) patients had neutrophil counts less
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should be minimized and reserved for patients who have rapid than 0.5 × 10 /L and received granulocyte colony-stimulating factor
decreases in hemoglobin levels, extremely low hemoglobin levels, or (G-CSF) treatment, which artificially altered the natural history of
pronounced anemia-related symptoms. A number of clinical trials of neutropenia in this patient population.
antiretroviral medication combinations (HAART) have shown that Decreased in vitro colony growth of the CFU-granulocyte mac-
suppression of HIV replication is associated with improvement in rophage (GM) progenitor cell has been reported, which may explain
anemia. In addition, improvement of anemia on HAART has been the neutropenia observed with HIV infection alone. Inhibitory
found to occur independent of the patients’ sex, race, mode of HIV substances produced by HIV infected cells have been reported to
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infection, change in CD4 lymphocyte count, and additional thera- suppress neutrophil growth and differentiation in vitro. A number of
pies for anemia. Improvement in anemia, with an increase in the inflammatory cytokines including TGF-β and TNF-α may directly
reticulocyte count, can be seen as early as 8 to 12 weeks, with suppress myelopoiesis or inhibit the production of important myeloid
maximum improvement usually obtained by 12 months. growth factors, G-CSF and GM-CSF. Decreased serum levels of
Erythropoietin supplementation has been shown to be beneficial G-CSF have been observed in afebrile neutropenic HIV-infected
in HIV-infected patients with well-established anemia and when the patients. The HIV proteins tat and p24 have also been reported
hemoglobin level is decreasing or has decreased slowly. A blunted capable of suppressing myelopoiesis.