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1250 Part IX: Lymphocytes and Plasma Cells Chapter 81: Hematologic Manifestations of Acquired Immunodeficiency Syndrome 1251

Histiocytosis Society 2004 protocol (Chapter 71). Caution regarding TABLE 81–9. Causes of Anemia in Human
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interaction of cyclosporine with specific ART medications is warranted.
Immunodeficiency Virus
ANEMIA AND HUMAN DECREASED PRODUCTION
IMMUNODEFICIENCY VIRUS HIV effect on hematopoiesis
Anemia is common in people living with HIV. The multisite Adult and Marrow infiltration (e.g., Mycobacterium avium complex, histoplas-
mosis, non-Hodgkin lymphoma, Hodgkin lymphoma)
Adolescent Spectrum of HIV Disease Surveillance Project included
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approximately 32,000 HIV+ people living in the United States in the Pure red cell aplasia (Parvovirus B19)
pre-ART era, 1990 to 1996. In this study, the first hemoglobin measured Drug suppression of hematopoiesis (e.g., Zidovudine)
was less than 10 g/dL in 37 percent of men and 43 percent of women Nutritional deficiency (e.g., vitamin B , folate, iron)
with clinical AIDS (an AIDS-defining illness). Even patients with a 12
CD4 count of greater than 200 cells/μL and no AIDS-defining illness Inflammation
had a high prevalence of anemia: 28 percent of men and 31 percent of INCREASED DESTRUCTION
women had anemia defined as hemoglobin less than 14 g/dL for men
or less than 12 g/dL for women. At the 1-year followup, the incidence Thrombotic thrombocytopenic purpura
of anemia was 3.2 percent for HIV+ people without immunologic or Immunohemolytic anemia
clinical AIDS, 12.1 percent for those with immunologic AIDS, and 36.9 Glucose-6-phosphate dehydrogenase deficiency (e.g., dapsone,
percent for those with clinical AIDS. Notably, anemia was associated trimethoprim-sulfamethoxazole)
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with a 1.5- to 2.5-fold increased risk of death during followup. One Hemophagocytic syndrome
prospective study showed a moderate correlation between the hemo-
globin and CD4 count at entry into the cohort, and found that initiation LOSS
of ART could increase the hemoglobin value. Similarly, interruption Gastrointestinal bleeding (e.g., Kaposi sarcoma in gastrointestinal
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of ART increased the risk of anemia. An investigation of 2056 HIV+ tract)
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women at six sites in the United States showed that use of ART for as
little as 6 months was associated with improvement of anemia, while
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several factors, including CD4 count less than 200 cells/μL, HIV viral
load greater than 50,000 copies/mL, and mean corpuscular volume less progenitor cells was an infrequent event. However, subsequent studies
than 80 fL were associated with decreased ability to correct the ane- of HIV subgroup C (the subtype that predominates in African popu-
mia. Anemia was identified as a key prognostic factor in large Euro- lations) showed that a proportion of burst-forming unit–erythroid
pean and South African HIV+ cohorts. 241,242 The Veterans Aging Cohort (BFU-E), granulocyte-macrophage colony-forming units (CFU-GM),
Study evaluated HIV+ patients who had been on ART for 1 year, to and granulocyte-erythrocyte-monocyte and megakaryocyte colony-
identify factors predictive of mortality. This study identified age, CD4 forming units (CFU-GEMM) can be infected with HIV in vitro. The
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count, HIV viral load, hemoglobin, glomerular filtration rate, presence proportion of hematopoietic progenitor cells that could be infected with
or absence of hepatitis C, and a composite measure of liver function as HIV subtype B (the predominant subtype in the United States and in
predictive factors for mortality. Even a mild decrease in the hemoglobin Europe) was smaller (in the 1 percent range). Proviral HIV was detected
contributed significantly to mortality in this index. The Veterans Aging by PCR in a small fraction of isolated CD34+ cells from some but not
Cohort Study Index was subsequently validated in an independent all HIV+ patients on ART with an undetectable viral load, suggesting
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cohort. Thus, even in the ART era, anemia is associated with a worse that HIV can latently infect hematopoietic progenitor cells in vivo; sim-
prognosis, independent of the traditional risk markers such as the CD4 ilar results were obtained using CD133+ sorted marrow cells. Recent
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count and the HIV viral load. studies using a specific strain of humanized mice showed that some
human CD34+, CD38+ intermediate progenitor cells could be infected
Pathophysiology of Anemia in Human Immunodeficiency with HIV in vivo, and that these progenitor cells when cultured in vitro
Virus had impaired growth, particularly in the erythroid and megakaryocytic
There are many pathophysiologic causes of anemia in HIV+ people lineages. 251
(Table 81–9), and often anemia in an individual is multifactorial in The normal response of the kidneys to a decline in hemoglobin is to
origin. Unique to HIV are the effects of the virus on hematopoiesis, produce more erythropoietin. However in HIV+ people, the incremen-
including direct infection of hematopoietic progenitor cells (impairing tal increase in erythropoietin is blunted. 252,253 Additionally, antierythro-
their survival, proliferation, differentiation, and maturation), infection poietin antibodies can be detected in a portion of HIV+ patients and are
of marrow stromal cells (affecting their ability to support hematopoiesis associated with increased risk of anemia. The antierythropoietin anti-
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in the marrow microenvironment ), and alterations in hematopoietic bodies recognize a peptide that is needed for erythropoietin binding to
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growth factor production or function. Additionally, HIV infection is the erythropoietin receptor. This peptide has sequence homology to an
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associated with a chronic inflammatory state that may also contrib- HIV protein, suggesting molecular mimicry as a potential mechanism
ute to ineffective erythropoiesis. Markers of inflammation, including for development of the antierythropoietin antibodies. 255
IL-6, are higher in HIV+ individuals than in their HIV– counterparts, A cross-sectional study of 200 HIV+ patients in San Francisco
and this holds true even for those on ART with an undetectable viral during the ART era suggested an association between low testosterone
load. Inflammation, in part mediated by IL-6, upregulates hepcidin, a levels and anemia in men living with HIV. Hypogonadism is associ-
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key regulator of iron trafficking, and serum hepcidin levels are inversely ated with weight loss, osteoporosis, and AIDS wasting syndrome, but
correlated with CD4 counts. 246,247 whether testosterone treatment can correct anemia in these patients
Attempts to infect normal hematopoietic progenitor cells in vitro awaits further study.
with HIV and studies of hematopoietic progenitor cells obtained from Another, occasionally dramatic, cause of anemia in those living
HIV+ patients initially suggested that HIV infection of hematopoietic with HIV is pure red cell aplasia caused by parvovirus B19. Parvovirus

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