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HIV IN HEMATOLOGY: WHAT’S NEW?

Pathogenesis and clinical implications of HIV-related


anemia in 2013
Amanda J. Redig1 and Nancy Berliner1,2

1Department of Medicine, and 2Division of Hematology, Department of Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, MA

Anemia is a common feature of HIV-related disease and has been uniformly demonstrated to be an independent
predictor of morbidity and mortality. Although anemia often responds to combination antiretroviral therapy, many
patients remain anemic despite therapy and such persistent anemia continues to negatively affect prognosis
regardless of drug response. Anemia is also a common feature of normal aging. We postulate that the pathophysiology
of anemia in HIV, especially that which persists in the face of combination antiretroviral therapy, is a reflection of
underlying proinflammatory pathways that are also thought to contribute to anemia in the elderly, as well as other
age-related chronic diseases such as cardiovascular disease and chronic obstructive pulmonary disease. This
suggests that HIV induces inflammatory pathways that are associated with a pattern of accelerated aging and that
anemia is a biomarker of these processes. A better understanding of the pathophysiology of HIV-related anemia may
provide important entry points for improving the chronic manifestations of HIV-related disease.

Introduction hemoglobin concentration of ⬍ 13 g/dL for men and ⬍ 12 g/dL for


Anemia is among the most common hematologic abnormalities in nonpregnant women.5 Although this definition is widely used in the
patients with HIV and has been associated with disease progression literature, many of the largest cohort studies on HIV are done in
and poor clinical outcomes.1 Study of the unique pathophysiology Africa or Asia, where a more stringent hemoglobin cutoff of ⬍ 10
of anemia in HIV has been recognized as an important step toward g/dL is often used for clinical stratification. However, even while
improving therapeutic options and disease management. Recent acknowledging differences in definitions, there is no doubt that
emerging studies have also begun to suggest that there may be a anemia is a significant clinical challenge for the HIV⫹ population,
connection between the underlying mechanisms driving the develop- because somewhere between 1.3% and 95% of patients in published
ment of anemia in the context of HIV infection and the pathophysi- cohorts meet diagnostic criteria.1
ology of anemia in the elderly. A growing body of data has
established that HIV infection is associated with increased expres- A closer review of epidemiological data within this population
sion of proinflammatory cytokines,2 including many of the same reveals several noteworthy trends. First, it appears that the degree of
biomarkers previously associated with inflammation and anemia of anemia is correlated with HIV/AIDS disease progression in both
aging.3 Ongoing studies of the development and progression of retrospective and prospective analyses.1 Several of these studies
anemia in the HIV⫹ population will help characterize whether this suggested that the anemia in some advanced AIDS patients results
common clinical presentation reflects an acceleration of the sys- from therapy-related toxicity,1,6 but adverse drug effects alone are
temic inflammation already well known to be associated with the not sufficient to account for the consistent association between
biology of aging. Because effective antiretroviral therapy (ART) has anemia and HIV stage. Furthermore, several studies in a range of
dramatically increased the life expectancy of patients with HIV, patient cohorts demonstrated that anemia has prognostic signifi-
improved understanding of the ways in which HIV infection alters cance for morbidity and mortality measures in HIV⫹ patients,7,8
physiologic parameters will be an important component of develop- supporting the possibility that the virus itself may play an indepen-
ing targeted therapies to affect morbidity and mortality in this dent role in driving dysfunctional erythropoiesis. Studies evaluating
population. anemia in patients undergoing cART compared with patients not on
active treatment extend this hypothesis, because cART appears to
Clinical features and outcomes of anemia in HIV correct the anemia associated with HIV effectively in a significant
Anemia in HIV⫹ patients is a well-documented phenomenon. An number of patients in both adult and pediatric populations.9,10
earlier systemic review of the literature identified 31 distinct studies Conversely, a recent study demonstrated that ongoing anemia is
reporting either the incidence or prevalence of anemia in the HIV⫹ statistically associated as a marker of treatment failure in patients
population,1 and the connection between anemia and HIV continues newly initiated on cART who fail to achieve appropriate viral
to be an active area of research investigation.4 Anemia has been suppression.11
recognized as a clinical problem in HIV⫹ patients both before and
after the advent of combination ART (cART), suggesting that there A wealth of older literature has established anemia as a prognostic
may be a fundamental physiologic change in the regulation of marker for mortality in HIV⫹ patients.6,8,12 Emphasizing the central-
erythropoiesis resulting from viral infection. However, when evalu- ity of the role played by anemia in this patient cohort, anemia has
ating the large body of literature on this topic, it is important to note been associated with shortened median survival in HIV⫹ patients
the various definitions used to clinically diagnose a patient with irrespective of their initial CD4⫹ count.12 Risk factor stratification
anemia. The World Health Organization (WHO) defines anemia as a demonstrates that when a range of potentially relevant demographic

Hematology 2013 377


and clinical variables are considered, CD4 count and hemoglobin EPO were decreased.21 Furthermore, after ex vivo differentiation of
are the 2 factors independently associated with mortality.8 More peripheral blood CD34⫹ cells, an increase was noted in the early
recently, several studies in Europe,13 Africa,7 and Asia14,15 have BFU-E stage of erythropoiesis in untreated HIV⫹ patients compared
evaluated the association between anemia and outcomes specifically with uninfected controls.21 The addition of exogenous EPO to the
in patients initiating cART. Once again, despite the widely diver- growth media for these studies suggests that the progenitor cells
gent socioeconomic factors that characterize HIV worldwide, the from the HIV⫹ patients were intrinsically refractory to the growth
degree of clinical anemia remains an independent risk factor for effects of EPO, resulting in accumulation of colonies at a relatively
predicting mortality from HIV even upon initiation of therapy. undifferentiated stage of erythroid development. However, after
These findings identify anemia as an important variable in monitor- initiation of cART therapy, circulating levels of EPO and transferrin
ing HIV disease progression and management, particularly in levels increased in patient serum, and the number of BFU-E
resource-limited settings. These data also begin to suggest that colonies normalized compared with uninfected controls in ex vivo
understanding the mechanisms by which HIV causes anemia may studies.21 Although this was a small patient cohort, these findings
have significant prognostic and therapeutic significance. suggest that HIV may have a direct suppressive effect on the
cytokine cascade responsible for normal erythropoiesis. The hema-
Multifactorial pathogenesis of anemia in HIV topoietic stem cell may even be a reservoir for latent viral infection,
There are several factors believed to contribute to the pathophysiol- although this remains controversial. Several studies have suggested
ogy of anemia observed in HIV⫹ patients. First, many of the that CD34⫹ cells are resistant to HIV infection,22-24 but others have
opportunistic infections or malignancies to which HIV⫹ patients are identified detectable virus in the CD34⫹ hematopoietic progenitor
susceptible can lead to anemia. This is particularly problematic in pool in patients with well-controlled disease, including undetectable
the developing world, where endemic infections such as malaria or serum viral loads.25 A recent study extended these findings to the
hookworm can lead to substantial anemia even in those without CD133⫹ cohort within the BM of patients on cART.26
concomitant HIV infection. Similarly, HIV infection rates are also
particularly high in regions of the world with a high prevalence of Studies evaluating hematopoiesis in patients undergoing HIV
thalassemia or sickle cell trait. Furthermore, as with anemia in the treatment also support a direct role for the virus in inducing anemia.
HIV⫺ population, micronutrient deficiencies can play a role in In animal studies of HIV infection using glycolipid administration
contributing to either microcytic or macrocytic anemia in HIV⫹ to activate natural killer cells, decreased HIV-1 viral replication was
patients. Finally, as mentioned previously, many of the most accompanied by restoration of normal hematopoiesis in treated
common drugs included in standard cART also have a negative mice.27 At the molecular level, BM from HIV⫹ patients receiving
effect on hematopoiesis and can thus contribute to anemia in HIV⫹ cART but without adequate response—so-called immunologic
patients undergoing therapy. nonresponders— demonstrated reduced clonogenic ability and a
decrease in the number of the more multipotent primitive progenitor
Despite the role of such nonspecific factors in potentiating anemia in cells compared with those with response to therapy.28 Actively
many HIV patients, several lines of evidence suggest that the replicating virus thus appears to suppress the normal physiologic
pathophysiology of anemia in HIV may include direct effects of the response to anemia and the complex network of regulatory cyto-
virus itself. First, studies from the pediatric literature indicate that, kines that maintain normal hematopoiesis. Intriguingly, the cytokine
even in populations in which micronutrient deficiency is expected to profile produced by the BM cells from patients without immuno-
be highly prevalent, the HIV⫹ cohort is less likely to be affected logic response to cART was notable for decreased IL-2 and
directly compared with the general population. HIV⫹ children in increased TNF-␣ and IL-7, consistent with a proinflammatory
Malawi were less likely to be iron deficient than HIV⫺ children,16 In milieu.28
a cohort of Thai children, the majority of HIV⫹ children with
anemia were not iron deficient.17 If HIV itself did not have
pathogenic effects on the development of anemia, then the relative HIV and aging: the inflammatory connection
role of other risk factors such as nutritional deficiencies would likely The emerging role of an active proinflammatory state in contribut-
be more extensive. In addition, HIV infection may also contribute to ing to anemia in patients with HIV suggests a potential connection
aberrant immune activation that exacerbates other etiologies of to the pathophysiology of anemia in the aging population, because
anemia. A recent report demonstrates that molecular mimicry this is also a process associated with a shift toward a proinflamma-
between erythropoietin (EPO) and the HIV-1 p17 protein can lead to tory state. An individual HIV⫹ patient may present with any type of
circulating auto-antibodies against endogenous EPO in some HIV⫹ anemia and may well have obvious risk factors such as micronutri-
patients, blunting the normal physiologic cytokine response to ent deficiency or use of specific cART medications, but anemia in
anemia.18 the HIV⫹ population is most often characterized by a low reticulo-
cyte count, normochromic and normocytic erythrocytes, normal
Several studies have also demonstrated a direct effect of HIV on iron stores, and impaired erythropoietin response. These descriptive
hematopoietic progenitor cells and EPO responsiveness. HIV-2 features are also classically associated with anemia of inflammation
infection of BM progenitor cells in the in vitro setting has been (previously known as anemia of chronic disease), a state that is
shown previously to inhibit erythyropoiesis directly at the BFU-E particularly well described in the aging population.29 cART therapy
and CFU-E stage of differentiation.19 More recently, in a pediatric has led to a growing number of aging adults with HIV, thereby
cohort in Malawi, BM analysis demonstrated that HIV⫹ children providing a growing database of patients in which to examine the
with anemia have a decreased number of both CD34⫹ progenitor relationships between HIV infection, aging, and inflammation.
cells and primitive erythroid progenitors compared with HIV⫺
children with anemia.20 In an evaluation of EPO signaling in the The overlap between the mechanisms linking the anemia of aging
setting of HIV infection, a small cohort of HIV⫹ patients was and the anemia of HIV begins with aberrant cytokine expression. It
monitored before and after cART initiation.21 Compared with has been established previously that a host of markers associated
uninfected controls, serum levels of soluble transferrin receptor and with inflammation, including IL-1, IL-6, acute phase proteins, and

378 American Society of Hematology


TNF-␣, are increased in the aging population, sometimes irrespec- The Veterans Aging Cohort Study (VACS) has become a particu-
tive of underlying health status.29 In the aging population, elevation larly useful clinical tool in investigating the overlapping contribu-
in these cytokines has been linked with multiple comorbidities, tions of aging and inflammation to the anemia associated with HIV.
including anemia. IL-6 may play a particularly significant role in The VACS is a well-described patient cohort of 1302 HIV⫹ patients
potentiating anemia of inflammation through its role in regulating on cART with age/race/site-matched HIV⫺ controls on whom blood
hepcidin, an acute phase reactant that is a critical regulator of iron and DNA specimens have been banked.38 This patient cohort has
stores and iron-limited erythropoiesis and has been linked with been used to develop the VACS index, an evaluation of 7 variables
anemia of inflammation.29 In a striking overlap with the aging (age, CD4 count, HIV-1 status, hemoglobin, FIB-4 index, hepatitis
population, proinflammatory cytokines and altered iron metabolism C infection, and eGFR) used to help predict mortality.39 The VACS
have also been linked to HIV infection. Several independent studies index is more predictive of mortality than the Restricted Index,
have identified an association between inflammatory biomarkers which only considers age, CD4 count, and HIV-1 status.40 This
and morbidity and mortality in HIV⫹ patients, specifically soluble improved predictive value based on measures of clinical end points
CD14 (a marker of monocyte activation), D-dimer, and IL-6.2,30 In associated with inflammation (anemia, liver injury, kidney injury)
addition, hepcidin regulation is altered in HIV infection, suggesting supports a central role for inflammation in disease progression
an overlap with the mechanisms driving anemia of inflammation. In caused by HIV.38 In the case of anemia, what is particularly striking
vitro T-cell cultures have shown that hepcidin induces HIV-1 is that when analyzing the factors that make up the VACS index,
transcription.31 In a cross-sectional study of 200 HIV⫹ women in anemia was not only correlated with other markers of inflammation,
Rwanda, 6% of the population was noted to have a mutation in the but was also found to be an independent prognostic factor for
iron transporter ferroportin, rendering it resistant to the negative mortality.41 When serum levels of sCD14, IL-6, and D-dimer were
regulatory effects of hepcidin.32 The women with the ferroportin evaluated in the VACS cohort and included in mortality predictions,
mutation had significantly increased rates of some opportunistic D-dimer and sCD14 further improved predictive accuracy. These
infections. These findings provide a possible mechanistic link for findings suggest that IL-6 likely plays a role in contributing to the
other parameters already assessed by the VACS index and further
the previously discussed hypothesis that HIV infection contrib-
support the centrality of inflammatory pathways in mediating
utes directly to anemia and thus poor outcomes in HIV⫹ patients.
adverse outcomes in HIV.38
The alterations in iron metabolism and resulting anemia in the
context of viral infection continue to be an active area of research
investigation.33 Anemia and HIV: unanswered questions
Moving forward with an evaluation of the role of anemia in HIV and
Studies evaluating the inflammatory axis in the context of obesity connections with the biology of aging and inflammation, several
and adipokines secreted by adipose tissue have also demonstrated a outstanding questions remain and are likely to drive future research
efforts. First, several large studies evaluating the epidemiology of
noteworthy connection between the aging population and the HIV⫹
anemia in the HIV⫹ population have noted that more significant
population. Leptin, a protein associated with body mass and energy
anemia is often found in women and in those of black race.12,35 A
metabolism, is known to induce hepcidin, thus linking inflammation
similar ethnic association has also been noted in studies of the aging
and iron metabolism.29 However, decreased leptin expression is also
population, specifically data reported from the Third National
correlated with impaired response to EPO in the elderly, suggesting
Health and Nutrition Examination Survey (NHANES III) study.42
that metabolic dysregulation at the molecular level may be associ-
Whether race or gender-specific genetic differences contribute to
ated with anemia in this population.34 Similarly, in the HIV⫹
differential regulation of inflammatory pathways and thus divergent
population, leptin is now emerging as a regulator of anemia. A
outcomes in the HIV⫹ population remains to be determined.
recent analysis of a large cohort of more than 2000 HIV⫹ patients However, given disparities in HIV outcomes in women and
with matched controls revealed that a specific polymorphism in the minorities, the answer to this question is of significant clinical and
leptin gene promoter was associated with the development of social significance. The VACS cohort offers a particularly valuable
anemia in HIV⫹ but not HIV⫺ subjects.35 Body habitus and clinical context in which to address one aspect of these questions,
inflammation have also been linked in patients undergoing cART. In because it includes a significant number of non-Hispanic African-
one study, incremental increases in body mass index were associ- American patients. However, it is not surprising that the number of
ated with increasing levels of C reactive protein and TNF-␣, women enrolled in this study is small. Additional studies specifi-
whereas increased expression of IL-6 and migration inhibitory cally enrolling women may be required to further address the
factor were specifically correlated with patients considered to be overlap between anemia and inflammation in HIV⫹ patients.
obese by BMI measurements.36
Second, the role of genetic polymorphisms in modulating leptin and
Finally, there is evidence that EPO signaling can be impaired both hepcidin signaling suggests that polymorphisms in other key
during aging and in HIV infection, a process that may be accelerated mediators of inflammatory pathways may play a role in contributing
by the inflammation also associated with both processes. EPO levels to outcomes in patients with HIV. Some studies suggest that
rise with age, suggesting that, over time, hematopoietic progenitors variation in the balance between pro- and anti-inflammatory cyto-
become less responsive to EPO.29 The role of a proinflammatory kines in those exposed to HIV may play a role in determining rates
milieu in impairing progenitor cell EPO responsiveness or mediat- of postexposure infection.43 In addition, variation in inflammatory
ing increased EPO expression remains to be determined, but it is mediators has already been linked to outcomes in other diseases
noteworthy that in aging patients with comorbidities associated with associated with chronic inflammation.44 The correlation between
increased inflammation, the rate of EPO elevation is diminished,37 anemia and morbidity and mortality in HIV⫹ patients raises the
suggesting that inflammation may play a role in blunting the normal intriguing possibility that a more targeted genetic evaluation of the
physiologic compensation for aging. As discussed above, HIV inflammatory cytokines linked to anemia may provide further
infection can have direct effects on decreasing the function of insight into the mechanistic underpinnings of this process and
hematopoietic progenitors and specifically their response to EPO. suggest possible targets for therapy. Anemia itself may function as a

Hematology 2013 379


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Disclosures PLoS One. 2012;7(8):e43375.
Conflict-of-interest disclosure: The authors declare no competing 15. Fregonese F, Collins IJ, Jourdain G, et al. Predictors of 5-year
financial interests. Off-label drug use: None disclosed. mortality in HIV-infected adults starting highly active antiretro-
viral therapy in Thailand. J Acquir Immune Defic Syndr.
Correspondence 2012;60(1):91-98.
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