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Abstract

Anemia is a clinically significant complication of infection with HIV, especially in patients who develop clinical AIDS. Several large studies have demonstrated that HIV-infected women, particularly African–American women, are disproportionately affected by anemia. These studies also reveal an association between anemia and statistically significant decreases in survival. In this review, the impact of anemia, the demographic characteristics of affected patients and the known risk factors for development of anemia in HIV-infected women are discussed. In addition, the diverse etiologies of anemia in the setting of HIV infection are reviewed, as are current treatment recommendations.

Keywords

AIDS Anemia HIV women

HIV-infected women have a higher prevalence of anemia and a higher incidence of anemia unrelated to medications than do HIV-infected males [1,2]. Several large studies have sought to better characterize the demographics and outcomes of HIV-infected women with anemia and other complications [3 –5]. In these studies, HIV-infected women had a significantly higher prevalence of anemia than women in the uninfected control groups, suggesting that anemia among HIV-infected women cannot simply be attributed to risk factors affecting women in general, such as iron deficiency due to menstrual blood loss and/or pregnancy.

In women with HIV infection, anemia is associated with a decreased quality of life (QoL) and impaired physical functioning, and has also been associated with statistically significant decreases in survival [1,3,5 –9]. In uninfected adults in general, a myriad of processes may induce anemia in HIV-infected women. Identifying the underlying etiology of the anemia and treating the patient promptly and appropriately can significantly impact both daily functioning and the long-term outcome of the HIV-infected woman. In this review, the epidemiology, etiology, clinical correlates, impact and treatment of anemia among HIV-infected women are discussed.

Epidemiology & prevalence of anemia among HIV-infected women

The Adult/adolescent Spectrum of HIV Disease (ASD) group performed a multicenter medical-record review of 32,867 HIV-infected patients, of whom 19,213 had sufficient data available for assessment of the prevalence and 1-year incidence of anemia [1]. The study included 15,939 men and 3274 women. The overall prevalence of anemia at baseline was similar, with 31% of females and 28% of males having subnormal hemoglobin (Hg) values. When patients were grouped by severity of HIV disease, the prevalence of baseline anemia was higher in patients with clinical AIDS (87% of men and 77% of women) than in asymptomatic patients (28% of men and 31% of women). Furthermore, the 1-year incidence of anemia not attributable to medications such as zidovudine (AZT), trimethoprim–sulfamethoxazole and/or ganciclovir was higher among patients with CD4 counts less than 200 cells/ml than those with CD4 counts greater than 200 cells/ml (23.6 vs 2.5% in men, 34.1 vs 7.3% in women). While the prevalence of baseline anemia did not appear to be significantly higher among infected women in this study, a logistic regression model of factors associated with incident anemia revealed that women were twice as likely as men to develop anemia unrelated to prescribed medications [1]. A review of 10,000 HIV-infected patients by the Anemia Prevalence Study Group revealed a higher prevalence of anemia in women than in men in the era of highly active antiretroviral therapy (HAART) [2]. Other large epidemiologic studies do not report their results separately by gender [3]. Nonetheless, taken together, these studies revealed a need for more targeted clinical research among HIV-infected women.

The Women's Interagency HIV Study (WIHS) is a prospective study of over 2000 HIV-infected women and uninfected controls, who have been evaluated every 6 months since 1994. At baseline, anemia was more common among HIV-infected women than uninfected controls (37 vs 17%; p < 0.001) [4]. HIV-infected women were also significantly more likely than their uninfected counterparts to have severe anemia, defined as a Hg count of less than 10 g/dl (7.2 vs 2%, p < 0.001). The association of anemia with HIV infection in the WIHS was independent of age, education, prior blood transfusions or intravenous drug use.

The HIV Epidemiology Research Study (HERS) is a prospective study of 871 HIV-positive women and uninfected controls, who were assessed every 6 months. The baseline prevalence of anemia among HIV-infected women in the HERS was 28.1 compared with 15.1% of uninfected controls (p < 0.0001) [5]. The estimated cumulative incidence of anemia at 5-year follow-up was 74% in the HIV-infected group and 48% in the uninfected controls (p < 0.0001). A summary of the prevalence of anemia in HIV-infected individuals is shown in Table 1.

Table 1.

Prevalence of anemia in HIV-infected individuals.

Status of HIV infection	Prevalence of anemia (%)			Ref.

	Overall	Men	Women
HIV positive, no AIDS		28	31	[1]
Immunologic AIDS		55	52	[1]
Clinical AIDS		87	77	[1]
All categories	59.6			[3]
All categories			37.0	[4]
CD4 >500			22.3	[4]
CD4 200–499			30.4	[4]
CD4 <200			58.1	[4]
Clinical AIDS			47.5	[4]
All categories			28.1	[5]

Clinical & demographic correlates of anemia in HIV-infected women

In the WIHS, anemia was significantly more common among HIV-infected African–American women than among any other racial or ethnic group (45 vs 26% of Caucasians, 25% of Latin/Hispanics; p < 0.001) [4]. Aside from African–American race, the factors most consistently associated with anemia in HIV-infected women were use of AZT monotherapy and a CD4 count of less than 200 cells/ml, the latter of which has retained its significance in the era of HAART [5,7]. In addition, anemia was more common at plasma HIV-1 viral loads of more than 50,000 copies/cm³ among women in the WIHS cohort, attesting to the role of more advanced HIV disease in the development of this complication [4]. The HER study also revealed a significant increase in the overall risk of anemia among women with HIV-related infections, such as oral candidiasis and bacterial pneumonia [5]. These data would suggest that more advanced HIV disease is associated with anemia, as are certain demographic and treatment factors. A summary of the causes of anemia is shown in Box 1.

Etiology of anemia in HIV-infected women

The etiology of anemia in HIV-infected women includes all of the causes implicated in non-infected patients, as well as some interesting mechanisms attributable to opportunistic infections (OIs) and to the HIV virus itself.

Hypoproliferative anemias

This group includes disorders that decrease the production of red blood cells in the bone marrow and can be identified by a low reticulocyte count. Iron-deficiency anemia is the most common cause of anemia in menstruating women. As with uninfected women, menstrual blood loss and pregnancy may decrease iron stores in HIV-infected women. Blood and iron loss from pathologic involvement of the gastrointestinal (GI) tract by Kaposi's sarcoma (KS), lymphoma or from infections, such as atypical mycobacterium or cytomegalovirus (CMV) infection, must also be considered in HIV-infected patients [10].

Bone-marrow suppression in the setting of HIV infection may occur as a consequence of OIs, similar to the marrow suppression that occurs in most infectious processes. Infections can cause anemia, either by directly involving the bone marrow or by indirect, cytokine-mediated dysregulation of iron incorporation (anemia of chronic disease). The most common OIs directly involving the bone marrow include the Mycobacterium avium complex (MAC) and histoplasmosis [11]. Other infections more rarely found in the bone marrow include Mycobacterium tuberculosis, Cryptococcos neoformans and parvovirus B19. In addition to anemia, these infections are also often associated with leucopenia, when they directly involve the bone marrow.

HIV-related malignancies can also cause anemia by involving the bone marrow directly (myelophthisis) or secondarily, via cytokine-mediated bone-marrow suppression. The most common of the HIV-related malignancies to involve the bone marrow are non-Hodgkin's and Hodgkin's lymphoma [11].

Medications commonly used to treat HIV and OIs may also be implicated in HIV-related hypoproliferative anemia. The most common of these are AZT (which causes a macrocytic anemia), trimethoprin–sulfamethoxazole (used to prevent Pneumocystis carinii pneumonia [PCP]), and the antifungal agents amphotericin and flucytosine [10]. In contrast to the use of single-agent AZT, use of HAART therapy has not been associated with anemia. In fact, HAART has been shown to improve HIV-related anemia, especially if AZT is not part of the regimen [9,12].

HIV itself appears to contribute to anemia directly through various mechanisms. Investigations into the pathophysiology of HIV-induced anemia have not been undertaken specifically in women and may not reflect the contribution of hormonal factors, iron storage, pregnancy or different AIDS-defining illnesses. Nonetheless, HIV infection of bone marrow stromal cells has been shown to inhibit the production of hematopoietic growth factors [13,14], impairing regeneration of red blood cells. This may be secondary to inadequate upregulation of serum erythropoietin (EPO) in response to anemia, an impairment which seems to be more pronounced in untreated than in treated AIDS patients or asymptomatic patients with HIV [16]. In this regard, a transcriptional defect in EPO production has been described in anemic HIV-infected individuals [16]. Furthermore, anti-EPO antibodies have been identified in HIV-infected patients with anemia. Sipsas and colleagues identified anti-EPO autoantibodies in 31 out of 73 HIV-infected patients with anemia, as opposed to only 17 out of 131 nonanemic patients [17]. The impact of these antibodies on anemia was independent of other risk factors and seemed to have the greatest impact on the Hg count in patients without other causes of anemia. In addition to these factors, committed hematopoietic progenitors are decreased in HIV-infected patients [13], which may also lead to hypoproliferative anemia.

Anemias due to increased destruction of red blood cells

This group includes disorders in which bone marrow increases its production of red blood cells in response to increased destruction or loss. These anemias are usually characterized by elevated levels of reticulocytes, indirect bilirubin and lactate dehydrogenase (LDH).

Ineffective erythropoiesis occurs when red blood cells are produced in the marrow but are destroyed before effective release into the circulation as reticulocytes. In these conditions, the reticulocyte count is low, while indirect bilirubin and LDH levels are high. Ineffective erythropoiesis is typically caused by deficiency of folate and/or vitamin B12. In HIV-infected patients, such nutritional deficiencies can result from lesions of the GI tract, causing malabsorption of either B12 or folate, or from abnormalities of B12-binding proteins [18]. Furthermore, since folic acid is heat labile, with relatively small tissue stores, inadequate dietary intake may also be etiologic, especially in patients with underlying HIV infection, who may be ill and/or unable to eat properly.

Hemolysis is the destruction of red blood cells within the circulation, leading to an elevated reticulocyte count as the bone marrow attempts to compensate. Peripheral destruction of red blood cells can occur in the vasculature, as with thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation, or in the spleen, as with autoimmune hemolytic anemia (AIHA). TTP has been well described in HIV infection, but the precise etiology is not known [19 –21]. TTP is more common in women in the general population, but no prospective study has documented a greater incidence in HIV-infected women than men. Due to its known association with HIV and its high mortality rate among HIV-infected and -uninfected patients, TTP must be considered in any HIV-infected patient with antibody-negative hemolysis and a low platelet count, especially in the setting of fever, neurologic changes and renal insufficiency [19,20].

Premature destruction of red blood cells in the spleen occurs in the setting of AIHA and hypersplenism. AIHA is diagnosed by a positive Coombs test in the setting of extravascular redblood-cell destruction, usually occurring in the spleen. AIHA affects women twice as commonly as men in the general population, but is a rare clinical event in the setting of HIV. Among HIV-infected patients who do develop AIHA, potential etiologies include medications, infectious complications such as MAC, histoplasmosis and CMV, and dysregulated antibody production by B-lymphocytes [22]. This latter hypothesis is supported by the finding of positive direct antiglobulin tests in 20–40% of patients with AIDS, despite a low prevalence of clinical hemolysis. Splenic sequestration among HIV-infected patients can be related to splenomegaly due to liver disease caused by coinfection with hepatitis B and/or C. Current literature suggests that hepatitis B and C can safely and effectively be treated in the setting of HIV infection [23,24], thus preventing long-term complications such as cirrhosis. Nonetheless, the treatment of hepatitis C with ribavirin can cause hemolytic anemia, which can safely be managed with exogenous EPO [24,25].

Box 1.

Causes of anemia in HIV-infected individuals.

Hypoproliferative anemias in HIV:

Iron deficiency

– Gastrointestinal blood loss from Kaposi's sarcoma lymphoma or infection

– Menstrual blood loss

– Pregnancy

Bone marrow suppression

– Infection

– Malignancy

Medications

– Zidovudine, trimethoprim-sulfamethoxazole, antifungals

HIV virus-induced suppression

– Inhibition of stromal growth factors

– Impaired erythropoeitin secretion/effect

– Anti-erythropoietin antibodies

Hyperproliferative anemia in HIV:

Ineffective production

– B12/folate deficiency

– Infectious or neoplastic involvement of the gastrointestinal tract

– Inadequate dietary intake

Increased destruction

– Hemolytic anemias

– Thrombotic thrombocytopenic purpura

– Medications (e.g., ribavirin)

– Autoimmune hemolytic anemia (rare)

Splenic sequestration

– Hepatitis B or C cirrhosis

Impact of anemia on HIV-infected women

Many prospective studies have documented the negative impact of anemia on QoL measures in HIV-infected patients [6 –9]. The Community HIV/AIDS Mobilization Project (CHAMPS) Study Group conducted a prospective, multicenter study of 650 anemic, HIV-infected patients receiving HAART to evaluate the effect of treatment with EPO on QoL measures [6]. QoL was assessed by two validated self-report assessment tools (linear analogue self-assessment [LASA] and medical outcomes study [MOS]-HIV). In this study, enrolled patients had Hg levels of less than 11 g/dl at baseline; their corresponding QoL scores on the LASA instrument were consistent with functional impairment in all three parameters (energy level, daily activity and overall QoL). This study also demonstrated that patients whose anemia improved in response to therapy reported significant improvement on both QoL instruments in all parameters (energy level, daily activity, overall QoL, fatigue and social functioning). These improvements were notable as early as week 8 of therapy with EPO and were sustained through the 16-week follow-up period. The effect was most pronounced when the Hg increased from 11 to 12 g/dl.

In addition to its negative impact on QoL measures, anemia has also been shown to be an independent risk factor for shorter survival in patients with HIV infection [1,3,5,9]. In the ASD study, anemia at baseline was associated with a significant reduction in median survival at all CD4 counts [1]. In the EuroSIDA cohort, survival was evaluated for patients with no anemia, mild anemia (Hg 8–14 g/dl for men, 8–12 g/dl for women) and severe anemia (Hg < 8 g/dl) [3]. At 1-year follow-up, 3.1% of patients without anemia had died, as opposed to 15.9% of patients with mild anemia and 40.8% of patients with severe anemia. In a multivariate analysis of these data, anemia and CD4 count were significantly and independently associated with risk of death; for each 1 g/dl decline in Hg, the relative hazard of death was 1.57 (p < 0.0001). Among patients with severe anemia but with CD4 counts of more than 200 cells/ml, the relative hazard of death was 29-times that of nonanemic patients, corroborating the independent negative impact of anemia on survival.

The association of anemia with inferior survival holds true for HIV-infected women. In the HERS, only 63% of anemic women survived to follow-up compared with 78% of nonanemic women [5]. The association of anemia with mortality was independent of CD4 count and body mass index; the hazard ratio (HR) of death for women who were anemic at baseline was 1.64 (confidence interval [CI]: 1.21–2.23).

Similarly, among the WIHS participants, anemia at any time during the study was independently associated with decreased survival [9]. To determine whether anemia was simply reflective of more advanced systemic illness, this study also evaluated the impact of a large number of factors indicative of more advanced HIV disease on survival. Multivariate analysis confirmed an independent increase in the HR of death among patients with anemia (HR: 2.58; p < 0.0001). The effect of anemia on risk of death was of a similar magnitude to the impact of clinical diagnosis of AIDS (HR: 3.14; p < 0.001) and viral load (HR for HIV-1 plasma RNA > 50,000 copies/ml: 2.12; p < 0.0001), but perhaps less powerful than the impact of a CD4 count of less than 200 cells/ml (HR: 5.83; p < 0.0001). Thus, while a relationship between anemia and survival certainly exists, it remains to be determined whether anemia acts independently or actually reflects other parameters of disease progression not fully captured by CD4 count and viral load.

Treatment of anemia in HIV-infected women

When faced with anemia in the HIV-infected patient, the treating physician must consider the broad differential diagnosis discussed above in a search for treatable causes. If all such causes have been ruled out, the use of EPO should be considered. EPO, a recombinant form of the human glycoprotein produced by the kidneys to stimulate increased erythropoeisis in the bone marrow, was approved by the US Food and Drug Adminstration (FDA) in 1989 for use in AZT-related anemia among HIV-infected patients. The need to screen pretreatment endogenous EPO levels is controversial [9,10,12].

EPO is effective in correcting AZT-related anemia in HIV-infected patients. In the early 1990s, two different studies confirmed the safety and efficacy of administering exogenous EPO to anemic patients with AIDS who were receiving AZT therapy [26,27]. In a study by Fischl and colleagues, 63 patients (including only one woman) were evaluated; the primary efficacy end point was a reduction in transfusion requirements [26]. There was a significant decline in monthly transfusions over time for the group receiving EPO 100 units intravenously three-times weekly (1.31 units/month at baseline to 0.84 units/month at study end point), while the transfusion requirement increased in the group receiving placebo (1.68 units/month to 2.74 units/month). Of note, no significant reduction in transfusion requirement was achieved among treated patients in whom the endogenous EPO level was greater than 500 international units (IU)/l. Henry and colleagues evaluated the effect of exogenous EPO in 255 primarily white male patients with anemia, a clinical diagnosis of AIDS and reported use of AZT therapy [27]. Among patients with endogenous serum EPO levels of 500 IU or less, the hematocrit level increased by 4.6% in the treated group, compared with increase of only 0.5% among those given placebo (p = 0.0002).

Unfortunately, there are no large studies examining the efficacy of exogenous EPO specifically among women. The CHAMPS study investigated the impact of once-weekly exogenous EPO on anemia and QoL in 650 HIV-infected patients, 34% of whom were women [6]. Study subjects received 40,000 units of epoetin-α weekly if their baseline serum EPO level was 500 mU/ml or less. Men and women had the same mean baseline Hg (9.7 g/dl ± 1.1); the mean increase in Hg was 2.2 ± 1.5 g/dl for women and 2.7 ± 2.1 g/dl for men over the 16-week follow-up period. These data suggest that weekly EPO is a safe and effective intervention for anemia among HIV-infected women with endogenous EPO levels of 500 mU/ml or less.

Aside from EPO, the use of HAART has also been shown to improve anemia in HIV-infected women and injection drug users [9,12]. In the WIHS cohort, use of HAART for at least 6 months was associated with a correction of anemia (overall response [OR]: 1.45; p = 0.01) [9]. AZT use, however, impaired the correction of anemia, whether used alone or in conjunction with other antiretrovirals (OR: 0.80 for correction of anemia; p = 0.04). Among HIV-infected male and female intravenous drug users from the AIDS Link to IntraVenous Experience (ALIVE) study, 102 patients who reported being on HAART for at least 6 months were compared with 103 untreated patients [12]. Subjects were ineligible if use of EPO therapy was reported. Patients receiving HAART had higher baseline plasma HIV-1 viral loads, lower baseline CD4 counts, lower baseline Hg concentrations and a higher prevalence of OIs than patients in the control group. Nonetheless, at a median follow-up time of 1 year, HAART use was associated with a mean Hg increase of 3.6 ± 1.7 g/l, as opposed to a mean Hg loss of 4.2 ± 1.1 g/l (p = 0.04) among the untreated patients. The mechanisms for the increased Hg are unclear, but may include the impact of fewer OIs in patients receiving HAART, reduction of cytokines related to uncontrolled HIV viral replication, amelioration of the suppression of hematopoietic progenitor cells and/or reduction of HIV-related GI lesions and resultant blood loss.

In order to better reflect the important findings of the various studies discussed above, the Anemia in HIV Working Group convened in 2002 to update their recommendations on the treatment of HIV-related anemia [10]. For HIV-infected women, they recommend routine assessment of QoL along with Hg measurements and diligent work up for treatable causes of anemia. They advised the use of 40,000 units of epoetin-α weekly for women with Hg counts of less than 12 g/dl in whom treatable causes have been ruled out; epoetin should be discontinued when the Hg count rises above 12 g/dl. They also advised prompt use of HAART when indicated on the basis of underlying HIV disease.

Future perspective

The treatment of HIV infection has evolved tremendously since the virus was first identified. However, along with the many advances came the clear need for more research on the special issues of women, African–Americans and other understudied populations. As described herein, various large cohort studies have been undertaken to examine these special populations. The clinician treating HIV-infected women is now armed with many tools for managing the range of complications associated with HIV – from anemia to OIs to malignancies. Nonetheless, important questions remain as to the pathophysiology of anemia, the interaction between iron balance and bone marrow signaling and the complex effect of immune dysregulation in HIV-infected women. Further studies are clearly warranted, especially given the association of anemia and worsened survival.

Executive summary

Approximately 30% of HIV-infected women are anemic (hemoglobin count < 12 g/dl).

50–80% of women with clinical AIDS are anemic.

A CD4 count of less than 200, a HIV-1 viral load of more than 50,000, African-American race and zidovudine therapy are well established risk factors for anemia.

Anemia is an independent risk factor for decreased survival in HIV-infected women.

The correction of anemia in HIV-infected women significantly improves quality of life and overall survival.

Treatment of underlying HIV infection with highly active antiretroviral therapy (HAART) improves anemia.

Weekly erythropoietin therapy is safe and effective in anemic women with HIV infection; treatment should be suspended once hemoglobin levels are greater than 12 g/dl.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

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Mildvan

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Managing Anemia in HIV-Positive Women

Abstract

Keywords

Epidemiology & prevalence of anemia among HIV-infected women

Clinical & demographic correlates of anemia in HIV-infected women

Etiology of anemia in HIV-infected women

Hypoproliferative anemias

Anemias due to increased destruction of red blood cells

Impact of anemia on HIV-infected women

Treatment of anemia in HIV-infected women

Future perspective

References