Associations of Anemia, Treatments for Anemia, and Survival in Patients with Human Immunodeficiency Virus Infection

S138 Associations of Anemia, Treatments for Anemia, and Survival in Patients with Human Immunodeficiency Virus Infection Patrick Sullivan Fred Hutchinson Cancer Research Center, Seattle, Washington Introduction Three large observational cohort studies suggest that, after controlling for virus load and CD4 cell count, anemia is related to disease progression and survival in patients with human immunodeficiency virus (HIV) infection. Recovery from anemia has been linked to improved survival outcomes. Blood transfusion has been associated with accelerated disease progression and mortality in patients with HIV infection, and review of related literature suggests that the mechanism for negative transfusion-associated outcomes may be transfusion-related immunosuppression. Therefore, the use of transfusion should be restricted to patients with acute or severe anemia. Prescription of epoetin alfa has been associated with increased survival in an observational cohort among patients with HIV infection and anemia. In the absence of data from a clinical trial documenting the effect of treating anemia on survival, clinicians should consider non-transfusion options for management of anemia on the basis of clinical status and patient functional ability. Plasma virus load and CD4 cell count are important prognostic markers that are commonly used in the management of patients with human immunodeficiency virus (HIV) infection and AIDS [1 3]. In addition, other factors, such as opportunistic infections [4 9], serum albumin concentrations [10, 11], markers of immune activation [12, 13], loss of body weight [10], and patient age [14, 15], have been associated with clinical outcomes of HIV disease. These factors differ widely in the degree to which they accurately and independently predict disease progression or survival. In some cases, such factors may have a causal relationship with decreased survival; in others, factors may be markers for severe or progressive HIV disease. Recent epidemiologic studies of HIV-related anemia have strongly and repeatedly associated low hemoglobin level with disease progression and mortality [15 22]. Patients who are at greater risk for anemia may include those of African-American ancestry, and those with low CD4 cell counts, high virus load, and low mean corpuscular volume and those receiving zidovudine [18, 23, 24]. While the association between anemia and decreased survival in HIV infection has not been proven to be causal, the consistent findings of large observational cohort studies suggest that hemoglobin level is an important factor in understanding the clinical course of patients living with HIV infection. Reprints or correspondence: Dr. Patrick Sullivan, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, Mailstop MW-500, Seattle, WA 98109. The Journal of Infectious Diseases 2002;185(Suppl 2):S138 42 q 2002 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2002/18510S-0007$02.00 Association of Anemia and Survival The results of multiple epidemiologic studies suggest that HIVinfected patients with anemia are at a greater risk for mortality than are patients without anemia, even after controlling for various factors known to affect survival, such as virus load or CD4 cell count. The Centers for Disease Control and Prevention (CDC) conducted an analysis of data from a large observational cohort study that collected information from the medical records of 32,867 HIV-positive patients who were treated at hospitals, clinics, and private medical practices throughout the United States between January 1990 and August 1996 [18]. Anemia was defined as a hemoglobin level,10 g/dl or a diagnosis of anemia based on the International Classification of Diseases-9 diagnosis codes (280 281.99, 283 284.79, 284.9 285.99, and 648.2 648.29) [25]. That study showed that in the 19,213 patients with HIV infection, median survival was significantly shorter for patients with anemia than for those without anemia (P, :0001) (table 1). This phenomenon occurred regardless of CD4 cell count, clinical AIDS, age, neutropenia, thrombocytopenia, antiretroviral therapy, or Pneumocystis carinii pneumonia (PCP) prophylaxis. Of note, the association of anemia and survival varied by the first CD4 cell count. Thus, although the hazard of dying was greater in patients who developed anemia for all CD4 strata, the hazard associated with anemia increased as CD4 cell counts increased (table 1). For example, the hazard of death among patients with incident anemia was 1.4 1.9 for CD4 cell counts of,200 cells/ml, versus 2.5 for CD4 cell counts of >200 cells/ml. The EuroSIDA study group conducted an analysis of retrospective observational cohort data collected in Europe and reported a wide variation in clinical outcome among 6725 patients with normal hemoglobin levels, mild anemia, or severe anemia at baseline [16]. Normal hemoglobin levels were defined as levels.14 g/dl for men and.12 g/dl for women. Mild anemia was defined as hemoglobin levels of 8 14 g/dl for men and 8 12

JID 2002;185 (Suppl 2) Anemia, Treatments, and Survival in HIV S139 Table 1. Association of anemia and survival in 19,213 HIV-infected patients [18]. Median survival (months) CD4 stratum (cells/ml) Anemia (99% CI) No anemia (99% CI) Risk ratio a (99% CI) P b 0 49 12 (12 12) 15 (15 17) 1.4 (1.3 1.6).0001 50 99 20 (19 21) 25 (22 29) 1.4 (1.2 1.7).0001 100 149 25 (24 28) 33 (29 40) 1.4 (1.1 1.8).0001 150 199 29 (26 32) 48 (40 58) 1.9 (1.4 2.5).0001 >200 48 (46 51) c 2.5 (2.1 2.9).0001 NOTE. CI, confidence interval. a Hazard of death associated with incident anemia in a Cox proportional hazards regression model. b P values are from the log rank test. c Unable to calculate median survival because of low death rate. g/dl for women. Severe anemia was defined as hemoglobin levels of,8 g/dl for men or women. Kaplan-Meier estimates were established for the proportion of patients who died in the months after first observation (figure 1). For patients without anemia, 3.1% died by 12 months. In contrast, for patients with mild anemia, 15.9% had died, and for patients with severe anemia, 40.8% had died. The difference among the 3 groups was statistically significant (P, :001, log-rank test). In proportional hazards regression models controlling for HIV RNA concentration and CD4 cell count, the hazard of death was increased by 57% (relative hazard, 1.57; 95% confidence interval [CI], 1.41% 1.75%; P, :0001) for each 1-g/dL reduction in hemoglobin. Moore et al. [15] analyzed the relationship between hemoglobin levels and survival in 2343 HIV-infected patients. Anemia was defined as a hemoglobin level of,9.5 g/dl. Their results indicated that the development of anemia was associated with a significantly greater risk of death (P ¼ :0001). This association was independent of CD4 cell count, development of selected opportunistic infections, age, and the use of antiretroviral and opportunistic infection drug therapies. On the basis of criteria for anemia used by the AIDS Clinical Trials Group, patients with grade 3 or 4 anemia had hazard estimates for mortality of 3.8 (95% CI, 2.8 5.2) (table 2). The findings from these epidemiologic studies provide consistent evidence of an association between anemia and mortality in HIV-infected patients. Two important questions arise from these findings: Can treatment of anemia modify this relationship and improve clinical outcome, and is there a causal association between anemia and mortality in HIV infection? level that was >1 g/dl higher than that seen at the time that anemia was diagnosed, thus permitting an assessment of the association of amelioration of anemia and clinical outcome. Recovery from anemia was significantly associated with a reduced risk of death (P ¼ :001, log-rank test), even after controlling for clinical AIDS diagnosis, CD4 cell count, neutropenia, thrombocytopenia, antiretroviral therapy, and PCP prophylaxis (figure 2). For example, median survival for patients with CD4 cell counts of 50 99 cells/ml was 31 months for those who recovered from anemia, 18 months for those who did not recover from anemia, and 25 months for those who never developed anemia. For patients with CD4 cell counts of at least 200 cells/ml, recovery from anemia was associated with a median survival of 64 months, compared with 36 months for those who did not recover from anemia (P ¼ :0001). Using data from 2343 HIV-infected patients, Moore et al. [15] described the results for 91 patients with anemia (hemoglobin level,9.5 g/dl) who were treated with epoetin alfa for an average of 6 months (range, 2 weeks to 28 months). Patients treated with epoetin alfa experienced improved hemoglobin levels (mean increase, 1.5 g/dl; range, 0.2 7.1). The use of epoetin alfa was associated with a significantly reduced risk of death (relative hazard, 0.57; range, 0.40 0.81; P ¼ :002) compared with no epoetin alfa treatment. The survival benefit associated with epoetin alfa was maintained even after controlling for other variables with known prognostic value. Is the Relationship between Anemia and Survival in HIV Infection Causal? Although epidemiologic findings are important, they are limited in their ability to substantiate causality. Observational cohort studies do not randomly assign patients to anemic or non-anemic status and do not randomly assign treatment or placebo for those Association of Recovery from Anemia and Survival In the observational cohort study conducted by the CDC, subsequent hemoglobin levels were available for 3203 anemic patients (hemoglobin,10 g/dl) [18]. Of these patients, 1341 (42%) were treated with either recombinant human erythropoietin (epoetin alfa) or blood transfusion, and 1208 (38%) recovered from anemia (hemoglobin >10 g/dl) and achieved a hemoglobin Figure 1. Kaplan-Meier curve of time to death in HIV-infected patients with normal hemoglobin (Hb), mild anemia, or severe anemia in the EuroSIDA study. Reprinted with permission from [16]. The indicated P value is a log-rank statistic.

S140 Sullivan JID 2002;185 (Suppl 2) Table 2. Association of anemia and survival in 2343 HIV-infected patients [15]. Anemia grade a (hemoglobin level) Relative hazard (95% CI) b P c 1 (8.0 9.4 g/dl) 3.06 (2.54 3.68).0001 2 (7.0 7.9 g/dl) 2.90 (2.25 3.72).0001 3 and 4 (,6.9 g/dl) d 3.80 (2.76 5.23).0001 NOTE. CI, confidence interval. a The severity of the anemia was based on hemoglobin levels used by the AIDS Clinical Trials Group. b Hazard of death associated with incident anemia in a Cox proportional hazards regression model. c P values are from the log rank test. d Grades 3 and 4 were combined to increase the power of the analysis. patients who develop anemia. Thus, the questions of whether the relationship between anemia and decreased survival for people with HIV infection is causal and whether aggressive treatment of anemia may be associated with survival benefit cannot be answered conclusively by an observational cohort study. To assess causality when only results from observational studies are available, epidemiologists rely on at least 6 criteria [26, 27]: consistency among studies, dose-response effect, coherence (biologic plausibility), strength of association, exposure precedes disease, and specificity of association. In the case of the results of studies of anemia and HIV infection, satisfaction of 5 of these criteria is consistent with a causal relationship. In short, there is consistency across the epidemiologic studies conducted to date; there is a dose-response effect such that greater grades of anemia are associated with greater risk of mortality; the relationship is strong and independent of other variables; causality is biologically plausible (coherence); and in the analytical design, the exposure (anemia) precedes the outcome (death). The criterion of specificity of the association (i.e., the putative causative agent is both necessary and by itself sufficient to result in the outcome) is infrequently satisfied, even in relationships where causality is clear. Although many of the traditional criteria for causality are met, there exists the possibility of biases, including survival bias, which might result in data that suggest a causal relationship where one does not in fact exist. A prospective, randomized clinical trial would be required to evaluate the practical consequence of the question of causality: Does a particular intervention to correct anemia improve survival? If the relationship between anemia and survival is not causal, then anemia may be a marker for some aspect of progressive HIV disease that is not measured by CD4 cell count or HIV RNA concentration. In the latter case, even if the relationship between anemia and shorter survival is not causal, anemia represents an important clinical consideration for providers caring for patients with HIV infection and an important area for further research. Data from a randomized clinical trial would ultimately best inform evidence-based recommendations for management of anemia in patients with HIV infection. Association of Treatments for Anemia and Survival The cohort study by Moore et al. [15] evaluated the survival effects of blood transfusion and epoetin alfa prescription among persons with HIV infection and anemia. The results of that analysis indicated that blood transfusion was associated with shorter survival, while epoetin alfa prescription was associated with improved survival. A follow-up analysis of data from the same cohort in the late 1990s was reported, with similar results [19]. A review of related literature suggests mechanisms that may explain these observed associations. The standard treatment for acute, severe, or life-threatening anemia is blood transfusion, and the main advantage of this modality compared with drug therapy is rapid recovery from anemia with relief of symptoms [28]. However, blood transfusion, even early in the course of HIV disease, has been associated with increased risk of death [15, 19, 29] and death rate [30] for patients with HIV infection. There are several hypotheses that might explain this phenomenon, including the risk for transfusion-associated infection with another infectious agent, transfusion-associated immunosuppression, or activation of HIV replication. Although current screening practices have resulted in marked reduction in the risk of transfusion transmission of HIV, hepatitis B virus, hepatitis C virus, and human T cell lymphotropic viruses I/II, there are still risks of infection with other agents, such as cytomegalovirus or parvovirus B19 [31 33]. Transfusionassociated immunosuppression, thought to be mediated by inflammatory cytokines, is demonstrated by a reduced function in Figure 2. Median survival time from baseline CD4 cell count, stratified by whether the patient recovered from anemia, and first observed CD4 cell count among 3203 persons with anemia (hemoglobin,10 g/dl) and HIV infection [18]. Bars indicate median survival times; the indicated P value is a log-rank statistic. Nos. appearing below each CD4 stratum indicate the hazard of death (with 99% confidence intervals [CI]) associated with recovering from anemia (defined as hemoglobin >10 g/dl and an increase in hemoglobin of at least 1 g/dl) in a Cox proportional hazards regression model for patients in that CD4 cell stratum. Data from [18].

JID 2002;185 (Suppl 2) Anemia, Treatments, and Survival in HIV S141 lymphocytes, natural killer cells, and monocytes [34 36]. Transfusion has been associated with the recurrence of malignancy in persons with colorectal cancer and with prolonged allograft survival in patients with renal transplants, both of which would be predicted from putative transfusion-associated immunosuppression. Last, transfusion has been associated with the transient activation of HIV expression [37, 38]. Although the clinical significance of brief break-through cycles of HIV replication is not clear and vaccine-associated activation of HIV expression seems not to be associated with decreased survival [39], active HIV replication in the context of antiretroviral therapy represents an opportunity for development of resistance, which could in turn be associated with reduced survival. Although transfusion is clearly appropriate and important for patients with acute blood loss or severe or life-threatening anemia, these findings suggest that for patients with HIV infection and less acute or severe anemia, non-transfusion options for management of anemia, including epoetin alfa, should be considered; clinical evaluation and transfusion and non-transfusion options are discussed in detail elsewhere (see article by S. Claster in this supplement). This conclusion is also consistent with current transfusion recommendations [33], which assert that blood transfusion should not be administered on the basis of a trigger hemoglobin set point but should be based on the patient s risk of developing inadequate oxygenation [40] and that avoidance of transfusion [should be] the ideal, to the extent that avoidance [is] not likely to be a more serious risk than the transfusion [33]. The question of whether prescription of epoetin alfa may be plausibly causally associated with improved survival may also be considered in the context of evidence from clinical trials of patients with cancer-associated and renal anemia. In a recently reported randomized, double-blind, placebo-controlled trial to evaluate the effects of epoetin alfa on hematologic parameters for patients with cancer (solid or non-myeloid hematologic malignancies)-related anemia, there was a trend in overall survival favoring epoetin alfa [41]. Other studies have suggested that use of epoetin alfa may improve survival outcomes for patients with renal anemia and early-stage cardiac disease [42] and for patients undergoing chemoradiation for head and neck tumors [43]. The mechanisms suggested to substantiate plausibility in these studies have included cellular compromise (impaired cellular oxygenation) and general patient compromise (decreased quality of life and treatment delivery) [44]. Conclusions The results of multiple epidemiologic studies suggest an inverse relationship between anemia and survival in patients with HIV infection. Conversely, recovery from anemia is associated with better survival outcomes. The nature of the relationship between anemia and survival is not completely defined by these studies, and a randomized clinical trial would be required to make definitive recommendations regarding the potential survival benefit of managing anemia aggressively. Available evidence suggests that blood transfusion for the management of anemia in patients with HIV infection is associated with accelerated mortality, plausibly because of transfusion-related immunosuppression. These findings should be interpreted in the broader context of knowledge about anemia and quality of life (see article by P. Volberding in this supplement) and of available non-transfusion options for management of anemia (see article by S. Claster in this supplement). References 1. 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