Epidemiology of Anemia in Human Immunodeficiency Virus (HIV)-Infected Persons: Results From the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project

IV. Discussion

We found that anemia is a frequent complication of HIV infection that is associated with an increased risk of death and that recovery from anemia is associated with decreased risk of death for HIV-infected persons who do develop anemia. According to our analysis, for most CD4 strata the median survival for persons who never became anemic was similar to the median survival for those who became anemic but later recovered (Tables 6 and 7).

The incidence of anemia was strongly and consistently associated with the progression of HIV disease as measured by diagnosis of an AIDS-defining opportunistic illness and measurement of a CD4 count of <200 cells/µL. This association is mostlikely explained by the increasing viral burden as HIV disease progresses, which could cause anemia by increased cytokine-mediated myelosuppression. Alternatively, anemia may be a surrogate marker for some aspect of disease progression not captured by controlling for CD4 count and clinical AIDS diagnosis. When adequate data are available for viral load measurements, quantitative RNA measurements should be included as a covariate in analyses like the ones presented here.

The administration of ZDV is recognized to cause anemia because of myelosuppression.⁽¹⁴⁾ In our analysis, the prescription of ZDV was positively associated with a diagnosis of drug-related anemia but was protective against a diagnosis of anemia unrelated to drugs. This protective effect may occur because patients in whom anemia develops while they are prescribed ZDV are likely to be given a diagnosis of drug-related anemia, and the diagnoses of drug-related anemia and anemia unrelated to drugs were mutually exclusive in our analysis. The protective effect may also be explained by the fact that for patients who do not develop anemia related to ZDV and continue to take the drug, ZDV treatment may slow the progression of the HIV disease and the HIV replication rate. Lower viral burden, in turn, may be associated with a decreased incidence of anemia because of less cytokine-mediated myelosuppression. The prescription of ganciclovir, known to cause myelosuppression, was also associated with the incidence of anemia, whether identified as drug related or unrelated to drugs. This suggests that anemia associated with prescription of ganciclovir may be less likely to be recognized or recorded in medical records as drug-related than anemia associated with ZDV prescription. Fluconazole may cause myelosuppression when taken concurrently with ZDV, because taking both reduces the serum half life of ZDV and increases its serum concentrations.⁽²⁶⁾

An unexpected finding was the negative association between prescription of TMP-SMX and anemia. Although administration of TMP-SMX can cause drug-associated aplastic anemia or immune-mediated destruction of specific populations of blood cells, this effect would not be expected to have a significant influence on the AOR in this analysis because the effect is sporadic.⁽¹⁶⁾ It is likely that the protective effect of TMP-SMX is associated with the prevention of other conditions, such as Mycobacrerium avium complex⁽²⁷⁾ or bacterial septicemia, which are more predictable causes of anemia, or other infections that could promote the development of the anemia associated with chronic disease or with inflammation.

An increased incidence of anemia not recognized as drug related was observed in black persons, although black race was not associated with drug-related anemia. This association could be because of several factors or a combination of these factors. A small percentage of black persons have sickle cell anemia. The prevalence of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may be 4% to 13% for black men^{(28, 29)} and 3% for black women.⁽²⁹⁾ For persons with G-6-PD deficiency, dapsone⁽³⁰⁾ or sulfamethoxazole,⁽³¹⁾ both of which are prescribed for prophyaxis for P carinii pneumonia in patients with HIV infection, may cause hemolytic anemia. Persons with G-6-PD deficiency may also develop hemolytic anemia after infection with certain bacteria (including Salmonella).⁽³²⁾ The diagnoses of sickle cell anemia and G-6-PD were not consistently collected in the Adult and Adolescent Spectrum of HIV Disease Project, so a direct evaluation of these hypotheses was not possible. It is also possible that black race is a marker for other factors that are associated with increased incidence of anemia but that were not included in our analysis.

Anemia was also associated with thrombocytopenia and neutropenia, perhaps because myelosuppression caused by chemotherapeutics may affect production of all the cell lineages. The association of anemia with lymphoma may be because of myelophthisis, the secondary effects of therapies administered for lymphoma, or anemia associated with chronic disease. Myelosuppression is commonly observed in patients with bacterial septicemia, regardless of HIV infection status.

For an analysis of factors associated with incidence of anemia, the outcomes of drug-related anemia and anemia unrelated to drugs were evaluated separately because the effect of ZDV prescription, one of the most recognized causes of anemia in HIV-infected persons, differed by type of anemia. Because these two types of anemia were distinguished only on the basis of physician diagnosis as recorded in the medical record, there was no standard criterion for drug-related anemia. The condition may have been under diagnosed or under documented in medical records or the association between ZDV prescription and drug-related anemia could be overestimated if physicians assume a drug-related cause for anemia in a patient who is taking ZDV.

In all analyses, some patients were excluded because of prevalent anemia, inadequate length of follow-up, or missing data that were necessary for our analysis. In general, the characteristics of the patients excluded from the analyses were similar to the characteristics of those who were included (Tables 1 and 2). A possible bias is introduced in the analysis of incidence by including persons who developed anemia during the second semester after baseline review but had no further semester reviews, but not including persons with two semesters of review and no anemia. This tends to cause an overestimate of the incidence of anemia.

The main limitation of our analysis is that outcomes and exposures in this project are reported only as occurring or not occurring in each 6-month interval of chart abstraction, and the exact dates of drug-related anemia diagnosis, concurrent illnesses, or specific drug administration were not collected. Therefore, our ability to define exact temporal relationships between exposures and anemia is limited. Exposures to drugs could occur from 1 day to 12 months before anemia, and this decreases our ability to detect associations between anemia and a drug. This should result in conservative estimates of excess risk. Data that would allow the classification of the cause of anemia, such as reticulocyte counts, erythropoietin levels, and parvovirus IgM titers, were not collected in this project.

The Adult and Adolescent Spectrum of HIV Disease Project includes diverse study sites and populations,⁽²⁴⁾ but these data are not necessarily representative of all HIV-infected persons in the United States. Because HIV-infected patients must have been receiving medical care at a clinic for at least 12 months to be included in our analysis, there may be a selection bias for asymptomatic people with earlier knowledge of HIV infection status or with more access to care.

The definition of anemia chosen for this study (hemoglobin <10 g/dL) was different from clinical reference ranges for hemoglobin concentration in men and women. We chose this cutoff for defining anemia to exclude hereditary causes for mild anemia, such as thalassemia trait, and to allow for use of a single cutoff that would clearly exclude normal hemoglobin concentrations for both men and women. As a result, our estimates of anemia incidence underestimate the true impact of anemia in this population. Physicians should consult their local laboratories to determine appropriate reference ranges for clinical interpretation of hemoglobin concentrations, and any anemia in HIV-infected persons, regardless of severity, should be investigated.

Anemia in HIV-infected patients, if persistent, is associated with substantially decreased survival. Although our analyses cannot show whether this relationship is causal, our findings are consistent with those of other studies of anemia as a prognostic factor in HIV infection,^{(20, 21)} and consideration should be given to evaluating the effects of treating anemia in a prospective study design. If recovery from anemia is shown to directly increase survival, screening for anemia should be aggressive and patients with anemia should be treated.

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