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Community and International Nutrition

Iron Status Is an Important Cause of Anemia in HIV-Infected Tanzanian Women but Is Not Related to Accelerated HIV Disease Progression^1,2

Departments of ³ Nutrition and ⁴ Epidemiology, Harvard School of Public Health, Boston, MA, 02125 and ⁵ Departments of Community Health and ⁶ Internal Medicine, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania

^* To whom correspondence should be addressed. E-mail: rkupka{at}post.harvard.edu.

	ABSTRACT

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
In HIV-infected populations from developing countries, it is unclear what proportion of anemia is attributable to iron deficiency (ID) and whether high body iron stores worsen HIV disease progression. We therefore evaluated these research questions in 584 HIV-infected Tanzanian women. Hemoglobin (Hb), serum ferritin (SF), serum transferrin receptor (sTfR), and C-reactive protein (CRP) concentrations were evaluated between 13 and 43 wk after women gave birth. ID was defined as SF or sTfR outside normal ranges, and ID anemia (IDA) as ID plus low Hb. In multivariate Cox regression models, the association between SF and HIV disease progression was assessed. Participants received iron + folate supplements during pregnancy. Hb (r = –0.159; P = 0.0001), SF (r = 0.355; P < 0.0001), and sTfR/log SF index (r = –0.119; P = 0.004) were related to CRP, whereas sTfR (r = 0.029; P = 0.48) was not. Prevalence estimates were 39.7% for ID and 23.6% for IDA. ID was associated with 48.9% of anemia cases. Categories of SF were not significantly associated with HIV-related mortality or progression to stage 4. Nevertheless, SF > 150.0 µg/L was related to a nonsignificantly elevated risk of progression to stage 4 (rate ratio = 1.78; 95% CI = 0.68–4.64; P = 0.24) compared with SF < 12.0 µg/L. In HIV-infected, parous women from sub-Saharan Africa, ID is of moderately high prevalence and is an important underlying cause of anemia. High storage iron does not appear to be related to HIV disease progression in this population, but more research on the role of iron during HIV disease is needed.

	Introduction

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

Based on a small number of studies, between 35 and 69% of HIV-infected pregnant women from sub-Saharan Africa, the geographic region most heavily affected by the HIV epidemic, are iron deficient (5–7). Although there are no studies to our knowledge in HIV-infected women of reproductive age, there is evidence based on HIV-untested women that the prevalence of ID may be similar to pregnant women. Furthermore, these studies indicate that more than one-half of anemia may be associated with ID (8,9).

The paucity of studies on iron status in HIV-infected women in sub-Saharan Africa is an important research gap, as there is evidence that ID (10), as well as elevated storage iron (5,11–17), may lead to adverse HIV-related outcomes. The potential risks of ID and high storage iron are of special relevance for treatment programs recommending supplemental iron for women of reproductive age (1). To expand the knowledge on iron status and its relation to anemia as well as HIV disease progression in sub-Saharan Africa, we conducted an observational study in HIV-infected women of childbearing age from Dar es Salaam, Tanzania.

	Materials and Methods

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
Starting in April 1995, 1078 HIV-infected pregnant women were enrolled into a randomized, placebo-controlled trial to examine the efficacy of multivitamin supplements given pre- and postpartum to improve maternal and child health outcomes. Details of the trial have been published elsewhere (18,19). Briefly, women were randomized to a daily dose of 1 of the following regimens: 1) vitamin A + ß-carotene (1500 µg retinol + 30 mg of ß-carotene); 2) vitamins B, C, and E (20 mg vitamin B-1, 20 mg riboflavin, 25 mg vitamin B-6, 100 mg niacin, 50 µg vitamin B-12, 0.8 mg folic acid, 500 mg vitamin C, and 30 mg all rac--tocopheryl acetate); 3) vitamins B, C, and E + vitamin A + ß-carotene; or 4) placebo. In accordance with national guidelines for antenatal care at that time, all women received 400 mg ferrous sulfate (equivalent to 120 mg ferrous iron) and folate (5 mg) for anemia prophylaxis during pregnancy. For malaria prophylaxis during pregnancy, women received weekly doses of 500 mg chloroquine phosphate (equivalent to 300 mg of chloroquine base). Antiretroviral therapy was not available at the time of the study.

The study was approved by the College Research and Publications Committee of Muhimbili University College of Health Sciences, the Ethics Committee of the National AIDS Control Program of the Tanzanian Ministry of Health, and the Institutional Review Board of the Harvard School of Public Health.

    Follow-up procedures. Women were followed during and after pregnancy through monthly clinic visits. Study physicians conducted complete physical examinations and trained study nurses determined the weight, height, and mid-upper arm circumference of study participants. HIV disease stage was assessed at each visit in accordance with WHO criteria (20). Women were asked to provide a blood specimen at baseline of the parent trial (i.e. between gestational ages 12 and 27 wk), at 6-wk postpartum, and at 6-mo intervals thereafter for measurement of hemoglobin (Hb) and CD4 cell counts. Aliquots were stored for future analyses of additional variables. In anemic women, infectious causes of anemia were investigated. This included stool and blood analyses to test for intestinal helminthes and malaria parasites, respectively. Anemic women were treated based on physician diagnosis; they were also encouraged to consume iron-rich foods. Furthermore, pregnant women were counseled about the importance of taking iron + folate supplements, whereas nonpregnant anemic women received iron + folate supplements and were counseled about their use.

WHO HIV disease stage was assessed at each clinic visit on the basis of the woman's morbidity history and physical examination (20). In case a woman missed a scheduled clinic visit, a home visit was conducted to inquire about her vital status. Neighbors or relatives were contacted if necessary but not to collect data on a woman's morbidity. The cause of death was ascertained using medical records, interviews with relatives, or both. Women whose cause of death could not be ascertained or for whom death was deemed unrelated to AIDS were not counted as events in analyses with the endpoint ‘Death from AIDS-related cause,’ but contributed follow-up time until their date of death.

    Laboratory methods. At the baseline visit of the parent trial (i.e. between gestational ages 12 and 27 wk), viral load was determined from a subset of 115 women. Additional viral load measurements were performed later on a random sample of 300 women. For each of those 300 clients, we analyzed a minimum of 3 stored aliquots (baseline, last sample at the time of selection, and the sample at approximately the midpoint between the 2). After study closure in August 2003, we drew on additional stored aliquots to measure serum ferritin (SF), serum transferrin receptor (sTfR), and serum C-reactive protein (CRP) in 610 women whose blood was taken at 30 wk after delivery. From the available viral load data and the routinely collected Hb and CD4 data, we identified those measurements that were available within ± 4 wk of the sample used to determine SF, sTfR, and CRP. Observations with missing Hb were deleted, whereas observations with missing viral load or CD4 were retained in analyses.

Hb was determined with a CBC5 Coulter Counter; because of a machine breakdown, some samples were analyzed with by the cyanmethemoglobin method using a colorimeter (Corning). Daily standards were analyzed for each method. CD4 cell counts were determined using the FACScount and FACSCAN systems (Becton Dickinson). Viral load was measured using the Roche Amplicor version 1.5 assay. SF, sTfR, and CRP were analyzed at the Clinical and Epidemiologic Research Laboratory, Boston Children's Hospital using immunoturbidimetric assays (Roche Diagnostics) on a Hitachi 917 analyzer. SF below the detectable limit of 0.2 µg/L were imputed as 0.1 µg/L and sTfR < 0.5 mg/L were imputed as 0.25 mg/L.

    Data analyses. The following cutoffs were used for analyses. Anemia was defined as Hb < 110 g/L, according to the WHO-recommended cutoff of 120 g/L minus a 10-g/L adjustment to account for lower Hb reported in blacks (21). Elevated sTfR was defined as >4.4 mg/L (22) and elevated CRP as >10 mg/L (23). Data from Malawi indicate that SF < 30 µg/L represent low iron stores more accurately than the commonly used cutoff of <12 µg/L in cohorts experiencing high levels of inflammation (24). The level of inflammation in the Malawian cohort (median CRP = 30.5 mg/L) was substantially higher than in our postpartum cohort (median CRP = 1.94 mg/L), making it unclear whether a cutoff of <30 µg/L was warranted for our entire cohort. We therefore defined low SF as <12.0 µg/L in the absence of inflammation (CRP 10.0 mg/L) and as <30.0 µg/L in the presence of inflammation (CRP > 10.0 mg/L) (1). Anemia (Hb <110 g/L) was classified as ID anemia (IDA) in cases where SF was low, sTfR was elevated, or both. Anemia without ID was classified as Hb <110 g/L and no signs of ID based on SF and sTfR. sTfR was divided by log₁₀ SF to create the sTfR-SF index (25). In prospective analyses, 5 categories of SF were defined to denote 2 degrees of low (<12.0 µg/L and 12.0–29.9 µg/L) and adequate (30.0–89.9 and 90.0–150.0 µg/L) iron stores, as well as high storage iron (>150.0 µg/L) (1). To evaluate the significance of a trend, a test was constructed based on category medians.

Spearman rank correlations were used to investigate associations between continuous measurements of Hb, SF, sTfR, CRP, CD4 cell count, and viral load. We used Cox proportional hazards regression models to investigate the association between SF and death from AIDS-related causes, progression to stage 4, and a composite endpoint of AIDS-related death or progression to stage 4. All models were adjusted for the trial regimen (4 groups) and maternal age at baseline (<25, 25 y). In multivariate analyses, a first set of models was also adjusted for Hb (<110, 110 g/L) and CRP (<1.49, 1.50–10.00, 10.01–32.16, >32.16 mg/L) concentrations, while a second set of models was additionally adjusted for CD4 cell count (<200, 200–499, 500 cells/mm³), viral load (<50,000, 50,000 copies/mm³), BMI (<18.5, 18.5 kg/m²), and mid-upper arm circumference (<22, 22 cm).

From the 610 samples analyzed for sTfR, SF, and CRP, we deleted 4 samples because they had hemolyzed and 22 samples because there were no Hb measurements available within ± 4 wk, leaving a sample size of 584 for cross-sectional analyses and mortality (Fig. 1). Such samples were obtained between 13 and 43 wk (median = 30, interquartile range = 30–31) after delivery. Of these 584 participants, 569 were not at HIV stage 4 and were thus eligible to enter analysis on progression to HIV stage 4 and the composite endpoint AIDS-related death or progression to stage 4. The median follow-up time with regard to survival status was 63 mo (interquartile range = 50–71).

View larger version (18K): [in this window] [in a new window]   FIGURE 1  Study profile. 1Viral load was measured in a subset of clients only. 2Not eligible for models examining the endpoints ‘Progression to stage 4’ or ‘AIDS- death or progression to stage 4’. 3In models examining the endpoint ‘AIDS-death or progression to stage 4’, follow-up time for these 54 clients ended at the time of progression to stage 4.

	Results

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 
At the start of this study, women were aged 25.8 ± 4.8 y and had been part of the original randomized, controlled trial for 48.0 ± 6.0 wk. Anemia was present among 48.3% of participants and the prevalence estimates for low SF and elevated sTfR were 25.2 and 24.3%, respectively (Table 1). The prevalence of ID was 39.7% and IDA was present in 23.6% of the total cohort and 48.9% of the participants with anemia (Table 2).

	Discussion

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

The deficiency progresses on a continuum from low iron stores without dysfunction to a deficiency with functional consequences and finally to IDA, its most severe form (1). The fact that only one-half of anemia was related to ID in this cohort indicates that there are other causes of anemia. In our setting, these may include parasitic infections, hemoglobinopathies, inflammation, dyserythropoiesis, and other nutritional deficiencies, such as in folate, vitamin A, and vitamin B-12 (1,28,29).

We defined ID as SF or sTfR outside normal ranges. Although SF <12 µg/L is a definite sign of low iron stores (4), the sensitivity of this indicator can be increased if a higher cutoff value (<30 µg/L) is chosen in the presence of inflammation (1). With an inflammation-dependent cutoff, low SF occurred in 25.2% of participants and evidence for low iron stores was thus less prevalent than in pregnant HIV-positive women from Zimbabwe (prevalence = 64%; SF <12 µg/L) (5) and Malawi (prevalence = 35%; SF < 12 µg/L) (6), as well as in HIV-untested nonpregnant women from Ivory Coast (prevalence = 40%; SF < 12 µg/L). Elevated sTfR signal an increased tissue need for iron that occurs after body stores have been depleted (4). Using the assay-specific recommended cutoff to define elevated sTfR for premenopausal women (22) yielded a prevalence of elevated sTfR of 24.3%, which is comparable to the prevalence of low SF.

However, the prevalence of ID, as based on abnormal SF or sTfR, substantially exceeded the prevalence as based on either indicator alone. This illustrates low agreement between the 2 indicators, also shown by the low (albeit significant) correlation between the 2 variables. SF is a positive acute phase reactant, as illustrated by its positive correlation with CRP (30). The underlying mechanism may be an iron block that prevents the release of stored iron and leads to the deposition of iron in body stores (31). Despite some evidence to the contrary (32), sTfR is considered to be unaffected by acute phase response to infection (8,33). The lack of correlation with CRP in this cohort supports this finding. Therefore, sTfR is considered an ideal indicator in populations experiencing high levels of inflammation, as long as high rates of erythropoiesis, such as due to malarial disease, can be excluded (34).

Hb was not correlated with SF in the overall cohort, possibly because low Hb signals a more advanced form of ID than SF, which reflects low iron stores. Furthermore, low Hb may be due to other nutritional or nonnutritional causes that are unrelated to iron status (1,28,29). The sTfR-SF index has been successfully used to diagnose depleted iron stores in the presence of inflammation (25,35,36). However, the sTfR-SF index was significantly related to CRP in this cohort, raising concerns that it is influenced by inflammation. More evidence is therefore needed to indicate the usefulness of sTfR-SF to diagnose ID in the presence of inflammation.

All women received standard ferrous iron + folate supplements during pregnancy to prevent anemia. Although this therapy is likely to have improved women's iron status, it is unclear whether it accounts for the signs of increased iron stores (defined as SF >150 µg/L) among 11.1% of the participants. High storage iron may accelerate HIV replication by facilitating the production of reactive oxygen species (37) and increasing the activity of the iron-dependent ribonucleotide reductase required for viral replication (38). It may also promote the growth of invading pathogens and impair innate and acquired immune responses (39). Consistent with these mechanisms, SF was inversely related to CD4 cell counts, which indicate the level of HIV disease progression, and positively related to viral load, which represents the level of HIV disease activity. The correlations were stronger among the subset of participants with CRP >10 mg/L, possibly because of the joint influence of inflammation on SF, immune function, and viral replication. Even though sTfR itself was not correlated with inflammation, sTfR became strongly and inversely related to viral load in the presence of inflammation. These findings may support an adverse effect of high iron stores in HIV-infected populations, especially in the presence of inflammation.

In age-adjusted univariate analyses, high iron stores were associated with significantly elevated risk of adverse events and point estimates remained elevated in multivariate models, albeit nonsignificantly (P 0.24). A range of studies from industrialized countries also examined the role of iron status in HIV disease progression. In a European multi-center study, the rate of HIV disease progression was compared among thalassemia major patients receiving different dosages of the iron-chelating drug desferrioxamine (13). Clients who received a high dosage of the drug progressed more slowly to HIV disease stage 4 compared with those receiving a low dosage of the drug, which is deemed less effective at binding iron. The benefit of the high dosage may have been mediated by lowering the amount of storage iron in the form of SF, as clients in the cohort with SF >1935 µg/L (the median) were more likely to progress to HIV disease stage compared with clients with SF 1935 µg/L (14). Such severely elevated iron stores can occur in thalassemia patients due to frequent blood transfusions (40). Among HIV-infected adults from the US, high bone marrow macrophage iron stores were associated with increased mortality risk (15). A French study compared the efficacies of aerosolized pentamidine and dapsone for Pneumocystis carinii prophylaxis and described an increased risk of mortality in the dapsone group (41). The dapsone included 60 mg elemental iron, which was hypothesized to have accounted for the adverse effects. In a study from Belgium and Luxembourg, haptoglobin phenotype Hp 2–2 was associated with higher SF compared with other phenotypes that have a higher Hb-binding potential. The phenotype was also associated with decreased survival (16). In a case-control study among participants from the Women's Interagency HIV Study, higher log10 ferritin concentrations and higher transferrin receptor-log10 ferritin ratios were associated with reduced survival (12).

Several studies evaluated the association between high iron status and adverse HIV-related outcomes in sub-Saharan Africa. Among HIV-infected pregnant women from Zimbabwe, those with severely depleted iron stores (SF <6 µg/L) had only 0.27 times the viral load (95% CI = 0.13,0.53) compared with participants with SF >24 µg/L (11), whereas in HIV-infected pregnant women from Malawi, sTfR and SF were not associated with CD4 cell count and viral load (42). In an evaluation from Kenya in 32 HIV-infected adults, 60 mg elemental iron given twice weekly for 4 mo did not affect viral load (43).

Collectively, the available evidence indicates that among nonpregnant populations from developed countries, iron overload disorders occur and may lead to adverse HIV-related outcomes, possibly due to high exposure to iron for extended periods of time. The risk of iron overload appears to be lower in developing countries and less evidence links it to adverse outcomes.

There are several limitations to our study. We were unable to account for the contribution of hemoglobinopathies to anemia and for a potentially biasing effect of hepatocellular dysfunction on SF (44). Cross-sectional analyses relating indicators of iron status to advanced HIV disease may have been subject to reverse causality. Residual or unmeasured confounding may have biased the relation between SF and clinical outcomes. However, because we were able to capture important known confounding variables, a large confounding effect due to extraneous variables appears unlikely. Lastly, our findings may not be generalizable to all nonpregnant women or, in fact, to all pregnant women living in sub-Saharan Africa, given that our study participants delivered several months before indicators of iron status were measured and that participants received iron + folate prophylaxis during pregnancy.

High storage iron was not significantly related to accelerated HIV-disease progression, but the elevated point estimates, coupled with low statistical power, do not allow us to rule out adverse effects of high iron stores. Given that iron supplements may raise iron stores (45), there are concerns that iron supplementation may not be safe among HIV-infected populations. As pointed out by several research groups (12,42,46) and WHO (47), evidence from randomized, controlled trials is needed to examine the safety, as well as efficacy, of iron supplements among HIV-infected individuals in settings such as sub-Saharan Africa. While such evidence is awaited, it is prudent to continue routine iron (and folate) supplementation in both HIV-infected and HIV-uninfected populations. Despite its apparent efficacy to lower ID, iron + folate supplements appear to be insufficient to prevent a large part of anemia among HIV-infected women. Additional effective strategies are likely to include highly active antiretroviral therapy (when indicated), prevention and treatment of parasitic infections, and other micronutrient supplementation.

	FOOTNOTES

 
¹ Supported by grants from the National Institute of Child Health and Human Development (R01 32257) and the Fogarty International Center, NIH.

² R. Kupka, G. I. Msamanga, F. Mugusi, P. Petraro, D. J. Hunter, and W. W. Fawzi, no conflicts of interest.

⁷ Abbreviations used: CRP, C-reactive protein; Hb, hemoglobin; ID, iron deficiency; IDA, iron deficiency anemia; RR, rate ratio; SF, serum ferritin; sTfR, serum transferrin receptor.

Manuscript received 19 March 2007. Initial review completed 5 April 2007. Revision accepted 20 July 2007.

	LITERATURE CITED

TOP ABSTRACT Introduction Materials and Methods Results Discussion LITERATURE CITED

 

1. WHO/UNICEF/UNU. Iron deficiency anemia, assessment, prevention and control: a guide for programme managers. Geneva: WHO/NHD/01.3. WHO; 2001.

2. Stoltzfus R. Defining iron-deficiency anemia in public health terms: a time for reflection. J Nutr. 2001;131:S565–7.[Abstract/Free Full Text]

3. Jurado RL. Iron, infections, and anemia of inflammation. Clin Infect Dis. 1997;25:888–95.[Medline]

4. Cook JD. Defining optimal body iron. Proc Nutr Soc. 1999;58:489–95.[Medline]

5. Friis H, Gomo E, Kastel P, Ndhlovu P, Nyazema N, Krarup H, Michaelsen KF. HIV and other predictors of serum folate, serum ferritin, and hemoglobin in pregnancy: a cross-sectional study in Zimbabwe. Am J Clin Nutr. 2001;73:1066–73.[Abstract/Free Full Text]

6. Semba RD, Kumwenda N, Hoover DR, Taha TE, Mtimavalye L, Broadhead R, Eisinger W, Miotti PG, Chiphangwi JD. Assessment of iron status using plasma transferrin receptor in pregnant women with and without human immunodeficiency virus infection in Malawi. Eur J Clin Nutr. 2000;54:872–7.[Medline]

7. Antelman G, Msamanga GI, Spiegelman D, Urassa EJ, Narh R, Hunter DJ, Fawzi WW. Nutritional factors and infectious disease contribute to anemia among pregnant women with human immunodeficiency virus in Tanzania. J Nutr. 2000;130:1950–7.[Abstract/Free Full Text]

8. Asobayire FS, Adou P, Davidsson L, Cook JD, Hurrell RF. Prevalence of iron deficiency with and without concurrent anemia in population groups with high prevalences of malaria and other infections: a study in Cote dIvoire. Am J Clin Nutr. 2001;74:776–82.[Abstract/Free Full Text]

9. Massawe SN, Urassa EN, Nystrom L, Lindmark G. Anaemia in women of reproductive age in Dar-es-Salaam, Tanzania. East Afr Med J. 2002;79:461–6.[Medline]

10. O'Brien ME, Kupka R, Msamanga GI, Saathoff E, Hunter DJ, Fawzi WW. Anemia is an independent predictor of mortality and immunologic progression of disease among women with HIV in Tanzania. J Acquir Immune Defic Syndr. 2005;40:219–25.[Medline]

11. Friis H, Gomo E, Nyazema N, Ndhlovu P, Krarup H, Madsen PH, Michaelsen KF. Iron, haptoglobin phenotype, and HIV-1 viral load: a cross-sectional study among pregnant Zimbabwean women. J Acquir Immune Defic Syndr. 2003;33:74–81.[Medline]

12. Gordeuk VR, Onojobi G, Schneider MF, Dawkins FW, Delapenha R, Voloshin Y, von Wyl V, Bacon M, Minkoff H, et al. The association of serum ferritin and transferrin receptor concentrations with mortality in women with human immunodeficiency virus infection. Haematologica. 2006;91:739–43.[Abstract/Free Full Text]

13. Costagliola DG, de Montalembert M, Lefrere JJ, Briand C, Rebulla P, Baruchel S, Dessi C, Fondu P, Karagiorga M, et al. Dose of desferrioxamine and evolution of HIV-1 infection in thalassaemic patients. Br J Haematol. 1994;87:849–52.[Medline]

14. Salhi Y, Costagliola D, Rebulla P, Dessi C, Karagiorga M, Lena-Russo D, de Montalembert M, Girot R. Serum ferritin, desferrioxamine, and evolution of HIV-1 infection in thalassemic patients. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:473–8.[Medline]

15. de Monye C, Karcher DS, Boelaert JR, Gordeuk VR. Bone marrow macrophage iron grade and survival of HIV-seropositive patients. AIDS. 1999;13:375–80.[Medline]

16. Delanghe JR, Langlois MR, Boelaert JR, Van Acker J, Van Wanzeele F, van der Groen G, Hemmer R, Verhofstede C, De Buyzere M, et al. Haptoglobin polymorphism, iron metabolism and mortality in HIV infection. AIDS. 1998;12:1027–32.[Medline]

17. Weinberg GA. Iron overload as a mechanism for the lowered survival in AIDS patients receiving dapsone-iron protoxalate for secondary prophylaxis of Pneumocystis carinii pneumonia. J Infect Dis. 1996;174:241–2.[Medline]

18. Fawzi WW, Msamanga GI, Spiegelman D, Urassa EJ, McGrath N, Mwakagile D, Antelman G, Mbise R, Herrera G, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet. 1998;351:1477–82.[Medline]

19. Fawzi WW, Msamanga GI, Spiegelman D, Urassa EJ, Hunter DJ. Rationale and design of the Tanzania Vitamin and HIV Infection Trial. Control Clin Trials. 1999;20:75–90.[Medline]

20. WHO. Interim proposal for a WHO staging system for HIV infection and disease. Wkly Epidemiol Rec. 1990;65:221–4.[Medline]

21. Johnson-Spear MA, Yip R. Hemoglobin difference between black and white women with comparable iron status: justification for race-specific anemia criteria. Am J Clin Nutr. 1994;60:117–21.[Abstract/Free Full Text]

22. Kolbe-Busch S, Lotz J, Hafner G, Blanckaert NJ, Claeys G, Togni G, Carlsen J, Roddiger R, Thomas L. Multicenter evaluation of a fully mechanized soluble transferrin receptor assay on the Hitachi and cobas integra analyzers: the determination of reference ranges. Clin Chem Lab Med. 2002;40:529–36.[Medline]

23. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448–54.[Free Full Text]

24. van den Broek NR, Letsky EA, White SA, Shenkin A. Iron status in pregnant women: which measurements are valid? Br J Haematol. 1998;103:817–24.[Medline]

25. Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood. 1997;89:1052–7.[Abstract/Free Full Text]

26. Miettinen O. Theoretical epidemiology. New York: John Wiley & Sons; 1985.

27. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, FaNB Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001.

28. Stoltzfus RJ, Dreyfuss ML, Chwaya HM, Albonico M. Hookworm control as a strategy to prevent iron deficiency. Nutr Rev. 1997;55:223–32.[Medline]

29. van Lettow M, West CE, van der Meer JW, Wieringa FT, Semba RD. Low plasma selenium concentrations, high plasma human immunodeficiency virus load and high interleukin-6 concentrations are risk factors associated with anemia in adults presenting with pulmonary tuberculosis in Zomba district, Malawi. Eur J Clin Nutr. 2005;59:526–32.[Medline]

30. Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an index of iron stores. N Engl J Med. 1974;290:1213–6.[Medline]

31. Boelaert JR, Weinberg GA, Weinberg ED. Altered iron metabolism in HIV infection: mechanisms, possible consequences, and proposals for management. Infect Agents Dis. 1996;5:36–46.[Medline]

32. Kasvosve I, Gomo ZA, Nathoo KJ, Matibe P, Mudenge B, Loyevsky M, Nekhai S, Gordeuk VR. Association of serum transferrin receptor concentration with markers of inflammation in Zimbabwean children. Clin Chim Acta. 2006;371:130–6.[Medline]

33. Kuvibidila S, Mark JA, Warrier RP, Yu L, Ode D, Tshefu KA. Soluble transferrin receptor as an index of iron status in Zairian children with malaria. J Trop Med Hyg. 1995;98:373–8.[Medline]

34. Verhoef H, West CE, Ndeto P, Burema J, Beguin Y, Kok FJ. Serum transferrin receptor concentration indicates increased erythropoiesis in Kenyan children with asymptomatic malaria. Am J Clin Nutr. 2001;74:767–75.[Abstract/Free Full Text]

35. Thomas C, Thomas L. Biochemical markers and hematologic indices in the diagnosis of functional iron deficiency. Clin Chem. 2002;48:1066–76.[Abstract/Free Full Text]

36. Lee EJ, Oh EJ, Park YJ, Lee HK, Kim BK. Soluble transferrin receptor (sTfR), ferritin, and sTfR/log ferritin index in anemic patients with nonhematologic malignancy and chronic inflammation. Clin Chem. 2002;48:1118–21.[Free Full Text]

37. Sappey C, Boelaert JR, Legrand-Poels S, Forceille C, Favier A, Piette J. Iron chelation decreases NF-kappa B and HIV type 1 activation due to oxidative stress. AIDS Res Hum Retroviruses. 1995;11:1049–61.[Medline]

38. Hoffbrand AV, Ganeshaguru K, Hooton JW, Tattersall MH. Effect of iron deficiency and desferrioxamine on DNA synthesis in human cells. Br J Haematol. 1976;33:517–26.[Medline]

39. Schaible UE, Kaufmann SH. Iron and microbial infection. Nat Rev Microbiol. 2004;2:946–53.[Medline]

40. Riera A, Gimferrer E, Cadafalch J, Remacha A, Martin S. Prevalence of high serum and red cell ferritin levels in HIV-infected patients. Haematologica. 1994;79:165–7.[Abstract/Free Full Text]

41. Salmon-Ceron D, Fontbonne A, Saba J, May T, Raffi F, Chidiac C, Patey O, Aboulker JP, Schwartz D, et al. Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia. Study Group. J Infect Dis. 1995;172:656–64.

42. Semba RD, Taha TE, Kumwenda N, Mtimavalye L, Broadhead R, Miotti PG, Chiphangwi JD. Iron status and indicators of human immunodeficiency virus disease severity among pregnant women in Malawi. Clin Infect Dis. 2001;32:1496–9.[Medline]

43. Olsen A, Mwaniki D, Krarup H, Friis H. Low-dose iron supplementation does not increase HIV-1 load. J Acquir Immune Defic Syndr. 2004;36:637–8.[Medline]

44. Eastham EJ, Bell JI, Douglas AP. Serum ferritin levels in acute hepatocellular damage from paracetamol overdosage. BMJ. 1976;1:750–1.[Free Full Text]

45. Beaton GH, McCabe GP. Efficacy of intermittent iron supplementation in the control of iron deficiency anaemia in developing countries: an analysis of experience. Ottawa: Micronutrient Initiative; 1999.

46. Weinberg GA, Friis H, Boelaert JR, Weinberg ED. Iron status and the severity of HIV infection in pregnant women. Clin Infect Dis. 2001;33:2098–100.[Medline]

47. WHO. Iron supplementation of young children in regions where malaria transmission is intense and infectious disease highly prevalent. Geneva: WHO; 2006.

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