TABLE 2.
Prospective studies of anemia, iron status and mortality among HIV-infected adults1
| Study | Sample size | Female, % | Mean age | Country | Baseline anemia, % | Antiretroviral use, % | Outcome | Exposures | Categories | Result estimate (95% CI)2 | Confounders adjusted for |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Brentlinger, 2016 (61) | 324 | 0 | NR | Mozambique | 100 moderate anemia | NR | Hospitalization or death | Hemoglobin at baseline, g/L | Continuous | OR: 0.73 (0.53, 1.00) | None |
| Hemoglobin at nadir, g/L | Continuous | OR: 0.43 (0.25, 0.73) | Study site, CD4, cotrimoxazole use, bacteremia, any bleeding | ||||||||
| De Monye, 1999 (62) | 348 | NR | NR | USA | NR | NR | Time from bone marrow aspirate to death | Bone marrow iron stores | Grade 0–2/4–5 | HR: 1.00/2.1 (1.3, 3.5) | Lymphocyte count, blood transfused, hemoglobin, neutrophil count, year of bone aspiration, history of infection with MAI |
| Time from HIV diagnosis to death | Bone marrow iron stores | Grade 0–2/4–5 | HR: 1.00/2.8 (1.5, 4.9) | ||||||||
| Ezeamama, 2018 (63) | 398 | 69 | NR | Uganda | 49 | Baseline: 50Follow-up: 100 | Hospitalizaton or death | Hemoglobin, g/L at baseline | No anemiaAnemia | HR: 1.002.03 (1.18, 3.56) | Age, female sex, wealth, baseline CRP, HAART at enrollment, multivitamin use history, baseline vitamin D, smoking status, baseline BMI, baseline CD4 |
| No anemia/mild/moderate to severe | HR: 1.00/3.9 (2.1, 7.2)/6.7 (3.6, 12.7) | ||||||||||
| Hemoglobin, g/L at baseline and follow-up | Group 1. No anemia | HR: 1.00 | |||||||||
| Group 2. Baseline anemia, resolved | 1.11 (0.4, 2.9) | ||||||||||
| Group 3. Baseline anemia, not resolved | 2.1 (0.8, 5.5) | ||||||||||
| Group 4. Incident moderate/severe or persistent mild | 2.27 (1.01, 5.1) | ||||||||||
| Group 5. Baseline mild or single mild episode | 4.70 (2.0, 10.9) | ||||||||||
| Group 6. Baseline moderate or single moderate/severe | 3.1 (1.4, 6.5) | ||||||||||
| Ferritin, μg/L | Normal3/low/high | HR: 1.00/1.86 (0.85, 4.1)/1.75 (0.92, 3.3) | |||||||||
| Ezeamama, 2019 (11) | 400 | 69 | NR | Uganda | 49 | Baseline: 50Follow-up: 100 | Hospitalizaton or death | Baseline anemia type | No anemia Microcytic anemia | HR: 1.000.73 (0.33, 1.62) | Age, female sex, wealth, baseline CRP, HAART at enrollment, multivitamin use history, alcohol use, smoking status |
| Macrocytic anemia | 1.25 (0.64, 2.46) | ||||||||||
| ACD | 1.10 (0.68, 1.78) | ||||||||||
| Gordeuk, 2006 (64) | 302 | 100 | NR | USA | NR | 85 | All-cause mortality | Log10 Ferritin | Continuous | OR: 1.67 (0.98, 2.86) | Ethnicity, baseline ART use, and smoking status, and all baseline characteristics associated with mortality |
| Log10 sTfR | Continuous | OR: 0.52 (0.12, 2.22) | |||||||||
| Log10 sTfR–ferritin index | Continuous | OR: 0.89 (0.81, 0.99) | |||||||||
| Ferritin, μg/L | Cases/controls | Med (IQR): 392 (161–736)/330 (84–625) | None | ||||||||
| sTfR, mg/L | Cases/controls | Med (IQR): 6.5 (4.8–9.4)/5.5 (4.4–8.3) | |||||||||
| sTfR–ferritin index | Cases/controls | Med (IQR): 2.6 (1.9–3.8)/2.7 (1.8–3.9) | |||||||||
| Haider, 2019 (5) | 40,6574 | 66 | 37 | Tanzania | 85 | 100 | Early all-cause mortality | Baseline hemoglobin, g/L | ≥1205/100 to <120/70 to <100/<70 | RR: 1.00/1.26 (1.09, 1.45)/1.90 (1.65, 1.45)/3.32 (2.86, 3.86) | Sex, age, facility, BMI, CD4 cell count, WHO disease stage, ALT, HAART regimen, iron use, TB history, TB treatment, oral candidiasis, diarrhea, and calendar year of HAART initiation, and season of visit |
| Baseline hemoglobin, g/L and MCV | No anemia or ID | RR: 1.00 | |||||||||
| ID without anemia | 1.23 (0.90, 1.69) | ||||||||||
| Anemia without ID | 1.74 (1.44, 2.10) | ||||||||||
| IDA | 2.16 (1.79, 2.61) | ||||||||||
| Overall all-cause mortality | Hemoglobin during follow-up, g/L | ≥120/100 to <120/70 to <100/<70 | RR: 1.00/1.28 (1.17, 1.40)/2.00 (1.82, 2.19)/3.90 (3.51, 4.32) | ||||||||
| Hemoglobin during follow-up, g/L and MCV | No anemia or ID | RR: 1.00 | |||||||||
| ID without anemia | 1.02 (0.85, 1.24) | ||||||||||
| Anemia without ID | 1.63 (1.46, 1.82) | ||||||||||
| IDA | 1.87 (1.68, 2.09) | ||||||||||
| Iron supplements across anemia categories | All-cause mortality | No iron + no anemia | HR: 1.00 | ||||||||
| + mild anemia | 1.33 (1.17, 1.53) | ||||||||||
| + moderate | 2.02 (1.76, 2.31) | ||||||||||
| + severe | 4.06 (3.46, 4.77) | ||||||||||
| Iron + no anemia | 3.84 (2.43, 6.06) | ||||||||||
| + mild | 4.14 (3.25, 5.28) | ||||||||||
| + moderate | 4.10 (3.43, 4.91) | ||||||||||
| + severe | 6.33 (5.23, 7.65) | ||||||||||
| Isanaka, 2012 (60) | 362 | NR | NR | Tanzania | NR | NR | All-cause mortalityDisease progression or death | Ferritin, μg/LFerritin, μg/L | <30/30–150/>150<30/30–150/>150 | RR: 0.82 (0.33, 2.05)/1.00/2.70 (1.72, 4.24)RR: 0.82 (0.37, 1.84)/1.00/1.34 (0.87, 2.06) | Sex, age, food expenses, number of colonies in AFB culture, Karnofsky score, BMI, history of TB disease, HIV infection status, CD4 T-cell count (cells/μL) and log HIV RNA (copies/mL), trial regimen and CRP (mg/L). |
| Isanaka, 2012 (66) | 417 | NR | NR | Tanzania | NR | NR | All-cause mortality | Hemoglobin, g/L and ferritin, μg/L | No anemia, no ID/ID, no anemia/anemia, no ID/IDA | RR: 1.00/2.78 (1.33, 5.81)/2.53 (1.36, 4.68)/1.99 (1.01, 3.93) | Sex, age, food expense, number of colonies in AFB culture, Karnofsky score, BMI, prior TB, HIV, CD4, log HIV RNA, malaria. Trial regimen |
| Kerkhoff, 2016 (94) | 155 | 77 | 34 | South Africa | NR | 44 | All-cause mortality | Hemoglobin, g/L | Continuous | HR: 0.93 (0.69, 1.25) | Age, CD4+ T-cell count, HIV load, hemoglobin, eGFR, and CRP |
| Hepcidin, per 10 ng/mL | HR: 1.09 (1.05, 1.14) | ||||||||||
| McDermid, 2007 (17) | 1362 | 57 | 33 | Gambia | NR | 0 | All-cause mortality | Transferrin | >1.89/1.26–1.89/<1.26 | HR: 1.00/1.64 (1.19, 2.26)/2.18 (1.51, 3.14) | Sex, age, BMI, plasma α1-antichymotrypsin, HIV type, CD4 count, hemoglobin |
| Ferritin | <12/12–300/>300 to 1000/>1000 | HR: 1.00/1.54 (0.96, 2.48)/1.96 (1.17, 3.29)/2.98 (1.73, 5.12) | |||||||||
| sTfR-ferritin index | >−0.55 | HR: 1.00 | |||||||||
| −1.22 to −0.55 | 1.11 (0.85, 1.46) | ||||||||||
| Min to <-1.22 | 1.60 (1.18, 2.16) | ||||||||||
| TSAT, % | ≤55/>55 | HR: 1.00/1.38 (0.99, 1.90) | |||||||||
| Serum iron | <6.6/6.6–11/>11 | HR: 1.00/1.18 (0.92, 1.51)/1.20 (0.90, 1.59) | |||||||||
| sTfR | >80/>29.9 to 80/10.6–29.9/<10.6 | HR: 1.00/1.07 (0.57, 2.02)/1.19 (0.63, 2.24)/1.15 (0.54, 2.45) | |||||||||
| Hemoglobin, g/L | <90/90–110/>110 | HR: 1.00/1.04 (0.82, 1.32)/0.72 (0.54, 0.97) | |||||||||
| Minchella, 2015 (16) | 196 | 55 | 34.3 y | Gambia | 79 | 0 | All-cause mortality | Hepcidin, μg/L | ≤7.8/>7.8 to <57.6/≥57.6 | HR: 1.00/0.97 (0.56, 1.67)/1.11 (0.59, 2.08) | Age, sex, BMI, CD4, α1 chymotrypsin |
| Ferritin, μg/L | <12/12 to < 2006/200 to <1000/≥1000 | HR: 0.58 (0.28, 1.21)/1.00/1.90 (1.14, 3.18)/2.78 (1.49, 5.17) | |||||||||
| Transferrin, g/L | 2.0–3.6/<2.0 | HR: 1.00/1/03 (0.57, 1.88) | |||||||||
| Transferrin, g/L | ≥1.89/>1.47 to <1.89/≤1.47 | HR: 1.00/0.79 (0.40, 1.58)/2.13 (1.21, 3.75) | |||||||||
| Iron, μmol/L | <20/20–55/>55 | HR: 1.02 (0.68, 1.54)/1.00/0.78 (0.18, 3.27) | |||||||||
| sTfR, nmol/L | <10.6/10.6–29.9/>29.9 | HR: 0.52 (0.20, 1.35)/1.00/0.90 (0.58, 1.38) | |||||||||
| Hemoglobin, g/L | Nonanemic | HR:1.00 | |||||||||
| Anemic | 2.72 (1.29, 5.72) | ||||||||||
| O'Brien, 2005 (68) | 1078 | 100 | NR | Tanzania | 83 | 0 | All cause mortality | Hemoglobin, g/L | ≥110/85 to <110/<85 | HR: 1.00/2.06 (1.52, 2.79)/2.06 (1.52, 2.79) | CD4 count, WHO clinical stage, age, pregnancy, treatment, BMI |
| Erythrocyte morphology | Normal | HR: 1.00 | |||||||||
| Hypochromasia, microcytosis | 2.90 (2.12, 3.96) | ||||||||||
| Hypochromasia, no microcytosis | 2.39 (1.79, 3.19) | ||||||||||
| Other abnormality | 2.17 (0.53, 8.94) | ||||||||||
| Rawat, 2009 (69) | 643 | 100 | NR | Zimbabwe | 100 | 0 | All-cause mortality | Hemoglobin, g/L | Continuous | HR: 0.80 (0.65, 1.00) | Age, marital status, maternal education, AGP, only crude sTfR was presented |
| Log10 ferritin, μg/L | Continuous | HR: 4.10 (1.64, 10.23) | |||||||||
| Log10 sTfR, mg/L | Continuous | HR: 0.46 (0.07, 3.08) | |||||||||
| Sun, 2016 (71) | 32 | 0 | 41 | China | NR | 9 | Death | Ferritin, μg/L | Nonsurvivors/survivors | Mean (SD): 1790 (1879)/871 (702) | None |
| Wisaksana, 2011 (70) | 6117 | 32 | 28 | Indonesia | NR | 0 | All-cause mortality | Hemoglobin, g/L | >1208/105 to <120/≤105 | HR: 1.00/2.2 (0.6, 7.6)/6.5 (2.0, 21.2) | Sex, age, BMI, injection drug use, ART at baseline |
| Ferritin, μg/L | <1509 | HR: 1.00 | |||||||||
| >150 | 1.3 (0.4, 4.6) | ||||||||||
| sTfR, kU/L | >1870 | HR: 1.00 | |||||||||
| <1870 | 1.7 (0.5, 5.3) |
1
ACD, anemia of chronic disease; AGP, acid glycoprotein; ART, antiretroviral therapy; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; HAART, highly active antiretroviral therapy; ID, iron deficiency; IDA, iron deficiency anemia; MAI, Mycobacterium avium-intracellulare infection; MCV = mean corpuscular volume; NR, not reported; sTfR, soluble transferrin receptor; TB, tuberculosis; TSat, transferrin saturation.
2
Estimates are HRs or ORs with 95% CIs. One study (64) instead reported estimates that were medians with interquartile range (IQR).
3
High ferritin was defined as >200 μg/L for men and >150 μg/L for women.
4
The sample size for analyses involving MCV was 27,569.
6
The upper limit of the range of normal ferritin was defined as 200 in men aged 18–44 y and women aged ≥45 y and 150 in women aged 18–44 y and 300 in men aged ≥45 y.
7
Serum ferritin was only available among 95 participants.
9
Threshold for high ferritin was defined as 400 μg/L for men (70).