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. Author manuscript; available in PMC: 2017 Jul 12.
Published in final edited form as: HIV Med. 2016 Apr 28;18(1):13–20. doi: 10.1111/hiv.12387

Prognostic Implications of Baseline Anemia and Changes in Hemoglobin Concentrations with Amphotericin B therapy for Cryptococcal Meningitis

Lillian Tugume 1, Bozena M Morawski 2,3, Mahsa Abassi DO 1,2, Nathan C Bahr 1,2,4, Reuben Kiggundu 1, Henry W Nabeta 1, Kathy Huppler Hullsiek 6, Kabanda Taseera 7, Abdu K Musubire 1,2, Charlotte Schutz 8, Conrad Muzoora 7, Darlisha A Williams 1,2, Melissa A Rolfes 5, Graeme Meintjes 8,9, Joshua Rhein 1,2, David B Meya 1,2,10, David R Boulware 2,4
PMCID: PMC5507613  NIHMSID: NIHMS872085  PMID: 27126930

Abstract

Background

Anemia represents a common toxicity with amphotericin B-based induction therapy for HIV-infected persons with cryptococcal meningitis. We sought to examine the impact of amphotericin-related anemia on survival.

Methods

We used data from Ugandan and South African trial participants to characterize variation of hemoglobin concentrations from diagnosis to 12 weeks post-diagnosis. Anemia severity was classified based on hemoglobin at cryptococcal meningitis diagnosis, and nadir hemoglobin values during amphotericin induction. Cox proportional hazard models estimated 2-and 10-week mortality risk. We also estimated 10-week mortality risk among participants with nadir hemoglobin <8.5g/dL during amphotericin induction and who survived ≥2 weeks post-enrollment.

Results

The median hemoglobin concentration at meningitis diagnosis was 11.5g/dL (IQR: 9.7 to 13; n=311) with a decline of 4.2g/dL (95%CI: −4.6 to −3.8; P<0.001; n=148) from diagnosis to nadir value among participants with baseline hemoglobin ≥8.5g/dL. At 2 weeks, median hemoglobin was 8.1g/dL (IQR: 6.5 to 9.5) increasing to 9.4g/dL (IQR: 8.2 to 10.9) by 4 weeks and continuing to increase through 12 weeks. Among participants with hemoglobin <8.5g/dL at diagnosis, mortality risk was elevated through 2-weeks (Hazard Ratio (HR)=2.7; 95%CI: 1.5-4.9; P<0.01) and 10-weeks (HR=1.8; 95%CI: 1.1-2.2 P=0.03), relative to those with hemoglobin ≥8.5g/dL. New onset anemia occurring with amphotericin did not have a statistical association with 10-week mortality (HR=2.0; 95%CI: 0.5-9.1; P=0.4).

Conclusion

Amphotericin induces significant hemoglobin declines, which were mostly transient and did not impact 10-week mortality. Individuals with moderate to life-threatening anemia at baseline had a higher mortality risk at 2- and 10-weeks post-enrollment.

Keywords: Amphotericin B, Anemia, Cryptococcal Meningitis, HIV

Introduction

Anemia is the most common hematologic complication of HIV-infection, affecting approximately 15% of individuals with advanced AIDS.[1] HIV-associated anemia is an independent predictor of mortality, with an increased risk of death as hemoglobin levels decline.[2-6] Development of anemia in HIV infection is multifactorial and includes decreased red blood cell production from the effects of chronic viral HIV infection, co-infection with opportunistic pathogens, nutritional deficiencies (e.g iron, folic acid vitamin B12), anemia of chronic disease with inflammatory cytokine production, and myelosuppression due to chemotherapeutic agents including antiretroviral therapy (ART).[7, 8] Furthermore, HIV-infected individuals with an AIDS-defining opportunistic infection are 4.5 times more likely to develop anemia when compared to individuals without an opportunistic infection.[1]

Cryptococcal meningitis accounts for approximately 15% of AIDS-related mortality in Sub-Saharan Africa.[9-11] The World Health Organization recommends 14 days of amphotericin B in combination with flucytosine or fluconazole as induction therapy in cryptococcal meningitis treatment [12-14] which cause frequent clinically significant toxicities, including anemia[15-17]. Amphotericin associated-anemia is a sub-acute drug-related reaction resulting from blunted erythropoietin secretion and suppression of red blood cell production.[18, 19] In a small cohort of 30 individuals treated with amphotericin for systemic fungal infections, 75% of individuals had a reduction of their hematocrit by 11%.[20] This degree of hematocrit decline could further compromise oxygen delivery to vital tissues among individuals, who are already at an elevated risk of death from cryptococcal meningitis. Previous studies have evaluated the relationship between pre-existing anemia and mortality in cryptococcal meningitis patients. In a combined cohort of 501 HIV-infected persons with cryptococcal meningitis, a baseline hemoglobin concentration of <7.5g/dL prior to initiation of amphotericin therapy was independently associated with a three-fold higher odds of mortality at 10 weeks.[21]

In order to better understand the impact of anemia on acute mortality in persons with HIV-associated cryptococcal meningitis receiving amphotericin, we characterized the relationship between amphotericin administration and hemoglobin levels during and after treatment. We also assessed the relationship between hemoglobin levels in individuals receiving amphotericin therapy and 2-week and 10-week mortality.

Methods

Data from the Cryptococcal Optimal ART Timing (COAT) trial (ClinicalTrials.gov: NCT01075152) and the pilot phase of the Adjunctive Sertraline for Treatment of Cryptococcal Meningitis (ASTRO-CM) trial (Clinicaltrials.gov: NCT01802385) were used for the analyses included herein. The COAT trial enrolled Ugandan and South African HIV-infected, ART-naïve individuals diagnosed with a first episode cryptococcal meningitis who were randomized to either early or deferred ART initiation from 2010-2012, as described elsewhere.[22] The pilot phase of the ASTRO-CM trial was an open-label dose finding study conducted from August 2013 to August 2014 in Kampala, Uganda. All COAT trial participants were ART-naïve at the time of meningitis diagnosis whereas 45% of ASTRO participants were receiving ART at meningitis diagnosis and 5% (18/339) had received treatment for a prior episode of cryptococcal meningitis.

Participants were ≥18 years of age, and pregnant women were excluded. Cryptococcal meningitis was diagnosed by cerebrospinal fluid (CSF) cryptococcal antigen testing and confirmed via quantitative culture at Mulago National Referral Hospital, Kampala, Uganda (COAT and ASTRO-CM), Mbarara Hospital, Mbarara, Uganda (COAT), or G.F. Jooste Hospital, Cape Town, South Africa (COAT). Participants in both trials universally received combination induction therapy with amphotericin B deoxycholate (0.7-1.0 mg/kg/day) and fluconazole 800mg/day. In addition, sertraline (100-400mg/day) was administered to all participants in the ASTRO-CM pilot trial. All participants were followed for at least 12 weeks post-enrollment.

Hemoglobin levels were obtained from participants at the time of cryptococcal meningitis diagnosis in both trials, and among COAT trial participants only additionally at days 5, 7, 10 and 14 of amphotericin induction therapy and at weeks 4, 8, and 12. Anemia severity was defined per the National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) toxicity scale, version 2009.[23] Moderate anemia (Grade 2) was defined as hemoglobin concentrations from 7.5 – 8.4g/dL, severe anemia (Grade 3) as hemoglobin concentrations of 6.5 – 7.4g/dL, and potentially life-threatening anemia (Grade 4) as hemoglobin concentrations <6.5g/dL.

Statistical Analysis

Median hemoglobin concentration at diagnosis (both cohorts) and 14-day induction therapy nadir values (COAT only) are summarized. Change in hemoglobin concentrations from diagnosis to 1) the 14-day nadir hemoglobin and 2) the end of induction therapy were evaluated via linear mixed models with random intercepts for an individual. Rates of change for these two periods were also evaluated across sex and baseline hemoglobin status (hemoglobin ≥8.5g/dL versus <8.5g/dL) via interaction terms in linear mixed models. Additionally, differences in rates of hemoglobin change from diagnosis through 12 weeks post-diagnosis were evaluated across sex and baseline anemia severity via interaction terms of the linear mixed models among COAT participants only.

Composite exposures of grades 2-4 and 3-4 anemia at diagnosis were used in Cox proportional hazards models to estimate 2-week and 10-week mortality among COAT and ASTRO-CM participants. Fixed effects for ART status at diagnosis (receiving any ART in the last 30 days versus not), prior history of treatment for cryptococcal meningitis, sex, age (>50 years), log10 quantitative cryptococcal cultures/mL CSF, and altered mental status (Glasgow Coma Score <15) were included in these models. Among those COAT participants with hemoglobin <8.5g/dL at diagnosis and who survived 2 weeks, the risk of 10-week mortality was assessed by nadir hemoglobin values during induction therapy. Kaplan-Meier curves displayed the 10-week mortality, with corresponding Cox model results. Analyses were conducted in Stata/IC 13.1 (StataCorp, College Station, TX), and all results were evaluated against a two-sided alpha of 0.05.

Results

A total of 350 participants were enrolled in both trials (177 in COAT; 173 in the pilot phase of ASTRO-CM). Of these, 339 participants had at least one hemoglobin measurement and were included in descriptive analyses, of which 311 were included in survival analyses. Twenty eight participants were missing hemoglobin concentration at diagnosis and were excluded from the survival analyses. The baseline characteristics of these participants are described in Table 1.

Table 1.

Demographic and clinical characteristics of participants in the COAT and ASTRO-CM trials.

COAT ASTRO-CM Combined
Characteristic at Diagnosis N n (%) or Median [IQR] N n (%) or Median [IQR] N n (%) or Median [IQR] p-value
Age, years 177 35 [29, 40] 162 36 [31, 41] 339 36 [30, 41] 0.19
Women 177 84 (47%) 162 56 (35%) 339 140 (41%) 0.02
Receiving ART 177 0 (0.0%) 161 78 (48%) 338 78 (23%) <0.001
Prior diagnosis of cryptococcal meningitis 177 0 (0.0%) 162 18 (11.1%) 339 18 (5.3%) -
Glasgow Coma Scale<15 176 47 (27%) 162 56 (35%) 338 103 (30%) 0.12
Opening pressure, cm H2O 152 27 [18, 38] 149 30 [19, 48] 301 28 [18, 40] 0.12
Opening Pressure >25cm H2O 152 83 (55%) 149 91 (61%) 301 174 (58%) 0.26
CSF Culture log10 CFU/mL 168 5.1 [4.0, 5.6] 158 4.3 [3.1, 5.3] 326 4.8 [3.6, 5.5] <0.001
CD4+ T cells/μL 175 23 [10, 74] 162 18 [7, 54] 301 20 [8, 70] 0.05
Hemoglobin (all), g/dL 149 11.4 [9.3, 12.9] 162 11.7 [10.1, 13.0] 311 11.5 [9.7, 13.0] 0.04
 Hemoglobin (women), g/dL 73 10.5 [8.9, 11.9] 56 10.4 [9.2, 12.2] 129 10.5 [9.0, 12.0] 0.86
 Hemoglobin (men), g/dL 76 11.8 [9.7, 13.6] 106 12.2 [10.7, 13.3] 182 12.1 [10.5, 13.5] 0.17
Hemoglobin <8.5g/dL 149 29 (19.5%) 162 12 (7.4%) 311 41 (13.2%) <0.01
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The median age was 36 years (IQR 30-41), and 41% (140/339) were women. At the time of diagnosis, 23% (78/338) of the participants were receiving ART. The median CD4+ T cell count was 20 cells/μL (IQR 8 to 70), and median quantitative cryptococcal culture was 63,000 CFU/mL CSF (IQR, 3,900 to 316,000). The median baseline hemoglobin concentration in participants from both cohorts was 11.5g/dL (IQR, 9.7 to 13; n=311), with COAT participants having slightly lower baseline hemoglobin concentrations (P=0.04). All COAT participants were ART-naïve. At diagnosis, 13% (41/311) of individuals presented with moderate to life-threatening anemia (Grade 2: n=23; Grade 3: n=11; Grade 4: n=7).

Among COAT participants who received frequent longitudinal monitoring, plasma hemoglobin declined by 3.1g/dL (95%CI: −3.6, −2.6; P<0.001) from cryptococcal meningitis diagnosis through the end of induction therapy (14 days). Among patients enrolled in COAT who had hemoglobin ≥8.5g/dL at diagnosis, there was a significant decline of 4.2g/dL (95% CI, −4.6, −3.8; P<0.001) hemoglobin from diagnosis to nadir values (Figure 1); overall median nadir hemoglobin concentration was 7.4g/dL (IQR, 6.2 to 8.9) during the first 14 days of cryptococcal meningitis therapy. While men had consistently higher hemoglobin concentrations relative to women during the course of follow-up, changes from baseline to nadir hemoglobin values were similar across the two groups (interaction term P=0.38). Men experienced an average 4.0g/dL (95%CI: 3.4, 4.5) decrease in hemoglobin, while women experienced an average 4.3g/dL (95%CI: 3.8, 4.9) decrease in hemoglobin concentrations from diagnosis to nadir values. The nadir hemoglobin occurred at a median time of 14 days (IQR: 8 to 14) from diagnosis.

Figure 1. Median (IQR) hemoglobin concentrations from amphotericin B initiation through 12 weeks post-diagnosis among patients in the COAT trial.

Figure 1

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among patients with Grade ≤1 anemia vs. those with Grade ≥2 anemia (<8.5g/dL) at diagnosis. Overall median nadir hemoglobin among all COAT participants was 7.4g/dL (IQR 6.2, 8.9). The median percentage change from baseline to nadir was a decrease of 31% (IQR −44%, −22%). Patients with ≤Grade 1 anemia at diagnosis shown as solid line; patients with ≥Grade 2 anemia (hemoglobin <8.5g/dL) at diagnosis shown as long dashed line.

Despite the clinically significant decline in hemoglobin levels during amphotericin induction therapy, we observed that effects were mostly transient. Among COAT participants, we observed median hemoglobin levels had increased to 9.4g/dL (IQR: 8.1 to 10.8) by 2 weeks post-induction therapy from 7.8g/dL (IQR: 6.4 to 9.3) at the end of induction, and rose to nearly 100% of baseline hemoglobin values by 12 weeks post-diagnosis (11.3g/dL; IQR: 9.8 to 12.6). Additionally, among COAT participants who survived past the induction period, we did not observe any significant difference in rate of hemoglobin recovery by anemia severity at baseline (interaction P=0.95).

Individuals who had hemoglobin <8.5g/dL at diagnosis were at higher risk of death at 2 weeks and 10 weeks (Table 2). For participants with moderate to life-threatening anemia (Grade 2-4), sex, altered mental status, cryptococcal meningitis history, age, quantitative culture and ART-status adjusted hazard ratios for 2-week mortality was 2.7 (95%CI: 1.5, 4.9; P<0.01) and for 10-week mortality was 1.8 (95%CI: 1.1, 3.2; P=0.03), respectively, relative to those with Grade 1 or no anemia (i.e. hemoglobin ≥8.5 g/dL). For participants presenting with Grade 3 or 4 anemia versus those without, the adjusted hazard ratios for 2-week and 10-week mortality were 1.4 (95%CI: 0.6, 3.4; P=0.46) and 1.2 (95%CI: 0.5, 2.6; P=0.69), respectively. These persons with were more likely to be transfused; however, transfusion data were not systematically collected. The difference in 2-week and 10-week survival between those with baseline anemia of moderate to life-threatening severity versus those with no or mild anemia is displayed in Figure 2.

Table 2.

Short-term Mortality Risk by Hemoglobin Status.

Grade 2-4 Baseline Hemoglobin, <8.5g/dL Grade 3-4 Baseline Hemoglobin, <7.5g/dL
Unadjusted Adjusted‡ Unadjusted Adjusted‡
N HR (95%CI) p-value HR (95%CI) p-value HR (95%CI) p-value HR (95%CI) p-value
2-week mortality 311 1.97 (1.12, 3.45) 0.02 2.69 (1.46, 4.93) <0.01 1.23 (0.52, 2.91) 0.64 1.41 (0.57, 3.45) 0.46
10-week mortality 311 1.55 (0.95, 2.52) 0.08 1.82 (1.05, 3.15) 0.03 1.24 (0.62, 2.45) 0.54 1.18 (0.53, 2.62) 0.69
Grade 2-4 Nadir Hemoglobin, <8.5g/dL Grade 3-4 Nadir Hemoglobin, <7.5g/dL
Unadjusted Adjusted‡ Unadjusted Adjusted‡
N HR (95%CI) p-value HR (95%CI) p-value HR (95%CI) p-value HR (95%CI) p-value
10-week mortality* 98 2.80 (0.82, 9.50) 0.10 2.03 (0.45, 9.12) 0.35 1.10 (0.44, 2.78) 0.83 0.70 (0.25, 1.92) 0.49
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‡

Comparison of patients with hemoglobin <8.5g/dL to those with hemoglobin ≥8.5g/dL, adjusted for patient sex, age (>50 years or ≤50 years), ART status at enrollment, prior history of cryptococcal meningitis, log10 quantitative CSF cultures/mL, and Glasgow Coma Scale score <15 at baseline.

*

Among COAT participants who survived for two weeks only, which had systematic follow up hemoglobin measurements during the first two weeks.

Figure 2.

Figure 2

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Kaplan-Meier survival curves by anemia status at cryptococcal meningitis diagnosis. HIV-infected persons with cryptococcal meningitis who had hemoglobin ≤8.4g/dL (≥Grade 2 adverse event severity) at diagnosis had higher 2-week mortality (Hazard Ratio =2.3; 95%CI: 1.3-4.1; P<0.01) and 10-week mortality (Hazard Ratio =1.7; 95%CI: 1.0-2.9; P=0.05).

Among participants from COAT, of the 119 individuals who presented with hemoglobin ≥8.5g/dL at diagnosis and survived to have further hemoglobin measurements, 66% (79/119) developed moderate to life-threating anemia (Grade 2: n=21; Grade 3: n=24; Grade 4: n=34) during the two-week induction period with amphotericin therapy. The overall median nadir hemoglobin among all COAT participants was 7.4g/dL (IQR 6.2, 8.9). The median percentage change among all COAT participants was a decrease of 31.4% (IQR −43.8%, −21.7%).However, the development of anemia during induction therapy was not associated with an increased risk of mortality at 10 weeks. The unadjusted 10-week hazard ratio for death among participants who developed Grade 2-4 (hemoglobin level <8.5g/dL) anemia was 2.8 (95%CI: 0.8, 9.5; P=0.10). The unadjusted 10-week hazard ratio for participants who developed Grade 3-4 anemia (hemoglobin ≤7.4g/dL) was 1.1 (95%CI: 0.4, 2.8; P=0.83). Adjusting for sex, age, quantitative cultures and altered mental status further attenuated these results(P=0.19). Among those without substantial anemia at baseline (hemoglobin ≥8.5g/dL), 10-week mortality between those who developed anemia (grade 2-4) during the induction phase relative to those who did not develop anemia is displayed in Figure 3.

Figure 3.

Figure 3

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10-week survival based on nadir hemoglobin level during amphotericin induction therapy among persons with hemoglobin ≥8.5 g/dL at diagnosis who survived >14 days post-diagnosis. Participants developing moderate to life-threatening anemia (Grade 2-4 adverse event, i.e. hemoglobin ≤8.4 g/dL) during amphotericin therapy had non-statistically higher 10-week mortality (adjusted Hazard Ratio = 2.58; 95%CI: 0.64-10.48; P=0.19).

Discussion

Our analysis demonstrates that persons presenting with CM experience an acute drop in hemoglobin concentration over the 14-day induction period with amphotericin. Although not a new finding, our study quantifies the change from diagnosis through 12 weeks in hemoglobin concentrations in persons undergoing amphotericin-based treatment for HIV associated cryptococcal meningitis, Joly et al reported hemoglobin changes in 44 patients receiving amphotericin B deoxycholate from baseline to end of therapy [17]; however, changes after amphotericin were not reported. Another study carried out in South Africa reported changes from baseline to 4 weeks only [24]. Clinicians should anticipate the changes in hemoglobin concentrations in persons requiring amphotericin therapy and prepare appropriately for persons who are likely to require blood transfusion. We also investigated the association between hemoglobin values and mortality. Paradoxically, those with the most severe anemia at baseline (hemoglobin <7.5 g/dL) had less hazard of mortality. This group was more likely to receive prompt blood transfusions, although the timing was not systematically captured and should be explored in the future. In resource-limited settings where there is a shortage of blood products, persons at high-risk for developing moderate to life-threatening anemia should be considered as a priority for blood transfusions.

In the context of cryptococcal meningitis, other options for the management of anemia may include shortened or interrupted courses of amphotericin. Small prospective studies have shown comparable efficacy and decreased toxicity using shorter courses of amphotericin (five to seven days). Specifically, there was no severe or life-threatening anemia (hemoglobin ≤7.4g/dL) reported in a 30 person Ugandan cohort receiving short course amphotericin.[25, 26] Testing of whether short course amphotericin has equivalent efficacy is ongoing with results expected in 2017 (International Standard Randomised Controlled Trials Number 45035509).

We also found that individuals with hemoglobin concentration <8.5g/dL at the time of cryptococcal meningitis diagnosis were at elevated risk of death at both 2 and 10 weeks post diagnosis when compared to persons who were not anemic or had mild anemia. A number of previous studies among HIV infected individuals have shown that anemia is independently associated with mortality.[2-6] In fact, in persons with AIDS, the risk of death increases as hemoglobin levels decline.[27] Therefore, it is not surprising that individuals who present with moderate – life-threatening anemia at cryptococcal meningitis diagnosis are at higher risk of death. A similar observation was noted in South Africa, where persons with HIV-associated cryptococcal meningitis and a baseline hemoglobin <7.5g/dL were at three-fold higher odds of death at 10 weeks.[21]. Although there was a significant decline in hemoglobin levels during the 14-days of treatment with amphotericin, we noted that median hemoglobin level had increased to 9.5g/dL by 4 weeks post-diagnosis from 8.1g/dL at the end of induction. The hemoglobin values rose further to 90% of their original (pre-treatment) values at 12-weeks post-diagnosis. This is similar to findings from a prior study where change in median hemoglobin levels was reported from baseline to 4 weeks only. Values at baseline, week 2, and week 4 were 10.4, 7.7, and 8.5 g/dL, respectively [24]. While transfusion data were not available for these patients, future studies should assess whether transfusions at the onset of amphotericin administration in persons presenting with grade 3-4 anemia (hemoglobin <7.5g/dL) can impact survival.

The anemia-mortality association seems to be driven by factors present at diagnosis, rather than treatment toxicity itself. Having anemia at baseline is likely marker of a combination of more advanced HIV, more disseminated OIs, and in some patients an undiagnosed OI, and may explain the increase in mortality seen in individuals presenting with a baseline hemoglobin level <8.5mg/dL. We believe that persons at high-risk to develop life-threatening anemia (i.e. persons with baseline anemia, often female) should be given priority when considering additional interventions.

There were several limitations to our study. There were only a few participants who presented with grade 3 and 4 anemia and the study may be underpowered to detect a statistical difference in mortality. Additionally, some participants received blood transfusions when hemoglobin levels dropped below 6.5g/dL, although this was not universal given the limited availability of blood products. Unfortunately, data on blood transfusions were not comprehensively captured.

In summary, we have found that this African cohort of HIV-infected persons with cryptococcal meningitis experienced a drop of 3.1g/dL over the 14-day amphotericin-based induction period. Once amphotericin therapy was completed, hemoglobin levels rebounded to 90% of baseline hemoglobin within 12 weeks post-diagnosis. Ultimately, the development of acute anemia during the 14-day induction period with amphotericin was not found to affect 10 week mortality. Importantly, anemia even of moderate severity at time of cryptococcal meningitis diagnosis can be used as a prognostic indicator of mortality. We believe that our results can be generalized to persons with AIDS receiving amphotericin for systemic fungal infections other than cryptococcosis. If efficacy of shorter durations (5 to 7 days) of amphotericin induction therapy is confirmed in larger studies, shorter courses of amphotericin should be considered for persons at high risk (i.e. persons with baseline anemia, often female) of developing severe to life-threatening anemia while on amphotericin.

Table 3.

Incidence of anemia and mortality during the 14-day amphotericin induction period among COAT participants with hemoglobin ≥8.5g/dL at diagnosis.

Anemia Adverse Event (AE) Incidence Status at 2 Weeks
Alive Died Overall
Hemoglobin remained≥8.5g/dL 33 (33.7%) 7 (33.3%) 40 (33.6%)a
Grade 2 AE, hemoglobin 7.5-8.4g/dL 18 (18.4%) 3 (14.3%) 21 (17.7%)
Grade 3 AE, hemoglobin 6.5-7.4g/dL 21 (21.4%) 3 (14.3%) 24 (20.2%)
Grade 4 AE, hemoglobin <6.5g/dL 26 (26.5%) 8 (38.1%) 34 (28.6%)
Total 98 21 119
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a

One person died prior to receiving an additional hemoglobin measurement.

Acknowledgments

This work was supported by the National Institute of Neurologic Disorders and Stroke, the National Institute of Allergy and Infectious Disease, and the Fogarty International Center at the National Institutes of Health (U01AI089244, R01NS086312, T32AI055433, R25TW009345). The authors wish to thank Drs. Paul Bohjanen and Andrew Kambugu for support and input. We also thank Dr. Ali El Bireer and the laboratory staff at Makerere University Johns Hopkins University Laboratory in Kampala as well as Mr. Richard Kwizera for phlebotomy.

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