Incidence and Risk Factors of Zidovudine-Induced Anemia in Patients With HIV Infection Receiving Zidovudine-Containing Antiretroviral Therapy

Abstract

Background

Anemia is among the frequently observed conditions among people living with HIV (PLWH). Zidovudine (AZT) is the most common ART that causes anemia. This study aimed to identify the incidence and risk factors of AZT-induced anemia in PLWH receiving AZT-containing regimens.

Methods

A retrospective cohort study was conducted on nonpregnant PLWH aged >18 years who received AZT-containing regimens for >6 months and had normal baseline hemoglobin levels. Data on medical history, clinical characteristics, and laboratory examination were collected. Cox proportional hazard regression analysis was performed to determine the risk factors of AZT-induced anemia.

Results

A total of 401 individuals were included in the study. In total, 71 individuals presented with AZT-induced anemia. The incidence rate of anemia was 1.98 per 100 person-years of observations. Female sex, low-normal baseline hemoglobin level, low recent and low baseline CD4 cell count were independently associated with an increased risk of anemia. However, a higher body mass index was independently associated with a decreased risk of anemia.

Conclusion

Routine screening, early detection, and treatment of anemia should be considered in PLWH receiving AZT-containing regimens.

Plain Language Summary

Incidence and risk factors of zidovudine-induced anemia in patients with HIV infection

Anemia is among the major hematological issues frequently observed among people living with HIV. The etiology of anemia in people living with HIV (PLWH) could be related to multiple factors. The most common ART that causes anemia is zidovudine (AZT), one of the nucleoside reverse transcriptase inhibitor class. The current study aimed to identify the incidence and risk factors of AZT-induced anemia in PLWH receiving AZT. A retrospective cohort study was conducted on nonpregnant PLWH aged greater than 18 years who received AZT-containing regimens for more than 6 months and had normal baseline hemoglobin levels. Data on medical history, clinical characteristics, and laboratory examination were collected. Cox proportional hazard regression analysis was performed to determine the risk factors of AZT-induced anemia. Finally, a total of 401 individuals were included in the study. The mean (±standard deviation) follow-up time was 4.18 (±1.73) years/person. In total, 71 individuals presented with AZT-induced anemia. The incidence rate of anemia was 1.98 per 100 person-years of observations. Female sex (adjusted hazard ratio [AHR]: 1.91, 95% CI [1.14-3.21], P = .014), low recent CD4 cell count (AHR: 1.96, 95% CI [1.01-3.84], P = .049), low baseline CD4 cell count (AHR: 1.98, 95% CI [1.03-3.81], P = .041), and low-normal baseline hemoglobin level (AHR: 2.74, 95% CI [1.69-4.43], P < .001) were independently associated with an increased risk of anemia. However, a higher body mass index (BMI) (AHR: 0.91, 95% CI [0.84-0.98], P = .022) was independently associated with a decreased risk of anemia. In addition, the mean (±SD) mean cell volume (90.95 ± 7.79 vs. 106.89 ± 12.86 fL; P < .001) was higher during AZT-induced anemia diagnosis than during the baseline complete blood count (CBC) examination. However, there were no significant differences in the WBC, platelet, and absolute neutrophil count during the diagnosis of AZT-induced anemia and the baseline CBC examination.

Keywords

AIDS anemia antiretroviral therapy incidence zidovudine

Introduction

Anemia is among the major hematological issues frequently observed among people living with HIV (PLWH). The incidence rate of anemia varies from 30% to 90%, and patients with advanced disease have the greatest burden.¹ Severe anemia is associated with rapidly progressing HIV infection and is a strong independent predictor of mortality in PLWH.² The etiology of anemia in PLWH could be related to multiple factors such as nutritional deficiency, opportunistic infections, HIV-associated malignancy, HIV treatment medications, and the virus itself.³ Increasing access to potent antiretroviral therapy (ART) has improved the prognosis of HIV infection. However, adverse events may still occur after therapy initiation. Some ARTs lead to anemia. The most common ART that causes anemia is zidovudine (AZT), which is an analog of thymidine, one of the nucleoside reverse transcriptase inhibitor (NRTI) class. This drug was the first breakthrough in AIDS therapy. AZT was approved for AIDS treatment in 1987.⁴ At present, this drug is used as one of the combination drugs in HIV treatment regimens. The pathogenesis of AZT-induced anemia is the suppression of bone marrow function.⁵ The other common side effects are neutropenia, myopathy, lactic acidosis, and skin discoloration. Based on long-term experience, AZT is safe in pregnant women. Accordingly, this drug is still used in the recommendation guideline for preventing perinatal HIV transmission, which is one of the NRTIs recommended in the alternative regimen.⁶

Recently, the use of more novel ART drugs, with fewer side effects and a better tolerability, has been approved. Therefore, the usage of AZT, with higher side effects, has decreased. However, this drug is still important in some individuals, such as PLWH who had some genotypic-resistant mutations and those who cannot tolerate the side effects of first-line drugs. Therefore, based on the recommendations of the World Health Organization, AZT should be used as an alternative NRTI in second-line regimens.⁷ In addition to the fact that AZT is cost-effective, it also has favorable outcomes, particularly in resource-constrained countries.

AZT-induced anemia often occurs immediately after initiating treatment, and this toxicity is believed to be dose-dependent.⁸ The prevalence rate of AZT-induced anemia varies, ranging from 5% to 16%, according to the regions and the stage of HIV infection.^9,10 The risk factors of anemia in PLWH using AZT were African-American natives, low BMI and body weight, low CD4 cell count, and high HIV viral load.^11–14 A few studies from Thailand showed that PLWH with a. low body weight have a high incidence of anemia. Thus, the AZT dose must be decreased from 600 to 400 mg per day in patients with a body weight of <40 kg.^15,16 The current study aimed to identify the incidence and risk factors of AZT-induced anemia in PLWH receiving AZT along with other drugs used in HIV treatment regimens.

Methodology

Patient Data

A retrospective cohort study was performed on nonpregnant PLWH aged >18 years who received AZT-containing regimens for >6 months and had normal baseline hemoglobin levels from routine complete blood count (CBC) at Vajira Hospital, Navamindradhiraj University, between January 1, 2015, and December 31, 2020. Vajira Hospital is a 900-bed capacity university hospital in Bangkok, Thailand. This hospital accommodates more than 700 000 outpatient visits and admits approximately 30 000 inpatients each year. To reduce potential bias, patients were identified and enrolled consecutively through the examination of electronic medical records. Patients with an incomplete medical record and those with anemia of other causes (ie, thalassemia trait or disease, G6PD deficiency, iron deficiency anemia, chronic kidney disease, active cancer, abnormal bleeding, and active infection) were excluded from the study. HIV infection was confirmed using 3 sets of diagnostic tests, either the rapid test or enzyme-linked immunosorbent assay each using different antigens according to the national guidelines. The time to anemia was calculated from the date of AZT initiation to the date of anemia occurrence. Data on the patient's medical history and clinical characteristics were obtained from the electronic database. Anemia was defined according to the World Health Organization classification.¹⁷ Briefly, anemia was defined as adjusted hemoglobin levels <13 g/dL (11-12.9, 8-10.9, and <8 g/dL for mild, moderate, and severe anemia, respectively) in men and <12 g/dL (11-11.9, 8-10.9, and <8 g/dL for mild, moderate, and severe anemia, respectively) in adult nonpregnant women. A low-normal baseline hemoglobin level was defined as a hemoglobin level of 13 to 13.9 g/dL in men and 12 to 12.9 g/dL in women. AZT-induced anemia was defined as the development of anemia after AZT initiation. Anemia caused by other conditions must be ruled out. Bone marrow investigation can be further performed according to the hematologist's opinion. Data on medical history, patient's clinical characteristics, CBC and baseline laboratory examination results, dose and duration of AZT regimen, HIV clinical status including CD4 cell count and HIV viral load, and use of concomitant medications including folic acid and cotrimoxazole were recorded. The patient's medical history was reviewed to evaluate the condition of anemia and to rule out other causes of anemia. This observational study was reported according to the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines¹⁸ (Supplemental File).

Ethical Approval and Informed Consent

This study was approved by the Institutional Review Board (IRB) of the Faculty of Medicine Vajira Hospital (COA 182/2564) and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments. The IRB waived the requirement to obtain consent for the collection, analysis, and publication of the retrospectively obtained and anonymized data for this noninterventional study.

Statistical Analysis

The incidence of anemia in patients receiving AZT varied between studies based on different geographic areas and diagnostic criteria. A study conducted in India reported that the incidence rate of AZT-induced anemia was 5% to 16%.^9,10 In our study, the sample size was determined using a single population proportion formula. Assuming that the proportion of anemia in patients using AZT-containing regimens was 10% with 95% confidence (CI) and a margin of error of 3%, this study required a total sample size of at least 385. Categorical variables were presented as counts (n) and percentages (%), while numerical variables were presented as means with standard deviations (mean ± SD) or medians with interquartile range (IQR), depending on the distribution of the data. Hazard ratios (HRs) and their 95% CI were obtained from both univariate and multivariate Cox proportional hazard regression analyses to identify the risk factors of AZT-induced anemia. The candidate risk factors with a P-value of <.1 in the univariate analysis were included in the multivariate model. A dependent t-test was performed to compare the CBC result before and during anemia in the anemia group. The follow-up time was censored at the date when anemia was diagnosed. In cases without AZT-induced anemia, the follow-up time was censored at the time of AZT discontinuation, death, loss to follow-up, transfer to other care, or at the end of the study period. Data were analyzed using the Statistical Package for the Social Sciences software version 22.0 (SPSS Inc., Chicago, IL, USA). A P-value of <.05 indicated statistically significant differences in all analyses.

Results

From January 1, 2015, to December 31, 2020, 652 individuals were included in this study. Meanwhile, 251 individuals were excluded from the analysis. Among them, 61 received AZT for <6 months, 30 had insufficient patient information for further analysis, 28 had an active infection, and 132 had anemia of other causes (iron deficiency anemia, n = 47; thalassemia trait or disease, n = 38; chronic kidney disease, n = 22; abnormal bleeding, n = 15; active cancer, n = 7; and G6PD deficiency, n = 3). In total, 401 individuals were enrolled and included in this analysis. The total follow-up time was 1674.50 person-years (PY) (mean ± SD: 4.18 ± 1.73 years/person). In total, 71 individuals were diagnosed with AZT-induced anemia. Figure 1 shows the study flow chart. Table 1 presents the demographic and clinical characteristics of 401 participants.

Figure 1.

Study flow.

Table 1.

Demographic at Baseline.

Characteristics	Number (%) (N = 401)
Sex
Male	202 (50.40)
Age, mean ± SD	43.474 ± 8.4451
<50 years	300 (74.81)
≥50 years	101 (25.18)
Body weight (kg), mean ± SD	60.326 ± 11.3118
Body mass index, mean ± SD	22.7404 ± 3.60778
<18.5 kg/m²	28 (6.98)
18.5-22.9 kg/m²	209 (52.1)
>23 kg/m²	164 (40.9)
Underlying diseases
Dyslipidemia	275 (68.6)
Hypertension	66 (16.50)
Diabetes mellitus	32 (8.00)
Psychiatric disease	11 (2.7)
Stroke	6 (1.5)
Asthma/COPD	6 (1.50)
Cirrhosis	5 (1.2)
Other^a	4 (1)
No underlying disease	92 (22.9)
Number of comorbidity
0-1 underlying disease	299 (74.56)
≥2 underlying diseases	102 (25.44)
Hepatitis B coinfection^b	13 (3.2)
Hepatitis C coinfection^c	30 (7.5)
Duration HIV infection (yr), mean ± SD	12.79 ± 3.421
Baseline CD4 cell count, median (IQR)	132 (47, 256)
≤100 cells/mm³	171 (42.6)
≤250 cells/mm³	297 (74.1)
Duration of AZT use (years), mean ± SD	8.85 ± 3.456
AZT daily dose (mg/kg/d), mean ± SD	8.37 ± 0.084
HIV drug regimens
NNRTI-based regimens	307 (76.6)
Efavirenz	43 (14)
Nevirapine	262 (85.3)
Rilpivirine	2 (0.7)
PI-based regimens	87 (21.7)
Lopinavir/ritonavir	64 (73.6)
Darunavir/ritonavir	4 (4.6)
Atazanavir/ritonavir	19 (21.8)
Other	7 (1.8)
Concomitant medications
Co-trimoxazole	19 (4.7)
Dapsone	3 (0.7)
Fluconazole	12 (3.0)
Folic acid	79 (19.7)
Recent CD4 cell count, median (IQR)	513 (363, 687)
≤100 cells/mm³	7 (1.7)
≤250 cells/mm³	39 (9.7)
HIV viral load
Undetectable	366 (91.3)
Detectable	35 (8.7)
HIV viral load >200 copies/ml	13 (3.2)
viral load >1000 copies/ml	8 (2.0)

COPD, chronic obstructive pulmonary disease; IQR, interquartile range; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitor; SD, standard deviation.

Other; CAD = 1, SLE = 1, hypothyroid = 1, thyrotoxicosis = 1.

Unknown HBsAg result, n = 4.

Unknown anti-HCV result, n = 5.

The mean age of the participants was 43.47 ± 8.45 years, and 50.4% were men. Their mean body weight was 60.33 ± 11.32 kg. In total, 164 (40.9%) individuals were overweight (BMI > 23 kg/m²). Further, 397 (99.8%) and 396 (98.7%) individuals tested for hepatitis B and C virus, respectively, based on the serologic test. Among them, 13 (3.2%) were reactive for the hepatitis B surface antigen (HBsAg) and 30 (7.5%) for the antihepatitis C virus (anti-HCV) antibody. Regarding underlying diseases, the 3 most common underlying diseases were dyslipidemia (n = 275, 68.6%), hypertension (n = 66, 16.5%), and diabetes mellitus (n = 32, 8.0%), respectively. In total, 92 (22.9%) individuals did not present with underlying diseases.

The mean (±standard deviation [SD]) duration of HIV infection was 12.79 (±3.42) years. Further, 345 (86.0%) individuals presented with an HIV infection duration of ≥10 years. Before initiating ART treatment, the patients’ baseline CD4 cell count was low. That is, 297 (74.1%) individuals presented with a baseline CD4 cell count of <250 cells/mm³. Further, the baseline CD4 cell count of 171 (42.6%) individuals was <100 cells/mm³.

The mean (±SD) duration of AZT treatment was 8.85 (±3.46) years. The daily dose of the AZT regimen was 400 to 600 mg/day, with the mean (±SD) AZT dose having based on a weight of 8.365 (±0.08) mg/kg/day. Regarding the ART regimens, 307 (76.6%) individuals were receiving nonnucleoside reverse transcriptase inhibitor-based regimens. The most common nonnucleoside reverse transcriptase inhibitor used was nevirapine (n = 262, 85.3%). Eighty-seven (21.7%) individuals were on protease inhibitor (PI)-based regimens. The most common PI used was boosted lopinavir (n = 64, 73.6%). Folic and cotrimoxazole were the most common prophylactic drugs against concomitant opportunistic infections. After ART initiation, the median CD4 cell count was 513 (IQR: 363, 687) cells/mm³. In total, 366 (91.3%) individuals presented with virological control with undetectable HIV viral load results.

Seventy-one individuals (17.7%, 95% CI [14.34-21.87]) presented with AZT-induced anemia. Among them, 49 (69%) were women. The incidence rate of anemia among PLWH in the follow-up period was 1.98 (95% CI [1.58-2.50]) per 100 PY of observations. There were 8, 13, and 1 men and 16, 33, and 0 women with mild, moderate, and severe anemia, respectively. The median time to anemia development was 29.63 (IQR: 18.33-57.97) months.

Table 2 shows the estimated HR and 95% CI of the characteristics of individuals with and without AZT-induced anemia based on the univariate analyses. Different factors, such as female sex, a higher daily dose of AZT (in mg/kg/day), low baseline CD4 cell count, low recent CD4 cell count, and low-normal baseline hemoglobin level, were associated with anemia. In contrast, a high BMI was associated with decreased risk of anemia. Based on the multivariate logistic regression analysis, female sex (adjusted HR [AHR]: 1.91, 95% CI [1.14-3.21], P = .014), low recent CD4 cell count (AHR: 1.96, 95% CI [1.01-3.84], P = .049), low baseline CD4 cell count (AHR: 1.98, 95% CI [1.03-3.81], P = .041), and low-normal baseline hemoglobin level (AHR: 2.74, 95% CI [1.69-4.43], P < .001) were independently associated with an increased risk of anemia. Meanwhile, a high BMI (AHR: 0.91, 95% CI [0.84-0.98], P = .022) was independently associated with a decreased risk of anemia. Table 3 shows the multivariate logistic regression analysis.

Table 2.

Univariate Analyses of the Estimated HR and 95%CI of the Characteristics Compared Between Individuals with and Without AZT-Induced anemia.

Factor	With AZT-induced anemia 71 individuals (%)	Without AZT-induced anemia 330 individuals (%)	HR [95% CI]	P-value
Sex, female	49 (69)	150 (45.5)	2.13 [1.29-3.52]	.003
Age, mean ± SD	44.761 ± 8.42	43.197 ± 8.44	1.01 [0.98-1.04]	.637
≥50 years	22 (31)	79 (23.9)	1.24 [0.75-2.06]	.396
Body mass index, mean ± SD	21.7052 ± 3.09	22.9632 ± 3.68	0.89 [0.82-0.96]	.004
<18.5 kg/m²	7 (9.86)	21 (6.36)	1.28 [0.58-2.82]	.549
18.5-22.9 kg/m²	47 (66.20)	162 (49.10)	Ref
>23 kg/m²	17 (23.94)	147 (44.55)	0.43 [0.25-0.75]	.003
Underlying disease(s)
Comorbid disease ≥ 2	17 (23.9)	85 (25.8)	0.85 [0.49-1.46]	.556
HIV drug regimens
NNRTI-based (307)	56 (78.9)	251 (76.1)	1.24 [0.70-2.20]	.453
PI-based (87)	15 (21.1)	72 (21.8)	0.89 [0.50-1.57]	.676
Duration of AZT use (years), mean ± SD	8.93 ± 3.07	8.92 ± 3.47	0.94 [0.87-1.01]	.130
AZT daily dose (mg/kg/d), mean ± SD	9.10 ± 1.69	8.21 ± 1.65	1.29 [1.14-1.46]	.002
Concomitant medications
Co-trimoxazole	5 (7)	14 (4.2)	1.92 [0.77-4.78]	.159
Fluconazloe	1 (1.4)	11 (3.3)	.69 [0.10-4.97]	.711
Folic acid	22 (31)	57 (17.3)	1.41 [0.85-2.34]	.178
Recent CD4, median (IQR)	457 (329, 628)	518.5 (366.75, 689.25)	0.999 [0.998-1.000]	.084
≤250 cells/mm³	11 (15.5)	28 (8.5)	2.51 [1.31-4.78]	.005
Baseline CD4, median (IQR)	97 (47, 211)	138.5 (46.5, 265.5)	0.999 [0.997-1.00]	.070
≤250 cells/mm³	60 (84.5)	237 (71.8)	2.03 [1.07-3.87]	.031
HIV viral load undetectable	67 (94.4)	299 (90.6)	1.79 [0.65-4.90]	.260
Low normal baseline Hemoglobin level	37 (52.1)	71 (21.5)	3.33 [2.09-5.30]	<.001

CI, Confidence interval; HR, hazard ratio; IQR, interquartile range; NNRTI, nonnucleoside reverse transcriptase inhibitors; PI, protease inhibitor; SD, standard deviation.

Table 3.

Unadjusted and Adjusted Hazard Ratio (HR) of AZT-Induced anemia.

Factor	Unadjusted HR [95% CI]	Adjusted HR (95% CI)	P-value
Female sex	2.13 [1.29-3.52]	1.91 [1.14-3.21]	.014
Body mass index (kg/m²)	0.89 [0.82-0.96]	0.91 [0.84-0.98]	.022
Recent CD4 ≤ 250 cells/mm³	2.51 [1.31-4.78]	1.96 [1.01-3.84]	.049
Baseline CD4 ≤ 250 cells/mm³	2.03 [1.07-3.87]	1.98 [1.03-3.81]	.041
AZT daily dose (mg/kg/d), mean ± SD	1.29 [1.14-1.46]	1.10 [0.89-1.36]	.390
Low normal baseline hemoglobin level	3.33 [2.09-5.30]	2.74 [1.69-4.43]	<.001

CI, confidence interval; HR, hazard ratio.

In 71 individuals with AZT-induced anemia, the mean (±SD) hemoglobin level (12.52 ± 1.13 vs 10.57 ± 1.00 g/dL; P < .001), hematocrit level (37.20% ± 3.18% vs 30.87% ± 2.92%; P < .001) was lower during AZT-induced anemia diagnosis than during the baseline CBC examination. In addition, the mean (±SD) mean cell volume (MCV) (90.95 ± 7.79 vs 106.89 ± 12.86 fL; P < .001) and neutrophil count (50.13% ± 10.07% vs 54.43% ± 14.71%; P = .017) was higher during AZT-induced anemia diagnosis than during the baseline CBC examination. However, there were no significant differences in the WBC, platelet, and absolute neutrophil count during the diagnosis of AZT-induced anemia and the baseline CBC examination. Table 4 shows the CBC results during the baseline examination and AZT-induced anemia diagnosis. Of the 71 patients diagnosed with AZT-induced anemia, 39 discontinued AZT, resulting in improved hematocrit, while the remaining 32 continued AZT with a dosage adjustment. Six patients (5 women and 1 man) with moderate to severe anemia required blood transfusions. All 6 of these patients discontinued AZT and were switched to tenofovir disoproxil fumarate, and their follow-up hematocrit values returned to normal baseline levels. No patient reported discontinuing AZT due to myositis or myopathy.

Table 4.

The Comparison of the CBC Results at Baseline and While Anemia in Individuals With AZT-Induced Anemia.

Factor	Individuals with AZT-induced anemia (N = 71)		P-value
Factor	At baseline	While anemia	P-value
Hemoglobin (Hb) (g/dL), mean ± SD	12.52 ± 1.13	10.57 ± 1.00	<.001
Hematocrit (Hct) (%), mean ± SD	37.20 ± 3.18	30.87 ± 2.92	<.001
White blood cell count (×10³ cells/mm³), mean ± SD	5.95 ± 1.73	6.05 ± 2.99	.739
Neutrophil count (%), mean ± SD	50.13 ± 10.07	54.43 ± 14.71	.017
Absolute neutrophil count, mean ± SD	3023.82 ± 1211.58	3524.64 ± 2563.31	.72
Platelet count (×10³ cells/mm³), mean ± SD	270.73 ± 74.88	262.69 ± 95.29	.347
Mean cell volume (fL), mean ± SD	90.95 ± 7.79	106.89 ± 12.86	<.001

SD, standard deviation; CBC, complete blood count.

Discussion

This study evaluated 401 adult PLWH who received AZT-containing regimens for >6 months. Results showed that the overall incidence of anemia was 17.7% (n = 71). This finding is consistent with that of a previous study conducted in eastern India, which reported the incidence of anemia in 16.2% of individuals receiving AZT.¹⁹ The overall prevalence rate in this study was significantly lower than that in other studies conducted in northwest Ethiopia (41.6%)²⁰ and northeastern Nigeria (22.3%).²¹ The difference in the prevalence of anemia could be attributed to differences in study populations in terms of HIV clinical stages. The relatively lower incidence rate of anemia in our study could be explained by the fact that the PLWH enrolled in our study were commonly healthy, with a high median CD4 cell count at >500 cells/mm³ and a virological control rate of >90%. According to a study conducted in Ethiopia,²² a high CD4 count and good virological control are associated with a decreased risk of anemia. The development of opportunistic infections can be decreased with improvement in the immunity of PLWH with good virological control. Moreover, ART could improve erythropoiesis and reduce the destruction of hematopoietic stem cells.²³

The association between the use of AZT and anemia via myelosuppression has been established. AZT can inhibit bone marrow activity, which leads to a decreased production of red blood cells and platelets.^24,25 Various studies have revealed that multiple potential factors are associated with AZT-induced anemia among PLWH. These factors include old age, female sex, advanced-stage HIV infection, low BMI, CD4 cell count, and hemoglobin level at the time of AZT initiation, and concomitant use of cotrimoxazole prophylaxis.^26–29 In our study, low-normal baseline hemoglobin level, female sex, low recent CD4 cell count, and low baseline CD4 cell count (≤250 cells/mm³) were independent risk factors of anemia development. By contrast, a higher BMI decreases the risk of anemia.

Female sex was a predictor of anemia in our study. Further, it was considered a risk factor of anemia in a few studies conducted in China and northwest and southern Ethiopia.^30–32 The possible explanation could be attributed to obstetric and gynecological factors such as menstruation. Moreover, men can store more iron than women.³³ Hence, women are at a higher risk of developing anemia.

Low baseline hemoglobin level was a predictor of anemia in our study. A previous study conducted in Cambodia reported that AZT discontinuation was significantly associated with lower hemoglobin levels during AZT initiation.¹¹ A randomized controlled trial conducted in Uganda and Zimbabwe and another study performed on a cohort from the U.S. HIV care center identified a significant correlation between baseline hemoglobin levels at ART initiation and the subsequent risk of AZT-related anemia.^26,34

Both baseline and recent CD4 cell count were found to be predictors of anemia in our study. A study conducted in northwest Ethiopia³⁵ reported that patients with a baseline CD4 cell count of ≤350 cells/mm³ was 1.7 times higher than that of patients with a CD4 cell count of >350 cells/mm³. This result was comparable to that of our study. Moreover, 2 large U.S. cohort studies and studies conducted in India and northwest Ethiopia showed an association between CD4 cell count and anemia.^14,36–38 Similarly, a low recent CD4 cell count is also associated with anemia. Our findings were in agreement with those of various studies conducted in several parts of Ethiopia.^13,22,31 This relationship could be explained by the fact that PLWH with a low CD4 cell count are at risk of various opportunistic infections, which could cause anemia. In addition, the disrupted erythropoiesis and the failed hemoglobin production caused by the release of inflammatory cytokines, along with the decline in the production of hematopoietic growth factors could also explain this finding. A recent study conducted in Thailand reported that the CD4 cell count prior to AZT initiation, hematocrit level at the development of macrocytosis, and the duration of AZT regimen were significant predictive factors of anemia progression.³⁹ Our study did not find an association between the duration of AZT regimen and the development of anemia.

A high BMI is associated with a decreased risk of anemia. Similar to our findings, a study conducted in Ethiopia reported that the participants with a BMI of <18.5 kg/m² were almost 4 times at higher risk of anemia than those with a BMI of ≥25 kg/m².³¹ This finding is in accordance with various studies conducted in Rwanda,⁴⁰ southern and east Ethiopia,^32,41 and Malawi.⁴² Further, it can be possibly explained by the relatively high dose of AZT received by PLWH with a low BMI. Moreover, a lower BMI may be caused by deficiencies in several micronutrients, including iron, folate, and B12, which contribute to anemia.

In our study, the concomitant use of cotrimoxazole was not a risk factor of AZT-related anemia. Moreover, previous studies conducted in northeastern Nigeria and Congo reported that the concomitant use of cotrimoxazole was identified an independent risk factor of AZT-related anemia. Hence, patients who concomitantly received cotrimoxazole and AZT are at higher risk of anemia than those who did not receive cotrimoxazole.^21,43 The current finding could be explained by the myelosuppressive effect of cotrimoxazole. However, this association was not found in our study. The lack of association between cotrimoxazole use and anemia could be explained by the small number of patients using cotrimoxazole and the concomitant preventive use of folic acid in this study. Our finding is similar to that of a cohort study performed at the U.S. HIV care center. The previous study showed an association between cotrimoxazole and AZT use and anemia based on a univariate proportional hazards analysis. However, the result was not significant after adjustment in the multivariate analysis.³⁴ A randomized control trial conducted in Uganda and Zimbabwe did not identify any correlation between the incidence of anemia in individuals receiving ART and cotrimoxazole.²⁶ Nevertheless, we believe that the preventive effect of cotrimoxazole against various opportunistic infections that cause anemia could outweigh its risk.

In our study, PLWH with AZT-induced anemia had a higher mean (±SD) red blood cell MCV during anemia diagnosis compared during baseline. This could be attributed to the fact that AZT may also cause macrocytosis of RBCs by interfering with DNA synthesis, leading to erythrocyte damage.^44,45

The current study had some limitations. First, data quality might be a concern on a retrospective study, which uses collected program data. Moreover, information bias might have occurred because of underreporting/missing data elements. However, missing data in most cases were not the main variables of interest. Second, there is a lack of relevant information on the nutritional and socioeconomic status of the participants. Since the information was collected retrospectively, the diagnosis of AZT-induced anemia could be affected by other conditions that cause megaloblastic anemia, such as vitamin B12 and folate deficiency. However, because we enrolled patients with normal hematocrit at baseline, any preexisting anemia would be excluded from our study. Nevertheless, prospective data collection could provide us with more accurate data and additional information. Third, AZT is now seldom used for HIV treatment globally and the implication of the findings may have limited public health implications. Lastly, considering that the causes of anemia in patients with HIV infection are multifactorial, a single study might not effectively identify its specific causes. The current study also had some strengths. That is, the duration of AZT regimen in our cohort was long, and the follow-up duration was long. Moreover, the follow-up laboratory investigations were complete, which led to accurate data analysis. Moreover, most studies on AZT-induced anemia were conducted in African regions, and our study was conducted in Asia. Thus, our study could provide additional information on the participants with different ethnic and regions, reflecting the generalizability of the information on the risk factors of AZT-induced anemia.

Conclusion

Based on the incidence of anemia in the current study, this condition is considered a public health concern. Low-normal baseline hemoglobin level, female sex, and low recent and baseline CD4 cell count (≤250 cells/mm³) were significant risk factors of anemia. Meanwhile, a high BMI was associated with a low risk of anemia. Therefore, routine screening, early detection, and treatment of anemia are important and should be considered in PLWH receiving AZT-containing regimens.

Supplemental Material

sj-docx-1-jia-10.1177_23259582251321577 - Supplemental material for Incidence and Risk Factors of Zidovudine-Induced Anemia in Patients With HIV Infection Receiving Zidovudine-Containing Antiretroviral Therapy

Supplemental material, sj-docx-1-jia-10.1177_23259582251321577 for Incidence and Risk Factors of Zidovudine-Induced Anemia in Patients With HIV Infection Receiving Zidovudine-Containing Antiretroviral Therapy by Lakkana Boonyagars, Peerawit Thinpangnga and Warangkana Munsakul in Journal of the International Association of Providers of AIDS Care (JIAPAC)

Footnotes

Acknowledgments

The authors would like to thank all of the staff of the HIV Clinic and Infectious Diseases Division of Vajira Hospital, Navamindradhiraj University, Bangkok, Thailand, for their help and support.

Author Contributions

Conceptualization: LB and WM; data collection: LB and PT; data validation: LB and PT; data analysis: LB and PT; manuscript preparation: LB and WM; revision and approval of the final manuscript: LB, PT, and WM. All authors have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.

Data Availability

The datasets used for the current study are available from the corresponding author on reasonable request.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval and Informed Consent

This study was approved by the Institutional Review Board of the Faculty of Medicine Vajira Hospital (COA 182/2564) and was conducted in accordance with the 1964 Helsinki Declaration and its later amendments. The IRB waived the requirement to obtain consent for the collection, analysis, and publication of the retrospectively obtained and anonymized data for this noninterventional study.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Navamindradhiraj University Research Fund (Grant No. 13/2564).

ORCID iD

Lakkana Boonyagars

Supplemental Material

Supplemental material for this article is available online.

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