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10.1136/bmjopen-2024-083939
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Original Research
HIV/AIDS
1506
Incidence of anaemia and its predictors among HIV-infected children receiving highly active antiretroviral treatment in North-West Ethiopia: a multicentre retrospective follow-up study
http://orcid.org/0009-0007-9451-2128
Alemu Gebrie Getu 1gebryegetu27@gmail.com

Tesfie Tigabu Kidie 1tigabukidie@gmail.com

Yayeh Azmeraw Tadele 2tadeleazme@gmail.com

Woleli Dessalew Abelneh 3dessalewabelneh14@gmail.com

Aweke Mekuriaw Nibret 4mekunib@gmail.com

1 Department of Epidemiology and Biostatistics, College of Medicine and Health Sciences, Institute of Public Health, University of Gondar, Gondar, Ethiopia
2 Department of Medical Nursing, University of Gondar Comprehensive Specialized Hospital, Gondar, Ethiopia
3 Department of Internal Medicine, Felege-Hiwot Comprehensive Specialized Hospital, Bahir Dar, Ethiopia
4 Department of Human Nutrition, College of Medicine and Health Sciences, Institute of Public Health, University of Gondar, Gondar, Ethiopia
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

None declared.

Gebrie GetuAlemu; gebryegetu27@gmail.com
2024
12 9 2024
14 9 e08393903 1 2024
13 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
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Abstract

Background

Anaemia is one of the most common problems in HIV-infected patients associated with increased HIV progression, decreased functional capacity, survival and quality of life. For better interventions, up-to-date information concerning anaemia among HIV-infected children less than 5 years of age on antiretroviral therapy (ART) is vital. Thus, this study aims to determine the predictors of anaemia among HIV-infected children less than 5 years of age receiving ART in North-West Ethiopia.

Design

An institution-based retrospective follow-up study was conducted.

Study setting

Amhara region Comprehensive Specialized Hospitals, North-West Ethiopia.

Participants

In total, we examined 460 HIV-infected children less than 5 years of age who had followed highly active antiretroviral treatment from 2010 to 2020.

Outcome measures

The outcome measures were median time to detection of anaemia, the incidence and the effects of cotrimoxazole preventive therapy (CPT), ART adherence, tuberculosis (TB), WHO clinical stage and wasting on anaemia.

Results

The overall follow-up time was 9234 person-months of observation. The incidence density of anaemia was 8.34 per 1000 person-months of observation (95% CI 6.67 to 10.43). The cumulative survival probability of children after the last months of follow-up was 0.54. The independent predictors of anaemia were not receiving CPT (adjusted HR (AHR)=4.44; 95% CI 2.48 to 7.93), poor adherence to ART (AHR=2.46; 95% CI 1.37 to 4.42), TB (AHR=3.40; 95% CI 1.72 to 6.72), severe WHO clinical stage (AHR=3.03; 95% CI 1.40 to 6.58) and severe wasting (AHR=1.98; 95% CI 1.08 to 3.64).

Conclusion and recommendation

The incidence rate of anaemia was high and it was provoked by predictors like CPT, ART adherence, TB, WHO clinical stage and wasting. Therefore, it is necessary to emphasise for these predictors.

HIV & AIDS
community child health
public health
==== Body
pmcSTRENGTHS AND LIMITATIONS OF THIS STUDY

The primary strength of this study was the inclusion of multiple health institutions, which enhances the accuracy of the estimate.

The other strength was the extended follow-up period, that could increase observation time.

Since the data were collected from a secondary source of medical records, some predictors of anaemia were not assessed.

Retrospective studies had shortcomings in the establishment of temporal relationships.

Introduction

Anaemia is one of the most severe and common nutritional deficiency disorders of public health concern in low-income and middle-income countries.1 It is defined as a decrease in the concentration of circulating red blood cells and a corresponding reduction in their ability to carry oxygen. Anaemia in children less than 5 years of age is classified as mild (haemoglobin (Hgb=10.0–10.9 g/dL)), moderate (Hgb=7.0–9.9 g/dL), severe (Hgb<7.0 g/dL) or normal (Hgb≥11.0 g/dL).2

HIV is a virus that affects the natural defence mechanisms of humans and causes AIDS. It is a virus that targets the body’s immune system, specifically the cluster of differentiation 4 (CD4) T cells.3 The loss of CD4+ T cells weakens the immune system, making the individual susceptible to opportunistic infections (OIs). Overall, the interaction between HIV and CD4 molecules is fundamental to the virus’s ability to infect and replicate within the host, and it remains a major focus of research and treatment efforts in the fight against HIV/AIDS.4

Anaemia is the most common haematological abnormality among people living with HIV and is a widespread public health problem.5 It impairs physical functioning, affects quality of life, increases HIV progression and reduces the survival of HIV-infected children.6 Moreover, it is a common manifestation of paediatric HIV infection and is a significant negative predictor of survival.3 In countries with limited resources, haematological abnormalities are the second leading cause of morbidity and mortality among HIV-positive children.7

Anaemia in children with HIV infection is a new public health concern. Twenty-five perecent of the people in the world suffer from anaemia, with 293 million (47%) children younger than 5 years8 and more than 100 million anaemic children living in Africa.9 According to reports from Asia, after starting antiretroviral therapy (ART), the incidence density of severe anaemia in children was 5.4 per 100 person-years.10 Similarly, in previous studies in Ethiopia, there were 10.5 per 100 person-years of observation (PYO)11 and 6.9 per 100 PYO.12 Furthermore, according to the Ethiopian Demographic and Health Survey 2016 reports, 57% of children aged 6–59 months suffer from some degree of anaemia. Of this, 25% of children are classified as having mild anaemia, 29% present with moderate anaemia and 3% have severe anaemia.13

Ethiopia is among the many nations that have increased access to ART in the past few years.14 There are various solutions to prevent and control the incidence of anaemia among HIV-positive children. In particular, measuring the serum haemoglobin level before starting ART,15 early initiation of ART16 and starting with a non-zidovudine -based ART regimen17 are measures used to prevent and control anaemia.

Some previous research evidence states that sociodemographic, clinical and treatment-related factors like age,18 cotrimoxazole preventive therapy (CPT),9 12 19 20 baseline WHO clinical stage,6 12 19 21 22 ART adherence,6 12 23 tuberculosis (TB),5 21 23 24 nutrition21 25 and CD4 cell count12 25 were found to be predictors of anaemia.

Anaemia has attracted the attention of both the government and researchers since there has been no prior study on the time to detection of anaemia and its predictors among HIV-infected children less than 5 years of age in the country in general or in the study area in particular. Therefore, the results of this study will provide valuable information for policy makers, clinicians and researchers to enhance decision-making and planning of appropriate interventional approaches to reduce the incidence of anaemia in HIV-infected children. Hence, this study aimed to assess the time to detection of anaemia, the incidence and its predictors among HIV-infected children less than 5 years of age with highly active antiretroviral treatment in comprehensive specialised hospitals in the Amhara region, North-West Ethiopia.

Methods and materials

Study design, period, area and participants

From January 2010 to December 2020, a multicenter institution-based retrospective follow-up study was carried out at comprehensive specialised hospitals at Debre Markos, Felege Hiwot, Debre Tabor and the University of Gondar, whose respective locations are 299 km, 565 km, 660 km and 738 km from Addis Ababa, the capital city of Ethiopia. These hospitals were selected because they provide ART follow-up and care services to a significant number of HIV-positive patients in the region. All four hospitals provide inpatient and outpatient care for more than 20 million people in the Amhara region and surrounding areas. Our target population included all HIV-infected children less than 5 years of age who were newly enrolled in ART at comprehensive, specialised hospitals. Study participants who were randomly selected and received ART for at least 3 months during the follow-up period at the study hospitals were included. Children who had incomplete records of age or ART initiation date at the time of data collection were excluded. The follow-up period ranged from enrolment in the ART clinic until the development of the event (anaemia), death, loss to follow-up, transfer or no event at the end of the study.

Sample size and sampling procedure

The sample size was calculated by using log-rank survival data analysis of the two-population proportion formula based on the following important assumptions: 95% confidence level, exposure to an unexposed ratio of 1:1, 80% power and 5% significance level. The minimum required sample size was estimated based on the following variables: CD4 counts or percentages, CPT, WHO clinical stages III and IV, and ART adherence according to a study conducted in North-West Ethiopia.12 However, the maximum calculated sample size was obtained by taking ART adherence as a predictor variable (on good ART adherence as an unexposed group denoted by q1 (0.86) and poor ART adherence as an exposed group denoted by q0 (0.75)). After adding 10% contingency for incomplete medical records (missing), the final sample size for this study was 460 (online supplemental table 1). The four selected hospitals providing ART services were included, and children less than 5 years of age on treatment were extracted from the ART registry. At this stage, a sampling frame was developed, and the total sample size was compared with the total sample size of children less than 5 years of age on ART. Then, a total of 460 study units were selected using a computer-generated random sampling method (figure 1).

Figure 1 Schematic representation of the sampling procedure among HIV-infected children receiving highly active antiretroviral treatment (HAART) in comprehensive specialised hospitals in Amhara region, North-West Ethiopia, 2022.

Data collection tools and procedures

After reviewing the charts of some HIV-infected children and similar articles, a standardised data extraction checklist was carefully developed. Initially, the medical records of eligible HIV-positive children less than 5 years of age on ART were gathered from the card room using the patient’s medical registration number. Then, basic sociodemographic, clinical, laboratory and treatment-related variables of HIV-infected children were extracted from the selected charts. The most recent laboratory and clinical measurements documented at ART initiation were used as baseline values. However, variables such as a history of treatment failure, history of regimen change, level of adherence and history of OIs were collected on a follow-up basis. In addition, relevant patient data that were not available on the patient’s chart were retrieved from the ART smart care file. Finally, the consistency between the records and collected data was confirmed by the principal investigator through randomly selected reviews of previously extracted medical records.

Patient and public involvement

Patients and the public did not participate in the study’s design, conduct, reporting or distribution strategies.

Variables of the study

Dependent variable: Incidence of anaemia.

The independent variables include

Sociodemographic variables: Age and sex of the child, the caregiver’s age and sex, residence, the caregiver’s relationship with the child, the status of the parents.

Clinical characteristics: WHO clinical staging, CD4 count/percentage, developmental status and OIs.

ART and other medication-related variables: Baseline ART regimens, regimen changes, treatment failure, CPT, isoniazid preventive therapy (IPT) and adherence to ART.

Nutritional variables: Underweight, wasting and stunting.

Operational definitions

Anaemia: Anaemia among children less than 5 years of age was defined based on the recommendation of the WHO guidelines, taking age into consideration: Hgb<11 g/dL.26

Event: The occurrence of anaemia during the follow-up time.

Censored: When the participants were lost, formally transferred to other health facilities, died, or the study period ended before the occurrence of anaemia.

Time to event: The time interval (months) between ART initiation and the occurrence of anaemia

Incidence rate of anaemia: The rate of anaemia during the follow-up period to the total person-months of observation.

Data processing and analysis

Data were entered into EpiData V.3.1 and then exported to STATA V.14 software for statistical analysis. A Kaplan‒Meier survival curve was used to estimate the anaemia-free survival time, and a log-rank test was used to compare the anaemia-free survival times between different categorical explanatory variables. A life table was constructed to estimate survival probabilities. Graphical tests such as the log-log survival probability plot, Schoenfeld residual plot and Schoenfeld residual global proportional hazard test were used to assess the proportional hazard assumption of the model. A value of p>0.05 on the Schoenfeld residuals proportional hazard test was used to determine whether the proportional hazard assumption was satisfied or violated. A Cox-Snell residual test was used to evaluate the Cox proportional hazards model’s goodness of fit. Variables with values of p<0.25 in the bivariable analysis27 were considered for the multivariable analysis. We used adjusted HRs (AHRs) with 95% CIs and p values to measure the strengths of the associations and identify statistically significant predictors.

Results

Sociodemographic characteristics

The medical records of a total of 460 HIV-infected children were retrieved. Of these, 442 HIV-infected children less than 5 years of age on ART were included in this study. The remaining 18 studies were excluded from the analysis due to incomplete data (missing). The median age of the study participants was 34 months (IQR=19–48). Approximately half (50.68%) of the study participants were male, and two-thirds (66.52%) were from urban areas. The median age of the caregivers was 31 years (IQR: 27–37), and more than three-fourths (78.05%) of the parents were both alive (online supplemental table 2).

Clinical, immunological, laboratory and treatment-related characteristics

More than a third (37.78%) of the study participants had OIs at ART initiation, and 47.51% had CD4 counts below the threshold. A total of 38 (8.6%) patients had TB and 191 (43.21%) had a history of OIs. Regarding developmental milestones, 85.97%, 11.76% and 2.26% of the study participants were appropriate, delayed and regressed, respectively. Moreover, less than three-quarters (72.4%) had good ART drug adherence. Furthermore, 18.10% of the study participants had a history of treatment failure. A third (33.71%) of the participants changed their original ART regimen. Regarding prophylaxis use, 374 (84.62%) of the participants received CPT, whereas half (50.23%) did not receive IPT. About half (51.58%) of the participants started ART at mild WHO clinical stage (I and II). A fifth (19.91%) of the study participants were moderately underweight, 15.61% were moderately wasted and 13.35% were moderately stunted. Furthermore, 19.68% of children less than 5 years of age who were malnourished were severely underweight, 21.49% had severe wasting and 20.36% had severe stunting (online supplemental table 3).

Incidence of anaemia and survival characteristics during the follow-up period

A total of 442 HIV-infected children were followed for an overall follow-up period of 9234 person-months of observation (769.5 PYO), with a minimum of 3 months and a maximum of 48 months. The median follow-up period was 18.5 months (IQR=11–32). At the end of the follow-up period, 77 (17.42%, 95% CI 14.15% to 21.25%) children were anaemic, while 365 (82.58%, 95% CI 78.75% to 85.85) were non-anaemic (figure 2).

Figure 2 Outcome status of HIV-infected children receiving highly active antiretroviral treatment (HAART) in comprehensive specialised hospitals in Amhara region, North-West Ethiopia, 2022.

The incidence rate of anaemia was 8.34 per 1000 person-months of observation (95% CI 6.67 to 10.43). The cumulative survival probabilities of being anaemia-free at 6 months, 12 months, 24 months, 36 months and 48 months after ART initiation were 0.97, 0.91, 0.82, 0.74 and 0.54, respectively (figure 3).

Figure 3 Overall Kaplan-Meier survival estimates of HIV-infected children receiving highly active antiretroviral treatment (HAART) in Amhara region comprehensive specialised hospitals, North-West Ethiopia, 2022.

In this study, there was a significant difference in the status of the parents (p<0.001), OIs (p<0.001), CD4+ T cells (p<0.001), ART adherence (p<0.001), CPT (p<0.001), isoniazid prophylaxis (p<0.001), treatment failure (p<0.001), TB (p<0.001), WHO clinical stage (p<0.001), underweight (p<0.013), and wasting (p<0.001) between anaemic and non-anaemic patients (online supplemental table 4).

Anaemia-free survival time of HIV-infected children less than 5 years of age on ART

The median time to develop anaemia was 13 months (IQR=11–16). The anaemia-free survival time of children who had ever taken CPT was greater than that of children who had never taken CPT (online supplemental figure 1). Furthermore, those children who had poor ART adherence had shorter anaemia-free survival than did those who had good ART drug adherence (online supplemental figure 2). Moreover, those children who developed TB had a shorter anaemia-free survival time than did those who did not develop TB (TB-negative) (figure 4).

Figure 4 Kaplan-Meier survival curves comparing anaemia-free survival time between TB-positive and TB-negative patients on ART in comprehensive specialised hospitals in Amhara region, North-West Ethiopia, 2022. ART, antiretroviral therapy; TB, tuberculosis.

Moreover, children less than 5 years of age who presented with baseline WHO clinical stages III and IV had shorter anaemia-free survival than did children who presented with WHO stages I and II (online supplemental figure 3). Furthermore, children who experienced severe wasting had a shorter anaemia-free survival time than did those in the normal cohort (online supplemental figure 4).

Predictors of anaemia

The multicollinearity among independent variables was assessed using variance inflation factor (VIF). The results indicated no multicollinearity, as the VIF value for each independent variable was <7. In the bivariable Cox proportional regression analysis, 16 variables (p<0.25) were selected for the multivariable Cox regression analysis. Those variables were age of the child, age of the caregiver, sex of the child, sex of the caregiver, status of parents, residence, OI at baseline, CD4 count, underweight, wasting, ART adherence, CPT, isoniazid prophylaxis, treatment failure, TB and WHO clinical stage. According to the multivariate analysis, five variables were found to be statistically significant predictors of anaemia. Those significant variables were CPT, ART adherence, TB, WHO clinical stage and wasting.

The hazard of anaemia in children who had never taken CPT was 4.4 times greater (AHR=4.44; 95% CI 2.48 to 7.93) than that in children who had taken CPT. Additionally, HIV-infected children on ART who had poor ART adherence were 2.5-fold (AHR=2.46; 95% CI 1.37 to 4.42) more likely to develop anaemia than were those who had good ART adherence. Moreover, the hazard of anaemia in HIV-infected children less than 5 years of age who were TB-positive was 3.4 times greater (AHR=3.40; 95% CI 1.72 to 6.72) than in those who were TB-negative. Furthermore, the hazard of anaemia in children with WHO stages III and IV was threefold greater than that in children with WHO stages I and II (AHR=3.03; 95% CI 1.40 to 6.58). Finally, the hazard of anaemia with severe wasting in children was two times greater (AHR=1.98, 95% CI 1.08 to 3.64) than that in the normal cohort (table 1).

Table 1 Bivariable and multivariable Cox regression analyses of anaemia among HIV-infected children receiving ART in North-West Ethiopia, 2022

Variables	Outcome status	CHR (95% CI)	AHR (95% CI)	P value	
Age of the child	Anaemic	Non-anaemic				
Less than 12 months, n (%)	12 (20.34)	47 (79.66)	0.67 (0.36 to 1.24)	1.51 (0.73 to 3.12)	0.270	
12–59 months, n (%)	65 (16.97)	318 (83.03)	1	1		
Sex of the child						
 Male, n (%)	44 (19.64)	180 (80.36)	1	1		
 Female, n (%)	33 (15.14)	185 (84.86)	0.72 (0.46 to 1.13)	0.84 (0.5 to 1.4)	0.499	
Age of the caregiver						
 18–30 years, n (%)	31 (14.83)	178 (85.17)	1	1		
 31–40 years, n (%)	27 (15.98)	142 (84.02)	1.20 (0.72 to 2.02)	0.92 (0.51 to 1.65)	0.782	
 41–50 years, n (%)	15 (32.61)	31 (67.39)	3.52 (1.87 to 6.63)	1.44 (0.63 to 3.31)	0.389	
 >51 years, n (%)	5 (27.78)	13 (72.22)	3.88 (1.34 to 11.2)	2.50 (0.72 to 8.68)	0.148	
Sex of the caregiver						
 Male, n (%)	44 (19.64)	180 (80.36)	1	1		
 Female, n (%)	33 (15.14)	185 (84.86)	0.58 (0.35 to 0.96)	1.15 (0.61 to 2.16)	0.666	
Residence						
 Urban, n (%)	50 (17.01)	244 (82.99)	1	1		
 Rural, n (%)	27 (18.24)	121 (81.76)	1.36 (0.85 to 2.19)	1.05 (0.59 to 1.85)	0.865	
Current status of parents						
 Both alive, n (%)	47 (13.62)	298 (86.38)	1	1		
 Father dead, n (%)	7 (20)	28(80)	1.56 (0.70 to 3.45)	0.80 (0.31 to 2.07)	0.651	
 Mother dead, n (%)	7 (33.33)	14 (66.67)	2.76 (1.24 to 6.12)	0.45 (0.17 to 1.20)	0.110	
 Both dead, n (%)	16 (39.02)	25 (60.98)	5.58 (3.12 to 9.99)	1.60 (0.71 to 3.61)	0.257	
OI at baseline						
 Yes, n (%)	66 (24)	209 (76)	3.82 (2.02 to 7.24)	1.38 (0.58 to 3.24)	0.466	
 No, n (%)	11 (6.59)	156 (93.41)	1	1		
CD4 count, n (%)						
 Above the threshold, n (%)	28 (13.33)	182 (86.67)	1	1		
 Below the threshold, n (%)	49 (21.12)	183 (78.88)	1.39 (0.87 to 2.22)	1.23 (0.72 to 2.09)	0.455	
CPT						
 Yes, n (%)	47 (12.57)	327 (87.43)	1	1		
 No, n (%)	30 (44.12)	38 (55.88)	6.98 (4.35 to 11.21)	4.44 (2.48 to 7.93)*	<0.001	
Isoniazid prophylaxis						
 Yes, n (%)	40 (18.18)	180 (81.81)	1	1		
 No, n (%)	37 (16.67)	185 (83.33)	1.42 (0.90 to 2.22)	1.30 (0.80 2.12)	0.290	
ART adherence status						
 Good, n (%)	35 (10.94)	285 (89.06)	1	1		
 Fair, n (%)	14 (25)	42 (75)	2.41 (1.29 to 4.48)	1.56 (0.80 to 3.09)	0.185	
 Poor, n (%)	28 (42.42)	38 (57.58)	4.17 (2.53 to 6.89)	2.46 (1.37 to 4.42)*	0.003	
Treatment failure						
 Yes, n (%)	27 (33.75)	53 (66.25)	2.14 (1.34 to 3.43)	1.18 (0.70 to 1.99)	0.533	
 No, n (%)	50 (13.81)	312 (86.19)	1	1		
TB during the follow-up						
 Positive, n (%)	15 (39.47)	23 (60.53)	3.11 (1.76 to 5.47)	3.40 (1.72 to 6.72)*	<0.001	
 Negative, n (%)	62 (15.35)	342 (84.65)	1	1		
WHO clinical staging						
 Mild (stages I and II), n (%)	13 (5.7)	215 (94.3)	1	1		
 Advanced (stages III and IV), n (%)	64 (29.91)	150 (70.09)	5.72 (3.15 to 10.39)	3.03 (1.40 to 6.58)*	0.005	
Underweight						
 Normal, n (%)	37 (13.86)	230 (86.14)	1	1		
 Moderate, n (%)	16 (18.18)	72 (81.81)	1.21 (0.67 to 2.17)	0.92 (0.45 to 1.88)	0.825	
 Severe, n (%)	24 (27.59)	63 (72.41)	1.71 (1.02 to 2.86)	0.70 (0.36 to 1.38)	0.304	
Wasting, n (%)						
 Normal, n (%)	32 (11.51)	246 (88.49)	1	1		
 Moderate, n (%)	14 (20.29)	55 (79.71)	1.83 (0.97 to 3.42)	1.36 (0.68 to 2.71)	0.379	
 Severe, n (%)	31 (32.63)	64 (67.37)	3.12 (1.91 to 5.12)	1.98 (1.08 to 3.64)*	0.027	
1: Reference category.Bol

Bold values are statistically significant variables.

* Statistically significant variables in the multivariable analysis at 5% level of significance.

AHRadjusted HRARTantiretroviral therapyCD4cluster of differentiation 4CHRcrude HRCPTcotrimoxazole preventive therapyOIopportunistic infectionTBtuberculosis

Since the p values of all variables in the final multivariable Cox regression model and the overall global test were greater than 0.05, the proportional hazards assumption for such variables were satisfied (online supplemental table 5). Based on the finding of Cox-Snell residuals, the Nelson-Aelon hazard line followed almost the 45° alignment with the reference line which indicated the model appears to suit the data fairly well (online supplemental figure 5).

Discussion

This multicentre facility-based retrospective follow-up study identified predictors of anaemia among HIV-infected children less than 5 years of age receiving ART. The incidence rate of anaemia among HIV-infected children receiving ART was 8.34 (95% CI 6.67 to 10.43) per 1000 child-months of observation. Our finding is in line with studies conducted in Ethiopia (for which the incidence rate of anaemia was 6.87 to 6.9).6 12 However, the incidence rate of this finding was greater than that in a study conducted in Asia (Cambodia, India, Indonesia, Malaysia, Vietnam and Thailand), which reported 5.4 per 100 PYO,10 and in West African countries (Benin, Burkina Faso, Cote d'Ivoire, Gambia, Ghana, Mali and Senegal), which reported 2.47 per 100 child-years of observation in those on regimens containing AZT compared with 4.25 for those on non-AZT-based regimens.28 The variations might be due to differences in the study area, socioeconomic and cultural differences, and differences in study time because governments may have devised intervention strategies to alleviate the problem and healthcare policies. In addition, this difference might be due to variations in the ART regimen, clinical characteristics of the study participants, and study settings. Both previous studies were performed at multiple centres at the country level, but this study was performed at multiple centres at the health facility level. Moreover, previous studies reported only severe anaemia incidence, but the current study reported the incidence of all types of anaemia.

In this study, the hazard of anaemia was 4.4-fold greater for children less than 5 years of age who did not receive CPT than for those who did receive CPT. This finding is consistent with previous studies from Ethiopia conducted in Ethiopia 9 12 29 and Gambia.20 The possible reason for this could be that CPT is a safe, practical, and affordable technique for preventing comorbidities and mortalities associated with HIV/AIDS and improving quality of life.30 Additionally, CPT can prevent or lessen the incidence of OIs and subsequent complications; for this reason, it is essential to increase immune systems to decrease viral replication, which increases the likelihood of survival by treating and preventing OIs.31

This study also revealed that children less than 5 years of age who had poor ART adherence increased the hazard of anaemia by 2.46-fold compared with those who had good ART adherence. This finding is supported by studies conducted in Ethiopia.6 12 32 This could be explained by the fact that children with low ART adherence are more likely to have drug resistance, OIs, rapid disease progression, high viral load replication and suppression of the immune system.12 33 Additionally, because children depend on their caregivers for care, caretakers may feel pessimistic or reckless, and if the child exhibits no change, the therapy may cascade.34 If children would not take their medication appropriately, anaemia may be developed.

The hazard of anaemia in children with an advanced WHO clinical stage of disease during ART increased threefold compared with their counterparts. This result is supported by studies conducted in Ethiopia,6 12 Kenya,22 Mozambique,21 Uganda19 and India.35 A possible explanation could be that advanced WHO clinical staging is associated with depletion of immunity and can lead to severe medical illnesses such as anaemia due to the depletion of CD4+ T cells, viral replication, and the additional burden of co-infections.36 This can also be explained by the fact that severe disease compromises immunity, which increases the risk of OIs and increases viral replication.6 This causes anaemia through increased cytokine-mediated myelosuppression and a greater burden of comorbidities.19

Furthermore, this study also showed that TB in children was one of the significant determinants of anaemia. Children with TB had a 3.4-fold greater hazard of developing anaemia than children without TB. This finding is supported by studies performed in Ethiopia,5 Uganda,23 South Africa24 and Mozambique.21 A possible justification for this could be that a typical trait of chronic TB is substantial weight loss that concurs with a decrease in blood haemoglobin levels, causing anaemia.37 Moreover, patients with TB often have poor nutritional status which could lead to deficiencies in iron, vitamin B12 and folate. These nutrients are essential for red blood cell production and their deficiency can result in anaemia.5 Furthermore, TB can directly affect the bone marrow, where blood cells are produced. The infection can suppress bone marrow function, leading to a reduced production of red blood cells and if red blood cells are not produced well, anaemia will be the outcome.

Lastly, the hazard of anaemia with severe wasting was twofold greater than that in the normal cohort. Similar findings have been reported in Egypt25 and Mozambique.21 A possible justification for this could be that children with wasting will have intestinal malabsorption and micronutrient deficiencies such as iron, folic acid, vitamin A and vitamin B12, which can lead to anaemia.38 Anaemia and nutrition are closely linked, as an inadequate nutrition is one of the most common causes of anaemia. Ensuring a well-balanced diet with sufficient vitamins and minerals is crucial for preventing and treating anaemia. In some cases, dietary supplements or medical interventions may be necessary to address specific deficiencies. This implies that clinicians should place more emphasis on malnourishment in HIV-infected children.

Strengths and limitations

The inclusion of several health facilities in this study is its main strength, since it improves the accuracy of the estimate. This is, to the best of our knowledge, the first study to examine the time to detection of anaemia, incidence rates and predictors among HIV-infected children less than 5 years of age in Ethiopia.

Because of the retrospective nature of the data, the relationship between some predictors like income, food diversification, intestinal parasite infestations, maternal serum haemoglobin level, serum ferritin level and the educational status of the caregiver, with anaemia was not assessed. The ability to establish temporal relationships was limited in retrospective studies. However, in countries with limited resources, retrospective studies are crucial.

Conclusion and recommendations

The incidence rate of anaemia in our study was high. The hazard of anaemia was increased in children who do not use CPTs, children with poor ART adherence, TB, WHO clinical stages III and IV, and wasting. Since many risk factors are present routinely, even within a single patient, emphasis should be given to improving CPT and the level of adherence. Additionally, special consideration and close monitoring should be given to children presenting with TB, wasting and WHO clinical stages III and IV.

supplementary material

10.1136/bmjopen-2024-083939 online supplemental file 1

Acknowledgements

The authors thank the administrators and healthcare professionals working in the ART clinic of Felege Hiwot, Debre Tabor, Debre Markos and University of Gondar Compressive Specialized Hospitals for their support during data collection and chart retrieval. The authors also thank all individuals who participated in the study, notably data collectors and supervisors.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Review Process File
12 09 2024

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2024-083939).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Ethics approval: Ethical clearance was obtained from the Institutional Review Board (IRB) of Bahir Dar University (protocol number 285/2021). As the study was conducted through a review of medical records, the individual patient was not subject to harm and the official letter of cooperation to each hospital was taken from Bahir Dar University. Permission was taken from each study hospital manager. Informed consent from parents or legal guardians was not required as confidentiality and anonymity were strictly maintained. Besides, it was waived by the IRB of Bahir Dar University. The names and other identifiers of patients and healthcare professionals were not recorded on the data extraction form. Confidentiality was maintained through anonymity and privacy measures were taken to preserve the rights of the participants throughout the research work and the data were not disclosed to anyone other than the principal investigator. This study was conducted in accordance with the declaration of Helsinki.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
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