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HIV/AIDS, ART, mortality, survival, predictors, children, Ethiopia
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Zemariam AB. Survival Dynamics: Mortality Rates and its Predictors among HIV-Infected Pediatric Patients on Antiretroviral Therapy after the Era of Test and Treat Strategy in Amhara Region, Ethiopia [version 1; peer review: awaiting peer review]. F1000Research 2025, 14:1267 (https://doi.org/10.12688/f1000research.171911.1)
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Research Article
Survival Dynamics: Mortality Rates and its Predictors among HIV-Infected Pediatric Patients on Antiretroviral Therapy after the Era of Test and Treat Strategy in Amhara Region, Ethiopia
[version 1; peer review: awaiting peer review]
PUBLISHED 17 Nov 2025
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This article is included in the Global Public Health gateway.
Abstract
Corresponding author:
Alemu Birara Zemariam
Competing interests:
No competing interests were disclosed.
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The author(s) declared that no grants were involved in supporting this work.
Copyright:
© 2025 Zemariam AB.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Zemariam AB. Survival Dynamics: Mortality Rates and its Predictors among HIV-Infected Pediatric Patients on Antiretroviral Therapy after the Era of Test and Treat Strategy in Amhara Region, Ethiopia [version 1; peer review: awaiting peer review]. F1000Research 2025, 14:1267 (https://doi.org/10.12688/f1000research.171911.1)
First published: 17 Nov 2025, 14:1267 (https://doi.org/10.12688/f1000research.171911.1)
Latest published: 17 Nov 2025, 14:1267 (https://doi.org/10.12688/f1000research.171911.1)
Introduction
The HIV epidemic poses a significant global challenge, with children bearing a disproportionate burden, particularly in developing countries.1 Mother-to-child transmission (MTCT) remains the primary route of HIV infection in children, accounting for over 90% of paediatric cases, occurring during pregnancy, childbirth, or breastfeeding.2 In the absence of effective interventions, the risk of transmission to infants born to HIV-positive mothers ranges from 20% to 45%.3,4 However, with the implementation of prevention methods and antiretroviral therapy (ART), this risk can be reduced to below 5%.1,5
In Ethiopia, as of 2020, approximately 44,138 children under the age of 15 are living with HIV, with an alarming 11,967 deaths annually attributed to HIV/AIDS-related causes.6,7 Despite the provision of free ART services since 2005 and the establishment of over 1,474 health facilities offering care,7 mortality rates among HIV-positive children remain high, particularly in resource-limited settings.8 Children in these contexts often begin ART with higher viral loads and lower CD4 counts, leading to mortality rates ranging from 12.4 to 21.7 deaths per 1,000 child years.9,10
Several factors influence mortality among these children, including WHO stage, CD4 count, anaemia, age, baseline functional status, and adherence to ART.4,11 However, the evidence regarding the impact of the WHO stage, CD4 count, and cotrimoxazole preventive therapy (CPT) on mortality is inconsistent.12–14 Early diagnosis and ART initiation have been demonstrated to significantly reduce child mortality and HIV progression, yet persist.15
To address these issues, the national ART guidelines were updated in 2014 to recommend ART for all HIV-positive children under 15,16 regardless of CD4 count or WHO stage. This study aimed to evaluate mortality rates and predictors among Ethiopian children following ART initiation, providing updated insights into the effectiveness of these interventions.
Methods and materials
Study design, period, and setting
A multicentre retrospective follow-up study was conducted from January 1, 2015, to December 31, 2024. The study was conducted in Amhara region’s comprehensive specialized hospitals. These include Woldia, Dessie, Debrebirhan, Tibebe Gion, Debretabor, the University of Gondar, Felege Hiwot, and Debre Markos comprehensive specialized hospital. The hospitals serve more than 2.7 million, 2.5 million, 2.8 million, 4.5 million, 3.1 million, 7 million, 5 million, and 3.5 million peoples who came from the catchment area in their respective orders. Apart from other services, pediatric antiretroviral therapy services have been delivered in all public hospitals since 2005. From January 1, 2015, to December 31, 2024, a total of 1004 HIV-infected children aged younger than 14 years have been initiated ART services across these hospitals and all children were followed till the event of interest developed or become censored. Moreover, the follow-up was stopped when the child become adult (age >=15) during the course of treatment by considering them as right censored. From the eight hospitals, four comprehensive specialized hospitals were selected: University of Gondar hospital, Felege Hiwot, Woldia, and Debre Birhan hospital.
Source population
All children under 15 years of age started ART in Amhara region comprehensive specialized hospital.
Study population
All children under 15 years of age who started anti-retroviral therapy in four randomly selected Comprehensive hospitals in Amhara region after the implementation of the new guideline, from January 01, 2015, to December 31, 2024.
Inclusion criteria
Children aged less than 15 who started ART from January 01, 2015, to December 31, 2024, after the implementation of the new guideline.
Exclusion Criteria include
Incomplete patient charts on the day of ART initiation and children transferred out to other facilities during the study period were excluded from the study.
Sample size determination and sampling technique
Sample size determination
The sample size was calculated using a double population proportion formula by Epi-Info 7. To determine the sample size, a cohort study conducted at Felege Hiwot Referral Hospital in Bahirdar, Ethiopia was considered.17 In that study, the statistically significant predictors of mortality were taking cotrimoxazole prophylaxis, low hemoglobin level, delayed developmental milestone, and absolute CD4 count below the threshold. Therefore, the sample size was calculated using the mortality rate of 10% in children with low hemoglobin levels (exposed) and the mortality rate of 4% in children with normal hemoglobin levels (unexposed), by using 95% CI, with a 1:1 ratio, 80% power and 5% type I error. The resulting sample size was 204 in unexposed and 204 in exposed with a total sample size of 408. After multiplying by a design effect of 1.5 to adjust for the sampling error due to the two-stage sampling method we used and to increase the precision of the study estimates, the final sample size became 612.
Sampling technique
Among eight hospitals that had pediatric ART clinics in the region with strong pediatric HIV/AIDS care and treatment centers, four comprehensive hospitals (University of Gondar Hospital, Felege Hiwot, Woldia, and Debrebirhan) were randomly selected. The sample size was proportionally allocated to the four selected hospitals based on the number of target children. The records of children aged less than 15 who started anti-retroviral therapy from January 01, 2015, to December 31, 2024, were filtered from the database. Then, the required samples were selected from each of the four selected hospitals using simple random sampling.
Study variables
Independent variable
The independent variables were socio-demographic and socio-economic characteristics and family care (child age, child sex, caregiver educational status, caregiver marital status, caregiver and caregiver employment status). Clinical and immunologic information like the presence of Tuberculosis (TB), TB treatment, opportunistic infections (OI), developmental milestones, WHO clinical stages, prophylaxis, anthropometric measurement, CD4 count, ART adherence, hemoglobin level, and ART treatment regimen.
Dependent variable
The dependent variable was the time to death of HIV-infected children after initiation of HAART.
Data collection procedure
A data extraction tool was used for recording the data from electronic databases and patient cards. This form was developed using a standardized ART entry and follow-up form employed by the ART clinic. The laboratory results recorded before starting ART were used as baseline values. If there was no pretreatment laboratory test, the results obtained within one month of ART initiation were considered baseline values. In each facility, two ART nurses collected the data, and the data collection was supervised by a trained supervisor.
Data quality assurance
The data review tool was carefully designed and prepared in the English language using a standardized ART entry and follow-up form employed by the ART clinic. Before actual data collection, a pre-test was done to check data review tool validity and reliability using 5% of the sample size in one of the facilities not selected for the actual study. The training was given to both data collectors and a supervisor about how to use data review tools, how to select study participants according to eligibility criteria, and how to collect the data. The filled record review tools were gathered and checked for completeness by the supervisor daily. The principal investigator also checked the data collection process and supervised overall research project activities.
Data processing and analysis
After data entry was completed, the data was exported and analyzed using Stata software. Data cleaning followed by exploration was undertaken to see if there were items that were not logical and then subsequent edits were made. The patients’ cohort characteristics were described in terms of mean with standard deviation (SD) and median value with interquartile range (IQR) for continuous data and in terms of frequency and percentage for categorical data. The study participants were followed from the date of ART initiation until the occurrence of death confirmed by reviewing medical registration in the hospital or registration by ART adherence supporters (from patient card) or, date lost to follow up (last visit) or the end date of the follow-up period (December 31, 2024). During analysis, the status of each participant was dichotomized into censored or death.
Life Table analysis was carried out to estimate the mortality rate of children and Kaplan Meier survival curve with a log-rank test was fitted to test for the presence of a difference in survival time among different predictor variables. Cox-proportional hazard regression analysis was used to identify predictors of time to death. Multicollinearity between predictor variables was checked using variance inflation factors (VIF) and there was no multicollinearity between predictor variables. The proportionality of the hazard assumption was checked using the Log (-Log) S (t) plots. The crude and adjusted hazard ratios with their 95% confidence intervals (CI) were estimated and a p-value less than 0.05 was used to declare the presence of a significant association between time to death and covariates.
Results
Socio-demographic characteristics of the child and caregiver
From the 612 reviews done, 10 patient cards were excluded with many missing values, and 602 cards were reviewed which gave an enrollment rate of 98.3%. The mean age of children under follow-up was 7 years with a standard deviation (SD) of 4 years. Regarding the sex of the children, 318 (52.8%) of them were males. The majority of the caregivers, 356 (64.6%), were married, 390 (72.5%) had primary level and above educational status and 222 (41.4%) were government-employed. Regarding the place of residence, 394 (78.2%) live in the catchment area of the hospitals ( Table 1).
Table 1. Socio-demographic characteristics of children on ART in Comprehensive hospitals and their caregivers, Amhara region, Ethiopia, 2016-2020.
Baseline clinical, laboratory, and ART information
Among under five years children, 172 (91.9%) had an appropriate developmental status at admission and among five years and older children about 379 (93.5%) of them had working functional status. Regarding the WHO clinical staging of the children at the baseline, 157 (26.1%) of them were at WHO clinical stage two, and 222 (36.9%) of children were at WHO clinical stage three. The CD4 count at the baseline was below the threshold among 227 (38.9%) of the children and 105 (19.2%) were found to be anemic during the baseline hemoglobin measurement ( Table 2).
Table 2. Baseline clinical, laboratory, and ART information of children on ART in comprehensive hospitals, Amhara, Ethiopia, 2015-2024.
Medical follow-up of children and ART information
From the total of 602 children under follow-up, 269 (44.7%) developed OI, and diarrhea and TB were the common OIs; 94 (34.9%) and 75 (27.9%) respectively. CPT is given to children under ART either as a prophylaxis or as a treatment for different OIs and 436 (72.4%) of children took CPT. Similarly, anti-TB drugs were given to the children under ART either as a prophylaxis or as a treatment for those who had TB, and 92 (15.3%) of the total children under follow-up took these anti-TB drugs.
Regarding the children in the follow-up ART drug regimen, the majority of them took first-line ART regimen particularly; 287 (47.7%) of the children took 4g and 4f ART drug regimen and 184 (30.6%) them took 4j and 1j ART drug regimen. Only 14 (2.3%) took the second-line ART regimen. Among the total of 602 children under follow-up, 468 (77.7%) had a good or fair ARV treatment adherence while the rest 62 (10.3%) had poor adherence to ARV treatment ( Table 3).
Table 3. Children follow-up medical and ART information of children on ART in Amhara region Comprehensive Specialized hospitals, Amhara, Ethiopia, 2015-2024.
Incidence of death during the follow-up
Of the total children who were initiated on ART under the follow-up period, 45 (7.5%) of them died, 468 (77.7%) were alive and 89 (14.8%) were lost from follow-up. The overall median (IQR) follow-up time was 47 (26-60) months with a total follow-up time of 2140 years. The overall death rate was 2.1 (95% CI: 1.6-2.8) per 100 person-years of follow-up. The cumulative survival probabilities of HIV-infected children after 6, 12, 36, and 60 months of ART initiation were 98%, 97%, 93% and 89% respectively ( Table 4).
Table 4. Life Table analysis of children on ART in Comprehensive hospitals, Amhara, Ethiopia, 2015-2024.
Comparison of the survival function
Using the Kaplan-Meir survival function, the survival experience of children was assessed among different categories of predictors. Among all independent variables, four children’s status and two caregiver characteristics showed significant differences within the different categories. Under five children have a shorter survival experience than children older than five years (Log-rank test X2-value=12.9, P-value=0.002). Children with OIs have shorter survival experiences than those without OIs (Log-rank test X2-value =24.4, P-value=0.0001). The survival experience of children who took TB prophylaxis/treatment during the follow-up was significantly longer than those who didn’t take TB prophylaxis/treatment (Log-rank test X2-value =8.3, P-value=0.004). Children with good and fair ARV adherence have longer survival experiences than those with poor ARV treatment adherence (Log-rank test X2-value=20.9, P-value=0.0001). Children with normal CD4 count at the baseline assessment have longer survival experiences than those with below the threshold CD4 count (Log-rank test X2-value=25.1, P-value=0.0001). Similarly, children with baseline WHO classification of stage I & II have longer survival experiences than those with baseline WHO classification of stage III & IV (Log-rank test X2-value =7.2, P-value=0.007) ( Figures 1-4).
Figure 1. Kaplan-Meier estimate of survival with Opportunistic infections (OIs) among children on ART in Comprehensive hospitals, Amhara, Ethiopia, 2015–2024.
Figure 2. Kaplan-Meier estimate of survival with WHO clinical stage among children on ART in Comprehensive hospitals, Amhara, Ethiopia, 2015–2024.
Figure 3. Kaplan-Meier estimate of survival with ARV treatment adherence among children on ART in Comprehensive hospitals, Amhara, Ethiopia, 2015–2024.
Figure 4. Kaplan-Meier estimate of survival with CD4 counts status among children on ART in Comprehensive hospitals, Amhara, Ethiopia, 2015–2024.
From the caregiver characteristics; children with a caregiver of no educational status had shorter survival experiences than those who attended a formal educational status (Log-rank test X2-value=13.3, P-value=0.004). Finally, children from a married caregiver had a longer survival experience than children from a widowed or divorced caregiver (Log-rank test X2-value=11.1, P-value=0.01).
Predictors of survival of children under ART drugs
The Cox proportional regression model was used to determine the predictors of survival of HIV-infected children. Before fitting the covariate into the model, the proportional hazard assumption was checked by examining Log (-Log S (t)) plots. Overall, five variables; child age, CD4 counts, WHO Clinical Stage, OI, ART adherence, and Caregiver educational status were found to be significantly associated with time to death.
According to the final Cox proportional regression model, children with a baseline CD4 count below the threshold were 2.6 times more likely to die than those children with normal baseline CD4 count [AHR: 2.6; 95% CI: 1.2-5.8], children with OIs during the follow up were 3.7 times more likely to die than children without OIs during the follow-up time [AHR: 3.7; 95% CI: 1.7-7.9]. Likewise, those who had poor ARV adherence are nearly three times more likely to die than their counterparts [AHR: 2.9; 95% CI: 1.4-5.7]. In addition, children whose caregivers with no formal educational status were 3.4 times more likely to die than those children with caregiver educational status of tertiary or above education [AHR: 3.4; 95% CI: 1.1-11.6] ( Table 5).
Table 5. Cox Regression analysis of predictors of mortality among children on ART in Comprehensive hospitals, Amhara, Ethiopia, 2015-2024.
| Characteristics | Censored number (%) | Dead number (%) | CHR (95% CI) | AHR (95% CI) |
|---|---|---|---|---|
| Child Age | ||||
| < 5 years | 174 (88.3) | 23 (11.7) | 3.6 (1.6-8.0)* | 1.8 (0.7-4.7) |
| 5-10 years | 205 (93.6) | 14 (6.4) | 1.6 (0.7-3.9) | 1.6 (0.6-3.9) |
| Above 10 years | 178 (95.7) | 8 (4.3) | 1 | 1 |
| CD4 counts | ||||
| Below threshold | 192 (85.7) | 32 (14.3) | 4.5 (2.4-8.7)* | 2.6 (1.2-5.8)** |
| Above threshold | 346 (96.4) | 346 (96.4) | 1 | 1 |
| WHO Clinical Stage | ||||
| Stage I/II | 243 (95.7) | 11 (4.3) | 1 | |
| Stage III/IV | 314 (90.2) | 34 (9.8) | 4.3 (1.9-9.6)* | 1.2 (0.5-2.4) |
| Opportunistic Infection | ||||
| Yes | 233 (86.9) | 233 (86.9) | 4.9 (2.4-9.9)* | 3.7 (1.7-7.9)** |
| No | 324 (97.0) | 10 (3.0) | 1 | 1 |
| ART adherence | ||||
| Good/Fair | 507 (94.2) | 31 (5.8) | 1 | 1 |
| Poor | 50 (78.1) | 14 (21.9) | 3.2 (1.7-6.2)* | 2.9 (1.4-5.7)** |
| Caregiver education | ||||
| No education | 128 (86.5) | 18 (8.8) | 3.9 (1.2-13.3)* | 3.4 (1.1-11.6)** |
| Primary education | 187 (91.2) | 18 (8.8) | 2.3 (0.7-7.8) | 2.6 (0.7-8.8) |
| Secondary Education | 103 (97.2) | 3 (2.8) | 0.7 (0.2-3.6) | 0.7 (0.1-3.3) |
| Tertiary and above | 76 (96.2) | 3 (3.8) | 1 | 1 |
Discussion
This research determined the incidence of mortality rate and its predictors in younger than 14 years children who had been on ART in Amhara region Comprehensive Specialized Hospitals, Ethiopia. The study found that the overall incident rate of mortality among children who are on ART was 2.1 per 100 person-years of follow-up. The current finding was comparable with most studies done in Ethiopia.18–23 However, this finding was relatively lower than the mortality incidence rate reported in other studies in Ethiopia; which ranged from 3.2 to 6.3 per 100 person-years.10,21–26 Similarly, it is lower than most reports from sub-Saharan African countries,27–30 ranging from 2.9 deaths per 100 child years in Zimbabwe31 to 6.9 deaths per 100 child years in Mozambique,32 and in India 3 deaths per 100 child-years.33 These differences might be related to the variations in sample size, study setting, follow-up period, study participants’ clinical characteristics, quality of ART services, and awareness of patients’ caregivers to comply with the advice of the counselors.30,34 Ethiopia launched the national ART guideline in 2014 based on the 2013 WHO guideline which recommends ART for all children less than 15 years regardless of CD4 counts and WHO clinical stages. The lower rate of death rate in this research reflected that this country’s ART program has been effective in improving the survival rate of children in Ethiopia and suggests early initiation of ART in children with close monitoring during follow-up could further reduce mortality.34
The research indicated that the rate of death among children with a baseline CD4 count below the threshold was significantly higher than those children with a normal baseline CD4 count. This finding is also supported by other similar previous studies in Ethiopia.35–39 After progressive depletion of CD4+ T cells, the risk of opportunistic infections increases. Antiretroviral therapy (ART) can suppress viral replication; improve the CD4+ T cell counts and re-establish the immunity to fight against infections.34,40 However, studies also found poor immunological recovery and survival in patients who initiated ART at low CD4 counts.41 Studies conducted in northern Ethiopia also revealed lower immunological recovery among immunosuppressed children with HIV after initiation of ART.42,43 Moreover, HIV patients with poor immune recovery have been shown to have a higher risk of developing associated comorbidities and death.34
This study also found that children who had poor ARV treatment adherence died nearly three times faster rate than their good ART adherence counterparts. Similarly, studies have shown that good adherence to ART medications among children infected with HIV was significantly associated with their longer survival.21,22,25 This is because antiretroviral medication adherence is necessary to obtain the full benefit of ART drugs.34 On the other hand, poor adherence to ART could attributed to a failure in suppression of viral replication, reduction of the viral load, and failure to enhance the patients’ immunity levels making the child susceptible to developing opportunistic infections and causing mortality.42,43 It might also result in treatment failure by increasing the chance of mutation that can cause a drug-resistant virus leading to death.34,40,41 This poor adherence could be related to insufficient counselling and education of caregivers and inadequate knowledge of caregivers.44,45
Caregiver’s educational level was also a significant predictor of children’s mortality rate. Children whose caregivers had no formal educational status had a significantly higher risk of mortality than those children with caregiver tertiary or above educational status. Similarly, maternal educational status was significantly associated with mortality in a study done in Axum, Ethiopia.25 This could be due to the more educated caregivers having better knowledge regarding the disease as well as its management including the understanding of the instructions provided by health care providers working in ART clinics that could help the child to have relatively better medication compliance adhering to ART treatments and enhanced the child’s health outcomes.44,45 On the contrary, children with caregivers with no education could be attributed to the children’s poor adherence to ART which could negatively affect the suppression of viral replication, increasing the risk of drug resistance and treatment failure which increased the risk of death.34
The result also revealed that the rate of death among children with OI during the follow-up time was significantly higher than children without OIs. This finding is supported by reports from Ethiopia and other developing countries which document that HIV-infected children presenting with OIs at ART initiation had a higher risk of mortality.26–28 Research from Ethiopia39 and Tanzanian46 found that children who had comorbidities like TB at ART initiation had a lower rate of survival. Likewise, studies done in Ethiopia36 and South Africa47 reported opportunistic infection of chronic diarrhea as a determinant of mortality among HIV-infected children. Patients could also die as a result of the side effects and drug toxicity of the common drugs used to treat these infections besides the direct effect of these opportunistic infections. Research revealed that HIV-infected patients treated with anti-TB medications usually experience drug toxicity as compared to HIV-uninfected persons.48 Since opportunistic comorbidities are the leading causes of poor health outcomes including mortality in HIV-infected patients in Ethiopia, the country’s national ART guidelines strongly recommend treating OIs before ART initiation.49
The finding of this study suggested that the current mortality rate of children on ART in Amhara region comprehensive hospitals is above the expected 5% mortality rate among children on ART. Therefore, close monitoring should be given for children who had CD4 counts below the WHO threshold and those children with OIs. Drug adherence of the patients should be assessed with caution as it will determine the survival status of the children. Furthermore, the caregivers’ knowledge and other similar individual factors need to be in consideration, since they are the ones who follow their medications.
Limitations
I want to inform our readers that the incidence of death may be undermined by the absence of survival data on the patient card, hence we, considered them as lost follow-up. Also, incomplete information concerning important variables like nutritional status and other clinical variables was not found, which might confound the results. In addition, the exact day of lost follow-up is unknown which may reduce the survival time which could affect the estimations and the need to get adequate information about the cause of death to identify the actual cause of death for those patients reported as dead.
Ethics approval and consent to participate
Ethical clearance was obtained from University of Gondar, College of Medicine and Health Sciences, Ethical Clearance Review Committee on March 25, 2024 with protocol number 456/2024. The Institutional Review Board decision, and consent waiver was obtained from the Ethics committee because the data was secondary source (patients charts). Then, the data were collected after getting a permission letter from each hospital and Amhara public health institute. Information in the data abstraction tool was confidentiality kept. This study was done in compliance with the Declaration of Helsinki.
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Zemariam AB. Survival Dynamics: Mortality Rates and its Predictors among HIV-Infected Pediatric Patients on Antiretroviral Therapy after the Era of Test and Treat Strategy in Amhara Region, Ethiopia [version 1; peer review: awaiting peer review]. F1000Research 2025, 14:1267 (https://doi.org/10.12688/f1000research.171911.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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