Incidence and Predictors of Virologic Failure Among Children on First-Line Antiretroviral Therapy in Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study

Abstract

Background

Virologic failure in children is a significant public health concern in sub-Saharan Africa. This study aims to assess the incidence rate of virologic failure and its predictors among children undergoing first-line antiretroviral therapy (ART) in Ethiopia.

Methods

A multicenter retrospective follow-up study was conducted in HIV-infected children on first-line ART from January 1, 2013, to December 31, 2022, in Ethiopia. A simple random sampling method was employed to select the sample. Data entry was performed using EpiData, and analysis was conducted using STATA version 14. Kaplan–Meier curves and log-rank tests were utilized for survival analysis.

Result

Among 537 HIV-infected children followed over the study period, 12.29% developed virologic failure, yielding an incidence rate of 17 per 10 000 person-month observations (95% confidence interval [CI]: 13.4, 21.7). Factors independently associated with an increased risk of virologic failure included poor ART adherence (adjusted hazard ratio [AHR] = 2.63; 95% CI: 1.38, 4.97), advanced World Health Organization (WHO) Treatment (T) stages III and IV (AHR = 2.71; 95% CI: 1.15, 6.37), no history of regimen change (AHR = 5.88; 95% CI: 3.23, 10.71), and age at ART initiation above 10 years (AHR = 2.97; 95% CI: 1.30, 6.78). In contrast, having a caregiver younger than 40 years was associated with a significantly lower risk of virologic failure (AHR = 0.42; 95% CI: 0.25, 0.72). These findings emphasize the importance of monitoring adherence, providing closer follow-up for children in advanced treatment stages, and considering caregiver-related factors to reduce virologic failure.

Conclusions

Virologic failure among HIV-infected children on first-line ART in Northwest Ethiopia was a relatively low incidence. Interventions targeting poor adherence, children with advanced WHO Treatment (T) stage, older age at ART initiation, and those with no history of regimen change are essential. Additionally, caregiver characteristics, such as age below 40 years, play a protective role and should be considered when designing adherence support and monitoring strategies to further reduce the risk of virologic failure.

Plain Language Summary Title

How Often HIV Treatment Fails and Why Among Children Receiving First-Line Antiretroviral Therapy in Northwest Ethiopia

Plain Language Summary

Children living with HIV need lifelong treatment to keep the virus under control. Antiretroviral therapy (ART) helps reduce the amount of HIV in the body, allowing children to grow and live healthier lives. However, in some children, the treatment stops working well. This is known as virologic failure, meaning the virus is no longer adequately suppressed.

This study looked at how often virologic failure occurred and what factors were linked to it among children receiving first-line ART in several health facilities in Northwest Ethiopia. We reviewed the medical records of children who had been on ART for a period of time and followed their treatment outcomes.

We found that a notable number of children experienced virologic failure while on first-line treatment. Several factors were linked to a higher risk of treatment failure. These included poor adherence to medication, advanced stage of HIV disease at the start of treatment, low immune status, and treatment-related factors such as drug substitutions and missed clinic visits.

Understanding why HIV treatment fails in children is important because early identification of these risk factors can help healthcare providers intervene sooner. Improving medication adherence, providing close follow-up for high-risk children, and strengthening routine viral load monitoring may help prevent treatment failure.

The findings of this study can support healthcare workers, program managers, and policymakers in improving pediatric HIV care and strengthening treatment programs, especially in resource-limited settings like Ethiopia.

Keywords

incidence virologic failure predictors children ART Ethiopia

Introduction

Human immunodeficiency virus (HIV) is a viral infection that attacks the immune system, making the body vulnerable to opportunistic infections (OIs).¹ Pediatric HIV infection is a significant global public health concern, particularly affecting children in underdeveloped nations. As of the end of 2021, 38.4 million people were living with HIV globally, of which 36.7 million were adults and 1.8 million were children. Notably, more than 80% of these 1.8 million children reside in sub-Saharan Africa, where only 52% have received antiretroviral therapy (ART).^2,3 Despite substantial progress in preventing new HIV infections and reducing the number of individuals living with HIV, the annual number of AIDS-related deaths continues to rise.⁴ ART involves the use of a combination of 3 or more ART drugs aimed at suppressing HIV replication and reducing HIV-related morbidity and mortality.^3,5 In 2021, approximately 1.5 million new HIV infections were reported, with 45% of these cases occurring in sub-Saharan Africa.⁶ According to a report from the Federal Ministry of Health of Ethiopia in 2020, 42 971 children required ART; however, only 40.03% were receiving ART.⁷

Virologic failure is defined as a plasma viral load (VL) exceeding 1000 copies/ml based on 2 consecutive measurements taken after 3 months of enhanced adherence support and at least 6 months of ART. For patients who are stable on ART, VL monitoring is recommended at 6 months, 12 months, and then annually.³ The United Nations Programme on HIV and AIDS (UNAIDS) and the World Health Organization (WHO) established the “Three 90s” target by 2020, which aims for 90% of individuals with HIV to know their status, 90% to be linked to care and receiving treatment, and 90% to achieve VL suppression. This target has since been raised to “Three 95s” by 2030.^3,8 The prevalence of virologic failure reported in various studies varies significantly. In the United Kingdom and Ireland, the prevalence was found to be 34%.⁹

Based on previous studies, predictors associated with virologic failure were WHO clinical stage, lower CD4 count, Indonesia 45.8%,¹⁰ sub-Saharan Africa 17.25%.¹¹ Additionally, cross-sectional studies conducted in resource-limited countries indicated that the risk of virologic failure ranged from 33% to 66%,^12–16 age,¹⁷ poor adherence,¹⁸ and being orphan.¹⁹

According to studies, underdeveloped countries frequently experience delays in the detection of virologic failure and in the transition to second-line ART.²⁰ Most studies conducted in these regions have relied on a combination of clinical, immunological, and virologic criteria. However, current immunological and clinical failure criteria are inadequate for accurately diagnosing treatment failure.^21–24

The WHO recommends VL monitoring as the preferred tool for diagnosing and confirming treatment failure.^3,25 Globally, various strategies have been implemented to decrease virologic failure among children receiving ART, including modifications to ART drug preparations and combinations. However, sustaining prolonged VL suppression among children remains a significant challenge.²⁶

In Ethiopia, the “Three 95s” initiative⁷ and the Sustainable Development Goal 3 aim to achieve an HIV-free generation by 2030.²⁷ Early detection of treatment failure is crucial for the efficacy of second-line regimens and for reducing mortality. Despite these efforts, virologic failure continues to pose a public health problem in Ethiopia, with most available data focusing on adults.^28–30

To address this problem, recent evidence on the incidence and predictors of virologic failure among children is essential. The investigator found a scarcity of information regarding the incidence and predictors of virologic failure among HIV-infected children in Ethiopia, particularly in the Amhara region. Therefore, this study aims to assess the incidence rate and predictors of virologic failure among children under 18 years of age receiving first-line ART in the West Amhara region of Northwest Ethiopia. The findings will assist healthcare providers in identifying patients who are more likely to experience virologic failure, allowing them to provide additional support during follow-up visits. Moreover, this study will contribute valuable information on the incidence and predictors of virologic failure in children, serving as evidence for future research. It will also aid policymakers and program planners in designing effective interventions and treatment guidelines. Furthermore, understanding the incidence of virologic failure is crucial for developing strategies to prevent early treatment failure, thereby avoiding unnecessary switches to second-line therapy and reducing the risk of HIV-related premature death.

Method and Materials

Study Setting

This study was conducted in comprehensive specialized hospitals located in the Western Amhara region of Northwest Ethiopia. The Amhara Regional State is one of the largest regions in Ethiopia, comprising 12 zones and 3 municipalities. According to the Ethiopia Central Statistics Agency, the region has an estimated population of 21.5 million people, of which 80% are rural farmers.⁴⁵ In the western part of the Amhara region, there are 5 hospitals: the University of Gondar Comprehensive Specialized Hospital, Debre Markos Comprehensive Specialized Hospital, Debre Tabor Comprehensive Specialized Hospital, Tibebe Gion Comprehensive Specialized Hospital, and Feleg Hiwot Comprehensive and Specialized Hospital. Each hospital serves an estimated catchment population of 5 million. These hospitals provide a range of services, including surgery, pediatrics, medicine, obstetrics and gynecology, dentistry, orthopedics, psychiatry, and ophthalmology. From January 1, 2013, to December 31, 2022, a total of 880 HIV-infected children began ART. Among these, 320, 215, and 345 children received treatment at the University of Gondar Comprehensive Specialized Hospital, Debre Tabor Comprehensive Specialized Hospital, and Feleg Hiwot Comprehensive and Specialized Hospital, respectively.

Study Design and Periods

An institution-based multicenter retrospective follow-up study was conducted among HIV-infected children receiving ART from January 1, 2013, to December 31, 2022, in comprehensive specialized hospitals in the West Amhara region of Northwest Ethiopia. Data collection was conducted from April 3, 2023, to April 28, 2023.

Participants

The source population for this study consisted of all children living with HIV/AIDS under the age of 18 who were receiving ART in public comprehensive and specialized hospitals in the West Amhara region of Northwest Ethiopia. The study population included all HIV-infected children who initiated and have been taking first-line ART for at least 6 months in selected public health facilities from January 1, 2013, to December 31, 2022.

Inclusion and Exclusion Criteria

Children who were newly initiated on ART or transferred with baseline information into selected hospitals in the West Amhara region of Northwest Ethiopia and who had been taking ART for at least 6 months were included in the study. Conversely, charts with incomplete data regarding ART initiation and unknown dates of VL measurement were excluded from the study.

Sample Size Determination

For the first objective, the sample size was calculated based on OpenEpi software.³¹

Two-sided significance level (1 − alpha) = 95, power = 80, percent of unexposed with outcome = 41%, percent of exposed with outcome = 64%.

Total sample size for the first objective was 188, with 10% of incomplete data.

For the second objective, survival sample size calculation power approach with Cox proportional hazards using STATA version 14 was used. Sample size calculation was done based on predictors including referral case, CD4 count, and WHO stages 3 and 4. A retrospective follow-up study conducted in Indonesia was used¹⁰ (Table 1).

Table 1.

Sample Size Determination by Determinants for HIV-Infected Children on First-Line ART in Comprehensive Specialized Hospitals of West Amhara Region, Northwest, Ethiopia, 2023.

Variables	Probability of Event	Hazard Ratio	Probability of Withdrawal	Sample Size	Assumption
Referral case	0.64	1.74	0.1	178	Power = 80, significant level = 5%, 2-sided test
CD4 count	0.50	1.66	0.1	271
WHO stages 3 and 4	0.48	2.34	0.1	101

Abbreviation: ART, antiretroviral therapy.

Therefore, by comparing the first and second objectives, the final required sample size was 542 with considering 10% incomplete data and a design effect of 2.

Sampling Procedure

In this study, a multistage sampling approach was employed to select the study area, utilizing a simple random sampling method. The West Amhara region contains 5 comprehensive and specialized hospitals, from which 3 were selected using a lottery method. The sample was allocated proportionally to each of the selected hospitals.

Medical record numbers were retrieved from the Smart Care system, and charts were selected from the electronic medical records using a simple random sampling method (computer-generated random numbers). This process involved listing the medical registration numbers of patients who initiated ART between January 1, 2013, and December 31, 2022. Ultimately, a total of 542 medical charts were used for the study.

Variables and Measurements

The dependent variable in this study was the incidence of virologic failure among children receiving first-line ART. The predictor variables included various sociodemographic factors such as age at ART initiation, sex, residence, parental status, age of caregivers, caregiver marital status, and caregiver occupation.

Additionally, the following clinical factors were considered: baseline and recent WHO stage, baseline nutritional status, history of baseline OIs, recent OIs, comorbidities, tuberculosis (TB) infection, baseline functional status, baseline developmental history, case classification, baseline hemoglobin level, baseline CD4 count, and HIV disclosure. Regarding caregiver serology, the predictor variables included baseline ART regimen, any regimen changes, cotrimoxazole prophylaxis, TB prophylaxis, and adherence to treatment.

The outcome variable was measured as a binary indicator (yes or no) for the development of virologic failure between 2 consecutive measurements taken 3 months apart during the study period.

Operational Definition

Event is where children developed with virology failure.

Censored is defined as children who did not experience virologic failure, including lost to follow-up, transferred out, died, or did not experience an event at the end of follow-up time.

Survival time is defined as the time in months from the start of ART to the development of virology failure or censored.

Lost to follow-up is defined as patients have no follow-up visit for 3 months and above.⁷

Virologic failure is defined as VL above 1000 copies/ml based on 2 consecutive measurements 3 months apart with enhanced adherence counseling after the initial VL test result is unsuppressed.³

Baseline measurement is defined as those measurements taken during ART initiation.

Anemia is defined as hemoglobin level from the record for age less than 60 months less than 11 g/dl, for 5 to 11 years less than 11.5 g/dl, and for 12 to 15 years and women aged 15 and above less than 12 g/dl and men aged 15 and above less than 13 g/dl were anemic while others were not.³²

Adherence was measured as the percentage of prescribed doses of antiretroviral therapy (ART) taken by the patient over a one-month period. It was calculated by dividing the number of doses taken by the total number of prescribed monthly doses and multiplying by 100. Adherence was categorized as follows: Good adherence: = 95% (= 3 missed doses per month) Fair adherence: 85-94% (4-9 missed doses per month) Poor adherence: < 85% (= 10 missed doses per month).⁷

Nutritional status was assessed using WHO growth standards. For children under 5 years of age, Weight-for-Height/Length (WFH) and Weight-for-Age (WFA) indices were calculated using WHO Anthro software. Nutritional status was classified as normal (= -2 Z-score) and undernutrition/underweight (< -2 Z-score). For children aged 5 years and above, Body Mass Index-for-Age (BMI-for-age) was calculated using WHO AnthroPlus software. Nutritional status was categorized as normal (= -2 Z-score) and undernutrition/underweight (< -2 Z-score).³³

HIV disclosure is classified as age below 7 years is not applicable for HIV disclosure, age 7 to 10 years is for partial disclosure, and age above 10 years is for full disclosure.⁷

Why Regimen Change was Included

Regimen change is an important variable in the studies of virologic failure because modifications to a child's ART regimen can influence treatment effectiveness. Changes may occur due to:

Drug toxicity or adverse effects, treatment failure or suboptimal response, updated national or WHO treatment guidelines, stock-outs, or availability of ART drugs.

Any modification in the child's first-line ART regimen, including substitution or switching of 1 or more antiretroviral drugs, that occurred prior to the occurrence of virologic failure.

Statistical Analysis

Data Collection Technique and Procedures

Data extraction tools were developed from the Ethiopian Ministry of Health ART follow-up form updated in 2022.⁷ Information was gathered from the cohort registers, patient card, electronic Smart Care, and case manager registration. The data were collected from 3 comprehensive and specialized hospitals from April 3 to April 28, 2023 by a trained degree nurse.

Data Quality Assurance

Data quality was ensured through several measures. Data collectors and supervisors received half-day training on the objectives of the study, data collection procedures, and the checklist to be used. The data collection tool was pretested on 5% of the sample (n = 27) at the University of Gondar Comprehensive and Specialized Hospital, which was not included in the final study. Necessary modifications were made based on the pretest findings. During data collection, supervisors and the principal investigator closely monitored the process. Completed checklists were reviewed daily for completeness and consistency. Any identified errors or missing information were immediately corrected by cross-checking with patient charts and the electronic SmartCare database.

Data Analysis Procedure

After checking the data for completeness, it was entered into EpiData data manager software and was exported to STATA version 14 for cleaning and analysis. Descriptive statistics, such as median and interquartile range (IQR), were performed for continuous variables and proportion, and frequency for categorical variables. Incidence rate of virologic failure was calculated by person-month observation. A Kaplan–Meier curve was used to estimate survival time and log-rank test was used to compare the survival time curves by different categories of predictors. The proportional hazards assumption was checked using the Schoenfeld residual test. The best-fitted model was selected based on Akaike’s information criteria (AIC) and Bayesian information criteria (BIC) by comparing semiparametric and parametric survival models.^34,35 The Weibull regression survival model was the best-fitted model for this data set. Then, a bivariable Weibull regression analysis was done to identify independent variables eligible for entering into the final model with a p-value ≤0.20. Then, a multivariable Weibull regression analysis was done and variables with a p-value <0.05 were considered statistically significant predictors of virologic failure. The fitness of the Weibull regression was checked by using Cox–Snell residuals. Finally, the result of this study was presented by adjusted hazard ratio (AHR) and 95% confidence interval (CI) using tables and graphs.

Ethical Consideration

Ethical clearance was obtained from the Institutional Review Board of the College of Medicine and Health Sciences at the University of Gondar, with an ethical review number (Institutional Review Board dated March 31, 2023, protocol number Institutional Review Board 2497). A permission letter was also obtained from the Amhara Public Health Institution. Oral consent, along with written agreements, was secured from the heads of the ART clinics and care providers at the University of Gondar Comprehensive Specialized Hospital, Feleg Hiwot Comprehensive Specialized Hospital, and Debre Tabor Comprehensive Specialized Hospital.

Confidentiality of the data collected from individual patient cards in the ART clinics was maintained, and the study assumed that there would be no negative impact on the patients included in the research.

Results

Sociodemographic Characteristics

In this retrospective follow-up study, a total of 537 medical records of HIV-infected children receiving first-line ART were retrieved and included in the final analysis. The median age of the children at ART initiation was 7 years (IQR: 0.7–14). Among the participants, 285 (53%) were female. Approximately 302 (56%) of the children resided in urban areas. Nearly one-third, or 181 (34%), were under 5 years at the time of ART initiation, and 172 (32%) of the children had both parents who had passed away (Table 2).

Table 2.

Distribution of Sociodemographic Characteristics Among HIV-Infected Children in Comprehensive Specialized Hospitals of West Amhara Region, Northwest, Ethiopia, 2023 (N = 537).

Independent Variables	Categories	Status
Independent Variables	Categories	Event, n (%)	Censored, n (%)
Age	<5 years old	22 (12)	159 (88)
	5-10 years old	34 (12)	247 (88)
	>10 years old	10 (13)	65 (87)
Sex	Female	24 (8)	261 (92)
Sex	Male	42 (17)	210 (83)
Residence	Rural	30 (13)	205 (87)
Residence	Urban	36 (12)	266 (88)
Current status of parents	Both alive	25 (11)	205 (89)
	Either died	17 (13)	118 (87)
	Both died	24 (14)	148 (86)
Age of caregivers	<40 years old	30 (9)	306 (91)
Age of caregivers	≥40 years old	36 (18)	165 (82)
Marital status of caregivers	Divorced	9 (13)	63 (87)
	Married	43 (12)	310 (88)
	Widowed	14 (13)	98 (87)
Occupation of caregivers	Private	29 (12)	207 (88)
Occupation of caregivers	Others	37 (12)	264 (88)
Relation of caregivers	Parents	44 (12)	324 (88)
	Blood relatives	20 (14)	127 (86)
	Others	2 (9)	20 (91)

Baseline Clinical and Immunological Characteristics of HIV-Infected Children

Among the total of 537 patients, 231 (43%) were children classified as having advanced WHO Treatment (T) stages III and IV. Nearly one-third, or 200 (37%), were considered immunocompromised, and 342 (64%) had baseline OIs. Additionally, 253 (47%) of the children were transferred into the study hospitals. Of the total participants, 101 (19%) had a history of TB infection, and 33 (6%) had comorbidities (Table 3).

Table 3.

Baseline Clinical and Immunological Characteristics Among HIV-Infected Children in Comprehensive Specialized Hospitals in West Amhara Region Northwest, Ethiopia, 2023 (N = 537).

Variables	Categories	Status
Variables	Categories	Event, n (%)	Censored, n (%)
Baseline WHO stage	Early stages (I and II)	19 (6)	287 (94)
Baseline WHO stage	Advanced stages (III and IV)	47 (20)	184 (80)
Baseline CD4 count	Immune-compromised	42 (21)	158 (79)
Baseline CD4 count	Nonimmune-compromised	24 (7)	313 (93)
Baseline anemic status	Anemic	28 (11)	166 (89)
Baseline anemic status	Not anemic	38 (14)	305 (86)
Nutritional status (WFH)	Normal	47 (12)	342 (88)
Nutritional status (WFH)	Undernutrition	19 (13)	129 (87)
Nutritional status (WFA)	Normal	45 (13)	311 (87)
Nutritional status (WFA)	Underweight	21 (12)	160 (88)
Baseline opportunistic infection	Yes	54 (16)	288 (84)
Baseline opportunistic infection	No	11 (6)	183 (94)
Baseline functional status for age ≥5 years (356)	Working	9 (12)	68 (88)
	Ambulatory	17 (8)	194 (92)
	Bedridden	18 (26)	50 (74)
Baseline developmental status for age <5 years (181)	Appropriate	11 (9)	110 (91)
	Delay	10 (19)	42 (81)
	Regression	1 (13)	7 (87)
Case classification	New	25 (9)	259 (91)
Case classification	Transfer in	41 (16)	212 (84)
History of TB infection	Yes	27 (27)	74 (73)
History of TB infection	No	39 (9)	397 (91)
History of comorbidity	Yes	6 (18)	27 (82)
History of comorbidity	No	60 (12)	444 (88)
Recent WHO Treatment stage	Early stages (I and II)	26 (6)	420 (96)
Recent WHO Treatment stage	Advanced stages (III and IV)	40 (44)	51 (56)
Recent opportunistic infection	Yes	47 (32)	100 (68)
Recent opportunistic infection	No	19 (5)	371 (95)
Serology of caregivers	Reactive	40 (11)	312 (89)
	Nonreactive	20 (21)	76 (79)
	Unknown	6 (7)	83 (93)
Disclosure to children	Full disclose	22 (9)	217 (91)
	Not full disclose	21 (15)	121 (85)
	Partial	18 (17)	87 (83)
	Not applicable	5 (10)	46 (90)

Abbreviations: TB, tuberculosis; WHO, World Health Organization; WFH, weight-for-height; WFA, weight-for-age.

Treatment-Related Characteristics of HIV-Infected Children on ART

Nearly three-fourths of the children, 406 (76%), received cotrimoxazole preventive therapy, while 389 (72%) were on TB preventive therapy. Almost half of the children, 290 (54%), started ART with a nevirapine-based regimen. Among the total participants, 265 (49%) demonstrated good adherence to ART, and nearly three-fourths, 406 (76%), had a history of regimen change (Table 4).

Table 4.

Treatment-Related Characteristics Among HIV-Infected Children In Comprehensive Specialized Hospitals in West Amhara Region Northwest, Ethiopia, 2023 (N = 537).

Variables	Categories	Status
Variables	Categories	Event, n (%)	Censored, n (%)
ART started regimen	NVP-based	48 (17)	242 (83)
	EFV-based	17 (10)	147 (90)
	DTG/LPV/r-based	1 (1)	82 (99)
History of regimen changed	Yes	35 (9)	371 (91)
History of regimen changed	No	31 (24)	100 (76)
Adherence to ART	Good	14 (5)	251 (95)
	Fair	6 (6)	88 (94)
	Poor	46 (26)	132 (74)
History of CPT prophylaxis	Yes	51 (13)	355 (87)
History of CPT prophylaxis	No	15 (11)	116 (89)
History of TB prophylaxis	Yes	39 (10)	349 (90)
History of TB prophylaxis	No	27 (18)	122 (82)
Virology failure		66 (12.3)	471 (87.7)

Abbreviations: ART, antiretroviral therapy; NVP, nevirapine; EFV, efavernice; CPT, cotrimoxazole preventive therapy; TB, tuberculosis; DTG, dolutegravir; LPV/r, lopinavir/ritonavir.

Incidence of Virology Failure Among HIV-Infected Children on First-Line ART

A total of 537 HIV-infected children receiving first-line ART were included in a 10-year retrospective follow-up study. The median follow-up time was 74 months, with a minimum of 18 months and a maximum of 119 months, resulting in a total person-time observation of 38 679 person-months. The cumulative incidence of virologic failure among these children was 12.29% (95% CI: 9.76, 15.35). The incidence rate was 17 per 10 000 person-months (95% CI: 13.4, 21.7).

In this study, 66 (12.29%) children developed virologic failure, while 18 (3.35%) were lost to follow-up, 35 (6.52%) were transferred out, and 18 (3.35%) died. A total of 400 (74.5%) children remained alive (Table 5).

Table 5.

Incidence Rate of Virology Failure in Three Comprehensive Specialized Hospitals in the West Amhara Region from January 1, 2013, to December 31, 2022.

Facility Name	Cumulative Incidence (%)	Incidence Rate Per 10 000 Person-Month Observation
UGCSH	12.2	16.7 (95% CI: 11.1, 24.9)
FHCSH	12.7	17.6 (95% CI: 12.0, 25.6)
DTCSH	11.8	16.8 (95% CI: 10.1, 27.9)
Over all	12.29	17 (95% CI: 13.4, 21.7)

Abbreviations: UGCSH, University of Gondar Comprehensive Specialized Hospital; FHCSH, Felege Hiwot Comprehensive Specialized Hospital; DTCSH, Debre Tabor Comprehensive Specialized Hospital; CI, confidence interval.

Kaplan–Meier Survival Estimates of Virologic Failure Among HIV-Infected Children Taking First-Line ART

A Kaplan–Meier curve was used to estimate the survival time of HIV-infected children, showing a high survival probability of 99.63% (95% CI: 98.51, 99.91) at 17 months. However, this probability decreased as the follow-up time increased. By the end of the follow-up period, the cumulative probability of survival for the children was 80.98% (95% CI: 75.59, 85.30) (Figure 1).

Figure 1.

Overall Kaplan–Meier survival estimate of HIV-infected children taking first-line ART in comprehensive specialized hospitals of West Amhara region, Northwest, Ethiopia, from January 1, 2013, to December 31, 2022. Abbreviation: ART, antiretroviral therapy.

Survival Function of Different Categorical Variables Among Seropositive Children Taking First-Line ART

To identify the survival time of children based on various categorical variables, Kaplan–Meier curves and log-rank tests were utilized. Both statistical analyses indicated significant differences between the categories of the variables. Based on these tests, factors such as age at ART initiation, history of regimen change, recent WHO treatment stage, age of caregivers, and adherence to ART were assessed to determine differences in survival time across categories.

In this study, children with poor adherence to ART had lower survival times compared to those with good adherence. At the end of the follow-up period, the overall survival rates were 92.48% for good adherence and 59.74% for poor adherence. A significant variation in survival time was observed, with a p-value of <0.0001 (Figure 2).

Figure 2.

The Kaplan–Meier survival estimates survival time of HIV-infected children taking first-line ART by adherence to ART categories in comprehensive specialized hospitals of West Amhara region, Northwest, Ethiopia, from January 1, 2013, to December 31, 2022. Abbreviation: ART, antiretroviral therapy.

Based on this retrospective follow-up study, children with no history of regimen change had lower survival times compared to those who had experienced a regimen change. At the end of the follow-up period, the survival rate for children without a regimen change was 0%, while it was 90.31% for those with a regimen change. This difference was statistically significant, with a p-value of <0.0001.

Additionally, HIV-infected children with advanced WHO treatment (T) stages III and IV had lower survival times compared to those in earlier stages (I and II). At the end of the follow-up period, the overall survival rates were 24.09% for advanced stages and 91.91% for early stages. The difference between the early and advanced treatment stages was also significant, with a p-value of <0.0001 (Figure 3).

Figure 3.

The Kaplan–Meier survival estimates survival time of HIV-infected children taking first-line ART by history regimen changed categories in comprehensive specialized hospitals of West Amhara region, Northwest, Ethiopia, from January 1, 2013, to December 31, 2022. Abbreviation: ART, antiretroviral therapy.

Assessing of Proportional Hazards Assumption

The proportional hazards assumption of the Cox regression model states that the hazard of virologic failure among the study subjects must remain constant over time, and the effect of covariates must also be constant throughout the study period. The overall full model satisfied the proportional hazards assumption, which was assessed using Schoenfeld residuals. The global test for the proportional hazards assumption indicated that it was not statistically significant, with p-values for each variable ranging from 0.1363 to 0.9306. The global chi-square statistic was 15.13, with a corresponding p-value of 0.5153. Therefore, the proportional hazards assumption was not violated.

The proportional hazards assumption of HIV-infected children by history of regimen change, the hazard of virologic failure was constant, and the graph is parallel over time (Figure 4).

Figure 4.

The Kaplan–Meier survival estimates survival time of HIV-infected children on first-line ART by recent WHO T stage categories in comprehensive specialized hospitals of West Amhara region, Northwest, Ethiopia, from January 1, 2013, to December 31, 2022. Abbreviation: ART, antiretroviral therapy.

The proportional hazards assumption of HIV-infected children by adherence to ART, the hazard of virologic failure was constant, and the graph is parallel over time (Figure 5).

Figure 5.

Graphical presentation of the proportional hazards assumption by history of regimen changed of HIV-infected children on first-line ART. Abbreviation: ART, antiretroviral therapy.

Graphical presentation of the proportional hazards assumption by adherence to ART of HIV-infected children on first-line ART from January 1, 2013 to December 31, 2022 is provided in Figure 6.

Figure 6.

Graphical presentation of the proportional hazards assumption by adherence to ART of HIV-infected children on first-line ART from January 1, 2013, to December 31, 2022. Abbreviation: ART, antiretroviral therapy.

Model Comparison of Semiparametric and Parametric Survival Models

After the proportional hazards assumption was checked, both parametric and semiparametric survival models were fitted to estimate survival time to virologic failure and predictors among HIV-infected children taking first-line ART. AIC and BIC were used to select the best-fitted model. Based on this, from semiparametric and parametric survival models, the Weibull regression model (with AIC = 273.28 and BIC = 350.43) was the best-fitted model (Table 6).

Table 6.

Summary of Model Comparison Among Semiparametric and Parametric Survival Models Using AIC and BIC Criteria.

Model	AIC	BIC	Likelihood Ratio
Cox regression	649.67	718.67	−308.83
Weibull regression	273.28	350.43	−118.64
Exponential	349.74	422.61	−157.87
Lognormal regression	275.82	352.96	−119.91
Log logistic regression	273.96	351.10	−118.97
Gompertz	289.96	367.11	−126.98
Generalized Gamma	274.22	355.65	−118.11

Abbreviations: AIC, Akaike’s information criteria; BIC, Bayesian information criteria.

The model fit was assessed using the Nelson–Aalen cumulative hazard function in comparison to the Cox–Snell residuals. The plot of the Weibull regression model demonstrated a relatively linear pattern, forming a straight line at a 45-degree angle to the Cox–Snell residuals graph, which was more indicative of a good fit than the Cox regression model and other parametric survival models. Overall, the Weibull regression model was determined to be the best-fitting model for this data set compared to the Cox regression model and other parametric survival models (Figure 7).

Figure 7.

Model fitness of the Weibull regression model of HIV-infected children on ART using Cox–Snell residuals. Abbreviation: ART, antiretroviral therapy.

Predictors of Virologic Failure Among HIV-Positive Children on First-Line ART

In this retrospective follow-up study, the finding of the bivariable Weibull regression analysis showed that the age of children at ART initiation, sex of children, age of caregiver, serology of caregivers, baseline WHO stage, recent WHO treatment stage, baseline immunological status, baseline OI, case classification, recent OI, history of TB infection, history of regimen changed, adherence to ART were significantly associated with virologic failure. However, after multivariable Weibull regression analysis was done, age of children at ART initiation, caregivers’ age, adherence to ART, recent WHO treatment stage, and history of regimen change were statistically significant with virologic failure.

Keeping other variables constant, the hazard of developing virologic failure among children aged greater than 10 years was 3 times (AHR = 2.97; 1.30, 6.78) higher than those of children aged less than 5 years. The caregivers aged less than 40 years reduced the hazard of virologic failure by 58% (AHR = 0.42; 0.25, 0.72) than those aged 40 years and above. Keeping other variables constant, for children who had recent advanced WHO treatment (T) stages III and IV the hazard of virologic failure was 2.7 times (AHR = 2.71; 1.15, 6.37) than early stages (I and II), and children who had no history regimen changed was 5.9 times (AHR = 5.88; 3.23, 10.71) higher hazard of virologic failure than those who had a history of regimen changed. Regarding poor adherence to ART, the hazard of virologic failure was 2.6 times (AHR = 2.63; 1.38, 4.97) higher than those who had good adherence (Table 7).

Table 7.

Bi-variable and Multivariable Weibull Regression Analysis of Factors Associated with Time to Event among HIV-infected Children in Comprehensive Specialized Hospitals of West Amhara Region, Northwest Ethiopia, 2023 (N = 537).

Variables	Categories	Event	Censored	CHR (95% CI)	AHR (95% CI)	P-value
Sex of children	Female	24	261	1	1
Sex of children	Male	42	210	1.92 (1.16–3.18)	1.55 (0.93–2.60)	0.090
Age at ART initiation (years)	<5	22	159	1	1
	5–10	34	247	0.82 (0.48–1.40)	1.22 (0.66–2.25)	0.520
	>10	10	65	2.25 (1.18–4.50)	2.97 (1.30–6.78)	0.009
Caregiver age (years)	<40	30	306	0.50 (0.31–0.82)	0.42 (0.25–0.72)	<0.001
Caregiver age (years)	≥40	36	165	1	1
Caregiver serology	Reactive	40	312	1	1
	Non-reactive	20	76	1.76 (1.03–3.02)	0.71 (0.37–1.36)	0.309
	Unknown	6	83	0.50 (0.21–1.17)	0.45 (0.18–1.12)	0.088
Baseline WHO stage	Stage I & II	19	287	1	1
Baseline WHO stage	Stage III & IV	47	184	3.64 (2.13–6.20)	1.28 (0.49–3.36)	0.605
Recent WHO stage	Stage I & II	26	420	1	1
Recent WHO stage	Stage III & IV	40	51	10.86 (6.59–17.92)	2.71 (1.15–6.37)	0.022
Baseline immunological status	Not immunocompromised	24	313	1	1
Baseline immunological status	Immunocompromised	42	158	3.42 (2.07–5.64)	1.37 (0.63–2.97)	0.415
Baseline opportunistic infection	No	11	183	1	1
Baseline opportunistic infection	Yes	54	288	2.36 (1.26–4.41)	0.69 (0.27–1.75)	0.443
History of TB infection	No	39	397	1	1
History of TB infection	Yes	27	74	2.87 (1.76–4.69)	1.22 (0.71–2.09)	0.460
History of regimen change	No	31	100	14.11 (8.16–24.40)	5.88 (3.23–10.71)	<0.001
History of regimen change	Yes	35	371	1	1
ART adherence	Good	14	251	1	1
	Fair	6	88	1.26 (0.48–3.28)	1.00 (0.37–2.70)	1.000
	Poor	46	132	5.54 (3.04–10.08)	2.63 (1.38–4.97)	0.003
Case classification	New	25	259	1	1
Case classification	Transfer in	41	212	1.80 (1.10–2.97)	1.09 (0.63–1.86)	0.748
Recent opportunistic infection	Yes	47	100	1	1
Recent opportunistic infection	No	19	371	0.12 (0.07–0.21)	0.46 (0.18–1.15)	0.097

Bold values indicate statistically significant variables at p < 0.05 in the multivariable Weibull regression analysis.

Discussion

This multicenter retrospective follow-up study provides important information on the incidence rate and predictors of virologic failure among HIV-infected children taking first-line ART in comprehensive specialized hospitals in the West Amhara region, Northwest Ethiopia. The overall incidence rate of virologic failure in this study was 17 per 10 000 person-month observations. The incidence rate of virologic failure in this study aligns with studies conducted in the Oromia region, which reported 16 per 10 000 person-month observations.³⁶ Conversely, it is lower than the studies conducted previously in Indonesia (3.3 per 1000 person-month observations),¹⁰ Asia (3.3-4 per 100 person-years),^37,38 South Africa (18.7 per 100 person-year observation),³⁹ Zimbabwe (4 per 100 person-years),²⁶ and Kenya (13.8 per 100 person-years).⁴⁰

The disparity in these study findings could be due to how the virologic failure is defined, the length of the study time, the study setting, and the VL cutoff point. Studies conducted previously had a longer duration compared to this study. To give an illustration, this could be explained by a South African study conducted 9 years before this study,³⁹ virologic failure is diagnosed using a single VL measurement in Asia.³⁸ The VL cutoff point to diagnosis virologic failure was 500 copies/ml and above in Kenya.⁴⁰ Due to this cutoff point, the incidence rate of virologic failure was increased in these countries. Additionally, in Ethiopia, the HIV/AIDS preventive and control program recently focused particularly on persons living with HIV/AIDS to meet the three 95s targets as a national policy may potentially have an impact to reduce this finding.⁷

According to the results of this study, HIV-infected children who had poor adherence to their ART had 2.6 times higher hazard of developing virologic failure than those who had good adherence. The findings of this study were comparable with studies conducted in Uganda,⁴¹ Kenya,¹⁸ Addis Ababa,²² and Southeast Ethiopia.⁴²

This finding may be attributed to several factors, including pill burden, the complexity of the medication regimen, difficulties in swallowing tablets, and malnutrition, all of which can hinder adherence to ART. When patients struggle with these issues, they may be less likely to take their medication consistently, which can lead to the development of drug resistance and ultimately result in virologic failure.^43,44 Patients living with HIV/AIDS are strongly advised to adhere to ART to lower VLs, maintain healthy immune systems, and prevent premature mortality. However, for ART to be effective, it is crucial that patients strictly follow the recommended treatment regimen. Nonadherence can compromise the effectiveness of the therapy, leading to adverse health outcomes, including increased VLs and the potential for drug-resistant strains of the virus.³

Poor treatment compliance results in lower treatment effectiveness, which lowers immunity, increases medication resistance, increases the vulnerability to OIs, and leading to virologic failure.⁴⁵ Maintaining good adherence is essential for reducing viral replication and enhancing immunological and clinical outcomes, which in turn decreases medication resistance, OIs, and HIV-related untimely death.⁷ In this retrospective follow-up study, children with advanced WHO treatment (T) stages III and IV had 2.7 times higher hazard of virologic failure than early stages (I and II), the finding was in line with a study conducted in Southeast Ethiopia,⁴² this could be due to children who have advanced WHO treatment stage is more likely to have severe immunosuppression and risk of developing comorbidities as the result, the risk of virologic failure could be higher. According to the WHO and Ethiopia, treatment guidelines stated that children on ART who have advanced HIV diseases the risk of virologic failure was higher than nonadvanced HIV diseases.^3,7 Regarding children who have no history of regimen change, they had 5.9 times higher hazard of developing virologic failure than those who have a history of regimen change. This finding is consistent with a study conducted in Addis Ababa.²² This might be due to HIV-positive children following a long-term, unchanged regimen developing treatment resistance and being ineffective to control viral replication, and finally developing virologic failure.^20,43 Additionally, current regimen changes or substitutions for treatment optimization in children involve protease inhibitors and integrase inhibitors, which help reduce drug resistance and virologic failure.³

In this study, children above 10 years had 3 times higher hazard of virologic failure than those below 5 years at ART initiation. This finding is consistent with studies conducted in Ireland and United Kingdom,⁹ Asia,³⁸ Thailand,⁴⁶ Kenya,⁴⁵ and Europe and Thailand.⁴⁷ This finding could be due to the behavioral and developmental changes of older children which make it difficult to administer ART and have influences on adherence, VL suppression, and prevention of OIs.⁷ Children over the age of 10 years often have limited opportunities to discuss their concerns with family members and begin to take greater responsibility for their own care. They may also have concerns about disclosing their condition to partners or colleagues, which can result in insufficient attention to their antiretroviral therapy.

Finally, the study indicates that virologic failure, advanced HIV disease, and early mortality can occur among affected individuals.⁴³ Notably, caregivers aged below 40 years significantly reduce the hazard of virologic failure by 58% compared to those aged 40 years and older. This finding aligns with research conducted in southern and eastern Africa, suggesting a consistent trend across different regions.²⁰ The observed difference may be attributed to the level of attention that older caregivers may provide regarding the nutritional status of HIV-positive children and adherence to ART. Caregivers aged 40 years and above might be less engaged in ensuring proper nutrition and medication compliance, which are crucial for the health of these children.⁴⁴ Additionally, older caregivers may not prioritize the follow-up and support needed for the children, potentially leading to poorer health outcomes.³

In contrast, younger caregivers are often more proactive in disclosing the HIV status of children and are generally more attentive to adherence to ART. This increased vigilance can help reduce the incidence of advanced HIV infection and, consequently, virologic failure among children. Furthermore, the WHO emphasizes the need for primary interventions targeting child caregivers to effectively reduce the VLs in children living with HIV. This highlights the importance of caregiver involvement in the management of HIV-positive children to improve health outcomes.

Strengths and Limitations

Strengths: This study is a multicenter retrospective follow-up investigation conducted across 3 comprehensive specialized hospitals, which enhances the generalizability of the findings. The use of a computer-generated simple random sampling method improved the representativeness of the sample. Data collection was conducted by a trained Bachelor of Science (BSc) nurse, contributing to the quality and reliability of the collected data. The study highlights the role of caregiver involvement in ART adherence and virologic outcomes, emphasizing a critical and actionable factor in pediatric HIV care.

Limitations: The study relied on secondary data, resulting in some missing covariates, such as the distance from health facilities and caregiver educational status, which were not included as predictors. Behavioral and emotional factors that may influence treatment outcomes were not assessed. Selection bias may have occurred due to the exclusion of charts with incomplete data, which could affect the representativeness of the findings.

Conclusions

The incidence rate of virologic failure among HIV-infected children on ART in the hospitals of the West Amhara region was notably low, recorded at 17 cases per 10 000 person-month observations. Key predictors of virologic failure identified in this population include poor adherence, advanced WHO Treatment (T) stages III and IV, age above 10 years at ART initiation, lack of regimen changes, and caregivers aged below 40 years.

To mitigate virologic failure and achieve the Three 95s by the end of 2030, healthcare providers should prioritize these factors during follow-up visits. It is essential to emphasize the importance of adherence, monitor treatment stages closely, and take into account the age of both children and caregivers. Furthermore, it is advisable to develop policies and strategies aimed at reducing virologic failure in children. Future research should focus on prospective cohort studies that address additional variables, such as the distance from health facilities, the educational status of caregivers, and behavioral and emotional factors affecting treatment adherence.

Supplemental Material

sj-docx-1-jia-10.1177_23259582261447448 - Supplemental material for Incidence and Predictors of Virologic Failure Among Children on First-Line Antiretroviral Therapy in Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study

Supplemental material, sj-docx-1-jia-10.1177_23259582261447448 for Incidence and Predictors of Virologic Failure Among Children on First-Line Antiretroviral Therapy in Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study by Zemene Mesafint Kassie, Nebiyu Mekonnen Derseh and Tadesse Awoke Ayele, Meron Asmamaw Alemayehu, Agerie Mengistie Zeleke, Yeshiwas Ayale Ferede, Worku Chekol Tassew, Jember Ayelgne Beyene in Journal of the International Association of Providers of AIDS Care (JIAPAC)

Supplemental Material

sj-docx-2-jia-10.1177_23259582261447448 - Supplemental material for Incidence and Predictors of Virologic Failure Among Children on First-Line Antiretroviral Therapy in Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study

Supplemental material, sj-docx-2-jia-10.1177_23259582261447448 for Incidence and Predictors of Virologic Failure Among Children on First-Line Antiretroviral Therapy in Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study by Zemene Mesafint Kassie, Nebiyu Mekonnen Derseh and Tadesse Awoke Ayele, Meron Asmamaw Alemayehu, Agerie Mengistie Zeleke, Yeshiwas Ayale Ferede, Worku Chekol Tassew, Jember Ayelgne Beyene in Journal of the International Association of Providers of AIDS Care (JIAPAC)

Supplemental Material

sj-docx-3-jia-10.1177_23259582261447448 - Supplemental material for Incidence and Predictors of Virologic Failure Among Children on First-Line Antiretroviral Therapy in Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study

Supplemental material, sj-docx-3-jia-10.1177_23259582261447448 for Incidence and Predictors of Virologic Failure Among Children on First-Line Antiretroviral Therapy in Northwest Ethiopia: A Multicenter Retrospective Follow-Up Study by Zemene Mesafint Kassie, Nebiyu Mekonnen Derseh and Tadesse Awoke Ayele, Meron Asmamaw Alemayehu, Agerie Mengistie Zeleke, Yeshiwas Ayale Ferede, Worku Chekol Tassew, Jember Ayelgne Beyene in Journal of the International Association of Providers of AIDS Care (JIAPAC)

Footnotes

Abbreviations

Acknowledgments

We would like to acknowledge the University of Gondar, Amhara Public Health Institute, and the respective hospitals for their support and cooperation. We also thank the data collectors and healthcare providers for their valuable contributions.

ORCID iDs

Agerie Mengistie Zeleke

Yeshiwas Ayale Ferede

Worku Chekol Tassew

Jember Ayelgne Beyene

Ethical Considerations

This study was approved by the Institutional Review Board (IRB) of the Institute of Public Health, University of Gondar. Ethical clearance was obtained with the reference number: IRB March 31, 2023; Protocol No. IRB-2497.

Informed Consent

Permission letters were obtained from the Amhara Public Health Institute. Oral and written consent were obtained from ART clinic heads and healthcare providers at the University of Gondar Comprehensive Specialized Hospital, Felege Hiwot Comprehensive Specialized Hospital, and Debre Tabor Comprehensive Specialized Hospital. Patient confidentiality was strictly maintained, and the study posed no harm to participants.

Author Contributions

ZMK designed the study. NMD, TAA, MAA, AMZ, YAF, and WCT supervised the data collection and cleaned and analyzed the data. ZMK and JAB interpreted the data and wrote the manuscript. All authors have read and approved the final manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

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

Data Availability Statement

The data used and analyzed during the current study are available from the corresponding author upon reasonable request.

Supplemental Material

Supplemental material for this article is available online.

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