Incidence of lost to follow up among HIV-positive children on antiretroviral therapy in Ethiopia: Systematic review and meta-analysis

Desalegn Girma; Zinie Abita; Lidya Gutema Lemu; Daniel Asmelash; Getachew Mesfin Bambo; Melesew Setegn Alie; Gossa Fetene Abebe

doi:10.1371/journal.pone.0304239

. 2024 May 22;19(5):e0304239. doi: 10.1371/journal.pone.0304239

Incidence of lost to follow up among HIV-positive children on antiretroviral therapy in Ethiopia: Systematic review and meta-analysis

Desalegn Girma ^1,^*, Zinie Abita ², Lidya Gutema Lemu ¹, Daniel Asmelash ³, Getachew Mesfin Bambo ³, Melesew Setegn Alie ², Gossa Fetene Abebe ¹

Editor: Zewdu Gashu Dememew⁴

PMCID: PMC11111029 PMID: 38776343

Abstract

Background

At the end of 2022, globally, only 46% of children (aged 0–14 years) on ART had suppressed viral loads. Viral load suppression is crucial to reduce HIV-related deaths. To suppress the viral load at the expected level, children must be retained in ART treatment. Nevertheless, lost to follow-up from ART treatment continues to be a global challenge, particularly, in developing countries. Previously, primary studies were conducted in Ethiopia to assess the incidence of lost to follow-up among HIV-positive children on ART treatment. However, variations have been seen among the studies. Therefore, this systematic review and meta-analysis aimed to estimate the pooled incidence of lost to follow-up among HIV-positive children on ART and identify its associated factors in Ethiopia.

Methods

We searched PubMed, HINARI, Science Direct, Google Scholar, and African Journals Online to obtain articles published up to November 20, 2023. Critical appraisal was done using the Joanna Briggs Institute checklist. Heterogeneity was identified using I-square statistics. Funnel plot and Egger’s tests were used to identify publication bias. Data was presented using forest plots and tables. Random and fixed-effect models were used to compute the pooled estimate.

Results

Twenty-four studies were included in the final analysis. The pooled incidence of lost to follow-up among HIV-positive children on ART was 2.79 (95% CI: 1.99, 3.91) per 100-child-year observations. Advanced HIV disease (HR: 2.20, 95% CI: 1.71, 2.73), having opportunistic infection (HR: 2.59, 95% CI: 1.39; 4.78), fair or poor ART treatment adherence (HR: 2.92, 95% CI: 1.31; 6.54) and children aged between 1–5 years (HR: 2.1,95% CI: 1.44; 2.95) were factors associated with lost to follow up among HIV positive children on ART.

Conclusions

The overall pooled incidence of lost to follow-up among HIV-positive children on ART is low in Ethiopia. Therefore, counseling on ART drug adherence should be strengthened. Moreover, emphasis has to be given to children with advanced HIV stage and opportunistic infection to reduce the rate of lost to follow up among HIV-positive children on ART.

Trial registration

Registered in PROSPERO with ID: CRD42024501071.

Introduction

Human Immunodeficiency Virus (HIV) continues to be one of the global public health concerns, particularly in sub-Saharan Africa. At the end of 2022, an estimated 1.5 million children aged 0–14 years were living with HIV infection and about 130,000 of them were newly infected [1]. In the same year, globally, about 84,000 children died from HIV-related diseases [2]. Despite multiple efforts made, about 43% of children living with HIV were not receiving treatment [3].

To avert the burden of HIV, different efforts have been made globally. In 2015, the United Nations, under its sustainable development goal (SDGS), set a global target to end HIV epidemic by 2030 through the provision of antiretroviral therapy (ART) [4]. ART has profound importance in prolonging the life of people living with HIV infection, mainly, by suppressing the viral load, improving the immune system, and reducing the risk of opportunistic infections [5]. To increase the accessibility and coverage of ART, currently, the United Nations has commenced a 95-95-95 ambitious treatment target for the year 2025, which implies that 95% of people living with HIV know their status, 95% of people living with HIV who know their status are receiving treatment and 95% of people on treatment have suppressed viral loads by the year 2025 [6].

To achieve the aforementioned ambitious treatment targets, HIV-infected children must be retained in a cohort of ART treatment and have regular follow-ups [7]. During follow-up, children are checked for clinical progression, ART side effects, drug adherence, and viral load suppression and should be counseled for optimal drug utilization [8].

Lost to follow-up (LTFU) from ART is one of the global public health concerns, particularly in developing countries. A systematic review conducted in resource-limited settings found that about 5–29% of children living with HIV were lost from ART within the first 12 months of ART initiation [9]. In Sub-Saharan African countries, the proportion of LTFU among HIV-positive children after two years of ART initiation varied from the lowest 9.0% in Southern Africa to the highest 21.8% in West Africa [10]. Children who drop out of the treatment are at an increased risk of drug-resistant virus and treatment failure. These can jeopardize the effectiveness of HIV treatments and increase HIV-related deaths [11, 12].

In Ethiopia, there is a paucity of evidence regarding the national incidence of LTFU among HIV-positive children on ART. Moreover, previous primary studies also confirmed that the incidence of LTFU among HIV-positive children on ART varied across regions in Ethiopia [13–21], ranging from 3.3 per 100 child years in the Oromia region [21] to 6.3 per 100 child years in the Amhara region [15]. Conducting an aggregated study using those primary studies is important to know about the national burden of LTFU among HIV-positive children on ART. Therefore, the main objective of this systematic review and meta-analysis is to estimate the pooled incidence of LTFU among HIV-positive children on ART and identify its associated factors in Ethiopia.

Methods

Search strategy

The result was reported using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guideline [22]. We searched PubMed, HINARI, Science Direct, Google Scholar, and African Journals Online to obtain relevant studies. Online database searching was done on November 20, 2023. The following terms and phrases search as “incidence rate”, “lost to follow-up”, “LTFU”, “treatment outcome”, “attrition”, “pediatrics”, “children” “child”, “newborn”, “Human Immunodeficiency virus”, “HIV”, “ART”, “antiretroviral therapy” “antiretroviral drugs”, “AIDS drugs”, “Anti-HIV drugs” and “Ethiopia” were the main key search terms used in this systematic review and meta-analysis. We used Boolean operators such as “AND” and “OR” during database searching (S1 File).

Eligibility criteria

The inclusion criteria were: 1) studies conducted in Ethiopia, 2) studies that report the incidence of LTFU or the number of LTFU for children aged 0–14 years living with HIV, 3) studies that report the child person year, 4) studies published in English languages, 5) studies that report at least one predictors with hazard function and 6) studies available at the electronic source up to November 20, 2023 were included in the study. On the other hand, studies that didn’t report the child person’s years or studies that report predictors other than hazard function were excluded from the study. Furthermore, citations without abstract and/or full-text, anonymous reports, editorials, and qualitative studies were excluded from the analysis.

Data extraction

All studies identified via the online database were exported to EndnoteX7 to identify and remove duplication. A standardized data extraction tool was used and independently extracted by four authors (GF, ZA, GM, and MS). Any disagreements among the data extractors were discussed and it was handled by the principal authors (DG). From each study, the author’s name, publication year, the event or number of LTFU, study region, study design, the total person year, incidence rate, and the predictor of LTFU with hazard ratios were extracted.

Quality assessment/Critical appraisal

Quality appraisal was done using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for cohort study design [23]. The qualities of the primary studies were independently assessed by two authors (LG and DA). Any discrepancy between the two authors was handled by taking the mean score of the two authors. The tool has Yes, No, Unclear, and Not Applicable options: “1” is given for “Yes” and “0” is given for other options. The scores were summed and changed to percentages. Studies with >50% quality scores were included in this meta-analysis. Finally, twenty-four studies that received a quality score of >50% were included in the final analysis (S2 File).

Outcome measurement

The first outcome was the incidence of LTFU among HIV-positive children on ART. The incidence of LTFU among HIV-positive children on ART was calculated by dividing the number of children who lost from ART treatment for one to three months by the total child follow-up years and multiplying it by 100. Identifying the associated factors of LTFU among HIV-positive children on ART was the second outcome of this study. Accordingly, the hazard ratio of predictors with its 95% confidence intervals (CI) was extracted from the original studies to compute the pooled hazard ratio of predictors.

Lost to follow-up

When HIV-positive children miss an appointment or drug pick-up for one month to three months and are not yet classified as dead or transferred out [24].

Follow-up period (time)

Is measured from the beginning of the study until the event (LTFU) occurs, transferred-out, death, and the study ends.

Advanced HIV disease

Children older than five years whose WHO clinical stages are III and IV. Whereas, children younger than five years living with HIV are considered as having advanced HIV disease, regardless of the clinical stages. Mild WHO clinical stages: HIV-positive children whose WHO clinical stages are stages I and II [24].

ART adherence. Good (> 95%)—if missed doses is ≤ 2 doses of 30 doses or ≤ 3 doses of 60 doses; Fair: (85–94%) if missing doses is between 3–4 of 30 doses or 4–9 of 60 doses; poor: (< 85%) if missed doses are >5 doses of 30 doses or 10 and above doses of 60 doses of ART drug [24].

Statistical analysis

Data entry was done using Microsoft Excel 2013 and then imported into R software version 4.1.3 for further analysis. Meta-package was used to analyze the data. I-square was used to check heterogeneity between studies [25]. Heterogeneity was declared as low, medium, and high if the I² value was 25%, 50%, and 75%, respectively [26]. Subgroup analysis was done using the study region with evidence of heterogeneity. Univariate meta-regression analysis was done using publication years and sample size to identify the possible source of heterogeneity. Sensitivity analyses were done by omitting individual studies to detect the contribution of each study in the final pooled incidence of LTFU among HIV-positive children on ART. Funnel plot visual inspection was done to identify publication bias. Finally, the Egger test was done to assess any significant publication bias. Further, Trim and fill analyses were conducted to correct publication bias. Tables and forest plots were used to present data. The random and fixed effect models were used to compute the pooled estimates. Results are presented using the random effect model (if there is heterogeneity among studies) and fixed-effect (if there is no heterogeneity among studies).

Results

Characteristics of included studies

A total of 5,225 articles were identified from PubMed, HINARI, Science Direct, Google Scholar, and African Journals Online. Of these, 2,514 studies were from PubMed, 1,127 studies were from HINARI, 1,509 studies were from Science Direct, and the rest 75 studies were identified from Google Scholar and African Journals online. From these studies, 1035 studies were excluded due to duplication. From the remaining 4190 articles, 4083 studies were excluded as not being relevant to the study after reviewing the titles and abstracts. The rest 107 articles were assessed by reviewing the full text. Finally, twenty-four studies were eligible and incorporated in the final analysis (Fig 1) [13–21, 27–41]. All studies were conducted using the cohort study design. These studies were done from different parts of Ethiopia (Addis Ababa, Amhara, Oromia, SNNPR (South Nation, Nationalities and People Region), and, Tigray) (Table 1).

Table 1. Characteristics of studies included in the meta-analysis for the pooled incidence of LTFU among HIV-positive children on ART, Ethiopia, 2023.

Author	Region	Sample sizes	Number of LTFU	Follow-up time in month (IQR)	PMO	PYO	IR per 100 child years
Mulgeta et al (2017) [27]	Addis Ababa	757	92	62.0–83.0	49344	4112
Edessa et al (2015) [28]	Oromia	305	22	18–30	7, 312	609	---
Adem et al (2014) [29]	Oromia	560	46	29–62	24936	2078	---
Bimer et al (2021) [13]	SNNPR	254	70	1–84	8145.33	678.78	---
Chanie et al (2022) [14]	Amhara	344	76	(4–167	19,081	1590.1	4.8
Menshw et al (2021) [15]	Amhara	488	101	-------	-------	---	6.3
Fetene et al(2018) [16]	Amhara	533	46	42–11	15288	1274	3.6
Sidamo et al (2017) [30]	SNNPR	421	43	24–80	21,175	1764.58	---
Haile(2021) [31]	SNNPR	429	38	32–122	30595.2	2549.6	---
Fisiha et al (2020) [17]	Amhara	361	79	14–70	15369.6	1280.8	6.2
Sifr et al (2021) [18]	SNNPR	143	18	-------	-------	356.06	5
Bankere et al (2022) [21]	Oromia	269	43	24–92	15588	1299	3.3
Alebel et al (2020) [32]	Amhara	538	38		14,600	1216	---
Hibstie et al (2020) [19]	Amhara	408	70	2–136	18,755	1562.9	4.5
Melaku et al (2017) [33]	Amhara	6815	2090	------	------	---	---
Koye et al (2012) [34]	Amhara	549	32	1–62	12300	1025	---
Gebremedihn et al (2013) [35]	Tigray	416	23	17–50	14,235	1186.25	---
Gemech et al (2022) [36]	SNNPR	284	32	1–120	15086.04	1257.17	---
Tagesse et al (2020) [37]	Addis Ababa	410	20	18–44	13236	1103	---
Biru et al (2018) [20]	Adiss Ababa	304	18	10–13	3452.4	287.7	9.12
Atallel et al (2018) [38]	Amhara	271	25	1–144	14012.04	1167.67	---
Biyazin et al (2022) [39]	Amhara	251	16	60	7512	626	---
seid (2023) [40]	SNNPR	261	11	43–107	18,955	9477.5	---
Alemu et al(2022) [41]	Amhara	415	18	3–48	8700.5	725.04	---

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LTFU: Lost to follow up, IQR: Inter Quartile Range, PMO: Person Month Observation, PYO: Person Year Observation, IR: incidence rate

The pooled incidence of LTFU among HIV‑positive children on ART

Twenty-two studies were included to estimate the pooled incidence of LTFU among HIV-positive children on ART in Ethiopia [13, 14, 16–21, 27–32, 34–41]. Accordingly, the pooled incidence of LTFU among HIV-positive children on ART in Ethiopia was 2.79 (95% CI: 1.99, 3.91) per 100-child-year observations using a random effect model. Heterogeneity (I² = 94%, P-value <0.01) was identified (Fig 2). Hence, subgroup analysis was done based on the study regions. Accordingly, the incidence of LTFU among HIV-positive children on ART ranged from 1.98 per 100 child years in SNNPR to 3.54 per 100 child years in the Amhara region (Fig 3). Univariate meta-regression analysis was done to identify the possible source heterogeneity using the publication years and sample size. Of these factors, none of them were statistically significant (Table 2). Finally, sensitivity analysis was done. In sensitivity analysis, except for one study [40], nearly all studies have equal contributions to the pooled incidence of LTFU among HIV-positive children on ART in Ethiopia (Fig 4).

Table 2. Meta-regression analysis using publication year and sample size for the possible source of heterogeneity of LTFU among HIV-positive children on ART, Ethiopia, 2023.

Variables	Coefficients	P-value
Publication years	-0.0405 (-0.1613, 0.0519)	0.3
Sample size	0.0010 (- 0.0006,0.0026)	0.23

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Publication bias

Asymmetric distribution was displayed in the funnel plot visual inspection (Fig 5). The Egger test also shows a statistically significant publication bias with B₀ = -2.36, p-value = 0.02. Due to the presence of statically significant publication bias, meta-trim and fill analysis were done. Hence, eight studies were filled and the pooled incidence of LTFU among HIV-positive children on ART became 4.29 (95% CI: 2.87; 6.41) per 100 child years (Fig 6).

Factors associated with LTFU among HIV-positive children on ART

In this systematic review and meta-analysis, seven studies were incorporated to identify the factors associated with LTFU among children on ART [15–17, 19–21, 33]. Advanced HIV disease, poor or fair ART treatment adherence, history of opportunistic infection, and age between 1–5 years were factors associated with a higher hazard of LTFU among HIV-positive children on ART. Accordingly, the likelihood of LTFU was 2.20 times (HR: 2.20, 95% CI: 1.71, 2.73) higher among children with advanced HIV disease as compared to children with mild WHO clinica stages [15, 17, 33]. The hazard of LTFU was 2.92 times (HR: 2.92, 95% CI: 1.31; 6.54) higher among children with poor or fair ART treatment adherence as compared to children with good ART treatment adherence [15, 17, 19]. The hazard of LTFU was 2.1 times (HR: 2.1,95% CI:1.44; 2.95) higher among children aged between 1–5 years as compared to children aged ≥ 5 years [15, 16, 20]. The likelihood of LTFU was 2.59 times (HR: 2.59, 95% CI:1.39; 4.78) higher among children who had opportunistic infection as compared to their counterparts [16, 21] (Table 3).

Table 3. Predictors of lost to follow up among HIV positive children on ART, Ethiopia, 2023.

Predictors	Included studies	HR (95% CI)	Pooled HR (95% CI)
Advanced HIV disease	Menshw et al (2021)	2.2 0 (1.40; 3.34)	2.20 (1.71,2.73)	I² = 0%, p-value = 0.94
	Fisiha et al (2020)	2.00 (1.10; 3.10)
	Melaku et al (2017)	2.20 (1.6; 3.10)
Poor or fair ART treatment adherence	Menshw et al (2021)	6.6 0 (4.11; 10.56)	2.92 (1.31; 6.54)	I² = 90.8%, p-value < 0.001
	Fisiha et al (2020)	1.70 (1.10; 2.11)
	Hibstie et al (2020)	2.30 (1.40; 3.70)
Having Opportunistic infection	Fetene et al(2018)	2.26(1.08; 4.71)	2.59 (1.39; 4.78)	I² = 0%, p-value = 0.51
Having Opportunistic infection	Bankere et al (2022)	3.54 (1.152; 10.87)	2.59 (1.39; 4.78)	I² = 0%, p-value = 0.51
Age between 1–5 years	Menshw et al (2021)	1.60 (1.05; 2.46)	2.10 (1.44; 2.95)	I² = 57.5%, p-value = 0.095
	Fetene et al(2018)	3.86 (1.73; 8.61)
	Biru et al (2018)	3.76 (1.16; 12.27)
Rural residence	Hibstie et al (2020)	3.20 (2.00; 5.50)	1.15 (0.15; 8.84)	I² = 95%. p-value < 0.001
	Melaku et al (2017)	0.40 (0.20; 0.90)
	Biru et al (2018)	3.57 (11.64; 11.64)

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Discussion

This systematic review and meta-analysis unveiled the pooled incidence of LTFU among HIV-positive children on ART in Ethiopia. Accordingly, the pooled incidence of LTFU among HIV-positive children on ART is found to be 2.79 (95% CI: 1.99, 3.91) per 100-child-year observations. The incidence is lower than the studies conducted in Asia (4.2 per 100 child years) [42], in Uganda (12.6 per 100 child years) [43], in Kenya (14.65 per 100 child years [44], in South Africa (10.8 per 100 person-years) [45], in Malawi (12.6/ per 100 person-years) [46], in Tanzania (18.2 per 100 person-years) [47], in South Africa (5.0 per 100 person-years) [48], in Nigeria (40 per 100 child-years) [49], in western Kenya (18.4 per 100 person-years) [50], in Côte d’Ivoire’s(9.3 per 100 person-years) [51] and in Mozambique (6.9/per 100 person-years) [52]. This can be justified that LTFU was considered when HIV-positive children interrupt ART treatment and with unknown tracing outcomes. Thus, the low incidence of LTFU among HIV-positive children on ART might be due to the improvement in tracing, recording, and reporting systems of health institutions for people living with HIV.

In this systematic review and meta-analysis, the hazard of LTFU is higher among children with advanced HIV disease as compared to children with mild WHO clinical stages. The finding is supported by studies conducted elsewhere [49, 53–55]. This can be justified as children with advanced HIV stage are at higher risk of developing opportunistic infections that cause unregistered HIV-related morbidity and mortality.

In this systematic review and meta-analysis, children with poor or fair ART treatment adherence have a higher hazard of LTFU than children with good ART treatment adherence. The finding is consistent with studies conducted elsewhere [56–58]. This is the fact that ART can suppress viral replication, boost immune function, and prevent opportunistic infection [59, 60]. Such that, fair or poor ART treatment adherence can open a window for viral replication, cause HIV viral resistance, decrease drug effectiveness, and cause treatment failure. This increases the risk of opportunistic infection and unregistered deaths.

The hazard of LTFU is higher among children who develop opportunistic infections as compared to their counterparts. The fact that opportunistic infections occur in advanced HIV disease, which further exacerbates the clinical outcome of people living with HIV [61]. Thus, the poor improvement in children with opportunistic infection may make parents feel hopeless or careless and they may fail to bring their child for treatment follow-up. This implies that strict and frequent follow-ups are needed for children with opportunistic infection than children without opportunistic infection.

In this systematic review and meta-analysis, children aged between 1–5 years are at an increased risk of LTFU from ART treatment as compared to children aged ≥ 5 years. The finding is supported by studies conducted elsewhere [55, 62, 63]. This might be due to the immature immune system in infants and young children increases the risk of rapid progression of HIV disease than older children. Thus, infants and young children are highly susceptible to opportunistic infections, which indirectly increases the incidence of LTFU from ART treatment.

The clinical and public health implications of this systematic review and meta-analysis are to take prompt intervention against the identified factors and response to reduce the burden of LTFU among HIV-positive children on ART and increase ART retention, later, to reduce HIV-related deaths. Therefore, researchers, program implementers, and policymakers should consider the aforementioned factors in their strategic plans.

Limitations

This systematic review and meta-analysis have the following limitations: in this analysis, articles published only in English were included. Only five regions were included in the analysis, such that some regions may not be represented. Moreover, some variables associated with LTFU among HIV-positive children on ART were excluded from the analysis because it reported in only one primary article and/or classified in a different way from the included articles. Furthermore, only seven studies reported the predictors of LTFU among HIV-positive children on ART, such that limited factors were identified. Finally, because of the previous primary studies didn’t report the event (number of LTFU) at 6 months, 12 months, 24 months, and more, the segregated incidence of LTFU among HIV-positive children on ART was not pooled for the respective months.

Conclusion

The overall pooled incidence of LTFU among HIV-positive children on ART is low in Ethiopia. Advanced HIV disease, having an opportunistic infection, fair or poor ART treatment adherence, and children aged between 1–5 years were factors associated with LTFU among HIV-positive children on ART. Therefore, counseling on ART drug adherence should be strengthened. Moreover, emphasis has to be given to children with advanced HIV stage and opportunistic infection to reduce the rate of LTFU among HIV-positive children on ART.

Supporting information

S1 Checklist. PRISMA 2020 checklist.

(DOCX)

pone.0304239.s001.docx^{(35.4KB, docx)}

S1 File. Search terms summary.

(DOCX)

pone.0304239.s002.docx^{(14.5KB, docx)}

S2 File. Critical appraisal of studies included in the systematic review and meta-analysis for pooled incidence of lost to follow-up among HIV-positive children on ART, Ethiopia, 2023.

(DOCX)

pone.0304239.s003.docx^{(22.9KB, docx)}

Abbreviations

ART: Antiretroviral therapy
HIV: Human immunodeficiency virus
AIDS: Acquired Immune Deficiency Syndrome
PYO: Person-year observation
PMO: Person-month observation
WHO: World Health Organization
SNNPR: South Nation, Nationalities and People Region
JBI: The Joanna Briggs Institute Critical Appraisal Checklist
PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analysis Statement
LTFU: lost to follow u
HR: hazard ratio and
CI: confidence interval

Data Availability

The data used for this study was publicly available at the Harvard Dataverse Network repository: URL: https://doi.org/10.7910/DVN/BQ6MU0.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0304239.r001

Decision Letter 0

Zewdu Gashu Dememew

1 Feb 2024

PONE-D-23-40483Incidence of lost to follow up among HIV-positive children on antiretroviral treatment: systematic review and meta-analysis.PLOS ONE

Dear Dr. Girma,

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Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #3: Yes

**********

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Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: • Lost to follow-up language has been changed to interruption in treatment in recent times. Use it since it is becoming mainstream terminology.

• Line 36: Incidence seems low: 2.79 per 100-child-year

• Time period of the study

• Are all the studies for ages 0-14?

• Line 84-85: ‘the rise of questioning regarding the reason for taking ART medication’. The language is incorrect. I assume you mean to say: difficulty for parents to properly respond when children ask why they are taking medications.

• Lines 87-88: Remove the statement ‘Those, lost from follow-up, may interrupt the treatment or may continue taking the treatment until no longer medications are available’ as it doesn’t make any sense. Or rephrase it and convey a clear message.

• Line 98-99: Remove the statement ‘Thereby to develop a comprehensive strategic plan for 99 the identified factors at the national level.’ as it is redundant.

• Line 113: you mean to say ‘1) studies conducted in Ethiopia’. Correct it.

• Line 125: remove ‘included’.

• Line 127: remove ‘for this study’ at the end of the sentence.

• The literature review you did and LTFU definition you provided is clear in that it describes the clinical/programmatic definition of LTFU as applied by clinicians or public health experts to follow programmatic outcome of ART treatment. If you are truly measuring LTFU as used routinely in clinical settings, the value reported should be much higher than this since you should label all children who interrupted treatment at least once for 1 month, no matter what their final follow-up status is, as LTFU. However, most studies don’t do such intensive analysis. They rather simply take final status at a certain date and calculate incidence of ‘LTFU’ at a certain date they decided to censor study participants. This underestimates the incidence of LTFU as defined in clinical settings since deaths will automatically be excluded from LTFU classification, which is incorrect for the most part. The reason is that most deaths occur at home and many ART clients are labeled as LTFU before they are traced, and their final status adjusted to ‘dead’. So, there are two options to move forward:

1. to study attrition at the end of follow-up including both death and LTFU (considering worst case scenario that all deaths were LTFU cases), OR

2. to study LTFU at the end of follow-up, which is true LTFU for clients with unknown status for more than 1 month.

Note that whichever option you choose, you need to update your operational definition of LTFU and additionally, you need to define the follow-up period to report your outcome to make the incidence rate give more sense by indicating the number of follow-up months. Most common times for reporting outcomes are: 6-month, 12-month, 18-month, 24-month, and yearly then after.

• Language needs to be edited by a professional to make it more readable for all audiences including international readers.

Reviewer #2: Congratulations on the manuscript that addresses LTFU in Ethiopia with lessons that can be applied to other settings. The paper is well written but can be improved by addressing a couple of comments and typos and grammatical errors some of which i have pointed out.

Review: Incidence of lost to follow up among HIV-positive children on antiretroviral treatment:

systematic review and meta-analysis

The manuscript reviews loss to follow up in studies conducted in Ethiopia. This is an important review addressing a topic important in improving treatment outcomes for children. Although it primarily focusses on studies conducted in Ethiopia, lessons have the potential to be applied elsewhere.

The paper is generally well written but can be improved by addressing grammatical errors and typos throughout the manuscript and the following specific comments;

Specific comments:

Title: Should be revised to include “Ethiopia”. The revised title should read “Incidence of lost to follow up among HIV-positive children on antiretroviral treatment: systematic review and meta-analysis of studies conducted in Ethiopia”

Abstract: In conclusion, the reference to lower incidence should probably be removed since the goal was not a comparison.

Background: Generally, gives the context. There are a few grammatical errors that should be removed. Live 67: end of the sentence should be “died from HIV related disease”. Line 74-78 should be revised to clarify the 95-95-95 goals are not only for children but all PLHIV.

Line 85, 88, 89: have grammatical errors. Line 95: replace “predicting” with “establishing”. Line 115 has a typo

Methods: Well written. Line 108 explain why “ADIS” was included as a search term,Line 113, replace “connected” with “conducted”

Statistical analysis: Not clear what this phrase means “The data synthesis was done via tabulating”. Please define the was HIV disease stage was assessed in the study as well as measures of adherence to ART.

Results

Line 161: should be results not result. Results are well summarized, tables and figures are well labeled. Table 2 is difficult to understand. Line 168 should be “titles and abstracts”

Line 200-201- correct statement. Did you mean advanced HIV disease. Please explain how HIV disease staging was assessed in methods since all children 5 and below are considered to have advanced HIV disease according to WHO.

Discussion: discusses the findings.

Line 221. Delete ART “follow up”. Line 223, replace “finding” with “incidence”. Line 223-230, the authors compared the pooled incidence with reported incidence from single studies. Not sure that this is a fair comparison.

Line 248-9: statement not clear since people get opportunistic infections because they have lower immunity. Requires editing to make scientific sense. OIs do not reduce the CD4 rather they occur or manifest in the setting of reduced immunity.

Reviewer #3: 1. Yes, it is technically sound.

2. Yes, the right statistical analysis for a systematic review was performed appropriately and rigorously.

3. Yes, the authors made all data underlying the findings in the manuscript fully available

4. Yes, the manuscript was presented in an intelligible fashion and written in standard English.

However, there were lots of minor typos. Thoroughly review is needed.

For example,

In the abstract

Background section -

Line 7 - change "variations were seen between the studies" to "variations were seen among the studies"

Line 8 - change incidence of lost follow-up to "incidence of lost to follow-up". Insert to between lost and follow up

Method -

Line 1 - change "we searched" to "We searched" with capital W

Line 5 - change "Fixed effect models" to "fixed effect models" with a small case letter 'f'

Similar errors were observed in the abstract. Do correct.

Line 69, change 'different' effort to 'several or much or various or multiple' effort

Line 71, change "By" to small case b'' as in by.

It will be okay to define 'fair or poor ART treatment'

**********

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Reviewer #1: Yes: Kesetebirhan Delele Yirdaw

Reviewer #2: No

Reviewer #3: No

**********

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PLoS One. 2024 May 22;19(5):e0304239. doi: 10.1371/journal.pone.0304239.r002

Author response to Decision Letter 0

19 Feb 2024

Academic editor comments and respective author’s response

Editor comment 1: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Authors Response: Thanks very much for this comment. The whole part of the manuscript has been updated as per the PLOS ONE style templates.

Editor comment 2. In the online submission form, you indicated that "The data is available at the corresponding author and may be provided upon request".All PLOS journals now require all data underlying the findings described in their manuscript to be freely available to other researchers, either 1. In a public repository, 2. Within the manuscript itself, or 3. Uploaded as supplementary information.This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If your data cannot be made publicly available for ethical or legal reasons (e.g., public availability would compromise patient privacy), please explain your reasons on resubmission and your exemption request will be escalated for approval.

Authors Response: We declared that all the data underlying the results presented in the study are publicly available in Harvard Dataverse Network repository: https://doi.org/10.7910/DVN/BQ6MU0. Editor comment 3 .Please include a separate caption for each figure in your manuscript.

Authors Response: Thanks very much dear editor for this helpful comment. A separate caption has been included for each Supporting Information files

Editor comment 4: Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our SupportingInformation guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Authors Response: Thanks very much dear editor for this helpful comment. A separate caption has been included for each Supporting Information files

Reviewer #1 comments and an author response

We thank you very much for your big constructs and your devoting time to review our manuscript.

Comment 1: Lost to follow-up language has been changed to interruption in treatment in recent times. Use it since it is becoming mainstream terminology.

Authors Response: dear reviewer, thank you for your concern, dear reviewer, we accept the comment as comment and we also considered the terminology during the conception of the study, however, all of the primary studies used in this study were reported and measured as left to follow up, such that, 1) to be in line and consistent with those primary studies used for pooling LTFU and 2) by considering that both of the terminology have comparable definition, we used the terminology “Left to follow up” as it is in our study. Dear, reviewer, this all about our concern. Dear, reviewer, If you have any concern regarding this, we are happy to look it in our next revisions.

Comment 2: Incidence seems low: 2.79 per 100-child-year

Authors Response: Thanks very much for your comments, dear reviewer, yes, you are right, dear, reviewer please look the conclusions indicated on pages 2 , from lines number 42-43.

Comments 3: Time period of the study, Are all the studies for ages 0-14.

Authors Response: dear reviewer, thank you for your comments and comments were accepted corrections have made in the revised manuscript. Dear reviewer, all studies were conducted for children under 15 years that published up to November, 20/2023. Dear reviewer, all information were incorporated under heading eligibility criteria on pages 6 from lines 113-117.

Comment 4: Line 84-85: ‘the rise of questioning regarding the reason for taking ART medication’. The language is incorrect. I assume you mean to say: difficulty for parents to properly respond when children ask why they are taking medications.

Authors Response: Thanks very much for your comments, dear reviewer, comments were accepted; modification was made in the revised manuscript. Please, look from pages 4-5 from line numbers 84-89.

Comment 5: Lines 87-88: Remove the statement ‘Those, lost from follow-up, may interrupt the treatment or may continue taking the treatment until no longer medications are available’ as it doesn’t make any sense. Or rephrase it and convey a clear message.

Author’s response: dear reviewer, we thank you heartily for your constructive and supportive comments. Modification was made in the revised manuscript. Please, look from pages 5 from line numbers 89-91.

Comment 5: Line 98-99: Remove the statement ‘Thereby to develop a comprehensive strategic plan for 99 the identified factors at the national level.’ as it is redundant,• Line 113: you mean to say ‘1) studies conducted in Ethiopia’. Correct it, Line 125: remove ‘included’, Line 127: remove ‘for this study’ at the end of the sentence.

Authors Response: Thanks very much, for your insightful comments, dear reviewer, correction were made for all indicated comments in the revised manuscript.

Comment 6: The literature review you did and LTFU definition you provided is clear in that it describes the clinical/programmatic definition of LTFU as applied by clinicians or public health experts to follow programmatic outcome of ART treatment. If you are truly measuring LTFU as used routinely in clinical settings, the value reported should be much higher than this since you should label all children who interrupted treatment at least once for 1 month, no matter what their final follow-up status is, as LTFU. However, most studies don’t do such intensive analysis. They rather simply take final status at a certain date and calculate incidence of ‘LTFU’ at a certain date they decided to censor study participants. This underestimates the incidence of LTFU as defined in clinical settings since deaths will automatically be excluded from LTFU classification, which is incorrect for the most part. The reason is that most deaths occur at home and many ART clients are labeled as LTFU before they are traced, and their final status adjusted to ‘dead’. So, there are two options to move forward:

1. to study attrition at the end of follow-up including both death and LTFU (considering worst case scenario that all deaths were LTFU cases), OR

2. to study LTFU at the end of follow-up, which is true LTFU for clients with unknown status for more than 1 month.

Authors Response: Thanks very much, dear reviewer, the comment was accepted; correction was made in the revised manuscript. Please look the operational definition of LTFU and follow-up period on page 7 from line numbers 145-148. Dear reviewer, we also indicate the person month observation, person year observation, follow up months (please look table 1).

Dear reviewer, the segregated event (number LTFU) at 6-month, 12-month, 18-month, 24-month, and yearly then after were not reported in the primary studies. Dear reviewer, due to this we can’t pooled the incidence of LTFU for the respective months. Dear reviewer, this is one of our limitation and we incorporate it as our limitation, please look it under heading of limitation on page 17 from lines numbers 290-292.

Reviewer 2 comments and an author response

Congratulations on the manuscript that addresses LTFU in Ethiopia with lessons that can be applied to other settings. The paper is well written but can be improved by addressing a couple of comments and typos and grammatical errors some of which i have pointed out. The manuscript reviews loss to follow up in studies conducted in Ethiopia. This is an important review addressing a topic important in improving treatment outcomes for children. Although it primarily focusses on studies conducted in Ethiopia, lessons have the potential to be applied elsewhere. The paper is generally well written but can be improved by addressing grammatical errors and typos throughout the manuscript and the following specific comments;

Authors: Dear reviewer, we thank you for your constructive comments, suggestion and devoted times. Here, we are happy to respond your comments.

Comment 1: Title: Should be revised to include “Ethiopia”. The revised title should read “Incidence of lost to follow up among HIV-positive children on antiretroviral treatment: systematic review and meta-analysis of studies conducted in Ethiopia”

Authors Response: Dear reviewer, thank you very much for your constructive comments. Corrections were made in the revised manuscript as the following “Incidence of lost to follow up among HIV-positive children on antiretroviral therapy in Ethiopia: systematic review and meta-analysis”.

Comment 2: Abstract: In conclusion, the reference t” lower incidence should probably be removed since the goal was not a comparison.

Authors Response: Dear reviewer, thank you very much for your constructive comments. Corrections were made in the revised manuscript indicated on page 2 from lines 42-43.

Comment 3: Background: Generally, gives the context. There are a few grammatical errors that should be removed. Live 67: end of the sentence should be “died from HIV related disease”. Line 74-78 should be revised to clarify the 95-95-95 goals are not only for children but all PLHIV.

Authors Response: Thanks very much for your constructive comments, dear reviewer. Correction was made in the revised manuscript as per your suggestion.

Comment 4: Line 85, 88, 89: have grammatical errors. Line 95: replace “predicting” with “establishing”. Line 115 has a typo.

Authors Response: Thanks very much for your insightful comments, dear reviewer; we accepted your comment. Modification was made in the revised manuscript indicated from pages 4-5, from lines 84-91.

Comment 5: Methods: Well written. Line 108 explain why “ADIS” was included as a search term, Line 113, replace “connected” with “conducted”

Authors Response: Dear reviewer, thank you very much for your constructive comments and correction. Type error was corrected. We used “ADIS” as searching term because of to incorporate articles that may state AIDS as term in the title or topic. Dear reviewer, it has no impact on our searching but it increase the inclusiveness of our searching.

Comment 6: Statistical analysis: Not clear what this phrase means “The data synthesis was done via tabulating”.

Authors Response: Thanks very much for your critical insight, dear reviewer, this edition problem and it was removed from the manuscript.

Comments 7: Please define the was HIV disease stage was assessed in the study as well as measures of adherence to ART.

Authors Response: dear reviewer, Thanks very much for your critical insight, dear reviewer, this edition problem and it was removed from the manuscript. Operational definition was incorporated in the revised manuscript, please look from pages 7-8, from line numbers 145-154.

Comment 8: Line 161: should be results not result. Results are well summarized, tables and figures are well labeled. Table 2 is difficult to understand. Line 168 should be “titles and abstracts”

Authors Response: Dear reviewer, Thank you for your corrective comments. Corrections were made in the revised manuscript, please, look on pages 11, from lines numbers 206-207.

Comment 9: Line 200-201- correct statement. Did you mean advanced HIV disease? Please explain how HIV disease staging was assessed in methods since all children 5 and below are considered to have advanced HIV disease according to WHO

Dear, reviewer, Thank you for your constructive comments. Comments are accepted. Corrections were made in the revised manuscript. Please, look on page 7 from lines 149-151

Discussion

Comment 9: Line 221. Delete ART “follow up”. Line 223, replace “finding” with “incidence”. Line 223-230, the authors compared the pooled incidence with reported incidence from single studies. Not sure that this is a fair comparison.

Authors Response: dear, reviewer, thank you for your constructive comments. Dear reviewer, we absolutely accept your concern, yes you are right. Dear reviewer, though we browsed for systematic and meta-analysis studies conducted on Incidence of lost to follow up among children, we can’t access systematic and meta-analysis studies conducted in other countries. Because of this we are obligated to use primary study for comparing our pooled estimate of Incidence of lost to follow. However, some of those studies were nationwide and were representative of the countries.

Comment 10: Line 248-9: statement not clear since people get opportunistic infections because they have lower immunity. Requires editing to make scientific sense. OIs do not reduce the CD4 rather they occur or manifest in the setting of reduced immunity.

Authors Response: dear, reviewer, thank you for your constructive comments, comments were accepted, corrections were made in the revised manuscript, please look on page 15 from lines 251-257.

Reviewer 3 comments and an author response

Yes, the right statistical analysis for a systematic review was performed appropriately and rigorously.

3. Yes, the authors made all data underlying the findings in the manuscript fully available

4. Yes, the manuscript was presented in an intelligible fashion and written in standard English.

Authors: Dear reviewer, we thank you for your constructive comments, suggestion and devoted times. Here, we are happy to respond your comments.

Comments 1: However, there were lots of minor typos. Thoroughly review is needed.

For example, in the abstract Background section

� Line 7 - change "variations were seen between the studies" to "variations were seen among the studies"

� Line 8 - change incidence of lost follow-up to "incidence of lost to follow-up". Insert to between lost and follow up

Author’s response: Dear reviewer, thank you very much for your constructive comments and correction. Corrections were made in the revised manuscript as per your suggestion.

Comments 2: Method -

� Line 1 - change "we searched" to "We searched" with capital W

� Line 5 - change "Fixed effect models" to "fixed effect models" with a small case letter 'f'

� Similar errors were observed in the abstract. Do correct.

Author’s response: Dear reviewer, thank you very much for your constructive comments and correction. Corrections were made in the revised manuscript as per your suggestion.

Comments 3: Line 69, change 'different' effort to 'several or much or various or multiple' effort

Line 71, change "By" to small case b'' as in by.

Author’s response: Dear reviewer, thank you very much for your constructive comments and correction. Corrections were made in the revised manuscript as per your suggestion, please look on page 4 on line number 68.

Comments: It will be okay to define 'fair or poor ART treatment'

Author’s response: Dear reviewer, thank you very much for your constructive comments and suggestion. Comment were accepted and corrections were made in the revised manuscript as per your suggestion, please look on page 8 from line numbers 152-155.

Attachment

Submitted filename: Response to reviewers final.docx

pone.0304239.s004.docx^{(30.3KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0304239.r003

Decision Letter 1

Zewdu Gashu Dememew

2 May 2024

PONE-D-23-40483R1Incidence of lost to follow up among HIV-positive children on antiretroviral therapy in Ethiopia: systematic review and meta-analysis.PLOS ONE

Dear Dr. Girma,

The authors may try to address the following. comments/suggestion before reconsidering the manuscript for publication.

General Comments and suggestions

The author may revise the English language throughout the manuscript: punctuation, grammar… may be rechecked. Revising the manuscript against the journal requirement; specifically, the way reference is listed and written be looked into.

Specific comments and suggestions

#32, 104, Change ‘November 20/2023’ to November 20, 2023

# 42, 104, 116, 144, 168: Change ‘Left to follow up’ and ‘loss to follow-up’ to lost to follow-up and make consistent throughout.

#43: why “Counseling’ started with capital letter?

#65-67: could be two separate sentences. You may put a full stop after ‘… end of 2022’.

# 91-92, 187: check if you need to add ’ after ART initiation’ at end the sentence and the title in # 187. Note there a are a lot of LTFU incidence evidence among HIV children, but fewer while after they put on ART.

#122,123: ‘… three 123 authors (GF, ZA, GM, and MS).’ Check if these are these three or four.

# 123: you may replace ‘between’ with ‘among’

#124: “The each study…’’ what does this mean? Or you may replace ‘The’ with ‘In’

#133: ‘Twenty-four studies...’ could be replaced by ‘twenty-four studies...”

#159: ‘’… 25, 50, and 75%,’’ make the % uniform to all numbers.

#242: check whether “Waster Kenya” is right?

#181-288: (limitation): consider revising, summarize this section. May omit numbers 1-5.

Reference: Try to revise the write up of the reference per the journal requirement.

Please submit your revised manuscript by Jun 16 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Zewdu Gashu Dememew, M.D,PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

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6. Review Comments to the Author

Reviewer #1: Most of the comments have been addressed. However, the fact that LTFU incidence is low doesn't mean that retention was optimal. This is because the operational definition of LTFU is re-defined as those who interrupted treatment and has not been classified as dead or transferred out. This means, LTFU incidence in this meta-analysis measures cases whose tracing outcome remains unknown. This is a positive finding for the tracing mechanism put in place since deaths, and transfer out cases are being identified and reported. However, the way the paper is written, it seems to suggest LTFU was "generally low" for children with HIV. This is far from reality since retention among children with HIV is far lower that adults with HIV and adult retention at 12 months has not been more than 85% in many cases.

In order to avoid this confusion, clearly state this in the discussion section that

1. LTFU means those with unknown tracing outcome

2. LTFU is not a reflection of improved retention in care rather the improved tracing and reporting mechanism

Finally, make sure to proof read the paper since words like 'ADIS' still remain in the revised version, which should have been edited out as per reviewers comment.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: Yes: Kesetebirhan Delele Yirdaw

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Attachment

Submitted filename: Incidence of lost to follow up among HIV_min rev.docx

pone.0304239.s005.docx^{(14.3KB, docx)}

PLoS One. 2024 May 22;19(5):e0304239. doi: 10.1371/journal.pone.0304239.r004

Author response to Decision Letter 1

3 May 2024

Academic editor comments and respective author’s response

We thank you very much for your big constructs and your constructive comments

Editor comment 1: The author may revise the English language throughout the manuscript: punctuation, grammar… may be rechecked. Revising the manuscript against the journal requirement; specifically, the way reference is listed and written be looked into.

Authors Response: Thanks very much for this comment. The punctuation, grammar was rigorously rechecked

Editor comment 2. #32, 104, Change ‘November 20/2023’ to November 20, 2023