Estimation of lifetime survival and predictors of mortality among TB with HIV co-infected children after test and treat strategies launched in Northwest, Ethiopia, 2021; a multicentre historical follow-up study.

INTRODUCTION: In resource-limited settings, the mortality rate among tuberculosis and human Immunodeficiency virus co-infected children is higher. However, there is no adequate evidence in Ethiopia in general and in the study area in particular. Hence, this study aims to estimate lifetime survival and predictors of mortality among TB with HIV co-infected children after test and treat strategies launched in Northwest Ethiopia Hospitals, 2021.
METHODS: Institution-based historical follow-up study was conducted in Northwest Ethiopia Hospitals among 227 Tuberculosis and Human Immunodeficiency Virus co-infected children from March 1, 2014, to January 12, 2021. The data were entered into Epi info-7 and then exported to STATA version 14 for analysis. The log-rank test was used to estimate the curve difference of the predictor variables. Bivariable cox-proportional hazard models were employed for each predictor variable. Additionally, those variables having a p-value < 0.25 in bivariate analysis were fitted into a multivariable cox-proportional hazards model. P-value < 0.05 was used to declare significance associated with the dependent variable.
RESULTS: From a total of 227 TB and HIV co-infected children, 39 died during the follow-up period. The overall mortality rate was 3.7 (95% CI (confidence interval): 2.9-4.7) per 100 person-years with a total of 1063.2-year observations. Cotrimoxazole preventive therapy (CPT) non-users [Adjusted Hazarded Ratio (AHR) = 3.8 (95% CI: 1.64-8.86)], presence of treatment failure [AHR = 3.0 (95% CI: 1.14-78.17)], and Cluster of differentiation 4(CD4) count below threshold [AHR = 2.7 (95% CI: 1.21-6.45)] were significant predictors of mortality.
CONCLUSION: In this study, the mortality rate among TB and HIV co-infected children was found to be very high. The risk of mortality among TB and HIV co-infected children was associated with treatment failure, CD4 count below the threshold, and cotrimoxazole preventive therapy non-users. Further research should conduct to assess and improve the quality of ART service in Northwest Ethiopia Hospitals.

Introduction

Human immunodeficiency virus(HIV) and TB(Tuberculosis) are infectious diseases that usually occur together with each worsening one another [1]. HIV is a virus that attacks the body’s immune system CD4 cells. Over time, untreated HIV reduces the number of CD4 cells in the body that the body can’t fight off infections [2]. HIV is increasing the risk of acquiring TB infection, and TB enhances HIV replication by accelerating the natural evolution of HIV infection [3]. Globally, TB is the leading cause of death from a single infectious agent [4], including persons living with HIV [5].

Globally, there were 10 million people with TB in 2020, 1.2 million deaths from HIV-negative people and an additional 208,000 deaths from HIV-positive individuals [6]. Nowadays, the prevalence of TB/HIV co-infection has been increased and become a major public health concern in worldwide, Indeed the highest cases were reported in Sub-Saharan African countries [7]. TB and HIV co-infections are often called a twin epidemic [8], one to four HIV-related death is a result of TB in children [9], and TB carries significant mortality regardless of the ART and adequate anti-tuberculosis treatment in these children [10].

In fact, children living with HIV are highly vulnerable to mortality than adults, due to a very young age rely on their parents/caregivers to access health care services [11]. worldwide in 2018, 251,000 people who had both TB /HIV are estimated to have died. Of these, 211,000 TB/HIV death from Africa, and 30,000 were children (male, 0-14(16,000)) and (Female 0-14(14,000)) [12], and almost all from sub-Saharan Africa [13]. Indeed, TB has the lion’s share in HIV-related deaths [8].

HIV and TB are the leading causes of death from infectious diseases worldwide in HIV-infected children [14], and they are major public health concerns particularly in resource-limited countries like Ethiopia.

HIV/TB co-infection mortality in Sub-Saharan countries continues taking the leading position and heavily affected [15], and Ethiopia ranked seventh among the 22 heavily affected countries [3]. For this reason, data on HIV/TB co-infection in children are still lacking in resource-limited settings [16], and TB -HIV-associated mortality often remains unascertained [17].

Africa countries including Ethiopia adopted the WHO "Global TB program in 2015” launched to achieve the Sustainable Development Goals (SDG) and END-TB strategies, which targeted to decrease TB death and incidence by 90% and 80% respectively by 2030 through joint efforts to the burden of the two epidemics [18]. There are efforts at a global and national level that have been done to achieve the Sustainable Development Goals (SDG) and END-TB strategies. However, TB accounts for approximately 40% of facility-based HIV/AIDS-related deaths in the resource-limited settings among TB/HIV co-infected children [17], and Ethiopia is one of them [3]. Besides, the burden of TB/HIV co-infection is still intolerable in Ethiopia in general and in the study area in particular, and it attracts the attention of the government and researchers. Hence, this study aims to estimate lifetime survival and predictors of mortality among TB with HIV co-infected children after test and treat strategies launched in northwest Ethiopia hospitals, 2021.

Methods and materials

Study settings and subjects

A historical follow-up study was conducted from March 1, 2014, to January 12, 2021, in Northwest Ethiopia Hospitals, The Hospitals namely Debre Tabor Compressive Specialized Hospital, Gondar Compressive Specialized Hospital, and South Gondar primary Hospitals. ART service is one of the services delivered in the Hospitals by ART case-team includes physicians, nurses, pharmacists, laboratory technicians who took comprehensive ART training. A total of 239 TB HIV co-infected children were enrolled during the study period in the above hospitals. All TB and HIV co-infected children in the above hospitals from March 1, 2014, to January 12, 2021, were included. Whereas TB and HIV co-infected children incomplete baseline information TB status and the outcome variable(mortality) were excluded.

Sample size determination

The sample size was calculated by using Log-rank survival data analysis of the two-population proportion formula based on the following important assumptions- 95% confidence level, 80% optimum statistical power, and taking type one error 5%. By considering a study was conducted in eastern Ethiopia [19], by taking sex as a predictor variable (on the male as the exposed group denoted by q1 (0.38) and female group denoted by q0 (0.53), and then the total sample size, after adding 5% as incomplete medical records, and the final sample size was 372. However, all TB and HIV co-infected children from March 1, 2014, to January 12, 2021, were 239. Hence, all study participants were included in the study.

Data collection tools and procedures

The data extraction tool was developed from the patient registry book prepared by the Ethiopian Federal Ministry of Health. Data were collected from patient ART record cards and registers from March 1, 2014, to January 12, 2021. The data extraction tool contained socio-demographic, clinical, and treatment-related information. The data were collected by six BSc Nurse and supervised by two MSc in paediatrics and child health Nursing practitioners. A pretest was conducted among 5% of the sample size of medical records at Debre Tabor Compressive Specialized Hospital to check the completeness of the medical records. Two-days training was given about data collection procedures and supervisions.

Operational definition

Time to death

The time from TB/HIV co-infection to the occurrence of the event (i.e., death) during the follow-up period.

Censored

A child was considered as censored if the child is lost to follow-up or transfer out to another service or if the child was alive until the end of the study period.

Test-and-treat

Is an intervention strategy in which the population at risk is screened for HIV infection and diagnosed HIV infected individuals receive early treatment, aiming to eliminate HIV as it reduces the rate of spreading the virus to other people. In Ethiopia test and treat strategies among HIV infected children were launched since in 2014 G.C.

A CD4 count

CD4 below the threshold level was classified based on the age of the child’s (i.e. infants CD4<1500/mm3, 12–35 months <750/mm3, 36–59 months <350/mm3 and ≥5 years <200/mm3) [20].

Underweight or stunting

Was defined as weight for age Z-score < −2 SD for under-five children and BMI for age Z-score < −2 SD for older children [3].

Anemia

Was defined as having a hemoglobin level ≤ of 10 mg/dl [20].

Adherence to ART

Was classified based on the percentage of drug dosage calculated from the total monthly doses of ART drugs. (Good >95%, fair 85–94%, and poor <85%) [7].

Data processing and analysis

The data were entered into Epi info -7 and then exported to STATA version 14 for analysis. The descriptive statics were explored through tables and graphs. The mortality rate was calculated by dividing the number of children who died during the follow-up period by the Child-Years of follow-up. Kaplan Meier curve was used to estimate the survival time. Besides, the log-rank test was used to estimate the curve difference of the predictor variables. The required assumption of the Cox-proportional hazard regression model was checked through Schoenfeld residual ph test and Log ph plot. Bivariable cox-proportional hazard models were employed for each predictor variable. Additionally, those variables having p-value < 0.25 in bivariate analysis were fitted into a multivariable cox-proportional hazards model. P-value < 0.05 was used to declare a significant association with the dependent variable.

Ethics approval and consent to participate

Ethical clearance was granted from the Institutional Review Board (IRB) of Debre Tabor University Ethical Review Committee with Ref No 842/21. Besides, a permission letter was obtained from each hospital administrators. The informed written consent was obtained from the ART focal person in each hospital on behalf of the study participants. Since it is secondary data. A total of 239 patient records were used in this retrospective study, including the date range (4–167 months) in which medical records were accessed during the follow-up period.

Results

Socio-demographic characteristics

A total of 239 TB/HIV co-infected children enrolled on ART during the follow-up period, 12 were excluded due to incomplete data. Of 227 TB/HIV co-infected children, nearly half of 117 (51.54% and 122(53.74%) age between 6.10 years and males respectively. Besides, nearly half of 125 (55.07%) of the caregivers of the child were housewife, whereas 100 (44.05%) of the caregivers were unable to read and write. The majority 187 (82.38%) and 204 (89.87%) of children were urban residence and livening with their parents in the follow-up period respective (Table 1).

Table 1

Socio-demographic characteristics among TB and HIV co-infected children after test and treat strategies launched in northwest Ethiopia hospitals, 2021.

Characteristics		Frequency	Percent
Age (years)	< 1	3	1.32
	1–5	61	26.87
	6–10	117	51.54
	>11	46	20.26
Sex	Male	122	53.74
	Female	105	46.26
Residence	Urban	187	82.38
	Rural	40	17.62
Child lives Orphaned	Yes	23	10.13
	No	204	89.87
Caregiver’s occupational status	Housewife	125	55.07
	Governmental employee	50	22.03
	Non-governmental employee	23	10.13
	Merchant	29	12.78
Caregivers of educational status	Unable	100	44.05
	Primary	68	29.96
	Secondary and above	59	25.99

Clinical and treatment-related characteristics

Out of 227 TB/HIV co-infected children, 66 (29.07%) were initiated ART with EFV regimen based. From the total children, 103 (45.37%) had initial regimen change. Of these, 43 (41.75%) change their initial regimen due to treatment failure. Besides, 68 (29.96%) of TB/HIV co-infected children were reported different kinds of drug side effects.

From the total 277 TB/HIV co-infected children, the majority 183 (80.62%) of them were taken CPT, while less proportion 152 (66.96%) were taking IPT. A large portion of TB/HIV co-infected children, 177 (77.97%), 186 (81.94%),161 (70.93%), and 169 (74.45%) were CD4 counts above the threshold level, Hgb level > = 10 mg/dl, WHO stage III, a good level of adherence to ART during the follow-up period respectively. On the other hand, nearly half of children, 118 (51.98%), 99 (43.61%), and 103 (45.37%) of TB/HIV co-infected children were underweight, stunting, and had an opportunistic infection in the follow-up period respectively. From the 227 TB/HIV co-infected children, 98 (43.17%) were followed for more than 60 months (Table 2).

Table 2

Clinical and treatment-related characteristics among TB and HIV co-infected children after test and treat strategies launched in northwest Ethiopia hospitals, 2021.

Characteristics		Frequency	Percent
Initial ART regiments based on NNRTIs	EFV-based	66	29.07
	NVP, PI, and others	161	70.93
Initial regiment change	Yes	103	45.37
	No	124	54.63
Reason for regiment change(n = 103)	Side effect/toxicities	21	20.39
	Stockout	39	37.86
	Treatment failure	43	41.75
Treatment failure	Yes	43	18.94
	No	184	81.06
Drug side effect	Yes	68	29.96
	No	159	70.04
Duration On ART	<60 months	129	56.83
	≥60 months	98	43.17
Isoniazid	Yes	152	66.96
	No	75	33.04
Co-trimoxazole preventive therapy	Yes	183	80.62
	No	44	19.38
CD4 counts or % level	Below threshold	50	22.03
	Above threshold	177	77.97
HGB level	< 10 mg/dl	41	18.06
	> = 10 mg/dl	186	81.94
WHO stage	Stage III	161	70.93
	Stage IV	66	29.07
Opportunistic infections	Yes	103	45.37
	No	124	54.63
ART adherence	Good	169	74.45
	Poor/Fair	58	25.55
Height for age	Stunting	99	43.61
	Normal	128	56.39
Weight for age	Underweight	118	51.98
	Normal	109	48.02

NNRTIs = Non-Nucleoside Reverse Transcriptase Inhibitors, EFV = Efavirenz, NVP = Nevirapine, PI = Protease Inhibitor.

Kaplan-Meier survival curve

From a total of 227 TB/HIV co-infected children, 39 were died, which a proportion of 17.2% during the follow-up period (Fig 1).

Fig 1

Proportion of mortality among TB and HIV co-infected children by CD4 counts below the threshold level in northwest Ethiopia hospitals, 2021.

The total mortality rate among TB/HIV co-infected children was 3.7 (95%CI: 2.9–4.7) per 100 person-years. The children followed with the range from 04 to 167 months days, which yields a total of 12,758 months or 1,063.17 years at risk (Fig 2).

Fig 2

Kaplan-Meier of survival curve among TB and HIV co-infected children after test and treat strategies launched in northwest Ethiopia hospitals, 2021.

Predictors of mortality

In bivariate cox proportional hazard model, residence, occupation of the mother, residence, a child lives orphaned, caregiver’s occupational status, caregivers of educational status, initial ART regimen, initial regiment change, treatment failure, duration on ART, IPT, CPT, CD4 counts or % level, Hgb level, WHO stage, history of OI, and level of adherence to ART of variable had P-value less than or equal to 0.25 and entered into for multivariate cox proportional hazard.

In the multivariate cox proportional hazard model, treatment failure, CPT non-users, and CD4 counts below threshold level were significant predictors of mortality among TB/HIV co-infected children.

The hazards of mortality in children with a CD4 count below threshold level were 2.7 times higher than those children with a CD4 count above threshold level [AHR: 2.7(95% CI: 1.21, 6.45)].

The hazards of mortality in children with treatment failure were 3.0 times higher than those children without treatment failure [AHR: 3.0(95% CI: 1.14, 8.17)].

The hazards of mortality in children with CPT non-users were 3.8 times higher than those children with CPT users [AHR: 3.8(95% CI: 1.64, 8.86)] (Table 3). Additionally, the log-rank test of the between the categories variable of the predictors was estimated (Figs 3–5).

Table 3

Bivariable and multivariable Cox-regression of predictor variable among TB and HIV co-infected children after test and treat strategies in northwest Ethiopia hospitals, 2021.

Characteristics		Survival status		CHR (95% CI)	AHR (95% CI)	P-Value
		No	Yes
Age (years)	< 1	1	2	2.7(0.33–21.5)	-
	1–5	9	52	1.1(0.41–2.78)	-
	6–10	21	96	1.1(0.47–2.41)	-
	>11	8	38	Ref
Sex	Male	18	104	0.8(0.42–1.51)	-
	Female	21	84	Ref
Residence	Urban	30	157	Ref	Ref
	Rural	9	31	1.9(0.88–4.01)	1.7(0.70–5.51)	0.248
Child lives Orphaned	Yes	9	14	2.5(1.18–5.25)	1.5(0.63–3.59)	0.351
	No	30	174	Ref	Ref
Caregiver’s occupational status	Housewife	21	104	1.3(0.44–3.78)	-
	Governmental employee	6	44	0.8(0.24–2.97)	-
	Non-governmental employee	8	15	2.5(0.75–8.31)	-
	Merchant	4	25	Ref
Caregiver’s of educational status	Unable	20	80	1.2(0.57–2.61)	-
	Primary	9	59	0.8(0.30–1.85)	-
	Secondary and above	10	49	Ref
ART adherence	Good	21	148	Ref	Ref
	Poor/Fair	18	40	4.0(2.14–7.60)	1.6(0.75–3.41)	0.228
Height for age	Stunting	18	81	1.1(0.59–2.08)
	Normal	21	107	Ref
Weight for age	Underweight	22	96	1.4(0.74–2.63)
	Normal	17	92	Ref
Initial ART regimen	EFV-based	20	46	2.5(1.35–4.76)	1.1(0.52–2.49)	0.744
	NVP, PI and others based	19	142	Ref	Ref
Initial regiment change	Yes	28	75	4.0(1.99–8.17)	1.1(0.41–3.12)	0.804
	No	11	113	Ref	Ref
Reason for regiment change(n = 103)	Treatment failure	21	22	2.1(0.7–16.7)	-
	Side effect/toxicities	3	18	0.7(0.15–3.11)	-
	Stockout	4	35	Ref
Drug side effect	Yes	13	55	1.2(0.64–2.43)	-
	No	26	133	Ref
Treatment failure	Yes	21	22	8.6(4.50–16.4)	3.0(1.14–8.17)	0.031 *
	No	18	166	Ref	Ref
IPT	Yes	34	118	3.4(1.33–8.80)	2.0(0.71–5.51)	0.194
	No	5	70	Ref	Ref
CPT	No	25	19	10.7(5.5–20.7)	3.8(1.64–8.86)	0.002 **
	Yes	14	169	Ref	Ref
CD4 counts or % level	Below threshold	25	25	7.4(3.85–14.4)	2.7(1.21–6.45)	0.026 *
	Above threshold	14	163	Ref	Ref
HGB level	< 10 mg/dl	21	20	7.0(0.37–13.1)	1.7(0.35–2.37)	0.856
	> = 10 mg/dl	18	168	Ref	Ref
WHO stage	Stage III	16	145	Ref	Ref
	Stage IV	23	43	4.5(2.39–8.63)	1.9(0.9–2.7)	0.791
Opportunistic infection	Yes	29	74	3.9(1.92–8.07)	1.8(0.71–4.53)	0.213
	No	10	114	Ref	Ref

*Significant at <0.05

** Significant at <0.01; CHR = Crude hazard ratio; AHR = adjusted hazard ratio; Ref = reference category; CI = confidence interval.

Fig 3

Kaplan-Meier of survival curve of among TB and HIV co-infected children by CD4 counts below the threshold level in northwest Ethiopia hospitals, 2021.

Fig 5

Kaplan-Meier of survival curve of among TB and HIV co-infected children by treatment failure in northwest Ethiopia hospitals, 2021.

Discussion

In this study, the overall mortality rate among TB HIV co-infected children in Northwest Ethiopia Hospitals was found to be 3.7 (95% CI: 2.9–4.7) per 100 person-years. Additionally, the proportion of mortality was found to be 17.2%. This finding is comparable with the study conducted in Gondar Ethiopia was 3.27 PPY [20], in Tanzania was 17.5% [21], and in Thailand was 17% [22]. However, the finding of this study was higher than the studies conducted in seven referral Hospitals in Ethiopia was 14% [19], in Uganda was 10.47% (38), in Nigeria was 1.4 PPY [23], in South Africa was 12.4% [24], in Botswana was 13.6% [25], and the Democratic Republic of the Congo was 13% [26]. On the other hand, the finding of this study is lower than the study conducted in Jimma, Ethiopia was 20.2% [27].

The possible justification might be that developed/developing countries have better quick tests or screening for TB and/or HIV infection than resource-limited setting countries such as Ethiopia that can help the patient treatment in a timely and then to improve. Moreover, there is a constraint of knowledge and skill of the health care providers to screen, diagnose, and treat the diseases of TB/HIV co-infection and its related complication in Africa [28, 29]. Even the healthcare providers have adequate knowledge, there is resource limitation to combat TB/HIV co-infection.

The hazards of mortality in children with a CD4 count below the threshold level were 2.7 times higher than those children with a CD4 count above the threshold level. This finding is supported by the studies conducted in another setting [7, 19, 26, 27, 30]. In fact, patients with depilation of CD4 count can develop more severe disease or advanced opportunistic infections including pneumocystis pneumonia, diarrhoea, oral/oesophagal candidiasis which leads to compilation and death [31, 32].

The hazards of mortality in children with treatment failure were 3.0 times higher than those children without treatment failure. This finding is supported by the studies conducted in another setting [30]. Generally, children not on effective HIV treatment in overtime, then HIV has done a lot of damage to the immune system. Since taking HIV medicines as prescribed can help keep the viral suppression and your CD4 cell count high [33, 34]. Moreover, treatment failure worsens the risk of mortality of the patient as a result of ARV combination and treatment duration, which implies the antiretroviral drugs are no longer able to suppress the virus or prevent the deterioration of your immune system [35, 36].

The hazards of mortality in children with CPT non-users were 3.8 times higher than those children with CPT users. This finding is supported by the studies conducted in another setting (25,31,33). Actually, cotrimoxazole prophylaxis is given for HIV-infected children to avoid either the first occurrence or their recurrence of opportunistic infection that can increase the survival of the children. On the other hand, children who had co-trimoxazole non-user will face several problems such as treatment failure, CD4 count depletion, and the occurrence of opportunistic infection that could lead to death [37, 38]. This study does have inherent limitations due to the retrospective nature of the study. Also, some of the important predictors might have a significant association with mortality but were not investigated due to unavailability in the medical or ART registers logbook.

Conclusion

In this study, the mortality rate among TB and HIV co-infected children was found to be very high. The risk of mortality among TB and HIV co-infected children was associated with treatment failure, CD4 count below the threshold, and cotrimoxazole preventive therapy non-users. Further research should conduct to assess and improve the quality of ART service in Northwest Ethiopia Hospitals.

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4 May 2021

PONE-D-21-04696

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in South Gondar Public Hospitals, Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

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Reviewer #1: In this study, the authors performed institution-based retrospective follow-up study conducted from March 1, 2014, to January 12, 2021 on survival and predictors of mortality among 227 TB and HIV co-infected children in Ethiopia. They found that this population of children had a high mortality rate of 17% and that cotrimoxazole preventive therapy (CPT) non-users, ART treatment failure, and CD4 count below threshold were significant predictors of mortality. The study was well done, but the writing needs substantial improvement. There are no other major concerns. The following are some minor concerns and questions.

1) Please provide explanation to the test and treat strategies and ART service

2) Does duration on ART mean that the following time of the patients during the study.

3) How many patients in Stage III & IV were in Stage IV? Would Stage IV be a predictor of mortality?

4) In Table 3 CPT, the Yes and No groups were mislabeled.

5) The Figure legends for Kaplan-Meier survival curves of CD4 counts are mixed-up. The legends for CPT user and non-user were the same.

6) What were the major causes of death?

Reviewer #2: the manuscript "Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected

Children After Test and Treat Strategies Launched in South Gondar Public Hospitals, Northwest,

Ethiopia, 2021; A Multicentre Historical Follow-up Study" by Chanie et al touched a very important heath issue among the HIV/TB co-infected people. However, the studies are not very organized so its enthusiasm is reduced.

Major concerns:

1. language: The whole paper is very hard to understand, current wiring is very sloppy.

2. Statistical analysis is lacking for the Tables 1 and 2. Although the statistical power (p value) was shown for the Table 3, it lacks a description of how the authors did the statistical analysis.

3. As the authors concluded "In this study, mortality among TB and HIV co-infected children was found to be very high. Treatment failure and CD4 count below the threshold were the independent predictors of mortality.

Hence, it is better a special emphasis on monitoring and managing regularly of these contributing

factors. Besides, strengthen the WHO recommendation of cotrimoxazole preventive therapy for all

patients living with HIV is crucial." it is not novel at all, e.g. people have known the importance of CD4 count.

suggest the authors making Bar graphs for Table 1 and Table 2 to show more detailed data in clearer manner.

**********

6. 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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

21 May 2021

Dear professor Qigui Yu (PLOS ONE journal chief Editor)

After going through the entire manuscript entitled "Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in South Gondar Public Hospitals, Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study" you forwarded your constructive comments which we missed to touch. Therefore, we are glad enough to express our sincerest thanks for your constructive Editors and reviewers’ comment that could help improve novelty of our effort. Additionally, those comments are all valuable and very helpful for revising and improving our paper, as well as an important guiding to significance the article.

We hope you find our manuscript suitable for publication and look forward hearing from you. It is needless to state that we are happy to provide any more details in support of this manuscript. Hence, we are living in resource limited setting that unable access the international English language experts to write very clearly. The main corrections in the paper and the responds to the Editor’s and reviewer’s comments are as flowing. The revised portion are marked in the yellow highlighted in revised version manuscript.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

22 Jul 2021

PONE-D-21-04696R1

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

PLOS ONE

Dear Ermias Sisay Chanie,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by October 1, 2021. 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'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Qigui Yu, M.D./Ph.D

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.

[Note: HTML markup is below. Please do not edit.]

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)

Reviewer #3: (No Response)

**********

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

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Partly

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #3: Yes

**********

6. 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: The major issue had been poor English writing, which was improved in this revised version. However, there are still many grammar mistakes and the overall flow of the sentences need to be fixed. There are also some misstatements and typos, some of which are listed below.

The statement in the Abstract “However, there is no prior evidence in Ethiopia.” is not accurate as the authors themselves cited a reference to show the opposite (ref #18, Survival and predictors of mortality among children co-infected with tuberculosis and human immunodeficiency virus at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. A retrospective follow-up study. PLoS ONE [Internet]. 2018 May 22”). It appears that this current study and the above-mentioned 2018 study both recruited patients from the same Gondar Comprehensive Specialized Hospital. Were there any patients included in both studies? Some discussion on the similarities and differences between both studies would be helpful.

As the risk of mortality is associated with CPT therapy non-users, the concluding should emphasize CPT use along with ART therapy.

Some of the references need to be updated. For example, World Health Organization. Global tuberculosis report 2020 is available (ref #4); The data shown in the sentences “In 2015 worldwide, 1.6 million people…” should be replaced with more recent data.

Should the overall mortality rate be 3.7 per 100 person-years instead of 3.7 per person-years.

Should Debre Tabor compressive specialized hospital be Debre Tabor Comprehensive Specialized Hospital?

In “by taking sex as a predictor variable (on the male as the exposed group

denoted by q1 (0.38) and female group denoted by q0 (0.53)”, where the numbers come from?

The sentence “The patients provided informed written consent to have data/samples from their medical records used in research.” needs re-wording as the patients were too young to provide such consent.

In “half of 117 (51.54% and 122(53.74%) male and age between 6.10 years respectively.”, the order was wrong: 122 is for male and 117 for the age group.

In “118 (51.98%), 99 (43.61%), 103 (45.37%), and 218 (77.03%)…), what 218 is for?

Reviewer #3: The authors studied lifetime survival and predictors of mortality in children with TB and HIV coinfection. Overall mortality rate was 3.7, which as associated with treatment failure, especially CD4 count below the threshold. The manuscript has improved adequately, but there are minor concerns that should be made clear for the conclusion in relation to treatment failure.

1. Antiretroviral drug (ARV) combination in the patient cohorts and groups, especially those with treatment failure, since 18.94% co-infected children showed treatment failure;

2. Did the ART cessation happen in the co-infected patients, which likely contribute to treatment failure, such as CD4 decline to the levels of threshold and emergence of opportunistic infection. These are important to make statistical analysis and conclusion;

3. The ARV combination and treatment duration in cohort with treatment failure should be considered in the group classification in the statistical analysis, at least discussed.

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Submitted filename: PONE-D-21-04696R1.docx

Click here for additional data file.

24 Jul 2021

Reviewer#1:

Comments #1: The major issue had been poor English writing, which was improved in this revised version. However, there are still many grammar mistakes and the overall flow of the sentences need to be fixed. There are also some misstatements and typos, some of which are listed below.

Author’s response: Undoubtedly! It is modified based on the given comment.

After frequent proofreading of the manuscript had several grammatical wordings and spelling errors. Hence, based on the given comment revision was made. These changes are found throughout the manuscript. These changes are found throughout the revised version manuscript

Comments #2: The statement in the Abstract “However, there is no prior evidence in Ethiopia.” is not accurate as the authors themselves cited a reference to show the opposite (ref #18, Survival and predictors of mortality among children co-infected with tuberculosis and human immunodeficiency virus at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. A retrospective follow-up study. PLoS ONE [Internet]. 2018 May 22”). It appears that this current study and the above-mentioned 2018 study both recruited patients from the same Gondar Comprehensive Specialized Hospital. Were there any patients included in both studies? Some discussion on the similarities and differences between both studies would be helpful. As the risk of mortality is associated with CPT therapy non-users, the conclusion should emphasize CPT use along with ART therapy

Author’s response: We strongly agree with the essence of incorporating this comment!

Sure, we are stated that there is no prior evidence in Ethiopia regarding to estimation of lifetime survival and predictors of mortality among TB with HIV co-infected children after test and treat strategies launched in Northwest, Ethiopia, 2021. What makes this research differ from the previous one (i.e., ref #18 from 2005-2018) is: This study was conducted in after test and treat strategies launched (i.e., after 20014), recent evidence, and multicenter. However, we are concluded to revised as limited evidence than no evidence.

Comments #3: Some of the references need to be updated. For example, World Health Organization. Global tuberculosis report 2020 is available (ref #4); The data shown in the sentences “In 2015 worldwide, 1.6 million people…” should be replaced with more recent data.

Author’s response: Unquestionably! It is modified based on the given comment as Globally, there were 10 million people with TB in 2020, 1.2 million deaths from HIV-negative people and an additional 208,000 deaths from HIV-positive individuals.

Comments #3: Should the overall mortality rate be 3.7 per 100 person-years instead of 3.7 per person-years.

Author’s response: Yes indeed! It is amended based on the given comment

Comments #4: Should Debre Tabor compressive specialized hospital be Debre Tabor Comprehensive Specialized Hospital?

Author’s response: Sure! it has been modified based on the given comment

Comments #5: In “by taking sex as a predictor variable (on the male as the exposed group

denoted by q1 (0.38) and female group denoted by q0 (0.53)”, where the numbers come from?

Author's Response: Absolutely! we found this comment with the greatest relevance because it helps to convince readers who ask the same question after reading this paper.

The sample size can be determined by considering the previous study by taking its proportion/prevalence, incidence and associated/predictor factors. In this case, the sample size was determined based on the second objective (i.e., predictors. sex) from the previous study as we tried to cite after categorized as the probability of survival in exposed and non-exposed groups.

Comments #6: The sentence “The patients provided informed written consent to have data/samples from their medical records used in research.” needs re-wording as the patients were too young to provide such consent.

Author’s response: Accepted! In genuinely speaking, the informed written consent was obtained from ART focal person in each hospital on behalf of the study participants. Since it is secondary data. Hence, it is modified based on the given comment

Comments #7: In “half of 117 (51.54% and 122(53.74%) male and age between 6.10 years respectively.”, the order was wrong: 122 is for male and 117 for the age group.

Author’s response: Appreciated! Hence, it is revised based on the given comment!

Comments #8: In “118 (51.98%), 99 (43.61%), 103 (45.37%), and 218 (77.03%) …), what 218 is for?

Author’s response: Undoubtedly! it is removed since it is a typing error.

Reviewer #3:

Comments #1: The authors studied lifetime survival and predictors of mortality in children with TB and HIV coinfection. The overall mortality rate was 3.7, which as associated with treatment failure, especially CD4 count below the threshold. The manuscript has improved adequately, but there are minor concerns that should be made clear for the conclusion in relation to treatment failure.

Author’s response: Great thanks for having this comment and concern in the following statements!

Comments # 2. Antiretroviral drug (ARV) combination in the patient cohorts and groups, especially those with treatment failure, since 18.94% co-infected children showed treatment failure;

Author’s response: We were categorized the study participants in a group at the very beginning of the study in the different predictor variables. In this case, the baseline of the study participants (i.e., co-infected children) regarding to treatment failure was grouped. and then we follow them up to the interesting outcome (i.e., death) development or censored.

Comments #3. Did the ART cessation happens in the co-infected patients, which likely contribute to treatment failure, such as CD4 decline to the levels of threshold and emergence of opportunistic infection.

Author’s response: Sure! You know and we know that if TB and HIV co-infected children have treatment failure, the risk of CD4 decline and the emergence of opportunistic infection increased.

In the meantime, CD4 decline and emergence of opportunistic infection can increase the risk of treatment failure. So that, we were categorized the study participant via different predictor variables of the dependent variable at the entrance of the study, which implies in controlling the confounding effect of one predictor variable on another predictor (the effect of treatment failure over CD4 count and OI to towards mortality).

Comments #4. These are important to make statistical analysis and conclusion; The ARV combination and treatment duration in cohort with treatment failure should be considered in the group classification in the statistical analysis, at least discussed.

Author’s response: Appreciated! In this study, the effect of ARV combination (i.e. EFV-based

NVP, and PI) and treatment duration (<60 months vs ≥60 months) for the outcome variable was assessed/analyzed. However, it is not discussed and analysed with treatment failure. Hence, it is discussed the revised version manuscript in the discussion section that can be can be seen from in yellow highlighted manuscript.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

17 Aug 2021

PONE-D-21-04696R2

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

PLOS ONE

Dear Dr. Chanie,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the poor English writing, particularly in your discussion section.

Please submit your revised manuscript by November 16, 2021. 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'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Qigui Yu, M.D./Ph.D

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.

Additional Editor Comments (if provided):

Suggest to seek professional English editing services to improve the flow and writing of your manuscript.

Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

26 Aug 2021

Point by point Author’s response to Editors and reviewers

Editors

[General Comment] 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.

Response: Thank you very much for the reminder. We have made revisions accordingly.

[General Comment] Suggest to seek professional English editing services to improve the flow and writing of your manuscript.

Response: In genuine speaking, we can’t obtain native English language experts to revised the manuscript intensively since we are living in highly resource limited setting. However, we have carefully considered the comments and tried our best to address every one of them to revised and to made the manuscript beauty.

[General Comment] If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

Response: We are needless to state that we are happy to provide any more details in support of this manuscript as required.

We are observed the attachment file in action link, and there is one attachment file. However, all comments and suggestion in the attached file was addressed in the first round. Now, we are attached once ana again as follows.

Reviewer#1:

Comments #1: The major issue had been poor English writing, which was improved in this revised version. However, there are still many grammar mistakes and the overall flow of the sentences need to be fixed. There are also some misstatements and typos, some of which are listed below.

Author’s response: Undoubtedly! It is modified based on the given comment.

After frequent proofreading of the manuscript had several grammatical wordings and spelling errors. Hence, based on the given comment revision was made. These changes are found throughout the manuscript. These changes are found throughout the revised version manuscript

Comments #2: The statement in the Abstract “However, there is no prior evidence in Ethiopia.” is not accurate as the authors themselves cited a reference to show the opposite (ref #18, Survival and predictors of mortality among children co-infected with tuberculosis and human immunodeficiency virus at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. A retrospective follow-up study. PLoS ONE [Internet]. 2018 May 22”). It appears that this current study and the above-mentioned 2018 study both recruited patients from the same Gondar Comprehensive Specialized Hospital. Were there any patients included in both studies? Some discussion on the similarities and differences between both studies would be helpful. As the risk of mortality is associated with CPT therapy non-users, the conclusion should emphasize CPT use along with ART therapy

Author’s response: We strongly agree with the essence of incorporating this comment!

Sure, we are stated that there is no prior evidence in Ethiopia regarding to estimation of lifetime survival and predictors of mortality among TB with HIV co-infected children after test and treat strategies launched in Northwest, Ethiopia, 2021. What makes this research differ from the previous one (i.e., ref #18 from 2005-2018) is: This study was conducted in after test and treat strategies launched (i.e., after 20014), recent evidence, and multicenter. However, we are concluded to revised as limited evidence than no evidence.

Comments #3: Some of the references need to be updated. For example, World Health Organization. Global tuberculosis report 2020 is available (ref #4); The data shown in the sentences “In 2015 worldwide, 1.6 million people…” should be replaced with more recent data.

Author’s response: Unquestionably! It is modified based on the given comment as Globally, there were 10 million people with TB in 2020, 1.2 million deaths from HIV-negative people and an additional 208,000 deaths from HIV-positive individuals.

Comments #3: Should the overall mortality rate be 3.7 per 100 person-years instead of 3.7 per person-years.

Author’s response: Yes indeed! It is amended based on the given comment

Comments #4: Should Debre Tabor compressive specialized hospital be Debre Tabor Comprehensive Specialized Hospital?

Author’s response: Sure! it has been modified based on the given comment

Comments #5: In “by taking sex as a predictor variable (on the male as the exposed group

denoted by q1 (0.38) and female group denoted by q0 (0.53)”, where the numbers come from?

Author's Response: Absolutely! we found this comment with the greatest relevance because it helps to convince readers who ask the same question after reading this paper.

The sample size can be determined by considering the previous study by taking its proportion/prevalence, incidence and associated/predictor factors. In this case, the sample size was determined based on the second objective (i.e., predictors. sex) from the previous study as we tried to cite after categorized as the probability of survival in exposed and non-exposed groups.

Comments #6: The sentence “The patients provided informed written consent to have data/samples from their medical records used in research.” needs re-wording as the patients were too young to provide such consent.

Author’s response: Accepted! In genuinely speaking, the informed written consent was obtained from ART focal person in each hospital on behalf of the study participants. Since it is secondary data. Hence, it is modified based on the given comment

Comments #7: In “half of 117 (51.54% and 122(53.74%) male and age between 6.10 years respectively.”, the order was wrong: 122 is for male and 117 for the age group.

Author’s response: Appreciated! Hence, it is revised based on the given comment!

Comments #8: In “118 (51.98%), 99 (43.61%), 103 (45.37%), and 218 (77.03%) …), what 218 is for?

Author’s response: Undoubtedly! it is removed since it is a typing error.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

11 Oct 2021

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

PONE-D-21-04696R3

Dear Dr. Ermias Sisay Chanie

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Qigui Yu, M.D./Ph.D

Academic Editor

PLOS ONE

Reviewers' comments:

19 Nov 2021

PONE-D-21-04696R3

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

Dear Dr. Chanie:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Qigui Yu

Academic Editor

PLOS ONE