Delayed ART initiation in "Test and Treat era" and its associated factors among adults receiving antiretroviral therapy at public health institutions in Northwest Ethiopia: A multicenter cross-sectional study.

BACKGROUND: Antiretroviral therapy (ART) has shown promising effects on the reduction of new HIV infection as well as HIV-related morbidity and mortality. In order to boost the effect of ART on ending HIV epidemics by 2030, the World Health Organization (WHO) indeed introduced a universal test and treat strategy in 2015 that recommends rapid (within seven days) initiation of ART for all HIV-positive patients. However, in low-income countries, a substantial number of HIV-positive patients were not enrolled in time, and information on delayed ART initiation status in Ethiopia is limited.
METHOD: A multicenter cross-sectional study was conducted on 400 HIV-positive adults receiving ART at public health institutions in Bahir Dar city, Northwest Ethiopia. A structured checklist was used to extract data from the patient's medical record. Data was entered into Epi-data version 4.6 and exported to SPSS version 26 for further analysis. Both simple and multivariable binary logistic regressions were executed, and variables with a p-value < 0.05 in the final model were considered significant predictors of delayed ART initiation.
RESULTS: The magnitude of delayed ART initiation was 39% (95% CI: 34%-44%). Being male [Adjusted odds ratio(AOR) = 1.99, 95%CI:1.3-3.2], having opportunistic infections (OIs) [AOR = 2.50, 95%CI:1.4-4.6], having other chronic diseases [AOR = 3.70,95%CI:1.7-8.3], substance abuse [AOR = 3.79, 95%CI: 1.9-7.4], having ambulatory functional status [AOR = 5.38, 95%CI: 1.4-9.6] and didn't have other HIV-positive family member [AOR = 1.85, 95%CI: 1.2-2.9] increases the odds of delayed ART initiation. CONCLUSION AND RECOMMENDATION: The burden of delayed ART initiation is found to be high. The presence of OIs and other chronic problems, substance abuse, ambulatory functional status, being male, and not having other HIV-positive family members were identified as significant predictors of delayed ART initiation. Special emphasis needs to be considered for those individuals with the identified risk factors.

1. Introduction

By the end of 2020, UNAIDS reported that nearly 37.7 million individuals were living with HIV/AIDS worldwide, of which 20.6 million (52.2%) reside in the Eastern and South African regions [1]. Ethiopia is one of the countries in this region that has a high HIV/AIDS-related morbidity and mortality rate, with over 670,000 people living with the disease and nearly 12,000 deaths by the end of 2019 [1, 2]. The combined use of ART has been the mainstay treatment and prevention option to control this catastrophic infection since the late 1980s. ART has also shown promising effects on the reduction of new HIV infections as well as HIV-related morbidity and mortality. According to the UNAIDS 2020 report, ART has contributed to a 30% and 42% reduction in new HIV infection and HIV-related mortality, respectively, since 2010 [1]. In order to boost the effect of ART on ending HIV epidemics by 2030, the World Health Organization (WHO) indeed launched a universal test and treat strategy in 2015 [3]. The universal test and treat (UTT) strategy is explained as the initiation of ART within seven days (including same-day) of confirmation of HIV status, regardless of the patient’s WHO clinical stage or CD4+ count [3-5]. Furthermore, Ethiopia adopted this UTT strategy in 2016 and has begun to implement it since then [5]. The Federal Ministry of Health (FMOH) in Ethiopia immediately revised its comprehensive HIV care and treatment guidelines, and subsequent training was provided for the health care professionals to create a common understanding on the way forward, and it is now universally practiced throughout 1,224 ART-service providing health facilities in the country [5].

The rapid initiation of ART has been found to have numerous positive effects on reducing HIV-related morbidity and mortality. It plays a pivotal role in increasing access to ART, ensuring maximal and durable viral load suppression, restoring and preserving immune function, improving quality of life, and preventing further transmission of HIV/AIDS [6-10]. Despite such remarkable benefits, the magnitude of delayed ART initiation is high, particularly in low-income settings, which continues as a major challenge for the success of UNAIDS 2030 ending HIV epidemic goals [11]. A study conducted in Taiwan immediately after the endorsement of the UTT reported that nearly 68.3% of the newly diagnosed HIV-positive individuals were initiated into ART within seven days of confirmation of diagnosis [6]. In Africa, a study conducted in Ekurhuleni District, South Africa, revealed that only 54% of HIV-positive people were initiated into ART within seven days of confirmation of diagnosis [12]. Likewise, related studies in South Africa and Zimbabwe found that approximately 40.1% and 65% of HIV-positive patients were enrolled in ART on the same day as their diagnosis, indicating that there is still a problem with early ART initiation [13, 14]. Though there is a paucity of evidence that directly investigates the burden of delayed initiation following the implementation of the UTT strategy in Ethiopia, a prior study conducted at Nekemte hospital, Western Ethiopia, showed that more than two-thirds (34%) of HIV-positive patients were enrolled in ART after seven days of diagnosis [15]. Another related study done in northwest Ethiopia revealed that only 41.9% of HIV-positive adults were initiated into ART on the "same day" of confirmation of diagnosis [16].

Delayed ART initiation is strongly associated with poor treatment outcomes, including lower immunologic response, poor virologic suppression, an increase in the incidence of OIs and other chronic problems, a high treatment failure rate, increased patient hospitalization, and, finally, an increase in the morbidity and mortality rate of HIV-positive patients [16-19]. People living with HIV/AIDS who didn’t know other ART users, had tuberculosis and HIV (TB/HIV) co-infection, visited traditional healers, had CD4 count > 351 cells/mm3, and had normal body mass index (BMI) status were more likely to have enrolled into ART lately than their respective counterparts [15, 18]. Furthermore, residence, educational status, marital status, age, alcohol abuse, distance from ART center, perceived susceptibility and severity towards HIV/AIDS, and perceived home-based care status significantly affects the time to ART initiation [11, 15–18, 20]. To overcome this problem, solutions such as continuous professional development on HIV/AIDS management protocols, timely updating of management guidelines, scaling up ART centers, providing client-centered follow-up systems, formulating fixed-dose combination ART regimens, and providing continuous health education and promotion activities were proposed and implemented worldwide [4, 5, 21]. Indeed, the HIV continuum of care model, which includes activities such as HIV testing for identified risk groups, prompt linkage of HIV positive people to ART, and monitoring viral suppression rate, was utilized to track and evaluate the performance of the universal test and treat strategy [5].

Despite such efforts, a significant portion of HIV-positive patients in low and middle-income countries have not been timely engaged into ART, and data on delayed ART initiation status in Ethiopia is limited. Hence, this study is intended to fill the gap by estimating the magnitude of delayed ART initiation with its predictor variables.

2. Methods and materials

2.1 Study design and period

Institution-based cross-sectional study was conducted among 400 individuals who were enrolled into ART from November 2016 to December 2020 in public health institutions of Bahir Dar city. The city is the area of the earliest ART service center in Amhara regional state whereby it starts providing ART care since 2003 initially in Felegehiwot comprehensive specialized hospital. It is located at 565 km Northwest of Addis Ababa, the capital city of Ethiopia. Currently, the city has around 11 (two hospitals and nine health center) functional ART centers. These ART centers offer services including early HIV-testing of risk groups, providing ART for HIV-Positive individuals and continuous follow-up of patients’ progress. According to the report of the Amhara Regional Health Bearou (ARHB) in Ethiopia, the city bears the highest burdens of HIV/AIDS patients load in the region by which nearly 14024 individuals were ever enrolled at those institutions for ART services since 2003. From the above figure, a total of 2822 HIV-positive patients were newly enrolled in to ART after the implementation of the treat-all strategy.

2.2. Study subjects

The source population for this study was all adults receiving ART after the test and treat era at public health institutions in Bahirdar city. The study population was all adults newly initiated into ART from November 2016 to December 2020 at public health institutions in Bahirdar city. People living with HIV/AIDS (PLHIV) who had TB/HIV co-infection at presentation, Cryptococcus meningitis, and individuals with an incomplete record of HIV diagnosis and initiation date were excluded from the study.

2.3 Sample size determination and sampling technique

The minimum sample size required to conduct this study was calculated by double population proportion formula through EPINFO version 7.2.3.1 software. Parameters such as 80% power, 95% confidence level, the proportion of outcomes in the unexposed group (25.8%), the proportion of outcomes in the exposed group (39.5%), and an odds ratio of 1.87 [15] were used, and finally, a sample size of 400 was estimated to complete this study. Study participants were selected by computer generated simple random sampling technique. Initially, the unique ART number of eligible HIV-positive patients were gathered from all ART centers, then exported to version 10 Microsoft excel, and finally, 400 individuals were selected through computer generated simple random sampling technique.

2.4 Study variables

The main dependent variable for this study is the occurrence of delayed ART initiation. Whereas, variables like age, sex, level of education, marital status, occupation, residence, catchment area, have HIV positive family member, having cell phone status, baseline CD4 count, baseline WHO clinical stage, baseline BMI level, baseline functional status, presence of OIs, baseline substance abuse status, and HIV disclosure status of HIV-positive patients were categorized as independent predictor variables.

2.5 Operational definitions

Time to ART initiation is the time interval in a day from the confirmation of HIV status till the patient is enrolled into ART. Universal test and treat strategy is defined as the rapid(within seven days) initiation of ART irrespective of patients WHO clinical staging as well as CD4+ cell counts [3, 5]. On the other hand, delayed ART initiation could be explained as the initiation of ART beyond seven days of confirmation of HIV status except for those who had either TB or Cryptococci meningitis opportunistic infections which requires differing of ART for two up to eight weeks to prevent serious adverse effects [4, 5]. The functional status of the patient is categorized as “working” if daily activities of Peoples living with HIV/AIDS was not altered due to illness, “ambulatory” if the patient was not fully working but was able to do minor tasks at home, and “bedridden” when the patient remained in bed most of the time [5]. BMI status was calculated by dividing body weight by height squared. It was classified as “Normal weight” when BMI level of patients is between (18.5–24.99 Kg/m2), underweight (BMI <18.5 kg/m2), and overweight (BMI ≥25kg/ m2) [5]. Disclosure is recorded as “yes” when one’s HIV positive status is informed to at least one individuals [5]. Individuals will be categorized as substance abused when the patient scores two or more on Cut down, Annoyed, Guilty, and Eye-opener (CAGE) substance abuse screening tool [22].

2.6 Data collection instrument and procedures

The data abstraction tool was adapted from the Ethiopian FMOH ART follow-up, the patient intake, and monitoring formats. The data was collected by three BSc Nurse Professionals under the close supervision of one master’s in public health expert. To assure data quality, one day training was given for both data collectors and supervisors about the purpose of the study, the way to extract relevant data, and ensure the confidentiality issue of the patient information. In addition, the consistency of the data abstraction checklist with the medical recording system was verified by using 10 randomly selected charts, and hence little modification was done on the formatting of the questionnaire.

2.7 Data processing and analysis procedures

The data was initially coded, entered into Epi data version 4.6.0 and simultaneously exported to SPSS version 26 software for further statistical analysis. Before proceeding to descriptive and inferential analysis of the data, missing records for variables like BMI, occupational status, educational status, and CD4 levels were handled and managed using the multiple imputations missing data management method. Then, a sensitivity analysis was executed to check the consistency of the output of the model with original and imputed data.

The data was summarized using the median with interquartile range (IQR) for continuous variables and proportions for categorical variables, respectively. Moreover, tables and graphs were also used to present data. Both simple binary and multivariable binary logistic regression was fitted to identify the predictors of delayed ART initiation. A total of nine (09) variables with a P-value of < 0.25 in simple binary logistic regression were fitted to a multivariable binary logistic regression model, and finally, five variables with p-value of <0.05 were considered as significant predictors of delayed ART initiation. The backward likelihood ratio elimination method was used to select predictor variables by removing the least contributing variables until all variables left in the model are significantly associated with the outcome variable. “Hosmer and Lomeshow” goodness of fit test was used to assess the overall goodness of the model with the fitted data. In addition, the receiver operating characteristic curve (ROC curve), which is produced by plotting the sensitivity against 1-specificity (false positivity rate) of the model was used to check the discriminative power of the final model. The model was classified as "excellent" in discriminating patients with and without delayed ART initiation when the area under the curve (AUC) value in the ROC is ≥70%.

2.8 Ethical considerations

An ethical approval letter was obtained from the Institutional Review Board (IRB) of Bahirdar University, College of Medicine and Health Science with a protocol number of 058/2021. Because the study was conducted retrospectively from a patient’s medical record, informed consent from patient was waived; instead, a supportive letter was sent from the IRB to each public health institution in Bahirar Dar City. Then a permission letter that ensures the use of patients’ charts as a source of information was obtained from the directors and ART clinic focal person of those health institutions, respectively. During data collection and entry, patient identifiers (patient’s medical registration number (MRN)) were replaced by new identification numbers or codes. Besides, the collected data was treated with confidentiality.

3. Result

3.1 Socio demographic characteristics

A total of 400 HIV-positive adults who were enrolled in ART following Test and Treat strategy were included for final analysis. Of these, more than half of them were females (57.3%), married (51.5%), and had HIV-positive family members (59.0%). The median age of the study participants was 32 years, with an interquartile range (IQR 40–27) of years. Regarding to their residence, around 229 (57.3%) of individuals reside beyond their catchment area (Table 1).

Table 1

Socio-demographic characteristics adults receiving ART at public health institutions in Bahir Dar city, Northwest Ethiopia,2022.

Variables (N = 400)	Category	Total frequency	%
Sex	Male	171	42.8
	Female	229	57.3
Age category	Age 15–24	61	15.2
	Age 25–34	176	44.0
	Age 35–45	128	32.0
	Age >45	35	8.8
Marital status	Married	206	51.5
	Not Married	194	48.5
Educational status	No formal education	117	29.3
	Primary education	99	24.7
	Secondary	106	26.5
	Tertiary and above	78	19.5
Occupation	Daily-laborer	82	20.5
	Farmer	24	6.0
	Merchant	59	14.8
	House-wife	67	16.8
	Employed	119	29.8
	Student	23	5.8
	1Others	26	6.5
Had positive family member	Yes	164	41.0
	No	236	59.0
Reside on catchment area	Yes	229	57.3
	No	171	42.7
Having cell-phone	Yes	358	89.5
	No	42	10.5

Others:- include those individuals who are drivers and do not have jobs, N- sample size and %- Indicates column percentage

3.2 Clinical, treatment-related and behavioral characteristics

The median CD4 and BMI status of the study participants during their enrollment to ART was 316 cell/mm3 with an interquartile range (IQR 502- 148cell/mm3) and 20.42 with IQR (22.67–18.59) respectively. On the other hand, nearly 13% of individuals abused at least one of the common substances, including chat, cigarettes, and alcohol. About one fourth (26%) of the study participants had at least one OIs. Indeed, a substantial number of individuals (8.5%) had at least one additional chronic coexisting problem (Table 2).

Table 2

Clinical and behavioral characteristics of adults receiving ART at public health institutions in Bahir Dar city, Northwest Ethiopia, 2022.

Variables (N = 400)	Categories of a variable	Total frequency	%
Baseline BMI Status	Under weight	94	23.5
	Normal weight	270	67.5
	Over weight	36	9.0
Baseline CD4+ count	< 200	118	29.5
	From 200–499	149	37.3
	Greater than 500	133	33.3
Baseline WHO clinical stage	WHO stage I&II	308	77.0
	WHO stage III&IV	92	23.0
functional status	Working	317	79.3
	Ambulatory	66	16.5
	Bedridden	17	4.3
History of OIs	Yes	104	26.0
	No	296	74.0
Presence of Chronic diseases	Yes	34	8.5
	NO	366	91.5
Substance abuse status	Yes	54	13.5
	No	346	86.5

%- indicates column percentage, BMI- Body Mass Index, OIs- opportunistic infections

3.3 Magnitude of delayed ART initiation

A total of 156 (39%) HIV-positive adults were categorized as having delayed ART initiation (Fig 1). However, the proportion of delayed ART initiation varied substantially across HIV-positive adults based on their socio-demographic, clinical, and treatment-related characteristics.

Fig 1

Delayed ART initiation status of adults receiving ART following Test and Treat strategy at public health institutions in Bahir Dar city, Northwest Ethiopia, 2022.

3.4 Predictors of delayed ART initiation

In the final multivariable logistic regression model, at 5% of the level of significance, the following six variables, namely sex, having HIV-positive family member, substance abuse, chronic disease, OIs, and functional status of the patients, were found to be significant predictors of delayed ART initiation. Accordingly, the odds of delayed ART initiation is nearly two times in males than females (AOR 1.78:- 95% CI 1.13–2.8). HIV positive individuals who didn’t have at least one HIV positive family member had nearly two or more odds of delayed ART initiation than individuals who knew at least one family member. The odds of delayed ART initiation among individuals who had at least one other chronic diseases was 3.7 times (AOR 3.7, 95% CI:1.7–8.3) than individuals with no other chronic diseases. Substance abused HIV-positive individuals were 3.79 times more at risk of having delayed ART initiation than their counterparts (AOR 3.79, 95%CI: 1.9–7.4). The odds of delayed ART initiation among individuals with ambulatory functional status (AOR 5.38, 95%CI: 1.4–9.6) was nearly five-times greater than among individuals with working functional status (Table 3).

Table 3

Bivariable and multivariable logistic regression analysis result of delayed ART initiation among adult receiving ART at public health institutions in Bahir Dar city, Northwest Ethiopia, 2022.

Variable (N = 400)	Category	Outcome status		COR [95% CI]	AOR [95%CI]	p-value
		Delayed initiation	Early initiated
Sex	Male	83	88	2.02 (1.34–3.03) *	1.99(1.26–3.16) **	0.01
	Female	73	156	1	1
Age category	Age 15–24	21	38	0.39 (0.25–1.71)
	Age 25–34	63	115	0.65 (0.27–1.53)
	Age 35–45	61	78	0.92 (0.38–2.2)
	Age >45	11	13	1
Marital status	Married	78	128	1
	Not Married	78	116	0.63 (0.74–1.64)
Educational status	No formal education	47	70	0.81(0.56–1.93)
	Primary education	42	57	0.59 (0.64–2.16)
	Secondary	37	69	0.62 (0.47–1.57)
	Tertiary and above	30	48	1
Occupation	Daily-laborer	24	58	1
	Farmer	14	10	3.38 (1.32–8.67)*
	Merchant	26	33	1.9 (0.95–3.84)
	House-wife	26	41	1.53 (0.77–3.03)
	Employed	44	75	1.42(0.78 2.59)
	Student	11	12	2.21(0.86–5.70)
	Others	11	15	1.77(0.71–4.41)
Had HIV-positive family member	Yes	48	116	1	1
	No	108	128	2.04 (1.33–3.11)*	1.85(1.2–2.9) **	0.01
Reside on catchment area	Yes	148	81	1
	No	96	75	1.42 (0.47–1.05)
Having Cell _phone	Yes	214	144	1	1
	No	30	12	0.59 (0.29–1.12)	0.5 (0.2–1.11)	0.09
Baseline BMI status	Under weight	57	37	1
	normal weight	161	109	1.04 (.645–1.685
	Overweight	26	10	0.59 (0.26–1.370)
Baseline CD4+ count	< 200	43	75	1
	From 200–499	54	95	0.99 (0.6–1.64)
	Greater than 500	59	74	1.39 (0.837–2.31)
Baseline WHO clinical stage	Stage I and II	115	195	0.67 (0.41–1.06)
	Stage III and IV	41	49	1
Functional status	Working	136	198	1	1
	Ambulatory	14	41	1.82 (0.63–5.3)	5.38(1.4–9.6) **	0.01
	Bedridden	6	5	1.82 (0.46–7.12)	0.95 (0.2–3.67)	0.94
History of OIs	NO	106	190	1	1
	Yes	50	54	1.66 (1.05–2.6)**	2.5 (1.4–4.6) **	0.03
Presence of Chronic diseases	NO	133	233	1	1
	Yes	23	11	3.67(1.73–7.75) *	3.7(1.7–8.3) **	0.01
Substance Abuse	Yes	225	125	1	1
	No	22	35	3.42 (1.88–6.24) *	3.79(1.9–7.4) **	0.01

1-Reference category, COR -crude odds ratio, AOR-adjusted odds ratio, CI- confidence interval,

*—statistically significant with simple binary logistic regression,

** -statistically significant at multivariable regression model

3.5 Assumption of binary logistic regression

Hosmer and Lomeshow goodness of test for multi logistic regression revealed that the model constituting such variables is good to predict the outcome variable i.e delayed ART initiation (P-value = 0.639). Indeed the discrimination power of the model was checked by ROC analysis and the area under the curve value (AUC value = 0.744 (74%)) illustrated that the model is excellent to discriminate individuals with delayed ART initiation (true positives) and individuals without delayed ART initiation (Fig 2).

Fig 2

ROC curve graph showing model discrimination power towards delayed ART initiation among adults receiving ART at public health institutions in Bahir Dar city, Northwest Ethiopia, 2022.

4. Discussion

There is a dearth of studies that address the time of ART initiation following the implementation of the Test and Treat strategy in Ethiopia. This study has found that about 39% (95%CI: 34–44%) of HIV-positive adults were initiated into ART beyond seven days. This finding is in line with recent studies conducted in Nekemete, Western Ethiopia [15], Ekurhuleni district in South Africa [12], On the other hand, this finding is slightly lower than a study conducted in Taiwan [6], which might be due to a difference in socioeconomic and educational status between the two countries.

In the current study, male HIV-positive individuals had higher odds of being delayed for ART initiation than their counterparts. In the current study, male HIV-positive individuals had a higher odds of being delayed for ART initiation than their counterparts. This finding is congruent with previous studies conducted in Nekemte [15] and South Africa [13]. The possible elucidation for this might be the fact that women’s decision to immediately seek ART will be highly influenced by physician’s counseling than males [23]. On top of the above, there is a claim that giving special attention to maternal and child health services by both global and national health policies may result in females getting stronger counseling, education, and monitoring by health care providers when compared to males, and this finally might influence women’s decision to early engage in ART.

When compared to patients without documented baseline OIs, HIV-positive people with OIs had a two-fold increased odds of delaying ART initiation time. This finding is in parallel with prior studies conducted at South Wollo Zone and Nekemte Hospital in Ethiopia [15, 24]. Because of worries about potential drug interactions, toxicities, poor adherence owing to pill burden, and systemic inflammatory reconstitution syndrome (SIRS), both the patient and the healthcare provider may decide to delay ART initiation. Nevertheless, the latest evidence and guidelines recommend the immediate initiation of ART except for patients with TB/HIV co-infection and Cryptococcus meningitis [5].

The risk of delayed ART commencement is nearly four times greater among HIV-positive individuals with chronic problems than their counterparts. This finding is in line with previous systematic review and meta-analysis studies conducted before the current test -and -treat era in Ethiopia [20]. The possible justification for this might also be due to unjustified fears by patients and even by health professionals about drug-drug interactions, high pill burdens, and toxicities happening as a result of treating both chronic diseases simultaneously. This implies that healthcare providers’ experience in the management of chronic diseases and comorbidities of HIV/AIDS should be continuously updated, so patients may receive adequate education and counseling about it. This further implies that continuous professional development of healthcare providers through expanding on-the-job training, and short-term and long-term capacity-building sessions needs to be strengthened.

The odds of delayed ART initiation among individuals who don’t have other HIV-positive family member are higher than individuals with other HIV-positive family member. The possible elucidation of this link might be due to the fact that HIV-positive people with other HIV-positive family members may get better reinforcement and social support and then build confidence to engage in ART sooner than their counterparts [25].

HIV-positive individuals who were abused for at least one of the common substances (chat, alcohol, and cigarettes) had higher odds of being late on ART initiation. The possible explanation for this finding might be due to the fact that substance abuse has an overwhelming effect on each aspect of HIV/AIDS. Substance abusers, for example, will experience cognitive impairment, which will further hamper their decision-making abilities and rigorous adherence to their ART therapy. The finding is consistent with literature conducted in the previous era in South Wollo and Myanmar [24, 26].

The time it takes for HIV-positive people to start taking antiretroviral therapy (ART) has a significant association with their baseline functional status. This is congruent with a study done in South Africa [13]. Patients who were ambulatory, for example, had a higher chance of being delayed in receiving ART when compared with working individuals. It could be driven by the fact that HIV-positive individuals with working functional status believe they are healthy enough and that initiating antiretroviral therapy (ART) while they are relatively healthy may not be beneficial.

4.1 Limitation of the study

We acknowledge that our findings should be considered in light of the following limitations: Because of the incompleteness of the records, we can’t measure the effect of healthcare provider and institution-level factors on the ART initiation time of HIV-positive adults. The data was collected at a single point in time; a lack of temporal relationship might happen between some predictor variables and the outcome variable.

5. Conclusion and recommendation

In this test-and-treat era, the magnitude of delayed ART initiation is significantly high. Males, in particular, had a high rate of delayed ART initiation compared to their counterparts. Moreover, the presence of OIs and chronic problems, substance abuse, ambulatory functional status and not knowing other HIV-positive family members were identified as significant predictors of late ART initiation. This study highlighted the importance of providing intensive counseling and education about the early invitation of ART for those risk groups. Further research shall be undertaken to explore the effect of other socio-economical, behavioral, institutional, and contextual factors on delayed ART initiation.

(RAR)

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7 Mar 2022

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Reviewer #3: Partly

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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3. 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: No

Reviewer #2: Yes

Reviewer #3: No

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4. 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: Yes

Reviewer #2: No

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: Abstract:

1) Please avoid abbreviations in abstract (e.g. "G.C" in line number 3)

2) inconsistent writing pattern of 95% CI (some have hyphen and some doesn't have hyphen between the two values)

3) Better to mention what is delayed ART initiation in abstract (e.g. delayed (ART initiation more than seven days from HIV confirmation))

Introduction:

1) Need a brief backgroud or context of the study sites, such as when was the policy for test and treat endorsed in ethiopia, current practice and procedures for test & treat strategy and challenges... also about a brief on HIV epidemic of ethiopia as well as study sites.

2) line number 33, please use correct tense for "define"

3) line number 41, what is meant by the phrase "ART rapidly" ? same day or within 7 days?

Methods and Materials

1) line number 116, please write more about data verification: need to write how to sample these 10 charts (e.g. random picking or something else?)

2) Data processing and analysis procedure : Need to tell if there was missing data or not and how missing data were handled ?

Results

1) line number 142: what is meant by "positive" , please re-phrase as "HIV positive" to be more specific

2) Table 1 and Table 2: To add foot note about % whether it is a row percentage or column percentage

3) line number 151: writing pattern of IQR should be consistent with others (e.g. Q1 - Q3). in line 151 the pattern is Q3 - Q1

4) line number 154: use of wording "significant number" should be rephrased. We can't say significant by seeing only the absolute numbers and percentages only

5) line number 180 & 181 : the reference is working functional status , so, it is better to rephrase this sentence (it is written bedridden as reference)

Figure 2 Title:

To write long form of FHCSH as figures should be stand alone and abbreviation should not be used.

Both Figures and Tables

- to add footnotes for every abbreviations used in figures and tables

Reviewer #2: Manuscript Number: PONE-D-21-39787

Manuscript Title: Delayed ART initiation in “Test and Treat era” and its associated factors among adults receiving ART at Public health institution in Northwest Ethiopia: A multicenter cross-sectional study

Abstract

Page 2, line 2: The background explanation is different from the first page of article.

Page 2, line7: In the patient’s chart, is HIV testing date is available? It is not clearly mentioned.

Page 2, line 14: Definition of chronic problem is not clear. Why social support is recommended?

Introduction

It would be better to include HIV morbidity and mortality data of Ethiopia.

Page 3, line 43 & Page 4, line 47: Reference 10,11 & 13, majority of patients received ART initiation within a day of diagnosis confirmed. May need to revise the sentences to show still need to reach the global target because in this study delay is defined for >7 days of diagnosis

Methods and Materials

It would be better to explain ART diagnosis and ART initiation processes. It can be performed at the same center or is there any patient take ART test from different places enrolled into ART service center? Can delay in ART initiation happen due to service factors?

Study Design and Period

Page 4, line 67: The author mentioned that study participants were 400 participants enrolled into ART from November 2016 to October 2020. But in page, line 78, the study population was selected from the record from November 2016 to December 2017. The study inclusion period is different.

Study Subjects

Page5, line 79: Why study subjects were selected from two years periods 2016-2017? Is there any changes in ART health care system after 2017? Using 2016-2017, the result may not reflect to the current situations? Adult is >15 years?

Page 5, line 80: Why TB/HIV coinfection at presentation, Cryptococcus meningitis infection are excluded from the study?

Sample size determination and Sampling technique

Page 5, line 85: It would be better to include the reference of using 25.8% proportion of outcome in unexposed group and Odds ratio of 1.87 for sample size calculation.

Operational Definitions

Page 6, line 98: It would be better to use delay initiation of ART for outcome definition.

Result

The name of outcome variable “Delayed ART initiation” like title should be better to use constantly in tables and texts.

Line 160, page 10: In Table 1 and Table 2, only overall frequency and percentage of all variables should be better to be mentioned without showing the classification of delay and early initiation of ART. Because data is duplicated with Table 3. (OR) Otherwise, the information of Prevalence of late ART initiation should be better presented first in the result before the Sociodemographic characteristics of participants. What is median time to ART initiation?

In Table 1, Had positive family member or know other HIV positive family member??

In Table 2, categorization of BMI is underweight or undernourished?? It would be better to use the same. Presence of Chronic Problems or chronic health problems?? It is not clear. Need foot note for BMI, OI etc

In Table 2 and table 3, Presence of chronic problem and History of chronic diseases?? Variables names are changed. It would be better to use constant variable name through the paper.

In Table 1 and table 3, Had positive family member or HIV-positive family member or know other HIV positive family member?? It would be better to use constant variable name through the paper.

In Table 1 and table 3, Reside on Catchment area or Catchment area Residence?? It would be better to use constant variable name through the paper.

Serial of variable names in Table 3 should be the same with that in Table 1 and Table 2. In table 3, Marital status should be before education like in Table 1. The same for Reside on Catchment area. In table 3 bivariate association of BMI and delay was not included.

In Table 3, what is ** in COR and what is COR and AOR? “-“signs should be shown between numbers showing 95% CI.

Table 3, In variables of HIV-positive family member, History of OIs, History of chronic diseases and Substance, first row should be used for reference by changing row positions. It is difficult to interpret the data. It can lead to misinterpretation.

Figure 2. How ROC curved is developed and how it is useful for your study should be written in data analysis portion. It should not be 2021 in Figure 2 title. Page 12 line 189, AOC or AUC??

Page 10, line 160: Prevalence of late ART initiation: It is better to use constant outcome variable name ”Delayed ART initiation”. Prevalence?

In Figure 1, I think I should not be 2021. Name of outcome variable should be constant with that in title. If median time taken and proportion of delay in ART initiation are shown in texts, figure 1 may not need.

Page 10, line 168: What is Predictors of loss to follow up?

Discussion

May to need to discuss about generalizability of the result. Why social support is recommended for reducing delay in this study? The result can reflect to the current situation?

Reviewer #3: conclusion is partly okay, but need much more evidence for what the authors brought up in the discussion session : some reasons / sentences went quite off. See line 211,226, 228, 240 (Please see the attached reviewed file for more details). Discussion and conclusion would be better if the authors can point out the limitations and generalisability of their research. Though the statistical analyses were performed appropriately and rigorously, the writing needs to be modified - for eg., instead of the word "bivariable logistic regression", it will be much correct to use "simple binary logistic regression for each potential predictor". Should have provided more details in the statistical analyses section so that the readers could understand the backward elimination process before going deep dive into the result section.

In this draft, the authors claimed that all relevant data are within the manuscript - which is true, but the data aren't fully available - this totally makes sense as this is a study of PLHIV where the study participants' confidentiality and privacy must be valued / taken care of.

There are some grammar mistakes and spelling errors, and found some necessary words and/or symbols dropped out of the sentences. So, the English of this draft will be acceptable after fixing up those mistakes/errors. (Please see the attached file for more details).

**********

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.

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Reviewer #1: No

Reviewer #2: Yes: Kyaw Ko Ko Htet

Reviewer #3: Yes: Nilar Aye Tun

[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.]

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Submitted filename: Journal_reviewPONE-D-21-39787.docx

Click here for additional data file.

Submitted filename: PONE-D-21-39787_reviewer_v1 27 Feb.pdf

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6 Apr 2022

A rebuttal letter which address the points raised by academic editor and reviewers

Manuscript Number: PONE-D-21-39787

Manuscript Title: Delayed ART initiation in “Test and Treat era” and its associated factors among adults receiving ART at Public health institution in Northwest Ethiopia: A multicenter cross-sectional study

1.Comments and their responses for points raised by academic editor

1. Please ensure that your manuscript meets PLOS-ONE’s style requirements, including for file names?

�  We the authors thoroughly observe PLOS –ONE formatting .pdf files and try to comply with it through the whole manuscript

2. Please provide additional details regarding participants consent. in the ethics statement in methods and online submission forms ,please ensure you have specified what type of consent you obtained .

�  As noted in the method section of the abstract, the research is conducted ART service providing institution by using patient’s medical record (secondary data) as a source of information for data collection. Since we didn.t collect the information directly from patients, consent directly from patients is waived. Whereas, Ethical approval letter is obtained from IRB of Bahiradr university, followed by a permission letter which ensures the use of patients chart as source of information was obtained from director and ART focal-person of each sites. Then the data is collected from patients chart using the permission letter. ( page 9, line# 176)

3. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found?

Answer- Since the study is conducted on peoples living with HIV AIDS (PLHIV), we share the minimal data set by keeping potentially identifier of the patient to keep confidential (Minimal data set file.

4. Please Amend either the abstract on the online submission form or the abstract in the manuscript.

�  Response- We accept and made them uniform

2. Reviewer #1 . Abstract

1. Please avoid abbreviation like G.C in Abstract -- Corrected as suggested ,Page 2, line#4-5

2. inconsistent writing pattern of 95% CI (some have hyphen and some doesn't have hyphen between the two values)- Corrected as suggested , Page 2,line# 16-19

3. Better to mention what is “delayed ART intimation in the abstract)- In order to maintain the flow of idea with the previous sentence , we prefer to explain about the “ test and treat strategy” including its definition i.e individuals will easily comprehend the initiation of the study. --- page 2#, Line # 3 -6

Introduction section

1. Need a brief background or context of the study sites, such as when was the policy for test and treat endorsed in Ethiopia, current practice and procedures for test & treat strategy and challenges. Also about a brief on HIV epidemic of Ethiopia as well as study sites.? Answer- Accepted and we try to incorporate such important ideas on introduction part , Page 3, Line# 30-32, 41-46,

2. In line # 33 ,please use the correct word for “define”-

Answer- Accepted and modified accordingly , page3, Line# 39

3. ) line number 41, what is meant by the phrase "ART rapidly" ? same day or within 7 days?

Response- Accepted and modified as “within seven days of confirmation of diagnosis , page 4, line # 59

Method and material section

1. Line number 116, please write more about data verification: need to write how to sample these 10 charts (e.g. random picking or something else?)---

Response:- In order to check the consistency between the data abstraction checklist and recording system on patients chart , we use 10 randomly selected charts which are excluded for the final study , page 8,line#151

2. Need to tell if there was missing data or not and how missing data were handled ?)- Response- Accepted and we just incorporate how we handle missed data. Before proceeding to descriptive and inferential analysis of the data, missed records for variables like BMI, occupational status educational status, and CD4 levels were handled and managed. Initially, we observe the missing patterns of the variables and we conclude that there is no clear missing pattern, hence we use multiple imputations missing data management method and impute those data’s accordingly. Then, sensitivity analysis was executed to check the consistency of the output of the model with original and imputed data ( Page 8, 155-159)

Result section

1. line number 142: what is meant by "positive" , please re-phrase as "HIV positive" to be more specific

Response- rephrased as HIV-positive, page 10, line 189

2. Table 1 and Table 2: To add foot note about % whether it is a row percentage or column percentage-

Response - Accepted and modified accordingly including %( which it indicates the column %), table 1 on page 10, table 2 on page 11

3. Line#151, writing pattern of IQR is not consistent-

Response- Accepted and corrected accordingly, page 10 line 190, page 11 line 197

4. Line number 154: use of wording "significant number" should be rephrased. We can't say significant by seeing only the absolute numbers and percentages only-

Answer- Accepted and rephrased it as “substantial number of individuals” ( page 11, line 200)

5. line number 180 & 181 : the reference is working functional status , so, it is better to rephrase this sentence (it is written bedridden as reference)-

Answer-Accepted and reference for both of them is working functional status ( Table3, page 14)

Figure

�  To write long form of FHCSH as figures should be stand alone and abbreviation should not be used.- Response- Accepted and modified accordingly , Figure 02, page 15

Figures and footnote-

�  to add footnotes for every abbreviations used in figures and tables -

Response- Accepted and foot notes are added in each figure and table , (Table 1.2.3 on page 10,11 and 13

3. Reviewer # 2.

Abstract section

1. Page 2, line 2: The background explanation is different from the first page of article) –

Response- we accept it, and we simultaneously try to make the two ideas consistent. Currently, the background of the abstract almost compatible with the first paragraph of the introduction. Both of them tell about the effects of ART on HIV/ AIDS and its initiation time in this test and treat era. – (Page 2 line 3 and page 3, line 39-43)

2. Page 2, line 7( Page 2, line7: In the patient’s chart, is HIV testing date is available? It is not clearly mentioned.) -

Response - Yes, the patient medical record( chart) includes history sheet, progress sheet, nursing sheet and ART intake and monitoring formats where by Patients HIV testing data and result are mainly documented in history sheet as well as ART intake and motoring form ( page 2,line 13) .

3. Page 2, line 14 (Page 2, line 14: Definition of chronic problem is not clear. Why social support is recommended?)-

Answer- Chronic problem is modified in to chronic diseases. Patient is said to has chronic diseases whenever they have a documented history one or more of the following diseases such as, diabetes mellitus, Hypertension (HTN), chronic heart dieses (CHD) , Stroke Chronic obstructive pulmonary diseases(COPD),asthma, chronic liver and kidney diseases and cancer in any of the body parts.

Why social support is recommended-

Response - The recommendation was modified as ‘ Special emphasis shall be considered for individuals with identified risk factors in order to make recommendation short and concise. However, we initially recommend social support because as it is indicated on discussion part, the likely explanation for delayed initiation for those individuals who didn’t have other HIV-positive family member and who is abuse of substance is lack of social support from the family as well as the significant others . ( page 3,line 25-27)

Introduction section

1. It would be better to include HIV morbidity and mortality data of Ethiopia.

Response - Accepted and incorporated ( page 3,line 32-34)

2. Page 3, line 43 & Page 4, line 47: Reference 10,11 & 13, majority of patients received ART initiation within a day of diagnosis confirmed. May need to revise the sentences to show still need to reach the global target because in this study delay is defined for >7 days of diagnosis -

Response- The sentence was having edition problem and it is also revised as follows to clearly show as there’s gap to reach WHO target. In Africa, a study conducted in Ekurhuleni District, South Africa, revealed that 54% of HIV-positive people were initiated into ART with the UTT strategy[12] . Similarly , related studies in South Africa and Zimbabwe reported that, only 40.1% and 65% of HIV-positive individuals were initiated into ART on the same day of confirmation of HIV/AIDS, respectively (page 4, line #55)

Methods and Material section

1. It would be better to explain ART diagnosis and ART initiation processes. It can be performed at the same center or is there any patient take ART test from different places enrolled into ART service center? Can delay in ART initiation happen due to service factors?

Response - we try to explain about the ART diagnosis and ART initiation processes. “ All ART centers provide ART service starting from early diagnosis of HIV positive adults, immediately linking them to ART , monitoring their progress through continuous follow-up” page 6 , line 94-96

Study Design and Period

1. Page 4, line 67: The author mentioned that study participants were 400 participants enrolled into ART from November 2016 to October 2020. But in page, line 78, the study population was selected from the record from November 2016 to December 2017. The study inclusion period is different.

Response—The study participants were selected from November 206 to December 2020 not December 2017. This is an edition problem and we revised it accordingly

( page 5, line 901 and page 6,line# 106)

�  Page5, line 79: Why study subjects were selected from two years periods 2016-2017? Is there any changes in ART health care system after 2017? Using 2016-2017, the result may not reflect to the current situations?

Response- As noted above, the study participants were selected from November 206 to December 2020 not December 2017. This is an edition problem and we revised it accordingly ( page 6, line 106).

Adult is >15 years? Response- In Ethiopian health care management system including HIV management protocol , adults were considered as those individuals whose age is ≥ 15 years of age .

2. Page 5, line 80: Why TB/HIV coinfection at presentation, Cryptococcus meningitis infection are excluded from the study?

Answer- Since the latest Ethiopian or World health organization HIV management guideline recommends differing ( extending) of ART initiation time for at least 2-8 weeks for patients with TB co-infection, and 4-6 weeks for patients with Cryptococcus meningitis to prevent serious drug reactions as well as immune reconstitution inflammatory condition. Therefore, we the exclude those patients not to have a biased finding ( which results overestimation of the true finding) . (page 7 ,line 133) and Reference # 4 and 5

Sample size determination and Sampling technique

3. Page 5, line 85: It would be better to include the reference of using 25.8% proportion of outcome in unexposed group and Odds ratio of 1.87 for sample size calculation. Response -Accepted and referenced accordingly ( page 6,line 114))

4. Page 6, line 98: It would be better to use delay initiation of ART for outcome definition.- Response- Accepted and operationalized ( page 7 ,line131)

Result section

1. The name of outcome variable “Delayed ART initiation” like title should be better to use constantly in tables and texts--- Accepted (page 7,121)

2. Line 160, page 10: In Table 1 and Table 2, only overall frequency and percentage of all variables should be better to be mentioned without showing the classification of delay and early initiation of ART. Because data is duplicated with Table 3. (OR) Otherwise, the information of Prevalence of late ART initiation should be better presented first in the result before the Sociodemographic characteristics of participants. What is median time to ART initiation?-

Response - Accepted and revised according to the comment ,and data duplication is minimized ( page 10, line 192 , table 1 and page 11,line 202 ,,table 2)

�  What is median time- Response - The median time to ART initiation was 5.5 days with IQR( 10.00- 1.00 days) . . page 12,,line#209

3. In Table 1, Had positive family member or know other HIV positive family member??- Response- as individuals who” Had HIV-positive family member” is the correct one and used consistently – ( table 1, page 10,line 192)

4. In Table 2, categorization of BMI is underweight or undernourished?? It would be better to use the same. Presence of Chronic Problems or chronic health problems?? It is notclear. Need foot note for BMI, OI etc ---

Response- Accepted and modified accordingly:_ BMI categorization is underweight , normal weight and overweight and Chronic problems is modified into chronic diseases consistently )( Tale 2, page 11,line 202)

5. In Table 2 and table 3, Presence of chronic problem and History of chronic diseases?? Variables names are changed. It would be better to use constant variable name through the paper. ---

Response- Accepted and revised accordingly ( table 2, page 11 and table 3,page 13,line

6. In Table 1 and table 3, Had positive family member or HIV-positive family member or know other HIV positive family member?? It would be better to use constant variable name through the paper. ---

Response -As noted above Accepted and Revised accordingly ( table 1 and 3)

7. In Table 1 and table 3, Reside on Catchment area or Catchment area Residence?? It would be better to use constant variable name through the paper.

Response- Accepted and revised accordingly ( reside on catchment area is the correct one) ( Table 1 and Table 3)

8. Serial of variable names in Table 3 should be the same with that in Table 1 and Table 2. In table 3, marital status should be before education like in Table 1. The same for Reside on Catchment area. In table 3 bivariate association of BMI and delay was not included.---- Response- The order of marital status and educational level was made to be uniform across tables ( Table 1 and Table 3 ), Bivariable analysis result of BMI was included in the revised manuscript which was missed unintentionally on first draft. ( Table 1,2and 3)

9. In Table 3, what is ** in COR and what is COR and AOR? “-“signs should be shown between numbers showing 95% CI. ---

Response - Accepted and Revised Accordingly ( table 3,page 15)

10. Table 3, In variables of HIV-positive family member, History of OIs, History of chronic diseases and Substance, first row should be used for reference by changing row positions. It is difficult to interpret the data. It can lead to misinterpretation.-

Response - Accepted and Revised Accordingly ( Table 3, page 14 and 15)

11. Figure 2. How ROC curved is developed and how it is useful for your study should be written in data analysis portion. It should not be 2021 in Figure 2 title. Page 12 line 189, AOC or AUC??----

Response- The receiver operating characteristic curve (ROC curve), which is produced by plotting the true positive rate against the false positive rate of the model at various thresholds, was used to check the discriminative power of the model, and an area under the curve (AUC) value of greater than 70 was used to categorize the model as it can adequately classify individuals with and without the outcomes (Page 9, line 170)

12. Page 10, line 160: Prevalence of late ART initiation: It is better to use constant outcome variable name” Delayed ART initiation”. Prevalence?-

Response- Accepted and Revised Accordingly(

13. In Figure 1, I think I should not be 2021. Name of outcome variable should be constant with that in title.

Response - The Name of the outcome variable made to be constant throughout the paper

If median time taken and proportion of delay in ART initiation are shown in texts, figure 1 may not need. –

Response- We are interested in using a pie chart to explain the result of the study because graphs make the data more sound, easily interpretable, and attractive. In particular, if the category of the outcome is less than 3 or 4, pie charts will be recommended to present the data.,

14. Page 10, line 168: What is Predictors of loss to follow up? -----

Response- It is to say predictors of Delayed ART initiation , so it is revised accordingly ( page 13, line #215)

15. May to need to discuss about generalizability of the result. Why social support is recommended for reducing delay in this study? The result can reflect to the current situation----

Response- We incorporate the limitations of the study to provide a clear image of the generalizability of the study. Social support is recommended because the root cause why those high-risk individuals (those who do not have HIV-positive family members or substance abuse) end up with Delayed ART initiation will probably be a lack of strong family/social support, which motivates them to early engage in ART as well as retain them for a long time. Therefore ,we finally revised the recommendation as follows” Special emphasis shall be considered on those individuals with other comorbidities, and had not had other HIV-positive family member who will provide enough support on his/ her care”. ( page 18, line 302-307)

Reviewer # 3

Abstract

1. Page 2, line#7 - shouldn’t it be "public health institutions"?? Because you said multicenter cross-sectional study. Response- Accepted and revised ( page 1, line 10)

2. Page 2, line#10- Change bivariable in to “ simple binary logistic regression for each potential predictor would be a better usage.-

Response- Accepted and Revised ( page 1,line #13)

3. Page 2, line #20- recommendation goes off evidences—Modified to be aligned to the finding.

Answer- Accepted and t he recommendation was modified as ‘Special emphasis shall be considered for individuals with identified risk factors” in order to make recommendation short and concise. How ever, we initially recommend social support because as it is indicated on discussion part, the likely explanation for delayed initiation for those individuals who didn’t have other HIV-positive family member and who is abuse of substance is lack of social support from the family as well as the significant others . Therefore, we indirectly recommend as social support need to be strengthen. ( page 3,line 24)

Introduction section

1. page 2 ,line 29- what is 30 ?– Response – It is to say 30% ( page 3,line 36)

2. page 2, line 34 -What do you mean by this? 3 goals (or) 95 goals ??

Response- Those the sentence is modified to make short and precise, the three 95% 2030 targets of UNAIDS states 95% of HIV-infected individuals should know their status, 95 % of individuals who knew their result should get access to (ART), and 95 % of individuals on ART should achieve virology suppression .( Page 3,line 37-38)

3. page 2,line#33,37,43, 46, 48 and 61 grammar and punctuation issues were

Response- Thoroughly examine and edited by language experts and individuals who had good experience on writing scientific papers (page 3,line#39, page 4,,line 50,59,64,66)

4. Page 2, line 60 – at national level indicates which country—

Response – It is to indicate “Ethiopia”, so it is revised contextually (page 5,line 80)

Method Section

1. Page 5, line #79 - what do you mean by this? is it 2020 or 2017??-

Answer- It is edition problem and revised as 2020(page 6,line 106)

2. Page 5,line#79, state full words of abbreviations at initial and put in bracket if you use it before -

Response- Accepted and revised(page 6,line 105)

3. Page 5, line# 85- From which literature you took you sampling parameters -

Response- We miss to cite it initially and we revised it now (page 6,line 114)

4. Page 6,line# 95--- disclosure status of what? -

Response- Accepted and modified as “HIV disclosure status of HIV positive patients “(page 7,line 125)

5. Page 6, line 103 and 105- Citation for reference of BMI operational definition

Response- reference for operational definitions were addressed(Page 7,line 137)

6. Page 6,line 105- status of what –

Response- Revised as “Disclosure is recorded as “yes” when one’s HIV positive status is informed to at least one individual ( page 8,line 140

7. Page 7, line 117- provide more details of selection of variables for the models and more on backward elimination technique which were stated later in the results section.--

Answer - The authors try to incorporate more information’ on how variables were selected for the final multivariable model and how backward elimination technique is applied to obtain significant predictors of the outcome variable( page 9, 166-170)

Result section

1. Page 8,140 – 400( 100%)– No need to write % ---

Response- Accepted and revised ( page 10,,line #187)

2. Page 8, table # 1 foot note (rewrite this sentence to make grammatically correct)---

Response- Accepted and modified accordingly ( Page 11,line #192, table 1)

3. Page 9, line#155- spelling error-

Response- Accepted and revised ( page 11, line #198)

4. Page 10, line #160= You don't need 95% CI for your descriptive summary. Only state 156 (39%). ---

Response- Accepted and it is deleted( page 12, 11line 207)

5. Page 10, line 169- 173—better to take these points on analysis procedure part---

Response - As noted above we the authors try to incorporate these and other points on variable selection portion. On the other hand, we the authors consider that ideas on line# 171-173 were highly related with the result part because they entirely talks the names and categories of the variable which are identified as statistical predictors of delayed ART initiation. (page 9,line 162-166)

6. Page 12, Figure 2. Have you spell out FHCSH---

Respond- It is writing error and modified accordingly( page 16,figure 2)

Discussion section

1. Page 13, Line 111 and 112- how it is related to the previous sentence

Response- We just revise the explanation as follows to relate it with previous one and it is a hypothesis, not referenced.

�  “Giving special attention towards maternal and child health services by both global and national health policies may result in females getting stronger counseling, education, and monitoring by health care providers when compared to males, and this finally might influence women’s decision to early engage in ART” ( line 16, line#259 -263)

2. Page 13, line 120 – Citation needed—

Response- Accepted and done accordingly ( page 17,line 271)

3. Page 13, line 226- How?? Seems disconnected from your previous sentences.

Response- This sentence is used to indirectly indicate the root cause why patients with chronic problem would be delayed. As noted in preceding sentence, the possible explanation of delayed ART initiation for patients with other chronic diseases might be due to unjustified fear by the patients as well as by health care providers about drug-drug interactions, high pill burdens and toxicities happening as a result of treating both chronic diseases simultaneously. This suggests that health care providers professionals' knowledge of the management of chronic diseases comorbidities of HIV/AIDS may be insufficient, and patients may not receive adequate education and counseling about it. This further implies that continuous professional development of healthcare providers through expanding on job training, short term and long-term capacity building sessions needs to be strengthened. (page 17,line 275-282)

4. Page 13, line # 230,233, 236- Grammar issues

Response- Accepted and Corrected accordingly (page 18, line 281,285,286)

5. Page 13,line # 241-seems disconnected from your previous sentence.

Response- - Accepted and we decided to delete the sentence because it states about the future consequences of delayed initiation on substance abuse patients ( page 18,line 292)

Recommendation and conclusion section

1. Include limitation of the study before generalization-

Response- Accepted and we try to incorporate the main limitation of the study which has to be undertaken when we interpret and generalize the finding of the study. ( page 19, line #302)

N.B:- The English language issues were thoroughly assessed and edited by language experts working as a lecturer in university and individuals who have good experience in writing scientific papers and manuscripts. This goes to both editors and reviewers

Submitted filename: A rebuttal letter to commnets.docx

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30 May 2022

Submitted filename: Review2.docx

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1 Jun 2022

. Reviewer 1

Response- We, the authors, appreciate the time and effort you dedicated to providing feedback on our manuscript and are grateful for your constructive comments, which add significant value to the betterment of our paper

The data should be provided as part of the manuscript or its supporting information, or deposited in a public repository. For example, in addition to summary statistics, the data points behind means, medians, and variance measures should be available

Response— Thank you for your genuine comment. Regarding the availability of the data, we try to access all the relevant data on the manuscript and its supporting file( SPSS file 1) without any restriction. Additionally, summary statics measures like mean, and median were selected based on the nature of the data( categorical vs continuous), and considering the distribution ( skewed and normally distributed) for continuous variables. So that we are trying to adhere to this assumption.

Reviewer # 2.

Initially, we, the authors, appreciate the time and effort you dedicated to providing feedback on our manuscript and are grateful for your constructive comments, which add significant value to the betterment of our paper. We have incorporated the comments and suggestions given by you. The quality of the manuscript has significantly changed after we made a strong revision based on your recommendations. Those changes are highlighted in the manuscript and below are responses that address each question and concerns

I only have some minor comments.

In Title, should it be public health institutions? Because you included multicenter sites of public health institutions.

Response—Thank you for your marvelous comments, It is revised accordingly ( Title)

I think Title should not have an abbreviation such as ART.

Response—Accepted and revised accordingly

In abstract, it would be better to have a long explanation for ART, HIV, AOR,)

Response—Accepted and revised accordingly (page 2, line #2, page 2, line #16), but for HIV, we consider it as a well-known abbreviation so writing the full term of a well-known abbreviation will not have significant value.

In abstract, sometimes used two decimal for AOR but some used ARO. It would be better to be the same.

Response—Thank you for the insightful comment, we revised it to make it consistent across the manuscript( page 2, lines # 16-19)

In the background, page 3 line 42: for Ministry of Health in Ethiopia (FMOH), is it EMOH?

Response- Thank you and it is revised accordingly ( page 3, line #42)

In Figure 1. Piechart. It would be better to include (n=??)

Response- Accepted and revised accordingly ( page 12, Figure 1)

It is not clear how it is useful for ROC curve analysis. There is no discussion and it does not mention its usefulness in the methods session.

Response—Thank you for your genuine comment and we revised the manuscript to make it more clear. As stated in the result section, the ROC curve is used to differentiate the discrimination power of the model i.e if the graph of the ROC curve is above the diagonal line (the line where the area under the curve (AUC) value=0.5/50%), the model is enough to discriminate those who will have delayed ART initiation( True positives) with individuals who will have not delayed ART initiation ( false positives ). But if the AUR value is less than or equal to 50%, the model will not good to differentiate between Delayed ART initiation from those who have rapid ART initiation. ( page 9, lines 169-173)

In discussion, males were more likely to delay than females. I think the first two reasons were not clear. We could not have any evidence to support the assumption of physicians’ counseling women influences women decisions. It would be better to include a reference. And then, we could not have any information on several pregnancies in this study. Therefore, this explanation may be irrelevant to providing the reasons behind delays in male ART seeking.

Response— Thank you for your genuine comment and we revised it accordingly. besides, the followings are our views regarding the first justification of why males will have delayed ART initiation compared to females.

The first reason is linked with the women’s decision-making power not only in their home but rather in health care services is highly influenced by anybody else. Therefore, If females were tested positive, and immediately got adequate counsel to begin ART soon, they will have a higher probability to engage in ART soon compared to males( page 16, line#251).

�  The second justification was deleted

N.B:- The English language issues were thoroughly assessed and edited by language experts working as a lecturer in universities and individuals who have good experience in writing scientific papers and manuscripts. This goes to both editors and reviewers.

Submitted filename: Arebuttal letter for the second revsion .1.docx

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24 Jun 2022

Delayed ART initiation in “Test and Treat era” and its associated factors among adults receiving antiretroviral therapy at Public health institutions in Northwest Ethiopia: A multicenter cross-sectional study

PONE-D-21-39787R2

Dear Dr. Tesema,

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Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Manuscript Number: PONE-D-21-39787R2

Title: Delayed ART initiation in “Test and Treat era” and its associated factors among adults

receiving antiretroviral therapy at Public health institutions in Northwest Ethiopia: A

multicenter cross-sectional study

Thanks authors. I agree with your response. I have no comments on it.

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Reviewer #2: Yes: Kyaw Ko Ko Htet

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Submitted filename: PONE-D-21-39787R2.docx

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14 Jul 2022

PONE-D-21-39787R2

Delayed ART initiation in “Test and Treat era” and its associated factors among adults receiving antiretroviral therapy at Public health institutions in Northwest Ethiopia: A multicenter cross-sectional study

Dear Dr. Bantie:

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.

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