Depressive symptoms and associated factors among HIV positive patients attending public health facilities of Dessie town: A cross-sectional study.

BACKGROUND: Depressive symptoms are the most common psychiatric complication of Human Immunodeficiency Virus (HIV) infection. They are associated with poor drug adherence, treatment failure, and increase the risk for suicide. There was limited evidence of depressive symptoms among HIV-positive patients in the study area. So, this study aimed to determine the prevalence of depressive symptoms and associated factors among HIV-positive patients attending public health facilities of Dessie town, North-central Ethiopia, 2019.
METHOD: A cross-sectional study was conducted on 380 HIV-positive patients attending ART clinics in Dessie town, North-central Ethiopia, 2019. Samples were selected using systematic random sampling and the data were collected by using structured, pretested, and interviewer-administered questionnaires. Patient Health Questionnaire (PHQ-9) at a cut-off point of 5 was used to assess depressive symptoms. The data were entered by Epi data version 3.1 and analyzed by SPSS version 25. A binary logistic regression model was used to identify factors associated with depressive symptoms. The Adjusted Odds Ratio (AOR) along with a 95% Confidence Interval (CI) was estimated to measure the association. The level of significance was declared at a p-value of less than 0.05. RESULT: The prevalence of depressive symptoms among HIV positive patients was 15.5% (95% CI: (12.4%, 19.2%)). Age 40-49 years compared to 30-39 years (AOR = 2.96, 95% CI: (1.01, 8.68)), age ≥50 years compared to 30-39 years (AOR = 3.81, 95% CI: (1.05, 13.8)), having perceived stigma (AOR = 10.2, 95%CI: (4.26, 24.4)) taking medication other than Antiretroviral Therapy (ART) (AOR = 2.58, 95% CI: (1.25, 5.33)) and history of opportunistic infections (AOR = 5.17, 95% CI: (1.31, 20.4)) were factors associated with depressive symptoms.
CONCLUSION: The prevalence of depressive symptoms was low compared to previous studies. Age, perceived stigma, taking medication other than ART, and history of opportunistic infections were factors associated with depressive symptoms. Health education and counseling programs should be strengthened and target older patients, patients who took medications other than ART, patients who experienced perceived stigma and patients with a history of history opportunistic infections.

Introduction

HIV has become a major health challenge for the global population. Currently, it affects more than 37.9 million world population and 70% of patients were from sub-Saharan African (SSA) countries [1, 2]. In Ethiopia, it was estimated in 2018 that 399,000 of the urban population were living with HIV/AIDS [3].

Depressive symptoms are the fourth leading cause of disability affecting 350 million people worldwide [4, 5]. It disproportionately affects people living with HIV, with a recent meta-analysis indicating a two-fold higher risk compared to the general population [6]. Sub-Saharan African countries are highly affected by depressive symptoms in which 3.63 million people living with HIV (PLHIV) have major depressive symptoms [7]. In Ethiopia, previous studies assessing the prevalence of depression among PLWH have differed considerably, with estimates ranging from 11.7–76.7% [8-12].

Depressive symptoms impose a significant adverse effect on HIV-positive patients. They affect the patient’s ability to adhere to their ART medication. A recent study showed that HIV patients with depressive symptoms were 3.3 times more likely to be non-adherent to their ART medication as compared to their counterparts [13]. They also lead to ART treatment failure, drug resistance, and early disease progression as a result of poor adherence to ART medication [14, 15]. Depressive symptoms affect a patient’s quality of life, it decreases life expectancy and increases suicidal ideation. They have an association with risky sexual behavior which increases the risk of HIV transmission [16-21].

Depressive symptoms have been associated with a wide range of socio-demographic factors, including age, sex [11], lower socio-economic class [11, 22], unemployment [22] and living alone [8]. In addition, clinical factors like HIV status non-disclosure [8], advanced World Health Organization (WHO) clinical stage [9, 11], presence of stigma [8, 10, 23–25], adverse drug reaction [9, 24], presence of opportunistic infection [24], low Cluster Differentiation4 (CD4) count [11] and presence of comorbid illness [24] were another groups of factors affecting depressive symptoms.

The Sustainable Development Goals (SDGs) particularly Goal 3 aims to end the HIV/AIDS epidemic by 2030 [26]. The Joint United Nations Program on HIV/AIDS (UNAIDS) also plans to achieve 90-90-90 targets by 2020 [27]. So, Intervening factors linked to depression is an essential strategy to achieve these two major international commitments as it leads to poor ART drug adherence and further transmission of HIV/AIDS.

There was limited evidence on depressive symptoms among HIV-positive patients in Dessie town. The finding of this study could be an input to provide evidence-based intervention to prevent depressive symptoms among HIV-positive patients. Thus, this study aimed to determine the prevalence of depressive symptoms and associated factors among HIV-positive patients in Dessie town.

Materials and methods

Study area, study design, and participants

A cross-sectional study was conducted from March 1-30/2019 in the public health facilities of Dessie Town, which is a city located within North-central Ethiopia. Dessie is the center of the south Wollo Zone located 401KM away from Addis Ababa, the capital city of Ethiopia and 480 km away from Bahir Dar. According to the 2019 Dessie town administrative health office report, two public hospitals, and three health centers were providing ART services for a total of 9953 adult HIV-positive patients. The study population was randomly selected from all adults with HIV attending public health facilities of Dessie town. Adult HIV-positive patients greater than or equal to 18 years old and who were on ART for at least six months were included in this study.

Sample size and sampling procedure

The study sample size was calculated for the primary risk factor as presence of antiretroviral drug side effects, considered as a binary variable. Based on previous research [9], we wished to detect differences in adjusted odds ratios of at least 4.7, assuming an underlying prevalence of 10.1%, power of 80% and 5% Type I error. After adjustment for 10% non-response, the minimum required sample size was 388. Systematic random sampling was used to select participants using the antiretroviral drug dispensary registration book as the sampling frame. Study participants were invited to participate when attending the health facility for antiretroviral drug collection.

Data collection procedures and measurements

Data were collected by face-to-face interviews using a structured and pretested Amharic version questionnaire. The patient’s medical record was also reviewed to identify clinical markers like CD4 count and WHO clinical staging. Three trained nurses have collected the data with the supportive supervision of the principal investigator and one public health officer supervisor. The questionnaire collected data on socio-demographic, clinical, psycho-social, and behavioral characteristics [9, 11, 22–25, 28, 29].

Depressive symptoms were assessed using the PHQ-9 scale. The PHQ score ranged from 0 to 27, a score of 0–4, represents no depression and a score of 5–9, 10–14, 15–19 and 20–27 represent mild, moderate, moderately severe and severe depressive symptoms respectively. In this study, PHQ score ≥ 5 was used as a benchmark to categorize depression. Accordingly, patients were said to have depressive symptoms if they scored ≥ 5 and have no depressive symptoms if they scored <5 [24, 29].

Perceived stigma was measured using ten questions with ‘yes’ or ‘no’ response options. These questions were adapted from the HIV stigma index validation survey conducted in six Iranian cities. It has been validated in our country as well (in Iimma town) and hasn’t a cutoff point like the PHQ-9 depression scale. The overall score of perceived stigma was calculated out of ten and the distribution was checked for normality. Since the data was not normally distributed, we use the median value to classify perceived stigmas as ’yes’ or ’no’. So, patients who scored above the median score (>0) were considered as they had perceived stigma whereas patients who scored less than or equal to the median score (≤0) had no perceived stigma [30].

Statistical analysis

Data were coded and entered into Epi Data Version 3.1 and analyzed by using Statistical Package for Social Science (SPSS) Version 23 statistical software. Descriptive statistics like mean, median, frequency, and proportion were computed. The association between independent variables and depressive symptoms was made using a binary logistic regression model and a p-value less than 0.2 was used to screen eligible variables for multivariable analysis. Hosmer and Lemeshow goodness of test and standard error were used to check the model fitness and Multicollinearity respectively. Variables having an adjusted odds ratio with a 95% confidence interval not inclusive of the null value were considered as associated factors of depressive symptoms. Statistical significance was declared at a p-value less than 0.05.

Ethical approval

Ethical clearance was obtained from the Ethical Review Committee (ERC) of Wollo University. A permission letter to conduct the study was obtained from the school of public health and it was submitted to ART clinics of Dessie town. After explaining the objective of the study, verbal informed consent was obtained from each study participant. They were informed about their rights to withdraw from the interview at any time. Patients who were assumed to have depressive symptoms were linked to the psychiatric department for investigation and treatment. The information they provide was used only for the study purpose.

This manuscript was organized and written according to strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 2007 (v4) Statement checklist for cross-sectional studies (S1 Table).

Results

Socio-demographic characteristics

In this study, a total of 380 patients were participated making a response rate of 97.9%. The median age of the study participants was 36 years with an interquartile range of 12 years. The overall prevalence of depressive symptoms among HIV-positive patients was 59(15.5%). Twenty-eight (47.5%) HIV-positive patients aged 18–29 years and 7 (11.9%) patients aged greater than or equal to 50 years old had depressive symptoms. The prevalence of depressive symptoms among female patients was 66.1%. Depressive symptoms were higher among married patients (54.2%) and patients who live in urban areas (78%) compared to their counterparts. Forty-six (78%) study participants who live with their families had depressive symptoms compared to 13 (22%) those who live alone (Table 1).

Table 1

Socio-demographic characteristics of HIV positive patients attending public health facilities of Dessie town, Northeast Ethiopia, 2019.

Variable	Depression symptoms (n = 380)			X2, df
	Yes	No	Total
Age
18–29 years	28 (47.5%)	85 (26.5%)	113 (29.7%)	13.730, 3
30–39 years	14 (23.7%)	142 (44.2%)	156 (41.1%)
40–49 years	10 (16.9%)	68 (21.2%)	78 (20.5%)
≥50 years	7 (11.9%)	26 (8.1%)	33 (8.7%)
Sex
Male	20 (33.9%)	143 (44.5%)	163 (42.9%)	2.308, 1
Female	39 (66.1%)	178 (55.5%)	217 (57.1%)
Marital status
Single	27 (45.8%)	140 (43.6%)	167 (43.9%)	0.093,1
Married	32 (54.2%)	181 (56.4%)	213 (56.1%)
Residence
Urban	46 (78%)	254 (79.1%)	300 (78.9%)	0.040, 1
Rural	13 (22%)	67 (20.9%)	80 (21.1%)
Ethnicity
Amhara	57 (96.6%)	289 (90%)	346 (91.1%)	2.648, 1
Othersa	2 (3.4%)	32 (10%)	34 (8.9%)
Religion
Christian	26 (44.1%)	135 (42.1%)	161 (42.4%)	0.083, 1
Muslim	33 (55.9%)	186 (57.9%)	219 (57.6%)
Level of education
Have no formal education	16 (27.1%)	74 (23.1%)	90 (23.7%)	7.518, 3
Grade1-8	18 (30.5%)	131 (40.8%)	149 (39.2%)
Grade9-12	12 (20.3%)	82 (25.5%)	94 (24.7%)
College and above	13 (22%)	34 (10.6%)	47 (12.4%)
Occupation
Government employed	13 (22%)	38 (11.8%)	51 (13.4%)	8.412, 4
Private employed	10 (16.9%)	45 (14%)	55 (14.5%)
Housewife	10 (16.9%)	42 (13.1%)	52 (13.7%)
Farmer	11 (18.6%)	59 (18.4%)	70 (18.4%)
Othersb	15 (25.4%)	137 (42.7%)	152 (40%)
Living condition
Family	46 (78%)	284 (88.5%)	330 (86.8%)	4.816, 1
Alone	13 (22%)	37 (11.5%)	50 (13.2%)
Wealth index
Poorest quintile	19 (32.2%)	62 (19.3%)	81 (21.3%)	9.849, 4
Poorer quintile	14 (23.7%)	81 (25.2%)	95 (25.0%)
Middle quintile	5 (8.5%)	36 (11.2%)	41 (10.8%)
Richer quintile	8 (13.6%)	92 (28.7%)	100 (26.3%)
Richest quintile	13 (22%)	50 (15.6%)	63 (16.6%)

a Tigray and Oromo;

b student, merchant, daily laborer and jobless.

Clinical, psycho-social and behavioral characteristics

Forty-one (69.5%) patients who took medication other than ART had depressive symptoms as compared to 30.5% of patients who didn’t take medication other than ART. Similarly, 44 (74.6%) patients who disclosed their HIV serostatus to anyone else had depressive symptoms compared to 15 (25.4%) patients who didn’t disclose their HIV serostatus to somebody else. Of a total of 114 (30.0%) study participants who experienced perceived stigma, 42 (71.2%) of them had depressive symptoms (Table 2).

Table 2

Clinical, psycho-social, and behavioral characteristics of HIV positive patients attending public health facilities of Dessie town, Northeast Ethiopia, 2019.

Variable	Depression (n = 380)			X2, df
	Yes	No	Total
Number of ART pills taken per day
1	27 (45.8%)	124 (38.6%)	151 (39.7%)	1.169, 2
2	11 (18.6%)	74 (23.1%)	85 (22.4%)
3	21 (35.6%)	123 (38.3%)	144 (37.9%)
Frequency of dosage of ART drug
Once	31 (52.5%)	144 (44.9%)	175 (46.1%)	1.184, 1
Twice	28 (47.5%)	177 (55.1%)	205 (53.9%)
Taking medication other than ART
Yes	41 (69.5%)	126 (39.3%)	167 (43.9%)	18.501, 1
No	18 (30.5%)	195 (60.7%)	213 (56.1%)
Presence of ART drug side effect
Yes	8 (13.6%)	11 (3.4%)	19 (5.0%)	10.772, 1
No	51 (86.4%)	310 (96.6%)	361 (95.0%)
Current CD4 count
<200 cells/mm3	5 (8.5%)	29 (9%)	34 (8.9%)	4.199, 3
200–350 cells/mm3	18 (30.5%)	83 (25.9%)	101 (26.6%)
351–500 cells/mm3	22 (37.3%)	91 (28.3%)	113 (29.7%)
>500 cells/mm3	14 (23.7%)	118 (36.8%)	132 (34.7%)
Current WHO stage
I	54 (91.5%)	309 (96.3%)	363 (95.5%)	2.616, 1
≥II	5 (8.5%)	12 (3.7%)	17 (4.5%)
Presence of opportunistic infections
Yes	5 (8.5%)	10 (3.1%)	15 (3.9%)	3.776, 1
No	54 (91.5%)	311 (96.9%)	365 (96.1%)
HIV serostatus disclosure to any person
Yes	44 (74.6%)	301 (93.8%)	345 (90.8%)	21.956, 1
No	15 (25.4%)	20 (6.2%)	35 (9.2%)
Currently drink alcohol
Yes	13 (22%)	65 (20.2%)	78 (20.5%)	0.097, 1
No	46 (78%)	256 (79.8%)	302 (79.5%)
Currently chew chat
Yes	5 (8.5%)	21 (6.5%)	26 (6.8%)	0.292, 1
No	54 (91.5%)	300 (93.5%)	354 (93.2%)
Currently smoke cigarettes
Yes	1 (1.7%)	8 (2.5%)	9 (2.4%)	0.137, 1
No	58 (98.3%)	313 (97.5%)	371 (97.6%)
Perceived stigma
Yes	42 (71.2%)	72 (22.4%)	114 (30.0%)	56.418, 1
No	17(28.8%)	249 (77.6%)	266 (70.0%)

Prevalence of depression

In our study, the prevalence of depressive symptoms among HIV-positive patients was 59(15.5%) with a 95% CI: (12.4%, 19.2%).

Factors associated with depression

In this study, a p-value of 0.2 was used to screen eligible variables for multivariable logistic regression analysis. As a result, 13 out of 22 variables (age, sex, ethnicity, level of education, occupation, living condition, wealth index, taking medication other than ART, drug side effect, perceived stigma, presence of opportunistic infection, and HIV serostatus disclosure) became eligible for multivariable logistic regression analysis. In the multivariable logistic regression analysis, age, perceived stigma, taking medication other than ART and history of opportunistic infections showed a statistically significant association with depressive symptoms.

Patients aged 40–49 years were 2.9 times more likely to have depressive symptoms compared to patients aged 30–39 years (AOR = 2.96, 95% CI: (1.01, 8.68)). Similarly, the odds of depressive symptoms among patients aged greater than or equal to 50 years was 3.8 times higher compared to patients aged 30–39 years (AOR = 3.81, 95% CI: (1.05, 13.8)).

HIV-positive patients who took medication other than ART were 2.6 times more likely to develop depressive symptoms as compared to patients who didn’t take medication other than ART (AOR = 2.58, 95% CI: (1.25, 5.33)). Similarly, patients who experienced perceived stigma were 10.2 times more likely to have depressive symptoms as compared to patients who didn’t experience perceived stigma (AOR = 10.2, 95%CI: (4.26, 24.4)). The odds of depressive symptoms among patients who had a history of opportunistic infections was 5.2 times higher compared to their counterparts (AOR = 5.17, 95% CI: (1.31, 20.4)) (Table 3).

Table 3

Factors associated with depressive symptoms among HIV positive patients attending public health facilities of Dessie town, Northeast Ethiopia, 2019.

Variables	COR1(95%CI2)	p-value	AOR3(95%CI)	p-value
Age
18–29 years	3.34 (1.67, 6.70)	0.005	1.93 (0.79, 4.70)	0.145
30–39 years	1		1
40–49 years	1.49 (0.63, 3.53)		2.96 (1.01, 8.68)	0.048
≥50 years	2.73 (1.006, 7.42)		3.81 (1.05, 13.8)	0.041
Sex
Male	0.64 (0.36, 1.14)	0.131	0.68 (0.30, 1.55)	0.365
Female	1		1
Marital status
Single	1.09 (0.63, 1.91)	0.76
Married	1
Residence
Urban	1
Rural	1.07 (0.55, 2.10)	0.841
Ethnicity
Amhara	1		1
Othersa	0.32 (0.07, 1.36)	0.122	0.34 (0.06, 2.02)	0.235
Religion
Christian	1.09 (0.62, 1.90)	0.774
Muslim	1
Level of education
Have no formal education	1.57 (0.76, 3.27)	0.066	1.88 (0.69, 5.16)	0.220
Grade1-8	1		1
Grade 9–12	1.07 (0.49, 2.33)		0.74 (0.27, 2.05)	0.566
College and above	2.78 (1.24, 6.24)		1.67 (0.38, 7.37)	0.501
Occupation
Government employed	3.13 (1.37, 7.13)	0.090	1.33 (0.31, 5.77)	0.702
Private employed	2.03 (0.85, 4.84)		2.17 (0.76, 6.20)	0.149
Housewife	2.18 (0.91, 5.20)		2.32 (0.72, 7.42)	0.157
Farmer	1.70 (0.74, 3.93)		1.35 (0.44, 4.12)	0.600
Othersb	1		1
Living condition
Family	1		1
Alone	2.17 (1.07, 4.39)	0.031	0.76 (0.21, 2.69)	0.671
Wealth index
Poorest quintile	1.18 (0.53, 2.62)	0.054	1.28 (0.47, 3.49)	0.624
Poorer quintile	0.66 (0.29, 1.53)		0.65 (0.22, 1.93)	0.434
Middle quintile	0.53 (0.18, 1.63)		0.66 (0.17, 2.56)	0.546
Richer quintile	0.33 (0.13, 0.86)		0.37 (0.11, 1.27)	0.115
Richest quintile	1		1
Number of ART pills taken per day
1	1
2	0.68 (0.32, 1.46)	0.559
3	0.78 (0.42, 1.46)
Frequency of dosage of ART drug
Once	1.36 (0.78, 2.37)	0.278
Twice	1
Taking medication other than ART
Yes	3.53 (1.94, 6.41)	0.000	2.58 (1.25, 5.33)	0.011
No	1		1
Presence of ART drug side effect
Yes	1		1
No	0.23 (0.09, 0.59)	0.002	0.42 (0.13, 1.43)	0.166
History of opportunistic infections
Yes	2.88 (0.95, 8.75)	0.062	5.17 (1.31, 20.4)	0.019
No	1		1
HIV sero-status disclosure4
Yes	1		1
No	5.13 (2.45, 10.76)	0.000	1.24 (0.35, 4.43)	0.744
Currently drink alcohol
Yes	1.11 (0.57, 2.18)	0.775
No	1
Currently chew chat
Yes	1.32 (0.48, 3.66)	0.590
No	1
Currently smoke cigarettes
Yes	0.68 (0.08, 5.50)	0.713
No	1
Perceived stigma
Yes	8.54 (4.59, 15.91)	0.000	10.2 (4.26, 24.4)	0.000
No	1		1

1 crude odds ratio.

2 confidence interval.

3 adjusted odds ratio.

4 the question used to define the variable “HIV serostatus disclosure" is have you ever disclosed your HIV serostatus disclosure to someone else like a sexual partner, families, friends, relatives, etc.

Discussion

This study assessed the prevalence of depressive symptoms and associated factors among HIV-positive patients in Dessie town. The prevalence of depressive symptoms among HIV-positive patients was 59 (15.5%) with a 95% CI: (12.4%, 19.2%). Age, perceived stigma, taking medication other than ART and history of opportunistic infections were factors associated with depressive symptoms.

The prevalence of depressive symptoms is in line with a study done in Aksum town (14.6%) [9]. It is lower than studies conducted in Brazil (57.7%) [31], Bihar, India (57%) [32], Pradesh, India (67.3%) [33], Jos, Nigeria (31%) [29] and Southwest Nigeria (39.6%) [34]. The finding is also lower than studies conducted in Cameron (26.7%) [28], Sudan (63.1%) [35], Harar (45.8%) [11], Tigray (43.9%) [22], Alert Hospital (41.2%) [23] and Hawassa (48.6%) [10].

But the prevalence of depressive symptoms is slightly higher than a study conducted in Debre Markos town (11.7%) [8]. This discrepancy could be due to the difference in the study setting, study period, sample size and difference in the depression diagnostic tools used. For example, in our study, the PHQ-9 depression scale at a cutoff of 5 was used to assess depression. But, a study conducted in Pardesh, India used Montgomery Asberg Depression Rating Scale (MADRS) to assess depression [33]. Likewise, the Hamilton Depression Rating Scale (HAM-D) at a cut-off point of 7 and the Hospital Anxiety Depression Scale (HADS) cut-off points of 8 were used to assess depressive symptoms among studies done in Tigray and Alert hospital respectively [22, 23]. Studies conducted in Jos Nigeria, Cameron and Harar used the PHQ-9 depression scale at a cutoff of 5 to assess depression [11, 28, 29].

Being 40–49 years old and being ≥50 years old had a positive association with depressive symptoms. The finding is in line with a study conducted in Jos, Nigeria [29]. This might be because older age usually had an association with other chronic illnesses like diabetic Malthus, hypertension, heart disease, and kidney disease. A recent study showed that patients with comorbid illness had six times the risk for depressive symptoms than their counterparts [24]. In addition to this, chronic HIV disease and its challenges are more severe in older age patients due to low immune systems. This predisposes them to the vulnerability of depressive symptoms.

Having perceived stigma had a positive association with depressive symptoms. The finding is supported by studies conducted in Alert Hospital [23] and Debre Markos town [8]. It is also in line with studies conducted in Hawassa town [10] and Botswana [25]. HIV/AIDS is one of the chronic life-long diseases which is highly liable to stigma and discrimination. HIV-positive patients usually prefer to be alone to avoid stigma or discrimination. They also lose their work and social values, develop poor self-image and feel valueless as a result of stigma or discrimination. All of these factors contribute to the development of depressive symptoms [36].

The odds of depressive symptoms were 2.6 times more among patients who took medication other than ART as compared to their counterparts. In Ethiopia, HIV-positive patients are on efavirenz and nevirapine-based ART medications. Although ART medication can keep the patients healthy, it is associated with adverse drug reactions and drug toxicity [37]. The most common side effects associated with efavirenz and nevirapine-based ART medications are hepatotoxicity and central nervous system disorders typically, depression and sleep disorder [38, 39]. Taking other medication in addition to ART drugs may cause pill burden, worsen drug toxicity leading to poor medication adherence and depressive symptoms [13, 40, 41].

Patients who had a history of opportunistic infections were more likely to develop depressive symptoms as compared to those who had no history of opportunistic infections. The reason could be, patients with opportunistic infection might be excessively worried about their health and their physical appearance which might be a cause for the occurrence of depressive symptoms. The finding is supported by studies conducted in Fitche, Gimbi and Addis Ababa [12, 24, 42].

Limitation of the study

This study includes patients who came to the health facility for drug refill. So, the finding cannot be generalized to all people living with HIV because it misses individuals with severe depressive symptoms who may not attend clinics regularly. This study is also prone to information bias which affects the prevalence of depressive symptoms. The issue of establishing a causal relationship due to the cross-sectional nature of the study is the other potential limitation of the study.

Conclusions

The prevalence of depressive symptoms was low compared to the previous studies. Being 40–49 years old, being ≥50 years old, having perceived stigma, taking medication other than ART and history of opportunistic infections had a statistically significant association with depressive symptoms. Health care providers who are working in ART clinics should give special attention to older individuals, individuals who took medication other than ART, patients who experienced perceived stigma and patients with a history of opportunistic infections. Programs on counseling should be strengthened and health education should be given for the patients and the community at large to decrease HIV-related stigma. Further study with a qualitative study design would be recommended to support this finding.

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) 2007 (v4) Statement checklist for cross-sectional studies.

(DOCX)

Click here for additional data file.

The data set used to determine the prevalence of depression and associated factors among HIV-infected patients attending public health facilities of Dessie town.

(SAV)

Click here for additional data file.

19 Apr 2021

PONE-D-21-03982

Depression and associated factors among HIV infected patients attending Public Health Facilities of Dessie town: A cross-sectional study.

PLOS ONE

Dear Dr. Damtie,

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 May 31 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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,

Colette Smith, PhD

Academic Editor

PLOS ONE

Additional Editor Comments:

Please carefully consider the comments from the reviewers in your revision, particularly regarding making sure the language is clear and that it is clear that this is a cross-sectional study which cannot investigate cause-and-effect, and so you can only investigate associations rather than predictors.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

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

and

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

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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: Partly

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: No

**********

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

**********

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: This manuscript describes the results of a cross-sectional survey during one month in 2019 in several hospitals and health centres in Dessie Town in Ethiopia, to assess the prevalence of depression and factors associated with depression among persons living with HIV. Participants had to be linked into HIV care at one of the health centres and had to have been on ART for at least 6 months. A wide range of data were collected from face-to-face interviews with study nurses, and with further data extracted from clinical records. Assessing and thereby highlighting the extent of depression among PLWH is a good objective. There are a number of ways in which the manuscript should be revised to exploit the data collected more fully.

Introduction:

1) Line 54 (and also Abstract line 25): The statement that depression affects 121 million HIV infected patients worldwide is not correct (given that there are currently 37.9 million PLWH globally) – indeed reference 5 quotes this figure as the global total number of people with depression in 2012.

2) As this is a cross-sectional study, the objective would be to determine the prevalence of depression and other factors. Here and elsewhere (line 78, 153-154, 170, 173 etc.) please avoid the term ‘magnitude’ (instead of prevalence) at his term might be understood to refer to the severity of depression.

3) Please cite the meta-analysis (line 55–56) and cite some more recent reviews on depression, stigma and associated factors to put the study in context.

Methods:

Please provide more precise details on the methods, including:

1) Please provide more details of the systematic random sampling (not systematic sampling) approach and how this was divided between the two hospitals and three health centres. How were patients were invited to take part in the study?

2) It is important to know more of how the sampling was done so as to assess generalisability and bias in the selection of study participants. Restricting to individuals linked into care and on ART may exclude individuals with severe depression who may not attend clinic regularly.

3) The sample size calculation is difficult to follow: Is the assumption that 89% of PLWH will have depression? How do drug side effects, a 1:1 ratio of exposed to unexposed (which exposure?) affect the calculation, and what does the assumed odds ratio of 4.7 refer to?

4) I assume that 388 individuals were invited to take part, and 380 agreed? This could be more explicit. The 380 figure is more relevant for the abstract.

5) The PHQ-9 was used to assess for depression, using the cut-point of 5 to include any depression (including mild depression). Did the authors look at severe depression as well?

6) Since perceived stigma is a main outcome of the analysis, please specify how this was measured (more detail on the 10-question instrument) and how it was scored (range of responses, overall cut points etc). How does it work to use the median as the cut-point?

7) Statistical analysis – what do you mean by “using texts”?

8) How does the standard error predict multicollinearity?

9) Please clarify other variables / associated factors, specifically

a. Meal frequency – is this a socio-economic measure of how many meals/day the person can afford, or an indication of dietary habits?

b. How is the wealth index calculated, i.e. what factors is it based on, and has it been validated? I assume the strata are presented as quintiles, so should be referred to as ‘the richest quintile’ (line 139).

c. If meal frequency is a socio-economic measure, there may be collinearity with the wealth index.

d. the clinical, psycho-social and behavioural variables also need clearer definitions. E.g. please clarify the ‘number of tablets taken per day’ and ‘frequency of dosage’ variables – does this refer to the ARV medication, other medications or the sum of pill burden, and what does a dosage of ‘once’ and ‘twice’ refer to?

e. How is the ‘side effects’ variable defined, which side effects are of interest, and from which treatment or medication (ARVs or other medication)?

f. Please list the conditions included in ‘comorbid illnesses’ and ‘opportunistic infections’ – are you referring to non-AIDS and AIDS-related clinical conditions? How do these variables relate to ‘concomitant illness’ reported in Table 3?

g. Please explain the ‘HIV disclosure’ variable vs. who reported disclosing what to whom?

h. Please specify for alcohol and Chat use and for smoking status, are you looking at current or ever use?

10) Line 120: Why were the variables considered predictors of ART adherence?

1) Data presentation: Tables 1 and 2 would be more informative if they showed data stratified by the outcome, depression (i.e. present numbers and % of those with depression and those without, in addition to the overall totals) with a chi-squared test for significance. Stratified data should be shown for all variables, not only those selected in Table 3.

2) The descriptions for Table 1 (lines 134-139) and Table 2 (lines 144-149) simply reiterate apparently random lines from the tables. If the tables were stratified according to whether participants had depression or not, this would allow a description of how depression varies across the different variables.

3) Please state which variables were included in the multivariable regression models? A table showing the unadjusted odds ratios for all variables, and the adjusted odds ratios for those included in the multivariable model would be more informative. P values should be listed in full, not categorised to *.

4) How were the reference categories chosen, e.g. for age or education. For age, the category of ≥50 years, which contains fewer than 10% of the individuals overall is shown as the reference category. If, alternatively, the largest age group, 30-39 is used as reference, individuals in the youngest age category (18-29 years old) have more than 3x the odds of depression than those 30-39 years old (unadjusted OR 3.34, CI 1.67-6.70, = 0.0007), which would agree with the high rates of depression observed in adolescents and adults under 25 years old in other populations.

5) While it is not clear how these variables are defined, could there be collinearity between ‘Taking medication other than ART’ and ‘concomitant illness’.

6) The main factors associated that are commented on in the paper are perceived stigma, taking medication other than ART, and living alone. But other variables also showed significant associations (stage of AIDS, alcohol use and drug side effects, and younger age if the reference group is changed as I indicated). Why are these other factors not described?

Discussion

1) Since this is a cross-sectional study, cause and effect are less clear, and the variables found to be associated with depression should not be described as predictors (line 172, also line 42). Indeed, depression might lead someone to prefer to live alone, or to use alcohol.

2) Please describe possible reasons for the observed associations in more detail, and how the associated factors might be related, e.g. have you considered whether there is collinearity for individuals to suffer from other illnesses and using medications other than ARVs.

3) Please describe the strengths and limitations of the study more fully, including selection bias and information bias and how these may affect the study results, and generalisability to PLWH in Ethiopia and elsewhere.

4) Lines 180-185: Listing numbers of diagnosed individuals in the different comparator studies is meaningless without knowing denominators and does not inform the discussion

Minor errors:

There are some grammatical errors or omission of words; these are too numerous to list all, but some examples are:

- Line 27: HIV infected patients attending or HIV infected patients who attended.

- As per UN terminology guidelines, avoid the terms ‘HIV-infected’ or ‘patient’ in a setting such as this – these descriptors may themselves be stigmatising.(https://www.iasociety.org/Web/WebContent/File/unaids_terminology_guide_en.pdf)

- Line 43-44 add the word 'who': patients who experienced (persons who experienced)

- Remove the extra space in Line 49 - the figure should be 399,000

- Line 70: CD4 – the 4 is not a subscript (also elsewhere)

- Line 71 change 'has' to 'have' in factors linked to depression has been recognized

- Line 85 change 'adults who attending' to 'adults who attended'

- Line 98 missing word 'was' in The patient's card also reviewed…

- Line 100 missing word 'was' in The questionnaire composed of

- Lines 134-139 – please ensure consistent use of the past tense

- Line 161 should be the odds of depression

- Line 167 – what is meant by bi-variable? These are univariable/unadjusted/crude odds ratios with one dependent and one independent variable.

Data would be fully available on request

Reviewer #2: I think this is an interesting paper that adds to the literature. However, it is not well written and needs extensive editing.

1) In the abstract the first sentence is confusing. Is the 121 million people those with HIV or HIV and depression? You need to put how depression was diagnosed in the abstract- both the tool used and the cutoff used.

2) Page 3, line 53- most common not commonest

3) Page 3 lines 55-57 you need a citation. There has been a review on the prevalence of depression in Africa and a CDC survey of multiple African countries. Lofgren, S.M., al. Burden of Depression in Outpatient HIV-Infected adults in Sub-Saharan Africa; Systematic Review and Meta-analysis. AIDS Behav 24, 1752–1764 (2020). https://doi.org/10.1007/s10461-019-02706-2

Seth P, Kidder D, Pals S, et al. Psychosocial functioning and depressive symptoms among HIV-positive persons receiving care and treatment in Kenya, Namibia, and Tanzania. Prev Sci. 2014;15(3):318–28.

4) There are many sentences that are long and compound. These should be split. Examples Page 3 line 60-64, Page 3 67-71. There are also multiple paragraphs with one sentence. Paragraphs have at least 3. Examples Page 3 line 67-71, Page 4 72-75.

5) The sample size calculation on pages 4-5 is confusing to me. I don't understand what the 89.9% depression means.

6) Results page 6- The pulling out of the percentage of age 18-29 was odd. Why not use median age or present multiple categories. The spacing in this paragraph has multiple errors. Finally the sentences included multiple unrelated datapoints. Ex people live with their families, eat 3+ meals, % of richest. The % eating 3+ meals and wealth category are related but living with one's family is note.

7) Page 9 you reference tables and I assume you mean ART pill but you need to say that. Again, you have many compound complex sentences that need to be broken up.

8) again in the discussion there are paragraphs with 2 sentences. The sentences are not really arranged into coherent paragraphs.

9) You need a more nuanced comparison between studies. You start it but the tool used and the cutoff are critical in comparing incidence and prevalence. Also if the individuals were just diagnosed with HIV. Or if they were otherwise sick such as with TB. Finally are they inpatient sor outpatients. All of these factors need a more careful discussion.

10) You use the cutoff of 5 with the PHQ-9 which is a less common cutoff to use. It is the cutoff for mild depression. The cutoff of 10 is more commonly used. I think you can use it if you justify what it is used but more justification is needed. Also you should discuss the cutoff when you compare to other studies.

11) In the discussion you reference ART side effects and toxicity as possible causes of depression. However, you do not state what ART the individuals are on. Most of Africa switched to dolutegravir based therapy in 2019. You can make the claim of side effects if your participants were on efavirenz but most individuals on dolutegravir have almost no side effects.

12) You have a limitations paragraph before the conclusion but this should be labeled as such.

13) The first sentence of the conclusion is really confusing and should be re-written.

14) Throughout paper lots of grammatical errors

**********

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.

3 Jul 2021

Colette Smith, PhD

Academic Editor, PLOS ONE

RE: Manuscript ID: PONE-D-21-03982 (Depression and associated factors among HIV infected patients attending Public Health Facilities of Dessie town: A cross-sectional study.)

Dear Dr. Colette Smith,

Thank you very much for your email and the comments/suggestions of the reviewers and academic editor. We have looked at the comments and have revised our paper accordingly. We hope our paper improved as a result of incorporating the reviewers' and academic editor's comments and suggestions.

Please find for your kind consideration the following:

� A rebuttal letter that responds to each point raised by the academic editor and reviewer labeled 'Response to Reviewers'. The point-by-point responses are written in italic font style.

� A revised manuscript with track changes labeled 'Revised Manuscript with Track Changes'.

� A revised paper without tracked changes labeled 'Manuscript'

While hoping that these changes would meet with your favorable consideration, we are happy to hear if there are more comments and suggestions. Please do not hesitate to let us know if you have any questions.

Yours Sincerely,

Yitayish Damtie

School of Public Health, Wollo University

Dessie, Ethiopia

Tel:+251943517982

E-mail: yitutile@gmail.com

Point by point response

Additional Editor Comments:

Please carefully consider the comments from the reviewers in your revision, particularly regarding making sure the language is clear and that it is clear that this is a cross-sectional study that cannot investigate cause-and-effect, and so you can only investigate associations rather than predictors.

� Thank you. We have tried to make sure the language clear and revise our manuscript based on reviewers' comments accordingly. In addition, we have tried to use the term associated factors instead of predictors throughout the manuscript accordingly.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

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

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

� Thank you. We have tried to organize our manuscript based on PLOS ONE's style requirements including those for file naming.

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

a) We ask great excuse for this. There are no legal or ethical restrictions on sharing data publicly.

In your revised cover letter, please address the following prompts:

A) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

� Thank you for your comment. But there are no ethical or legal restrictions on sharing the data set of this study publicly.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

� We have tried to upload the data set of this study as a supporting information file accordingly.

Reviewer #1:

This manuscript describes the results of a cross-sectional survey during one month in 2019 in several hospitals and health centers in Dessie Town in Ethiopia, to assess the prevalence of depression and factors associated with depression among persons living with HIV. Participants had to be linked into HIV care at one of the health centers and had to have been on ART for at least 6 months. A wide range of data were collected from face-to-face interviews with study nurses, and with further data extracted from clinical records. Assessing and thereby highlighting the extent of depression among PLWH is a good objective. There are several ways in which the manuscript should be revised to exploit the data collected more fully.

� Thank you. We have tried to revise our manuscript accordingly.

Introduction:

1) Line 54 (and also Abstract line 25): The statement that depression affects 121 million HIV infected patients worldwide is not correct (given that there are currently 37.9 million PLWH globally) – indeed reference 5 quotes this figure as the global total number of people with depression in 2012.

� Yes, we acknowledge the problem. We have tried to delete it and revise the abstract and introduction section accordingly.

2) As this is a cross-sectional study, the objective would be to determine the prevalence of depression and other factors. Here and elsewhere (line 78, 153-154, 170, 173 etc.) please avoid the term ‘magnitude’ (instead of prevalence) at his term might be understood to refer to the severity of depression.

� Thank you. We have tried to use prevalence instead of magnitude throughout our manuscript (line 27, 42, 83, 168, 191, 195, 200 and 241

3) Please cite the meta-analysis (line 55–56) and cite some more recent reviews on depression, stigma and associated factors to put the study in context.

� We have tried to cite the meta-analysis and more recent reviews in the introduction line 56-57 and line 59-60 accordingly.

Methods:

Please provide more precise details on the methods, including:

1) Please provide more details of the systematic random sampling (not systematic sampling) approach and how this was divided between the two hospitals and three health centers. How patients were invited to take part in the study?

� We have tried to provide a detail description regarding systematic random sampling and its approach in the method section line 99-107.

2) It is important to know more of how the sampling was done to assess generalisability and bias in the selection of study participants. Restricting to individuals linked into care and on ART may exclude individuals with severe depression who may not attend clinic regularly.

� Yes, you are right. The study was restricted to individuals linked into care and on ART. This may underestimate depression because it is prone to miss individuals with severe depression who may not attend the clinic regularly. Since it is one of the potential limitations of this study, we have tried to include it under the limitation section line 234-236.

3) The sample size calculation is difficult to follow: Is the assumption that 89% of PLWH will have depression? How do drug side effects, a 1:1 ratio of exposed to unexposed (which exposure?) affect the calculation, and what does the assumed odds ratio of 4.7 refer to?

� Thank you for your comment. We used epi Info software to calculate the sample size. To calculate sample size using Epi Info, one requires to provide the following information i.e. confidence level: usually set at 95%, power: usually set at 80%, % of outcome in unexposed group: the proportion of unexposed patients with the outcome of interest (in our case, the proportion of depression among HIV patients without ART drug side effect), the ratio of exposed to unexposed: usually taken as 1 for cross-sectional study and adjusted odds ratio of the exposure variable taken from the previous studies. We have tested several exposure variables which are taken from previous literature to get the maximum sample size. As a result ART drug side effects from Beyene Gebrezgiabher B, et al (reference 12) gives the maximum sample size. So, 89% is the proportion of depression among HIV patients who don’t experience ART drug side effects and 4.7 is the AOR of ART drug side effects.

4) I assume that 388 individuals were invited to take part, and 380 agreed? This could be more explicit. The 380 figure is more relevant for the abstract.

� Yes, 388 individuals were invited to take part, and 380 agreed. We have tried to make it 380 in the abstract section line 29.

5) The PHQ-9 was used to assess for depression, using the cut-point of 5 to include any depression (including mild depression). Did the authors look at severe depression as well?

� Yes.

6) Since perceived stigma is a main outcome of the analysis, please specify how this was measured (more detail on the 10-question instrument) and how it was scored (range of responses, overall cut points etc). How does it work to use the median as the cut-point?

� Thank you. As we have stated in the manuscript, perceived stigma was measured using ten questions with ‘yes’ or ‘no’ response options. These questions were adapted from the HIV stigma index validation survey conducted in six Iranian cities. It has been validated in our country as well (in Iimma town) and hasn't a cutoff point like the PHQ-9 depression scale. We calculate the overall score of perceived stigma out of ten and have checked its distribution. Since the data was not normally distributed, we use the median value to classify perceived stigmas as ‘yes’ or ‘no’.

7) Statistical analysis – what do you mean by “using texts”?

� It is to mean in text form (in narration). But since it is irrelevant we have deleted it.

8) How does the standard error predict multicollinearity?

� Thank you. As we know multicollinearity is a condition in which two or more predictors are highly correlated with one another. One of the features of multicollinearity is that the standard errors of the affected coefficients tend to be large. If the standard error is between -2 and + 2, we can say that there is no multicollinearity.

9) Please clarify other variables / associated factors, specifically

a. Meal frequency – is this a socio-economic measure of how many meals/day the person can afford, or an indication of dietary habits?

� Yes. It is the socio-economic measure. In our country, the majority of the people afford three meals/day

b. How is the wealth index calculated, i.e. what factors is it based on, and has it been validated? I assume the strata are presented as quintiles, so should be referred to as ‘the richest quintile’ (line 139).

� Thank you. The wealth index was calculated for urban and rural areas separately using principal component analysis. It includes a wide range of factors like source of drinking water, type of toilet, owner of the house, number of class in the house, source of energy for food cooking, having mobile, cycle, motorcycle, car, ox bees, sheep gout, hen, etc. it has been validated and the strata were presented as quintiles. So, we have tried to revise it accordingly.

c. If meal frequency is a socio-economic measure, there may be collinearity with the wealth index.

� Thank you. We remove meal frequency from the analysis due to its collinearity with the wealth index.

d. the clinical, psycho-social and behavioral variables also need clearer definitions. E.g. please clarify the 'number of tablets taken per' day and 'frequency of dosage' variables – does this refer to the ARV medication, other medications or the sum of pill burden, and what does a dosage of 'once' and 'twice' refer to?

� Thank you. ‘Number of tablets taken per day’ and ‘frequency of dosage’ refer to the ARV medication. When we say a dosage of ‘once’, the number of tablets might be either one or more than one but it is taken once per day (in medical terms it is commonly known as stat). On the other hand, when we say a dosage of ‘twice’, the tablet is taken twice per day regardless of its number (12 hours apart or commonly known as BID).

e. How is the ‘side effects’ variable defined, which side effects are of interest, and from which treatment or medication (ARVs or other medication)?

� Thank you. The variable 'side effects' represents the side effect of ARV medication. It includes skin rash, anemia, gastrointestinal disorder, jaundice, sleep disorder and headache.

f. Please list the conditions included in ‘comorbid illnesses’ and ‘opportunistic infections’ – are you referring to non-AIDS and AIDS-related clinical conditions? How do these variables relate to ‘concomitant illnesses reported in Table 3?

� Thank you. ‘Comorbid illnesses’ refers to non-AIDS illness. It includes hypertension, asthma, diabetic Malthus and cancer. On the other hand ‘opportunistic infections’ refers to AIDS-related clinical conditions like tuberculosis, herpes zoster, oral thrush, esophageal candidacies, pneumocystis carnie pneumonia etc. Concomitant illness is used to refer to comorbid illnesses.

g. Please explain the ‘HIV disclosure’ variable vs. who reported disclosing what to whom?

� Thank you. HIV serostatus disclosure was reported if study participants tell their serostatus to any other person i.e. to their sexual partner, family members, friends or relatives.

h. Please specify for alcohol and Chat use and for smoking status, are you looking at current or ever use?

� Thank you. We have to look at the current use. We have tried to specify it in Table 2 and 3

10) Line 120: Why were the variables considered predictors of ART adherence?

� Thank you. It is an editorial issue, we accept the problem and correct it accordingly.

1) Data presentation: Tables 1 and 2 would be more informative if they showed data stratified by the outcome, depression (i.e. present numbers and % of those with depression and those without, in addition to the overall totals) with a chi-squared test for significance. Stratified data should be shown for all variables, not only those selected in Table 3.

� Thank you. We have tried to present the data stratified by the outcome, depression with a chi-squared test for significance in Table 1 and 2. But we delete the stratification presented in Table 3 because of repetition.

2) The descriptions for Table 1 (lines 134-139) and Table 2 (lines 144-149) simply reiterate apparently random lines from the tables. If the tables were stratified according to whether participants had depression or not, this would allow a description of how depression varies across the different variables.

� We have tried to stratified the tables with respect to the outcome variable and rewrite the descriptions for Table 1 and 2 in the result section line 149-155 and line 160-164 respectively.

3) Please state which variables were included in the multivariable regression models? A table showing the unadjusted odds ratios for all variables, and the adjusted odds ratios for those included in the multivariable model would be more informative. P values should be listed in full, not categorised to *.

� We have tried to list variables included in the multivariable regression models in the result section line 173-176. We also put the unadjusted odds ratios for all variables, the adjusted odds ratios for those included in the multivariable model, and the p-value in Table 3 of the revised manuscript.

4) How were the reference categories chosen, e.g. for age or education. For age, the category of ≥50 years, which contains fewer than 10% of the individuals overall is shown as the reference category. If, alternatively, the largest age group, 30-39 is used as reference, individuals in the youngest age category (18-29 years old) have more than 3x the odds of depression than those 30-39 years old (unadjusted OR 3.34, CI 1.67-6.70, = 0.0007), which would agree with the high rates of depression observed in adolescents and adults under 25 years old in other populations.

� Thank you. We have tried to change the reference category for both variable in Table 3 accordingly.

5) While it is not clear how these variables are defined, could there be collinearity between ‘Taking medication other than ART’ and ‘concomitant illness’.

� Thank you. We removed concomitant illness from the analysis due to its colinearity with taking medication other than ART

6) The main factors associated that are commented on in the paper are perceived stigma, taking medication other than ART, and living alone. But other variables also showed significant associations (stage of AIDS, alcohol use and drug side effects, and younger age if the reference group is changed as I indicated). Why are these other factors not described?

� Thank you. We have changed the reference group for these variables (stage of AIDS, alcohol use and drug side effects, and younger age) accordingly. But none of them showed significant associations except age.

Discussion

1) Since this is a cross-sectional study, cause and effect are less clear, and the variables found to be associated with depression should not be described as predictors (line 172, also line 42). Indeed, depression might lead someone to prefer to live alone or to use alcohol.

� Thank you. We have tried to make it associated factors in the abstract and discussion section line 41 and 195 respectively.

2) Please describe possible reasons for the observed associations in more detail, and how the associated factors might be related, e.g. have you considered whether there is collinearity for individuals to suffer from other illnesses and using medications other than ARVs.

� We have tried to make the detail of the reasons and removed the variable ‘concomitant illness’ from the analysis.

3) Please describe the strengths and limitations of the study more fully, including selection bias and information bias, and how these may affect the study results, and generalizability to PLWH in Ethiopia and elsewhere.

� Thank you for your comment. Discussing the strengths of this study is not as important since our study shared all the strengths of a certain cross-sectional study. However, we have tried to describe the limitations of the study in detail (line 235-240).

4) Lines 180-185: Listing numbers of diagnosed individuals in the different comparator studies is meaningless without knowing denominators and does not inform the discussion

� Thank you. We have tried to delete it from paragraph three of the discussion section accordingly.

Minor errors:

There are some grammatical errors or omission of words; these are too numerous to list all, but some examples are:

� Thank you. We have tried to revise the grammatical errors accordingly.

- Line 27: HIV infected patients attending or HIV infected patients who attended.

- As per UN terminology guidelines, avoid the terms 'HIV-infected or 'patient' in a setting such as this –these descriptors may themselves be stigmatizing. (https://www.iasociety.org/Web/WebContent/File/unaids_terminology_guide_en.pdf)

- Line 43-44 add the word 'who': patients who experienced (persons who experienced)

- Remove the extra space in Line 49 - the figure should be 399,000

- Line 70: CD4 – the 4 is not a subscript (also elsewhere)

- Line 71 change 'has' to 'have' in factors linked to depression has been recognized

- Line 85 change 'adults who attending' to 'adults who attended'

- Line 98 missing word 'was' in the patient's card also reviewed…

- Line 100 missing word 'was' in the questionnaire composed of

- Lines 134-139 – please ensure consistent use of the past tense

- Line 161 should be the odds of depression

- Line 167 – what is meant by bi-variable? These are univariable/unadjusted/crude odds ratios

with one dependent and one independent variable.

Data would be fully available on request

Reviewer #2:

I think this is an interesting paper that adds to the literature. However, it is not well written and needs extensive editing.

� Thank you. We have tried to revise the whole part of the manuscript accordingly.

1) In the abstract the first sentence is confusing. Is the 121 million people those with HIV or HIV and depression? You need to put how depression was diagnosed in the abstract- both the tool used and the cutoff used.

� Thank you. We have tried to modify it accordingly. We put the tool and the cutoff used to assess depression in the abstract section line 32.

2) Page 3, line 53- most common not commonest

� Thank you. The comment is accepted and addressed accordingly.

3) Page 3 lines 55-57 you need a citation. There has been a review on the prevalence of depression in Africa and a CDC survey of multiple African countries. Lofgren, S.M., al. Burden of Depression in Outpatient HIV-Infected adults in Sub-Saharan Africa; Systematic Review and Meta-analysis. AIDS Behav 24, 1752–1764 (2020). https://doi.org/10.1007/s10461-019-02706-2

Seth P, Kidder D, Pals S, et al. Psychosocial functioning and depressive symptoms among HIV-positive persons receiving care and treatment in Kenya, Namibia, and Tanzania. Prev Sci. 2014; 15(3):318–28.

� Thank you. We have tried to put the citation for the meta-analysis and add additional literature in the introduction section line 56-57 and line 59-60 respectively.

4) There are many sentences that are long and compound. These should be split. Examples Page 3 line 60-64, Page 3 67-71. There are also multiple paragraphs with one sentence. Paragraphs have at least 3. Examples Page 3 line 67-71, Page 4 72-75.

� Thank you. We acknowledged the problem have tried to split it accordingly.

5) The sample size calculation on pages 4-5 is confusing to me. I don't understand what the 89.9% depression means.

� Thank you for your comment. We used epi Info software to calculate the sample size. To calculate sample size using Epi Info, one requires to provide the following information i.e. confidence level: usually set at 95%, power: usually set at 80% and % of outcome in unexposed group: the proportion of unexposed patients with the outcome of interest (in our case, the proportion of depression among HIV patients without ART drug side effect). We have tested several exposure variables which are taken from previous literature to get the maximum sample size. As a result ART drug side effects from Beyene Gebrezgiabher B, et al (reference 12) gives the maximum sample size. So, 89% is the proportion of depression among HIV patients without ART drug side effects and 4.7 is the AOR of ART drug side effects.

6) Results page 6- The pulling out of the percentage of age 18-29 was odd. Why not use median age or present multiple categories. The spacing in this paragraph has multiple errors. Finally the sentences included multiple unrelated data points. Ex people live with their families, eat 3+ meals, % of richest. The % eating 3+ meals and wealth category are related but living with one's family is note.

� Thank you. We have tried to revise it accordingly.

7) Page 9 you reference tables and I assume you mean ART pill but you need to say that. Again, you have many compound complex sentences that need to be broken up.

� Thank you, the comment is accepted and addressed accordingly.

8) again in the discussion there are paragraphs with 2 sentences. The sentences are not really arranged into coherent paragraphs.

� We acknowledge the problem and tried to revise it accordingly.

9) You need a more nuanced comparison between studies. You start it but the tool used and the cutoff are critical in comparing incidence and prevalence. Also if the individuals were just diagnosed with HIV. Or if they were otherwise sick such as with TB. Finally are they inpatient or outpatients. All of these factors need a more careful discussion.

� Thank you. We have tried to compare the tool used and the cutoff points in the discussion section line 204-210. But all the studies mentioned in the discussion section included HIV-infected outpatients in their study. So, there is no need to compare each study concerning the characteristics of their study participants.

10) You use the cutoff of 5 with the PHQ-9 which is a less common cutoff to use. It is the cutoff for mild depression. The cutoff of 10 is more commonly used. I think you can use it if you justify what it is used but more justification is needed. Also you should discuss the cutoff when you compare to other studies.

� Thank you. But we left the cutoff of 5 as it is since the most published study used the cutoff of 5 to categorize patients as having depression and not having depression.

11) In the discussion you reference ART side effects and toxicity as possible causes of depression. However, you do not state what ART the individuals are on. Most of Africa switched to dolutegravir based therapy in 2019. You can claim side effects if your participants were on efavirenz but most individuals on dolutegravir have almost no side effects.

� Thank you. We have tried to state the type of ART drug that the individuals are on and its side effects in the discussion line 227-231.

12) You have a limitations paragraph before the conclusion but this should be labeled as such.

� The comment is accepted and addressed accordingly.

13) The first sentence of the conclusion is confusing and should be re-written.

� Yes, you are correct. We have tried to re-write it accordingly.

14) Throughout the paper lots of grammatical errors

� Thank you. We have tried our best to revise our paper accordingly

.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

15 Jul 2021

PONE-D-21-03982R1

Depression and associated factors among HIV infected patients attending public health facilities of Dessie town: A cross-sectional study.

PLOS ONE

Dear Dr. Damtie,

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 Aug 29 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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,

Colette Smith, PhD

Academic Editor

PLOS ONE

Journal Requirements:

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

Additional Editor Comments (if provided):

Thank you for revising and re-submitting your manuscript. I have the following suggestions for you to consider.

Throughout - please use "HIV positive" or "people living with HIV" or "PLWH" rather than "HIV-infected"

Throughout - please refer to "depressive symptoms" instead of "depression".

Abstract - Please clarify that Dessie town is in Ethiopia and give the calendar dates over which the survey was conducted

Abstract - please change line to "PHQ-9) at a cut-off point of 5 was used to assess depressive symptoms". This is because these tools screen for symptomology, rather than confer a clinical diagnosis.

Abstract, result: PLease change "The magnitude of depression among..." to "The prevalence of depression among..."

Abstract, result: Please add in what the comparison group was for the age association (e.g. "Age 40-49 compared to 30-39 years (AOR=3.00; "

Abstract, conclusion: Please change the first sentence to "The prevalence of depression was low compared to previous studies."

Introduction, line 52: Please reword as "In Ethiopia, it was estimated in 20XX that 399,000 of the urban population were living with HIV/AIDS."

Introduction, line 56: Please change to "It disproportionately affects people living with HIV, with a recent meta-analysis indicating a two-fold higher risk compared to the general population [8]".

Introduction, line 58-60 (sentence beginning "The lifetime prevalence of depression..."). I would suggest cutting this sentence as it contradicts the sentence in lines 55-56, and the context for these numbers is not clear.

Introduction, line 61-62. I would suggest rewording as "In Ethiopia, previous studies assessing the prevalence of depression among PLWH have differed considerably, with estimates ranging from 11.7-76.7% [11-15]."

Introduction, line 71. Please change to "Depression has been associated with a wide range of factors, including age, sex, ....".

Introduction, lines 78-81. Is this paragraph necessary? Although i completely agree that ending the HIV/AIDS epidemic is important, its direct link to depression requires more explanation, and is not directly relevant to the manuscript. So this section could be cut.

Methods, line 88. Please clarify that Dessie town is in Ethiopia, and perhaps indicate where Dessie is within Ethiopia (e.g. "A cross-sectional study was conducted between 1-30 March 2019 in public health facilities of Dessie Town, which is a city located within north-central Ethiopia").

Methods, line 91. SHould this be "The study population was randomly selected from all adults with HIV attending public health facilities...."

Methods, sample size. Do you mean that you assumed that 10.1% would have depressive symptoms (so that 89.9% did not)? Otherwise this prevalence seems a little high.

Methods, lines 95-108. This section is perhaps a little long. It could be considerable shortened. For example: "The study sample size was calculated for the primary risk factor as presence of antiretroviral drug side effects, considered as a binary variable. Based on previous research [12], we wished to to detect differences in adjusted odds ratios of at least 4.7, assuming an underlying prevalence of 10.1%, power of 80% and 5% Type I error. After adjustment for 10% non-response, the minimum required sample size was 388. Systematic random sampling was used to select participants using the antiretroviral drug dispenary registration book as the sampling frame. Study participants were invited to participate when attending the health facility for antiretroviral drug collection."

Methods, line 111. Please clarify if the card reviewed was the medical record?

Methods, line 114. Please consider rewording as "The questionnaire collected data on socio-demographic, clinical, psycho-social, and behavioural characteristics."

Methods, line 116. Please clarify that the PHQ-9 is use to measure depressive symptoms rather than depression directly.. Please also clarify that the cut-off of 5 typically corresponds to mild, moderate or severe depressive symptoms as other cut-offs are sometimes used

Methods, line 125. Please give the median score (out of 10?) used to define "high" and "low" stigma. Also, where was this median obtained from, as it appears that only 30% had perceived stigma in Table 2 (instead of the 50% you would expect if the median was taken from this present study).

Methods, line 131. as the study is cross-sectional, the independent variables are not really "predictors". Perhaps "explanatory variables", "factors" or "independent variables" would be better?

Methods, line 135. As this is a cross-sectional study, it may not be appropriate to use the word "determinents". "associated factors" could be an alternative?

Results, line 152. It would be good to give the overall prevalence of depression (for the whole population), before giving it in the sub-groups.

Results, Table 3. Would it be possible to add the question used to define the variable "HIV sero-status disclosure" in a footnote to the table?

Results, Table 3. CD4 count, opportunistic infections and WHO stage are quite correlated - is it reasonable to include all in the model?

Discussion, line 227. Please say "times the odds" rather than "times the risk" here.

Discussion, line 237. You could consider adding the word all, so it reads "cannot be generalised to all people living with HIV".

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

[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.

20 Jul 2021

Colette Smith, PhD

Academic Editor, PLOS ONE

RE-2: Manuscript ID: PONE-D-21-03982R1 (Depression and associated factors among HIV infected patients attending public health facilities of Dessie town: A cross-sectional study.)

Dear Dr. Colette Smith,

Thank you very much for your email and the comments/suggestions of the reviewers and academic editor. We have looked at the comments and have revised our paper accordingly. We hope our paper improved as a result of incorporating the reviewers' and academic editor's comments and suggestions.

Please find for your kind consideration the following:

� A rebuttal letter that responds to each point raised by the academic editor and reviewer labeled 'Response to Reviewers'. The point-by-point responses are written in italic font style.

� A revised manuscript with track changes labeled 'Revised Manuscript with Track Changes'.

� A revised paper without tracked changes labeled 'Manuscript'

While hoping that these changes would meet with your favorable consideration, we are happy to hear if there are more comments and suggestions. Please do not hesitate to let us know if you have any questions.

Yours Sincerely,

Yitayish Damtie

School of Public Health, Wollo University

Dessie, Ethiopia

Tel:+251943517982

E-mail: yitutile@gmail.com

Point by point response

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.

� Thank you. Reference #1, #18, #24, #29 and #30 have been retracted and replace with relevant current references. But reference #2 is retracted and used as it is due to the absence of relevant literature. We indicated its retracted status in the References list.

Additional Editor Comments (if provided):

Throughout - please use "HIV positive" or "people living with HIV" or "PLWH" rather than "HIV-infected"

� Thank you. We have tried to use "HIV positive" throughout the document accordingly.

Throughout - please refer to "depressive symptoms" instead of "depression".

� Thank you. The comment is accepted and addressed accordingly.

Abstract - Please clarify that Dessie town is in Ethiopia and give the calendar dates over which the survey was conducted.

� Thank you. We have tried to clarify it in the abstract section line 29.

Abstract - please change line to "PHQ-9) at a cut-off point of 5 was used to assess depressive symptoms". This is because these tools screen for symptomology, rather than confer a clinical diagnosis.

� Thank you. The comment is accepted and addressed in the abstract section line 33-34.

Abstract, result: PLease change "The magnitude of depression among..." to "The prevalence of depression among..."

� We have tried to address it in the abstract section line 39.

Abstract, result: Please add in what the comparison group was for the age association (e.g. "Age 40-49 compared to 30-39 years (AOR=3.00; "

� Thank you. The comment is accepted and addressed in the abstract section line 40-41 accordingly.

Abstract, conclusion: Please change the first sentence to "The prevalence of depression was low compared to previous studies."

� We have tried to address it in the abstract section line 45 accordingly

Introduction, line 52: Please reword as "In Ethiopia, it was estimated in 20XX that 399,000 of the urban population were living with HIV/AIDS."

� Thank you. The comment is accepted and addressed in the introduction section line 55-56 accordingly.

Introduction, line 56: Please change to "It disproportionately affects people living with HIV, with a recent meta-analysis indicating a two-fold higher risk compared to the general population [8]".

� Thank you. We have addressed it in the introduction section line 58-59 accordingly

Introduction, line 58-60 (sentence beginning "The lifetime prevalence of depression..."). I would suggest cutting this sentence as it contradicts the sentence in lines 55-56, and the context for these numbers is not clear.

� Thank you. We have tried to remove it accordingly.

Introduction, line 61-62. I would suggest rewording as "In Ethiopia, previous studies assessing the prevalence of depression among PLWH have differed considerably, with estimates ranging from 11.7-76.7% [11-15]."

� The comment is accepted and addressed in the introduction section line 61-63 accordingly.

Introduction, line 71. Please change to "Depression has been associated with a wide range of factors, including age, sex ...”.

� Thank you. We have tried to address it in the introduction section line 72-73 accordingly.

Introduction, lines 78-81. Is this paragraph necessary? Although i completely agree that ending the HIV/AIDS epidemic is important, its direct link to depression requires more explanation, and is not directly relevant to the manuscript. So this section could be cut.

� Yes it is necessary. Depression imposed substantial effects on the health of HIV positive patients. It leads to poor ART drug adherence and further transmission of HIV/AIDS. One of the seventeen goal of SDG is to end the HIV/AIDS epidemic by 2030. So, it is difficult to achieve SDG goal (end AIDS epidemic) in the presence of depression as it leads to poor ART drug adherence and further transmission of HIV/AIDS. We have tried to revise it in the introduction section line 81-83.

Methods, line 88. Please clarify that Dessie town is in Ethiopia, and perhaps indicate where Dessie is within Ethiopia (e.g. "A cross-sectional study was conducted between 1-30 March 2019 in public health facilities of Dessie Town, which is a city located within north-central Ethiopia").

� Thank you. We have tried to clarify it in the method section line 91-94 accordingly.

Methods, line 91. Should this be "The study population was randomly selected from all adults with HIV attending public health facilities...."

� We have accepted the comment and addressed it in the method section line 96-97 accordingly.

Methods, sample size. Do you mean that you assumed that 10.1% would have depressive symptoms (so that 89.9% did not)? Otherwise this prevalence seems a little high.

� Thank you. It is editorial issue. It is to mean that 10.1% of patients without ART side effects have depressive symptoms.

Methods, lines 95-108. This section is perhaps a little long. It could be considerable shortened. For example: "The study sample size was calculated for the primary risk factor as presence of antiretroviral drug side effects, considered as a binary variable. Based on previous research [12], we wished to to detect differences in adjusted odds ratios of at least 4.7, assuming an underlying prevalence of 10.1%, power of 80% and 5% Type I error. After adjustment for 10% non-response, the minimum required sample size was 388. Systematic random sampling was used to select participants using the antiretroviral drug dispensary registration book as the sampling frame. Study participants were invited to participate when attending the health facility for antiretroviral drug collection."

� Thank you. The comment is accepted and addressed in the method section line 100-107 accordingly.

Methods, line 111. Please clarify if the card reviewed was the medical record?

� Yes it was the medical record. We have tried to clarify it in the method section line 110 accordingly.

Methods, line 114. Please consider rewording as "The questionnaire collected data on socio-demographic, clinical, psycho-social, and behavioral characteristics."

� We have revised it in the method section line 113-114 accordingly.

Methods, line 116. Please clarify that the PHQ-9 is used to measure depressive symptoms rather than depression directly. Please also clarify that the cut-off of 5 typically corresponds to mild, moderate or severe depressive symptoms as other cut-offs are sometimes used

� Thank you. We used PHQ-9 scale to assess depressive symptoms. In the PHQ scale, a score of 0-4, represents no depression and a score of 5-9, 10-14, 15-19 and 20-27 represent mild, moderate, moderately sever and sever depressive symptoms respectively. In this study, PHQ score ≥ 5 was used as a bench mark to categorize depression. Accordingly, patients said to have depressive symptoms if they scored ≥ 5 and have no depressive symptoms if they scored <5.

Methods, line 125. Please give the median score (out of 10?) used to define "high" and "low" stigma. Also, where was this median obtained from, as it appears that only 30% had perceived stigma in Table 2 (instead of the 50% you would expect if the median was taken from this present study).

� Stigma was assessed by using ten ‘yes’ or ‘no’ questions and the score ranged from 0 to 10. In our study, out of 380 study participants, 266 of them scored 0, 11 of them scored 1, 4 patients scored 2, 9 patients scored 3, 14 patients scored 4, 29 patients scored 5, 23 patients scored 6, 16 patients scored 7, and the remaining 8 patients scored ≥8 out of 10. The median score is the middle number in a given sequence of numbers when it’s ordered by rank. In this study, the median score is 0. Accordingly, having perceived stigma was defined if patients scored above the median score (i.e. above 0) which is 30%. Perceived stigma cannot be 50% since a score of greater than the median value was used to define perceived stigma. You can confirm it in manual calculation using the above frequency distribution. Median value can be calculated manually or using SPSS.

Methods, line 131. as the study is cross-sectional, the independent variables are not really "predictors". Perhaps "explanatory variables", "factors" or "independent variables" would be better?

� We have tried to use the term "independent variables" accordingly.

Methods, line 135. As this is a cross-sectional study, it may not be appropriate to use the word "determinents". "associated factors" could be an alternative?

� We have tried to use the term "associated factors" accordingly.

Results, line 152. It would be good to give the overall prevalence of depression (for the whole population), before giving it in the sub-groups.

� We have tried to put the overall prevalence of depression in the result section line 154 accordingly.

Results, Table 3. Would it be possible to add the question used to define the variable "HIV sero-status disclosure" in a footnote to the table?

� We have tried to put it as a table footnote accordingly.

Results, Table 3. CD4 count, opportunistic infections and WHO stage are quite correlated - is it reasonable to include all in the model?

� We have tried to re-analyze the data by removing ‘CD4 count’ and ‘WHO stage’ from the model accordingly.

Discussion, line 227. Please say "times the odds" rather than "times the risk" here.

� Although it is not clear, we have tried to revise it as “The odds of depressive symptoms were 2.6 times more among patients who took medication other than ART as compared to their counterparts”.

Discussion, line 237. You could consider adding the word all, so it reads "cannot be generalised to all people living with HIV".

� The comment is accepted and addressed accordingly.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

26 Jul 2021

Depressive symptoms and associated factors among HIV positive patients attending public health facilities of Dessie town: A cross-sectional study.

PONE-D-21-03982R2

Dear Dr. Damtie,

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,

Colette Smith, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

28 Jul 2021

PONE-D-21-03982R2

Depressive symptoms and associated factors among HIV positive patients attending public health facilities of Dessie town: A cross-sectional study.

Dear Dr. Damtie:

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. Colette Smith

Academic Editor

PLOS ONE