Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study

Tadesse Sime; Lemessa Oljira; Aboma Diriba; Gamachis Firdisa; Wubishet Gezimu

doi:10.1371/journal.pone.0277021

. 2022 Oct 31;17(10):e0277021. doi: 10.1371/journal.pone.0277021

Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study

Tadesse Sime ¹, Lemessa Oljira ², Aboma Diriba ³, Gamachis Firdisa ¹, Wubishet Gezimu ^1,^*

Editor: Ari Samaranayaka⁴

PMCID: PMC9621427 PMID: 36315573

Abstract

Background

In resource-limited countries such as Ethiopia, tuberculosis is the major cause of morbidity and mortality among people living with the human immunodeficiency virus. In the era of antiretroviral therapy, the effect of tuberculosis on the survival of patients who are living with human immunodeficiency virus has been poorly understood in Ethiopia. Therefore, this study aimed to determine the effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy in public hospitals in Eastern Ethiopia.

Methods

An institution-based retrospective cohort study was conducted among 566 participants from January 1, 2014, to June 30, 2018. The collected data were entered into EpiData version 3.1 before being exported to Stata version 14 for analysis. A Cox proportional hazard model was used to determine the effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy, and a p-value less than 0.05 and a 95% confidence level were used to declare statistical significance.

Result

Of the 566 patients included in the study, 76 died. The mortality rate was 11.04 per 100 person-years in tuberculosis co-infected patients, while it was 2.52 per 100 person-years in non-tuberculosis co-infected patients. The patients with tuberculosis co-infection had a 2.19 times higher hazard of death (AHR: 2.19; 95% CI: 1.17, 4.12) compared to those without tuberculosis. Advanced clinical stage, low CD4+ cell count, and previous episodes of an opportunistic infection other than tuberculosis were found to be independent predictors of mortality.

Conclusion

Co-infection with tuberculosis at antiretroviral therapy initiation increases the hazard of death approximately two-fold. Hence, we recommend key organizations to enhance the region’s collaborative interventional and preventative strategies for TB and HIV.

Introduction

Human health has been significantly impacted by the human immune virus-tuberculosis (HIV-TB) syndemic, which disproportionately affects people in Africa [1]. In 2015, of an estimated 10.4 million cases of tuberculosis (TB) disease globally, 1.2 million (11%) cases were among people living with human immune viruses (PLHIV), and 60% of TB cases among PLHIV were not diagnosed or treated, resulting in 390,000 TB-related deaths among HIV patients [2]. PLHIV are 15–22 times more likely to develop TB than people without.

TB is the most common illness among PLHIV and it is the major cause of HIV-related deaths, particularly resource-limited settings. Sub-Saharan Africa bears the brunt of the dual epidemic, accounted for approximately 84% of all deaths from HIV-associated TB in 2018 [3]. A recent study conducted on the effect of TB on mortality in PLHIV found that TB increases overall mortality in HIV patients [4, 5].

Ethiopia is one of the 30 nations with a higher prevalence of TB-HIV co-infection worldwide, and in 2016, out of the 36,761 HIV-positive patients who were newly enrolled in antiretroviral therapy (ART), 5.9% had TB as well [6, 7]. According to Ethiopia’s 2014 TB-HIV surveillance report, 9.1% of HIV-infected clients newly enrolled in HIV care had active TB. In particular, the percentages of active TB patients in Harar Regional State and Dire Dawa City Administration were 14.2% and 11.5%, respectively [8]. According to some empirical evidence, being co-infected with TB increases the risk of death in HIV-infected patients when compared to those who are not co-infected with TB [9–12].

Regarding the predictors of mortality, scientific evidence has identified a few baseline socio-demographic and clinical predictors of mortality in HIV-infected patients [11, 13–15]. TB mortality among HIV-positive patients is one of the key indicators that measure the impact of TB-HIV collaborative activities [16]. Ethiopia has been implementing national collaborative activities between TB and HIV/AIDS control programs like routine HIV testing among presumptive and diagnosed TB cases; TB screening among PLHIV; early initiation of ART; improved infection control; and provision of TB preventive treatment to decrease the burden of TB in PLHIV [17].

Despite the various evidence across the world showing the causal effect of TB on the mortality of TB-HIV co-infected patients before the ART era, there has been insufficient data to draw firm conclusions about the phenomenon in the ART era [18]. Therefore, this study aimed to determine the effect of TB co-infection at ART initiation on the survival of HIV-infected adults initiated on ART in public hospitals in Eastern Ethiopia. The study’s hypothesis was that there is no significant difference in survival between HIV-infected people with and without TB at the start of ART.

Methods and materials

Study design, period and area

An institution-based retrospective cohort study was conducted from January 1, 2014, to June 30, 2018, at public hospitals in Harar Regional State and Dire Dawa City Administration of Eastern Ethiopia. The study included all the public hospitals (Hiwot Fana Specialized University Hospital, Jugol Hospital, Dil Chora Referral Hospital, and Sabian General Hospital) in the two regions.

Study participants and eligibility criteria

Inclusion criteria

PLHIV who started ART from January 1, 2014, to June 30, 2018, were included in the study and classified into TB co-infected and not-infected groups. Patients with TB co-infected were included in the exposed group, whereas those not co-infected with TB were included in the non-exposed group.

Exclusion criteria

Patients with incomplete registration cards on the date of ART initiation, patients who started ART from other healthcare institutions (transferred in), and mothers who initiated ART for the prevention of mother-to-child transmission (PMTCT) were excluded.

Sample size calculation

The sample size for the Cox proportional hazard (PH) regression was calculated using Stata software, assuming a 95% confidence interval (CI), 80% power, 0.05 alpha, 0.2 beta, 20% loss to follow-up, 0.1 overall probability of the event, 2.3 adjusted hazard ratio (AHR) taken from the Somali Region study [11], and a 1:1 exposed to unexposed group ratio, which gives a total sample size of n = 566. Of the 566 patients, 283 were included in the exposed group, whereas 283 were in the non-exposed group. Both groups were selected by a simple random sampling technique using a unique identification number and, after enrollment, retrospectively followed for six months until December 31, 2018 [Fig 1].

Sampling techniques

Of the two regions (Harar and the Somali Regional States) and a city administration (Dire Dawa City Administration) found in eastern Ethiopia, we randomly selected the Dire Dawa City administration and Harar Regional State. All the public hospitals (Hiwot Fana Specialized University Hospital, Jugol Hospital, Dil Chora Referral Hospital, and Sabian General Hospital) found in the two regions were included in the study. A random sampling stratified by hospital and exposure status was used to select the study participants. First, the required sample was proportionally allocated to the four hospitals. Then the population in each hospital was stratified based on their exposure status. Finally, every study participant was selected randomly from each stratum [Fig 1].

Data collection tool, procedures, and quality control

The data collection instrument was adapted from the standardized national ART entry and follow-up form of the Ethiopian Federal Ministry of Health (FMOH) and other similar literatures [S1 Table].

Data extraction was done by eight nurses who work in ART clinics and, likewise, supervised by two BSc nurses. The profiles of all selected HIV-infected patients who initiated ART in the period between January 1, 2014, and June 30, 2018, were reviewed; lab requests, follow-up forms, ART intake forms, and patient cards were reviewed. If there were no laboratory tests at ART initiation, results obtained within one month of ART initiation were used as the baseline. The patient’s date of death was extracted from the ART follow-up registration form and from the patient death summary sheet for hospital death.

To ensure data quality, training was provided for data extractors and supervisors. Data supervisors, data clerks, and investigators checked the completeness and consistency of data before and after data entry. Moreover, double data entry was performed to prevent data entry errors.

Study variables

The outcome variable of this study was the time from ART initiation to death due to any cause during the follow-up time. Age, sex, place of residence, marital status, level of education, occupation, World Health Organization (WHO) clinical stage, CD4+ cell count, hemoglobin level, adherence to ART, the status of co-trimoxazole prophylaxis, body mass index (BMI), functional status, and opportunistic infection (other than TB) were independent variables included in this study.

Operational definitions

Event: All-cause mortality ascertained from death certificates if patients died in hospital and from ART registration reported by adherence supporters via phone calls.

Censor: Patient was censored on their last visit if they lost to follow up, date of transfer for transferred out or at the end of the study (on December 31, 2018) if they still alive.

Time scale: The survival time was calculated in months using the time between the dates of treatment initiation and the date of the event (death) or date of censoring. The maximum and the minimum follow-up were 60 months and 6 months, respectively.

TB co-infection: was any confirmed active TB (pulmonary as well as extra pulmonary) at ART initiation or within the first three months of ART initiation. (1) Definitive tuberculosis (TB) is defined as TB confirmed by the GeneXpert test, acid-fast Bacillus (AFB) in sputum or body fluid/tissue, and chest radiography. (2) Presumptive TB: TB diagnosed clinically and anti-TB treatment initiated.

Adherence to ART: Adherence to ART was evaluated by the percentage of missed doses documented by the ART physician and ranked as good (if < 5% (< 2 doses of 30 doses or <3 doses of 60 doses), fair (if between 5−15% (3–5 doses of 30 doses or 3−9 doses of 60 doses) or poor (if >15% (>6 doses of 30 doses or >9 doses of 60 doses) as documented by the ART physician.

Initiation of Co-trimoxazole prophylactic therapy: Patients who had been taking Co-trim oxazole for more than a month for prophylaxis.

Patient functional status:

Working: able to perform usual work in or out of the house.

Being ambulatory patient: able to perform activities of daily living.

Being bedridden patient: not able to perform activities of daily living.

Statistical analysis

The collected data were coded and entered into Epi Data version 3.1 before being exported to Stata software version 14.2 for analysis. The data were cleaned and edited prior to analysis using simple frequencies and cross-tabulation. The clinical and demographic characteristics of the HIV cohort with and without TB co-infection were described. A Chi-square test (Fisher’s exact) and T-test were used to compare categorical and continuous variables between the two cohorts, respectively. The survival time was calculated from the date of ART initiated to death among HIV patients who initiated ART from January 1, 2014, to June 30, 2018, and retrospectively followed for an additional six months until December 31, 2018. The patient exited on the date of the last follow-up if the patient was lost to follow-up or transferred out; December 31, 2018, if the patient is still alive; or the date of death if the patient died. The Kaplan-Meier survival estimate was used to estimate the probability of death and the median time to death among HIV patients co-infected with TB and patients not co-infected with TB at the initiation of ART. The log-rank test was used to test the equality of survival functions between patients with TB and those without TB. A life table was used to calculate the cumulative survival probability of the cohorts. The fitness of the Cox PH model was checked using graphic and Schoenfield residual tests. The predictors were considered when the resultant curves were parallel and the Schoenfield residuals test was statistically insignificant. Moreover, multicollinearity was checked by using a variance inflation factors (VIF) test. A test value of less than 10 was considered to indicate the absence of multicollinearity between the study variables. The multivariable model was built using the backward elimination method of variable selection and confounding was checked. The percentage change in the regression coefficients (β) of less than 20% reveals the absence of confounders [19]. A Cox PH model was used to identify factors associated with mortality, and a p-value < 0.05 declares the significance of the variables at a 95% confidence level.

Ethical approval and informed consent

Ethical clearance was obtained from the Institutional Health Research and Ethical Review Committee (IHRERC) of Haramaya University College of health and medical sciences. Following the approval, an official letter of cooperation was written to public hospitals in Harar and Dire Dawa towns. Informed, voluntary, written and signed consent was obtained from the medical directors of the hospitals. To preserve patient confidentiality, nurses working in the ART clinics extracted the data from patients’ medical records at each hospital. Moreover, no personal identifiers were used on the data collection form.

Results

Socio-demographic characteristics of the participants

A total of 566 HIV-infected patients (283 TB co-infected and 283 not TB co-infected cohorts) were followed retrospectively for a median of 18.8 months with an interquartile range (IQR) of 7.0–36.3 months in TB co-infected and 24.3 months (IQR = 13.7–40.2) months among not TB co-infected cohorts. Both cohorts were statistically different for place of residence (p = 0.003), sex (p = 0.003), and occupation (p = 0.001) attributes of the socio-demographic. The majority of study subjects were urban residents, 238(84.1%) and 261(92.2%) in TB co-infected and not TB co-infected cohorts, respectively. The median age of study subjects was 35 years with an IQR of 28–42 years and 34 with an IQR of 28–40 years in TB co-infected cohorts and non-TB co-infected patients, respectively [Table 1].

Table 1. Socio-demographic characteristics of the study participants who initiated ART in the public hospitals of Eastern Ethiopia (from January 1, 2014, to June 30, 2018), n = 566.

Variables	Categories	TB co-infected	Not TB co-infected	X² Value (df)	p- value
Residence	Urban	238(84.1%)	261(92.2%)	8.955	0.003
Residence	Rural	45(15.9%)	22(7.8%)	(1)
Age	Mean (±SD)	35 ± 10	35.13 ± 10.92	- 0.116	0. 907
Age	Median (IQR)	35(28–42)	34(28–40)
Sex	Male	144 (50.9%)	107 (37.3%)	8.784	0.003
Sex	Female	139 (49.1%)	176 (62.2%)
Religion	Muslim	113 (40%)	87(30.7%)	5.897	0.117
	Orthodox	147 (52%)	164(58.7%)	(3)
	Protestant	20 (7%)	24(8.5%)
	Other ^4,5	3 (1%)	6(2.1%)
Marital status	Married	115(40.6%)	128(45.2%)	5.664	0.226
	Never married	71(25.1%)	50(17.7%)	(4)
	Divorced	55(19.4%)	54(19.1%)
	Widowed	33(11.7%)	37(13%)
	Separated	9 (3.2%)	14(5%)
Level of education	No formal education	68(24.4%)	55(19.8%)	3.765	0.288
	Primary	112(40.1%)	103(37%)	(3)
	Secondary	69(24.7%)	84(30.2%)
	Tertiary and above	30(10.8%)	36(13%)
Occupation	Merchant	43(15.2%)	38(13.5%)	25.083	0.001
	Government employee	30(10.6%)	59(20.9%)	(7)
	Non-governmental employee	16(5.7%)	6(2.1%)
	Day laborer	39(13.8%)	31(11%)
	Driver	8(2.8%)	12(4.3%)
	Farmer	18(6.4%)	4(1.4%)
	Jobless	117(41.3%)	118(41.8%)
	Other^b	12(4.2%)	14(5%)

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Note: others

^a: Catholic and traditional believers; others

^b: student, housewife and commercial sex worker; SD: standard deviation; IQR: interquartile range.

Baseline clinical and immunological characteristics

In this study, there was a statistical difference in the WHO clinical stage (p<0.001) between the two cohorts. The majority of TB co-infected patients group were in the WHO clinical stage III at ART initiation (202, 71.4%), and among the cohort without TB, only 69(24.4%) were in WHO clinical stage III. Both cohorts were also statistically different in functional status (p<0.001) and BMI level (p<0.001). Patients’ CD4+ cell count (p<0.001) and hemoglobin level (p<0.001) also showed a statistical differences between the two cohorts. The majority of patients had at least one episode of opportunistic infection other than TB in the past. Of them, 156 (55.1%) were from TB co-infected groups, and 126 (42.86%) were from non-TB co-infected groups (p<0.001) [Table 2].

Table 2. The baseline clinical and immunologic characteristics of study participants who initiated ART in the public hospitals of Eastern Ethiopia (from January 1, 2014, to June 30, 2018), n = 566.

Variables	Categories	TB co-infected	Not TB co-infected	X² Value (df)	p- value
WHO clinical stage	Stage I/II	13(4.6%)	185(65.4%)	230.367	< 0.001
	Stage III\	202(71.4%)	69(24.4%)	(2)
	Stage IV	68(24%)	29(10.3%)
BMI	<16kg/m²	66 (23.4%)	29(10.4%)	41.798	< 0.001
	16–18.5kg/m²	105 (37.2%)	66(23.6%)
	> = 18.5kg/m²	111(39.4%)	185(66%)
Functional status	Working	140(49.5%)	221(78.1%)	53.430	< 0.001
	Ambulatory	96(33.9%)	50(17.7%)	(2)
	Bedridden	47(16.6%)	12(4.2%)
Hemoglobin	Mean (± SD)	11.3 ± 2.46	12.5 ± 2.52	-5.453	< 0.001
Hemoglobin	Median (IQR)	11.4(9.7–13.2)	12.6 (11–14.4)
CD4+ cell count level in cells/mm3 (n = 552)	Mean (± SD)	189.8 ± 178.2	352.9 ± 265.6	-8.475	< 0.001
CD4+ cell count level in cells/mm3 (n = 552)	Median (IQR)	137 (69–262)	304(137–489)
Initial ART regimen	1c = AZT+ 3TC + NVP	4 (1.4%)	5 (1.8%)	-	0.395
	1d = AZT+ 3TC + EFV	1 (0.4%)	3 (1%)
	1e = TDF + 3TC + EFV	276 (97.4%)	271 (95.8%)
	1f = TDF + 3TC + NVP	1(0.4%)	3 (1%)
	1g = ABC_+3TC_+EFV	1(0.4%)	1(0.4%)
ART adherence	Good	229 (82.1%)	250 (88.7%)	6.015	0.049
	Fair	13(4.7%)	12 (4.3%)	(2)
	Poor	37(13.3%)	20 (7%)
Co-trimoxazole prophylaxis	Yes	257(90.8%)	235(83%)	7.524	0.006
Co-trimoxazole prophylaxis	No	26(9.2%)	48(17%)	(1)
OPI other than TB	Yes	156(55.1%)	203(71.7%)	16.824	< 0.001
OPI other than TB	No	127(44.9%)	80(28.3%)	(1)
Follow-up outcome	Dead	60(21.2%)	16(5.7%)	31.468	< 0.001
	Transferred out	18(6.4%)	18(6.4%)	(3)
	Loss to follow up	25(8.8%)	21(7.4%)
	Alive / On treatment	180(63.6%)	228(80.6%)

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Note: OPI: opportunistic infection, df: degree of freedom.

Comparison of survival based on TB co-infection status

There were 76 (13.4%) deaths in this study cohort, with the majority of deaths (50, or 65.7%) occurring in the first 6 months. All the study participants (566) had contributed a total of 13910.8 person-months; 6455.8 person-months in the TB co-infected cohort and 7455 person-months in the non-TB co-infected cohort, respectively. The overall mortality rate was 6.55 per 100 person year observation (PYO) (95% CI: 5.28, 8.16 per 100 PYO). The incidence of death in TB co-infected cohorts was 11.04 per 100 PYO of follow-up (95% CI: 8.64, 13.2 per 100 PYO) and 2.52 per 100 PYO of follow-ups (95% CI: 1.56, 4.2 per 100 PYO) in non-TB co-infected cohorts.

The median time to death during follow-up has shown variation between the two groups. The median time to death was 2.5 months and 12.2 months in the TB co-infected cohort and non-TB co-infected cohort, respectively. Based on actuarial life table analysis, the estimated survival probability of the whole cohort at 6, 12, 24, 36, 48, and 60 months was 91%, 89.4%, 86.2%, 84.6%, 84.6%, and 80%, respectively. The survival probability at 1 year of ART initiation was 81.6% (95% CI: 76.4% to 85.7%) and 97.1% (95% CI: 94.1% to 98.5%) among those with TB and without TB, respectively. The cumulative survival probability at 60 months of follow-up was approximately 69% (95% CI: 57%-78.9%) in TB co-infected groups and 93% (88.5% -95.6%) among non-TB co-infected groups. The overall survival probability in the TB co-infected was significantly lower than in the non-TB co-infected group throughout the study period (log-rank statistic = 31.01, df = 1, P 0.001) [Fig 2].

Predictors of mortality

After adjusting for WHO clinical stage, past opportunistic infection other than TB, and CD4+ cell count, the hazard of death was more than two-folds (AHR: 2.19: 95% CI 1.17, 4.12) higher among TB-co-infected patients at ART initiation than those without TB at ART initiation in multivariable Cox regression analysis. Patients in WHO clinical stage IV had nearly three times the hazard of death (AHR 3.06, 95% CI: 1.16, 8.09) than those in WHO clinical stage I/II. Patients with a CD4+ cell count of less than 50 cells/mm3 at the start of ART had a nearly fourfold increased hazard of death (AHR 3.75; 95% CI: 2.00, 7.03) when compared to those with a CD4+ cell count greater than 200 cells/mm³. Moreover, the hazard of death was 65% (AHR 1.65, 95% CI: 1.01, 2.68) higher among patients with at least one opportunistic infection other than TB compared to those without an opportunistic infection other than TB [Table 3].

Table 3. Results of the multivariable Cox regression analysis of mortality in study participants who initiated ART in the public hospitals of Eastern Ethiopia (from January 1, 2014, to June 30, 2018), n = 552.

Variables	Categories	Survival status		Crude HR (95%CI)	Adjusted HR (95%CI)	P-value
Variables	Categories	Dead	Censored	Crude HR (95%CI)	Adjusted HR (95%CI)	P-value
TB co-infection	Yes	60 (79%)	223 (45.5%)	4.22(2.43, 7.32)	2.19 (1.17, 4.12)	0.014
TB co-infection	No	16 (21%)	267 (54.5%)	(1)	(1)
Sex	Male	40(52.6%)	209 (42.6%)	1.45 (0.93, 2.28)	1.41 (0.87, 2.27)	0.154
Sex	Female	36(47.4%)	281 (57.4%)	(1)	(1)
WHO clinical stage	Stage I/II	7 (9.2%)	191 (39%)	(1)	(1)
	Stage III	42 (56.3%)	229 (46.7%)	4.79(2.15,10.66)	1.80 (0.72, 4.52)	0.206
	Stage IV	27 (35.6%)	70 (14.3%)	9.26(4.03,21.28)	3.06 (1.16, 8.09)	0.024
BMI	<18.5 kg/m2	49 (66.2%)	228 (46.3%)	2.21 (1.37, 3.58)	1.54 (0.93, 2.55)	0.091
BMI	> = 18.5kg/m2	25 (33.8%)	260 (53.3%)	(1)	(1)
Functional status	Working	36 (47.3%)	325 (66.3%)	(1)	(1)
	Ambulatory	20 (26.3%)	126 (25.7%)	1.47(0.85, 2.54)	0.79 (0.44–1.42)	0.446
	Bedridden	20(26.3%)	39 (8%)	4.40 (2.55, 7.62)	1.70 (0.90, 3.23	0.101
CD4+ cell count level in cells/mm3	< 50	23 (30.7%)	49 (10.2%)	6.23(3.39,11.46)	3.75 (2.00, 7.03)	<0.001
	50–199	33 (44%)	160 (33.5%)	2.86(1.63, 5.04)	1.78 (0.99, 3.19)	0.051
	> = 200	19 (25.3%)	268 (56.2%)	(1)	(1)
ART adherence	Good	58 (77.3%)	421 (86.6%)	(1)	(1)
	Fair	5 (6.7%)	20 (4.1%)	1.73(0.69, 4.32)	2.08 (0.79, 5.44)	0.136
	Poor	12 (16%)	45 (9.3%)	2.18(1.17, 4.07)	1.60 (0.84, 3.03)	0.146
OPI other than TB	Yes	43 (56.4%)	164 (33.5%)	2.45(1.56, 3.86)	1.65 (1.01, 2.68)	0.044
OPI other than TB	No	33 (43.4%)	326 (66.5%)	(1)	(1)

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Note: 1 = reference category; BMI: body mass index; HR: hazard ratio

Discussion

In the current study, the overall mortality rate was 6.55 per 100 PYO in the entire follow-up period. This finding is comparable with previous studies conducted in the seven University Teaching Hospitals and the Somali Regional State of Ethiopia [11, 13]. However, it is higher compared to the studies conducted in Jinka Hospital, South Omo zone of Ethiopia, and other countries of Africa [14, 20, 21]. The reason for this difference might be due to the fact that in this study, over 65% of study participants started antiretroviral therapy while at WHO stage III or IV of the disease severity, and the small number of TB co-infected patients in latter studies.

In this study, the mortality rate among TB co-infected and those without TB was 11.04 per 100 PYO and 2.52 per 100 PYO, respectively. This finding showed a higher mortality rate among TB co-infected cohorts when compared to a finding from South Africa [22], in which the mortality rate among TB co-infected patients on ART was 4.84 per 100 PYO. This difference might be due to the fact that the country has made robust efforts to tackle the two diseases simultaneously and has stipulated the integration of HIV and TB services nationwide through the co-location of services. Additionally, the variation may be due to the two countries’ diverse socioeconomic situations.

In the present study, the estimated survival probability of the cohort at the end of the follow-up period was 80%, and the majority (65.7%) of deaths occurred in the first six months of ART initiation. The survival probability at 1 year of ART initiation was 81.6% among the cohort with TB, whereas it was 97% among those without TB. This finding is in agreement with a retrospective cohort study conducted in the United Kingdom [4]. However, this survival probability is lower than that of a study conducted in the Somali region in which the overall survival probability was 85.9% [11]. This difference might be due to less follow-up time and a higher loss of follow-up in the latter study. On the other hand, the death rate in the first six months was comparable to retrospective cohort studies conducted in Ethiopia [11, 13].

In our study, the hazard of mortality was two-fold higher in patients who were TB co-infected at ART initiation. This finding is consistent with the studies conducted in the United States of America (USA), Uganda, and Ethiopia [5, 11, 12]. This result contrasts with research from South African and Ethiopian studies that found no link between active TB at the start of ART and patients’ overall survival [23, 24]. This difference might be due to variations in the study settings and the level of care given. The country has also provided integrated HIV/TB services for people in correctional facilities, the communities surrounding the industry, and community-based TB-HIV screening and early linkage to care where transmission of both HIV and TB is high. Moreover, the difference might be due to the small number of TB co-infected patients who participated in the latter study.

Regarding the predictors, the present study revealed that patients presenting with an advanced disease stage (WHO clinical stage IV) had a nearly three times higher hazard of death as compared to patients not in an advanced disease stage (WHO clinical stage I and II). This finding is in line with a study conducted in Tanzania [21] and it is also congruent with the previous studies conducted in Ethiopia [11, 14, 25, 26]. This might be due to the fact that HIV weakens the immune system and thereby leads to more opportunistic infections likely to occur, which adversely affect the survival of HIV patients.

In this study, having a lower CD4+ cell count was found to be an independent predictor of death. When comparing patients with a CD4+ cell count of less than 50 cells/mm³ to those patients with a CD4+ cell count of greater than 200 cells/mm³, the hazard of death nearly quadrupled. This result is consistent with previous studies conducted in Ethiopia [11, 26, 27]. This might be due to the fact that late ART initiation is a pervasive problem in sub-Saharan Africa, which results in poor prognosis and an increased risk of opportunistic infection [28].

In our study, patients who suffered from opportunistic infections other than TB had a 65% higher hazard of death as compared to those patients who were free of opportunistic infections in the past. When compared to a study conducted in the United Kingdom, which discovered that prior opportunistic infections increased the risk of death by 7.4 fold [4], this effect is less pronounced. This difference might be due to the difference in baseline exposure to ART; in this study, patients were followed after ART initiation, while in the later study, follow-up of patients were started from HIV diagnosis.

Limitation of the study

This research has a few limitations. First, in observational cohort studies, uncontrolled confounding can never be completely eliminated. Although all deaths were determined to be related to disease and not accidental based on patient death certificates and telephone conversations with ART adherence support, the cause-specific mortality was not reported due to a lack of cause-specific data. Thus, the death rate might have been slightly overstated by this condition. Factors like patient social conditions were left out of the analysis since they were insufficient for the majority of patients. This result might be slightly biased as a result of the exclusion of patients who transferred out.

Conclusion

This study showed that HIV patients who were co-infected with TB at ART initiation experienced substantial mortality rates. In HIV-infected patients who initiated ART in the study area, having active TB at the time of ART commencement substantially doubles the chance of death. The study also showed that past experiences of opportunistic disease, low CD4+ cell count, and advanced clinical WHO stage (stage IV) were independent predictors of mortality. Therefore, we recommend that key organizations to improve the region’s collaborative interventional and preventative programs for TB and HIV.

Supporting information

S1 Table. Questionnaire.

(DOCX)

Click here for additional data file.^{(26.3KB, docx)}

S2 Table. STROBE statement checklist.

(DOCX)

Click here for additional data file.^{(23KB, docx)}

S1 Data

(DTA)

Click here for additional data file.^{(115.4KB, dta)}

Acknowledgments

We gratefully acknowledge and appreciate the ART clinic staff and medical record room staff of Hiwot Fana Specialized University Hospital, Jugol Hospital, Dil Chora Referral Hospital, and Sabian General Hospital for their invaluable cooperation during data collection. We are also grateful to the Harar Regional Health Bureau and Dire Dewa City Administration Health Bureau for facilitating conditions while carrying out this study.

Abbreviations

AHR: Adjusted Hazard Ratio
ART: Antiretroviral Therapy
BMI: Body Mass Index
CPT: Co-trimoxazole Prophylaxis Treatment
HIV: Human Immunodeficiency Virus
PLHIV: People living with Human Immunodeficiency Virus
PYO: Person year observation, TB: Tuberculosis
WHO: World health organization

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

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

References

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PLoS One. doi: 10.1371/journal.pone.0277021.r001

Decision Letter 0

Ari Samaranayaka

6 Sep 2022

PONE-D-22-21893Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort studyPLOS ONE

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2. We note you have included a table to which you do not refer in the text of your manuscript. Please ensure that you refer to Table 2 in your text; if accepted, production will need this reference to link the reader to the Table.

Additional Editor Comments:

Major comments:

1. Although authors say all data are within supporting files, supporting documents include the questionnaire and strobe list, not the data.

2. line 89-91. please rephrase to improve clarify. I assumed people who started ART treatment during these times points were included in the study, and classified into infected and not-infected groups.

3. line 96. How the sample size was calculated was explained, but the resultant sample size was not given, why? Appears N=566 recruitment was not based on above calculation.

4. Please explain patients identifying procedure more clearly. If people were randomly selected from health records, then their TB-infection status was determined, how did you ensure equal sized groups (N=283 in both TB-positive and TB-negative groups)?

5. line 114. “All the profiles of HIV-infected patients between January 1, 2014, and June 30, 2018, were reviewed”. why you review all patients, instead of reviewing only those selected, if patients were selected using simple random sampling?

6. Cox regression was used to analyse the duration from ART initiation to the death. What is the definition of death? Line 131 says “all-cause mortality”, but line 313 says disease-specific mortality.

7. line 168. “Kaplan-Meier test”. Is it correct to describe this estimation procedure as a test?

8. line 170. “The log-rank test was used to compare the median time to death between patients with TB and those without TB”. Can logrank test compare median times to death?

9. By looking at figure1 I assume proportional assumptions is ok, but for completeness please include in statistical analysis section how you assessed it.

10. tables 1 and 2. I think you have presented ttest statistics as chisquare statistics. Also, explain why test statistic not given for some; eg, fishers exact was used?

11. “median time to death was 2.5 months and 12.2 months in the TB co-infected cohort and non-TB co-infected cohort, respectively”. How many deaths were used in each of these groups to arrive at these estimates?

12. table3. Why N was reduced when there were no missing values in of the variables?

Minor comments

1. undefined abbreviations. eg; ART, PLWH, PMTCT, OPI, PY, spell out all abbreviations at first use.

2. line 54. what is meant by 5.9 patients, is it 5.9% ?.

3. line 57. why two percentages active TB patients (14.2% and 11.5%) for Harari?

4. line 68-72. Cannot understand this very long sentence with undefined abbreviations.

5. line 117. “a baseline” or “the baseline”?

6. Line 130. operational.

7. table2 title. repetition.

8. reference 19. what is meant by “Vol 618” when this is a text book?

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

Reviewer #4: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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: Yes

Reviewer #3: Yes

Reviewer #4: 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: 1. Is the manuscript technically sound, and do the data support the conclusions?

Yes, the manuscript is technically sound. The conclusions were drawn appropriately based ob the data presented. The retrospective study had experimental and control groups. The sample size was adequate from the power analysis of the study.

What is our baseline definition for this study? Is it tuberculosis co-infection at antiretroviral therapy initiation? If yes, clarify the WHO clinical staging for the experimental group with respect to TB co-infection. Lines 205 and 206 talked about 71.4% of TB co-infected patient group as being in WHO clinical stage III at ART initiation. By definition presence of TB infection automatically places a patient in at least clinical stage III. 4.6% of patients were reported to be in clinical stages I and I. Why do we have stages I and II with TB-confection for patients at baseline for the experimental group.

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

Yes, the statistical analyses were appropriate for the study

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

Yes, all data underlying the findings in the manuscript were made available by the authors

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

Some typos and grammatical errors were found.

Here are a few examples I found:

Line 130 - typo on "Operational"

Line 141 - correct word is "GeneXpert" not Gen Xpert

Line 150 - correct word is "Co-trimoxazole"

205 two cohorts. The majority of TB co-infected group patients were in WHO clinical stage III at. "Patients should come before group" corrected should be "The majority of TB co-infected patients group were in WHO clinical stage III at"

Line 305 "Africa, which faster prognosis of disease and increase opportunistic infection" is grammatically wrong

Reviewer #2: This study by Wubishet Gezimu, et al., was an institution-based retrospective cohort conducted in public hospitals in Eastern Ethiopia. The participants were randomly selected from January 1, 2014 to June 30, 2018.

The purpose of the study was to determine the effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy in public hospitals in Eastern Ethiopia.

Dependent (outcome) variables: Time from ART initiation to death

Independent (predictors) variables:

• sociodemographic features: age, sex, place of residence, marital status, educational status, occupation, and clinical.

• treatment-related characteristics: WHO clinical stage, CD4 count level, hemoglobin level, adherence to ART, co-trimoxazole prophylaxis status, BMI, and functional status

• opportunistic infections other than TB were included.

A total of 566 participants were randomly selected from January 1, 2014, to June 30, 2018. The collected data were entered into EpiData version 3.1 and then exported to Stata version 14

software for analysis. A Cox proportional hazard model was used to determine the

effect of active tuberculosis on the survival of HIV-infected adult patients who initiated

antiretroviral therapy, and a p-value less than 0.05 and a 95% confidence level was

used to declare statistical significance. Ethical clearance was obtained from the Institutional Health Research and Ethical Review Committee (IHRERC) of Haramaya University College of health and medical sciences.

had a 2.19 times higher hazard of death (AHR: 2.19; 95% CI: 1.17, 4.12) compared to those without tuberculosis. Advanced clinical stage, low CD4+ cell count, and previous episodes of an opportunistic infection other than tuberculosis were discovered to be independent predictors of mortality.

The authors made all data underlying the findings fully available. The data was tested for representativeness, analyzed using descriptive and inferential statistics which were rigorous and appropriate.

Discussions of the results were robust, citing similar studies conducted both within and outside Ethiopia.

Conclusions are in line with the findings

Writing quality and clarity requires editing especially the conclusion: e.g.

In this study showed that HIV patients who TB co-infected at ART initiation were experienced substantial mortality rates…………. should read: This study showed that HIV patients who are co-infected with TB at ART initiation experienced substantial mortality rates etc.

Other observations:

1. Limitations of the study: The authors did well to mention the limitations of the study

2. Inclusion/exclusion criteria clearly explained as a separate sub topic

Reviewer #3: The author in their manuscript 'Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated

antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study' elaborated the need of strengthening the tuberculosis screening among HIV positive patients by showing higher death rate of among HIV-TB coinfection that could be prevented by rigorous early screening.

However, there are some concern in the current manuscript.

1. The sample size is small, though the conclusion/outcome may not change with the increased sample size but the rigourness of data analysis will certainly increase.

2. The findings are not novel. Many studies already conducted in similar set up including in Ethiopia with similar outcome. In the current manuscript no new or novel information is added.

3. The discussion section need to be re written as there are repetition and redundancy in writing.

Reviewer #4: Abstract: Consider starting abstract with "In resource limited setting such as Ethiopia,.....". TB is a major cause of morbidity and mortality among PLHIV but the current sentence structure states that TB is a major cause of mortality in resource limited setting; the context for the analysis is among PLHIV. Likewise, the sentence structure needs to be adjusted throughout the manuscript.

Introduction: Spell out TB when first used earlier in the introduction rather than spelling it out in line 48. Grammatical error in line 55-57 makes sentence difficult to understand.

Line 70:spell out acronyms when first used in the paper eg. PLWH, HAART

Line 91: punctuation error. Review appropriateness of punctuations throughout the manuscript

**********

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Reviewer #1: No

Reviewer #2: Yes: Haruna Ismaila ADAMU, MBBS; MPH; PhD

Reviewer #3: No

Reviewer #4: No

**********

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PLoS One. 2022 Oct 31;17(10):e0277021. doi: 10.1371/journal.pone.0277021.r002

Author response to Decision Letter 0

21 Sep 2022

Response to Reviewers

Manuscript ID: PONE-D-22-21893

Title: Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study

Dear Editor and Reviewers, We are so pleased with your prompt feedback on our article. Thanks for your valuable and intellectual comments and suggestions. We have corrected and responded to all the comments and suggestions raised by the editor and each reviewer, point by point, hereunder.

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.

Author responses: Dear thanks so much for your suggestion. We have revised all our submissions as per the PLOS ONE’s styles.

Author responses: Thank you very much for your important suggestion. We are sorry for the editorial error. We have just corrected it (mentioned table 2 in the text).

Additional Editor Comments:

Major comments:

1. Although authors say all data are within supporting files, supporting documents include the questionnaire and strobe list, not the data.

Author responses: Dear Editor, Thank you so much for your suggestion. We have included the data used for this study within the revision file in the zipped supportive information file.

2. line 89-91. Please rephrase to improve clarify. I assumed people who started ART treatment during these times points were included in the study, and classified into infected and not-infected groups.

Author responses: Dear Editor, Thanks for your intellectual and constructive comments. The concept is exactly what you mentioned above. We have rephrased it as follows: PLHIV who started ART from January 1, 2014, to June 30, 2018, were included in the study and classified into tuberculosis co-infected and not-infected groups. Patients with TB co-infected were included in the exposed group, whereas those not co-infected with TB were included in the non-exposed group.

3. line 96. How the sample size was calculated was explained, but the resultant sample size was not given, why? Appears N=566 recruitment was not based on above calculation.

Author responses: Dear Editor Thanks a lot for your constructive comments. Considering the mentioned assumption, the calculated final sample size was 566. Finally, a minimum sample sizes of 566 was used for this study, which means 283 in the exposed cohort and 283 in the non-exposed cohort were assigned randomly.

Author responses: Dear Editor, thanks for your important comment. From January 1, 2014, to June 30, 2018, a total of 1785 patients initiated ART in public hospitals in Harar and Dire Dawa towns. Of these, 115 patients (10 who started ART for PMTCT, 25 with incomplete data, and 80 who transferred in) were excluded because they were ineligible. The ART registration and follow-up forms were used to determine the patient's TB status at ART initiation. Patients were categorized as exposed or non-exposed based on their TB status. Finally, a proportional allocation followed by a simple random sampling was applied to select TB co-infected and not-co-infected patients from each hospital. We have also briefly presented this section in Figure 1.

5. Line 114. “All the profiles of HIV-infected patients between January 1, 2014, and June 30, 2018, were reviewed”. why you review all patients, instead of reviewing only those selected, if patients were selected using simple random sampling?

Author responses: Dear Editor, Thank you for your insightful comments. Sorry for the editorial error. We have corrected it. As you exactly mentioned, the profiles of all selected HIV-infected patients between January 1, 2014, and June 30, 2018, were reviewed.

Author responses: Dear Editor, Thank you so much for your scholarly suggestion. For this study, we considered all-cause mortality while the patient is on ART. The death of any patient while on ART is reported as an HIV death since it is difficult to get cause-specific data. To consider competing for risk analysis, we tried to identify the cause of death. Fortunately, on our ascertainment from the patient's death certificate and through telephone by ART adherence supporters, all deaths were due to illness and not attributable to accidents or other unnatural causes.

7. line 168. “Kaplan-Meier test”. Is it correct to describe this estimation procedure as a test?

Author responses: Dear Editor, I really thank you very much for such an important comment. It was an editorial error. We have just corrected it as a Kaplan-Meier survival estimate.

8. line 170. “The log-rank test was used to compare the median time to death between patients with TB and those without TB”. Can logrank test compare median times to death?

Author responses: Dear Editor, thank you very much for such a productive comment. The log-rank test was used to test the equality of survival functions between patients with TB and those without TB.

9. By looking at figure1 I assume proportional assumptions is ok, but for completeness please include in statistical analysis section how you assessed it.

Author responses: Dear Editor Thanks a lot for your comment. Cox proportional hazard model fitness was checked using graphically and schoenfield residuals test. The resulting curves were parallel, and schoenfield residuals test was statistically not significant. Thus, none of the predictors violated the proportional hazard assumption. We have just explained the mentioned section in the statistical analysis section.

10. tables 1 and 2. I think you have presented ttest statistics as chisquare statistics. Also, explain why test statistic not given for some; eg, fishers exact was used?

Author responses: Dear Editor Thanks so much for your insightful comment. The Chi-square and T-test statistics were used to compare categorical and continuous variables between the two cohorts, respectively. We have used the fishers exact in case of the Chi-squared test statistics is invalid (when about 20% of the expected cell has less than value of 5),

Author responses: Dear Thanks a lot. Of the 76 total deaths, 60 patients were from TB infected and 16 were died from not TB infected group.

12. table3. Why N was reduced when there were no missing values in of the variables?

Author responses: Dear Editor Thank you very much for such an important suggestion. As we have also mentioned in the descriptive statistics part (in table 2), 14 patients data were missed on the baseline CD4+ cell count. Consequently, all variables included in the Cox regression analysis have been reduced to N =552.

Minor comments

1. undefined abbreviations. eg; ART, PLWH, PMTCT, OPI, PY, spell out all abbreviations at first use.

Author responses: Dear Editor Thanks for your comments. We have just spelled out all the mentioned abbreviations and others at their first use (ART=antiretroviral therapy, PLWH=people living with HIV, PMTCT=Prevention of Mother to Child Transmission, OPI= opportunistic infection, PY: Person year).

2. line 54. what is meant by 5.9 patients, is it 5.9% ?.

Author responses: Dear Editor Thanks a lot. As you mentioned, it is 5.9%. We have corrected it.

3. line 57. why two percentages active TB patients (14.2% and 11.5%) for Harari?

Author responses: Dear Editor Thanks for your most valuable comment. It was editorial error. We have just corrected the section. According to the Ethiopia’s 2014 TB-HIV surveillance report, 9.1% of HIV-infected clients newly enrolled in HIV care had active TB. The percentages of active TB patients in Harar Regional State and Dire Dawa City Administration were 14.2% and 11.5%, respectively.

4. line 68-72. Cannot understand this very long sentence with undefined abbreviations.

Author responses: Dear Editor Thank you so much for your important suggestion. We have corrected the mentioned sentence. The effect of active TB co-infection on the survival of HIV patients in the ART era remains inconclusive, and mortality among TB-HIV co-infected patients were strongly associated with the absence of ART.

5. line 117. “a baseline” or “the baseline”?

Author responses: Dear Editor Thanks a lot for you’re an important suggestion. We have just corrected the mentioned section. It was to mean the baseline.

6. Line 130. operational.

Author responses: Dear Editor Thanks so much. We have corrected the mentioned typo.

7. table2 title. repetition.

Author responses: Dear Editor Thanks for your suggestion. We have just corrected the mentioned section.

8. reference 19. what is meant by “Vol 618” when this is a text book?

Author responses: Dear Editor Thank you so much for the suggestion. We are sorry for the editorial error. We have corrected mentioned reference.

Reviewer #1

Author response: Dear Reviewer, Thank you very much for your knowledgeable comment. Indeed, as you pointed out, the presence of TB co-infection automatically places a patient in clinical stage III or IV. However, in our study, TB co-infection was considered within the first three months of ART initiation. During the document review, we considered the patients registered as clinical stage I or II at baseline, from which some (4.6%) of patients developed TB within the first three months of ART initiation.

Line 130 - typo on "Operational"

Author responses: Dear Reviewer Thanks so much for your important comment. We have corrected the mentioned typo.

Line 141 - correct word is "GeneXpert" not Gen Xpert

Author responses: Dear Reviewer Thanks a lot. We have corrected the mentioned section.

Line 150 - correct word is "Co-trimoxazole"

Author responses: Dear reviewer, thank you very much for your comment. We have corrected the mentioned term.

Author responses: Dear Reviewer Thank you so much. We have corrected the mentioned sentence.

Line 305 "Africa, which faster prognosis of disease and increase opportunistic infection" is grammatically wrong

Author responses: Thanks so much. We have just corrected the grammar error in the mentioned sentence.

Reviewer #2:

This study by Wubishet Gezimu, et al., was an institution-based retrospective cohort conducted in public hospitals in Eastern Ethiopia. The participants were randomly selected from January 1, 2014 to June 30, 2018.

Dependent (outcome) variables: Time from ART initiation to death

Independent (predictors) variables:

• sociodemographic features: age, sex, place of residence, marital status, educational status, occupation, and clinical.

• treatment-related characteristics: WHO clinical stage, CD4 count level, hemoglobin level, adherence to ART, co-trimoxazole prophylaxis status, BMI, and functional status

• opportunistic infections other than TB were included.

A total of 566 participants were randomly selected from January 1, 2014, to June 30, 2018. The collected data were entered into EpiData version 3.1 and then exported to Stata version 14 software for analysis. A Cox proportional hazard model was used to determine the effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy, and a p-value less than 0.05 and a 95% confidence level was used to declare statistical significance. Ethical clearance was obtained from the Institutional Health Research and Ethical Review Committee (IHRERC) of Haramaya University College of health and medical sciences.

The results revealed that of the 566 patients included in the study, 76 died. The mortality rate was 11.04 per 100 person-years in tuberculosis co-infected patient while 2.52 per 100 person years in non-tuberculosis co-infected patients. The patients with tuberculosis coinfection had a 2.19 times higher hazard of death (AHR: 2.19; 95% CI: 1.17, 4.12) compared to those without tuberculosis. Advanced clinical stage, low CD4+ cell count, and previous episodes of an opportunistic infection other than tuberculosis were discovered to be independent predictors of mortality.

Author response: Dear Reviewer Thanks for your intellectual and constructive comments.

Discussions of the results were robust, citing similar studies conducted both within and outside Ethiopia.

Author response: Dear Reviewer Thanks for your intellectual and constructive comments.

Conclusions are in line with the findings

Author response: Dear Reviewer Thanks for your intellectual and constructive comments.

Writing quality and clarity requires editing especially the conclusion: e.g.

Authors response: Dear Reviewer Thanks for your important suggestion. We have corrected the mentioned section as ‘’This study showed that HIV patients who were co-infected with TB at ART initiation experienced substantial mortality rates’’

Other observations:

1. Limitations of the study: The authors did well to mention the limitations of the study

Author response: Dear Reviewer, Thank you so much for your constructive comments. As you mentioned, we have clearly stated the limitations of our study.

2. Inclusion/exclusion criteria clearly explained as a separate sub topic

Author response: Thanks once again. We have clearly explained the inclusion and exclusion criteria as a separate subtopic.

Reviewer #3:

The author in their manuscript 'Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study' elaborated the need of strengthening the tuberculosis screening among HIV positive patients by showing higher death rate of among HIV-TB coinfection that could be prevented by rigorous early screening.

However, there are some concerns in the current manuscript.

1. The sample size is small, though the conclusion/outcome may not change with the increased sample size but the rigourness of data analysis will certainly increase.

Authors’ response: Dear reviewer thank you for your intellectual comment. Indeed the sample size was not large enough. However, it was calculated by using the probability of event by considering the interval in the enrolment period. And also appropriate scientific assumptions were utilized in the sample size calculation. Beside these, the sample was adequately distributed to all public hospitals included in the study. Additionally, we have conducted rigorous data analysis. Hence, we have no any doubt regarding the study’s conclusion.

2. The findings are not novel. Many studies already conducted in similar set up including in Ethiopia with similar outcome. In the current manuscript no new or novel information is added.

Authors’ response: Dear reviewer thank you for your scholarly comment. Actually, many studies were conducted in Ethiopia. A very important issue that makes the current study unique is that it was conducted at the era when an antiretroviral therapy is initiated at the time of HIV diagnosis (regardless of the patients’ CD4+ cell count). In contrary to this, many of the previous studies from Ethiopia were conducted at the era when ART initiation was based on the patients’ CD4+ cell count. Therefore, all participants were ART cohort (the effect of ART was controlled for both groups) in the current study. Additionally, as far as our knowledge, no study has been conducted in the current study area considering two explicit groups of exposed and unexposed. In the current study, both exposed and unexposed groups have an equal size to compare exposed with unexposed group.

3. The discussion section need to be re written as there are repetition and redundancy in writing.

Authors’ response: Dear Reviewer, Thank you so much for your helpful suggestions. We have just rewritten the discussion section. Thanks for your time with our manuscript.

Reviewer #4:

Abstract: Consider starting abstract with "In resource limited setting such as Ethiopia,.....". TB is a major cause of morbidity and mortality among PLHIV but the current sentence structure states that TB is a major cause of mortality in resource limited setting; the context for the analysis is among PLHIV. Likewise, the sentence structure needs to be adjusted throughout the manuscript.

Authors response: Dear Reviewer, Thanks for such an intelligent suggestion. We have corrected the structure of the mentioned section in the abstract and all over the document.

Introduction: Spell out TB when first used earlier in the introduction rather than spelling it out in

Author responses: Dear Reviewer, Thank you so much for your valuable suggestion. We have spelled out TB in first time use.

line 48. Grammatical error in line 55-57 makes sentence difficult to understand.

Authors Response: Dear reviewer thanks once again. We have corrected the mentioned section and currently it is understandable.

Line 70: spell out acronyms when first used in the paper eg. PLWH, HAART

Authors Response: Dear Reviewer Thanks a lot. We have spelled out the abbreviations. NOTE: We have replaced ‘’HAART’’ with ‘’ART’’ just to be consistent.

Line 91: punctuation error. Review appropriateness of punctuations throughout the manuscript

Authors Response: Dear Reviewer, Thanks for your suggestion. We have corrected the punctuation errors in the mentioned section and all throughout the manuscript.

Attachment

Submitted filename: Response to Reviewers.docx

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PLoS One. doi: 10.1371/journal.pone.0277021.r003

Decision Letter 1

Ari Samaranayaka

11 Oct 2022

PONE-D-22-21893R1Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort studyPLOS ONE

Dear Dr. Gezimu,

Please submit your revised manuscript by Nov 25 2022 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:

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We look forward to receiving your revised manuscript.

Kind regards,

Ari Samaranayaka, 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:

Newly added Figure 1 explain the recruitment procedure, it is clear. Required sample size of N=566 was proportionally divided between 4 hospitals. Then number required from in each hospital was divided equally between exposed and unexposed groups. Then those 8 numbers were recruited randomly. Therefore it is incorrect to describe the sampling process as simple random sampling, or as random selection from each hospital. They have used a type of stratified sampling (random sampling stratified by hospital and exposure status).

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

6. Review Comments to the Author

Reviewer #2: The authors have taken care of all the observations and suggestions I made during my first review. The paper should be ready for publication, subject to the satisfaction of the other reviewers and the editor.

Reviewer #3: The authors has adequately responded to the queries raised by the reviewer.

However, at the start of the discussion section some modification may be needed as commented below.

In the current study, the overall mortality rate was 6.55 per 100 PYO in the entire follow-up

period. This finding is “comparable with a previous study conducted in Ethiopia”[13]; [11].

However, it is “higher compared to the studies conducted in Ethiopia” and other countries of Africa.

The part of the sentences … “comparable with a previous study conducted in Ethiopia”.. and … “higher compared to the studies conducted in Ethiopia”…. are seems to be in disagreement and may need to be fixed.

Reviewer #4: Manuscript still has some grammatical errors that need to be corrected.

Lines 249 to 251 offers conflicting information for instance

**********

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Reviewer #2: Yes: Haruna Ismaila ADAMU MBBS; MPH; PhD

Reviewer #3: No

Reviewer #4: No

**********

PLoS One. 2022 Oct 31;17(10):e0277021. doi: 10.1371/journal.pone.0277021.r004

Author response to Decision Letter 1

14 Oct 2022

Response to Reviewers

Manuscript ID: PONE-D-22-21893R1

Title: Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study

Respected Reviewers and Editors, We are really grateful for your quick response to our article. We appreciate your considerate and insightful comments and recommendations. Each comment and recommendation made by the editor and each reviewer has been addressed in the following sections with corrections and responses.

Journal Requirements:

Please review you 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 status in the References list and also include a citation and full reference for the retraction notice.

Author response: Thank you so much for your important suggestion. We have checked the reference list for its completeness and correctness. We have not cited any retracted articles. We have cited reference number five (previously missed) in our discussion section of paragraph 4 (Page 17, line no. 276). Additionally, we have corrected reference 12. Thanks once again.

Additional Editor Comments:

Author response: Dear Editor, We are so grateful for your intellectual suggestions. Thanks a lot. What you mentioned is all about our sampling technique. We have corrected the previous description of the sampling technique as per your suggestion. As you stated, we used a random sampling stratified by hospital, and exposure status was used to select the study participants. First, the required sample was proportionally allocated to the four hospitals. Then the population in each hospital was stratified based on their exposure status. Finally, each study participant was selected randomly from each stratum. Thanks once again.

Reviewer #2

The authors have taken care of all observations and suggestions I made during my first review. The paper should be ready for publication, subject to the satisfaction of the other reviewers and the editor.

Author response: Dear Reviewer, Thanks for your time with our work.

Reviewer #3

The authors has adequately responded to the queries raised by the reviewer.

However, at the start of the discussion section some modification may be needed as commented below.

In the current study, the overall rate was 6.55 per 100 PYO in the entire follow-up period This finding is “comparable with a previous study conducted in Ethiopia”([13]; [11].

However, it is “higher compared to the studies conducted in Ethiopia” and other countries of African.

The part of these sentences…”comparable with a previous study conducted in Ethiopia”.. and …“higher compared to the studies conducted in Ethiopia” … are seems to be in disagreement and may need to be fixed.

Author response: Dear Reviewer, Thank you so much for your rational comment. We have corrected the mentioned section by specifying the particular study settings of those previous studies conducted in Ethiopia. It is corrected as “This finding is comparable with the previous studies conducted in the seven University Teaching Hospitals and Somali Regional State of Ethiopia[13]; [11].” “However, it is higher compared to the studies conducted in Jinka Hospital, South Omo zone of Ethiopia and other countries of Africa [14]; [20] : [21].”

Reviewer #4

Manuscript still has some grammatical errors that need to be corrected.

Author response: Dear Reviewer, Thanks for your suggestion. We have corrected all grammar errors throughout the manuscript.

Lines 241 to 251 offers conflicting information for instance.

Author response: Dear Reviewer, Thanks so much for you intellectual comments. We have corrected the mentioned section by specifying the particular study areas of those previous studies conducted in Ethiopia. It is corrected as “This finding is comparable with the previous studies conducted in the seven University Teaching Hospitals and Somali Regional State of Ethiopia[13]; [11].” “However, it is higher compared to the studies conducted in Jinka Hospital, South Omo zone of Ethiopia and other countries of Africa [14]; [20] : [21].”

Attachment

Submitted filename: Response to Reviewers.docx

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PLoS One. doi: 10.1371/journal.pone.0277021.r005

Decision Letter 2

Ari Samaranayaka

18 Oct 2022

Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study

PONE-D-22-21893R2

Dear Dr. Gezimu,

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,

Ari Samaranayaka, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0277021.r006

Acceptance letter

Ari Samaranayaka

21 Oct 2022

PONE-D-22-21893R2

Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study

Dear Dr. Gezimu:

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. Ari Samaranayaka

Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Questionnaire.

(DOCX)

Click here for additional data file.^{(26.3KB, docx)}

S2 Table. STROBE statement checklist.

(DOCX)

Click here for additional data file.^{(23KB, docx)}

S1 Data

(DTA)

Click here for additional data file.^{(115.4KB, dta)}

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Effect of active tuberculosis on the survival of HIV-infected adult patients who initiated antiretroviral therapy at public hospitals of Eastern Ethiopia: A retrospective cohort study

Tadesse Sime

Lemessa Oljira

Aboma Diriba

Gamachis Firdisa

Wubishet Gezimu

Roles

Abstract

Background

Methods

Result

Conclusion

Introduction

Methods and materials

Study design, period and area

Study participants and eligibility criteria

Inclusion criteria

Exclusion criteria

Sample size calculation

Fig 1. A schematic presentation of patient selection procedures.

Sampling techniques

Data collection tool, procedures, and quality control

Study variables

Operational definitions

Patient functional status:

Statistical analysis

Ethical approval and informed consent

Results

Socio-demographic characteristics of the participants

Table 1. Socio-demographic characteristics of the study participants who initiated ART in the public hospitals of Eastern Ethiopia (from January 1, 2014, to June 30, 2018), n = 566.

Baseline clinical and immunological characteristics

Table 2. The baseline clinical and immunologic characteristics of study participants who initiated ART in the public hospitals of Eastern Ethiopia (from January 1, 2014, to June 30, 2018), n = 566.

Comparison of survival based on TB co-infection status

Fig 2. Kaplan-Meier estimates of survival probability for TB co-infected and not TB co- infected HIV patients who initiated ART in the public hospitals of Eastern Ethiopia (from January 1, 2014 to June 30, 2018) n = 566.

Predictors of mortality

Table 3. Results of the multivariable Cox regression analysis of mortality in study participants who initiated ART in the public hospitals of Eastern Ethiopia (from January 1, 2014, to June 30, 2018), n = 552.

Discussion

Limitation of the study

Conclusion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Ari Samaranayaka

Roles

Author response to Decision Letter 0

Decision Letter 1

Ari Samaranayaka

Roles

Author response to Decision Letter 1

Decision Letter 2

Ari Samaranayaka

Roles

Acceptance letter

Ari Samaranayaka

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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