Associated Factories and Time to Occurrence of Tuberculosis Among Children on HIV/AIDS Care in Assosa and Pawe General Hospitals North West Ethiopia: A Retrospective Cohort Study 2020

Background: Tuberculosis (TB) incidence in peadtrics and children living with human immune-deciency virus (HIV) is an emerging global concern. Although, the incidence of TB among adult HIV patients is exhaustively studied in Ethiopia, but among children on HIV/AIDS care is overlooked. Knowledge of the time when TB develops during successive follow up could be helpful for time relevant intervention strategies. Methods: health institution based retrospective cohort study conducted among 421 children on HIV/AIDS from 2009-2018. Time to develop TB was dened as time from enrollment for ART care until development of TB among children on ART. Proportional hazard assumption was checked for each variable and no variable was found with Schoenfeld test <0.05. Variables with P-value <0.25 at bivariate Cox regression analysis were entered into multivariable Cox model. Multivariable Cox regression model with 95%CI and AHR was used to identify signicant predictor variables to develop TB at P< 0.05. Result: Totally 421 children were followed for a total of 662.5 Person Years of observation (PYO). The maximum and minimum follow up time on ART was 0.37 and 4.49 years, respectively. The median age of the children on ART at enrollment was 8 years (IQR=2-15). The Overall incidence density of tuberculosis in HIV infected children was 9.6/ 100 PYOs 95%CI (8.06-10.3). Tuberculosis occurrence among HIV infected children was signicantly associated within TB history of contact AHR=3.7, 95%CI (2.89-7.2), not started on cotrimoxazole(CPT) AHR=2.4: 95%CI (1.84-4.74), incomplete vaccination AHR=2.4, 95%CI (1.32-4.5), sever stunting AHR =2.99:95%CI (1.2-7.81), having hemoglobin (Hgb) ≤ 10 mg/dl AHR = 4.02, 95%CI (2.01-8.1). Conclusion: More than 80% of TB incidences occurred during two years of follow up after ART started. So intensied screening of


Introduction
The Intricate linkage of tuberculosis(TB) with HIV infection for the past three decades become major threat and hindrance for international public health effort to achieve Millennium development goal [1].
Globally, tremendous progress has been made over the past decades in diagnosing and treating of TB and achieved 2% per year new TB incidence reductions [2]. However, in 2017 6.4 million new incidence cases of TB were reported [3], among this 9% (0.3 million) were new incidence of TB-HIV co-infections and 50% of new infection including inborn seropositive children were located in resource limited settings [4]. It is mainly due to di culty in timely addressing prophylaxis and ART treatment gaps [5]. On the other hand, absence of sophisticated early HIV diagnosis technologies for inborn HIV infected children [6] increase early mortality by lethal opportunistic infections ,the commonest one is tuberculosis [7,8]. It is one of the leading lethal opportunistic infection with 30-40% lifetime incidence risk for seropositive children [9,10]. Global systemic review and meta-analysis on incidence of tuberculosis on people living with HIV/AIDS(PLWHV) in 2013 indicated, the incidence burden has variation in continental perspective Page 3/16 [11], which is 31.25% in African countries, 25.06% in Latin America countries, 17.21% in Asian countries, 20.11% in European countries, and 14.84% in the USA [12]. Several studies in African countries have shown that the incidence of TB among HIV positive children ranges from 1-9.9 per 100 person years [9][10][11]13] with different times of immunological and pathophysiological response for tuberculosis incidence [14,15]. For instance tuberculosis occurrence in, Uganda & Zimbabwe 1.9/100 P-Y [11], Tanzania 5.2/100 P-Y [10]. According to global TB report of 2018, Ethiopia found top 17 twine TB & HIV epidemic countries with 8.6-17/1000 new TB incident including seropositive children [3],With each year, 3900 HIV infected children develop morbidity by opportunistic infection especially by TB [15].Childhood TB incidence during successive follow up varied in different regions and health institutions in Ethiopia [16]. For example, in Adama 6.03/100 P-Y [17], Debre Markos 2.63/100P-Y [18], Gondar 4.9/ 100 PY [19], Northern Ethiopia 4.2 / 100 P-Y [20] and southern Ethiopia2.6 /100 P-Y [21]. On the other hand, factors associated with TB incidence were identi ed [17][18][19]22]. Notably ,functional status [20] WHO stage& anemia [20,23], residence [20], nutrition status [17] adherence status [18]. Currently, tuberculosis incidence among seropositive children is an emerging and global concern, in fact due to its one of leading lethal opportunistic infections [24]. Although, studies have been conducted on TB incidence among children on HIV/AIDS care in Ethiopia [4] ,however the time of TB occurrence among on HIV/AIDS care children is incompletely described and overlooked [20,25]. In addition, information on the time when TB develops is scarce [11,19]. The main aim of this research is to assess Associated Factories and Time to occurrence of Tuberculosis among seropositive children in Assosa and Pawe General Hospitals North West Ethiopia.

Study area, design and population
We conducted health institutions based retrospective cohort study among 421 children on HIV/AIDS care from January 1 / 2009 to December 31 /2018 at Assosa & Pawe general hospitals in Benishangule Gumuz regions. Both hospitals are located in this regional state in North West Ethiopia. This region is one of the nine regions in Ethiopia. Assosa is the capital city of this region and it is located at a distance of 659 km in west of Addis Ababa and Pawe hospital is also located a distance from 565 km from Addis Ababa in North West direction. This region has currently 2 general and 3 primary hospitals with one regional laboratory. This two selected Hospitals are routinely diagnose and treat tuberculosis based on the clinical ndings, chest x-ray, AFB and XpertTB for suspected TB patients [26]. In both general hospitals there has been given ART care service 2007 pediatric HIV/AIDS guideline [27]. Following the time of enrollment to ART care continuum, all children have started ARV at both hospitals. Among these, 238 and 191 children were on follow up and care at Assosa general hospitals and Pawe general hospitals, respectively. From the registration log book, eight children with incomplete outcome data were excluded from the study.
Sample size determination and sampling procedure Sample size for this study was calculated by using EPI INFO software using the following parameters. A) (α) of 5%, power 80%, Z = within 95% CI = 1.96 and AHR = 2.39 [20] (P1) = 6.6% and (P2) = 15.8% obtained 408 by adding 5% incomplete data nal sample size will be 421.Computer generated random number used for nal study subject of study subject from two hospitals.

Operational de nitions
Case ascertainment: The outcome variables (TB) was diagnosed based on bacteriological, molecular, histopathology and clinical methods by using ( microscope, sputum culture, chest x-ray, and Xpert or combinations) during patient presentation for TB symptoms [28].
Event: New occurrence of tuberculosis during HIV/AIDS care follows up times with study in periods.
Censored: HIV positive children who did not developed TB during HIV/AIDS follow up.
TB history of contact: Children during ART follow up before TB incidence developed, having history of survives or contact at any time with who has active PTB patient.
Opportunistic infection: for HIV infected children during the following if any one of diseased developed registered on ART follow up form by their code (BP = Bacterial pneumonia ,UL = oral ulcer, Z = Herpes zoster, PCP = pneumocystis carnie pneumonia ,DC/DA -chronic / acute diarrhea, CT = central nervous toxoplasmosis CM streptococcal meningitis [29].
CD4 :was classi ed as below the threshold according to the following age-speci c thresholds: less than 15% for children aged 12-35 months, less than 10% for children aged 36-59 months or less than 100 cells/mm3 for children aged 5-15 years [20].
Stunting, underweight and wasting: The child being 2 standard deviations (SDs) below the normal for height for age, weight for age, or weight for height, according to the WHO 2006 curve. For children under or equal age 2, wasting was measured by weight for length Z-score; for children above age 2, wasting was de ned by Z-score. Z-score ≥ − 2 was de ned as non-wasting; −3 ≤ Z-score ≤ − 2 was de ned as moderate wasting; Z-score ≤ − 3 was de ned as severe wasting. Stunting was measured by height/length for age Z-score. Z-score ≥ − 2 was de ned as non-stunting; −3 ≤ Z-score ≤ − 2 was de ned as moderate stunting; Z-score ≤ − 3 was de ned as severe stunting [10,17,22].
Data collection tools, procedures, and quality control Four bachelor nurses and two supervisors were selected for data collection processes and all had took ART training. For quality of data collection process, one-day traing was given in two hospitals with two supervisors for data collectors. The principal investigator and two supervisor followed data. Data were collected using the data abstraction tool and medical history sheet prepared from Ethiopian Federal ministry of health HIV/AIDS follow up forms [15].
Data processing and analysis

Discussion
The nding of this study indicated that the overall incidence of tuberculosis was found 9.6/ 100 Person per years (PYOs) 95%CI (8.06-10.39). This is not comparable with study nding in southern Ethiopia 2.6/ 100 PYOs [21], Debre Markos 2.63 /100 PYOs [18], Gonder 4.9/ 100 PYOs [19], Adama 6.03 /100 PYOs [17]. In fact the study area has predominant distribution of tuberculosis [26]. The nding of this study revealed that not started Cotrimoxazoles prophylaxis was independently associated with occurrence of TB. This is agreed with northern Ethiopia [20] Adama hospitals [17].This might be due to Cotrimoxazoles preventive therapy signi cantly reduces HIV related morbidity and mortality from lethal opportunistic infections [3]. On the same way, seropositive children having TB history of contact is associated with TB incidence. This is in line with south Africa [9].In fact lack of awareness about transmission of TB might easily acquire the infection from nearby active patients [33]. Also this study indicates; having incomplete vaccination was signi cantly associated with TB occurrence. This is similar with nding in Adama [17] and Gondar [19]. On the same way HIV infected children having sever stunting was independently associated with incidence of TB .This in line with the study nding Tanzania [10] and Uganda & Zimbabwe [11]. The fact is human immune virus increases nutrient mal-absorption due to metabolic alterations that culminate in weight loss and stunting with time leads early exposed for opportunistic infections [29],this facilitate rapid viral replication consumed body energy and create arena for incidence of TB [2,34].This study nding also showed that children having hemoglobin ≤ 10 mg/dl was independently associated with TB incidence as compared with hemoglobin level > 10 mg/dl having children. This is in line with the study nding in Adama hospitals [17],university of Gonder [19], Dar es Salaam, Tanzania [10], England and wales [23]. In fact hemoglobin levels had high predictive value for incident TB and death's ,and incidence TB is directly associated with severe anemia [35]. Regardless of starting HAART moderate or severe anemia can be independent predictor for TB [35,36] .

Limitation of the study
Retrospective nature of this study is one of the limitations of this study .due to this some of clinical important predictor variable which has independently associated with incidence of TB occurrence in other studies like educational status of children, economic status of family were not included in these study.

Conclusion
Incidence of TB was an important medical problem for children living with HIV ART treated in both Hospitals. This study nding concluded that baseline not ever taking cotrimoxazoles, ,having moderate stunting ,hemoglobin level lower than standard, incomplete vaccination ,having previous history of contact with TB has signi cantly and independently associated TB incidence. So intensi ed screening of cotrimoxazoles and malnutrition was highly recommended for intervention. tuberculosis, predictors among HIV infected children receiving antiretroviral therapy, within two general hospitals, and permission was assured. All information collected from patient cards was kept strictly con dential and the names of patients were not included in the checklist. Con dentiality consent was not needed as it was a retrospective study was conducted on secondary data.

Funding
Not applicable Acknowledgment I would like to thank Pawe and Assosa general hospitals, administrative staffs, and data collectors assisting during data collection.

Data availability
The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Consent for publication
No consent for publication