Study design, setting and period
A hospital-based retrospective cohort study design was used in ART clinics at selected public hospitals in SNNPR, Ethiopia. The study was carried out from February to March 2020 in ART clinics of selected public hospitals in SNNPR. SNNPR is an administrative region in Ethiopia. It is Ethiopia's third-largest administrative region, with nine administrative regions. In terms of culture, language, and ethnicity, it is also the most diverse region in the country. It is divided into 14 zones, one city administration, and four special woredas. Hawassa is its capital city, located 273 kilometers from Addis Ababa, Ethiopia's capital city. According to the 2007 census, the region has an estimated population of 18.9 million people. The region has four referral hospitals and forty general hospitals. The study included six hospitals: three referral (Hawasa University Referral Hospital, Wolaita Sodo University Teaching Referral Hospital, and Nigist Eleni Mohammad Memorial Referral Hospital) and three general (Yirgalem, Arba Minch, and Jinka).
Sample size determination
The sample size was calculated using the double population proportion formula, with CPT and IPT as the key predictor factors, from a study done in Gondar (13). Then, it was calculated by using Epi info version 7 statistical packages by considering 95% CI and a power of 80%. Additionally, IPT (percent of exposed P1 =18.4%, percent of non-exposed P2=6.2%) was considered as independent predictor since it gives the maximum sample size. r: is the ratio of non-exposed to exposed 1:1. The largest sample size (N= 288) was then chosen as the final sample size for the investigation.
Sampling Procedure
The study was conducted at selected public hospitals in SNNPR. Purposive sampling was used to select the hospitals with high patient volume. Then, medical record numbers of children who are TB/HIV co-infected and on ART from January 1st, 2009 to December 31, 2019 were identified. The ART log book was used to look for those with history of tuberculosis. Then, since the number of the co-infected children in the selected hospitals was manageable, all of the children who fulfilled the inclusion criteria were included in the study. From 325 identified charts, 284 charts were finally selected. The rest of the charts were excluded due to incompleteness.
Measurement of terms
ART adherence- classified as Good (≥95% or Miss≤3 doses per month), Fair (85-94% or Miss 4-8 doses), and Poor (< 85% or Miss> 9 doses) according to calculated percentage of ART drug taken from the total monthly dosage.
Loss to Follow Up- When the child misses appointment for more than three months
Transferred Out- when a child is transferred to other health facility
Treatment Failure- classified by clinical criteria, immunologic criteria and virologic criteria
Clinical Treatment Failure is the detection of new or recurrent WHO clinical stage of III or IV
Immunologic Treatment Failure is a drop in CD4 level, after the initial immune recovery next to ART initiation to values at or below the age-related CD4 threshold for treatment initiation OR 30% drop of CD4% or value from highest levels after therapy.
Virologic Failure -persistent viral load exceeding 5000 copies/ml in a child who is fully adhered to treatment and who was on ART for at least 24 weeks.
Time to death- the time between the diagnosis of TB/HIV co-infection and occurrence of the event (death) during the follow up period
Censored- If the child is loss to follow up or transferred out before developing the event or if the child is alive at the end of the study period
Drug resistant TB; classified in to Multi drug resistant (MDR), resistance to isoniazid and rifampicin, and Extensive drug resistant (XDR). XDR- resistance to at least four core anti TB drugs involving isoniazid, rifampicin, any of the fluroquinolons like moxifloxacin or levofloxacin and to at least one of the second line drugs which are amicacin, capreomaycin or kanamycin
Immune suppression: classified as severe, advanced, and none or not significant based on WHO classification as shown in Table 1.
Table 1
Immune suppression-Based on WHO classification
HIV-associated immunodeficiency
|
Age-related CD4+ values
|
<11 months (%CD4+)
|
12–35 months (%CD4+)
|
36–59 months (%CD4+)
|
>5 years (absolute number per mm3 or %CD4+)
|
None or not significant
|
>35
|
>30
|
>25
|
>500
|
Mild
|
30–35
|
25–30
|
20–25
|
350−499
|
Advanced
|
25–29
|
20–24
|
15−19
|
200−349
|
Severe
|
<25
|
<20
|
<15
|
<200 or <15%
|
Data Collection Procedure
A data extraction tool was developed from the national ART entry and follow up form that is currently used by the ART clinics of the study area. The data was collected by six BSc and five diploma nurses working in the ART clinic of respective hospitals. They used the data collection tool to extract the information from children’s charts. Charts were collected by using the children’s registration number which is found in the data base in the computer system. In addition, data clerks helped in identifying the charts.
Data quality control
To maintain the quality of the data, data extraction tool was carefully adapted from the national follow-up care forms with some modification. One-day training was given regarding the objectives and variables of the study and how to extract data by using the tool was given. Moreover, a periodic supervision took place. In addition, the data extraction tool was pretested to check the consistency.
Data Processing and Analysis
Before data entry, all questionnaires were checked for completeness. Cleaned and coded data was entered into Epi Data version 4.6 and analysis of the data was conducted by using the statistical package for social sciences (SPSS) version 23. Cox proportional hazard model assumption was checked using Schoenfeld, residual test. Patients’ cohort characteristics for continuous data were described in terms of central tendency (mean or median) and dispersion (standard deviation or inter quartile range). Frequency distribution was used for categorical data. The Kaplan Meier survival curve was used to estimate and compare survival time and log rank tests was used to compare survival curves. Bivariate Cox-proportional hazards regression model was fitted for each explanatory variables and multivariable Cox model was used to identify predictors of mortality among TB/HIV co-infected children. Adjusted Hazard Ratio with its 95% confidence interval was used to estimate the strength of association and p value ≤ 0.05 was considered as statistically significant.