Study design, area, and period
A retrospective record review was conducted at Debre-Markos Referral Hospital from January 1, 2012 to December 31, 2017. Debre Markos Referral Hospital is found in Debre Markos Town which is located 299 km far from Addis Ababa, the capital city of Ethiopia and 265 km from Bahir-Dar, the main city of Amhara Regional State. The hospital serves for more than 3.5 million people in East Gojjam Zone and neighboring areas. Apart from other services, the hospital has been providing ART follow-up care services since 2005. In the hospital, the recorded number of HIV-positive people ever started ART was 3,716. Of whom, about 1, 569 HIV-positive adults started ART care from January 1, 2012 to December 31, 2017.
Population
All HIV-positive adults who had ART follow-up at Debre Markos referral hospital from January 1, 2012 to December 31, 2017 were the target population for this study. All HIV-positive adults started ART from January 1, 2012 to December 31, 2017, and who had at least one month of ART follow-up were included. However, HIV-positive adults on ART who had TB or started anti-TB treatment at the beginning of the follow-up as well as who had incomplete baseline data for important variables (WHO stage, CD4 counts, Hgb, IPT, CPT and level of ART adherence) were excluded from the study.
Sample size determination and sampling procedures
The minimum required sample size was calculated using a sample size determination formula for survival analysis using Stata Version 13 statistical software by considering CD4 count, functional status, and WHO clinical staging as major exposure variables. It was calculated by considering the following statistical assumptions: two-sided significant level (α) of 5 %, power 80 %, Za/2= value at 95 % CI =1.96, q1: proportion of subjects that are in group 1 (exposed), q0: proportion of subjects that are in group 2 (unexposed); 1-q1, HR: hazard ratio, and probability of event (E) for functional status were taken from a study conducted at the University of Gondar Teaching Hospital (0.33) [23]. Then, the final sample size for this study was 544. To select the study participants, the records of all HIV-positive adults started ART and registered from January 1, 2012 to December 31, 2017 were sorted. Then, the study participants were selected using a simple random sampling technique through computer-generated numbers. We selected this follow-up period in order to have a nearest six years of follow up. In addition, during this time, the hospital adapted a standardized ART documentation and reporting formats at this time.
Data collection tool and procedures
The data extraction tool was prepared from the ART entry and follow-up forms. Trained health professionals (BSc Nurses) who have been working in the ART clinic of Debre Markos Referral Hospital collected the data. The most recent laboratory test results before starting ART were considered as a baseline value. If there were no pre-treatment laboratory test results, obtained at the time of ART initiation, test results done within one month of ART initiation were used as a baseline data. In case of two results obtained within a month, the mean value was computed and taken as a baseline. At the time of data collection, to assure data quality, the data extraction tool was prepared carefully from a standardized ART intake and follow up forms. In addition, as a data collector, we recruited staff nurses who have been working in ART clinic and, preferably, who had comprehensive ART care training certificate. Moreover, training was given for both data collectors and supervisor concerning the data collection tool and data collection process for two days. Furthermore, before the beginning of data collection, the consistency in the recording was checked by taking few charts and few amendments were done on the data collection tool. The supervisor and principal investigators performed a strict follow up and supervision throughout the entire data collection period.
Variables of the Study
The dependent variable was the time to develop TB.
The predictor variables were : Socio demographic characteristics (age, sex, marital status, residence, family size, level of education, and occupation), Baseline clinical and laboratory characteristics (WHO clinical stage, CD4 cell count, hemoglobin level, history of TB, and history of OI and body mass index (BMI), and ART and other medications related characteristics (ART regimen, presence of regimen change, ART side effects, taking IPT, ART adherence and taking CPT).
Operational definitions
In this study, the study participants were classified as event (the occurrence of TB), if they had any documented history of TB and took ant-TB medications during the follow-up time (from January 1, 2012 to December 31, 2017). This was ascertained by reviewing patient records.
In this study, the study participants were classified as censored in either of the following conditions: If the study participants lost from follow-up or died before developing TB or if the study participants who were alive at the end of the study, but they didn’t develop TB and took anti-TB medications. This was ascertained by reviewing patient records.
Lost was defined as when the patient missed his or her appointment for three months.
Adherence was classified as good, fair and poor, according to the percentage of drug dosage calculated from a monthly total dose of ART drugs. Describe as good (equal to or greater than 95% or ≤ 3 dose missing per months), fair (85-94% or 4-8 dose missing per months), or poor (less than 85% or ≥ 9 dose missing per months [26].
low hemoglobin level was defined as HIV-positive adults who had Hgb level less than to 10 g/dl.
OIs were diagnosed if HIV-positive adults developed any morbidities after starting ART, as documented by health care professionals.
Data processing and analysis
Data were entered using EPI-data Version 4.2, and analyzed using STATA Version 13 statistical software. Patients’ follow-up characteristics for continuous data were described in terms of central tendency, dispersion, and frequency distribution for categorical data. At the end of follow up, the outcome of each study participant was dichotomized into censored or event. The necessary assumption of Cox proportional hazard regression model was checked using Schoenfeld residual and Log-Log plot tests. In addition, the model goodness of fit was assessed using Cox-Snell residual test and model with the least value of Akaike’s information criteria was selected as the best model. The Kaplan Meier survival curve was used to estimate the TB free survival time of HIV-positive adults on ART. Log rank test was used to compare the survival curves of different categorical explanatory variables. Bi-variable Cox-proportional hazard regression model was used to screen variables for the final model. Variables having p-value ≤ 0.25 in the bivariable analysis were fitted into the multivariable Cox-proportional hazard regression model. Finally, adjusted hazard ratio with its corresponding 95% confidence interval was reported to declare the presence of significant association between the explanatory and outcome variables.