Determinants of isoniazid preventive therapy completion among people living with HIV attending care and treatment clinics from 2013 to 2017 in Dar es Salaam Region, Tanzania. A cross-sectional analytical study

Background Tuberculosis (TB) disease is a common opportunistic infection among people living with HIV (PLHIV). WHO recommends at least 6 months of isoniazid Preventive Therapy (IPT) to reduce the risk of active TB. It is important to monitor the six-month IPT completion since a suboptimal dose may not protect PLHIV from TB infection. This study determined the six-month IPT completion and factors associated with six-month IPT completion among PLHIV aged 15 years or more in Dar es Salaam region, Tanzania. Methods Secondary analysis of routine data from PLHIV attending 58 care and treatment clinics in Dar es Salaam region was used. PLHIV, aged 15 years and above, who screened negative for TB symptoms and initiated IPT from January, 2013 to June, 2017 were recruited. Modified Poisson regression with robust standard errors was used to estimate prevalence ratios (PR) and 95% confidence interval (CI) for factors associated with IPT completion. Multilevel analysis was used to account for health facility random effects in order to estimate adjusted PR (APR) for factors associated with IPT six-month completion. Results A total of 29,382 PLHIV were initiated IPT, with 21,808 (74%) female. Overall 17,092 (58%) six-month IPT completion, increasing from 42% (773/1857) in year 2013 to 76% (2929/3856) in 2017. Multilevel multivariable model accounting for health facilities as clusters, showed PLHIV who were not on ART had 46% lower IPT completion compared to those were on ART (APR: 0.54: 95%CI: 0.45–0.64). There was 37% lower IPT completion among PLHIV who transferred from another clinic (APR: 0.63: 95% CI (0.54–0.74) compared to those who did not transfer. PLHIV aged 25–34 years had a 6% lower prevalence of IPT completion as compared to those aged 15 to 24 years (APR:0.94 95%CI:0.89–0.98). Conclusion The IPT completion rate in PLHIV increased over time, but there was lower IPT completion in PLHIV who transferred from other clinics, who were aged 25 to 34 years and those not on ART. Interventions to support IPT in these groups are urgently needed.

Isoniazid is the common name for isonicotinylhydrazide (INH) and is one of the drugs used for first line treatment for TB infection [17]. Among PLHIV, INH is also used to prevent TB infection through the Isoniazid Preventive Therapy (IPT) intervention [10]. In epidemiological studies from different countries, IPT has been shown to reduce risks of TB incidence occurrence by 33-90% among HIV infected people [7, 10,[18][19][20][21][22][23][24][25][26][27]. WHO recommends the completion of at least 6 months IPT for the successful prevention of active tuberculosis among PLHIV [4,10]. Globally, six-month IPT completion has been reported to range from 39 to 99% [28][29][30][31][32][33][34][35][36][37], and in Tanzania studies reported 65-98% of those who initiated IPT, completed the 6 month treatment course [6,20,[38][39][40]. Most epidemiological studies have shown that IPT completion reduces the risks of mortality among PLHIV [8,26,41], decreases the need for expensive TB treatment needs and lowers the cost of HIV services. Successful use of IPT will help Tanzania achieve the sustainable development goals (SDG) by 2030 and is part of the national strategy to control TB in Tanzania [6,7,42,43]. However, it shows that a good number of PLHIV do not complete the full sixmonth IPT treatment course and little is known about the determinants of IPT completion in routine HIV clinics settings. The iinformation on IPT completion would be useful to the Ministry of Health, Community Development, Gender, Elderly and Children (MOHCDGEC) in order to plan better interventions to prevent TB in among PLHIV [14,20,38,[44][45][46]. This study aimed to determine six-month IPT completion and factors associated with IPT completion among PLHIV aged 15 years or more in Dar es Salaam region, Tanzania.

Methods
A cross-section study using secondary analysis of deidentified routinely collected data from PLHIV attending HIV services in 58 care and treatment clinics (CTC) was conducted in Dar es Salaam region. The study retrieved data from the CTC electronic database, which is used to record the clinical management of PLHIV attending CTC.
The national TB/HIV and HIV guidelines recommend that all PLHIV should be screened for TB at every clinic visit using standard TB screening tools [4]. All PLHIV aged 15 years or more who screened negative for TB and who were initiated on IPT between January 2013 and June 2017 were included in the analysis (Fig. 1).
All subsequent clinic records of those who initiated IPT were reviewed for six-month IPT completion at their scheduled monthly visits. The outcome variable, six-month IPT completion, was defined as the collection of IPT drugs for the full 6 months following initiation. The independent variables were sex, age, functional status, pregnancy status, marital status, ART status, WHO clinical stage as well as CD4 count cells/μL at IPT initiation. The study used the records of all patients who initiated IPT in care and treatment centres (CTC) from all health facilities in Dar es Salaam region from January, 2013 to June, 2017. Figure 1 shows the total clients enrolled in HIV care, and the exclusion for different reasons (Fig. 1).
Data analysis was performed using STATA version 15.0 (STATA Corp, College station, TX). Descriptive statistics were summarized using means, standard deviation (SD)) and medians (IQR) for continuous variables; frequency and proportion for category variables. The chi-square test was used to compare the differences in the proportion of completing IPT across the patient characteristics. A modified Poisson regression model was used to determine the prevalence ratio (PR) and 95% confidence interval (95% CI) of factors associated with IPT completion. Multilevel modelling was used to estimate the independent determinants of IPT completion, while accounting for the dependency of individuals within health facilities. Intra class correlation was used to measure the proportion of variability explained by the between health facilities variation.
The study involved analysis of unlinked data; hence, there was no contact with human subjects. Ethics approval for the study was obtained from the Kilimanjaro Christian Medical University college -Research and Ethical Review Committee in 2018 (KCMUCo-RERC approval number 2388). Secondary use of the data from the electronic database was requested and approved by National Aids Control Program (NACP). NACP owns the data on behalf of MoHCDGEC. Patient consent was not required for the analysis of anonymised routine data.

Results
A total of 142,837 PLHIV were registered in CTC in Dares-Salaam in the study period. Of these 2223 (0.2%) had no record of TB screening. Of 140,614 PLHIV, 124,747 (88.7%) had record of a negative TB screening results. Of those who screened negative 51,266 (41%) initiated IPT, but we excluded 6700 (13.1%) who were aged less than 15 years and 15,184 who initiated after 1st June 2017, leaving a total of 29,382 PLHIV in the analysis (Fig. 1).
Over the period January 2013 to December 2017, the overall IPT completion prevalence was 58%, but the IPT completion increased from 42% in 2013 to 76% in 2017 (Fig. 2).
Univariate analysis accounting for clustering at health facility level, indicated that the six-month IPT completion was 50% lower among those who were not on ART

Discussion
These data show the completion of IPT among PLHIV who are attending routine HIV services in Dar-es-Salaam, Tanzania. The overall IPT completion was 58% and it increased over the 4 years from 42% in 2013 to 76% in 2017. This probably reflects the improved HIV services provided in the health facilities in Tanzania with better linkage between TB and HIV services, increased HIV testing and immediate ART initiation for those testing positive [47]. Since 2013 TB and HIV services have been devolved to lower level health facility in Tanzania [47].
Among the clients who did not complete IPT in the recommended period of 6 months, 96.2% discontinued IPT within the first 3 months of initiation. This is consistent with findings from Malawi, Zimbabwe and Ethiopia, which showed of those who stopped, 85, 89 and 89% respectively stopped in the first month [32,48,49]. Patients may be discouraged by the long treatment duration of IPT and the need to attend clinic every month [32,48,49]. Interventions have been considered to help new patients in those first few months, such as automated mobile phone short message services (SMS), smart-phone applications and home visits by lay counsellors as these have been shown to be effective in Malawi [49].
PLHIV who were transferred to another clinics within Dar es Salaam region after IPT initiation had significantly lower IPT completion as compared to those attended the same clinic for the whole 6 months. This result is similar to the findings from Zimbabwe and Ethiopia [27,32]. The significantly higher IPT completion rate among PLHIV on ART is consistent with results obtained in Kenya, Zimbabwe and Brazil [30,32,37]. These results indicate that patients who are already linked with ART services have an increased prevalence of IPT completion. The significantly lower prevalence of IPT completion among those aged 25-34 years compared to those aged 15-24 years was consistent with a study in Uganda, but contrary to the results from Malawi [36,49]. HIV patients with high CD4 counts ≥350 cells/μL had lower prevalence of IPT completion compared with those with CD4 counts < 100 cells/μL. This is consistent with studies in Kenya and Brazil [30,37]. Possibly patients with high CD4 counts perceive themselves healthy and not at risk of progressing to active TB, so they stop taking IPT before completing the full treatment course of six months. There was non-significant lower IPT completion among clients with advanced stage HIV disease, as shown by PLHIV with low CD4 counts, differed from findings from a study in Malawi [48]. PLHIV with advanced HIV stage are at higher risk of death which would be a reason for them not completing IPT although this was not statistically significant in a study in Zimbabwe [32]. PLHIV attending private health facilities had higher IPT completion compared to those attending public facilities althouhg this was not significant in this analysis. The differential might imply socio-economic inequities and difference in services costs between private and public health facilities, which was shown to influence IPT completion in Jamaica and Uganda [36,50]. Although Tanzanian guidelines for HIV services cover both public and private facilities, more could be done to harmonize the practice styles and skills between private and public clinics.
The current study had strenghs due to large sample size and high power ≥ 90% to detect the true association between IPT completion and with its determinants. The study used routinely collected data, which reflected the real practices in Dar es Salaam, and the same analysis can be incorporated into regular analyses of the CTC data across Tanzania. The study included longer time interval which helped to account for population changes since IPT program was rollout in Tanzania. The study used modified Poisson regression, with robust standard errors, to avoid biases and to account for overdispersion. The study accounted for the effects of health facilities by using random effects to adjust for the clustering in the health facility. One limitation was the incompleteness and missing data which might have underestimated or overestimated the estimated prevalence ratios of IPT completion. Another limitation is that the study used routinely collected data which are collected for patient mangaement and programatic purposes, and not for research puporses. Therefore some important variables which are possibly associated with IPT completion are not routinely collected and recorded in the CTC2 database.

Conclusions
IPT completion rate prevalence in Dar es Salaam region was low in 2013 but increased over time. This corresponds with a general improvement in HIV services, and the monitoring and evaluation of HIV services in Tanzania. It is important to maintain that increase to ensure people living with HIV are protected against TB disease. Targeted interventions need to be developed to assist patients with lower IPT completion. Further analysis of routinely collected health data should be done to monitor the changes in IPT completion among PLHIV. More research is needed on the effects of IPT non-completion rates and its reasons among PLHIV who initiate IPT in Tanzania. Acknowledgements Acknowledgement of the MoHCDGEC in Tanzania which provides the HIV services to the people of Tanzania, as without this service many PLHIV would not be alive today. Appreciation for all the staff at NACP specifically the Strategic Information Unit for their support to the analysis, and to the interpretation of the results. Appreciation to the MoHCDGEC for their permission to use the data. Acknowledgement of the health workers who managed the patients and collected the data in health facilities. Appreciation to the staff and students at KCMUCO who helped with the work and encouraged the final product.

Declarations
Authors are declaring that this manuscript is our original work had never been submitted to any other journal for publication, and will not be submitted to any other for similar or any other for similar purpose. All source of information used have been acknowledged.