Trends of notification rates and treatment outcomes of tuberculosis cases with and without HIV co-infection in eight rural districts of Uganda (2015 – 2019)

In 2019, tuberculosis (TB) was the leading cause of death from an infectious agent accounting for 1.2 million deaths among HIV-uninfected people and 208,000 deaths among HIV-infected individuals globally [1]. The End TB Strategy aims to reduce the TB incidence rate by 90% and reduce TB deaths by 95% between 2015 – 2035 [2]. An interim milestone for the year 2020 is to reduce TB incidence and deaths by 20% and 35% respectively. However, the global incidence of TB and TB deaths has fallen by only 8.8% and 14%, respectively, between 2015 and 2019 [1]. The global annual percentage change in the incidence rate (APCIR) was -1.1% between 2015 and 2017 against a target of -4%; for which only 2 of 21 Global Burden of Disease regions were on target [3].

Sub-Saharan Africa (SSA) accounts for a quarter of the global TB cases of which 32% are co-infected with HIV [4]. A recent analysis of TB case notification rates (CNR) between the year 2000 and 2018 from 58 countries found a 0.6% reduction in CNR in Africa that was partly attributed to the roll out and access to antiretroviral therapy (ART) among people with HIV [5]. Nevertheless, the region is not on course to realise the End TB Strategy goals. The East SSA region registered the least APCIR in SSA of -0.2% between 2015 – 2017 [3]. There is need to identify “hot spot” sub-regions where progress is slow. This would help in designing targeted interventions for specific sub-groups and areas.

Uganda is a TB/HIV high-burdened country where TB and TB/HIV co-infection show different spatial clustering patterns [6]. The decline in TB incidence in Uganda is slow due to the rise in the number of new TB cases among HIV-uninfected individuals, although HIV co-infected TB cases have declined between 2000 and 2018 [7]. Moreover, there is significant variation in treatment success rate (TSR) across the country among TB cases with and without HIV [8]. Rural settings in Uganda typically report a TSR of < 70% and are likely to lag behind their urban counterparts in achieving the End TB Strategy [8, 9]. In this study we determined the trend of the CNRs among individuals with and without HIV and treatment outcomes of TB cases with and without HIV co-infection in rural Uganda to provide an interim evaluation of progress towards the End TB Strategy in rural settings.

The period under study was 2015 – 2019. The analyses were performed between March and April 2021.

In this study we determined the trend of the TB CNRs among people with and without HIV and treatment outcomes of TB cases with and without HIV co-infection in eight districts of rural Uganda. We found that during 2015 -2019, the CNRs increased significantly among people with and without HIV. Additionally, the TSR reduced among HIV-negative but increased among HIV positive TB cases in this region.

The CNR of 141 per 100,000 population that we observed in 2019 is comparable to the national CNR (149 per 100,000 population) in the same year [1]. However, there are few reports from rural Uganda with which to compare the trend of the CNRs observed in our study. Similar to our finding, an increase in the number of notified cases was observed between 2015 – 2017 in a study that abstracted data from Kiboga, Mityana and Nakaseke district hospitals [16]. TB detection among HIV-infected and HIV-uninfected individuals could be increasing in this region. This might be attributed to an increase in access to TB diagnostic services following allocation of district-specific targets for TB notification by the national TB program. In this region, there has been improvement in implementing-partner support to TB program activities at public health facilities. Specifically, facilities have been supported to scale up TB screening, provide free chest X-ray vouchers to cover imaging costs and build the confidence of health workers, through mentorship activities, to clinically diagnose TB. This may have contributed to the increase in the CNRs in pulmonary bacteriologically confirmed TB and clinically diagnosed TB. However, the specific impact of these interventions on the trend of CNRs in rural Uganda needs to be evaluated further.

Uganda rolled out the Xpert MTB/RIF assay, a cartridge-based nucleic acid amplification test, for the diagnosis of pulmonary TB in 2012 and the use of the urine lipoarabinomannan (LAM) among ill people with HIV in 2017 [11]. However, the roll out of the Xpert MTB/RIF assay has seen very low utilisation rates among HIV-infected and HIV-uninfected individuals with suspected TB in rural settings [17]. Less than 20% of presumptive TB patients are referred for sputum evaluation with Xpert MTB/RIF assay [18]. Moreover, historically, the roll out of the Xpert MTB/RIF assay in Uganda has had no effect on the CNRs [19]. Further, we did not observe a significant increase in the CNRs of drug resistant TB for which the Xpert MTB/RIF assay is the commonest drug susceptibility test in Uganda. Additionally, the combination of the Xpert MTB/RIF assay and urine LAM in the diagnostic algorithm of TB results in a dismal (1 – 4%) increment in identified new cases [20, 21]. Therefore, it is unclear whether the increase in the CNR in our study is solely attributed to increased access to TB testing. The effect of the Xpert MTB/RIF assay and the urine LAM on the CNRs in rural settings needs to be evaluated by future studies.

The increase in pulmonary bacteriologically confirmed and new/relapse cases observed in the study is concerning as it suggests an increased risk of TB transmission in rural settings. Several factors in rural settings could facilitate TB transmission. Rural settings in Uganda are experiencing population growth, urbanization and lifestyle changes that could increase the risk for TB infection [13, 22]. Poverty levels, a key risk factor for TB, have also been increasing in Uganda over the period under study. Poverty levels in central Uganda increased from 4.7% in 2012 to 12.7% in 2017 [23]. Further, cigarette smoking and alcohol use, which are other risk factors for TB, positively correlate with poverty levels in rural Uganda [24]. Also, the prevalence of HIV has stagnated over the last decade in rural Uganda where men, the most-at-risk gender for TB, have a higher incidence of HIV infection than urban men [15]. From our study, the frequency of TB/HIV co-infection was stable across the period of study (between 49%—52%). More studies are needed to ascertain whether the increase in the CNRs is due to TB transmission or detection in rural settings. There is, also, a need to increase uptake of TB preventive therapies and intensify case finding in rural areas. An increase in the TB CNR in rural settings has also been reported in Ethiopia which was attributed to increased access and utilisation of TB services particularly in the older populations [25]. In Uganda, the incidence of TB has dropped by only -1% between 2015 – 2019 [1]. This reduction is small and likely to stem from a reduction of TB incidence in urban settings [26‐28]. WHO has recently redesignated Uganda as a TB high-burdened country [29]. The contribution of rural settings to the high burden of TB in Uganda needs to be addressed.

From our findings it remains unclear why the TSR decreased from 82 to 64% among HIV-uninfected individuals over the study period. We observed a decrease in the rate of cure and treatment completion among HIV-negative cases and a higher rate of TB lost-to-follow-up and failure. Moreover, more HIV-negative cases were either transferred out or not evaluated. It is likely that a combination of these factors affected TSR among HIV-negative TB cases. The decline in the TSR among HIV negative cases in the face of an increasing CNR in HIV negative individuals is worrying. It implies that interventions to increase CNRs without a concurrent focus on ensuring treatment completion will result in higher rates of treatment attrition and failure as observed in this study. Moreover, cases that are lost to follow up or fail treatment propagate community transmission of TB and drug resistant TB. The Uganda national TB program aims to have a < 5% rate of lost-to-follow-up [30]. Therefore, the overall lost-to-follow-up rate among HIV negative cases in our study is thrice the target. This is alarming and deserves further evaluation. People with HIV are usually more integrated in the health care system and any disengagement with the system prompts tracing of the person by both TB and HIV care teams. This could explain the higher TSR in HIV-positive TB cases. Additionally, HIV programming in Uganda receives considerable funding from PEPFAR which could explain why the TSR and lost-to-follow-up rate among TB/HIV cases improved from 69.9% and 18.0% in 2015 to 81.9% and 6.7%, in 2019 respectively. Organisations implementing HIV care activities in districts sometimes run siloed activities that focus on achieving treatment success in HIV/TB co-infected cases, although they report to the ministry of health through the health information management systems [31]. This can inadvertently affect TSR in HIV-negative cases. Programs need to identify and address these disparities in treatment success in HIV-negative and positive TB cases in rural settings. In Uganda, creating incentives for TB focal persons at health facilities and improving the implementation of community-based directly observed therapy short course strategy might improve the TSR in rural areas [32].

Similar to our findings, a decline in the TSR was observed between 2015 – 2017 (from 73.4% to 64.4%) in a study that included data from Kiboga, Mityana and Nakaseke district hospitals, although data were not reported by HIV status [16]. Likewise, the majority with an unfavourable outcome in that study were mostly lost-to-follow up. However, unlike our findings that show a relatively high overall TSR (74%) among HIV positive cases, Musaazi and colleagues found the TSR to be 67% in a study that included Kiboga and Kyankwanzi districts [9]. However, almost all (92%) of their cases were treated with a less efficacious TB regimen consisting of 2 months of rifampicin, isoniazid, ethambutol and pyrazinamide and a continuation phase of 6 months with ethambutol and isoniazid [33].

Our study has limitations. We could not assess predictors of treatment success to explain why the TSR among HIV-negative cases was on a decline. Patient-level data were unavailable to us to conduct this analysis. The use of secondary data could introduce documentation bias. Treatment outcomes and notification could have been preferentially documented among TB cases with HIV co-infection since they are perceived to be at risk of TB disease and mortality. Lastly, the trends in the sub-group analyses should be interpreted with caution because of the small number of cases in these categories.

The CNR increased among people with and without HIV in rural Uganda between 2015-2019. The TSR reduced among HIV-negative TB cases but increased among HIV negative cases. The results highlight a gap in TB prevention services in rural settings. Refocusing programs to address barriers to treatment success among HIV-negative TB cases is important for programs to achieve the goals of the End TB strategy.