Tuberculosis remains one of the most important opportunistic infections among people living with HIV. HIV increases the risk of progression from latent Mycobacterium tuberculosis infection to active TB disease and is associated with bad performance of the existing TB diagnostics and high mortality among the coinfected TB patients, particularly when the diagnosis or treatment is delayed. TB preventive treatment, including Isoniazid Preventive Therapy, is therefore a core intervention in comprehensive HIV care when active TB disease has been excluded [1][2].

TB and HIV coinfection leads to poor TB treatment outcomes. HIV weakens the immune system and makes TB harder to diagnose with unusual symptoms and Laboratory tests. It lowers TB cure and TB success rates, and raises morbidity and mortality rates among the coinfected, as noted by Habitamu et al. (2024) and the World Health Organization (2022) [3][4]. Furthermore, WHO documents that “TB remains the leading cause of death among PLHIV globally, accounting for 167,000 (27%) of global AIDS-related deaths in 2022” and that People Living With HIV (PLHIV) are 12 - 16 times more likely to develop TB disease, have more than two-fold higher mortality during TB treatment compared to people without HIV, and have poorer TB treatment outcomes, such as TB success rate of 79%, (lower than WHO recommendation), TB/HIV coinfection rate of 64%, and a TB diagnosis of 46% before death [5].

In the early HIV pandemic, Botswana had high latent Tuberculosis rates with indurations of 10mm or more, with about 100% of workers in an office outbreak testing positive [6]. Meanwhile, TB notification rates jumped from 199/100,000 in 1999 to a peak of 623/100,000 in 2002, representing a 10% - 15% annual increase [7]. The surge was tied directly to HIV and TB reactivation across Sub-Saharan Africa and globally [8][9].

Simultaneously, Botswana faced a severe HIV epidemic, ranking one of the highest globally, with approximately 300,000 people estimated to be living with HIV. A national prevalence of 35.4% was estimated from the sentinel surveillance carried out among the tested pregnant women across 22 health districts in 2002 [10]. Coupled with the massive spike in tuberculosis cases, TB-related morbidity and mortality among HIV-infected persons increased substantially, with a coinfection rate of 83% documented in a study on the baseline evaluation of routine HIV testing among TB patients in Botswana [11]. These trends plummeted from 2010, with a coinfection rate of 68% in 2010 [12] and fell further to 44% by 2023 [5]; HIV prevalence among adults aged 15 to 49 fell to 16.6% by 2023, and TB incidence decreased to 244 cases per 100,000 people by 2023 [13]. These downward trends resulted from the intensification of TB and HIV collaborative activities (including IPT) recommended by WHO and represent a huge advancement toward the control of both TB and HIV in the country [4][14].

To aggressively address these high TB/HIV coinfection rates globally, the WHO and United Nations Programme on HIV/AIDS (UNAIDS) released a policy document in1998, and an interim policy in 2004 (updated in 2012). The key policy landmarks in 1998 Recommended the use of Isoniazid Preventive Therapy for PLHIV to stop latent TB infection from progressing into active TB disease; the 2004 Interim Policy, introduced the collaborative TB/HIV guidelines for a stronger global response on fighting both TB and HIV/AIDS together, while the 2012 updated guidelines, were meant to guide member states and partners to best respond to TB/HIV coinfection [15]-[18].

Subsequently, Botswana adopted a ‘Treat All’ strategy which provided lifelong ART to all HIV diagnosed individuals regardless of CD4 count [19][20]. Likewise, the simultaneous use of both ART and IPT is purported to have an additive effect in preventing TB, thereby reducing TB-related morbidity and mortality [1][21]-[23].

Botswana introduced IPT for HIV-infected persons in 2002 and rolled out the programme nationally to public health facilities. The IPT regimen given included a six-month daily dose of Isoniazid 300 mg (eradicates the dormant TB bacillus lying in the lungs to prevent reactivation), and 25 mg Pyridoxine (to counteract the side effects of INH), following thorough screening and exclusion of active TB disease. A TB screening algorithm was designed and tested for use by all health care workers before enrolling and during the client’s repeated visits to the clinic for IPT refill. Physical examination was also supposed to be done to exclude enlarged lymph nodes, which may be suggestive of active extra-pulmonary TB. Also, a sputum sample was collected for microscopy in case of TB suspicion. The inclusion criteria were that the client had to be HIV positive, 16 years (Botswana’s age of consent to HIV testing), and in whom active TB disease had been excluded, and that only one course of this preventive therapy be given in one’s lifetime and had been enrolled in IPT at any time between the inception of the IPT programme and 2010. The programme was designed to reduce TB morbidity among people living with HIV by preventing progression to active disease [24].

However, implementation challenges were reported: low adherence levels (65%), incomplete IPT follow-up, missing documentation, and concerns among health workers about active TB exclusion and the possibility of perpetuating INH drug resistance. These programme issues created a need to describe IPT programme completion and to characterize persons who subsequently developed TB after or during IPT exposure. Conversely, these concerns were disputed by WHO, which stated that ‘no evidence exists that links IPT to widespread MDR-TB globally’ and that “concerns regarding the development of INH resistance should not be a barrier to providing IPT” [25], a claim also supported by Akolo C et al. (2006) and Mills et al. 2013 who also underscored that symptom screening is a reliable method of excluding active TB disease to prevent enrolling active TB patients into IPT. Furthermore, the importance of closely monitoring IPT clients for possible development of active TB, with thorough investigation of TB suspects followed by immediate termination from IPT once active TB is established, could not be overemphasized. The global scale-up of IPT implementation was also recommended [26][27].

The aim of this study was first, to describe IPT completion and defaulting, and factors associated with IPT completion, among HIV-infected clients enrolled in the Botswana IPT programme in selected facilities; and second, to describe the characteristics, timing of TB after IPT exposure, and TB treatment outcomes among IPT-exposed clients who subsequently developed active TB.

In this study, there were more females (64%) than men (35.6%), which is not consistent with the annual BNTP reports, as shown in Table 1, whereby men are always more in numbers than females, but probably consistent with the fact that more women are infected with HIV than men. The IPT programme analysis demonstrates substantial non-completion: only 35.0% of programme completer/defaulter records completed IPT as shown in Table 2 & Figure 1. Completion was lower among men and younger clients, refer to suggesting that adherence support may need to be intensified early and tailored to groups at higher risk of default. This suboptimal IPT completion rate of 35% is comparable to lower rates experienced regionally, such as 32% and 58% in Uganda and Tanzania, respectively. [28][29] compared to better-performing regional peers like Zimbabwe (73%), Uganda (83%), and Namibia (89%), though still below the WHO-recommended goal [22][29][30]. This 65% default rate in IPT, which is notably high among young adults and males, is comparable to results of IPT studies conducted among the TB/HIV coinfected in Uganda and Malawi [31][32]. The low completion rates undermine tuberculosis prevention for people with HIV, as such patients lose protection against latent TB activating into active disease, driving up preventable illness among people living with HIV, driving risks of INH drug resistance, and raising healthcare costs [33]. These low completion rates were attributable to high loss to follow-up of clients who missed treatments, suboptimal documentation of patients’ records by healthcare workers (HCWs), and overburdened healthcare [34]. Moreover, a study that sought to identify the missing men with tuberculosis has established that challenges related to the health system, community, health worker, and individual, such as: delayed health-seeking, unfavorable facility operating hours, and long waiting times that conflicted with men’s work schedules, also purported by WHO Report 2021 [35][36]. However, Table2 shows a higher completion rate among older clients and those tested because of a known HIV-positive partner; A view that may be related to the differences in perceived risk among the age groups, the continuous counseling, health education counselling, and the effectiveness of the health care system [34].

The analysis also revealed that the majority of the TB records as depicted in Table 4, were new TB cases (206/233, 88.4%), most of whom had pulmonary (PTB) TB (162/233, 69.5%), and 122 (52.4%) were on ART; 65 (27.9%) had not yet accessed ART, while 46 (19.7%) had no documented ART status. The high PTB cases of 69.5% remained the dominant clinical manifestation of TB, documented consistently in the BNTP annual reports, which aligns with the standard epidemiological patterns where the lungs are the primary site of reactivation and airborne transmission, inferring that most patients had not previously received anti-tuberculosis therapy, pointing to primary disease progression or recent transmission rather than direct relapse from past treatment failure [37][38]. The BNTP has constantly documented higher rates of PTB (77.3% to 87.3%) than extrapulmonary tuberculosis (EPTB) (12.7% to 22.7%) across all available historical surveillance and retrospective cohort periods. This also aligns with the WHO global reports that 84% of notified tuberculosis cases are pulmonary and 16% are EPTB [39]. In the main documented-outcome model (n = 196), sex, age, and TB disease classification were not strongly associated with TB treatment success; See Table 2. The sensitivity model and age show an age-connection, indicating that age was linked to treatment success, but with a very small effect size estimate. The challenge is missing outcome records and incomplete ART documentation, which adds to high uncertainty about these results.

Table 4. Characteristics of IPT-exposed records that developed active TB.

Continued

The 52.4% ART uptake (shown in Table 4) documented in this study demonstrates overlapping coverage, which also aligns with the WHO TB/HIV collaborative policy guidelines, though still below the WHO recommendation that all eligible PLHIV be commenced on ART, irrespective of their IPT status. However, a substantial fraction was either not on ART (27.9%) or had unrecorded/untested status (19.7%). This gap emphasizes the historical operational challenges in harmonizing the parallel HIV and TB care programmes. During the same period, efforts were made to fully integrate IPT into both the voluntary testing centers and the HIV clinics, and were met with some reluctance, particularly from medical officers who were skeptical about the possibility of generating INH resistance to one of the anti-tuberculosis drugs. The Challenge of Undocumented ART (see Figure 2) often reflects strained clinical record-keeping or missed screening opportunities at the primary care level, such as missing medical records, non-disclosure of prior treatment by patients (which is not supposed to be an issue in Botswana, as patients’ ART records are electronically documented, hence making it easy for tracking of patients across the facilities (see Figure 3). and unrecorded care transitions or self-transfers. These significantly hinder program monitoring, distort retention metrics, severely skew treatment outcomes, and compromise patient safety [39]-[41].

TB/HIV coinfection significantly worsens treatment success by lowering cure rates, evidenced by Figure 2, increasing death risks, and complicating drug therapies, including delaying recovery. The two diseases act together in the body to weaken the immune system through HIV, making it harder for TB drugs to work well. In addition, HIV and TB drugs can cause heavy side effects or interact poorly together. These studies advocated for integrated screening, simultaneous or staged multi-drug regimens, and robust prophylaxis to ensure effective coinfection management [42].

Figure 3. TB treatment success by documented ART status among developed-TB records.

In this retrospective record review, IPT programme non-completion was common among HIV-infected IPT-exposed clients in selected Botswana facilities, particularly among men and younger adults. Among IPT-exposed persons who developed active TB, most had new pulmonary TB (Table 3), and most with documented outcomes completed TB treatment, but outcome documentation was incomplete. The study supports strengthening early adherence counselling, active tracing after missed IPT visits, documentation of complete ART and TB outcome, and linkage of IPT, ART, and TB information systems. In addition, Etoori D etal. (2020) underscored the importance of improving linkages between clinics to reduce patient loss between clinics, and improving record-keeping systems, training and motivation of workers on the need for completeness of data, and that they should take ownership of their data. Finally, training of community health workers may improve sustained motivation and improve their ability to respond appropriately to their clients’ needs [43].

The findings should not be interpreted as evidence that IPT completion did or did not prevent TB, because the dataset did not include a complete underlying cohort with follow-up time and incident TB ascertainment for all IPT-exposed individuals. Likewise, the analysis cannot determine whether IPT contributed to isoniazid resistance because the dataset did not have drug-susceptibility testing results. Resistance should therefore be discussed as a programme concern requiring appropriate TB screening, follow-up, and drug-resistance surveillance, not as a direct finding of this analysis.

A key strength of the study is that it uses routine programme records from multiple health facilities and directly addresses an important TB/HIV prevention question in Botswana. The analysis also uses reproducible definitions and separates the programme completion analysis from the developed-TB outcome analysis.

The study has important limitations. Districts and facilities were selected purposively and by convenience, limiting generalizability. Routine programme records had missing and incomplete documentation. IPT duration, number of supplies, and completion dates were not collected for developed-TB records, preventing direct analysis of IPT completion as a predictor of TB treatment outcomes. ART status and TB treatment outcome were incompletely documented among developed-TB records. Drug-susceptibility data were not available, preventing conclusions about INH resistance.