Violet Chihota

Background: Tuberculosis-preventive treatment (TPT) is recommended for those at risk of tuberculosis, but despite encouraging trial data, evidence of its effectiveness from routine settings with diverse TPT regimens is limited. We describe routine TPT implementation outcomes in people living with human immunodeficiency virus (HIV; PLWH) to identify bottlenecks and opportunities for improvement along the cascade of care. Methods: From 2021–2023, we conducted a 24-month prospective cohort study of PLWH facilities in Ethiopia, South Africa and Zimbabwe. Sociodemographic and clinical data were collected at enrollment. During follow-up, we collected TPT initiation, TPT-related adverse effects, and completion data. A subgroup was allocated digital boxes as a proxy measure for assessing treatment completion. Tuberculosis diagnoses were confirmed from clinic records or symptom agnostic sputum testing using Xpert MTB/RIF assay and mycobacteria growth indicator tube (MGIT) culture at 12- and 24 months after enrollment. Results: We enrolled 2095 participants, mostly female (n = 1489 [71.1%]), with a median age of 42 years (interquartile range, 35–50 years). Approximately 60% (n = 1312) were considered eligible for TPT, and 1110 (84.6%) initiated TPT within 60 days of antiretroviral therapy initiation or refill during follow-up (rifapentine and isoniazid [3HP] in 625 and 6 or 12 months of isoniazid [6H/12H] in 487). TPT was completed in 55.4% (406 of 733). Mild symptoms compatible with TPT adverse effects were commonly reported in 3HP versus 6H/12H (190 [31.0%] vs 51 [11.0%], respectively; P < .001]. The tuberculosis incidence rate was 1.27/100 person-years (95% confidence interval, .95–1.69) during study follow-up in a mostly long-term antiretroviral therapy population and was lower for PLWH who completed TPT (adjusted incidence rate ratio, 0.39 [.20–.78]; P = .01). Conclusions: There were losses along the cascade, particularly at completion. In programmatic settings, we observed more potential mild symptoms from 3HP compared to 6H/12H use. Interventions to support TPT completion are needed.

Introduction: Tuberculosis (TB) preventive treatment (TPT) is effective in preventing TB among people living with HIV (PLHIV). Patient experiences and preferences contribute to optimising the delivery cascade for TPT among PLHIV. We describe patient-level reasons for initiation, completion, refusal and discontinuation of 3HP (high-dose rifapentine (RPT) 900 mg plus isoniazid (INH) 900 mg weekly for 3 months) and INH in Ethiopia, South Africa and Zimbabwe. Methods: We conducted a total of 141 4560 min in-depth interviews (IDIs) with adult PLHIV in Ethiopia (n=45), South Africa (n=45) Zimbabwe (n=51) between March and June 2022. Participants were attending routine HIV care in nine healthcare facilities and interviewed using a study-designed interview guide. The guide explored three categories: TB and TPT knowledge, reasons for TPT initiation and experiences of taking TPT and antiretroviral therapy (ART). Recordings were transcribed verbatim, translated and thematically analysed on MAXQDA using an abductive coding scheme incorporating the information-motivation-behavioural (IMB) skills model to understand reasons behind TPT uptake patterns. Results: Of the 141 participants, 28 were still on TPT, 66 completed, 22 discontinued and 25 refused to initiate TPT. The majority were female (88%, 124/141), with an average of 36 years. IMB constructs were reflected in participants TPT uptake patterns, with illustrative quotes highlighting key patterns across the dataset. In relation to information, participants demonstrated knowledge of TPT and its benefits; however, there was confusion about the role of TPT in the absence of TB disease. Prior TB experiences, social support and engagements with healthcare workers were motivations for uptake. The main behaviours found included adoption of adherence strategies and use of medication reminders. Side effects, fears of pill burden and contraindications had negative outcomes for TPT uptake and completion. Conclusions: The findings underscore the need to enhance the understanding of TPT through targeted interventions at clinic and community levels. Strengthening these efforts may improve TPT uptake and completion rates.

Background: The safety of a 3-month weekly rifapentine-isoniazid (3HP) for tuberculosis prevention in HIV-positive pregnant women on antiretroviral treatment is unknown. As part of the WHIP3TB trial, 3HP administered once or annually for 2 years was compared to 6 months of isoniazid. We report outcomes among women who became pregnant, with drug exposure in early pregnancy. Methods: Women were classified as exposed if conception occurred while taking study drug, and unexposed if conception occurred after the last dose. Outcomes included live birth, stillbirth, or abortion. A composite adverse pregnancy outcome was defined as any of the following: stillbirth, spontaneous abortion, low birth weight (<2500 g), preterm delivery (<37 weeks’ gestation), or major congenital anomalies. Outcomes were compared between exposed and unexposed groups. Results: Among 2207 women aged 15–49 years enrolled between November 2016 and November 2017, 236 pregnancies occurred in 222 participants. Fifty-seven (24%) were exposed to study drug (51 in 3HP arm, 6 in 6 months of isoniazid arm) and 179 were unexposed. Median age was 32 years, median antiretroviral treatment duration 2.9 years (interquartile range; 1.2–4.9 years) and median CD4 count 522 cells/L; [interquartile range, 345–684). Of 219 pregnancies with known outcomes, 162 (74%) were live births, 51 (23%) abortions, and 6 (3%) stillbirths. Spontaneous abortions occurred at similar frequencies among exposed (12% [7/57]) and unexposed (14% [22/162]) groups with comparable rates of composite adverse outcomes (33% [19/57] vs 35% [56/162]). Conclusions: Spontaneous abortion and composite adverse pregnancy outcomes following first-trimester exposure to 3HP were comparable between exposed and unexposed groups, supporting the safety of 3HP in pregnancy.

Mycobacterium tuberculosis (TB) antigen-based skin tests, known as TB-specific skin tests (TBSTs), have been recommended by the World Health Organization (WHO) to test for TB infection (TBI). In light of these new recommendations, we conducted a situational analysis and market assessment to evaluate the utility of testing for TBI in general and of the new TBSTs in South Africa. We found the following barriers to acceptability of testing for TBI overall, regardless of the test: the perceived high prevalence of TBI; prior experiences of poor TB preventive treatment (TPT) uptake, which has led to the removal of TBI tests from the current TPT guidelines; and a poor sensitivity of previous TBI tests in people living with HIV (PLHIV). In addition, further barriers to the new TBSTs in particular were as follows: patient level barriers linked to repeat visits; the need for cold chains; and the need for a strong laboratory system, which reduces the need for point-of-care options. TBI testing was thought to be potentially useful to determine the eligibility for TPT in these use cases: healthcare workers, pregnant women living with HIV and prisoners. One other use case was in the TB diagnoses of children, where it was thought that a positive immunological test (TST/IgRA/TBST) could indicate a TB contact and serve as a ‘rule in’ test to strengthen the evidence for TB disease as a cause.

Intensified tuberculosis (TB) case finding is recommended for people living with HIV (PLHIV) at every clinical encounter using the World Health Organization (WHO) screening tool (W4SS), comprising any of current cough, fever, night sweats or weight loss. We determined the frequency of W4SS symptoms at repeat visits among individuals without TB attending for HIV care in Gauteng province, South Africa. In a cohort study, we enrolled PLHIV (adults) attending clinics for routine HIV care. At enrolment, patients were screened using W4SS, and categorised into high (cough, body mass index (BMI) ≤ 18.5, CD4 < 100 cells/mm3, fever ≥ 3 weeks, and unintentional weight loss ≥ 10%), medium (1 ≥ W4SS symptoms but not fulfilling criteria for high priority) or low priority (no W4SS symptoms) for TB testing with Xpert MTB/RIF; and anyone diagnosed with TB was excluded. This analysis was restricted to individuals with no TB diagnosis by month three. We enrolled 3,738 patients in the parent study. Of this, 88.5% (3,309/3,738) completed month three follow up visits, of whom 71.0% (2,349/3,309) were female, median CD4 count 427 [interquartile range (IQR) 275–607] cells/mm3, 71.8% (2,377/3,309) on antiretroviral therapy (ART) with median duration 4 [IQR 2–7] years). At enrolment, 29.9% (991/3,309) were positive on W4SS, among whom 62.7% (621/991) were pre-ART. The proportion of patients who reported any of the four symptoms on W4SS was 15.1% (331/2,191) at month one, 13.5% (276/2,052) at month two, and 8.9% (294/3,309) at month three. Cough was the symptom most frequently reported at all time points, followed by weight loss and then night sweats. W4SS symptoms remained relatively common at repeat visits among people without TB in HIV care. Repeat testing of symptomatic patients with Xpert MTB/RIF would have substantial resource implications. Sensitive and specific TB screening tools which are not dependent on symptoms are needed.

Introduction: Tuberculosis (TB) remains a public health concern, and people at risk for TB are hesitant to seek care. The first South African National TB prevalence survey, conducted in 2017–2019, found that most participants with TB symptoms did not seek care for TB. In 2022, an estimated 23% of people with TB in South Africa were undiagnosed, contributing to the country’s burden of “missing” TB cases. This study explores health-seeking behaviour among people with TB (PwTB) in South Africa, focussing on barriers and facilitators to care-seeking and the quantification of TB-related stigma from a patient and community perspective. Methods: We conducted a mixed-method study in the City of Johannesburg (COJ) Metropolitan Municipality from February to March 2022. PwTB aged 18 and older initiating TB treatment for microbiologically confirmed pulmonary TB were recruited from three primary healthcare facilities in the COJ. After providing written informed consent, they participated in a one-time, in-depth, face-to-face interview. The interviews were digitally recorded and conducted by trained facilitators. We used thematic analysis with deductive approaches to develop themes. We used the Van Rie TB stigma assessment scale to quantify perceived stigma. Results: We interviewed 23 PwTB with an overall median age of 39 years and 14 (61%) males. Patient-level barriers to accessing TB care included visiting traditional healers and pharmacists before their TB diagnosis; wrong or missed diagnosis by private doctors; work commitments; scarcity of resources to attend the clinic or walk long distances; perceived and experienced stigma; and a lack of TB knowledge. Facility-level barriers included long clinic queues and uncertainty about where to receive TB care in the clinic. Facilitators for TB care-seeking included being in contact with someone who had TB, receiving encouragement from family, or having knowledge about TB transmission and early diagnosis. The overall median total stigma score among 21 PwTB was 53 (IQR: 46–63), with median community and patient stigma scores of 25 (IQR: 22–30) and 31 (IQR: 21–36), respectively. Conclusions: We found important considerations for the TB programme to improve the uptake of services. Since PwTB consult elsewhere before visiting a facility for TB care, TB programmes could establish private–public partnerships. TB programmes could also increase TB awareness in the community, especially among males, and mobile clinics could be considered to assist with TB case detection and treatment provision. Applying behavioural design techniques and co-designing interventions with patients and providers could improve TB health-seeking behaviours.

Objective: In July of 2021, the Brazilian National Ministry of Health integrated three months of once-weekly isoniazid plus rifapentine (3HP) into the National Guidelines for Tuberculosis Control as a first-line tuberculosis preventive therapy (TPT) option for people living with HIV (PLHIV) and tuberculosis household contacts (HHCs). As part of the Unitaid-sponsored Increasing Market and Public Health Outcomes through Scaling up Affordable Access Models of Short Course Preventive Therapy for TB project to implement short-course TPT, we evaluated 3HP uptake, completion, and tolerability among PLHIV and pediatric HHCs in Brazil. Methods: We conducted a multicenter single-arm pragmatic project to roll out 3HP for PLHIV and HHCs in the 2- to 14-year age bracket in the cities of Rio de Janeiro and Manaus, Brazil. Participants were identified, treated, and monitored in accordance with Brazilian national tuberculosis guidelines. De-identified patient-level data on treatment initiation, adverse events, and completion were collected and analyzed. Results: From October of 2021 to March of 2023, 380 PLHIV (77.6% of whom were male; median age, 40 years [IQR, 31-51]) and 74 HHCs (54.1% of whom were male; median age, 8.6 years [IQR, 5.1-11.8]) were enrolled in the study. Treatment completion rates were 83.7% among PLHIV and 82.4% among HHCs. Completion rates were higher in Rio de Janeiro than in Manaus (PLHIV: 86.0% vs. 79.6%; HHCs: 85.2% vs. 80.9%), although completion of 10 doses was similar (PLHIV: 86.4% vs. 86.1%). Adverse event-related discontinuation was low (PLHIV: 2.4%; HHCs: 2.7%). One person living with HIV developed active tuberculosis during treatment. At six months of follow-up, 99.6% of the PLHIV remained free of tuberculosis. Conclusions: The 3HP regimen was successfully introduced, had high treatment completion rates, and was well tolerated. Widespread use of 3HP for TPT may accelerate tuberculosis elimination in Brazil.

Background: Tuberculosis (TB) preventive treatment (TPT) is crucial in reducing the TB burden among people living with HIV (PLHIV), particularly in high TB/HIV burden countries like Ethiopia, South Africa, and Zimbabwe. Despite the availability of shorter TPT regimens, suboptimal treatment completion persists, and subnational variations remain poorly understood. Methods: This study utilized geospatial analyses of treatment completion data from the Opt4TPT study, a prospective cohort conducted in Ethiopia, South Africa, and Zimbabwe (2021–2023). Participants’ demographic and clinical data were included, and geospatial patterns were assessed using QGIS and local indicators of spatial autocorrelation (LISA) to identify clusters of treatment outcomes. Results: Of the 1,320 participants enrolled, 1,076 (81.5%) had geolocated data, and 90.1% reported completing TPT. Treatment non-completion clustered near clinics in all three countries. LISA analysis identified spatial cold spots for low treatment completion near clinics in South Africa and Zimbabwe, but not in Ethiopia. Distribution of demographic and clinical factors did not align with treatment outcomes. Conclusions: Geospatial analyses revealed clustering of non-completion near clinics, warranting further research on contextual factors, including stigma and facility-switching behavior. These findings emphasize the potential of geospatial tools in optimizing TPT programs through locally tailored interventions.

Sputum collection continues to limit TB testing, resulting in undiagnosed TB. Innovative interventions are needed to expand point-of-care TB diagnosis particularly in low-to-middle income countries (LMICs). Novel non-sputum sample types currently under development can increase TB testing, however there is limited knowledge on end-user perceptions on these tests. Between March and June 2023, we conducted a mixed methods study to assess end-user insights on a tongue swab and urine test currently under development for TB diagnosis. To describe the sample types to respondents, we used visual information sheets. Surveys were conducted among TB care recipients, healthcare workers, public health experts and civil society stakeholders, while semi-structured interviews were with all groups except for TB care recipients. The surveys were analysed descriptively, and thematic analysis was used for the semi-structured interviews. The median acceptability for the urine test and tongue swab were 94.85% and 96.8% respectively. While the acceptability of the novel tests was high, respondents identified potential barriers that would negatively impact effective implementation and utility if not addressed. The identified barriers included patient level factors such as collection of midstream urine for the urine test, clinic and healthcare provider factors such as the time required to process test results, and contextual factors such as power and water outages, as well as stock shortages common in South African health facilities. Both novel sample types were highly acceptable and preferred over sputum collection. There are however potential barriers identified by end-users that need that would affect effective implementation and utility if not addressed. Manufacturers need to consider patient, provider, gender, and context specific factors during the development of novel innovations for effective uptake and implementation.

Introduction Differentiated service delivery (DSD) models, which are mechanisms of HIV care that reduce provider visits and offer varied ART delivery methods, are scaling up across sub- Saharan Africa. It is unknown how the movement of patients to DSD models impacts services beyond ART, including the uptake and completion of tuberculosis preventive therapy (TPT). Methods Using the RE-AIM framework, we analyzed data from Opt4TPT, a longitudinal cohort study examining TPT delivery in South Africa and Zimbabwe. We constructed multivariate logistic regression models to evaluate the association of receiving ART from a DSD model with the proportion of participants who initiated and completed TPT, as measured by electronic medication boxes. We constructed a Cox proportional hazards model to assess the association between DSD models and time to TPT initiation. Results Among 1193 participants, 276 received ART through a DSD model, while 917 used the conventional model. Overall, 1035 (87%) initiated TPT, including 242 (88%) in DSD models and 793 (86%) in conventional models. Receiving ART from a DSD model was not significantly associated (OR 1.11, 95% CI 0.74-1.67, p = 0.61) with TPT initiation. DSD models had a significantly longer mean time to initiation (6.5 vs. 2.7 days, p = 0.01). Of the 731 (71%) participants with MERM box data, 356 (49%) completed TPT. Bivariate analysis showed significantly higher odds of completing TPT among those in DSD models (OR 1.53, 95% CI 1.06- 2.21, p=0.024). This association was not significant in multivariate analysis after adjusting for demographic and clinical factors (OR 0.89, 95% CI 0.58-1.36, p=0.58). Conclusions We found high TPT uptake in DSD and conventional models of care, indicating that TPT delivery in DSD models is feasible. We found low TPT completion in both models of care, showing a need to focus on improving TPT completion overall.