Targeting Non-Replicating Mycobacterium tuberculosis and Latent Infection: Alternatives and Perspectives (Mini-Review)

Latent tuberculosis infection (LTBI) represents a major challenge to curing TB disease. Current guidelines for LTBI management include only three older drugs and their combinations—isoniazid and rifamycins (rifampicin and rifapentine). These available control strategies have little impact on latent TB elimination, and new specific therapeutics are urgently needed. In the present mini-review, we highlight some of the alternatives that may potentially be included in LTBI treatment recommendations and a list of early-stage prospective small molecules that act on drug targets specific for Mycobacterium tuberculosis latency.

1407. The Latent Tuberculosis Infection Cascade of Care during the COVID-19 Pandemic Response in a Mid-Sized US City

Background The COVID-19 pandemic response may unintendedly disrupt multiple public health services, including tuberculosis control programs. We aimed to assess the cascade of care of latent tuberculosis infection (LTBI) in an urban US city during the COVID-19 pandemic response. Methods We conducted a retrospective cohort study of adult patients who presented for LTBI evaluation at the Hamilton County Public Health Tuberculosis Clinic in Ohio between 2019 and 2020. We defined 01/2019 to 02/2020 as the pre-COVID-19 response period, and 04/2020 to 12/2020 as the COVID-19 pandemic response period. We reviewed electronic medical records and extracted sociodemographic information, medical history, and follow-up and treatment data to define steps within the LTBI cascade of care. Logistic regressions were used to assess factors associated with LTBI treatment acceptance and completion, adjusted by potential confounders and COVID-19 period. Results Data from 312 patients were included. There was a significant decrease in the number of monthly LTBI referrals (median, 18 vs. 8, p=0.02) and LTBI evaluations (median, 17.5 vs. 7, p< 0.01) during COVID-19. There was a decrease in the proportion of immigrants as indication for LTBI testing (30% vs. 9%; p< 0.01), and an increase in LTBI diagnoses based on interferon-gamma release assay (IGRA; 30% vs. 49%; p< 0.01) during COVID-19. The proportion of people who were recommended LTBI treatment was similar before and during COVID-19 (76% vs. 81%, p=0.41), as well as the LTBI treatment acceptance rates (56% vs. 64%, p=0.28), and LTBI treatment completion rates (65% vs. 63%, p=0.85). In multivariate analysis, LTBI treatment acceptance was associated with Hispanic ethnicity, younger age, male sex, IGRA use, no comorbidities, and non-healthcare occupation, independent of COVID-19 period. LTBI treatment completion was associated with taking a rifamycin-containing regimen, independent of COVID-19 period. Conclusion We observed a significant decline in the number of monthly LTBI referrals and evaluations during COVID-19. Our findings indicate an unintended negative impact of the COVID-19 response in LTBI screening efforts in our region. LTBI treatment acceptance and completion rates were not affected during COVID-19. Disclosures All Authors: No reported disclosures

The Dynamic Change of Immune Checkpoints and CD14+ Monocytes in Latent Tuberculosis Infection

Controlling latent tuberculosis infection (LTBI) is important for preventing tuberculosis (TB). However, the immune regulation of LTBI remains uncertain. Immune checkpoints and CD14+ monocytes are pivotal for immune defense but have been scarcely studied in LTBI. We prospectively enrolled participants with LTBI and controls from January 2017 to December 2019. We measured their CD14+ monocytes and the expression of immune checkpoints, including programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoglobulin mucin domain-containing-3 (TIM3) on T lymphocytes in peripheral blood mononuclear cells before and after LTBI treatment. A total of 87 subjects were enrolled, including 29 IGRA-negative healthy controls (HC), 58 in the LTBI group (19 without chronic kidney disease (non-CKD), and 39 with end-stage renal disease (ESRD)). All PD-1, CTLA-4, and TIM3 on lymphocytes and monocytes were higher in the LTBI group than that in the HC group. Total CD14+ monocytes were higher and PD-L2+CD14+ over monocytes were lower in patients with LTBI-non-CKD than that in the HC group. After LTBI treatment, CD14+ monocytes, TIM3+ on CD4+ and monocytes, and CTLA-4 on lymphocytes decreased significantly. Multivariable logistic regression indicated that CD14+ monocytes was an independent factor for LTBI-non-CKD from the HC group, whereas PD-L2+CD14+ monocytes and TIM3+ monocytes were significant for LTBI-ESRD from the HC group. In conclusion, LTBI status was associated with increasing CD14+ monocytes plus low PD-L2 expression. By contrast, increased expression of immune checkpoints over all immune cells might be due to Mycobacterium tuberculosis related immune exhaustion, which decreased after treatment.

Comparative efficacy of rifapentine alone and in combination with isoniazid for latent tuberculosis infection: a translational pharmacokinetic-pharmacodynamic modelling study

Background Rifapentine has facilitated treatment shortening of latent tuberculosis infection (LTBI) in combination with isoniazid once weekly for 3 months (3HP) or daily for 1 month (1HP). Objective We determine the optimal rifapentine dose for a 6-week monotherapy regimen (6wP) and predict clinical efficacy. Methods Rifapentine and isoniazid pharmacokinetics were simulated in mice and humans. Mouse lung colony-forming unit data were used to characterize exposure-response relationships of 1HP, 3HP, and 6wP and translated to predict clinical efficacy. Results A 600 mg daily dose for 6wP delivered greater cumulative rifapentine exposure than 1HP or 3HP. The maximum regimen effect (E max ) was 0.24 day −1 . The regimen potencies, measured as concentration at 50% of E max (EC 50 ), were estimated as 2.12 mg/L for 3HP, 3.72 mg/L for 1HP, and 4.71 mg/L for 6wP, suggesting that isoniazid contributes little to 1HP efficacy. Clinical translation predicted that 6wP reduces bacterial load at a faster rate than 3HP and a greater extent than 3HP and 1HP. Conclusions 6wP (600 mg daily) is predicted to result in equal or better efficacy than 1HP and 3HP for LTBI treatment without the potential added toxicity of isoniazid. Results from ongoing and future clinical studies will be required to support these findings.

Predicting the impact of control strategies on the tuberculosis burden in South and North Korea using a mathematical model

BackgroundAmong high-income countries, South Korea has a considerable tuberculosis (TB) burden; North Korea has one of the highest TB burdens in the world. Predicting the impact of control strategies on the TB burden can help to efficiently implement TB control programmes.MethodsWe designed a deterministic compartmental model of TB in Korea. After calibration with notification of incidence data from South Korea, the TB burden for 2040 was predicted according to four different intervention strategies: latent TB infection (LTBI) treatment, rapid diagnosis, active case-finding and improvement of the treatment success rate. North Korea’s burden in 2040 was similarly estimated by adjusting the model parameters.ResultsIn South Korea, the number of patients with drug-susceptible TB (DS-TB) and multidrug-resistant TB (MDR-TB) were predicted to be 27 581 and 625, respectively, in 2025. Active case-finding would lower DS-TB by 6.2% and MDR-TB by 26.7%, respectively, in 2040. The improvement in the success rate of DS-TB treatment would reduce the MDR-TB burden by 34.5%. In North Korea, the number of patients with DS-TB and MDR-TB are, respectively, predicted to be 77 629 and 5409 in 2025. Active case-finding would reduce DS-TB by 22.2% and MDR-TB by 69.7%. LTBI treatment would reduce DS-TB by 20.6% and MDR-TB by 38.6%.ConclusionThe impact of control strategies on the TB burden in South and North Korea was investigated using a mathematical model. The combined intervention strategies would reduce the burden and active case-finding is expected to result in considerable reduction in both South and North Korea.

Challenges in LTBI care in the United States identified using a nationwide TB medical consultation database

BACKGROUND: Identifying and treating individuals with latent TB infection (LTBI) represents a critical and challenging component of national TB elimination. Medical consultations by the Centers for Disease Control and Prevention (CDC) funded TB Centers of Excellence (COEs) are an important resource for healthcare professionals (HCPs) caring for individuals with LTBI. This study aimed to identify the most common clinical concerns regarding LTBI care and to describe epidemiologic and clinical features of patients discussed in these consultations.METHODS: This mixed-methods study randomly sampled 125 consultation inquiries related to LTBI from the COEs’ medical consultation database in 2018. Text from consultation records were reviewed and coded to identify reasons for the inquiries and common epidemiologic and clinical patient characteristics.RESULTS: The most common topics of inquiry for consultation included accurate LTBI diagnosis (36%), management of LTBI treatment-related issues (22%), and choice of appropriate LTBI treatment regimen (17%). Patients for whom consultations were requested commonly had another medical condition (34%), were non-U.S. born (31%), were children (25%), and had a history of travel to TB-endemic areas (18%).CONCLUSION: Our findings emphasize the challenge of managing patients with either suspected or confirmed LTBI, highlighting the need for ongoing medical consultation support for nuanced clinical and epidemiologic scenarios.

Experiences with latent TB cascade of care strengthening for household contacts in Calgary, Canada

SETTING: Identification, assessment, and treatment of latent TB infection (LTBI), collectively known as the LTBI cascade of care, is critical for TB prevention.OBJECTIVE: The objective of this research, conducted within the ACT4 trial, was to assess and strengthen the LTBI cascade of care for household contacts at Calgary TB Services, a clinic serving a predominately foreign-born population in Western Canada.DESIGN: Baseline assessment consisted of a retrospective LTBI cascade analysis of 32 contact investigations, and questionnaires administered to patients and health care workers. Four solutions were implemented in response to identified gaps. Solution impact was measured for 6 months using descriptive statistics.RESULTS: Pre-implementation, 56% of household contacts initiated treatment. Most contacts were lost to care because the tuberculin skin test (TST) was not initiated, or physicians did not recommend treatment. Evening clinics, a patient education pamphlet, a nursing workshop, and treatment recommendation guidelines were implemented. Post-implementation, losses due to LTBI treatment non-recommendation were reduced; however, the overall proportion of household contacts initiating treatment did not increase.CONCLUSION: Close engagement between researchers and TB programmes can reduce losses in the LTBI cascade. To see sustained improvement in overall outcomes, long-term engagement and data collection for ongoing problem-solving are required.

Identifying factors affecting latent tuberculosis treatment acceptance among healthcare workers: a retrospective analysis in a tertiary care centre

ObjectiveOfficial guidelines recommend tuberculosis (TB) screening programmes for all healthcare workers (HCWs), along with offering treatment when latent TB infection (LTBI) is diagnosed. However, adherence to treatment among HCWs is lower compared with non-HCWs. The aim of the present study was to examine the rate of LTBI treatment acceptance among HCWs and to characterise the factors associated with non-acceptance.Design and settingThis was a retrospective cohort study. All HCWs diagnosed with LTBI, who had tuberculin skin test (TST) conversion during their work, between 2000 and 2015, in a single tertiary academic medical centre, and who consented to answer a questionnaire, were enrolled.ResultsOverall, 147 of 219 (67%) with TST conversion agreed to participate. Acceptance rate for LTBI treatment was only 16%. The overall completion rate among those who accepted treatment was 87%. HCWs’ recall of discussing the importance of LTBI treatment with their caregiver had the strongest association with LTBI treatment acceptance: 23 of 52 HCWs (44%) who recalled this discussion accepted treatment (adjusted OR=10.2, 95% CI: 2.2 to 47.6, p=0.003). Knowing the risk of developing TB was associated with 3.7 increased odds to accept treatment (95% CI: 1.2 to 11.8, p=0.02).ConclusionsLTBI acceptance rate was very low among our HCWs. Focusing on educating HCWs is potentially the key step towards an increased rate of LTBI treatment acceptance.

TB stigma and its correlates among HIV-positive people who inject drugs in Ukraine

BACKGROUND: TB is commonly stigmatized. Correlates of perceived TB stigma have not been assessed specifically among HIV-positive people who inject drugs (PWIDs). It is also unclear how perceived TB stigma intersects with other forms of stigma affecting this population. We aimed to evaluate perceived TB stigma, its correlates and its intersection with HIV and substance use stigma among HIV-positive PWIDs in Ukraine.METHODS: Among 191 participants at three sites across Ukraine, we assessed stigma scores, socio-demographic, behavioral and health-related variables by TB status (history of active TB infection, history of treatment for latent TB infection LTBI, no history of TB infection). We used self-reported history of LTBI treatment as a proxy for LTBI status. We used ordinary least squares to estimate factors associated with perceived TB stigma.RESULTS: Lower perceived TB stigma scores were associated with LTBI status (adjusted beta (aβ) –0.2, 95% CI –0.3 to 0.0; P = 0.032). Higher perceived TB stigma scores were associated with higher substance use stigma scores (aβ 0.1, 95% CI 0.0 to 0.2; P = 0.004). Depressive symptoms were common in this sample, although not significantly associated with TB status.CONCLUSION: History of LTBI treatment appears to impact beliefs about perceived TB stigma. Individuals who endorse higher substance use stigma are more likely to hold stigmatizing perceptions about people with TB. HIV-positive PWIDs with history of active TB infection or LTBI treatment commonly experience mental health distress. This stigma intersection needs further exploration in this population, including of its relation with mental health, to provide further insights for targeted interventions.

Prevention of Tuberculosis Reactivation

It is not known if screening for latent tuberculosis infection (LTBI) is useful for reducing the risk of tuberculosis reactivation among people at risk (no evidence was found). In people with LTBI, providing treatment for the latent infection may be helpful for preventing the development of active tuberculosis disease. (In addition, LTBI treatments do not appear to increase the risk for hepatotoxicity.) Treatment effectiveness may depend on the specific LTBI treatment regimen used. For people at an increased risk for tuberculosis ― including those from areas with high rates of tuberculosis ― guidelines recommend screening and treatment for LTBI, as this may help prevent TB reactivation. Treatment is recommended for those who are 65 years old or younger and with a positive LTBI result (recommendation from 1 high-quality guideline).