Tuberculosis Preventive Therapy Adherence and Factors Associated with it among Household Contacts of Tuberculosis Patients in Western Uttar Pradesh: A Prospective study

Background: This study aimed to identify the prevalence of diabetes mellitus (DM) and tuberculosis (TB) among household contacts of index TB patients in Yangon, Myanmar. Method: Household contacts were approached at their home. Chest X-ray and capillary blood glucose tests were offered based on World Health Organization and American Diabetes Association guidelines. Crude prevalence and odds ratios of DM and TB among household contacts of TB patients with and without DM were calculated. Results: The overall prevalence of DM and TB among household contacts were (14.0%, 95% CI: 10.6–18.4) and (5%, 95% CI: 3.2–7.6), respectively. More than 25% of DM cases and almost 95% of TB cases among household contacts were newly diagnosed. Almost 64% of known DM cases among household contacts had poor glycaemic control. The risk of getting DM among household contacts of TB patients with DM was significantly higher (OR—2.13, 95% CI: 1.10–4.12) than those of TB patients without DM. There was no difference in prevalence of TB among household contacts of TB patients with and without DM. Conclusion: Significant proportions of the undetected and uncontrolled DM among household contacts of index TB patients indicate a strong need for DM screening and intervention in this TB–DM dual high-risk population.

In this paper we will present an overview of what is known about prevention of HIV associated infections in sub-Saharan Africa. We will focus on primary prophylaxis aiming to prevent first episodes of infections as feasibility and access to secondary prophylaxis cannot be separated from the treatment of opportunistic infections. (excerpt)

The primary objective of this study was to ascertain the acceptance, initiation, implementation and treatment completion rates of tuberculosis (TB) preventive therapy (TPT) using 3HP (INH-Rifapentine) among household contacts of microbiologically confirmed drug sensitive TB cases on anti-tubercular treatment under programmatic real-world settings. The secondary objectives were to estimate the prevalence and predictors of latent TB infection (LTBI) in household contacts of the index TB cases. We also ascertained the safety profile of the 3HP TPT regimen in the household contacts. This prospective observational study was conducted at 10 TB chest clinics in Delhi, India during 2022-2023. Household contacts aged 14 and older who tested positive for TB infection on a Tuberculin Skin test were initiated on the 3HP regimen. Logistic regression was performed by including statistically significant independent variables in multiple prediction models. p < 0.05 was considered statistically significant. STATA, version 15.1, was used to compute all analyses. A total of 1067 (84.68%) eligible contacts of microbiologically confirmed, drug sensitive TB cases underwent screening with tuberculin skin test (TST), 614 (95.6%) LTBI positive contacts accepted the initiation of TPT, and 564 (91.8%) of those initiated on TPT completed the treatment. The major reason for refusal of screening was the lack of perception of risk of TB disease due to asymptomatic status. The prevalence of LTBI positivity through TST was 61.5% (95% CI, 58.5%, 64.4%). Adverse events were reported by 195 (31.8%) contacts initiated on 3HP of which 20 participants discontinued TPT. None of the sociodemographic factors showed a significant association with LTBI positivity (except age) or TPT completion rates. LTBI management with 3HP is feasible among adolescent and adult household contacts in India with high rates of adherence from initiation until treatment completion. The maximum attrition of participants occurred at the time of screening for LTBI using TST.

Background: Pakistan holds rank 8 th among the world countries in which high prevalence of tuberculosis (TB) is present. There is evidenced that up to 30% of close contacts of TB patients become infected and at least half of them progress to active disease. The aim of this study was to screen active contacts of sputum positive pulmonary TB (SS +ve PTB) among household contacts (HHCs) of TB patients in Karachi, Pakistan. Materials and Methods: Cross-sectional study, which was conducted at chest clinics of Karachi. Total 750 HHCs were screened out of which 135 diagnosed smear positive TB patients was registered as index cases (ICs) from July 2012 till March 2013. Logistic regression analysis was carried out to estimate the odds ratio (OR) of different associated factors. Results: Prevalence among males (6.1%) compared with female (5.6%). The crude OR for age less than 15 years was 0.28 (95% confidence interval (CI) 0.14-0.55). Eighty-eight HHCs (11.73%) were found to have SS +ve TB. Disease frequency was significantly higher in HHCs who were smokers (adjusted OR 36.41; 95% CI 12.07, 109.79), had age less than 12 years (adjusted OR 3.63; 95% CI 1.68, 7.86), and who lived in houses less than 80 square yards (adjusted OR 3.77; 95% CI 1.27, 6.05). Conclusion: The IC with positive sputum smear constitutes great risk for TB infection and disease in HHC. There is needed for contact tracing strategy in the high-risk population.

BackgroundScreening household contacts of active tuberculosis (TB) patients is recommended for TB control. Due to resource constraints this rarely occurs in lower income countries. Demographic and clinical features of index cases may influence the likelihood of onwards TB transmission. It has also been proposed that accumulation of intracellular lipid bodies within M. tuberculosis cells may also enhance bacterial transmissibility. This study explored whether clinical and bacteriological observations recorded at baseline in TB cases in Malawi could help identify those with the highest risk of onwards transmission, to prioritise contact tracing.MethodsIn this case-contact study, data on clinical presentation, sputum bacterial load and the percentage of lipid body positive acid-fast bacilli (%LB + AFB) on sputum smears were recorded in adults with sputum smear and culture positive pulmonary TB before initiation of therapy. The Tuberculin Skin Test (TST) was used to detect infection with M. tuberculosis amongst household contacts under the age of 15 years. TST positivity of the child contacts was related to characteristics of the index case.ResultsThirty four index cases brought 56 contacts (median: 1, range: 1–4 contacts each). 37 (66%) of contacts had a positive TST. Cavities or a high percentage of lung affected on index patient CXRs were associated with TST positivity. Multivariate analysis of non-radiological factors showed that male sex, HIV-negative status and raised peripheral blood white blood count (WBC) in index patients were also independent risk factors of TST positivity. Lower %LB + AFB counts were associated with TST positivity on univariate analysis only.ConclusionTST positivity is common amongst household contacts of sputum smear positive adult TB patients in Malawi. Contact tracing in this high risk population could be guided by prioritising index cases with CXR cavities and extensive radiological disease or, in the absence of CXRs, those who are HIV-negative with a raised WBC.

BackgroundNon-sputum based predictive biomarkers capable of identifying individuals with high risk of progression to active tuberculosis (TB) are critical for global TB control. MicroRNAs (miRNAs) are significant regulators involved in TB pathogenesis and hence we aimed to identify a miRNA signature capable of predicting progression to TB disease.MethodsWe compared the differential miRNA expression profile of QuantiFERON supernatants of TB Progressors, defined as healthy household contacts (HHCs) of TB patients, who developed active TB disease during a 2-year follow-up period, and Non-progressors defined as HHCs from the same longitudinal cohort who did not develop TB disease during the entire follow-up period, using the nanostring nCounter platform. Receiver Operator Characteristic (ROC) analysis was performed to evaluate the diagnostic accuracy of the identified miRNA biomarkers, followed by random forest analysis to determine the best predictive model.ResultsWe identified 30 differentially regulated miRNAs between the two groups. Of these, hsa-miR-585-3p and hsa-miR-92a-3p were up-regulated with a maximum fold change of 1.74 and 1.71 respectively, while hsa-miR-223-3p and hsa-miR-451a were down-regulated by −2.05 and −2.04 fold respectively. Random forest analysis revealed that hsa-miR-181a-5p, hsa-miR-204-5p, hsa-miR-197-3p, hsa-miR-92a-3p, hsa-miR-451a, hsa-miR-24-3p, and hsa-miR-487a-3p exhibited 100% accuracy in identifying Progressors. This panel of 7 miRNAs demonstrated excellent diagnostic performance characteristics with 100% sensitivity and specificity.ConclusionWe propose that the identified miRNA signature has the potential to serve as a very useful tool for early identification of individuals who bear the highest risk of progression to TB, so that they can be targeted for timely intervention.

In the current study, we followed 839 household contacts (HHCs) of tuberculosis (TB) patients for 2 years and identified the factors that enhanced the development of TB. Fourteen of the 17 HHCs who progressed to TB were in the 15- to 30-year-old age group. At baseline (the “0“ time point, when all the individuals were healthy), the concentration of the thyroid hormone thyroxine (T4) was lower, and there were increased numbers of Tregs in PBMCs of TB progressors. At baseline, PBMCs from TB progressors stimulated with early secretory antigenic target 6 (ESAT-6) and 10 kDa culture filtrate antigen (CFP-10) produced less IL-1α. Thyroid hormones inhibited Mycobacterium tuberculosis (Mtb) growth in macrophages in an IL-1α–dependent manner. Mtb-infected Thra1PV/+ (mutant thyroid hormone receptor) mice had increased mortality and reduced IL-1α production. Our findings suggest that young HHCs who exhibit decreased production of thyroid hormones are at high risk of developing active TB disease.

HIV markedly increases the risk of tuberculosis. We implemented active tuberculosis case-finding in a prevention of mother-to-child transmission programme in South Africa. Of 438 tuberculin-tested HIV-infected patients, 49% had a reaction >= 5 mm induration, 120 underwent further evaluation for active disease. The prevalence of active tuberculosis was 11%, a high rate of tuberculosis in this population, and underscores the need for tuberculosis active case-finding to prevent mortality and transmission, and preventive therapy for latent tuberculosis infection. Recent reports have demonstrated a high maternal mortality rate associated with tuberculosis in HIV-infected patients in South Africa [1]. HIV-infected individuals with latent tuberculosis infection have up to a 10% annual risk of developing active tuberculosis, with increased mortality. Furthermore, tuberculosis preventive therapy has been shown to be effective in reducing the incidence of tuberculosis in HIV-infected, tuberculin skin test (TST)-positive individuals. Tuberculosis active case-finding and preventive therapy have been advocated as an essential strategy for the reduction of the incidence of tuberculosis in both developed and developing countries [2]. We report the prevalence of undiagnosed active tuberculosis in HIV-infected, TST-positive individuals attending a programme to prevent mother-to-child HIV transmission in Soweto, South Africa. Patients were recruited at the Chris Hani Baragwanath Hospital Perinatal HIV Research Unit. All patients received pre and post-HIV voluntary counselling and testing (VCT) as part of the routine antenatal services. Tuberculosis screening was performed after delivery during the postnatal follow-up for HIV-infected women and their male partners. Two tuberculin units of purified protein derivative RT-23 were administered by the Mantoux method, and induration was measured after 2–3 days. If 5 mm or greater induration was present, the patient was referred to the study physician for a clinical evaluation. Patients had chest radiography, and those with symptoms suggestive of tuberculosis underwent detailed physical examination, fluorescence microscopy and BACTEC cultures on three sputum specimens, and other tests as indicated. 'Definite tuberculosis' was defined as a positive culture for Mycobacterium tuberculosis from any site. 'Probable tuberculosis' was defined as one or more positive acid fast smears from sputum or an extrapulmonary site without a positive culture, or typical pathological findings on a biopsy. 'Possible tuberculosis' included signs and symptoms consistent with tuberculosis, as well as the clinical response to therapy, but without a positive smear or culture. This evaluation was approved by the Ethical Review Committee of the University of the Witwatersrand, South Africa, and the Joint Committee on Clinical Investigation of the Johns Hopkins Medical Institutions, Baltimore, MD, USA. From May to November 2001, 438 HIV-infected patients had skin tests performed. The mean age was 30 years (± 6) and over 95% were women. A total of 318 (73%) returned for results, with 157 of these (49%) having 5 mm or greater induration. Among individuals with a positive TST, 120 patients (76%) underwent complete tuberculosis screening, of whom 13 (11%) were found to have active tuberculosis (3% of the total population; Fig. 1). The median CD4 cell count among tuberculosis cases was 230 cells/mm3 versus 508 cells/mm3 for patients without tuberculosis (P < 0.01). Among the 13 patients with active tuberculosis, six had definite tuberculosis, including two with positive cultures from lymph node aspirates, three from sputum (one smear positive), and one from both sputum and urine. Five patients had probable tuberculosis with positive acid-fast bacillus (AFB) smears from lymph node aspirates (three), bone marrow aspirate (one) and bronchial washings (one). Two patients had possible tuberculosis, with symptoms and signs consistent with tuberculosis, as well as hilar adenopathy on chest X-ray (one) or pericardial effusion on echocardiogram (one) and clinical improvement with subsequent tuberculosis treatment. Therefore, nine out of 13 patients had extrapulmonary tuberculosis and four out of 13 had culture-positive pulmonary tuberculosis, including one patient with an AFB-positive smear.Fig. 1. Tuberculosis case-finding at Chris Hani Baragwanath Perinatal HIV Research Unit in Soweto, South Africa.: TB, Tuberculosis; TST, tuberculin skin test.Nearly 50% of our study sample of mostly women in a prevention of mother-to-child transmission programme had latent tuberculosis infection. More importantly, however, we found that 11% of the TST-positive HIV-infected individuals we examined had undiagnosed active tuberculosis. This is a minimal estimate, as TST-negative patients were not further evaluated. Individuals with active tuberculosis act as a reservoir that may contribute to ongoing transmission in the home and community. All of these individuals had a newborn, HIV-exposed infant at home to whom the transmission of M. tuberculosis could be devastating. The AFB smear identifies the most infectious tuberculosis patients; however, individuals with smear-negative, culture-positive tuberculosis may also serve as a significant source of community transmission of tuberculosis [3]. Our findings are in concordance with earlier reports [4] suggesting that active tuberculosis case-finding, as part of HIV counselling and testing, can have a substantial yield. These findings suggest two possible courses of action. First, active tuberculosis case-finding should be considered whenever feasible in HIV-infected individuals living in high HIV and tuberculosis-endemic areas. Settings suitable for active case-finding are those where HIV-positive individuals are concentrated, such as healthcare facilities, VCT centres, HIV support organizations, and prisons. Second, HIV-infected individuals with latent tuberculosis infection should receive tuberculosis preventive therapy. The feasibility of tuberculosis preventive therapy in developing countries has been questioned because of operational difficulties; however, a recent operational assessment of isoniazid prophylaxis in a community VCT centre in Uganda [5] demonstrated that tuberculosis preventive therapy can be successfully implemented. Even as the treatment of HIV infection with antiretroviral drugs increases, tuberculosis preventive therapy will remain important. Antiretroviral therapy reduces the rate of tuberculosis substantially, but the incidence is still high, and many patients will develop tuberculosis before antiretroviral therapy is indicated [6]. The median CD4 cell count in our patients who had tuberculosis was 230 cells/mm3, meaning that antiretroviral drugs would not have been offered even if they were available. Given the substantial benefits to HIV-infected patients of case-finding, proper treatment, and preventive therapy against tuberculosis, the development of innovative ways of integrating tuberculosis prevention and treatment services and HIV care should be a priority on the research agenda.

Tuberculosis (TB) preventive therapy (TPT) is an effective strategy to eliminate TB in low-incidence settings. Shorter TPT regimens incorporating the antimicrobial class of rifamycins are designed to improve adherence and completion rates but carry the risk of modifications to the gut microbiota. We enrolled six subjects diagnosed with latent TB infection (LTBI) who accepted to initiate TPT. We also enrolled six healthy volunteers unexposed to the rifamycins. We profiled the gut microbiota using 16S rRNA amplicon sequencing (V1-V2 region) to document the immediate effect of rifamycin-based TPT on the gut microbiota composition and tracked recovery to baseline two months after TPT. Overall, TPT accounted for 17% of the variance in gut microbial community dissimilarity. This rifamycin-based TPT induced dysbiosis was characterized by a depletion of butyrate-producing taxa (Clostridium-XIVa and Roseburia) and expansion of potentially pathogenic taxa within the Firmicutes and Proteobacteria phyla. Recovery of the gut microbial composition was incomplete two months after TPT. Robust clinical studies are necessary to comprehensively catalogue TPT-induced gut microbiota dysbiosis to inform strategies to mitigate potential long-term sequelae of this important TB control intervention.

ObjectivesHousehold contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNγ produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNγ levels in HHCs correlate with tuberculosis development.MethodsA cohort of 2060 HHCs was followed for 2–3 years after exposure to a tuberculosis case. Besides TST, IFNγ responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination.ResultsUsing TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNγ response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNγ responders to CFP-10 (HR 1.82 95% CI 0.79–4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNγ producers was observed (trend Log rank p = 0.007).DiscussionCFP-10-induced IFNγ production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprohylaxis to child contacts regardless of BCG vaccination.

Tuberculosis in household contacts of tuberculosis patients in sub-Saharan African countries: A systematic review and meta-analysis

Towards the 'End TB Strategy' targets, the WHO recommends the provision of tuberculosis (TB) preventive therapy (TPT) for high-risk groups including people living with HIV (PLWH). 3 years after the release of the updated 2020 WHO guidelines, we investigated the implementation of TPT services at HIV clinics in low-income and middle-income countries (LMICs), focusing on TB screening, populations eligible for TPT and available TPT regimens. In 2023, we surveyed HIV care clinics in the International Epidemiology Databases to Evaluate AIDS consortium in Africa, the Asia-Pacific and Latin America and the Caribbean. We used descriptive statistics to summarise TPT implementation according to WHO guidelines and multivariable logistic regression models to estimate associations with clinic characteristics. Of 172 HIV clinics included, 142 (83%) were in Africa, 22 (13%) in the Asia-Pacific and 8 (5%) in Latin America; 108 (63%) were located in urban areas. After ruling out active TB, TPT was reportedly offered to PLWH (122 clinics, 71%), household contacts of individuals with active TB (120 clinics, 70%) and other high-risk populations. TPT for PLWH was more frequently available in clinics in lower-income and low-middle-income countries, in high TB burden countries, and in district hospitals compared with other facility types. Clinics reported use of isoniazid-based (160 clinics, 93%) and shorter rifamycin-based (129 clinics, 75%) TPT regimens. Reported barriers to TPT initiation included patient refusal at 71 (41%) and drug shortages at 67 (39%) clinics. TPT was available at most HIV care clinics in LMICs but further efforts are needed to reinforce WHO recommendations and ensure that TPT is consistently accessible to people at higher risk of developing active TB, especially PLWH.

ObjectiveTo evaluate the impact of socioeconomic support on tuberculosis preventive therapy initiation in household contacts of tuberculosis patients and on treatment success in patients.MethodsA non-blinded, household-randomized, controlled study was performed between February 2014 and June 2015 in 32 shanty towns in Peru. It included patients being treated for tuberculosis and their household contacts. Households were randomly assigned to either the standard of care provided by Peru’s national tuberculosis programme (control arm) or the same standard of care plus socioeconomic support (intervention arm). Socioeconomic support comprised conditional cash transfers up to 230 United States dollars per household, community meetings and household visits. Rates of tuberculosis preventive therapy initiation and treatment success (i.e. cure or treatment completion) were compared in intervention and control arms.FindingsOverall, 282 of 312 (90%) households agreed to participate: 135 in the intervention arm and 147 in the control arm. There were 410 contacts younger than 20 years: 43% in the intervention arm initiated tuberculosis preventive therapy versus 25% in the control arm (adjusted odds ratio, aOR: 2.2; 95% confidence interval, CI: 1.1–4.1). An intention-to-treat analysis showed that treatment was successful in 64% (87/135) of patients in the intervention arm versus 53% (78/147) in the control arm (unadjusted OR: 1.6; 95% CI: 1.0–2.6). These improvements were equitable, being independent of household poverty.ConclusionA tuberculosis-specific, socioeconomic support intervention increased uptake of tuberculosis preventive therapy and tuberculosis treatment success and is being evaluated in the Community Randomized Evaluation of a Socioeconomic Intervention to Prevent TB (CRESIPT) project.

BackgroundTuberculosis incidence in resource poor countries remains high. We hypothesized that immune modulating co-infections such as helminths, malaria, and HIV increase susceptibility to latent tuberculosis infection (LTBI), thereby contributing to maintaining the tuberculosis epidemic.MethodsAdults with sputum-positive tuberculosis (index cases) and their eligible household contacts (HHCs) were recruited to a cohort study between May 2011 and January 2012. HHCs were investigated for helminths, malaria, and HIV at enrolment. HHCs were tested using the QuantiFERON-TB Gold In-Tube (QFN) assay at enrolment and six months later. Overnight whole blood culture supernatants from baseline QFN assays were analyzed for cytokine responses using an 11-plex Luminex assay. Associations between outcomes (LTBI or cytokine responses) and exposures (co-infections and other risk factors) were examined using multivariable logistic and linear regression models.ResultsWe enrolled 101 index cases and 291 HHCs. Among HHCs, baseline prevalence of helminths was 9% (25/291), malaria 16% (47/291), HIV 6% (16/291), and LTBI 65% (179/277). Adjusting for other risk factors and household clustering, there was no association between LTBI and any co-infection at baseline or at six months: adjusted odds ratio (95% confidence interval (CI); p-value) at baseline for any helminth, 1.01 (0.39–2.66; 0.96); hookworm, 2.81 (0.56–14.14; 0.20); malaria, 1.06 (0.48–2.35; 0.87); HIV, 0.74 (0.22–2.47; 0.63). HHCs with LTBI had elevated cytokine responses to tuberculosis antigens but co-infections had little effect on cytokine responses. Exploring other risk factors, Th1 cytokines among LTBI-positive HHCs with BCG scars were greatly reduced compared to those without scars: (adjusted geometric mean ratio) IFNγ 0.20 (0.09–0.42), <0.0001; IL-2 0.34 (0.20–0.59), <0.0001; and TNFα 0.36 (0.16–0.79), 0.01.ConclusionsWe found no evidence that co-infections increase the risk of LTBI, or influence the cytokine response profile among those with LTBI. Prior BCG exposure may reduce Th1 cytokine responses in LTBI.

Tuberculosis (TB) preventive therapy (TPT) reduces the incidence of TB among people living with the human immunodeficiency virus (PLHIV). However, despite an increase in TPT uptake, TB/HIV coinfection remains stagnant in Uganda especially in areas of increasing HIV incidence such as the Bunyoro sub-region. This study was a retrospective review records (antiretroviral therapy [ART] files) of PLHIV who were active on ART and completed TPT in 2019/2020 at three major hospitals in the Bunyoro sub-region, Uganda: Masindi General Hospital, Hoima Regional Referral Hospital, and Kiryandongo General Hospital. The sample size (987) for each facility was determined using a proportionate sampling method to ensure the study’s power and precision. Factors independently associated with acquiring TB disease post TPT were determined using modified Poisson regression analysis. An adjusted prevalence risk ratio (aPRR) with corresponding 95% confidence intervals were reported. The participants’ mean age was 38.23 (±11.70) and the majority were female (64.94%). Overall, 9.63% developed active TB disease post TPT completion. In the adjusted analysis, factors associated with active TB disease were a history of an unsuppressed viral load after TPT (aPRR 4.64 (2.85–7.56), p<0.001), opportunistic infections after TPT completion (aPRR 4.31 (aPRR 2.58–7.2), p<0.001), a history of TB active TB disease (aPRR 1.60 (1.06–2.41), p = 0.026), and chronic illness during or after TPT (aPRR 1.68 (1.03–2.73), p = 0.038). To reduce the development of TB disease post TPT thereby improving the effectiveness of TPT, ART adherence should be emphasized to resolve viral suppression and active management of chronic and opportunistic infections. Further clinical management consideration and research is needed for PLHIV who receive TPT but have a previous history of TB disease.