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Project description:We hypothesized that individuals with immunological sensitization to Mycobacterium tuberculosis (Mtb), conventionally regarded as evidence of latent tuberculosis infection (LTBI), would demonstrate binary responses to preventive therapy. This would reflect the differential immunological consequences of the sterilization of viable infection in those with an active Mtb infection versus no Mtb killing in those who, despite T cell recognition of Mtb antigens, did not harbor viable Mtb bacilli. We investigated the blood transcriptional profiles of 18 individuals with a positive IGRA result and known recent exposure to an index person with isoniazid and rifampicin susceptible pulmonary tuberculosis, at baseline, 2 weeks after initiating combined rifampicin/isoniazid (RH) preventive therapy and at treatment completion. Healthy control volunteers with no history of TB exposure and negative IGRA results were also included. RNA from unstimulated and M. tuberculosis peptide stimulated whole blood (from QuantiFERON TB1 and TB2 tubes) was measured using Agilent microarrays. A set of 474 genes showed the greatest interpersonal and temporal expression variability in antigen-stimulated blood. By performing longitudinal unsupervised clustering analysis with the subset of most variable genes, the IGRA+ participants were separated into two distinct groups. The IGRA-negative controls clustered within one of these groups suggesting that, in contrast to the other subgroup of IGRA+ individuals, RH had no discernible effect in this subgroup. 117 genes were significantly differentially expressed over time between these two groups, with the majority of them associated with immunological pathways known to be important in mycobacterial control. We contend that the different host RNA response reflects lack of Mtb viability in the group that clustered with the IGRA- unexposed healthy controls, and Mtb viability in the one that clustered away. Gene expression patterns in the blood of IGRA+ individuals emerging during the course of RH treatment which reflect Mtb viability could have major implications in the identification of risk of progression/reactivation, treatment stratification and clinical trials for LTBI therapy.
2021-01-19 | GSE153326 | GEO
Project description:We hypothesized that individuals with immunological sensitization to Mycobacterium tuberculosis (Mtb), conventionally regarded as evidence of latent tuberculosis infection (LTBI), would demonstrate binary responses to preventive therapy. This would reflect the differential immunological consequences of the sterilization of viable infection in those with an active Mtb infection versus no Mtb killing in those who, despite T cell recognition of Mtb antigens, did not harbor viable Mtb bacilli. We investigated the blood transcriptional profiles of 18 individuals with a positive IGRA result and known recent exposure to an index person with isoniazid and rifampicin susceptible pulmonary tuberculosis, at baseline, 2 weeks after initiating combined rifampicin/isoniazid (RH) preventive therapy and at treatment completion. Healthy control volunteers with no history of TB exposure and negative IGRA results were also included. RNA from unstimulated and M. tuberculosis peptide stimulated whole blood (from QuantiFERON TB1 and TB2 tubes) was measured using Agilent microarrays. A set of 474 genes showed the greatest interpersonal and temporal expression variability in antigen-stimulated blood. By performing longitudinal unsupervised clustering analysis with the subset of most variable genes, the IGRA+ participants were separated into two distinct groups. The IGRA-negative controls clustered within one of these groups suggesting that, in contrast to the other subgroup of IGRA+ individuals, RH had no discernible effect in this subgroup. 117 genes were significantly differentially expressed over time between these two groups, with the majority of them associated with immunological pathways known to be important in mycobacterial control. We contend that the different host RNA response reflects lack of Mtb viability in the group that clustered with the IGRA- unexposed healthy controls, and Mtb viability in the one that clustered away. Gene expression patterns in the blood of IGRA+ individuals emerging during the course of RH treatment which reflect Mtb viability could have major implications in the identification of risk of progression/reactivation, treatment stratification and clinical trials for LTBI therapy.
2021-01-19 | GSE153340 | GEO
Project description:Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals
| PRJNA642111 | ENA
Project description:Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals: PAXgene ex vivo samples
| PRJNA642118 | ENA
Project description:Host transcriptional response to TB preventive therapy differentiates two sub-groups of IGRA-positive individuals: in vitro (Quantiferon tube)-stimulated blood
| PRJNA642243 | ENA
Project description:BACKGROUND: There has been slow uptake of isoniazid preventive therapy (IPT) among people living with HIV (PLWH).METHODS: We surveyed adults recently diagnosed with HIV in 14 South African primary health clinics. Based on the literature and qualitative interviews, sixteen potential barriers and facilitators related to preventive therapy among PLWH were selected. Best-worst scaling (BWS) was used to quantify the relative importance of the attributes. BWS scores were calculated based on the frequency of participants' selecting each attribute as the best or worst among six options (across multiple choice sets) and rescaled from 0 (always selected as worst) to 100 (always selected as best) and compared by currently receiving IPT or not.RESULTS: Among 342 patients surveyed, 33% (n = 114) were currently taking IPT. Having the same standard of life as someone without HIV was most highly prioritized (BWS score = 67.3, SE = 0.6), followed by trust in healthcare providers (score, 66.3 ± 0.6). Poor standard of care in public clinics (score, 30.6 ± 0.6) and side effects of medications (score, 33.7 ± 0.6) were least prioritized. BWS scores differed by IPT status for few attributes, but overall ranking was similar (spearman's rho = 0.9).CONCLUSION: Perceived benefits of preventive therapy were high among PLWH. IPT prescription by healthcare providers should be encouraged to enhance IPT uptake among PLWH.
| S-EPMC7518293 | biostudies-literature
Project description:SettingChildren especially those <5 years of age exposed to pulmonary tuberculosis (TB) are at a high risk of severe TB disease and death. Isoniazid preventive therapy (IPT) has been shown to decrease disease progression by up to 90%. Kenya, a high TB burden country experiences numerous operational challenges that limit implementation of TB preventive services. IPT completion in child contacts is not routinely reported in Kenya.ObjectiveThis study aims to review the child contact management (CCM) cascade and present IPT outcomes across 10 clinics in western Kenya.DesignA retrospective chart review of programmatic data of a TB Reach-funded active, clinic-based CCM strategy.ResultsOf 553 child contacts screened, 231 (42%) were reported symptomatic. 74 (13%) of the child contacts were diagnosed with active TB disease. Of those eligible for IPT, 427 (90%) initiated IPT according to TB REACH project data while 249 (58%) were recorded in the IPT register with 49 (11%) recorded as a transfer to other facilities. Of the 249 recorded in the IPT register, 205 (82%) were documented to complete therapy (48% of project initiation children).ConclusionOur evaluation shows gaps in the routine CCM care cascade related to completeness of documentation that require further programmatic monitoring and evaluation to improve CCM outcomes.
| S-EPMC7907885 | biostudies-literature
Project description:BackgroundCollaborative TB/HIV management is essential to ensure that HIV positive TB patients are identified and treated appropriately, and to prevent tuberculosis (TB) in HIV positive patients. The purpose of this study was to assess HIV case finding among TB patients and Co-trimoxazole Preventive Therapy (CPT) for HIV/TB patients in Addis Ababa.MethodsA descriptive cross-sectional, facility-based survey was conducted between June and July 2011. Data was collected by interviewing 834 TB patients from ten health facilities in Addis Ababa. Both descriptive and inferential statistics were used to summarize and analyze findings.ResultsThe proportion of TB patients who (self reported) were offered for HIV test, tested for HIV and tested HIV positive during their anti-TB treatment follow-up were; 87.4%, 69.4% and 20.2%; respectively. Eighty seven HIV positive patients were identified, who knew their status before diagnosed for the current TB disease, bringing the cumulative prevalence of HIV among TB patients to 24.5%. Hence, the proportion of TB patients who knew their HIV status becomes 79.9%. The study revealed that 43.6% of those newly identified HIV positives during anti-TB treatment follow-up were actually treated with CPT. However, the commutative proportion of HIV positive TB patients who were ever treated with CPT was 54.4%; both those treated before the current TB disease and during anti-TB treatment follow-up.ConclusionsHIV case finding among TB patients and provision of CPT for TB/HIV co-infected patients needs boosting. Hence, routine offering of HIV test and provision of CPT for PLHIV should be strengthened in-line with the national guidelines.
| S-EPMC3911916 | biostudies-literature
Project description:Mycobacterium tuberculosis (Mtb) is known to subvert immune responses to establish infection and cause disease. Thus, host-directed therapy (HDT), as adjunctive treatment to traditional antitubercular regimens, is an attractive strategy. Statins are a class of drugs used to lower cholesterol levels by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A reductase, a crucial enzyme in the cholesterol biosynthesis pathway. Here, we conducted a preclinical animal study aimed at comparing the bactericidal activities of the standard TB regimen (rifampin, isoniazid, pyrazinamide and ethambutol; RHZE) with or without escalating doses of pravastatin against chronic TB in BALB/c mice. Antibiotics were given five times weekly for 8 weeks (continuous phase) beginning 6 weeks after infection. Treatment with RHZE plus pravastatin at doses ranging from 30 mg/kg to 180 mg/kg demonstrated a dose-dependent increase in bactericidal activity, reducing lung bacillary counts by 0.2–0.6 log10, 0.3–0.6 log10 and 0.3–0.8 log10 compared to RHZE alone at weeks 2, 4 and 8, respectively. After 8 weeks of treatment, the degree of lung inflammation correlated with the bactericidal activity of each drug regimen. In order to gain insight into the anti-TB mechanism of action of pravastatin in vivo, the lungs of mice treated with pravastatin adjunctive therapy and those treated with RHZE alone were analyzed by whole-genome microarrays and RT-PCR. Mouse sera were studied by multiplex enzyme-linked immunosorbent assays. Treatment with pravastatin for 1 month had a profound effect on the global transcription in mouse lungs.
2018-08-02 | GSE99625 | GEO
Project description:BackgroundShort-course, rifamycin-based regimens could facilitate scale-up of tuberculosis preventive therapy (TPT), but it is unclear how stringently tuberculosis (TB) disease should be ruled out before TPT use.MethodsWe developed a state-transition model of a TPT intervention among two TPT-eligible cohorts: adults newly diagnosed with HIV in South Africa (PWH) and TB household contacts in Pakistan (HHCs). We modeled two TPT regimens-4 months of rifampicin [4R] or 6 months of isoniazid [6H]-comparing each to a reference of no intervention. Before initiating TPT, TB disease was excluded either through symptom-only screening or with additional radiographic screening that could detect subclinical TB but might limit access to the TPT intervention. TPT's potential curative effects on both latent and subclinical TB were modeled, as were both acquisitions of resistance and prevention of drug-resistant disease. Although all eligible individuals received the screening and/or TPT interventions, the modeled TB outcomes comprised only those with latent or subclinical TB that would have progressed to symptomatic disease if untreated.ResultsWhen prescribed after only symptom-based TB screening (such that individuals with subclinical TB were included among TPT recipients), 4R averted 45 active (i.e., symptomatic) TB cases (95% uncertainty range 24-79 cases or 40-89% of progressions to active TB) per 1000 PWH [17 (9-29, 43-94%) per 1000 HHCs]; 6H averted 37 (19-66, 52-73%) active TB cases among PWH [13 (7-23, 53-75%) among HHCs]. With this symptom-only screening, for each net rifampicin resistance case added by 4R, 12 (3-102) active TB cases were averted among PWH (37 [9-580] among HHCs); isoniazid-resistant TB was also reduced. Similarly, 6H after symptom-only screening increased isoniazid resistance while reducing overall and rifampicin-resistant active TB. Screening for subclinical TB before TPT eliminated this net increase in resistance to the TPT drug; however, if the screening requirement reduced TPT access by more than 10% (the estimated threshold for 4R among HHCs) to 30% (for 6H among PWH), it was likely to reduce the intervention's overall TB prevention impact.ConclusionsAll modeled TPT strategies prevent TB relative to no intervention, and differences between TPT regimens or between screening approaches are small relative to uncertainty in the outcomes of any given strategy. If most TPT-eligible individuals can be screened for subclinical TB, then pairing such screening with rifamycin-based TPT maximizes active TB prevention and does not increase rifampicin resistance. Where subclinical TB cannot be routinely excluded without substantially reducing TPT access, the choice of TPT regimen requires weighing 4R's efficacy advantages (as well as its greater safety and shorter duration that we did not directly model) against the consequences of rifampicin resistance in a small fraction of recipients.
| S-EPMC8670249 | biostudies-literature