Browsing by Subject "Antitubercular agents"

Now showing 1 - 3 of 3
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    Isoniazid preventive therapy and tuberculosis transcriptional signatures in people with HIV
    (Wolters Kluwer, 2022) Valinetz, Ethan D.; Matemo, Daniel; Gersh, Jill K.; Joudeh, Lara L.; Mendelsohn, Simon C.; Scriba, Thomas J.; Hatherill, Mark; Kinuthia, John; Wald, Anna; Cangelosi, Gerard A.; Barnabas, Ruanne V.; Hawn, Thomas R.; Horne, David J.; Medicine, School of Medicine
    Objectives: To examine the association between isoniazid preventive therapy (IPT) or nontuberculous mycobacteria (NTM) sputum culture positivity and tuberculosis (TB) transcriptional signatures in people with HIV. Design: Cross-sectional study. Methods: We enrolled adults living with HIV who were IPT-naive or had completed IPT more than 6 months prior at HIV care clinics in western Kenya. We calculated TB signatures using gene expression data from qRT-PCR. We used multivariable linear regression to analyze the association between prior receipt of IPT or NTM sputum culture positivity with a transcriptional TB risk score, RISK6 (range 0-1). In secondary analyses, we explored the association between IPT or NTM positivity and four other TB transcriptional signatures. Results: Among 381 participants, 99.7% were receiving antiretroviral therapy and 86.6% had received IPT (completed median of 1.1 years prior). RISK6 scores were lower (mean difference 0.10; 95% confidence interval (CI): 0.06-0.15; P < 0.001) among participants who received IPT than those who did not. In a model that adjusted for age, sex, duration of ART, and plasma HIV RNA, the RISK6 score was 52.8% lower in those with a history of IPT ( P < 0.001). No significant association between year of IPT receipt and RISK6 scores was detected. There was no association between NTM sputum culture positivity and RISK6 scores. Conclusion: In people with HIV, IPT was associated with significantly lower RISK6 scores compared with persons who did not receive IPT. These data support investigations of its performance as a TB preventive therapy response biomarker.
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    Organocatalytic Multicomponent Reaction for the Acquisition of a Selective Inhibitor of mPTPB, a Virulence Factor of Tuberculosis
    (Royal Society of Chemistry, 2013) He, Rongjun; Zeng, Li-Fan; He, Yantao; Wu, Li; Gunawan, Andrea Michelle; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of Medicine
    Mycobacterium protein tyrosine phosphatase B (mPTPB) is essential for the survival and persistence of Mycobacterium in the host. Thus small molecule inhibitors of mPTPB are potential anti-TB agents. We developed an efficient organocatalytic multicomponent reaction (MCR) between pyrrole, formaldehyde and aniline, affording a potent and selective mPTPB inhibitor with an IC(50) value of 1.5 μM and >50-fold specificity. Our studies provide a successful example of using organocatalysis as a discovery tool for the acquisition of PTP inhibitors.
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    Real-world use and outcomes of dolutegravir-containing antiretroviral therapy in HIV and tuberculosis co-infection: a site survey and cohort study in sub-Saharan Africa
    (Wiley, 2022) Romo, Matthew L.; Brazier, Ellen; Mahambou-Nsondé, Dominique; De Waal, Reneé; Sekaggya-Wiltshire, Christine; Chimbetete, Cleophas; Muyindike, Winnie R.; Murenzi, Gad; Kunzekwenyika, Cordelia; Tiendrebeogo, Thierry; Muhairwe, Josephine A.; Lelo, Patricia; Dzudie, Anastase; Twizere, Christelle; Rafael, Idiovino; Ezechi, Oliver C.; Diero, Lameck; Yotebieng, Marcel; Fenner, Lukas; Wools-Kaloustian, Kara K.; Shah, N. Sarita; Nash, Denis; International epidemiology Databases to Evaluate AIDS (IeDEA); Medicine, School of Medicine
    Introduction: Dolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co-infection, its use is complicated by a drug-drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug-drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co-infection receiving dolutegravir or efavirenz. Methods: Within the four sub-Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015-2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months. Results: In the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice-daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice-daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3-63.3%), switching ART regimen was 4.1% (95% CI: 2.6-6.2%) and loss to program/death was 23.4% (95% CI: 19.7-27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28-1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08-1.51). Conclusions: At a programmatic level, dolutegravir was being widely prescribed in sub-Saharan Africa for people with HIV and tuberculosis co-infection with a dose adjustment for the drug-drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression.