666 results on '"Aarnoutse, R.E."'
Search Results
2. Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder
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Vos, C.F., Hark, S.E. ter, Schellekens, A.F.A., Spijker, J., Meij, A. van der, Grotenhuis, A.J., Mihaescu, R., Kievit, W., Donders, R., Aarnoutse, R.E., Coenen, M.J.H., Janzing, J.G.E., and Clinical Chemistry
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Experimental Psychopathology and Treatment ,All institutes and research themes of the Radboud University Medical Center ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,General Medicine ,Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18] - Abstract
ImportanceEvidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects.ObjectiveTo determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD).Design, Setting, and ParticipantsThis randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications.InterventionIn the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage.Main Outcomes and MeasuresThe primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores).ResultsOf 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10.2] days; Kaplan-Meier χ21 = 4.30; P = .04). No significant difference in reduction of depressive symptoms was observed. Linear mixed-model analyses showed that the interaction between group and time differed for the frequency (F6,125 = 4.03; P = .001), severity (F6,114 = 3.10; P = .008), and burden (F6,112 = 2.56; P = .02) of adverse effects, suggesting that adverse effects decreased relatively more for those receiving PIT.Conclusions and RelevanceIn this randomized clinical trial, PIT resulted in faster attainment of therapeutic TCA concentrations, with potentially fewer and less severe adverse effects. No effect on depressive symptoms was observed. These findings indicate that pharmacogenetics-informed dosing of TCAs can be safely applied and may be useful in personalizing treatment for patients with MDD.Trial RegistrationClinicalTrials.gov Identifier: NCT03548675
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- 2023
3. Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin.
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Sekaggya-Wiltshire, C., Nabisere, R., Musaazi, J., Otaalo, B., Aber, F., Alinaitwe, L., Nampala, J., Najjemba, L., Buzibye, A., Omali, D., Gausi, K., Kengo, A., Lamorde, M., Aarnoutse, R.E., Denti, P., Dooley, Kelly E., Sloan, D.J., Sekaggya-Wiltshire, C., Nabisere, R., Musaazi, J., Otaalo, B., Aber, F., Alinaitwe, L., Nampala, J., Najjemba, L., Buzibye, A., Omali, D., Gausi, K., Kengo, A., Lamorde, M., Aarnoutse, R.E., Denti, P., Dooley, Kelly E., and Sloan, D.J.
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Item does not contain fulltext, BACKGROUND: Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug-drug interactions with antiretroviral therapy (ART) and safety in people with human immunodeficiency virus (HIV) have not been evaluated. METHODS: This was a randomized, open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily-dose rifampicin. ART treatment-naive patients were randomized to dolutegravir- or efavirenz-based ART. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. HIV viral load was measured at week 24. RESULTS: Among 128 patients randomized, the median CD4 count was 191 cells/mm3. The geometric mean ratio (GMR) for trough dolutegravir concentrations on higher- vs standard-dose rifampicin was 0.57 (95% confidence interval [CI], .34-.97; P = .039) and the GMR for mid-dose efavirenz was 0.63 (95% CI, .38-1.07; P = .083). There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs 14.0%, P = .901), as was the incidence of drug-related grade 3-4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higher-dose rifampicin (18.6% vs 37.0%, P = .063). CONCLUSIONS: Compared with standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures, but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion. CLINICAL TRIALS REGISTRATION: NCT03982277.
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- 2023
4. Adequacy of the 10 mg/kg Daily Dose of Antituberculosis Drug Isoniazid in Infants under 6 Months of Age.
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López-Ramos, M.G., Vinent, J., Aarnoutse, R.E., Colbers, A., Velasco-Arnaiz, E., Martorell, L., Falcón-Neyra, L., Neth, O., Prieto, L., Guillén, S., Baquero-Artigao, F., Méndez-Echevarría, A., Gómez-Pastrana, D., Jiménez, A.B., Lahoz, R., Ramos-Amador, J.T., Soriano-Arandes, A., Santiago, B., Farré, R., Fortuny, C., Soy, D., Noguera-Julian, A., López-Ramos, M.G., Vinent, J., Aarnoutse, R.E., Colbers, A., Velasco-Arnaiz, E., Martorell, L., Falcón-Neyra, L., Neth, O., Prieto, L., Guillén, S., Baquero-Artigao, F., Méndez-Echevarría, A., Gómez-Pastrana, D., Jiménez, A.B., Lahoz, R., Ramos-Amador, J.T., Soriano-Arandes, A., Santiago, B., Farré, R., Fortuny, C., Soy, D., and Noguera-Julian, A.
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Item does not contain fulltext, In 2010, the WHO recommended an increase in the daily doses of first-line anti-tuberculosis medicines in children. We aim to characterize the pharmacokinetics of the once-daily isoniazid (INH) dose at 10 mg/kg of body weight in infants <6 months of age. We performed a multicenter pharmacokinetic study in Spain. The N-acetyltransferase 2 gene was analyzed to determine the acetylation status. Samples were analyzed using a validated UPLC-UV assay. A non-compartmental pharmacokinetic analysis was performed. Twenty-three pharmacokinetic profiles were performed in 20 infants (8 females) at a median (IQR) age of 19.0 (12.6-23.3) weeks. The acetylator statuses were homozygous fast (n = 1), heterozygous intermediate (n = 12), and homozygous slow (n = 7). INH median (IQR) C(max) and AUC(0-24h) values were 4.8 (3.7-6.7) mg/L and 23.5 (13.4-36.7) h*mg/L and the adult targets (>3 mg/L and 11.6-26.3 h*mg/L) were not reached in three and five cases, respectively. The age at assessment or acetylator status had no impact on C(max) values, but a larger INH AUC(0-24h) (p = 0.025) and trends towards a longer half-life (p = 0.055) and slower clearance (p = 0.070) were observed in homozygous slow acetylators. Treatment was well tolerated; mildly elevated alanine aminotransferase levels were observed in three cases. In our series of young infants receiving isoniazid, no major safety concerns were raised, and the target adult levels were reached in most patients.
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- 2023
5. Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.
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Gafar, F., Wasmann, R.E., McIlleron, H.M., Aarnoutse, R.E., Schaaf, H.S., Marais, B.J., Agarwal, D., Antwi, S., Bang, N.D., Bekker, A., Bell, D.J., Chabala, C., Choo, L., Davies, G.R., Day, J.N., Dayal, R., Denti, P., Donald, P.R., Engidawork, E., Garcia-Prats, A.J., Gibb, D., Graham, S.M., Hesseling, A.C., Heysell, S.K., Idris, M.I., Kabra, S.K., Kinikar, A., Kumar, A.K.H., Kwara, A., Lodha, R., Magis-Escurra, C., Martinez, N., Mathew, B.S., Mave, V., Mduma, E., Mlotha-Mitole, R., Mpagama, S.G., Mukherjee, A., Nataprawira, H.M., Peloquin, C.A., Pouplin, T., Ramachandran, G., Ranjalkar, J., Roy, V., Ruslami, Rovina, Shah, I., Singh, Y., Sturkenboom, M.G., Svensson, E.M., Swaminathan, S., Thatte, U., Thee, S., Thomas, T.A., Tikiso, T., Touw, D.J., Turkova, A., Velpandian, T., Verhagen, L.M., Winckler, J.L., Yang, H., Yunivita, V., Taxis, K., Stevens, J., Alffenaar, J.C., Gafar, F., Wasmann, R.E., McIlleron, H.M., Aarnoutse, R.E., Schaaf, H.S., Marais, B.J., Agarwal, D., Antwi, S., Bang, N.D., Bekker, A., Bell, D.J., Chabala, C., Choo, L., Davies, G.R., Day, J.N., Dayal, R., Denti, P., Donald, P.R., Engidawork, E., Garcia-Prats, A.J., Gibb, D., Graham, S.M., Hesseling, A.C., Heysell, S.K., Idris, M.I., Kabra, S.K., Kinikar, A., Kumar, A.K.H., Kwara, A., Lodha, R., Magis-Escurra, C., Martinez, N., Mathew, B.S., Mave, V., Mduma, E., Mlotha-Mitole, R., Mpagama, S.G., Mukherjee, A., Nataprawira, H.M., Peloquin, C.A., Pouplin, T., Ramachandran, G., Ranjalkar, J., Roy, V., Ruslami, Rovina, Shah, I., Singh, Y., Sturkenboom, M.G., Svensson, E.M., Swaminathan, S., Thatte, U., Thee, S., Thomas, T.A., Tikiso, T., Touw, D.J., Turkova, A., Velpandian, T., Verhagen, L.M., Winckler, J.L., Yang, H., Yunivita, V., Taxis, K., Stevens, J., and Alffenaar, J.C.
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Item does not contain fulltext, BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC(0-24)) and peak plasma concentration (C (max)) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC(0-24) and C (max) were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC(0-24) were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L(-1)), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L(-1)), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L(-1)) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L(-1)). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC(0-24) for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC(0-24) for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC(0-24) and slow acetylators had higher isoniazid AUC(0-24) than intermediate acetylators. Determinants of C (max) were generally similar to those for AUC(0-24). CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specif
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- 2023
6. Effectiveness of genotype-specific tricyclic antidepressant dosing in patients with major depressive disorder: A randomized clinical trial
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Vos, C.F., Hark, S.E. ter, Schellekens, A.F.A., Spijker, J., Meij, A. van der, Grotenhuis, A.J., Mihaescu, R., Kievit, W., Donders, R., Aarnoutse, R.E., Coenen, M.J.H., Janzing, J.G.E., Vos, C.F., Hark, S.E. ter, Schellekens, A.F.A., Spijker, J., Meij, A. van der, Grotenhuis, A.J., Mihaescu, R., Kievit, W., Donders, R., Aarnoutse, R.E., Coenen, M.J.H., and Janzing, J.G.E.
- Abstract
Contains fulltext : 292567.pdf (Publisher’s version ) (Open Access), Evidence of the clinical benefit of pharmacogenetics-informed treatment (PIT) with antidepressants is still limited. Especially for tricyclic antidepressants (TCAs), pharmacogenetics may be of interest because therapeutic plasma concentrations are well defined, identification of optimal dosing can be time consuming, and treatment is frequently accompanied by adverse effects.To determine whether PIT results in faster attainment of therapeutic TCA plasma concentrations compared with usual treatment in patients with unipolar major depressive disorder (MDD).This randomized clinical trial compared PIT with usual treatment among 111 patients at 4 centers in the Netherlands. Patients were treated with the TCAs nortriptyline, clomipramine, or imipramine, with clinical follow-up of 7 weeks. Patients were enrolled from June 1, 2018, to January 1, 2022. At inclusion, patients had unipolar nonpsychotic MDD (with a score of ≥19 on the 17-item Hamilton Rating Scale for Depression [HAMD-17]), were aged 18 to 65 years, and were eligible for TCA treatment. Main exclusion criteria were a bipolar or psychotic disorder, substance use disorder, pregnancy, interacting comedications, and concurrent use of psychotropic medications.In the PIT group, the initial TCA dosage was based on CYP2D6 and CYP2C19 genotypes. The control group received usual treatment, which comprised the standard initial TCA dosage.The primary outcome was days until attainment of a therapeutic TCA plasma concentration. Secondary outcomes were severity of depressive symptoms (measured by HAMD-17 scores) and frequency and severity of adverse effects (measured by Frequency, Intensity, and Burden of Side Effects Rating scores).Of 125 patients randomized, 111 (mean [SD] age, 41.7 [13.3] years; 69 [62.2%] female) were included in the analysis; of those, 56 were in the PIT group and 55 were in the control group. The PIT group reached therapeutic concentrations faster than the control group (mean [SD], 17.3 [11.2] vs 22.0 [10
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- 2023
7. Early bactericidal activity studies for pulmonary tuberculosis: A systematic review of methodological aspects.
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Koele, S.E., Phillips, P.P., Upton, C.M., Ingen, J. van, Simonsson, U.S.H., Diacon, A.H., Aarnoutse, R.E., Svensson, E.M., Koele, S.E., Phillips, P.P., Upton, C.M., Ingen, J. van, Simonsson, U.S.H., Diacon, A.H., Aarnoutse, R.E., and Svensson, E.M.
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Item does not contain fulltext, A milestone in the development of novel antituberculosis drugs is the demonstration of early bactericidal activity (EBA) in a phase IIa clinical trial. The significant variability in measurements of bacterial load complicates data analysis in these trials. A systematic review and evaluation of methods for determination of EBA in pulmonary tuberculosis studies was undertaken. Bacterial load quantification biomarkers, reporting intervals, calculation methods, statistical testing, and handling of negative culture results were extracted. In total, 79 studies were identified in which EBA was determined. Colony-forming units on solid culture media and/or time-to-positivity in liquid media were the biomarkers used most often, reported in 72 (91%) and 34 (43%) studies, respectively. Twenty-two different reporting intervals were presented, and 12 different calculation methods for EBA were identified. Statistical testing for a significant EBA compared with no change was performed in 54 (68%) studies, and between-group testing was performed in 32 (41%) studies. Negative culture result handling was discussed in 34 (43%) studies. Notable variation was found in the analysis methods and reporting of EBA studies. A standardized and clearly reported analysis method, accounting for different levels of variability in the data, could aid the generalization of study results and facilitate comparison between drugs/regimens.
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- 2023
8. Model-based analysis of bactericidal activity and a new dosing strategy for optimised-dose rifampicin.
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Susanto, B.O., Svensson, E.M., Brake, L.H.M. te, Aarnoutse, R.E., Boeree, M.J., Simonsson, U.S.H., Susanto, B.O., Svensson, E.M., Brake, L.H.M. te, Aarnoutse, R.E., Boeree, M.J., and Simonsson, U.S.H.
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01 juni 2023, Item does not contain fulltext, BACKGROUND: Higher doses of rifampicin for tuberculosis have been shown to improve early bactericidal activity (EBA) and at the same time increase the intolerability due to high exposure at the beginning of treatment. To support dose optimisation of rifampicin, this study investigated new and innovative staggered dosing of rifampicin using clinical trial simulations to minimise tolerability problems and still achieve good efficacy. METHODS: Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10-50 mg/kg rifampicin to characterise the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure were performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as a relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events. RESULTS: The linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy starting the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared with a regimen of 35 mg/kg daily. CONCLUSIONS: Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy.
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- 2023
9. Effect of a customized digital adherence tool on retention in care and adherence to antiretroviral treatment in breastfeeding women, children and adolescents living with HIV in Tanzania: a mixed-methods study followed by clinical trials
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Marion Sumari-de Boer, I., Ngowi, K.M., Swai, Iraseni U., Masika, L., Maro, Rehema A., Mtenga, Alan E., Rinke de Wit, Tobias F., Aarnoutse, R.E., Marion Sumari-de Boer, I., Ngowi, K.M., Swai, Iraseni U., Masika, L., Maro, Rehema A., Mtenga, Alan E., Rinke de Wit, Tobias F., and Aarnoutse, R.E.
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Contains fulltext : 293127.pdf (Publisher’s version ) (Open Access)
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- 2023
10. A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis.
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Dierig, A., Hoelscher, M., Schultz, S., Hoffmann, L., Jarchow-MacDonald, A., Svensson, E.M., Brake, L.H. te, Aarnoutse, R.E., Boeree, M.J., McHugh, T.D., Wildner, L.M., Gong, X., Phillips, P., Minja, L.T., Ntinginya, N. Elias, Mpagama, S., Liyoyo, A., Wallis, R.S., Sebe, M., Mhimbira, F.A., Mbeya, B., Rassool, M., Geiter, L., Cho, Y.L., Heinrich, N., Dierig, A., Hoelscher, M., Schultz, S., Hoffmann, L., Jarchow-MacDonald, A., Svensson, E.M., Brake, L.H. te, Aarnoutse, R.E., Boeree, M.J., McHugh, T.D., Wildner, L.M., Gong, X., Phillips, P., Minja, L.T., Ntinginya, N. Elias, Mpagama, S., Liyoyo, A., Wallis, R.S., Sebe, M., Mhimbira, F.A., Mbeya, B., Rassool, M., Geiter, L., Cho, Y.L., and Heinrich, N.
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Item does not contain fulltext, BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinone
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- 2023
11. Treatment Strategy for Rifampin-Susceptible Tuberculosis.
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Boeree, M.J., Heinrich, N., Aarnoutse, R.E., Boeree, M.J., Heinrich, N., and Aarnoutse, R.E.
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Item does not contain fulltext
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- 2023
12. Clinical standards for the management of adverse effects during treatment for TB.
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Singh, K.P., Carvalho, A.C.C., Centis, R., Ambrosio, L.D., Migliori, G.B., Mpagama, S.G., Nguyen, B.C., Aarnoutse, R.E., Aleksa, A., Altena, R. van, Bhavani, P.K., Bolhuis, M.S., Borisov, S., Boveneind-Vrubleuskaya, N. Van't, Bruchfeld, J., Caminero, J.A., Carvalho, I., Cho, J.G., Davies Forsman, L., Dedicoat, M., Dheda, K., Dooley, K., Furin, J., García-García, J.M., Garcia-Prats, A., Hesseling, A.C., Heysell, S.K., Hu, Y., Kim, H.Y., Manga, S., Marais, B.J., Margineanu, I., Märtson, A.G., Munoz Torrico, M., Nataprawira, H.M., Nunes, E., Ong, C.W.M., Otto-Knapp, R., Palmero, D.J., Peloquin, C.A., Rendon, A., Rossato Silva, D., Ruslami, R., Saktiawati, A.M.I., Santoso, P., Schaaf, H.S., Seaworth, B., Simonsson, U.S.H., Singla, R., Skrahina, A., Solovic, I., Srivastava, S., Stocker, S.L., Sturkenboom, M.G.G., Svensson, E.M., Tadolini, M., Thomas, T.A., Tiberi, S., Trubiano, J., Udwadia, Z.F., Verhage, A.R., Vu, D.H., Akkerman, O.W., Alffenaar, J.W.C., Denholm, J.T., Singh, K.P., Carvalho, A.C.C., Centis, R., Ambrosio, L.D., Migliori, G.B., Mpagama, S.G., Nguyen, B.C., Aarnoutse, R.E., Aleksa, A., Altena, R. van, Bhavani, P.K., Bolhuis, M.S., Borisov, S., Boveneind-Vrubleuskaya, N. Van't, Bruchfeld, J., Caminero, J.A., Carvalho, I., Cho, J.G., Davies Forsman, L., Dedicoat, M., Dheda, K., Dooley, K., Furin, J., García-García, J.M., Garcia-Prats, A., Hesseling, A.C., Heysell, S.K., Hu, Y., Kim, H.Y., Manga, S., Marais, B.J., Margineanu, I., Märtson, A.G., Munoz Torrico, M., Nataprawira, H.M., Nunes, E., Ong, C.W.M., Otto-Knapp, R., Palmero, D.J., Peloquin, C.A., Rendon, A., Rossato Silva, D., Ruslami, R., Saktiawati, A.M.I., Santoso, P., Schaaf, H.S., Seaworth, B., Simonsson, U.S.H., Singla, R., Skrahina, A., Solovic, I., Srivastava, S., Stocker, S.L., Sturkenboom, M.G.G., Svensson, E.M., Tadolini, M., Thomas, T.A., Tiberi, S., Trubiano, J., Udwadia, Z.F., Verhage, A.R., Vu, D.H., Akkerman, O.W., Alffenaar, J.W.C., and Denholm, J.T.
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Item does not contain fulltext, BACKGROUND: Adverse effects (AE) to TB treatment cause morbidity, mortality and treatment interruption. The aim of these clinical standards is to encourage best practise for the diagnosis and management of AE.METHODS: 65/81 invited experts participated in a Delphi process using a 5-point Likert scale to score draft standards.RESULTS: We identified eight clinical standards. Each person commencing treatment for TB should: Standard 1, be counselled regarding AE before and during treatment; Standard 2, be evaluated for factors that might increase AE risk with regular review to actively identify and manage these; Standard 3, when AE occur, carefully assessed and possible allergic or hypersensitivity reactions considered; Standard 4, receive appropriate care to minimise morbidity and mortality associated with AE; Standard 5, be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring. In addition: Standard 6, healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management; Standard 7, there should be active AE monitoring and reporting for all new TB drugs and regimens; and Standard 8, knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research.CONCLUSION: These standards provide a person-centred, consensus-based approach to minimise the impact of AE during TB treatment.
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- 2023
13. Combined quantitative tuberculosis biomarker model for time-to-positivity and colony forming unit to support tuberculosis drug development.
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Ayoun Alsoud, R., Svensson, R.J., Svensson, E.M., Gillespie, S.H., Boeree, M.J., Diacon, A.H., Dawson, R., Aarnoutse, R.E., Simonsson, U.S.H., Ayoun Alsoud, R., Svensson, R.J., Svensson, E.M., Gillespie, S.H., Boeree, M.J., Diacon, A.H., Dawson, R., Aarnoutse, R.E., and Simonsson, U.S.H.
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Contains fulltext : 291556.pdf (Publisher’s version ) (Open Access), Biomarkers are quantifiable characteristics of biological processes. In Mycobacterium tuberculosis, common biomarkers used in clinical drug development are colony forming unit (CFU) and time-to-positivity (TTP) from sputum samples. This analysis aimed to develop a combined quantitative tuberculosis biomarker model for CFU and TTP biomarkers for assessing drug efficacy in early bactericidal activity studies. Daily CFU and TTP observations in 83 previously patients with uncomplicated pulmonary tuberculosis after 7 days of different rifampicin monotherapy treatments (10-40 mg/kg) from the HIGHRIF1 study were included in this analysis. The combined quantitative tuberculosis biomarker model employed the Multistate Tuberculosis Pharmacometric model linked to a rifampicin pharmacokinetic model in order to determine drug exposure-response relationships on three bacterial sub-states using both the CFU and TTP data simultaneously. CFU was predicted from the MTP model and TTP was predicted through a time-to-event approach from the TTP model, which was linked to the MTP model through the transfer of all bacterial sub-states in the MTP model to a one bacterial TTP model. The non-linear CFU-TTP relationship over time was well predicted by the final model. The combined quantitative tuberculosis biomarker model provides an efficient approach for assessing drug efficacy informed by both CFU and TTP data in early bactericidal activity studies and to describe the relationship between CFU and TTP over time.
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- 2023
14. Pretomanid-resistant tuberculosis.
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Koehler, N., Andres, S., Merker, M., Dreyer, V., John, A., Kuhns, M., Krieger, D., Choong, E., Verougstraete, N., Wiesch, P.A. Zur, Wicha, S.G., König, C., Kalsdorf, B., Sanchez Carballo, P.M., Schaub, D., Werngren, J., Schön, T., Peloquin, C.A., Schönfeld, N., Verstraete, A.G., Decosterd, L.A., Aarnoutse, R.E., Niemann, S., Maurer, F.P., Lange, C de, Koehler, N., Andres, S., Merker, M., Dreyer, V., John, A., Kuhns, M., Krieger, D., Choong, E., Verougstraete, N., Wiesch, P.A. Zur, Wicha, S.G., König, C., Kalsdorf, B., Sanchez Carballo, P.M., Schaub, D., Werngren, J., Schön, T., Peloquin, C.A., Schönfeld, N., Verstraete, A.G., Decosterd, L.A., Aarnoutse, R.E., Niemann, S., Maurer, F.P., and Lange, C de
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Item does not contain fulltext
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- 2023
15. High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance.
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Martinecz, A., Boeree, M.J., Diacon, A.H., Dawson, R., Hemez, C., Aarnoutse, R.E., Abel Zur Wiesch, P., Martinecz, A., Boeree, M.J., Diacon, A.H., Dawson, R., Hemez, C., Aarnoutse, R.E., and Abel Zur Wiesch, P.
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01 april 2023, Item does not contain fulltext, BACKGROUND: Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic persistence or heteroresistance. Persistence is defined as the switching back and forth between susceptible and non-susceptible states, while heteroresistance is defined as the coexistence of bacteria with heterogeneous susceptibilities. Both are also thought to cause a slowdown in the decline of bacterial populations in patients and therefore complicate and prolong antibiotic treatments. Reduced bacterial death rates over time are also observed within tuberculosis patients, yet the mechanistic reasons for this are unknown and therefore the strategies to mitigate them are also unknown. METHODS AND FINDINGS: We analyse a dose ranging trial for rifampicin in tuberculosis patients and show that there is a slowdown in the decline of bacteria. We show that the late phase of bacterial killing depends more on the peak drug concentrations than the total drug exposure. We compare these to pharmacokinetic-pharmacodynamic models of rifampicin heteroresistance and persistence. We find that the observation on the slow phase's dependence on pharmacokinetic measures, specifically peak concentrations are only compatible with models of heteroresistance and incompatible with models of persistence. The quantitative agreement between heteroresistance models and observations is very good ([Formula: see text]). To corroborate the importance of the slowdown, we validate our results by estimating the time to sputum culture conversion and compare the results to a different dose ranging trial. CONCLUSIONS: Our findings indicate that higher doses, specifically higher peak concentrations may be used to optimize rifampicin treatments by accelerating bact
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- 2023
16. Physiologically-Based Pharmacokinetic Modelling to Predict the Pharmacokinetics and Pharmacodynamics of Linezolid in Adults and Children with Tuberculous Meningitis.
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Litjens, C.H.C., Verscheijden, L.F.M., Svensson, E.M., Broek, P.H.H. van den, Hove, H. van, Koenderink, J.B., Russel, F.G.M., Aarnoutse, R.E., Brake, L.H. te, Litjens, C.H.C., Verscheijden, L.F.M., Svensson, E.M., Broek, P.H.H. van den, Hove, H. van, Koenderink, J.B., Russel, F.G.M., Aarnoutse, R.E., and Brake, L.H. te
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Item does not contain fulltext, Linezolid is used off-label for treatment of central nervous system infections. However, its pharmacokinetics and target attainment in cranial cerebrospinal fluid (CSF) in tuberculous meningitis patients is unknown. This study aimed to predict linezolid cranial CSF concentrations and assess attainment of pharmacodynamic (PD) thresholds (AUC:MIC of >119) in plasma and cranial CSF of adults and children with tuberculous meningitis. A physiologically based pharmacokinetic (PBPK) model was developed to predict linezolid cranial CSF profiles based on reported plasma concentrations. Simulated steady-state PK curves in plasma and cranial CSF after linezolid doses of 300 mg BID, 600 mg BID, and 1200 mg QD in adults resulted in geometric mean AUC:MIC ratios in plasma of 118, 281, and 262 and mean cranial CSF AUC:MIC ratios of 74, 181, and 166, respectively. In children using ~10 mg/kg BID linezolid, AUC:MIC values at steady-state in plasma and cranial CSF were 202 and 135, respectively. Our model predicts that 1200 mg per day in adults, either 600 mg BID or 1200 mg QD, results in reasonable (87%) target attainment in cranial CSF. Target attainment in our simulated paediatric population was moderate (56% in cranial CSF). Our PBPK model can support linezolid dose optimization efforts by simulating target attainment close to the site of TBM disease.
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- 2023
17. The effect of a customised digital adherence tool on HIV treatment outcomes in young people living with HIV (YPLHIV) in Blantyre, Malawi: a protocol for a randomised controlled trial.
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Msosa, T.C., Swai, I., Sumari-de Boer, M., Ngowi, K., Rinke de Wit, T.F., Aarnoutse, R.E., Nliwasa, M., Msosa, T.C., Swai, I., Sumari-de Boer, M., Ngowi, K., Rinke de Wit, T.F., Aarnoutse, R.E., and Nliwasa, M.
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Contains fulltext : 296061.pdf (Publisher’s version ) (Open Access), BACKGROUND: People living with HIV (PLHIV) have to take lifelong antiretroviral treatment, which is often challenging. Young people living with HIV (YPLHIV) have the lowest viral load suppression rates in Malawi and globally, mostly due to poor treatment adherence. This is a result of complex interactions of multiple factors unique to this demographic group. The use of digital health interventions, such as real-time medication monitor (RTMM)-based digital adherence tools (DATs), could improve ART adherence in YPLHIV and subsequently improve viral load suppression which in turn could lead to reduced HIV-associated morbidity and mortality. AIM: To provide the evidence base for a digital adherence intervention to improve treatment outcomes in YPLHIV on ART. OBJECTIVES: 1. The primary objective is to determine the efficacy of a customised DAT compared to the standard of care in improving ART adherence in YPLHIV. 2. The secondary objective is to determine the efficacy of the customised DAT compared to the standard of care in improving viral load suppression in YPLHIV. METHODOLOGY: This will be a parallel open-label randomised control controlled two-arm trial in which non-adherent YPLHIV in selected ART facilities in Blantyre will be randomised in a 1:1 ratio to a customised DAT and standard care arms and followed up for 9 months. The primary outcome is the proportion adherent at 9 months (> = 95% by pill count), and the secondary outcome is the proportion with viral load suppressed at 9 months (< 200 copies/ml). DISCUSSION: There is a paucity of good quality evidence on effective digital health interventions to improve ART adherence and viral load suppression in YPLHIV globally and particularly in HIV high-burden settings like Malawi. This study will provide good-quality evidence on the effectiveness of a customised DAT in improving ART adherence and viral load suppression in this important demographic. TRIAL REGISTRATION: The trial has been registered in the Pan African
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- 2023
18. Analytical and Clinical Validation of Assays for Volumetric Absorptive Microsampling (VAMS) of Drugs in Different Blood Matrices: A Literature Review.
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Nugraha, R.V., Yunivita, V., Santoso, P., Hasanah, A.N., Aarnoutse, R.E., Ruslami, R., Nugraha, R.V., Yunivita, V., Santoso, P., Hasanah, A.N., Aarnoutse, R.E., and Ruslami, R.
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Item does not contain fulltext, Volumetric absorptive microsampling (VAMS) is the newest and most promising sample-collection technique for quantitatively analyzing drugs, especially for routine therapeutic drug monitoring (TDM) and pharmacokinetic studies. This technique uses an absorbent white tip to absorb a fixed volume of a sample (10-50 µL) within a few seconds (2-4 s), is more flexible, practical, and more straightforward to be applied in the field, and is probably more cost-effective than conventional venous sampling (CVS). After optimization and validation of an analytical method of a drug taken by VAMS, a clinical validation study is needed to show that the results by VAMS can substitute what is gained from CVS and to justify implementation in routine practice. This narrative review aimed to assess and present studies about optimization and analytical validation of assays for drugs taken by VAMS, considering their physicochemical drug properties, extraction conditions, validation results, and studies on clinical validation of VAMS compared to CVS. The review revealed that the bio-analysis of many drugs taken with the VAMS technique was optimized and validated. However, only a few clinical validation studies have been performed so far. All drugs that underwent a clinical validation study demonstrated good agreement between the two techniques (VAMS and CVS), but only by Bland-Altman analysis. Only for tacrolimus and mycophenolic acid were three measurements of agreement evaluated. Therefore, VAMS can be considered an alternative to CVS in routine practice, especially for tacrolimus and mycophenolic acid. Still, more extensive clinical validation studies need to be performed for other drugs.
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- 2023
19. Developing contents for a digital adherence tool: A formative mixed-methods study among children and adolescents living with HIV in Tanzania
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Swai, I.U., Bergen, L.L. Ten, Mtenga, A., Maro, R., Ngowi, K., Mtesha, B., Lekashingo, N., Msosa, T., Rinke de Wit, T.F., Aarnoutse, R.E., Sumari-de Boer, M., Swai, I.U., Bergen, L.L. Ten, Mtenga, A., Maro, R., Ngowi, K., Mtesha, B., Lekashingo, N., Msosa, T., Rinke de Wit, T.F., Aarnoutse, R.E., and Sumari-de Boer, M.
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Item does not contain fulltext, Optimal adherence (>95%) to antiretroviral treatment (ART) remains a challenge among children and adolescents living with HIV (CALHIV). Digital adherence tools (DAT) with reminder cues have proven feasible among adult people living with HIV (PLHIV), with some concerns about the risk of HIV status disclosure. We aimed to assess the needs, contents and acceptability of an SMS-based DAT among CALHIV. We first conducted a survey to understand potential barriers to using DAT among CALHIV, then tested the DAT intervention among purposively selected participants. The DAT intervention included using the Wisepill device, receiving daily reminder SMS and receiving adherence reports on how they had taken medication in the past month. The content of the reminder SMS differed over time from asking if the medication was taken to a more neutral SMS like "take care". Afterwards, we conducted exit interviews, in-depth interviews, and focus-group discussions. We analysed quantitative findings descriptively and used thematic content analysis for qualitative data. We included 142 children and 142 adolescents in the survey, and 20 of each used the intervention. Eighty-five percent (121/142) of surveyed participants indicated they would like to receive reminder SMS. Most of them (97/121-80%) of children and 94/121(78%) of adolescents would prefer to receive daily reminders. Participants who used the DAT mentioned to be happy to use the device. Ninety percent of them had good experience with receiving reminders and agreed that the SMS made them take medication. However, 25% experienced network problems. Participants preferred neutral reminder SMSs that did not mention the word 'medication', but preserved confidentiality. The provided adherence reports inspired participants to improve their adherence. None of the participants experienced unwanted disclosure or stigmatisation due to DAT. However, 5% of adolescents were concerned about being monitored daily. This study showed that DAT is acc
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- 2023
20. First-Line Antituberculosis Drug Concentrations in Infants With HIV and a History of Recent Admission With Severe Pneumonia.
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Chabala, C., Jacobs, T.G., Moraleda, C., Ndaferankhande, J.M., Mumbiro, V., Passanduca, A., Namuziya, N., Nalwanga, D., Musiime, V., Ballesteros, A., Domínguez-Rodríguez, S., Chitsamatanga, M., Cassia, U., Nduna, B., Bramugy, J., Sacarlal, J., Madrid, L., Nathoo, K.J., Colbers, A., Burger, D.M., Mulenga, V., Buck, W.C., Mujuru, H.A., Brake, L.H.M. te, Rojo, P., Tagarro, A., Aarnoutse, R.E., Chabala, C., Jacobs, T.G., Moraleda, C., Ndaferankhande, J.M., Mumbiro, V., Passanduca, A., Namuziya, N., Nalwanga, D., Musiime, V., Ballesteros, A., Domínguez-Rodríguez, S., Chitsamatanga, M., Cassia, U., Nduna, B., Bramugy, J., Sacarlal, J., Madrid, L., Nathoo, K.J., Colbers, A., Burger, D.M., Mulenga, V., Buck, W.C., Mujuru, H.A., Brake, L.H.M. te, Rojo, P., Tagarro, A., and Aarnoutse, R.E.
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Contains fulltext : 299969.pdf (Publisher’s version ) (Open Access), Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants.
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- 2023
21. Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.
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Galileya, L.T., Wasmann, R.E., Chabala, C., Rabie, H., Lee, J., Njahira Mukui, I., Hesseling, A., Zar, H., Aarnoutse, R.E., Turkova, A., Gibb, D., Cotton, M.F., McIlleron, H., Denti, P., Galileya, L.T., Wasmann, R.E., Chabala, C., Rabie, H., Lee, J., Njahira Mukui, I., Hesseling, A., Zar, H., Aarnoutse, R.E., Turkova, A., Gibb, D., Cotton, M.F., McIlleron, H., and Denti, P.
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Contains fulltext : 300019.pdf (Publisher’s version ) (Open Access), BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. METHODS AND FINDINGS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% C, 01 november 2023
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- 2023
22. Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.
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Stemkens, R., Jager, V.d., Dawson, R., Diacon, A.H., Narunsky, K., Padayachee, S.D., Boeree, M.J., Beek, S.W. van, Colbers, A.P., Coenen, M.J.H., Svensson, E.M., Fuhr, U., Phillips, P.P., Brake, L.H.M. te, Aarnoutse, R.E., Stemkens, R., Jager, V.d., Dawson, R., Diacon, A.H., Narunsky, K., Padayachee, S.D., Boeree, M.J., Beek, S.W. van, Colbers, A.P., Coenen, M.J.H., Svensson, E.M., Fuhr, U., Phillips, P.P., Brake, L.H.M. te, and Aarnoutse, R.E.
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Contains fulltext : 300036.pdf (Publisher’s version ) (Open Access), Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.
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- 2023
23. Effect of seven anti-tuberculosis treatment regimens on sputum microbiome: a retrospective analysis of the HIGHRIF study 2 and PanACEA MAMS-TB clinical trials.
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Musisi, E., Wyness, A., Eldirdiri, S., Dombay, E., Mtafya, B., Ntinginya, N.E., Heinrich, N., Kibiki, G.S., Hoelscher, M., Boeree, M.J., Aarnoutse, R.E., Gillespie, S.H., Sabiiti, W., Musisi, E., Wyness, A., Eldirdiri, S., Dombay, E., Mtafya, B., Ntinginya, N.E., Heinrich, N., Kibiki, G.S., Hoelscher, M., Boeree, M.J., Aarnoutse, R.E., Gillespie, S.H., and Sabiiti, W.
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Contains fulltext : 299993.pdf (Publisher’s version ) (Open Access), BACKGROUND: Respiratory tract microbiota has been described as the gatekeeper for respiratory health. We aimed to assess the impact of standard-of-care and experimental anti-tuberculosis treatment regimens on the respiratory microbiome and implications for treatment outcomes. METHODS: In this retrospective study, we analysed the sputum microbiome of participants with tuberculosis treated with six experimental regimens versus standard-of-care who were part of the HIGHRIF study 2 (NCT00760149) and PanACEA MAMS-TB (NCT01785186) clinical trials across a 3-month treatment follow-up period. Samples were from participants in Mbeya, Kilimanjaro, Bagamoyo, and Dar es Salaam, Tanzania. Experimental regimens were composed of different combinations of rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), moxifloxacin (M), and a new drug, SQ109 (Q). Reverse transcription was used to create complementary DNA for each participant's total sputum RNA and the V3-V4 region of the 16S rRNA gene was sequenced using the Illumina metagenomic technique. Qiime was used to analyse the amplicon sequence variants and estimate alpha diversity. Descriptive statistics were applied to assess differences in alpha diversity pre-treatment and post-treatment initiation and the effect of each treatment regimen. FINDINGS: Sequence data were obtained from 397 pre-treatment and post-treatment samples taken between Sept 26, 2008, and June 30, 2015, across seven treatment regimens. Pre-treatment microbiome (206 genera) was dominated by Firmicutes (2860 [44%] of 6500 amplicon sequence variants [ASVs]) at the phylum level and Streptococcus (2340 [36%] ASVs) at the genus level. Two regimens had a significant depressing effect on the microbiome after 2 weeks of treatment, HR(20mg/kg)ZM (Shannon diversity index p=0·0041) and HR(35mg/kg)ZE (p=0·027). Gram-negative bacteria were the most sensitive to bactericidal activity of treatment with the highest number of species suppressed being under the moxiflo, 01 november 2023
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- 2023
24. The role of rifampicin within the treatment of Mycobacterium avium pulmonary disease
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Schildkraut, J.A., Raaijmakers, J., Aarnoutse, R.E., Hoefsloot, W., Wertheim, H.F.L., Ingen, J. van, Schildkraut, J.A., Raaijmakers, J., Aarnoutse, R.E., Hoefsloot, W., Wertheim, H.F.L., and Ingen, J. van
- Abstract
Contains fulltext : 298931.pdf (Publisher’s version ) (Open Access)
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- 2023
25. A Single-Run HPLC-MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis.
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Köhler, N., Karaköse, H., Grobbel, H.P., Hillemann, D., Andres, S., König, C., Kalsdorf, B., Brehm, T.T., Böttcher, L., Friesen, I., Hoffmann, H., Strelec, D., Schaub, D., Peloquin, C.A., Schmiedel, S., Decosterd, L.A., Choong, E., Wicha, S.G., Aarnoutse, R.E., Lange, C., Sánchez Carballo, P.M., Köhler, N., Karaköse, H., Grobbel, H.P., Hillemann, D., Andres, S., König, C., Kalsdorf, B., Brehm, T.T., Böttcher, L., Friesen, I., Hoffmann, H., Strelec, D., Schaub, D., Peloquin, C.A., Schmiedel, S., Decosterd, L.A., Choong, E., Wicha, S.G., Aarnoutse, R.E., Lange, C., and Sánchez Carballo, P.M.
- Abstract
Contains fulltext : 299618.pdf (Publisher’s version ) (Open Access), The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography-mass spectrometry (HPLC-MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20-25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.
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- 2023
26. Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin
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Kengo, A., Gausi, K., Nabisere, R., Musaazi, J., Buzibye, A., Omali, D., Aarnoutse, R.E., Sekaggya-Wiltshire, C., Denti, P., Kengo, A., Gausi, K., Nabisere, R., Musaazi, J., Buzibye, A., Omali, D., Aarnoutse, R.E., Sekaggya-Wiltshire, C., and Denti, P.
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Item does not contain fulltext
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- 2023
27. Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV
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Chabala, C., Turkova, A., Kapasa, M., LeBeau, K., Tembo, C.H., Zimba, K., Weisner, L., Zyambo, K., Choo, L., Chungu, C., Lungu, J., Mulenga, V., Crook, A., Aarnoutse, R.E., Gibb, D., McIlleron, H., Chabala, C., Turkova, A., Kapasa, M., LeBeau, K., Tembo, C.H., Zimba, K., Weisner, L., Zyambo, K., Choo, L., Chungu, C., Lungu, J., Mulenga, V., Crook, A., Aarnoutse, R.E., Gibb, D., and McIlleron, H.
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Item does not contain fulltext, BACKGROUND: Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. METHODS: Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. RESULTS: Of 20 children enrolled; 15, 1-7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve 0-24 55.32 mg/h/L [0.30-398.7 mg/h/L]; C max 3.04 mg/L [0.03-18.6 mg/L]; C 8hr 0.90 mg/L [0.01-13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve 24 121.63 mg/h/L [2.56-487.3 mg/h/L]; C max 9.45 mg/L [0.39-26.4 mg/L]; C 12hr 3.03 mg/L [0.01-17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. CONCLUSIONS: Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis
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- 2023
28. Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin
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Magis-Escurra, C., Later-Nijland, H.M.J., Alffenaar, J.W.C., Broeders, J., Burger, D.M., van Crevel, R., Boeree, M.J., Donders, A.R.T., van Altena, R., van der Werf, T.S., and Aarnoutse, R.E.
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- 2014
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29. Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections
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Magis-Escurra, C., Alffenaar, J.W., Hoefnagels, I., Dekhuijzen, P.N.R., Boeree, M.J., van Ingen, J., and Aarnoutse, R.E.
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- 2013
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30. Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling
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Litjens, C.H.C., Verscheijden, L.F.M., Bolwerk, Celine, Greupink, R., Koenderink, J.B., Broek, P.H.H. van den, Heuvel, J.J.M.W. van den, Svensson, E.M., Boeree, M.J., Magis-Escurra, C., Hoefsloot, W., Crevel, R. van, Laarhoven, A. van, Ingen, J. van, Kuipers, S., Ruslami, R., Burger, D.M., Russel, F.G., Aarnoutse, R.E., Brake, L.H. te, Litjens, C.H.C., Verscheijden, L.F.M., Bolwerk, Celine, Greupink, R., Koenderink, J.B., Broek, P.H.H. van den, Heuvel, J.J.M.W. van den, Svensson, E.M., Boeree, M.J., Magis-Escurra, C., Hoefsloot, W., Crevel, R. van, Laarhoven, A. van, Ingen, J. van, Kuipers, S., Ruslami, R., Burger, D.M., Russel, F.G., Aarnoutse, R.E., and Brake, L.H. te
- Abstract
Item does not contain fulltext, Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.
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- 2022
31. Model-Predicted Impact of ECG Monitoring Strategies During Bedaquiline Treatment
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Beek, S.W. van, Tanneau, Lenaig, Meintjes, Graeme, Wasserman, Sean, Gandhi, Neel R., Campbell, A., Aarnoutse, R.E., Brust, James C.M., Svensson, E.M., Beek, S.W. van, Tanneau, Lenaig, Meintjes, Graeme, Wasserman, Sean, Gandhi, Neel R., Campbell, A., Aarnoutse, R.E., Brust, James C.M., and Svensson, E.M.
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Item does not contain fulltext
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- 2022
32. Knowledge, attitude and practice of community pharmacy personnel in tuberculosis patient detection: a multicentre cross-sectional study in a high-burden tuberculosis setting
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Pradipta, Ivan Surya, Khairunnisa, Khairunnisa, Bahar, Muh Akbar, Kausar, Mersa Nurain, Fitriana, Efi, Ruslami, R., Aarnoutse, R.E., Abdulah, Rizky, Pradipta, Ivan Surya, Khairunnisa, Khairunnisa, Bahar, Muh Akbar, Kausar, Mersa Nurain, Fitriana, Efi, Ruslami, R., Aarnoutse, R.E., and Abdulah, Rizky
- Abstract
Contains fulltext : 252254.pdf (Publisher’s version ) (Open Access)
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- 2022
33. Interleukin-1 receptor antagonist anakinra as treatment for paradoxical responses in HIV-negative tuberculosis patients: A case series
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Arkel, C. van, Boeree, M.J., Magis-Escurra, C., Hoefsloot, W., Carpaij, N., Ingen, J. van, Pegge, S.A.H., Wielders, P.L.M.L., Smeenk, F., Aarnoutse, R.E., Netea, M.G., Crevel, R. van, Laarhoven, A. van, Arkel, C. van, Boeree, M.J., Magis-Escurra, C., Hoefsloot, W., Carpaij, N., Ingen, J. van, Pegge, S.A.H., Wielders, P.L.M.L., Smeenk, F., Aarnoutse, R.E., Netea, M.G., Crevel, R. van, and Laarhoven, A. van
- Abstract
Item does not contain fulltext, BACKGROUND: Paradoxical inflammatory responses can occur during microbiologically successful antituberculous therapy. Optimal treatment is unknown, but corticosteroids are used most often. It is likely that interleukin-1 (IL-1) plays a central role in the development of these paradoxical responses, and if corticosteroids fail or are undesirable because of adverse effects, anti-IL-1 therapy may therefore be a rational choice. METHODS: We present seven HIV-negative tuberculosis patients with paradoxical responses, two with exclusively pulmonary and five with extrapulmonary tuberculosis. All had received corticosteroids, with unsatisfactory effect. Patients were treated with the IL-1 receptor antagonist anakinra and monitored for reduction of fever and inflammatory markers, imaging evidence of stabilization or regression of lesions, and respiratory improvement. FINDINGS: Six patients had anemia and four patients had lymphopenia at the start of the antituberculosis treatment. Fever was present in six patients at the moment of paradoxical response. Anakinra resulted in the decrease of fever within days, followed by resolution of symptoms and radiological improvement in five patients. Anakinra induced neutropenia, necessitating its cessation in two patients, who recovered quickly afterward. CONCLUSION: Anakinra can be considered in HIV-negative tuberculosis patients with paradoxical responses when steroids fail or are undesired. Given its favorable safety profile and reversible side effects, it is conceivable that anakinra might also be used as first-line adjuvant treatment for paradoxical responses. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781).
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- 2022
34. Biomarkers as predictors of treatment response to tricyclic antidepressants in major depressive disorder: A systematic review
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Hark, S.E. ter, Vos, C.F., Aarnoutse, R.E., Schene, A.H., Coenen, M.J.H., Janzing, J.G.E., Hark, S.E. ter, Vos, C.F., Aarnoutse, R.E., Schene, A.H., Coenen, M.J.H., and Janzing, J.G.E.
- Abstract
Contains fulltext : 251161.pdf (Publisher’s version ) (Open Access), Tricyclic antidepressants (TCAs) are frequently prescribed in case of non-response to first-line antidepressants in Major Depressive Disorder (MDD). Treatment of MDD often entails a trial-and-error process of finding a suitable antidepressant and its appropriate dose. Nowadays, a shift is seen towards a more personalized treatment strategy in MDD to increase treatment efficacy. One of these strategies involves the use of biomarkers for the prediction of antidepressant treatment response. We aimed to summarize biomarkers for prediction of TCA specific (i.e. per agent, not for the TCA as a drug class) treatment response in unipolar nonpsychotic MDD. We performed a systematic search in PubMed and MEDLINE. After full-text screening, 36 papers were included. Seven genetic biomarkers were identified for nortriptyline treatment response. For desipramine, we identified two biomarkers; one genetic and one nongenetic. Three nongenetic biomarkers were identified for imipramine. None of these biomarkers were replicated. Quality assessment demonstrated that biomarker studies vary in endpoint definitions and frequently lack power calculations. None of the biomarkers can be confirmed as a predictor for TCA treatment response. Despite the necessity for TCA treatment optimization, biomarker studies reporting drug-specific results for TCAs are limited and adequate replication studies are lacking. Moreover, biomarker studies generally use small sample sizes. To move forward, larger cohorts, pooled data or biomarkers combined with other clinical characteristics should be used to improve predictive power.
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- 2022
35. Model-informed pharmacological interventions against tuberculosis and malaria
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Aarnoutse, R.E., Heine, R. ter, Svensson, E.M., Beek, S.W. van, Aarnoutse, R.E., Heine, R. ter, Svensson, E.M., and Beek, S.W. van
- Abstract
Radboud University, 21 november 2022, Promotor : Aarnoutse, R.E. Co-promotores : Heine, R. ter, Svensson, E.M., Contains fulltext : 283471.pdf (Publisher’s version ) (Open Access)
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- 2022
36. Predicting viral load suppression by self-reported adherence, pharmacy refill counts and real time medication monitoring among people living with HIV in Tanzania
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Ngowi, K.M., Minja, L., Boer, Imke J.M. de, Aarnoutse, R.E., Masika, L., Sprangers, M.A.G., Pima, F.M., Mmbaga, B.T., Reiss, P., Nieuwkerk, P.T., Ngowi, K.M., Minja, L., Boer, Imke J.M. de, Aarnoutse, R.E., Masika, L., Sprangers, M.A.G., Pima, F.M., Mmbaga, B.T., Reiss, P., and Nieuwkerk, P.T.
- Abstract
Item does not contain fulltext, INTRODUCTION: Monitoring of adherence to antiretroviral treatment (ART) is of utmost importance to prevent treatment failure. Several measures to monitor adherence have been applied in low-resource settings and they all have pros and cons. Our objective was to examine whether any of the following adherence measures is a better predictor of participants' viral load suppression: (1) self-report, (2) pharmacy refill count, (3) Real Time Medication Monitoring (RTMM), (4) a combination of self-report and pharmacy refill count or (5) all three adherence assessment methods combined. METHODOLOGY: This was a post-hoc analysis of data from our 48-week REMIND-HIV randomized controlled trial in which adherence to ART was measured using self-report, pharmacy refill counts and RTMM among ART-experienced adults living with HIV subjectively judged to be nonadherent to ART. For each adherence measure, we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting virological failure defined as a viral load (VL) of > 20 copies/mL. To determine at which percentage of adherence the prediction was strongest, we evaluated adherence cut-offs of 80%, 85%, 90%, 95% and 100% using receiver operating characteristic (ROC) curves. VL data were obtained after 48 weeks of follow-up in the trial. RESULTS: A total of 233 people living with HIV (PLHIV) were included in this analysis. When comparing the ability of self-reported adherence with pharmacy refill count and RTMM adherence to predict viral load > 20 copies/ml, self-reported adherence had the lowest sensitivity, ranging from 6 to 17%, but the highest specificity, ranging from 100 to 86%, depending on cut-off values from 80 to 100%. Area under the ROC curves (AUC) were 0.54 for RTMM, 0.56 for pharmacy refill count and 0.52 for self-report, indicating low discriminatory capacity for each of the adherence measures. When we combined the self-report and pharmacy refill count measures, se
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- 2022
37. Pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents treated for tuberculous meningitis
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Ruslami, R., Gafar, F., Yunivita, V., Parwati, I., Ganiem, A.R, Aarnoutse, R.E., Wilffert, B., Alffenaar, J.C., Nataprawira, H.M., Ruslami, R., Gafar, F., Yunivita, V., Parwati, I., Ganiem, A.R, Aarnoutse, R.E., Wilffert, B., Alffenaar, J.C., and Nataprawira, H.M.
- Abstract
Contains fulltext : 249114.pdf (Publisher’s version ) (Open Access), OBJECTIVE: To assess the pharmacokinetics and safety/tolerability of isoniazid, rifampicin and pyrazinamide in children and adolescents with tuberculous meningitis (TBM). DESIGN: Prospective observational pharmacokinetic study with an exploratory pharmacokinetic/pharmacodynamic analysis. SETTING: Hasan Sadikin Hospital, Bandung, Indonesia. PATIENTS: Individuals aged 0-18 years clinically diagnosed with TBM and receiving first-line anti-tuberculosis drug dosages according to revised WHO-recommended treatment guidelines. INTERVENTIONS: Plasma and cerebrospinal fluid (CSF) concentrations of isoniazid, rifampicin and pyrazinamide were assessed on days 2 and 10 of treatment. MAIN OUTCOME MEASURES: Plasma exposures during the daily dosing interval (AUC(0-24)), peak plasma concentrations (C (max)) and CSF concentrations. RESULTS: Among 20 eligible patients, geometric mean AUC(0-24) of isoniazid, rifampicin and pyrazinamide was 18.5, 66.9 and 315.5 hour∙mg/L on day 2; and 14.5, 71.8 and 328.4 hour∙mg/L on day 10, respectively. Large interindividual variabilities were observed in AUC(0-24) and C (max) of all drugs. All patients had suboptimal rifampicin AUC(0-24) for TBM treatment indication and very low rifampicin CSF concentrations. Four patients developed grade 2-3 drug-induced liver injury (DILI) within the first 4 weeks of treatment, in whom anti-tuberculosis drugs were temporarily stopped, and no DILI recurred after reintroduction of rifampicin and isoniazid. AUC(0-24) of isoniazid, rifampicin and pyrazinamide along with C (max) of isoniazid and pyrazinamide on day 10 were higher in patients who developed DILI than those without DILI (p<0.05). CONCLUSION: Higher rifampicin doses are strongly warranted in treatment of children and adolescents with TBM. The association between higher plasma concentrations of isoniazid, rifampicin and pyrazinamide and the development of DILI needs confirmatory studies.
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- 2022
38. Clinical standards for the dosing and management of TB drugs
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Alffenaar, J.W.C., Stocker, S.L., Forsman, L.D., Garcia-Prats, A., Heysell, S.K., Aarnoutse, R.E., Akkerman, O.W., Aleksa, A., Altena, R. van, Oñata, W.A. de, Bhavani, P.K., Boveneind-Vrubleuskaya, N. Van't, Carvalho, A.C.C., Centis, R., Chakaya, J.M., Cirillo, D.M., Cho, J.G., Ambrosio, L.D., Dalcolmo, M.P., Denti, P., Dheda, K., Fox, G.J., Hesseling, A.C., Kim, H.Y., Köser, C.U., Marais, B.J., Margineanu, I., Märtson, A.G., Torrico, M.M., Nataprawira, H.M., Ong, C.W.M., Otto-Knapp, R., Peloquin, C.A., Silva, D.R., Ruslami, R., Santoso, P., Savic, R.M., Singla, R., Svensson, E.M., Skrahina, A., Soolingen, D. van, Srivastava, S., Tadolini, M., Tiberi, S., Thomas, T.A., Udwadia, Z.F., Vu, D.H., Zhang, W., Mpagama, S.G., Schön, T., Migliori, G.B., Alffenaar, J.W.C., Stocker, S.L., Forsman, L.D., Garcia-Prats, A., Heysell, S.K., Aarnoutse, R.E., Akkerman, O.W., Aleksa, A., Altena, R. van, Oñata, W.A. de, Bhavani, P.K., Boveneind-Vrubleuskaya, N. Van't, Carvalho, A.C.C., Centis, R., Chakaya, J.M., Cirillo, D.M., Cho, J.G., Ambrosio, L.D., Dalcolmo, M.P., Denti, P., Dheda, K., Fox, G.J., Hesseling, A.C., Kim, H.Y., Köser, C.U., Marais, B.J., Margineanu, I., Märtson, A.G., Torrico, M.M., Nataprawira, H.M., Ong, C.W.M., Otto-Knapp, R., Peloquin, C.A., Silva, D.R., Ruslami, R., Santoso, P., Savic, R.M., Singla, R., Svensson, E.M., Skrahina, A., Soolingen, D. van, Srivastava, S., Tadolini, M., Tiberi, S., Thomas, T.A., Udwadia, Z.F., Vu, D.H., Zhang, W., Mpagama, S.G., Schön, T., and Migliori, G.B.
- Abstract
Item does not contain fulltext, BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.
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- 2022
39. Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children
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Turkova, A., Wills, G.H., Wobudeya, E., Chabala, C., Palmer, M., Kinikar, A., Hissar, S., Choo, L., Musoke, P., Mulenga, V., Mave, V., Joseph, B., LeBeau, K., Thomason, M.J., Mboizi, R.B., Kapasa, M., Zalm, M.M. van der, Raichur, P., Bhavani, P.K., McIlleron, H., Demers, A.M., Aarnoutse, R.E., Love-Koh, J., Seddon, J.A., Welch, S.B., Graham, S.M., Hesseling, A.C., Gibb, D.M., Crook, A.M., Turkova, A., Wills, G.H., Wobudeya, E., Chabala, C., Palmer, M., Kinikar, A., Hissar, S., Choo, L., Musoke, P., Mulenga, V., Mave, V., Joseph, B., LeBeau, K., Thomason, M.J., Mboizi, R.B., Kapasa, M., Zalm, M.M. van der, Raichur, P., Bhavani, P.K., McIlleron, H., Demers, A.M., Aarnoutse, R.E., Love-Koh, J., Seddon, J.A., Welch, S.B., Graham, S.M., Hesseling, A.C., Gibb, D.M., and Crook, A.M.
- Abstract
Contains fulltext : 249121.pdf (Publisher’s version ) (Open Access), BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis
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- 2022
40. Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization-Recommended Weight Band Doses and Formulations
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Chabala, C., Turkova, A., Hesseling, A.C., Zimba, K.M., Zalm, M. van der, Kapasa, M., Palmer, M., Chirehwa, M., Wiesner, L., Wobudeya, E., Kinikar, A., Mave, V., Hissar, S., Choo, L., LeBeau, K., Mulenga, V., Aarnoutse, R.E., Gibb, D., McIlleron, H., Chabala, C., Turkova, A., Hesseling, A.C., Zimba, K.M., Zalm, M. van der, Kapasa, M., Palmer, M., Chirehwa, M., Wiesner, L., Wobudeya, E., Kinikar, A., Mave, V., Hissar, S., Choo, L., LeBeau, K., Mulenga, V., Aarnoutse, R.E., Gibb, D., and McIlleron, H.
- Abstract
Item does not contain fulltext, BACKGROUND: Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization-recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. METHODS: Children weighing 4.0-7.9, 8.0-11.9, 12.0-15.9, or 16.0-24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0-36.9 kg received doses recommended for adults <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. RESULTS: In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4-6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1-45.1), 16.7 (9.2-25.9), 317 (263-399), and 9.5 (7.5-11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0-7.9-, 8-11.9-, and ≥25-kg weight bands, isoniazid in the 4.0-7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. CONCLUSIONS: Recommended weight band-based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization-recommended doses requires further evaluation.
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- 2022
41. Simultaneous determination of the azoles voriconazole, posaconazole, isavuconazole, itraconazole and its metabolite hydroxy-itraconazole in human plasma by reversed phase ultra-performance liquid chromatography with ultraviolet detection
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Verweij-van Wissen, C.P.W.G.M., Burger, D.M., Verweij, P.E., Aarnoutse, R.E., and Brüggemann, R.J.M.
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- 2012
- Full Text
- View/download PDF
42. Pharmacodynamic biomarkers for quantifying the mycobacterial effect of high doses of rifampin in patients with rifampin-susceptible pulmonary tuberculosis
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Said, B.N., Heysell, S.K., Yimer, G., Aarnoutse, R.E., Kibiki, G.S., Mpagama, S., Mbelele, P.M., Said, B.N., Heysell, S.K., Yimer, G., Aarnoutse, R.E., Kibiki, G.S., Mpagama, S., and Mbelele, P.M.
- Abstract
Contains fulltext : 244671.pdf (Publisher’s version ) (Open Access), BACKGROUND: Suboptimal drug exposure in patients with drug-susceptible tuberculosis (DS-TB) can drive treatment failure. Pharmacodynamics (PD) biomarkers such as the plasma TB drug-activity (TDA) assay may guide dose finding studies and predict microbiological outcomes differently than conventional indices. METHODS: A study was nested from phase 2b randomized double-blind controlled trial of Tanzanian patients who received a 600 mg, 900 mg, or 1200 mg with a standard dose for DS-TB. Serum at 6 weeks collected over 24-h at 2-h intervals was collected for rifampin area under the concentration-time curve relative to minimum inhibitory concentration (AUC(0-24)/MIC) or peak concentration and MIC (C(max)/MIC). TDA was the ratio of time-to-positive growth of the patient's Mycobacterium tuberculosis isolates with and without coculture of patient's plasma collected at C(max). Spearman's rank correlation (r) between PD parameters and culture convention on both liquid and solid culture media. RESULTS: Among 10 patients, 600 mg (3), 900 mg (3), and 1200 mg (4) of rifampin dosages. The mean ± standard deviation (SD) of AUC(0-24)/MIC for patients on 600 mg was 168 ± 159 mg·h/L, on 900 mg was 169 ± 166 mg·h/L, and on 1200 mg was 308 ± 238 mg·h/L. The mean-TDA (SD) was 2.56 (±0.75), 1.5 (±0.59), and 2.29 (±1.08) for patients on 600 mg, 900 mg, and 1200 mg rifampin doses, respectively. Higher TDA values correlated with faster time to culture convention on both liquid (r = -0.55, P = 0.099) and solid media (r = -0.65, P = 0.04). CONCLUSIONS: TDA and rifampin AUC(0-24)/MIC did not trend as expected with rifampin dose, but TDA better predicted the time to sputum culture conversion. TDA may provide additional discrimination in predicting treatment response for some regimens distinct from plasma exposure relative to MIC or mg/kg dose.
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- 2021
43. Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial
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Garcia-Prats, A.J., Svensson, E.M., Winckler, Jana, Draper, Heather R., Fairlie, Lee, Laan, L. van der, Aarnoutse, R.E., Denti, P., Hesseling, A., Garcia-Prats, A.J., Svensson, E.M., Winckler, Jana, Draper, Heather R., Fairlie, Lee, Laan, L. van der, Aarnoutse, R.E., Denti, P., and Hesseling, A.
- Abstract
Item does not contain fulltext
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- 2021
44. First international quality control programme for laboratories measuring antimicrobial drugs to support dose individualization in critically ill patients
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Wallenburg, E., Bruggemann, R.J.M., Asouit, K., Teulen, M.J., Haan, A.F.J. de, Franssen, E.J.F., Aarnoutse, R.E., Wallenburg, E., Bruggemann, R.J.M., Asouit, K., Teulen, M.J., Haan, A.F.J. de, Franssen, E.J.F., and Aarnoutse, R.E.
- Abstract
Contains fulltext : 231600.pdf (Publisher’s version ) (Open Access)
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- 2021
45. Population Pharmacokinetics and Bayesian Dose Adjustment to Advance TDM of Anti-TB Drugs
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Sturkenboom, M.G., Märtson, A.G., Svensson, E.M., Sloan, D.J., Dooley, Kelly E., Elsen, S.H.J. van den, Denti, P., Peloquin, C.A., Aarnoutse, R.E., Alffenaar, J.C., Sturkenboom, M.G., Märtson, A.G., Svensson, E.M., Sloan, D.J., Dooley, Kelly E., Elsen, S.H.J. van den, Denti, P., Peloquin, C.A., Aarnoutse, R.E., and Alffenaar, J.C.
- Abstract
Contains fulltext : 235795.pdf (Publisher’s version ) (Open Access), Tuberculosis (TB) is still the number one cause of death due to an infectious disease. Pharmacokinetics and pharmacodynamics of anti-TB drugs are key in the optimization of TB treatment and help to prevent slow response to treatment, acquired drug resistance, and adverse drug effects. The aim of this review was to provide an update on the pharmacokinetics and pharmacodynamics of anti-TB drugs and to show how population pharmacokinetics and Bayesian dose adjustment can be used to optimize treatment. We cover aspects on preclinical, clinical, and population pharmacokinetics of different drugs used for drug-susceptible TB and multidrug-resistant TB. Moreover, we include available data to support therapeutic drug monitoring of these drugs and known pharmacokinetic and pharmacodynamic targets that can be used for optimization of therapy. We have identified a wide range of population pharmacokinetic models for first- and second-line drugs used for TB, which included models built on NONMEM, Pmetrics, ADAPT, MWPharm, Monolix, Phoenix, and NPEM2 software. The first population models were built for isoniazid and rifampicin; however, in recent years, more data have emerged for both new anti-TB drugs, but also for defining targets of older anti-TB drugs. Since the introduction of therapeutic drug monitoring for TB over 3 decades ago, further development of therapeutic drug monitoring in TB next steps will again depend on academic and clinical initiatives. We recommend close collaboration between researchers and the World Health Organization to provide important guideline updates regarding therapeutic drug monitoring and pharmacokinetics/pharmacodynamics.
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- 2021
46. 'I Wish to Continue Receiving the Reminder Short Messaging Service': A Mixed Methods Study on the Acceptability of Digital Adherence Tools Among Adults Living with HIV on Antiretroviral Treatment in Tanzania
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Ngowi, K., Pima, F., Mmbaga, B.T., Aarnoutse, R.E., Reiss, P., Nieuwkerk, P.T., Sprangers, M., Sumari-de Boer, M., Ngowi, K., Pima, F., Mmbaga, B.T., Aarnoutse, R.E., Reiss, P., Nieuwkerk, P.T., Sprangers, M., and Sumari-de Boer, M.
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Contains fulltext : 232004.pdf (Publisher’s version ) (Open Access), INTRODUCTION: Digital Adherence Tools (DAT) to promote adherence to antiretroviral treatment (ART) for HIV are being increasingly adopted globally, however their effectiveness and acceptability in limited resource settings has been challenging. In this study, we examine the acceptability of DATs to improve adherence to ART. METHODS: This study was part of a three-arm randomized controlled trial (REMIND) which investigated the effect of two different DAT's: SMS text messages (SMS) or real-time medication monitoring (RTMM) on treatment adherence; compared to standard of care. Exit interviews and in-depth interviews were conducted at 48 weeks follow-up, to collect data on their experiences (successes, challenges, and barriers) and behaviours regarding the implementation of the interventions. Translated transcripts, memos and field notes were imported to NVivo software version 12. We used a thematic framework analysis which drew from Sekhon's theoretical framework of acceptability (TFA), which comprises of seven constructs (affective attitude, perceived burden, perceived effectiveness, ethicality, self-efficacy, intervention coherence and opportunity costs). RESULTS: Of the 166 participants enrolled, 143 (86%) were interviewed (68 in the SMS arm and 75 in the RTMM arm). Participants were highly satisfied (98%) with the DAT system and the majority of them reported it motivated them to take their medication (99%). The majority of participants reported they were confident in their ability to comply with the intervention and understood how the intervention worked (97%). Very few reported negatively about the devices (carrying the device), with only 6% reporting that they did not feel comfortable and 8% had ethical concerns with the SMS-content A few participants reported challenges with their connectivity/network and that the visits were too time-consuming. A few participants reported that they incurred extra cost for the sake of the study. CONCLUSION: Overall, the acceptab
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- 2021
47. Effect of Digital Adherence Tools on Adherence to Antiretroviral Treatment Among Adults Living With HIV in Kilimanjaro, Tanzania: A Randomized Controlled Trial
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Sumari-de Boer, I.M., Ngowi, K.M., Sonda, T.B., Pima, F.M., Bpharm, L.V. Masika, Sprangers, M.A.G., Reiss, P., Mmbaga, B.T., Nieuwkerk, P.T., Aarnoutse, R.E., Sumari-de Boer, I.M., Ngowi, K.M., Sonda, T.B., Pima, F.M., Bpharm, L.V. Masika, Sprangers, M.A.G., Reiss, P., Mmbaga, B.T., Nieuwkerk, P.T., and Aarnoutse, R.E.
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Item does not contain fulltext, BACKGROUND: Lifelong adherence to antiretroviral treatment remains challenging for people living with HIV (PLHIV). The aim of this study was to investigate whether any of 2 digital adherence tools could improve adherence among PLHIV in Kilimanjaro, Tanzania. METHODS: We performed a parallel 3-arm, nonblinded, randomized controlled trial with 1:1:1 allocation. We included adults aged between 18 and 65 years, living in Kilimanjaro region, and who were on antiretroviral treatment for at least 6 months. Their adherence, as judged by the study nurses, had to be suboptimal. In one arm, participants received reminder short message service (SMS) texts, followed by a question SMS. In the second arm, participants received a real-time medication monitoring (RTMM) device (Wisepill) with SMS reminders. In the third arm, participants received standard care only. The primary outcome of mean adherence over 48 weeks was compared between arms using between-group t tests in a modified intention-to-treat analysis. RESULTS: In each arm, we randomized 83 participants: data of 82 participants in the RTMM arm, 80 in the SMS arm, and 81 in the standard care arm were analyzed. The average (over 48 weeks) adherence in the SMS, RTMM, and control arms was 89.6%, 90.6%, and 87.9% for pharmacy refill; 95.9%, 95.0%, and 95.2% for self-report in the past week; and 97.5%, 96.6%, and 96.9% for self-report in the past month, respectively (P values not statistically significant). CONCLUSIONS: Receiving reminder SMS or RTMM combined with feedback about adherence levels and discussion of strategies to overcome barriers to adherence did not improve adherence to treatment and treatment outcome in PLHIV. CLINICAL TRIAL NUMBER: PACTR201712002844286.
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- 2021
48. Building bridges between preclinical and clinical pharmacology in tuberculosis treatment
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Aarnoutse, R.E., Russel, F.G.M., Brake, L.H.M. te, Koenderink, J.B., Litjens, C.H.C., Aarnoutse, R.E., Russel, F.G.M., Brake, L.H.M. te, Koenderink, J.B., and Litjens, C.H.C.
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Radboud University, 18 mei 2021, Promotores : Aarnoutse, R.E., Russel, F.G.M. Co-promotores : Brake, L.H.M. te, Koenderink, J.B., Contains fulltext : 232626.pdf (Publisher’s version ) (Open Access)
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- 2021
49. Optimising pyrazinamide for the treatment of tuberculosis
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Zhang, Nan, Savic, R., Boeree, M.J., Peloquin, C.A., Weiner, M.H., Heinrich, Norbert, Aarnoutse, R.E., Dooley, Kelly E., Zhang, Nan, Savic, R., Boeree, M.J., Peloquin, C.A., Weiner, M.H., Heinrich, Norbert, Aarnoutse, R.E., and Dooley, Kelly E.
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Contains fulltext : 238450.pdf (Publisher’s version ) (Closed access)
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- 2021
50. Increased bactericidal activity but dose-limiting intolerability at 50 mg.kg(-1) rifampicin
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Brake, L.H.M. te, Jager, V. de, Narunsky, K., Vanker, Naadira, Svensson, E.M., Phillips, P.P., Aarnoutse, R.E., Boeree, M.J., Brake, L.H.M. te, Jager, V. de, Narunsky, K., Vanker, Naadira, Svensson, E.M., Phillips, P.P., Aarnoutse, R.E., and Boeree, M.J.
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Contains fulltext : 238428.pdf (Publisher’s version ) (Open Access)
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- 2021
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