EDCTP Alumni Network

Title

Research Capacity Strengthening Programme for Emerging and Re-emerging Infectious Diseases Control in Tanzania

Objectives

Primary Objective • To assess the differences in changes of hearing thresholds in MDR-TB patients using NAC at a dose of 900mg daily or 900mg twice a day in combination with the aminoglycoside based regimen and compare with patients using the standard aminoglycoside based regimen. Secondary objectives • To assess the effect of NAC at a dose of 900mg daily or 900mg twice a day on pharmacokinetics of second-line anti-TB drugs • To assess safety and tolerability of patients on NAC at a dose of 900mg and 900 mg twice a day in combination with second-line anti-TB regimen • To characterize molecular mechanisms of drug-resistance in MTB from MDR-TB patients using TAC • To assess the effect of NAC on clearance of MTB using molecular bacterial load (MBL) Assay in MDR-TB patients

Host Organisation

Institution	Country
Kibong'oto Infectious Diseases Hospital	Tanzania, United Republic of

Study Design

Phase 2b randomized double-blind clinical trial

Sites

Kibong'oto Infectious Diseases Hospital

Phd Study

Title	University	Start Date	End Date
Molecular Diagnostics for characterizing and monitoring of Mycobacterium tuberculosis complex for clinical Management of Multidrug-resistant Tuberculosis: A strategy to Optimize favorable treatment outcome in Tanzania”	The Nelson Mandela African Institution of Science and Technology (NM-AIST)	2017-06-16	2020-10-15

Students Supervised

Type	Name	Title	University	Start Date	End Date
Infectious Diseases Fellow	Sagal Mohamed	M.D.	University of Virginia -USA	2018	2019
Novartis Fellow supported by the EDCTP	Alphonce Liyoyo	M.D. MPH	None	2018	2019
MSc Life Science	Happiness Mvungi	M.D.	Nelson Mandela African Institution of Science and Technology	2016	2018
Infectious Diseases Fellow	Andrews Eber	M.D.	University of Virginia	2016	2017
MSc Clinical Research	Kenneth Byashalira	M.D.	Kilimanjaro Christian Medical University College	2016	2018
Master of Public Health	Alphonce Liyoyo	M.D	Kilimanjaro Christian Medical University College	2015	2016
Ph.D	Vesla Kulaya	BSc, MSc Immunology , Microbiology and Molecular Biology	Radb	2013	2016
Ph.D	Margareth Sariko	BSc, MSc Microbiology, Immunology and Molecular Biology	Kilimanjaro Christian Medical University College	2013	2019
MSc	Edson Mollel	M.D.	Kilimanjaro Christian Medical University College	2013	2015
MPH	Amon Sabasaba	M.D.	Kilimanjaro Christian Medical University College	2015	2017
Ph.D.	Kenneth Byashalira	M.D.MSc	Kilimanjaro Christian Medical University College	2019	2023
Ph.D	Happiness Mvungi	M.D. MSc	Kilimanjaro Christian Medical University College	2019	2023
Ph.D	Nyasatu Chamba	M.D.MSc	Kilimanjaro Christian Medical University College	2019	2023
Ph.D	Shabani Mziray	M.D. MSc	Kiilmanjaro Christian Medical University College	2019	2023
Ph.D	Peter Mbelele	M.D. MMED Microbiology & Immunology	Nelson Mandela African Institution of Science and Technology	2016	2020
MSc Clinical Trials	Bibie Saidi	M.D.	University of Addis Ababa	2019	2021
MSc Life Science	Donatus Tsere	M.D.	Nelson Mandela African Institution of Science and Technology	2020	2022

Publications

Mbelele P, Aboud S, Mpagama S, Matee M. Improved performance of Xpert MTB/RIF assay on sputum sediment samples obtained from presumptive pulmonary tuberculosis cases at Kibong’oto infectious diseases hospital in Tanzania. BMC Infect Dis. 2017;17(1):808.

Heysell S, Pholwat S, Mpagama S, Pazia S, Kumburu H, Ndusilo N, Gratz J, Houpt E, Kibiki G: Sensititre MYCOTB plate compared to Bactec MGIT 960 for first and second-line anti-tuberculosis drug susceptibility testing in Tanzania: a call to operationalize minimum inhibitory concentrations. Antimicrob Agents Chemother 2015, Epub.

Mpagama SG, Lekule IA, Mbuya AW, Kisonga RM, Heysell SK: The Influence of Mining and Human Immunodeficiency Virus Infection Among Patients Admitted for Retreatment of Tuberculosis in Northern Tanzania. The American journal of tropical medicine and hygiene 2015, 93(2):212-215.

Mpagama SG, Mtabho C, Mwaigwisya S, Mleoh LJ, Boer IM, Heysell SK, Houpt ER, Kibiki GS: Comparison of overnight pooled and standard sputum collection method for patients with suspected pulmonary tuberculosis in northern Tanzania. Tuberculosis research and treatment 2012, 2012:128057.

Heysell S, Mtabho C, Mpagama S, Mwaigwisya S, Pholwat S, Ndusilo N, Gratz J, Aarnoutse R, Kibiki G, Houpt E: Plasma drug activity assay for treatment optimization in tuberculosis patients. Antimicrobial agents and chemotherapy 2011, 55(12):5819-5825.

Mpagama S, Heysell S, Ndusilo N, Kumburu H, Lekule I, Kisonga R, Gratz J, Boeree M, Houpt E, Kibiki G: Diagnosis and interim treatment outcomes from the first cohort of multidrug-resistant tuberculosis patients in Tanzania. PloS one 2013, 8(5):e62034.

Mpagama S, Houpt E, Stroupt S, Kumburu H, Gratz J, Kibiki G, Heysell S: Application of quantitative second-line drug susceptibility testing at a multidrug-resistant tuberculosis hospital in Tanzania. BMC infectious diseases 2013, 13:432.

Sariko ML, Mpagama SG, Gratz J, Kisonga R, Saidi Q, Kibiki GS, Heysell SK: Glycated hemoglobin screening identifies patients admitted for retreatment of tuberculosis at risk for diabetes in Tanzania. Journal of infection in developing countries 2016, 10(4):423-426.

Nyaki F, Taksdal M, Mbuya A, Sariko M, Lekule I, Kisonga R, Kibiki G, Mmbaga B, Heysell S, Mpagama S: Predictors of Nutritional Status in Patients Treated for Multidrug-Resistant Tuberculosis at a Referral Hospital in Tanzania. j Clin Infect Dis Pract 2016, 1(2):115.

Sariko M, Anderson C, Mujaga BS, Gratz J, Mpagama SG, Heysell S, Kibiki G, Mmbaga B, Houpt E, Thomas T: Evaluation of the Antibody in Lymphocyte Supernatant Assay to Detect Active Tuberculosis. PloS one 2017, 12(1):e0169118.

Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja T, Hunt RD, Charalambous,S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M: High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. The Lancet Infectious Diseases 2016.

Liyoyo AA, Heysell SK, Kisonga RM, Lyimo JJ, Mleoh LJ, Mutayoba BK, Lekule IA, Mmbaga BT, Kibiki GS, Mpagama SG. Gridlock from Diagnosis to Treatment of Multidrug Resistant Tuberculosis (MDR-TB) in Tanzania: Illuminating Potential Factors for Possible Intervention. EAHRJ, Vol 1.Issue 2 2018

Mollel E,Chilongola J, Mpagama SG, Kibiki GS. Evaluation of XpertMTB/RIF performance for diagnosis of tuberculosis among HIV positive patients in Northern Tanzania. Tanzania Journal of Health Research Dec 2016

Ebers A, Stroup S, Mpagama S, Kisonga R, Lekule IA, Liu J, Heysell S. Determination of plasma concentrations of levofloxacin by high performance liquid chromatography for use at a multidrug-resistant tuberculosis hospital in Tanzania. 2017. PLoS One 12 (1). e0170663. doi:10.1371/journal.pone.0170663

Operario D, Koeppel AF,Turner SD,Bao Y,Pholwat S,Banu S,Foongladda S, Mpagama SG, Gratz J,Ogarkov O,Zhadova S, Heysell SK, Houpt ER.2017. Prevalence and Extent of Heteroresistance by next generation sequencing of multidrug resistance tuberculosis. PLoS One 12(5). e0176522.

Aarnoutse R, Kibiki G, Reither K, Semvua H, Haraka F, Mtabho C, Mpagama S, Boogaard J, Sumari-de Boer MI, Magis-Escurra C, Wattenberg M, Logger J, te Brake L, Hoelscher M, Gillespie S, Colbers A, Phillips P, Plemper van Balen G,Boeree MJ. "Pharmacokinetics, tolerability and bacteriological response of 600, 900 and 1200 mg rifampicin daily in patients with pulmonary TB" Antimicrobial Agents Chemotherapy 2017 Oct 24;61(11):e01054-17. doi: 10.1128/AAC.01054-17.

Kullaya V, van den Ven A, Mpagama S, Mmbaga B, de Groot P, Kibiki G,de Mast Q. Platelet monocyte interaction in Mycobacterium tuberculosis infection. Tuberculosis. Vol 111.86-93.

Zentner I, Modongo C, Zetola N, Pasipanodya J, Srivastava S, Heysell S, Mpagama S, Schlect HP, Gumbo T,Bisson G, Vinnard C. Urine colorimetryic for therapeutic drug monitoring of pyrazinamide during tuberculosis treatment. Int J Infect Dis 2018. 3.18-23

Devyani Deshpande, Jotam G. Pasipanodya, Stellah G. Mpagama, Paula Bendet, Shashikant Srivastava, Thearith Koeuth, Pooi S. Lee, Sujata M. Bhavnani, Paul G. Ambrose, Guy Thwaites, Scott K. Heysell, Tawanda Gumbo. Levofloxacin pharmacokinetics-pharmacodynamics, dosing, and susceptibility breakpoints, and artificial intelligence in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis 2018, 28;67(suppl_3):S293-S302. doi: 10.1093/cid/ciy611.

Devyani Deshpande, Jan-Willem C. Alffenaar, Claudio U. Köser, Keertan Dheda, Moti L. Chapagain, Noviana Simbar, Thomas Schön, Marieke G.G. Sturkenboom, Helen McIlleron, Pooi S. Lee, Thearith Koeuth, Stellah G. Mpagama, Sayera Banu, Suporn Foongladda, Oleg Ogarkov, Suporn Pholwat, Eric R. Houpt, Scott K. Heysell, Tawanda Gumbo. D-cycloserine pharmacokinetics-pharmacodynamics, susceptibility, and dosing implications in multidrug-resistant tuberculosis: a Faustian deal. Clin Infect Dis 2018, 28;67(suppl_3):S308-S316. doi: 10.1093/cid/ciy624.

Zentner I, Modongo C, Zetola N, Pasipanodya J, Srivastava S, Heysell S, Mpagama S, Schlect HP, Gumbo T,Bisson G, Vinnard C. Urine colorimetryic for therapeutic drug monitoring of pyrazinamide during tuberculosis treatment. Int J Infect Dis 2018. 3.18-23

Devyani Deshpande, Jotam G. Pasipanodya, Stellah G. Mpagama, Paula Bendet, Shashikant Srivastava, Thearith Koeuth, Pooi S. Lee, Sujata M. Bhavnani, Paul G. Ambrose, Guy Thwaites, Scott K. Heysell, Tawanda Gumbo. Levofloxacin pharmacokinetics-pharmacodynamics, dosing, and susceptibility breakpoints, and artificial intelligence in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis 2018, 28;67(suppl_3):S293-S302. doi: 10.1093/cid/ciy611.

Devyani Deshpande, Jan-Willem C. Alffenaar, Claudio U. Köser, Keertan Dheda, Moti L. Chapagain, Noviana Simbar, Thomas Schön, Marieke G.G. Sturkenboom, Helen McIlleron, Pooi S. Lee, Thearith Koeuth, Stellah G. Mpagama, Sayera Banu, Suporn Foongladda, Oleg Ogarkov, Suporn Pholwat, Eric R. Houpt, Scott K. Heysell, Tawanda Gumbo. D-cycloserine pharmacokinetics-pharmacodynamics, susceptibility, and dosing implications in multidrug-resistant tuberculosis: a Faustian deal. Clin Infect Dis 2018, 28;67(suppl_3):S308-S316. doi: 10.1093/cid/ciy624.

Devyani Deshpande, Jotam Pasipanodya, Stellah G. Mpagama, ShashikantSrivastava, Paula Bendet, Thearith Koeuth, Pooi S. Lee, Scott K. Heysell, Tawanda Gumbo. Ethionamide pharmacokinetics-pharmacodynamics-derived dose, the role of MICs in clinical outcome, and the resistance arrow of time, in multi-drug resistant tuberculosis. Clin Infect Dis 2018 28;67(suppl_3):S317-S326. doi: 10.1093/cid/ciy609.

van den Elsen SHJ, Sturkenboom MGG, Van't Boveneind-Vrubleuskaya N, Skrahina A, van der Werf TS, Heysell SK, Mpagama S, Migliori GB, Peloquin CA, Touw DJ, Alffenaar JC. Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients. Antimicrob Agents Chemother. 2018. 26;62(12).

Jan-Willem C Alffenaar, Scott K Heysell, Stellah G Mpagama, Therapeutic Drug Monitoring. The need for practical guidance. Clin Infect Dis 2018

Mpagama SG, Mangi E, Chongolo AM, Lyimo JJ, Houpt ER, Kibiki GS, Heysell SK: Gridlock from Diagnosis to Treatment of Multidrug Resistant Tuberculosis in Tanzania: Patient Perspectives from Focus Group Discussions. doi: https://doi.org/10.1101/402594 .

Mpagama SG, Mbelele PM, Chongolo AM, Lekule IA, Lyimo JJ, Houpt ER, Kibiki GS, Heysell SK: Gridlock from Diagnosis to Treatment of Multidrug Resistant Tuberculosis in Tanzania: Cross Sectional Survey of Health Facilities with TB and HIV services in 28 Districts. BMC Public Health. 2019; 19(1):395. doi: 10.1186/s12889-019-6720-6.

Mpagama SG, Chongolo A, Taksdal M, Kiwia R, Kisonga R, Kachallah J, Heysell SK. Roll-out of Audiometry for MDR-TB in Tanzania. High rates of Ototoxicity were observed despite treatment modification. Submitted 2017

Heinrich N, te Brake LHM, Konsten SLJL, Svensson EM, Phillips PPJP, Ntinginya N, Manyama C, Minja L, Kibiki GS, Mpagama S, Sanne I, Rassool M, Reither K, McHugh T, Diacon AH, Hanekom M, Dawson R, Churchyard G, Framhein A, Mekota A, Plemper van Balen G, Gillespie SH, Boeree MJ , Hoelscher M, Aarnoutse RE, Dose-response and Pharmacokinetic-pharmacodynamic relations of first-line anti-tuberculosis drugs in the PanACEA-MAMS-TB study. Submitted. 2017

Framhein A, Mpagama S, Ntinginya NE, Kibiki G, Mangu C, Semvua H, Rojas-Ponce G, Kuchaka D, Mtafya B, Lioyo A, Ngatemelela D, Aarnoutse R, Boeree M, Gillespie G, Michael Hoelscher M, Heinrich N, A two-site study of tuberculosis patients to observe decline of bacterial load and compare culture-based endpoints under standard anti-tuberculosis treatment in Tanzania.

Perumal R, Naidoo K, Naidoo A, Ramachandran G, Mendez AR, Sekaggya-Wiltshire C, Mpagama S, Matteelli A, Fehr J, Heysell, Padayatchi N. A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes. Int J Tuberc Lung Dis 2020;24(1):48-64. doi: 10.5588/ijtld.19.0025.

Juma SP, Maro A, Pholwat S, Mpagama SG, Gratz J, Liyoyo A, Houpt ER, Kibiki GS, Mmbaga BT, Heysell SK. Underestimated pyrazinamide resistance may compromise outcomes of pyrazinamide containing regimes for treatment for treatment of drug susceptible and multidrug resistance tuberculosis in Tanzania. BMC Infect Dis. 2019 ;19(1):129. doi: 10.1186/s12879-019-3757-1.

Mbelele PM, Mohamed SY, Sauli E, Mpolya EA, Mfinanga SG, Addo KK, Heysell SK, Mpagama SG. Meta-narrative review of molecular methods for diagnosis and monitoring of multidrug resistant tuberculosis treatment in adults. Int J Mycobacteriol. 2018;7(4):299-309. doi: 10.4103/ijmy.ijmy_135_18.

Mvungi HC, Mbelele PM, Buza JJ, Mpagama SG, Sauli E. Blood cytokine responses to early secreted protein antigen-5/culture filtrate protein-10 tuberculosis antigens 2 months after Antituberculosis treatment among patients with drug-susceptible pulmonary tuberculosis . Int J Mycobacteriol. 2019;;8(1):53-59. doi: 10.4103/ijmy.ijmy_30_19.

Ahmed MIM, Ntinginya NE, Kibiki G, Mtafya BA, Semvua H, Mpagama S, Mtabho C, Saathoff E, Held K, Loose R, Kroidl I, Chachage M, von Both U, Haule A, Mekota AM, Boeree MJ, Gillespie SH, Hoelscher M, Heinrich N, Geldmacher C. Phenotypic Changes on Mycobacterium Tuberculosis-Specific CD4 T Cells as Surrogate Marker for Tuberculosis Treatment Efficacy. Front Immunol. 2018; 9:2247. doi: 10.3389/fimmu.2018.02247. eCollection 2018.

Mbelele PM, Aboud S, Mpagama SG, Matee MI. Improved performance of Xpert MTB/RIF assay on sputum sediment samples obtained from presumptive pulmonary tuberculosis cases at Kibong’oto Infectious Diseases Hospital in Tanzania. BMC Infect Dis.;17(1):808. doi: 10.1186/s12879-017-2931-6.

Sumari de-Boer M, Pima FM, Ngowi KM, Chelangwa GM, Mtesha BM,Minja LM, Semvua HH, Mpagama SG, Mmbaga BT, Nieuwkerk PT, Aarnoutse RE. Implementation and effectiveness of envriMED with short message service (SMS) reminders and tailored feedback compared to standard care on adherence to treatment among tuberculosis patients in Kilimanjaro. Tanzania: Proposal for a cluster randomized controlled trial. Trials. 2019; 20: 426. . doi: 10.1186/s13063-019-3483-4

Allwood, B., M. van der Zalm, G. Makanda, K. Mortimer, A. Andre F.S, E. Uzochukwu, E. Denise, G. Diane, H. Graeme, I. Olena, J. Rupert, M. Florian M, M. Jamilah, Mpagama. S, v. K. Sanne, R. Andrea, S. Ingrid, S. Cari, v. D. Dalene, W. Naomi and W. Robert (2019). "The long shadow post-tuberculosis." The Lancet Infectious Diseases 19(11): 1170-1171.

Byashalira, K., P. Mbelele, H. Semvua, J. Chilongola, S. Semvua, A. Liyoyo, B. Mmbaga, S. Mfinanga, C. Moore, S. Heysell and S. Mpagama (2019). "Clinical outcomes of new algorithm for diagnosis and treatment of Tuberculosis sepsis in HIV patients." International Journal of Mycobacteriology 8(4).

Katale, B. Z., P. M. Mbelele, N. A. Lema, S. Campino, S. E. Mshana, M. M. Rweyemamu, J. E. Phelan, J. D. Keyyu, M. Majigo, E. V. Mbugi, H. M. Dockrell, T. G. Clark, M. I. Matee and S. Mpagama (2020). "Whole genome sequencing of Mycobacterium tuberculosis isolates and clinical outcomes of patients treated for multidrug-resistant tuberculosis in Tanzania." BMC Genomics 21(1): 174.

Kim, H. Y., S. K. Heysell, S. Mpagama, B. J. Marais and J.-W. Alffenaar (2020). "Challenging the management of drug-resistant tuberculosis." The Lancet 395(10226).

Mpagama, S. (2019). "Transfer of Leadership: What do we need?" BMJ Glob Health.

Mpagama, S. G. (2018). "Diagnostic Opportunities for Optimizing Management of Multidrug-Resistant Tuberculosis (MDR-TB) in Tanzania." East African Health Res J 2(1): 26-28.

Szipszky, C., D. Van Aartsen, S. Criddle, P. Rao, I. Zentner, M. Justine, E. Mduma, S. Mpagama, M. H. Al-Shaer, C. Peloquin, T. A. Thomas, C. Vinnard and S. K. Heysell (2020). "Determination of Rifampin Concentrations by Urine Colorimetry and Mobile Phone Readout for Personalized Dosing in Tuberculosis Treatment."