“Ukatamanga weka utamangisa, tikatamanga awili, tifikapatali - When you run alone, you run fast. When you run together, you run far Zambian Proverb

UNZA-UCLMS

Research and Training Programme

Host Directed Therapies TB Clinical Trials Network

Inaugural meeting of the newly formed Host Directed therapies network - Cape Town, Apr 2015

Standing (Left to right): Andrie Steyn, Sayoki Mfinanga; Ian Sanne; Neil Martinson; Ali Zumla; Bob Wallis; Gibson Kibiki; Martin Grobusch; Eileen van Helden; Derek Tait; Paula Munderi; Roxana Rustomjee; Markus Maeurer;  Johan Louw ; Esusebio Macete; Nathan Kapata; Voahangy Rasolofo; Rob Wilkinson; Thomas Nyirenda;

Sitting (Left to Right): Rajh Madansein; Dororhty Yeboah-Manu; Candice Roux; Cristina Vilaplana; Modest Mulenga; Nalani Singh

Rationale

(For Institutional information click here)

Alimuddin Zumla

Salim Abdulla

Eleni Akililu

Martin Antonio

Abraham Aseffa

Matthew Bates

Maryline Bonnet

Pere-Joan Cardona

Jeremiah Chakaya

Gavin Churchyard

Tumena Corrah

Gill Craig

Bassirou Diarra

Tandakha N Dieye

Sarah Edwards

Paul Elkington

Sebestian Gagneux

Vanya Gant

Albert Garcia-Basteiro

Martin Grobusch

Richard Hafner

Michael Hoelscher

Giuseppe Ippolito

Pontiano Kaleebu

Nathan Kapata

Stefan Kaufmann

Gibson Kibiki

Eusebio Macete

Bruce Macrae

Almoustapha Maiga

Rajhmun Mandansein

Neil Martinson

Bongani Mayosi

Leonard Mboko

Tim McHugh

Clara Menendez

Sayoki Mfinanga

Elirehema Mfinanga

Emma Morris

Modest Mulenga

Paula Munderi

Peter Mwaba

Maddy Noursadeghi

Francine Ntoumi

Thomas Nyirenda

Matt Oliver

Nesri Padayatchi

Eskild Petersen

Shreemanta Parida

Niaina Rakotosamimanana

Gita Ramjee

Voahangy Rasolof

Klaus Reither

James BW Russell

Roxana Rustomjee

Ian Sanne

Aziz Sheik

Nalini Singh

Andrie Steyn

Leopold Tientcheu

Cristina Vilaplana

Robert S. Wallis

Christian Wejse

Robert J Wilkinson

Dorothy Yeboah-Manu

Markus Maeurer

The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR-TB, and those with co-morbidity of TB with HIV and NCDs, in sub-Saharan Africa is unacceptable [1-5]. New innovations for shortening duration of therapy, improving treatment outcomes, preventing relapse, reducing drug resistance, and preventing long term lung damage, are urgently required [2,3,6]. The TB drug pipeline remains sparse [4,6]. A broad of range of Host Directed Therapies (HDT) now provide hope for improving treatment outcomes and reducing duration of therapy [7-15]. These require evaluation in randomized, placebo-controlled clinical trials (RCTs) as adjuncts to current TB treatment regimens.

The objectives of HDT-NET are:

1. To evaluate in RCTs a range of Adjunct Host Directed Therapies (see list) for:

a). Shortening duration of treatment for:

   i). drug sensitive TB (DS-TB).

   ii). multi-/extensively drug resistant TB (MDR-TB/XDR-TB).

b). Improving treatment outcomes (mortality/morbidity) for MDR/XDR-TB patients.

c). Improving treatment outcomes for specific clinical conditions associated with tissue injury:

   i). HIV co-infected individuals with DS-TB and MDR/XDR-TB.

   ii). TB pericarditis.

   iii).Miliary TB and TB meningitis.

   iv).TB-associated Immune Reconstitution inflammatory syndrome (IRIS).

d). Preventing recurrence of TB or relapse or TB drug resistance.

e). Reducing excessive lung inflammation and preventing long term lung matrix destruction

and complications.

f). Improving treatment outcomes of people with co-morbidities such as NCDs (eg diabetes

COAD, any cancers, NIDs. This will create a more holistic approach for high quality care.

HDT could also benefit cancer services in Africa.


2. To develop high quality clinical trials and laboratory infrastructure at all African partner

sites irrespective of current capabilities

This will include staffing, infrastructure, facilities for cell and culture, immunology,

mycobacteriology including drug sensitivity testing, diagnostics, data entry/storage,

protocol harmonization, communication, biobanking, end user involvement, ethics,

continuing professional development, and networking with other trials consortia.


3. To produce a high calibre cadre of African researchers (scientists, health and laboratory personnel) who will be suitably empowered to take leadership and conduct of high quality research and clinical trials. 


At each site, a range of postdocs, PhDs, Masters and Diploma students will be mentored closely aligned to the design and development of clinical trials, cohorts and biobanks. The multidisciplinary consortium will allow for access to a broader range of expertise training and supervision, wider knowledge and resource acquisition and enable trials of other PRDs to be hosted in each country.


For correspondence please contact:

Alimuddin Zumla MD.PhD, University College London, UK. Email: a.zumla@ucl.ac.uk

Markus Maeurer MD.PhD, Karolinska Institute, Stockholm, Sweden Email: Markus.Maeurer@ki.se

HDT-NET Publications

Host-Directed Therapies for Tackling Multi-Drug Resistant Tuberculosis: Learning From the Pasteur-Bechamp Debates. Zumla A, Maeurer M; and the Host-Directed Therapies Network (HDT-NET) Consortium; and the Host-Directed Therapies Network HDT-NET Consortium. Clin Infect Dis. 2015 Jul 28.

Towards host-directed therapies for tuberculosis. Zumla A, Chakaya J, Hoelscher M, Ntoumi F, Rustomjee R, Vilaplana C, Yeboah-Manu D, Rasolof V, Munderi P, Singh N, Aklillu E, Padayatchi N, Macete E, Kapata N, Mulenga M, Kibiki G, Mfinanga S, Nyirenda T, Maboko L, Garcia-Basteiro A, Rakotosamimanana N, Bates M, Mwaba P, Reither K, Gagneux S, Edwards S, Mfinanga E, Abdulla S, Cardona PJ, Russell JB, Gant V, Noursadeghi M, Elkington P, Bonnet M, Menendez C, Dieye TN, Diarra B, Maiga A, Aseffa A, Parida S, Wejse C, Petersen E, Kaleebu P, Oliver M, Craig G, Corrah T, Tientcheu L, Antonio M, Rao M, McHugh TD, Sheikh A, Ippolito G, Ramjee G, Kaufmann SH, Churchyard G, Steyn A, Grobusch M, Sanne I, Martinson N, Madansein R, Wilkinson RJ, Mayosi B, Schito M, Wallis RS, Maeurer M.

Nat Rev Drug Discov. 2015 Jul 17.

Cellular therapy in Tuberculosis. Parida SK, Madansein R, Singh N, Padayatchi N, Master I, Naidu K, Zumla A, Maeurer M. Int J Infect Dis. 2015 Mar;32:32-8.

Host-directed therapies for tuberculous pericarditis. Zumla A, Maeurer M, Moll G, Mayosi BM. Int J Infect Dis. 2015 Mar;32:30-1.

Host-directed therapy: tuberculosis vaccine development. Rao M, Zumla A, Maeurer M. Lancet Respir Med. 2015 Mar;3(3):172-3.

Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options. Zumla A, Memish ZA, Maeurer M, Bates M, Mwaba P, Al-Tawfiq JA, Denning DW, Hayden FG, Hui DS. Lancet Infect Dis. 2014 Nov;14(11):1136-49

Progress in tuberculosis vaccine development and host-directed therapies--a state of the art review. Kaufmann SH, Lange C, Rao M, Balaji KN, Lotze M, Schito M, Zumla AI, Maeurer M. Lancet Respir Med. 2014 Apr;2(4):301-20.

Inflammation and tuberculosis: host-directed therapies. Zumla A, Rao M, Parida SK, Keshavjee S, Cassell G, Wallis R, Axelsson-Robertsson R, Doherty M, Andersson J, Maeurer M. J Intern Med. 2015 Apr;277(4):373-87.

New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects. Zumla AI, Gillespie SH, Hoelscher M, Philips PP, Cole ST, Abubakar I, McHugh TD, Schito M, Maeurer M, Nunn AJ. Lancet Infect Dis. 2014 Apr;14(4):327-40.

Advances in the development of new tuberculosis drugs and treatment regimens. Zumla A, Nahid P, Cole ST. Nat Rev Drug Discov. 2013 May;12(5):388-404.

References

1. Maeurer M, Schito M, Zumla A. Totally-drug-resistant tuberculosis: hype versus hope. Lancet Respiratory Medicine. 2014 Apr;2(4):256-7.

2. Abubakar I, Zignol M, ..Maeurer M, Schito M, Zumla A. Drug-resistant tuberculosis: time for visionary political leadership. Lancet Infectious Diseases 2013 Jun;13(6):529-39.

3. Zumla A, Abubakar I, Raviglione M, Hoelscher M, Ditiu L, McHugh TD.., Maeurer M, Atun R. Drug-resistant tuberculosis--current dilemmas, unanswered questions, challenges, and priority needs. J Infectious Diseases 2012 May 15;205 Suppl 2:228-40.

4. Zumla A, Chakaya J, Centis R, D’Ambrosio L, Mwaba P, Bates M, Kapata N, Nyirenda T, Chanda D, Mfinanga S, Maeurer M, Hoelscher M, Migliori GB. Tuberculosis treatment and management- an update on treatment regimens, trials, new drugs and adjunct therapies. Lancet Respiratory Medicine 3:Mar 2015: 220-234.

5. Zumla A, Memish ZA, Maeurer M, Bates M, Mwaba P,…, Hui DS. Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options. Lancet Infectious Diseases 2014 Nov;14(11):1136-49.

6. Zumla A, Nahid P, Cole ST. Advances in the development of new tuberculosis drugs and treatment regimens. Nature Reviews Drug Discovery 2013 May;12(5):388-404.

7. Zumla A, Maeurer M. Rational development of adjunct immune-based therapies for drug-resistant tuberculosis: hypotheses and experimental designs. J Infectious Diseases 2012 May 15;205 Suppl 2:S335-9.

8. Parida S, Madansein R, Singh N, Padayatchi N, Master I, Naidu R, Zumla A, Maeurer M. Cellular therapy in tuberculosis. International Journal of Infectious Diseases. 2015: Mar;32:32-8.

9. Zumla A, Rao M, Parida SK, Keshavjee S, Cassell G, Wallis R, Axelsson-Robertsson R, Doherty M, Andersson J, Maeurer M. Inflammation and tuberculosis: host-directed therapies. Journal of Internal Medicine. 2014 Apr 10. doi: 10.1111/joim.12256.

10. Maeurer M, Zumla A. The host battles drug-resistant tuberculosis. Science Translational Medicine. 2014 Nov 19; 6(263):263fs47.

11. Skrahin A, Ahmed RK, Ferrara G, Rane L, Poiret T, Isaikina Y, Skrahina A, Zumla A, Maeurer MJ. Autologous mesenchymal stromal cell infusion as adjunct treatment in patients with multidrug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial. Lancet Respiratory Medicine 2014 Feb;2(2):108-22.

12. Parida SK, Axelsson-Robertson R, Rao M, Singh N, Master I, Lutckii A, Keshavjee S, Andersson J, Zumla A, Maeurer M. Totally drug-resistant tuberculosis and adjunct therapies. Journal of Internal Medicine. 2014 May 8. doi: 10.1111/joim.12264.

13. Zumla A, Maeurer M, Moll G, Mayosi B. Host-directed therapies for tuberculous pericarditis. International Journal of Infectious Diseases. 2015: -Mar;32:30-1.

14. Kaufmann SH, Lange C, Rao M, Balaji KN, Lotze M, Schito M, Zumla A, Maeurer M. Progress in tuberculosis vaccine development and host-directed therapies--a state of the art review. Lancet Respiratory Medicine 2014 Apr;2(4):301-20.

15. Uhlin M, Andersson J, Zumla A, Maeurer M. Adjunct immunotherapies for tuberculosis. J. Infectious Diseases 2012;205 Suppl 2:325-34.

16. Phillips PP, Gillespie SH, Boeree M, ..Hafner R, Mgone C, Zumla A, Nunn AJ, Hoelscher M. Innovative trial designs are practical solutions for improving the treatment of tuberculosis. Journal of Infectious Diseases 2012 May 15;205 2:250-7.

17. Rao M, Zumla A, Maeurer M. Host-directed therapy: tuberculosis vaccine development. Lancet Respiratory Medicine 2015 Mar;3(3):172-3.

18. Maeurer M, Rao M, Zumla A. Host directed therapies (HDTs) and immune response signatures: insights into a role for

Interleukin-32. Annals of Translational Medicine: 2015 –in press.


Other reading


Bento CF, Empadinhas N, Mendes V. Autophagy in the fight against tuberculosis. DNA Cell Biol. 2015

Apr;34(4):228-42.

Elkington PT, D'Armiento JM, Friedland JS.TB immunopathology: the neglected role of extracellular matrix destruction.

Sci Transl Med. 2011 Feb 23;3(71):71ps6

Wallis RS, Hafner R. Advancing host-directed therapy for tuberculosis. Nat Rev Immunol. 2015 Apr;15(4):255-63.