Mahidol-Oxford Tropical Medicine Research Unit (MORU) QuickTime and - PowerPoint PPT Presentation

Mahidol-Oxford Tropical Medicine Research Unit (MORU) QuickTime™ and a QuickTime™ and a TIFF (Uncompressed) decompressor TIFF (Uncompressed) decompressor are needed to see this picture. are needed to see this picture. 1979 – 2007

MORU - Aim To develop effective, practical means of diagnosing and treating tropical infections responsible for significant morbidity and mortality in the populous rural areas of Southeast Asia and elsewhere.

Strategic position…. Half of the world’s population within 2000 miles….

Methods 1. Clinical epidemiology 2. Pathophysiology of the disease and pathobiology of the pathogen 3. Diagnosis - developing and testing new tests 4. Pharmacokinetic and pharmacodynamic studies 5. Clinical trials 6. Dissemination and translation

Paradigm of large, multi-centre clinical trials • Severe malaria – SEAQUAMAT – AQUAMAT • Melioidosis – Thailand Melioidosis Clinical Trials Group – MERTH – ATOM • Scrub typhus – Vientiane + Udon Thani • Haemofiltration vs Haemodialysis (planned) – India + Viet Nam

Hub and Spoke topology…

MORU - 2007 Bangkok Unit Major field site / laboratory Laos project field site Collaborator’s site Mozambique AQUAMAT collaborative sites Sri Lanka

‘Thailand’ Unit - Clinical Study Sites Clinical study site Collaborative site

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MORU - Staff • 210 host country staff • 27 international staff – 8 British – 4 Dutch – 3 Swedish – 2 Americans – 2 Australians – 2 French – 1 Swiss – 1 Polish – 1 Japanese – 1 Singaporean – 1 Burmese – 1 Canadian

Diseases Malaria Melioidosis Rickettsial illnesses Staphylococcal infections Leptospirosis Cryptococcal meningitis Beriberi Dengue Typhoid Acute respiratory infections

Unit Publications Other Snake bite Other micro Melioidosis Malaria 1981 - 2004 2005-2006

Current treatment recommendations for - Uncomplicated malaria - Severe malaria - Malaria in pregnancy SMRU SEAQUAMAT

Treatment of severe malaria

IV Artesunate vs IV Quinine multi- centre trial in Asia - ‘SEAQUAMAT’ • Can we lower the mortality of severe malaria by using artesunate rather than quinine?

SEAQUAMAT Study sites

SEAQUAMAT Overall 35% (19% to 48%) reduction in mortality with artesunate

SEAQUAMAT ‘Numbers needed to treat’ (NNT) • Burma 12.6 (7.3 to 45) • Bangladesh 11.1 (5.8 to 121) • India 21.2 • Indonesia 16.6

‘Artesunate is the recommended first choice in areas of low malaria transmission’ ‘In pregnant women…. artsunate is the first and artemether the second option in the 2nd and 3rd trimesters’ ‘In the first trimester, until more evidence becomes available, both artesunate and quinine may be considered as options’

AQUAMAT • Artesunate vs quinine in African children with severe malaria • Powered to detect a 25% reduction in mortality from 8% to 6% • Sample size: 5,306 • Aiming for 12 sites in 8 countries • Funded by the Wellcome Trust

AQUAMAT • Mozambique - 1 sites • Kenya - 2 sites • The Gambia - 1 sites • Ghana - 1 site • Tanzania - 3 sites • Uganda - 1 site • Rwanda - 2 sites • Nigeria - 2 sites

AQUAMAT - Current status • Sites actively recruiting now – Mozambique - Beira – Ghana - Kumasi – Kenya - Kilifi – The Gambia - Banjul – Tanzania - Muheza & Korogwe • 1,236 cases recruited as of 6/9/07 • 123 deaths (10%)

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AQUAMAT - Current status • Sites actively recruiting now – Mozambique - Beira – Ghana - Kumasi – Kenya - Kilifi – The Gambia - Banjul – Tanzania - Muheza & Korogwe • 1,331 cases recruited as of 1/10/07 • 133 deaths (10%)

Levamisole in severe malaria • Chittagong Medical College • Pilot study • Outcome markers: – Serial parasite staging – Cytoscan – Lactate clearance • 30 patients randomised so far…

Fake antimalarials

Drug resistance

Developments 2006-2007 Artemisinin resistance? • West Africa - in vitro evidence?? • Cambodia – prolonged PCT – Currently under investigation • Artemisinin resistance would be a colossal disaster…

Pailin, SW Cambodia QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.

Pharmacology

The new pharmacology laboratory January 2007

Pharmacology Developments 2006-2007 • Development of new assays for: – Amoxycillin – Piperaquine • Plasma • Blood spots • Urine • High throughput – Lumefantrine - high throughput – Oseltamivir – Zanamivir – Artesunate / DHA • Piperaquine – Identification of metabolites – Identification of major manufacturing impurity • New method for assessing regression models for standard curves

PK studies in disease • In pregnancy – Amodiaquine – Arthemether-lumefantrine (levels reduced in pregnancy) – Artesunate • In uncomplicated malaria – Artesunate (Pailin) – Lumefantrine (OD dosing inadequate) – Piperaquine (OD dosing OK) • In melioidosis – Co-amoxiclav • In avian and severe seasonal influenza (SEA001) – Oseltamivir

Effect of loading dose – 1.5x (red), 2x (green) maintenance. Dose = 75mg / 12h. Effect of probenecid (orange). Dose = 75mg /24h. Ka different for the first dose. OC concentration (ng/ml) Time (h) Largest and most detailed pharmacokinetic evaluation of oseltamivir; 4 different doses, loading dose, probenecid ~1800 samples

Microbiology

Fever studies • Completed – Vientiane – Udon Thani – Nepal • Ongoing – Thai-Burmese border – Chiang Rai – Siem Riep – Colombo

Fever studies - major findings • Leptospirosis - common in rural areas • Rickettsial diseases – Scrub typhus – Murine typhus • Dengue and Chikungunya • Main blood culture pathogens variable – Vientiane & Nepal - typhoid – NE Thailand - melioidosis

Diagnostics • Need to be tailored to the region - targeted by fever study • Robust, accurate, cheap • Blood culture – Conventional and specialised (rickettsial, leptospire) • Dipsticks - Ag and Ab detection • PCR – Malaria, scrub and murine typhus, dengue, melioidosis, leptospirosis – Conventional, real time, LAMP • Fluorescence - Ag and Ab detection – Melioidosis, scrub and murine typhus

Dengue rapid tests - overall diagnostic performance n Core Diazyme Globalemed Panbio SD Teco Tulip Minerva Sn 501 22.9 17.8 62.9 65.3 21.8 9.5 6.4 8.6 (18.3-27.6) (13.8-22.4) (57.4-68.1) (59.9-70.5) (17.4-26.7) (6.6-13.2) (4.0-9.7) (5.8-12.2) Sp 501 98.9 97.7 68.0 96.6 98.3 95.4 99.4 100 (95.9-99.9) 94.3-99.4) (60.5-74.8) (92.7-98.7) (95.1-98.7) (91.2-98.0) (96.9-99.9) (97.9-100) PPV 501 97.4 93.6 78.5 97.3 96.0 79.5 95.5 100 (90.8-99.7) (84.3-98.2) (73.1-83.4) (94.1-99.0) (88.6-99.2) (63.5-90.7) (77.2-99.9) (87.7-100) NPV 501 40.7 39.0 49.6 59.9 40.3 36.2 36.3 37.0 (36.0-45.6) (34.4-43.7) (43.1-56.1) (54.0-65.7) (35.6-45.1) (31.8-40.7) (32.0-40.8) (32.6-41.5)

Tsutsugamushi disease (scrub typhus) – Acute febrile illness – Causative agent - Orientia tsutsugamushi – Transmitted to humans by bite of larval stage of Leptotrombidium spp . mite (chigger) – Well suited to antibiotic treatment – Untreated mortality 2% to 36% – No vaccine

O. tsutsugamushi culture - transport from clinical sites Udon Thani Mae sot 565 km 512 km Bangkok

Results - in vitro isolation Udon Thani (UT) Mae Sot (FPW) Patient samples 28 13 ( n=41 ) Isolates 14 3 ( n=17 ) Positivity rate = 41.5% Transit time (days) Median: 2.0* Median: 4.0* Range:1-5 Range: 2-7 Time to isolation (days) Median: 22** Median: 22** Range: 7-37 Range: 22-25 Luksameetanasan et al., 2006 - Monday’s poster session

O. tsutsugamushi MLST

Determining major infectious pathogens affecting rural populations • Fever studies • Development of cheap diagnostics – e.g. ‘fever stick’ • Rickettsial diseases, leptospirosis, dengue • Malaria antigen detection • CRP • Trials to determine appropriate empirical therapy

Leptospirosis in Udon Thani

L. kirschneri 0.00 A 0.01 0.02 ST-37 ST-41 0.03 ST-27 ST-34 Udon Thani Other Thai ST-46 Rodent isolate Reference strain ST-17 ST-49 ST-22 ST-29

G-CSF for severe melioidosis • Randomized, placebo controlled trial, was conducted to assess the efficacy of lenograstim (G-CSF 263 mcg iv daily) in patients with severe sepsis due to suspected melioidosis in Ubon Ratchathani, Thailand, during 2004-2006. • 60 patients were enrolled • Mortality was similar in both groups (G-CSF 70% vs placebo 87%, p=0.2) including 41 patients with confirmed melioidosis (83% vs 96%, p=0.3)

Hazard ratio 0.56 (95%CI 0.31-1.00, p=0.05)