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Current topics in tuberculosis All those news and innovations – in this enough to turn the tide against tuberculosis? Martin P Grobusch

Center for Tropical Medicine and Travel Medicine, Department of Infectious Diseases AMC, University of Amsterdam, Netherlands

Institute of Tropical Medicine University of Tübingen, Germany

Medical Research Unit, Albert Schweitzer Hospital Lambarene Gabon

Institute of Infectious Diseases and Molecular Medicine (IIDMM), University of Cape Town, South Africa

ESCMID Online Lecture Library 25th ECCMID Copenhagen, 26 April 2015 @ by author Tuberculosis: A global emergency

• TB incidence worldwide (2013): ~ 9 mill. million cases

• ~ 1.5 million deaths/year (0.4 mill. HIV+)

• TB mortality rate has fallen by 45% since 1990 and TB incidence rates are falling in most parts of the world • An estimated 37 million lives were saved between 2000 and 2013 through effective diagnosis and treatment • Progress has been made with development and roll-out of novel diagnostics and drugs

ESCMID Online Lecture Library WHO 2014 @ by author

ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture LibraryMcNerney et al. 2012

@ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author Tuberculosis: Novel drugs and treatment strategies

ESCMID Online Lecture Library @ by author Ma et al. Lancet 2010 Tuberculosis: targets of novel drugs

ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author High tuberculosis and HIV coinfection rate, Johannesburg MA John, CN Menezes, G Chita, I Sanne, MP Grobusch Emerging Infectious Diseases, 2007; 13:795-796

• Patients at Helen Joseph Hospital in Johannesburg, SA

• Academic teaching hospital with a >500 k catchment area of predominantly poor people

 270 (95 %) of 284 TB ESCMIDpatients HIV coinfected Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author Managing TB and HIV/AIDS together!

ESCMID Online Lecture Library @ by author • MDR TB: defined as MTB resistant against  isoniazid (INH)  rifampicin (RIF)

• XDR: MDR-TB plus resistance to

 any fluoroquinolone and  at least 1 of 3 injectables (ami-, kana- ESCMID or capreomycin) Online Lecture Library

@ by author • MDR TB: defined as MTB resistant against  isoniazide (INH)  rifampicin (RIF)

• XDR: MDR-TB plus resistance to

 any fluoroquinolone and  at least 1 of 3 injectables (ami-, kana- ESCMID or capreomycin) Online Lecture Library

@ by author ESCMID Online Lecture Library @ by author Lancet November 2006 ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author XDR-TB: Therapy – but how?

• Group 1 (1st line oral) • HD-Isoniazid, Rifampicin, Ethambutol, Pyrazinamide • Group 2 (injectable) • Streptomycin, Kanamycin, Amikacin, Capreomycin • Group 3 (Fluoroquinolones) • Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxacin, Gatifloxacin • Group 4 (oral bacteriostatic 2nd line) Ethionamide/Protionamide, Cycloserine/Terizidone, P-aminosalicylic acid, Thioacetazone • Group 5 (unclear efficacy) Clofazimine,ESCMID Amoxicillin/Clavulanate, Online Lecture Clarithromycin, Library Linezolid

@ by author XDR-TB: Therapy – but how?

• Group 1 (1st line oral) HD-Isoniazid, Rifampicin, Ethambutol, Pyrazinamide • Group 2 (injectable) Streptomycin, Kanamycin, Amikacin, Capreomycin • Group 3 (Fluoroquinolones) Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxazin, Gatifloxazin • Group 4 (oral bacteriostatic 2nd line) Ethionamide/Protionamide, Cycloserine/Terizidone, P-aminosalicylic acid, Thioacetazone • Group 5 (unclear efficacy) Clofazimine,ESCMID Amoxicillin/Clavulanate, Online Lecture Clarithromycin, Library Linezolid @ by author XDR-TB: Therapy – but how?

• Group 1 (1st line oral) HD -Isoniazid, Rifampicin, Ethambutol, Pyrazinamide • Group 2 (injectable) Streptomycin, Kanamycin, Amikacin, Capreomycin • Group 3 (Fluoroquinolones) Ciprofloxacin, Ofloxacin, Levofloxacin, Moxifloxazin, Gatifloxazin • Group 4 (oral bacteriostatic 2nd line) Ethionamide/Protionamide, Cycloserine/Terizidone, P-aminosalicylic acid, Thioacetazone • Group 5 (unclear efficacy) Clofazimine,ESCMID Amoxicillin/Clavulanate, Online Lecture Clarithromycin, Library Linezolid @ by author XDR-TB in Gauteng Province - Statistics for first 6 months of 2008 -

• Total number of patients diagnosed in the Province 54 • Total number of patients discharged 10 • Total number of deaths in hospital 13 • Total number of deaths outside the hospital 5 (before admission at Sizwe) • Total number of in-patients at present 21 • Transfers to other provinces 3 • Number of patients absconded 2 (1to Lesotho, 1 to KZN) • ESCMIDNumber of re-admissions Online (included Lecture in the 21 in-patients)Library 3

@ by author XDR-TB in Gauteng Province - Statistics as on 02 July 2008 -

• Total number of patients diagnosed in the Province 54 • Total number of patients discharged 10 • Total number of deaths in hospital 24 % 13 • Total number of deaths outside the hospital 5 (before admission at Sizwe) • Total number of in-patients at present 21 • Transfers to other provinces 3 • Number of patients absconded 2 (1to Lesotho, 1 to KZN) •ESCMID Number of re-admissions Online (included Lecture in the 21 in-patients)Library 3

@ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library Lancet May 2010 @ by author Key results (1) Dheda et al. Lancet 2010

DeathsESCMID in HIV-coinfected 34/82Online (41%) vs. 28/92Lecture (30%) in HIV-neg. Library (p=0.3) Significantly@ less by deaths author by HAART-treated HIV patients (p=0.2) Key results (2) Dheda et al. Lancet 2010

ESCMID Online Lecture Library 33/174 patients culture converted, of which 23/33 (70%) within 6 months @ by author Key results (2) Dheda et al. Lancet 2010

ESCMID Online Lecture Library 33/174 patients culture converted, of which 23/33 (70%) within 6 months @ by author ESCMID Online Lecture Library @ by author Severe None or mild to moderate

ESCMID Online Lecture Library @ by author The issue of culture re-conversion

ESCMID Online Lecture Library @ by author Janssen S et al. JCM 2013 Marais et al Infection 2013 ESCMID Online Lecture Library @ by author

ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author The strain seems to become more important with the level of care provided

ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author “There are no randomized studies assessing the added benefit of surgical resection over antituberculosis chemotherapy alone.”

“...It appears that surgery for MDR/XDR-TB can provide additional treatment benefit in selected patients...”

ESCMID DaleyOnline & Caminero Lecture 2013 Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author Centre de Recherches Médicales de Lambaréné, Gabon

ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author Lambaréné – (very basic) TB epidemiology

• 182 patients included (since June 2012) • Demography: • 153 adults (84%), 29 children (16%), 99 male (54%) • HIV status: 37% +, 56% -, 7% unknown • Pulmonary TB 93%, EPTB 7% • Follow up (n=88): • 48% treatment completed • 16% default, 19% lost to follow up ESCMID• 13% deceased, all OnlineHIV + Lecture Library • 5% treatment failure @ by author Bélard et al. unpublished data

DST – 1st line drugs

71 DSTs performed:

• Sensitive to all first line drugs 59/71; 83% • INH mono-resistance 4/71; 6% • Streptomycin mono-resistance 3/71; 4% • INH + streptomycin resistance 1/71; 1% • MDR 4/71; 6%

ESCMID Online Lecture Library @ by author 2nd/3rd line TB drugs available in Gabon – Amikamycin/ kanamycin/ capreomycin – Clarithromycin – Ciprofloxacin – Cycloserine – Ethionamide – Ofloxacin – Moxifloxacin – PAS – Levofloxacin – Terizidone – Thioacetazone ESCMID– Imipenem Online Lecture Library – Linezolid @ by author Bélard et al. 2014

2nd/3rd line TB drugs available in Gabon – Amikamycin/ kanamycin/ capreomycin – Clarithromycin – Ciprofloxacin – Cycloserine – Ethionamide – Ofloxacin – Moxifloxacin – PAS – Levofloxacin – Terizidone – Thioacetazone ESCMID– Imipenem Online Lecture Library – Linezolid @ by author Bélard et al. 2014

ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author NL - 5.59/100.000 D – ESCMID 5.30/100.000 Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library @ by author ESCMID Online Lecture Library WHO 2006 @ by author ESCMID Online Lecture Library @ by author Thank you!

ESCMID Online Lecture Library @ by authorTak!