DRUG RESISTANT TUBERCULOSIS: AN HISTORICAL OVERVIEW

Transcription

1 DRUG RESISTANT TUBERCULOSIS: AN HISTORICAL OVERVIEW SALMAAN KESHAVJEE MD, PhD, ScM JULY 10,

2 DRUG-RESISTANT TUBERCULOSIS: AN HISTORICAL OVERVIEW SALMAAN KESHAVJEE, MD, PhD, ScM PARTNERS IN HEALTH BRIGHAM AND WOMEN S HOSPITAL HARVARD MEDICAL SCHOOL TB CARE II DR-TB TRAINING COURSE BOSTON, MASSACHUSETTS, USA JULY 10, 2012

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4 Selman Waxman 1943 Streptomycin isolated in laboratory of Selman Waxman 1944 Shown to be active against Mycobacterium tuberculosis 1944 Given to the first human TB patient in November 1944

5 Other TB drugs: 1948 para-aminosalicylic acid (PAS) 1948 thioacetazone 1951 isonicotinic hydrazide (INH) 1952 pyrazinamide 1952 cycloserine 1957 rifampin 1962 ethambutol

6 Drug resistance: a surprise? 1942 Rene Dubos hypothesized that selection would occur with the use of antibiotics 1943 Salvador Luria and Max Delbruck demonstrated that random genetic mutations occur even in the absence of selection Salvador Luria and Max Delbruck

7 First observation: Drug resistance emerged with each new drug used and less drug resistance was observed when drugs were used in combination High relapse rate in the first 100 patients treated with streptomycin; isolates found to be resistant to streptomycin o When streptomycin given with PAS, less relapse and less development of resistance Rapid selection of INH resistant strains when INH used alone o When INH given with streptomycin, less INH resistance observed Rifampin resistance observed as soon as it was used

8 Second observation: Resistant strains from patients retained their ability to be transmitted to others Streptomycin resistant strains could be transmitted First national drug-resistance survey in Britain was conducted in Found primary drug resistance to streptomycin, PAS and INH In the U.S., primary INH resistance increased from 6.3% in the early 1960s to 9.7% in the late 1960s No tendency towards reversion to lower degrees of resistance

9 Third observation: When patients were started on an effective treatment regimen, they were less infectious Relative infectivity of patients*: Susceptible TB 61 Untreated (29 GPs) 100% 29 Treated (1 GP) 2% Riley Experimental TB Ward, Drug-resistant TB 6 Untreated (14 GPs) 28% 11 Treated (6 GPs) 5% *all smear positive patients, relative to the amount of time on the ward Source: Richard Riley, et al. Am J Hyg 1959; 70: (reprinted as classic Am J Epidemiol 1995; 142:3-14)

10 Basic principles of treatment Safest, most effective therapy in the shortest time Multiple drugs 1/10 6 organisms naturally resistant to one drug Each cavity has 10 9 to organisms Ensure adherence to therapy with direct observation

11 Short-course chemotherapy for tuberculosis First-line INH (H) RIF (R) SIX MONTHS SIX MONTHS EMB (E) PZA (Z) TWO MONTHS TWO MONTHS 2HREZ / 4HR

12 QUIZ NUMBER ONE

13 TB Funding History US Public Health Service & United States Centers for Disease Control and Prevention * $ Millions Categorical Grants Ceased '48 '52 '56 '60 '64 '68 '72 '76 '80 '84 '88 '92 '96 '00 '04 '08 Adapted from: Dr. Ken Castro, U.S. Centers for Disease Control and Prevention, Presentation, Harvard University, June 2012

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16 DOTS and the World Health Organization Source: Dr. Jim Kim, Dartmouth University

17 IDEAS ENSHRINED IN DOTS 1. Political commitment 2. Diagnosis with sputum-smear microscopy 3. Standardized short-course chemotherapy 4. Regular supply of high-quality drugs 5. Standardized recording and reporting

18 MDR-TB: DIVERGENCE IN TREATMENT FOR RICH AND POOR COUNTRIES

19 TB Funding History US Public Health Service & United States Centers for Disease Control and Prevention * $ Millions Categorical Grants Ceased '48 '52 '56 '60 '64 '68 '72 '76 '80 '84 '88 '92 '96 '00 '04 '08 Adapted from: Dr. Ken Castro, U.S. Centers for Disease Control and Prevention, Presentation, Harvard University, June 2012

20 Diagnosis using mycobacterial culture Access to quality-assured second-line anti-tb medications Proper infection control Delivery of care under direct observation, with management of adverse events

21 Poor Infection Control Evidence suggests that in NYC and San Francisco, at least 25% of TB cases due to recent transmission CDC examined 4 hospitals (three in NYC and one in Miami) for infection control. Found risk of getting MDR-TB for inpatients compared to outpatients were as follows: Hospital A: OR=26.1 Hospital B: OR=36.4 Hospital C: OR=7.6 Hospital D: OR=42.8 Sources: Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City turning the tide. NEJM 1995; 333(4): Bifani PJ, Plikaytis BB, Kapur V, et al. Origin and interstate spread of a New York City Multidrug-resistant Mycobacterium tuberculosis clone family. MMWR, Nosocomial Transmission of multidrug-resistant tuberculosis among HIV-infected persons Florida and New York,

22 The WHO/ IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance The 1st Global report covered 35 countries/geographic settings 2000 The 2nd Global report covered 58 countries/geographic settings 2003 The 3rd Global report covers 77 countries/ geographic settings 2008 The 4th Global report covers 93 countries/geographic settings

23 MDR-TB is too expensive to treat in poor countries; it detracts attention and resources from treating drug-susceptible disease. - World Health Organization Groups at Risk, 1996 Photo: Open Society Institute/Pep Bonet

24 best practice SCC may even reduce the incidence of MDR-TB where it has already become endemic - Dye et al. Science 2002 Photo: Open Society Institute/Pep Bonet

25 1996 MDR-TB treatment initiated in Lima s Northern Cone by Partners In Health and Harvard Medical School, with Peru s National TB Program 1998 Major policy meeting held in Cambridge, Massachusetts Creation of DOTS-Plus framework; Five initial pilot projects Photo: Partners In Health/Socios En Salud

26 The creation of a new technical mechanism to promote treatment of MDR-TB: Make drugs available Help projects successfully treat MDR-TB

27 Photo: James Nachtwey, XDRTB.org Where are we today with drug-resistant tuberculosis?

28 Photo: James Nachtwey, XDRTB.org Few patients have been treated using existing mechanisms 10 YEAR PICTURE ( ) ~5 million cases 3.5 million patients No treatment reported. Some treatment probably obtained, quality unknown. Continued transmission 0.5% Treated in GLC approved programmes 1.5 million patients DEAD

29 Drug prices have increased and are too much for some countries to afford Source: MSF/IUATLD 2011

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31 Many countries do not have the capacity to address the high burden of resistant disease Photo: James Nachtwey, XDRTB.org Source: Keshavjee and Farmer, IJTLD, 2010

32 There is limited capacity to diagnose patients with drug resistant disease Photo: James Nachtwey, XDRTB.org Source: WHO, Tuberculosis Control Report, 2010

33 New data from Minsk, Belarus The disease continues to spread in many settings Photo: James Nachtwey, XDRTB.org Results: Multidrug-resistant tuberculosis was found in 35.3% (95%CI: ) of new patients and 76.5% (95%CI: ) of those previously treated. Overall nearly one in two patients enrolled had multidrugresistant tuberculosis. Extensively drugresistant tuberculosis was found in 15 of the 107 multidrug-resistant tuberculosis patients (14.0%; 95%CI: ). Patients under 35 years old have shown a 2 times higher odds of MDR-TB than those 35 and older. Skrahina et al., European Respiratory Journal (e-pub Oct 20 th, 2011)

34 Source: WHO, Global Progress Report, 2011

35 QUIZ NUMBER TWO Photo: Open Society Institute/Pep Bonet

36 This presentation has been developed by the TB CARE II project and is made possible by the generous support of the American people through the United States Agency for International Development.