MDR to XDR tuberculosis: Is evolution winning?

Transcription

1 University of Michigan School of Public Health Center for Health Preparedness 2010 Symposium : Can the World be TB Free MDR to XDR tuberculosis: Is evolution winning? UTSPH Brownsville has 9 faculty and about 45 staff. 350 miles south of Houston Joseph B. McCormick, MD Regional Dean and James Steele Professor University of Texas School of Public Health Brownsville Regional Campus This is the ecology of tuberculosis, where it lives, spreads and becomes drug resistant and it is where evolution plays its inlassable game. Joseph McCormick, MD, MS 1

2 A Brief History of TB Tuberculosis Is an Ancient Disease Identified in Egyptian Mummies History dates to BC Identified by PCR Source:Dr.T.V.Rao MD Joseph McCormick, MD, MS 2

3 The scientific academies noted that the triumphant discovery of 1882 was followed by a succession of failures: first of all, the failed attempt to present tuberculin as a remedy against tuberculosis in , 9, which severely e e damaged Koch's reputation Medical History, 2001, 45: 1 32 CHRISTOPH GRADMANN* Source:Dr.T.V.Rao MD (Attenuated strain Mycobacterium Calmette and Guerin) Vaccine (BCG) Bovis 1943 Streptomycin discovered by Selman Abraham Waksman 20th November 1944: Injections dramatically recovers patients with Tuberculosis Source:Dr.T.V.Rao MD Joseph McCormick, MD, MS 3

4 Source:Dr.T.V.Rao MD Combination therapy of INH and PZA cures TB 1955 Cycloserine 1962 Ethambutol 1963 Rifampicin Combination of Rifampicin and Isoniazid adopted as International regime for treatment of TB Source:Dr.T.V.Rao MD Joseph McCormick, MD, MS 4

5 Multidrug and extensively drug resistant TB (M/XDR TB) 2010 GLOBAL REPORT ON SURVEILLANCE AND RESPONSE WHO Drug resistant tuberculosis now at record levels 18 MARCH 2010 GENEVA World Health Organization (WHO) Multidrug and Extensively Drug Resistant Tuberculosis: 2010 Global Report on Surveillance and Response. In some areas of the world, one in four people with tuberculosis (TB) becomes ill with a form of the disease that can no longer be treated with standard drug regimens, Drug resistant tuberculosis (TB) is spreading to more areas Drug resistant tuberculosis (TB) is spreading to more areas across the globe, with China and India accounting for almost half of those infected by strains that don t respond to standard treatment, Joseph McCormick, MD, MS 5

6 How Quickly Things Change! Joseph McCormick, MD, MS 6

7 Years Urban Population (billions) More Developed Regions Less Developed Regions Billions of People What is the nature of the problem? So what is in our arsenal now? Joseph McCormick, MD, MS 7

8 3 Groups depending upon the degree of effectiveness and potential side effects First Line: (Primary agents) are the most effective and have lowest toxicity. Isoniazid Rifampin Second Line: Less effective and more toxic effects include (in no particular order): p-amino salicylic acid, Streptomycin, Ethambutol Third Line are least effective and most toxic. Amikacin, Kanamycin, Capreomycin, Viomycin, Kanamycin, Cycloserine MDR TB caused by strains of Mycobacterium Tuberculosis resistant both Rifampicin and Isoniazid with or without resistance to other drugs. Single Isoniazid or Rifampicin resistance is not MDR TB MDR TB is a laboratory diagnosis Source:Dr.T.V.Rao MD Joseph McCormick, MD, MS 8

9 Primary (Initial) resistance TB patient s initial Mycobacterium tuberculosis population resistant to drugs Secondary (Acquired) resistance Drug resistant M. tuberculosis in initial population selected by inappropriate p drug use (inadequate treatment or non adherence) Joseph McCormick, MD, MS 9

10 Resistance is a man made amplification of a natural phenomenon. Inadequate drug delivery is main cause of secondary drug resistance. Secondary drug resistance is the main cause of primary drug resistance due to transmission i of resistant strains. MDR due to spontaneous mutations is not possible as the genes encoding resistance for anti TB are unlinked. Average eagemutation Rate in M. tuberculosis s H 2.56*10 8 mutations per 1 bacterium /generation R 2.25*10 10 mutations per 1 bacterium / generation Eth 1.0*10 7 mutations per 1 bacterium / generation S 2.95*10 8 mutations per 1 bacterium / generation H +R 2.56*10 10 X 2.25*10 10 = 5.76*10 18 Joseph McCormick, MD, MS 10

11 Pulmonary cavities contain about 10 7 to 10 9 bacilli; thus, they are likely to contain a small number of bacilli resistant to each of the antituberculosis drugs but unlikely to contain bacilli resistant to two drugs simultaneously. The expected ratio of resistant bacilli to susceptible bacilli in an unselected population of M. tuberculosis: 1:10 6 for H 1:10 6 for S 1:10 8 for R 1:10 14 both for Hand R Joseph McCormick, MD, MS 11

12 INH RIF PZA H R Z INH H H H H H H First-line Second-line Third-line Isoniazid Injectable Rifampin Ethambutol Pyrazinamide Streptomycin Kanamycin Amikacin Capreomycin Quinolone Ofloxacin Ciprofloxacin Moxifloxacin Other 2 nd -line Ethionamide Cycloserine PAS Other agents AMX/CLV Clofazimine Clarithromycin Source : Partners in Health Source : Partners in Health Joseph McCormick, MD, MS 12

13 First-line Second-line Third-line Isoniazid Injectable Rifampin Ethambutol Pyrazinamide Streptomycin Kanamycin Capreomycin Quinolone Ofloxacin Moxifloxacin Other 2 nd -line Ethionamide Cycloserine PAS Other? agents AMX/CLV Clofazimine Clarithromycin Source : Partners in Health First-line Second-line Third-line INH (H) Injectable RIF (R) EMB (E) PZA (Z) SM KM AMK CM Quinolone OFLOX CIPRO MOXI Other 2 nd -line ETH CS PAS Other agents AMX/CLV Clofazamine Clarithromycin Resistant to the most effective first-line drugs (INH and RIF) Need aggressive management of side effects Requires 18 to 24 months of treatment given under direct observation and with assistance Joseph McCormick, MD, MS 13

14 Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB. XDR TB is defined as TB which is resistant to isoniazid and rifampin, plus resistant to any fluoroquinolone and at least one of three injectable second line drugs (i.e., amikacin, kanamycin, or capreomycin). Joseph McCormick, MD, MS 14

15 Because XDR TB is resistant to first line and secondline drugs, patients are left with treatment options that are much less effective. XDR TB is of special concern for persons with HIV infection or other conditions that can weaken the immune system. These persons are more likely to develop TB disease once they are infected, and also have a higher risk of death once they develop TB. Is Evolution Winning? i Joseph McCormick, MD, MS 15

16 Drug susceptible TB* MDR TB 1990 XDR TB 2006 Total DR? *or limited resistance manageable with 4 drug regimen DOTS Resistance Resistance to Resistance to to H&R 2 nd line drugs all available Treatment drugs Treatable with 2 nd options line seriously drugs restricted No treatment options Asia heads record levels of drug resistant tuberculosis Nearly one third of the 440,000 people with multidrug resistant form of the disease (MDR TB) in 2008 died, the report stated. In Africa, estimates show 69,000 cases emerged, the vast majority of which went undiagnosed. Joseph McCormick, MD, MS 16

17 Number of countries reporting resistance to first line drugs by WHO region Estimated number of MDR TB cases (primary and acquired) in 2008, by WHO region Joseph McCormick, MD, MS 17

18 2007 drug resistance survey in China China a high MDR TB burden country estimated to contribute 22% of the global burden of MDR TB Levels very close to those estimated by WHO in the past from subnational studies. proportion of MDR TB of 5.7% in new cases (95% CI: ) 25.6% in previously treated cases (95% CI: ) The overall proportion of MDR TB among all cases was 8.3% (95% CI: ). XDR TB was detected in 7.2% (95% CI: ) of 401 patients who were diagnosed with MDR TB Distribution of countries and territories reporting at least one case of XDR TB as of January 2010 Joseph McCormick, MD, MS 18

19 WESTERN COUNTRIES LOW MDR FORMER USSR HIGH MDR MIDDLE EAST MEDIUM MDR LATIN AMERICA MEDIUM MDR SUB-SAHARAN SAHARAN AFRICA HIGH MDR No information yet Second-line drugs NOT available Second-line drugs widely available Joseph McCormick, MD, MS 19

20 Joseph McCormick, MD, MS 20

21 Estimated mortality of MDR TB An estimated deaths caused by MDR TB occurred globally in 2008 including those with HIV infection (range: ). The estimated t number of MDR TB deaths excluding those with HIV infection was (range: ). MDR TB case fatality in HIV negative cases was estimated at 26% ( 16 58%). Joseph McCormick, MD, MS 21

22 Weak TB programs (DOTS) Low completion/cure rates Lack of treatment follow up and patient support Unreliable drug supply Diagnostic delay Absent or inadequate infection i control measures Uncontrolled use of 2 nd line drugs High proportion of retreatment cases Low cure rates Low DOTS coverage High default rates Low GNP per capita Joseph McCormick, MD, MS 22

23 1. Incomplete or inadequate therapy 2. On going transmission of drug resistant strains 3. Increased failures to short course chemotherapy 4. Amplification of drug resistance resistance 5. HIV/AIDS 1/1 NAIROBI, Kenya, Mar 19 The government has warned that some brands of Tuberculosis medication being sold by the private sector do not meet the required standards. The Head of the Division of Tuberculosis at the Ministry of Public Health, Dr Joseph Sitienei said on Friday that more than 10 brands available in some pharmacies and private hospitals do not meet the recommended World Health Organisation regulations. Some of the medicines could be well labeled but when you look at the ingredients, they do not meet the number or the quantities that is required per particular tablet and this will lead to problems, he warned. Joseph McCormick, MD, MS 23

24 17 Patients with Diabetes and Tuberculosis Serum rifampicinand i i metabolites measured Rifampicin levels 50% decreased in diabetics Different dose of rifampicin i i needed? d? * Hanneke M. J. Nijland Exposure to Rifampicin Is Strongly Reduced in Patients with Tuberculosis and Type 2 Diabetes Clinical Infectious Diseases, R.Brostrom DPH Slide 47 of 31 What about the Status of MDR in the United States? Joseph McCormick, MD, MS 24

25 10 % Resistant Isoniazid MDR TB *Updated as of May 20, Note: Based on initial isolates from persons with no prior history of TB. Multidrug resistant TB (MDR TB) is defined as resistance to at least isoniazid and rifampin. No. of Cases Percentage No. of Cases Percentage *Updated as of May 20, Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin. Joseph McCormick, MD, MS 25

26 % Resistant U.S.-born Foreign-born *Updated as of May 20, Note: Based on initial isolates from persons with no prior history of TB. 3 % Resistant U.S.-born Foreign-born *Updated as of May 20, Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least isoniazid and rifampin. Joseph McCormick, MD, MS 26

27 12 10 Case Count Year of Diagnosis Drug susceptibility test. *Reported incident cases as of May 20, Extensively drug resistant TB (XDR TB) is defined as resistance to isoniazid and rifampin, plus resistance to any fluoroquinolone and at least one of three injectable second line anti TB drugs. Social Context and solutions While vaccines and drugs are needed, the long term solutions is a sociopolitical one. Joseph McCormick, MD, MS 27

28 Drug resistant TB patients are a vulnerable population MDR TB has socioeconomic causes and consequences Addressing adherence is key to treatment success Community based models of care ideal for addressing these issues Poor housing Malnutrition Overcrowding Poverty Poor infrastructure Joseph McCormick, MD, MS 28

29 Adherence crucial in successful treatment of drug resistant TB Barriers to adherence are socioeconomic and must be addressed Adverse effects also contribute to poor adherence Prolonged infectiousness, which increases transmission to patients' relatives, friends and community. The development of drug resistance (in the case of second line medications, XDR) The development of unfavorable outcomes: Fil Failure Relapse Death Joseph McCormick, MD, MS 29

30 It is the control of side effects It allows a daily rechecking of the medications that patients are taking It is the direct observation of patients taking their medicines It is the documentation of the visit It involves home visits if patients do not come to the clinic It involves looking for patients who are non adherent or are defaulting Enablers Food Compensation for transport expenses Consultations with a psychologist and/or addiction specialist Help with clothes, documentation, registrations, housing, job search Incentives Financial supplementation Extra food assistance and household supplies Joseph McCormick, MD, MS 30

31 Peru: more than 4000 patients with 70% cure rate Russia: more than 1500 patients with 78% cure rate Haiti: more than 300 patients with 80% cure rate Joseph McCormick, MD, MS 31

32 Drug resistant TB is a disease with social causes that must be addressed Adherence is key to treatment success; improving adherence requires management of adverse effects and addressing barriers to care Community based treatment programs are an excellent model dl for managing drug resistant it t TB Joseph McCormick, MD, MS 32

33 Joseph McCormick, MD, MS 33

34 TB is a mirror of our global society and our global priorities. Thus far we have chased it with some science, few resources, and mostly ignorance We now need to chase it with more resolve, more resources and more passion. Joseph McCormick, MD, MS 34