Global TB: The TB world is flat too!

1. Global TB: The TB world is flat too! Drug Resistant TB: A world tour Juzar Ali M.D., FRCP(C), FCCP Russell C. Klein M.D.  LSU ALUMNI Professor of Medicine Vice Chair (Clinical) Department of Medicine Director: LSU Chest & LSU-Wetmore TB Clinics Section of Pulmonary & Critical Care Medicine Louisiana State University Health Sciences Center, New Orleans JUNE 6 2008

2. At the end of the presentation, the audience will have • Reviewed the global epidemiology of Drug-resistant TB including MDRTB and XDRTB • Identified risk factors in Drug – resistant Tuberculosis • Been given an overview of and emphasis on the focal points of management of Drug resistant TB.

3. References 1 Farmer P, Furin J, Shin S. The clinical management of multidrug-resistant tuberculosis. J Respir Dis 2000; 21:53-56. 2 Iseman M, Madsen L. Drug resistant tuberculosis. Clin Chest Med 1989; 10:341-353. 3 Iseman M. Management of multidrug-resistant tuberculosis.Chemotherapy 1999; 45(supl 2):3-4•• Centers for Disease Control and Prevention. Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs-worldwide, 2000-2004. 4. MMWR Morb Mortal Wkly Rep 2006; 55:301-305. 5 Pablos-Mendez A, Raviglione M, Laszlo A, et al. Global surveillance for antituberculosis drug resistance, 1994-1997. World Health Organization-International Union Against Tuberculosis and Luna Disease Working group on Antituberculosis Drug Resistance Surveillance. N Engl J Med 1998; 338:1641-1649. 6 Blumberg, HM, Burman, WJ, Chaisson, RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med 2003; 167:603. 7 Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months. Am Rev Respir Dis 1977; 115:727 8. Mitchison DA, Nunn Aj. Influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. Am Rev Respir Dis 1986; 133:423-430. 9. Hong Kong Chest Service, British Medical Research Council. Five-year follow-up of a controlled trial of five, 6 month regimens of chemotherapy for tuberculosis. Am Rev Respir Dis 1987;136:1339-1342. 10. Hong Kong Chest Service, British Medical Research Council. Controlled trial of 6-monthand 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Am Rev Respir Dis 1977;115:727-735.Am J Respir CritCare Med 2003; 167:603

4. Types • Primary drug resistance “ or in new cases” is said to occur in a patient who has never received anti- tuberculosis therapy. • Secondary drug resistance i.e. “acquired” refers to the development of resistance during or following chemotherapy, for what had previously been drug-susceptible tuberculosis.

5. Definition The term "drug-resistant tuberculosis" refers to cases of tuberculosis caused by an isolate of Mycobacterium tuberculosis, which is resistant to one of the first-line antituberculosis drugs: isoniazid, rifampin, pyrazinamide, ethambutol, or streptomycin

6. Multidrug-resistant tuberculosis (MDR-TB) is caused by an isolate of M. tuberculosis, which is resistant to at least isoniazid and rifampin, and possibly additional chemotherapeutic agents.

7. Extensively drug-resistant tuberculosis (XDR-TB) is caused by an isolate of M. tuberculosis, which is resistant to at least isoniazid, rifampin, fluoroquinolones, and either aminoglycosides (amikacin, kanamycin) or capreomycin, or both. WHO. Laboratory XDR-TB definitions. Geneva: Meeting of the global XDR TB task force 2006

9. The Story of DR- MDRTB ; not a new tale • Exists and ongoing throughout the world over the years.. Russia, Far East, South Asia; Globally 400K cases “reported” • 1990s Several outbreaks in hospitals and correctional facilities in NY and Florida; Mostly HIV, 80% mortality; Dx-Death time 4-16 weeks • Nosocomial transmission; not more contagious but more difficult to treat • Lower cure rate and increased cost

10. The story started…. • Late 1940’s • Streptomycin; its success and its limitations Concept of Multi drug regimens

11. In a survey of resistance in 58 sites on six continents conducted by the World Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease from 1996 through 1999, primary resistance to at least one drug ranged from a low of 1.7 percent in Uruguay to a high of 36.9 percent in Estonia (median value 10.7 percent. • Multi-drug resistance was present was 14.1, 10.8, 9.0, 9.0, and 5.0 percent in Estonia, Henan Province (China), Latvia, Russian Ivanovo, and Iran, respectively. • A mathematical model estimated that 3.2 percent of all cases of tuberculosis in the world in 2000 were caused by multidrug resistant strains. References available

12. Nearer home A survey of drug resistance among M. tuberculosis isolates in Mexico in 1997, showed a rate of primary resistance of 12.9 and 2.4 percent to one drug and multiple drugs, respectively, which rose to 50.5 and 22.4 percent, respectively, for re- treatment cases. Patients in this study were all smear positive and usually treated with three- as opposed to four-drug regimens; directly observed therapy was inconsistently applied. References available

13. Population-based data on drug susceptibility of TB isolates were obtained from the United States (for 1993--2004), Latvia (for 2000--2002),and South Korea (for 2004), where 4%, 19%, and 15% of MDR TB cases, respectively, were XDR. MMWR 3/2006. 55(11); 301-305

14. In the US • The emergence of drug resistance in the United States occurred unevenly. In New York state, 12.9 percent of isolates were resistant to isoniazid and rifampin in 1991, and New York City alone accounted for nearly 60 percent of all cases of MDR-TB in the entire United States] . • The rate of resistance in New York City in 1991 was 52.4 times higher than that in the rest of the country • Single drug resistance to isoniazid occurred in 8 percent of cases in the United States in 1995 and 1996, although it varied from less than 4 percent in North Carolina, West Virginia, and Wisconsin to greater than 10 percent in Delaware, Hawaii, New York, and Rhode Island. . DOT Focus Infection Control Initial 4 drug Rx

15. People The three P’s • Refugees • Migrants • Displaced • Homeless • Transitional MDs , HCWs, Infrastructure Support Protocols & Policies $$$$ Politics PHS ; Private ; Academia International National NGOs

16. TB: Refugees & Transients % of populations infected with TB 4 6 25 50 50 NA Europe Homeless (UK) LA Refugees Ref: UNHCR 1995 Crises study and LA 1997 stats

17. In the US!! A “revolving door” Health system The “Bermuda Triangle” of TB ED Lack of Accountabiliy Mobile Population

18. RESISTANCE PATTERNS • Initial resistance to I> E> S> R • Prognostic factors: Nutritional status Diabetic Renal Disease

19. Resistance to isoniazid (INH) was most common, occurring in 8 percent of all isolates, and this rate has remained steady through 2001. Resistance to rifampin, streptomycin, and ethambutol was detected in 1.7, 5.9, and 1.6 percent of isolates, respectively. Resistance to both INH and rifampin (ie, multidrug-resistance) was detected in 2.5 percent of the isolates in 1997; by 2001, fewer than two percent of cases of tuberculosis in the United States were caused by multidrug resistant strains • CDC. Reported tuberculosis in the United States, 2002. Center for Disease Control, 2003

20. Factors A multivariate analysis identified the following factors as associated with MDR-TB : • Previous TB diagnosis • Positive acid-fast bacilli sputum smear • Asian/Pacific Islander ethnicity • Time in the United States <5 years at diagnosis • An outcome of "died" or "moved” or “cold case” or “case closed” ( my terms ) Granich, RM, Oh, P, Lewis, B, et al. Multidrug resistance among persons with tuberculosis in California, 1994-2003. JAMA 2005; 293:2732.

21. The Perfect Storm • Multidrug-resistant (MDR) tuberculosis (TB) has emerged as a global epidemic, with ~425,000 new cases estimated to occur annually. • Institutional outbreaks of MDR-TB have primarily affected HIV-infected persons. Delayed diagnosis inadequate initial treatment, prolonged infectiousness • HIV infection may lead to malabsorption of anti-TB drugs and acquired rifamycin resistance. AUWells CD; Cegielski JP; Nelson LJ; Laserson KF; Holtz TH; Finlay A; Castro KG; Weyer K SOJ Infect Dis. 2007 Aug 15;196 Suppl 1:S86-107.

22. XDRTB During the time period 1993 to 2006, 49 XDR-TB isolates were identified in the United States. These 49 cases were reported from nine states, with the largest numbers occurring in New York and California. Among 41 persons with XDR-TB and known clinical outcomes, 12 (29%) died; 10 of those had HIV infection and the other two did not undergo HIV testing. WHO. Laboratory XDR-TB definitions. Geneva: Meeting of the global XDR TB task force 2006. D2D period : 16 days Gandhi et al South Africa 2006 Lancet

23. Previously demonstrated and proposed sites of action of isoniazid (INH), pyrazinamide (PZA), and rifampin (RMP) on the M tuberculosis cell. This figure is adapted in part from Parsons et al. Somoskovi et al.Respiratory Research 2001 2:164   doi:10.1186/rr54 • INH inhibits the synthesis of mycolic acids • PZA inhibits the synthesis of short-chain, fatty-acid precursors • RMP inhibits transcription by binding to the β-subunit of RNA polymerase].

24. The Molecular Basis • Virtually all isolates resistant to rifampin and related rifamycins have a mutation that alters the sequence of a 27-amino-acid region of the beta subunit of ribonucleic acid (RNA) polymerase. • Resistance to isoniazid (INH) is more complex. Many resistant organisms have mutations in the katG gene encoding catalase-peroxidase that result in altered enzyme structure. These structural changes apparently result in decreased conversion of INH to a biologically active form. • Some INH-resistant organisms also have mutations in the inhA locus or a recently characterized gene (kasA) encoding a beta-ketoacyl-acyl carrier protein synthase.

25. Streptomycin resistance is due mainly to mutations in the 16S rRNA gene or the rpsL gene encoding ribosomal protein S12. • Resistance to pyrazinamide in the great majority of organisms is caused by mutations in the gene (pncA) encoding pyrazinamidase that result in diminished enzyme activity. • Ethambutol resistance in approximately 60% of organisms is due to amino acid replacements at position 306 of an arabinosyltransferase encoded by the embB gene.

26. Amino acid changes in the A subunit of deoxyribonucleic acid gyrase cause fluoroquinolone resistance in most organisms. • Kanamycin resistance is due to nucleotide substitutions in the rrs gene encoding 16S rRNA. • Multidrug resistant strains arise by sequential accumulation of resistance mutations for individual drugs. • AURamaswamy S; Musser JM SOTuber Lung Dis 1998;79(1):3-29.   

27. What to doat a patient level ? • A careful history / “mycobacteriogram” must be obtained from every patient with tuberculosis before treatment begins, and while drug susceptibility data are pending. Clinical and radiographic features on presentation are not altered in comparison with drug-susceptible disease, but several demographic and historical features should raise the suspicion of drug-resistant tuberculosis. These include: • Previous treatment for active tuberculosis, particularly if therapy was self-administered or non documented • Tuberculosis treatment failure or relapse in a patient with advanced HIV infection treated with a highly intermittent anti-TB regimen • Acquisition of tuberculosis in a region with known high rates of drug resistance • Contact with a case of drug-resistant tuberculosis • Failure to respond to empiric therapy, particularly if adherence to therapy has been documented

28. Mono resistance Not much clinical significance And /or management issues PZA SM Q E ?synergy RI Remove the R Remove the I ( “low level , high level ) QEI or SPI *Longer duration But with issues * Use of Rb? REZ, REQ, RES Longer duration

29. Isoniazid monoresistance — Tuberculosis resistant to isoniazid (INH) should be treated with a rifamycin (rifampin or rifabutin), pyrazinamide, and ethambutol for six to nine months, or four months after culture conversion • Success rates of 95 to 98 percent with this type of regimen among • Some experts consider continuing isoniazid in the setting of "low-level" INH resistance, ie, resistant to a concentration of 0.2 µg/mL but sensitive to 2.0 µg/mL. • Some experts (Cat C evidence) recommend that a quinolone be added to this regimen for the duration of therapy in HIV and high burden cases] .

30. Rifampin monoresistance — Rifampin monoresistance most often occurs in HIV-positive patients and represents an uncommon but increasingly frequent clinical problem • Rifampin monoresistance may be more likely to develop in HIV-infected with advanced immunosuppression (eg, CD4 cell counts <100/µL) patients treated with highly intermittent (i.e., once or twice weekly) regimens. • Streptomycin, isoniazid, and pyrazinamide given together for nine months. This is the shortest duration regimen with good efficacy for use in rifampin monoresistance, and although it is our preferred regimen, as it has been evaluated in well-conducted clinical trials (in HIV-negative patients), many patients often object to the nine months of injections with their attendant side effects. Some experts recommend extending treatment to 12 months for HIV-infected patients who do not convert their sputum cultures and clinically improve during the first two months of treatment [8,16] . • Isoniazid, pyrazinamide, and ethambutol. The duration of this regimen should be at least 12 months, and some would treat for 18 months after culture conversion. Some recommend adding streptomycin for the first two to three months of treatment, or the addition of a quinolone such as levofloxacin or moxifloxacin throughout. • ").

31. Of the 14 mutant RNA polymerase alleles, which confer resistance to rifampin, 9 also confer high-level resistance to rifabutin] . Approximately 25 percent of rifampin-resistant clinical isolates are sensitive to rifabutin, which appears as effective clinically as rifampin in short-course regimens for patients with drug-sensitive disease] . • However, no data are available regarding short-course, rifabutin-containing regimens in patients with rifabutin-sensitive, but rifampin-resistant disease. Therefore, its use in this setting cannot be recommended at the present time.

32. MDR PSQE RI Resection Surgery Duration, tolerance, Cost Compliance, ADR’s

33. XDRTB RESECTIONAL Surgery Tailored chemotherapy 2-3 de novo / new drugs at least Prolonged Rx

34. Pyrazinamide monoresistance — Single drug-resistance to pyrazinamide requires a nine month regimen of isoniazid and rifampin. This combination is well studied, and has a greater than 96 percent success rate in large trials

35. Monoresistance to other agents — Single drug resistance to ethambutol, streptomycin, or second-line agents is of little clinical significance. Patients can still be treated with the standard short course regimen of two months of isoniazid, rifampin, and pyrazinamide followed by four months of isoniazid and rifampin, which yields success rates of around 97 percent

36. Isoniazid, pyrazinamide, and ethambutol. The duration of this regimen should be at least 12 months, and some would treat for 18 months after culture conversion. Some recommend adding streptomycin for the first two to three months of treatment, or the addition of a quinolone such as levofloxacin or moxifloxacin throughout.

37. Pyrazinamide monoresistance — Single drug-resistance to pyrazinamide requires a nine month regimen of isoniazid and rifampin. This combination is well studied, and has a greater than 96 percent success rate in large trials.

38. Outcome of MDRTB • Patients presenting with MDR-TB had been previously treated with a median of five to six drugs • The overall success rate of patients treated after 1990 was similar in reports from the United States, Turkey, Latvia, and other resource-limited countries (52 to 77 percent) • Predictors of successful therapy included surgical intervention, fluoroquinolone use and younger age • The outcome of patients with MDR-TB appears to vary with HIV status.

39. XDRTB • XDR-TB infection is also a particular problem in HIV-infected patients. • Time to sputum culture conversion is a useful interim indicator of treatment outcome in patients with MDR-TB • In one study conversion to negative cultures at a median time of 60 days (range 4 to 462 days) occurred in 129 (77 percent) of patients. Thirty-eight patients (23 percent) did not convert. • Predictors of a longer conversion time were: Previous treatment of MDR-TB High colony count on initial sputum culture Bilateral cavitation on chest radiography The number of drugs the initial isolate was resistant to at the time of treatment initiation The mortality rate varies depending on whether the individual has been previously treated for compared to newly diagnosed with tuberculosis

40. Treatment Regimens for TB Resistant Only to INH • HIV-Negative Persons • Carefully supervise and manage treatment to avoid • development of MDR TB • Discontinue INH and continue RIF, PZA, and EMB • or SM for the entire 6 months • Or, treat with RIF and EMB for 12 months • HIV-Positive Persons • Regimen should consist of a rifamycin, PZA, and EMB

41. Multidrug-Resistant TB (MDR TB) • Presents difficult treatment problems • Treatment must be individualized • Clinicians unfamiliar with treatment of MDR TB • should seek expert consultation • Always use DOT to ensure adherence

42. TB Control: Tackle head-on Elicit International support Get National commitment Shun Skepticism Develop database and identify priorities Develop pilot programs Structure control mechanisms Provide Incentives Evaluate and establish accountability Continued supervision

43. But , then …... Governmental malaise and corruption HCWs apathy and incompetence Family and social dynamics The “leeches” of the system; the profiteers and pilferers Overall Non-commitment, and cynicism

44. A story of a country 1/5 new cases ever diagnosed 1/7 Rx correctly no effective guidelines no standardized protocols HCW individual idiosyncrasies 1% budget on health care DOT costs $ 50 for full Rx; It costs $ 5 per year to save a life But, how ? And will we ?

45. Current Issues in Global TB Control:Heard these before? • Definition of Compliance • Public & Private Sector Partnership • What is “political will” ? • Will “Surrogate DOT” succeed? Is it reliable?

46. Treatment of TB • IDEAL WHAT WE HAVE • 1. Single combination multiple meds • 2. Uninterrupted supply Erratic • 3. Affordable Prohibitive cost • 4. Controlled environ “Open season” • 5. Topical solutions “one size fits all”

48. International Scenario Fragmented and disjointed system Hosp with in patient services TB Regional Centers Community Clinics TB Clinics In Hospital STIGMA OF THE DISEASE STIGMA OF BEING A “TB DOCTOR”

49. Case # 5 MDRTB

50. Case # 5 Rx response…what changed?