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Edward Nardell, MD Brigham & Womens Hospital Division of Global Health Equity Pulmonary Division Harvard Medical School Harvard School of Public Health.

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Presentation on theme: "Edward Nardell, MD Brigham & Womens Hospital Division of Global Health Equity Pulmonary Division Harvard Medical School Harvard School of Public Health."— Presentation transcript:

1 Edward Nardell, MD Brigham & Womens Hospital Division of Global Health Equity Pulmonary Division Harvard Medical School Harvard School of Public Health Partners In Health Annual New England Clinicians Conference Newport, Rhode Island May 1, 2010 Can the Global MDR/XDR TB Epidemic be Controlled?

2 Importance More than 50 of US cases are foreign-born Global TB problem is our TB problem As global MDR epidemic escalates, more foreign-born MDR/XDR cases will inevitably be seen here. International travel exposes tourists and students, and especially humanitarian and medical workers to the risk of MDR/XDR transmission.

3 Stemming the Tide of Multidrug Resistant TB: Major Barriers to Addressing the Growing Epidemic A White Paper for the Institute of Medicine of the National Academies – November, 2008 –Harvard Medical School –Partners in Health –Brigham & Womens Hospital Lead authors: Salmaan Keshavjee, MD, PhD Kwonjune Seung, MD

4 IOM Workshop (11/5/08) and Report IOM Report: Addressing the Threat of Drug- resistant Tuberculosis: A Realistic Assessment of the Challenge Key issues addressed: 1.Limitations of global TB estimates 2.Role of HIV in MDR spread 3.Importance of Transmission Control 4.Limited diagnostic capacity 5.Low rates of treatment 6.Bottleneck in the procurement and distribution of high quality drugs 7.The need for new TB drugs

5 The Problem 500,000 new MDR-TB cases per year –At least 1.5 million (est.) prevalent cases WHO Global Plan to Stop TB: 2006-2015 –800,000 people with active MDR-TB to be treated by 2015 –Revised goal stimulated by XDR concern Universal access to MDR-TB treatment Treat 1.6 million cases by 2015 –ONLY 10% cases currently being treated, and only 22,000 (1.5%) have ever been treated (since 1996) with quality assured drugs under the Green Light Committee (GLC) mechanism.

6 The 4th Global Report on anti-TB drug resistance in the world India Russia China Kenya Uganda DR Congo Indonesia South Africa Ethiopia Philippines Viet Nam Tanzania Brazil Thailand Nigeria Bangladesh Pakistan Afghanistan Mozambique Myanmar Zimbabwe Cambodia

7 Indicates survey data reported in an earlier phase of the project 19 settings with 6% MDR among new cases, 1994-2007

8 MDR-TB among new and previously treated cases, 1994- 2007

9 * Sub-national coverage in India, China, Russia, Indonesia. The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2006. All rights reserved MDR-TB among new TB cases, 1994-2007

10 * Sub-national coverage in India, China, Russia, Indonesia. The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2006. All rights reserved MDR-TB among previously treated TB cases, 1994-2007

11 489,000 (95% CI: 455,000 - 614,000) 4.8% of all cases (95% CI: 4.6% - 6.0%) Estimated MDR TB incident cases by region,2006

12 Trends: scenario I

13 Trends: scenario II

14 Trends: scenario III

15 Trends: scenario IV

16 The Pathogen is Changing: Emergence of aggressive Beijing strains In South Korea, aggressive Beijing strains comprise >90% of new cases. (Cliff Barry, MD) Some strains show a propensity toward acquiring drug resistance.

17 * Sub-national coverage in India, China, Russia, Indonesia. The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2006. All rights reserved XDR-TB among MDR-TB cases, 2002-2007

18 MDR-TB & HIV in the 4 th DRS Report Latvia, 2001-2005Donetsk, Ukraine, 2006

19 Resistance patterns (n=243)

20 Anti-tuberculosis medications received in individualized treatment regimens (N=244) Medication* (daily doses, unless specified) N% H (300 mg, 900 mg biweekly)52. R (600 mg)00 E (15-20 mg/kg)6326 Z (20-30 mg/kg)17873 S (1000 mg, 15 mg/kg)00 KM (1000 mg, 15 mg/kg)11447 CM (1000 mg, 15 mg/kg)15463 AMK (1000 mg, 15 mg/kg)21 Fluoroquinolone (CPX 1500 mg, OFX 800 mg, LFX 500 mg) 24199 CS (500-1000 mg)24399.6 Ethio / prothio (500-1000 mg)18475 PAS (8 mg)21789 Amox-Clav (1500-2000 mg)208 Rifabutin (300 mg)42 LEGEND: H isoniazid, R rifampin, E ethambutol, Z pyrazinamide, S streptomycin, KM kanamycin, CM capreomycin, AMK amikacin, CS cycloserine, CPX ciprofloxacin, OFX ofloxacin, Ethio ethionamide, Prothio prothionamide, PAS para-aminosalicylic acid, Amox-Clav amoxacillin-clavulanate) Most patients received ofloxacin as their fluoroquinolone

21 Median time in treatment : 18.5 months [range 1.0 to 42.4] Median duration of injectable drug: 8.6 months [0-27.5] Experienced at least one adverse event: 73.3% Event resulted in permanent discontinuation of a drug: 28.7% Regimen included: parenteral agent, FQ, PAS, prothio/ethio, CS Median number of drugs: 6 [range 4-7] Baseline comorbid conditions: 28.3% Patient Demographics (n=244)

22 Characteristics of MDR-TB patients (n=244) Characteristic (N, if not 244) Frequency (%) Median (range) Number of patients who received surgery Thoracoplasty Segmental resection (one or more) Lobectomy Pneumonectomy 24 (9.8) 4 5 14 1 Percent missed doses*5% [0, 45%] Time to culture conversion in months (n=218) 2 [1, 18] Duration of therapy in months All patients Cures Failures Deaths Defaults 18.5 [1.0, 42.4] 18.8 [16.1, 42.4] 18.9 [10.1, 28.1] 10.9 [1.8, 22.9] 9.2 [1.0, 15.7] * Defined as the percent of doses among all prescribed doses missed throughout DOTS-Plus treatment, as recorded on the treatment administration forms

23 Summary of adverse events, N=244

24 TREATMENT OUTCOMES (N=244)

25 Barriers to Large Scale Effective Treatment 1.Diagnostic capacity - extremely limited - True point of care testing non-existent 2.Drug supply - limited quality-assured second-line drugs even for the 2% being treated under GLC mechanism - Exacerbated by limited demand for quality-assured second-line drugs in high MDR burden countries 3.MDR-TB not integrated into NTP - pilot program mentality universal access

26 Barriers to Large Scale Effective Treatment 4. Technical assistance – inadequate – not long- term to build capacity 5. Transmission control – non-existent in congregate settings

27

28 Transmission Risk Unsuspected, inadequately treated cases –In 3 separate guinea pig exposure studies nearly all infections were due to drug resistant cases that were unsuspected and therefore on inadequate treatment.

29 Transmission stopped for 4 months: Treated drug susceptible patients – Study 1 GP infections stopped when drug susceptible patients on treatment were introduced, and resumed when drug resistant cases were admitted. Number of exposed GPs

30 Importance of Transmission in Tomsk Glemanova, et al., Bull WHO, 2007; 85:703-711. Retrospective study of the role of non-adherence and default and the acquisition of multidrug resistance Substance abuse was a strong predictor of non-adherence (OR 7.3 (2.89-18.46) –But non-adherence NOT associated with MDR-TB MDR-TB occurred among adherent patients who had been hospitalized in the course of therapy compared to those treated as out-patients –OR 6.34 (1.34 – 29.72) – began treatment in hospital –OR 6.26 (1.02 – 38.35) – hospitalized later during treatment

31 IOM White Paper Recommendations Diagnostics –Sustainable funding for building lab capacity in-country for DST/rapid testing with external QA –Technical assistance – long-term on-site –Laboratory networks in-country- specimen transport, data management, coordination and certification of private laboratories Use of excess laboratory capacity in wealthy nations while poor nations build capacity –Research – point of care testing, ie, a dipstick as used for HIV, 99% sensitive and costs $1 – revolutionized HIV treatment.

32 Recommendations Drug supply –WHO and partners to stimulate number of manufacturers of quality assured second-line drugs –Availability at pre-negotiated prices via the GDF and through direct purchase by countries –GDF should streamline approval of manufactures as they progress through WHO Essential Drug Monitoring (EDM) prequalifying process – allowing large countries to purchase QA drugs in-country –GLC should institute a transparent system to quantify demand for second-line drugs –GDF should maintain a buffer stock of drugs for 5,000 patients for rapid delivery. –Research to optimize current regimens and develop at least 3 new TB drugs with fast-track through the regulatory process

33 Recommendations Treatment Delivery –Universal treatment of MDR TB side-by side with drug susceptible TB and integrated with current HIV treatment initiatives. –Technical assistance – needs to be long-term regional assistance – regional centers of excellence –Community-based ambulatory MDR treatment in collaboration with private doctors and laboratories. –Transmission control – fully integrated into NTP programs with resources, training, and implementation strategies and monitoring –PEPFAR and other large global initiatives need to prioritize MDR TB treatment. GFATM and UNITAID have done so. Impact of vertical programs on other programs.

34 PEPFAR Approach US Presidents Emergency Plan for AIDS relief (PEPFAR) –Substantial funding: up to $7 billion in FY 2011 budget –Supply chain management for forecasting demand and delivering drugs, fast tracked FDA approval of ne w and generic ARVs, fostered community-based treatment, invested in laboratory surveillance, transport and reporting, with specific performance targets Downside: Local health infrastructure often inadequate and further strained by well-funded, focused programs –Training takes ½ staff out of the clinic in Malawi (Keith Joseph, MD) –Fewer HCWs available for other programs Huge HR problem in high MDR regions Health system strengthening is an essential part of the solution, but no small undertaking.

35 The short term prognosis is not good


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