Presentation on theme: "Can the Global MDR/XDR TB Epidemic be Controlled?"— Presentation transcript:
1Can the Global MDR/XDR TB Epidemic be Controlled? Edward Nardell, MDBrigham & Women’s HospitalDivision of Global Health EquityPulmonary DivisionHarvard Medical SchoolHarvard School of Public HealthPartners In HealthAnnual New England Clinicians ConferenceNewport, Rhode IslandMay 1, 2010
2Importance More than 50 of US cases are foreign-born Global TB problem is our TB problemAs 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, 2008Harvard Medical SchoolPartners in HealthBrigham & Women’s HospitalLead authors: Salmaan Keshavjee, MD, PhDKwonjune Seung, MD
4IOM Workshop (11/5/08) and Report IOM Report: “Addressing the Threat of Drug-resistant Tuberculosis: A Realistic Assessment of the Challenge”Key issues addressed:Limitations of global TB estimatesRole of HIV in MDR spreadImportance of Transmission ControlLimited diagnostic capacityLow rates of treatmentBottleneck in the procurement and distribution of high quality drugsThe need for new TB drugs
5The Problem 500,000 new MDR-TB cases per year At least 1.5 million (est.) prevalent casesWHO Global Plan to Stop TB:800,000 people with active MDR-TB to be treated by 2015Revised goal stimulated by XDR concernUniversal access to MDR-TB treatmentTreat 1.6 million cases by 2015ONLY 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.
6anti-TB drug resistance in the world The 4th Global Report onanti-TB drug resistance in the worldIndiaRussiaChinaKenyaUgandaDR CongoIndonesiaSouth AfricaEthiopiaPhilippinesViet NamTanzaniaBrazilThailandMozambiqueMyanmarZimbabweCambodiaNigeriaBangladeshPakistanAfghanistan
719 settings with ≥ 6% MDR among new cases, 1994-2007 Indicates survey data reportedin an earlier phase of the project
8MDR-TB among new and previously treated cases, 1994- 2007
9MDR-TB among new TB cases, 1994-2007 * 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 All rights reserved
10MDR-TB among previously treated TB cases, 1994-2007 * 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 All rights reserved
11Estimated MDR TB incident cases by region,2006 4.8% of all cases (95% CI: 4.6% - 6.0%)
16The 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.
17XDR-TB among MDR-TB cases, 2002-2007 * 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 All rights reserved
18MDR-TB & HIV in the 4th DRS Report Latvia,Donetsk, Ukraine, 2006
20Anti-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)E (15-20 mg/kg)6326Z (20-30 mg/kg)17873S (1000 mg, 15 mg/kg)KM (1000 mg, 15 mg/kg)11447CM (1000 mg, 15 mg/kg)154AMK (1000 mg, 15 mg/kg)21Fluoroquinolone (CPX 1500 mg, OFX 800 mg, LFX 500 mg) 24199CS ( mg)24399.6Ethio / prothio ( mg)18475PAS (8 mg)21789Amox-Clav ( mg)208Rifabutin (300 mg)4LEGEND: 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
21Patient Demographics (n=244) 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, CSMedian number of drugs: 6 [range 4-7]Baseline comorbid conditions: 28.3%
22Characteristics of MDR-TB patients (n=244) Characteristic (N, if not 244)Frequency (%)Median (range)Number of patients who received surgeryThoracoplastySegmental resection (one or more)LobectomyPneumonectomy24 (9.8)45141Percent missed doses*5% [0, 45%]Time to culture conversion in months (n=218)2 [1, 18]Duration of therapy in monthsAll patientsCuresFailuresDeathsDefaults18.5 [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
25Barriers to Large Scale Effective Treatment Diagnostic capacity - extremely limited- True point of care testing non-existentDrug 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 countriesMDR-TB not integrated into NTP- “pilot program” mentality ≠ universal access
26Barriers to Large Scale Effective Treatment 4. Technical assistance – inadequate – not long-term to build capacity5. Transmission control – non-existent in congregate settings
28Unsuspected, inadequately treated cases Transmission RiskUnsuspected, inadequately treated casesIn 3 separate guinea pig exposure studies nearly all infections were due to drug resistant cases that were unsuspected and therefore on inadequate treatment.
29Number of exposed GPs GP infections stopped when drug susceptible Transmission stopped for 4 months: Treated drug susceptible patients – Study 1Number of exposed GPsGP infections stoppedwhen drug susceptiblepatients on treatmentwere introduced, andresumed when drugresistant cases wereadmitted.
30Importance of Transmission in Tomsk Glemanova, et al Importance of Transmission in Tomsk Glemanova, et al., Bull WHO, 2007; 85:Retrospective study of the role of non-adherence and default and the acquisition of multidrug resistanceSubstance abuse was a strong predictor of non-adherence (OR 7.3 ( )But non-adherence NOT associated with MDR-TBMDR-TB occurred among adherent patients who had been hospitalized in the course of therapy compared to those treated as out-patientsOR 6.34 (1.34 – 29.72) – began treatment in hospitalOR 6.26 (1.02 – 38.35) – hospitalized later during treatment
31IOM White Paper Recommendations DiagnosticsSustainable funding for building lab capacity in-country for DST/rapid testing with external QATechnical assistance – long-term on-siteLaboratory networks in-country- specimen transport, data management, coordination and certification of private laboratoriesUse of excess laboratory capacity in wealthy nations while poor nations build capacityResearch – point of care testing, ie, a dipstick as used for HIV, 99% sensitive and costs $1 – revolutionized HIV treatment.
32Recommendations Drug supply WHO and partners to stimulate number of manufacturers of quality assured second-line drugsAvailability at pre-negotiated prices via the GDF and through direct purchase by countriesGDF should streamline approval of manufactures as they progress through WHO Essential Drug Monitoring (EDM) prequalifying process – allowing large countries to purchase QA drugs in-countryGLC should institute a transparent system to quantify demand for second-line drugsGDF 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
33Recommendations 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 excellenceCommunity-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 monitoringPEPFAR and other large global initiatives need to prioritize MDR TB treatment. GFATM and UNITAID have done so.Impact of vertical programs on other programs.
34PEPFAR Approach US President’s Emergency Plan for AIDS relief (PEPFAR) Substantial funding: up to $7 billion in FY 2011 budgetSupply 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 targetsDownside: Local health infrastructure often inadequate and further strained by well-funded, focused programsTraining takes ½ staff out of the clinic in Malawi (Keith Joseph, MD)Fewer HCWs available for other programsHuge HR problem in high MDR regionsHealth system strengthening is an essential part of the solution, but no small undertaking.
35The short term prognosis is not good Children in a village.The short term prognosis is not good