Monitoring and Evaluation of MDR TB Kęstutis Miškinis, Medical officer, WHO Ukrainian country office

What is multidrug-resistant tuberculosis (MDR-TB)? TB bacilli resistant to at least two of the most powerful anti-TB agents: isoniazid and rifampicin; One of the main aims of any national TB program is to minimize the development of drug (multidrug) resistance;

Effectiveness of National TB Programme High cure rate of new TB cases; Low (and constantly decreasing) MDR-TB rate; Ultimately, high case-detection rate; Potential criteria: Ability to analyze cohort data; Default and transfer rates less than 10%; Continual supply of 1st line anti-TB drugs; Application of DOT in 90% of all cases;

Effectiveness of National TB Programme (con’t.) Surveillance of anti-TB drug resistance is an essential tool for monitoring the effectivness of TB control programme in any country; The use of drug-sensitivity tests (DST) was recommended many years ago;

Cause of anti-TB drug resistance (M)DR-TB is man-made! Naturally drug- resistant organisms arising through spontaneous mutations are selected by inadequate drug regimens; Reasons – exposure to a single drug due to: Poor adherence; Inappropriate prescription; Irregular drug supply; Poor drug quality;

MDR-TB Problems: longer to treat (up to 24 months); more expensive (up to 100x); more side-effects; demanding follow-up mechanism; requires complex diagnostics;

Prevalence of (M)DR-TB in some regions WHO / IUATLD / DZK / AKM % 20% 40% 60% 80% 100% Germany Italy Israel Latvia Tomsk Oblast Ivanovo Oblast China Henan Estonia resistantMDR TB susceptible

Countries/settings with MDR rates higher than 10% among combined cases

Boxplots of MDR prevalence rates among New Cases by European Sub-regions 3rd Global Report of WHO

MDR Trends among New Cases in Lithuania and Estonia Confidence-bounded MDR trend among new patients in Estonia Confidence-bounded MDR trend among new patients in Lithuania

Establishment of drug-resistance surveillance system The sample of specimens should be representative of the TB patients; The patient’s history should be carefully obtained (available to determine whether the patient has previously received anti- TB drugs); The laboratory methods should meet internationally recommended standards;

DST methods Proportion; Resistance ratio; Absolute concentration; BACTEC 460 radiometric; Comparability of data is assured by: Quality assurance; Proficiency testing performed by Supranational Reference Laboratories

Choice of drugs Four out of six 1st line drugs: Isoniazid (H);Isoniazid (H); Rifampicin (R);Rifampicin (R); Streptomycin (S);Streptomycin (S); Ethambutol (E);Ethambutol (E); Why these four? Widely used;Widely used; Resistance can be reliably measured by standardized techniques;Resistance can be reliably measured by standardized techniques;

Definitions of resistance Resistance among previously treated cases (having been treated for tuberculosis for one month or more);Resistance among previously treated cases (having been treated for tuberculosis for one month or more); Resistance among new TB cases (denies having had prior anti-TB treatment);Resistance among new TB cases (denies having had prior anti-TB treatment); Multi-drug resistance;Multi-drug resistance;

National Reference Laboratory Is a reference institution on MDR surveillance. It: Prepares cultures;Prepares cultures; Undertakes identification of Mycobacteria;Undertakes identification of Mycobacteria; Undertakes DST;Undertakes DST; Ensures quality of DST performed by regional labs;Ensures quality of DST performed by regional labs; Establishes a regular “on-site” supervision;Establishes a regular “on-site” supervision;

Organizing of surveillance Laboratories and diagnostic centers;Laboratories and diagnostic centers; Sample size and sampling strategies;Sample size and sampling strategies; Organization and survey outline (preparation, sampling, training, logistics);Organization and survey outline (preparation, sampling, training, logistics); Intake of patients (inclusion criteria, sputum-collection, registration, transport);Intake of patients (inclusion criteria, sputum-collection, registration, transport); National Reference laboratory;National Reference laboratory; Data management and analysis;Data management and analysis;

Ukraine NRL is established, but not functioning; QA is not implemented; Proficiency testing hasn’t started yet; Laboratory standards are defined, but not strictly followed; Equipment is poor, purchase of new equipment and necessary supplies is often delayed; Staff needs retraining and rejuvenation;

Trends in Anti-TB-Drug- Resistance in Ukraine Feshchenko et al., Ukraine Chemotherapeutical Journal, 2000/3 YearNo of Isolates Number of stains % Number of strains % testedsusceptible with resistance(s) ,534846, ,438047, ,140247, ,851749, ,837549, ,342151, ,237850, ,137250, ,152554, ,758961,3

Year Drug resistance (%) Monodrug resistance Multidrug resistance MDR Polydrug resistance Trends in Anti-TB-Drug- Resistance in Ukraine Feshchenko et al., Ukraine Chemotherapeutical Journal, 2000/3

Civil sectorPenitentiary system Total newPrev trNewPrev trNewPrev tr Susceptible strains abs% % % % % % Resistant strains MDR MDR survey results in Donetska oblast ( )

Drug Resistance Surveillance Magnitude and trend of drug resistance prevalence among new and re-treatment cases; Useful parameter to evaluate current and past treatment programme; Useful information for selection of effective initial treatment and retreatment regimens;

Should we treat persons with MDR-TB? Yes…for humanitarian reasons But health policy is not only driven by values, facts also matter No... unless it is proven that it is feasible and cost-effective But can we afford not to respond?

DOTS-Plus: working definition DOTS-Plus is a case-management strategy under development designed to manage MDR-TB using 2nd line drugs within the DOTS strategy in low- and middle-income countries; DISCLAIMER: DOTS-Plus means DOTS first

Prevention of MDR TB Correct operations of the TB programme: Diagnosis based on bacteriological examination; Standard treatment under strict observation (DOT); Uninterrupted supply of good-quality TB drugs (recommended FDC); Proper recording and reporting;