Drug-Resistant TB in Children: Patterns, Epidemiology, Diagnosis, and Management

1. DRUG RESISTANT TB IN CHILDREN DR SAUMU WAYUWA KPA ANNUAL SCIENTIFIC CONFERENCE 2019

2. OUTLINE • Resistance patterns • Epidemiology • MDR TB in children • Diagnosis • Management

3. TB RESISTANCE PATTERNS • Mono-resistant TB • Resistant to any one drug. • Poly-resistant TB • Resistant to more than one drug but not both isoniazid and rifampicin. • Multi-drug resistant (MDR) TB • Resistant to at least both isoniazid and rifampicin. • Extensive drug resistant (XDR) TB • Resistant to rifampicin, isoniazid, an injectable and a quinolone.

4. BACILLARY POPULATIONS 1. Rapidly multiplying bacilli - Optimum medium: Extracellular. PH 6.5-7, maximum oxygenation (cavity wall) - Large number of bacilli → High probability of spontaneous mutations and natural resistance 2. Slowly multiplying bacilli - Intramacrophagic location. Acid pH.Population<105Relapse capacity 3. Intermittently growing bacilli - Unfavourable conditions. Solid caseum. Extracellular - Population <105. Relapse capacity 4. Bacilli in latent state: Not susceptible to drugs - Reactivations and relapses

5. M. TUBERCULOSISRESISTANCE • Natural resistance – characteristic of the bacilli • Acquired resistance – therapy problem (resistance in previously treated patients) • Primary resistance – transmission problem (resistance in previously untreated patients)

6. DR TB TRENDS IN KENYA

7. Since 2013, more than 50% of new cases of MDR-TBwereamongpeoplewhohaveneverbeentreatedfor TB before, highlightingtheimportance of transmissionand thelack of appropriateinfection control measures, particularly at communitylevel GLOBAL EPIDEMIC MDR-TB SITUATION WHO Reports 2014, 2015, 2016 and 2017

8. MDR-TB IN CHILDREN • Is mainly primary (transmitted) drug resistance • Disease in children usually (>90%) develops within 12 months of infection • Is more difficult to acquire because of the paucibacillary nature of primary disease • Possible if cavitary pulmonary disease • Children with DR TB are not major contributors to the spread of DR TB in the community • Good source for surveillance on drug resistant TB • May reflect the transmission of these organisms in the community

9. MDR-TB IN CHILDREN • Children at high risk • Contacts of patients with MDR-TB • Living in MDR-TB high prevalence areas

10. RATES OF MDR-TB AMONG CONTACTS OF MDR-TB PATIENTS

11. MDR-TB IN CHILDREN Furthersuspectdrug-resistant TB: • If a child gets worse on treatment or fails despite adherence to treatment • If an adult index case with unknown susceptibility pattern is: • a treatment failure (sputum smear positive after 5 months treatment) • a retreatment case • a chronic TB case (TB despite 2 previous treatment courses)

12. DIAGNOSIS OF MDR-TB IN CHILDREN Drug-susceptible vs. drug-resistant TB in children • No clinical or radiological difference between these two groups • Clinical features and chest radiography does not distinguish DS from DR/MDR TB • Confirmed MDR TB is a laboratory diagnosis

13. DIAGNOSIS OF MDR-TB IN CHILDREN Confirmed DR TB is a laboratory diagnosis : nucleic acid amplification test (e.g. Xpert MTB/RIF) or culture with DSTBacteriological diagnosis should always be attempted for drug sensitivity testingProbable DR TB is diagnosed in a child with active TB disease and a recent close contact with DR TBSuspected DR TB is when a child fails to improve while adherent to first-line anti-TB treatment OR if the adult source case is a treatment failure, a retreatment case or recently died from TB

14. DIAGNOSIS OF MDR-TB IN CHILDREN • Bacteriologic confirmation of TB is more difficult • Lower bacillary load • Less forceful cough • Difficult to obtain specimens • More extra pulmonary cases (< 5 years) • Important role for X-ray film • Gene Xpertisa useful tool

15. DIAGNOSIS OF MDR TB • History of contact/previous treatment • Sputum smear • Drug Susceptibility Test (DST) - Molecular DST Gene xpert LPA - ConventionalDST Liquid culture (MGIT) Solid culture

16. BASELINE LABORATORY INVESTIGATIONS • Sputum smear, FLD and SLD LPA, culture and DST • Hemogram • UECr • LFTs • TSH • HIV • CXR • Audiometry • ECG

17. DR TB CLINICAL REVIEW • County physician, Pediatrician, CTLC/SCTLC, CASCO, Pharmacist, Lab technologist, Nutritionist, Social worker, PHO, psychologist • Review team meets at central facility at county/sub county level • Patients brought by their facility DOTs nurse/clinician • Team reviews the following; • Patient’s progress • Patient`s suspected or documented ADR`s • Sputum smears and cultures • Biochemistry lab results • Deliberations and notes recorded in patient log book

18. PRINCIPLES OF MANAGEMENT OF MDR-TB IN CHILDREN The same principles apply as for adults. • Do not add a single drug to a failing regimen • At least 4 susceptible drugs. • Lower bacillary load  Probably enough with only 3 drugs?? • Use the adult index case’s isolate DST pattern if no isolate from child is available • Favorable treatment outcomes: adverse reactions are very infrequent, even with SLD • Caution with Bdq <6 years and Dlm <3 years • Longer oral or shorter MDR/RR-TB regimens - weight based dosing

19. DESIRABLE CHARACTERISTICS OF DRUGS Adapted from: Caminero JA, et al. Treatment of TB. EurRespirMonogr 2012; 58: 154–166 Caminero et al. Treatment of drug-susceptible and drug-resistant TB. EurRespirMonograph 2018: 205-227 • Bactericidal– to rapidly eliminate the bulk of active bacilli INH, RIF, Lfx/Mfx, SLD Inject, Lzd, Bdq, Dlm 2. “Sterilization” – killing dormant or intermittent growing bacilli RIF, PZA, hMfx, Lfx, Lzd, Cfz, Bdq, Dlm 3. Prevention of Resistancewith drug combination 4. Minimal Toxicity

20. WHO RECOMMENDATIONS FOR DR-TB TREATMENT WHO 2011 update WHO 2016 update

21. WHO DR-TB Guidelines 2018. Grouping Medicines for use in Longer MDR-TB Regimens

22. MDR TB TREATMENT REGIMENS Short term regimen Intensive phase 4-6 Km-Mfx-Pto-Cfz-E-Z-Hhigh-dose Continuation phase 5 Mfx-Cfz-Z-E Individualized regimen

23. CLINICAL AND LABORATORY FOLLOW UP

24. OUTCOMES OF MDR-TB TREATMENT IN CHILDREN • Systematic review and meta-analysis reviewed treatment outcomes for children with MDR-TB. • Eight studies, which reported outcomes on 315 patients, contributed to the database. • Average duration of treatment ranged from 6 months to 34 months. • The pooled estimate for treatment success (defined as a composite of cure and completion) was 81.7% with death in 5.9%, and default in 6.2% of patients. • Adverse reactions occurred in 39.1% of the children, the most common of which were nausea and vomiting followed by hearing loss, psychiatric effects and hypothyroidism. • Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012;12:449-56. • Good treatment outcomes due to paucibacillary disease and DOTS (as compared to adults with high bacilli load/presence of cavities making treatment difficult-resistance selection)

25. SUMMARY OF MANAGEMENT OF MDR-TB IN CHILDREN • Confirm MDR TB… if possible • Management and review by DR TB clinical review team • Use the adult index case’s isolate DST pattern if no isolate from child is available • Give at least 4 or more drugs to which the patient’s isolate is susceptible to and/or naïve • Counsel parents at every visit about possible adverse events, and the importance of adherence to treatment • DOT with daily treatment is essential • Close Follow-up is essential: clinical, radiologic and cultures

26. THANK YOU