Multidrug-Resistant Tuberculosis

Transcription

1 Pocket Book Multidrug-Resistant Tuberculosis National Clinical Management Training

2 Content 1. Abbreviations 3. Diagnosis of Tuberculosis 4. DS-TB Treatment Monitoring 5. IPT Screening Algorithm 6. ART while on DS-TB Treatment 7. ART while on DR-TB Treatment (Intensive Phase) 8. ART while on BDQ DR-TB Treatment 9. TB/HIV Drug Interactions 10. Tuberculosis Drug Resistance 11. Interpretation of GeneXpert Results 12. GeneXpert Diagnostic Algorithm 13. Baseline Investigations for DR-TB 14. WHO DR-TB Drug Grouping 15. Common Adverse Drug Reactions 16. Summary of MDR-TB Regimens in SA 17. MDR-TB Treatment Adult Dosing 18. Rifampicin Resistance Algorithm for Patient Management 19. Follow-up and Determining Duration of Intensive Phase 20. Treatment Monitoring & Evaluation 21. Measuring Renal Function 22. Ototoxicity Monitoring Flow 23. Monitoring QTc Prolongation 24. MDR-TB Treatment Outcomes

3 Abbreviations ABC Abacavir ddl Didanosine ADR Adverse drug reaction DNA Deoxyribonucleic acid AE Adverse event DOTS Directly observed treatment, short-course AFB Acid-fast bacilli DRS Drug Resistance Surveillance AIDS Acquired immunodeficiency DRT Drug-resistant therapy syndrome ALT Alanine aminotransferase DR-TB Drug-resistant tuberculosis Am Amikacin DST Drug susceptibility testing Amx/Clv Amoxicllin/Clavulanate E Ethambutol ART Antiretroviral treatment/therapy ECG Electrocardiogram ARV Antiretroviral EDL Essential drug list AST Aspartate aminotransferase EFV Efavirenz ATV Atazanavir EPTB Extrapulmonary Tuberculosis AZT Zidovudine (also known as ZDV) Eto Ethionamide bd Twice daily FBC Full blood count Bdq Bedaquiline FDC Fixed Dose Combination BD Twice a day FEV1 Forced expiratory volume in 1 second CBO Community-based organizations FIND Foundation for Innovative New Diagnostics CC Culture conversion FL-LPA First-Line LPA (Line Probe Assay) CDC Centers for Disease Control and Prevention FTC Emtricitabine Cfz Clofazimine Gfx Gatifloxicin Clr Clarithromycin GI Gastrointestinal Cm Capreomycin GXP GeneXpert CMV Cytomegalovirus H Isoniazid CNP Clinical nurse practitioner HAART Highly active antiretroviral therapy CNS Central nervous system HB Haemoglobin CP Continuation phase HBV Hepatitis B virus CPK Creatinine phosphokinase HCT HIV counseling and testing Cs Cycloserine HCT Hematocrit CSF Cerebrospinal fluid HCV Hepatitis C virus CPT Cotrimoxazole preventive therapy HCW Health care worker CTX Cotrimoxazole HIV Human immunodeficiency virus CXR Chest x-ray HPF High-power field d4t Stavudine Im Imipenem 1

4 IND Indinavir PMTCT Prevention of mother-to-child transmission INH Isoniazid PTB Pulmonary tuberculosis IP Intensive phase Pto Prothionamide IPC Infection prevention and control qd Once daily IPT Isoniazid preventive treatment R Rifampicin IRIS Immune reconstitution inflammatory syndrome RNA Ribonucleic acid Km Kanamycin RT Reverse transcriptase KS Kaposi sarcoma S Streptomycin Lfx Levofloxacin SCC Short-course chemotherapy LTB Latent TB infection SLD Second line drug LPA Line Probe Assay SL-LPA Second Line, LPA (Line Probe Assay) Lzd Linezolid SQV Saquinavir MC&S Microscopy and culture STIs Sexually transmitted infections MDR-TB Multidrug-resistant tuberculosis TAT Turn around time MGIT Mycobacterial growth indicator tube tds Three times daily MO Medical officer TB Tuberculosis Mfx Moxifloxacin TDF Tenofovir disoproxil fumarate NFV Nelfinavir Th Thioacetazone NGO Non-governmental organisation(s) TDS Three times a day NIMART Nurse initiated management of antiretroviral therapy TLC Total lymphocyte count NNRTI Non-nucleoside reverse transcriptase inhibitor TMP Trimethoprim NRTI Nucleoside reverse transcriptase inhibitor Trd Terizidone NTM Non-tuberculosis mycobacteria TSH Thyroid stimulating hormone NVP Nevirapine UIF Unemployment insurance fund OHL Oral hairy leukoplakia UTI Urinary tract infection Ofx Ofloxacin UVGI Ultraviolet germicidal irradiation OIs Opportunistic infections Vi Viomycin PAS Para-aminosalicylic acid VZV Varicella zoster virus PCP Pneumocystis Jiroveci (Carinii) pneumonia XDR-TB Extensively drug-resistant tuberculosis PCR Polymerase chain reaction WBC White blood cells PHCs Primary health care centres WHO World Health Organization PI Protease inhibitor Z Pyrazinamide pdst Phenotypic DST 2

5 Diagnosis of Tuberculosis Once there is suspicion of TB, the patient needs to undergo diagnostic testing: 01 X 0 GeneXpert (GXP) Result will identify TB and Rifampicin Resistance 02 If GXP Rifampicin Sensitive: Smear Microscopy If GXP Rifampicin Resistant: DR-TB Reflex Test FL-LPA & SL-LPA (Line Probe Assay) Smear/Culture Phenotypic Drug Susceptibility Test (pdst) for pre-xdr and XDR-TB Interpreting First-Line LPA results Mutation InhA KatG InhA and KatG Meaning & Resistance Caused Low level INH resistance and confers resistance to Ethionamide High level INH resistance and confers resistance to High dose INH Confers resistance to Ethionamide and High Dose INH Drugs you can use High Dose INH Ethionamide Neither INH nor Ethionamide May add BDQ** ** See Rifampicin Resistance Algorithm for Patient Management 3

6 DS-TB Treatment Monitoring New Smear Positive PTB At 7 weeks: Take one sputum smear Negative Positive Commence continuation phase of treatment with daily RH at the end of the 8th week of Intensive Phase Check Adherence Reassess patient clinically Send 1 sputum specimen for DR-TB Reflex Register the patient as negative Educate and counsel patient about importance of treatment adherence Continue intensive phase for 1 month & review Register the patient as positive Address treatment adherence by counselling the patient & identifying a treatment supporter Repeat smear at 11 weeks Follow-up DR-TB Reflex Negative & drug susceptible Change to continuation phase at end of week 12 Register as negative Negative and INH resistant Continue intensive phase Refer to DR-TB unit Register as INH mono resistant TB Positive and RR/MDR-TB Stop TB treatment Refer to DR-TB unit Register as MDR or RR-TB At 23 weeks: Take one sputum smear Negative Stop treatment when 6 months completed Discharge as cure Educate the patient about TB prevention & healthy lifestyle Positive Stop TB treatment Register as treatment failure Conduct DR-Reflex Drug Susceptible: Re-start TB treatment, counsel the patient and provide treatment support Drug Resistant: Refer to MDR-TB unit 4

7 IPT Screening Algorithm HIV Positive Adults/Adolescents TB Symptom Screen Current cough, fever, loss of weight, drenching night sweats YES Investigate for TB as per national TB management NO Assess for contraindications to IPT Exclude excessive alcohol use, liver disease, peripheral neuropathy, and history of ADRs to INH TB Treat for TB Assess for IPT eligibility after completion of TB treatment No TB Review after 3 months Assess for IPT eligibility after 3 months Other Diagnosis Give appropriate treatment Assess for IPT eligibility after 3 months Contraindications Defer IPT TST negative Pre ART *** On ART No Contraindications Do TST Read within hours TST positive No IPT IPT for 12 months IPT for 36 months Screen for TB regularly *** Note: With new test and treat guidelines, most HIV positive adults will be on ART and therefore qualify for IPT 5

8 ART while on DS-TB Treatment HIV Positive patient diagnosed with DS-TB On ART? Yes No Regimen 1 TDF + FTC (3TC) + EFV Regimen 2 AZT + 3TC + LPV/r Start TB Treatment first Send CD4 count Continue with no changes LPV/r should be doubled (from 2 tablets 12 hourly to 4 tablets 12 hourly) while on rifampicin based treatment Monitor ALT monthly Reduce LPV/r to standard dose 2 weeks after TB treatment is completed CD4 < 50 cells/μl Initiate ART within 2 weeks of starting TB treatment, when the patient s symptoms are improving and TB treatment is tolerated CD4 > 50 cells/μl Initiate ART within 2-8 weeks of starting TB treatment 6

9 ART while on DR-TB Treatment (Intensive Phase) HIV Positive patient diagnosed with DR-TB Patient on ART at time of diagnosis Patient not on ART at time of diagnosis Start DR-TB Treatment Immediately Start DR-TB Treatment first Send CD4 count If on First Line ART Regimen: TDF + FTC (3TC) + EFV CD4 < 50 cells/μl CD4 > 50 cells/μl Yes Is patient anaemic or Hepatitis B positive? Keep TDF in the regimen and monitor CrCl more frequently (at least every 2 weeks) Yes Check: Viral Load Hepatitis B status Haemoglobin Is VL undetectable? No Switch TDF to ABC No Switch to second line with LPV/r and monitor viral load Initiate ART within 2 weeks of starting TB treatment, when the patient s symptoms are improving and TB treatment is tolerated Initiate ART within 2-8 weeks of starting TB treatment Start First-Line ART Regimen (for DR-TB): ABC + 3TC + EFV Option 2: AZT* + 3TC + EFV * Note: If patient is anaemic substitute D4T for AZT or Option 3: FDC with more frequent CrCl monitoring NOTE: EFV cannot be used with BDQ Once DR-TB injectable is stopped: (Re)start TDF if CrCl >50ml/min 7

10 ART while on BDQ DR-TB Treatment HIV Positive patient diagnosed with DR-TB (Plan for BDQ Course) Patient on ART at time of diagnosis Patient not on ART at time of diagnosis For patients on EFV If on NVP or LPV/r and undetectable Start DR-TB Treatment first (Bedaquiline Regimen) Send CD4 count Is viral load undetectable? And is CD4 count <250 in women or <400 in men? Yes If yes to both, replace EFV with NVP for 7 days No If CD4 criteria is not met for NVP, replace EFV with LPV/r for 7 days Begin BDQ regimen after 7 day washout period Begin BDQ regimen immediately If detectable, refer to committee for 3 rd line regimen CD4 < 50 cells/μl Initiate ART within 2 weeks of starting TB treatment, when the patient s symptoms are improving and TB treatment is tolerated CD4 > 50 cells/μl Initiate ART within 2-8 weeks of starting TB treatment Work with an HIV Specialist when initiating ART regimen while on BDQ. Consider starting: AZT+ 3TC (or FTC) + NVP * or TDF + 3TC (or FTC) + NVP * or TDF + 3TC (or FTC) + RAL ** * CD4 count MUST be <250 for females and <400 in males to avoid hepatotoxicity of NVP ** RAL must be approved by 3 rd line regimen committee 8

11 TB/HIV Drug Interactions 9 2

12 RR Tuberculosis Drug Resistance DS MDR Pre-XDR XDR Rifampicin Rifampicin Rifampicin Rifampicin Isoniazid Isoniazid Isoniazid Isoniazid Fluoroquinolone Fluoroquinolone OR Amikacin or Kanamycin or Capreomycin Amikacin or Kanamycin or Capreomycin 10

13 Interpretation of GeneXpert Results MTB Complex Not Detected MTB Complex Detected / RIF Susceptible MTB Complex Detected / RIF Resistant MTB Complex Detected / RIF Indeterminate Error Xpert negative for TB MTB is present, and susceptible to rifampicin MTB is present, and may be resistant to rifampicin MTB is present, and RR could not be assessed Test failed Results could be correctly negative or a false negative (uncommon) Xpert is sensitive and specific for RR-TB (trust result) Second sputum specimen must be sent for microscopy, culture and confirmatory DST Second sputum specimen must be sent for DR-TB Reflex Treat patient as if they have DS-TB Submit a second specimen for Xpert 11

14 Xpert Diagnostic Algorithm Presumptive TB TB and DR-TB contacts, non-contact symptomatic individuals, re-treatment after relapse, failure and lost to folllow-up Collect one sputum specimen at the health facility under supervision Xpert Negative Xpert Unsuccessful Xpert positive Rifampicin unsuccessful Xpert positive Rifampicin resistant Xpert positive Rifampicin susceptible Collect one sputum specimen for a repeat Xpert HIV Negative HIV Positive including children <13yrs irrespective of HIV status Treat as Drug Susceptible TB Start on Regimen 1 Collect one specimen for DR-TB Reflex Treat as MDR-TB Refer to MDR-TB unit/ initiator Treat as Drug Susceptible TB Start on Regimen 1 Send one specimen for microscopy Treat with antibiotics Collect one specimen for culture and LPA or culture and DST (for R and H) Treat with antibiotics & review after 5 days Do chest X-ray Poor Response Consider other diagnosis Good Response No further follow up LPA/DST results resistant to R and H/R Poor response to antibiotics Collect one specimen for DR-TB Reflex Follow up with microscopy Advise to return if symptoms recur Advise to return if symptoms recur Clinically TB TB on CXR Treat as MDR-TB Refer to MDR-TB unit/initiator Treat as TB Start on Regimen 1 Review culture results Follow up with microscopy, culture, and LPA 12 6

15 Baseline Investigations for DR-TB DR-TB Reflex Test FL-LPA, SL-LPA, Smear/Culture, and pdst for Pre-XDR/XDR Height Weight Body Mass Index HIV Test/Screening Hepatitis B Screening Pregnancy Test Full Blood Count Urea & Electrolytes Serum Creatinine Serum Calcium, Magnesium Blood Glucose Alcohol Use Screening Liver Function Tests Chest X-ray Vision Test Audiometry ECG TSH All patients All patients All patients All patients Patients with unknown HIV status or those who have not been tested in the past 3 months All patients Women of child bearing age, presenting with history of amenorrhea and not on contraception All patients (May substitute for Haemoglobin) All patients All patients All patients All patients: Urine glucose & Ketones Symptomatic patients: Blood glucose (If elevated, obtain Haemoglobin A1c) Patients with a history of alcohol use/abuse ALT: All Patients Full LFTs: In patients with history of liver disease or excessive alcohol use All patients All patients All patients who will be receiving ototoxic medications All patients who will be receiving BDQ or Dlm All patients 13

16 WHO DR-TB Drug Grouping A. B. C. D. Fluoroquinolones Second-line injectable agents Other core second-line agents Add-on agents (not part of the core MDR-TB regimen) Levofloxacin Moxifloxacin Gatifloxacin Amikacin Capreomycin Kanamycin (Streptomycin) Ethionamide / Prothionamide Cycloserine / Terizidone Linezolid Clofazimine D1 D2 Pyrazinamide Ethambutol High-dose isoniazid Bedaquiline Delamanid Lfx Mfx Gfx Am Cm Km (S) Eto / Pto Cs / Trd Lzd Cfz Z E H h Bbq Dlm D3 p-aminosalicylic acid Imipenem-cilastatin Meropenem Amoxicillin-clavulanate (Thioacetazone) PAS Ipm Mpm Amx-Clv (T) 14

17 Common Adverse Drug Reactions ADR Agents Management Arrhythmias (QT prolongation) Bedaquiline Clofazimine Moxifloxacin 1. Monitor for mild reactions 2. Discontinue drug for severe ( >500msec). Consider re-challenge if moderate reaction resolves Arthralgia/ arthritis Pyrazinamide Fluoroquinolones 1. Initiate NSAID therapy 2. Exercise therapy Electrolyte Wasting GI upset Capreomycin Amikacin Kanamycin Ethionamide/Pto PAS Capreomycin Ethambutol Pyrazinamide 1. Mild/Moderate: Replete electrolytes as needed 2. Severe: stop injectable, usually reversible once discontinued 1. Administer drugs with small amount of food 2. Initiate anti-emetics before administration 3. Start Antacid, H2 blocker, or PPI 4. Give drug in separate doses if feasible 5. Lower dose or discontinue if severe Hearing Loss Injectable agents 1. Stop drug and refer to audiologist Hepatotoxicity Hypothyroidism Bedaquiline Pyrazinamide PAS Ethionamide/Pto Isoniazid PAS Ethionamide Impaired Vision Ethambutol Linezolid Nephrotoxicity Peripheral Neuropathy Psychiatric Symptoms Seizures Aminoglycosides Capreomycin Cycloserine Terizidone Capreomycin Amikacin Kanamycin Ethionamide/Pto Linezolid Cycloserine Terizidone Ethionamide Fluoroquinolones Cycloserine Terizidone Fluoroquinolones 1. Monitor LFTs every month 2. Rule out other causes of hepatitis 3. Discontinue BDQ if ALT/AST elevations severe or persist > 2 weeks. Consider re-challenge with BDQ if another drug identified as cause 1. Monitor closely 2. Initiate Thyroxine 1. Avoid in patients with impaired vision except those that have myopia, hyperopia or presbyopia 2. Stop the drug and refer to ophthalmologist 1. Adjust dosing/frequency or discontinue suspected drug 2. Continue for mild reaction; monitor every 2 weeks 3. Drug substitution for moderate to severe reaction 1. Pyridoxine (dose up to 200mg daily) 2. Exercise regimen 3. Start tricyclic antidepressant (amitriptyline) 4. Lower drug dose 5. Start gabapentin 1. Pyridoxine (dose up to 200mg daily) 2. Drug substitution for moderate or severe reaction 3. Refer to psychiatrist if not improving 1. Rule out and treat other suspected causes 2. Start anticonvulsant therapy (e.g. phenytoin, valproic acid, carbamazepine) 3. Pyridoxine (dose up to 200mg daily) 4. Lower dose or discontinue drug Skin Reactions Multiple 1. Desensitisation, may reintroduce drugs within 1 or 2 weeks 15

18 Summary of MDR-TB Regimens in SA Standard Short (9-12 month) Regimen STANDARD Intensive Phase (4-6 months) Km + Mfx + Cfz + Eto + Z + H h + E Continuation Phase (5 months) Mfx + Cfz + Z + E Standard Extended (18-20 month) Regimen Intensive Phase (6-8 months) Km + Mfx + Cfz + Eto + Z + H h + E Continuation Phase (12 months) Mfx + Cfz + Z + E BDQ Substitution in Standard Short Regimen Intensive Phase (4-6 months) Bdq + Lfx + Cfz + Eto + Z + H h + E Continuation Phase (5 months) Lfx + Cfz + Z + E 6 months minimum of BDQ Individualised Extended (18-24 month) Regimen Intensive Phase Continuation Phase Based on Expert Review **Modified Regimens to only be used under certain criteria. Must be implemented at Centres with Access to Newer Drugs [i.e. Centres of Excellence (COE) and select decentralized sites with guidance from MDR-TB Expert] 16

19 MDR-TB Treatment Adult Dosing Medicine Kanamycin Bedaquiline Weight <33kg 33-50kg 51-70kg >70kg 15mg/kg (max 1g), 6-7 times per year week 400mg daily for 2 weeks, then 200mg 3 times per week Moxifloxacin 400mg 400mg 400mg 400mg Levofloxacin 750mg 750mg 1000mg 1000mg Isoniazid (HD) 600mg 600mg 900mg 900mg Ethionamide 250mg 500mg 750mg 1000mg Clofazimine 50mg 100mg 100mg 100mg Ethambutol 800mg 800mg 1200mg 1600mg Pyrazinamide 1000mg 1500mg 1750mg 2000mg Kanamycin Dosing Amount (mg) Amount (ml) 333 mg 1.0 ml 416 mg 1.25 ml 500 mg 1.5 ml 583 mg 1.75 ml 666 mg 2.0 ml 750 mg 2.25 ml 833 mg 2.5 ml 915 mg 2.75 ml 1000 mg 3.0 ml 17

20 Rifampicin Resistance Algorithm for Patient Management GeneXpert with + Rif Resistance *Labs: HIV, FBC, U&E, Ca, Mg, TSH, Pregnancy Test, Hepatitis B Baseline Visit Evaluations Submit specimen for DR-TB Reflex (FL-LPA, SL-LPA, Smear/Culture, and pdst for prexdr & XDR), *Labs, CXR, Audio Start Short Course TB Treatment 4-6 Km + Mfx + Cfz + Eto + Z + H h + E / 5 Mfx + Cfz + Z + E Monitor monthly smear/culture If smear negative at month 4, STOP the intensive phase Excludes complicated EPTB (Bone, Joints, Meningitis) or prior SL-resistance to aminoglycosides or fluoroquinolones See Determining Duration Table Review DR-TB Reflex (FL-LPA & SL-LPA) Results after 7-14 days If no valid result, continue treatment and follow-up LPA results at Day 28 LPA results are generally available in two weeks for Smear + patients; Smear - patients take longer for LPA results Fluoroquinolone +/- Injectable Resistance Injectable Resistance Double mutation Both katg & inha Single mutation katg OR inha INH sensitive NO katg or inha Immediately Refer to Centre with Access to Newer Drugs Start new regimen inha only Drop Eto katg only Drop H h Continue Short Course If patient has prior SL treatment exposure, contact the lab for pdst Continue (Adjusted) Short Course Treat for months If patient has prior SL treatment exposure, contact the lab for pdst Patient will require regimen selection and initiation under the supervision of a Medical Officer Legend Ototoxicity or Renal Impairment (CrCl below 60mL/min) SL-LPA Second-Line LPA TSH Thyroid Stimulating Hormone U&E Urea/Electrolytes Z Pyrazinamide FBC Full Blood Count FL-LPA First-Line LPA H h Isoniazid (High Dose) Km Kanamycin Mg Magnesium BDQ Bedaquiline Ca Calcium Cfz Clofazamine pdst Phenotypic Drug Sensitivity Test EPTB Extrapulmonary TB Eto Ethionamide NO YES BDQ Substitution Required Continue Short Course 9-12 months See BDQ regimen details OR refer for access DR-TB Reflex: FL-LPA, SL-LPA, Smear, Culture, pdst for Pre-XDR/XDR 18

21 19

22 Treatment Monitoring & Evaluation Monitoring & Evaluation Evaluation by Provider DR-TB Reflex Test Sputum Smear and Culture Drug Susceptibility Testing (DST) Weight Height Body Mass Index Chest Radiograph Full Blood Count Urea & Electrolytes Serum Creatinine Serum Magnesium, Calcium Glucose Thyroid Stimulating Hormone Liver Serum Enzymes HIV Screening Recommended Frequency Outpatient: At least monthly, more frequent if clinically indicated Inpatient: At baseline, then 2-3 times per week for stable patients and daily for very sick patients until conversion At baseline At baseline (as part of DR-TB Reflex Test), and then monthly At baseline for pre-xdr/xdr For patients who remain smear positive at 4 months At baseline and then monthly At baseline in adults and children At baseline and then monthly At baseline, then every 6 months or when requested by clinician At treatment completion At baseline and repeat when clinically indicated At baseline, then at least monthly during injectable phase At baseline, then at least monthly during injectable phase At baseline and repeat when clinically indicated At baseline and repeat when clinically indicated Adults: At baseline, then every 3 months if receiving ethionamide and/or PAS Monitor monthly for signs of hypothyroidism Children: Every 2 months Adults: At baseline (ALT for all patients, full LFTs where indicated), and periodic monitoring (every 1-3 months) in patients receiving Pyrazinamide or for patients at risk of or with symptoms of hepatitis Children: If symptomatic or every 6 months At baseline and repeat if clinically indicated Hepatitis B Screening At baseline and repeat if clinically indicated Pregnancy Test Short Regimen At baseline for women of childbearing age, and repeat if indicated Audiometry ECG Vision Test Lung CT Scan At baseline, monthly during injectable phase and 3 months after the interruption of the injectable agent If on BDQ, at baseline then 2, 4, 8, 12, 16, 20 and 24 weeks after initiating treatment. More frequent if heart condition, hypothyroidism or electrolyte disturbances are present At baseline and monthly while taking Ethambutol When indicated 20

23 Measuring Renal Function CrCl/GFR in MEN (140 age) x weight in kilograms 72 x (Serum Creatinine in mg/dl) Normal CrCl/GFR in men is ml/min CrCl/GFR in WOMEN (140 age) x weight in kilograms x x (Serum Creatinine in mg/dl) Normal CrCl/GFR in women is ml/min Conversion for Serum Creatinine (umol/l mg/dl) Serum creatinine (umol/l) 88.4 Chronic Kidney Disease Stage Description GFR 1 Kidney damage with normal or high GFR 90 2 Kidney damage with mild GFR Moderate GFR Severe GFR End Stage/Kidney Failure <15 21

24 Ototoxicity Monitoring Flow Pre-Treatment Counselling & Education Baseline Assessment (Pre-Treatment Initiation) or Initial Audiometry Within 72 hours of Treatment Initiation Intensive Phase Normal Hearing Pre-Existing Hearing Loss Continue with Standard MDR-TB Regimen, containing the use of Aminoglycosides Patient excluded from Standard Regimen containing the use of Aminoglycosides Monthly Audiological Monitoring Symptomatic screening for hearing loss between audiology sessions Refer and Substitute Bedaquiline in Regimen If there s any significant threshold changes according to Asha Ototoxcity Criteria (1994) Send patient for additional diagnostic testing Audiological Assessment and Monitoring Stop Second-Line Injectable Audiological Monitoring at 3 and 6 months after discontinuation of treatment with ototoxic drug ASHA Ototoxicity Critera (1994) 10db - 15db threshold shift at two adjacent frequencies relative to baseline assessment 20db threshold shift at one frequency relative to baseline assessment No response at any frequency relative to baseline assessment Clinical Symptoms of Ototoxicity Subjective hearing loss Difficulty in understanding speech Ringing or buzzing noise in the ears Dizziness 22

25 Monitoring QTc Prolongation A normal value for the corrected QTcF interval is 0.45 seconds (450 ms) in males or 0.47 seconds (470 ms) in females QTc Prolongation Related Drugs Monitoring Tests BDQ, CFZ, MFX ECG - QTcF* interval (QT interval corrected using Frederica formula) Monitoring Schedule Baseline, 2, 4, 8, 12, 16, hours 20 and 24 weeks after initiating BDQ treatment Grading Mild Asymptomatic QTc interval msec OR increase in interval <30 msec Moderate Asymptomatic QTc interval msec OR increase in interval msec Severe Asymptomatic QTc interval >500 msec OR increase in interval >50 msec OR Life-threatening consequence, e.g. Torsades or other associated serious ventricular dysrhythmia Indicated Actions Drug withdrawal for severe Consider rechallenge if moderate reaction resolves Mild reactions should be monitored QTcF = QT / 3 RR RR = 60 / Heart Rate 23

26 MDR-TB Treatment Outcomes Short Regimen Cured 1. A patient who has had TB culture conversion 2. Received treatment for a total duration of 9 months or more 3. Has at least 3 consecutive negative TB Cultures during continuation phase (at least 30 days apart) 4. No evidence of clinical deterioration Treatment Completed 1. A patient who has had TB culture conversion 2. Received treatment for a total duration of 9 months or more 3. Has less than 3 consecutive negative TB Cultures during continuation phase (30 days apart) 4. No evidence of clinical deterioration Treatment Loss-to-Follow Up 1. A patient with Treatment interrupted a. >= 2 consecutive months b. Any reason without medical approval Transferred Out: A patient who has been 1. Referred from this facility to a facility in another district, province or country to continue treatment 2. The treatment outcome is reported by the facility where the patient is newly registered Treatment Failure 1. A patient who failed to culture convert by month 4 2. In the initial 6 months of treatment a. >= 2 of 5 cultures are positive b. Clinical condition deteriorating 3. Treatment stopped on clinical grounds 4. More than 2 new drugs added because of poor clinical response Died 1. Patient who dies for any reason during the course of treatment Moved Out: A patient who has been 1. Referred from this facility to a facility within the same district to continue treatment. This is not an outcome, but serves to match patient moving within the district in order to prevent double counting 2. The treatment outcome is reported by the facility where the patient is moved in Extended Regimen Not Evaluated 1. A Category IV Patient recorded in the register and who does not have the necessary recorded data to enable classification into one of the above outcomes. Long Regimen Cured 1. A patient who has TB culture converted 2. Received treatment for at least 12 months after TB culture conversion 3. Has at least 3 consecutive negative TB Cultures during continuation phase (at least 30 days apart) 4. Total duration of treatment not to be less than (18) months 5. No evidence of clinical deterioration Treatment Completed 1. A patient who has TB culture converted 2. Received treatment for at least 12 months after TB culture conversion 3. Has less than 3 consecutive negative TB Cultures during continuation phase (at least 30 days apart) 4. Total duration of treatment not to be less than (18) months 5. No evidence of clinical deterioration Treatment Loss-to-Follow Up 1. A patient with Treatment interrupted a. >= 2 consecutive months b. Any reason without medical approval Transferred Out: A patient who has been 1. Referred from this facility to a facility in another district, province or country to continue treatment 2. The treatment outcome is reported by the facility where the patient is newly registered Moved Out: A patient who has been 1. Referred from this facility to a facility within the same district to continue treatment. This is not an outcome, but serves to match patient moving within the district in order to prevent double counting 2. The treatment outcome is reported by the facility where the patient is moved in Treatment Failure 1. A patient who failed to culture convert by month 6 2. In the final 12 months of treatment a. >= 2 of 5 cultures are positive b. Clinical condition deteriorating 3. Treatment stopped on clinical grounds 4. More than 2 new drugs added because of poor clinical response Died 1. Patient who dies for any reason during the course of treatment Not Evaluated 1. A Category IV Patient recorded in the register and who does not have the necessary recorded data to enable classification into one of the above outcomes. Still on Treatment 1. Still on treatment after prescribed treatment 24

27 References Department of Health: Republic of South Africa (2015). Introduction of new drugs and drug regimens for the management of drug-resistant tuberculosis in South Africa: Policy framework. Department of Health: Republic of South Africa. (2013). Management of drugresistant tuberculosis: Policy guidelines. Department of Health: Republic of South Africa (2015). National consolidated guidelines for the prevention of mother-to-child transmission of HIV (PMTCT) and the management of HIV in children, adolescents and adults. Department of Health: Republic of South Africa (2014). National tuberculosis management guidelines. World Health Organization (2014). Companion handbook to the WHO guidelines for the programmatic management of drug-resistant tuberculosis. Management of drug-resistant tuberculosis. World Health Organization (2016). Global tuberculosis report. World Health Organization (2016). WHO treatment guidelines for drug-resistant tuberculosis: 2016 Update. World Health Organization - South Africa (2016). Towards universal health coverage: Report of the evaluation of South Africa drug resistant TB programme and its implementation of the policy Framework on decentralised and deinstitutionalised management of multidrug resistant TB. 25

28