1. Management of Side Effects in DR-TB Patients with Alcohol and Drug Addiction Askar Yedilbayev, MD, MPH, Irina Gelmanova, MD, MPH, Natalia Zemlyanaya, MD, PhD Partners In Health Session N.00245 Best practice in management of side effects among DR-TB patients to improve quality of care

2. Problem statement 18.5 liters of alcohol per year per person consumed in Russia; 2,9 million people or 2% of population of Russia involved in severe drinking (Ivanets et. al, 2004); –16% of male and 2.5% of female over 15 years of age suffer from alcohol-induced disorders; –27,415 people registered with alcoholism in Tomsk (2011); 537,000 people registered with diagnosis of drug addiction (2007, MOH of RF); –Estimated number is around 2.5 million people or 2% of population of the country; –Average duration of life after diagnosis of drug addiction is 5-7 years; –Incidence of drug addiction in Tomsk was 20.7 per 10,000 people (2011), 1.5 higher than country average. 2

3. Current therapy of MDR-TB 3

4. Substance dependency disorders and tuberculosis Increase the risk of certain adverse events during therapy of TB, including hepatotoxicity, peripheral neuropathy, and psychosis; May potentially increase the risk of additional adverse events, like electrolyte disturbance, depression, seizure and gastric intolerance, due to overlapping toxicities; Associated with worse treatment outcomes: –Deaths from alcohol-related and drug-induced causes; –Defaults or failure from due to non-adherence and adverse events. 4

5. The setting – Tomsk, Russia 5

6. Drugs in baseline regimens (N=244, Cohort 1, 2000-2002) N% H (300 mg, 900 mg biweekly)52.05 E (15-20 mg/kg)6325.82 Z (20-30 mg/kg)17872.95 KM (1000 mg, 15-20 mg/kg)11446.72 CM (1000 mg, 15-20 mg/kg)15463.11 AM (1000 mg, 15-20 mg/kg)20.82 FQ (OFX 800 mg, LFX 500 mg)24399.59 CS (500-1000 mg)24198.77 ETO/PAS (500-1000 mg)18475.41 AMX/CLV (1500-2000 mg)208.20 RFB (300 mg)41.64 6 Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. IJTLD 11(12):1314-1320, 2007, Shin S. et al.

7. Incidence and characteristics of adverse reactions (N=244, Cohort 1, 2000-2002) 7 Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. IJTLD 11(12):1314-1320, 2007, Shin S. et al.

8. Distribution of adverse events by month (N=244, Cohort 1, 2000-2002) 8 Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. IJTLD 11(12):1314-1320, 2007, Shin S. et al.

9. Study population and methods (1) 1,344 patients with laboratory confirmed MDR-TB from Tomsk Oblast, Russia; –Enrolled into MDR-TB Program between September 20, 2000 – April 6, 2009; –Some presented data are limited to sub-cohorts: Cohort 1 (2000-2002), Cohort 2 (2002-2004), Cohort 3 and 4 (2005- 2009); Funding sources: MOH, MOJ, GFATM, PIH; Three sources for SLD procurement: PIH, GFATM and MOH; Inpatient and outpatient model of care; Patient-centered approach throughout course of therapy. 9

10. Study population and methods (2) Standard procedures for bacteriology and drug susceptibility testing (DST); Individualized treatment regimens based on DST and prior history of treatment; At least five drugs confirmed to be susceptible or likely to be effective in the regimen; Treatment under strict directly observation (DOT) throughout treatment; Adverse events diagnosed and managed aggressively at no cost to the patient; –Routine laboratory tests performed and pre-established thresholds for laboratory-defined AE; All TB physicians trained using standardized protocols for diagnosis and management of AE associated with the use of TB drugs. 10

11. Study population and methods (3) 790 (58.8%) - diagnosed with substance addiction: –626 (79.2%) with alcohol addiction; –78 (9.8%) with drug addiction; –86 (10.8%) with alcohol and drug addiction; Confirmation of alcohol/drug addiction by initiation of MDR-TB therapy: –Alcohol addiction: 47% by psychiatrist; 26% by TB doctors (registered in TB database); –Drug addiction: 40% by psychiatrist; 32% by TB doctors (registered in TB database) 11

12. Confirmation of addiction Baseline Alcohol Use Disorder (AUD) or use during treatment: –Documented diagnosis of alcoholism at intake by TB physician or mental health provider (e.g. psychiatrist, psychologist of addiction specialist); –Physician documenting alcohol consumption and/or inebriation during treatment in patient’s chart; Baseline Drug Use Disorder (DUD) or use during treatment: –Documented diagnosis of drug addiction at intake by TB physician or mental health provider (e.g. psychiatrist, psychologist of addiction specialist); –Physician documenting consumption of narcotic drugs during treatment in patient’s chart. 12

13. Baseline characteristics (N=1,344, Cohorts 1-4, 2000-2009) Patients with diagnosed addiction (N=790) Patients without diagnosed addiction (N=524) N%N%p-value Female Male 143 647 18.1%204 320 38.9<0.001 Age, years, median (IQR)39 (30-42)33 (25-48)<0.001 History of incarceration35044.39217.6<0.001 Employed at time of treatment8911.314527.7<0.001 Homeless617.981.6<0.001 HIV152.020.40.013 Low BMI35444.818635.5<0.001 Bilateral and cavitary disease47861.122543.7<0.001 XDR-TB425.3295.50.860 13

14. Drugs in baseline regimens (N=407, Cohorts 1 and 2, 2000-2004) Drinkers (N=253)Non-drinkers (N154)p-value OFX249 (98.4%)150 (97.4%)0.47 CS248 (98.0%)150 (97.4%)0.68 PAS224 (88.5%)127 (82.4%)0.09 Z207 (81.8%)118 (76.6%)0.21 ETO/PTO206 (81.8%)125 (81.2%)0.28 CM157 (62.1%)84 (54.5%)0.13 KM90 (35.6%)65 (42.2%)0.18 E71 (28.1%)42 (27.3%)0.8 AMX/CLV8 (3.2%)8 (5.2%)0.31 RFB2 (0.7%)2 (1.3%)0.61 H2 (0.7%)4 (2.6%)0.18 MFX1 (0.4%)2 (1.3%)0.3 AM02 (1.3%)0.07 14

15. Definitions of adverse events (1) Adverse reactionDefinition of specific adverse reaction Nausea and vomiting Documentation of nausea and vomiting by physician DiarrheaDocumentation of diarrhea by physician DepressionAs diagnosed by a TB physician and/or as judged by psychiatrist, based on ICD-10 criteria PsychosisAs diagnosed by a TB physician and/or as judged by psychiatrist, based on ICD-10 criteria SeizureWitnessed or unwitnessed event consistent with seizure ArthralgiaJoint pain as reported by patient and documented by physician, with or without presence of arthritis RushDermatological reaction felt to be related to anti-TB medicines, as documented by physician 15

16. Definitions of adverse events (2) Adverse reactionDefinition of specific adverse reaction NeuropathySymptoms and signs consistent with neuropathy, as diagnosed by physician or electomyography NephrotoxicityElevation of at least one creatinine value >141 mmol/l HepatotoxicityElevation of serum bilirubin at least 3 times ULN 20.5 mmol/l Elevation of transaminases Elevation of serum transaminases at least 3 times ULN (AST/ALT ULN 0.45-0.68 mmol/l, depending on technique) HypokalemiaAt least one serum potassium value of <3 mEq/l HypothyroidismAt least one measure of TSH >10.0 IU/ml MyalgiaSymptoms and signs consistent with myalgia, as diagnosed by physician or electromyography OtotoxicityHearing loss or шум в ушах, as documented by TB physician and/or by ENT physician. 16

17. Frequency of adverse events (N=1,344, Cohorts 1-4, 2000-2009) (1) Patients with diagnosed addiction (790) Patients without diagnosed addiction (524) N%N%p-value Any adverse effect72992.348692.70.757 Nausea and vomiting39750.332662.2<0.001 Diarrhea17922.718535.3<0.001 Depression567.1458.60.321 Psychosis475.9275.20.520 Seizure749.4315.90.023 Arthralgia30738.919837.80.695 Rush688.66612.60.021 Neuropathy435.4183.40.089 17

18. Frequency of adverse events (N=1,344, Cohorts 1-4, 2000-2009) (2) Patients with diagnosed addiction (790) Patients without diagnosed addiction (524) N%N%p-value Nephrotoxicity12115.39618.30.153 Hypothyroidism12615.99117.40.498 Hypokalemia18022.812223.30.832 Hepatitis648.1397.40.669 Elevation of transaminases44656.524246.2<0.001 Myalgia779.7519.70.997 Severe allergy50.651.00.527 Pruritus (itching)19825.113525.80.774 Ototoxicity8610.96512.40.399 18

19. Management of adverse events (N=579 with AUD and DUD, Cohorts 3-4, 2004-2009) Total N of patients with AE Symptomatic therapy Temporary withdrawal of drug Permanent withdrawal of drug Nausea and vomiting 283220 (77.7%)25 (8.8%)33 (11.7%) Diarrhea10986 (78.9%)6 (5.5%)13 (11.9%) Depression3929 (74.4%)3 (7.7%)5 (12.8%) Psychosis294 (13.8%)17 (58.6%)7 (24.1%) Seizure4632 (69.6%)11 (23.9%)3 (6.5%) Arthralgia214180 (84.1%)9 (4.2%)13 (6.1%) Rush4136 (87.8%)5 (12.2%)0 Neuropathy2521 (84.0%)2 (8.0%)0 Hepatitis3714 (37.8%)8 (21.6%)2 (5.4%) Elevation of transaminases 317248 (78.2%)21 (6.6%)6 (1.9%) 19

20. Management of adverse events (N=579 with AUD and DUD, Cohorts 3-4, 2002-2009) Total N of patients with AE Discontinuation of treatment Dose decrease or intermittent TX No therapy Nausea and vomiting 28301 (0.4%)4 (1.4%) Diarrhea109003 (2.8%) Depression391 (2.6%) 0 Psychosis2901 (3.4%)0 Seizure46000 Arthralgia21402 (0.9%)10 (4.7%) Rush41000 Neuropathy25002 (8.0%) Hepatitis370010 (27%) Elevation of transaminases 31701 (0.3%)36 (11.4%) 20

21. Treatment outcomes (N=1,344, Cohorts 1-4, 2000-2009) Patients with diagnosed addiction Patients without diagnosed addiction N%N%p-value Cured + Treatment completed43154.636770.0<0.001 Died719.0275.20.009 Lost to follow-up16420.86111.6<0.001 Failure11314.35710.90.069 Treatment stopped due to SE30.451.00.342 Treatment stopped due to comorbidities 20.361.10.097 Other60.810.20.319 TOTAL790524 21

22. Conclusions Alcohol use and/or drug addiction pose challenges for successful MDR-TB treatment, including the potential for additional adverse events; Alcohol use and/or drug addiction during treatment was not associated with increased risk or number of majority of adverse events during MDR-TB therapy; The majority of adverse events are not severe and can be managed without discontinuation of therapy; Interventions to diagnose and aggressively manage adverse events during MDR-TB treatment in patients with AUD and DUD could result in better treatment outcomes. 22

23. References 1.Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. IJTLD 11(12):1314-1320, 2007, Shin S. et al. 2.Alcohol use and the management of multidrug-resistant tuberculosis in Tomsk, Russian Federation. IJTLD 16(7): 891-896, Miller A. et. al. 3.Integration of alcohol use disorders identification and management in the tuberculosis programme in Tomsk Oblast, Russia. Eur J Public Health, 2009; 19: 16-18 23

24. Thank you! email: askar@pih.orgaskar@pih.org 24