Management of Side Effects in DR-TB Patients with Alcohol and Drug Addiction Askar Yedilbayev, MD,...

Management of Side Effects in DR-TB Patients with Alcohol and Drug

Addiction

Askar Yedilbayev, MD, MPH,Irina Gelmanova, MD, MPH, Natalia Zemlyanaya, MD, PhDPartners In Health

Session N.00245 Best practice in management of side effects among DR-TB patients to improve quality of care

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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.

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Current therapy of MDR-TB

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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.

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The setting – Tomsk, Russia

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Drugs in baseline regimens (N=244, Cohort 1, 2000-2002)

N %

H (300 mg, 900 mg biweekly) 5 2.05

E (15-20 mg/kg) 63 25.82

Z (20-30 mg/kg) 178 72.95

KM (1000 mg, 15-20 mg/kg) 114 46.72

CM (1000 mg, 15-20 mg/kg) 154 63.11

AM (1000 mg, 15-20 mg/kg) 2 0.82

FQ (OFX 800 mg, LFX 500 mg) 243 99.59

CS (500-1000 mg) 241 98.77

ETO/PAS (500-1000 mg) 184 75.41

AMX/CLV (1500-2000 mg) 20 8.20

RFB (300 mg) 4 1.64

Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. IJTLD 11(12):1314-1320, 2007, Shin S. et al.

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Incidence and characteristics of adverse reactions (N=244, Cohort 1, 2000-2002)


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Distribution of adverse events by month (N=244, Cohort 1, 2000-2002)

0,0

75,0

150,0

225,0

300,0

0,0 7,5 15,0 22,5 30,0

Histogram of month_all

month_all

Co

un

t


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.

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• 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.


• 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)

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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.

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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

FemaleMale

143647

18.1% 204320

38.9 <0.001

Age, years, median (IQR) 39 (30-42) 33 (25-48) <0.001

History of incarceration 350 44.3 92 17.6 <0.001

Employed at time of treatment 89 11.3 145 27.7 <0.001

Homeless 61 7.9 8 1.6 <0.001

HIV 15 2.0 2 0.4 0.013

Low BMI 354 44.8 186 35.5 <0.001

Bilateral and cavitary disease 478 61.1 225 43.7 <0.001

XDR-TB 42 5.3 29 5.5 0.860

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Drugs in baseline regimens (N=407, Cohorts 1 and 2, 2000-2004)

Drinkers (N=253) Non-drinkers (N154) p-value

OFX 249 (98.4%) 150 (97.4%) 0.47

CS 248 (98.0%) 150 (97.4%) 0.68

PAS 224 (88.5%) 127 (82.4%) 0.09

Z 207 (81.8%) 118 (76.6%) 0.21

ETO/PTO 206 (81.8%) 125 (81.2%) 0.28

CM 157 (62.1%) 84 (54.5%) 0.13

KM 90 (35.6%) 65 (42.2%) 0.18

E 71 (28.1%) 42 (27.3%) 0.8

AMX/CLV 8 (3.2%) 8 (5.2%) 0.31

RFB 2 (0.7%) 2 (1.3%) 0.61

H 2 (0.7%) 4 (2.6%) 0.18

MFX 1 (0.4%) 2 (1.3%) 0.3

AM 0 2 (1.3%) 0.07

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Definitions of adverse events (1)

Adverse reaction Definition of specific adverse reaction

Nausea and vomiting

Documentation of nausea and vomiting by physician

Diarrhea Documentation of diarrhea by physician

Depression As diagnosed by a TB physician and/or as judged by psychiatrist, based on ICD-10 criteria

Psychosis As diagnosed by a TB physician and/or as judged by psychiatrist, based on ICD-10 criteria

Seizure Witnessed or unwitnessed event consistent with seizure

Arthralgia Joint pain as reported by patient and documented by physician, with or without presence of arthritis

Rush Dermatological reaction felt to be related to anti-TB medicines, as documented by physician

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Definitions of adverse events (2)

Adverse reaction Definition of specific adverse reaction

Neuropathy Symptoms and signs consistent with neuropathy, as diagnosed by physician or electomyography

Nephrotoxicity Elevation of at least one creatinine value >141 mmol/l

Hepatotoxicity Elevation 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)

Hypokalemia At least one serum potassium value of <3 mEq/l

Hypothyroidism At least one measure of TSH >10.0 IU/ml

Myalgia Symptoms and signs consistent with myalgia, as diagnosed by physician or electromyography

Ototoxicity Hearing loss or шум в ушах, as documented by TB physician and/or by ENT physician.

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Frequency of adverse events (N=1,344, Cohorts 1-4, 2000-2009) (1)


addiction (790)


addiction (524)N % N % p-value

Any adverse effect 729 92.3 486 92.7 0.757

Nausea and vomiting 397 50.3 326 62.2 <0.001

Diarrhea 179 22.7 185 35.3 <0.001

Depression 56 7.1 45 8.6 0.321

Psychosis 47 5.9 27 5.2 0.520

Seizure 74 9.4 31 5.9 0.023

Arthralgia 307 38.9 198 37.8 0.695

Rush 68 8.6 66 12.6 0.021

Neuropathy 43 5.4 18 3.4 0.089

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Frequency of adverse events (N=1,344, Cohorts 1-4, 2000-2009) (2)


addiction (790)


addiction (524)N % N % p-value

Nephrotoxicity 121 15.3 96 18.3 0.153

Hypothyroidism 126 15.9 91 17.4 0.498

Hypokalemia 180 22.8 122 23.3 0.832

Hepatitis 64 8.1 39 7.4 0.669

Elevation of transaminases 446 56.5 242 46.2 <0.001

Myalgia 77 9.7 51 9.7 0.997

Severe allergy 5 0.6 5 1.0 0.527

Pruritus (itching) 198 25.1 135 25.8 0.774

Ototoxicity 86 10.9 65 12.4 0.399

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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

drugNausea and vomiting

283 220 (77.7%) 25 (8.8%) 33 (11.7%)

Diarrhea 109 86 (78.9%) 6 (5.5%) 13 (11.9%)

Depression 39 29 (74.4%) 3 (7.7%) 5 (12.8%)

Psychosis 29 4 (13.8%) 17 (58.6%) 7 (24.1%)

Seizure 46 32 (69.6%) 11 (23.9%) 3 (6.5%)

Arthralgia 214 180 (84.1%) 9 (4.2%) 13 (6.1%)

Rush 41 36 (87.8%) 5 (12.2%) 0

Neuropathy 25 21 (84.0%) 2 (8.0%) 0

Hepatitis 37 14 (37.8%) 8 (21.6%) 2 (5.4%)


317 248 (78.2%) 21 (6.6%) 6 (1.9%)

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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

283 0 1 (0.4%) 4 (1.4%)

Diarrhea 109 0 0 3 (2.8%)

Depression 39 1 (2.6%) 1 (2.6%) 0

Psychosis 29 0 1 (3.4%) 0

Seizure 46 0 0 0

Arthralgia 214 0 2 (0.9%) 10 (4.7%)

Rush 41 0 0 0

Neuropathy 25 0 0 2 (8.0%)

Hepatitis 37 0 0 10 (27%)


317 0 1 (0.3%) 36 (11.4%)

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Treatment outcomes (N=1,344, Cohorts 1-4, 2000-2009)

Patients with diagnosed addiction

Patients without diagnosed addiction

N % N % p-value

Cured + Treatment completed 431 54.6 367 70.0 <0.001

Died 71 9.0 27 5.2 0.009

Lost to follow-up 164 20.8 61 11.6 <0.001

Failure 113 14.3 57 10.9 0.069

Treatment stopped due to SE 3 0.4 5 1.0 0.342

Treatment stopped due to comorbidities

2 0.3 6 1.1 0.097

Other 6 0.8 1 0.2 0.319

TOTAL 790 524

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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.

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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

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Management of Side Effects in DR-TB Patients with Alcohol and Drug Addiction Askar Yedilbayev, MD,...

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