ADVERSE EVENTS IN MDR-TB THERAPY - GHDonline...ADVERSE EVENTS IN MDR-TB THERAPY Adverse events • Patients who receive second-line anti-TB therapy for drug resistant TB may present

SALMAAN KESHAVJEE, MD, PHD

PARTNERS IN HEALTH HARVARD MEDICAL SCHOOL

BRIGHAM AND WOMEN’S HOSPITAL

ISTANBUL, TURKEYAPRIL 2008

ADVERSE EVENTS IN MDR-TB THERAPY

Adverse events

• Patients who receive second-line anti-TB therapy for drug resistant TB may present with a variety of adverse events.

• The majority of events are not severe and can be managed without discontinuation of therapy.

• Some adverse events are life threatening if not recognized and treated promptly.

• If adverse events are not well managed, there is a higher risk of default and treatment failure.

Adverse events

Neurological Adverse Events

Minor: Moderate to Severe:

• Dizziness • Headache • Insomnia• Vertigo

• Convulsions• Syncope• Peripheral neuropathy• Ototoxicity

Psychiatric Adverse Events

Minor: Moderate to Severe:

• Irritability• Anxiety• Personality change

• Depression • Psychosis• Suicidal ideation

Dermatologic Adverse Events

Minor: Moderate to Severe:

• Skin pigmentation• Photosensitivity• Dry skin

• Stevens-Johnsonsyndrome

Endocrine Adverse Events

Minor: Moderate to Severe:

• Poor glycemiccontrol in diabetics

• Hypothyroidism

Gastrointestinal Adverse Events

Minor: Moderate to Severe:

• Nausea• Vomiting• Diarrhea

• Gastritis• Ulcers• Hepatitis • Bowel obstruction

Electrolyte abnormalities

Minor: Moderate to Severe:• Dehydration • Hypokalemia

• Hypomagnesemia

Other adverse events

Minor: Moderate to Severe:• Arthritis• Myalgias• Candidiasis

• Weight loss• Renal insufficiency• Optic neuritis

Incidence of Adverse Events:Retrospective Chart Review of

244 MDR-TB Patients in Tomsk, Russia

Tomsk Oblast Tuberculosis ServicesPartners In Health

• Complete blood count• Electrolytes• Liver function tests• Urea and creatinine• HIV ELISA• Audiometry• Psychiatric evaluation• Pregnancy testing

Baseline Laboratory Testing

Monitoring of patients

Test Frequency CommentsChest radiograph

At initiation and then every 6 months

LFTs, Creatinine and Potassium

At initiation and then monthly If the creatinine doubles, adjust the dose of the injectable, then monitor creatinine every week until it stabilizes.

TSH Every two months

Resistance patterns (n=243)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

inh rif emb pza sm km cm ethio fq cs

not testedsensitiveresistant

Anti-tuberculosis medications received in individualized treatment regimens (N=244)

Medication* (daily doses, unless specified)N %

H (300 mg, 900 mg biweekly) 5 2.R (600 mg) 0 0E (15-20 mg/kg) 63 26Z (20-30 mg/kg) 178 73S (1000 mg, 15 mg/kg) 0 0KM (1000 mg, 15 mg/kg) 114 47CM (1000 mg, 15 mg/kg) 154 63AMK (1000 mg, 15 mg/kg) 2 1Fluoroquinolone (CPX 1500 mg, OFX 800 mg, LFX 500 mg) δ 241 99CS (500-1000 mg) 243 99.6Ethio / prothio (500-1000 mg) 184 75PAS (8 mg) 217 89Amox-Clav (1500-2000 mg) 20 8Rifabutin (300 mg) 4 2

LEGEND:H isoniazid, R rifampin, E ethambutol, Z pyrazinamide, S streptomycin, KM kanamycin, CM capreomycin, AMK amikacin, CS cycloserine, CPX ciprofloxacin, OFX ofloxacin, Ethio ethionamide, Prothio prothionamide, PAS para-aminosalicylic acid, Amox-Clav amoxacillin-clavulanate)

δMost patients received ofloxacin as their fluoroquinolone

• Median time in treatment : 18.5 months [range 1.0 to 42.4]

• Median duration of injectable drug: 8.6 months [0-27.5]

• Experienced at least one adverse event: 73.3%

• Event resulted in permanent discontinuation of a drug: 28.7%

• Regimen included: parenteral agent, FQ, PAS, prothio/ethio, CS

• Median number of drugs: 6 [range 4-7]

• Baseline comorbid conditions: 28.3%

Patient Demographics (n=244)

Characteristics of MDR-TB patients (n=244)

Characteristic (N, if not 244)Frequency(%)

Median (range)

Number of patients who receivedsurgery

ThoracoplastySegmental resection (one or more)LobectomyPneumonectomy

24 (9.8)45141

Percent missed doses* 5% [0, 45%]

Time to culture conversion in months(n=218)

2 [1, 18]

Duration of therapy in monthsAll patients

CuresFailuresDeathsDefaults

18.5 [1.0, 42.4]18.8 [16.1, 42.4]18.9 [10.1, 28.1]10.9 [1.8, 22.9]9.2 [1.0, 15.7]

* Defined as the percent of doses among all prescribed doses missed throughout DOTS-Plus treatment, as recorded on the treatment administration forms

Clinical and treatment characteristics of patient cohort (N=244)

Characteristics No adverse eventN=65

Adverse eventN=179

Age 31 [18, 54] 32.6 [17, 65]

Male gender 59 (90.8) 152 (84.9)

Prison sector 32 (49.2) 78 (43.6)

Number of years with TB 2.5 [0.1, 28.3] 3.5 [0.1, 22.1]

Number of drugs resistant 4.0 [3, 9] 5.0 [3, 9]

Low baseline body mass index 30 (46.2) 72 (40.2)

Baseline comorbidity* 21 (32.3) 48 (26.8)

Substance abuse

Alcohol use¶ 21 (32.3) 56 (31.3)

Illicit drug use¶ 4 (6.2) 9 (5.0)

Treatment outcome

Cure§ 42 (64.6) 145 (81.0)

Default 10 (15.4) 18 (10.1)

Failure 5 (7.7) 11 (6.2)

Death§ 7 (10.8) 5 (2.8)

Nonadherent 9 (13.9) 13 (7.3)

*Any of the following: diabetes mellitus, renal insufficiency, hepatic dysfunction, cardiovascular disorder, seizure diagnosis,gastritis/ulcer, psychiatric disorder¶ Alcohol or illicit drug use during DOTS-Plus treatment, per physician report § p < 0.05

Adverse events evaluated in the Tomsk cohort

• Nausea and vomiting• Diarrhea• Nephrotoxicity• Hepatotoxicity• Hypokalemia• Hypothyroidism

• Depression• Psychosis• Seizure• Ototoxicity• Arthralgia• Rash• Neuropathy

Peripheral Nervous System Adverse EventsNumber of patients: 10 patients (4.1%) presented with

peripheral neuropathy

Suspected medication: H, E, Ethio, FQ, CS, aminoglycosides, CM

Median time to adverse event: 14.0 months of treatment [4.9, 29.7]

Higher incidence in patients with comorbid disease (e.g. diabetes, HIV, alcoholism)

Management Strategies: •tricyclic antidepressants•physical therapy•look for other possible causes•change AG to CM•suspend suspected agent

Permanent interruption: 0%

Central Nervous System Adverse Events: SeizureNumber of patients: 28 patients (11.5%)

Suspected medication: FQ, CM, CS

Median time to adverse event: 5.4 months of treatment (seizure)

Management Strategies: •Anti-seizure medications•look for other possible causes•Lower doses of suspected agents

Permanent interruption: 10.7% (CS 1; CS 1)

Central Nervous System Adverse Events: PsychosisNumber of patients: 29 patients (11.9%)

Suspected medication: H, FQ, CM, CS, Ethio

Median time to adverse event:

3.3 months of treatment

Management Strategies: •Anti-psychotic therapy•lower the dose of CS •suspend CS for short periods•suspend other contributing non-anti-TB medications

Permanent interruption: 17.2% (CS 4)

OtotoxicityNumber of patients: 38 patients (15.6%) presented with

moderate to severe hearing loss

Suspected medication: S, KM, AMK, CM

Median time to adverse event: 6.6 months of treatment

Management Strategies: •Irreversible; however, progression washalted in all cases

•Change injectable to CM

•suspend injectable (if no other option)

Permanent interruption: 34.2% (CM 1; KM 12)

DepressionDepressionNumber of patients: 21 patients (8.3%)

Suspected medication: CS; socio-economic conditionsMedian time to adverse event:

7.3 months of treatment

Management Strategies: •address psychosocial and socioeconomicstressors•group therapy•antidepressant medications•lower the dose of CS

Permanent interruption: 14.3% (CS 1; OFL 2)

Hypothyroidism*Number of patients: 42 patients (17.2%)

Suspected medication: Ethio, PAS; (affect iodine uptake and organification)

Median time to adverse event: 6.0 months of treatment

Management Strategies: •Reversible 4 to 5 weeks after treatmentcompletion

•thyroid hormone supplementation for theduration of therapy; Responsive to low-doses of levo-thyroxine (25-75 mcg/day)

•substitute an equally effective medicationfor Ethio or PAS

Permanent interruption: 7.1% (PAS 2)*Defined as one report of TSH > 10.0 iU/mL

Nausea and VomitingNumber of patients: 184 patients (75.4%)

Suspected medication: Ethio, PAS, H, E, Z, KM, CM, OFL, CS, E, AMX-CLV

Median time to adverse event:

1.8 months of treatment

Management Strategies: •Supportive management withantiemetics, antacids, hydration

•monitor electrolytes

Permanent interruption: 14.6% (H 1, KM 3, CM 3, OFX 2, CS 2, PAS 9; Ethio 5; Z 8, E 4, AMX-CLV 1)

DiarrheaNumber of patients: 113 patients (46.3%)

Suspected medication: Ethio, PAS, H, E, Z, KM, CM, OFL, CS, E, AMX-CLV

Median time to adverse event: 2.3 months of treatmentManagement Strategies: •Supportive management with hydration,

anti-diarrheals if indicated

•monitor electrolytes

Permanent interruption: 5.3% (CM 4; OFX 1; PAS 3; Ethio 1)

Hepatotoxicity*Number of patients: 41 patients (16.8%)

Suspected medication: Z, H, R, E, Ethio, PAS, FQMedian time to adverse event: 5.8 months of treatmentManagement Strategies: •Dose of Z decreased to 15mg/kg with

success

•Other suspected agents stopped

Permanent interruption: 9.8% (Z 3, E 1, Ethio 1)

*Defined as elevation of either serum transaminases or serum bilirubin at least 3 times upper limit of normal values

Hypokalemia*Number of patients: 81 patients (33.2%)

Suspected medication: S, KM, AMK, CMMedian time to adverse event:

4.8 months of treatment

Management Strategies: •Repletion of potassium and magnesium

•Temporary suspension of injectable agent

•Permanent suspension of injectable agent

Permanent interruption: 7.4% (CM 6)

*Defined as at least one serum potassium value of < 3.0 mEq/L

Renal Tubules (after 2 months of treatment with CM)

Nephrotoxicity*Number of patients: 24 patients (9.8%)

Suspected medication: S, K, AMK, CMMedian time to adverse event:

4.8 months of treatment

Management Strategies: •Reduce dose of injectable agent

•suspend injectable agent if in renal failure

•Change AG to CM

Permanent interruption: 0%

*Defined as elevation of at least one serum creatinine value greater than 141 mmol/L

MusculoskeletalNumber of patients: 115 patients (47.1%)

Suspected medication: Z, FQ, EthioMedian time to adverse event:

3.7 months of treatment

Management Strategies: •Transient, well-controlled

•NSAIDS

•Physical Therapy

•Decrease dose of PZA

Permanent interruption: 9.6% (Z 6; Ethio 1; E 1; CM 2; PAS 1)

RashNumber of patients: 39 patients (16.0%)

Suspected medication: Z, Ethio, any medication

Median time to adverse event:

4.7 months of treatment

Management Strategies: •Usually transient

•Need to be mindful of severe drugreaction

Permanent interruption: 7.7% (Ethio 2; Z 1))

Summary of adverse events, N=244

0

10

20

30

40

50

60

70

80

Nause

a and

vomitin

gArth

ralgi

aDiar

rhea

Hypok

alemia

Hypoth

yroidi

smHep

atotox

icity

Rash

Ototox

icity

Psych

osis

Seizure

Nephro

toxici

tyDep

ressio

nNeu

ropath

y

Adverse Event

% o

f pat

ient

s

Distribution of Adverse Events by Month

Approximately 65% of adverse events occurred in the first 6 months

TREATMENT OUTCOMES (N=244)

Cure77.0%

Failure6.6%

Death4.9%

Default11.5%

Overlapping or Additive Toxicities

Toxicity Antiretroviral agent Anti-TB agent

Peripheral neuropathy D4T, ddI, ddC, H, E, CS

Nausea and Vomiting All All

Central Nervous System toxicity

Efavirenz H, CS

Skin Rash Abacavir, Nevirapine, Efavirenz and others

H, Z, PAS and others

Hepatotoxicity Nevirapine, Efavirenz, all NRTIs and PIs

H, R, E, Z, PAS, Ethio

Bone Marrow surpression AZT R, Rifabutin

Adverse Events in Patients with HIV infection

• Certain adverse events can be exacerbated by HIV and ART:

– Nausea and vomiting

– Nephrotoxicity

– Hypokalemia

– Hepatotoxicity

– Peripheral neuropathy

Community-Based Management of Adverse Events

• Use protocols and algorithms

• Ambulatory management

• Early diagnosis and treatment of adverse events

• Clinical evaluation is sufficient for diagnosis and management in resource-limited settings

• Medications and services relating to adverse events should be provided as part of a comprehensive DOTS-Plus treatment program

Supplementary medications

• Gastrointestinal adverse events:– Anti-emetics, antacids, anti-ulcer, antidiarrheals

• Psychiatric adverse events:– Anti-psychotic medication, antidepressants

• Endocrine adverse events:– Thyroid hormone replacement

• Neurological adverse events:– Analgesics, anticonvulsants, tricyclic antidepressants

• Electrolyte adverse events:– Potassium and magnesium supplements

Adverse EventsConclusions

• Adverse events are common

• Most adverse events can be successfully managed

• Do not stop TB drugs unless adverse events are severe or if the problem does not respond to other management strategies!

Thank You!