ADVERSE EVENTS IN MDR-TB THERAPY - GHDonline...ADVERSE EVENTS IN MDR-TB THERAPY Adverse events •...
Transcript of ADVERSE EVENTS IN MDR-TB THERAPY - GHDonline...ADVERSE EVENTS IN MDR-TB THERAPY Adverse events •...
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!