Post on 05-Feb-2020
1
TB TREATMENT
Bijan Ghassemieh, MD
Seattle TB Clinical Intensive 2019
Disclosures
• None
1
2
2
Objectives
• Understand the following• Rationale and goals for standard TB regimen
• Standard regimen and potential side effects
• How to monitor patients
• When to deviate from the standard TB regimen
• Treatment completion
• Management of treatment failure
What I’m Not Going To Talk About
• Treatment of latent TB infection
• Decision to Initiate TB Treatment
• Treatment of MDR‐TB
• Treatment of extrapulmonary TB
• Treatment of TB in special situations: HIV (much), pediatrics, pregnancy
• All possible side effects
• Every potential TB treatment scenario you have or will ever encounter
3
4
3
2016 US TB TREATMENT GUIDELINES
Nahid CID 2016
Nomenclature
DRUG ABBREVIATION SINGLE LETTER ABREVIATION
Isoniazid INH I (or H)
Rifampin RIF R
Pyrazinamide PZA P (or Z)
Ethambutol EMB E
Fluoroquinolones (Moxifloxacin, Levofloxacin)
FQ
5
6
4
Outline
• Rationale and Goals of TB treatment
• The standard TB regimen (“RIPE” or “HRZE”)
• Common side effects of first line TB medications
• Monitoring during TB treatment
• Managing treatment interruptions
• When to deviate from the standard regimen
• Treatment in special situations: liver disease, renal disease, advanced age
• Treatment failure / completion
Why Is TB Therapy So Long?
Horsburgh NEJM 2015
7
8
5
Why Is TB Therapy So Long?
Horsburgh NEJM 2015
Why Is TB Therapy So Long?
9
10
6
Why So Many Drugs?
Why So Many Drugs?
• In a population of TB bugs, there is a constant “natural” low level mutation rate resulting in drug resistance
• Single drug therapy causes selective pressure favoring resistant bugs
• In patients with high burden disease, the likelihood of naturally occurring mutations to…
• Single drug is likely
• Two drugs is possible
• Three drugs is highly unlikely
11
12
7
How Did We Get To The Standard 6 Month Regimen?
• First curative TB treatment: INH, SM, aminosalicylicacid for up to 2 years
• Series of clinical trials (late 1940s to mid 1980s)• RIF plus INH allowed shortening duration from 18 to 9 months
• Adding PZA to the first 2 months allowed shortening from 9 to 6 months (“short course regimen”)
• 2014: 4 trials of 4 month regimen including FQ showed unacceptable rates of relapse (13‐20%)
• EMB added to regimen to prevent resistance
Horsburgh NEJM 2015
3 Goals of TB Treatment
• Rapid killing of multiplying bacteria • Individual impact: Decrease severity of disease and prevent death
• Population impact: Decrease transmission
• Eradicate remaining bacteria (“persisters”) to achieve durable cure (“sterilization”)
• Prevent acquisition of drug resistance during therapy
13
14
8
First Line TB Drug Activity
Drug Early bactericidal Preventing Sterilizing activity drug resistance activity
Isoniazid ++++ +++ ++Rifampin ++ +++ ++++Pyrazinamide + + +++Ethambutol +/++ ++ +
Highest ++++, High +++, Intermediate ++, Low +
Slide c/o Masa Narita
First Line Drug Take Home Points
• Rapid killing of multiplying bacteria INH
• “Sterilizing Effect” preventing relapse PZA, RIF
• Prevent drug resistance INH, RIF, EMB• Not PZA (limited effectiveness against rapidly growing bacteria, and works in acidic microenvironments)
• EMB included in regimen to prevent drug resistance
15
16
9
Outline
• Rationale and Goals of TB treatment
• The standard TB regimen (“RIPE” or “HRZE”)
• Common side effects of first line TB medications
• Monitoring during TB treatment
• Managing treatment interruptions
• When to deviate from the standard regimen
• Treatment in special situations: liver disease, renal disease, advanced age
• Treatment failure / completion
Case 1: 21 yo M From India
• Close contact to infectious TB case
• 2 months of fever, cough, weight loss, sweats, hemoptysis
• Sputum: AFB smear positive, MTB PCR positive (rpoB mutation negative)
• What treatment to start?
17
18
10
Treatment Initiation Considerations:
• Risk for drug resistance? Obtain molecular DST• Previous treatment, non‐DOT and/or without RIF• From country with high rate of drug resistance• Known contact to drug resistant case
• Comorbidities: Liver disease, renal disease, HIV, severe gout
• Drug interactions • Few medications impact TB drugs• INH impacts a few drugs• RIF impacts MANY drugs
• Assess barriers to adherence
The Standard Regimen
Isoniazid*
Rifampin
Pyrazinamide
Ethambutol**
0 1 2 3 4 5 6
Months
Initial Phase Continuation Phase
*Administer B6 with INH to those at risk of peripheral neuropathy**EMB can be stopped if TB is sensitive to INH and RIF
19
20
11
Duration of Treatment
• Depends on• Severity of disease• Comorbidities• Drugs used (“weaker” drugs require a longer duration)• Response to treatment
• Most patients with drug susceptible pulmonary TB will be treated for 6 months
• Compromise: Accept overtreatment of some (many?) to ensure cure of the overall population
• Treatment shortened (culture negative TB) or prolonged in certain situations
Dosing Frequency
Intensive Phase Continuation Phase
Regimen Drugs Frequency Drugs Frequency
1 RIPE ‐7 days/wk X 8 wks‐5 days/wk X 8 wks
RI ‐7 days/wk X 18 wks‐5 days/wk X 18 wks
2 RIPE ‐7 days/wk X 8 wks‐5 days/wk X 8 wks
RI ‐TIW X 18 wks
3 RIPE ‐TIW X 8 wks RI ‐TIW X 8 wks
• Daily dosing is preferred• TIW during continuation phase an acceptable alternative • Use Regimen 3 with caution if: HIV, smear positive, or cavitary disease. Missed doses can
lead to risk of treatment failure, relapse, drug resistance • BIW dosing not recommended. Dose missed? weekly dosing (inferior)
STRONGER
WEAKER
21
22
12
Dosing Frequency and Relapse Risk
Cavitary Non‐cavitary
6 month regimens 2 month culture +
2 month culture ‐
2 month culture +
2 month culture ‐
Daily throughout 6.0% 2.2% 1.8% 0.6%
Daily intensive phase THENTIW continuation phase
6.1% 3.3% 2.2% 1.2%
Daily intensive phase THENBIW continuation phase
15.6% 5.7% 5.4% 1.9%
TIW throughout 14.5% 5.3% 4.6% 1.7%
Chang AJRCCM 2006
DOT
• DOT is recommended for all patients
• Growing familiarity/comfort/evidence for video DOT
• If logistically not feasible for all, priorities for DOT are (next slide)
23
24
13
DOT: Priorities
• Smear positive• Drug resistance • Treatment failure or relapse• HIV• Previous treatment• Intermittent dosing• Non‐adherent• Substance abuse• Children• Disability (mental, emotional, physical)• Congregate settings (correctional facility, nursing home)• Homeless
Outline
• Rationale and Goals of TB treatment
• The standard TB regimen (“RIPE” or “HRZE”)
• Common side effects of first line TB medications
• Monitoring during TB treatment
• Managing treatment interruptions
• When to deviate from the standard regimen
• Treatment in special situations: liver disease, renal disease, advanced age
• Treatment failure / completion
25
26
14
First Line TB Medication Side Effects
• Common (~5‐18% require regimen adjustment)
• Can be severe• Drug induced liver injury (PZA>INH>RIF)• Blindness (EMB)• Hypersensitivity reaction (RIF)
• General principals: • Goal is to kill the TB bugs without causing significant long‐term side effects
• Minor side effects managed symptomatically• Major side effects: Drugs stopped, likely offending agent avoided (may require drug challenge to identify culprit)
First Line TB Medication Side Effects
• Excellent Resource: Curry Center Drug Resistant TB Survival Guide. Chapter 5: Medication Fact Sheets
• Available free online
27
28
15
First Line TB Medication Side Effects
Adverse Reaction Drugs*Rash PZA, INH, RIF, EMB
Gastrointestinal intolerance
PZA, RIF
Liver toxicity PZA, INH, RIF
Peripheral neuropathy INH, (EMB)
Optic neuritis EMB
Gout PZA
Slide c/o Lisa Chen
*Listed in order of most likely offending agent
Drug Induced Liver Injury (DILI)
29
30
16
Drug Induced Liver Injury (DILI)
• Most common severe adverse reaction from RIPE
• Symptoms: anorexia, nausea/vomiting, abdominal pain, fatigue, jaundice (late finding)
• Caused by: PZA > INH > RIF
• Risks: Underlying liver disease, older age, hepatotoxic medications
Drug Induced Liver Injury (DILI)
• Definition: • ALT > 3 times ULN with symptoms
• ALT > 5 times ULN without symptoms
• Patterns: • Elevated ALT/AST: PZA, INH, RIF
• Cholestatic (elevated alk phos and bili): RIF
31
32
17
DILI Management
• Rule out other causes (viral hepatitis, alcohol, other meds, biliary tract disease)
• Severe (ie ALT >500): • Stop RIPE. No further PZA or INH• Start “liver sparing regimen”: FQ, EMB, injectable • Consider retrying RIF once ALT < ~ 2 times ULN
• Mild/moderate: • Stop RIPE• Once ALT < 2 times ULN, sequential drug challenge at ~3‐7 day intervals: RIF (+/‐ EMB) INH +/‐ PZA
• If cholestatic pattern, consider different sequence
Rash
33
34
18
Rash
• All TB meds can cause rash
• Minor: Manage symptomatically (ie antihistamine)
• Signs of more severe rash: • Mucous membrane involvement suggests SJS/TEN
• Fever, CBC abnormalities (eosinophilia, anemia, thrombocytopena), renal failure, transaminitis suggests potential hypersensitivity reaction
• Petechial rash suggests thrombocytopenia from RIF
Rash
• If concerned, check safety labs (CBC, Cr, LFTs) and hold medications
• Sequential drug challenge (q 2‐3 days): RIF INH EMB/PZA
35
36
19
Optic Neuritis
Optic Neuritis
• Cause: EMB >>>>>>>>>>>>>>> INH
• Onset: Usually after > 1 month of EMB, but can occur within days
• Challenging to differentiate DM related eye symptoms from EMB toxicity
• Low threshold to stop EMB if concerned (remember: main purpose of EMB is to prevent resistance)
• Ophtho consult if severe or persists
37
38
20
GI Upset
GI Upset
• Symptoms: Nausea/vomiting, epigastric discomfort, poor appetite
• Need to hold meds and rule out DILI
• Meds: Any, but PZA and RIF most common
39
40
21
GI Upset
• Strategies: • Take at bedtime
• Start antacid (may decrease absorption of FQs)
• Start PPI
• Start anti‐nausea medication
• Take with light snack (food decreases absorption of all meds except rifabutin)
• Split doses (not ideal: may decrease drug effectiveness)
Peripheral Neurotoxicity
41
42
22
Peripheral Neurotoxicity
• Symptoms: symmetric, length dependent numbness/tingling (no motor symptoms)
• Meds: INH, FQs, (rarely EMB)
• Risk factors indicating B6: DM, alcohol, pregnancy, infants, HIV, malnutrition, renal failure, elderly
• If signs/symptoms of neuropathy, can try increasing B6 dose (but caution that this can rarely actually make neuropathy worse)
Monitoring During Treatment
Nahid CID 2016
• Shaded: optional• With DOT, ask about: GI symptoms, joints, rash, vision, neuropathy• Checklists are your friend
43
44
23
Outline
• Rationale and Goals of TB treatment
• The standard TB regimen (“RIPE” or “HRZE”)
• Common side effects of first line TB medications
• Monitoring during TB treatment
• Managing treatment interruptions
• When to deviate from the standard regimen
• Treatment in special situations: liver disease, renal disease, advanced age
• Treatment failure / completion
Treatment Interruptions
• Interruptions are common (side effects, non‐adherence)
• The earlier and longer the interruption, the more the need to restart from beginning
• If prolonged interruption, obtain smear/culture (and DST) and if positive need to restart from beginning
• Limited evidence to guide decisions. Following slide has one approach (adapted from NYC TB program)
45
46
24
Treatment Interruption
Details Management
During Intensive Phase
Lapse < 14 days Continue treatment
Lapse > 14 days Restart
DuringContinuation Phase
Received >80% and smear negative at diagnosis
Further treatment may not be necessary
Received >80% and smear positive at diagnosis
Continue treatment, unless lapse >2 consecutive months (restart)
Received < 80% and lapse < 3 mo Continue treatment
Received < 80% and lapse > 3 mo Restart
Nahid CID 2016
Outline
• Rationale and Goals of TB treatment
• The standard TB regimen (“RIPE” or “HRZE”)
• Common side effects of first line TB medications
• Monitoring during TB treatment
• Managing treatment interruptions
• When to deviate from the standard regimen
• Treatment in special situations: shorter/longer duration, liver disease, renal disease, advanced age
• Treatment failure / completion
47
48
25
Adjusting The Standard Regimen: Risk Factors For Relapse
Cavitary Non‐cavitary
6 month regimens 2 month culture +
2 month culture ‐
2 month culture +
2 month culture ‐
Daily throughout 6.0% 2.2% 1.8% 0.6%
Daily intensive phase THENTIW continuation phase
6.1% 3.3% 2.2% 1.2%
Daily intensive phase THENBIW continuation phase
15.6% 5.7% 5.4% 1.9%
TIW throughout 14.5% 5.3% 4.6% 1.7%
Chang AJRCCM 2006
Adjusting The Standard Regimen: Risk Factors For Relapse
• If cavitary disease AND culture positive at 2 months…
• extend continuation phase to 7 months (9 total months of treatment)
• If cavitary disease OR culture positive at 2 months, consider extending to 9 total months if….
• IBW < 10% • Active smoker• Poorly controlled DM• HIV or other immunosuppression• Extensive disease on CXR
49
50
26
Adjusting The Standard Regimen: Culture Negative TB
• Culture Negative TB: • Clinical syndrome consistent with TB
• Radiographic findings consistent with TB
• Sputum AFB smear/culture negative
• Other conditions unlikely or ruled out
• Positive TST/IGRA (not required)
• Clinical/radiographic improvement (2 mo CXR)
• Treatment: 2 months RIPE, 2 months RI
• If didn’t get better at 2 months, stop therapy and considered them treated for LTBI
Adjusting The Standard Regimen: Liver Disease
• Options for severe underlying liver disease (iebaseline ALT > 3 times ULN or advanced cirrhosis):
• PZA free regimen: 2 months RIE, 7 months RI
• PZA and INH free: 12‐18 months of RE + FQ/injectable/cycloserine
• “Liver sparing regimen”: 18‐24 months of FQ, EMB, injectable, +/‐ cycloserine
• Need careful and frequent monitoring on treatment
• Consultation with expert advised
51
52
27
Adjusting The Standard Regimen: Renal Disease
• Therapeutic drug monitoring may be necessary
• If on HD or creatinine clearance < 30, need to change frequency to TIW (after HD) for….
• PZA
• EMB
• Levofloxacin
Adjusting The Standard Regimen: Advanced Age
• Guidance in advanced age: • Risk of hepatitis and other side effects increases
• Some experts avoid PZA for those > 75
• Consider PZA if high bacillary burden or drug resistance
• Higher risk for drug interactions
• Patients require careful monitoring
53
54
28
Adjusting The Standard Regimen: Summary
• Cavitary disease AND culture positive at 2 months: Extend continuation phase to 7 months
• Consider extension if Cavitary OR culture positive at 2 months with specific risk factors
• Culture negative TB: 4 total months of treatment
• Severe baseline liver disease: Consider avoiding hepatotoxic medications (PZA > INH > RIF)
• Severe renal disease: Decrease frequency of PZA and EMB, consider drug level monitoring
• Advanced age: Consider PZA free regimen
Adjusting The Standard Regimen: Mono‐resistance or intolerance
• Without INH:• 6‐9 months of REP +/‐ FQ
• 9‐12 months RE + FQ
• Without RIF: MUCH different than WHO guidelines• 12‐18 months of IE + FQ. PZA for at least 1st 2 months
• 18 months IPE
• Consider injectable for 1st 2 months if severe or shooting for 12 months
• Without PZA: • 9 months RI with initial use of EMB white waiting for DST
Curry Center Drug Resistant TB Survival Guide
55
56
29
Outline
• Rationale and Goals of TB treatment
• The standard TB regimen (“RIPE” or “HRZE”)
• Common side effects of first line TB medications
• Monitoring during TB treatment
• Managing treatment interruptions
• When to deviate from the standard regimen
• Treatment in special situations: liver disease, renal disease, advanced age
• Treatment failure / completion
Treatment Failure
• Definition: Culture positive at 4 months
• 90‐95% of patients will be culture negative at 3 months if on regimen with INH and RIF
• If culture positive at 3 months, look for• Adherence issues
• Occult drug resistance (repeat molecular and phenotypic DST)
• Malabsorption
• Consider therapeutic drug monitoring
57
58
30
Treatment Completion
• Based on number of doses, not duration
• Definition• Intensive phase completed in 3 months
• Continuation phase completed in 6 months
• So total therapy completed in 9 months
• If targets not met, manage as treatment interruption
• End of treatment counseling: • Inform future providers about previous TB and baseline CXR abnormalities
• Seek medical evaluation if signs/symptoms TB recurrence
Resources
• ATS/CDC/IDSA 2016 Treatment Guidelines• https://www.cdc.gov/tb/publications/guidelines/pdf/Clin‐Infect‐Dis.‐2016‐Nahid‐cid_ciw376.pdf
• Curry Center Drug Resistant TB Survival Guide• Great resource overall, details medication fact sheets
• Horsburgh. “Treatment of Tuberculosis.” NEJM Nov 26, 2015
• Good basic overview• Outlines differences between US and international guidelines
• Curry Center warm line
• Us!
59
60