05 TB Treatment Bijan · • Rationale and goals for standard TB regimen • Standard regimen and...

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TB TREATMENT

Bijan Ghassemieh, MD

Seattle TB Clinical Intensive 2019

Disclosures

• None

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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

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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

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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

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Horsburgh NEJM 2015


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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

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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

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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

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Outline









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?

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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

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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

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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)

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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









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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)


• Excellent Resource: Curry Center Drug Resistant TB Survival Guide. Chapter 5: Medication Fact Sheets

• Available free online

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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)

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• 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


• 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

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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

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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

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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

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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

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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

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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

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Outline









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)

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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







• Treatment in special situations: shorter/longer duration, liver disease, renal disease, advanced age


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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

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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

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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

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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

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Outline









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

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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!

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05 TB Treatment Bijan · • Rationale and goals for standard TB regimen • Standard regimen and...

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