TB Medications and TB Medications and the Liverthe Liver

Dr John P WatsonDr John P WatsonConsultant Respiratory PhysicianConsultant Respiratory Physician

Leeds Teaching Hospitals NHS TrustLeeds Teaching Hospitals NHS Trust

TB MedicationsTB MedicationsFirst LineFirst Line RifampicinRifampicin IsoniazidIsoniazid PyrazinamidePyrazinamide EthambutolEthambutol StreptomycinStreptomycin

Second LineSecond Line QuinolonesQuinolones

–– Moxi/LevofloxacinMoxi/Levofloxacin

InjectablesInjectables–– Amikacin, CapreomycinAmikacin, Capreomycin

ProthionamideProthionamide PASPAS CycloserineCycloserine LinezolidLinezolid ClofazimineClofazimine MacrolidesMacrolides

TB MedicationsTB Medicationswhich can cause liver injurywhich can cause liver injury

First LineFirst Line RifampicinRifampicin IsoniazidIsoniazid PyrazinamidePyrazinamide EthambutolEthambutol StreptomycinStreptomycin

Second LineSecond Line QuinolonesQuinolones

–– Moxi/LevofloxacinMoxi/Levofloxacin

InjectablesInjectables–– Amikacin, CapreomycinAmikacin, Capreomycin

ProthionamideProthionamide PASPAS CycloserineCycloserine LinezolidLinezolid ClofazimineClofazimine MacrolidesMacrolides

PathologyPathology

Isoniazid: Hepatocellular steatosis Isoniazid: Hepatocellular steatosis and necrosisand necrosis

Rifampicin; Centrilobular necrosis Rifampicin; Centrilobular necrosis +/+/-- cholestasischolestasis

MechanismsMechanisms

Not dose dependantNot dose dependant–– OverdoseOverdose

Not IgE mediated Not IgE mediated –– allergyallergy

IdiosyncraticIdiosyncratic Probably toxic metabolitesProbably toxic metabolites

Clinical featuresClinical features

Non specific symptoms of liver injuryNon specific symptoms of liver injury–– JaundiceJaundice–– Nausea / vomitNausea / vomit–– Abdominal painAbdominal pain–– Lethargy and malaiseLethargy and malaise

Differential Differential –– viral hepatitisviral hepatitis–– Toxic eg alcoholToxic eg alcohol

Laboratory diagnosisLaboratory diagnosis

Raised transaminase Raised transaminase Mild: ALT < 5 x ULN (<200)Mild: ALT < 5 x ULN (<200)Moderate: ALT 5Moderate: ALT 5--10 X ULN (200 10 X ULN (200 ––

400)400)Severe: ALT > 10 x ULN (>400)Severe: ALT > 10 x ULN (>400)

IncidenceIncidenceMonotherapy (prophylaxis for LTBI)Monotherapy (prophylaxis for LTBI) Isoniazid Isoniazid 0.5%0.5% Rifampicin Rifampicin 11--2%2% Pyrazinamide Pyrazinamide ??

Combination therapy (Active TB):Combination therapy (Active TB): Published range 2Published range 2--27%27%

–– Varied settings and definitionsVaried settings and definitions Leeds 2006Leeds 2006--2010 634 patients2010 634 patients

–– ALT > 2 x ULN: ALT > 2 x ULN: 46 46 (7.3%)(7.3%)–– ALT > 5 x ULN:ALT > 5 x ULN: 1414 (2.2%)(2.2%)

Time of OnsetTime of Onset

Most common in 1Most common in 1stst 2 months2 monthsCan occur any time in treatmentCan occur any time in treatment

Leeds 2006Leeds 2006--1010 Total: Mean 28/7 (range 3Total: Mean 28/7 (range 3--306)306)ModerateModerate--severe: Mean 42 dayssevere: Mean 42 days 12/14 within 56 days12/14 within 56 days

Risk factorsRisk factors

Increasing ageIncreasing age Female Female MalnutritionMalnutritionHepatitis B / CHepatitis B / CHIVHIVAbnormal baseline liver enzymesAbnormal baseline liver enzymes(Leeds 2006(Leeds 2006--2010 2010 –– age only)age only)

Case history (1)Case history (1)

72 year old female72 year old femaleRA on infliximabRA on infliximab

–– Negative mantoux pre treatmentNegative mantoux pre treatment

Pulmonary TBPulmonary TBStandard treatment RHEZStandard treatment RHEZDeveloped severe hepatits Developed severe hepatits ––

progressed despite stopping drugsprogressed despite stopping drugsDied liver failureDied liver failure

Case History (2)Case History (2) 38 year old Daughter of above 38 year old Daughter of above Contact screeningContact screening CXR NormalCXR Normal CoughCough Sputum AAFB smear posSputum AAFB smear pos Commenced RHEZCommenced RHEZ Within 2 weeks ALT > 5 x ULNWithin 2 weeks ALT > 5 x ULN Stopped drugsStopped drugs Subsequently culture identified as nonSubsequently culture identified as non--

tuberculous mycobacteriumtuberculous mycobacterium

Genetic factorsGenetic factors

Polymorphisms in drug metobilismPolymorphisms in drug metobilismSlow acetylatorsSlow acetylators

–– IsoniazidIsoniazid

Other possible enzymes Other possible enzymes Currently not able to test / predict.Currently not able to test / predict.

AdaptationAdaptation

In some cases, liver may adapt to In some cases, liver may adapt to drugdrug

After initial drug induced liver injury, After initial drug induced liver injury, may recover and then tolerate drug may recover and then tolerate drug subsequentlysubsequently

Monitoring Monitoring –– NICE adviceNICE adviceNICE CG117 NICE CG117 20112011

Monitoring: BTS AdviceMonitoring: BTS AdviceJoint Tuberculosis Committee Thorax Joint Tuberculosis Committee Thorax 1998 1998

PrePre--treatment LFTtreatment LFT Inform patients of possible side Inform patients of possible side

effectseffects Regular monitoring if preRegular monitoring if pre--existent existent

liver disease ( weekly for 2 weeks, liver disease ( weekly for 2 weeks, then 2 weekly for 2 months)then 2 weekly for 2 months)

Otherwise only repeat if symptomsOtherwise only repeat if symptoms

Monitoring: ATS AdviceMonitoring: ATS AdviceAm J Respir Crit Care MedAm J Respir Crit Care Med 20062006

Assessment of risk factors for Assessment of risk factors for hepatotoxicityhepatotoxicity

Baseline history and examination Baseline history and examination including symptoms / signs of liver including symptoms / signs of liver diseasedisease

Screen for viral hepatits in those with Screen for viral hepatits in those with risk factors risk factors

Educate patient re potential side Educate patient re potential side effectseffects

Monitoring Monitoring –– ATS advice ATS advice (continued)(continued)

LTBILTBIBaseline blood tests not Baseline blood tests not

recommended unless risk factorsrecommended unless risk factorsConsider baseline and regular Consider baseline and regular

monitoring of ALT if >35yearsmonitoring of ALT if >35years

Monitoring Monitoring –– ATS advice ATS advice (continued)(continued)

Active TBActive TBBaseline ALT / Bilirubin / Alk PhosBaseline ALT / Bilirubin / Alk PhosRoutine monitoring of ALT ifRoutine monitoring of ALT if

–– Abnormal baselineAbnormal baseline–– HIV / Hepatitis virus infectionHIV / Hepatitis virus infection–– Liver disease Liver disease –– Alcohol / other hepatotoxic drugsAlcohol / other hepatotoxic drugs–– ? Women? Women–– ? Older adults? Older adults

Routine MonitoringRoutine Monitoring

Disadvantages:Disadvantages:–– Multiple blood testsMultiple blood tests–– May result in discontinuing / interrupting May result in discontinuing / interrupting

treatment unnecessarilytreatment unnecessarily–– CostCost

Benefits:Benefits:–– If routine, avoid missing high risk patientIf routine, avoid missing high risk patient–– May identify Liver injury at earlier stage May identify Liver injury at earlier stage –– prevent serious complicationsprevent serious complications–– Cost cheaper than liver transplantCost cheaper than liver transplant

Leeds practiceLeeds practice

BaselineBaselineRepeat at 2/52, 4/52 and 8/52Repeat at 2/52, 4/52 and 8/52No further monitoring unless No further monitoring unless

abnormal or symptomsabnormal or symptoms

Abnormal baseline LFTAbnormal baseline LFT

Do NOT need to modify treatment Do NOT need to modify treatment regimeregime

DO monitor ALT DO monitor ALT In most cases, will IMPROVE on TB In most cases, will IMPROVE on TB

treatmenttreatment

Management of hepatotoxicityManagement of hepatotoxicity––NICE AdviceNICE Advice

1.3.6.2 1.3.6.2 ““If the patientIf the patient’’s liver function s liver function deteriorates significantly on drug deteriorates significantly on drug treatment, advice on management treatment, advice on management options should be sought from options should be sought from clinicians with specialist experience of clinicians with specialist experience of these circumstances.these circumstances.”” [2006][2006]

Management of Hepatotoxicity Management of Hepatotoxicity ––BTS AdviceBTS Advice

ALT > 5x ULN: Stop drugsALT > 5x ULN: Stop drugs If not unwell or infectious If not unwell or infectious –– wait for wait for

ALT to return to normalALT to return to normal If unwell / infectious If unwell / infectious –– Streptomycin Streptomycin

+ Ethambutol +/+ Ethambutol +/-- second line drug second line drug ––preferably as in patient.preferably as in patient.

Management of Hepatotoxicity Management of Hepatotoxicity ––BTS Advice (cont)BTS Advice (cont)

Rechallenge in order; Rechallenge in order; –– INH INH –– Rif Rif –– PyrazinamidePyrazinamide

Isoniazid: 50mg Isoniazid: 50mg –– inc to 300 over 2inc to 300 over 2--3 3 daysdays

Rifampicin: 75mg Rifampicin: 75mg –– 300 over 2300 over 2--3 days 3 days ––then 450/600mg over further 2then 450/600mg over further 2--3 days3 days

Pyrazinamide 250mg Pyrazinamide 250mg –– 1000 over 21000 over 2--3 3 days days –– then 1.5g / 2gthen 1.5g / 2g

If further reaction, remove latest added If further reaction, remove latest added drug.drug.

BTS rechallenge regimeBTS rechallenge regime

Allows for possibility of adaptationAllows for possibility of adaptationComplicated drug incrementsComplicated drug incrementsStarting doses smaller than single Starting doses smaller than single

tablettabletDaily monitoring Daily monitoring –– difficult if difficult if

outpatient outpatient

Management of Hepatotoxicity Management of Hepatotoxicity ––ATS AdviceATS Advice

Stop drugs if:Stop drugs if:ALT > 5 x ULNALT > 5 x ULNALT > 3 x ULN + jaundice or ALT > 3 x ULN + jaundice or

symptomssymptomsCheck Hepatits virus serology/ other Check Hepatits virus serology/ other

drugs / alcoholdrugs / alcohol If indicated, until cause determined, If indicated, until cause determined,

treat with 3 drugs less likely to cause treat with 3 drugs less likely to cause toxicitytoxicity

Management of HepatotoxicityManagement of Hepatotoxicity––ATS advice (cont)ATS advice (cont)

When ALT < 2 x ULN When ALT < 2 x ULN –– Start Rifampicin + EthambutolStart Rifampicin + Ethambutol After 3After 3--7 days restart Isoniazid7 days restart Isoniazid If symptoms recur or ALT increases again If symptoms recur or ALT increases again

–– stop last drug added.stop last drug added. If necessary reIf necessary re--challenge with challenge with

PyrazinamidePyrazinamide If tolerating Rifampicin and Isoniazid, and If tolerating Rifampicin and Isoniazid, and

drug sensitive drug sensitive –– continue without continue without pyrazinamide (9/12 regimen)pyrazinamide (9/12 regimen)

ConclusionConclusion

Consider risk factors, but most cases Consider risk factors, but most cases unpredicatbleunpredicatble

Educate patients re potential side Educate patients re potential side effectseffects

Check baseline ALTCheck baseline ALTBaseline ALT high Baseline ALT high –– standard regimestandard regimeMonitor if baseline ALT high or liver Monitor if baseline ALT high or liver

disease disease Consider routine monitoring 2/12Consider routine monitoring 2/12

Conclusion Conclusion -- continuedcontinued

ALT < 5 x ULN ALT < 5 x ULN –– monitormonitorALT > 5 x ULN ALT > 5 x ULN –– stop drugsstop drugs Investigate other causesInvestigate other causes If unwell / infectious If unwell / infectious –– alternative alternative

drugs safer for liverdrugs safer for liverWhen ALT normal When ALT normal –– rechallenge rechallenge

sequentiallysequentiallyReplan regime to take account of Replan regime to take account of

changeschanges