COMPLICATIONS OF TB TREATMENT AND THEIR

MANAGEMENT

Dr Liza Ahmad Fisal14 July 2010

Complications

• Adverse drug reaction

• Aggravate pre-existing conditions

– Renal impairment

– Liver impairment

– Peripheral neuropathy

• Interact with existing drugs

Adverse drug reaction

May seem mild and harmless but may herald serious complications: Nausea & vomiting – hepatitis Weakness / off legs - vestibulotoxicity Rash - Stevens Johnson syndrome

Identifying the culprit can be difficult because of the overlapping adverse effects.

Anti-TB and their side-effects & interactions

Isoniazid side-effects

Sleepiness and lethary

Peripheral neuropathy (especially in predisposing conditions)

Psychosis, fits, optic neuritis

Asymptomatic ↑ ALT

Hepatitis

Arthralgia

Lupus-like syndrome

Rare – fever, rash, SJS, haemolytic anaemia, vasculitis, neutrophilia

Isoniazid drug interactions

Microsomal enzyme inhibitor → ↑ plasma concentration of certain drugs → drug toxicity.

Examples: Warfarin Carbamazepine Valproate Paracetamol Theophylline

Rifampicin side-effects

Orange discolouration of bodily fluids

Abdominal pain, nausea & vomiting

Hyperbilirubinaemia & ↑ ALP

Asymptomatic ↑ ALT

Hepatitis

Fever & flu-like symptoms (esp with intermittent dosing)

Pruritus +/- rash

Exfoliative dermatitis (esp HIV-positive)

Rare – renal impairment, haemolysis, thrombocytopenia, shock

Rifampicin drug interactions

Microsomal enzyme inducer → ↓ plasma concentration of certain drugs → ↓ drug efficacy.

Examples: Combined-oral contraceptives

Warfarin

Corticosteroids

Phenytoin

Sulphonylurea hypoglycaemics

Statins

Theophylline

Methadone

T4

Rifampicin & COC

Less efficacious → unwanted pregnancy

Higher dose of oestrogen (50mcg) or alternative methods

Throughout treatment with rifampicin and at least 1 month after rifampicin completed

Pyrazinamide side-effects

Gastrointestinal intolerance Photosensitivity dermatitis Rash Asymptomatic hyperuricaemia Non-gouty arthralgia Acute gout Asymptomatic ↑ ALT Hepatitis (less common, more severe) Sideroblastic anaemia.

Pyrazinamide & DM

Labile sugar control – careful monitoring

Ethambutol side-effects

Dose-dependent optic neuritis Acuity / field Colour

Peripheral neuropathy (esp in lower limbs) Rash Arthralgia. Rare - hepatitis.

Streptomycin side-effects

Painful injections

Infection at injection site

Circumoral paraesthesia (usually after 1st month)

Rash

Impairment of hearing and vestibular function

Vertigo more common First 2 months Potentially reversible

Nephrotoxic

Rare - haemolytic anaemia, aplastic anaemia, agranulocytosis, thrombocytopenia and lupoid reactions

Streptomycin drug interactions

• Avoid other ototoxic or nephrotoxic drugs

• Avoid neuromuscular blocking agents causing crisis in myasthenia gravis patients

Management

Managing anti-TB side effects

Confirm diagnosis.Determine whether side effect is minor/major.Managing minor/major side effects

accordingly.

Principles of management

Minor adverse effects Continue TB treatment Give symptomatic treatment. Close monitoring

Major side-effects, Stop the drug responsible or TB treatment (if drug

responsible unknown) Refer

Major side-effects

Skin rash with or without itching DeafnessDizzinessJaundice*Visual impairmentShock*, purpura, acute renal failure

* Potentially fatal

Skin

Itching without a rash

Symptomatic treatment – anti-histamines & emollients

Continue TB treatment

Observing the patient closely

Skin rash

Stop all anti-TB drugs

Rechallenge with anti-TB drugs

Scabies

Liver

Drug-induced liver injury (DILI)

Rare but potentially fatal adverse effect Hepatotoxicity ALT > 3 x ULN ALP > 2 X ULN Culprits - Isoniazid, Rifampicin, Pyrazinamide Combining hepatotoxic drugs increases toxicity

V. J. Navarro and J. R. SeniorDrug-Related HepatotoxicityN. Engl. J. Med., February 16, 2006; 354(7): 731 - 739

Natural history DILI

Drug-induced acute liver failure: Significant morbidity High mortality - 20% survival in the absence of liver

transplantation

The clinical course after withdrawal of the drug is variable: Better after discontinuation Worsen for weeks before improvement is seen

Resolution of cholestatic injury take longer compared to the hepatitis form (?cholangiocytes regenerate more slowly)

Natural history of DILI

Patients rarely develop chronic liver disease after an acute severe DILI.

Patients with cholestatic/mixed liver disease were more prone to developing chronic injury (9%), than those with the hepatocellular form (4%)

Prolonged DILI was mostly seen in patients with cholestatic/mixed types of hepatotoxicity.

What to do?

Stop: ALT > 3 x ULN with symptoms* ALT > 5 x ULN without symptoms

• Screen:

– Hepatitis A, B, C

– USS HBS

– Other hepatotoxics – other drugs, TCM, alcohol

WHO management of drug-induced hepatitis

Re-introduce anti-TB when: LFTs normalised Asymptomatic

Bridge if persistent abnormal LFTs or serious TB: SEO

• Re-introducing anti-TB

– One at a time

– In this order: Rifampicin → Isoniazid → Pyrazinamide

– Monitor LFTs

– If symptoms recur or LFTs become abnormal as the drugs are reintroduced, the last drug added should be stopped

– If OK on Rifampicin & Isoniazid and hepatitis was severe, omit challenging with Pyrazinamide

• If rechallenge unsuccessful, give alternative regime:

– 2 hepatotoxics• 2HRE/7HR• 2SHRE/6HR• 6-9REZ

– 1 hepatotoxic• 2SHE/10HE

– 0 hepatotoxic• 18-24 SEO

Drug rechallenge

Rechallenging

* Rechalleging with anti-TB drug is done when the drug responsible is unknown.

• Identifying culprit drug necessary to continue TB treatment

• Girling protocol and its modified version is used

Contraindications to drug rechallenge

Rifampicin-induced thrombocytopenia, hemolytic anemia, acute renal failure, shock

Isoniazid-induced lupus Ethambutol-induced optic neuropathy Pyrazinamide-induced acute gouty arthritis Streptomycin-induced vestibuloneuropathy

Drug Challenge dose (mg)

Day 1 Day 2 Day 3

Isoniazid 50 300

Optimal dose

Rifampicin 75 300

Pyrazinamide 250 1000

Ethambutol 100 400

Streptomycin 125 500

Modified Girling’s Protocol

Changing regimen

• EHRZ (Dose 1-14)

• SEO (Dose 15-21)

• H introduced once LFT normalised

• R introduced when patient tolerate H, usually day 4 of rechallenge.

Dose Regimen Notes

1-14 EHRZ 1st regimen

15-21 SEO Bridging regimen

22 SEO + H1D1 rechallenge with H

23 SE0 + H2D2 rechallenge with H

24 SEO + H3D3 rechallenge with H

25 SHEO + R1D1 rechallenge with R

26 SHEO + R2D2 rechallenge with R

27 SHEO + R3D3 rechallenge with R

28 SHERO New regimen

New regimen

• SHERO

• SHER – 2SHER/6HR

• HER – 2HER/7HR

Reference

Diagnosis, management and prevention of drug-induced liver injury S Verma, N Kaplowitz Gut 2009;58:1555-1564

ATS Hepatotoxicity of Antituberculosis Therapy Subcommittee An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy Am. J. Respir. Crit. Care Med. 2006; 174: 935-952

WHO 2009 Treatment of tuberculosis: guidelines - 4th ed

Thank you