COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 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 Deafness Dizziness Jaundice* Visual impairment Shock*, 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. Senior Drug-Related Hepatotoxicity N. 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: Screen: 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

Modified Girling’s Protocol Drug Challenge dose (mg) Day 1 Day 2 Day 3 Isoniazid 50 300 Optimal dose Rifampicin 75 Pyrazinamide 250 1000 Ethambutol 100 400 Streptomycin 125 500

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 + H1 D1 rechallenge with H 23 SE0 + H2 D2 rechallenge with H 24 SEO + H3 D3 rechallenge with H 25 SHEO + R1 D1 rechallenge with R 26 SHEO + R2 D2 rechallenge with R 27 SHEO + R3 D3 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

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