1. COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT
Dr Liza Ahmad Fisal
14 July 2010

2. Complications Adverse drug reaction Aggravate pre-existing conditions
Renal impairment
Liver impairment
Peripheral neuropathy
Interact with existing drugs

3. 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.

4. Anti-TB and their side-effects & interactions

5. 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

6. Isoniazid drug interactions
Microsomal enzyme inhibitor → ↑ plasma concentration of certain drugs → drug toxicity.
Examples:
Warfarin
Carbamazepine
Valproate
Paracetamol
Theophylline

7. 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

8. 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

9. 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

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

11. Pyrazinamide & DM
Labile sugar control – careful monitoring

12. Ethambutol side-effects
Dose-dependent optic neuritis
Acuity / field
Colour
Peripheral neuropathy (esp in lower limbs)
Rash
Arthralgia.
Rare - hepatitis.

13. 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

14. Streptomycin drug interactions
Avoid other ototoxic or nephrotoxic drugs
Avoid neuromuscular blocking agents causing crisis in myasthenia gravis patients

15. Management

16. Managing anti-TB side effects
Confirm diagnosis.
Determine whether side effect is minor/major.
Managing minor/major side effects accordingly.

17. 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

20. Major side-effects Skin rash with or without itching Deafness
Dizziness
Jaundice*
Visual impairment
Shock*, purpura, acute renal failure
* Potentially fatal

21. Skin

22. 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

24. Scabies

25. Liver

26. 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

27. V. J. Navarro and J. R. Senior
Drug-Related Hepatotoxicity
N. Engl. J. Med., February 16, 2006; 354(7):

28. 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)

29. 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.

30. 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

31. WHO management of drug-induced hepatitis
Re-introduce anti-TB when:
LFTs normalised
Asymptomatic
Bridge if persistent abnormal LFTs or serious TB:
SEO

32. 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

33. If rechallenge unsuccessful, give alternative regime:
2 hepatotoxics
2HRE/7HR
2SHRE/6HR
6-9REZ
1 hepatotoxic
2SHE/10HE
0 hepatotoxic
18-24 SEO

34. Drug rechallenge

35. 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

36. 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

37. 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

38. 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

39. New regimen
SHERO
SHER – 2SHER/6HR
HER – 2HER/7HR

40. Reference
Diagnosis, management and prevention of drug-induced liver injury S Verma, N Kaplowitz Gut 2009;58:
ATS Hepatotoxicity of Antituberculosis Therapy Subcommittee An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy Am. J. Respir. Crit. Care Med. 2006; 174:
WHO 2009 Treatment of tuberculosis: guidelines - 4th ed

41. Thank you