Unit 8: Complications and Special Situations

1. Unit 8: Complications and Special Situations Botswana National Tuberculosis Programme Manual Training for Medical Officers

2. At the end of this unit, participants will be able to: Manage Category I, II, and second-line therapy in special situations: Peripheral neuropathy Psychiatric illness and MDR Paradoxical reactions Objectives • Pregnancy • Breastfeeding • Rash • Liver disease • Kidney Disease

3. Pregnancy • Every woman of child bearing age should be asked if she is pregnant prior to starting anti-TB treatment • Successful outcome of pregnancy largely depends on successful completion of anti-TB treatment • Category I- drugs are safe in pregnancy • Category II- Streptomycin should be avoided if possible as it can cause ototoxicity of the foetus

4. Pregnancy: Category IV If a woman is pregnant, if possible: • Avoid the first trimester and start treatment during the 2nd or 3rd trimester • Avoid amikacin (and streptomycin) until after delivery (fetal ototoxicity possible) • Avoid ethionamide (teratogenic in animals)

5. Breastfeeding • Women on Category I and II Regimens should continue breastfeeding • If mother has smear+ TB and baby does not have active TB, give baby INH, as appropriate for weight, for 6 months followed by BCG vaccination Courtesy of: Jeanne Raisler

6. Rash in TB Treatment (1) • Before attributing a skin symptom or rash to TB medications, assess • Was it present before TB therapy began? • Is it a condition unrelated to TB treatment? • Many persons on TB treatment also have HIV • Many people with HIV have skin conditions • ARVs can also cause skin conditions, especially NVP

7. Rash in TB Treatment (2) • Mild to Moderate rashes • Skin rash with mild itching • No blisters or mucous membrane involvement • Management • Consider other causes (scabies, etc.) • Aqueous cream, Calamine skin lotion • May need to stop TB medications • Chlorpheniramine 4 mg tds, or • Promethazine 25-50 mg nocte

8. Mild to Moderate Rash Mild Rash Source: I-TECH, 2006.

9. Severe Rash Rash with: • Persistent itchiness • Mucous membrane involvement and/or • Blistering • Urticaria (hives)

10. Severe Rash Source: I-TECH, 2006.

11. Severe Rash Management (1) • Stop all TB drugs together • Hospitalise the patient • Give IV fluids as required • Consider antibiotics for severe desquamation/exfoliation • Treat like a burn • Consider the use of steroids

12. Severe Rash Management (2) • Most patients can wait for the rash to resolve before resuming TB treatment • If the patient has life-threatening TB as well as life-threatening rash, may provide at least 2 TB drugs (3 drugs preferred) the patient has not taken before until the rash subsides

13. Treatment After Rash (1) If it is not obvious which caused the reaction, which is often the case, re-introduce TB medications in a step-wise fashion • Gradually increase the dose of each medication • If no reaction, continue the medication and gradually increase the dose of the next medication • Use in reverse order of likelihood of cause of rash

14. Schedule for Reintroduction of Anti-TB Drugs

15. Treatment After Rash (2) • If gradual reintroduction succeeds without a recurrence of rash, can continue treatment • If the offending drug causes a reaction, suspend it and replace the offending drug with another agent • May leave out pyrazinamide, ethambutol or streptomycin • Get expert advice; substitutions may require longer duration of therapy

16. Liver Disease • Three important issues complicate therapy: • Hepatotoxicity of anti-TB drugs • Acute liver disease with concurrent TB • Chronic liver disease with concurrent TB • Provided there is no clinical evidence of chronic liver disease, ATT is safe in patients with hepatitis virus carriage, history of acute hepatitis or excessive alcohol consumption

17. Acute Hepatitis Prior to TB Treatment • Evaluate the cause: • Viral (Hepatitis A, Hepatitis B) • Alcohol • ARVs • Traditional medicines • Other toxins • If possible, await resolution of acute hepatitis before starting TB treatment

18. Acute HepatitisPrior to TB Treatment (2) • Consult TB expert • Initial phase: SE for 3 months • Continuation phase: • RH for 6 months OR • SE for 9 additional months • Avoid Z, H, R and Eth (ethionamide) during acute hepatitis

19. Established Chronic Liver Disease Prior to TB Treatment • Evaluate the cause • Viral: Hepatitis B, Hepatitis C • Alcohol • Disseminated TB • Avoid PZA • Requires close monitoring • Liver function tests • Sputum samples • Experienced TB doctor

20. TB Treatment with Chronic Liver Disease • Preferred option • Initial: 2 months RHES • Continuation: 6 months RH • Second option • Initial: 2 months RES • 10 months RE • Third option • Initial: 2 months HES • Continuation: 10 months HE

21. Hepatotoxicity • Symptoms: Fever, malaise, right upper quadrant abdominal pain, nausea, vomiting, loss of appetite • Signs: • ALT or AST more than 3x increased if symptoms of hepatitis are present, or more than 5x increased without symptoms • Bilirubin or alkaline phosphatase more than 2x increased • Jaundice

22. Hepatotoxic Pyrazinamide and isoniazid are the most common causes Pyrazinamide causes the most severe Rifampicin hepatotoxicity is less common and less severe Ethionamide NOT Hepatotoxic Ethambutol Streptomycin TB Drugs & Hepatotoxicity

23. Hepatotoxicity • Try to rule out other causes of acute liver disease before attributing it to the TB treatment • In hepatotoxicity, stop all TB drugs until the patient improves • In case of severe TB, consider using “liver sparing regimen” (Ethambutol, streptomycin, and Ciprofloxacin) • Admit patients to the hospital if unable to maintain hydration or if hepatic failure develops

24. Acute Hepatitis: During TB Treatment • Rare • Decision whether to stop or continue anti-TB treatment requires good clinical judgment • Safest option in acute hepatitis not due to TB is to give streptomycin and ethambutol until the hepatitis has resolved (for a maximum of 3 months) followed by a continuation phase of INH and rifampicin for 6 months

25. Treatment After Hepatotoxicity (1) • When hepatitis has resolved, reintroduce therapy • If lab tests are not available, wait until 2 weeks after the jaundice ends • If lab tests are available wait until AST/ALT < 2x normal • Stepwise fashion, starting with safest drugs • Try to create a safe combination regimen

26. Reintroduction of Drugs After Hepatoxicity • Continue EMB, streptomycin, +/- ciprofloxacin • INH 300 mg daily x 4 days • If no symptoms, add • Rifampicin 600 mg daily x 4 days • If no symptoms, 2 options: • Do not try PZA • Try PZA • D/C streptomycin and ciprofloxacin when back on E, H, R

27. Treatment After Hepatotoxicity (2) • Pyrazinamide toxicity • 2 months RHES then 6 months RH • Check sputum at 2, 5, and 7 months • Pyrazinamide and isoniazid toxicity • 2 months RES then 10 months RE • Check sputum at 2, 5, 8, and 11 months • Pyrazinamide and rifampicin toxicity • 2 months HES then 10 months HE • Check sputum at 2, 5, 8, and 11 months

28. Renal Disease • Some patients with active TB will have renal disease due to either TB in the urinary tract or another condition • Adjust dose of ethambutol based on creatinine clearance if renal disease is suspected • Avoid streptomycin unless specialist care is available • Safest regimen: 2HRZ/4HR

29. Key Points • Careful assessment is needed to distinguish drug reactions from other conditions • Successful management of adverse drug reactions is necessary for patient health and integrity of the TB control program • Treatment of patients with chronic liver or kidney disease may require changes in regimen or dosing • Issues with category II regimen and second-line treatment are more complex