Key points • All close contact should be screen for active TB. • Testing for LTBI either TST or IGRA. • 3 HR regime is preferred when no contraindication (*may replace R with P if available). •If no contraindication, LTBI treatment should be administered. 51
Chapter 6 : TB in Pregnancy, Lactation & Use of Oral Contraceptive Pills Dr Subramaniam Ponnuvelu Tuberculosis in pregnancy poses a substantial risk of morbidity to both the pregnant woman and the fetus if not diagnosed and treated in a timely manner. Table 6.1: Pregnancy phases & suggested action plan for TB in pregnancy 52 No. Phase Plan of Action 1 Prepregnancy • All women of childbearing age should be asked about current or planned pregnancy prior to starting anti-TB drugs. • Women with TB on treatment should be enrolled into a pre-pregnancy clinic (PPC) and effective contraception should be given until the treatment coursed is completed.
Table 6.2: Pregnancy phases & suggested action plan for TB in pregnancy (cont.) 53 No. Phase Plan of Action 2 Booking • Screening of all pregnant mothers according to the checklist. • Diagnosis of active TB in pregnant patients consists of: • Clinical history (including epidemiological assessment) • Physical examination • Sputum AFB direct smear x 3 (induced sputum if unable to produce sputum) • Chest radiography is safe in pregnancy with abdominal shield • Biopsy if indicated (extrapulmonary tuberculosis) • If diagnosed with tuberculosis:(refer Chapter 3) • Refer for Pusat Rawatan 1 (PR1) and Family Medicine Specialist for follow-up • Notify and ensure contact tracing is carried out (Refer to Chapter 12) • Refer O&G specialist if presence of any maternal or fetal complication • Do VTE risk scoring o Tuberculosis in pregnancy equivalent to risk score of 3 which indicates moderate risk • Refer FMS at less than 26th week gestation for counselling • Refer O&G specialist at 28th week gestation for VTE prophylaxis • Treatment regime: (refer chapter 4) • Treatment regimes are similar with nonpregnant patient • Pyridoxine 30 mg daily should be given to all pregnant women on isoniazid to prevent peripheral neuropathy
Table 6.3: Pregnancy phases & suggested action plan for TB in pregnancy (cont.) Phase Plan of Action 3 Subsequent antenatal follow up • Check on DOTS • Consider inpatient DOTS if poor compliance • Continue anti-TB treatment • Monitor patient as per guidelines • Ultrasound monthly after 28 weeks to look for fetal growth restriction 4 Delivery • Hospital delivery 5 Postpartum • Refer the newborn to paediatrics team to initiate isoniazid prophylaxis if indicated. • Once active TB in the newborn is ruled out, the baby should be given six months isoniazid prophylaxis, followed by BCG vaccination. • Defer giving BCG if: • mother is diagnosed < 2 months before delivery or • mother is sputum positive just before delivery or • the newborn baby is symptomatic or • The newborn is at risk of perinatal TB until isoniazid prophylaxis is completed • Inform health clinic upon discharge to ensure continuity of TB treatment. 6 Lactation • Breastfeeding is not contraindicated 54
• The perinatal period is an important opportunity to screen, diagnose, and treat those at high risk for TB. • Pregnancy does not appear to increase susceptibility to TB infection or progression from latent TB infection to active TB disease. • However, pregnancy can make the diagnosis of TB more difficult owing to hesitancy to perform radiographs and the similarity of screening symptoms with those of the pregnant state for example, weakness, weight changes and shortness of breath. • Mantoux test is considered safe and valid for use in pregnancy. • Chest X-ray must not be delayed in diagnosis of PTB even before 12 weeks because the risk of ionizing radiation is low with an abdominal shield. • First-line anti-TB drugs are safe in pregnancy and breastfeeding. • Streptomycin causes fetal ototoxicity and should not be used during pregnancy. • A pregnant or lactating woman should be advised that successful treatment of TB with the standard regimen is important to ensure best outcome to the mother and her baby. • Breastfeeding should be encouraged because the concentrations of rifampicin and isoniazid in breast milk are too small to produce toxicity in the nursing newborn. • The amount of TB drugs in milk is insufficient to treat tuberculosis in the breastfed infant. • RIF can cause orange or yellow discoloration of breastmilk which is harmless to infant. • Surgical mask should be worn by infectious breastfeeding mothers to prevent transmission to neonates. • Patient on rifampicin should use alternative contraception methods other than oral contraceptives and progesterone-only pills. • Treatment for tuberculosis is free of charge once diagnosis is confirmed with the referral letter of Pegawai Diberi Kuasa di bawah Akta 342. 55
Table 6.4: Screening Questions for Tuberculosis in Pregnancy Contraception in Tuberculosis • Rifamycin drugs such as rifampicin and rifabutin reduce the contraceptive efficacy of both combined oral contraceptives and progesterone-only pills. • Patient on rifampicin should use alternative contraception methods other than oral contraceptives and progesterone-only pills. • Alternative contraceptive methods should be used during rifamycin therapy and for one month after stopping the therapy even if it has been administered for less than a week. Criteria Yes No Remarks Chronic cough? (More than 2 weeks) Hemoptysis Prolonged fever Loss of appetite Loss of weight Night sweat Co-morbid (DM, ESRF, RVD, COPD) TB contact Stays in TB hotspot area 56
Table 6.5: Type of contraceptives in TB 57 Types of contraceptives WHO Medical Eligibility criteria 1 • WHO MEC 1 • non- pelvic TB • pelvic TB • No contraindication to use with non- rifampicin containing regimes. • Advise patient to take OCPs apart from times when they may experience vomiting caused by anti-TB. • Use barrier method until a full month of the OCPs have been tolerated. • For patients on rifampicin containing regime, use OCPs with higher dose of estrogen (50µg) or use of other form of contraception. • Condoms can be used if patient do not want to take additional pills and/or when protection against sexually transmitted disease is also needed. 2 3 • WHO MEC 1 • non- pelvic TB • pelvic TB Progestogen only pills Combined hormonal contraception Medroxyprogesterone acetate
Table 6.6: Type of contraceptives in TB (cont.) Types of contraceptives WHO Medical Eligibility criteria 4 • WHO MEC 1 • non- pelvic TB • pelvic TB 5 • WHO MEC 1 • non- pelvic TB • WHO MEC 3 & 4 • pelvic TB 6 • WHO MEC 1 • non- pelvic TB • WHO MEC 3 & 4 • pelvic TB Implanon Levonogestrelreleasing IUDs Copper IUDs 58
Table 6.7: WHO Medical Eligibility criteria for contraceptive use in tuberculosis *Refer table 6.5 & 6.6 for explanation Table 6.8: Categories of medical eligibility for contraceptive use 1 A condition for which there is no restriction for the use of the contraceptive method. 2 A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 A condition that represents an unacceptable health risk if the contraceptive method is used. 59
60 Key points • All women of childbearing age should be referred to a Prepregnancy clinic (PPC) as soon as possible once a diagnosis of active TB is made. • All pregnant women diagnosed with TB should be referred to a specialist. • Careful evaluation of contraception method is needed to prevent drug interactions. • CXR should not be delayed in pregnancy if TB is suspected or diagnosed. • Breastfeeding is encouraged even if the mother is on ATT treatment. • The treatment regime for TB in pregnancy & breastfeeding mothers consists of EHRZ if no contraindications are present.
Chapter 7 : Pre-existing Liver and Renal Impairment Dr Hema Yamini Ramarmuty Chronic liver disease is known to increase the risk of drug induced liver injury (DILI). DILI in patients with chronic liver disease is potentially serious, even life-threatening. Thus, clinicians must carefully monitor hepatic function in patients with liver disease during the treatment of tuberculosis. The choice of the treatment regimen used in the setting of liver disease depends on the severity of both the liver disease and the tuberculosis. • Note that TB itself may involve the liver and cause abnormal liver function. • In some cases of concurrent acute (i.e. viral) hepatitis not related to TB or TB treatment, it may be possible to defer TB treatment until the acute hepatitis has resolved. Prior to treatment initiation • Before starting patient on ATT, clinician should identify patient at risk of developing DILI and patient with chronic liver disease. 61
Picture 7.1: Common hepatic related issue prior to ATT initiation Patients at Risk of Developing DILI (with No Evidence of Chronic Liver Disease) Hepatotoxic reactions to anti-TB drugs may be more common among these patients and should therefore be anticipated. Table 7.1: Patient at risk of developing DILI during ATT treatment Patients with the following conditions can receive the usual TB regimens however liver function need to be monitored monthly and remove any reversible risk factors such as alcohol and hepatotoxic medication. Patient at risk for DILI Hepatitis virus carriage (Inactive HBsAG carrier, Inactive HCV carrier) Past history of acute hepatitis Current excessive alcohol consumption Within 3 month post partum Previous abnormal LFT 62 How to start ATT in these groups of patients Patients at risk of developing DILI Patients with chronic liver disease
Patients with Chronic Liver Disease In patient with underlying chronic liver disease or abnormal liver function, clinician should identify any stigmata of chronic liver diesase. Investigations are similar with other TB (refer chapter 3). If any additional investigations needed (Ultrasound hepatobilliary system, connective tissue disease screening, etc) it should be case to case basis & need to discuss with specialist (FMS, physician or gastroenterologist). Picture 7.2: Approach to start ATT in chronic liver disease patient *Consider admission for inpatient management if having logistic issues 63 Check baseline LFT before starting ATT If ALT >2 times ULN (80 & above) Refer to specialist (FMS/Pulmonologist/ Gastroenterologist) Consider regime with fewer hepatotoxic drugs depending on the severity of chronic liver disease (Table 7.2)
Table 7.2: Suggested possible ATT regime in patient with abnormal baseline liver fuction or hepatotoxicity *Use newer generations of fluoroquinolones such as levofloxacin and moxifloxacin over the older generations (ofloxacin) Monitoring LFT should be taken weekly, followed by 2 weekly then monthly (case to case basis), followed by more widely spaced assessments all through the rest of treatment if stable. Renal Impairment Renal insufficiency complicates the treatment of tuberculosis because some anti-tuberculosis drugs are cleared by the kidney. Management may be further complicated by the removal of some antituberculosis drugs via hemodialysis. Isoniazid and rifampicin are eliminated by biliary excretion, so no change in dosing is necessary. There is significant renal excretion of ethambutol and metabolites of pyrazinamide and doses should therefore be adjusted. While receiving isoniazid, patients with severe renal insufficiency or failure should also be given pyridoxine in order to prevent peripheral neuropathy. 64 No. of hepatotoxic drugs Possible regimes 2 Hepatotoxic drugs 9HRE 9RZEL* 9RZL* 1 Hepatotoxic drug 9REL* 12HEL* No Hepatotoxic drug 18-24 SEL* Use only in bridging regime of palliative case
Table 7.3: Phases & suggested action plan for TB in renal impairment 65 No. Phase Plan of action 1 Prior to treatment initiation To identify PTB patients with renal impairment (CKD) or patient at risk of developing. 2 Clinical assessment • History • Physical examination History suggestive of renal impairment in patients with risk factors - diabetes, hypertension, obstructive uropathy, autoimmune disease, chronic NSAID use, renal transplant etc. 3 Investigation • Renal function test • UFEME • USG KUB if indicated 4 Anti TB Renal adjustments dosage for patients with CKD (eGFR less than 30ml/min) • Loose tablets are preferred. • Ethambutol, Pyrazinamide & Levofloxacin (renal doses 3x/week). • If eGFR > 30, continue same regime. *refer Table 7.4 5 Monitoring (stage 3B and above) RP should be taken weekly, followed by 2 weekly then monthly (case to case basis), followed by more widely spaced asessment all through the rest of treatment if stable. 6 Patients on haemodialysis (HD) Dosing intervals should be increased to three times weekly to reduce the risk of drug accumulation and toxicity. Treatment can be given immediately after HD to avoid premature drug removal. 7 Patients on Peritoneal dialysis Mechanisms for drug removal differ between haemodialysis and peritoneal dialysis. *Case by case basis, please consult nephrologist.
Table 7.4: ATT Dosing recommendations for patient with CKD (CrCl less than 30ml/min) and patients undergoing hemodialysis * Because of an increased risk of nephrotoxicity and ototoxicity, streptomycin should be avoided in patients with renal failure. If streptomycin must be used, the dosage is 15 mg/kg, two or three times per week, to a maximum of 1 gram per dose, and serum levels of the drug should be monitored. 66 Drugs Dosing recommendation Isoniazid No change Rifampicin No change Ethambutol 20-25 mg/kg, 3 times per week Pyrazinamide 25-30 mg/kg, 3 times per week Streptomycin 15 mg/kg, 3 times per week Pyridoxine 30 mg/day is recomended in CKD patients Key points • All patients with baseline ALT >80 before initiation of ATT need a referral to specialist for suitable regime. • Ethambutol, pyrazinamide, streptomycin should be given 3 times per week if EGFR < 30. • In patient that requiring HD, ATT should be serve after HD. • For patient who are at risk of developing DILI and/or AKI secondary to ATT, frequent blood monitoring and review is needed.
Chapter 8 : TB and HIV infection Dr Tang Jeat Thong HIV infection increases the likelihood of co- infection with M. tuberculosis due to immune suppression. • In Sabah, HIV & TB co-infection should be managed using a multidisiplinary approach involving the Infectious Disease Team and Respiratory Consultants, Family Medicine Specialists & General Medicine Physicians. • Among HIV-infected individuals, the lifetime risk of developing active TB is 50%, compared to 5-10% in persons who are not HIV-infected. 67
• In a person infected with HIV, the presence of opportunistic infections, including TB, allows HIV to multiply more quickly. This may result in more rapid progression of HIV infection. • In general, the ATT regimen is similar to treatment of non-HIV patients and consists of 2 phases: an intensive phase of 4 drugs administered daily for 2 months; followed by a continuation phase of 2 drugs given daily for at least 4 additional months depending on the site of TB infection. • Initiation of antiretroviral therapy (ART) for treatment of drugsusceptible pulmonary tuberculosis (TB) in HIV-infected adults must address potential drug interactions, adverse drug reactions including the immune reconstitution inflammatory syndrome (IRIS), and optimal timing for initiation of ART in ART-naïve patients. • The WHO recommends ART in all HIV-infected patients with active TB, regardless of CD4 cell count. ART should be started within 2-8 weeks after initiating anti-TB therapy rather than "sequential ART" (eg, after completion of antituberculous therapy) for all HIV-infected patients with active TB. ART initiation should not be delayed until the completion of TB treatment; this approach has been associated with increased morbidity and mortality. • TB medications and ART should not be initiated simultaneously. The optimal timing of integrated HIV and TB therapy depends on the patient's immune status: i. For patients with pulmonary TB and CD4 cell count <50 cells/microL, ART should be initiated as soon as possible but within 2 weeks after initiation of TB treatment. This approach reduces the combined risk of an AIDS-defining illness and death, despite an increased risk for TB IRIS. ii. For patients with pulmonary TB and CD4 count ≥50 cells/ microL, ART should be initiated within 8 weeks after initiation of TB treatment. In the absence of severe disease, early ART is not associated with a decreased risk of AIDS or death, and later initiation of ART (e.g. 8 weeks) is associated with a lower risk of IRIS regardless of baseline CD4 cell count. iii. For patients with TB involving the CNS, ART should be delayed for the first 8 weeks of antituberculous therapy, regardless of CD4 count. 68
• Other clinical considerations (apart from CD4) may influence clinical decisions regarding the timing of ART. Later initiation of ART (e.g. 8 weeks) may be preferred based on the patient's tolerance of TB medications and ability to swallow multiple pills, while earlier initiation of ART (e.g. within 2 weeks) may be considered in a patient with malnutrition or wasting, regardless of CD4 cell count. • The selection of the ART regimens depends on multiple factors including virologic potency, convenience, patient comorbidities, drug resistance, drug interactions with antituberculous therapy, and cost. When feasible, it is preferable to select an ART regimen that is compatible with a rifampicin-based antituberculous regimen. 69
Table 8.1: Phases and suggested action plan for TB in PLHIV 70 Phase Plan of action Remarks Diagnosis of active pulmonary TB in PLHIV (For diagnosis, do refer to Chapter 3) 1. Symptoms WHO-recommended four-symptom screen (Cough, fever, night sweats, or weight loss) 2. Investigations to be done: a) Acid-fast Bacilli (AFB) smear microscopy x3, and b) Chest X-ray, and c) Sputum culture and sensitivity, and - Done for all PHLIV - DST performed for all sputum AFB positive samples d) Xpert MTB/RIF - Done for all PLHIV/ immunocompromised for rapid detection of Rifampicin resistance - Done in advanced or critically PLHIV for rapid diagnosis Sensitivity 51% (PLHIV on ART) Sensitivity 89% (PLHIV not on ART) Performing 3 samples increases the sensitivity from 53.8% to 69.9%. First morning sample has 12% higher sensitivity compared to single spot sample and high specificity of >90% Low sensitivity among PLHIV. High specificity if abnormalities present Combined with WHOrecommended foursymptom screen– Sensitivity 93% and specificity 20% Sensitivity of 93% Able to detect 79% of PTB cases among PLHIV, which is 45% higher detection rate as compared to AFB
Table 8.2: Phases and suggested action plan for TB in PLHIV (cont.) 71 Phase Plan of action Remarks Diagnosis of active pulmonary TB in PLHIV e) Bronchioalveolar lavage (BAL) if indicated Positive yield 47.6% Diagnosis of extrapulmonary TB (EPTB) in PLHIV • Offer all patients chest X-ray and, if possible, sputum AFB and culture to exclude or confirm coexisting pulmonary TB. • Consider site-specific tests as described below to exclude or confirm additional sites of TB: (Refer to Chapter 3 for Site-specific tests) Xpert MTBRIF Ultra is an accurate, sensitive and specific test in diagnosing EPTB. Treatment of active drug sensitive TB in PLHIV • All TB patients must be ofered ATT first. (Refer to Chapter 4) • ART to be started based on CD4 When to initiate ART for PLHIV naïve patients. CD4 Initiation of ART • >50 cells/mm3 within 8 weeks of TB diagnosis • <50 cells/mm3 within 2 weeks • Efavirenz in combination with tenofovir disoproxil fumarate and emtricitabine is recommended as first-line ART. • Individuals who develop TB while on ART with undetectable HIV viral loads, to continue the current ART treatment (to consult Infectious Disease team).
Table 8.3: Phases and suggested action plan for TB in PLHIV (cont.) Phase Plan of action TB treatment in PLHIV already on ART • Rifampicin-based therapy is preferred if patients are on Efavirenz regime. • For patients on Protease inhibitors (PI) based therapy, rifabutin should be used when PIs are used for ART. (To consult Infectious Disease team if patient on ART regimes other than efavirenz based regimes) • Administration of rifampicin with boosted PIs is associated with reduction of PI levels by as much as 95 %. Pneumocystis Jiroveci Prophylaxis • Should be given in all PLHIV with active pulmonary TB and stopped when CD4 counts >200 cells/microL and if viral load has been undetectable for more than 3 months. ART Treatment in TB Meningitis • To treat TB first. • Delay ART 8 weeks later in view of risk of IRIS with earlier initiation. • Adjunctive glucocorticoid is recommended in PLHIV with CNS (TB). *Refer to Chapter 4 for steroid dosage 72
Table 8.3: Phases and suggested action plan for TB in PLHIV (cont.) Phase Plan of Action Immune reconstitution inflammatory syndrome (IRIS) Defined as a paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating antiretroviral therapy in HIV-infected patients. A. A diagnosis of exclusion. Other causes of clinical deterioration (e.g. superimposed infection, drug allergy, noncompliance, adverse reactions of drug, etc) need to be excluded. B. Determinants of IRIS are: • New or expanding lymph nodes or abscesses • Enlarging intracranial tuberculomas • Persistent pyrexia • Worsening pulmonary infiltrates • New serositis C. Time interval from initiation of ART to onset of IRIS varies from 10 to 180 days but tend to occur within the first 60 days of starting ART. D. If IRIS is suspected, to refer ID and follow their instructions for administration of NSAIDs or a short course of corticosteroid. 73
Pregnancy and Breastfeeding Pregnant women with HIV infection have a higher risk of developing active TB than HIV-negative pregnant women. Furthermore, mothers with HIV co-infection have a higher rate of infecting their children (30%) compared to those with TB alone (12%). Table 8.3: Phases and suggested action plan for TB in PLHIV (pregnancy & breastfeeding) 74 Phase Plan of Action Diagnosis • Four symptom screening: cough, fever, night sweats & weight loss. • Sputum AFB x3 and GeneXpert MTB/RIF in areas with high prevalence of TB (81% sensitivity, 97% specificity). • CXR with abdominal shield is safe. Management • WHO recommends that the treatment of TB is the same as that in non-pregnant women. • Start combination ART after starting TB treatment, preferably within 8 weeks. • Patients with CD4+ cell count <50 cells/mm3 are ofered ART as soon as is practicable and within 2 weeks. Breast feeding • Not recommended as it is associated with risk of HIV transmission up to 14%. • Mothers with active TB should be separated from their infants to prevent exposure for at least two weeks. • Refer the child to the paediatric team. • Infant formula milk is given to the child for two years. Contraception • Refer to Chapter 5
Key points • All PLHIV diagnosed with TB should be offered ATT first. • Timing of HAART initiation is crucial & needs to depend on the patient’s CD4 level. • Careful monitoring should be done in patients on HAART & ATT to prevent drug interactions. 75
Chapter 9 : Follow Up & Adverse Drug Events Dr Taufiq Rosli The most important aspect in management of TB patients is monitoring response and adverse drug reactions during follow up. Monitoring differs between smear positive and smear negative pulmonary TB patients. It is best to classify the follow up monitoring into these two groups. 76
Table 9.1: Monitoring schedule of adult patients on anti-TB treatment (non-complicated cases) * additional visit for PTB smear negative Visit Treatment Duration Regimen Investigations 1 0 months EHRZ FBC RBS RP LFT HIV screening Sputum AFB direct smear Sputum MTB C&S CXR 2 2 weeks EHRZ LFT *Sputum AFB direct smear – for return to work/school purposes 3* 1 month EHRZ CXR for PTB smear negative only 4 2 months HR LFT if indicated Sputum AFB direct smear Trace sputum MTB C&S CXR 5 5 months HR Sputum AFB direct smear 6 6 months (> 6 months duration for extended regime) Completion of treatment Sputum AFB direct smear CXR Trace sputum MTB C&S 77
PTB Follow Up Checklist (non-complicated case) Table 9.2: PTB follow up checklist for non-complicated cases Week Month 0 2 1 2 3 4 5 6 Full Blood Count Repeat if necessary Renal Profile Liver function test UPT *childbearing age women Repeat if necessary Random blood glucose HIV/ HEP B & HEP C *patient with risk factor Sputum AFB Monthly if AFB still positive Sputum MTB C&S Repeat if AFB still positive CXR Eye assessment Monthly if Ethambutol more than 3 month. *Snellen & Ishihara chart Weight *If smear negative 78
Problems During Follow Up and Adverse Drug Reactions Common problems encountered in managing TB are: • Adverse drug reaction: o Drug-induced liver injury (DILI) o Drug-induced rash (DIR) o Other common adverse drug reactions (ADR) • Delay conversion • Treatment interruption Drug-Induced Liver Injury (DILI) The most important aspect of DILI management is that the clinician should know when to stop and how to rechallenge. Cases should be divided into symptom and/or severity of transaminitis. Healthcare providers should be aware that the initial presentation of DILI could be as mild as: • Abdominal pain • Nausea • Vomiting • Lethargy Jaundice will usually increases later as severity increase. The most common drug causing transaminitis are as below: • Pyrazinamide • Isoniazid • Rifampicin In severe cases of hepatotoxicity, multidiciplinary team approach including gastroentrology and respiratory input are required especially if hepatic encephalopathy is suspected as mortality is high. 79
Picture 9.1: Algorithmic approach to drug-induced liver injury (DILI) 80
Table 9.3: Levels of Hepatic Toxicity Rechallenge Regime for DILI • Once ALT <100 & patient asymptomatic, ATT need to be reintroduced. • Various rechallenge regimes are available globally. • Clinicians should try their best to reintroduce back-bone of ATT (isoniazid & rifampicin) in their regime. • Selection of rechallenge regime may also require consideration of what is the most likely offending drug. Table 9.4: Suggested rechallenge regime for mild transaminitis *if necessary 81 ALT level (value) Levels of Toxicity ALT <3 times the upper limit of normal (<120) Mild ALT 3-5 times the normal limit (120-200) Moderate ALT >5 times the normal limit (>200) Severe Day ATT (if ALT normal or improving) 1 Ethambutol (full dose) + Rifampicin (full dose) 3 Ethambutol (full dose) + Rifampicin (full dose) + Isoniazid (full dose) 6 Ethambutol (full dose) + Rifampicin (full dose) + Isoniazid (full dose) 9 Ethambutol (full dose) + Rifampicin (full dose) + Isoniazid (full dose) + *Pyrazinamide (full dose)
Table 9.5: Suggested rechallenge regime for moderate to severe transaminitis *if necessary Drug-Induced Rashes (DIR) • DIR can occur either during intensive or maintenance phase. • Some patients are unable to tolerate fixed dose combination (FDC) which may be due to the inactive ingredients in FDC. • Be alert for the rare occurrence of severe cutaneous reactions e.g. Stevens-Johnsons Syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) or Toxic Epidermal Necrolysis (TEN) – to withold all ATT; for hospital admission with multidisciplinary team management. 82 Day ATT (if ALT normal or improving) 1 Ethambutol (full dose) + Rifampicin 150mg 3 Ethambutol (full dose) + Rifampicin (full dose) 6 Ethambutol (full dose) + Rifampicin (full dose) + Isoniazid 100mg 9 Ethambutol (full dose) + Rifampicin (full dose) + Isoniazid (full dose) 12 Ethambutol (full dose) + Rifampicin (full dose) + Isoniazid (full dose) + *Pyrazinamide 500mg 15 Ethambutol (full dose) + Rifampicin (full dose) + Isoniazid (full dose) + *Pyrazinamide (full dose) 18 Weekly LFT then monthly
Table 9.6: DIR grading and suggested management plan *BSA: Body Surface Area Rashes Grading Clinical features Actions I Macules/papules covering <10% BSA with or without symptoms (pruritus, burning & tightness). Daily rashes monitoring, Anti-histamine & topical medication. If worsening, withold ATT II Macules/papules covering 10%-30% BSA with or without symptoms (pruritus, burning & tightness). Limiting instrumental ADLs. Withold ATT. Anti-histamine & topical medication. Once resolverechallenge ATT (inpatient or outpatient) III Macules/papules covering > 30% BSA with or without symptoms (pruritus, burning & tightness). Limiting sefl-care ADLs. Skin sloughing covering <10% BSA. Withold ATT. Admit to the nearest hospital. Anti-histamine, topical medication & may consider corticosteroid. Once resolverechallenge ATT (inpatient). IV Papules/pustules covering any percentage of BSA with or without symptoms (pruritus, burning & tightness) associated with superinfection requiring IV-antibiotic. Skin sloughing covering 10%-30% BSA. Withold ATT. Admit to nearest hospital. Multidiciplinary team referral (Dermatology, Respiratory, etc). 83
Drug Challenge in DIR Multiple drug challenge for DIR available globally. Clinician should select most appropriate regime depending on resource availabitiy. If rashes recur during drug challenge, the offending drug should be stopped. Table 9.7: Drug challenge in drug-induced rashes (graded challenge) * suitable for grade 3 & 4, inpatient challenge 84 Day Anti-TB 1 Isoniazid 50mg OD 2 Isoniazid 100mg OD 3 Isoniazid (full dose) + Rifampicin 75mg OD 4 Isoniazid (full dose) + Rifampicin 150mg OD 5 Isoniazid (full dose) + Rifampicin 450mg OD 6 Isoniazid (full dose) + Rifampicin (full dose) 7 Isoniazid (full dose) + Rifampicin (full dose) + Ethambuthol 100mg OD 8 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol 400mg OD 9 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol (full dose) 10 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol (full dose) + Pyrazinamide 250mg OD 11 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol (full dose) + Pyrazinamide 1000mg OD 12 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol (full dose) + Pyrazinamide (full dose)
Table 9.8: Drug challenge in drug-induced rashes (rapid) *suitable for grade 1 & 2 (inpatient or outpatient) challenge Desensitization • Some patients with DIR can’t tolerate certain ATT despite rechallenge. • If a strong regime can’t be constructed, desensitization method is recommended especially involving backbone of ATT. • To choose either rapid or graded desensitisation method depending on resource setting. • To ensure that: • Continue all tolerated ATT during desensitisation period. • Do only one ATT desensitisation per-day. • If allergic reaction occurs, desensitisation protocol for that particular drug need to be withheld. • Prolongation of anti-histamine might be necessary. 85 Day Anti-TB 1 Isoniazid 100mg OD 2 Isoniazid (full dose) 3 Isoniazid (full dose) + Rifampicin 150mg OD 4 Isoniazid (full dose) + Rifampicin (full dose) 5 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol 400mg OD 6 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol (full dose) 7 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol (full dose) + Pyrazinamide 500mg OD 8 Isoniazid (full dose) + Rifampicin (full dose) + Ethambutol (full dose) + Pyrazinamide (full dose)
Proposed Method 1: Protocol for rapid desensitisation (suitable for inpatient) Table 9.9: Rapid desensitisation Isoniazid (Target dose 300mg) 86 Step Time from start (hr) Administered amount (mg) Cumulative dose (mg) Amount given (mL) Dilution 1 0 0.02 0.02 0.1 Isoniazid 50mg + 250ml D5% (0.2mg/ml) 2 1 0.04 0.06 0.2 3 2 0.1 0.16 0.5 4 3 0.2 0.36 1.0 5 4 0.4 0.96 2.0 6 5 0.8 1.76 4.0 7 6 1.6 3.36 0.8 Isoniazid 100mg + 50ml D5% (2mg/ml) 8 7 3 6.36 1.5 9 8 6 9.36 3 10 9 12 21.36 6 11 10 26 47.36 13 12 11 50 97.36 13 12 100 197.36 Tablet Tablet 14 13 100 297.36
Table 9.10: Rapid desensitisation Rifampicin (Target dose 600mg) 87 Step Time from start (hr) Administered amount (mg) Cumulative dose (mg) Amount given (mL) Dilution 1 0 0.03 0.03 0.1 Rifampicin 150mg + 500ml D5% (0.3mg/ml) 2 1 0.06 0.09 0.2 3 2 0.15 0.24 0.5 4 3 0.3 0.54 1.0 5 4 0.6 1.14 2.0 6 5 1.2 1.34 4.0 7 6 2.4 3.74 0.8 Rifampicin 150mg + 50ml D5% (3mg/ml) 8 7 4.5 8.24 1.5 9 8 9 17.24 3 10 9 18.6 35.84 6.2 11 10 37.5 73.34 12.5 12 11 75 148.34 25 13 12 150 298.34 Tablet Tablet 14 13 300 598.34
Table 9.11: Rapid desensitisation Ethambutol (Target dose 800mg) *can be considered if dose per body weight still not achieved 88 Step Time from start (hr) Administered amount (mg) Cumulative dose (mg) Amount given (mL) Dilution 1 0 0.1 0.1 0.1 Ethambutol 200mg + 200ml D5% (1mg/ml) 2 1 0.2 0.3 0.2 3 2 0.5 0.8 0.5 4 3 1 1.8 1 5 4 2 3.8 2 6 5 4 7.8 4 7 6 8 15.8 8 8 7 15 30.8 1.5 Ethambutol 400mg + 40ml D5% (10mg/ml) 9 8 30 60.8 3 10 9 60 120.8 6 11 10 100 220.8 10 12 11 200 420.8 Tablet Tablet 13 12 400 820.8 14* 13* 400* 1200.8*
Table 9.12: Rapid desensitisation Pyrazinamide (Target dose 1000mg) *can be considered if dose per body weight still not achieved 89 Step Time from start (hr) Administered amount (mg) Cumulative dose (mg) Amount given (mL) Dilution 1 0 0.3 0.3 0.1 Pyrazinamide 250mg + 83.3ml D5% (3mg/ml) 2 1 0.6 0.9 0.2 3 2 1.2 2.1 0.4 4 3 2.4 4.5 0.8 5 4 4.8 9.3 1.6 6 5 9.6 18.9 3.2 7 6 18 36.9 0.6 Pyraznamide 1500mg + 50ml D5% (30mg/ml) 8 7 36 72.9 1.2 9 8 75 147.9 2.5 10 9 150 297.9 5 11 10 250 547.9 12 11 500 1047.9 Tablet Tablet 13* 12* 500* 1547.9*
Proposed Method 2: Protocol for graded desensitisation (suitable for both inpatient & outpatient) Table 9.13: Graded desensitisation *H: Isoniazid, R: Rifampicin, E: Ethambutol, Z: Pyrazinamide; may consider additional dose if doses per body weight is not met Delayed Sputum Conversion Another common problem that occurs during ATT regime is delayed conversion. A few factors can contribute to this condition. Clinician should address this issue before proceeding to the next management option. Common issues are: a) Underdosage b) Non-compliance c) Immunosuppressed condition (uncontrolled DM , PLHIV) Patient with severe disease based on CXR (bilateral lung involvement or cavitary) will have higher chance of delayed conversion due to high bacilli load. In a setting whereby Xpert MTBRIF Ultra is easily available, it should be the priority in the management of delayed conversion. 90 Step Day Time from start (hr) Administered amount (mg) H E R Z 1 1 0 50 125 100 250 2 1 100 275 200 450 3 2 150 400 300 800 4 3 Observe Observe Observe Observe 5 2 4 100 300 200 500 6 5 200 500 400 1000 7 3 6 300 800 600 1500
Picture 9.2: Approach to delayed conversion 91
Other Common ATT Adverse Drug Reactions (ADR) Table 9.14: Other common ATT induced ADR 92 Type of ADR Likely Culprit Drug Identification Management Peripheral neuropathy Isoniazid Paresthesia, pricking pain, burning sensation in feet and hands. Common in HIVinfected, diabetic, uraemic or malnourished patients, and alcohol users. Frequency increases with higher doses of isoniazid. For prevention, give supplemental pyridoxine 10-25 mg daily. Thrombocytopenia Rifampicin Send peripheral blood film (PBF). Rule out other cause of thrombocytopenia. If confirmed drug induced, need to discontinue rifampicin. Discoloration of body fluids Rifampicin Orange urine, sweat or tears. Permanently stained soft contact lenses. Universal effect of rifampicin. To reassure patient.
Table 9.15: Other common ATT induced ADR (cont.) Type of ADR Likely Culprit Drug Identification Management GI symptoms - anorexia, nausea, vomiting, abdominal pain. All anti-TB drugs Rule out drug induced hepatotoxicity. Take ATT after light meal or before bedtime. May consider giving anti-emetic 30 minutes before ATT. Optic neuritis - decrease in visual acuity, redgreen colour blindness, blurring and central scotoma. Ethambutol Question monthly regarding visual disturbances. Repeat monthly testing for visual acuity (Snellen chart) and color vision (Ishihara) for patients whose dose exceeds 15– 20 mg/kg and those who have been receiving EMB for >2 months. Toxicity is dosedependent, recovery dependent on early withdrawal of the drug. Refer for Ophthalmology clinic assessment. 93
Table 9.16: Other common ATT induced ADR (cont.) Type of ADR Likely Culprit Drug Identification Management Isolated hyperbilirubinaemia Rifampicin Pyrazinamide Rule out other obstructive causes. May rechallenge with rifampicin once bilirubin normalized. Arthralgia Pyrazinamide Send serum uric acid level. Give analgesics, while continuing the drug. Asymptomatic hyperuricemia does not require treatment. If symptoms persist can discontinue pyrazinamide. Ototoxicity Streptomycin Vertigo, ataxia, tinnitus and hearing loss. Risk increases with dose and age (over 40 years). Causes fetal ototoxicity (to avoid in pregnancy). Neurotoxicity Streptomycin Transient circumoral paresthesia and tingling occurring soon after injection. Potentiates neuromuscular blocking agents. To avoid in patients with myasthenia gravis. 94
Treatment Interruption The most common problem in managing TB is treatment interruption. The attending clinician need to ensure all patient receiving ATT are compliant to their medication to prevent drug acquired resistance. Picture 9.3: Algorithm on approach to treatment interruption *please consider clinical assessment & CXR before stopping treatment 95 Maintenance phase
Picture 9.4: Algorithm on approach to defaulting DOTS 96
Modifying TB Treatment Duration After ADR Once drug challenge completed and most likely offending drug identified, appropriate treatment modification needs to be carried out in order to achieve an optimum regimen. If patient can tolerate ATT, clinician should aim for maximum recommended duration. Regular blood parameter monitoring at least monthly is recommended after patient on stable dose of ATT. Picture 9.5: Suggested regime after ATT modification *all decision for modifying PTB regime should be discussed with respiratory team 97
Key points • Follow up for PTB smear negative patients require review at 1 month to monitor response. • In DILI patients, ATT should be stop if ALT > 120 IU/L in symptomatic & ALT > 200 IU/L in asymptomatic. • In DIR, ATT should be withheld in grade 2 & above. • Careful evaluation needed in patient with delayed conversion to rule out drug resistant TB. 98
Chapter 10 : Drug Resistant TB Dr Kunji Kannan Treatment of drug resistant TB is challenging and often requires opinion from clinician who are experienced in managing MDR-TB. 99
Introduction A) Definition of various DR-TBs Mono-resistance: Resistant to one first line ATT drug Poly-resistance : Resistant to more than one first line drug other than BOTH Isoniazid and Rifampicin MDR: Resistant to at least BOTH Isoniazid and Rifampicin Extensively drug resistant: Resistant to any fluroquinolone AND at least one additional group A drug. (*MDR-TB Resistant to any fluroquinolone AND any second line injectable drugs- previous definition) Pre XDR: MDR with resistance to any Fluroquinolones (*MDR-TB with resistance to any fluroquinolone or any second line injectable drug- previous definition) Rifampicin Resistant (RR): Resistance to Rifampicin detected using genotypic (most commonly) or phenotypic method with/ without resistance to other drugs. 100