Principles and practice of treating drug-sensitive TB

Transcription

1 Principles and practice of treating drug-sensitive TB Brian Eley Paediatric Infectious Diseases Unit Red Cross War Memorial Children s Hospital Department of Paediatrics and Child Health University of Cape Town

2 Development of short-course therapy Schatz isolated & purified streptomycin (SM) PAS discovered, anti-tuberculosis activity demonstrated, became readily available from 1946 onwards st clinical trials: value of adding SM to bed rest 1948 Prevention of SM resistance: PAS vs SM vs PAS & SM 1951 Isoniazid antituberculosis activity discovered INH alone or in combination with PAS and/or SM PAS/INH x 2 years plus SM x 6 months 2% relapse rate Development of affordable regimens led to substitution of thiacetazone for PAS 1959 Home or ambulatory treatment was shown to almost effective as treatment in a sanatorium (cure rates: 82% vs 90%) 1961 Ethambutol discovered; shown to be 4X as active as SM; EMB soon replaced PAS in the standard regimen

3 Short-course therapy (2) 1957 Isolation of several compounds from Amycolatopis mediterranei, reduction of one of these compounds, rifamycin B produced rifamycin SV, active against M. tuberculosis, chemical modification resulted in rifampicin which is orally bioavailable 1967 Rifampicin in combination with INH exhibited spectacular antituberculosis activity in mice 1970s 9-month course of INH/RIF plus SM/EMB for initial 2 months equivalent to months of the standard regimen 1972 Pyrazinamide rediscovered East Africa & British Research councils short-course RCT 1984 Combining PZA and RIF led to the current 6-month short course regimen Ahmed Z, et al. Prog Respir Res Basel Karger 2011;40:2-9 Int J Tuberc Lung Dis 1999;3(10): Supplement

4 Principles of treatment Aim: to cure the child & prevent emergence of drug-resistant TB 1. Combination therapy to which the bacillus is sensitive 2. Short-course regimens comprising both bactericidal and sterilizing activity 3. Start with an induction phase to achieve a rapid reduction of the organism load 4. Continuation phase: to ensure effective eradication of dormant and intermittently metabolizing (persistent) bacilli, thus preventing disease relapse 5. Optimise adherence & minimise adverse effects MRC. Br Med J 1952;1: Mitchison DA. Int J Tuberc Lung Dis 2000;4(9):

5 Drug activity: first-line agents Isoniazid has high early bactericidal activity (EBA) that kills actively dividing bacteria, causing rapid decline in sputum bacilli Rifampicin is bactericidal; it is active against bacilli with spurts of metabolism and therefore a major sterilizing agent Pyrazinamide kills dormant or slow-growing bacilli; has a remarkable sterilizing effect Ethambutol is bacteristatic having some efficacy against actively replicating bacilli Ethionimide is bacteriostatic, targeting actively growing bacilli; high CSF penetration Jindini A, et al. Am J Respir Crit Care Med 2003;167: Donald PR, et al. Tuberculosis 2008;88 (Suppl 1): S75-S83

6 Mechanism of action Drug Isonazid (prodrug) Rifampicin Pyrazinamide (pro-drug) Ethambutol Ethionimide (pro-drug) Mechanism 1. Inhibits mycolic acid synthesis - INH is activated by KatG -NADH dehydrogenase II promotes INH-NAD adduct formation - INH-NAD adduct inhibits inha gene product 2. Inhibits catalase-peroxidase enzyme Inhibits DNA dependant RNA polymerase (rpob) i.e. Prevents DNA directed mrna synthesis Mechanism of action is unknown; active at low ph; converted to pyrazinoic acid by nicotinamidase pyrizinamidase (pnca) Mutations in pnca result in resistance to PZA Recent research: PZA inhibits trans-translation Prevents cell wall formation by blocking synthesis of arabinogalactan; primary target: arabinosyl transferase (emba & embb) Inhibits mycolic acid synthesis by inhibiting inha gene product; activated by KatG-independent mechanism i.e. etha

7 Current paediatric regimens TB diagnostic category New smear negative PTB (other than in next category) Intensive phase 2HRZ Continuation phase 4HR Less severe forms of EPTB: lymph node TB, pleural effusion New smear-positive PTB New smear-negative PTB with extensive parenchymal involvement / cavitatory disease 2HRZE 4HR Severe forms of EPTB (other than TB meningitis and osteoarticular TB) Osteoarticular TB 2HRZE 10HR H = Isoniazid, R = Rifampicin; Z = Pyrazinamide; E = Ethambutol; Eth = Ethionimide WHO. WHO

8 WHO daily recommended dosages Drug Previous Daily dosage in mg/kg (range) 2009 / 2010 Daily dosage in mg/kg (range) [maximum] Isoniazid 5 (4 6) 10 (10 15) [300 mg] Rifampicin 10 (8-12) 15 (10 20) [600 mg] Pyrazinamide 25 (20 30) 35 (30 40) [2000 mg] Ethambutol 15 (15-20) 20 (15 25) [1200 mg] Pyridoxine supplementation: Malnutrition, HIV infection, high dose INH (>10 mg/kg/day) WHO, WHO/HTM/TB/ , 2006; WHO: WHO

9 Evidence for revised dosages Isoniazid 1 Rifampicin 2 Ethambutol 3,4 RHZ 5 n=56; 22(39%) HIV+; median age: 3.22 (IQR: ) years At 4-6 mg/kg/day: C max was < 3mg/L in 70% of children At 8-12 mg/kg/day: All children achieved a C max > 3mg/L NAT2 genotype but not age/sex/hiv status was associated with C max 21 HIV+ and 33 HIV- children At mean dose of 9.61 mg/kg: 2-hour rifampicin concentrations were 3.9 and 4.8 l/ml in HIV+ and HIV- children respectively After 4 months of treatment: 3(6%) had 2-hour RMP concentration >8 l/ml and 25 (43%) were < 4 l/ml Children < 10 years old administered mg/kg/day may result in serum concentration below the MIC Literature review supported the revised WHO dose: 20 mg/kg (range: 15-25) Pk of INH, Rifampicin & PZA in children <2 years provided evidence supporting the revised WHO recommended dosages 1 McIlleron H, et al. Clin Infect Dis 2009;48: Schaaf S, et al. BMC Med 2009;7:19 3 Thee S, et al. Int J Tuberc Lung Dis 2007;11: Donald PR, et al. Int J Tuberc Lung Dis 2006;10: Thee S, et al. Antimicrob Agents Chemother 2011;55:

10 TB dosing, children < 8 years (2013) Target dose or dose range (mg/kg/dose) Formulation Body weight (kg) Uncomplicated TB disease Intensive phase 2 months Once daily 7 days a week RH R: H: RH 60/60mg dissolvable tablet (scored) Z Z 500mg tablet (scored) Continuation phase 4 months Once daily 7 days a week RH R: H: RH 60/60mg dissolvable tablet (scored) RH R: H: RH 60/60mg dissolvable tablet (scored) Complicated TB disease (excluding TB meningitis) Intensive phase 2 months Once daily 7 days a week Z Z 500mg tablet (scored) E E 400mg tablet (un-scored) OR 400mg/8ml # solution Continuation phase 4 months Once daily 7 days a week RH R: H: RH 60/60mg dissolvable tablet (scored) Target dose or dose range (mg/kg/dose) Formulation Body weight (kg) <2 Expert advice recommended < ½ 75mg (1/2 x ½ ½ 75mg (1/2 x 1ml ½ mg tab)* 150mg tab)* ¾ ¼ ¾ ¾ ¼ 1.5ml ¾ ¼ 1 1 ¼ 2ml / 2 ½ 1 1 / / 2 ½ 3ml 1 1 / 2 2 ½ 2 2 ½ ½ tab ¾ tab 3 3 ½ 1 3 ½ 3 ½ 1 1 tab 3 ½ ½ 1 ½ 4 ½ 4 ½ 1 ½ 1 tab 4 ½ / 2 tab

11 TB meningitis: daily recommended dosages Isoniazid Rifampicin Drug Daily dosing range in mg/kg [maximum] [400 mg] [600 mg] Pyrazinamide Ethionimide Pyridoxine supplementation Prednisolone [2000 mg] 20 (15 25) [1200 mg] Infants: Abidec / Vidaylin 0.6 ml/day Children: 12.5 mg per day 2 mg/kg/day (maximum 60 mg / day) for 4 weeks then taper over 2 weeks Department of Health. The South African Tuberculosis Control Programme: Practical Guidelines, 2004

12 TB dosing, children < 8 years (2013) Target dose or dose range (mg/kg/dose) Formulation Body weight (kg) TB meningitis / miliary TB Single phase of treatment 6-9 months, once daily, 7 days a week RH R: 20; H: 20 RH 60/60mg dissolvable tablet (scored) Z 40 Z 500mg tablet (scored) Eto Eto 250mg tablet (scored) Target dose or dose range (mg/kg/dose) Formulation Body weight (kg) <2 Expert advice recommended < ¾ 75mg (1/2 x ¼ mg tab)* ¼ 1 / ½ ¼ ½ / 4 1 / 2 ½ 3 ½ / /

13 Regimens for TB meningitis Intensive phase Continuation phase 2HRZE 10HR WHO, HRZ (E or Eth)* 7-10HR AAP, 2012 Source 6HRZEth Donald, HRZEth 7HR EDL, 2013 (proposed) 9HRZEth EDL, 2013 (proposed) * Discontinue Ethambutol or Ethionimide if isolate susceptible to all drugs and continue Z for 2 months WHO AAP Red Book 29 th edition, 2012 Donald PR, et al. Int J Tuberc Lung Dis 1998;2(9):

14 Intensive short-course therapy (prospective observational study) Results RHZE (20/20/40/20) N=95: 39 (41%) stage III, 52(55%) stage II, 4(4%) stage I 10 children: mildly elevated bilirubin; 1 child clinical jaundice due to Hep A; 13 children: mild transient elevation ALT/AST Outcome: 10 (III) plus 3 (II) died before completion of therapy; 1 child experienced recrudescence 1 month after discharge Comment Whether extending PZA beyond 2 months is of any benefit? Advantage of high-dose therapy No direct comparison with the more widely used 9 or 12 month regimens Donald PR, et al. Int J Tuberc Lung Dis 1998;2(9): Ruslami R, et al. Lancet Infect Dis 2013;13:27-35

15 TB dosing, children 8 years (2013) Body Weight (kg) All forms of TB disease (excl. drug resistant-tb) Continuation Intensive phase phase 2 months 4 months RHZE RH RH tablets tablets tablets 150/75/400/275m 150/75m 300/150 g g mg Body Weight (kg)

16 Formulations for young children Formulation R/H (60/30) RHZ (60/30/150) EMB (100) Current formulations RH (60/60) PZA (500) PZA (150) EMB (400) Eth (250) Comment Manufacturing discontinued 2011, unavailable from mid-2011 onwards Manufacturing discontinued January 2012, unavailable from April 2012 onwards Licensed, undertaking given to NDoH to recommence manufacturing in June 2012; undertaking not honoured PZA (500): scored tablet PZA (150): unregistered, requires MCC section 21 approval EMB (400): unscored tablet; can be crushed and dissolved in 8mL water (400mg/8mL) Eth (250): scored tablet

17 WHO Fixed Dose Combination recommendations 4-drug FDC: rifampicin 250mg, isoniazid 150mg, pyrazinamide 400mg & ethambutol 250mg 3-drug FDC: rifampicin 250mg, isoniazid 150mg & pyrazinamide 400mg 2-drug FDC: rifampicin 250mg & isoniazid 150mg Flexible oral solid dosage form e.g. dispersible tablets Suitable for children weighing 5 to 30 kg WHO:

18 Moxifloxacin vs Ethambutol Conde MB, et al. Lancet 2009;373: Rustomjee R, et al. Int J Tuberc Lung Dis 2008;12: Dorman SE, et al. Am J Respir Crit Cate Med 2009;180:

19 Fluoroquinolones for drug-sensitive TB Ziganshina LE, et al. Cochrane Database Syst Rev Jun 6;6:CD

20 Thrice-weekly 4-month moxifloxacin or gatifloxacin containing regimens vs thrice- Weekly standard regimen for 6 months REMox TB is a phase III clinical trial: comparing two four-month moxifloxacin-containing treatment regimens for DS-TB: 2MoRHZ 2MoRH and 2MoRZE 2MoR versus std 6-month regimen (2RHZE 4RH) - Enrolment completed in February ,900 patients were enrolled in Africa, Asia & Latin America. - Evaluation of participants for 1 year following completion of their treatment (late 2013). Jawahar MS, et al. Plos One 2013;8(7)e67030