MDR treatment Shanghai, May 2012 Arnaud Trébucq The Union
Why to diagnose MDR-TB?
Outcome of SS+ new MDR-TB cases, treated with First Line TB (FLD) drugs Setting Success Died Fail LFFU Transf. Corea 20(56) 1(3) 11(31) 0 4(11) Peru 14(58) 4(17) 6(25) 0 0 Hong Kong 42(60) 6(9) 3(4) 5(7) 14(20) Ivanovo Obl. 2(11) 4(22) 8(44) 3(17) 1(6) Dominic R 10(53) 1(5) 3(16) 4(21) 1(5) Italy 7(41) 0 8(47) 2(12) 0 Total 95(52) 16(9) 39(21) 14(7) 20(11) Espinal MA et al. JAMA 2000;283(19):2537-45
Is the cure rate with FLD true? Heilongjiang province, China 241 MDR cases: 179 (74%) cured with FLD 4 years later, among the cured, 101 were retrieved, 54% relapsed! Need for other treatment than First line drugs He GX et al. Follow-Up of Patients with Multidrug Resistant Tuberculosis Four Years after Standardized First-Line Drug Treatment. PLoS ONE 2010;5(5):e10799
Available TB drugs 1 st group : First line oral drugs Pyrazinamide (Z), Ethambutol (E), Isoniazid (H)?? 2 nd group : injectable Kanamycin (Km), Amikacin (Am), Viomycin (Vio), Capreomycin (Cm) 3 rd group : fluoroquinolones Ciprofloxacin (Cfx), Ofloxacin (Ofx), Levofloxacin (Lfx), Gatifloxacin (Gfx), Moxifloxacin (Mfx) 4 th group: oral bacteriostatic second line drugs Thioamides: Ethionamide (Eto) et Prothionamide (Pto), PAS, Cycloserine (Cs) 5 th group: Drugs with unclear efficacy Clofazimine (Cfz), Amoxicillin/clavulanate (Amx/Clv), Clarithromycin (Clr), Linezolid (Lzd)
Treatment outcomes, individualised MDR-TB treatments
Treatment outcomes, standardised versus individualised regimens for MDR-TB
Treatment outcomes for MDR-TB, new cases versus previously treated. GLC, Estonia, Latvia, Lima Nathanson et al.emerging Infectious Diseases 2006 (12);9;1389-1397
Time for sputum culture to convert, Latvia 2000 (Individualised treatments) TH Holtz et al. Ann Intern Med. 2006;144:650-659
Which treatment for MDR-TB? Individualised or standardised treatment? Which drugs? How many drugs? Which combination? Which length for intensive phase? Which length for continuation phase? Hospitalisation or ambulatory?
Basis of short-course chemotherapy Susceptible bacilli populations Active growth Cavities: >10 9 Intermittent growth Macrophages 10 5 A B INH Streptomycin Rifampicin Rifampicin INH Slow growth (Acid) 10 3 Dormant C Pyrazinamid (Ph acid) Rifampicin Adaptation from D. Mitchison and JM Dickinson Bull Int Un Tub 53,4, 1978 What could we have for MDR bacilli?
Some key elements on fluoroquinolones First quinolone generation: nalidixic acid Second-generation Ex. ciprofloxacin and ofloxacin Third-generation Ex. sparfloxacin and levofloxacin Fourth-generation Ex. gatifloxacin and moxifloxacin
Early Bactericidal Activity of new fluoroquinolones (40 TPM+) Johnson JL,Int.J.Tuberc.Lung Dis. 10 (2006): 605-12. Conclusion: 3 rd and 4 th generation of FQL as good as INH
Comparative early bactericidal activity (EBA*) of isoniazid and moxifloxacin Authors Place of study For day Isoniazid 300mg/day Moxifloxacin 400mg/day Pletz et al, 2004** Gillepsie et al., 2005 Germany 0-5 0.209 0.273 Tanzania 0-5 0.77 0.53 Johnson et al., 2006 Brazil 0-2 0.67 0.33 2-7 0.08 0.17 * Decline in log 10 CFU /ml of sputum per day ** Dosing of isoniazid was 6mg/kg
Comparative activities of fluoroquinolones against M. tuberculosis in mice Controls (From Ji et al., AAC 1995; 39: 1341-1344) Conclusion: levofloxacin is more active than ofloxacin at equal dose.
Comparative activities of isoniazid (INH), sparfloxacin (Spar) and moxifloxacin (Moxi) against M. tuberculosis in mice (From Ji et al., AAC 1998; 42: 2066-2069) Conclusion: the bactericidal activity of moxifloxacin is close to that of isoniazid
Comparative activity of oflo, levo and moxi in combination with second line drugs in TB infected mice Drug Regimen Untreated 7.86±0.25 Log 10 CFU counts in mouse lungs, different time points 0 Month 2 Month 6 Month 9 Month 12 2RHZ/4RH 3.21±0.54 < 0.07 2 OEZA/10OE 3.45±0.34 2.15±0.45 1.34±0.67 1.71±1.89 2 LEZA/10LE 3.38±0.22 0.91±0.63 0.29±0.36 0.07 2 MEZA/10ME 1.82±0.39 <0.07 <0.07 <0.07 O, ofloxacin, 200mg/kg; L, levofloxacin, 200mg/kg; M, moxifloxacin, 100mg/ kg; E, Ethionamide, 50mg/kg; A, amikacin, 150mg/kg Conclusion: Moxifloxacin 100 (M) > Levofloxacin 200 (L) > Ofloxacin 200 (O) during the initial and continuation phases * Veziris & al. Antimicrobial agents and chemotherapy 2003: 47: 3117 3122
Rustomjee & al. Sterilising activities of O, G and M in pulm TB. IJTLD 2008:12:128-138) Compara.ve bactericidal ac.vi.es of RHZE, RHZO, RHZG, & RHZM (S.S.C.C.) in pa.ents GaK GaK & Moxi Moxi SSCC= serial sputum CFU counts; R=rifampicin; H= isoniazid; Z= pyrazinamide; E= ethambutol; O= ofloxacin; G, gatifloxacin; M, moxifloxacin
Sterilising activity of moxifloxacin In vitro studies In vitro, selection M. tuberculosis persisters with some rifampicin by killing fast growing bacilli. Exposition of these selected bacilli to INH, or ofloxacin or levofloxacin or moxifloxacin Much better destruction of bacilli with moxifloxacin and gatifloxacin than with INH or ofloxacin Hu, Y., A. R. M. Coates, and D. A. Mitchison. "Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis." Antimicrob.Agents Chemother. 47 (2003): 653-57.
Viable counts for 100-day cultures of M. t exposed first to rifampin and then to various concentrations of fluoroquinolones
Pharmacodynamic values as a guide to antibiotic decision making* The area under the concentration curve (AUC) and the M.I.C. dictate the antimicrobial response. For «optimal» antimicrobial effect against rapidly growing organisms, it has been proposed: C max / MIC 90 should be >10 AUC 24 / MIC 90 (AUIC) should be >125 (best >250) * From Craig, CID. 1998; 26: 1-12; Wright et al., JAC 2000; 46: 669-683; Schentag et al., CID 2001; 32 (Suppl 1): S39-46; MacGowan et al., CID 2001; 33 (Suppl 3): S214- S220.
Pharmacodynamic values of fluoroquinolones against M. tuberculosis* Drug (-floxacin) MIC 90 C max /MIC 90 AUC 24 /MIC 90 Cipro- 500 1.0 1-2 10-20 O- 400 2.0 2 24 Levo- 500 1.0 5-7 40-50 Spar- 200 0.5 2 40 Moxi- 400 0.5 9 96 Gati- 400 0.5 8.4 68 * From Hooper et Wolfson AAC 1985 ; 28 : 716-721 ; Hooper, Clin. Inf. Dis. 2000 ; 30 : 243-254 ; Lubasch et al., AAC 2000 ; 44 : 2600-2603; Schentag et al., Clin. Inf. Dis. 2001 ; 32 : S39-46.
Which treatment for MDR-TB? Individualised or standardised treatment? Which drugs? How many drugs? Which combination? Which length for intensive phase? Which length for continuation phase? Hospitalisation or ambulatory? o No randomised clinical trial o Different results according to the setting o Expert opinions
PRINCIPAL WHO RECOMMENDATIONS Guidelines for the programmatic management of drug-resistant tuberculosis 2011 update. WHO/HTM/TB/2011.6
Composition of second-line antituberculosis regimens for MDR-TB (WHO) A fluoroquinolone should be used (strong recommendation, /very low quality evidence). A later-generation fluoroquinolone rather than an earliergeneration fluoroquinolone should be used (conditional recommendation, /very low quality evidence). Ethionamide (or prothionamide) should be used (strong recommendation, /very low quality evidence). Four second-line anti-tuberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase (conditional recommendation, /very low quality evidence). Regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (conditional recommendation, /very low quality evidence).
Duration of second-line anti-tuberculosis regimens for MDR-TB (WHO) An intensive phase of at least 8 months duration is recommended (conditional recommendation / very low quality evidence). A total treatment duration of at least 20 months is recommended in patients without any previous MDR-TB treatment (conditional recommendation /very low quality evidence).
WHO Grade evaluation system Conditional recommendation The Guideline Development Group concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects. Very low quality evidence ( ) Any estimate of effect is very uncertain.
Treatment results, cohort 2007, 44 GLC projects, 3499 MDR-TB patients Dead Lost for follow-up 15% 9% 31% No data or transferred Failure 5% Success 40% MDR WHO Progress report 2011
Individual data from more than 9,000 MDR-TB Lost for follow-up 23% Dead 15% 54% Success 8% Failure In Beijing, 53.4% success rate out of 716 MDR-TB cases Liu CH et al. PLoS ONE 2011;6(4): e19399
Alternative: 9-month treatment The Union Guide 2010 4 months daily Kanamycin (Km) (15 mg/kg) Gatifloxacin (400mg) (or moxifloxacin 400mg) Prothionamide(250mg) INH (10 mg/kg) Ethambutol (E) (400mg) Pyrazinamid (Z) (400mg mg) Clofazimine(50 mg) Then 5 months daily Gatifloxacin, E, Z, Clofazimine
9-month regimen treatment results, 206 MDR in Bangladesh (12 months after end treatment) Cured * 170 82,5% Treatment completed** 11 5,3% Died 11 5,3% LFFU 12 5,8% Failure 1 0,5% Relapse 1 0,5% Cured = 5 negative cultures Treatment completed = culture negative at the end but less than 5 Armand Van Deun, et al. Am J Respir Crit Care Med, 2010, 182: 684-692
Kaplan-Meier analysis of primary adverse endpoint 100 95 Probability remaining free of adverse outcome (%) 90 85 80 75 70 Failure Default Death Relapse Gatifloxacin-based regimen Ofloxacin-based regimens 65 Hazard ratio: 0.39 (95% CI 0.26-0.59) Ofloxacin 221 0 180 360 Time in 30-day intervals 540 720 200 188 177 171 160 156 151 149 208 195191 184 175172 167 158157 156152 151 203 177 164 149 Gatifloxaxin 206 193 190 182 176 172 165 163 128 198 192191 187 179177 175 168166 165164 139 195 186 175 131
Cameroon and Benin 4 Km H Gfx Pto Cfz E Z / 8 Gfx Pto Cfz E Z
Category of MDR-TB patients according to previous anti-tb treatment history Category Number Percentage New 0 Retreatment failure 77 67% New failure 22 19% Relapse 12 10% Other 4 3% Total 115 20 / 115 were HIV positive (17%)
Drug resistance profile Resistant to INH and RMP only 34% Resistant to INH, RMP and SM 31% Resistant to INH, RMP and EMB 5% Resistant to INH, RMP, EMB and SM 30%
Sputum and culture conversion during MDR treatment 100% 80% 60% 40% Smear Culture 20% 0% 0 2 4 6 8 10 12 Month
Outcomes of patients at end of treatment Outcome N=115 % Cured 108 94% Died 7 6% Failed 0 0 Defaulted 0 0 Transferred out 0 0 Among the 20 HIV+: 85% success and 15% death No relapse at one year for 55 patients
Niger 65 MDR-TB patients 4 KmGfxPtoCfzHEZ/8GfxCfzEZ N % Cured 58 89% Death 6 9% Failure 0 0% Default 1 2% Transfer 0 0% No relapse at one year
Basis of short-course chemotherapy MDR bacilli Active growth Cavities: >10 9 A Kanamycine Gati/Moxifloxacine Intermittent growth Macrophages 10 5 B Gati/Moxifloxacine Slow growth (Acid) 10 3 Dormant C Pyrazinamide Clofazimine? Moxi /GaK
National Drug Resistance Survey MDR-TB China, 2007 new patients: 5.7% (4.6 7.1) previously treated patients: 25.6% (21.7 30.0) overall: 8.3% (7.1 9.7) 27.4% (23.1-32.1) were fluoroquinoloneresistant MDR-TB 7.2% (4.9 10.2) MDR-TB are XDR-TB WHO/HTM/TB/2010.3
Anti-tuberculosis drug resistance in China WHO/HTM/TB/2008.394
Conclusions (1) If we diagnose MDR-TB, we must cure the patients! Most of WHO recommendations for MDR-TB treatment are conditional and of very low quality evidence Still a lot of uncertainties in this field Possibly some hopes for shorter regimens (9-month), but few data, resistance to fluoroquinolones? New drugs?? Not yet available
Conclusion (2) If we treat MDR-TB, we must avoid development of XDR-TB Control of Second line drugs is essential Directly observed treatment is essential
Thank you for your attention