Optimising patient care in MDR TB with existing molecular screening tests in high burden countries

Transcription

1 Optimising patient care in MDR TB with existing molecular screening tests in high burden countries Camilla Rodrigues MD Consultant Microbiologist Hinduja Hospital,India

2 Outline What is the best empiric combination treatment for MDR TB cases with available screening tests? Interpreting FLQ / SLID / Ethionamide / Ethambutol with molecular tests available

3 Case PK 25 F Received treatment for TB twice in the past Now on kana, oflox, linezolid PAS, clarithro for 4 months Severe cough, emaciation, fever with tingling & burning of feet Referred for ID opinion

4 Advised molecular screening tests

5 Optimising care after screening molecular tests in MDR TB Type of mutations found Local epidemiology Prior treatment history Source control Optimising dosing with site / co morbidities

6 < 30 SNPs in 6 genes could predict XDR with 90 98% sens J Clin Microbiol 2014 ;52(3): doi /JCM

7 Genotype MTBDRplus rpob possible mutations WT probes codons F505L WT L511P, T 508A, S509T WT Q513L/P, del WT2/ MUT probes mutation D516V/Y, del515 WT3/ MUT1 D516V del518, N518I WT4/ S522L/Q WT5/ H526Y/D/R/P/Q/N/L/S/C WT MUT2A H526Y MUT2B H526D S531L/P/Q/W, L533P WT MUT3 S531L rpob S531L katg WT probes codons MUT probes mutation WT 315 MUT1 S315T1 MUT2 S315T2 inha WT1 15 MUT1 C15T 16 MUT2 A16G WT2 8 MUT3A T8C katg S315T inha c15 t

8 Genotype MTBDR sl ( second line) gyra WT probes codons MUT probes mutation WT WT gyra MUT1 A90V gyra MUT2 S91P WT gyra MUT3A D94A gyra MUT3B D94N/Y gyra MUT3C D94G gyra MUT3D D94H rrs WT probes codons MUT probes mutation WT rrs MUT 1 A1401G WT rrs MUT 2 G1484T gyra Asp94Gly No rrs mutations embb M306V

9 Optimising care after screening molecular tests in MDR TB Type of mutations Local epidemiology Prior treatment history Source control Optimising dosing with site / co morbidities

10 Local epidemiology Mumbai : a DRTB hotspot India has a high TB burden, Mumbai is a MDR hotspot Among 1454 patients in RNTCP MDR 24% in new cases & 41% in retreatment cases Nerges Mistry, et.al.; Oper Res Health Care Jun;1(23):4553.

11 Local epidemiology Resistance patterns in MDRTB pts among 8 facilities in Mumbai, Ofloxacin Moxifloxacin Pyrazinamide Ethambutol Ethionamide PAS Dalal A. et.al.;plos One. 2015; 10(1): e

12 Rifampicin resistant TB using screening molecular tests What is the best empiric treatment at our centre while awaiting cultures? A modelling exercise to derive an appropriate initial regimen for MDR TB patients till DST is available Derivation cohort DST patterns over a 4 consecutive months to derive an empiric regimen Validation cohort Validated the above regimen in a cohort of patients with cultures available over the next 4 months U Sharma et al ERS 2015 doi /

13 Proportion of strains R to each drug in Derivation & Validation cohort U Sharma et al ERS 2015 doi /

14 Optimising care after screening molecular tests in MDR TB Type of mutations Local epidemiology Prior treatment history Source control Optimising dosing with site / co morbidities

15 In MDR TB, a regimen with at least 5 effective TB drugs During the intensive phase at least 4 four core second line drugs. 1 from group A,1 from group B, and at least 2 from group C with PZA X X X X X X NA NA X X X X WHO treatment guidelines for DR TB 2016 update

16 Outline What is the best empiric combination treatment for MDR TB cases with available screening tests? Interpreting Fluoroquinolones / SLID / Ethionamide / Ethambutol with screening molecular tests

17 FLQ resistance in high TB burden countries Jabeen K. Int J Infect Dis 2015;32:11823.

18 Resistance patterns in TB over time in 8 facilities in Mumbai High resistance rates to FLQs (Pre XDR TB ~60%) are commonly in the developing world A Dalal et al PLoS One 2015 :10(1):e

19 Despite so much drug resistance, can we use FLQs in DRTB?

20 Flouroquinolones are pivotal in DRTB Rx Choice of LFX vs MFX made no difference to the Rx outcome in pts with FQL Susceptible MDRTB MFX at a CC of 2mg/ml significantly impedes bacterial growth The optimal dose of MFX for DRTB Rx has not yet been established in clinical trials Pranger AD et.al.; Curr Pharm Des. 2011;17(27): Kang YA et.al.; Ann Am Thorac Soc Mar;13(3): McGrath et. Al.; Antimicrob Agts Chemother May; 58(5): Ganatra S et al ATS jmay 2016

21 Drug Group Drug DST methods WHO DST Critical Concentrations (μg/ml) Group 1 Firstline oral antitb drugs Isoniazid Rifampicin Ethambutol Pyrazinamide Solid, liquid Solid, liquid Solid, liquid Liquid L J Middlebrook 7H Middlebrook 7H MGIT Group 2 Injectable antitb drugs Streptomycin Kanamycin Amikacin Capreomycin Solid, liquid Solid, liquid Solid, liquid Solid, liquid Group 3 Fluoroquinolones Ofloxacin Levofloxacin Moxifloxacin Solid, liquid Solid, liquid Solid,liquid / / 2.0 Group 4 Oral bacteriostatic SLD Ethionamide Prothionamide Cycloserine PAS Solid, liquid Solid, liquid Solid Solid, liquid Group 5 Drugs with unclear efficacy (not routinely for MDRTB ) Clofazimine Amox / clav Clarithromycin Linezolid Liquid None None Liquid

22 Phenotypic DSTs are based on ECOFFs not on clinical breakpoints Number of Isolates = treatable by WHO Standards = treatable by Dosing Optimization WHO Critical Conc Clinical Breakpoint MICs above safely achievable serum concentration in patients Wild type ( susceptible ) Mutant ( resistant ) Low MIC

23 Moxifloxacin : better PK Methoxyfluoroquinolone makes it relatively resistant to efflux pumps. Lower MICs compared to ofloxacin with similar Cmax. Better Cmax/MIC and AUC/MIC compared to ofloxacin Ginsburg AS et. al.lancet Infectious Disease. 2003;3:

24 With standard dosing (400mg) Cmax >4mg.L 1 Mean Max Sr conc: 3.4 mg.l 1 AUC 024h : 30.2mg.h.L 1 PK of MFX in lung tissue 2.2 hrs mg.l 1 12 hrs mg.l 1 Epithelial lining Fluid hrs (mg.l 1 Alveolar Macrophage Bronchial Mucosa Eur Respir Rev ;25:1928.

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27 MUT 1 gyr A (A 90 V) & MUT 2 gyra ( S 91 P) showed lower MICs to MXF MUT 3B gyra (D94G), MUT3C gyra (D 94 N / Y) showed high MICs to both OFX & MXF

28 Frequency of mutations with FQ resistance by clinical site MUT 3C MUT 1 MUT 3A MUT 2 MUT 3B MUT 3D MUT 3B MUT 1 & 2 Antimicrob Agents Chemother 2016 doi: /aac.00222

29 Genotype MTBDRsl Assay Amino Acid Changes Nucleotide Mutations/ Abscence of WT2 with MUT1 Ala90Val GCG90GTG(25) FQL : MICs with gyra mutations MTBDRsl assay R / S DST at WHO MGIT Critical Concentrations No. of MGIT MIC OFX MXF LVX Strains (93) (mg/l) OFX MXF LVX R R S R R R S S R S S R R R S R R S S S R S S R Suggested Treatment MXF /HD MXF HD LVX Avoid OFX Absecnces of WT2 with MUT2 Ser91Pro TGC91CCG(6) Absence of WT3 with MUT3A Asp94Ala ( D 94 A) GAC94GCC (4) Absence of WT3 with MUT3B GAC94AAC/TAC ( D 94 N / Y) ASp94Asn/Tyr (13 ) Absence of WT3 with MUT3C GAC94GGC (D 94 G) Asp94Gly( 42) Absence of WT3 with MUT3D GAC94CAC (D 94 H) Asp94His (3) R R S R MXF/HD MXF R R S R HD LVX R R S S Avoid OFX R R S S HD MXF R R S R HD LVX R R S S Avoid OFX R R S R R R S R HD MXF R R S R Avoid OFX and LVX R R S R R R R R 1 > R R R R Avoid all FQL R R S R HD MXF R R S R Avoid OFX and LVX R R S R R R S R R R S R R R S R R R R R 1 > Avoid all FQL R R S R HD MXF R R S R Avoid OFX and LVX Kambli P et al.tuberculosis 2015 ; 95: Priti K et al Int J Tuberc Lung Dis :

30 Correlating MXF MGIT Critical Conc DST with LPA gyra mutations MXF 0.5 mg/l Total 10% Suscep (9/93) MXF 2mg/L Total 97% Suscep (90/93) Ala90Val MUT1 (25) Ser91Pro MUT2 (6) ASP94Ala MUT3A (4) Asp94Asn/Tyr MUT3B (13) Asp94Gly MUT3C (42) Asp9494His MUT3D (3) 0.5mg/L (%) 2.0mg/L (%) Kambli P et al.tuberculosis 2015;95( 2):13741.

31 Phenotypic DSTs are based on ECOFFs not on clinical breakpoints Number of Isolates = treatable by WHO Standards = treatable by Dosing Optimization WHO Critical Conc Clinical Breakpoint MICs above safely achievable serum concentration in patients Wild type ( susceptible ) Mutant ( resistant ) Low MIC 400mg/day 600mg/day High MIC

32 Significant no. of patients R at CC 0.5mg/L are still S at CC 2.0 mg/l In this group,higher doses of MFX 600mg & 800mg, could be effective with regular QTc interval monitoring Outcome studies with clinical FU are ongoing

33 Outline What is the best empiric combination treatment for MDR TB cases with available screening tests? Interpreting Fluoroquinlones / SLID / Ethionamide / Ethambutol with screening molecular tests

34 Frequency of mutations associated with SLID resistance by clinical site MUT 1 Antimicrob Agents Chemother 2016 doi: /aac.00222

35 Second Line Injectable Drugs MICs with rrs mutations detected by Genotype MTBDRsl Version 1 Genotype MTBDRsl Nucleotide mutation for rrs Absence Of WT1 With MUT1 A 1401 G R / S DST at WHO MGIT Critical Concentrations KAN 2.5 AMK 1.0 CAP 2.5 No. of strains (79) MGIT MIC (mg/l) KAN AMK CAP R R R 25 >20 >40 5 R R R 50 >20 >40 10 R R R 04 >20 >40 15 Suggested treatment Avoid SLID P Kambli et al.int J Mycobacteriology 2016;5(1) :16

36 SLID : MICs with additional eis promoter detected by pyrosequencing eis promoter region R/S DST at WHO MGIT Critical Concentrations KAN AMK CAP No. of strains (11) MGIT MIC (mg/l) KAN AMK CAP Suggested Treatment R S S G 10 C R S S R S S R S S G 10 A S S S R S S C 12 T R S S R S S AMK/CAP AMK/CAP AMK/CAP C 14 T R S S R S S S S S AMK/CAP P Kambli et al.int J Mycobacteriology 2016;5(1) :16

37 Second Line Injectables Drugs SLIDs rrs A1401G : high level / moderate resistance mutation to SLI rrs C1402T & rrs G1484T : check MICs to AMK eis promoter mutations : low level R to kana : S to AMK, CAP Version 2 MTBDRsl with eis promoter region

38 GenoType MTBDRsl : version 1.0 vs version 2.0 Detection of R to fluoroquinolones & Second Line Injectables Version 2 WHO endorsed May 2016 Smear neg pulmonary Addition of gyrb for FQL & eis promoter for Kana Deletion of embb

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40 MTBDRsl, demonstrated higher sensitivity for FQL : 95% (95%CI: ) compared to the WHO Expert Panel pooled sensitivity of 84% (95%CI: ) Sensitivity of detection of AMK & CAP resistance were comparable to that documented by the WHO Expert Panel (87% vs 86%) However, when a molecular test is negative, phenotypic DST is reqd. especially in settings with a high pretest probability for resistance PlosOne 2015: /journal.pone

41 Outline What is the best empiric combination treatment for MDR TB cases with available screening tests? Interpreting Fluoroquinolones / SLID / Ethionamide / Ethambutol with current screening molecular tests

42 Gene / mutation Isoniazid Ethionamide katg /S315T alone Avoid INH Ethionamide inha promoter / c15t alone Both katg and inha promoter High Dose INH Avoid INH Avoid ETH Avoid ETH

43 Ethionamide inha promoter mutations may help predict Ethionamide resistance

44 Frequency MUT of 1 mutations associated with INH resistance by clinical site MUT 1 MUT1 MUT3A Antimicrob Agents Chemother 2016 doi: /aac.00222

45 What about mutations in ethambutol?

46 Optimising care after screening molecular tests Type of mutations found : INH ( katg S315T with inha c15t), RIF (rpob S531L),FLQ (gyra D94N ), ETA (inha c15t), EMB (embb M306V ) SLID no mutations Local epidemiology in MDR TB : ( PZA, EMB ) Prior treatment history: ( Linezolid, PAS ) Source control

47 Advised source control ( surgery )

48 In MDR TB, a regimen with at least 5 effective TB drugs During the intensive phase at least 4 four core second line drugs. 1 from group A,1 from group B, and at least 2 from group C with PZA High Dose X X X X X NA NA X X X X WHO treatment guidelines for DR TB 2016 update

49 Targeted therapy based on individualized, tailored DST Kanamycin, PAS, clofazimine, cycloserine & linezolid R Soman et al J Assoc Physic India 2014;62:1517

50 Revisiting DST in MDR / XDR TB A single Critical Concentration used in phenotypic tests may not address the biological diversity in MTB Drug resistance in MTB is heterogenous ( low, moderate & High level R) Diff mutations are associated with diff levels of phenotypic drug R In areas of high prevalence of MDR TB, we will soon not only require individualised treatment, we will also need personalised DST

51 Thank you