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SUPRA-NATIONAL REFERENCE LABORATORY NETWORK

SUPRA-NATIONAL REFERENCE LABORATORY NETWORK. Possible research projects A. Van Deun. 1. RELEVANCE OF BORDERLINE R-RESISTANCE. Background: SRL rounds too many discordant strains in Rounds all with documented Rr-conferring mutation

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SUPRA-NATIONAL REFERENCE LABORATORY NETWORK

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  1. SUPRA-NATIONAL REFERENCE LABORATORY NETWORK Possible research projects A. Van Deun

  2. 1. RELEVANCE OF BORDERLINE R-RESISTANCE • Background: SRL rounds • too many discordant strains in Rounds • all with documented Rr-conferring mutation • WT fraction not visible by sequencing, so hetero-resistance or mixture cannot explain the discordance? • Background: clinical experience • poor results Cat. 2 retreatment after 6-months R Cat. 1 • far more failures within same (non-MDR) resistance-group than with weaker Cat 1  low-level Rr missed in retreatment cases??

  3. STUDY OUTLINE • Testing R at 20 and 40 µg/ml (or corresponding) • recommended in Canetti 1969 proportion method ref. paper • MIC 30-40 for +/- 10% probably R-resistant at coordinating lab  document frequency R20r/R40s • Use QA strains from random sampling surveys • request all retreatment strains for QA, including susc. • also collect outcome of treatment information (including relapse) • All strains for monitoring of resistance in retreatment strains (and DOTS-Plus) • if randomly sampled • i.e. systematic FU of Cat 1 / Cat 2 retreatments in SRL in HBC

  4. ACCURACY OF GENOTYPIC DST FOR R • Background: • literature: about 95% correlation • discordants: no mutation but phenotypic Rr • however: • too few phenoypic R-susceptible checked in these studies • clinical significance of pheno-Rr / geno Rs ??

  5. STUDY OUTLINE • Combine with first proposal on discordants • Same group of strains – random and representative samples from retreatment cases • Do also rpoB sequencing (or hybridisation) • cluster 1 or extended? • document outcome of standard treatment !! but MDR-TB treatment would interfere so only projects without DOTS-Plus in place?

  6. RELEVANCE OF E-TESTING • Background • high error-rates, lower reproducibility, discordance between systems (LJ versus BACTEC/MGIT) • interpretation problems: • potency adjustment or not? • microcolonies (at 4 weeks? at 6 weeks?) • significance?? • Er but still synergistic with amoxy-clavulanic in vitro • replacement by cycloserin in MDR-regimens • not done in standardised regimen in Bangladesh • cured : 98/122 (80%) of cured have HRE(S) resistant strain versus 7/9 (78%) of the failures

  7. STUDY OUTLINE • Study populations from DRS surveys • meta-analysis, lump surveys together? • only Cat 1 : 2EHRZ/6HE • failure / relapse (F/R) outcome • initally H(S)r versus initially H(S)Er • stratify for exact critical concentration (E-potency adjustment!); and method? • if possible: compare also acquired Rr in F/R strains, same arms (cf. Vietnam experience with 2SHRZ/6HE failures: 40% ADR to R)

  8. KANAMYCIN / ETHIONAMIDE / OFLOXACIN • Background • may be more important in panel than E and S (DOTS-Plus) • but not well standardised for LJ • and clinical significance less known • K resistance level and amikacin activity ? • O resistance level and moxi, gati activity ? • ETH / INH cross-resistance clinical relevance?

  9. STUDY PROPOSAL • Standardise K, O and ethionamide for LJ proportion method / other systems? • Document MIC values and determine critical concentrations • K, Ethion: outcome of MDR-TB standard regimen including K, thioamide (and quinolone susceptible) • O: outcome of MDR-TB standard regimen including moxi or gati (and other second-line susceptible)

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