SUPRA-NATIONAL REFERENCE LABORATORY NETWORK

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SUPRA-NATIONAL REFERENCE LABORATORY NETWORK

• Possible research projects
• A. Van Deun

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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??

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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

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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 ??

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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?

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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

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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)

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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?

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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)