TB casePoor response to first-line TB
treatment
Richard Lessells
5thInternational TB/HIV Course for clinicians in South Africa
May 2013
Clinical history
•21-year-old HIV-infected female
•Smear-positive pulmonary TB (first episode)
•Baseline AFB smears +++/+
•Smear non-conversion: two-month AFB smears +/+
•On ART for three months (TDF/3TC/EFV)
•Baseline CD4+ cell count 220 cells/µL
•Referred for assessment
Potential causes of AFB smear
non-conversionProblemAction/intervention
Suboptimal adherenceIntensive adherencecounselling + treatment supporter
IncorrectdrugdosageCheck dosageappropriate for weight
Substandard drug qualityProgrammatic/pharmaceutical servicesissue
Poor absorptionof drugsCheck for symptoms, signs or laboratory markers of
malabsorption
Drug-druginteractionsCheck concomitant medications
Slow smear conversionClinical examination/chest X-ray –extensive disease&
cavitation(highbacillary load) can lead to delayed
conversion
Non-tuberculousmycobacteria(NTM)
Check results of baseline culture
Microscopy/lab issuesNon-viable organisms canstill be observed on microscopy;
false positive smears (reader error); clinic or lab specimen
labelling errors (double check patient details)
Drug resistanceCheck results of baseline culture/DST ±send culture/DST
Xpert result
Pre-treatment culture positive –resistant to INH, sensitive to
RIF by line probe assay (INH monoresistance)
Clinical progress
•Continued RHZE
•Clinical deterioration –weight loss and persistent cough
•AFB smears at end month 3 +++/+++
•Referred back for review
Xpert result
Probe E detects rpoB
mutations at positions
531 and 533
Summary of results
XpertLPA*Phenotypic DST
Pre-treatment-INHresistant
RIF sensitive
INH resistant
RIF sensitive
2 monthsRIF sensitiveINH resistant
RIF sensitive
MDR
3 monthsRIF resistant-MDR
Both molecular tests did not detect RIF resistance at 2 months
This could be due to heteroresistance/mixed strains (mixed
populations of susceptible and resistant bacilli)
* Line probe assay only performed on culture isolate
Mixed strains & heteroresistance
Single strainHeteroresistanceMixed populations of
resistant and susceptible
bacilli but otherwise
genetically identical
strains
Mixed strainsMixed populations of
resistant and susceptible
bacilli -genetically
different strains
Drug-susceptible bacilli
Drug-resistant bacilli
How common are mixed strains?
•May be quite common in settings with high force of
infection
•Studies in South Africa have shown up to 20% of TB
cases may have mixed strains –may be higher in re-
treatment and drug-resistant cases
•Need to be aware of this when interpreting diagnostic
test results
AJRCCM 2004; 169: 610-4
AJRCCM 2005; 172: 636-42
J Clin Micro 2011; 49: 385-8
Xpert performance with mixed
strains
•Ability of assay to detect
resistance depends on
mutation
•For some mutations, may
only detect resistance if all
bacilli are resistant (e.g.
L533P)
J Clin Micro 2010; 48: 2495-2501
Key learning points
•There are several potential causes for AFB smear non-
conversion, of which drug resistance is one
•Molecular tests may not detect resistance if there is
mixture of susceptible and resistant bacilli
•Culture/DST remains an important investigation,
particularly for people on treatment with suspicion of
drug resistance (e.g. AFB non-conversion, treatment
failure)
Website: www.bioafrica.net/saturnTwitter: @drug_resistance
12
TB caseRifampicin resistance but what else?
Richard Lessells
5thInternational TB/HIV Course for clinicians in South Africa
May 2013
Clinical history
•15-year-old female
•Smear-positive pulmonary TB (first episode)
•Household contact two DR-TB cases
•AFB smear non-conversion at two months
•HIV uninfected (rapid HIV test and ELISA negative)
•Referred for assessment
•Pre-treatment culture no result (specimen leaked)
Xpert result
Probe B detects
mutations in rpoB at
positions 511-516
Contact history
Pre-XDR
28 yrs
XDR
15 yrs
RHZE
4 yrs
RHZ
2 yrs
RHZ
HIV +
1 yr
Grandmother died 10
months prior (pre-XDR-TB:
resistant to R, H, Km)
Uncle on treatment for
XDR-TB (evolved from
pre-XDR) –persistent
culture positive
TB disease in contacts of drug-
resistant cases
•Studies in Peru have demonstrated very high rates of
prevalent and incident TB disease in household
contacts of adult MDR-TB cases
•Majority of contacts had MDR-TB (72-91%)
•Not all secondary MDR-TB cases had the identical
susceptibility pattern (60-64%)
•Some MDR-TB transmission likely to have occurred in
the community
Lancet 2011; 377: 147–52
IJTLD 2011; 15: 1164-9
TB disease in contacts of drug-
resistant cases Msingasub-district, KwaZulu-Natal
221 indexMDR-TB cases
793 contacts32 TB cases
4035/100,000py
287 indexXDR-TB cases
973 contacts32 TB cases
3288/100,000py
Median follow-up
~1.4 yrs
93% of secondary cases with DST results had MDR/XDR-TB (51/55)
60% of secondary cases with DST results had identical DST pattern to
index case (33/55)
IJTLD 2011; 15: 1170-5
Xpert MTB/RIFDetection of rifampicin resistance mutations
rpoB!gene!511513516522526531533
Common!mutationsL511PQ513LD516VS522QH526YS531LL533P
H526D
Xpert!MTB/RIFProbe!AProbe!CProbe!E
Probe!BProbe!D
Comparison of Xpert results
Same probe (B) detected
mutation for this patient and
for grandmother
Probe B not most common
marker of resistance (~20%);
probe E most common
Case resolution
•Commenced on treatment at King George V Hospital
with pre-XDR regimen (Cm-Mfx-Eto-Trd-Cfz-PAS)
•Phenotypic DST on culture isolate confirmed pre-XDR-
TB (resistant to rifampicin, isoniazid and kanamycin but
susceptible to oflaxacin)
•Same phenotypic pattern as grandmother
•Good progress on treatment –smear & culture negative
after two months
Key learning points
•Detailed contact history important for drug-resistant TB
(‘reverse contact tracing’) -try to find out precise
susceptibility pattern and response to treatment
•Drug-resistant strains within a household may not
always be identical –community transmission also
important in areas with high burden of drug-resistant
disease
•Molecular tests could help to identify mutations
suggestive of similar M. tuberculosis strains
Website: www.bioafrica.net/saturnTwitter: @drug_resistance
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