lessells clinicalcase 2 - tb-ipcp.co.za · richard lessells 5 th international tb/hiv course for...
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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
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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)
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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Website: www.bioafrica.net/saturnTwitter: @drug_resistance
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