Open Access HIV & TB drug resistance clinical cases:

Here we provide you with cases published in the HIV/TB Drug Resistance & Clinical Management Case Book. These cases have been presented to over 1000 medical doctors in southern Africa at the annual SATuRN Drug Resistance Workshops.

The objective is to capacitate doctors, nurses and allied medical staff at all levels of the health system to prevent and manage HIV and TB drug resistance.


Clinical Cases Latest Cases

TB Case 3 - HIV-infected adult male with a laboratory report showing extensively drug-resistant TB (XDR-TB)

Authors: Richard Lessells

A result is received from the laboratory on a 38 year old male patient. It is the results of phenotypic drug susceptibility testing (DST) on a cultured M. tuberculosis isolate from a lymph node aspirate taken ten months previously. This reports XDR-TB (resistance to rifampicin, isoniazid, ofloxacin, and kanamycin). The patient is contacted and brought for review. He reports previous TB history as shown below:


On review he is asymptomatic with no evidence of lymph node disease. He reports that the lymph node swelling was in his neck in 2010 and TB treatment was started on clinical grounds, treatment was then stopped some time later (exact timing not clear) because it was not working.

He is HIV-infected and has been on ART for three years. His current regimen is TDF/3TC/EFV, the latest viral load is <40 copies/ml and CD4+ cell count 197 cells/ul.

Chest X-ray is performed which shows left lower zone and right lateral pleural opacification, consistent with previous TB disease. Sputum culture is sent and a decision is made to monitor his clinical condition.

Two months later he returns complaining of swelling of the right hand. On examination he has soft tissue swelling of the dorsal aspect of the first web space. Pus is aspirated and sent for TB culture & DST. The sputum culture sent previously has been reported as negative.


Clinical chart

The culture from the aspirate is positive for M. tuberculosis. The Genotype MTBDRplus assay is performed on the culture isolate and is reported as resistant to rifampicin but sensitive to isoniazid.

Interpretation

The Genotype MTBDRplus assay is an example of a line probe assay (LPA). This allows the simultaneous detection of M. tuberculosis complex and the most common mutations in the rpoB, katG and inhA genes. Line probe technology involves DNA extraction, DNA amplification by polymerase chain reaction (PCR) and hybridization of PCR products with oligonucleotide probes embedded in a strip. Subsequent colorimetric change as a result of hybridization allows discrimination between wild-type and mutant strains. Mutations are identified by lack of binding to wild-type probes combined with binding to a specific mutation probe (Figure 1).

In this case rifampicin monoresistance has been identified with the LPA. However, there is also the previous growth of XDR-TB from a lymph node aspirate to consider. It remains possible that the current isolate could be XDR-TB (or MDR-TB). The Genotype MTBDRplus assay has suboptimal sensitivity for INH resistance as not all mutations associated with INH resistance are incorporated in the assay.


Drug resistance


Recommendations

Treatment recommendation

The patient has active extrapulmonary TB disease, which seems on the current evidence to be confined to soft tissue disease. This certainly warrants antituberculous chemotherapy.

One option would be to wait for full phenotypic DST results on the current isolate to inform selection of an individualised drug regimen. However, that risks progression of soft tissue TB disease and possible dissemination to other sites.

The second option would to treat as rifampicin monoresistance, with a standardised regimen consisting of isoniazid, kanamycin, moxifloxacin, pyrazinamide, ethionamide, and terizidone. However, that risks suboptimal therapy and amplification of drug resistance if the isolate is confirmed as XDR-TB.

The third option is to take into account the previous growth of XDR-TB and to institute an XDR regimen such as capreomycin, moxifloxacin, ethionamide, terizidone, PAS, and clofazimine.

Evidence to inform which of these strategies is best is extremely limited. There is also limited information regarding penetration of second-line anti-TB drugs into different tissues, so the efficacy of selected drugs in different forms of extrapulmonary TB is relatively poorly understood.

Case resolution

The patient was commenced on a standardised regimen consisting of isoniazid, kanamycin, ofloxacin, pyrazinamide, ethionamide, and terizidone. Sputum cultures were negative. Phenotypic DST on the isolated cultured from the aspirate revealed monoresistance to rifampicin, with phenotypic susceptibility to isoniazid, ofloxacin, and kanamycin. The soft tissue swelling reduced significantly in the first month of treatment and his drug regimen including isoniazid was continued.


Questions

I. How common is drug-resistant TB in extrapulmonary TB disease?

II. Should this patient have been treated for XDR-TB when the initial laboratory result was received?


Answers

I. The burden of drug resistance in extrapulmonary TB has not been well characterised. Case series from uMzinyathi district in KwaZulu-Natal have suggested relatively high prevalence of XDR-TB from pleural and lymph node aspirates (7/21 or 33.3% of culture-positive isolates were XDR) and also from blood cultures (20/41 or 48.8% of culture-positive isolates were XDR). However, these series had inherent bias as aspirates were more likely to be performed when there was pre-existing concern about drug resistance. In addition this sub-district continues to have different epidemiology of drug resistance than elsewhere so the results may not be representative. There is some preliminary evidence that the Xpert MTB/RIF assay can be performed with extrapulmonary specimens and it is hoped this may bring some new understanding to the epidemiology of drug resistance in EPTB.

II. It is important to remember always to treat the patient and not the laboratory result. In this case, at the time the initial laboratory result (showing XDR-TB) was received, there was no strong evidence of active TB disease. Instituting treatment with the inherent risks of toxicity would not have been in the best interests of the patient. Full reassessment of the patient for active disease and then close follow-up and monitoring of symptoms and signs is appropriate. Ultimately the strain isolated from the soft tissue disease had a different susceptibility pattern and an appropriate treatment regimen has been instituted.


Key learning points

Drug-resistant extrapulmonary TB should generally be treated with the same regimens and for the same duration as for pulmonary disease

Always remember to treat the patient and not the laboratory result. Diagnostic test results should always be considered in conjunction with the clinical features before a management decision is made

Further Reading

Heysell SK, Moll AP, Gandhi NR, et al. Extensively drug-resistant Mycobacterium tuberculosis from aspirates, rural South Africa. Emerg Infect Dis 2010; 16: 557-560

Heysell SK, Thomas TA, Gandhi NR, et al. Blood cultures for the diagnosis of multidrug-resistant and extensively drug-resistant tuberculosis among HIV-infected patients from rural South Africa: a cross-sectional study. BMC Infect Dis 2010; 10: 344

Vadwai V, Boehme C, Nabeta P, et al. Xpert MTB/RIF: a new pillar in diagnosis of extrapulmonary tuberculosis? J Clin Microbiol 2011; 49: 2540-2545



Disclaimer:

Although every attempt has been made to ensure that the information in this book is accurate and up-to-date, the authors and publishers accept no responsibility for any loss or damage resulting from use of the information herein.

It is the responsibility of the individual clinician or health care worker to abide by national and local guidelines and protocols regarding management of HIV and TB. Information regarding drug indications and dosages should be checked with the national or local formulary, or with the pharmaceutical package insert.

None of the authors has declared any competing financial interests with regards to any material discussed within the HIV and TB Drug Resistance and Clinical Management Case Book.


SATuRN output, All cases...

HIV Case 1 - Adult female with virological failure on first line d4T/3TC/EFV
HIV Case 2 - Adult female patient with virological failure on first line therapy after substitution of EFV to NVP
HIV Case 3 - Adult female patient on treatment for epilepsy with virological failure on TDF/3TC/EFV; previous single dose NVP for PMTCT
TB Case 1 - HIV-infected TB suspect with previous history of TB treatment: Xpert MTB/RIF test
TB Case 2 - HIV-infected TB suspect with household MDR-TB contact: Xpert MTB/RIF test
TB Case 3 - HIV-infected adult male with a laboratory report showing extensively drug-resistant TB (XDR-TB)

SATuRN output, All cases...


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