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 4 - HIV-infected TB case with treatment failure on regimen 1 and previous unrecognised isoniazid mono-resistance

Authors: Richard Lessells

A 34 year old male patient is referred due to failure of TB treatment. He had been treated for smear-positive pulmonary TB with regimen 1. AFB smears had remained positive at 2 months so the intensive phase (HRZE) had been extended an extra month. AFB smears were then negative at 3 months and standard continuation phase (HR) was given for four months. AFB smears were positive (+++) at the end of treatment so the outcome was recorded as treatment failure and he was referred to the medical officer for further management.

He reported another previous episode of smear positive pulmonary TB four years previously for which he had completed six months of therapy (there was no documentation about whether or not he had been cured). He was HIV-infected and had been on ART for four years. His current regimen was TDF/3TC/EFV, his latest viral load <40 copies/ml and latest CD4+ cell count 371 cells/ul.

On review of his TB case file, a result was found of culture/DST taken prior to treatment for this latest TB episode. The culture was positive for M. tuberculosis and phenotypic DST was reported as resistant to isoniazid and streptomycin but susceptible to rifampicin, kanamycin and ofloxacin.

He remains symptomatic with cough, night sweats, chest pain, and weight loss. Sputum is obtained for Xpert MTB/RIF testing and culture/DST.


Clinical chart

Interpretation:

The clinical history gives a high degree of suspicion for MDR-TB. The result showing INH mono-resistance seemingly had gone unnoticed at the time and the patient had received standard regimen 1, albeit with an extra month of HRZE as intensive phase. The reversion of AFB smears to positive on HR continuation phase would be consistent with the emergence of MDR-TB.


Drug resistance

However, although the Xpert MTB/RIF assay has detected the presence of M. tuberculosis, it has not detected any mutations associated with rifampicin resistance. This would suggest that MDR-TB is not present, although it cannot exclude the continued presence of INH mono-resistance


Recommendations

Treatment recommendation

It is important to ensure that a specimen is sent for culture/DST given the clinical history. In the meantime, a standard regimen of HRZE should be commenced and continued until further results from the culture/DST are available. Streptomycin should not be included in the regimen as the previous isolate had demonstrated resistance to streptomycin and so the patient would be exposed to potential toxicity with very low likelihood of effectiveness.

Case resolution

The patient was commenced on HRZE. Culture was positive for M. tuberculosis and the Genotype MTBDRplus assay was reported as showing resistance to rifampicin and isoniazid. He was referred to the specialist MDR-TB referral centre and was commenced on a standardised MDR-TB regimen consisting of kanamycin, ofloxacin, ethionamide, terizidone, and pyrazinamide. Phenotypic DST subsequently confirmed resistance to rifampicin and isoniazid but susceptibility to kanamycin and ofloxacin.


Questions

I. How should his initial episode of INH mono-resistant TB have been managed?

II. Why did the Xpert MTB/RIF assay not detect resistance to rifampicin?


Answers

I. This case illustrates some of the deficiencies of existing diagnostics for TB. The DST result was received once the patient was well established on treatment and it was not brought to the attention of a doctor. The diagnostic test therefore did not lead to a beneficial outcome for the patient as the result was not appropriately acted upon. If the result was received at around two months, when the smears had not converted, then suspicion of further drug resistance should have prompted a repeat specimen for culture/DST.

Having said all that, national and international guidelines do not give clear guidance on management of INH mono-resistant TB and are informed by poor quality evidence. Historically it was thought that standardised regimens were appropriate for INH mono-resistant disease but there is now increasing evidence that outcomes with standardised regimens are often poor.

One option in this case would have been to continue rifampicin, ethambutol and pyrazinamide for a total duration of 6 months (this is recommended in US guidelines). This is, however, also not based on high quality evidence and there is an urgent need for better quality evidence to inform treatment strategies.

II. Further interrogation of the output from the Xpert MTB/RIF assay helps us to understand why it was reported as showing no rifampicin resistance in this case.

Analysis of the primary curves here and the assay result in section 2 show that one probe (probe E) has a delayed cycle threshold (Ct) and significantly lower endpoint (EndPt).

The definition of resistance is based on the difference between highest and lowest Ct. Under the original algorithm rifampicin resistance was defined with a difference between highest and lowest Ct >3.5. The algorithm was changed (to improve specificity of the assay) such that resistance is now defined with a difference between highest and lowest Ct >5. In this case the test would have been defined as resistant under the original algorithm (Difference between highest and lowest Ct = 3.6 [24.9-21.3])

The reason that there is some signal from this probe rather than complete probe drop-out (contrast with the results shown for case 1) may be due to mixed populations of RIF-resistant and RIF-sensitive strains, which would make sense given what we know about the evolution of resistance in this case. The initial analytical studies on the Xpert MTB/RIF assay showed that the ability to detect mutant DNA within mixed populations was dependent on the specific mutation, e.g. the L533P mutation could only be detected if 100% of the DNA was mutant.



Key learning points

Isoniazid mono-resistant disease should not be treated with normal TB regimens. Ideally patients should be referred to a specialist physician. A regimen consisting of 6HZE can be used but the patient should be monitored closely for the emergence of MDR-TB.

The Xpert MTB/RIF assay may not detect rifampicin resistance if there are mixed populations of RIF-resistant and RIF-sensitive strains.

Further reading

Menzies D, Benedetti A, Paydar A, et al. Standardized treatment of active tuberculosis in patients with previous treatment and/or with mono-resistance to isoniazid: a systematic review and meta-analysis. PLoS Med 2009, 6: e1000150

Jacobson KR, Theron D, Victor TC, et al. Treatment outcomes of isoniazid-resistant tuberculosis patients, Western Cape Province, South Africa. Clin Infect Dis 2011, 53: 369-372

Blakemore R, Story E, Helb D, et al. Evaluation of the analytical performance of the Xpert MTB/RIF assay. J Clin Microbiol 2010, 48: 2495-2501



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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