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 1 - HIV-infected TB suspect with previous history of TB treatment: Xpert MTB/RIF test

Authors: Richard Lessells

A 32 year old HIV-infected female presents with three weeks of cough, night sweats, chest pain, and dyspnoea. Her past medical history includes one previous episode of smear positive pulmonary TB in 2001, for which she took six months of therapy and was cured.

She had been diagnosed with HIV infection in 2008 and had been attending the primary health care clinic for regular CD4 monitoring but had not started antiretroviral therapy. Her most recent CD4 cell count five months before presentation was 350 cells/ul.


She reports that her sister, with whom she lived, had died whilst taking TB treatment 11 months prior to presentation. It was the first TB episode for her sister and she had been receiving regimen 1 (HRZE).

A sputum specimen is obtained and tested with the Xpert MTB/RIF system


Clinical chart

Interpretation

The result is MTB DETECTED LOW; Rif Resistance DETECTED. This molecular test has detected M. tuberculosis and at least one of the mutations in the rpoB gene which confer resistance to rifampicin. Rifampicin resistance is considered a reliable proxy for multidrug resistance (MDR) as rifampicin mono-resistance is relatively rare (>98% of rifampicin-resistant strains in the Xpert MTB/RIF demonstration study were MDR on conventional DST).

Given the relatively high pre-test probability of TB in this case from the clinical features, the detection of M. tuberculosis in sputum is very likely to indicate active TB disease.

The detection of rifampicin resistance is more complicated. In the large demonstration study for Xpert MTB/RIF, the sensitivity and specificity for detection of rifampicin resistance were 94.4% and 98.3% respectively (compared to the reference standard of phenotypic DST). To understand the significance of a positive result for rifampicin resistance, it is necessary to consider predictive values. Predictive values depend on the underlying prevalence of the condition in question.

The table below shows how the positive predictive value (PPV) varies according to the prevalence of rifampicin resistance (i.e. the proportion of TB isolates that are rifampicin resistant) and illustrates how this would translate to true positive and false positive resistance results in a hypothetical population of 1000 TB cases. In South Africa, approximately 5% of all TB cases are rifampicin resistant so the PPV for rifampicin resistance if used in unselected TB cases would be approximately 74%.

Certain groups have a much higher prevalence of rifampicin resistance, e.g. re-treatment cases and contacts of drug-resistant cases. Use in these selected groups will significantly reduce the occurrence of false positive rifampicin results.



Drug resistance


Recommendations

Treatment recommendation

She could be treated with a standard MDR-TB regimen. However, given the issue with false positives highlighted above this would risk treatment with suboptimal potency in the event of drug-sensitive TB. In actual fact, she was treated with a hybrid regimen pending confirmation of MDR-TB through culture & phenotypic drug susceptibility testing.

The regimen consisted of eight TB drugs: rifampicin (R), isoniazid (H), ethambutol (E), pyrazinamide (Z), kanamycin (Km), ofloxacin (Ofx), ethionamide (Eto), and terizidone (Trd). The rifampicin and isoniazid were subsequently discontinued when MDR-TB was confirmed with phenotypic DST.



Questions

I. By what mechanisms might this individual have developed drug-resistant TB disease?

II. Should she be commenced on antiretroviral therapy (ART)? If so, when should this be done and which regimen should be used?


Answers

I. There are three aspects of this case that might be of particular relevance in terms of the drug resistance:

Ia. It is plausible that she harboured drug-resistant strains from her first TB episode, despite the fact that this was 10 years prior to this episode and that she was documented to have been cured

Ib. The death h of the sister on TB treatment might be of relevance. The death of any household contact whilst on TB treatment in this setting should raise suspicion of possible drug-resistant TB

Ic. She has been attending her primary health care clinic regularly for HIV care and CD4 monitoring. The potential for health-care associated acquisition of drug-resistant TB therefore should be considered

II. Yes she should be commenced on ART. In South Africa patients with MDR-TB and XDR-TB are eligible for ART regardless of CD4 cell count. The use of ART will be a major factor in determining her outcome from MDR-TB. There is no evidence to inform the timing of ART specifically in drug-resistant TB but most practitioners would recommend initiation of ART within 4-8 weeks of the start of TB treatment, as long as the TB treatment is being tolerated. There is also no evidence on the optimal ART regimen. There are no known interactions between second-line TB drugs and NRTIs or NNRTIs so a standard first-line regimen can be used. The potential for overlapping toxicities (see table below) should be understood and patients should be monitored closely.


Key learning points

The positive predictive value of the Xpert MTB/RIF system for detection of drug resistance will depend on the prevalence of rifampicin resistance in the population being tested

All HIV-infected individuals with MDR-TB or XDR-TB should be commenced on antiretroviral therapy

Further reading

Boehme CC, Nicol MP, Nabeta P, et al (2011). Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet; 377: 1495-1505

World Health Organization (2011). Rapid implementation of the Xpert MTB/RIF diagnostic test: technical and operationalHow-to; practical considerations.

World Health Organization (2011). Guidelines for the programmatic management of drug-resistant tuberculosis -2011 update.



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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