Management of falsepositive rifampicin resistant Xpert MTB/RIF – Authors' reply
Authors: Jean Claude Semuto Ngabonziza, Tom Decroo, Gabriela Torrea, Patrick Migambi, Armand Van Deun, Leen Rigouts, Bouke Catherine de Jong
Journal: The Lancet Microbe (2020)

We thank Natalie Beylis and colleagues for highlighting the importance of adapting guidelines on the interpretation of Xpert MTB/RIF (Xpert) rifampicin-resistance results for local settings. The positive predictive value—the proportion of true rifampicin resistance in patients with a very low bacillary load on Xpert—ranged between nine (14%) of 63 patients in Rwanda and 192 (80%) of 239 patients in South Africa.1Ngabonziza J C S Decroo T Migambi P et al.Prevalence and drivers of false-positive rifampicin-resistant Xpert MTB/RIF results: a prospective observational study in Rwanda.Lancet Microbe. 2020; 1: e74-e83Summary Full Text Full Text PDF Scopus (15) Google Scholar The positive predictive value is strongly correlated with the pretest probability, which depends on the prevalence of rifampicin resistance (lower in Rwanda than in South Africa) and indications for Xpert testing. Confirmed rifampicin resistance after repeat Xpert testing reduces uncertainty. In Rwanda, all four patients with a very low bacillary load and rifampicin resistance after the first Xpert, which was confirmed after repeat Xpert, had true rifampicin resistance.1Ngabonziza J C S Decroo T Migambi P et al.Prevalence and drivers of false-positive rifampicin-resistant Xpert MTB/RIF results: a prospective observational study in Rwanda.Lancet Microbe. 2020; 1: e74-e83Summary Full Text Full Text PDF Scopus (15) Google Scholar If rifampicin resistance is not confirmed after repeat Xpert testing, a clinical decision is warranted. The probability of rifampicin-resistant tuberculosis required to treat a patient with a second-line drug instead of a first-line regimen is unknown. This threshold is affected by treatment duration, tolerability, and effectiveness, and is thus lower for the short (9 month) rifampicin-resistant tuberculosis regimen.2Trébucq A Decroo T Van Deun A et al.Short-course regimen for multidrug-resistant tuberculosis: a decade of evidence.J Clin Med. 2019; 9: 55Crossref Scopus (14) Google Scholar 50% or more of patients with true rifampicin-resistant tuberculosis treated with a first-line rifampicin-based regimen experienced an adverse outcome and continue spreading rifampicin-resistant tuberculosis.3Van Deun A Decroo T Aung K J M et al.The perceived impact of isoniazid resistance on outcome of first-line rifampicin-throughout regimens is largely due to missed rifampicin resistance.PLoS One. 2020; 15e0233500Crossref PubMed Scopus (9) Google Scholar Conversely, most patients with false rifampicin-resistant tuberculosis treated with a second-line regimen would have the infection resolved with no relapse after 2 years follow-up.2Trébucq A Decroo T Van Deun A et al.Short-course regimen for multidrug-resistant tuberculosis: a decade of evidence.J Clin Med. 2019; 9: 55Crossref Scopus (14) Google Scholar However, second-line regimens more frequently cause serious adverse events.4Nunn AJ Phillips PPJ Meredith SK et al.A trial of a shorter regimen for rifampin-resistant tuberculosis.N Engl J Med. 2019; 380: 1201-1213Crossref PubMed Scopus (152) Google Scholar, 5Boeree MJ Heinrich N Aarnoutse R et al.High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial.Lancet Infect Dis. 2017; 17: 39-49Summary Full Text Full Text PDF PubMed Scopus (188) Google Scholar In Rwanda, about 85% of patients treated with a second-line regimen had their infection resolved and reported manageable adverse events,6Ngabonziza JCS Habimana YM Decroo T et al.Reduction of diagnostic and treatment delays reduces rifampicin-resistant tuberculosis mortality in Rwanda.Int J Tuberc Lung Dis. 2020; 24: 329-339Crossref PubMed Scopus (17) Google Scholar thus lowering the threshold to start a second-line regimen.2Trébucq A Decroo T Van Deun A et al.Short-course regimen for multidrug-resistant tuberculosis: a decade of evidence.J Clin Med. 2019; 9: 55Crossref Scopus (14) Google Scholar Whereas, close monitoring allows the early identification of rifampicin resistance during treatment, and systematic testing of baseline samples at the reference laboratory informs regimen modifications. Moreover, considering the low positive predictive value of having true rifampicin-resistant tuberculosis, it seems justified to start a first-line regimen in patients with a very low bacillary load and unconfirmed rifampicin-resistant tuberculosis after repeat Xpert testing. One observational study will evaluate safety and outcomes retrospectively in patients with false rifampicin-resistant tuberculosis treated with a second-line regimen, and another study will prospectively assess patients with unconfirmed rifampicin-resistant tuberculosis treated with a first-line regimen. In other settings with a high prevalence of rifampicin-resistant tuberculosis or with poor access to laboratory monitoring a highly effective and tolerable rifampicin-resistant tuberculosis regimen would be beneficial. We recommend that tuberculosis programmes determine the proportion of patients with true rifampicin-resistant tuberculosis by Xpert bacillary load category and adapt algorithms taking into account the local setting. We declare no competing interests. Prevalence and drivers of false-positive rifampicin-resistant Xpert MTB/RIF results: a prospective observational study in RwandaThe Xpert testing algorithm should include an assessment of bacillary load and retesting in case rifampicin resistance is detected on a paucibacillary sputum sample. Only when rifampicin resistance has been confirmed on repeat testing should multidrug-resistant tuberculosis treatment be started. When rifampicin resistance has not been confirmed on repeat testing, we propose that patients should be given first-line anti-tuberculosis drugs and monitored closely during treatment, including by baseline culture, pDST, and further Xpert testing. Full-Text PDF Open AccessManagement of false-positive rifampicin resistant Xpert MTB/RIFWe read the study by Jean Claude Semuto Ngabonziza and colleagues1 in The Lancet Microbe, in which the authors identified an association between false-positive rifampicin-resistant Xpert MTB/RIF (Xpert; G4 cartridge; Cepheid, Sunnyvale, CA, USA) results and a very low bacillary load.1 This association has previously been described,2–4 and Xpert rifampicin-resistant results associated with a very low bacillary load were recommended to be confirmed by testing a second specimen. Ngaboninza and colleagues1 suggested that these patients should be managed with a drug susceptible tuberculosis regimen until confirmatory results are available. Full-Text PDF Open Access