Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials

Patrick P J Phillips, Carl M Mendel, Divan A Burger, Angela M Crook, Andrew J Nunn, Rodney Dawson, Andreas H Diacon, Stephen H Gillespie, Patrick P J Phillips, Carl M Mendel, Divan A Burger, Angela M Crook, Andrew J Nunn, Rodney Dawson, Andreas H Diacon, Stephen H Gillespie

Abstract

Background: Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials.

Methods: Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome.

Results: Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP.

Conclusions: Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.

Figures

Fig. 1
Fig. 1
Fit of non-linear mixed effects model of MGIT TTP during the first 56 days of treatment with three anti-tuberculosis regimens
Fig. 2
Fig. 2
Trial-level surrogacy plot. a Time to culture negative status on LJ. b Time to culture negative status in MGIT. c BA(0–56), daily rate of change in log10(TTP) to day 56. The difference between treatments on the intermediate marker is plotted against the difference in unfavourable outcome with 95 % confidence intervals. Points lying outside the yellow regions indicate that the treatment difference is in the opposite direction on the intermediate marker from the long-term clinical outcome
Fig. 3
Fig. 3
Estimates of probability of an unfavourable outcome by treatment arm and by intermediate marker. a Time to culture negative status on LJ. b Time to culture negative status in MGIT. c BA(0–56), daily rate of change in log10(TTP) to day 56. d Time to smear negative. Vertical solid and dashed lines show various centiles of the intermediate markers for patients in the control arm in the REMoxTB trial
Fig. 4
Fig. 4
Receiver operating characteristic (ROC) curves. All curves represent models adjusted for baseline covariates. a Control arm. b Isoniaizid arm. c Ethambutol arm

References

    1. Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014;371(17):1577–87. doi: 10.1056/NEJMoa1407426.
    1. Jindani A, Harrison TS, Nunn AJ, Phillips PP, Churchyard GJ, Charalambous S, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 2014;371(17):1599–608. doi: 10.1056/NEJMoa1314210.
    1. Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 2014;371(17):1588–98. doi: 10.1056/NEJMoa1315817.
    1. World Health Organization (WHO) Global tuberculosis report 2014. Geneva: WHO; 2014.
    1. Uplekar M, Weil D, Lonnroth K, Jaramillo E, Lienhardt C, Dias HM, et al. WHO’s new end TB strategy. Lancet. 2015;385(9979):1799–801. doi: 10.1016/S0140-6736(15)60570-0.
    1. Sloan DJ, Mwandumba HC, Garton NJ, Khoo SH, Butterworth AE, Allain TJ, et al. Pharmacodynamic modeling of bacillary elimination rates and detection of bacterial lipid bodies in sputum to predict and understand outcomes in treatment of pulmonary tuberculosis. Clin Infect Dis. 2015;61(1):1–8. doi: 10.1093/cid/civ195.
    1. Horne DJ, Royce SE, Gooze L, Narita M, Hopewell PC, Nahid P, et al. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect Dis. 2010;10(6):387–94. doi: 10.1016/S1473-3099(10)70071-2.
    1. Temple RJ. A regulatory authority’s opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, editors. Clinical measurement in drug evaluation. New York: Wiley; 1995. pp. 3–22.
    1. Phillips PPJ, Fielding K, Nunn AJ. An evaluation of culture results during treatment for tuberculosis as surrogate endpoints for treatment failure and relapse. PLoS One. 2013;8(5):e63840. doi: 10.1371/journal.pone.0063840.
    1. Phillips PP, Davies GR, Mitchison DA. Biomarkers for tuberculosis disease activity, cure, and relapse. [Correspondence] Lancet Infect Dis. 2010;10(2):69–70. doi: 10.1016/S1473-3099(09)70256-7.
    1. Wallis RS, Wang C, Doherty TM, Onyebujoh P, Vahedi M, Laang H, et al. Biomarkers for tuberculosis disease activity, cure, and relapse. Lancet Infect Dis. 2010;10(2):68–9. doi: 10.1016/S1473-3099(10)70003-7.
    1. Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371(8):723–32. doi: 10.1056/NEJMoa1313865.
    1. Rustomjee R, Lienhardt C, Kanyok T, Davies GR, Levin J, Mthiyane T, et al. A phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2008;12(2):128–38.
    1. Dawson R, Diacon AH, Everitt D, van Niekerk C, Donald PR, Burger DA, et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet. 2015;385(9979):1738–47. doi: 10.1016/S0140-6736(14)62002-X.
    1. Cox E, Laessig K. FDA approval of bedaquiline — the benefit-risk balance for drug-resistant tuberculosis. N Engl J Med. 2014;371(8):689–91. doi: 10.1056/NEJMp1314385.
    1. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis. 1999;3(10 Suppl 2):S231–79.
    1. Burger DA, Schall R. A Bayesian nonlinear mixed-effects regression model for the characterization of early bactericidal activity of tuberculosis drugs. J Biopharm Stat. 2015;25(6):1247–71. doi: 10.1080/10543406.2014.971170.
    1. Cuzick J. A Wilcoxon-type test for trend. Stat Med. 1985;4(1):87–90. doi: 10.1002/sim.4780040112.
    1. Royston P, Altman DG. Regression using fractional polynomials of continuous covariates - parsimonious parametric modeling. Appl Stat. 1994;43(3):429–67. doi: 10.2307/2986270.
    1. MacKinnon DP, Lockwood CM, Brown CH, Wang W, Hoffman JM. The intermediate endpoint effect in logistic and probit regression. Clin Trials. 2007;4(5):499–513. doi: 10.1177/1740774507083434.
    1. Chen RY, Dodd LE, Lee M, Paripati P, Hammoud DA, Mountz JM, et al. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Sci Transl Med. 2014;6(265):265ra166. doi: 10.1126/scitranslmed.3009501.
    1. Kayigire XA, Friedrich SO, van der Merwe L, Donald PR, Diacon AH. Simultaneous staining of sputum smears for acid-fast and lipid-containing Myobacterium tuberculosis can enhance the clinical evaluation of antituberculosis treatments. Tuberculosis (Edinb) 2015;95(6):770–9. doi: 10.1016/j.tube.2015.08.001.
    1. Hammond RJ, Baron VO, Oravcova K, Lipworth S, Gillespie SH. Phenotypic resistance in mycobacteria: is it because I am old or fat that I resist you? J Antimicrob Chemother. 2015;70(10):2823–7. doi: 10.1093/jac/dkv178.
    1. Walter ND, Dolganov GM, Garcia BJ, Worodria W, Andama A, Musisi E, et al. Transcriptional adaptation of drug-tolerant Mycobacterium tuberculosis during treatment of human tuberculosis. J Infect Dis. 2015;212(6):990–8. doi: 10.1093/infdis/jiv149.
    1. Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis. 2000;4(9):796–806.
    1. Wallis RS, Wang C, Meyer D, Thomas N. Month 2 culture status and treatment duration as predictors of tuberculosis relapse risk in a meta-regression model. PLoS One. 2013;8(8):e71116. doi: 10.1371/journal.pone.0071116.
    1. Wallis RS, Peppard T, Hermann D. Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: model validation and update. PLoS One. 2015;10(4):e0125403. doi: 10.1371/journal.pone.0125403.
    1. Conde MB, Efron A, Loredo C, De Souza GR, Graca NP, Cezar MC, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet. 2009;373(9670):1183–9. doi: 10.1016/S0140-6736(09)60333-0.
    1. Burman WJ, Goldberg S, Johnson JL, Muzanye G, Eagle M, Mosher AW, et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med. 2006;174(3):331–8. doi: 10.1164/rccm.200603-360OC.
    1. Li SY, Irwin SM, Converse PJ, Mdluli KE, Lenaerts AJ, Nuermberger EL. Evaluation of moxifloxacin-containing regimens in pathologically distinct murine tuberculosis models. Antimicrob Agents Chemother. 2015;59(7):4026–30. doi: 10.1128/AAC.00105-15.
    1. Nimmo C, Lipman M, Phillips PP, McHugh T, Nunn A, Abubakar I. Shortening treatment of tuberculosis: lessons from fluoroquinolone trials. Lancet Infect Dis. 2015;15(2):141–3. doi: 10.1016/S1473-3099(14)70885-0.
    1. Lanoix JP, Chaisson RE, Nuermberger EL. Shortening tuberculosis treatment with fluoroquinolones: lost in translation? Clin Infect Dis. 2016;62(4):484–90.
    1. Phillips PP, Gillespie SH, Boeree M, Heinrich N, Aarnoutse R, McHugh T, et al. Innovative trial designs are practical solutions for improving the treatment of tuberculosis. J Infect Dis. 2012;205(Suppl 2):S250–7. doi: 10.1093/infdis/jis041.
    1. Davies GR, Phillips PP, Jaki T. Adaptive clinical trials in tuberculosis: applications, challenges and solutions. Int J Tuberc Lung Dis. 2015;19(6):626–34. doi: 10.5588/ijtld.14.0988.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir