Culture Conversion in Patients Treated with Bedaquiline and/or Delamanid. A Prospective Multicountry Study

Molly F Franke, Palwasha Khan, Cathy Hewison, Uzma Khan, Helena Huerga, Kwonjune J Seung, Michael L Rich, Khin Zarli, Nazgul Samieva, Lawrence Oyewusi, Parvati Nair, Mishaz Mudassar, Nara Melikyan, Putri Lenggogeni, Leonid Lecca, Andargachew Kumsa, Munira Khan, Shirajul Islam, Kerow Hussein, Wisny Docteur, Nino Chumburidze, Elmira Berikova, Hakob Atshemyan, Sidney Atwood, Manzurul Alam, Saman Ahmed, Mathieu Bastard, Carole D Mitnick, Molly F Franke, Palwasha Khan, Cathy Hewison, Uzma Khan, Helena Huerga, Kwonjune J Seung, Michael L Rich, Khin Zarli, Nazgul Samieva, Lawrence Oyewusi, Parvati Nair, Mishaz Mudassar, Nara Melikyan, Putri Lenggogeni, Leonid Lecca, Andargachew Kumsa, Munira Khan, Shirajul Islam, Kerow Hussein, Wisny Docteur, Nino Chumburidze, Elmira Berikova, Hakob Atshemyan, Sidney Atwood, Manzurul Alam, Saman Ahmed, Mathieu Bastard, Carole D Mitnick

Abstract

Rationale: Bedaquiline and delamanid offer the possibility of more effective and less toxic treatment for multidrug-resistant (MDR) tuberculosis (TB). With this treatment, however, some patients remain at high risk for an unfavorable treatment outcome. The endTB Observational Study is the largest multicountry cohort of patients with rifampin-resistant TB or MDR-TB treated in routine care with delamanid- and/or bedaquiline-containing regimens according to World Health Organization guidance.Objectives: We report the frequency of sputum culture conversion within 6 months of treatment initiation and the risk factors for nonconversion.Methods: We included patients with a positive baseline culture who initiated a first endTB regimen before April 2018. Two consecutive negative cultures collected 15 days or more apart constituted culture conversion. We used generalized mixed models to derive marginal predictions for the probability of culture conversion in key subgroups.Measurements and Main Results: A total of 1,109 patients initiated a multidrug treatment containing bedaquiline (63%), delamanid (27%), or both (10%). Of these, 939 (85%) experienced culture conversion within 6 months. In adjusted analyses, patients with HIV had a lower probability of conversion (0.73; 95% confidence interval [CI], 0.62-0.84) than patients without HIV (0.84; 95% CI, 0.79-0.90; P = 0.03). Patients with both cavitary disease and highly positive sputum smear had a lower probability of conversion (0.68; 95% CI, 0.57-0.79) relative to patients without either (0.89; 95% CI, 0.84-0.95; P = 0.0004). Hepatitis C infection, diabetes mellitus or glucose intolerance, and baseline resistance were not associated with conversion.Conclusions: Frequent sputum conversion in patients with rifampin-resistant TB or MDR-TB who were treated with bedaquiline and/or delamanid underscores the need for urgent expanded access to these drugs. There is a need to optimize treatment for patients with HIV and extensive disease.

Keywords: extensively drug-resistant tuberculosis; interim outcome; multidrug-resistant tuberculosis; rifampicin-resistant tuberculosis; sputum conversion.

Figures

Figure 1.
Figure 1.
Overview of the analysis cohort. *During the study period, 12 patients initiated a second regimen with endTB containing bedaquiline and/or delamanid. These second regimens were excluded from analyses. BDQ = bedaquiline; DLM = delamanid; DPRK = Democratic People’s Republic of Korea; TB = tuberculosis.
Figure 2.
Figure 2.
Marginal predictions of the probability of culture conversion within 6 months, according to baseline (A) extent of disease, (B) resistance pattern, and (C) presence of comorbidity (n = 1,103). Each probability is adjusted for the other covariates shown in this panel and year of enrollment. CI = confidence interval; FQ = fluoroquinolone resistance; Hep C = hepatitis C; INJ = injectable resistance; MDR = multidrug resistant; XDR = extensively drug resistant.

References

    1. World Health Organization. Geneva, Switzerland: World Health Organization; 2019 [accessed 2020 Oct 28]. Global tuberculosis report 2019. Available from: .
    1. World Health Organization. Geneva, Switzerland: World Health Organization; 2018 [accessed 2020 Oct 28]. Global tuberculosis report 2018. Available from: .
    1. Isaakidis P, Rangan S, Pradhan A, Ladomirska J, Reid T, Kielmann K. ‘I cry every day’: experiences of patients co-infected with HIV and multidrug-resistant tuberculosis. Trop Med Int Health. 2013;18:1128–1133.
    1. Modongo C, Sobota RS, Kesenogile B, Ncube R, Sirugo G, Williams SM, et al. Successful MDR-TB treatment regimens including amikacin are associated with high rates of hearing loss. BMC Infect Dis. 2014;14:542.
    1. Arnold A, Cooke GS, Kon OM, Dedicoat M, Lipman M, Loyse A, et al. Adverse effects and choice between the injectable Agents amikacin and capreomycin in multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2017;61:e02586-16.
    1. Sagwa EL, Ruswa N, Mavhunga F, Rennie T, Leufkens HGM, Mantel-Teeuwisse AK. Comparing amikacin and kanamycin-induced hearing loss in multidrug-resistant tuberculosis treatment under programmatic conditions in a Namibian retrospective cohort. BMC Pharmacol Toxicol. 2015;16:36.
    1. Reuter A, Tisile P, von Delft D, Cox H, Cox V, Ditiu L, et al. The devil we know: is the use of injectable agents for the treatment of MDR-TB justified? Int J Tuberc Lung Dis. 2017;21:1114–1126.
    1. Gler MT, Skripconoka V, Sanchez-Garavito E, Xiao H, Cabrera-Rivero JL, Vargas-Vasquez DE, et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N Engl J Med. 2012;366:2151–2160.
    1. Pym AS, Diacon AH, Tang S-J, Conradie F, Danilovits M, Chuchottaworn C, et al. TMC207-C209 Study Group. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016;47:564–574.
    1. Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I, et al. TMC207-C208 Study Group. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med. 2014;371:723–732.
    1. Mbuagbaw L, Guglielmetti L, Hewison C, Bakare N, Bastard M, Caumes E, et al. Outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. Emerg Infect Dis. 2019;25:936–943.
    1. Mok J, Kang H, Koh W-J, Jhun BW, Yim J-J, Kwak N, et al. Final treatment outcomes of delamanid-containing regimens in patients with MDR-/XDR-TB in South Korea. Eur Respir J. 2019;54:1900811.
    1. von Groote-Bidlingmaier F, Patientia R, Sanchez E, Balanag V, Jr, Ticona E, Segura P, et al. Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial. Lancet Respir Med. 2019;7:249–259.
    1. Schnippel K, Ndjeka N, Maartens G, Meintjes G, Master I, Ismail N, et al. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. Lancet Respir Med. 2018;6:699–706.
    1. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D’Ambrosio L, Centis R, et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J. 2017;49:1700387.
    1. Skripconoka V, Danilovits M, Pehme L, Tomson T, Skenders G, Kummik T, et al. Delamanid improves outcomes and reduces mortality in multidrug-resistant tuberculosis. Eur Respir J. 2013;41:1393–1400.
    1. Gupta R, Geiter LJ, Wells CD, Gao M, Cirule A, Xiao H. Delamanid for extensively drug-resistant tuberculosis. N Engl J Med. 2015;373:291–292.
    1. Wells CD, Gupta R, Hittel N, Geiter LJ. Long-term mortality assessment of multidrug-resistant tuberculosis patients treated with delamanid. Eur Respir J. 2015;45:1498–1501.
    1. Bastard M, Guglielmetti L, Huerga H, Hayrapetyan A, Khachatryan N, Yegiazaryan L, et al. Bedaquiline and repurposed drugs for fluoroquinolone-resistant multidrug-resistant tuberculosis: how much better are they? Am J Respir Crit Care Med. 2018;198:1228–1231.
    1. Seung KJ, Khan P, Franke MF, Ahmed S, Aiylchiev S, Alam M, et al. Culture conversion at 6 months in patients receiving delamanid-containing regimens for the treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2020;71:415–418.
    1. World Health Organization. Geneva, Switzerland: World Health Organization; 2019 [accessed 2020 Oct 28]. Consolidated guidelines on drug-resistant tuberculosis treatment. Available from:
    1. World Health Organization. Geneva, Switzerland: World Health Organization; 2013 [accessed 2020 Oct 28]. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis interim policy guidance. Available from: .
    1. World Health Organization. Geneva, Switzerland: World Health Organization; 2014 [accessed 2020 Oct 28]. The use of delamanid in the treatment of multidrug-resistant tuberculosis interim policy guidance. Available from: .
    1. Bastos ML, Lan Z, Menzies D. An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis. Eur Respir J. 2017;49:1600803.
    1. Huangfu P, Ugarte-Gil C, Golub J, Pearson F, Critchley J. The effects of diabetes on tuberculosis treatment outcomes: an updated systematic review and meta-analysis. Int J Tuberc Lung Dis. 2019;23:783–796.
    1. Waitt CJ, Squire SB. A systematic review of risk factors for death in adults during and after tuberculosis treatment. Int J Tuberc Lung Dis. 2011;15:871–885.
    1. Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, Finlay A, et al. HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis. 2007;196:S86–S107.
    1. Ungo JR, Jones D, Ashkin D, Hollender ES, Bernstein D, Albanese AP, et al. Antituberculosis drug–induced hepatotoxicity: the role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med. 1998;157:1871–1876.
    1. Chang T-E, Huang Y-S, Chang C-H, Perng C-L, Huang Y-H, Hou M-C. The susceptibility of anti-tuberculosis drug-induced liver injury and chronic hepatitis C infection: a systematic review and meta-analysis. J Chin Med Assoc. 2018;81:111–118.
    1. Lomtadze N, Kupreishvili L, Salakaia A, Vashakidze S, Sharvadze L, Kempker RR, et al. Hepatitis C virus co-infection increases the risk of anti-tuberculosis drug-induced hepatotoxicity among patients with pulmonary tuberculosis. PLoS One. 2013;8:e83892.
    1. Khan U, Huerga H, Khan AJ, Mitnick CD, Hewison C, Varaine F, et al. The endTB observational study protocol: treatment of MDR-TB with bedaquiline or delamanid containing regimens. BMC Infect Dis. 2019;19:733.
    1. endTB Consortium. endTB clinical and programmatic guide for patient management with new TB drugs. Version 4.0; January 2018 [accessed 2020 Oct 28]. Available from: .
    1. Kurbatova EV, Cegielski JP, Lienhardt C, Akksilp R, Bayona J, Becerra MC, et al. Sputum culture conversion as a prognostic marker for end-of-treatment outcome in patients with multidrug-resistant tuberculosis: a secondary analysis of data from two observational cohort studies. Lancet Respir Med. 2015;3:201–209.
    1. Holtz TH, Sternberg M, Kammerer S, Laserson KF, Riekstina V, Zarovska E, et al. Time to sputum culture conversion in multidrug-resistant tuberculosis: predictors and relationship to treatment outcome. Ann Intern Med. 2006;144:650–659.
    1. Imperial MZ, Nahid P, Phillips PPJ, Davies GR, Fielding K, Hanna D, et al. A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nat Med. 2018;24:1708–1715.
    1. Muller CJ, MacLehose RF. Estimating predicted probabilities from logistic regression: different methods correspond to different target populations. Int J Epidemiol. 2014;43:962–970.
    1. Kim CT, Kim TO, Shin HJ, Ko YC, Hun Choe Y, Kim HR, et al. Bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis: a multicentre cohort study in Korea. Eur Respir J. 2018;51:1702467.
    1. Chamie G, Luetkemeyer A, Walusimbi-Nanteza M, Okwera A, Whalen CC, Mugerwa RD, et al. Significant variation in presentation of pulmonary tuberculosis across a high resolution of CD4 strata. Int J Tuberc Lung Dis. 2010;14:1295–1302.
    1. Hanrahan CF, Theron G, Bassett J, Dheda K, Scott L, Stevens W, et al. Xpert MTB/RIF as a measure of sputum bacillary burden: variation by HIV status and immunosuppression. Am J Respir Crit Care Med. 2014;189:1426–1434.
    1. Collins KR, Quiñones-Mateu ME, Toossi Z, Arts EJ. Impact of tuberculosis on HIV-1 replication, diversity, and disease progression. AIDS Rev. 2002;4:165–176.
    1. O’Donnell MR, Padayatchi N, Daftary A, Orrell C, Dooley KE, Rivet Amico K, et al. Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection. Lancet HIV. 2019;6:e201–e204.
    1. World Health Organization. Geneva, Switzerland: World Health Organization; 2019. Update of Recommendations on first-and second-line antiretroviral regimens. [accessed 2020 Oct 28]. Available from: .
    1. Kim WS, Lee SS, Lee CM, Kim HJ, Ha CY, Kim HJ, et al. Hepatitis C and not Hepatitis B virus is a risk factor for anti-tuberculosis drug induced liver injury. BMC Infect Dis. 2016;16:50.
    1. World Health Organization. Geneva, Switzerland: World Health Organization; 2019 [accessed 2020 Oct 28]. Hepatitis C key facts. Available from: .
    1. Davies HTO, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ. 1998;316:989–991.

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