Treatment of Highly Drug-Resistant Pulmonary Tuberculosis
Francesca ConradieFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andAndreas H. DiaconFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andNosipho NgubaneFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andPauline HowellFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andDaniel E. EverittFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andAngela M. CrookFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andCarl M. MendelFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andErica EgiziFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andJoanna MoreiraFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andJuliano TimmFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andTimothy D. McHughFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andGenevieve H. WillsFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andMatthew BatesFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andRobert HuntFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andChristo van NiekerkFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andMengchun LiFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andMorounfolu OlugbosiFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) andMelvin SpigelmanFrom the Clinical HIV Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg (F.C., N.N., P.H.), Sizwe Tropical Disease Hospital, Sandringham (F.C., P.H.), Task Applied Science and Stellenbosch University, Cape Town (A.H.D.), King DiniZulu Hospital Complex, Durban (N.N.), and the TB Alliance, Pretoria (C.V.N., M.O.) — all in South Africa; the TB Alliance, New York (D.E., C.M.M., E.E., J.M., J.T., M.L., M.S.); and the MRC Clinical Trials Unit at UCL (A.M.C., G.H.W.) and
2020en
ABI
Аннотация
BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS: In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS: A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).
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