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Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis

BACKGROUND: Human African trypanosomiasis is fatal without treatment. The long post-treatment follow-up (24 months) required to assess cure complicates patient management and is a major obstacle in the development of new therapies. We analyzed individual patient data from 12 programs conducted by Mé...

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Autores principales: Priotto, Gerardo, Chappuis, François, Bastard, Mathieu, Flevaud, Laurence, Etard, Jean-François
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367996/
https://www.ncbi.nlm.nih.gov/pubmed/22701752
http://dx.doi.org/10.1371/journal.pntd.0001662
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author Priotto, Gerardo
Chappuis, François
Bastard, Mathieu
Flevaud, Laurence
Etard, Jean-François
author_facet Priotto, Gerardo
Chappuis, François
Bastard, Mathieu
Flevaud, Laurence
Etard, Jean-François
author_sort Priotto, Gerardo
collection PubMed
description BACKGROUND: Human African trypanosomiasis is fatal without treatment. The long post-treatment follow-up (24 months) required to assess cure complicates patient management and is a major obstacle in the development of new therapies. We analyzed individual patient data from 12 programs conducted by Médecins Sans Frontières in Uganda, Sudan, Angola, Central African Republic, Republic of Congo and Democratic Republic of Congo searching for early efficacy indicators. METHODOLOGY/PRINCIPAL FINDINGS: Patients analyzed had confirmed second-stage disease with complete follow-up and confirmed outcome (cure or relapse), and had CSF leucocytes counts (CSFLC) performed at 6 months post-treatment. We excluded patients with uncertain efficacy outcome: incomplete follow-up, death, relapse diagnosed with CSFLC below 50/µL and no trypanosomes. We analyzed the 6-month CSFLC via receiver-operator-characteristic curves. For each cut-off value we calculated sensitivity, specificity and likelihood ratios (LR+ and LR−). We assessed the association of the optimal cut-off with the probability of relapsing via random-intercept logistic regression. We also explored two-step (6 and 12 months) composite algorithms using the CSFLC. The most accurate cut-off to predict outcome was 10 leucocytes/µL (n = 1822, 76.2% sensitivity, 80.4% specificity, 3.89 LR+, 0.29 LR−). Multivariate analysis confirmed its association with outcome (odds ratio = 17.2). The best algorithm established cure at 6 months with < = 5 leucocytes/µL and relapse with > = 50 leucocytes/µL; patients between these values were discriminated at 12 months by a 20 leucocytes/µL cut-off (n = 2190, 87.4% sensitivity, 97.7% specificity, 37.84 LR+, 0.13 LR−). CONCLUSIONS/SIGNIFICANCE: The 6-month CSFLC can predict outcome with some limitations. Two-step algorithms enhance the accuracy but impose 12-month follow-up for some patients. For early estimation of efficacy in clinical trials and for individual patients in the field, several options exist that can be used according to priorities.
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spelling pubmed-33679962012-06-13 Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis Priotto, Gerardo Chappuis, François Bastard, Mathieu Flevaud, Laurence Etard, Jean-François PLoS Negl Trop Dis Research Article BACKGROUND: Human African trypanosomiasis is fatal without treatment. The long post-treatment follow-up (24 months) required to assess cure complicates patient management and is a major obstacle in the development of new therapies. We analyzed individual patient data from 12 programs conducted by Médecins Sans Frontières in Uganda, Sudan, Angola, Central African Republic, Republic of Congo and Democratic Republic of Congo searching for early efficacy indicators. METHODOLOGY/PRINCIPAL FINDINGS: Patients analyzed had confirmed second-stage disease with complete follow-up and confirmed outcome (cure or relapse), and had CSF leucocytes counts (CSFLC) performed at 6 months post-treatment. We excluded patients with uncertain efficacy outcome: incomplete follow-up, death, relapse diagnosed with CSFLC below 50/µL and no trypanosomes. We analyzed the 6-month CSFLC via receiver-operator-characteristic curves. For each cut-off value we calculated sensitivity, specificity and likelihood ratios (LR+ and LR−). We assessed the association of the optimal cut-off with the probability of relapsing via random-intercept logistic regression. We also explored two-step (6 and 12 months) composite algorithms using the CSFLC. The most accurate cut-off to predict outcome was 10 leucocytes/µL (n = 1822, 76.2% sensitivity, 80.4% specificity, 3.89 LR+, 0.29 LR−). Multivariate analysis confirmed its association with outcome (odds ratio = 17.2). The best algorithm established cure at 6 months with < = 5 leucocytes/µL and relapse with > = 50 leucocytes/µL; patients between these values were discriminated at 12 months by a 20 leucocytes/µL cut-off (n = 2190, 87.4% sensitivity, 97.7% specificity, 37.84 LR+, 0.13 LR−). CONCLUSIONS/SIGNIFICANCE: The 6-month CSFLC can predict outcome with some limitations. Two-step algorithms enhance the accuracy but impose 12-month follow-up for some patients. For early estimation of efficacy in clinical trials and for individual patients in the field, several options exist that can be used according to priorities. Public Library of Science 2012-06-05 /pmc/articles/PMC3367996/ /pubmed/22701752 http://dx.doi.org/10.1371/journal.pntd.0001662 Text en Priotto et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Priotto, Gerardo
Chappuis, François
Bastard, Mathieu
Flevaud, Laurence
Etard, Jean-François
Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis
title Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis
title_full Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis
title_fullStr Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis
title_full_unstemmed Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis
title_short Early Prediction of Treatment Efficacy in Second-Stage Gambiense Human African Trypanosomiasis
title_sort early prediction of treatment efficacy in second-stage gambiense human african trypanosomiasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367996/
https://www.ncbi.nlm.nih.gov/pubmed/22701752
http://dx.doi.org/10.1371/journal.pntd.0001662
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