Conference Material > Poster
Cazes C, Phelan KPQ, Hubert V, Boubacar H, Tshibangu G, et al.
MSF Scientific Days International 2021: Research. 2021 May 18
Journal Article > ResearchAbstract
N Engl J Med. 2020 June 18; Volume 382; 2397-2410.; DOI:10.1056/NEJMoa1910708
Blanc FX, Badje AD, Bonnet MMB, Gabillard D, Messou E, et al.
N Engl J Med. 2020 June 18; Volume 382; 2397-2410.; DOI:10.1056/NEJMoa1910708
BACKGROUND
In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death.
METHODS
We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization.
RESULTS
A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment.
CONCLUSIONS
Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events.
ClinicalTrials.gov number NCT02057796
In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death.
METHODS
We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization.
RESULTS
A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment.
CONCLUSIONS
Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events.
ClinicalTrials.gov number NCT02057796
Journal Article > ResearchFull Text
PLOS Med. 2016 March 1; Volume 13 (Issue 3); DOI:10.1371/journal.pmed.1001967
Sissoko D, Laouenan C, Folkesson E, M’Lebing A, Beavogui A, et al.
PLOS Med. 2016 March 1; Volume 13 (Issue 3); DOI:10.1371/journal.pmed.1001967
Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies.
Journal Article > CommentaryFull Text
Infectious Diseases and Therapy. 2022 June 29; Online ahead of print; 1-15.; DOI:10.1007/s40121-022-00667-z
Ariza-Vioque E, Ello F, Andriamamonjisoa H, Machault V, González-Martín J, et al.
Infectious Diseases and Therapy. 2022 June 29; Online ahead of print; 1-15.; DOI:10.1007/s40121-022-00667-z
Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), with at least 100,000 cases per year and a mortality rate of up to 50% in individuals co-infected with human immunodeficiency virus type 1 (HIV-1). To evaluate the efficacy and safety of an intensified anti-tubercular regimen and an anti-inflammatory treatment, the INTENSE-TBM project includes a phase III randomised clinical trial (TBM-RCT) in four countries in sub-Saharan Africa (SSA). Within this framework, we designed a comprehensive capacity-building work package ensuring all centres had, or would acquire, the ability to conduct the TBM-RCT and developing a network of skilled researchers, clinical centres and microbiology laboratories. Here, we describe these activities, identify strengths/challenges and share tools adaptable to other projects, particularly in low- and lower-middle income countries with heterogeneous settings and during the coronavirus disease 2019 (COVID-19) pandemic. Despite major challenges, TBM-RCT initiation was achieved in all sites, promoting enhanced local healthcare systems and encouraging further clinical research in SSA. In terms of certified trainings, the achievement levels were 95% (124/131) for good clinical practice, 91% (39/43) for good clinical laboratory practice and 91% (48/53) for infection prevention and control. Platform-based research, developed as part of capacity-building activities for specific projects, may be a valuable tool in fighting future infectious diseases and in developing high-level research in Africa.
Journal Article > ResearchAbstract Only
Clin Infect Dis. 2023 March 8; Online ahead of print; DOI:10.1093/cid/ciad125
Bonnet MMB, Gabillard D, Domoua SK, Muzoora C, Messou E, et al.
Clin Infect Dis. 2023 March 8; Online ahead of print; DOI:10.1093/cid/ciad125
BACKGROUND
In people with HIV (PWH), the WHO-recommended tuberculosis four-symptom screen (W4SS) targeting those who need molecular rapid test may be suboptimal. We assessed the performance of different tuberculosis screening approaches in severely immunosuppressed PWH enrolled in the guided-treatment group of the STATIS trial (NCT02057796).
METHODS
Ambulatory PWH with no overt evidence of tuberculosis and CD4 cell count <100/µL were screened for tuberculosis prior to antiretroviral therapy (ART) initiation with W4SS, chest X-ray, urine lipoarabinomannan (LAM) test and sputum Xpert MTB/RIF® (Xpert). Correctly and wrongly identified cases by screening approaches were assessed overall and by CD4 count threshold (≤50 and 51-99 cells/µL).
RESULTS
Of 525 enrolled participants (median CD4 cell count: 28/µL), 48 (9.9%) were diagnosed with tuberculosis at enrollment. Among participants with a negative W4SS, 16% had either a positive Xpert, a chest X-ray suggestive of tuberculosis or a positive urine LAM test. The combination of sputum Xpert and urine LAM test was associated with the highest proportion of participants correctly identified as tuberculosis (95.8%) and non-tuberculosis cases (95.4%), with proportions equally high among participants with CD4 counts above or below 50 cells/µL. Restricting the use of sputum Xpert, urine LAM test or chest X-ray to participants with a positive W4SS reduced the proportion of wrongly and correctly identified cases.
CONCLUSIONS
There is a clear benefit to perform both sputum Xpert and urine LAM tests as tuberculosis screening in all severely immunosuppressed PWH prior to ART initiation, and not only in those with a positive W4SS.
In people with HIV (PWH), the WHO-recommended tuberculosis four-symptom screen (W4SS) targeting those who need molecular rapid test may be suboptimal. We assessed the performance of different tuberculosis screening approaches in severely immunosuppressed PWH enrolled in the guided-treatment group of the STATIS trial (NCT02057796).
METHODS
Ambulatory PWH with no overt evidence of tuberculosis and CD4 cell count <100/µL were screened for tuberculosis prior to antiretroviral therapy (ART) initiation with W4SS, chest X-ray, urine lipoarabinomannan (LAM) test and sputum Xpert MTB/RIF® (Xpert). Correctly and wrongly identified cases by screening approaches were assessed overall and by CD4 count threshold (≤50 and 51-99 cells/µL).
RESULTS
Of 525 enrolled participants (median CD4 cell count: 28/µL), 48 (9.9%) were diagnosed with tuberculosis at enrollment. Among participants with a negative W4SS, 16% had either a positive Xpert, a chest X-ray suggestive of tuberculosis or a positive urine LAM test. The combination of sputum Xpert and urine LAM test was associated with the highest proportion of participants correctly identified as tuberculosis (95.8%) and non-tuberculosis cases (95.4%), with proportions equally high among participants with CD4 counts above or below 50 cells/µL. Restricting the use of sputum Xpert, urine LAM test or chest X-ray to participants with a positive W4SS reduced the proportion of wrongly and correctly identified cases.
CONCLUSIONS
There is a clear benefit to perform both sputum Xpert and urine LAM tests as tuberculosis screening in all severely immunosuppressed PWH prior to ART initiation, and not only in those with a positive W4SS.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 2017 February 23 (Issue 2)
Nguyen TN, Guedj J, Anglaret X, Laouenan C, Madelain V, et al.
PLoS Negl Trop Dis. 2017 February 23 (Issue 2)
In 2014-2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations.
Conference Material > Abstract
Cazes C, Phelan KPQ, Hubert V, Boubacar H, Bozama LI, et al.
MSF Scientific Days International 2021: Research. 2021 May 19
INTRODUCTION
The Optimising MAlnutrition treatment (OptiMA) strategy aims to simplify current malnutrition treatment protocols for children with mid-upper arm circumference (MUAC)<125mm or oedema, by supplementing with one product—ready-to-use therapeutic food (RUTF), using gradually reducing doses as a child’s weight and MUAC increases.
METHODS
This non-inferiority, randomized controlled trial was conducted in Kasai province, Democratic Republic of Congo (DRC). It compared the OptiMA strategy with the effective standard DRC protocol, using increasing weight doses of RUTF for treating severe acute malnutrition (SAM) and ready to use supplementary food (RUSF) at fixed dose for moderate acute malnutrition. Children aged 6–59 months with MUAC<125mm or weight-for-height Z score<−3 or oedema, and without medical complications, were randomized to either OptiMA or the standard protocol, and followed up for six months. Primary outcome was a composite indicator at 6 months’ follow-up: child alive, not acutely malnourished per the study definition, and without any additional episode of acute malnutrition throughout the observation period. Non-inferiority was determined if the upper boundary of the 95% confidence interval (CI) for the difference between randomized arms in the proportion of children with favourable outcome was less than 10%, for both intention-to-treat (ITT) and per-protocol (PP) analyses. Superiority was determined if the upper boundary of the 95% CI for this difference was lower than 0%.
ETHICS
This study was approved by the National Congolese Health Ethics Committee and by the Ethics Evaluation Committee of Inserm, the French National Institute for Health and Medical Research. ClinicalTrials.gov number, NCT03751475.
RESULTS
Between July 2019 and July 2020, 981 children were enrolled. 896 children were included in ITT analysis, with 450 in the OptiMA arm and 446 standard; 792 were included in PP analysis. Over the entire follow-up, 450 (100%) children under OptiMA received RUTF treatment while under the standard protocol, 315 (71%) received RUTF or RUSF or both. ITT analysis found that 325 (72.2%) children had favourable outcome under OptiMA versus 282 (63.2%) in the standard arm (difference: -9.2%, 95%CI -15.9% to -2.0%). Under OptiMA, weight gain was greater (median weight gain, 1700g versus 1600g, p= 0.003), the nutritional treatment consumption lower (median of 64 of RUTF versus 102 sachets of RUTF/RUSF under standard; p= 0.018). Median time to recovery (i.e., MUAC>124mm without oedema for two consecutive visits) was lower under OptiMA than under standard: 5 weeks (95%CI 5–5) versus 9 weeks (95%CI 8–10), p<0.001. We did not observe a difference in hospitalization rates (10% OptiMA, 7% standard, p=0.228) or mortality rates (0.2% in both arms).
CONCLUSION
OptiMA led to better anthropometric status over a six-month period and expanded access to treatment, whilst the standard protocol partially addressed global acute malnutrition with higher consumption of nutritional products used in the trial. Our findings suggest it may be beneficial to address global acute malnutrition in one program using one product at a gradually adjusted dose.
CONFLICTS OF INTEREST
None declared.
The Optimising MAlnutrition treatment (OptiMA) strategy aims to simplify current malnutrition treatment protocols for children with mid-upper arm circumference (MUAC)<125mm or oedema, by supplementing with one product—ready-to-use therapeutic food (RUTF), using gradually reducing doses as a child’s weight and MUAC increases.
METHODS
This non-inferiority, randomized controlled trial was conducted in Kasai province, Democratic Republic of Congo (DRC). It compared the OptiMA strategy with the effective standard DRC protocol, using increasing weight doses of RUTF for treating severe acute malnutrition (SAM) and ready to use supplementary food (RUSF) at fixed dose for moderate acute malnutrition. Children aged 6–59 months with MUAC<125mm or weight-for-height Z score<−3 or oedema, and without medical complications, were randomized to either OptiMA or the standard protocol, and followed up for six months. Primary outcome was a composite indicator at 6 months’ follow-up: child alive, not acutely malnourished per the study definition, and without any additional episode of acute malnutrition throughout the observation period. Non-inferiority was determined if the upper boundary of the 95% confidence interval (CI) for the difference between randomized arms in the proportion of children with favourable outcome was less than 10%, for both intention-to-treat (ITT) and per-protocol (PP) analyses. Superiority was determined if the upper boundary of the 95% CI for this difference was lower than 0%.
ETHICS
This study was approved by the National Congolese Health Ethics Committee and by the Ethics Evaluation Committee of Inserm, the French National Institute for Health and Medical Research. ClinicalTrials.gov number, NCT03751475.
RESULTS
Between July 2019 and July 2020, 981 children were enrolled. 896 children were included in ITT analysis, with 450 in the OptiMA arm and 446 standard; 792 were included in PP analysis. Over the entire follow-up, 450 (100%) children under OptiMA received RUTF treatment while under the standard protocol, 315 (71%) received RUTF or RUSF or both. ITT analysis found that 325 (72.2%) children had favourable outcome under OptiMA versus 282 (63.2%) in the standard arm (difference: -9.2%, 95%CI -15.9% to -2.0%). Under OptiMA, weight gain was greater (median weight gain, 1700g versus 1600g, p= 0.003), the nutritional treatment consumption lower (median of 64 of RUTF versus 102 sachets of RUTF/RUSF under standard; p= 0.018). Median time to recovery (i.e., MUAC>124mm without oedema for two consecutive visits) was lower under OptiMA than under standard: 5 weeks (95%CI 5–5) versus 9 weeks (95%CI 8–10), p<0.001. We did not observe a difference in hospitalization rates (10% OptiMA, 7% standard, p=0.228) or mortality rates (0.2% in both arms).
CONCLUSION
OptiMA led to better anthropometric status over a six-month period and expanded access to treatment, whilst the standard protocol partially addressed global acute malnutrition with higher consumption of nutritional products used in the trial. Our findings suggest it may be beneficial to address global acute malnutrition in one program using one product at a gradually adjusted dose.
CONFLICTS OF INTEREST
None declared.
Journal Article > ResearchAbstract
J Acquir Immune Defic Syndr. 2013 April 15; Volume 62 (Issue 5); DOI:10.1097/QAI.0b013e3182821821
Gabillard D, Lewden C, Ndoye I, Moh R, Segeral O, et al.
J Acquir Immune Defic Syndr. 2013 April 15; Volume 62 (Issue 5); DOI:10.1097/QAI.0b013e3182821821
In resource-limited countries, estimating CD4-specific incidence rates of mortality and morbidity among patients receiving antiretroviral therapy (ART) may help assess the effectiveness of care and treatment programmes, identify program weaknesses, and inform decisions.
Conference Material > Poster
Cazes C, Phelan KPQ, Hubert V, Boubacar H, Tshibangu G, et al.
MSF Scientific Days International 2021: Research. 2021 May 18
Journal Article > CommentaryFull Text
PLoS Negl Trop Dis. 2017 June 22; Volume 11 (Issue 6); e0005545.; DOI:10.1371/journal.pntd.0005545
Carazo Perez S, Folkesson E, Anglaret X, Beavogui A, Berbain E, et al.
PLoS Negl Trop Dis. 2017 June 22; Volume 11 (Issue 6); e0005545.; DOI:10.1371/journal.pntd.0005545
During the large Ebola outbreak that affected West Africa in 2014 and 2015, studies were launched to evaluate potential treatments for the disease. A clinical trial to evaluate the effectiveness of the antiviral drug favipiravir was conducted in Guinea. This paper describes the main challenges of the implementation of the trial in the Ebola treatment center of Guéckédou. Following the principles of the Good Clinical Research Practices, we explored the aspects of the community's communication and engagement, ethical conduct, trial protocol compliance, informed consent of participants, ongoing benefit/risk assessment, record keeping, confidentiality of patients and study data, and roles and responsibilities of the actors involved. We concluded that several challenges have to be addressed to successfully implement a clinical trial during an international medical emergency but that the potential for collaboration between research teams and humanitarian organizations needs to be highlighted.