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Tuberculosis disease characteristics associated with mortality, severe morbidity and unsuccessful treatment in people living with HIV treated for tuberculosis – a secondary analysis of the ANRS 12300 Reflate TB2 trial

BMC Infectious Diseases volume 25, Article number: 695 (2025) Cite this article

Abstract

Background

Tuberculosis is a severe disease, not only due to its lethality but also to a significant morbidity occurring in people living with HIV (PLWH). If factors associated to mortality, severe morbidity and unsuccessful treatment related to the host are well identified in PLWH, there is scarce knowledge on factors related to the disease itself such as bacillary load, extent of lung involvement and disease dissemination to other organs. We sought to assess whether tuberculosis-related factors were associated with key patient outcomes in PLWH using data from an international clinical trial.

Methods

We conducted a secondary analysis of the ANRS 12300 Reflate TB2, an international phase III open-label randomized trial that assessed different antiretroviral regimens in PLWH treated for tuberculosis. We evaluated whether bacillary load (smear positivity grade), extent of lung involvement (cavitation on chest x-ray) and disease dissemination (urine LAM positivity) were associated with mortality using Cox proportional hazard models, and to severe morbidity and unsuccessful tuberculosis treatment using logistic regressions.

Results

Of 457 participants included in this study, 90 (20.4%) had grade 2 + or 3 + smear positivity, 39 (10.8%) had cavitation on chest X-ray, and 147 (32.2%) had a positive urinary LAM. Overall, 19 (4.2%) participants died, 113 (24.7%) presented severe morbidity, and 33 (7.2%) had unsuccessful tuberculosis treatment. Factors that remained independently associated with mortality were cavitation on chest x-ray (aHR = 7.92, 95% CI, 1.74–35.94, p = .0073) and LAM positivity (aHR = 5.53, 95% CI, 1.09–28.06, p = .0389). The only factor that remained significantly associated with severe morbidity was LAM positivity (aOR = 2.04, 95% CI, 1.06–3.92, p = .0323). No factor remained significantly associated with unsuccessful tuberculosis treatment.

Conclusions

In PLWH with tuberculosis enrolled in a trial, tuberculosis disease characteristics related to disease severity were cavitation on chest x-ray and urine LAM positivity. Early identification of these factors could help improve the management of PLWH with tuberculosis and improve their survival.

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Background

Tuberculosis (TB) is the leading cause of death from a single infectious agent, with 1.25 million deaths estimated in 2023 [1]. In people living with Human Immunodeficiency Virus (PLWH), TB is the leading opportunistic infection, with 662 000 cases in 2023, and the first cause of death, accounting for 161 000 deaths in the same year [1], as also shown by autopsy studies [2,3,4,5,6]. As such, in PLWH, TB is a severe disease, not only due to its lethality but also to significant morbidity requiring hospitalization or prolonged hospitalization, paradoxical clinical deterioration due to Immune Reconstitution Inflammatory Syndrome (IRIS), delayed cure, treatment failure or relapse [7,8,9,10,11,12].

Individuals admitted with HIV-associated tuberculosis are frequently acutely ill, with high incidence of inpatient deaths occurring early during hospitalization [2, 3, 13], despite appropriate antituberculosis treatment [13]. This highlights the urgent need for improving patient management strategies to increase survival in PLWH with tuberculosis, requiring a better understanding of the main determinants of severe morbidity and mortality. A better knowledge of factors associated with TB disease itself in mortality, severe morbidity or unsuccessful treatment in PLWH is then needed as it would help to identify those factors early and could contribute to improve the management of most severe patients with closer medical monitoring or a possible intensification of their treatment [14,15,16].

Most studies evaluating risk factors associated with TB mortality, severe morbidity or unsuccessful treatment in PLWH typically focus on factors related to the host, such as male sex [17,18,19,20,21], advanced age [8, 12, 17, 20, 22,23,24,25], co-morbidities [8, 23, 24, 26,27,28,29,30,31,32,33,34,35], poor adherence to treatment [24, 32, 36, 37], smoking [26, 38], alcohol use [29, 31, 32] or low socio-economic level [38, 39]. Very few studies focused on important characteristics of the TB disease itself such as bacillary load [8, 22, 40], extent of lung involvement on chest x-ray [36, 41,42,43], or disease dissemination [17, 44, 45]. Furthermore, most studies are retrospective and were not specifically designed for PLWH. Clinical trials are known to be the gold standard design in medical research, and even when only a secondary analysis with an aim different from that of the initial trial is conducted, the prospective collection of data on the outcomes of interest could provide more valid results than retrospective cohort studies, especially by reducing the risk of recall bias or inaccurate reporting.

We sought to assess the association between TB severity (mortality, severe morbidity and unsuccessful treatment) and three important characteristics of TB reported to be associated with the disease severity (bacillary load, extent of lung involvement on chest x-ray, and disease dissemination) in antiretroviral treatment (ART) naive PLWH enrolled and followed up in the ANRS 12300 Reflate TB2 trial, an international phase III open-label randomized trial assessing different antiretroviral regimens for treatment of HIV infection in PLWH treated for tuberculosis [46].

Methods

Study design and population

We conducted a secondary analysis of the ANRS 12300 Reflate TB2 trial, a multicenter, open-label, randomized, phase 3 trial that assessed non-inferiority of raltegravir- versus efavirenz-based antiretroviral therapy (ART) in ART-naive HIV-1 infected adults with bacteriologically confirmed or clinically diagnosed TB enrolled in six clinical sites in five countries (Brazil, Côte d’Ivoire, France, Mozambique, and Vietnam) between September 2015 and January 2018. The trial design and results, which did not show non-inferiority of raltegravir, have been reported elsewhere [46]. Participants who were on rifampicin-containing TB treatment for a maximum of 8 weeks, initiated ART with either raltegravir 400 mg 1 pill twice daily or efavirenz 600 mg once daily, to which they were randomly assigned, both in association with tenofovir 300 mg plus lamivudine 300 mg once daily. Participants with HIV-2 infection, TB meningitis, rifampicin-resistant TB, impaired hepatic or renal function, severe anemia, and those who were pregnant or breastfeeding were excluded. In the present study, we included all participants enrolled in the ANRS 12300 Reflate TB2 trial that were included in the intention to treat analysis and we considered follow-up until week 24, i.e. 6 months in the trial.

A screening visit was performed at any time between TB treatment initiation and TB treatment initiation + seven weeks, provided that inclusion would be feasible no later than eight weeks after tuberculosis treatment initiation, and within the first two weeks in participants whose CD4 T-cell count was known to be < 50 cells/μL. Smear microscopy, Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA), mycobacterial cultures on expectorated sputum, relevant extrapulmonary samples and chest radiographs performed at the time of tuberculosis diagnosis were collected, or done at the screening visit, if not already available. Once participants had provided written informed consent and eligibility criteria had been checked, they were randomized into one of the two trial arms. The inclusion (W0) visit was the ART initiation visit performed within 2 weeks of the screening visit.

All participants received standard TB treatment with isoniazid (4–6 mg/kg/day), rifampicin (8–12 mg/kg/day), pyrazinamide (20–30 mg/kg/day), and ethambutol (15–20 mg/kg/day) for 2 months (intensive phase), followed by isoniazid (4–6 mg/kg/day) and rifampicin (8–12 mg/kg/day) for 4 months (maintenance phase). As recommended by WHO, participants were initiated on ART after 2–8 weeks of tuberculosis treatment (depending on CD4 cell counts). Patients were offered trimethoprim-sulfamethoxazole (cotrimoxazole) prophylaxis against toxoplasmic encephalitis, Pneumocystis jirovecii pneumonia, and severe bacterial diseases, following national recommendations.

Follow-up visits were organized bi-monthly for the first month of follow-up in the trial, every month thereafter until W24. TB follow-up exams included sputum smear microscopy and culture in participants with pulmonary TB at month 2 and month 5 of treatment and chest radiographs at month 2 and month 6 of tuberculosis treatment. TB follow up exams were not performed at fixed visits in the trial but at different time points depending on the duration of TB treatment at inclusion.

Investigators recorded frequency, grade, and type of adverse events during the 48 weeks of the study in an unsolicited manner. Time to adverse events was collected and an endpoint review committee validated all grade 3 and 4 adverse events. Deaths were recorded as the outcome of a serious adverse event. Time to death and death certificates were collected whenever possible.

Outcomes and definitions

We focused on three main outcomes in the present study: 1) death during tuberculosis treatment, 2) severe morbidity during tuberculosis treatment and 3) unsuccessful tuberculosis treatment. We considered deaths due to all causes occurring between inclusion and the W24 visit in the trial. We defined severe morbidity as a composite outcome comprising i) hospitalizations due to any cause with a duration of at least 7 days, ii) grade 3 or 4 ART or tuberculosis related drug-induced adverse event and/or paradoxical TB-associated IRIS validated by the endpoint review committee, using experts' opinion for ART or tuberculosis related drug-induced adverse events and INSHI (International Network for the Study of HIV-associated IRIS) criteria for IRIS [47].We defined unsuccessful tuberculosis treatment as a composite outcome comprising i) death and/or ii) treatment failure, i.e., a treatment regimen that needed to be terminated or permanently changed to a new regimen or treatment strategy and/or iii) loss to follow up, i.e., participants whose treatment was interrupted for 2 consecutive months or more [48].

Main independent variables

Our main independent variables of interest were three important characteristics of TB reported to be associated with disease severity: 1) bacillary load documented through smear positivity grade, or gene expert positivity level, or delay to culture positivity, 2) extent of lung involvement on chest x-ray including presence of cavitation and proportion of the lung field, and 3) disease dissemination documented through urine lipoarabinomannan assay (LAM) positivity, involvement of other organs or miliary TB.

Statistical analysis

We described baseline characteristics using frequency and proportions for qualitative variables, and median and interquartile range (IQR) for quantitative variables. We compared characteristics across groups using Wilcoxon tests for quantitative variables, and χ2 or Fisher’s exact test for qualitative variables as appropriate.

We used Cox proportional hazard models to assess factors associated with mortality from inclusion to W24 and logistic regressions to assess factors associated with severe morbidity and unsuccessful tuberculosis treatment at W24. We tested in univariate models variables that we selected based on previous evidence from the literature and clinical relevance. Since three variables documenting bacillary load (smear positivity grade, gene expert positivity level, delay to culture positivity) are highly correlated, we selected for inclusion in the models the one with most data available. We selected the presence of cavitation to document extent of lung involvement on chest x-ray because the proportion of the lung field affected was not assessed in the original trial. We selected LAM positivity to document disease dissemination because, as a laboratory test, it appears more reliable than involvement of other organs or miliary TB which are subjective to the investigator’s judgement. In multivariate models, we included variables with a level of significance p = 0.20 in univariate models, along with CD4 count and HIV viral load. We derived final models using stepwise descending selection, retaining in the model all variables with a level of significance of p = 0.05 along with the three main variables of interest (bacillary load, cavitation and LAM positivity).. We analyzed data using the SAS® Studio software (version 3.82).

Results

We included 457 participants in this study, excluding 3 participants (2 with HIV 2 infection and 1 with HIV-1 RNA < 50 c/ml). Most participants were male (60.2%), their median age was 35.3 years, (IQR, 28.9–42.9), their median CD4 count was 103.0 cells per mm3, (IQR, 38.0–238.5) and a majority had pulmonary tuberculosis (Table 1).

Table 1 Baseline characteristics according to vital status at 6 months
Full size table

Tuberculosis diagnosis was done before the start of tuberculosis treatment and confirmed at enrollment. The median duration of TB treatment before enrollment was 20 days (IQR, 15–27).

Key tuberculosis disease characteristics are presented in Table 1. Regarding bacillary load, 90 (20.4%) participants had grade 2 + or 3 + smear positivity, 101 (23.6%) had medium or high Xpert positivity level and 198 (44.8%) had a time to MTB culture positivity > 14 days; regarding extent of lung involvement, 39 (10.8%) participants had cavitation on chest X-ray, 225 (49.2%) had bilateral lesions and 227 (50.2%) had cavitation or bilateral location; regarding tuberculosis disease dissemination, 147 (32.2%) of 305 participants with LAM available had a positive urinary test, 87 (19%) had involvement of other organs and 10 (2.2%) had miliary patterns (Table 1). How variables characterizing bacillary load and tuberculosis disease dissemination cross with each others is presented in supplementary tables S1, S2 and S3 in appendix.

Overall, 21 (4.6%) participants died from inclusion to W24, at a median time of 58 (IQR: 45—107) days; 6 (1.31%) participants were lost to follow up; 1 (0.21%) was transferred; and 429 (93.87%) were followed up until W24, for a total of 202.19 person-years (PY) of follow-up accrued during the study. The mortality rate was estimated to 10.4 (95% CI 5.96–14.83) deaths per 100 person-years (PY). Forty-six participants (10.1%) were hospitalized (≥ 7 days) at least once for a median duration of 17 (IQR, 12–28) days; the first hospitalization occurred at a median time of 49 (IQR, 32–79) days after tuberculosis treatment initiation, and 24 (IQR, 13–49) days after ART initiation. Overall, 121 (26.47%) participants presented grade 3 or 4 drug induced adverse events, 61 (13.3%) presented grade 3 or 4 IRIS; 6 (1.3%) experienced tuberculosis treatment failure, 37 (8.1%) had unsuccessful tuberculosis treatment cases, and a total of 118 (25.8%) participants were defined as having severe morbidity.

Factors that remained independently associated with mortality were cavitation on chest x-ray (aHR = 7.92, 95% CI, 1.74–35.94, p = 0.0073) and LAM positivity (aHR = 5.53, 95% CI, 1.09–28.06, p = 0.0389); mortality was not associated with smear positivity grade (p = 0.2963) (Table 2).

Table 2 Factors associated with mortality among people living with HIV with tuberculosis: univariate and multivariate analysis
Full size table

The only factor that remained significantly associated with severe morbidity was LAM positivity (aOR = 2.04, 95% CI, 1.06–3.92, p = 0.0323); severe morbidity was neither associated with cavitation on chest x-ray (p = 0.2499) nor with smear positivity grade (p = 0.0824) (Table 3).

Table 3 Factors associated with severe morbidity among people living with HIV with tuberculosis: univariate and multivariate analysis
Full size table

Unsuccessful tuberculosis treatment was neither associated with cavitation on chest x-ray (p = 0.1174), nor with smear positivity grade (p = 0.3812), nor with LAM positivity (p = 0.0766) (Table 4).

Table 4 Factors associated with unsuccessful treatment among people living with HIV with tuberculosis: univariate and multivariate analysis
Full size table

Discussion

In this secondary analysis of the Reflate TB2 trial, mortality was associated with cavitation on chest x-ray and LAM positivity; severe morbidity was associated with LAM positivity. These results show that characteristics selected as potential markers of tuberculosis disease severity, reflecting the extent of lung involvement and disease dissemination, were indeed associated with key patient outcomes.

The mortality rate was lower in our study than those reported in most longitudinal studies in PLHWH with TB that range between 10 and 25% [49,50,51,52]. This could be due to the fact that the most ill patients may not have been included in the trial since participants with TB meningitis, rifampicin-resistant TB, impaired hepatic or renal function, or severe anemia were excluded; another explanation could be that participants enrolled were more closely monitored in the framework of a clinical trial. The low mortality rate as well as very close monitoring in trial conditions probably contributed to low rates of loss to follow-up and treatment failure. The rate of unsuccessful treatment was also low when compared to those reported by other studies (12% to 33%) [25, 53,54,55]. However, the proportion of severe tuberculosis morbidity as we defined in this study was in the range between 23 and 33% usually reported [9,10,11, 56].

The extent of lung involvement on chest x-ray was previously reported as associated to mortality in adults with tuberculosis [41, 43]. Both the presence of cavitation and the percentage of lung affected are part of the Timika score, that predicts mortality based on chest x-ray severity in adult with smear-positive pulmonary TB [57]. Our study confirms these findings, which may be surprising in a population of PLWH with such a high immunosuppression level, since cavitations are more commonly seen at earlier stages of the HIV disease, when cellular immunity is relatively preserved [58]. Our finding shows that, even if uncommon at late stages of HIV infection, the presence of cavitation is a key marker of TB severity in PLWH, as it is in the general population [41, 43]. Beside cavitation, the proportion of lung affected is the other characteristic of the extent of lung involvement reported to be related to tuberculosis disease severity [41, 42, 59].

TB disease dissemination as captured by urine LAM positivity was associated with mortality and severe morbidity in our study. We chose LAM positivity as a marker of TB dissemination since it is associated with renal tuberculosis on autopsy [60], presence of mycobacteria in the urine [61] and in blood [62, 63], hence evidence that, beside the lungs, other organs are certainly also affected by Mycobacterium Tuberculosis. Even in immunocompetent patients, disseminated TB is a severe condition with a high risk of death [44, 64]; the impact of disseminated disease is even worse in PLWH [65,66,67]. In a study conducted in PLWHs hospitalized in South Africa, TB dissemination was quantified with a three-point score based on urine Xpert MTB/RIF, urine LAM test and blood culture; a higher dissemination score (ranging 0 to 3) was associated with higher mortality [68]. This confirms that the disease dissemination is a key marker of TB severity in PLWH.

Conversely to what was shown in patients from the general population i.e. HIV and non-HIV infected with tuberculosis, bacillary load as captured by the smear positivity grade was not associated with any of the outcomes in our study [8, 22, 69]. To our knowledge, this association has not previously been reported specifically among PLWH. One reason might be that PLWH have a higher rate of smear-negative disease and lower bacillary load in sputum [70, 71], with proportions of smear-negative pulmonary tuberculosis ranging from 24 to 61% [72].

Our study has limitations. A first limitation is that the Reflate TB2 trial was not initially designed to assess factors associated with tuberculosis severity. We performed a secondary analysis of trial data whose participants might differ from patients diagnosed and managed in routine non-research conditions. The standardized follow-up in the framework of a clinical trial was nevertheless an interesting strength for our study. A second limitation is the regional and epidemiological heterogeneity, since the trial was conducted in five countries representing four regions (Latin America, sub-Saharan Africa, Western Europe and Southeast Asia) among which patterns of both HIV and TB vary greatly; so we might not have the same factors associated with mortality or severe morbidity in all regions. A third limitation is the important proportion of missing data for some variables of interest such as LAM; this might impact the validity of our results since the effects found might have been underestimated or overestimated. Lastly, the analysis relied on a relatively few cases of cavitations [39] which introduced a wide confidence limit on the HR (1.74–35.94) and thus a lack of precision of the estimate.

Despite the above-mentioned limitations, this study contributes to a better knowledge of the determinants of TB disease severity. Prospective data collection in the framework of an international clinical trial may provide more valid results than previous retrospective cohort studies, notably by reducing the risk of recall bias or inaccurate reporting. Our secondary analysis of data from a clinical trial confirmed in PLWH results from previous retrospective cohort studies in the general population that had shown the association between tuberculosis severity and important disease characteristics such as bacillary load, extent of lung involvement and disease dissemination. These characteristics should be taken into account when targeting management strategies for PLWH with tuberculosis. Early identification of these factors early, could improve management of most severe disease by introducing closer medical monitoring or possible treatment intensification, which could contribute to increase survival in PLWH with tuberculosis.

Conclusion

In this secondary analysis of the Reflate TB2 trial, tuberculosis disease characteristics such as extent of lung involvement and disease dissemination were associated with disease severity and adverse outcomes. Interestingly, these important characteristics assocated with tuberculosis disease severity are not considered in existing severity scores such as the TBscore II [73], at the exception of the Timika score which includes extent of lung involvement [57]. Besides, most of these scores were not specifically designed for PLWH and may thus, not be optimal nor applicable to PLWH. Whence the need to develop a better tuberculosis severity score for PLWH including bacillary load, extent of lung involvement on chest x-ray and the disease dissemination.

Data availability

All data and materials are available upon request to the ANRS 12300 Reflate TB2 group.

Abbreviations

aHR:

Adjusted hazard ratio

aOR:

Adjusted odds ratio

ART:

Antiretroviral Treatment

BMI:

Body Mass Index

CI:

Confidence Interval

COVID:

Coronavirus Disease

HIV:

Human Immunodeficiency Virus

HR:

Crude hazard ratio

IRIS:

Immune Reconstitution Inflammatory Syndrome

LAM:

Lipoarabinomannan assay

OR:

Crude odds ratio

PLWH:

People Living With HIV

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Acknowledgements

The French National Agency for Research on AIDS and Viral Hepatitis (ANRS), Paris, France was the sponsor of the trial. This trial was funded by ANRS, the Brazilian Ministry of Health in Brazil, and Merck. The trial was done with the support of Merck Sharp and Dohme France as part of the Investigator-Initiated Studies Program of Merck Sharp and Dohme. We thank the National HIV and Tuberculosis programmes of participating countries for their support. We thank the members of the independent data and safety monitoring committee and all the participants who took part in the trial. ANRS 12300 Reflate TB 2 Study Consortium

Marie DE SOLERE1, Alice MONTOYO1, Claire REKACEWICZ1, Dr Alpha DIALLO1, Xavier ANGLARET2,6, Olivier MARCY2, Corine Chazallon2, Jérôme LE CARROU2, Aurélie BEUSCART2, Gemma Guylène Habiyambere2, Sophie KARCHER2, Beatriz GRINSZTEJN3, Valdilea VELOSO3, Sandra Wagner CARDOSO3, Rodrigo Otávio da Silva ESCADA3, Tânia KRSITIC3, Thiago Silva TORRES3, Ronaldo Ismerio MOREIRA3, Flávia LESSA3, Ana Cláudia ALVES3, Daniel de moura REBELO3, Luiz Ricardo Siqueira CAMACHO3, Sandro NAZER3, Soraia Santana de MOURA3, Luana MARINS3, Maura Lassance GONZALES3, Robson Pierre Nascimento da SILVA3, Tatiane GOMES3, Valéria Rita Teixeira RIBEIRO3, Ana Cristina Garcia FERREIRA3, Brenda HOAGLAND3, Débora Faber Marra BARRETO3, Desiree Vieira Gomes dos SANTOS3, Isabel Cristina Ferreira TAVARES3, Lara Esteves COELHO3, Lucimar Santos SALGADO3, Donald G. Diomandé4, Amani Anzian4, Joachim Gnokoro4, Etienne Etilé4, Jacqueline Amani4, Georgette Labibi4, Cecile A. Tchehy4, MC Kassy4, Antoine Toho BI4, Lambert Konan4, E. Messou4, Cyprien Rabe5, Frederick Ello5, Fulgence Eboumou5, Salimata Fanny5, Bonzou Amoakon5, Samuel Kan5, Robert GBEY5, Martin Y. Kouamé5, Yamissa Siloue5, Lehi Dano5, Florence Kouakou5, Kakou Aka5, Serge P. Eholié5, Jean-Baptiste N’takpé6, Suzanne Kouadio6, Irmine Ahyi6, Bertine Siloue6, Marcelin Irié6, Romuald Konan6, Arlette Emieme7, Thomas-d’Aquin Toni7, Fatoumata Koné7, Jean-Claude Kacou7, Hervé Menan7, Nathalie DE CASTRO8, Jean-Michel MOLINA8, Diane Ponscarme8, Miresta Previllon8, Constance DELAUGERRE8, Nilesh BHATT9, Celso KHOSA9, Isabel TIMANA9, Dilário NHUMAIO9, Emelva MANHIçA9, Arlindo VILANCULO9, Khalide AZAM9, Adolfo VUBIL9, Nádia SITOE9, Alcina ZITHA9, Jorge RIBEIRO9, Lectícia MATSINHE9, DO CHAU Giang10, NGUYEN DUC Bang10, NGUYEN NGOC Lan10, NGUYEN HUU Lân10, DANG THI Minh Há10, NGUYEN THI Hong10, NGUYEN NHU Viet10, BUI THI Kim Nhung10, TRAN PHAM PHUONG Thao10, PHAM THU Hang10, MAI THI THU Huyen10, TRAN HUU Loc10, TRAN THI KIM Quy10, Do HA Thanh Trang10, NGUYEN THI Cao Van10, MAI NGUYET Thu Huyen10, NGUYEN THI Nuoi10, CAO KHANH Tung10, TRAN THI THUY Tien10, HUYNH PHUONG Anh10, PHAM THI QUYNH Anh10, LONG DUONG Van10, LE THI NGOC Bich10, CONG THI Mai Luong10, TRAN Ton10, VU Xuan Thinh10, HUYNH HOANG Khanh Thu10, LUONG QUE Anh10, DO HA THANH Trang10, Delphine RAPOUD10, Anaïs DOMERGUE10, LE QUOC Khanh10, DONG QUYNH Nhu10, BUI VU HOANG Trang10, DINH PHUONG Thanh10, TRAN THI HIEU Nhi10, TRAN THI-HAI Ly10, Frederique GUIROY10, Didier LAUREILLARD10

French National Institut for Health and Medical Research–ANRS (France REcherche Nord&sud Sida-hiv Hépatites) (Paris, France)

University of Bordeaux, National Institute for Health and Medical Research (Inserm) UMR 1219, Research Institute for Sustainable Development (IRD) EMR 271, Bordeaux Population Health Centre, Bordeaux, France

National Institute of Infectious Diseases Evandro Chagas, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil

Centre de Prise en Charge de Recherche et de Formation, CePReF-Aconda-VS, Abidjan, Côte d’Ivoire

Département de Dermatologie et d'Infectiologie, UFR des Sciences Médicales, Université Félix Houphouët Boigny, Abidjan, Cote d’Ivoire

Programme PACCI/ANRS Research Center, Abidjan, Côte-d’Ivoire

Centre de Diagnostic et de Recherches sur le SIDA, Abidjan, Côte-d’Ivoire

Infectious Diseases Department, AP-HP-Hôpital Saint-Louis Lariboisière, Paris, France

Instituto Nacional de Saúde, Marracuene, Mozambique

Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam

Funding

The ANRS 12300 Reflate TB2 trial was funded by ANRS | Emerging Infectious Diseases, an autonomous agency of Inserm (French National Institute for Health and Medical Research).

Author information

Authors and Affiliations

  1. University of Bordeaux, National Institute for Health and Medical Research (Inserm) UMR 1219, Research Institute for Sustainable Development (IRD) EMR 271, Bordeaux Population Health Centre, 146 Rue Léo Saignat, Bordeaux, 33000, France

    Robert Akpata, Jean-Baptiste Ntakpe, Nathalie De Castro, Corine Chazallon & Olivier Marcy

  2. Programme PACCI/ANRS Research Center, Abidjan, Côte d’Ivoire

    Jean-Baptiste Ntakpe, Eugène Messou, Frédéric Ello Nogbou, Donald Diomande Glao & Serge Eholie

  3. Centre de Prise en Charge, de Recherche Et de Formation, CePReF-Aconda-VS, Abidjan, Côte d’Ivoire

    Eugène Messou

  4. Département de Dermatologie Et d’Infectiologie, UFR Des Sciences Médicales, Université Félix Houphouët Boigny, Abidjan, Côte d’Ivoire

    Eugène Messou, Frédéric Ello Nogbou, Donald Diomande Glao & Serge Eholie

  5. Infectious Diseases Department, AP-HP-Hôpital Saint-Louis Lariboisière, Paris, France

    Nathalie De Castro & Jean-Michel Molina

  6. Instituto Nacional de Saúde, Marracuene, Mozambique

    Isabel Timana, Nilesh Bhatt, Celso Khosa, Valdilea Veloso & Beatriz Grinsztejn

  7. National Institute of Infectious Diseases Evandro Chagas, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil

    Rodrigo Escada & Sandra Wagner Cardoso

  8. Department of Infectious and Tropical Diseases, Nimes University Hospital, Nimes, France

    Didier Laureillard

  9. Research Unit 1058, Pathogenesis and Control Chronical Infections, French Blood Center, INSERM, University of Montpellier, Montpellier, France

    Didier Laureillard

  10. Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam

    Giang Do Chau

  11. Inserm U944, Paris, France

    Jean-Michel Molina

  12. Université de Paris, Paris, France

    Jean-Michel Molina

  13. Université d’Abomey-Calavi, Cotonou, Benin

    Marcel Zannou

Authors
  1. Robert Akpata
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  2. Jean-Baptiste Ntakpe
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  3. Eugène Messou
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  4. Nathalie De Castro
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  5. Corine Chazallon
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  6. Isabel Timana
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  7. Rodrigo Escada
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  8. Sandra Wagner Cardoso
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  9. Nilesh Bhatt
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  10. Celso Khosa
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  11. Didier Laureillard
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  12. Giang Do Chau
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  13. Frédéric Ello Nogbou
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  14. Donald Diomande Glao
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  15. Valdilea Veloso
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  16. Jean-Michel Molina
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  17. Beatriz Grinsztejn
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  18. Marcel Zannou
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  19. Serge Eholie
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  20. Olivier Marcy
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Consortia

for the ANRS 12300 Reflate TB2 study Consortium

  • Marie De Solere
  • , Alice Montoyo
  • , Claire Rekacewicz
  • , Alpha Diallo
  • , Xavier Anglaret
  • , Olivier Marcy
  • , Corine Chazallon
  • , Jérôme Le Carrou
  • , Aurélie Beuscart
  • , Gemma Guylène Habiyambere
  • , Sophie Karcher
  • , Beatriz Grinsztejn
  • , Valdilea Veloso
  • , Sandra Wagner Cardoso
  • , Rodrigo Otávio da Silva Escada
  • , Tânia Krsitic
  • , Thiago Silva Torres
  • , Ronaldo Ismerio Moreira
  • , Flávia Lessa
  • , Ana Cláudia Alves
  • , Daniel de moura Rebelo
  • , Luiz Ricardo Siqueira Camacho
  • , Sandro Nazer
  • , Soraia Santana de Moura
  • , Luana Marins
  • , Maura Lassance Gonzales
  • , Robson Pierre Nascimento da Silva
  • , Tatiane Gomes
  • , Valéria Rita Teixeira Ribeiro
  • , Ana Cristina Garcia FerreIira
  • , Brenda Hoagland
  • , Débora Faber Marra Barreto
  • , Desiree Vieira Gomes dos Santos
  • , Isabel Cristina Ferreira Tavares
  • , Lara Esteves Coelho
  • , Lucimar Santos Salgado
  • , Donald G. Diomandé
  • , Amani Anzian
  • , Joachim Gnokoro
  • , Etienne Etilé
  • , Jacqueline Amani
  • , Georgette Labibi
  • , Cecile A. Tchehy
  • , MC Kassy
  • , Antoine Toho BI
  • , Lambert Konan
  • , E. Messou
  • , Cyprien Rabe
  • , Frederick Ello
  • , Fulgence Eboumou
  • , Salimata Fanny
  • , Bonzou Amoakon
  • , Samuel Kan
  • , Robert Gbey
  • , Martin Y. Kouamé
  • , Yamissa Siloue
  • , Lehi Dano
  • , Florence Kouakou
  • , Kakou Aka
  • , Serge P. Eholié
  • , Jean-Baptiste N’takpé
  • , Suzanne Kouadio
  • , Irmine Ahyi
  • , Bertine Siloue
  • , Marcelin Irié
  • , Romuald Konan
  • , Arlette Emieme
  • , Thomas-d’Aquin Toni
  • , Fatoumata Koné
  • , Jean-Claude Kacou
  • , Hervé Menan
  • , Nathalie De Castro
  • , Jean-Michel Molina
  • , Diane Ponscarme
  • , Miresta Previllon
  • , Constance Delaugerre
  • , Nilesh Bhatt
  • , Celso Khosa
  • , Isabel Timana
  • , Dilário Nhumaio
  • , Emelva Manhiça
  • , Arlindo Vilanculo
  • , Khalide Azam
  • , Adolfo Vubil
  • , Nádia Sitoe
  • , Alcina Zitha
  • , Jorge Ribeiro
  • , Lectícia Matsinhe
  • , Do Chau Giang
  • , Nguyen Duc Bang
  • , Nguyen Ngoc Lan
  • , Nguyen Huu Lân
  • , Dang Thi Minh Há
  • , Nguyen Thi Hong
  • , Nguyen Nhu Viet
  • , Bui Thi Kim Nhung
  • , Tran Pham Phuong Thao
  • , Pham Thu Hang
  • , Mai Thi Thu Huyen
  • , Tran Huu Loc
  • , Tran Thi Kim Quy
  • , Do Ha Thanh Trang
  • , Nguyen Thi Cao Van
  • , Mai Nguyet Thu Huyen
  • , Nguyen Thi Nuoi
  • , Cao Khanh Tung
  • , Tran Thi Thuy Tien
  • , Huynh Phuong Anh
  • , Pham Thi Quynh Anh
  • , Long Duong Van
  • , Le Thi Ngoc Bich
  • , Cong Thi Mai Luong
  • , TRAN Ton
  • , Vu Xuan Thinh
  • , Huynh Hoang Khanh Thu
  • , Luong Que Anh
  • , Do Ha Thanh Trang
  • , Delphine Rapoud
  • , Anaïs Domergue
  • , Le Quoc Khanh
  • , Dong Quynh Nhu
  • , Bui Vu Hoang Trang
  • , Dinh Phuong Thanh
  • , Tran Thi Hieu Nhi
  • , Tran Thi-Hai Ly
  • , Frederique Guiroy
  •  & Didier Laureillard

Contributions

Robert Akpata: conducted the secondary analysis of the ANRS 12300 Reflate TB2 trial and wrote the first draft. Jean-Baptiste Ntakpé coordinated the ANRS 12300 Reflate TB2 trial implementation in Côte d’Ivoire, reviewed and approved final version of the secondary analysis. Eugène Messou: led the ANRS 12300 Reflate TB2 trial in Côte d’Ivoire, implemented the trial and enrolled participants. reviewed and approved final version of the secondary analysis. Nathalie De Castro: conceived and designed the ANRS 12300 Reflate TB2 trial, led the trial at international level, accessed and verified the data, led the trial in France, contributed to the interpretation of the trial results, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Corine Chazallon: accessed and verified the ANRS 12300 Reflate TB2 trial data, contributed to the interpretation of the trial results, did the trial statistical analysis, prepared the trial report, validated the secondary analysis, reviewed and approved final version of the secondary analysis. Isabel Timana: coordinated the ANRS 12300 Reflate TB2 trial implementation in Mozambique, reviewed and approved final version of the secondary analysis. Rodrigo Escada: coordinated the ANRS 12300 Reflate TB2 trial implementation in Brazil, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Sandra Wagner Cardoso: implemented the ANRS 12300 Reflate TB2 trial and enrolled participants, reviewed and approved final version of the secondary analysis. Nilesh Bhatt: led the ANRS 12300 Reflate TB2 trial in Mozambique, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Celso Khosa: led the ANRS 12300 Reflate TB2 trial in Mozambique, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Didier Laureillard: conceived and designed the ANRS 12300 Reflate TB2 trial, led the trial in Vietnam, contributed to the interpretation of the results, reviewed and approved final version of the secondary analysis. Giang Do Chau: led the ANRS 12300 Reflate TB2 trial in Vietnam, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Valdilea Veloso: led the ANRS 12300 Reflate TB2 trial in Brazil, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Jean-Michel Molina: conceived and designed the ANRS 12300 Reflate TB2 trial, led the trial in France, implemented the trial and enrolled participants, contributed to the interpretation of the results, reviewed and approved final version of the secondary analysis. Beatriz Grinsztejn: conceived and designed the ANRS 12300 Reflate TB2 trial, led the trial at international level, led the trial in Brazil, contributed to the interpretation of the results, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Marcel Zannou: reviewed and approved final version of the secondary analysis Frédéric Ello Nogbou: implemented the trial in Côte d’Ivoire and enrolled participants Donald Diomande Glao: implemented the trial in Côte d’Ivoire and enrolled participants Serge Eholie: led the ANRS 12300 Reflate TB2 trial in Côte d’Ivoire, implemented the trial and enrolled participants, reviewed and approved final version of the secondary analysis. Olivier Marcy: conceived and designed the ANRS 12300 Reflate TB2 trial, accessed and verified the data, coordinated trial implementation at international level, contributed to the interpretation of the results, prepared the report, led the secondary analysis, reviewed and approved final version of the secondary analysis.

Corresponding author

Correspondence to Robert Akpata.

Ethics declarations

Ethics approval and consent to participate

The study was approved by Comité National d’Ethique et de la Recherche (Côte d’Ivoire), CEP IPEC (Brazil), Comité de Protection des Personnes Ile-de-France II (France), Comitê Nacional de Bioética para Saúde (Mozambique) and IRB PNTH (Vietnam).

The ANRS 12300 Reflate TB2 trial protocol was registered with ClinicalTrials.gov (NCT02273765, 22 October 2014) and was conducted in accordance with the Declaration of Helsinki. All participants provided signed informed consent before enrollment in the main trial.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Publisher’s Note

A list of authors and their affiliations appears at the end of the paper.

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Akpata, R., Ntakpe, JB., Messou, E. et al. Tuberculosis disease characteristics associated with mortality, severe morbidity and unsuccessful treatment in people living with HIV treated for tuberculosis – a secondary analysis of the ANRS 12300 Reflate TB2 trial. BMC Infect Dis 25, 695 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12879-025-10986-4

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12879-025-10986-4

Keywords

BMC Infectious Diseases

ISSN: 1471-2334

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