Journal Article > ResearchFull Text
AIDS. 2013 October 23; Volume 27 (Issue 16); DOI:10.1097/01.aids.0000432456.14099.c7
Laureillard D, Marcy O, Madec Y, Chea S, Chan S, et al.
AIDS. 2013 October 23; Volume 27 (Issue 16); DOI:10.1097/01.aids.0000432456.14099.c7
To analyze cases of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in the CAMbodian Early versus Late Introduction of Antiretrovirals (CAMELIA) randomized trial designed to compare early (2 weeks) versus late (8 weeks) antiretroviral therapy (ART) initiation after tuberculosis treatment onset in Cambodia (NCT00226434).
Journal Article > ResearchFull Text
N Engl J Med. 2011 October 20; Volume 365 (Issue 16); DOI:10.1056/NEJMoa1013911
Blanc FX, Sok T, Laureillard D, Borand L, Rekacewicz C, et al.
N Engl J Med. 2011 October 20; Volume 365 (Issue 16); DOI:10.1056/NEJMoa1013911
Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy.
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
Clin Infect Dis. 2014 August 1; Volume 59 (Issue 3); DOI:10.1093/cid/ciu283
Marcy O, Laureillard D, Madec Y, Chan S, Mayaud C, et al.
Clin Infect Dis. 2014 August 1; Volume 59 (Issue 3); DOI:10.1093/cid/ciu283
Shortening the interval between antituberculosis treatment onset and initiation of antiretroviral therapy (ART) reduces mortality in severely immunocompromised human immunodeficiency virus (HIV)-infected patients with tuberculosis. A better understanding of causes and determinants of death may lead to new strategies to further enhance survival.
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
Antivir Ther. 2008 September 11; Volume 13 (Issue 5); 697-703.
Spire B, Carrieri P, Sopha P, Protopopescu C, Prak N, et al.
Antivir Ther. 2008 September 11; Volume 13 (Issue 5); 697-703.
BACKGROUND
The long-term maintenance of antiretroviral therapy (ART) remains an important issue, especially in limited-resource settings where additional barriers exist. A cross-sectional study was performed 24 months after ART initiation for patients treated in Cambodia in order to estimate the prevalence and identify determinants of non-adherence.
METHODS
Adults receiving ART for 24 +/- 2 months were considered eligible for the study. Self-reported non-adherence was defined according to an algorithm based on six items. The questionnaire also assessed ART-related side effects and HIV disclosure. HIV-1 RNA plasma viral load was measured using real-time PCR. Multivariate rare events logistic regression analysis was used to identify independent factors associated with non-adherence.
RESULTS
A total of 346 patients participated in the study. At 24 months, 95% of patients were adherent, 80% had HIV RNA <40 copies/ml and 75% had CD4+ T-cell counts >200 cells/mm3. Virological success was significantly higher in adherent patients than in non-adherent patients (81% versus 56%, P=0.021). Living in a rural area, limited HIV disclosure and perceived lipodystrophy were independently associated with non-adherence.
CONCLUSIONS
At 24 months, adherence to ART was high and explained positive virological outcomes. In order to maintain adherence and long-term virological benefits, special attention should be given to patients living in rural areas, those with lipodystrophy-related symptoms and others who express difficulties disclosing their condition to close family members.
The long-term maintenance of antiretroviral therapy (ART) remains an important issue, especially in limited-resource settings where additional barriers exist. A cross-sectional study was performed 24 months after ART initiation for patients treated in Cambodia in order to estimate the prevalence and identify determinants of non-adherence.
METHODS
Adults receiving ART for 24 +/- 2 months were considered eligible for the study. Self-reported non-adherence was defined according to an algorithm based on six items. The questionnaire also assessed ART-related side effects and HIV disclosure. HIV-1 RNA plasma viral load was measured using real-time PCR. Multivariate rare events logistic regression analysis was used to identify independent factors associated with non-adherence.
RESULTS
A total of 346 patients participated in the study. At 24 months, 95% of patients were adherent, 80% had HIV RNA <40 copies/ml and 75% had CD4+ T-cell counts >200 cells/mm3. Virological success was significantly higher in adherent patients than in non-adherent patients (81% versus 56%, P=0.021). Living in a rural area, limited HIV disclosure and perceived lipodystrophy were independently associated with non-adherence.
CONCLUSIONS
At 24 months, adherence to ART was high and explained positive virological outcomes. In order to maintain adherence and long-term virological benefits, special attention should be given to patients living in rural areas, those with lipodystrophy-related symptoms and others who express difficulties disclosing their condition to close family members.
Journal Article > ResearchFull Text
Front Immunol. 2019 August 27; Volume 10; DOI:10.3389/fimmu.2019.02018
Pean P, Nouhin J, Ratana M, Madec Y, Borand L, et al.
Front Immunol. 2019 August 27; Volume 10; DOI:10.3389/fimmu.2019.02018
Background: Human Immunodeficiency Virus 1 (HIV-1) and Mycobacterium Tuberculosis (Mtb) co-infected patients are commonly at risk of immune reconstitution inflammatory syndrome (IRIS) when initiating antiretroviral treatment (ART). Evidence indicates that innate immunity plays a role in TB-IRIS. Here, we evaluate the phenotype of Gamma-delta (γδ) T cells and invariant Natural Killer (iNK) T cells in tuberculosis-associated IRIS. Methods: Forty-eight HIV+/TB+ patients (21 IRIS) and three control groups: HIV-/TB- (HD, n = 11), HIV+/TB- (n = 26), and HIV-/TB+ (n = 22) were studied. Samples were taken at ART initiation (week 2 of anti-tuberculosis treatment) and at the diagnosis of IRIS for HIV+/TB+; before ART for HIV+/TB-, and at week 2 of anti-tuberculosis treatment for HIV-/TB+ patients. γδ T cells and Invariant natural killer T (iNKT) cells were analyzed by flow cytometry. Results: Before ART, IRIS, and non-IRIS patients showed a similar proportion of γδpos T and iNKT cells. HLA-DR on γδpos T cells and δ2posγδpos T cells was significantly higher in TB-IRIS vs. non-IRIS patients and controls (p < 0.0001). NKG2D expression on γδpos T cells and the δ2posγδpos T cell subset was lower in HIV+/TB+ patients than controls. CD158a expression on γδpos T cells was higher in TB-IRIS than non-IRIS (p = 0.02), HIV+/TB-, and HIV-/TB- patients. Conclusion: The higher activation of γδposT cells and the γδ2posγδpos T cell subset suggests that γδ T cells may play a role in the pathogenesis of TB-IRIS.
Journal Article > ResearchFull Text
PLOS One. 2014 March 7; Volume 9 (Issue 3); e90350.; DOI:10.1371/journal.pone.0090350
Borand L, Madec Y, Laureillard D, Chou M, Marcy O, et al.
PLOS One. 2014 March 7; Volume 9 (Issue 3); e90350.; DOI:10.1371/journal.pone.0090350
OBJECTIVE
To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.
METHODS
HIV-infected adults with CD4+ T cell count ≤ 200/mm(3) received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis.
RESULTS
Efavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001).
CONCLUSION
Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity.
To assess efavirenz plasma concentrations and their association with treatment efficacy and tolerance of efavirenz 600 mg daily in HIV-tuberculosis co-infected patients.
METHODS
HIV-infected adults with CD4+ T cell count ≤ 200/mm(3) received standard 6-month tuberculosis treatment and antiretroviral therapy including a daily-dose of 600 mg of efavirenz, irrespective of their body weight. Mid-dose blood samples were drawn both on tuberculosis treatment (week +2 and week +6 after antiretroviral therapy initiation, and week 22 of follow-up) and off tuberculosis treatment (week 50 of follow-up). Considered therapeutic range was 1,000 to 4,000 ng/mL. Multivariate analysis was performed to evaluate the association between efavirenz concentration below 1,000 ng/mL and virological failure. Linear regression was used to test the association between efavirenz exposure and CD4+ T cell gain. Severe side effects potentially related to efavirenz were described and their association with efavirenz exposure was tested by multivariate analysis.
RESULTS
Efavirenz plasma concentrations were available in 540 patients. Median [interquartile range] efavirenz concentrations were 2,674 ng/mL [1,690-4,533], 2,667 ng/mL [1,753-4,494] and 2,799 ng/mL [1,804-4,744] at week +2, week +6, week 22, respectively, and 2,766 ng/mL [1,941-3,976] at week 50. Efavirenz concentrations were lower at week 50 (off rifampicin) compared to week 22 (on rifampicin) (p<0.001). Late attendance to study visit and low hemoglobinemia were the only factors associated with an increased risk of efavirenz concentration below 1,000 ng/mL. Efavirenz concentration below 1,000 ng/mL was not associated with treatment failure. Efavirenz concentration above 4,000 ng/mL was associated with higher risk of central nervous system side effects (p<0.001) and of hepatotoxicity (p<0.001).
CONCLUSION
Body weight and tuberculosis treatment were not associated with low efavirenz concentrations or treatment failure, supporting the 600 mg daily-dose of efavirenz in HIV-tuberculosis co-infected patients. High efavirenz concentrations were related to a higher risk of central nervous system side effects and hepatotoxicity.
Journal Article > ResearchFull Text
AIDS. 2007 January 30; Volume 21 (Issue 3); DOI:10.1097/QAD.0b013e328012c54f
Madec Y, Laureillard D, Pinoges LLP, Fernandez MAL, Prak N, et al.
AIDS. 2007 January 30; Volume 21 (Issue 3); DOI:10.1097/QAD.0b013e328012c54f
BACKGROUND: HAART efficacy was evaluated in a real-life setting in Phnom Penh (Médecins Sans Frontières programme) among severely immuno-compromised patients. METHODS: Factors associated with mortality and immune reconstitution were identified using Cox proportional hazards and logistic regression models, respectively. RESULTS: From July 2001 to April 2005, 1735 patients initiated HAART, with median CD4 cell count of 20 (inter-quartile range, 6-78) cells/microl. Mortality at 2 years increased as the CD4 cell count at HAART initiation decreased, (4.4, 4.5, 7.5 and 24.7% in patients with CD4 cell count > 100, 51-100, 21-50 and < or = 20 cells/microl, respectively; P < 10). Cotrimoxazole and fluconazole prophylaxis were protective against mortality as long as CD4 cell counts remained < or = 200 and < or = 100 cells/microl, respectively. The proportion of patients with successful immune reconstitution (CD4 cell gain > 100 cells/microl at 6 months) was 46.3%; it was lower in patients with previous ART exposure [odds ratio (OR), 0.16; 95% confidence interval (CI), 0.05-0.45] and patients developing a new opportunistic infection/immune reconstitution infection syndromes (OR, 0.71; 95% CI, 0.52-0.98). Similar efficacy was found between the stavudine-lamivudine-nevirapine fixed dose combination and the combination stavudine-lamivudine-efavirenz in terms of mortality and successful immune reconstitution. No surrogate markers for CD4 cell change could be identified among total lymphocyte count, haemoglobin, weight and body mass index. CONCLUSION: Although CD4 cell count-stratified mortality rates were similar to those observed in industrialized countries for patients with CD4 cell count > 50 cells/microl, patients with CD4 cell count < or = 20 cells/microl posed a real challenge to clinicians. Widespread voluntary HIV testing and counselling should be encouraged to allow HAART initiation before the development of severe immuno-suppression.
Journal Article > ResearchFull Text
Pathogens. 2023 October 13; Volume 12 (Issue 10); 1241.; DOI:10.3390/pathogens12101241
Pean P, Madec Y, Nerrienet E, Borand L, Laureillard D, et al.
Pathogens. 2023 October 13; Volume 12 (Issue 10); 1241.; DOI:10.3390/pathogens12101241
IRIS is a common complication in HIV-infected patients treated for tuberculosis (TB) and cART. Our aim was to evaluate NK cell reconstitution in HIV-infected patients with TB-IRIS compared to those without IRIS. 147 HIV-infected patients with TB from the CAMELIA trial were enrolled. HIV+TB+ patients were followed for 32 weeks. The NK cell repertoire was assessed in whole blood at different time points. As CAMELIA has two arms (early and late cART initiation), we analysed them separately. At enrolment, individuals had low CD4 cell counts (27 cells/mm3) and high plasma viral loads (5.76 and 5.50 log/mL for IRIS and non-IRIS individuals, respectively). Thirty-seven people developed IRIS (in the early and late arms). In the early and late arms, we observed similar proportions of total NK and NK cell subsets in TB-IRIS and non-IRIS individuals during follow-up, except for the CD56dimCD16pos (both arms) and CD56dimCD16neg (late arm only) subsets, which were higher in TB-IRIS and non-IRIS individuals, respectively, after cART. Regarding the repertoire and markers of NK cells, significant differences (lower expression of NKp30, NKG2A (CD159a), NKG2D (CD314) were observed in TB-IRIS compared to non-IRIS individuals after the start of cART. In the late arm, some changes (increased expression of CD69, NKG2C, CD158i) were observed in TB-IRIS compared to non-IRIS individuals, but only before cART initiation (during TB treatment). KIR expression by NK cells (CD158a and CD158i) was similar in both groups. CD69 expression by NK cells decreased in all groups. Expression of the NCR repertoire (NKp30, NKp44, NKp46) has similar kinetics in TB-IRIS subjects compared to non-IRIS subjects regardless of the arm analysed. NK cell reconstitution appeared to be better in TB-IRIS subjects. Although NK cell reconstitution is impaired in HIV infection after cART, as previously reported, it does not appear to be affected by the development of IRIS in HIV and TB-infected individuals.