François-Xavier Blanc

Earlier versus Later Start of Antiretroviral Therapy in HIV-Infected Adults with Tuberculosis

BACKGROUND 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. METHODS We tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower. After beginning the standard, 6-month treatment for tuberculosis, patients were randomly assigned to either earlier treatment (2 weeks after beginning tuberculosis treatment) or later treatment (8 weeks after) with stavudine, lamivudine, and efavirenz. The primary end point was survival. RESULTS A total of 661 patients were enrolled and were followed for a median of 25 months. The median CD4+ T-cell count was 25 per cubic millimeter, and the median viral load was 5.64 log(10) copies per milliliter. The risk of death was significantly reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), as compared with 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% confidence interval [CI]; 0.44 to 0.86; P=0.006). The risk of tuberculosis-associated immune reconstitution inflammatory syndrome was significantly increased in the earlier-ART group (hazard ratio, 2.51; 95% CI, 1.78 to 3.59; P<0.001). Irrespective of the study group, the median gain in the CD4+ T-cell count was 114 per cubic millimeter, and the viral load was undetectable at week 50 in 96.5% of the patients. CONCLUSIONS Initiating ART 2 weeks after the start of tuberculosis treatment significantly improved survival among HIV-infected adults with CD4+ T-cell counts of 200 per cubic millimeter or lower. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.).

Sarcoidosis in HIV-Infected Patients in the Era of Highly Active Antiretroviral Therapy

To analyze the impact of highly active antiretroviral therapy (HAART) on the characteristics and outcome of sarcoidosis in patients infected with human immunodeficiency virus (HIV), we identified HIV-infected patients in whom sarcoidosis was diagnosed between 1996 and 2000 from the admission registers of the pneumology departments of 12 hospitals in the Paris region (France). Sarcoidosis was diagnosed in 11 HIV-infected patients, of whom 8 were receiving HAART. HIV infection was diagnosed before sarcoidosis in 9 cases. At diagnosis of sarcoidosis, the mean CD4 cell count (+/-SD) was 390+/-213 cells/mm(3), and the mean plasma virus load was 4002+/-10,183 copies/mL. Sarcoidosis occurred several months after HAART introduction, when the CD4 cell count had increased and the plasma HIV load had decreased. Clinical and radiological characteristics, laboratory values for bronchoalveolar lavage fluid samples, and outcome after a long follow-up were similar for the patients receiving HAART and for HIV-uninfected patients.

Treatment Strategies for HIV-Infected Patients with Tuberculosis: Ongoing and Planned Clinical Trials

Currently, there are limited data to guide the management of highly active antiretroviral therapy (HAART) for human immunodeficiency virus type 1 (HIV-1)-infected patients with active tuberculosis (TB), the leading cause of death among individuals with acquired immunodeficiency syndrome (AIDS) in resource-limited areas. Four trials to take place in Southeast Asian, African, and South American countries will address the unresolved question of the optimal timing for initiation of HAART in patients with AIDS and TB: (1) Cambodian Early versus Late Introduction of Antiretrovirals (CAMELIA [ANRS 1295/NIH-CIPRA KH001]), (2) Adult AIDS Clinical Trials Group A5221, (3) START, and (4) a trial sponsored by the World Health Organization/Special Programme for Research and Training in Tropical Diseases. Two other clinical questions regarding patients with TB and HIV-1 coinfection are also undergoing evaluation: (1) the benefits of short-term HAART when CD4 cell counts are >350 cells/mm(3) (PART [NIH 1 R01 AI051219-01A2]) and (2) the efficacy of a once-daily HAART regimen in treatment-naive patients (BKVIR [ANRS 129]). Here, we present an overview of these ongoing or planned clinical studies, which are supported by international agencies.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in a randomized clinical trial.

Objective: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). Methods:ART-naive adults with CD4+ cell count of 200 cells/&mgr;l or less, newly diagnosed tuberculosis, and at least one follow-up visit after ART initiation were included in this analysis. Each case of suspected TB-IRIS was systematically validated by two physicians not involved in patients’ management. Factors associated with occurrence of TB-IRIS were identified using the Cox proportional hazard model. Results:Among 597 patients, 26% experienced TB-IRIS with an incidence rate of 37.9 cases per 100 person-years [95% confidence interval (CI) 32.4–44.4]. Main clinical manifestations included new or worsening lymphadenopathy (77.4%) and fever (68.4%). Chest radiograph revealed new or worsening abnormalities in 53.4%. Symptoms resolved in 95.5% of patients. Six deaths were directly related to TB-IRIS. Initiating ART early increased the risk of TB-IRIS by 2.61 (95% CI 1.84–3.70). Extrapulmonary or disseminated tuberculosis, CD4+ cell count of 100 cells/&mgr;l or less, and HIV RNA concentration more than 6 log10 copies/ml were also significantly associated with higher risk of TB-IRIS. Conclusion:Shortening the delay between tuberculosis treatment onset and ART initiation to 2 weeks was associated with an increased risk of developing TB-IRIS. However, TB-IRIS was generally easily manageable. Given the marked reported survival advantage of early ART initiation after tuberculosis treatment onset, these data indicate that fear of TB-IRIS should not be an impediment to early ART in adults with advanced immunodeficiency in resource-limited, high burden settings.

Mechanics and crossbridge kinetics of tracheal smooth muscle in two inbred rat strains

The aim of the study was to determine whether the nonspecific in vivo airway hyperresponsiveness of the inbred Fisher F‐344 rat strain was associated with differences in the intrinsic contractile properties of tracheal smooth muscle (TSM) when compared with Lewis rats. Isotonic and isometric contractile properties of isolated TSM from Fisher and Lewis rats (each n=10) were investigated, and myosin crossbridge (CB) number, force and kinetics in both strains were calculated using Huxleys equations adapted to nonsarcomeric muscles. Maximum unloaded shortening velocity and maximum extent of muscle shortening were higher in Fisher than in Lewis rats (∼46% and ∼42%, respectively), whereas peak isometric tension was similar. The curvature of the hyperbolic force/velocity relationship did not differ between strains. Myosin CB number and unitary force were similar in both strains. The duration of CB detachment and attachment was shorter in Fisher than in Lewis rats (∼−46% and −34%, respectively). In Fisher rats, these results show that inherited, genetically determined factors of airway hyperresponsiveness are associated with changes in crossbridge kinetics, contributing to an increased tracheal smooth muscle shortening capacity and velocity.

Dependence of Efavirenz- and Rifampicin-Isoniazid–Based Antituberculosis Treatment Drug-Drug Interaction on CYP2B6 and NAT2 Genetic Polymorphisms: ANRS 12154 Study in Cambodia

We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were administered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant inhibitory effect of isoniazid on efavirenz clearance.

Causes and Determinants of Mortality in HIV-Infected Adults With Tuberculosis: An Analysis From the CAMELIA ANRS 1295-CIPRA KH001 Randomized Trial

BACKGROUND 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. METHODS We assessed mortality rates, causes of death, and factors of mortality in Cambodian HIV-infected adults with CD4 count ≤200 cells/µL and tuberculosis, randomized to initiate ART either 2 weeks (early ART) or 8 weeks (late ART) after tuberculosis treatment onset in the CAMELIA clinical trial. RESULTS Six hundred sixty-one patients enrolled contributed to 1366.1 person-years of follow-up; 149 (22.5%) died. There were 8.3 deaths per 100 person-years (95% confidence interval [CI], 6.4-10.7) in the early-ART group and 13.8 deaths per 100 person-years (95% CI, 11.2-16.9) in the late-ART group (P = .002). Tuberculosis was the primary cause of death (28%), followed by other HIV-associated conditions (19%). Factors independently associated with mortality in the first 26 weeks were the age, body mass index, hemoglobin, interrupted or ineffective tuberculosis treatment before identification of drug resistance, disseminated tuberculosis, and nontuberculous mycobacterial disease. After 50 weeks in the trial, the most frequent causes of death were non-HIV related or tuberculosis related, including drug toxicity; factors associated with mortality were late ART, loss to follow-up, and absence of cotrimoxazole prophylaxis. CONCLUSIONS Despite ART introduction, mortality remained high, with tuberculosis as the leading cause of death. Reducing tuberculosis-related mortality remains a challenge in resource-limited settings and requires innovative strategies. Clinical Trials Registration. NCT00226434.

TB-IRIS, T-cell activation, and remodeling of the T-cell compartment in highly immunosuppressed HIV-infected patients with TB

Objective:To investigate the impact of tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) upon immunological recovery and the T-cell compartment after initiation of TB and antiretroviral therapy (ART). Design and methods:We prospectively evaluated T-cell immunophenotypes by flow cytometry and cytokines by Luminex assays in a subset (n = 154) of highly immunosuppressed HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretrovirals randomized clinical trial. We compared findings from patients who developed TB-IRIS with findings from patients who did not develop TB-IRIS. Data were evaluated with mixed-effect linear regression, Kaplan–Meier estimates, and Wilcoxon rank-sum tests, and q-values were calculated to control for multiple comparisons. Results:Development of TB-IRIS was associated with significantly greater pre-ART frequencies of HLA-DR+CD45RO+CD4+, CCR5+CD4+, OX40+CD4+, and Fas+ effector memory CD8+ T cells, and significantly elevated levels of plasma interleukin (IL)-6, IL-1&bgr;, IL-8, and IL-10, and viral load. Post-ART initiation, effector memory CD4+ and Fas+ effector memory CD4+ T-cell frequencies significantly expanded, and central memory CD4+ T-cell frequencies significantly contracted in patients who experienced TB-IRIS. By week 34 post-TB treatment initiation, effector memory/central memory CD4+ T-cell ratios were markedly higher in TB-IRIS versus non-TB-IRIS patients. Conclusions:A distinct pattern of pre-ART T-cell and cytokine markers appear to poise the immune response of certain patients to develop TB-IRIS. Experience of TB-IRIS is then associated with long-term remodeling of the CD4+ T-cell memory compartment towards an effector memory-dominated phenotype. We speculate that these pre and post-ART TB-IRIS-associated immune parameters may contribute to superior immune control of TB/HIV co-infection and better clinical outcome.

Effects of initial length on intrinsic tone in guinea pig tracheal smooth muscle

In the guinea pig, tracheal smooth muscle (TSM) exhibits intrinsic tone (IT). The active nature of IT suggests that it could be influenced by muscle length and load. In the guinea pig, IT is entirely suppressed by the cyclooxygenase inhibitor indomethacin. IT could be measured as the difference between resting tone before and after indomethacin addition. We examined, in electrically stimulated TSM strips (n = 9), the influence of initial muscle length (Li) on IT, the relationship between IT and the maximum extent of relaxation (DeltaF1), and the influence of indomethacin on active isometric force. When Li decreased from 100 to 75% of optimal Li, there was a significant decrease in IT (from 12.0 +/- 0.2 to 5.3 +/- 0.1 mN; P < 0.001). Over the range of Li studied, DeltaF1 underestimated the amount of IT, but there was a close linear relationship between DeltaF1 and IT (r = 0.9). Compared with the basal state, indomethacin increased active isometric force (from 9.5 +/- 1.0 to 19.7 +/- 2.0 mN at optimal Li; P < 0.001) and induced its length dependency. In guinea pig TSM, Li was an important determinant of IT.In the guinea pig, tracheal smooth muscle (TSM) exhibits intrinsic tone (IT). The active nature of IT suggests that it could be influenced by muscle length and load. In the guinea pig, IT is entirely suppressed by the cyclooxygenase inhibitor indomethacin. IT could be measured as the difference between resting tone before and after indomethacin addition. We examined, in electrically stimulated TSM strips ( n= 9), the influence of initial muscle length ( L i) on IT, the relationship between IT and the maximum extent of relaxation (ΔF1), and the influence of indomethacin on active isometric force. When L i decreased from 100 to 75% of optimal L i, there was a significant decrease in IT (from 12.0 ± 0.2 to 5.3 ± 0.1 mN; P < 0.001). Over the range of L i studied, ΔF1 underestimated the amount of IT, but there was a close linear relationship between ΔF1 and IT ( r = 0.9). Compared with the basal state, indomethacin increased active isometric force (from 9.5 ± 1.0 to 19.7 ± 2.0 mN at optimal L i; P < 0.001) and induced its length dependency. In guinea pig TSM, L i was an important determinant of IT.

Plasma Concentrations, Efficacy and Safety of Efavirenz in HIV-Infected Adults Treated for Tuberculosis in Cambodia (ANRS 1295-CIPRA KH001 CAMELIA Trial)

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/mm3 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. Trial Registration ClinicalTrials.gov NCT01300481