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BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug–drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/μL (interquartile range: 223–455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes −7.4%; 95% confidence interval [CI] −20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, −7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772.

Background Both pregnancy and human immunodeficiency virus (HIV) increase the risk of tuberculosis disease, which results in poor maternal, pregnancy, and infant outcomes. Isoniazid preventive therapy (IPT) reduces mortality among individuals living with HIV in high-burden settings but has recently been associated with adverse pregnancy outcomes when initiated during pregnancy. Methods In this secondary analysis, we used multivariable logistic regression to evaluate the association between IPT exposure and adverse pregnancy outcomes (fetal demise, prematurity, low birth weight, congenital anomaly) in pregnant women living with HIV enrolled as controls in the Tshepiso study, a prospective observational cohort of pregnant women living with HIV with and without tuberculosis disease in Soweto, South Africa, from 2011–2014. Results There were 151 women enrolled with known pregnancy outcomes; 69 (46%) reported IPT initiation during pregnancy. Of the 69 IPT-exposed women, 11 (16%) had an adverse pregnancy outcome compared with 23 (28%) IPT-unexposed women. The adjusted odds of having an adverse pregnancy outcome was 2.5 (95% confidence interval, 1.0–6.5; P = .048) times higher in IPT-unexposed women compared with IPT-exposed women after controlling for maternal age, CD4 count, viral load, antiretroviral regimen, body mass index, and anemia. Conclusions IPT exposure during pregnancy was not negatively associated with pregnancy outcomes after controlling for demographic, clinical, and HIV-related factors. These results provide some reassurance that IPT can be safely used in the second or third trimester of pregnancy. Additional research is needed to evaluate the safety of IPT and new short-course tuberculosis preventive therapies during pregnancy., In this secondary analysis of pregnant women living human immunodeficiency virus (HIV) with and without isoniazid exposure for tuberculosis prevention during pregnancy, we did not observe a negative association between isoniazid preventive therapy use and pregnancy outcomes after controlling for demographic, clinical, and HIV-related confounding factors.

BackgroundRifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.MethodsIn an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.ResultsAmong 2516 participants who had undergone randomization, 2343 had a culture positive for Mycobacterium tuberculosis that was not resistant to isoniazid, rifampin, or fluoroquinolones (microbiologically eligible population; 768 in the control group, 791 in the rifapentine-moxifloxacin group, and 784 in the rifapentine group), of whom 194 were coinfected with human immunodeficiency virus and 1703 had cavitation on chest radiography. A total of 2234 participants could be assessed for the primary outcome (assessable population; 726 in the control group, 756 in the rifapentine-moxifloxacin group, and 752 in the rifapentine group). Rifapentine with moxifloxacin was noninferior to the control in the microbiologically eligible population (15.5% vs. 14.6% had an unfavorable outcome; difference, 1.0 percentage point; 95% confidence interval [CI], -2.6 to 4.5) and in the assessable population (11.6% vs. 9.6%; difference, 2.0 percentage points; 95% CI, -1.1 to 5.1). Noninferiority was shown in the secondary and sensitivity analyses. Rifapentine without moxifloxacin was not shown to be noninferior to the control in either population (17.7% vs. 14.6% with an unfavorable outcome in the microbiologically eligible population; difference, 3.0 percentage points [95% CI, -0.6 to 6.6]; and 14.2% vs. 9.6% in the assessable population; difference, 4.4 percentage points [95% CI, 1.2 to 7.7]). Adverse events of grade 3 or higher occurred during the on-treatment period in 19.3% of participants in the control group, 18.8% in the rifapentine-moxifloxacin group, and 14.3% in the rifapentine group.ConclusionsThe efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Additional file 2: Supplementary Table S2.

Additional file 1: Supplementary Table S1.

BACKGROUND: Before the wide availability of antiretroviral therapy (ART), tuberculosis and human immunodeficiency virus (HIV) disease among pregnant women resulted in poor maternal and neonatal outcomes, including high rates of mother-to-child transmission of both HIV and tuberculosis. We aimed to describe the impact of tuberculosis among HIV-infected mothers on obstetric and infant outcomes in a population with access to ART. METHODS: In this prospective cohort study, we followed up HIV-infected pregnant women with or without tuberculosis disease from January 2011 through January 2014 in Soweto, South Africa. Two controls were enrolled for each case patient, matched by enrollment time, maternal age, gestational age, and planned delivery clinic and followed up for 12 months after delivery. RESULTS: We recruited 80 case patients and 155 controls, resulting in 224 live-born infants. Infants of mothers with HIV infection and tuberculosis disease had a higher risk of low birth weight (20.8% vs 10.7%; P = .04), prolonged hospitalization at birth (51% vs 16%; P < .001), infant death (68 vs 7 deaths per 1000 births; P < .001), and tuberculosis disease (12% vs 0%; P < .001) despite appropriate maternal therapy and infant tuberculosis preventive therapy. HIV transmission was higher among these infants (4.1% vs 1.3%; P = .20), though this difference was not statistically significant. Obstetric outcomes in coinfected women were also poorer with higher risks of maternal hospitalization (25% vs 11%; P = .005) and preeclampsia (5.5% vs 0.7%; P = .03). CONCLUSIONS: Tuberculosis in HIV coinfected pregnant women remains a significant threat to the health of both mothers and infants. Improving tuberculosis prevention and early diagnosis among pregnant women is critical.

Tuberculosis is an important cause of maternal morbidity, but little is known about the effects of pregnancy on antituberculosis drug concentrations. We developed population pharmacokinetic models to describe drug dispositions of isoniazid, pyrazinamide, and ethambutol in pregnant women with tuberculosis and HIV. HIV-positive pregnant women with tuberculosis receiving standard first-line tuberculosis treatment and participating in Tshepiso, a prospective cohort study in Soweto, South Africa, underwent sparse pharmacokinetic sampling at >36 weeks of gestation and 7 weeks postpartum. The effects of pregnancy on the pharmacokinetics of isoniazid, pyrazinamide, and ethambutol were investigated via population pharmacokinetic modeling. Isoniazid, pyrazinamide, and ethambutol concentrations were available for 29, 18, and 18 women, respectively. Their median weight was 66 kg while pregnant and 64 kg postpartum. No significant differences were observed in drug clearance, volume of distribution, or bioavailability during and after pregnancy. The model-estimated isoniazid, pyrazinamide, and ethambutol area under the concentration-time curve from 0 to 24 h (AUC(0–24)) medians were, respectively, 6.88, 419, and 16.5 mg · h/liter during pregnancy versus 5.01, 407, and 19.0 mg · h/liter postpartum. The model-estimated maximum concentration (C(max)) medians for isoniazid, pyrazinamide, and ethambutol were, respectively, 1.39, 35.9, and 1.82 mg/liter during pregnancy versus 1.43, 34.5, and 2.11 mg/liter postpartum. A posteriori power calculations determined that our analysis was powered 91.8%, 59.2%, and 90.1% at a P of

Increased access to and improved sensitivities of methods for diagnosing Mycobacterium tuberculosis infection and detecting rifampicin and isoniazid resistance are needed. Herein, the performance of the new cobas MTB assay for use on cobas 6800/8800 Systems (Roche) was assessed and compared with two other commercial assays: RealTime MTB (Abbott), and Xpert MTB/RIF (Cepheid). Molecular PCR-based assays were conducted on sputum specimens from individuals with presumptive and confirmed tuberculosis (n = 294) from two clinical facilities in South Africa between December 2016 and October 2017. Liquid mycobacterial culture was the reference. Test sensitivities were 94.7% (95% CI, 88%–98%), 92.6% (95% CI, 85%–97%), and 91.6% (95% CI, 84%–96%) for cobas MTB, RealTime MTB, and Xpert MTB/RIF assays, respectively. cobas MTB sensitivity was unaffected by HIV coinfection (95.7%; 95% CI, 88%–99%; n = 176) and sediment testing (94.7%; 95% CI, 88%–98%). Sensitivities were 81.8% (95% CI, 60%–95%), 72.7% (95% CI, 50%–89%), and 72.7% (95% CI, 50%–89%) among smear-negative, culture-positive individuals (n = 221) for cobas MTB, RealTime MTB, and Xpert MTB/RIF assays, respectively. cobas MTB specificity was 95.7% (95% CI, 89%–99%) and 99% (95% CI, 94%–100%) among HIV coinfected and uninfected individuals, respectively. The cobas 6800/8800 system is already implemented in South Africa for high-throughput HIV viral load testing, making it suitable for integrated HIV/tuberculosis diagnostics.

The current intersection of the COVID-19 and HIV-1 pandemics, has raised concerns about the risk for poor COVID-19 outcomes particularly in regions like sub-Saharan Africa, disproportionally affected by HIV. DPP4/CD26 has been suggested to be a potential therapeutic target and a biomarker for risk in COVID-19 patients with high risk co-morbidities. We therefore evaluated soluble DPP4 (sDPP4) levels and activity in plasma of 131 HIV-infected and 20 HIV-uninfected South African individuals. Flow cytometry was performed to compare cell surface expression of DPP4/CD26 and activation markers on peripheral blood mononuclear cells of extreme clinical phenotypes. Progressors had lower specific DPP4 activity and lower frequency of CD3+ T-cells expressing CD26 than HIV-1 controllers, but more activated CD3+CD26+ T-cells. The frequency of CD26-expressing T-cells negatively correlated with HLA-DR+ and CD38+ T-cells. Divergent DPP4/CD26 expression between HIV-1 controllers and progressors may have implications for risk and treatment of COVID-19 in people living with HIV., Graphical abstract Unlabelled Image

While some healthcare systems have shifted to molecular diagnostics, culture still remains the gold standard for tuberculosis diagnosis, but it is limited by its long duration to a positive result. Methods to reduce time to culture positivity (TTP) are urgently required. We determined if growth factor supplementation in the mycobacterial growth indicator tube (MGIT) culture system reduces TTP. MGITs were supplemented with fresh culture filtrate (CF) as a source of growth stimulatory molecules from axenic Mycobacterium tuberculosis culture. Different volumes of CF and media components were tested. The performance of these modified MGITs was assessed with sputum from HIV-TB co-infected individuals. Reducing the volume of MGIT cultures and removal of detergent from cultures grown to generate CF had a marginal but significant benefit on reducing TTP. In a subset of specimens, CF inhibited growth. Following optimization of methods, a reduced TTP occurred in specimens with low bacillary load as measured by GeneXpert, smear microscopy and colony forming units. Three specimens that were negative under standard conditions flagged positive following CF supplementation. Our data provide preliminary evidence that addition of CF to MGIT cultures can enhance detection of M. tuberculosis in HIV-TB co-infected patients with low sputum bacillary loads.

Background To determine the association of human leukocyte antigen (HLA) alleles as correlates of risk for and protection against tuberculin skin test (TST) positivity and active TB disease amongst HIV-infected adults. Methods Genomic DNA was extracted from 754 HIV-infected adults whole-blood. HLA-A, -B, -C and -DRB1 loci were genotyped by next generation sequencing methods. HLA alleles were analysed by the presence/absence of TST immune conversion and active TB disease and further stratified by exposure to a household TB contact, CD4+ T-cell count and, for active TB disease, TST-positivity. Results HLA-A*29:11 and - B*45:01/07 were associated with TST-positivity, while HLA-A*24:02, -A*29:02 and -B*15:16 with TST-negativity. In participants with a household TB contact, HLA-A*66:01, -A*68:02 and -B*49:01 were associated with TST-negativity. For TB disease, HLA-B*41:01, -C*06:02, -DRB1*04:01 and -DRB1*15:01 were associated with susceptibility, while HLA-B*07:02 and -DRB1*11:01 were protective, even for CD4+ T-cell count Conclusion Several HLA alleles are noted as correlates of TB infection, risk and natural protection in HIV-infected individuals. HLA associations may enable risk stratification of those with HIV infection. Protective alleles may assist in future TB vaccine development.

Chronic HIV-infection modulates the expression of Fc gamma receptors (FcγRs) on immune cells and their antibody-dependent effector function capability. Given the increasingly recognized importance of antibody-dependent cellular cytotoxicity (ADCC) in HIV-specific immunity, we investigated the cellular distribution of FcγRIIIa on cytotoxic lymphocytes—natural killer cells and CD8+ T cells—and the effect of the FcγRIIIa-F158V variant on ADCC capacity in HIV-infected individuals (n = 23) and healthy controls (n = 23). Study participants were matched for F158V genotypes, carried two copies of the FCGR3A gene and were negative for FcγRIIb expression on NK cells. The distribution of CD56dimFcγRIIIabright and CD56negFcγRIIIabright NK cell subsets, but not FcγRIIIa surface expression, differed significantly between HIV-1 negative and HIV-1 positive donors. NK cell-mediated ADCC responses negatively correlated with the proportion of the immunoregulatory CD56brightFcγRIIIadim/neg cells and were lower in the HIV-1 positive group. Intriguingly, the FcγRIIIa-F158V variant differentially affected the NK-mediated ADCC responses for HIV-1 negative and HIV-1 positive donors. Healthy donors bearing at least one 158V allele had higher ADCC responses compared to those homozygous for the 158F allele (48.1 vs. 34.1%), whereas the opposite was observed for the HIV-infected group (26.4 vs. 34.6%), although not statistically significantly different. Furthermore, FcγRIIIa+CD8bright and FcγRIIIa+CD8dim T cell subsets were observed in both HIV-1 negative and HIV-1 positive donors, with median proportions that were significantly higher in HIV-1 positive donors compared to healthy controls (15.7 vs. 8.3%; P = 0.016 and 18.2 vs. 14.1%; P = 0.038, respectively). Using an HIV-1-specific GranToxiLux assay, we demonstrate that CD8+ T cells mediate ADCC through the delivery of granzyme B, which was overall lower compared to that of autologous NK cells. In conclusion, our findings demonstrate that in the presence of an HIV-1 infection, the cellular distribution of FcγRIIIa is altered and that the functional consequence of FcγRIIIa variant is affected. Importantly, it underscores the need to characterize FcγR expression, cellular distribution and functional consequences of FcγR genetic variants within a specific environment or disease state.

The SMA-TB Consortium has developed a leaflet with basic information on Tuberculosis to be distributed to general public during communication activities. This leaflet was created within the SMA-TB Project jointly by the IGTP team andthe Public Health Agency of Barcelona (ASPB). The Fundació Lluita contra les Infeccions (Fight Infections Foundation)has also contributed to it,and Laura Ginès and Pepón Meneses illustrated it. Theleaflethas been translated toseveral languagesbymembers of theSMA-TB Consortium partners (all listed as contributors)in order others can reuse it: Catalan Spanish French Italian Portuguese Polish Deutsch Norwegian Ukrainian Georgian Afrikaans Per each language, two versions are provided: one to be printed in a home printer and another one to be printed in a printshop.

1st Newsletter of SMA-TB Project, Dec 2020