Interferon-gamma release assays (IGRAs) in high-endemic settings: could they play a role in optimizing global TB diagnostics? Evaluating the possibilities of using IGRAs to diagnose active TB in a rural African setting

SummaryThe number of patients suffering from tuberculosis (TB) globally is increasing. Due to the HIV epidemic, most patients suffering from TB reside in sub-Saharan Africa. In order to improve TB diagnostics, new tests – interferon-gamma release assays (IGRAs) – have been developed over the last decade. In this paper we evaluate the possible use of these tests in diagnosing or excluding active TB in high HIV-burden, resource-limited settings. The inability to differentiate between active and latent TB, limited data on IGRA performance in HIV-infected patients, observed false-negative results, high costs, and logistic problems limit the potential benefit of IGRAs. We also present two theoretical study designs in order to further assess IGRAs. Setting up a study on this subject is complicated by the frequent unavailability of mycobacterial cultures, the difficulty in acquiring prospective data, and the impossibility of denying treatment to a patient suspected of having active TB. We feel that current evidence does not support the implementing of IGRAs in clinical practice in settings with high endemic latent TB infection (LTBI) and high HIV prevalence. As these settings are the ones that suffer the most from the TB epidemic, we believe that the role of IGRAs in global TB control is questionable

Origin Of The Far Off-Axis GRB171205A

We show that observed properties of the low luminosity GRB171205A and its afterglow, like those of most other low-luminosity (LL) gamma ray bursts (GRBs) associate with a supernova (SN), indicate that it is an ordinary SN-GRB, which was produced by inverse Compton scattering of glory light by a highly relativistic narrowly collimated jet ejected in a supernova explosion and viewed from a far off-axis angle. As such, VLA/VLBI follow-up radio observations of a superluminal displacement of its bright radio afterglow from its parent supernova, will be able to test clearly whether it is an ordinary SN-GRB viewed from far off-axis or it belongs to a distinct class of GRBs, which are different from ordinary GRBs, and cannot be explained by standard fireball models of GRBs as ordinary GRBsComment: 5 pages, 6 figures, updated data in Fig. 3, Corrected GRB angular distance used in Fig.

Estimating regional prevalence of chronic hepatitis C with a capture-recapture analysis

Background: The hepatitis C virus (HCV) infection is a candidate disease for micro-elimination. Accurate baseline HCV prevalence estimation is essential to monitor progress to micro-elimination but can be methodologically challenging in low-endemic regions like the Netherlands due to lack of disaggregated data by age or risk-groups on the number of chronic HCV patients (i.e. HCV RNA positive). This study estimates the number of patients that has had a chronic HCV infection (ever-chronic) in the Utrecht region of the Netherlands. Methods: In the Utrecht province in the Netherlands, positive HCV tests from the period 2001–2015 from one diagnostic center and four hospital laboratories were collected. A two-source capture-recapture method was used to analyze the overlap between the two registries (with 92% HCV RNA and 8% HCV immunoblot confirmed infections) to obtain the number of ever-chronic HCV infections in the Utrecht region. The Utrecht region was defined as an area with a 25 km radius from the Utrecht city center. The current viremic HCV prevalence was calculated by taking into account the proportion of cured and deceased HCV patients from a local HCV retrieval (REACH) project. Results: The estimated number of ever-chronic HCV patients was 1245 (95% CI 1164–1326) and would indicate a prevalence of 0.10 (95% CI 0.09–0.10) in the Utrecht region. This is 30% (95% CI 21–38%) more than the number of known HCV patients in the records. The ever-chronic HCV prevalence was highest in the 1960–1969 age cohort (0.16; 95% CI 0.14–0.18). Since 50% of the HCV patients were cured or deceased in the REACH-project, the number of current viremic HCV patients was estimated at 623 individuals in the Utrecht region (prevalence 0.05%). Conclusion: The results of this study suggest a low ever-chronic and current HCV prevalence in the Utrecht area in the Netherlands, but other studies need to confirm this

No long-term effect of past Pneumocystis jirovecii pneumonia on pulmonary function in people with HIV

Objective:To assess the impact of past Pneumocystis jirovecii pneumonia (PJP) on the pulmonary diffusion capacity in people with HIV (PWH) with a history of advanced immunodeficiency.Design:Prospective cross-sectional study.Methods:Adult PWH with past PJP >1 year ago were included as the study group. The control group consisted of PWH with a nadir CD4+ lymphocyte count <200 cells/mm3, matched by age, sex, smoking status and time since HIV diagnosis. All PWH completed a pulmonary function test (PFT) consisting of pre-bronchodilation spirometry, body plethysmography and single-breath carbon monoxide transfer factor (TLCO) measurement. TLCO, diffusion impairment (defined as a TLCO Z-score <-1.645), total lung capacity (TLC) and forced expiratory volume in one second/forced vital capacity (FEV1/FVC) Z-scores were assessed. Multivariable regression analyses were conducted with Z-scores and odds of diffusion impairment as outcomes.Results:PFTs of 102 participants were analyzed, 51 of whom had past PJP with a median of 10 years since PJP. Mean TLCO Z-score and diffusion impairment rate did not differ significantly between groups (P = 0.790; P = 0.650). Past PJP was not independently associated with TLCO Z-score [β = 0.14; 95% confidence interval (CI) -0.30-0.57], diffusion impairment (odds ratio 1.00; 95% CI 0.36-2.75) nor TLC or FEV1/FVC Z-scores, whereas current (vs. never) smoking was associated with more diffusion impairment and lower TLCO Z-scores.Conclusion:In our study, past PJP was not associated with long-term diffusion impairment. Our findings suggest that smoking plays a more important role in persistent pulmonary function impairment whereas PJP-related changes seem to be reversible

Persistence of frequently transmitted drug-resistant HIV-1 variants can be explained by high viral replication capacity

Background: In approximately 10% of newly diagnosed individuals in Europe, HIV-1 variants harboring transmitted drug resistance mutations (TDRM) are detected. For some TDRM it has been shown that they revert to wild type while other mutations persist in the absence of therapy. To understand the mechanisms explaining persistence we investigated the in vivo evolution of frequently transmitted HIV-1 variants and their impact on in vitro replicative capacity. Results: We selected 31 individuals infected with HIV-1 harboring frequently observed TDRM such as M41L or K103N in reverse transcriptase (RT) or M46L in protease. In all these samples, polymorphisms at non-TDRM positions were present at baseline (median protease: 5, RT: 6). Extensive analysis of viral evolution of protease and RT demonstrated that the majority of TDRM (51/55) persisted for at least a year and even up to eight years in the plasma. D

Integrated analysis of viral blips, residual viremia, and associated factors in people with HIV: Results from a retrospective cohort study

The etiology of viral blips is not yet fully elucidated. One of the hypotheses is that blips reflect variations in residual viremia (RV) near the detectability threshold. In this study, we evaluated whether RV is associated with viral blips and which factors are associated with RV. All treatment regimens in 2010–2020 consisting of two nucleos(-t)ide reverse transcriptase inhibitors and one anchor (integrase strand transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor [NNRTI], or protease inhibitor [PI]) in people with HIV (PWH) were evaluated for RV (detectable viremia <50 cp/mL) and blips (isolated viral loads [VLs] 50–499 cp/mL between measurements <50 cp/mL). All medical records were reviewed and regimens in which a VL ≥ 50 cp/mL was deemed to result from non-adherence (based on the documented conclusion by the treating physician) were excluded. Factors associated with blips and RV were identified using generalized linear mixed models. In total, 24 518 VLs from 1658 PWH were analyzed. VLs were measured during INSTI- (n = 5119; 20.9%), PI- (n = 8935; 36.4%), and NNRTI-use (n = 10 464; 42.7%). VLs were categorized as blips in 1.4% (n = 332). The 24,186 non-blip VLs were RNAneg (no RV) (n = 15 326; 63.4%), 1–19 cp/mL (n = 6318; 26.1%), 20–49 cp/mL (n = 1620; 6.7%), or <50 cp/mL with an unknown RV level (n = 922; 3.8%). In 193/1658 PWH (11.6%), the RV level was RNAneg in all VLs assessed. RV 1–19 cp/mL and 20–49 cp/mL (vs. RNAneg) were significantly associated with subsequent viral blips (respective odds ratio 2.66 and 4.90 [95% confidence intervals: 1.98–3.58 and 3.41–7.04]). Zenith VL and use of PIs (vs. INSTIs/NNRTIs) were associated with higher RV and blip odds. This large cohort study showed that blips were associated with higher preceding RV. Both the anchor type and factors previously linked to the latent viral reservoir were associated with RV, suggesting blips having a multifactorial origin

Underlying Neural Mechanisms of Cognitive Improvement in Fronto-striatal Response Inhibition in People Living with HIV Switching Off Efavirenz: A Randomized Controlled BOLD fMRI Trial

Introduction: It is unclear whether neurotoxicity due to the antiretroviral drug efavirenz (EFV) results in neurocognitive impairment in people living with HIV (PLWH). Previously, we found that discontinuing EFV was associated with improved processing speed and attention on neuropsychological assessment. In this imaging study, we investigate potential neural mechanisms underlying this cognitive improvement using a BOLD fMRI task assessing cortical and subcortical functioning. Methods: Asymptomatic adult PLWH stable on emtricitabine/tenofovirdisoproxil/efavirenz were randomly (1:2) assigned to continue their regimen (n = 12) or to switch to emtricitabine/tenofovirdisoproxil/rilpivirine (n = 28). At baseline and after 12 weeks, both groups performed the Stop-Signal Anticipation Task, which tests reactive and proactive inhibition (indicative of subcortical and cortical functioning, respectively), involving executive functioning, working memory, and attention. Behavior and BOLD fMRI activation levels related to processing speed and attention Z-scores were assessed in 17 pre-defined brain regions. Results: Both groups had comparable patient and clinical characteristics. Reactive inhibition behavioral responses improved for both groups on week 12, with other responses unchanged. Between-group activation did not differ significantly. For reactive inhibition, positive Pearson coefficients were observed for the change in BOLD fMRI activation levels and change in processing speed and attention Z-scores in all 17 regions in participants switched to emtricitabine/tenofovir disoproxil/rilpivirine, whereas in the control group, negative correlation coefficients were observed in 10/17 and 13/17 regions, respectively. No differential pattern was observed for proactive inhibition. Conclusion: Potential neural mechanisms underlying cognitive improvement after discontinuing EFV in PLWH were found in subcortical functioning, with our findings suggesting that EFV’s effect on attention and processing speed is, at least partially, mediated by reactive inhibition. Trial Registration: Clinicaltrials.gov identifier [NCT02308332]