T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection

CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation

Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe

Background: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.Methods: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy.Results: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM.Conclusion: During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring

Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

BACKGROUND: Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD-program systematically collects data to gain insight into TDR occurring in Europe since 2001. METHODS: Demographic, clinical and virological data from 4,140 antiretroviral-naive HIV-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002-2007. Baseline susceptibility to antiretroviral drugs was predicted using Stanford HIVdb v7.0. RESULTS: The overall prevalence of TDR did not change significantly over time and was 8.3% (95%CI 7.2-9.5) in 2008-2010. The most frequent indicators of TDR were NRTI-mutations (4.5%), followed by NNRTI-mutations (2.9%) and PI-mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine respectively, independent of current NRTI backbones. CONCLUSIONS: Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affecte

The EuResist expert model for customised HAART optimisation: 2010 update and extension to newest compounds

7‐11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, U

Challenges in modelling the proportion of undiagnosed HIV infections in Sweden

BACKGROUND: Sweden has a low HIV prevalence. However, among new HIV diagnoses in 2016, the proportion of late presenters and migrants was high (59% and 81%, respectively). This poses challenges in estimating the proportion of undiagnosed persons living with HIV (PLHIV). AIM: To estimate the proportion of undiagnosed PLHIV in Sweden comparing two models with different demands on data availability and modelling expertise. METHODS: An individual-based stochastic simulation model of HIV positive populations (SSOPHIE) and the incidence method of the European Centre for Disease Prevention and Control (ECDC) HIV Modelling Tool were applied to clinical, surveillance and migration data from Sweden 1980–2016. RESULTS: SSOPHIE estimated that the proportion of undiagnosed PLHIV in 2013 was 26% (n = 2,100; 90% plausibility range (PR): 900–5,000) for all PLHIV, 17% (n = 600; 90% PR: 100–2,000) for men who have sex with men (MSM), 35% in male (n = 300; 90% PR: 200–700) and 34% in female (n = 400; 90% PR: 200–800) migrants from sub-Saharan Africa (SSA). The estimates for the ECDC model in 2013 were 21% (n = 2,013; 95% confidence interval (CI): 1,831–2,189) for all PLHIV, 15% (n = 369; 95% CI: 299–434) for MSM and 21% (n = 530; 95% CI: 436–632) for migrants from SSA. CONCLUSIONS: The proportion of undiagnosed PLHIV in Sweden is uncertain. SSOPHIE estimates had wide PR. The ECDC model estimates were unreliable because migration was not accounted for. Better migration data and estimation methods are required to obtain reliable estimates of proportions of undiagnosed PLHIV in similar settings

Results from a European multi-cohort study

Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.Background: INSTIs have become a pillar of first-line ART. Real-world data are needed to assess their effectiveness in routine care. Objectives: We analysed ART-naive patients who started INSTI-based regimens in 2012-19 whose data were collected by INTEGRATE, a European collaborative study including seven national cohorts. Methods: Kaplan-Meier analyses assessed time to virological failure (VF), defined as one viral load (VL) ≥1000 copies/mL, two consecutive VLs ≥50 copies/mL, or one VL ≥50 copies/mL followed by treatment change after ≥24 weeks of follow-up, and time to INSTIs discontinuation (INSTI-DC) for any reason. Factors associated with VF and INSTI-DC were explored by logistic regression analysis. Results: Of 2976 regimens started, 1901 (63.9%) contained dolutegravir, 631 (21.2%) elvitegravir and 444 (14.9%) raltegravir. The 1 year estimated probabilities of VF and INSTI-DC were 5.6% (95% CI 4.5-6.7) and 16.2% (95% CI 14.9-17.6), respectively, and were higher for raltegravir versus both elvitegravir and dolutegravir. A baseline VL ≥100 000 copies/mL [adjusted HR (aHR) 2.17, 95% CI 1.55-3.04, P 3 drugs versus 3 drugs (aHR 2.73, 95% CI 1.55-4.79, P < 0.001) and starting ART following availability of dolutegravir (aHR 0.64, 95% CI 0.48-0.83, P = 0.001). Major INSTI mutations indicative of transmitted drug resistance occurred in 2/1114 (0.2%) individuals. Conclusions: This large multi-cohort study indicates high effectiveness of elvitegravir- or dolutegravir-based first-line ART in routine practice across Europe.publishersversionpublishe

EuCARE-hospitalised study protocol: a cohort study of patients hospitalised with COVID-19 in the EuCARE project

Background: Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), can lead to hospitalisation, particularly in elderly, immunocompromised, and non-vaccinated or partially vaccinated individuals. Although vaccination provides protection, the duration of this protection wanes over time. Additional doses can restore immunity, but the influence of viral variants, specific sequences, and vaccine-induced immune responses on disease severity remains unclear. Moreover, the efficacy of therapeutic interventions during hospitalisation requires further investigation. The study aims to analyse the clinical course of COVID-19 in hospitalised patients, taking into account SARS-CoV-2 variants, viral sequences, and the impact of different vaccines. The primary outcome is all-cause in-hospital mortality, while secondary outcomes include admission to intensive care unit and length of stay, duration of hospitalisation, and the level of respiratory support required. Methods: This ongoing multicentre study observes hospitalised adult patients with confirmed SARS-CoV-2 infection, utilising a combination of retrospective and prospective data collection. It aims to gather clinical and laboratory variables from around 35,000 patients, with potential for a larger sample size. Data analysis will involve biostatistical and machine-learning techniques. Selected patients will provide biological material. The study started on October 14, 2021 and is scheduled to end on October 13, 2026. Discussion: The analysis of a large sample of retrospective and prospective data about the acute phase of SARS CoV-2 infection in hospitalised patients, viral variants and vaccination in several European and non-European countries will help us to better understand risk factors for disease severity and the interplay between SARS CoV-2 variants, immune responses and vaccine efficacy. The main strengths of this study are the large sample size, the long study duration covering different waves of COVID-19 and the collection of biological samples that allows future research. Trial registration: The trial has been registered on ClinicalTrials.gov. The unique identifier assigned to this trial is NCT05463380

Consensus statement of the European guidelines on clinical management of HIV-1 tropism testing

Tenth International Congress on Drug Therapy in HIV Infection 7-11 November 2010 Glasgow, UKIntroduction: Testing for HIV tropism is recommended before prescribing a chemokine receptor blocker. To date, in most European countries HIV tropism is determined using a phenotypic test. Recently, new data have emerged supporting the use of a genotypic HIV V3-loop sequence analysis as the basis for tropism determination. The European guidelines group on clinical management of HIV-1 tropism testing was established to make recommendations to clinicians and virologists. Methods: We searched online databases for articles from Jan 2006 until March 2010 with the terms: tropism or CCR5-antagonist or CCR5 antagonist or maraviroc or vicriviroc. Additional articles and/or conference abstracts were identified by hand searching. This strategy identified 712 potential articles and 1240 abstracts. All were reviewed and finally 57 papers and 42 abstracts were included and used by the panel to reach a consensus statement. Results: The panel recommends HIV-tropism testing for the following indications: i) drug-naïve patients in whom toxicity or limited therapeutic options are foreseen; ii) patients experiencing therapy failure whenever a treatment change is considered. Both the phenotypic Enhanced Trofile assay (ESTA) and genotypic population sequencing of the V3-loop are recommended for use in clinical practice. Although the panel does not recommend one methodology over another it is anticipated that genotypic testing will be used more frequently because of its greater accessibility, lower cost and shorter turnaround time. The panel also provides guidance on technical aspects and interpretation issues. If using genotypic methods, triplicate PCR amplification and sequencing testing is advised using the G2P interpretation tool (clonal model) with an FPR of 10%. If the viral load is below the level of reliable amplification, proviral DNA can be used, and the panel recommends performing triplicate testing and use of an FPR of 10%. If genotypic DNA testing is not performed in triplicate the FPR should be increased to 20%. Conclusions: The European guidelines on clinical management of HIV-1 tropism testing provide an overview of current literature, evidence-based recommendations for the clinical use of tropism testing and expert guidance on unresolved issues and current developments. Current data support both the use of genotypic population sequencing and ESTA for co-receptor tropism determination. For practical reasons genotypic population sequencing is the preferred method in Europe.Ye