: PLoS One

International audienceIn 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations

EBioMedicine

BACKGROUND: Previous epigenome-wide association studies have shown that HIV infection can disrupt the host DNA methylation landscape. However, it remains unclear how antiretroviral therapy (ART) affects the HIV-induced epigenetic modifications. METHODS: 184 individuals with HIV from the NEAT001/ANRS143 clinical trial (with pre-ART and post-ART samples [96 weeks of follow-up]) and 44 age-and-sex matched individuals without HIV were included. We compared genome-wide DNA methylation profiles in whole blood between groups adjusting for age, sex, batch effects, and DNA methylation-based estimates of leucocyte composition. FINDINGS: We identified 430 differentially methylated positions (DMPs) between HIV+ pre-ART individuals and HIV-uninfected controls. In participants with HIV, ART initiation modified the DNA methylation levels at 845 CpG positions and restored 49.3% of the changes found between HIV+ pre-ART and HIV-uninfected individuals. We only found 15 DMPs when comparing DNA methylation profiles between HIV+ post-ART individuals and participants without HIV. The Gene Ontology enrichment analysis of DMPs associated with untreated HIV infection revealed an enrichment in biological processes regulating the immune system and antiviral responses. In participants with untreated HIV infection, DNA methylation levels at top HIV-related DMPs were associated with CD4/CD8 ratios and viral loads. Changes in DNA methylation levels after ART initiation were weakly correlated with changes in CD4+ cell counts and the CD4/CD8 ratio. INTERPRETATION: Control of HIV viraemia after 96 weeks of ART initiation partly restores the host DNA methylation changes that occurred before antiretroviral treatment of HIV infection. FUNDING: NEAT-ID Foundation and Instituto de Salud Carlos III, co-funded by European Union

J Acquir Immune Defic Syndr

BACKGROUND: The NEAT 001/ANRS 143 trial demonstrated non-inferiority of darunavir-ritonavir combined with either raltegravir (RAL+DRV/r) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC+DRV/r) in HIV-positive, antiretroviral-naive adults. In post-hoc analyses however, RAL+DRV/r showed inferiority in patients with baseline CD4+ /=100,000 copies/mL. This pre-planned ancillary study was conducted to assess whether differences in adherence might explain efficacy results SETTIN

J Infect Dis

Background. Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown. Methods. NEAT001/ANRS143 is a randomized trial that showed noninferiority over 96 weeks of ritonavir-boosted darunavir plus raltegravir versus tenofovir disoproxil fumarate/emtricitabine in 805 antiretroviral antiretrovrial-naive HIV-infected adults. We compared changes in whole-blood telomere length measured with quantitative polymerase chain reaction in 201 randomly selected participants (104 raltegravir and 97 tenofovir disoproxil fumarate/emtricitabine). We performed multivariable estimative and predictive linear regression. Results. At week 96, participants receiving tenofovir disoproxil fumarate/emtricitabine had a statistically significant higher gain in telomere length than participants receiving raltegravir. Difference in mean telomere length change between groups (tenofovir disoproxil fumarate/emtricitabine minus raltegravir) from baseline to week 96 adjusted by baseline telomere length was 0.031 (P = .009). This difference was not significantly confounded by age, gender, known duration of HIV infection, CD4 (baseline/nadir), CD8 cells, CD4/CD8 ratio, HIV viral load (baseline/week 96), tobacco and alcohol consumption, statins, or hepatitis C. Conclusion. Antiretroviral-naive HIV-infected adults receiving ritonavir-boosted darunavir and tenofovir disoproxil fumarate/emtricitabine had a significant higher gain in blood telomere length than those receiving ritonavir-boosted darunavir and raltegravir, suggesting a better initial recovery from HIV-associated immunosenescence

Changes in Bone Mineral Density (BMD) over 96 Weeks on Darunavir/Ritonavir (DRV/r) + Raltegravir (RAL) or DRV/r + Tenofovir/Emtricitabine (TDF/FTC)

NEAT 001/ANRS 143 Study Groupinfo:eu-repo/semantics/nonPublishe

HIV Med

OBJECTIVES: Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naive HIV-positive adults. METHODS: A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics. RESULTS: The baseline characteristics of the 201 participants did not differ from those of the 805 participants in the parent trial population: 89% were male, the mean age was 39 years, 83.6% were Caucasian, 93% acquired HIV infection via sexual transmission, the mean estimated time since HIV diagnosis was 2.1 years, the mean HIV-1 RNA load was 4.7 log10 HIV-1 RNA copies/mL, the mean nadir and baseline CD4 counts were 301 and 324 cells/muL, respectively, and the mean CD4:CD8 ratio was 0.4. In the univariate analysis, shorter telomere length was associated with older age (per 10 years) (P /= 100 000 copies/mL (P = 0.001), CD4 count /= 100 000 copies/mL (P = 0.054) were independently associated with shorter telomere length. CONCLUSIONS: Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.European AIDS Treatment Networ

Correlation between blood telomere length and CD4+ CD8+ T-cell subsets changes 96 weeks after initiation of antiretroviral therapy in HIV-1-positive individuals

In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations

Body composition and adipokines changes after initial treatment with darunavir-ritonavir plus either raltegravir or tenofovir disoproxil fumarate-emtricitabine: A substudy of the NEAT001/ANRS143 randomised trial

BACKGROUND: Comparison of changes in body composition, adipokines and inflammatory markers after initial therapy with a nucleos(t)ide reverse transcriptase inhibitor (N(t)RTI)- sparing or containing regimen are scarce. DESIGN: Randomised Clinical Trial. METHODS: This is the body composition substudy of NEAT 001/ANRS 143, a randomised trial comparing darunavir/ritonavir (DRV/r) plus either raltegravir (RAL) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 805 ART naïve HIV-infected adults. The primary endpoint was percentage change in limb fat at week 96. Secondary endpoints were associations among these changes and metabolic markers (IL-6, insulin, leptin, adiponectin, FGF-23). RESULTS: 126 subjects (61 DRV/r + RAL and 65 DRV/r + TDF/FTC) were included. The rate of change in BMI between groups for RAL versus TDF/FTC at week 96 was 1.5% per 48-week period (p = 0.015). The rate of change in limb fat mass, trunk fat mass, total body fat and total lean mass was for RAL versus TDF/FTC at week 96 was 2.5% (p = 0.38), 7.3% ((p = 0.021), 4.9% (p = 0.061) and 1.3% (p = 0.12) respectively. Baseline insulin and leptin levels were correlated with baseline limb fat and trunk fat mass [r = 0.31 (p = 0.0043)/r = 0.28 (p = 0.0011) for limb fat, and r = 0.63 (p<0.0001)/r = 0.50(p<0.0001) for trunk fat]. After adjustment, a 10% faster increase in leptin between baseline and week 48 was associated with a more rapid increase in limb fat at week 48 (0.5% per 48 weeks, p<0.001), total body fat mass (0.6% per 48 weeks, p<0.001), and trunk fat mass (0.3% per 48 weeks, p = 0.0026). CONCLUSIONS: After week 96 a N(t)RTI sparing regimen of DRV/r + RAL produced a numerically greater percentage increase in body composition variables with only change in trunk fat mass and BMI being significant.NEAT is a project funded to the Instituto Superiori di Sanitá-Rome, by the European Union under the Sixth Framework Programme, project number LSHP-CT-2006-037570. This analysis was also partially funded by a grant from the Ministerio de Sanidad y Asuntos Sociales de España (2009/TRA-054). The trial was also supported by Gilead Sciences, Janssen Pharmaceuticals, and Merck Laboratories, and the French National Institute for Health and Medical Research-France Recherche Nord&Sud SIDA-HIV Hépatites (Inserm-ANRS) is the sponsor and a funder of the trial

Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial

BACKGROUND: DNA methylation-based estimators of biological age are reliable biomarkers of the ageing process. We aimed to investigate a range of epigenetic ageing biomarkers in a substudy of the NEAT001/ANRS143 clinical trial, which compared ritonavir-boosted darunavir with either raltegravir or tenofovir disoproxil fumarate and emtricitabine in antiretroviral therapy (ART)-naive adults. METHODS: We analysed frozen whole blood samples from 168 ART-naive participants with HIV from the NEAT001/ANRS143 trial, before ART initiation and after 2 years of ART (84 participants on ritonavir-boosted darunavir with raltegravir and 84 participants on ritonavir-boosted darunavir with tenofovir disoproxil fumarate and emtricitabine). We also included 44 participants without HIV with a similar age and sex distribution. We analysed DNA methylation. Epigenetic age estimators (Horvath's clock, Hannum's clock, GrimAge, and PhenoAge) and estimated leucocyte compositions were generated using Horvath's New Online Methylation Age Calculator and Houseman's method. We calculated epigenetic age acceleration measures for each estimator of epigenetic age. The NEAT001/ANRS143 trial is registered with ClinicalTrials.gov, NCT01066962. FINDINGS: Compared with the HIV-uninfected group, ART-naive participants with HIV showed higher epigenetic age acceleration (EAA) according to all EAA estimators (mean 2·5 years, 95% CI 1·89-3·22 for Horvath-EAA; 1·4 years, 0·74-1·99 for Hannum-EAA; 2·8 years, 1·97-3·68 for GrimAge-EAA; and 7·3 years, 6·40-8·13 for PhenoAge-EAA), with all differences being statistically significant except for Hannum-EAA (Horvath-EAA p=0·0008; Hannum-EAA p=0·059; GrimAge-EAA p=0·0021; and PhenoAge-EAA p<0·0001). Epigenetic ageing was more pronounced in participants who had CD4 counts less than 200 cells per μL (significant for PhenoAge and Hannum's clock, p=0·0015 and p=0·034, respectively) or viral loads over 100 000 copies per mL at baseline (significant for PhenoAge, p=0·017). After 2 years of ART, epigenetic age acceleration was reduced, although PhenoAge and GrimAge remained significantly higher in participants with HIV compared with participants without HIV (mean difference 3·69 years, 95% CI 1·77-5·61; p=0·0002 and 2·2 years, 0·47-3·99; p=0·013, respectively). There were no significant differences in the ART effect on epigenetic ageing between treatment regimens. At baseline, participants with HIV showed dysregulation of DNA methylation-based estimated leucocyte subsets towards more differentiated T-cell phenotypes and proinflammatory leucocytes, which was also partly restored with ART. INTERPRETATION: ART initiation partly reversed epigenetic ageing associated with untreated HIV infection. Further studies are needed to understand the long-term dynamics and clinical relevance of epigenetic ageing biomarkers in people with HIV. FUNDING: NEAT-ID Foundation

ESMO Open

Background Whole exome sequencing and RNA sequencing (WES/RNASeq) should now be implemented in the clinical practice in order to increase access to optimal care for cancer patients. Providing results to Tumour Boards in a relevant time frame—that is, compatible with the clinical pathway—is crucial. Assessing the feasibility of this implementation in the French care system is the primary objective of the Multipli study, as one of the four pilot projects of the national France Genomic Medicine 2025 (FGM 2025) plan. The Multipli study encompasses two innovative trials which will be driven in around 2400 patients suffering from a soft-tissue sarcoma (Multisarc) or a metastatic colorectal carcinoma (Acompli). Methods Prior to launching the FGM 2025 cancer pilot study itself, the performance of the Multipli genomic workflow has been evaluated through each step, from the samples collection to the Molecular Tumour Board (MTB) report. Two Multipli-assigned INCa-labelled molecular genetics centres, the CEA-CNRGH sequencing platform and the Institut Bergonié’s Bioinformatics Platform were involved in a multicentric study. The duration of each step of the genomic workflow was monitored and bottlenecks were identified. Results Thirty barriers which could affect the quality of the samples, sequencing results and the duration of each step of the genomic pathway were identified and mastered. The global turnaround time from the sample reception to the MTB report was of 44 calendar days. Conclusion Our results demonstrate the feasibility of tumour genomic analysis by WES/RNASeq within a time frame compatible with the current cancer patient care. Lessons learnt from the Multipli WES/RNASeq Platforms Workflow Study will constitute guidelines for the forthcoming Multipli study and more broadly for the future clinical routine practice in the first two France Genomic Medicine 2025 platforms