BackgroundEven during long-term combination antiretroviral therapy (cART), people living with HIV (PLHIV) have a dysregulated immune system, characterized by persistent immune activation, accelerated immune ageing and increased risk of non-AIDS comorbidities. A multi-omics approach is applied to a large cohort of PLHIV to understand pathways underlying these dysregulations in order to identify new biomarkers and novel genetically validated therapeutic drugs targets.MethodsThe 2000HIV study is a prospective longitudinal cohort study of PLHIV on cART. In addition, untreated HIV spontaneous controllers were recruited. In-depth multi-omics characterization will be performed, including genomics, epigenomics, transcriptomics, proteomics, metabolomics and metagenomics, functional immunological assays and extensive immunophenotyping. Furthermore, the latent viral reservoir will be assessed through cell associated HIV-1 RNA and DNA, and full-length individual proviral sequencing on a subset. Clinical measurements include an ECG, carotid intima-media thickness and plaque measurement, hepatic steatosis and fibrosis measurement as well as psychological symptoms and recreational drug questionnaires. Additionally, considering the developing pandemic, COVID-19 history and vaccination was recorded. Participants return for a two-year follow-up visit. The 2000HIV study consists of a discovery and validation cohort collected at separate sites to immediately validate any finding in an independent cohort.ResultsOverall, 1895 PLHIV from four sites were included for analysis, 1559 in the discovery and 336 in the validation cohort. The study population was representative of a Western European HIV population, including 288 (15.2%) cis-women, 463 (24.4%) non-whites, and 1360 (71.8%) MSM (Men who have Sex with Men). Extreme phenotypes included 114 spontaneous controllers, 81 rapid progressors and 162 immunological non-responders. According to the Framingham score 321 (16.9%) had a cardiovascular risk of >20% in the next 10 years. COVID-19 infection was documented in 234 (12.3%) participants and 474 (25.0%) individuals had received a COVID-19 vaccine.ConclusionThe 2000HIV study established a cohort of 1895 PLHIV that employs multi-omics to discover new biological pathways and biomarkers to unravel non-AIDS comorbidities, extreme phenotypes and the latent viral reservoir that impact the health of PLHIV. The ultimate goal is to contribute to a more personalized approach to the best standard of care and a potential cure for PLHIV.

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IntroductionPeople living with HIV (PLHIV) experience higher levels of mental health issues compared to the general population. Especially depression, anxiety, impulsivity and substance use occur frequently in PLHIV. This is thought to have important consequences for quality of life, sexual risk behaviour and antiretroviral treatment (ART) adherence. Both in PLHIV as well as in the general population, divergent psychiatric symptoms often co-occur, and influence one another.ObjectivesTo assess the interrelatedness of psychiatric symptoms and their potential consequences in PLHIV.MethodsData from 1615 outpatient PLHIV using suppressive ART from the 2000HIV study (NCT03994835) were analysed. Participants reported on the severity of substance use (MATE-Q), depression and anxiety (HADS), impulsivity (BIS-11), quality of life (EQ-5D-5L), ART adherence (MASS-8) and sexual risk behaviour. For these variables, prevalence rates and mean scores were calculated. After binarizing the data, an Ising network model was constructed. Using this network, interrelations between psychiatric symptoms were assessed, the centrality of symptoms was estimated and connections with clinical consequences were explored.ResultsIn our cohort of PLHIV, the increased prevalence of substance use was most pronounced, as shown by a prevalence rate of 28.7% for smoking, 13.6% for cannabis use, 11.1% for heavy alcohol drinking and 9.2% for ecstasy use in the past month. The network analysis revealed that symptoms of depression and anxiety were most strongly interrelated. The depressive symptom “feeling slowed down” was one of the most central symptoms, and was most strongly connected with quality of life. Substance use was associated with a higher occurrence of sexually transmitted diseases, and this relationship was mediated by a higher number of sexual partners. Notably, ART adherence did not display any connections with depression, anxiety, impulsivity or substance use.Image:ConclusionsThe high occurrence of substance use and its link with sexual risk behaviour, emphasizes it’s role as a potential target for prevention of HIV transmission. Contrary to general assumption, psychiatric symptoms are not associated with lower levels of ART adherence in our cohort. Treatment of depression in PLHIV might be improved by focussing on the symptom of feeling slowed down, since this symptom was most strongly connected with quality of life.Disclosure of InterestE. Meeder Grant / Research support from: ViiV Healthcare, M. Blaauw: None Declared, L. van Eekeren: None Declared, A. Groenendijk: None Declared, W. Vos: None Declared, Q. de Mast: None Declared, W. Blok: None Declared, A. Verbon: None Declared, M. Berrevoets: None Declared, J. van Lunzen Employee of: ViiV Healthcare, L. Joosten: None Declared, M. Netea: None Declared, V. Matzaraki: None Declared, A. van der Ven: None Declared, A. Schellekens: None Declared