Non-AIDS co-morbidities

Non-alcoholic fatty liver disease (NAFLD) is considered as a hepatic manifestation of metabolic syndrome. The main feature of NAFLD is liver steatosis, the accumulation of fat in hepatic tissue of more than 5% of the liver weight in the absence of substantial alcohol consumption. Liver steatosis may progress into more harmful entities including non-alcoholic steatohepatitis, fibrosis and cirrhosis. Prevalence of NAFLD is on a rise in the general population worldwide and it is suggested that it is even more prevalent in people living with HIV (PLHIV).

We aim to discover underlying biological pathways for liver steatosis and fibrosis and factors that drive progression of these diseases in PLHIV.

Hepatic steatosis and fibrosis are assessed with Fibroscan and B-mode ultrasound during baseline and follow-up. For liver steatosis, the controlled attenuation parameter (CAP) in dB/m was measured using Fibroscan and the residual attenuation coefficient (RAC) in dB/cm/MHz using computer-aided ultrasound (CAUS). For liver fibrosis, the liver stiffness measurements in kPa were performed with transient elastography (Fibroscan) and shear-wave elastography with conventional ultrasound.

In depth multi-omics characterization with plasma proteomics, (lipo)metabolomics, bulk transcriptomics, genomics, epigenomics and metagenomics will be performed to link these measurements with baseline liver fibrosis and steatosis and progression at follow-up. At baseline, liver steatosis, defined as a CAP > 248 dB/m, was found in 47.5% of the study population. Liver fibrosis, defined as a liver stiffness measurement of equal to or over 7 kPa, was found in 8.8% at baseline.

Psychiatric symptoms are highly prevalent in people living with HIV (PLHIV). For example, in PLHIV the prevalence rates of depression and alcohol use disorder are  both approximately two times higher as compared to the general population. The high occurrence of psychiatric symptoms in PLHIV is of major importance, since it is one of the main factors determining quality of life. In addition, psychiatric symptoms in PLHIV may cause suboptimal combination antiretroviral therapy adherence and increase transmission risk behaviour, and the frequent use of various substances in PLHIV could affect immune function.

Several mechanisms may be involved in the increased prevalence of psychiatric symptoms in PLHIV. Besides psychological mechanisms (such as social stress due to HIV-related stigma), also biological mechanisms are likely to play a role. For example, HIV infection has been shown to decrease dopamine sensitivity, which has been associated with vulnerability for addiction. Moreover, chronic HIV infection is known to involve persistent inflammation, and pro-inflammatory cytokines have been associated with the development of depression.

The 2000HIV study aims to obtain a deeper insight in biological mechanisms involved in psychiatric symptoms in PLHIV. We focus on symptoms of depression, anxiety, impulsivity and substance use, which we measure using the following self-questionnaires: the Hospital Anxiety and Depression Scale (HADS), the Barratt Impulsiveness Scale (BIS-11), and the Measurements in the Addictions for Triage and Evaluation Q (MATE-Q).

Where previous studies commonly explored a single set of psychiatric symptoms in relation to a single set of biomarkers, the 2000HIV study will use an transdiagnostic, multi-omics approach. This will allow an unbiased assessment of numerous biological pathways on a highly detailed level, and can potentially result in the discovery of new mechanisms involved in depression, anxiety, impulsivity and substance use in PLHIV.

In the end of 2019, a few months after the inclusions for the 2000HIV study started, the Netherlands was struck by COVID-19, a pandemic that disrupted normal life to an extend that had not been seen in the Netherlands for decades. The result is that most of the Dutch population had a COVID-19 infection, a small proportion developed severe or long-term illness and over 20.000 people died. To mitigate the effects of the pandemic, social distancing measures were implemented and new vaccines were introduced. The (long-term) effect of these events and the pandemic are unclear.

Between 2019 and 2021, 1895 virally suppressed, asymptomatic PLWH were included. 1514 participants enrolled after the start of the COVID-19 pandemic were separated into a discovery and validation cohort. A total of 471 persons had a COVID-19 vaccination and 242 people had a past coronavirus infection as defined by previous positive PCR or positive serology. In-depth multi-omics characterisation and functional immune assays together with registration of clinical data and psychological questionnaires with 2 years follow up was performed.

The extensive characterization of participants enrolled at all the different stages of the COVID-19 pandemic, provides an unique opportunity to describe the impact of COVID-19, social distancing and COVID-19 vaccination on functional immune capacity, systemic inflammation and to unravel the mechanisms behind these effects. This will provide not only a clear view on how the pandemic influenced our main study parameters and outcomes, but also increases understanding of its effects on the immune system to guide policies for the next pandemic to come.