Effects of ART Simplification on Inflammatory Markers in coRis (AIR)

Study Overview
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Brief Summary
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The effects of the number of drugs included in antiretroviral therapy (ART) regimens of inflammatory markers remains undefined. We will evaluated in participants in the Spanish AIDS Research Network, whether triple ART, dual ART or monotherapy affect differentially the dynamics of inflammatory markers.

Detailed Description
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During treated HIV infection, higher levels of the inflammatory and coagulation markers interleukin-6 (IL-6), D-dimers, and high-sensitivity C-reactive protein (hs-CRP) are associated with an increased risk of cardio-vascular disease (CVD), cancer, and all-cause mortality. While ART decreases IL-6, D-dimer and hs-CRP levels, these biomarkers remain elevated relative to the general population even when the plasma HIV RNA is suppressed. Markers of inflammation and coagulation have been widely studied in the general population, and related to higher risk of CVD, cancer, kidney function decline and all-cause mortality. These data collectively suggest that chronic inflammation and/or hyper-coagulation contribute to the pathogenesis of these serious non-AIDS events during otherwise effective ART. Given the assumed, albeit unproven, role of these pathways in causing disease, both vascular and non-vascular, there is intense interest in studying interventions that reduce inflammation and/or coagulation. Recent simplification strategies have demonstrated that once HIV RNA suppression is achieved, the extent of virological control does not appear to depend so much on the number of drugs, but on the time of HIV RNA suppression before the simplification. In fact, some simplification therapies, including dual regimens based in boosted-protease inhibitors (PI) have proved to be non-inferior to triple ART, provided that drug resistance has been excluded. More recently, dual therapies based in other combinations not based in boosted-PI have emerged as viable therapeutic strategies. While these approaches of ART simplification seems to be non-inferior to standard triple therapy in terms of short-term plasma HIV RNA suppression and CD4+ T cell count dynamics, it is unknown whether ART simplification will prove safe in the long term. Mounting evidence support that the concentration of drugs, which may be related to the number of drugs, affects the extent of virological control in the tissues in which HIV persists and replicates, generating low-level viremia and contributing to chronic inflammation. It is likely that clinical trials powered to detect differences in clinical events will not be performed. Hence, the long-term clinical efficacy of ART simplification must be assessed in cohort studies and the long-term effects on inflammatory markers that independently predict mortality must be assessed.

Official Title
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Effects of ART Simplification on Inflammatory Markers in coRis (AIR)

Conditions
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HIV

Intervention / Treatment
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* Drug: Number of drugs in the ART regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects initiating ART in CoRIS from 2004 with triple therapy. HIV RNA suppression achieved in the first 48 weeks of ART. Exclusion Criteria: ART initiation with regimens with less than three drugs Virologic failure in the first 48 weeks of ART AIDS conditions or serious non-AIDS events in the first 48 weeks of ART.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Triple ART<br>Patients who remain in triple ART during the follow-up. | Drug: Number of drugs in the ART regimen<br>* Triple therapy vs. dual therapy vs. monotherapy<br>|
| Dual ART<br>Patients switched to dual ART during the follow-up. | Drug: Number of drugs in the ART regimen<br>* Triple therapy vs. dual therapy vs. monotherapy<br>|
| Monotherapy<br>Patients switched to monotherapy during the follow-up. | Drug: Number of drugs in the ART regimen<br>* Triple therapy vs. dual therapy vs. monotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammation | Plasma IL-6 levels in plasma | From baseline through study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune activation | CD4/CD8 ratio in blood | From baseline through study completion, an average of 3 years | 
| Coagulation | D-dimers levels in plasma | From baseline through study completion, an average of 3 years | 
| Gut epithelial integrity | Intestinal fatty acid binding protein (IFABP) levels in plasma | From baseline through study completion, an average of 3 years | 
| Monocyte activation/bacterial translocation | Soluble CD14 levels in plasma | From baseline through study completion, an average of 3 years | 
| Immunological variables | Nadir CD4+ T cell count, highest CD8+ T cell count and nadir CD4/CD8 ratio. | From baseline through study completion, an average of 3 years | 
| Comorbidities | Number and type of comorbidities, including HCV coinfection. | From baseline through study completion, an average of 3 years | 
| Period | Year of ART initiation | Baseline | 
| ART history | Number of previous ART regimens | From baseline through study completion, an average of 3 years | 
| Available virological information | Number of HIV RNA determinations | From baseline through study completion, an average of 3 years | 
| ART exposure | Number and reasons of previous ART modifications | From baseline through study completion, an average of 3 years | 
| Sociodemographics | Country of origin | At baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, inflammation, antiretroviral therapy, cohort studies, mortality, non-AIDS events