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

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.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Number of drugs in the ART regimen

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 177

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28034
    • Hospital Ramón y Cajal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

HIV-infected patients

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Triple ART; Patients who remain in triple ART during the follow-up.	Drug: Number of drugs in the ART regimen; Triple therapy vs. dual therapy vs. monotherapy
Dual ART; Patients switched to dual ART during the follow-up.	Drug: Number of drugs in the ART regimen; Triple therapy vs. dual therapy vs. monotherapy
Monotherapy; Patients switched to monotherapy during the follow-up.	Drug: Number of drugs in the ART regimen; Triple therapy vs. dual therapy vs. monotherapy

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2018
• Primary Completion (Actual): March 1, 2022
• Study Completion (Actual): March 1, 2022

Study Registration Dates

• First Submitted: March 22, 2018
• First Submitted That Met QC Criteria: April 10, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): March 22, 2022
• Last Update Submitted That Met QC Criteria: March 18, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: HIV; inflammation; mortality; antiretroviral therapy; cohort studies; non-AIDS events
• Other Study ID Numbers: 133-17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes