Incidence of Dyslipidemia in People With HIV Who Are Treated With Integrase Inhibitors Versus Other Antiretroviral Agents: The RESPOND Study Group

Dathan M. Byonanebye; Mark N. Polizzotto; Josip Begovac; Katharina Grabmeier-Pfistershammer; Irene Abela; Antonella Castagna; Stéphane DeWit; Cristina Mussini; Jörg J. Vehreschild; Antonella d'A Monforte; Ferdinand W.N.M. Wit; Christian Pradier; Nikoloz Chkhartishvili; Anders Sönnerborg; Jennifer Hoy; Jens Lundgren; Bastian Neesgaard; Loveleen Bansi-matharu; Lauren Greenberg; Josep M. Llibre; Vani Vannappagari; Joel Gallant; Coca Necsoi; Piotr Cichon; Peter Reiss; Inka Aho; Tengiz Tsertsvadze; Marianna Mennozzi; Andri Rauch; Camilla Muccini; Matthew Law; Amanda Mocroft; Lene Ryom; Kathy Petoumenos

Disclosures

AIDS. 2021;35(6):869-882. 

In This Article

Abstract and Introduction

Abstract

Objective: To compare the incidence of dyslipidemia in people with HIV receiving integrase inhibitors (INSTI) versus boosted protease inhibitors (PI/b) and nonnucleoside reverse transcriptase inhibitors (NNRTI) within RESPOND consortium of prospective cohorts.

Methods: Participants were eligible if they were at least 18 years, without dyslipidemia and initiated or switched to a three-drug antiretroviral therapy (ART)-regimen consisting of either INSTI, NNRTI, or PI/b for the first time, between 1 January 2012 and 31 December 2018. Dyslipidemia was defined as random total cholesterol more than 240 mg/dl, HDL less than 35 mg/dl, triglyceride more than 200 mg/dl, or initiation of lipid-lowering therapy. Poisson regression was used to determine the adjusted incidence rate ratios. Follow-up was censored after 3 years or upon ART-regimen discontinuation or last lipid measurement or 31 December 2019, whichever occurred first.

Results: Overall, 4577 people with HIV were eligible (INSTI = 66.9%, PI/b = 12.5%, and NNRTI = 20.6%), 1938 (42.3%) of whom were ART-naive. During 1.7 (interquartile range, 0.6–3.0) median years of follow-up, 1460 participants developed dyslipidemia [incidence rate: 191.6 per 1000 person-years, 95% confidence interval (CI) 182.0–201.7]. Participants taking INSTI had a lower incidence of dyslipidemia compared with those on PI/b (adjusted incidence rate ratio 0.71; CI 0.59–0.85), but higher rate compared with those on NNRTI (1.35; CI 1.15–1.58). Compared with dolutegravir, the incidence of dyslipidemia was higher with elvitegravir/cobicistat (1.20; CI 1.00–1.43) and raltegravir (1.24; CI 1.02–1.51), but lower with rilpivirine (0.77; CI 0.63–0.94).

Conclusion: In this large consortium of heterogeneous cohorts, dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine.

Introduction

Following the expanded access to antiretroviral therapy (ART), cardiovascular diseases (CVDs) have emerged as the leading cause of death in people with HIV (PLWH) in developed countries.[1,2] Dyslipidemia is the most prevalent CVD risk factor in PLWH[3,4] and is responsible for approximately 50% of the overall CVD risk.[5,6] Although HIV seroconversion is followed by a reduction in total cholesterol (TC) and LDL cholesterol levels, it is associated with hypertriglyceridemia and a reduction in HDL cholesterol (HDL) levels.[7,8]

Initiation of ART reverses the reductions in cholesterol[7,8] and is sometimes associated with elevations in the levels of triglycerides (TRIGs), TC, LDL, and HDL.[7,9,10] These abnormalities are individually associated with a higher CVD risk.[4,11] In the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort, the risk of myocardial infarction (MI) increased by 26% for every 1 mmol/l increase in TC and reduced by 28% for every 1 mmol/l decrease in HDL.[12] The mechanisms potentially implicated in the development of dyslipidemia in PLWH include HIV-mediated chronic inflammation, immune activation,[13,14] and ART-induced dyslipidemia.[15–17]

Studies following the introduction of combination ART suggested that older nonnucleoside reverse transcriptase inhibitors (NNRTI) and boosted protease inhibitors (PI/b) were associated with a higher risk of dyslipidemia than contemporary antiretrovirals in the same classes.[18–20] The last decade has seen the introduction of new antiretroviral classes, including integrase inhibitors (INSTI). Data from clinical trials suggest that INSTI may have a better lipid safety profile than other antiretroviral agents.[21–23] In vitro, INSTI prevent endoplasmic reticulum stress,[25] a key pathway for ART-induced dyslipidemia.[16] However, INSTI induce oxidative stress and insulin resistance[24] and are generally associated with significant weight gain in some PLWH.[25–27]

Although the clinical impact of INSTI-induced metabolic changes is unclear, they may be associated with an increase in CVD risk factors, including dyslipidemia.[21,28] Despite the increasing use, there are limited data from large cohorts on the lipid safety of INSTI versus other ART regimens. Therefore, we sought to compare the incidence of dyslipidemia in PLWH treated with INSTI versus other contemporary ART regimens within the International Cohort Consortium of Infectious Disease (RESPOND).

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