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

Discussion

In this large consortium of heterogeneous HIV cohorts, the incidence of dyslipidemia in PLWH treated with INSTI was lower than that in those taking PI/b but higher than those treated with NNRTI. The results were consistent across secondary and sensitivity analyses, including in ART-naive and ART-experienced PLWH. Compared with DTG, dyslipidemia rates were higher with EGV/c and RAL but lower with RPV.

The relative safety of INSTI compared with PI/b has also been reported in other studies.[10,23,33] However, most studies were either conducted before the introduction of the newer INSTI or were focused on DTG alone. The relative safety of INSTI may be attributable to the prevention of endoplasmic reticulum stress, a key pathway for protease inhibitors-induced dyslipidemia.[34] The higher risk of dyslipidemia in PLWH taking INSTI versus NNRTI may be due to a greater increase in HDL associated with NNRTI.[10,18,35] The greater increase in HDL associated with NNRTI may reduce the overall CVD risk.[10,12,36] In addition, RPV, the most used NNRTI in this study, is associated with a better lipid profile compared with EGV/c and DTG[37] and older-class NNRTI.[20,38] In the present analysis, dyslipidemia was less common in participants taking RPV than in those taking DTG. Only one in three PLWH taking NNRTI received EFV, the most dyslipidemic NNRTI.[39] Therefore, the lower incidence of dyslipidemia in participants taking NNRTI may be attributed to RPV.

Participants taking EVG/c or RAL had slightly higher rates of dyslipidemia than those taking DTG. While the mechanisms underlying EVG/c-induced dyslipidemia are unclear, in vitro studies have suggested that elvitegravir impairs adipocyte function and increases proinflammatory cytokines similar to EFV.[40] These mechanisms may also explain dyslipidemia in vivo. Indeed, several studies have reported a higher risk of dyslipidemia in PLWH who receive EVG/c-based ART.[28,41] Although clinical trials have not found a significantly higher risk of abnormal lipids in PLWH treated with RAL versus DTG,[21,42] experimental studies suggest that RAL may cause elevations in LDL.[43] Further research is needed to understand the relative lipid safety of RAL versus DTG. In the present analysis, TAF was associated with a higher incidence of hypercholesteremia and hypertriglyceridemia, consistent with results from other cohorts.[28,44–48] Therefore, TAF may be used with caution in combination with potentially dyslipidemic antiretroviral drugs or in individuals with dyslipidemia. However, a lower rate of low HDL may mitigate the overall CVD risk due to TAF.

The traditionally known risk factors for dyslipidemia – diabetes mellitus, high BMI, and older age – as well as low CD4+ cell count (<350 cells/μl), were also associated with a higher incidence of dyslipidemia. PLWH with these risk factors should be monitored and counseled on lifestyle changes. Being female and black ethnicity were associated with a lower risk of dyslipidemia, consistent with results from other studies.[49,50] Compared with ART-naive individuals, ART-experienced PLWH had a lower risk of dyslipidemia. This may be due to a higher prevalence of dyslipidemia and exclusion from the analysis of ART-experienced participants. In addition, ART-induced lipid changes may represent a reversal of the HIV-induced lipid changes which is then followed by a decline in lipid levels.[51]

Our analysis is not without limitations. First, we cannot rule out unmeasured confounding as the analysis involved observational cohorts. Second, there was a change in the guidelines on dyslipidemia during the study period, the uptake of which may have differed between cohorts. This may explain the differences in the lipid testing frequency. However, the analyses adjusted for the cohort period. Third, there was limited data on the fasting status of lipid test samples. Nevertheless, nonfasting lipids are comparable and equally predictive of adverse cardiovascular events like fasting lipids[52–56] and are acceptable for dyslipidemia monitoring and diagnosis.[57,58] Fourth, this analysis mainly focuses on ART class comparisons with a few drug comparisons. In addition, the analysis lacks data on bictegravir, an increasingly used INSTI. Despite these limitations, this study has several strengths. We used data from heterogeneous cohorts; all participants were receiving routine HIV care. In addition, the participants were relatively old and represent a population with considerable CVD risk.

The results of this study may have several implications for HIV treatment and policy. First, INSTI were associated with a lower incidence of dyslipidemia, despite prior reports of excessive weight gain, especially in women and black people.[25–27,59,60] The present analysis reassures that INSTI may be used safely, including in sub-Saharan African countries, where ART options are limited and the prevalence of dyslipidemia is high.[61] Second, in well resourced countries, these data can inform the choice between multiple agents that have comparable virologic efficacy. This is particularly important in PLWH with existing CVD risk factors. The progressive improvement in the life expectancy of PLWH globally following the successful expansion of ART means that the majority of PLWH will have CVD risk factors while taking ART.[62] The lower incidence of dyslipidemia in PLWH taking RPV compared with DTG means that it could be considered as an ART option in PLWH with suppressed HIV RNA and high cardiovascular risk. However, RPV may also be used with caution as it has been associated with excessive weight gain compared with other NNRTI.[63] Taken together with recent studies reporting fewer cardiovascular events in PLWH treated with INSTI,[64] the present analysis suggests that INSTI could remain the antiretroviral anchor agent of choice in PLWH with high CVD risk.

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