Here we present the changes of lipid parameters at 12 months of follow-up in a prospective cohort of HIV-infected patients switching from an EFV or PI/r-based regimen to a RPV or a once-daily INSTI-based regimen. We found that replacing PI/r gives advantages on both TC and TC/HDL ratio regardless of the switch group (to DTG, EVG or RPV) and that in case of switch to RPV these advantages extend also on TG and LDL. Also, EFV interruption has a favourable effect on all the studied parameters only if replaced by RPV. These findings suggest that, among the analysed antiretroviral switches, the most favourable lipid impact is obtained by replacing PI/r and EFV with RPV, but significant advantages can also be obtained by replacing PI/r with once-daily INSTI regimens. Other published studies found that switching to RPV-containing regimens leads to an improvement of lipid profile, with some differences among the analysed variables. The SPIRIT study, a randomized clinical trial on safety and efficacy of switching from a PI-based regimen to TDF/emtricitabine (FTC)/RPV in virologically suppressed patients, found significant improvements in TC, LDL, TG and TC/HDL ratio in the immediate switch arm compared with the delayed switch arm [
16]. In a multicentre, retrospective study, Pinetti et al. analysed efficacy and safety of treatment simplification to RPV/FTC/TDF in a real-life setting. They found that both TC and TG significantly decreased in patients switching from PI-based regimens, while only TC significantly decreased in patients switching from NNRTI [
17]. A significant decrease in TC has also been described in switches from unboosted PIs to RPV [
18]. Finally, in a recent study Gagliardini et al. described a significant TC and HDL reduction at one, two and three-year follow-up after switching from EFV/FTC/TDF to RVP/FTC/TDF, while LDL and TG improvement was observed only up to two-year follow-up and no difference was found in TC/HDL ratio over time [
19].
In our study, favourable lipids effects were also found in patients switching from boosted PI to DTG or EVG. Two clinical trials on switch from PI to DTG previously reported similar results in both patients with Framingham risk score > 10%, that experienced TC, TC/HDL, LDL and TG significant decrease [
20], and in patients with any cardiovascular risk scores, that had TC and TG significantly lower and HDL significantly higher if switched to DTG, compared to patients who continued PIs [
21]. In contrast, total cholesterol did not decrease in patients switching from any triple ART to ABC/3TC/DTG in a double-blind randomized trial [
22]. Favorable effects on lipids have also been reported in switches to EVG. In the STRATEGY-PI clinical trial patients switching from lopinavir (but not from atazanavir) to TDF/FTC/cobicistat(C)/EVG obtained significant TC decline after 96 weeks [
23] and the same was also seen in the SRTATEGY-NNRTI trial in patients switching from EFV to TDF/FTC/C/EVG, although without significant changes in TC/HDL ratio [
24]. It has been widely demonstrated that TG/HDL ratio correlates with insulin resistance [
25]. Interestingly, in our study only patients switching from PI/r to DTG or EVG (groups D and E) reached the desired outcome of higher HDL and lower TG, that is related to lower insulin resistance [
26], while in all the other groups the trend of HDL had the same direction as that of TG. This result suggests that a favorable effect on insulin resistance could be achieved with the withdrawal of the PI/r, a drug class with possible implications in insulin resistance [
27]. One of the most interesting finding of our study is that the greater effect on lipids, in switches to once-daily INSTI- or RPV-based regimens, was obtained in patients with higher baseline values of each variable (
p < .0001 for all) and in diabetic patients as compared to non diabetic ones. This result highlights the importance of ART optimization with low-metabolic impact-regimens especially in patients who have the highest need of lipid control, that are exactly the ones who achieve better outcomes. Current guidelines [
15,
28] do not provide indications for type of ART switch in case of dyslipidemia, also if dyslipidemia is mentioned as an adverse event for both EFV, and PI/r and both INSTI and RPV are considered drugs with lower impact on lipids [
15,
28]. In Italian guidelines, in the setting of high cardiovascular risk, it is suggested to substitute PI/r with NNRTIs, or with other PIs with lower metabolic impact or with raltegravir [
29,
30]. We think that the present study should suggest that, in HIV-infected patients with high cardiovascular risk and who are treated with PI/r or EFV, a switch to RPV or INSTI should be considered. However, ART switch alone is not enough to significantly change the risk of cardiovascular event in HIV-infected patients, as demonstrated by the lack of significant change of the Framingham risk score across time in our series. Although our results encourage switching ART in patients with high cholesterol or triglycerides levels, lifestyle interventions and lipid lowering agents prescription remain keystones for the prevention of cardiovascular disease, and cannot be fully substituted by a switch strategy.
Finally, a low number of virological failures is observed in this study, pointing out that a careful evaluation of patients’ characteristics, historical HIV genotype and drug-drug interactions should always have the priority before planning any therapeutic modifications.
The present study has some limitations. Despite the prospective data collection, the cohorts of patients with different antiretroviral therapies have been enrolled at different times and the study was purely observational. Thus, it is possible that the choice of ART regimen was guided by different patients’ characteristics that may have influenced the results of the analysis, and that the reasons that have guided the decision of starting each single regimen in different study groups have played a confounding role in the analysis. For the same reason, we do not have a randomized control group and cannot demonstrate the causality between ART switch and the measured outcomes. Moreover, lifestyle interventions during follow up have not been registered, and thus we cannot estimate their impact on the study outcomes.