Limiting cardiovascular events associated with HIV and antiretroviral therapy

The success of antiretroviral therapy (ART) has enabled people living with HIV to enjoy longer life expectancy as well as an improved quality of life. There does, however, remain a growing concern of the potential clinical impact of the cumulative use of ART on cardiovascular disease (CVD) and long-term population health. A number of studies have documented an association between HIV infection, ART, and CVD [1]. There is a 1.5 to two-fold increase in the risk of myocardial infarction (MI) associated with HIV that persists in individuals who are virally suppressed on ART [2,3]. The Data Collection on Adverse Events of Anti-HIV drugs have documented an increased risk of MI associated with the cumulative use of protease inhibitors and abacavir exposure [4,5]. In a heterogeneous cohort of HIV-positive persons, the Data Collection on Adverse Events of Anti-HIV drug study showed that the cumulative use of darunavir, but not atazanavir, was independently associated with gradually increasing CVD risk following 7 years [6]. Dolutegravir, an unboosted integrase strand transfer inhibitor, is a preferred drug option in first-line drug regimens based on its improved efficacy, tolerability, dosing, and high genetic barrier to resistance [7,8]. In clinical trials, regimens containing dolutegravir showed superiority to efavirenz at 144 weeks (SINGLE) or ritonavir-boosted darunavir (FLAMINGO), as well as noninferiority to raltegravir (SPRING-2) [9–11]. Moreover, dolutegravir demonstrated more improved lipid profiles than that observed with efavirenz or boosted darunavir, regardless of the choice of two-drug nucleoside analogue regimen backbones [12]. Dolutegravir may be a treatment option of choice for an aging population with risk factors for CVD. The STRIIVING trial found switching to dolutegravir/abacavir/lamivudine noninferior to maintaining a stable suppressive regimen [2]. Against this background, the current issue of AIDS presents the important findings from the NEAT022 randomized clinical trial designed to assess the clinical impact of switching from a protease inhibitor to a dolutegravir regimen in a HIV-infected population at high risk for CVD. Selection criteria included participants who were 50 years of age or older or participants with Framington scores of greater than 10%, defined as having a more than 10% likelihood for MI, angina, or a serious coronary event in the next 10 years. As in other recent switch trials, any patients with prior virologic failures or documented resistance mutations were excluded from the study. The trial followed 415 participants who were virally suppressed on a protease inhibitor-based regimen for at least 6 months (median 5 years) and were randomized to either maintain their current protease inhibitor regimen or replace their protease inhibitor component for dolutegravir retaining their two-drug nucleoside backbone. After 48 weeks, 93.1% of the persons in the dolutegravir group and 95.2% in the protease inhibitor group remained virally suppressed, establishing noninferiority of switching to dolutegravir. At 48 weeks, there were significant improvements in lipid profiles in the dolutegravir arm of the study. There were significant reductions from baseline in total cholesterol, (−8.7%) non-high-density lipoprotein (HDL) cholesterol (−11.3%), low-density lipoprotein cholesterol (−7.7%), and triglyceride (−18.4%) in the dolutegravir group as compared to slight elevations from baseline in the protease inhibitor group. Overall, the total cholesterol-to-HDL ratio fell by 7% in the dolutegravir and rose by 0.4% in the protease group. Serious adverse effects in both arms did not significantly differ. This is the first switch trial targeting a population with moderate to high cardiovascular risk. With longer life expectancy, patients over 50 years of age represent a growing share of the HIV population. In United States, 12% of the new HIV diagnosis were aged 50–59, and 5% were aged 60 and over in 2015 [13]. In many countries, including the United States, the median age in the HIV population is now over 50 [14]. Age being an important component of the Framingham score, the proportion of people leaving with HIV categorized with higher cardiovascular risk will increase. The study demonstrated that switching to dolutegravir was able to maintain viral suppression and improve lipid profiles in patients with no prior virologic failure and no resistance mutations. It remains to be demonstrated if a strategy of switching from a boosted PI regimen to dolutegravir could be done safely in those with proven or suspected resistance mutations. In earlier SWITCHMRK phase 3 trials, which included patients with prior resistance or suboptimal HIV therapy exposure, switching from lopinavir-ritonavir to raltegravir-based regimen was also associated with favorable reductions in serum lipid concentrations. Trials were however, terminated at week 24 when efficacy results failed to establish noninferiority of raltegravir to lopinavir-ritonavir [15]. Genotypic analysis revealed acquisition of raltegravir-associated resistance mutations affected treatment outcome [15]. The STRATEGY-PI study, which included patients with no known resistance to study treatments, demonstrated switching to a coformulated elvitegravir–cobicistat–tenofovir–emtricitabine regimen was superior to continuation on ritonavir-boosted protease inhibitor-containing regimens with no emergent resistance mutations at week 96 [16]. Although fasting triglycerides was reported to decline in the elvitegravir group at week 48, there were no significant changes in other lipid parameters [17]. The findings of the NEAT-022 trial highlight the potential benefit of switching from a protease inhibitor-based regimen to a dolutegravir-based regimen for patients at high risk for CVD gives significantly improved lipid profiles. With the prolonged survival of HIV-infected persons, it may be beneficial to cautiously tailor antiretroviral therapies, promote healthier lifestyles and, if necessary, add lipid-lowering agents, such as statins to avert the risk of CVD. Acknowledgements Conflicts of interest There are no conflicts of interest.

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