Secondary Logo

Journal Logo

Limiting cardiovascular events associated with HIV and antiretroviral therapy

Brenner, Bluma G.a; Baril, Jean-Guyb

doi: 10.1097/QAD.0000000000001676
Editorial Comments
Free

aLady Davis Institute, Jewish General Hospital

bClinique de Médecine Urbaine du Quartier Latin, Montreal, Quebec, Canada.

Correspondence to Bluma G. Brenner, PhD, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada. E-mail: bluma.brenner@mcgill.ca

Received 5 September, 2017

Accepted 27 September, 2017

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.

Back to Top | Article Outline

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

References

1. Triant VA, Grinspoon SK. Epidemiology of ischemic heart disease in HIV. Curr Opin HIV AIDS 2017; 12:540–547.
2. Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL. Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Quebec's public health insurance database. J Acquir Immune Defic Syndr 2011; 57:245–253.
3. Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med 2013; 173:614–622.
4. Sabin CA, Reiss P, Ryom L, Phillips AN, Weber R, Law M, et al. Is there continued evidence for an association between abacavir usage and myocardial infarction risk in individuals with HIV? A cohort collaboration. BMC Med 2016; 14:61.
5. Kamara DA, Smith C, Ryom L, Reiss P, Rickenbach M, Phillips A, et al. Longitudinal analysis of the associations between antiretroviral therapy, viraemia and immunosuppression with lipid levels: the D:A:D study. Antivir Ther 2016; 21:495–506.
6. Ryom L LD, El-Sadr WM, Reiss P, Phillip A, Kirk O, Weber R, Sabin C, Mocrof A8. Association between cardiovascular disease and contemporarily used protease inhibitors. In: Conference on Retroviruses and Opportunistic Infections. Seattle; 2017 pp. 128LB
7. Mesplede T, Quashie PK, Zanichelli V, Wainberg MA. Integrase strand transfer inhibitors in the management of HIV-positive individuals. Ann Med 2014; 46:123–129.
8. Osterholzer DA, Goldman M. Dolutegravir: a next-generation integrase inhibitor for treatment of HIV infection. Clin Infect Dis 2014; 59:265–271.
9. Walmsley S, Baumgarten A, Berenguer J, Felizarta F, Florence E, Khuong-Josses MA, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr 2015; 70:515–519.
10. Molina JM, Clotet B, van Lunzen J, Lazzarin A, Cavassini M, Henry K, et al. FLAMINGO study team. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV 2015; 2:e127–e136.
11. Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, noninferiority trial. Lancet Infect Dis 2013; 13:927–935.
12. Quercia R, Roberts J, Martin-Carpenter L, Zala C. Comparative changes of lipid levels in treatment-naive, HIV-1-infected adults treated with dolutegravir vs. efavirenz, raltegravir, and ritonavir-boosted darunavir-based regimens over 48 weeks. Clin Drug Investig 2015; 35:211–219.
13. Center for Disease Control and Prevention. HIV surveillance report. Vol 27, 2015, (https://www.cdc.gov/hiv/pdf/library/reports/surveillance/cdc-hiv-surveillance-report-2015-vol-27.pdf). [Accessed 5 September 2017]
14. Wing EJ. HIV and aging. Int J Infect Dis 2016; 53:61–68.
15. Eron JJ, Young B, Cooper DA, Youle M, Dejesus E, Andrade-Villanueva J, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet 2010; 375:396–407.
16. Arribas JR, DeJesus E, van Lunzen J, Zurawski C, Doroana M, Towner W, et al. Simplification to single-tablet regimen of elvitegravir, cobicistat, emtricitabine, tenofovir DF from multitablet ritonavir-boosted protease inhibitor plus coformulated emtricitabine and tenofovir DF regimens: week 96 results of STRATEGY-PI. HIV Clin Trials 2017; 18:118–125.
17. Arribas JR, Pialoux G, Gathe J, Di Perri G, Reynes J, Tebas P, et al. Simplification to coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): k results of a randomised, open-label, phase 3b, noninferiority trial. Lancet Infect Dis 2014; 14:581–589.
Keywords:

aging; antiretroviral therapy; cardiovascular disease; HIV-1

Copyright © 2017 Wolters Kluwer Health, Inc.