Cardiovascular risks associated with protease inhibitors for the treatment of HIV

ABSTRACT

Introduction: Cumulative use of some first-generation protease inhibitors has been associated with higher rates of dyslipidemia and increased risk of cardiovascular disease. The protease inhibitors most commonly in use are atazanavir and darunavir, which have fewer detrimental lipid effects and greater tolerability. This paper aims to review the evidence of a potential association of these contemporary protease inhibitors with the risk of ischemic CVD and atherosclerotic markers.

Areas covered: We searched for publications of randomized trials and observational studies on PubMed from 1 January 2000 onwards, using search terms including: protease inhibitors; darunavir; atazanavir; cardiovascular disease; cardiovascular events; dyslipidemia; mortality; carotid intima media thickness; arterial elasticity; arterial stiffness and drug discontinuation. Ongoing studies registered on clinicaltrials.gov as well as conference abstracts from major HIV conferences from 2015-2020 were also searched.

Expert opinion: Atazanavir and darunavir are no longer part of first-line HIV treatment, but continue to be recommended as alternative first line, second- and third-line regimens, as part of two drug regimens, and darunavir is used as salvage therapy. Although these drugs will likely remain in use globally for several years to come, baseline CVD risk should be considered when considering their use, especially as the population with HIV ages.

KEYWORDS:

• Atazanavir
• darunavir
• hiv
• cardiovascular disease
• atherosclerotic markers
• boosters
• clinical management

Article highlights

• History and biological properties of PIs

• Association of contemporary PIs with surrogate markers for atherosclerotic CVD

• Contemporary PIs and association with clinical CVD

• PI boosters and risk of CVD

• Possible biological mechanisms for contemporary PIs and association with CVD

• Clinical approach to the use of contemporary PIs

ABBREVIATIONS

PI: Protease inhibitor; cART: combined Antiretroviral Therapy; NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; INSTI: integrase strand transfer inhibitors; PLWH: people living with HIV; CVD: cardiovascular disease; MI: myocardial infarction; ARV: antiretroviral drug; ABC: abacavir; IDV: indinavir; (f) APV: (fos)amprenavir; RTV: ritonavir; NFV: nelfinavir; SQV: saquinavir; LPV: lopinavir; RCT: randomized controlled trial; ATV: Atazanavir; ATV/b: atazanavir/boosted; ATV/r: atazanavir/ritonavir; ATV/c: atazanavir/cobicistat; DRV: darunavir; DRV/b: darunavir/boosted; DRV/r:darunavir/ritonavirDRV/c: darunavir/cobicistat; CIMT: carotid intima media thickness; EACS: European Clinical AIDS Society; LPV/r: lopinavir/ritonavir; RAL: raltegravir; DTG: dolutegravir; EFV: efavirenz; TDF: tenofovir disoproxil fumarate; FTC: emtricitabine; HDL: high density lipoprotein; LDL: low density lipoprotein; CTA: chest computer tomography angiography; CRP: C-reactive protein; IL-6: interleukin-6; TC: total cholesterol; TAF: tenofovir alafenamide; The D:A:D Study: The Data collection on adverse effects of anti-HIV drugs Study; ACC: American College of Cardiology; NNTH: number needed to harm; UPS: ubiquitin–proteasome system; ER: endoplasmic reticulum; UPR: unfolded protein response; 3TC: lamivudine

Declaration of interest

C Sabin has received funding for the preparation of educational materials and for participation in Data Safety and Monitoring Boards and Advisory Boards from Gilead Sciences, ViiV Healthcare and Janssen-Cilag. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.