The risk of new heart failure associated with protease inhibitor: Systematic scoping review

Abstract

Background

Protease inhibitors (PIs) have contributed to the long-term survival of persons with human immunodeficiency virus (PHIV). While there is a concern linking protease inhibitors to an increased risk of heart failure (HF), the evidence linking protease inhibitors and heart failure has been uncertain.

Methods

Following the PRISMA Extension for Scoping Reviews, we searched MEDLINE and EMBASE for peer-reviewed articles using keywords including “protease inhibitor,” “heart failure,” and “human immunodeficiency virus” from their inception to December 21, 2022.

Results

Five articles, including three observational studies and two randomized controlled trials, were included in the review. While protease inhibitors seem to be associated with atherosclerotic cardiovascular disease through their effects on metabolic markers, there is scarce evidence suggesting a direct association between protease inhibitors and heart failure. Although one study showed a possible correlation between protease inhibitor use and lower left ventricular ejection fraction and increased heart failure admission, the results were subject to confounders, and participants had poor medication adherence.

Conclusion

Although current data are conflicting, there could be an association between PIs and HF in PHIV. Future prospective studies are warranted to evaluate the incidence of heart failure stratified on the generation of PIs and with adjustment for other metabolic risk factors.

Keywords

Protease inhibitor heart failure scoping review

Introduction

Human Immunodeficiency Virus (HIV) infection is a chronic condition that requires lifelong treatment with antiretroviral therapy (ART) since presently there is no treatment to eradicate the virus in humans. However, the development of multiple antiretroviral agents targeting various phases of the HIV life cycle has contributed to the transformation of HIV infection from an inevitably fatal disease into a manageable chronic condition. In recent decades, the long-term survival of persons with human immunodeficiency virus (PHIV) has improved due to more efficacious ART regimens with fewer adverse effects.^1,2

Protease inhibitors (PIs) are one of the most critical components of ART, which act by binding to the catalytic site of the HIV protease, thereby blocking functional proteins that are essential for viral replication.³ The Food and Drug Administration (FDA) approved the first PI, ritonavir, for clinical use in 1995, and multiple PIs have since been used for HIV.⁴ The most commonly used PIs are currently atazanavir and darunavir due to the more favorable adverse effects on lipid profiles and better tolerability.^5,6 Currently, boosted PIs, including ritonavir-boosted darunavir and atazanavir, are part of the recommended alternative combination treatments.

However, there is growing concern that PIs may increase the risk of cardiovascular disease in PHIV, whose cardiovascular risks are already elevated by the HIV infection itself.^7,8 Evidence shows that PI use has been associated with accelerated atherosclerotic cardiovascular disease. For example, previous findings from the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study group, which recruited 23,437 PHIV demonstrated that increased exposure to PIs is associated with an increased risk of myocardial infarction and dyslipidemia.⁹

Specifically for heart failure (HF), prior literature showed declining left ventricular ejection fraction (LVEF) and an increased rate of HF hospitalization in PHIV on PIs therapy.¹⁰ Additionally, PIs are shown to be linked to an increase in transforming growth factor beta-1 in animal studies, which resulted in myocardial fibrosis and decreased cardiac function.^11,12 Regardless, evidence on the association between PIs and HF has been scarce and has not been well-summarized. This review aims to evaluate the current evidence on the association between PIs and HF in PHIV.

Methods

Study design

This is a scoping review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews (PRISMA-ScR).^13,14

Search strategy

We searched MEDLINE and EMBASE for all peer-reviewed articles from inception to December 21st, 2022. No filters for study design and language were used. A manual screening for additional pertinent articles was done using the reference lists of all articles that met the eligibility criteria. The search strategy involved relevant keywords, including “protease inhibitor,” “heart failure,” and “human immunodeficiency virus.” The search was conducted by two authors (MG and YN) independently. See Appendix 1 for detailed search terms.

Eligibility criteria

The criteria for the inclusion of articles are the following:

1. Peer-reviewed articles describing the relationship between PIs and heart failure.

2. Randomized controlled trials (RCTs), case-control studies, cohort studies (prospective or retrospective), and cross-sectional studies.

3. Adult patients (age ≥18 years).

The exclusion criteria included the following:

1. Qualitative studies, review articles, commentaries, and conference abstracts

Study selection

Articles selected for full-text assessment were assessed independently by WT and YN using EndNote 20 reference management software. Articles considered eligible were then evaluated in full length with the inclusion and exclusion criteria.

Data extraction and definition

A standardized data collection form that followed the PRISMA and Cochrane Collaboration guidelines for systematic reviews was used to obtain the following information from each study: title, name of authors, year of publication, country of origin, study characteristics, target outcome, aims, study and comparative groups, key findings, and limitations.

Results

Search results and study selection

Figure 1 demonstrates a PRISMA flow diagram summarizing the identification, screening, eligibility, and inclusion and exclusion processes of the studies involved. The initial review of MEDLINE and EMBASE databases yielded 36 and 234 articles, respectively. Twenty duplicate studies were removed. Two hundred and fifty articles were screened based on their relevance and article type, and 221 articles that were either review articles, editorials, or focused on matters irrelevant to the research question were excluded from the study. Twenty-nine articles were then evaluated for full-text review for study inclusion per our eligibility criteria. Review articles or papers describing different topics were excluded. As a result, five articles were included in the review.

Figure 1.

PRISMA flowchart of the search strategy.

Description of included studies

Table 1 describes the main characteristics of the five studies from the scoping review. INITIO, an open-label RCT, compared two-agent nucleoside reverse transcriptase inhibitor (NRTI) background therapy combined with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) (efavirenz), PI (nelfinavir), or both an NNRTI and PI.¹⁵ After 3 years of follow-up, the incidence of grade 3 or 4 adverse events due to HF, shock, or pulmonary edema was similar between the three groups, though numerically more frequent in the PI group: 1.3% (4/297) in the NRTI plus NNRTI group, 0.96% (3/311) in the NRTI plus PI groups, and 0.66% (2/303) in the NRTI plus NNRTI and PI group. The incidence of non-specific cardiovascular adverse events, including MI, HF, cardiogenic shock, pulmonary edema, angina, and ischemic heart disease, was 4.0% (12/297), 2.89% (9/311), and 3.96% (12/303) in the NRTI plus NNRTI group, the NRTI plus PI groups, and the NRTI plus NNRTI and PI group, respectively. Similarly, the incidence is numerically lower in the PI group.

Table 1.

Characteristics of the Included Studies.

Author, Year, Country	Study type	Aim	Outcome	Population	Comparative groups	Study findings Related to HF	Limitations
INITIO committee 2006 International (Australia, Brazil, Canada, New Zealand, European Countries)	Randomized controlled trial	With the same NRTI backbone, to compare the benefits of EFV, NFV, or both on viral load and CD4 count	The proportion of participants at 3 years with viral load <50 copies/mL and the change in CD4 count from baseline	Those with HIV-1 infection (n = 911)	N/A	No significant difference between the strategies in time to first serious adverse event (including CV events)	Open-label Virological failure prompts start of second-line highly-active ART, which can restore CD4 count Greater proportion of participants in the EFV group substituted at least one drug
Alvi et al 2018 United States	Retrospective	To study the association between PI use and CV outcomes in PHIV with HF	CV mortality, defined as death resulting from HF, sudden cardiac death, arrhythmias, and/or acute ischemic events	PHIV hospitalized with HF who received PI-based ART (n = 145)	PHIV hospitalized with HF who received NPI-based ART (n = 249)	Patients with PI-based ART regimen were more likely to have hyperlipidemia (p < .001), diabetes mellitus (p = .012), coronary artery disease (p < .001), higher pulmonary artery pressure (p < .001), and lower LVEF (p = .003) The CV mortality rate was higher among PHIV hospitalized with HF who were taking a PI versus an NPI (p < .001) 30-days hospital readmission rate was higher for those taking PI versus NPI (p < .001)	Single-center study Retrospective Study population includes hospitalized patients (high-risk group), making it unclear if PI use is associated with difference in outcomes among those who were not hospitalized Viral suppression was noted in 62%, although ART was prescribed in 90% of the cohort Adherence could not be assessed
Ryom et al 2018 International (Australia, Europe, USA)	Prospective	To assess whether cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted duranavir was associated with increased incidence of CVD in people living with HIV To investigate the associations between ART and serious non-AIDS adverse events	Composite endpoint of CVD, including myocardial infarctions, strokes, sudden cardiac deaths, and invasive cardiovascular procedures	Those with HIV-1 infection receiving routine clinical care (n = 35,711)	N/A	Cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted darunavir was associated with significantly increased rates of CVD Cumulative use of ritonavir-boosted darunavir was independently associated with progressively increased risk of CVD events	Observational Study did not collect data on drug dosages Inadequate data for analysis with alternative PI boosting agent than ritonavir
Fukuda et al 2019 Japan	Prospective surveillance	To assess the use of fosamprenavir	The safety and effectiveness of fosamprenavir	Fosamprenavir -treated patients (n = 364)	N/A	Most common ADRs were diarrhea (10.4%), hyperlipidemia (8.5%), and hypertriglyceridemia (6.9%)	Unable to define clear causal relationship between adverse events and fosamprenavir; patients were treated with other anti-HIV drugs in addition to fosamprenavir Data collected from Japanese sites Characterizing ADRs, causal relationship, and treatment discontinuation were left to discretion of physicians
Dirajlal-fargo et al 2015 United States	Randomized, double-blind, placebo-controlled	To measure the effect of rosuvastatin on markers of CV risk, skeletal health, and immune activation in HIV disease	The changes in NT-proBNP levels from baseline to 48 and 96 weeks	Those with HIV-1 infection on stable ART for at least 3 months with cumulative ART duration of at least 6 months HIV-1 RNA <1000 copies/mL, fasting LDL-C ≤ 130 mg/dL, and triglyceride ≤500 mg/dl (n = 123)	N/A	NT-proBNP decreased significantly at 96 weeks for the rosuvastatin group (p = .04) NT-proBNP was increased in the placebo group at 96 weeks (p = .005). Higher baseline NT-proBNP was associated with lower total lean mass, higher sTNF-RII, and higher CD8⁺ activation	Lack of echocardiograms precludes observations regarding structural heart indices and relationship to NT-proBNP levels Population included heightened inflammation but normal LDL cholesterol level

Abbreviations: ADR, adverse drug reaction; AIDS, acquired immunodeficiency syndrome; ART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease; EFV, efavirenz; HF, heart failure; HIV, human immunodeficiency virus; LVEF, left ventricular ejection fraction; NFV, nelfinavir; NPI, non-protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PHIV, persons with human immunodeficiency virus; PI, protease inhibitor; sTNF-RII, tumor necrosis factor receptor II.

Alvi et al. examined 394 PHIV on ART hospitalized for decompensated HF, stratified by LVEF (<40%, 40%–49%, and >50%).¹⁰ Over a median ART treatment duration of 8.5 years with either ritonavir-boosted PI or non-PI ART, PI treatment was associated with a significantly higher incidence of hyperlipidemia (52% vs 35%), diabetes (44% vs 31%), and coronary artery disease (52% vs 33%). The PI group also had increased pulmonary artery systolic pressures (48 mmHg vs 43 mmHg), lower LVEF (44% vs 49%), an increase in 30-days HF readmissions (68% vs 34%), and a two-fold increase in the rate of cardiovascular death (35% vs 17%). The difference in CV death was maintained across all classifications of LVEF. When examining the incidence of HF across the reduced, mildly-reduced, or preserved LVEF, the effect of PI use was similar across the three subgroups. A higher readmission rate for HF remained significant regardless of the LVEF and across various PI drugs. Notably, this study was likely limited by patient adherence to ART, with subsequently limited viral clearance.

The D:A:D study by Ryom et al. was an observational multicohort of ART with a PI (either ritonavir-boosted darunavir or ritonavir-booster atazanavir) or without a PI, for a median treatment duration of 6.96 years in 35,711 PHIV.¹⁶ The incidence of cardiovascular events, defined as myocardial infarction, stroke, sudden cardiac death, or requiring invasive cardiovascular interventions such as bypass or coronary angioplasty, was significantly higher in those taking PIs compared to those not taking PIs (13.6 events per 1000 patient-years vs 4.91 events per 1000 patient-years), and was the most pronounced in patients taking ritonavir with darunavir compared to ritonavir and atazanavir. The increase in cardiovascular events persisted in the ritonavir with darunavir group even after adjustments using a multivariate analysis correcting for factors such as dyslipidemia, BMI, or CKD, however, it was not upheld in the ritonavir plus atazanavir group.

Fukuda et al. conducted a post-marketing surveillance study in Japan of fosamprenavir calcium hydrate between 2005 through 2014.¹⁷ During the study period, 364 patients received fosamprenavir. Cardiac-related adverse drug reactions, including hyperlipidemia, hypertriglyceridemia, hypertension, and angina pectoris, were noted in 8.5%, 6.9%, 1.7%, and 0.27%, respectively. The incidence of HF was not assessed due to a rarity of incidence, with the authors concluding the safety of this PI was further supported by this study.

In the SATURN-HIV trial, 147 PHIV with low-density lipoprotein-cholesterol levels less than 130 on ART, and without the diagnosis of HF were randomized in a double-blind fashion to either rosuvastatin 10 mg daily or placebo.¹⁸ N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, metabolic markers, inflammatory markers, body composition, coronary artery calcium scores, and carotid intima-media thickness were measured at 48 and 96 weeks 46% of participants were on PI therapy at the start. At 96 weeks, NT-pro-BNP levels were decreased significantly with rosuvastatin compared to placebo (-53% vs +71%), even after adjusting for demographic differences, renal function, and body composition. Results were not stratified by PI use.

Discussion

In this review, we thoroughly reviewed the available literature and evidence concerning PI use and HF. While the number of available studies was small, with different types of studies with conflicting data, it seems that there could be an association between PIs and HF. While the use of PIs has decreased significantly in recent years due to factors such as higher levels of drug interactions and pill burden, as well as the availability and improvement of integrase inhibitors in single-tablet regimens, it is important to note that there are still patients on PIs for specific medical conditions. With the development of newer generation PIs with fewer metabolic side effects, PHIV may be managed with aggressive cardiovascular risk modification, and primary prevention regardless of PI uses.

HF was previously named a severe complication associated with PHIV receiving PIs.^10,16 PIs have been shown to cause metabolic disturbances, glucose intolerance, changes in body fat distribution, and increased risk of cardiovascular disease, which are major risk factors for HF.^19–21 While cardiac remodeling with fibrotic changes was postulated to be a significant mechanism for PI-associated cardiomyopathy in PHIV on PIs, the study was animal-based, and no human studies have been conducted to reproduce the effect in PHIV.²² The other possible hypothesis is that PIs downregulate the enzyme called ZMPSTE24, which is responsible for the process of a pro-cardiomyopathic protein, prelamin A.²³ Future studies are necessary to validate the hypothesis in vivo.

Several studies demonstrated the risk of HF among PHIV on PIs.^10,24,25 However, except for the study by Alvi et al., most were conference abstracts. Also, Engstrom et al. mentioned cardiovascular risk factors, including elevated systolic blood pressure, elevated low-density lipoprotein, diabetes mellitus prevalence, and myocardial infarction incidence, but did not report other pertinent factors such as smoking, use of medications for hypertension, statins, or aspirin.²⁴ The study by Jacob et al. was based on de-identified patient data from healthcare organization networks using ICD-10 codes, thus, it may not reflect the true prevalence of HF in PHIV.²⁵ Several confounding factors concerning the risks of HF in PHIV include HIV infection itself, body weight, age, lifestyle factors including smoking, alcohol and substance use, adherence to medication regimens, and co-morbidities that may contribute to the conflicting results. Given its metabolic effects and the apparent correlation between PIs and both atherosclerotic disease and atherosclerotic risk factors, it is plausible that PIs could enhance the risk of developing ischemic cardiomyopathy via accelerated development of coronary artery disease. However, this remains conjecture. Future studies may need to comprehensively address these confounders upon research planning and data collection to estimate the true prevalence and risks of HF related to PI use in PHIV.

We acknowledge several limitations in this study. First, we excluded so-called gray articles, such as conference abstracts, due to a lack of reliability in their data, leading to selection bias. Also, we did not include manuscripts published in non-English languages. Despite the limitations, the review provides readers with the results of extensive literature mapping and the current level of evidence related to PIs and HF, which is helpful for clinicians to manage those with PHIV and decide the extent of efforts for cardiovascular risk modification and workup.

In conclusion, while current data are conflicting, PIs could be associated with an increased risk of cardiovascular diseases and HF in PHIV. At present, aggressive cardiovascular risk modification and primary prevention are recommended for PHIV regardless of PI use similar to other high cardiovascular-risk populations. Future prospective studies are warranted to evaluate the incidence of heart failure stratified on the generation of PIs and with adjustment for other metabolic risk factors.

Footnotes

Author’s contribution

MG, YN, and JK searched the literature, and assessed the quality of the studies. MG and YN drafted the paper. WT, AP, KB, and JK revised the manuscript. YN supervised the process.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Maan Gozun

Yoshito Nishimura

Data Availability Statement

The presented in this study are available on request from the corresponding author.

Appendix

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