Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium

Neesgaard, Bastian; Greenberg, Lauren; Miró, José M.; Grabmeier‐Pfistershammer, Katharina; Wandeler, Gilles; Smith, Colette; Wit, Stéphane De; Wit, Ferdinand W. N. M.; Pelchen–Matthews, Annegret; Mussini, Cristina; Castagna, Antonella; Pradier, Christian; Monforte, Antonella d’Arminio; Vehreschild, Jörg Janne; Sönnerborg, Anders; Anne, Alain Volny; Carr, Andrew; Bansi‐Matharu, Loveleen; Lundgren, Jens D; Garges, Harmony P.; Rogatto, Felipe; Zangerle, Robert; Günthard, Huldrych F.; Rasmussen, Line Dahlerup; Necsoi, Coca; Valk, Marc van der; Menozzi, Marianna; Muccini, Camilla; Peters, Lars; Mocroft, Amanda; Ryom, Lene

doi:10.1016/s2352-3018(22)00094-7

Cited by 72 publications

(59 citation statements)

References 26 publications

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“…Integrase inhibitors are thought to be have a more favourable cardiovascular side effect profile compared with protease inhibitors that have well-described pro-atherogenic effects [ 44 ]. However, a recent publication has shown a possible link with myocardial infarction, stroke, and cardiovascular intervention [ 45 ]. ART side effects with a co-existing subclinical cardiomyopathy remains unstudied.…”

Section: Discussionmentioning

confidence: 99%

Evolution of myocardial oedema and fibrosis in HIV infected persons after the initiation of antiretroviral therapy: a prospective cardiovascular magnetic resonance study

Robbertse

Doubell

Lombard

et al. 2022

Journal of Cardiovascular Magnetic Resonance

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Background Human immunodeficiency virus (HIV) infected persons on antiretroviral therapy (ART) have been shown to have functionally and structurally altered ventricles and may be related to cardiovascular inflammation. Mounting evidence suggests that the myocardium of HIV infected individuals may be abnormal before ART is initiated and may represent subclinical HIV-associated cardiomyopathy (HIVAC). The influence of ART on subclinical HIVAC is not known. Methods Newly diagnosed, ART naïve persons with HIV infection were enrolled along with HIV uninfected, age- and sex-matched controls. All participants underwent comprehensive cardiovascular assessment, including contrasted cardiovascular magnetic resonance (CMR) with multiparametric mapping on a 1.5T CMR system. The HIV group was started on ART (tenofovir/lamivudine/dolutegravir) and prospectively evaluated 9 months later. Cardiac tissue characterisation was compared in, and between groups using the appropriate statistical tests for the cross sectional data and the paired, prospective data respectively. Results Seventy-three ART naïve HIV infected individuals (32 ± 7 years, 45% female) and 22 healthy non-HIV subjects (33 ± 7 years, 50% female) were enrolled. Compared with non-HIV healthy subjects, the global native T1 (1008 ± 31 ms vs 1032 ± 44 ms, p = 0.02), global T2 (46 ± 2 vs 48 ± 3 ms, p = 0.006), and the prevalence of pericardial effusion (18% vs 67%, p < 0.001) were significantly higher in the HIV infected group at diagnosis. Global native T1 (1032 ± 44 to 1014 ± 34 ms, p < 0.001) and extracellular volume (ECV) (26 ± 4% to 25 ± 3%, p = 0.001) decreased significantly after 9 months on ART and were significantly associated with a decrease in the HIV viral load, decreased high sensitivity C-reactive protein, and improvement in the CD4 count (p < 0.001). Replacement fibrosis was significantly higher in the HIV infected group than controls (49% vs 10%, p = 0.02). The prevalence of late gadolinium enhancement did not change significantly over the 9-month study period (49% vs 55%, p = 0.4). Conclusion Subclinical HIVAC may already be present at the time of HIV diagnosis, as suggested by the combination of subclinical myocardial oedema and fibrosis found to be present before administration of ART. Markers of myocardial oedema on tissue characterization improved on ART in the short term, however, it is unclear if the underlying pathological mechanism is halted, or merely slowed by ART. Mid- to long term prospective studies are needed to evaluate subtle myocardial changes over time and to assess the significance of subclinical myocardial fibrosis.

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Section: Discussionmentioning

confidence: 99%

Evolution of myocardial oedema and fibrosis in HIV infected persons after the initiation of antiretroviral therapy: a prospective cardiovascular magnetic resonance study

Robbertse

Doubell

Lombard

et al. 2022

Journal of Cardiovascular Magnetic Resonance

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“…INSTIs were included based on previous RESPOND findings of an association between the INSTI class and CVD incidence independent of estimated CVD risk strata. [25] We further explored the inclusion of antiplatelet medication use as a potential confounder. An unknown category accounted for missing data for categorical variables in the regression model.…”

Section: Methodsmentioning

confidence: 99%

“…Individuals with a CVD event prior to baseline were included in the primary analysis for consistency with prior RESPOND and D:A:D analyses [24,25]. During follow-up, an incident CVD event was only counted if the type of event differed from the CVD event experienced prior to baseline (e.g.…”

Section: Methodsmentioning

confidence: 99%

“…Individuals with a CVD event prior to baseline were included in the primary analysis for consistency with prior RESPOND and D:A:D analyses. [24,25] During FU, an incident CVD event was only counted if the type of event differed from the CVD event experienced prior to baseline (e.g. a stroke followed by a MI) and was not an invasive cardiovascular procedure (ICP; coronary angioplasty/stenting, coronary bypass surgery, carotid endarterectomy) performed in relation to a MI or stroke.…”

Section: E P T E D a C C E P T E Dmentioning

confidence: 99%

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Recent abacavir use and incident cardiovascular disease in contemporary-treated people with HIV

Jaschinski

Greenberg

Neesgaard

et al. 2022

Aids

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Assessing whether the previously reported association between abacavir (ABC) and cardiovascular disease (CVD) remained amongst contemporarily treated people living with HIV (PLWH). Design: Multinational cohort collaboration.Methods: RESPOND participants were followed from latest of 01/01/2012 or cohort enrolment until the first of a CVD event (myocardial infarction [MI], stroke, invasive cardiovascular procedure [ICP]), last follow-up or 31/12/2019. Logistic regression examined odds of starting ABC by 5-year CVD or chronic kidney disease (CKD) D:A:D risk score. We assessed associations between recent ABC use (use within past six months) and risk of CVD with negative binomial regression models, adjusted for potential confounders.Results: Of 29,340 individuals, 34% recently used ABC. Compared to those at low estimated CVD and CKD risks, the odds of starting ABC were significantly higher among individuals at high CKD risk (odds ratio 1.12 [95% confidence interval, 1.04-1.21]) and significantly lower for individuals at moderate, high or very high CVD risk (0.

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“…An ongoing prospective, multicenter study including almost 30,000 people living with HIV examining INSTI exposure and the incidence of cardiovascular disease reported that after an average of six years of follow up, patients exposed to an INSTI experienced an increased cardiovascular risk within the first two years of INSTI exposure compared to those with no INSTI exposure. However, with continued follow-up, it was found that cardiovascular risk subsequently decreased to levels similar to those never exposed to an INSTI [ 137 ]. These findings merit further exploration into the possible relationship between INSTIs and cardiovascular disease, including attributable potential mechanisms responsible for this association and whether these risks vary by choice of INSTI.…”

Section: Main Textmentioning

confidence: 99%

A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection

Zhao

Crutchley

Guduru³

et al. 2022

Retrovirology

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Integrase strand transfer inhibitors (INSTIs) have improved the treatment of human immunodeficiency virus (HIV). There are currently four approved for use in treatment-naïve individuals living with HIV; these include first generation raltegravir, elvitegravir, and second generation dolutegravir and bictegravir. The most recent INSTI, cabotegravir, is approved for (1) treatment of HIV infection in adults to replace current antiretroviral therapy in individuals who maintain virologic suppression on a stable antiretroviral regimen without history of treatment failure and no known resistance to its components and (2) pre-exposure prophylaxis in individuals at risk of acquiring HIV-1 infection. Cabotegravir can be administered intramuscularly as a monthly or bi-monthly injection depending on the indication. This long-acting combination has been associated with treatment satisfaction in clinical studies and may be helpful for individuals who have difficulty taking daily oral medications. Worldwide, second generation INSTIs are preferred for treatment-naïve individuals. Advantages of these INSTIs include their high genetic barrier to resistance, limited drug-drug interactions, excellent rates of virologic suppression, and favorable tolerability. Few INSTI resistance-associated mutations have been reported in clinical trials involving dolutegravir, bictegravir and cabotegravir. Other advantages of specific INSTIs include their use in various populations such as infants and children, acute HIV infection, and individuals of childbearing potential. The most common adverse events observed in clinical studies involving INSTIs included diarrhea, nausea, insomnia, fatigue, and headache, with very low rates of treatment discontinuation versus comparator groups. The long-term clinical implications of weight gain associated with second generation INSTIs dolutegravir and bictegravir warrants further study. This review summarizes key clinical considerations of INSTIs in terms of clinical pharmacology, drug-drug interactions, resistance, and provides perspective on clinical decision-making. Additionally, we summarize major clinical trials evaluating the efficacy and safety of INSTIs in treatment-naïve patients living with HIV as well as individuals at risk of acquiring HIV infection.

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Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium

Cited by 72 publications

References 26 publications

Evolution of myocardial oedema and fibrosis in HIV infected persons after the initiation of antiretroviral therapy: a prospective cardiovascular magnetic resonance study

Evolution of myocardial oedema and fibrosis in HIV infected persons after the initiation of antiretroviral therapy: a prospective cardiovascular magnetic resonance study

Recent abacavir use and incident cardiovascular disease in contemporary-treated people with HIV

A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection

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