HIV and statins: REPRIEVE studies at CROI 2024
6 June 2024. Related: Conference reports, Lipodystrophy and metabolic complications, CROI 2024 Denver.
Kirk Taylor, HIV i-Base
CROI 2024 included three oral and three poster abstracts providing updates on REPRIEVE, a large randomised global study of cardiovascular disease (CVD) risk factors for people living with HIV. [1-4]
The major study findings were reported at CROI last year and published in the New England Journal of medicine in July 2023. [5] Participants (n=7,769) were female (31%), Black (48%), Asian (15%) and median age was 50 years (IQR: 45 to 55 years). Importantly, entry criteria included CVD risk scores that were low to moderate and that wouldn’t meet guidelines for statin use. Participants were randomised 1:1 to pitavastatin (4 mg QD) or placebo.
The main results included that statin use reduced the primary endpoint of major adverse cardiovascular events (MACE) by 35% (HR 0.65; 95% CI 0.48 to 0.90).
The results also led to BHIVA publishing guidance last year on statin use for people living with HIV in the UK, which were updated after CROI this year. [6]
A useful webcast from NATAP following CROI 2024 highlighted the benefits of statin therapy for people living with HIV with CVD risk ≥5%. [7]
Sex differences and CVD risk in REPRIEVE
HIV is associated with higher CVD risk and the underlying mechanisms are influenced by biological sex. [1] Adjusted data from people living with HIV in the US partners healthcare database study show that women have double the MI risk reported for men (2.98, 95% CI: 2.33 to 3.75 vs 1.40, 95% CI: 1.16 to 1.67). Similar sex differences in stroke risk were reported in 2014.
Statins are recommended for CVD prevention in people with LDL ≥190 mg/dL, family history of CVD, and people with diabetes with LDL ≥70 mg/dL. Other guidance is based upon 10-year CVD risk scores using pooled cohort equations. These scores consider age, sex, ethnicity, blood pressure, lipid levels, hypertension and smoking status. They do not consider HIV-related factors, immune activation or inflammatory markers. Sex significantly influences the risk score with example parameters yielding a 5.1% risk for men, but only 2.2% for women.
In REPRIEVE, baseline median (IQR) CVD risk scores were 1.9% (0.8% to 4.3%) for women and 5.4% (3.3% to 7.8%) for men. In the placebo group, CVD risk ≥2.5% was associated with increased MACE rates. Women living with HIV were not protected against MACE after adjusting for demographic, metabolic and HIV-associated risk factors. CVD risk predictions also underestimated risk for women living with HIV in higher income regions by 2.56-fold.
Statin therapy reduced MACE by 35% in the global cohort. However, the benefit was less clear for women (HR 0.64, 95% CI 0.38 to 1.08) compared to men (HR 0.66, 95% CI 0.48 to 0.90).
Mechanisms for sex differences in CVD risk
The REPRIEVE CT substudy (n=755) explored sex differences in immune activation and inflammatory markers. Women had greater levels of sCD14, IL-6, hs-CRP and D-dimer but had reduced Lp-PLA2 levels and less coronary plaque. [1]
Relationships were observed between CVD risk scores and baseline menopause status, immune activation and inflammation. Menopause was linked to elevation of sCD14 and increased waist circumference. Coronary artery plaque or small vessel dysfunction might therefore underpin increased CVD risk for women living with HIV.
Consideration should be given to use of CVD risk scores for women living with HIV to manage MACE. Statin therapy should be considered to modify risk factors. CVD risk scores should be calibrated for people living with HIV to inform risk prevention strategies that serve key populations (e.g. women).
Physical function decline, risk factors and inflammatory biomarkers
An oral presentation discussed the impact of statin use on physical function decline in the PREPARE substudy. [2] Participants (n=602) were female (20%), Black (40%), Hispanic (18%) and median age was 51 years. Physical function was assessed across 5 years through a battery of tests (chair rise time, gait speed, balance and grip strength). Although statins did not slow the decline in physical function, this finding might be confounded by cohort demographics with 8% participants aged ≥60 years.
A poster at CROI 2024 included the baseline factors contributing to MACE in the REPRIEVE cohort. [3] REPRIEVE participants had baseline CD4 counts of 621 cells/mm3, low incidence of diabetes (<1%), and baseline LDL was 108 mg/dL.
Similarly to HIV negative people, adjusted models confirm increased MACE risk for people living with HIV aged >50 (HR: 1.98, 95% CI: 1.48 to 2.34), Black people (HR: 1.75, 95% CI: 1.27 to 2.41), current or former smokers (HR: 1.66, 95% CI: 1.26 to 2.19) and people diagnosed with hypertension (HR: 1.68, 95% CI: 1.30 to 2.18). HIV-associated factors for increased MACE risk included detectable viral load (HR: 1.46, 95% CI: 1.04 to 2.04), but not CD4 nadir.
Data from the mechanistic REPRIEVE substudy evaluating inflammatory biomarkers and changes in atherosclerotic plaque was also included as a poster. [4]
Participants (n=563), were female (16%) Black (35%) and mean age was 51 years. Baseline CVD risk was 4.5% and 48% had atherosclerotic plaque. While use of pitavastatin reduced levels of oxLDL and PLA2, these changes were not associated with altered plaque volume.
CVD and ageing for people living with HIV
Following CROI this year, NATAP hosted a webcast delivered by Professor Hsue on the current landscape for CVD and ageing for people living with HIV. [7]
Guidelines indicate that people with diabetes or a CVD risk score ≥7.5% should be on a moderate intensity statin. There is limited data on statin use for people living with HIV but lowering LDL is likely to reduce CVD risk.
There is mixed guidance for statin use for people living with HIV. REPRIEVE data indicate that statins are likely to benefit people living with HIV that have CVD risk ≥5%. However, European Society of Cardiology guidelines state that people living with HIV should aim for an LDL target <70 mg/dL.
BHIVA guidelines broadly recommend statin use for anyone living with HIV who is older than 40 years old, irrespective of their lipid profile or CVD risk, as calculators underestimate the impact of HIV. They also stress that managing CVD risk should be part of a holistic approach that includes lifestyle modifications.
In the USA, new guidance was published in February 2024 from the DHHS, HIVMA, ACC and AHA. For people living with HIV, moderate intensity statins are recommended for people aged 40 to 75 years with diabetes or CVD risk ≥20%. High intensity statins are recommended for people aged 20 to 75 years with LDL ≥190 mg/dL.
EACS published European guidance in June 2024 that still recommend assessing risk using the SCORE2 calculator for people aged 40 to 69 and SCORE2-OP for those older than 70. Statins are strongly recommended when CVD risk is >5% and considered based on individual risks and benefits when the risk is <5%. [8]
In practice, uptake of statins by people living with HIV remains a challenge with only 44% uptake in a study from San Francisco. Wider use of statins under the new guidelines could reduce coronary plaque and CVD risk for people living with HIV.
Pitavastatin is a moderate intensity statin that lowers LDL by 30 to 49% but which, until the recent patent expiry, was expensive compared to high intensity statins. Generic versions should now be much cheaper. Use of high intensity statins (e.g. atorvastatin) by people living with HIV is also an effective lower cost alternative with fewer concerns about drug interactions.
COMMENT
The BHIVA ‘Best of CROI’ virtual feedback session included a detailed overview of co-morbidity studies by Dr Caroline Sabin. [9]
The REPRIEVE proteomics substudy reported that pitavastatin led to a significant reduction in non-calcified plaque volume. The INTREPID study gave similar findings for pitavastatin and pravastatin, suggesting this could be a general benefit of statin therapy. Dr Sabin emphasised that whilst therapeutic interventions can manage CVD risk, modifiable risk factors remain supremely effective, and diet and exercise should be considered a first line of defence.
The BHIVA guidelines on statin use for primary prevention of CVD were updated following CROI. [7]
Updated guidance does not recommend imaging as part of CVD risk assessment. However, this could be considered for people who have already undergone imaging. Additional guidance for people with diabetes is also included.
References
Unless stated otherwise, all references are to the programme and abstracts of the Conference on Retroviruses and Opportunistic Infections, 3 – 6 March 2024, Denver, Colorado, USA.
www.croiconference.org/search-abstracts
- Zanni MV et al. Sex differences in atherosclerotic CVD risks and mechanisms: insights from REPRIEVE. Oral abstract 45.
https://www.croiconference.org/abstract/sex-differences-in-atherosclerotic-cvd-risks-and-mechanisms-insights-from-reprieve/ (abstract)
https://www.croiwebcasts.org/p/2024croi/croi/45 - Erlandson K et al. Pitavastatin has no effect on long-term, objective physical function in REPRIEVE. Oral abstract 152.
https://www.croiconference.org/abstract/pitavastatin-has-no-effect-on-long-term-objective-physical-function-in-reprieve/
https://www.croiwebcasts.org/p/2024croi/croi/152 (webcast) - Zanni MV et al. Factors contributing to risk of major adverse cardiovascular events among people with HIV in REPRIEVE. Poster abstract 781.
https://www.croiconference.org/abstract/factors-affecting-risk-of-major-adverse-cardiovascular-events-among-people-with-hiv-in-reprieve/ (abstract) - Grinspoon SK et al. Relating pitavastatin effects on inflammatory biomarkers to plaque changes in REPRIEVE. Poster abstract 773.
https://www.croiconference.org/abstract/relating-pitavastatin-effects-on-inflammatory-biomarkers-to-plaque-changes-in-reprieve/ (abstract) - Grinspoon SK et al. Pitavastatin to prevent cardiovascular disease in HIV infection. New England Journal of Medicine, DOI: 10.1056/NEJMoa2304146. (23 July 2023)
- BHIVA. BHIVA rapid guidance on the use of statins for primary prevention of cardiovascular disease in people living with HIV. (2023, updated 2024)
https://www.bhiva.org/file/655cdf1d7dcb1/BHIVA-rapid-guidance-on-the-use-of-statins.pdf (pdf)
- Hsue P. NATAP: Aging and Heart disease in HIV: where are we in 2024? (10 May 2024)
https://event.webcasts.com/viewer/event.jsp?ei=1652048&tp_key=d4c5ffd603
- EACS. Interim guidance on the use of statin therapy for the primary prevention of cardiovascular disease in people with HIV. June 2024.
https://www.eacsociety.org/guidelines/interim-guidance/ (webpage)
https://www.eacsociety.org/media/eacs_interim_guidance_on_statin_use_for_primary_prevention_cvd_in_people_with_hiv_2.pdf (PDF document) - BHIVA. BHIVA ‘Best of CROI 2024’ webinar. Comorbidities and ageing section. Sabin C et al. 25 and 27 March 2024.