For people with HIV, a successfully managed virus is no longer the primary threat. The new danger is silent, chronic, and strikes at the very core of our cardiovascular system.
When the world first encountered HIV/AIDS in the 1980s, the clinical picture was dominated by severe opportunistic infections and unusual cancers. Among these devastating manifestations was a rapidly progressive heart muscle disease known as cardiomyopathy, which frequently proved fatal. Today, thanks to effective antiretroviral therapy (ART), HIV has transformed into a chronic manageable condition. But this medical triumph has revealed an unexpected consequence: people with HIV now face nearly double the risk of developing heart failure compared to the general population, even when their viral load is well-controlled 1 .
This article explores the complex relationship between HIV and heart failure, tracing how the pathophysiology has evolved from the pre-ART era to today, examining the persistent immune dysregulation that drives cardiovascular damage, and highlighting recent breakthroughs that are reshaping clinical practice.
In the early days of the HIV epidemic, heart failure typically appeared as a rapidly evolving cardiomyopathy with pericardial involvement, often in patients with advanced immunosuppression. Studies from this era reported alarming rates of systolic dysfunction, with one prospective study finding an incidence of nearly 17% over just 18 months 1 . This form of heart disease was strongly associated with CD4 counts falling below 100 cells/mm³ and carried a dismal prognosis.
Contemporary research reveals that people with HIV (PWH) experience increased risk for both main types of heart failure:
| Era | Dominant HF Type | Key Characteristics | Primary Drivers |
|---|---|---|---|
| Pre-ART (1980s-1990s) | Systolic dysfunction (HFrEF) | Rapid progression, poor prognosis | Opportunistic infections, myocardial necrosis, severe immunosuppression |
| Early ART Era | Mixed HFrEF and HFpEF | Chronic course, improved survival | Direct HIV cardiotoxicity, initial ART side effects |
| Modern ART Era | HFpEF increasingly dominant | Insidious onset, association with aging | Chronic inflammation, immune dysregulation, comorbidities |
A striking finding from multiple studies is that the risk of heart failure remains elevated even in virologically suppressed individuals, though it attenuates somewhat compared to those with uncontrolled viremia 1 . This persistent risk suggests that while ART is lifesaving, it doesn't fully reverse the underlying processes that damage the heart.
Despite effective viral suppression with ART, people with HIV live in a state of chronic immune activation and inflammation. This phenomenon represents a fundamental shift in our understanding of HIV—from a simple viral infection to a chronic inflammatory disorder with cardiovascular consequences.
Several interconnected mechanisms drive this persistent inflammatory state:
How does this persistent immune activation translate into actual heart damage? Research has revealed multiple pathways:
| Inflammatory Pathway | Effect on Heart | Clinical Manifestation |
|---|---|---|
| Cytokine release (IL-6, TNF-α) | Impaired contractility, apoptosis of cardiomyocytes | Systolic dysfunction (HFrEF) |
| Macrophage activation | Myocardial fibrosis, remodeling | Diastolic dysfunction (HFpEF) |
| Endothelial dysfunction | Accelerated atherosclerosis, reduced coronary flow | Ischemic cardiomyopathy |
| Platelet hyperreactivity | Increased thrombotic risk | Myocardial infarction |
Despite ART, HIV persists in reservoirs, maintaining chronic immune activation.
Intestinal barrier disruption allows bacterial products to enter circulation.
Elevated inflammatory markers (IL-6, CRP) and T-cell activation.
Direct myocardial injury, fibrosis, accelerated atherosclerosis, autoimmune responses.
Development of HFrEF, HFpEF, or mixed phenotypes.
The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), presented at CROI 2025, represents a watershed moment in our understanding of cardiovascular protection for people with HIV. This international, multicenter study investigated whether statin therapy could reduce cardiovascular risk in PWH who had low to moderate traditional risk.
The trial enrolled 7,769 participants with HIV who were on antiretroviral therapy, had viral suppression, and had low to moderate atherosclerotic cardiovascular disease (ASCVD) risk scores. Participants were randomly assigned to receive either pitavastatin or placebo and followed for approximately 5 years 2 .
REPRIEVE delivered practice-changing results: pitavastatin treatment reduced the risk of major cardiovascular events by 35% in people with HIV at low to moderate risk 2 . This protective effect was greater than what would be expected from cholesterol reduction alone, suggesting that statins might provide additional benefits through anti-inflammatory mechanisms in this population.
Ancillary analyses presented at CROI 2025 provided deeper insights into the potential mechanisms. Liu and colleagues found that participants with elevated levels of inflammatory markers (IL-6) and cardiac damage markers derived particularly strong benefits from pitavastatin treatment 5 .
| Outcome Measure | Result | Clinical Significance |
|---|---|---|
| Major Cardiovascular Events | 35% risk reduction with pitavastatin | First evidence for statin benefit in low-moderate risk PWH |
| Effect by hs-cTnT levels | HR 5.5 for MACE with elevated hs-cTnT; greater statin benefit | Suggests role in mitigating myocardial injury |
| Effect by plaque type | Greater benefit in non-calcified plaque | Targets specific HIV-related atherosclerosis |
| Effect by IL-6 levels | HR 2.9 for MACE with elevated IL-6; modified by statin | Supports inflammation reduction as mechanism |
The REPRIEVE trial has already influenced clinical guidelines. In 2024, the Department of Health and Human Services updated its HIV treatment guidelines to include a recommendation for statin therapy for HIV-positive people ages 40 to 75 with low to moderate cardiovascular risk scores, specifically citing REPRIEVE findings 7 .
Understanding the complex relationship between HIV and heart failure requires sophisticated tools and methodologies. Here are some essential components of the research toolkit:
| Tool/Reagent | Function | Research Application |
|---|---|---|
| High-sensitivity troponin T (hs-cTnT) | Marker of myocardial injury | Identifies subclinical heart muscle damage in REPRIEVE subanalysis 5 |
| Interleukin-6 (IL-6) assays | Quantification of inflammatory cytokine levels | Correlated with MACE risk in PWH; modified by statin therapy 5 |
| Coronary CT angiography | Visualizes coronary artery plaque | Characterized non-calcified plaque burden in HIV patients 5 |
| Speckle tracking echocardiography | Measures myocardial deformation | Detected subclinical systolic dysfunction in asymptomatic PWH 3 |
| Cardiac magnetic resonance spectroscopy | Quantifies myocardial triglyceride content | Revealed cardiac steatosis in PWH despite viral suppression 3 |
| Soluble CD14 (sCD14) | Marker of monocyte activation and microbial translocation | Predicts mortality and CVD events in HIV infection 6 |
While REPRIEVE marks a major advance, optimal cardiovascular care for people with HIV extends beyond statin therapy. Recent studies highlight several critical aspects of management:
A concerning finding across multiple studies is the high prevalence of subclinical cardiac dysfunction in apparently healthy PWH. A meta-analysis of 2,242 well-controlled, asymptomatic HIV-positive patients found a prevalence of systolic dysfunction of 8.3% and diastolic dysfunction of 43.4% 3 .
This underscores the importance of routine cardiovascular screening and risk factor management in this population, even in the absence of symptoms.
Focus on managing opportunistic infections; limited cardiovascular interventions.
Recognition of ART-related metabolic complications; management of traditional risk factors.
Focus on chronic inflammation and immune activation; recognition of increased CVD risk.
Landmark evidence for statin therapy in PWH with low-moderate CVD risk.
Targeted anti-inflammatory therapies, novel cardioprotective agents, personalized approaches.
The journey of understanding heart failure in people with HIV has evolved dramatically—from viewing it as an AIDS-related complication to recognizing it as a chronic condition driven by persistent immune dysregulation and inflammation. This shift in understanding carries profound implications:
The focus must remain on understanding the precise mechanisms linking HIV persistence to cardiovascular damage, and developing targeted interventions to interrupt these pathways.
Comprehensive HIV care must now include proactive cardiovascular risk assessment and management, including appropriate statin therapy based on updated guidelines.
Successful viral suppression is just the beginning; attention to heart-healthy lifestyles and management of traditional risk factors remains crucial.
The silent shift in HIV-related heart disease underscores a fundamental truth of modern medicine: our success in controlling one threat often reveals new challenges, reminding us that the pursuit of health is always an evolving story.