It’s clear that lipid-lowering statins can benefit people in the general population with a higher risk of heart attack or stroke, but uncertainty remains regarding precisely how much statins help prevent cardiovascular disease (CVD) in people living with HIV (PLWH), at least among those with only a slightly elevated risk of CVD. Two recent studies out of Europe aimed to give data on which patients with HIV benefit most from lipid-lowering medications, but they both ultimately concluded that better CVD risk-assessment tools—targeted specifically for PLWH—are needed.
One of the studies, a retrospective analysis of cardiovascular risk conducted by Polish researchers and published in PLOS ONE, sought to determine the effectiveness of lipid-lowering treatments for people living with HIV at various risk levels, using three European guidelines for preventing CVD through cholesterol management. Researchers looked at the risk for 389 PLWH—most of them men, with a mean age of just under 42 years—using several risk-score tools: the Anti-HIV drug score (D:A:D), SCORE (Systematic Coronary Risk Evaluation), and the Framingham CVD scale. SCORE and Framingham are typically used to assess CVD risk in the general population, while the D:A:D model has been proposed to identify risks specifically for PLWH.
Participants were divided into categories based on risk, determined by SCORE, Framingham, and D:A:D guidelines. Researchers concluded that SCORE and Framingham, which are primarily used for the general population, significantly underestimated the CVD risk for people with HIV. Meanwhile, the D:A:D scale, which calculates the five-year risk of CVD specifically for PLWH, was impractical and difficult to use. “To calculate the five-year risk of developing cardiovascular disease, cumulative NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors) and PIs (protease inhibitors) exposure is required,” the team wrote. “This requirement unfortunately makes the D:A:D scale almost useless in everyday outpatient clinical practice, because tools used in screening should be easy to apply.”
The authors reached a surprising conclusion: that the effectiveness of lipid-lowering therapy for all people with HIV in the study was “unsatisfactory” from the standpoint of all three European guidelines, although the findings “may be related to the use of statins at low doses and rarely combining statin with ezetimibe.”
The biggest takeaway, however, was the lack of a unified, practical, and simple CVD risk-assessment tool for PLWH. The D:A:D scale, developed specifically for PLWH, was particularly disappointing, given that it “requires 13 variables and could not be used in 79.7% of our HIV patients due to insufficient data,” the study authors wrote.
A second retrospective analysis, this one conducted by German researchers and published in the European Heart Journal, also showed inconsistencies in cardiovascular guidelines for predicting CVD in PLWH.
Patients were enrolled between January 2018 and December 2019; 61% of participants in this analysis were women, while the median age was just under 48 years. Median time since HIV diagnosis was almost 10 years, and participants had been on ART for a median time of nearly six years.
Much like in the Polish study, when identifying their cohort for CVD risk, the researchers saw a great disparity of statin indication across these three methods, ranging between 35% and 92%. They concluded that standard CVD risk scales for the general population (Framingham and SCORE) miss many PLWH with a high risk of CVD, and said that D:A:D—even while difficult to use, just as the Polish study acknowledged—might nonetheless provide more accurate guidance regarding statin intervention for PLWH.
The two European studies add to a growing body of research concluding that CVD risk-prediction tools for the general public are probably inadequate for PLWH.
How Best to Integrate CVD Prevention Into HIV Care? Answers Remain Elusive
These two recent studies point to a conundrum for health care practitioners who seek to better integrate CVD prevention into HIV care.
A body of research shows that PLWH face twice the risk of CVD that HIV-negative people do. The fact that HIV is an independent risk enhancer for cardiovascular disease has been acknowledged in the 2018 American College of Cardiology/American Heart Association/Multisociety cholesterol management guidelines.
While it’s known that CVD risk—including higher rates of myocardial infarction, heart failure, stroke, pulmonary hypertension, and sudden cardiac death—is higher for people with HIV even when viral load is well controlled, there remain many questions about why this is so. Research so far suggests that there is not one single factor that explains the higher rates of heart disease in people with HIV.
Traditional risk factors like smoking, diabetes, hypertension, and family history are important, but experts also point to the independent impact of inflammation related to chronic infection (i.e., HIV persistence). The length of time a person has had HIV and exposure to earlier antiretrovirals could be factors as well: Older antiretrovirals, including protease inhibitors and NRTIs, have been linked to increased fat gain, which is one risk factor for CVD.
Given this uncertainty, how can a health care practitioner effectively reduce the risk of CVD in otherwise healthy patients with HIV? For example, would it be wise to recommend cholesterol-lowering statins for a healthy 35-year-old with HIV, but with no other health issues? The answers are not clear.
“Managing HIV is relatively straightforward,” said E. Turner Overton, M.D., an associate professor of medicine at the University of Alabama-Birmingham and medical director of the University of Alabama HIV Clinic. “What changes are the comorbidities, and the fact that their prevalence is above what you’d expect for someone of the same age without HIV, and that we don’t know why. When you have a disease with many factors, it’s hard to decide on targeted therapies.”
Emma Kaplan-Lewis, M.D., an assistant clinical professor of medicine and infectious diseases at the Icahn School of Medicine at Mount Sinai, said that health care practitioners and their patients need a shared decision-making process, especially for those who are not at high risk of CVD.
“For people living with HIV who already have CVD, you treat them like the rest of the population, using platelet therapies, statins, etc. What’s tricky is the low- to medium-risk person with slightly high cholesterol and no comorbidities. You include HIV as a risk factor, and it could be a tipping point for someone already at risk. But, especially with an aging population, you risk a high medication burden.”
Kaplan-Lewis added that there have been no definitive studies showing what works best for lowering CVD risk in PLWH. Not yet, anyway.
REPRIEVE May Finally Better Illuminate CVD Risks for People Living With HIV
One large, multi-year study should provide clarity on the HIV-CVD relationship. REPRIEVE, which stands for Randomized Trial to Prevent Vascular Events in HIV, enrolled a massive and diverse cohort of 7,770 to provide essential clinical-trial data on the HIV-CVD connection, which could help in determining targeted therapies to prevent CVD.
Overton, who is one of the leaders of the study, said that this randomized trial will, among other goals, provide information on whether statins should be used for PLWH with a slight risk of CVD.
“We will gather a lot of data on other things, including kidney and liver functions, malignancies, and opportunistic infections, and better understand the risk factors and how they overlap [with HIV and CVD],” Overton told TheBodyPro.
Matthew Feinstein, M.D., an assistant professor of medicine at the Northwestern University Feinberg School of Medicine and chair of a committee that wrote a scientific statement on the CVD-HIV connection, said REPRIEVE will provide important data on the net clinical benefit from statins for people with HIV.
“Applied to the HIV population, one would anticipate that, similarly, people at higher risk for CVD would get more benefit from statins. But at this point we definitely do not have data to support a blanket recommendation of statins for people with HIV across all age ranges,” Feinstein told TheBodyPro.
“This is where REPRIEVE will be so helpful, because it focuses specifically on the primary prevention group and includes a number of lower-risk people,” he said. “So we will be able to better understand how helpful moderate-intensity statins [the study drugs used in REPRIEVE] are or are not in preventing CVD in this group.”
Most of the data in the REPRIEVE trial are expected by 2023.