"Our understanding of mechanisms of HIV-associated cardiovascular disease (CVD) has not yet translated into tailored clinical interventions," says Virginia Triant, M.D., M.P.H., of Massachusetts General Hospital. Triant provided a state-of-the-art presentation on cardiovascular complications in people living with HIV at IDWeek 2014.
The first article in this series covered the context and causes of HIV-related CVD. This second article focuses on how healthcare providers can integrate the prevention and management of CVD into HIV chronic care -- addressing both the traditional risk factors of CVD, and other risk factors that are HIV-specific.
Part of the challenge for clinicians is that it is unclear to what extent general population guidelines can be applied in the management of CVD in people living with HIV.
It isn't clear that any of the available tools to predict CVD risk in the general population underestimate risk in HIV. For instance, the Framingham risk score (FRS) was found to underestimate risk of AMI (acute mydocardial infarction) and stroke in people living with HIV on antiretroviral therapy in the D.A.D study and stroke in the Multicenter AIDS Cohort study.
However, new cardiovascular risk guidelines from the 2013 American College of Cardiology/American Heart Association (ACC/AHA) have added some complexity to HIV-specific risk prediction. These guidelines employ new CVD risk prediction equations -- the pooled cohorts equations (PCE). There have been reports that they may overestimate risk in the general population but they also appear to underestimate risk in people living with HIV.
Furthermore, the Framingham risk score and ACC/AHA guidelines do not seem to be in complete agreement about which people living with HIV are at low or high risk of CVD -- with discordant results in about 17% of cases.
Triant suggested that clinicians should consider calculating both the Framingham risk score and the ACC/AHA risk score.
Patients who are in a high-risk category by at least one score (greater than 10% for FRS and greater than 7.5% for ACC/AHA) merit:
- Suppressive antiretroviral therapy, if not already treated
- Strong consideration of statins
- Aggressive CVD risk-factor reduction
Management of Dyslipidemia in HIV
Some questions about the ACC/AHA guidelines remain. Rates of dyslipidemia are much higher in people living with HIV than in control patients, with a distinctive pattern of low high-density lipoprotein (HDL) and high triglycerides. Although statins are the main treatment, dyslipidemia may be more difficult to treat in people living with HIV, and the effects as well as drug interactions with antiretroviral drugs need to be considered.
In patients living with HIV, the use of statins has been shown to effectively lower low-density lipoprotein (LDL). Data presented at CROI 2014 also suggested that statin use may also decrease immune activation, and contribute to immune reconstitution independently of antiretroviral therapy. In addition, in at least one observational cohort, statin use was associated with significantly decreased mortality in people living with HIV who were on suppressive antiretroviral therapy.
There are controversies, however, regarding the approach to treating cholesterol recommended by the 2013 ACC/AHA cholesterol treatment guidelines. These recommend statin initiation in four major benefit groups:
- Those with clinical atherosclerotic cardiovascular disease (ASCVD)
- LDL ≥ 190 mg/dL
- Diabetes age 40-75
- Estimated 10-year ASCVD risk ≥ 7.5%
In contrast to the past, the guidelines set no LDL treatment targets and recommend no non-statin therapies. Using the new risk calculator (the PCEs) to estimate 10-year ASCVD risk, the guidelines recommend substantially increased statin treatment in general population -- with 12.8 million additional adults eligible for statin therapy (mostly among older patients without cardiovascular disease).
They also recommend significantly increased statin use in people living with HIV without traditional risk factors for CVD -- despite the fact that people living with HIV have a different typical cholesterol profile and for whom the mechanism of CVD is different. At present, there is not much evidence of efficacy and safety from randomized clinical trials for treating people living with HIV at risk as determined by the new ACC/AHA risk calculator and the guidelines statin intensity definition is not directly applicable in this population.
Nevertheless, Triant believes it is likely that that statins will be effective in the risk groups outlined by guidelines. The question might rather be, "Do they go far enough?" Even using both Framingham and PCE risk calculation, the risk of CVD appears to be underestimated in HIV, and there is a chance that a larger segment of the population living with HIV may benefit from statins. Future research will address some of these gaps.
In the meantime, on the basis of the available guidelines and published data on the use of statins in people living with HIV to date, Triant recommended the following clinical strategy for the management of dyslipidemia in HIV:
- Check fasting lipids
- At HIV diagnosis
- Prior to and within 1-3 months after starting or changing antiretroviral therapy
- Every 6-12 months
- Consider starting statins based on ACC/AHA cholesterol guidelines
- Consider therapy with:
- Statins, if LDL is above ATP-III (adult treatment panel) goal, or TG (triglyceride) is between 200-500 with elevated non-HDL
- Fibrates, if TG > 500
- 2013 HIV primary care guidelines include detailed statin-antiretroviral interaction chart
Management of HIV-specific CVD Risk Factors
In addition, CVD risk in HIV disease may be reduced by targeting HIV-associated inflammation and immune activation using established anti-inflammatory therapies (such as aspirin), antiretroviral therapy or novel immunomodulatory agents, according to Triant.
Aspirin, which is commonly used to reduce CVD from traditional risk, may also have potential reducing CVD in HIV disease, but studies suggest that aspirin is dramatically underused by people living with HIV who meet the traditional CVD-risk criteria. One paper reported that 31% of people living with HIV met the criteria for using aspirin to reduce CVD risk, but only 1.6% were receiving it. A reasonable clinical strategy, however, is that anyone with low bleeding risk who has known CVD or a high predicted CVD risk, should be taking aspirin.
There are also data to show that aspirin can decrease immune activation and platelet activation in people with HIV but whether it should be used more widely to prevent AMI or stroke in people living with HIV who don't meet the usual criteria for CVD is unclear.
"Interventions targeted at HIV-specific inflammation and immune activation may better reflect pathogenesis and reduce CVD," said Triant.
Antiretroviral therapy, may help since the most direct intervention would be treating the virus itself. Although the START trial will be the first randomized clinical trial to look at the rates of comorbidities including CVD in patients started on early versus deferred antiretroviral therapy, there has already been a paradigm shift in the role of treatment in relation to CVD risk in HIV.
"The CVD-related benefit from virologic suppression and immune reconstitution achieved by treating HIV are thought to outweigh possible proatherogenic effects of individual medications," said Triant.
This change has been reflected in current HIV treatment guidelines. For instance, in 2010, the IAS-USA HIV treatment guidelines, recommended the initiation of antiretroviral therapy specifically for patients with high cardiovascular risk regardless of CD4 count; and the current DHHS HIV treatment guidelines, recommend antiretroviral therapy for all people living with HIV based upon the "growing awareness that untreated HIV infection or uncontrolled viremia may be associated with the development of many non-AIDS defining diseases, including cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and malignancy."
So the clinical strategy is now to treat HIV to reduce inflammation, immune activation, and associated cardiovascular risk, but to consider underlying CVD risk when selecting specific antiretroviral medications that may have varying risk.
However, there appears to be a limit to this strategy as treatment intensification seems to have little or no effect in patients who already have suppressed viral loads. For instance, recent studies have found that when raltegravir (Isentress) was added to suppressive treatment, there was no effect on either flow mediated dilatation (FMD) or markers of viral replication.
Novel interventions, immune-modulators, such as using maraviroc (Selzentry, Celsentri) may be an exception to this rule, by virtue of its activity as a CCR5 antagonist, rather than as an antiretroviral. Recent papers in the literature explore its theoretical role in preventing/delaying atherosclerosis, and one study in mice found that maraviroc reduced the atherosclerotic progression by interfering with inflammatory cell recruitment into plaques suggesting that it could have a potential cardioprotective effect in HIV.
Similarly, Triant believes a number of older immune-modulators may have potential for reducing CVD risk in people living with HIV. These include methotrexate, which has been reported to decrease CVD risk in the general population. A randomized controlled trial is currently underway to assess the effect of low-dose methotrexate on inflammatory markers and endothelial function in HIV-positive patients on suppressive antiretroviral therapy. Meanwhile, current data on other immune modulators has been mixed.
Managing Traditional Risk Factors
The other key strategy for fighting CVD in people living with HIV is to manage traditional CVD risk factors (e.g. smoking, diabetes and hypertension) aggressively.
People living with HIV on suppressive ART may lose more years of life due to smoking than HIV.
Triant's recommended clinical strategy for smoking cessation:
- Apply guidelines for general population to all HIV smokers:
- Routine screening integrated into HIV primary care
- Strong, brief, intensive repeated counseling
- Pharmacologic interventions (varenicline is safe and effective in HIV)
- Consider systematic approaches to identify HIV smokers and ensure smoking cessation interventions are applied
Diabetes and Hypertension Management
Additionally, Triant suggests using the follow strategy to monitor and manage diabetes and hypertension:
- Check fasting glucose or HbA1C (glycated hemoglobin) at HIV diagnosis, 1-3 months after starting or changing treatment regimen, and every 6-12 months thereafter
- Check HbA1C every 6 months in patients with diabetes
- Diet and exercise intervention recommended:
- Shown to decrease HbA1C for HIV patients
- Check blood pressure annually
- Follow existing 2014 Hypertension Guidelines for general population
- No HIV-specific guidelines
- Consider drug-drug interactions
- Use of some calcium-channel blockers contraindicated with protease inhibitors
Many questions remain regarding the optimal management of CVD risk in people living with HIV, such as whether to use statins more broadly, whether immune-modulators will work and whether CVD prevention strategies should be the same in HIV-infected women and patients in resource-limited settings?
However, it is clear that clinicians should build CVD risk assessment into their clinical practice, start statins in those who qualify, have a low threshold for diagnostic work-ups in their patients living with HIV, treat HIV and manage traditional CVD risk factors.
"The intensity and consistency of HIV care provide opportunities to prevent and manage chronic disease complications," Triant concluded.
Read Part 1 to review the context and pathophysiology of cardiovascular disease in people living with HIV.
Theo Smart is an HIV activist and medical writer with more than 20 years of experience. You can follow him on Twitter @theosmart.