Cardiovascular risks in HIV: interview with Dr. Steven Grinspoon from Harvard Medical School (transcript)

This is the transcript of my recent podcast interview with Dr. Steven Grinspoon.David E. Williams: This is David Williams, co-founder of MedPharma Partners and author of the Health Business Blog.  Yesterday I attended a public meeting in Washington, DC that was organized by the Forum for Collaborative HIV Research.  It brought together regulators, clinicians, researchers, industry and patients to discuss the topic of cardiovascular risk in HIV.Dr. Steven Grinspoon, professor of medicine at Harvard Medical School, was one of the participants in the meeting. I'm speaking with him about it today.Dr. Grinspoon, why is the topic of cardiovascular risk in HIV coming up now?Dr. Steven Grinspoon: Well, first thank you for the opportunity to speak with you.  It's coming up now because there is increasing awareness that cardiovascular disease rates are increased in two ways. They are increased relative to non-HIV infected patients (these are data that we've seen from a number of ongoing cohorts) and they also appear to be increased in relationship to the use of specific drugs that patients with HIV may be taking.The recognition of increased cardiovascular rates has led to investigations of mechanisms. These mechanisms point out a number of metabolic problems including lipid problems, glucose problems, and body composition problems. These could contribute to traditional risk factors but also suggest non-traditional pathways, perhaps related to HIV itself or inflammation.So based on these rates and the potential mechanisms there's been an increased interest in this topic.Williams: Is it something that's just been noticed recently or has it simply not been a priority until now?Grinspoon: The first reports are over a decade old but there was more inconsistency in the early reports.  Some of the later reports are more consistent and the mechanistic possibility is stronger, therefore I think that the data are more believable now.There are also increasing efforts focusing on cardiovascular health in the non-HIV population and there is some spillover of that concern into the HIV population. The focus on obesity, abdominal adiposity, and lipids has become very important in the non-HIV world, and it’s also becoming important in the HIV world.So it's a confluence of factors: more data, more consistent data, and concern in other arenas that has led people to focus on this.Of course the ultimate reason is that in the beginning of HIV --when patients sadly were not doing well and were dying from the HIV-- there really wasn't time to be concerned with other problems. Now, thankfully, the patients are living longer.  They're really living with a chronic disease. Clinicians have begun to focus on these other problems, which were not taking up the mental space previously.  For example cardiovascular disease is becoming one of the major co-morbidities and causes of death among patients with chronic HIV. Therefore I think it's apt to focus on that.Williams: How big is the increased risk for somebody who has HIV?  Is it something that varies based on how old they are or whether they're male or female?Grinspoon: There seems to be some consistency among the data and the cohorts comparing HIV versus non-HIV. At the Forum I showed a slide with the major studies in that regard. The average increase in relative risk is about 1.8 to 2 fold, so there's approximately a doubling of cardiovascular risk specifically with respect to myocardial infarction rates.It's important to stress the implications of that.  For a young person, there does appear to be an increased risk in a relative sense, but the absolute risks are very small, so the doubling of a very small rate will not lead to a major absolute increase in rate. However, for an older person for whom the risk is already high, the doubling of that relative risk may lead to a much larger absolute risk.It's also important to point out that the data (particularly by Triant et al.) suggest that the relative risk is increasing with age.  In other words there's a greater relative risk between HIV and non-HIV patients in older age groups.  There's an increasing absolute risk in older patients and perhaps an increasing relative risk. As HIV patients live longer and live with a chronic disease they're becoming older, so it's a very important concern as HIV patients age.With respect to gender differences, another surprising finding is that some of the studies, particularly the Triant study and the Currier study, suggest that myocardial infarction rates are higher relative to non-HIV in women. That is the data may suggest that HIV-infected women may have relatively higher rates of myocardial infarction than men. We don't know why that is.  Some conjecture revolves around body composition abnormalities, which may be more severe in women.Truthfully we don't know 100 percent why, but there does seem to be a signal in some studies, although it's far from definitively proven.  I would suggest at least that women deserve to be included in these studies and deserve to be focused on. Unlike the non-HIV world where women are really protected at least until menopause, that may not be the case.It may be a case of premature aging; the benefit of being a woman is neutralized with age, and it may be occurring at a relatively earlier age in HIV-infected women.Williams: You mentioned up front the role of traditional risk factors, by which I assume you mean things like smoking and high blood pressure, but you also talked about non-traditional factors.  Can you say a little bit more about that?Grinspoon: Yes, let me just circle back to smoking.  It's very, very important to mention in any kind of dialogue that smoking rates are higher in HIV-infected patients.  It's the number one modifiable risk and it really should be focused on. And yes, that is what I meant by traditional risk factors, along with lipids, glucose and hypertension.Non-traditional risks is a big term that refers largely to inflammation but potentially also immune activation. The first inkling of this came from the SMART study in which patients were randomized to conservative therapy or continuous therapy. It was postulated that patients with continuous therapy would have more myocardial infarctions because they would be exposed to more toxic anti-retroviral medicines.In fact the opposite was seen and those on drug conservation protocols had more. That has been postulated to occur because of inflammation that occurs when you release your hold on the virus.  It replicates and patients become more inflamed.They looked at D-Dimer and IL-6 as potential mediators and they saw that.  So there has been a lot of talk about inflammation --the sense that the virus replicates and there is an inflammatory process going on, which would affect the endothelial function, local cytokines and mediators attracting monocytes and leading to oxidized LDL and plaque at the vessel wall.There is another school of thought (and they're not mutually exclusive), which is that immune activation per se might affect this. For example patients with the lowest CD4 count or an abnormal CD4 to CD8 ratio may through immune activation or change in immune function, have more vessel wall damage as well. There have been studies to show that even patients who are elite controllers with little virus replicating have altered endothelial function.  So I think that there are different potential mechanisms.The other possibility is there may be particles of the viral wall and other particles --GP120 and other factors--, which are direct viral products. They may actually affect endothelial function and lead to those processes.  So there are a number of potential mechanisms that I would count in the non-traditional risk factor category, all of which are being aggressively pursued.Williams: So for HIV patients and their physicians reading this interview, what are the implications?  Are there things that we should be doing right now or should we wait for more research to be done?Grinspoon: I think it's time to act. In my opinion the evidence is strong enough to suggest that there is an increased risk associated with HIV in terms of cardiovascular disease.  It's not of epidemic proportion but it seems to be consistent across multiple studies, perhaps a doubling of myocardial infarction rates and perhaps an increasing risk with aging.In my opinion the clinical implications are as follows: First of all we should pay meticulous attention to traditional cardiovascular risk factors even in young patients; HIV patients who are seemingly asymptomatic with reasonable overall cardiovascular risks.  Those things that can be modified should be modified.Even among pre-menopausal women we should pay particular attention. Even groups that were not thought to be of high risk should be looked at. I would recommend that Framingham Risk Scores be calculated and used, that smoking is combated, etc.  So that's number one.Number two, I think there are emerging data that consistent, good, antiviral therapy to reduce viral replication is actually good for the patient and trumps any ill effect of specific anti-retroviral medicines on myocardial infarction.  There may be some exceptions to that but in general I think that's where the field is moving.  I think the next big thing will be whether we can show in the START study whether earlier initiation of anti-retroviral therapy will actually be a kind of prevention treatment for myocardial infarction, i.e., you decrease the virus and replication earlier on and allow less build-up of inflammation in effect on the vessel wall.In summary I think meticulous attention to traditional risk factors, regular visits to look at those, and use of Framingham and other risk stratification algorithms are important. In addition there should be consistent use of anti-retroviral therapy --albeit those therapies that are least likely to cause metabolic problems-- and potentially earlier up-front therapy if studies like the START study suggests that's the case.Williams: I've been talking today with Dr. Steven Grinspoon, professor of medicine at Harvard Medical school.  Thank you very much.Grinspoon: You're welcome.