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James A. Underberg, MD: [00:00:06] Hello, and welcome to this program entitled Examining HIV and Atherosclerosis: Statin Benefits Beyond LDL-C Reduction. I am
Dr James Underberg, a clinical assistant professor of medicine at the NYU School of Medicine, Director of the Belleview Hospital
Lipid Clinic, and the NYU Center for Cardiovascular Disease Prevention in New York City. I am here with my colleague, Dr Steven
Grinspoon, a Professor of Medicine at Harvard Medical School, Director of the program in Nutritional Metabolism, Nutrition
Obesity Research Center at Massachusetts General Hospital in Boston, Massachusetts. Welcome.
Steven Grinspoon, MD: [00:00:41] Thank you. Great to be here.
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Dr Underberg: [00:00:43] I think this is going to be a great conversation, and I just want to get the whole thing set off by going over the burden
of cardiovascular disease in these patients with HIV. Where were we and where are we now? Take us through that.
Dr Grinspoon: [00:00:57] Well, it is a really important question, and I think there are a number of large epidemiological studies comparing HIV-infected
and non-HIV-infected patients. To sum up those studies, basically the increased risk of myocardial infarction and cardiovascular
disease is about 50% to 100% in those studies. There is variability in the studies, and different types of endpoints are used
in different populations, et cetera, but on average about that. Where that excess risk is going in the future as we improve
our care of those patients is not clear, but the data suggests now about 50% to 100% increase.
Dr Underberg [00:01:36] Alright. Understanding that, where is the risk coming from? How do you break this down?
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Dr Grinspoon: [00:01:40] The risk is broken down into two primary factors, traditional risks and nontraditional risks. Traditional risks encompass
your sugar, your lifestyle, your lipids, your blood pressure, etc., smoking. Those traditional risks account for about 25%
of the excess risk, which is important, and it means we need to focus on those particular risk factors, managing the blood
pressure, the glucose, the smoking, the lipids, which we will talk about. It also means that 75% of the risk is unaccounted
for by those traditional risk factors, and that risk has traditionally been thought to be inflammation. Our knowledge of that
is increasing dramatically and rapidly, and now I think we have come to realize it is an excess immune activation that persists
even among well-treated HIV-infected patients.
Dr Underberg: [00:02:27] When we think about those traditional risk factors, obviously we are going to be focusing today on the lipids. Can we dive
a little deeper into that, and are lipid abnormalities in patients with HIV different than the traditional lipid abnormalities
we see in the general population?
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Dr Grinspoon: [00:02:42] They are different, and they need to be considered in that regard. I think as we first started to investigate this, the primary
dyslipidemia that stuck out was hypertriglyceridemia, high triglycerides, low HDL, kind of an insulin resistance diabetic-type
pattern. Over time, that has improved, I think, as patients had less metabolic abnormalities. Regarding LDL, it is not particularly
elevated in most HIV patients. It is not a primary problem. In fact, some HIV patients who are acutely infected will have
low LDL, and that will increase in the return to health phenomena with antiretroviral therapy. On average, the LDL level is
normal if not slightly increased but not significantly increased in those patients.
Dr Underberg: [00:03:30] With the evolution of the disease, there has obviously been an evolution of treatment.
Dr Grinspoon: [00:03:36] Yes.
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Dr Underberg: [00:03:36] One of the things I also wanted you to discuss is the perception or role of the therapeutic agents in driving some of the
lipid abnormalities that we see in patients treated with HIV.
Dr Grinspoon: [00:03:47] Some of the older protease inhibitors had a particular impact on triglycerides.
Dr Underberg: [00:03:54] I remember.
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Dr Grinspoon: [00:03:54] Ritonavir and others. Those agents are less often used today, and I think, in general, I mean although there are some modest
effects of the agents on lipids, they are not significant really effects. If an agent is on a legacy regimen and has dyslipidemia,
that should be investigated, but some of the newer regimens integrate inhibitors. Others are fairly neutral toward lipids.
Dr Underberg: [00:04:22] If there is a lipid abnormality in a patient being treated with agents for HIV, in general one would not change medications
if you felt those were the right ones for the patient. Correct?
Dr Grinspoon: [00:04:35] That is a really important point. It is not like you can just switch off a blood pressure agent, substitute one for another.
These patients can develop resistance to the virus if you switch around their antiretroviral therapy too much, so people are
very conservative in doing that. You use the best regimen possible. You take into account the lipids. You take into account
any resistance patterns in that particular patient, and then if you have to manage the lipids, you go with your other tools
in your toolbox. That includes lifestyle management and also antilipid therapy.
Dr Underberg: [00:05:09] That was actually a perfect segue into where we are going to move to. As a lipidologist, I always would say that I would
never tell an obstetrician when to deliver a baby, and I would never tell an HIV specialist what changes to make in the medication
regimen because it can often cause more harm than good. We have got a whole regimen now of ways to impact lipids. That is
where I want to go next is the role of lipid management in cardiovascular risk reduction in patients who are suffering with
HIV. Statins really are the cornerstone of this, are they not?
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Dr Grinspoon: [00:05:42] Yes, in drawing from the data in the non-HIV population, they have been proven to be effective in study after study after
study. They are an interesting class of drugs. First of all, they obviously lower LDL, which is important, and we have learned
recently that lower LDL is better, so even if the level started only moderate increases, lowering them is good. That is important.
Number two, they can have sort of off-LDL effects. Certain statins might raise HDL a little bit or lower triglycerides a little
bit. That is not their primary duty, but they are not harmful in that regard and sometimes can help. They also have very unique
properties to lower inflammation, and I think that is the novelty and utility of them in the HIV population. We now have studies
to show that these statins lower markers of immune activation soluble CD 14, markers of arterial inflammation Lp-PLA2, so
it is really important. That is a very interesting off-target effect. Now, utilizing them in HIV is a little more difficult
than in the non-HIV population because there are some drug-drug interactions.
Dr Underberg: [00:06:55] In fact, a lot of people avoid statins because I think they are scared about the drug-drug interactions.
Dr Grinspoon: [00:07:01] They can be managed very easily.
Dr Underberg: [00:07:03] Exactly.
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Dr Grinspoon: [00:07:03] There are some statins, simvastatin and lovastatin, which are to be avoided, but there are others that have less risk, and
there are others that have really very little drug-drug interaction. Out of your toolbox, you can easily find statins that
can mix easily with the antiretroviral therapy the patient is on.
Dr Underberg: [00:07:24] That is always good for people to know, and I think understanding some of the differences between these statins helps people
understand which ones they can choose in the right setting. We are very lucky. Our Lipid Clinic, which is adjacent to our
HIV Clinic, we have a wonderful Pharm D who works with us on these drug-drug interactions. Electronic medical records can
help you a lot in complex combination therapy and make it a little easier. All that put aside, could you go through the statins
and point out any differences or ones that stand out with regard to drug-drug interactions, and then maybe other effects,
such as blood sugar, or maybe some of these anti-inflammatory issues?
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Dr Grinspoon: [00:08:04] Simvastatin and lovastatin to be avoided. Atorvastatin and rosuvastatin moderate interactions [unintelligible] with PIs,
particularly, but they can be dose adjusted. Now those two, particularly rosuvastatin, in studies among HIV-infected patients
have been shown to increase glucose. It is a very important point you make. That leaves pravastatin and pitavastatin, which
are probably the two drugs most highly recommended in most guidelines if you are going to use a statin in HIV-infected patients.
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The INTREPID trial, which is a large trial of comparing prava to pitava in HIV-infected patients, showed that neither drug
aggravated glucose. That is important. It showed that both drugs lowered LDL. That is important. Now the LDL lowering was
more with pitavastatin that pravastatin, and pitavastatin in studies done by our group also had a greater effect on these
inflammatory markers and immune markers.
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If you had to weigh the whole thing, you would probably say use pitava or prava if you are going to use a statin or dose adjust
atorva. You can probably expect your best result from pitava based on the data.
Dr Underberg: [00:09:20] When it comes to thinking about guidance for using these, we have talked about the drugs that may be a little better and
more desirable in some settings. Just recently this weekend in Chicago, new cholesterol guidelines finally recognized patients
with HIV as a high-risk population, certainly just reminding those who are using these drugs to think about it in these populations.
On the infectious disease side of the HIV side, are there any specific recommendations with regard to managing patients with
statins?
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Dr Grinspoon: [00:09:53] Yes. I think the point you just raised is an important one. For years, we have been considering HIV as risk factor in cardiovascular,
and I think the recognition of that by the new guidelines is important. The guidelines do suggest that lipids and glucose
be measured once a year and/or after any switch in antiretroviral therapy, so that is important, and that is part of the guidelines.
I think beyond that, you have 2 questions based on what do you put people on, based on which guidelines. I think we are going
probably to talk a little bit more about the AHA guidelines and then also what levels do you manage them to.
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Dr Underberg: [00:10:37] I think a large part of this is assessing risk, right? This is what I always remind our trainees. If you have a patient who
has HIV and is a smoker and a diabetic, that obviously puts them at a higher risk for more aggressive therapy. Similarly,
someone who already has preexisting atherosclerosis. You want to manage them aggressively. Another, I think, important factor,
which we really have not touched upon yet, is are patients with HIV being managed as aggressively as they should? Are they
being identified and put on statins the way they should?
Dr Grinspoon: [00:11:10] Probably not. I think the issue revolves around some reticence in drug interactions. I think as you are suggesting, anyone
with cardiovascular disease is that is a secondary prevention scenario, and it is clear as a bell. You really need to be aggressive
with those patients. For patients with low-to-moderate risk in the primary prevention scenario, I think it is a clinician
judgment issue utilizing the history of the patient and the guidelines, the LDL level, and coming to a consensus with your
patient.
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I think the field is lacking data on whether primary prevention at low-to-moderate risk levels works, and that will be answered
by the REPRIEVE trial, which I am involved with. That is a randomized double-blind placebo-controlled trial of pitavastatin
vs placebo following patients over the long term with low-to-moderate risk to see if the statin improves MACE, or major adverse
cardiovascular events. That study will be ready in 2022-2023, and the data will really inform the field in that regard.
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Dr Underberg: [00:12:19] I think it is an interesting thing to note that in that trial, which is a large trial, the drug chosen in that trial actually
was pitavastatin. I think probably for the reasons you pointed out earlier. One of the other unique things about pitavastatin,
it is also one of the longer-acting statins along with rosuvastatin and atorvastatin. When you consider drug-drug interaction,
you consider possible effects on inflammation and effects on glucose, it is certainly understandable why they chose it. It
will be very exciting because it is really one of the last of the large statin trials, and in this case, looking a primary
prevention population. I think it informs us a lot also about the role of inflammation in cardiovascular disease. What other
exciting things do we need to know about in the emerging data around this field, especially from someone like yourself who
is really in the middle of it?
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Dr Grinspoon: [00:13:16] I think one interesting aspect of this is not only is it a unique disease in terms of biomarkers of inflammation, it is a
unique disease in terms of the type of plaque. The plaque in these patients is typically noncalcified as opposed to calcified.
These are typically younger patients with high risk noncalcified plaque, which is vulnerable and liable to rupture more than
calcified plaque, so that is really important. The question is will statins prevent events, of course, but also what effect
will it have on the biology of plaque in these patients. Now we know from a small study that was published a few years ago
that over the year that these drugs, actually atorvastatin in this particular case, did significantly reduce noncalcified
plaque. We have built into REPRIEVE an 800-person CT angiography study to look at plaque, to look at incidence of new plaque
and a regression of existing plaque in these patients.
Dr Underberg: [00:14:20] It will also be interesting to see the change in plaque over time because there are some studies suggesting the patients
on statins actually develop more calcification as their plaques stabilize.
Dr Grinspoon: [00:14:32] Yes. We are really interested to learn that and how the changes in plaque relate to events. You know, maybe that is not such
a bad thing if their plaque stabilizes. Maybe it is more important in that population, the HIV, to reduce the noncalcified
plaque and whether the calcified rises in compensation. It is unclear if the medical benefit or not of that.
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Dr Underberg: [00:14:53] That is great. That is really interesting, and I think it is exciting. In fact, it fits very much into the new guidelines
where they really featured coronary calcium scoring as a way of re-stratifying, but based on what you are saying, that might
not necessarily apply to an HIV population with more soft plaque than hard plaque. I think we have really come to a good stopping
point here. What I would like to do is just kind of summarize. Maybe you could just go over some high points of our discussion.
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One thing that I do want to just bring up before we finish is the importance of team-based care in managing patients with
HIV, nurses, physician assistants, pharmacists as we have discussed, registered dieticians even, and making sure that all
of those people are involved in the management of those patients hits on a lot of things we talked about, including lifestyle
modification and complexities of the pharmacologic management. Any other takeaway points for our audience especially regarding
statin choices?
Dr Grinspoon: [00:15:54] I think we have covered a lot. Clearly the HIV patient population along with other inflammatory diseases like psoriasis has
increased risk. We are learning more about that risk. It is probably due to atypical inflammatory factors, but statins may
be a two-for-one approach. That may be the one class of drugs that kind of lower lipids traditional risk and lower inflammation.
We did not discuss whether antiretroviral therapy itself is enough by quelling inflammation, and studies suggest that, of
course it is necessary and saves lives, but it is not enough to completely reduce the inflammation. The newer theory is that
you need adjunctive therapy, if you will, and statins may serve the role. We talked about which statins you should not use
because of CYP3A and the reactions we talked about, ones that might be better, which are glucuronidated and are less interactive.
We talked about the ones that are less likely to affect glucose. I think we have covered a lot of ground in terms of how to
use them, etc. When to use them and their ultimate efficacy, I think most people believe they will work as a primary prevention,
but we have to determine their safety. A big, definitive trial is necessary in that regard, and I think we have hit upon that
too. I could not agree more with your comment about a team approach. These are complex patients. It takes a village, and it
takes a team.
Dr Underberg: [00:17:25] This has been a wonderful session. I want to thank you for participating in this activity. Please click on the Earn CME/CE credit link. The CME/CE post test will follow. Please also take a moment to complete the program evaluation at the end. Thank you very much.
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