- Email: [email protected]
JCL roundtable: Managing lipid disorders in patients with HIV
Accepted Manuscript JCL Roundtable: Managing Lipid Disorders in Patients with HIV W.Virgil Brown, MD, Judith A. Aberg, MD, Karen E. Aspry, MD, Chris T. Longenecker, MD, Merle Myerson, MD PII:
S1933-2874(16)30450-0
DOI:
10.1016/j.jacl.2016.12.003
Reference:
JACL 1029
To appear in:
Journal of Clinical Lipidology
Received Date: 30 November 2016 Accepted Date: 6 December 2016
Please cite this article as: Brown WV, Aberg JA, Aspry KE, Longenecker CT, Myerson M, JCL Roundtable: Managing Lipid Disorders in Patients with HIV, Journal of Clinical Lipidology (2017), doi: 10.1016/j.jacl.2016.12.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
JCL Roundtable: Managing Lipid Disorders in Patients with HIV W. Virgil Brown, MD*; Judith A. Aberg, MD; Karen E. Aspry, MD; Chris T. Longenecker, MD; Merle Myerson, MD
RI PT
Emory University School of Medicine, 3208 Habersham Rd., NW, Atlanta, GA 30305, USA (Dr. Virgil Brown); Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA (Dr. Judith Aberg); Brown University Alpert Medical School, 222 Richmond St., Providence, RI 02903, USA (Dr. Karen Aspry); Case Western Reserve University School of Medicine, 2109 Adelbert Rd., Cleveland, OH 44106, USA (Dr. Chris Longenecker); Columbia University College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032, USA (Dr. Merle Myerson)
M AN U
SC
Keywords: HIV AIDS Anti-retroviral drugs Infectious diseases Immunodeficiency Lipid disorders
EP
TE D
Abstract: The HIV-AIDS epidemic has provided one of the more challenging problems in treatment of infectious diseases. As anti-retroviral drugs made a very marked improvement in controlling the immunodeficiency state and patients gained in their longevity, the concern with lipid abnormalities came to the fore. The initial drugs produced a form of metabolic syndrome accompanied by very elevated plasma triglyceride concentrations. Furthermore, the drugs used to control the virus were often metabolized in a manner that interfered with lipid lowering drug therapy. The antiviral agents have improved in many respects and the experience in managing the lipid disorders has added greatly to our ability to control these problems as well. This roundtable discussion has been conducted with four physicians who have been involved in management of large cohorts of patients with HIV infection and who have had a special interest in reduction of vascular disease risk.
AC C
*Corresponding author Email address: [email protected]
ACCEPTED MANUSCRIPT
Clinical Lipidology Roundtable Discussion
W. Virgil Brown, MD Judith A. Aberg, MD Karen E. Aspry, MD Chris T. Longenecker, MD Merle Myerson, MD
RI PT
JCL Roundtable: Managing Lipid Disorders in Patients with HIV
TE D
M AN U
SC
INTRODUCION: The HIV-AIDS epidemic has provided one of the more challenging problems in treatment of infectious diseases. As antiretroviral drugs made a very marked improvement in controlling the immunodeficiency state and patients gained in their longevity, the concern with lipid abnormalities came to the fore. The initial drugs produced a form of metabolic syndrome accompanied by very elevated plasma triglyceride concentrations. Furthermore, the drugs used to control the virus were often metabolized in a manner that interfered with lipid lowering drug therapy. The antiviral agents have improved in many respects and the experience in managing the lipid disorders has added greatly to our ability to control these problems as well. This Roundtable Discussion has been conducted with four physicians who have been involved in management of large cohorts of patients with HIV infection and who have had a special interest in reduction of vascular disease risk. They are: Judith A. Aberg, MD, Karen E. Aspry, MD, MS; Chris T. Longenecker, MD; and Merle Myerson, MD, EdD. Their full titles and institutional affiliation are included below. (Recorded during the Scientific Sessions of the National Lipid Association in New Orleans, LA on May 21, 2016.)
AC C
EP
DR. BROWN: I will start by asking Dr. Myerson to review for us, the common lipid disorders found in patients who are infected with HIV at the initial presentation? Are there interesting lipid disorders before antiviral treatment has been instituted? DR. MERLE MYERSON: I think the first point is that we (as cardiologists and lipidologists) are seeing patients who are already treated and much less frequently those recently diagnosed. Overall, however, the lipid pattern is similar to that seen in metabolic syndrome with the lower HDL-C, small dense LDL particles, and higher triglycerides. DR. ABERG: In the United States because we're identifying and diagnosing individuals at a higher CD4 count, they typically do not manifest the severe lipid abnormalities found in chronic inflammatory states. The most common abnormality we see is the low HDL. The vast majority of participants in current day antiretroviral naïve studies have normal LDL cholesterol. Their triglycerides are around 100, their LDL area around 90, but their HDLs are usually always in the upper 30s. I would say that today at the time of HIV diagnosis these values are
ACCEPTED MANUSCRIPT the most common.
SC
RI PT
DR. LONGENECKER: I would agree that the most common lipid abnormality we see today in patients on modern regimens is low HDL while other lipid fractions are relatively normal. This contrasts with the early ART treatment era. Take for example, the Multicenter AIDS Cohort Study (MACS), which is a long running prospective cohort of HIV infected and HIV-uninfected men who have sex with men. They could track lipids in some of the uninfected men who later acquired HIV infection. This study published in JAMA in 2003 showed that after HIV acquisition and as immunodeficiency progressed-- all lipid fractions go down. LDL, triglycerides and HDL concentrations go down. Then with therapy LDL rises and triglycerides climbed even much more dramatically, while HDL remained low. That was in the era of older protease inhibitors. Things are different now with the newer drugs.
M AN U
DR. KAREN ASPRY: I agree, but we still see a lot of HIV patients who were treated late, and hypertriglyceridemia is almost always seen, often with lipodystrophy. As mentioned, protease inhibitors worsened this picture. Whole body lipid kinetic studies with highly active antiretroviral treatment (HAART) and lipodystrophy from a decade ago showed increased intracellular lipolysis in the fed and fasting states due to defective adipocyte function, leading to increased fatty acids, hepatic VLDL secretion and ectopic fat deposition. Newer data in treatment-naïve subjects suggest that HIV-specific factors also alter adipocyte and lipoprotein physiology.
TE D
DR. BROWN: Do we know anything about mechanism of these lipoprotein changes?
EP
DR. LONGENECKER: We do know that some of the virus proteins such as the nef protein can affect HDL concentration and functionality, which will impair reverse cholesterol transport. That may be one of the mechanisms by which active viremia promotes atherosclerotic vascular disease in HIV. Generalized systemic inflammation, as we've mentioned before, is probably the dominant mechanism.
AC C
DR. ASPRY: Yes, there is evidence that the virus may interfere with ABCA1 function and cholesterol efflux. There is also evidence that an HIV viral protein that circulates in both untreated individuals and those with full viral suppression inhibits PPAR-gamma and up-regulates the glucocorticoid receptor in mice, causing peripheral lipolysis and hepatic steatosis. There is also data that HIV-mediated gut mucosal injury causes a translocation of bacterial products to the liver and that may also cause hepatic inflammation and steatosis.
DR. MYERSON: I think we can all agree that some of the things we're seeing are similar to metabolic syndrome. For example, we have discordance between LDL cholesterol and other measures such as APOB or LDL particle number, which we also see in diabetics and those with metabolic syndrome.
ACCEPTED MANUSCRIPT DR. BROWN: The APOB, which is a reflection of particle number, would be elevated higher than one would expect from the LDL cholesterol values?
RI PT
DR. MYERSON: We gave a poster here at this conference showing that there's a greater percentage of HIV positive patients that have discordance--a higher LDL particle number than a comparable level of calculated LDL cholesterol. This is the second time we've looked at it and found consistent results. The clinical relevance is that a patient infected with HIV may appear to be at goal using LDL-C but their atherosclerotic particle burden can still be too high. DR. BROWN: Some of these patients may present with relatively low or normal triglycerides and yet still have a low HDL. Is that correct?
SC
DR. ABERG: That is correct. Over time, as with the duration of disease, you'll start to see that there's more of a rise in triglycerides.
M AN U
DR. BROWN: Have there been studies on interleukin-10 in this disorder? DR. LONGENECKER: There have been many studies on interleukin-10 in HIV. With regards to antiretroviral therapy and lipid changes, the investigators of the SPIRAL trial looked at whether switching a boosted protease inhibitor to an integrase inhibitor improved lipids compared to continuing the boosted PI. They also looked at inflammation biomarkers, and found no difference in IL-10 between groups.
TE D
DR. BROWN: Interleukin-10 in the inflammatory state can markedly reduce HDL production. Dr. Alan Remaley at the NIH, has reported on this in the Journal of Clinical Lipidology. He demonstrated that an infusion of interleukin-10 in patients can drive HDL to very low levels.
EP
DR. LONGENECKER: In SPIRAL, there was no correlation between baseline levels or changes in IL-10 and HDL. This is just one study, but there may be other mechanisms in HIV.
AC C
DR. BROWN: There's also an interesting set of data on ANGPTL4, which is a down-regulator of lipoprotein lipase function in adipose tissue, but it may allow continued activity of macrophage lipoprotein lipase. If you inactivate the gene for this protein in a mouse and feed saturated fat, you can create huge lymph nodes to the point that it obstructs lymphatic flow with fat bloated macrophages. I do not know whether viral infections can suppress this protein but it may be of interest. DR. ABERG: There has been some work on the impact of specific antiretrovirals on human adipocytes, gene expression and secretion of adipokines and cytokines but I cannot recall any data regarding ANGPTL4 in HIV. DR. ASPRY: I think that whatever the molecular mechanisms, chronic inflammation and adipocyte dysfunction appear to play roles in creating dyslipidemia in HIV.
ACCEPTED MANUSCRIPT
RI PT
DR. ABERG: Our management of HIV has changed over the past few years with the emphasis now that everyone with HIV infection should be offered antiretroviral therapy (ART) regardless of their CD4 T-cell count. A large randomized controlled study called START showed that individuals who have a T-cell count greater than 500 derive a significant benefit in both morbidity and mortality when taking antiretroviral therapy immediately compared with delaying ART until their CD4 count declines to less than 500.
SC
DR. LONGENECKER: We have patients who have a legacy of having had a very low CD4 T-cell count in their past. We call that the nadir CD4 count- the lowest CD4 count they ever had. Those are the ones that tend to have a higher inflammatory set-point. It's in these patients that we often see this low HDL. The low HDL, high triglycerides phenomenon may be a “low nadir-CD4 disease.”
M AN U
DR. ABERG: But they are treated now, too, so that's a different population and question. DR. BROWN: In the past, why did we routinely wait to until the CD4 count became very low before beginning treatment of known HIV infection? DR. ASPRY: Probably because data from the early HAART era showed some protease inhibitors were associated with a 1.1-fold increase in MI risk per year which was obviously cumulative, which led to reluctance to treat people with CD4 counts that were still elevated.
EP
TE D
DR. MYERSON: I just wanted also to drive home the point about the less toxicity of the anti-retrovirals. You know, now that we are giving anti-retroviral therapy (ART) as pre-exposure prophylaxis (PrEP), to people who are not infected. I think that shows that we've come into a new and very different era in anti-retrovirals although we still should remember that these drugs are not without side effects and risks
AC C
DR. BROWN: Are you referring to people who have been exposed because they had a needle stick, or are we talking about just high risk people like prostitutes? DR. ABERG: Yes, but it's not a medicine without side effects; it is safer, less toxic to the point that it can be used in a high risk and healthy person to help prevent HIV. There are side effects, as we've seen in some individuals, not so much lipid abnormalities but bone mineral density may be decreased and individuals with pre-existing kidney disease may have a decline in kidney function. DR. BROWN: At present, what are the first line therapeutic agents for HIV and how do they affect the lipoproteins? DR. ABERG: For all naïve patients, the first-line for the most part in the United States is an integrase inhibitor. There is still one protease inhibitor, darunavir, which remains first-line. There is more controversy regarding choosing a specific nucleoside
ACCEPTED MANUSCRIPT
RI PT
than which integrase inhibitor to use. It's subtle, but for the most part the integrase inhibitors are well-tolerated. Concern about drug interactions remains a predominant reason for the choice. Dolutegravir has been more preferred by many as it has the least number of drug interactions. The problem is that the fixed dose combination is with a nucleoside called abacavir that requires a genetic screening test before use to identify those at risk of having a hypersensitivity reaction to abacavir. There is controversy as to whether abacavir itself is associated with increased risk of cardiovascular disease. However, it is the drug that is preferred in those with chronic kidney disease which is a population at risk for heart disease.
SC
DR. BROWN: Are there baseline clinical or laboratory measures that would affect the choice of these drug classes or combinations?
M AN U
DR. LONGENECKER: I would mention that some of the protease inhibitors that are still in use today cause less elevation of triglycerides than the first and the second generation. Atazanavir and darunavir certainly cause triglycerides to become elevated, but maybe on average only 20 milligrams per deciliter. The integrase inhibitors do not cause elevation of triglycerides except for those that are boosted with cobicistat. Cobicistat is similar to the protease inhibitor ritonavir. Either of these can be helpful in boosting levels of other ART drugs.
TE D
DR. ABERG: Efavirenz can affect lipids adversely but does raise HDL-C. It's been shown that efavirenz works similar as a CETP inhibitor. However, it can increase LDL and more importantly, efavirenz has some central nervous system effects with a potential for increasing suicidal thoughts.
AC C
EP
It is of note that in AIDS Clinical Trials Group A5257 comparing atazanavir versus darunavir versus raltegravir; the protease inhibitors, not surprisingly were associated with increased LDL-C and triglycerides. Interestingly though, persons receiving atazanavir had the least progression of carotid intima thickness in the metabolic sub-study. DR. MYERSON: I think that that's a good point. When we're talking about classes of drugs - - we had mentioned tenofovir, which forms a basis of so many drug regimens. It was known as tenofovir disoproxil fumarate (TDF)and there is a new version known as tenofovir alafenamide (TAF) which causes less bone and renal problems. Less in known about TAF effects on lipids but Joel Gallant presented data at the Conference on Retroviruses and Opportunistic Infections (CROI) showing that although HDL-C increased, LDL-C and Triglycerides also increased more than with TDF. DR. BROWN: I agree with what Dr. Myerson said earlier, that these lipoproteins as altered by inflammation and are different in their composition and physiology in ways that epidemiologists have not
ACCEPTED MANUSCRIPT defined for us. It may be that using particle numbers as measured by apoB or with NMR will be more predictive of outcomes. DR. MYERSON: ApoB is usually covered by insurance whereas other tests of particle number are not.
RI PT
DR. ASPRY: While some modern anti-retrovirals may improve or not be associated with dyslipidemia, some like raltegravir have been associated with increased waist circumference and increases in insulin resistance and metabolic syndrome. Even though lipids may not be as deranged, insulin resistance may still occur with some integrase inhibitors.
SC
We haven't used these newer agents long enough to know if they do or do not increase future myocardial infarction (MI) risk.
M AN U
DR. ABERG: The necessity to use combination therapy makes it difficult to lay blame on any single drug. The nucleosides affect the sterol regulatory element-binding proteins, right? The nucleosides affected fatty acid synthesis. The protease inhibitors (PIs) were mainly affecting the 1c pathway. You have different drugs competing at different metabolic pathways plus HIV infection altering immune function and inflammatory pathways. It is very complicated. Extensive cellular metabolic studies have not been performed with the integrase inhibitors largely because we are not seeing the same metabolic phenotypes as with the older nucleosides and protease inhibitors.
TE D
I would like to point out, though, even when we were doing euglycemic clamps with ritonavir, you could see insulin resistance even after a single dose. daSilva presented clamp data after 24 weeks on lopinavir, and there was complete glucose homeostasis again.
EP
DR. ABERG: Understanding the longer-term effects has been challenging since some effects may be transient or unique to particular individuals due to possible underlying pharmacogenomics.
AC C
DR. BROWN: With our current experience, what are the aspects of a patient that would guide you to choose one regimen versus another? Do you use metabolic features? DR. ABERG: The newly diagnosed patient is looking for convenience and simplicity. One pill once a day is the expectation because of marketing. We do need to consider the patient's complete history. What are their co-morbidities? Are any drug interactions possible? Are they smoking? Our patients with HIV smoke at a much higher rates. The message to stop smoking is even more important in this population. Diet change is also important. In selecting the best combination of ART, the top considerations are the co-morbidities…the kidney and liver function and lipid levels. Again, the integrase inhibitors are first-line because of their safety profile and there is less virologic resistance. We do a genotypic resistance test at the initial diagnosis of HIV to
ACCEPTED MANUSCRIPT determine if the HIV virus is resistant. If they have been on previous ART regimens, this is even more useful. Based on the genotype results and underlying co-morbidities we choose a preferred regimen. Of course, many patients prefer a single tablet regimen even if we believe a multi-pill combination will be better for that individual. You have to educate and negotiate to settle the issue and usually patients will agree to the recommended therapy.
SC
RI PT
DR. MYERSON: One point is that as cardiologists and lipidologists we tend to see the patients after they've been genotyped and phenotyped and started on ART. Patients generally come us with a good CD4 count and are virally suppressed, tolerating their regimen—and then we deal with lipids and other risk factors. We rarely attempt to change the antiretroviral regimen. I tend to work around their ART regimen with lipid medications and lifestyle modification while looking for other secondary causes of dyslipidemia.
M AN U
DR. LONGENECKER: I agree that first line regimens today are based on an integrase inhibitor. In choosing specific drugs, with high cardiovascular disease (CVD) risk, I would try to avoid abacavir. In Patients with chronic kidney disease I avoid tenofovir and there tend to choose the abacavir containing regimen. Though that may change now with the introduction of tenofovir alafenamide (TAF) mentioned earlier.
TE D
Occasionally I do feel it appropriate to discuss ART changes with the primary HIV provider. Most are are open to considering a change if there is a good reason. DR. BROWN: In HIV infected patients, is there a first-line drug treatment for lipid disorders? We're usually dealing with higher triglycerides and these are often accompanied by high LDL particle numbers.
AC C
EP
DR. ASPRY: I think it's going to vary, and the practice is changing. In years past with the many drug-drug interactions between protease inhibitors and statins, the first-line drug was pravastatin. Then as safety data accrued and we started feeling more comfortable with rosuvastatin and atorvastatin where lowered doses may be safe and affected. Although atorvastatin with tipranavir was still felt to be contraindicated. It remains important to refer to the statin safety and drug interactions data updated regularly by the NLA. I think the practice may be changing now in support of pitavastatin because it has no major interactions or requirements to keep doses low no matter which ART the patient is on. In some health care systems, pitavastatin is not available. The statin of choice may depend on what the patient’s insurance company will pay for. DR. BROWN: Is there evidence that rosuvastatin or atorvastatin is less safe than pravastatin? Some of our patients could use greater efficacy than pravastatin offers.
ACCEPTED MANUSCRIPT DR. ABERG: Many providers of care in HIV have been using high intensity statins for a very long time. We were prescribing 40 milligrams of atorvastatin, and with a protease inhibitor that certainly is equivalent to 80 milligrams.
SC
RI PT
We used pravastatin initially because of the fear of drug interactions. The drug interactions were limiting everything that we could use. The other is that triglyceride elevations were our major concern with the initial ART drugs. I recall patient whose triglycerides rose well over 1000 while their HDLs were in single digits. You did not get much improvement in their lipid profiles when you prescribed a statin. I was chair of at one of the first studies in the AIDS Clinical Trials Group A5087, which tested pravastatin versus fenofibrate. Those medications did exactly what they were supposed to do. Pravastatin reduced LDL by 20 to 25%. Fenofibrate lowered triglycerides by 35%. However, you often could not achieve the NCEP composite goal.
M AN U
Previously, HIV providers were referring many patients with dyslipidemia to lipid experts. Today, with these new drugs, less than ten percent of patients in the HIV primary care clinics have dyslipidemia.
AC C
EP
TE D
There still are two discrete populations in which lipid management may differ. The first is the group with lipid abnormalities before they acquired HIV infection. Treating HIV is not going to correct their dyslipidemia. You just need to diagnose their lipid condition and treat them as you would anyone else. With high triglycerides (> 500 mg/dL) attributable to HIV disease or secondary to ART, I treat the triglycerides first because of the risk for pancreatitis. Both hypertriglyceridemia and mitochondrial toxicity of the nucleosides can contribute to initiation of pancreatitis. We rarely see pancreatitis with the newer anti-retrovirals and hypertriglyceridemia is uncommon. Nevertheless, if they do not have an immediate cardiac concern, I will lower the triglycerides first and then assess their LDL-C. When LDL-C, non-HDL-C or both are elevated as the major lipid abnormality, statins are first-line. Unfortunately, the choice of the statin is not always in our control as we must deal with preferred formularies and obtain pre-authorization. DR. BROWN: The old rationale was that there were several of these that inhibited the cytochrome enzyme CYP-A4 and other pathways of metabolism. The old protease inhibitors were a particular problem in this respect. Pravastatin, rosuvastatin and pitavastatin are not metabolized by the Cyp A4 system but there may be other vulnerabilities in there metabolism? DR. ABERG: The drug interactions can be quite complex. Rosuvastatin is mainly metabolized via CYP2C9. There are lesser contributions from CYP2C19 and CYP3A4 isoenzymes but these can cause significant drug-
ACCEPTED MANUSCRIPT
RI PT
drug interactions. Rosuvastatin can also interact with various PIs through non-CYP mechanisms. It is a substrate of organic aniontransporting polypeptide 1B1 (OATP1B1) and breast cancer-resistance protein (BCRP). Protease inhibitor (PI) induced inhibition of OATP1B1can can cause a decrease in hepatocyte uptake of rosuvastatin while inhibition of breast cancer resistance protein (BCRP) decreases hepato-biliary excretion and increases rosuvastatin absorption. There are additional transporters and polymorphisms in drug metabolism genes that also may affect drug concentrations potentially leading to adverse outcomes.
M AN U
SC
Trying to predict who will or will not have a drug interaction is very difficult but fortunately clinically uncommon. It is not cost or time effective to evaluate drug metabolism genes on everyone and the reality is the major drug interactions are known. Most individuals on ART will do fine with either atorvastatin or rosuvastatin with the dose adjusted as per the package inserts. Pravastatin is widely used as it has minimal drug interactions except with darunavir. However, pravastatin has less efficacy in reducing LDL choesterol. Pitavastatin is the cleanest, but is not on some formularies as it has not been widely studied in the USA.
TE D
DR. LONGENECKER: I feel pretty strongly about this. I've had a lot of patients who have come to me on pravastatin who were not nearly close to a desirable LDL-C goal. Often their providers were overly cautious about using any other statin. The NLA panel on recommendations for lipid management felt strongly that we should recommend higher dose statins for patients that might benefit. Atorvastatin and rosuvastatin can be used at moderately high doses in someone who is on ritonavir or other protease inhibitors.
AC C
EP
DR. MYERSON: It is common to need to address the elevated Triglycerides first. However, this tends to be more complicated in HIV patients. They may have co-morbidities, Hepatitis infection, alcohol and substance abuse and require more careful consideration of drug choices. Then there is often an issue with drug coverage and formulary restrictions. Gemfibrozil may be the only available fibrate but this has more complications with statins. Omega-3 fatty acid and fish oil extracts may be helpful but they are also not covered by all plans and can be expensive. Compliance can be a problem with high doses. So, there are layers of complexities here that influence our decision. DR. ABERG: We have a wide choice of statins. Pitavastatin was superior to pravastatin in lowering LDL in the Intrepid study. So, it can be in the game. In my practice, it seems that more develop signs of type 2 diabetes on rosuvastatin than atorvastatin but this is a relatively small occurrence. Dr. Brown:
When do you choose to use drugs other than statins or in
ACCEPTED MANUSCRIPT combination with statins in HIV patients?
RI PT
DR. MYERSON: The American College of Cardiology recently had a statement about non-statins. I tend not to use the bile acid sequestrants. I do not believe that I have a HIV-positive patient on them. They tend to raise triglycerides. Also, they interact with other medications. For patients taking medications throughout the day waiting four hours between other drugs is not feasible. I also tend not to use niacin with the concern about glucose intolerance and the difficulty in adherence.
M AN U
SC
DR. LONGENECKER: Another class of drugs—the PCSK9 inhibitors are very promising. Admittedly, there are very limited data in HIV patients, but there were six patients treated in the evolocumab trials. They had a similar LDL response on top of high-dose statin compared to the uninfected subjects. Priscilla Hsue from UCSF has reported these data at the AHA and ACC. In a larger cohort of patients in San Francisco, those with HIV tended to have higher blood levels of PCSK9 measured by ELISA. Patients with HCV co-infection had particularly high levels of PCSK9. Although they will not be routinely used, I think that in certain patients these drugs will be quite effective. DR. MYERSON: I do use ezetimibe, generally as an add-on to statin therapy.
AC C
EP
TE D
DR. ASPRY: I believe many of these individuals need combination therapy. Which lipid drug to start first obviously depends on the patient’s baseline triglyceride level and cardiovascular risk. The big question is: What is the best first agent for those with triglycerides in the 500 to less than 1,000 range? This is a grey area even in non-HIV infected individuals. I support treating these individuals with statins first because they are the best agents for lowering non-HDLcholesterol, which tracks best with LDL-particle number, I choose a fibrate as a first-line drug only if triglycerides are 1000 mg/dl or higher. I think that while there is subgroup data to support fibrates – when HDL is very low and triglycerides are very elevated, I believe if a patient is diabetic, near diabetic or has multiple vascular risk factors, which is common in HIV, there's more data to support a statin first as long as triglycerides are less than 1000 mg/dl. We are still awaiting more hard endpoint studies. There are placebo controlled data in HIV patients using CT angiography showing that statins are associated with atherosclerosis regression although it was a small study. Statins also improve markers of immune activation and of inflammation, as well as non-invasive measures of endothelial function, in individuals with HIV. DR. BROWN: I would agree. Previously I felt that you should treat with fibrates first because you couldn't interpret the LDL cholesterol even with triglycerides over 300 mg/dl. Now we have APOB or particle numbers. With these you can make a judgment about the statin effect even though the LDL cholesterol value is so distorted by the hypertriglyceridemia. With triglycerides below 1000, it doesn't
ACCEPTED MANUSCRIPT
RI PT
matter whether you start with fibrates. The non-HDL-C is important to evaluate in this instance. If it is lower than expected, the predominant particle may be chylomicrons and there, fibrates are clearly drugs of choice. If the non-HDL-C is quite elevated, statins may be the best initial treatment. Combinations of the two are often best in the patients with triglycerides over 500 mg/dL. However, it is important to start them in sequence since you want to determine the efficacy of each addition.
M AN U
SC
DR. ABERG: I would just counter that a little bit for all patients. I agree totally about assuring someone with CHD gets on a statin immediately. You as a cardiologist are seeing patients that have known or suspected coronary heart disease, and I agree patients that need a statin should be on a statin. The person that I usually see is the typical 30-year-old that comes in and they have medication induced hypertriglyceridemia or newly diagnosed HIV with high triglycerides. I am going to treat that triglyceride first because that's not a person that I feel is in immediate threat of CHD. These are completely different populations and management needs to be individualized. In the ACTG A5087 study I mentioned before, we actually showed that the sequencing of using a fibrate first and a statin resulted in the best overall lipid profiles. DR. BROWN: Those are usually judged on the basis of LDL cholesterol, and the LDL fattens up when you use fibrates but particle number tends to go down.
TE D
DR. ABERG: Of course, that is correct.
EP
DR. BROWN: These patients that you're worried about here, the 500 to 1000 or above are at more immediate risk from pancreatitis and that can be a logical reason to start with a triglyceride lowering drug. In that I agree. Do you use fish oil in those presenting with very high triglycerides?
AC C
DR. ABERG: The AIDS Clinical Trials Group did a study of comparing fenofibrate versus 3 grams fish oil, and then after 12 weeks using combination therapy for those who did not meet goal. The fibrate produced a larger reduction of 58% compared with 46% decrease in triglycerides with fish oil. The combination reduced triglycerides by 65%. I still do use combination therapy in some people that have high triglycerides. I've had patients that are on fibrate, fish oil, and niacin and still cannot achieve goal. Thankfully such high triglyceride levels are much less common now. We just did a database search in over 10,000 patients in our recruiting for the REPRIEVE trial. Less than one percent of patients had a triglyceride concentration of over 500 mg/dL. DR. BROWN: About one percent in the general population has triglyceride values above 500 mg/dL. The question of managing the triglyceride disorder seems to be much less frequent as we've used these new regimens.
ACCEPTED MANUSCRIPT I would like to hear of your experiences regarding lifestyle change. Drugs usually dominate our therapeutic decisions in these HIV patients but does lifestyle play an important role?
RI PT
DR. LONGENECKER: I run an HIV cardio-metabolic risk clinic in an HIV medical home. I believe that HIV is a disease where you have an opportunity to work together with primary care providers, often dietitians and social workers to create programs in a community that has a very strong social cohesion and identity.
SC
For example, we have a community garden at our HIV clinic where patients help to tend the garden. They can take produce home with them. There's a lot of emphasis on lifestyle changes. We have yoga and walking groups and that sort of thing. We're running a clinical trial trying to determine ways to help people redesign their environment in such a way that they are not totally dependent on personal motivation to make healthy lifestyle choices.
M AN U
DR. BROWN: Community support helps them develop and maintain healthful habits? DR. LONGENECKER: It's very important in a community where there are limited food choices. In East Cleveland, for example, where we are it's very difficult for people to access foods that we consider healthy. I think you'll find that in many of the HIV communities around the country.
TE D
DR. BROWN: Do you all feel that this is an important part of the therapy?
EP
DR. ASPRY: I do. As we mentioned at the outset, HIV has become a chronic disease and individuals now have a chance to live a normal lifespan. So, we must treat it like a chronic disease, which means using teambased approaches to deliver multidisciplinary longitudinal care. I think that includes, obviously, aggressive dietary interventions. A review in 2012 showed that diet interventions do work in this disease, lowering triglycerides in the 50-point range, which is significant.
AC C
However, a focus group study showed that the barriers to diet change in HIV patients are probably greater than in the general population. There are obviously financial barriers. Fresh produce, fish and lean meats that we're asking people to consume are expensive.. There are also many psychological barriers. Individuals who experience a lot of wasting in the beginning stages of the disease often feel that they need to consume more calories, and that is often from fat rich and unhealthy foods. The family and cultural barriers may also be greater. The family eating patterns might be difficult for people to overcome. Some are homeless and have unstable living situations without social or family support. The focus groups did show these individuals are helped by a regular contact with providers. It may be physician or non-physician provider like a dietitian that provides psychological support.
ACCEPTED MANUSCRIPT Experiential learning may also help. Group visits to the market and cooking classes teach important and practical lessons about healthy eating.
RI PT
DR. BROWN: Is there a growing population of people who have been through this HIV experience and dealt with all the issues that you have described here in terms of medical treatment - patients that are beginning to live a normal life with families and jobs?
M AN U
SC
DR. LONGENECKER: Not only would I say that our patients can have families and good jobs, I think that it should be our expectation that our patients live a normal life. In fact, people can live very well with HIV. I think that in many ways they have an opportunity to live even better than they would have if they didn't have HIV. There's some data to suggest in the Kaiser Permanente system, for example, that the rates of myocardial infarction are going down, and the relative risk due to HIV is going down over time. Some have attributed this to very good medical care. The average man in his 30s or 40s may not get good primary care; but if he has HIV, they're often engaged in a medical system where good primary care is inherent. They often have a community where healthy lifestyle decisions are communicated.
EP
TE D
DR. ASPRY: As Dr. Longenecker mentioned, early data from Northern and Southern California Kaiser has shown that between 1996 and 2011 the relative risk of MI in their HIV-infected population of almost 25,000 dropped essentially to that of a matched HIV-negative cohort. This is likely because these are all insured patients treated within an integrated healthcare system that uses systematic and multidisciplinary approaches to deliver chronic care. More than a third of their HIV infected individuals are now taking lipid lowering and blood pressure lowering medications, a prevalence greater than in non-infected individuals. Also 90% are now on ART with mean CD4 counts of >600. Hopefully as healthcare in the U.S. transitions to similar value-based care delivery models, we can achieve these outcomes nationally.
AC C
DR. BROWN: On that hopeful note, I want to ask one final question here. What studies are underway now that are going to add to our knowledge about managing HIV and that will be very significant in the future? Dr. ABERG: REPRIEVE is a study of 6500 individuals with HIV who do not have a clinical indication to be on a statin, defined as having no known existing coronary heart disease and an ACC/AHA risk score of less than ten percent. The patients are randomized to either go on pitavastatin or placebo. They will be followed for five years. It's similar to the JUPITER study. There is a substudy of 800 individuals in which various biomarkers are being monitored for signals of risk and responsiveness. Dr. Longenecker has been very engaged in one study called SATURN, which was looking at rosuvastatin versus placebo, trying to enrich for people that seem to have more inflammation and whether or not
ACCEPTED MANUSCRIPT there was a benefit in taking a statin. They did see some improvement in some markers which he might elaborate on. However, in the several studies of this type, there has not been a consistent decrease in any one biomarker. The AIDS Clinical Trials Group just completed a study evaluating atorvastatin versus placebo in a crossover design. All the biomarkers were completely flat.
M AN U
SC
RI PT
We have observed the consistent lowering of LDL, oxidized LDL and lipoprotein-associated phospholipase A2, all lipoprotein related markers. I just don't think we understand the pathogenesis enough to tease this out. The problem with these smaller studies is that we're trying to enrich for the population most at risk without knowing what biomarker can identify the population that would benefit the most. Using these markers in selecting the cohort for study, you often exclude those who do not have elevated immune activation, the vast majority of HIV patients. They don't have high hs-CRP. They don't have a high IL-6. If you only enroll patients who do have elevated markers of immune activation, inflammation or coagulation, you may wind up with a study population whose results may not be applicable to the majority.
TE D
DR. LONGENECKER: Studies that consider inflammation as a target include the testing of biologics such as those used in rheumatoid arthritis and psoriasis. The hypothesis is that a lot of the residual immune dysfunction in some patients is caused by high inflammation. In Cleveland, we’re conducting a trial of tocilizumab, for example, which is an IL-6 receptor blocker. Some of the secondary outcomes include lipid sub-fractions and lipoprotein functionality as well brachial artery endothelial function. Methotrexate and IL-1β blockade with canakinumab are two other interventions that are being tested in small randomized clinical trials.
AC C
EP
DR. ABERG: One of my Sinai colleagues, Meagan O’Brien has been studying aspirin, and we have a pilot study that's evaluating aspirin versus clopidogrel as there is some data to suggesting that platelets are highly activated and potentially contributing to inflammation and thrombosis. DR. ASPRY: I think that identifying and targeting new biomarkers is important, but the impact from controlling traditional risk factors in the HIV population must not be underestimated. For example, there is an almost three-fold higher prevalence of smoking in HIV positive patients, and modeling within the large DAD cohort showed that smoking cessation had the largest impact on reducing future vascular risk. DR. ABERG: We also have the problem that we haven't had people living with HIV for the duration of time to have the numbers to compare to the general population and truly test our current data for such modeling. Dr. Brown:
I want to thank you for answering my questions and
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
participating in this discussion. This has been very informative and potentially very useful for the readership of our Journal. Your experience in managing vascular disease risk factors and particularly lipoprotein related risk is important to share with the clinical lipidologists who have very few HIV infected patients. Most importantly, you have made clear that well managed patients with HIV can have a much improved and often completely normal life managed with current tools. Active research in this area may provide new knowledge that will not only help those with HIV but also all patients with lipid abnormalities.
ACCEPTED MANUSCRIPT
Reading list:
AC C
EP
TE D
M AN U
SC
RI PT
1. Longenecker CT, Sullivan C, Baker JV. Immune Activation and Cardiovascular Disease in Chronic HIV Infection. Current Opinion in HIV/AIDS. 2016 Mar;11(2):216-25. 2. Longenecker CT, Eckard AR, McComsey GA. Statins to improve cardiovascular outcomes in treated HIV infection. Current Opinion in Infectious Diseases. 2016 Feb;29(1):1-9. 3. Lo J, Lu MT, Ihenachor EJ, Wei J, Looby SE, Fitch KV, Oh J, Zimmerman CO, Hwang J, Abbara S, Plutzky J, Robbins G, Tawakol A, Hoffmann U, Grinspoon S. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIVinfected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015 Feb;2(2):e52-63. 4. Nou E, Lo J and Grinspoon SK. Inflammation, immune activation, and cardiovascular disease in HIV. AIDS 2016, 30:1495–1509. 5. Kaplan-Lewis E, Aberg J & Lee M. Atherosclerotic Cardiovascular Disease and Anti-Retroviral Therapy. Curr HIV/AIDS Rep (2016) 13:297–308. 6. Eckard AR, Meissner EG, Singh I, and McComsey GA. Cardiovascular Disease, Statins, and HIV. J Inf Dis. 2016:214 (Suppl 2) S83-S92.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1933-2874(16)30450-0
DOI:
10.1016/j.jacl.2016.12.003
Reference:
JACL 1029
To appear in:
Journal of Clinical Lipidology
Received Date: 30 November 2016 Accepted Date: 6 December 2016
Please cite this article as: Brown WV, Aberg JA, Aspry KE, Longenecker CT, Myerson M, JCL Roundtable: Managing Lipid Disorders in Patients with HIV, Journal of Clinical Lipidology (2017), doi: 10.1016/j.jacl.2016.12.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
JCL Roundtable: Managing Lipid Disorders in Patients with HIV W. Virgil Brown, MD*; Judith A. Aberg, MD; Karen E. Aspry, MD; Chris T. Longenecker, MD; Merle Myerson, MD
RI PT
Emory University School of Medicine, 3208 Habersham Rd., NW, Atlanta, GA 30305, USA (Dr. Virgil Brown); Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, USA (Dr. Judith Aberg); Brown University Alpert Medical School, 222 Richmond St., Providence, RI 02903, USA (Dr. Karen Aspry); Case Western Reserve University School of Medicine, 2109 Adelbert Rd., Cleveland, OH 44106, USA (Dr. Chris Longenecker); Columbia University College of Physicians and Surgeons, 630 W. 168th St., New York, NY 10032, USA (Dr. Merle Myerson)
M AN U
SC
Keywords: HIV AIDS Anti-retroviral drugs Infectious diseases Immunodeficiency Lipid disorders
EP
TE D
Abstract: The HIV-AIDS epidemic has provided one of the more challenging problems in treatment of infectious diseases. As anti-retroviral drugs made a very marked improvement in controlling the immunodeficiency state and patients gained in their longevity, the concern with lipid abnormalities came to the fore. The initial drugs produced a form of metabolic syndrome accompanied by very elevated plasma triglyceride concentrations. Furthermore, the drugs used to control the virus were often metabolized in a manner that interfered with lipid lowering drug therapy. The antiviral agents have improved in many respects and the experience in managing the lipid disorders has added greatly to our ability to control these problems as well. This roundtable discussion has been conducted with four physicians who have been involved in management of large cohorts of patients with HIV infection and who have had a special interest in reduction of vascular disease risk.
AC C
*Corresponding author Email address: [email protected]
ACCEPTED MANUSCRIPT
Clinical Lipidology Roundtable Discussion
W. Virgil Brown, MD Judith A. Aberg, MD Karen E. Aspry, MD Chris T. Longenecker, MD Merle Myerson, MD
RI PT
JCL Roundtable: Managing Lipid Disorders in Patients with HIV
TE D
M AN U
SC
INTRODUCION: The HIV-AIDS epidemic has provided one of the more challenging problems in treatment of infectious diseases. As antiretroviral drugs made a very marked improvement in controlling the immunodeficiency state and patients gained in their longevity, the concern with lipid abnormalities came to the fore. The initial drugs produced a form of metabolic syndrome accompanied by very elevated plasma triglyceride concentrations. Furthermore, the drugs used to control the virus were often metabolized in a manner that interfered with lipid lowering drug therapy. The antiviral agents have improved in many respects and the experience in managing the lipid disorders has added greatly to our ability to control these problems as well. This Roundtable Discussion has been conducted with four physicians who have been involved in management of large cohorts of patients with HIV infection and who have had a special interest in reduction of vascular disease risk. They are: Judith A. Aberg, MD, Karen E. Aspry, MD, MS; Chris T. Longenecker, MD; and Merle Myerson, MD, EdD. Their full titles and institutional affiliation are included below. (Recorded during the Scientific Sessions of the National Lipid Association in New Orleans, LA on May 21, 2016.)
AC C
EP
DR. BROWN: I will start by asking Dr. Myerson to review for us, the common lipid disorders found in patients who are infected with HIV at the initial presentation? Are there interesting lipid disorders before antiviral treatment has been instituted? DR. MERLE MYERSON: I think the first point is that we (as cardiologists and lipidologists) are seeing patients who are already treated and much less frequently those recently diagnosed. Overall, however, the lipid pattern is similar to that seen in metabolic syndrome with the lower HDL-C, small dense LDL particles, and higher triglycerides. DR. ABERG: In the United States because we're identifying and diagnosing individuals at a higher CD4 count, they typically do not manifest the severe lipid abnormalities found in chronic inflammatory states. The most common abnormality we see is the low HDL. The vast majority of participants in current day antiretroviral naïve studies have normal LDL cholesterol. Their triglycerides are around 100, their LDL area around 90, but their HDLs are usually always in the upper 30s. I would say that today at the time of HIV diagnosis these values are
ACCEPTED MANUSCRIPT the most common.
SC
RI PT
DR. LONGENECKER: I would agree that the most common lipid abnormality we see today in patients on modern regimens is low HDL while other lipid fractions are relatively normal. This contrasts with the early ART treatment era. Take for example, the Multicenter AIDS Cohort Study (MACS), which is a long running prospective cohort of HIV infected and HIV-uninfected men who have sex with men. They could track lipids in some of the uninfected men who later acquired HIV infection. This study published in JAMA in 2003 showed that after HIV acquisition and as immunodeficiency progressed-- all lipid fractions go down. LDL, triglycerides and HDL concentrations go down. Then with therapy LDL rises and triglycerides climbed even much more dramatically, while HDL remained low. That was in the era of older protease inhibitors. Things are different now with the newer drugs.
M AN U
DR. KAREN ASPRY: I agree, but we still see a lot of HIV patients who were treated late, and hypertriglyceridemia is almost always seen, often with lipodystrophy. As mentioned, protease inhibitors worsened this picture. Whole body lipid kinetic studies with highly active antiretroviral treatment (HAART) and lipodystrophy from a decade ago showed increased intracellular lipolysis in the fed and fasting states due to defective adipocyte function, leading to increased fatty acids, hepatic VLDL secretion and ectopic fat deposition. Newer data in treatment-naïve subjects suggest that HIV-specific factors also alter adipocyte and lipoprotein physiology.
TE D
DR. BROWN: Do we know anything about mechanism of these lipoprotein changes?
EP
DR. LONGENECKER: We do know that some of the virus proteins such as the nef protein can affect HDL concentration and functionality, which will impair reverse cholesterol transport. That may be one of the mechanisms by which active viremia promotes atherosclerotic vascular disease in HIV. Generalized systemic inflammation, as we've mentioned before, is probably the dominant mechanism.
AC C
DR. ASPRY: Yes, there is evidence that the virus may interfere with ABCA1 function and cholesterol efflux. There is also evidence that an HIV viral protein that circulates in both untreated individuals and those with full viral suppression inhibits PPAR-gamma and up-regulates the glucocorticoid receptor in mice, causing peripheral lipolysis and hepatic steatosis. There is also data that HIV-mediated gut mucosal injury causes a translocation of bacterial products to the liver and that may also cause hepatic inflammation and steatosis.
DR. MYERSON: I think we can all agree that some of the things we're seeing are similar to metabolic syndrome. For example, we have discordance between LDL cholesterol and other measures such as APOB or LDL particle number, which we also see in diabetics and those with metabolic syndrome.
ACCEPTED MANUSCRIPT DR. BROWN: The APOB, which is a reflection of particle number, would be elevated higher than one would expect from the LDL cholesterol values?
RI PT
DR. MYERSON: We gave a poster here at this conference showing that there's a greater percentage of HIV positive patients that have discordance--a higher LDL particle number than a comparable level of calculated LDL cholesterol. This is the second time we've looked at it and found consistent results. The clinical relevance is that a patient infected with HIV may appear to be at goal using LDL-C but their atherosclerotic particle burden can still be too high. DR. BROWN: Some of these patients may present with relatively low or normal triglycerides and yet still have a low HDL. Is that correct?
SC
DR. ABERG: That is correct. Over time, as with the duration of disease, you'll start to see that there's more of a rise in triglycerides.
M AN U
DR. BROWN: Have there been studies on interleukin-10 in this disorder? DR. LONGENECKER: There have been many studies on interleukin-10 in HIV. With regards to antiretroviral therapy and lipid changes, the investigators of the SPIRAL trial looked at whether switching a boosted protease inhibitor to an integrase inhibitor improved lipids compared to continuing the boosted PI. They also looked at inflammation biomarkers, and found no difference in IL-10 between groups.
TE D
DR. BROWN: Interleukin-10 in the inflammatory state can markedly reduce HDL production. Dr. Alan Remaley at the NIH, has reported on this in the Journal of Clinical Lipidology. He demonstrated that an infusion of interleukin-10 in patients can drive HDL to very low levels.
EP
DR. LONGENECKER: In SPIRAL, there was no correlation between baseline levels or changes in IL-10 and HDL. This is just one study, but there may be other mechanisms in HIV.
AC C
DR. BROWN: There's also an interesting set of data on ANGPTL4, which is a down-regulator of lipoprotein lipase function in adipose tissue, but it may allow continued activity of macrophage lipoprotein lipase. If you inactivate the gene for this protein in a mouse and feed saturated fat, you can create huge lymph nodes to the point that it obstructs lymphatic flow with fat bloated macrophages. I do not know whether viral infections can suppress this protein but it may be of interest. DR. ABERG: There has been some work on the impact of specific antiretrovirals on human adipocytes, gene expression and secretion of adipokines and cytokines but I cannot recall any data regarding ANGPTL4 in HIV. DR. ASPRY: I think that whatever the molecular mechanisms, chronic inflammation and adipocyte dysfunction appear to play roles in creating dyslipidemia in HIV.
ACCEPTED MANUSCRIPT
RI PT
DR. ABERG: Our management of HIV has changed over the past few years with the emphasis now that everyone with HIV infection should be offered antiretroviral therapy (ART) regardless of their CD4 T-cell count. A large randomized controlled study called START showed that individuals who have a T-cell count greater than 500 derive a significant benefit in both morbidity and mortality when taking antiretroviral therapy immediately compared with delaying ART until their CD4 count declines to less than 500.
SC
DR. LONGENECKER: We have patients who have a legacy of having had a very low CD4 T-cell count in their past. We call that the nadir CD4 count- the lowest CD4 count they ever had. Those are the ones that tend to have a higher inflammatory set-point. It's in these patients that we often see this low HDL. The low HDL, high triglycerides phenomenon may be a “low nadir-CD4 disease.”
M AN U
DR. ABERG: But they are treated now, too, so that's a different population and question. DR. BROWN: In the past, why did we routinely wait to until the CD4 count became very low before beginning treatment of known HIV infection? DR. ASPRY: Probably because data from the early HAART era showed some protease inhibitors were associated with a 1.1-fold increase in MI risk per year which was obviously cumulative, which led to reluctance to treat people with CD4 counts that were still elevated.
EP
TE D
DR. MYERSON: I just wanted also to drive home the point about the less toxicity of the anti-retrovirals. You know, now that we are giving anti-retroviral therapy (ART) as pre-exposure prophylaxis (PrEP), to people who are not infected. I think that shows that we've come into a new and very different era in anti-retrovirals although we still should remember that these drugs are not without side effects and risks
AC C
DR. BROWN: Are you referring to people who have been exposed because they had a needle stick, or are we talking about just high risk people like prostitutes? DR. ABERG: Yes, but it's not a medicine without side effects; it is safer, less toxic to the point that it can be used in a high risk and healthy person to help prevent HIV. There are side effects, as we've seen in some individuals, not so much lipid abnormalities but bone mineral density may be decreased and individuals with pre-existing kidney disease may have a decline in kidney function. DR. BROWN: At present, what are the first line therapeutic agents for HIV and how do they affect the lipoproteins? DR. ABERG: For all naïve patients, the first-line for the most part in the United States is an integrase inhibitor. There is still one protease inhibitor, darunavir, which remains first-line. There is more controversy regarding choosing a specific nucleoside
ACCEPTED MANUSCRIPT
RI PT
than which integrase inhibitor to use. It's subtle, but for the most part the integrase inhibitors are well-tolerated. Concern about drug interactions remains a predominant reason for the choice. Dolutegravir has been more preferred by many as it has the least number of drug interactions. The problem is that the fixed dose combination is with a nucleoside called abacavir that requires a genetic screening test before use to identify those at risk of having a hypersensitivity reaction to abacavir. There is controversy as to whether abacavir itself is associated with increased risk of cardiovascular disease. However, it is the drug that is preferred in those with chronic kidney disease which is a population at risk for heart disease.
SC
DR. BROWN: Are there baseline clinical or laboratory measures that would affect the choice of these drug classes or combinations?
M AN U
DR. LONGENECKER: I would mention that some of the protease inhibitors that are still in use today cause less elevation of triglycerides than the first and the second generation. Atazanavir and darunavir certainly cause triglycerides to become elevated, but maybe on average only 20 milligrams per deciliter. The integrase inhibitors do not cause elevation of triglycerides except for those that are boosted with cobicistat. Cobicistat is similar to the protease inhibitor ritonavir. Either of these can be helpful in boosting levels of other ART drugs.
TE D
DR. ABERG: Efavirenz can affect lipids adversely but does raise HDL-C. It's been shown that efavirenz works similar as a CETP inhibitor. However, it can increase LDL and more importantly, efavirenz has some central nervous system effects with a potential for increasing suicidal thoughts.
AC C
EP
It is of note that in AIDS Clinical Trials Group A5257 comparing atazanavir versus darunavir versus raltegravir; the protease inhibitors, not surprisingly were associated with increased LDL-C and triglycerides. Interestingly though, persons receiving atazanavir had the least progression of carotid intima thickness in the metabolic sub-study. DR. MYERSON: I think that that's a good point. When we're talking about classes of drugs - - we had mentioned tenofovir, which forms a basis of so many drug regimens. It was known as tenofovir disoproxil fumarate (TDF)and there is a new version known as tenofovir alafenamide (TAF) which causes less bone and renal problems. Less in known about TAF effects on lipids but Joel Gallant presented data at the Conference on Retroviruses and Opportunistic Infections (CROI) showing that although HDL-C increased, LDL-C and Triglycerides also increased more than with TDF. DR. BROWN: I agree with what Dr. Myerson said earlier, that these lipoproteins as altered by inflammation and are different in their composition and physiology in ways that epidemiologists have not
ACCEPTED MANUSCRIPT defined for us. It may be that using particle numbers as measured by apoB or with NMR will be more predictive of outcomes. DR. MYERSON: ApoB is usually covered by insurance whereas other tests of particle number are not.
RI PT
DR. ASPRY: While some modern anti-retrovirals may improve or not be associated with dyslipidemia, some like raltegravir have been associated with increased waist circumference and increases in insulin resistance and metabolic syndrome. Even though lipids may not be as deranged, insulin resistance may still occur with some integrase inhibitors.
SC
We haven't used these newer agents long enough to know if they do or do not increase future myocardial infarction (MI) risk.
M AN U
DR. ABERG: The necessity to use combination therapy makes it difficult to lay blame on any single drug. The nucleosides affect the sterol regulatory element-binding proteins, right? The nucleosides affected fatty acid synthesis. The protease inhibitors (PIs) were mainly affecting the 1c pathway. You have different drugs competing at different metabolic pathways plus HIV infection altering immune function and inflammatory pathways. It is very complicated. Extensive cellular metabolic studies have not been performed with the integrase inhibitors largely because we are not seeing the same metabolic phenotypes as with the older nucleosides and protease inhibitors.
TE D
I would like to point out, though, even when we were doing euglycemic clamps with ritonavir, you could see insulin resistance even after a single dose. daSilva presented clamp data after 24 weeks on lopinavir, and there was complete glucose homeostasis again.
EP
DR. ABERG: Understanding the longer-term effects has been challenging since some effects may be transient or unique to particular individuals due to possible underlying pharmacogenomics.
AC C
DR. BROWN: With our current experience, what are the aspects of a patient that would guide you to choose one regimen versus another? Do you use metabolic features? DR. ABERG: The newly diagnosed patient is looking for convenience and simplicity. One pill once a day is the expectation because of marketing. We do need to consider the patient's complete history. What are their co-morbidities? Are any drug interactions possible? Are they smoking? Our patients with HIV smoke at a much higher rates. The message to stop smoking is even more important in this population. Diet change is also important. In selecting the best combination of ART, the top considerations are the co-morbidities…the kidney and liver function and lipid levels. Again, the integrase inhibitors are first-line because of their safety profile and there is less virologic resistance. We do a genotypic resistance test at the initial diagnosis of HIV to
ACCEPTED MANUSCRIPT determine if the HIV virus is resistant. If they have been on previous ART regimens, this is even more useful. Based on the genotype results and underlying co-morbidities we choose a preferred regimen. Of course, many patients prefer a single tablet regimen even if we believe a multi-pill combination will be better for that individual. You have to educate and negotiate to settle the issue and usually patients will agree to the recommended therapy.
SC
RI PT
DR. MYERSON: One point is that as cardiologists and lipidologists we tend to see the patients after they've been genotyped and phenotyped and started on ART. Patients generally come us with a good CD4 count and are virally suppressed, tolerating their regimen—and then we deal with lipids and other risk factors. We rarely attempt to change the antiretroviral regimen. I tend to work around their ART regimen with lipid medications and lifestyle modification while looking for other secondary causes of dyslipidemia.
M AN U
DR. LONGENECKER: I agree that first line regimens today are based on an integrase inhibitor. In choosing specific drugs, with high cardiovascular disease (CVD) risk, I would try to avoid abacavir. In Patients with chronic kidney disease I avoid tenofovir and there tend to choose the abacavir containing regimen. Though that may change now with the introduction of tenofovir alafenamide (TAF) mentioned earlier.
TE D
Occasionally I do feel it appropriate to discuss ART changes with the primary HIV provider. Most are are open to considering a change if there is a good reason. DR. BROWN: In HIV infected patients, is there a first-line drug treatment for lipid disorders? We're usually dealing with higher triglycerides and these are often accompanied by high LDL particle numbers.
AC C
EP
DR. ASPRY: I think it's going to vary, and the practice is changing. In years past with the many drug-drug interactions between protease inhibitors and statins, the first-line drug was pravastatin. Then as safety data accrued and we started feeling more comfortable with rosuvastatin and atorvastatin where lowered doses may be safe and affected. Although atorvastatin with tipranavir was still felt to be contraindicated. It remains important to refer to the statin safety and drug interactions data updated regularly by the NLA. I think the practice may be changing now in support of pitavastatin because it has no major interactions or requirements to keep doses low no matter which ART the patient is on. In some health care systems, pitavastatin is not available. The statin of choice may depend on what the patient’s insurance company will pay for. DR. BROWN: Is there evidence that rosuvastatin or atorvastatin is less safe than pravastatin? Some of our patients could use greater efficacy than pravastatin offers.
ACCEPTED MANUSCRIPT DR. ABERG: Many providers of care in HIV have been using high intensity statins for a very long time. We were prescribing 40 milligrams of atorvastatin, and with a protease inhibitor that certainly is equivalent to 80 milligrams.
SC
RI PT
We used pravastatin initially because of the fear of drug interactions. The drug interactions were limiting everything that we could use. The other is that triglyceride elevations were our major concern with the initial ART drugs. I recall patient whose triglycerides rose well over 1000 while their HDLs were in single digits. You did not get much improvement in their lipid profiles when you prescribed a statin. I was chair of at one of the first studies in the AIDS Clinical Trials Group A5087, which tested pravastatin versus fenofibrate. Those medications did exactly what they were supposed to do. Pravastatin reduced LDL by 20 to 25%. Fenofibrate lowered triglycerides by 35%. However, you often could not achieve the NCEP composite goal.
M AN U
Previously, HIV providers were referring many patients with dyslipidemia to lipid experts. Today, with these new drugs, less than ten percent of patients in the HIV primary care clinics have dyslipidemia.
AC C
EP
TE D
There still are two discrete populations in which lipid management may differ. The first is the group with lipid abnormalities before they acquired HIV infection. Treating HIV is not going to correct their dyslipidemia. You just need to diagnose their lipid condition and treat them as you would anyone else. With high triglycerides (> 500 mg/dL) attributable to HIV disease or secondary to ART, I treat the triglycerides first because of the risk for pancreatitis. Both hypertriglyceridemia and mitochondrial toxicity of the nucleosides can contribute to initiation of pancreatitis. We rarely see pancreatitis with the newer anti-retrovirals and hypertriglyceridemia is uncommon. Nevertheless, if they do not have an immediate cardiac concern, I will lower the triglycerides first and then assess their LDL-C. When LDL-C, non-HDL-C or both are elevated as the major lipid abnormality, statins are first-line. Unfortunately, the choice of the statin is not always in our control as we must deal with preferred formularies and obtain pre-authorization. DR. BROWN: The old rationale was that there were several of these that inhibited the cytochrome enzyme CYP-A4 and other pathways of metabolism. The old protease inhibitors were a particular problem in this respect. Pravastatin, rosuvastatin and pitavastatin are not metabolized by the Cyp A4 system but there may be other vulnerabilities in there metabolism? DR. ABERG: The drug interactions can be quite complex. Rosuvastatin is mainly metabolized via CYP2C9. There are lesser contributions from CYP2C19 and CYP3A4 isoenzymes but these can cause significant drug-
ACCEPTED MANUSCRIPT
RI PT
drug interactions. Rosuvastatin can also interact with various PIs through non-CYP mechanisms. It is a substrate of organic aniontransporting polypeptide 1B1 (OATP1B1) and breast cancer-resistance protein (BCRP). Protease inhibitor (PI) induced inhibition of OATP1B1can can cause a decrease in hepatocyte uptake of rosuvastatin while inhibition of breast cancer resistance protein (BCRP) decreases hepato-biliary excretion and increases rosuvastatin absorption. There are additional transporters and polymorphisms in drug metabolism genes that also may affect drug concentrations potentially leading to adverse outcomes.
M AN U
SC
Trying to predict who will or will not have a drug interaction is very difficult but fortunately clinically uncommon. It is not cost or time effective to evaluate drug metabolism genes on everyone and the reality is the major drug interactions are known. Most individuals on ART will do fine with either atorvastatin or rosuvastatin with the dose adjusted as per the package inserts. Pravastatin is widely used as it has minimal drug interactions except with darunavir. However, pravastatin has less efficacy in reducing LDL choesterol. Pitavastatin is the cleanest, but is not on some formularies as it has not been widely studied in the USA.
TE D
DR. LONGENECKER: I feel pretty strongly about this. I've had a lot of patients who have come to me on pravastatin who were not nearly close to a desirable LDL-C goal. Often their providers were overly cautious about using any other statin. The NLA panel on recommendations for lipid management felt strongly that we should recommend higher dose statins for patients that might benefit. Atorvastatin and rosuvastatin can be used at moderately high doses in someone who is on ritonavir or other protease inhibitors.
AC C
EP
DR. MYERSON: It is common to need to address the elevated Triglycerides first. However, this tends to be more complicated in HIV patients. They may have co-morbidities, Hepatitis infection, alcohol and substance abuse and require more careful consideration of drug choices. Then there is often an issue with drug coverage and formulary restrictions. Gemfibrozil may be the only available fibrate but this has more complications with statins. Omega-3 fatty acid and fish oil extracts may be helpful but they are also not covered by all plans and can be expensive. Compliance can be a problem with high doses. So, there are layers of complexities here that influence our decision. DR. ABERG: We have a wide choice of statins. Pitavastatin was superior to pravastatin in lowering LDL in the Intrepid study. So, it can be in the game. In my practice, it seems that more develop signs of type 2 diabetes on rosuvastatin than atorvastatin but this is a relatively small occurrence. Dr. Brown:
When do you choose to use drugs other than statins or in
ACCEPTED MANUSCRIPT combination with statins in HIV patients?
RI PT
DR. MYERSON: The American College of Cardiology recently had a statement about non-statins. I tend not to use the bile acid sequestrants. I do not believe that I have a HIV-positive patient on them. They tend to raise triglycerides. Also, they interact with other medications. For patients taking medications throughout the day waiting four hours between other drugs is not feasible. I also tend not to use niacin with the concern about glucose intolerance and the difficulty in adherence.
M AN U
SC
DR. LONGENECKER: Another class of drugs—the PCSK9 inhibitors are very promising. Admittedly, there are very limited data in HIV patients, but there were six patients treated in the evolocumab trials. They had a similar LDL response on top of high-dose statin compared to the uninfected subjects. Priscilla Hsue from UCSF has reported these data at the AHA and ACC. In a larger cohort of patients in San Francisco, those with HIV tended to have higher blood levels of PCSK9 measured by ELISA. Patients with HCV co-infection had particularly high levels of PCSK9. Although they will not be routinely used, I think that in certain patients these drugs will be quite effective. DR. MYERSON: I do use ezetimibe, generally as an add-on to statin therapy.
AC C
EP
TE D
DR. ASPRY: I believe many of these individuals need combination therapy. Which lipid drug to start first obviously depends on the patient’s baseline triglyceride level and cardiovascular risk. The big question is: What is the best first agent for those with triglycerides in the 500 to less than 1,000 range? This is a grey area even in non-HIV infected individuals. I support treating these individuals with statins first because they are the best agents for lowering non-HDLcholesterol, which tracks best with LDL-particle number, I choose a fibrate as a first-line drug only if triglycerides are 1000 mg/dl or higher. I think that while there is subgroup data to support fibrates – when HDL is very low and triglycerides are very elevated, I believe if a patient is diabetic, near diabetic or has multiple vascular risk factors, which is common in HIV, there's more data to support a statin first as long as triglycerides are less than 1000 mg/dl. We are still awaiting more hard endpoint studies. There are placebo controlled data in HIV patients using CT angiography showing that statins are associated with atherosclerosis regression although it was a small study. Statins also improve markers of immune activation and of inflammation, as well as non-invasive measures of endothelial function, in individuals with HIV. DR. BROWN: I would agree. Previously I felt that you should treat with fibrates first because you couldn't interpret the LDL cholesterol even with triglycerides over 300 mg/dl. Now we have APOB or particle numbers. With these you can make a judgment about the statin effect even though the LDL cholesterol value is so distorted by the hypertriglyceridemia. With triglycerides below 1000, it doesn't
ACCEPTED MANUSCRIPT
RI PT
matter whether you start with fibrates. The non-HDL-C is important to evaluate in this instance. If it is lower than expected, the predominant particle may be chylomicrons and there, fibrates are clearly drugs of choice. If the non-HDL-C is quite elevated, statins may be the best initial treatment. Combinations of the two are often best in the patients with triglycerides over 500 mg/dL. However, it is important to start them in sequence since you want to determine the efficacy of each addition.
M AN U
SC
DR. ABERG: I would just counter that a little bit for all patients. I agree totally about assuring someone with CHD gets on a statin immediately. You as a cardiologist are seeing patients that have known or suspected coronary heart disease, and I agree patients that need a statin should be on a statin. The person that I usually see is the typical 30-year-old that comes in and they have medication induced hypertriglyceridemia or newly diagnosed HIV with high triglycerides. I am going to treat that triglyceride first because that's not a person that I feel is in immediate threat of CHD. These are completely different populations and management needs to be individualized. In the ACTG A5087 study I mentioned before, we actually showed that the sequencing of using a fibrate first and a statin resulted in the best overall lipid profiles. DR. BROWN: Those are usually judged on the basis of LDL cholesterol, and the LDL fattens up when you use fibrates but particle number tends to go down.
TE D
DR. ABERG: Of course, that is correct.
EP
DR. BROWN: These patients that you're worried about here, the 500 to 1000 or above are at more immediate risk from pancreatitis and that can be a logical reason to start with a triglyceride lowering drug. In that I agree. Do you use fish oil in those presenting with very high triglycerides?
AC C
DR. ABERG: The AIDS Clinical Trials Group did a study of comparing fenofibrate versus 3 grams fish oil, and then after 12 weeks using combination therapy for those who did not meet goal. The fibrate produced a larger reduction of 58% compared with 46% decrease in triglycerides with fish oil. The combination reduced triglycerides by 65%. I still do use combination therapy in some people that have high triglycerides. I've had patients that are on fibrate, fish oil, and niacin and still cannot achieve goal. Thankfully such high triglyceride levels are much less common now. We just did a database search in over 10,000 patients in our recruiting for the REPRIEVE trial. Less than one percent of patients had a triglyceride concentration of over 500 mg/dL. DR. BROWN: About one percent in the general population has triglyceride values above 500 mg/dL. The question of managing the triglyceride disorder seems to be much less frequent as we've used these new regimens.
ACCEPTED MANUSCRIPT I would like to hear of your experiences regarding lifestyle change. Drugs usually dominate our therapeutic decisions in these HIV patients but does lifestyle play an important role?
RI PT
DR. LONGENECKER: I run an HIV cardio-metabolic risk clinic in an HIV medical home. I believe that HIV is a disease where you have an opportunity to work together with primary care providers, often dietitians and social workers to create programs in a community that has a very strong social cohesion and identity.
SC
For example, we have a community garden at our HIV clinic where patients help to tend the garden. They can take produce home with them. There's a lot of emphasis on lifestyle changes. We have yoga and walking groups and that sort of thing. We're running a clinical trial trying to determine ways to help people redesign their environment in such a way that they are not totally dependent on personal motivation to make healthy lifestyle choices.
M AN U
DR. BROWN: Community support helps them develop and maintain healthful habits? DR. LONGENECKER: It's very important in a community where there are limited food choices. In East Cleveland, for example, where we are it's very difficult for people to access foods that we consider healthy. I think you'll find that in many of the HIV communities around the country.
TE D
DR. BROWN: Do you all feel that this is an important part of the therapy?
EP
DR. ASPRY: I do. As we mentioned at the outset, HIV has become a chronic disease and individuals now have a chance to live a normal lifespan. So, we must treat it like a chronic disease, which means using teambased approaches to deliver multidisciplinary longitudinal care. I think that includes, obviously, aggressive dietary interventions. A review in 2012 showed that diet interventions do work in this disease, lowering triglycerides in the 50-point range, which is significant.
AC C
However, a focus group study showed that the barriers to diet change in HIV patients are probably greater than in the general population. There are obviously financial barriers. Fresh produce, fish and lean meats that we're asking people to consume are expensive.. There are also many psychological barriers. Individuals who experience a lot of wasting in the beginning stages of the disease often feel that they need to consume more calories, and that is often from fat rich and unhealthy foods. The family and cultural barriers may also be greater. The family eating patterns might be difficult for people to overcome. Some are homeless and have unstable living situations without social or family support. The focus groups did show these individuals are helped by a regular contact with providers. It may be physician or non-physician provider like a dietitian that provides psychological support.
ACCEPTED MANUSCRIPT Experiential learning may also help. Group visits to the market and cooking classes teach important and practical lessons about healthy eating.
RI PT
DR. BROWN: Is there a growing population of people who have been through this HIV experience and dealt with all the issues that you have described here in terms of medical treatment - patients that are beginning to live a normal life with families and jobs?
M AN U
SC
DR. LONGENECKER: Not only would I say that our patients can have families and good jobs, I think that it should be our expectation that our patients live a normal life. In fact, people can live very well with HIV. I think that in many ways they have an opportunity to live even better than they would have if they didn't have HIV. There's some data to suggest in the Kaiser Permanente system, for example, that the rates of myocardial infarction are going down, and the relative risk due to HIV is going down over time. Some have attributed this to very good medical care. The average man in his 30s or 40s may not get good primary care; but if he has HIV, they're often engaged in a medical system where good primary care is inherent. They often have a community where healthy lifestyle decisions are communicated.
EP
TE D
DR. ASPRY: As Dr. Longenecker mentioned, early data from Northern and Southern California Kaiser has shown that between 1996 and 2011 the relative risk of MI in their HIV-infected population of almost 25,000 dropped essentially to that of a matched HIV-negative cohort. This is likely because these are all insured patients treated within an integrated healthcare system that uses systematic and multidisciplinary approaches to deliver chronic care. More than a third of their HIV infected individuals are now taking lipid lowering and blood pressure lowering medications, a prevalence greater than in non-infected individuals. Also 90% are now on ART with mean CD4 counts of >600. Hopefully as healthcare in the U.S. transitions to similar value-based care delivery models, we can achieve these outcomes nationally.
AC C
DR. BROWN: On that hopeful note, I want to ask one final question here. What studies are underway now that are going to add to our knowledge about managing HIV and that will be very significant in the future? Dr. ABERG: REPRIEVE is a study of 6500 individuals with HIV who do not have a clinical indication to be on a statin, defined as having no known existing coronary heart disease and an ACC/AHA risk score of less than ten percent. The patients are randomized to either go on pitavastatin or placebo. They will be followed for five years. It's similar to the JUPITER study. There is a substudy of 800 individuals in which various biomarkers are being monitored for signals of risk and responsiveness. Dr. Longenecker has been very engaged in one study called SATURN, which was looking at rosuvastatin versus placebo, trying to enrich for people that seem to have more inflammation and whether or not
ACCEPTED MANUSCRIPT there was a benefit in taking a statin. They did see some improvement in some markers which he might elaborate on. However, in the several studies of this type, there has not been a consistent decrease in any one biomarker. The AIDS Clinical Trials Group just completed a study evaluating atorvastatin versus placebo in a crossover design. All the biomarkers were completely flat.
M AN U
SC
RI PT
We have observed the consistent lowering of LDL, oxidized LDL and lipoprotein-associated phospholipase A2, all lipoprotein related markers. I just don't think we understand the pathogenesis enough to tease this out. The problem with these smaller studies is that we're trying to enrich for the population most at risk without knowing what biomarker can identify the population that would benefit the most. Using these markers in selecting the cohort for study, you often exclude those who do not have elevated immune activation, the vast majority of HIV patients. They don't have high hs-CRP. They don't have a high IL-6. If you only enroll patients who do have elevated markers of immune activation, inflammation or coagulation, you may wind up with a study population whose results may not be applicable to the majority.
TE D
DR. LONGENECKER: Studies that consider inflammation as a target include the testing of biologics such as those used in rheumatoid arthritis and psoriasis. The hypothesis is that a lot of the residual immune dysfunction in some patients is caused by high inflammation. In Cleveland, we’re conducting a trial of tocilizumab, for example, which is an IL-6 receptor blocker. Some of the secondary outcomes include lipid sub-fractions and lipoprotein functionality as well brachial artery endothelial function. Methotrexate and IL-1β blockade with canakinumab are two other interventions that are being tested in small randomized clinical trials.
AC C
EP
DR. ABERG: One of my Sinai colleagues, Meagan O’Brien has been studying aspirin, and we have a pilot study that's evaluating aspirin versus clopidogrel as there is some data to suggesting that platelets are highly activated and potentially contributing to inflammation and thrombosis. DR. ASPRY: I think that identifying and targeting new biomarkers is important, but the impact from controlling traditional risk factors in the HIV population must not be underestimated. For example, there is an almost three-fold higher prevalence of smoking in HIV positive patients, and modeling within the large DAD cohort showed that smoking cessation had the largest impact on reducing future vascular risk. DR. ABERG: We also have the problem that we haven't had people living with HIV for the duration of time to have the numbers to compare to the general population and truly test our current data for such modeling. Dr. Brown:
I want to thank you for answering my questions and
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
participating in this discussion. This has been very informative and potentially very useful for the readership of our Journal. Your experience in managing vascular disease risk factors and particularly lipoprotein related risk is important to share with the clinical lipidologists who have very few HIV infected patients. Most importantly, you have made clear that well managed patients with HIV can have a much improved and often completely normal life managed with current tools. Active research in this area may provide new knowledge that will not only help those with HIV but also all patients with lipid abnormalities.
ACCEPTED MANUSCRIPT
Reading list:
AC C
EP
TE D
M AN U
SC
RI PT
1. Longenecker CT, Sullivan C, Baker JV. Immune Activation and Cardiovascular Disease in Chronic HIV Infection. Current Opinion in HIV/AIDS. 2016 Mar;11(2):216-25. 2. Longenecker CT, Eckard AR, McComsey GA. Statins to improve cardiovascular outcomes in treated HIV infection. Current Opinion in Infectious Diseases. 2016 Feb;29(1):1-9. 3. Lo J, Lu MT, Ihenachor EJ, Wei J, Looby SE, Fitch KV, Oh J, Zimmerman CO, Hwang J, Abbara S, Plutzky J, Robbins G, Tawakol A, Hoffmann U, Grinspoon S. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIVinfected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015 Feb;2(2):e52-63. 4. Nou E, Lo J and Grinspoon SK. Inflammation, immune activation, and cardiovascular disease in HIV. AIDS 2016, 30:1495–1509. 5. Kaplan-Lewis E, Aberg J & Lee M. Atherosclerotic Cardiovascular Disease and Anti-Retroviral Therapy. Curr HIV/AIDS Rep (2016) 13:297–308. 6. Eckard AR, Meissner EG, Singh I, and McComsey GA. Cardiovascular Disease, Statins, and HIV. J Inf Dis. 2016:214 (Suppl 2) S83-S92.
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT