There is evidence that statin therapy may prevent the progression of coronary atherosclerosis (hardening and narrowing of arteries that irrigate the heart) in people living with HIV, according to the results of two randomized clinical trials reported last week at the 2015 on Retroviruses and Opportunistic Infections (CROI) in Seattle.
In the first study, the use of atorvastatin (Lipitor) reduced the total volume of plaque deposits in the coronary arteries in people with HIV, including plaques known as "high-risk morphology plaques", which are particularly vulnerable to acute rupture leading to heart attacks, stroke and sudden cardiac death. The second study of statin therapy in people on antiretroviral therapy found that rosuvastatin (Crestor) prevented the progression of layer intima-mediaA surrogate marker for vascular disease and disease atherosclerotic.
It still needs to be demonstrated if statin therapy will actually translate into fewer cardiac events and fewer deaths among people living with HIV; statin use was investigated to reduce cardiovascular disease (CVD) and provide a survival benefit to people in the general population, not limited to HIV-positive people. However, the risk factors for CVD are somewhat different for HIV-positive people in relation to HIV-negative and thus the issue is being addressed by the study "Reprieve ", A large multicenter clinical trial that is now beginning.
CVD in people with HIV
"Even though rates of death and HIV-related mortality have been reduced with the use of more potent antiretroviral therapy, rates of cardiovascular disease including myocardial infarction, stroke, and sudden cardiac death remain extremely prevalent among HIV-positive patients for HIV - insistently so - and are leading causes of morbidity and mortality, "Steven Grinspoon of Harvard Medical School told conference participants during a plenary talk on the morning of the last day of the conference.
"But, unfortunately, there is only a limited understanding of the mechanisms and treatment strategies for cardiovascular disease in HIV."
Several cohort studies have suggested that heart attack rates and CHD are up to two times higher in HIV-positive people than in HIV-negative population. Both Traditional and non-traditional risk factors contribute to increased risk. For example, smoking is more common among people living with HIV than in the general population. According to recently published analysis of 17.995 people with HIV in the Cohort Collaboration ART , those who smoke had a greater than six-fold higher mortality rate related to cardiovascular disease than those who did not smoke.
However, even when traditional risk factors are excluded, there is clear evidence of an increased risk of cardiovascular disease in people with HIV. An analysis of the Veterans Aging Cohort Study (VACS) found that the hazard ratio (HR) of acute myocardial infarction (MI) was almost 50% higher in HIV-positive patients compared to HIV-negative veterans, even after adjustment for traditional risk factors, comorbidities and use of psychotropic substances.
At the beginning of therapy (ART) was antiretroviral, much of the responsibility for the increase in heart attacks among people living with HIV was linked to specific antiretroviral drugs, such as abacavir (Ziagen, also in Kivexa -There is no data available on Wikipedia regarding this word), although this association has been controversial because of conflicting evidence.
More recent data suggest that ART (antiretroviral therapy) effectively has a positive effect on the risk of cardiovascular disease, most likely to improve immune function and reduce immune activation.
According to Grinspoon, recent studies support a mechanistic-emerging paradigm in which the immune activation and the persistent inflammation contribute to a unique presentation of atherosclerotic disease in people living with HIV.
Studies using coronary computed tomography angiography (CTA) have shown that people with HIV have a higher prevalence of deposits of non-calcified coronary plaques in your arteries, with morphology characteristics of high-risk plaques that have been associated with heart attacks, stroke and sudden death.
The chronic inflammation in the blood surface and, perhaps, cholesterol metabolic disorders could facilitate the formation of these plaque deposits. It is believed that inflammation may be due to the action of T-cells and activation of monocytes as a result of enhanced viral replication or microbial translocation (the leakage of bacteria from the gut to the systemic circulation). Studies have found evidence of changes in intestinal flora and damage to intestine and impaired mucosal integrity even among people with undetectable viral load in therapy Antiretroviral (TAR). In fact, much of the damage to the intestine may take place before the patients had started treatment, since this wear begins soon after infection.
Therefore, prevention and treatment of heart disease in people living with HIV, require action that addresses traditional risk factors and also related to the immune system - and Grinspoon believes statins may do just that. Statins lead to lower low density lipoprotein index (LDL) cholesterol "bad" at a similar level in both HIV-positive person HIV-negative person as but Grinspoon noted that in the general population studies have shown a greater effect on a reduction in cardiovascular events could be explained by the reduction of LDL alone. Some of the advantages may be due to anti-inflammatory effects of statinsSince statins have demonstrated the ability to reduce inflammation and reduce blood and monocyte activation traffic.
Although statins have been used to lower LDL cholesterol in people on ART, Antiretroviral Therapy, only now the scholars are beginning to evaluate the effects of statin therapy in the course of cardiovascular disease in people living with HIV. The results of two of the first studies were reported soon after the lecture Grinspoon.
In addition to reducing cardiovascular events, intravascular ultrasound have shown that the statin therapy may lead to regression of plaques in the general population. However, "no study has evaluated yet directly the effects of statins on coronary plaque in people living with HIV," said Janet Lo, Grinspoon fellow at Massachusetts General Hospital and Harvard Medical School.
So she and her colleagues conducted a double-blind, randomized, placebo-controlled trial to see if atorvastatin would prevent the progression of coronary plaque and reduce vascular inflammation in HIV-positive people with no signs or symptoms of clinical cardiovascular disease and optimal levels of LDL cholesterol or near optimal (<3,36 mmol / L / 130 mg / dl).
However, the study participants had all one or more plates, assessed by coronary angiography and computed tomography. Eligible participants then underwent positron emission tomography (FDG-PET) scanning fluorodeoxyglucose and those with arterial inflammation, aortic top target 1,6, were included in the study.
A total of 40 qualified participants were randomized to one year of treatment with placebo or atorvastatin to determine the effects on coronary atherosclerotic plaque. Most (about 80%) were men, the average age was about 50 years and almost 30% were smokers.
There were no statistically significant differences in baseline characteristics of the participants in both arms of the study. Framingham Risk scores (predicting the risk of a cardiac event in the next ten years, based on the presence of traditional cardiovascular risk factors) were very low and the average level was about LDL 3,23 mmol / L (125 mg / dL).
The majority of patients had well controlled HIV infection and C-reactive protein (a marker of systemic inflammation) was not elevated baseline.
During the first three months of atorvastatin was given at doses of 20 mg per day, and if the participant tolerated atorvastatin without safety laboratory abnormalities, the dose was increased to 40 mg for the remaining nine months of the study. The two groups, both control, placebo, as well as the active drug group also received guidance on healthy lifestyle and nutritional counseling according to National Cholesterol Education Program guidelines.
The CT images of the analysis was performed by a single specialist in cardiac imaging, very experienced, blinded to the treatment group and clinical status of patients. The main diagnosis was the volume of the plate; Plates were examined and also the morphology of high-risk features such as low attenuation, irregular calcification and positive remodeling rate.
As expected, LDL cholesterol decreased in the atorvastatin group by 0,98 mmol / L (-38 (+/- 29) mg / dl), while the placebo group increased by 0,28 mmol / L (11 (+/- 21 ) mg / dl). The overall volume measure plaque in coronary CTA decreased 4,7% with atorvastatin. Notably, there was an increase of 18% in plaque volume within just one year in the placebo group. Additionally, atorvastatin reduced the volume of non-calcified plaque 19,4% but concern in the placebo arm, the volume of non-calcified plaque growth weaves over one year of 20,4%.
Likewise, while 80% of the participants in the placebo arm experienced a progression of the plate over a period of one year, 65% of those receiving atorvastatin experienced a plaque regression. Three patients in the placebo group developed clinically significant progression of stenosis (narrowing of the valve). There were no changes in calcium scores (used to predict the risk of future cardiac events). However, there was an increase in high-risk features morphologies of the plates in the placebo group, compared to a slight regression of resources in the atorvastatin arm.
Due to technical limitations, the effects of statins in arterial inflammation by FDG-PET could not be properly evaluated. However, researchers have also examined the vascular inflammation using another technique: The phospholipase A2 associated lipoprotein levels, an enzyme secreted by inflammatory cells, has been implicated in atherosclerosis. They found that levels decreased significantly with atorvastatin, consistent with findings in other studies, including the SATURN-HIV study.
The levels of glucose and hemoglobin A1C not deteriorated in the atorvastatin group. Although the study was not designed to specifically evaluate endpoints inflammatory, a decrease was observed in a number of immune activation markers of inflammation - as C-reactive protein, soluble CD14. Estimated GFR (a marker of renal function) deteriorated in the placebo group but not in the atorvastatin group, while the comparisons between groups were not statistically significant.
The rate of adverse events was low and similar between those using atorvastatin or placebo.
The second study, presented by Grace McComsey of Case Western Reserve University in Cleveland, reported conclusions of the SATURN-HIV study, showing that rosuvastatin therapy may also be beneficial using some health measures and risk of CVD different.
SATURN-HIV was a 96 weeks of double-blind study in a randomized clinical trial format of rosuvastatin 10 mg daily versus placebo among people with HIV 147 stable HAART with LDL cholesterol <3,36 mmol / L (130 mg / dl ). Baseline characteristics were well balanced between the two arms. Most (80%) were men and about two-thirds were smokers. Half was taking protease inhibitors at baseline and mean cell count was greater than CD4 600 cells / mm3. At baseline, the carotid IMT was similar in both arms. At least one third had carotid plaque (% by rosuvastatin 33 43% versus placebo) or detectable coronary artery calcification (% vs 33 40%, respectively).
To be eligible, participants had to have increased T cell activation indications (+ CD8 CD38 + HLA-DR +> 19%) or increased inflammation (high-sensitivity C-reactive protein> 2 mg / l). Randomization was stratified by use of protease inhibitors (given the potential for drug interactions) and coronary artery calcium score (CAC).
Ultrasound was used to measure the intima-media thickness (IMT) of the common carotid artery and the presence of carotid plaque. Scans cardiac gated CT were used to measure the CAC score.
As expected, there were significant reductions in LDL cholesterol levels of rosuvastatin as compared to the placebo group. The average carotid IMT progression was slower than expected, but has progressed significantly in the placebo group during 96 weeks, remaining unchanged in the rosuvastatin group. The differences between the two arms were more pronounced among participants with a baseline calcification of the coronary artery. There was no change in the prevalence of carotid plaques by study arm. The overall prevalence of detectable coronary calcification seemed to increase slightly in the rosuvastatin arm during the study, but the change in CAC score in the subgroup of patients with coronary artery calcification at baseline decreased significantly in rosuvastatin.
Changes in IMT was independently of the use of protease inhibitors, LDL level, HOMA-IR (insulin resistance measurement), the CD4 count, C-reactive protein or T-cell activation. Further declines in carotid IMT were seen among participants with higher IMT at baseline and IL-6 greater and greater proportion of patrol CD14dimCD16 + monocytes (both markers of inflammation and immune activation).
A total of 28 participants - nine in the rosuvastatin arm, the rest in the placebo arm - left the study prematurely, and yet there were only three, including two rosuvastatin recipients, who did so for reasons possibly related to the study drug . These include an individual with myalgia and high CreatineAnd the possible exacerbation of symptoms of neuropathy.
Moving Forward: risk prediction more accurate becomes necessára
The effects of atorvastatin and rosuvastatin in people living with HIV appear to be of a similar magnitude to that seen in the general population, but both Lo and McComsey concluded that more studies are needed to determine whether statins and other anti-inflammatory agents reduce the number of cardiac events in people with HIV.
The study REPRIEVE , who uses pitavastatin (Livalo) - which is differently metabolized and has no known drug interactions with antiretrovirals - should be able to provide this response, and may also shed light on the mechanisms by which statins work in people with levels LDL close to ideals.
But the study will take more than 7.000 years and several participants to reach a conclusion. It is not clear that all living with HIV have time to wait. Meanwhile, it is essential to better identify what people with HIV are truly at risk of cardiac events - and treat them if necessary.
Translated and adapted by Claudio Souza with revision of M. *. M. between the 10 March 2015 noitede, from the original Published on March 10 2015 in English located in "Studies offer mounting evidence que statins may reduce the risk of heart disease in people living with HIV"By Theo Smart
Grinspoon S. Cardiovascular disease in HIV Patients: an emerging paradigm and call to action. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, abstract 134, 2015.
J Lo et al. Statin therapy coronary angiograms noncalcified plaque volume in HIV Patients: a randomized controlled trial. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, abstract 136, 2015.
CT Longenecker et al (McComsey G presenting). Rosuvastatin Arrests progression of carotid intima-media thickness in treated HIV. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, abstract 137, 2015.