 |
|
|
| |
Metabolics, Inflammation, Complications, and Aging at CROI
|
| |
| |
David Alain Wohl, MD - The University of North Carolina
The last session of the 19th CROI was titled, The Long and Winding Road of HIV Complications. What an apt description of a field that was launched with the study of the toxicity of antiretrovirals (Got Mitochondria?), morphed into the realm of metabolism (remember Crix Belly?), and now is centered on an axis of immune activation, inflammation and gut microbe translocation.
At the conference several of the studies presented in this area were provocative and promise to light the fuse on additional research to improve our understanding of the long term effects of HIV disease on the body. In addition, the aforementioned final session featured expert analyses intended to put what we currently know into perspective. All the oral sessions were videotaped and are available for viewing (www.retroconference.org). Most of the presentations are 10-20 minutes in length (and many posters are reproduced on the conference website). Therefore, it is possible to 'attend' the conference virtually and I encourage the reader to do so. Below I highlight and comment on the presentations worth looking at:
Inflammation in the aorta is high among HIV+ patients
One of the most interesting presentations regarding the toll of HIV on well-being came from the prolific group headed by Steven Grinspoon at The Massachusetts General Hospital in Boston (1). Dr. Grinspoon has long been active in probing the ways HIV and its therapies affect complex metabolic mechanisms. He presented data from a study that looked at the presence of inflammation of the aorta among three groups of people:
- 27 HIV-positive patients without known cardiovascular disease (CVD), on stable ART
- 27 HIV-negative individuals without known CVD and matched to the HIV+ group for age, gender and Framingham Risk Score (FRS) for 10-year risk of CVD
- 27 HIV-negative controls with known atherosclerotic disease, matched to HIV+ group by gender
All participants underwent fluorodeoxyglucose positron emission tomography (FDG-PET) to detect metabolic active cells, particularly macrophages, in the arterial wall as a measure of arterial inflammation. FDG is an analogue of glucose and metabolically active cells like active macrophages take up this marker as a source of energy. In addition, CT scanning for coronary calcium scoring was conducted.
The HIV+ patients had a mean CD4 of 592/mm3 and almost all had either undetectable (74%) or low level plasma HIV RNA levels. Average age of the participants was 52 years for the HIV+ group, 54 years for the controls without CVD, and 69 years for the controls with CVD. Coronary calcium scores were high in the controls with CVD , practically zero among the controls without CVD and in between for the HIV+ group.
Aortic FDG-PET uptake (i.e., aortic wall inflammation) was significantly higher for those with HIV than for the matched controls. In fact, the uptake of the tracer for the HIV+ group was similar to that of the HIV-negative group with known CVD and who were a decade older. Subgroup analyses were conducted to slice the data in all sorts of ways to minimize bias due to confounding (i.e., restrict analyses only to non-smokers or those with no coronary calcium) and the risk of having more FDG uptake was consistently higher for the HIV+ individuals compared to the matched HIV- controls. In a multivariable analysis, being HIV+ was an independent predictor of aortic wall inflammation while FRS (Framignham Score), statin use, calcium score and LDL cholesterol were not. Additionally, ART class (half the HIV+ patients were on a protease inhibitor) was not associated with arterial inflammation.
Of a host of circulating inflammation markers examined, only sCD163, a marker of monocyte activation that has been linked to atherosclerosis, was correlated with the FDG uptake.
The Bottom Line: This elegant study finds that HIV+ persons on ART with controlled viremia and without known cardiovascular disease have inflammation of the wall of their aortas on par with that of older HIV-uninfected patients with known CVD. Other studies have shown an increase in carotid artery wall thickness, dysfunction of the arterial endothelium and an array of biomarkers of generalized inflammation among HIV+ people compared to HIV-uninfected controls. Here we see actual evidence suggestive of an exaggerated inflammatory process at the wall of the aorta itself in persons with HIV on ART with controlled viremia.
The study cannot tell us why this is occurring. It was cross-sectional and, therefore, is unable to describe changes over time. HIV+ patients were on ART but the duration of therapy was not reported and presumably all had untreated HIV for a prolonged period prior to initiating therapy. This is a critical area for further exploration. When does this inflammation start? How do traditional risk factors for CVD play into this type of inflammation? Is it a process that starts with infection and, if so, what is the impact of ART and viral suppression? Does it reverse the process, or slow its progression or, god-forbid facilitate it?
Larger longitudinal studies will address these questions. Further, interventions that may slow such inflammation can also be studied. Statin therapy was not found to be protective in this small study, but this and other anti-inflammatory approaches need to be studied.
Other studies at the conference looking at evidence of CVD examined different populations and used different methodologies. For example, Boyd et al in Paris found that among male, non-smokers on ART those with low-level residual viremia (between 1 and 40 copies/mL) had worse CIMT than those with less than 1 copy of virus/mL (2). Markers of inflammation in this small study tended to be higher in those with residual viremia. In the Grinspoon FGD-PET study some patients had low-level viremia and to what extent that influenced aortic inflammation is not known.
When looking for associations between HIV and CVD, traditional factors prevail
While the Grinspoon study raises serious concerns regarding the health of the cardiovascular system of HIV-positive persons, it cannot tell us why there is more evidence of inflammation in the aorta of infected individuals and if this will indeed lead to atherosclerotic disease. There have been a number of studies looking at actual atherosclerosis in HIV-infected and -uninfected controls with most finding more disease among those with the virus. But, often there are cofounders that even the best case matching system can miss.
Another study to look at evidence of CVD in HIV-infected and -uninfected controls came from the Multi-Center AIDS Cohort (MACS) (3). Here 343 HIV+ men and 176 HIV- men underwent CT angiography to obtain coronary calcium scores. Both total and non-calcified plaques were assessed and compared between the two groups. The mean age of men was in the 50's. Both had high rates of prior smoking and the prevalence of hypertension and diabetes was similar.
In a multivariate model, older age, hypertension, dyslipidemia, and smoking history were associated with higher total plaque score, but there were no interactions with HIV serostatus. These traditional risk factors plus diabetes were associated with non-calcified plaques, which are an earlier stage of artherogenesis and more prone to rupture. These non-calcified plaques were more prevalent in the HIV-infected men but the association between these plaques and HIV was attenuated with adjustment for the traditional risk factors. Among the HIV+, there were independent associations between having stenosis (abnormal narrowing of blood vessels) of 50% or more and HAART treatment for at least 10 years, CD4 nadir and detectable HIV RNA.
A different study looking at risks associated with CVD conducted by investigators from the AIDS Clinical Trials Group (ACTG) examined baseline data from a metabolic substudy of A5257 - a large ART trial (4). All the 331 participants were ART-naïve and underwent ultrasound-based carotid intima thickness (CIMT) and brachial artery flow mediated dilation (FMD). The former detects plaques in the carotid artery and the latter measures endothelial dysfunction, a precursor of atherosclerosis. Most of the participants were male (89%) and less than half were white (44%); 38% were current smokers. Median CD4 cell count was 349/mm3 and HIV RNA was 4.5 log10 copies/mL.
The FRS for CVD within 10 years was fairly low at a median of 1%. As expected, low HDL-cholesterol and smoking were major CVD risk factors for this group. Of the cohort, 8% had evidence of carotid plaques and this was associated with older age (44% of those with lesions were over age 50), higher IL-6 (a marker of inflammation), metabolic syndrome and lower HIV RNA (don't ask me why).
CIMT, in general, was independently associated with increased age, height, weight, plus black race, FRS, and small LDL particles. After adjustment for traditional risk factors, independent associations between HIV disease activity, inflammation, or immune activation and CIMT or FMD were not seen (p>0.12).
The Bottom Line: As in the FDG-PET study, we see that HIV+ individuals had more evidence of disease than expected. Here, though, the role of traditional risk factors for CVD can better be appreciated. In the study from the MACS Cohort, these classical factors seem to be driving plaque formation. Similarly, the cross sectional analysis of baseline data from ART-naïve participants of the A5257 metabolic substudy suggests that traditional factors for CVD can overwhelm any related to HIV. This study does not say that inflammation or immune activation have no role in causing CVD disease or its precursors, only that these factors were not independently associated with these outcomes when risks such as age and the elements of the metabolic syndrome were thrown in.
In the US, such traditional factors have been reported to be common among HIV-infected persons. In the ACTG study, however, it was interesting that FRS was very low and there were fewer smokers than one would have expected. The median age of the group was a relatively young 36 years, and this reduced the overall risk profile of this cohort. Of course, there was not control arm of HIV-negative people for comparison. Again, as in the Grinspoon study, markers of inflammation were generally not associated with actual cardiovascular pathology, suggesting the genesis of these lesions is complex and not simply explained in terms of a model of immune activation triggering inflammation.
Reducing Coronary Calcium Scores with Lifestyle and Metformin
Another study from the Mass General group did look at interventions to improve coronary artery calcium score among patients with HIV and metabolic syndrome but no diabetes (5). These included use of the diabetes drug, metformin, which has been shown to reduce CVD risk in non-diabetics, as well as a lifestyle modification program. Similar to previous work from this group, the sample size was economical at 50 patients who were randomized to one of four study interventions for 12 months:
- Diet and exercise program (60 minutes, three times a week of aerobic and weight training plus weekly nutrition counseling)
- Metformin 500 mg a day for 3 months then 850 mg twice daily, thereafter
- Both the diet/exercise program and metformin
- Placebo and no diet/exercise program
At baseline there were some imbalances in smoking and lipid lowering therapy but with 11-15 individuals per arm these were not statistically significant. CD4 cell counts were generally high (400-700/mm3). Importantly, at baseline, about half of each group had a coronary calcium score of zero.
At 12 months, coronary calcium score decreased in the combined interventions arm (metformin + diet/exercise), while in all the other arms the scores increased. Those on metformin alone had the smallest progression followed by the lifestyle modification alone, and then the control group without any intervention. As expected, exercise and diet led to increases in strength and endurance, as well as improved HDL and hsCRP; insulin resistance improved with metformin. Adherence to the metformin and the lifestyle program were reported to be excellent at over 80%.
The Bottom Line: There are a number of notable findings from this small trial. First, coronary calcium scores of HIV+ persons with metabolic syndrome declined with the combined intervention while in the other arms more coronary calcium was detected. Second, the rate of progression in the placebo arm that received no interventions was quite high (56%) - much higher than would be expected at one year in the general population - again, it is unclear what is driving this progression or if a preponderance of traditional risk factors alone were responsible. Third, the lifestyle modification intervention was found to be effective in terms of cardiorespiratory and strength parameters, albeit not on coronary calcium or pant size. Lastly, adherence to these interventions over the course of a year and in the context of a clinical trial was very high.
The study of metformin in HIV+ patients is nothing new and this group and others have evaluated the drug for the treatment of HIV-associated metabolic disorders. Here, the correlation of the use of metformin and diet/exercise with a direct measurement of coronary artery disease is significant. Importantly, the drug was well tolerated, but again, this was a small study and the adverse effects of the drug are well known from clinical practice.
A major limitation is the very small sample size. Further, the study included persons with coronary calcium scores of zero. These participants could not possibly improve their coronary calcium scores and, in fact, could only stay the same or progress. It was interesting that the diet/exercise program did not lead to any change in waist circumference or body mass index. If confirmed to reduce coronary calcification in the setting of HIV, metformin may finally find a non-diabetic niche in HIV care.
Statins for Life?
An analysis of data collected in a cohort of participants of AIDS Clinical Trials Group (ACTG) studies, led by Turner Overton, looked at use of statin use on development of non-AIDS-defining diseases (6). Included in the analysis were participants not on a statin at study entry; the outcomes of interest were non-accidental death, liver disease, CVD, renal disease, non-AIDS cancers, non-traumatic bone fractures, severe bacterial infections, diabetes mellitus and thrombosis or pulmonary embolism that occurred at least 8 weeks after starting on statin therapy.
A total of 3,601 participants were included and were diverse in terms of race; over 80% were male, and 38% were smokers. Relevant median baseline data included BMI of 25, systolic blood pressure of 120, LDL cholesterol of 106, proportion with Framingham 10-year CVD risk score of > 10% was 10%, and CD4 was 346/mm3. Within the cohort, 481 started a statin.
With 15,135 person-years of follow-up there were 616 events: diabetes in 23%, bacterial infections in 20%, renal disease in 19%, non-AIDS cancers in 13%, non-accidental death in 12%, CVD in 7% and clots, fractures, and liver disease accounting for the remainder. Looking at weighted event rates after adjusting for baseline variables for those who started a statin compared to those who did not there was a trend that did not achieve statistical significance for a protective affect of statins on overall events. Focusing on specific events, statin use did not impact development of CVD or death, although there was a reduction in rates of non-AIDS malignancies. Older age and nadir CD4 cell count was associated with more of a statin effect but again these did not achieve statistical significance.
The Bottom Line: Statins are important and useful medications for the prevention of CVD in HIV-uninfected and -infected individuals. The anti-inflammatory properties of these agents have proved very seductive to HIV researchers in this era of awareness of inflammation as a mediator of badness in HIV. As such, there is considerable interest in some quarters for a large randomized study of the effects of statins on clinical outcomes of interest in people living with HIV. Statins have had near magical power to reduce death due to CVD in the general population and has also been associated with reductions in cancers and clinical improvements in rheumatologic disorders. A study from the Kasier Permanente found a lower risk of non-Hodgkin's lymphoma among HIV+ patients receiving a statin,
However, the exact effect of these drugs on inflammation is not clear, nor is it understood if these effects are beneficial to those with inflammation due to HIV. Further, statins are not without adverse effects such as liver toxicity, muscle breakdown (particularly in those who are physically active), diabetes, and perhaps memory loss.
This retrospective analysis found some interesting associations with statin use but these did not reach accepted levels of significance. Therefore, it is hard for this study to forward any arguments for an epic study of these drugs on non-AIDS endpoints. The more consistent finding across studies of an association between statin use and a reduced risk of certain malignancies is interesting and requires further exploration.
Intensifying ART does not improve endothelial function
A pair of presentations by a University of San Francisco (UCSF) team led by Priscilla Hsue examined the impact of intensifying HIV therapy on markers of inflammation. A number of studies have demonstrated that even those with controlled viremia (i.e., undetectable viral load) have evidence of on going immune activation, presumably from some residual response to chronic HIV infection, leading to low-level inflammation. The investigators tested whether intensifying HIV therapy could reduce this inflammation.
In the first study, 52 patients with controlled HIV were randomized to add maraviroc, a blocker of the CCR5 T-cell receptor, or a matching placebo (7). The hypothesis was that maraviroc might be active not as just an antiretroviral but that inhibition of CCR5 may interfere with T-cell signaling that occurs during inflammatory processes. In HIV-uninfected patients CCR5 deletion has been associated with lower risk of heart attacks. In HIV-infected people, however, there were slightly higher rates of CVD among those receiving marviroc in the MOTIVATE trial. Further, in a prior analysis of this maraviroc intensification trial, increases in T-cell activation in gut-associated lymphoid tissue were observed with maraviroc as well as a rise in sCD14, a marker if monocyte activation.
The design called for 24 weeks of blinded study therapy followed by 12 weeks off study drug. Changes in brachial artery FMD, a marker of endothelial function, and inflammation markers were assessed. Patients were almost exclusively male and median CD4 was in the 300-350/mm3 range.
At 24 weeks, there was no effect of maraviroc on FMD. However, there was an increase in monocyte activation markers including sCD14 and sCD163, a macrophage activation factor. Interestingly, even after cessation of the drug, these markers remained elevated and even tended to increase.
In a similarly designed study, Dr. Hsue looked at using raltegravir as the intensifying antiretroviral (8). Here the idea was to reduce inflammation by piling on the ART firepower to reduce any residual HIV replication and immune activation. 56 patients with suppressed viremia were randomized to add raltegravir twice a day or placebo. Brachial artery FMD and and hyperemic velocity, an assessment of microvascular function, were performed at baseline and weeks 24 and 36. Participants were again almost all male and most were white. Median age was in the early 50's in both arms.
The average change in FMD was similar in the placebo (+0.023 per week, 95%CI:-0.001, 0.047, p=0.059) and raltegravir arms (+0.032, 95%CI 0.007, 0.058, p=0.014); test for difference in slopes, p=0.60 (+0.009, 95%CI -0.026, 0.044). There were no statistically significant differences between treatment arms in change in FMD, markers of immune activation (CD38+HLA-DR+ CD4 and CD8 + T cells), cell-associated RNA or proviral DNA, or ultrasensitive plasma RNA at any visit. There were no significant difference in hyperemic velocity between treatment arms. In multivariable analysis, older age, longer HIV duration, and current abacavir use were associated with lower (worse) FMD, and lower CD4 cell count and abacavir use were associated with lower hyperemic velocity. The proportion of subjects receiving abacvir were not presented.
The Bottom Line: Intensification with maraviroc did not affect endothelial function in patients on effective ART. However, there were significant increases in monocyte activation markers. It is possible that blockage of the CCR5 receptor allowed a build up of its ligands and these found alternative pathways to activate monocytes. This did not seem to affect endothelial dysfunction, but may have other pro-inflammatory effects. This is a concern and there needs to be further understanding of the meaning of the activation in immune cells seen here with maraviroc to determine whether this is a harmless artifact or a deleterious effect vis-a-vis inflammation. Complete data regarding other inflammation markers and lipopolysaccharide (LPS) levels in the blood were not reported, but were promised to be included in subsequent reports.
The finding that raltegravir intensification did not yield much of a benefit in endothelial function is not too surprising. ART intensification has not been shown to do much to immune activation or residual viremia in fully suppressed patients on ART. The most interesting aspect of the study was the finding again by this group of an association between abacavir and worse FMD readings. As described below, this is an important observation that remains unique to this group. The number of participants receiving abacavir was not reported nor was it clear what was adjusted for in the multivariable analysis.
The Mediterranean Diet is Good
There are not much data about what HIV positive folks in the US eat or how different their diets are than people like them without HIV. But, with concern for increased risk of CVD and other metabolic disorders, the diets of people living with HIV may need to be healthier than the super-size-me general population.
A study presented by a team from Croatia examined the relationship between diet, specifically adherence to the Mediterranean diet rich in fruits, nuts, vegetables, grains and olive oil with modest intake of fish, wine, dairy (preferably eaten outdoors with large extended family and joyful music playing), and atherosclerosis assessed by carotid ultrasound in HIV-positive and HIV-negative controls (9). At total of 131 HIV-infected people were enrolled - most male, all white, and 40% smokers. An equal number of uninfected controls were included, but how these controls were chosen was not reported and they were certainly not matched on any characteristic - they were older, fatter and adhered less to the Med diet, but did smoke less. In both groups, about a third had evidence of atherosclerosis by carotid ultrasound.
In a multivariate analysis, low adherence to the Med diet was independently associated with atherosclerotic disease (OR 2.48 [1.24-4.97]) and was on par with other risks including HIV infection (OR 2.26 [1.08-4.78]), smoking (OR 3.52 [1.64-7.58]) and hypertension (OR2.79 [1.33-5.89]).
The Bottom Line: We can't fix everything with a good diet (see Grinspoon study #2 above), but there is every reason to believe that it can help reduce some of the risk of atherosclerosis in people with HIV. This study is small and has limitations, yet its findings punctuate the need to concentrate not just on magic pills (see metformin and statin, above) to reduce CVD risk. Well powered studies of the effects of dietary interventions in persons with HIV are important, especially as the waist circumferences of our patients increases along with our concerns for their health as they age.
Sick of the abacavir-causing-CVD debate? Skip to the next section.
Pick up a daisy, start plucking petals and follow along: Does it? Or, does it not? Keep going and after a few flowers you will reach the same conclusions as the studies that have been conducted looking for a link between abacavir and CVD or markers thereof. At CROI, results of a metabolic substudy of A5202, a very large trial of treatment initiation with tenofovir/emtricitiabine versus abacavir/lamivudine along with atazanavir/ritonavir or efavirenz, were presented and added another arrow in the quiver of those who see abacavir as a CVD risk (10).
The substudy collected blood from a subset of 244 trial participants (about 60 participants in each of the study arms) for markers of inflammation and endothelial function including hsCRP, IL-6, sTNFR-I & II and sVCAM-1 at baseline, week 24 and week 96.
At weeks 24 and 96, there was a significant increase in hsCRP in the abacavir/lamivudine plus efavirenz arm and hsCRP levels at these time points were higher (by about 40%) with abacavir/lamivudine compared to tenofovir/emtricitabine with third drug components combined. Interestingly, hsCRP also was higher in the efavirenz arms than the atazanavir/ritonavir arms with the NRTI components combined.
IL-6 levels declined in both the tenofovir/emtricitabine and abacavir/lamivudine arms over 96 weeks, but with smaller drops for the latter NRTI combination.
In contrast, there were no significant differences between abacavir and tenofovir in terms of hsCRP, IL-6 or brachial artery FMD among patients who had been assigned their NRTI during a clinical trial in a cross-sectional study I led. That study included 72 patients on tenofovir and 48 on abacavir (11).
The Bottom Line: There was not settling of the abacavir debate in Seattle this year. Again, study results were mixed. The ACTG finding of an actual increase in hsCRP with abacavir and also with efavirenz are unexpected and requires further study. In the HEAT Trial comparing abacavir/lamivudine versus tenofovir/emtricitabine in patients also receiving lopinavir/ritonavir, hsCRP and sVCAM-1 levels dropped with both NRTI combinations. In A5095, a study of abacavir/lamivudine/zidovudine plus efavirenz versus zidovudine/lamivudine plus efavirenz versus abacavir/lamivudine/zidovudine alone, hsCRP levels were observed to remain flat over 96 weeks of therapy with efavirenz (but did increase among women) and abacavir therapy had no effect on changes in hsCRP levels.
The A5202 finding, coupled with the observation of worse FMD with abacavir by Hsue et al in their study of raltegravir intensification, feed perceptions that this drug has CVD risks. The cross-sectional study I led offers a contrary finding but has its own set of limitations. Until more definitive data become available, this controversy will continue with each side pointing to data that support their position. For clinicians, there seems to be an appreciation that there is a potential risk associated with abacavir, however, it is used when needed (i.e., when tenofovir is not a good option). Abacavir is not going away and getting to the bottom of this is still a clinically relevant puzzle that should be solved.
Aging, inflammation and CVD - Putting it all into perspective
Entering the conference one could firmly believe the story line that immune activation begets inflammation, which begets end-organ disease. In Seattle this story became a bit murkier. Inflammation, at least the way we measure it, was not always present when CVD was and, as the presentations above indicate, it turns out that accounting for traditional risk factors for CVD can explain a good deal of the excess burden of disease carried by those with HIV.
So, do people living with HIV suffer more from CVD and other conditions we associate with aging? Probably, but the answer depends who we are comparing our patients to. If we hold them up to a 'control' population that has lower rates of smoking and higher HDL cholesterol levels, then, yes, they do have higher rates of these morbidities. Even when we try to find a comparable control population we really can't. In a paper published from the VA Cohort Study that compared 33,000 HIV-positive patients with 66,000 HIV-negative controls matched for age, gender, race/ethnicity and geography, those with HIV had a higher risk of liver disease, renal disease, and substance use disorder (12). Interestingly, the HIV-infected veterans had a lower risk of hypertension, diabetes, vascular disease, and psychiatric disorders than the HIV-uninfected controls. But, even when matched on crude demographic characteristics these were two different groups of people. Maybe the HIV+ vets smoked more or had more childhood trauma or stress - factors that could influence well-being in all sorts of ways. It is hard to point to the effects of HIV or specific HIV medications in such muddy waters.
At the concluding session of CROI 2012, Dr. Amy Justice of Yale described this dilemma well in a provocative and brave presentation (13). She took on the commonplace assertion that HIV-positive people experience "accelerated aging" by essentially asking, "relative to what?" It is an important point and one that is illustrated nicely in each of the studies described above that included controls. She also warned against over-screening in response to over-estimation of the risk for non-AIDS disease in our patients. Such screening can be not just time-consuming, but time-all-encompassing and lead to poly-pharmacy and toxicity. Instead, she called for a realistic assessment of the risk our patients face and measured responses that prioritize care based on that risk.
The concept of accelerated aging has spread among the HIV-positive community, causing fear. Dr. Justice rather than minimizing the problem of co-morbid conditions in the HIV+, asks for us to take a reality check as the data tell us that the pace of the slow burn we call aging may not be all that much hastened for those living with HIV and that the excess morbidity we do see among the HIV+ are likely due to multiple and complex interactions between host, virus, environment and treatment.
Her comments were echoed in a subsequent presentation by James Stein, a cardiologist at the University of Wisconsin (14). Dr. Stein also placed into perspective the actual risk for CVD conferred by being HIV-positive. He stressed that the traditional risk factors for CVD remain powerful in the HIV-infected and cannot be ignored, especially as infected patients tend to accumulate these risks. However, most people with HIV are younger than 50 years of age and, thus, have low short-term risk of CVD. Therefore, what is needed is more direct research on mechanism of CVD in this population and long-term longitudinal studies involving large numbers of HIV+ and HIV- individuals. Like Dr. Justice, he recommended we pick our battles when trying to counter CVD risk and set our sights on the factors we know from the HIV-uninfected to be the most dangerous.
Dr. Stein's presentation also was a nice capstone for a conference where the presented data was at times conflicted regarding the role of inflammation in the genesis of CVD in HIV. Such inconsistencies, he points out, reflect the lack of specificity of our biomarkers, the differences in techniques used to measure disease, disparate populations studied and the small sample sizes included in these, mostly, observational investigations. He ended by advising us to treat the virus and the known CVD risk factors and who can argue with that?
References:
1. S Subramanian, A Tawakol, T Burdo, et al. Increased Arterial Inflammation in Association with Monocyte Activation in HIV+ Patients. Abstract 121
2. Anders Boyd, J-L Meynard, L Morand-Joubert, et al. Effects of Life-style Modification and Metformin on Coronary Calcium in HIV/supersc> Patients with the Metabolic Syndrome. Abstract 803
3. Post W, Jacobson L, Li X, et al. HIV Infection Is Associated with Greater Amounts of Non-Calcified Coronary Artery Plaque: MACS. Abstract 809.
4. James Stein, T Brown, H Ribaudo, et al. Ultrasonographic Measures of CVD Risk in a Modern Cohort of ART-naïve HIV+ Individuals: Baseline Results from ACTG Study 5260s. Abstract 801
5. Kathleen Fitch, S Abbara, H Lee, E Stavrou, et al. Effects of Life-style Modification and Metformin on Coronary Calcium in HIV+ Patients with the Metabolic Syndrome. Abstract 119
6. Edgar Overton, D Kitch, P Tebas, et al. Effect of Statin Therapy on Reducing the Risk of Serious Non-AIDS-Defining Events and Non-Accidental Death: ACTG ALLRT Cohort. Abstract 124
7. Priscilla Hsue, R Scherzer, L Gilman, et al. Effect of Maraviroc Intensification on Endothelial Function in Treated HIV Infection. Abstract 123
8. Priscilla Hsue, R Scherzer, Y Wu, et al. Effect of Raltegravir Intensification on Endothelial Function in Treated HIV Infection. Abstract 828
9. K Viskovic, G Rutherford, G Sudario, et al. Subclinical Carotid Atherosclerosis Is Related to HIV Infection and Low Adherence to a Mediterranean Diet. Abstract 811
10. Todd Brown, J Currier, Y Chen, et al. The Association between Body Composition, Soluble and Cellular Immune Activation Biomarkers, and BMD in ART-naïve HIV-1+ Persons: Baseline Results of ACTG Study A5260s. Abstract 875
11. David Wohl, G Arnoczy, C Fichtenbaum, et al. CVD Risk Markers in Patients Receiving Abacavir, Tenofovir, and Zidovudine: The Nucleoside Inflammation, Coagulation, and Endothelial Function (NICE) Study. Abstract 838
12. Goulet JL, et al , CID 2007
13. Amy Justice. Aging with HIV: One Size Does Not Fit All. Abstract 175
14. James Stein. CVD Risk: Are Patients with HIV any Different? Abstract 177
|
| |
|
|
|
|
|
