icon-    folder.gif   Conference Reports for NATAP  
  Conference on Retroviruses
and Opportunistic Infections (CROI)
February 22-25, 2016, Boston MA
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HIV and Cardiovascular Disease: Report back from 2016 Conference on Retroviruses and Opportunistic Infections
  by Priscilla Hsue MD
Professor of Medicine, UCSF
This year the Conference on Retroviruses and Opportunistic Infection had some interesting studies presented on cardiovascular disease in the setting of HIV. Dr. Judith Currier started the session with a Program Committee Workshop for New Investigators and Trainees in which she addressed pathogeneses and interventions of cardiovascular disease in the setting of treated HIV infection which is an area that is rapidly evolving and certainly a rich topic for research for new and young investigators alike.
CROI:Immunopathogenesis of Metabolic Complications in Treated HIV Infection
WEBCAST to Judy Currier
In Abstract 41, using the infrastructure of the START study (Strategic Timing of Antiretroviral Treatment) Dr. Jason Baker and colleagues used assessment of arterial stiffness among individuals with early ART initiation (ie CD4 counts > 500 cells/mm3) with untreated HIV /deferred ART (CD4<350 cells/mm3). There were 332 individuals studied with a median age of 35 and 10-year Framingham risk score of 1.2%. There were no significant within-person changes in arterial stiffness indices associated with early ART initiation. The lack of impact of early ART on arterial stiffness may be a function of the young age group of individuals studied and the overall low Framingham risk. These findings mirror the lack of an effect of early vs deferred ART on CVD in the SMART study (Insight SMART Study Group, NEJM August 2015 [http://www.natap.org/2015/IAS/IAS_36.htm]). Overall there were a low number of CVD events (12 in the immediate ART vs. 15 in the deferred group) and additional longer followup in an older patient population may shed additional information on the CV risks and benefits of long-term ART.
CROI abs. 41: Early Antiretroviral Therapy Does Not Improve Vascular Function: A START Substudy
CROI abs. 659: Changes in CVD Risk Factors with Immediate and Deferred ART in the START Trial
using the CFAR Network of Integrated Systems (CNICS), Dr. Heidi Crane and coauthors developed a screening algorithm and adjudication protocol for the validation of incident myocardial infarction. The Framingham, ATP-3, 2013 ACC/AHA ASCVD and DAD risk calculators. In this study (Abstract 42) , investigators also classified MI into Type 1 MI which is from atherosclerotic plaque and Type 2 MI which is due to demand/supply mismatch and builds upon their presentation on the importance of Type 2 MI in the setting of HIV from CROI 2015. In the 243 MIs that were studied, the ASCVD risk score had a significantly better AuC value as compared to other calculators for all types of MI. Interestingly, the DAD HIV-specific calculator did not improvement discrimination of MI events as compared to the ASCVD calculator.
CROI abs. 42:Comparing Cardiovascular Disease Risk Scores for use in HIV-Infected Individuals.......Optimal cardiovascular disease risk score for HIV
In Abstract 43, the incidence of stroke and risk factors in HIV-infected individuals was studied in the ACTG Longitudinal Linked Randomized Trials (ALLRT) cohort by Dr. Chow and coauthors. Among 6933 individuals without stroke at baseline who initiated ART from June 1998 to June 2011, there were 54 stroke/TIAS over 32,0234 person-years. Interestingly, the rate of stroke/TIA was highest in women (0.29 per 100 PY vs 0.14 per 100 PY in men, for an age-adjusted RR for female sex of 1.72, 95% CI 0.96 to 3.08). Incidence of strokes/TIA was also higher in non-Hispanice Blacks as compared to Hispanics and Whites. Traditional risk factors including older age, LDL ≥ 160mg/dL and hypertension were associated with greater risk of stroke/TIA along with CD4 count ≤ 200 cell/ul and HIV RNA > 200 copies/ml. These findings suggest that similar to cardiovascular disease that immunodeficiency and uncontrolled viremia contribute to stroke risk in HIV.
There was a latebreaker presentation (Abstract 44LB) presented by Dr. O'Brien which evaluated the impact of aspirin in ACTG A5331. This was a prospective double-blinded randomized placebo-controlled study of treated and suppressed HIV-infected individuals on 3 arms: 100mg aspirin, 300 mg aspirin, and placebo for 12 weeks followed by a 4 week washout period. Primary outcome was sCD14 and secondary outcomes included endothelial function as assessed by flow-mediated vasodilation of the brachial artery (FMD) including other inflammatory, coagulation, and immune activation markers. Overall, there was no significant difference between the two aspirin arms vs. placebo for any of the endpoints. However, individuals treated with 300mg aspirin had a greater increase in sCD163 as compared to placebo. There was less of an increase in sCD163 among smokers and women treated with aspirin and greater reductions in D-dimers in smokers treated with aspirin.
CROI: Aspirin fails to impact immune activation or endothelial function in treated HIV - In the poster sessions there were several studies evaluating risk of stroke in HIV.
In Abstract 636, again using the CNICS cohort, a stroke adjudication protocol was proposed by study investigators including Dr. Heidi Crane and colleagues. Both traditional and HIV-specific features including low CD4 count and higher HIV RNA level were independently associated with stroke. Abstract 637 evaluated risk factors associated with ischemic and hemorrhagic stroke. Authors found that in HIV, traditional risk factors were more strongly related to ischemic strokes while hypertension and low eGFR were more strongly related to hemorrhagic stroke, and older age, elevated BP and low CD4 count were the strongest predictors for both stroke subtypes. In Abstract 638, HIV-infected women had a higher incidence rate ratio (2.34, 95%CI 1.60-3.34) compared to HIV-uninfected women. This increased risk was independently of sex-specific risk factors for stroke such as hormone replacement therapy, pregnancy, eclampsia, etc. The impact of HCV coinfection on stroke was evaluated in Abstract 639 using patients from a dataset in Spain with authors focusing on 3 different time periods (1st: 1997-1999, 2nd: 2000-2003, and 3rd: 2004-2011). Investigators found that rates decrease significantly during all time periods for HIV-mono-infected individuals but in contrast, HIV/HCV coinfected individuals had higher rates in the first two periods, with a reversal of this trend in the 3rd period. Finally, in Abstract 640, using a registry, 248 HIV-infected individuals free of CVD who underwent a contrast neck CT from 2005-2014 were studied. Increased carotid plaque and noncalcified plaque were associated with subsequent CV events.
CROI abs. 636:Design, implementation, and findings of next generation stroke adjudication in HIV
CROI abs. 638:
Persistently Increased Ischemic Stroke Risk in HIV-Infected Women
Juan Berenguer reports stroke rates going down among HIV+ BuT stroke rates going up among HCV/HIV coinfected patients.
Finally, the following is a summary of some of the other posters on CVD presented at CROI 2016:
In Abstract 641, MI rates were found to be higher in NA-ACCORD as compared to two other CVD cohorts of uninfected individuals (Ie MESA and ARIC) which may be a feature of more stringent exclusion criteria in the non-HIV cohorts such as MESA. The study was unable to control for certain CVD risk factors such as hypertension and hyperlipidemia.
CROI: Myocardial Infarction Risk in the NA-ACCORD Compared to MESA and ARIC
Risk model prediction was also a theme in this year's CROI studies. In Abstract 642, the Pooled Cohort Equations (PCE), D:A:D, and VA models had similar discrimination by ROC curve for prediction of risk of CVD outcomes.
Implications of clinical care in HIV were also evaluated in several Abstracts. Comparing new 2013 ACC/AHA with older 2004 ATPII guidelines, both guidelines failed to recommend statin therapy to HIV-infected adults with evidence of carotid atherosclerosis and/or plaque using carotid ultrasound (Abstract 643). In Abstract 644, Feinstein, MJ et al showed that HIV-infected individuals who were referred for cardiovascular stress tests had a greater burden of CAD and were more likely to undergo percutaneous coronary intervention (PCI) as compared to controls.
CROI abs, 644: Differences by HIV Serostatus in Coronary Artery Disease Severity following Stress Testing
The association between pericardial fat and diastolic dysfunction was evaluated in Abstract 649. In this study they found "Higher pericardial fat volume and lower density are associated with LV diastolic dysfunction independent of age, gender, and body mass index."
CROI:Diastolic Function Correlates With Pericardial Fat [fat around the heart] and Vascular Remodeling in HIV
Novel biomarkers remained a large focus of studies presented this year. In Abstract 652, non-classical monocytes and MCP-1 were associated with change in coronary calcium and IMT progression in the bifurcation region. Higher D-Dimer, TNF-α and sCD14 along with specific T-cell markers were associated with worsened reactive hyperemia (microvascular disease) and the stimulus for FMD in Abstract 654. In Abstract 659, the impact of immediate vs. deferred ART on CVD risk factors was evaluated in the START Trial. As compared to deferred ART, after around 3 years of followup, immediate ART was associated with increased total-C, LDL-C and lipid lowering agents and increased HDL-C.
CROI:Effect of T-Cell Activation on Endothelial Dysfunction in HIV
Changes in CVD Risk Factors with Immediate and Deferred ART in the START Trial
Oxidized LDL was also the focus of several studies in HIV. First, following ART initiation, no association between oxidized lipoproteins and carotid IMT were demonstrated in A5260s (Abstract 672). using a case-control design, hsCRP, oxidized LDL, and D-dimer were associated with Type 1 MI in HIV-infected individuals in the CAR Network of Integrated Clinical Systems (CNICS) along with low CD4/CD8 ratio (Abstract 671). Finally, in Abstract 673, in the setting of a 12 month placebo controlled study of atorvastatin in HIV, oxidized LDL was found to decrease with statin treatment. In turn, reductions in oxidized LDL were associated with non-calcified plaque volume, total plaque volume, positively remodeled plaque and low attenuation plaque.
CROI abs 673: Statin Effects on oxLDL in Relationship to Plaque and Arterial Inflammation in HIV.....statin reduced LDL
In summary, cardiovascular disease and stroke continue to be significant health issues among individuals with HIV infection and this is reflected by the numerous studies at CROI. While many advances have been made in the field including impact of immediate ART on overall mortality, the impact of these advances with respect to CVD remain unclear. In addition, optimal risk calculators, best biomarkers to assess CV risk and finally best therapies to treat HIV-related CVD are all topics that remain poorly understood; as researchers and clinicians caring for individuals with HIV, we look forward to future advances in the field and studies and to CROI 2017.