Cytomegalovirus IgG is Associated With Physical Function But Not Muscle Density in People With HIV.

BACKGROUND: Cytomegalovirus (CMV) seropositivity is associated with poor outcomes, including physical function impairment, in people without HIV. We examined associations between CMV IgG titer and physical function in virologically suppressed people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating pitavastatin for primary prevention of atherosclerotic cardiovascular disease in PWH. This analysis focused on participants enrolled in a substudy with additional biomarker testing, imaging [coronary CT angiography], and physical function measures at entry. CMV IgG was measured using quantitative enzyme immunoassay, physical function by Short Physical Performance Battery, and muscle density and area by CT. Associations between CMV IgG (risk factor) and outcomes were evaluated using the partial Spearman correlation and linear and log-binomial regression. RESULTS: Among 717 participants, 82% male, the median CMV IgG was 2716 (Q1, Q3: 807, 6672) IU/mL, all above the limit of quantification. Among 631 participants with imaging, there was no association between CMV IgG and CT-based muscle density or area, controlling for age (r = -0.03 and r = -0.01, respectively; P ≥ 0.38). Among 161 participants with physical function data, higher CMV IgG was associated with poorer overall modified Short Physical Performance Battery score ( P = 0.02), adjusted for age, nadir CD4, and high-sensitivity C-reactive protein. CONCLUSIONS: Higher CMV IgG titer was associated with poorer physical function, not explained by previous immune compromise, inflammation, or muscle density or area. Further mechanistic studies are needed to understand this association and whether CMV-specific therapy can affect physical function in PWH.

Optimizing tobacco treatment delivery for people with HIV: trial protocol for a randomized controlled trial.

BACKGROUND: With advances in antiretroviral therapy, people with HIV (PWH) are living longer and are less likely to die from AIDS-related complications. Yet, prior research has shown that smoking is often not addressed in the context of HIV care, and few individuals are offered cessation treatment. Optimizing tobacco treatment delivery for PWH may increase engagement with evidence-based treatments and successful quit attempts. METHODS: The current study is a type 1 hybrid effectiveness-implementation trial to evaluate the impact of a proactive, opt-out tobacco treatment intervention on cessation outcomes and advance understanding of key barriers and facilitators of implementation processes. A total of 230 PWH who smoke will be recruited from an infectious diseases clinic at an academic medical center and will be randomized to receive (1) treatment as usual (TAU) or (2) Proactive Outreach with Medication Opt-out for Tobacco Treatment Engagement (PrOMOTE). Primary outcomes include: biochemically verified 7-day point prevalence abstinence (PPA) rates, continuous abstinence (Weeks 9-12), and the number of 24-hour quit attempts at the end of study treatment (Week 12). Secondary outcomes include: participant reach (proportion reached out of contact attempts), implementation fidelity (including number of prescriptions written), participant adherence to prescribed pharmacotherapy, acceptability (participant and provider satisfaction with intervention delivery and content), and perceived barriers. DISCUSSION: This study will examine a novel approach to optimizing tobacco treatment delivery for PWH. Integrating effectiveness and implementation results will help define best practices for engaging PWH with evidence-based tobacco treatment interventions. The intervention is low-cost, has the potential to be highly scalable, and could be translatable to other ambulatory HIV clinic settings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05019495 (August 24, 2021).

Optimizing the Implementation of Tobacco Treatment for People with HIV: A Pilot Study.

People with HIV (PWH) have higher rates of tobacco use compared to their societal counterparts and are disproportionately affected by tobacco-related morbidity and mortality. A needs assessment was conducted to assess provider beliefs and opinions on tobacco treatment barriers and treatment approaches. The results highlighted a disconnect between the known importance of quitting smoking and barriers in linking patients to treatment, such as lack of patient interest and other patient issues being a higher priority. Using this assessment data, a treatment delivery approach, Proactive Outreach with Medication Opt-out for Tobacco Treatment Engagement (PrOMOTE), was devised and piloted. PrOMOTE consisted of an outpatient clinical pharmacist trained in tobacco treatment proactively contacting patients for counseling and to prescribe smoking cessation pharmacotherapy (varenicline or dual nicotine replacement therapy (NRT)) using an opt-out approach. The pilot was conducted with 10 PWH and patient reach and opt-out rates were evaluated. Of the 10 patients contacted, 7 were reached and none opted out of the pharmacotherapy prescription (varenicline = 6; NRT = 1). Providers know the importance of smoking cessation for PWH but encounter several barriers to implementing treatment. Using PrOMOTE methods to deliver tobacco treatment increased the reach and pharmacotherapy acceptance rate of PWH who smoke.

Remestemcel-L Therapy for COVID-19-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a serious postinfectious immune dysregulation associated with coronavirus disease 2019 that may present with severe and life-threatening cardiovascular dysfunction, hemodynamic instability, shock, and multisystem organ failure. Optimal treatment is unknown. Current standard of care consists of nonspecific anti-inflammatory and antithrombotic therapies. Interventions that target MIS-C's distinctive clinical features and immunophenotype are indicated. Remestemcel-L, an investigational mesenchymal stromal cell therapy, is a promising candidate for treatment of MIS-C because of its beneficial anti-inflammatory, immunomodulatory, endothelial function and vascular stabilizing effects, which align well with the pathophysiology of MIS-C. Here, we present the first two patients with life-threatening MIS-C ever treated with remestemcel-L under an expanded access program. Both were previously healthy children without any indication of previous coronavirus disease 2019 infection or exposure. They presented with severe clinical illness including myocardial dysfunction, hemodynamic instability, hypotension, acute kidney injury, and shock. At the time of hospital admission, both had negative polymerase chain reaction (PCR) test results and positive serology results for severe acute respiratory syndrome coronavirus 2. Both children received standard of care MIS-C treatment. Although the patients showed some clinical improvement, left ventricular ejection fraction remained reduced and inflammatory biomarkers remained significantly elevated. When treated with two intravenous doses of remestemcel-L separated by 48 hours, rapid normalization of left ventricular ejection fraction, notable reductions in biomarkers of systemic and cardiac inflammation, and improved clinical status occurred. Neither child experienced adverse effects associated with remestemcel-L administration. This treatment appears promising as a novel immunomodulatory cellular therapy for children with clinically significant cardiovascular manifestations of MIS-C.

Fecal Calprotectin Is Elevated in HIV and Related to Systemic Inflammation.

BACKGROUND: Fecal calprotectin (FC), a biomarker of gastrointestinal (GI) inflammation, is used in the diagnosis and management of inflammatory bowel disease. HIV infection severely damages gut-associated lymphoid and epithelial tissues leading to GI inflammation that drives systemic inflammation and increases subsequent risk of comorbidities. For the first time, we compared FC concentrations by HIV and antiretroviral therapy (ART) status and determined the relationship to systemic inflammation. METHODS: People with and without HIV were enrolled and underwent a comprehensive clinical and laboratory assessment. Stool samples were collected, and FC was measured by enzyme-linked immunosorbent assay ELISA. Plasma biomarkers of inflammation were also measured. RESULTS: One hundred one participants with HIV (83 ART-treated and 18 ART-naive) and 89 uninfected controls were enrolled. There were no significant differences between ART-naive and ART-treated participants, but both HIV groups had significantly higher FC concentrations than controls when FC was considered as a continuous variable or by cut-offs used in inflammatory bowel disease. The highest median and largest proportion of participants with FC >100 µg/g were seen in ART-naive, followed by ART-treated and then controls. Among HIV participants, FC concentrations were positively associated with high-sensitivity C-reactive protein, soluble tumor necrosis factor receptor II, and soluble vascular cellular adhesion molecule and inversely associated with CD4 counts. CONCLUSIONS: FC concentrations are elevated in HIV regardless of ART status. ART and immune reconstitution seem to reduce FC but not to concentrations seen in uninfected controls. Our results suggest a role for FC as a noninvasive surrogate measurement of GI inflammation and associated systemic inflammation in HIV.

Weight gain and integrase inhibitors.

PURPOSE OF REVIEW: Weight gain and obesity among people living with HIV (PLWH) is a serious problem that occurs often after initiation of antiretroviral therapy but may be worse with integrase strand transfer inhibitors (INSTIs). This article comprehensively reviews available data and summarizes our current understanding of the topic. RECENT FINDINGS: Recent studies support the concept that weight gain and treatment emergent obesity are worse with INSTI-based regimens, particularly dolutegravir. Women and nonwhites appear to be the most at risk, and the accompanying nucleoside reverse transcriptase inhibitor may play a role. Lipohypertrophy, an abnormal accumulation of visceral fat and/or ectopic fat depots, continues to be a problem among PLWH, but the role of INSTIs is inconsistent. The pathogenesis of weight gain and changes in body composition in HIV, especially with INSTIs, is poorly understood but may lead to serious comorbidities, such as cardiovascular disease and diabetes. SUMMARY: Although INSTI-based regimens are highly efficacious for viral suppression, they appear to cause more weight gain and treatment emergent obesity than non-INSTI-based regimens and may increase the risk of weight-related comorbidities. More studies are needed to understand the pathogenesis of weight gain with INSTIs in PLWH, in order to prevent this serious complication.

Contemporary Issues in Pregnancy (and Offspring) in the Current HIV Era.

PURPOSE OF REVIEW: Although antiretroviral therapy (ART) has dramatically reduced mother to child transmission of HIV, data continue to mount that infants exposed to HIV in utero but are not infected (HEU) have serious negative health consequences compared to unexposed infants. This review evaluates recent literature on contemporary issues related to complications seen in pregnant women with HIV and their offspring. RECENT FINDINGS: Current studies show that HEU infants are at a high risk of adverse outcomes, including premature birth, poor growth, neurodevelopmental impairment, immune dysfunction, infectious morbidity, and death. Etiologies for the observed clinical events and subclinical alterations are complex and multifactorial, and the long-term consequences of many findings are yet unknown. HEU infants have an unacceptable rate of morbidity and mortality from perinatal HIV and ART exposure, even in the modern ART era. Continual monitoring and reporting is imperative to protect this vulnerable population in our everchanging landscape of HIV treatment and prevention.

Association of Bacterial Vaginosis with Vitamin D in Pregnancy: Secondary Analysis from the Kellogg Pregnancy Study.

Objective Bacterial vaginosis (BV) is associated with vitamin D deficiency and poor pregnancy outcomes. We studied a nested cohort from a randomized controlled trial to investigate the association between BV and vitamin D concentration in pregnancy. Study Design Subjects with randomly assigned 400 versus 4,400 IU of daily cholecalciferol (vitamin D 3 ) had vaginal swabs collected for Gram staining and Nugent score calculation, as well as plasma 25-hydroxyvitamin D (25(OH)D) measurement at three pregnancy time points. Results Fifty-two (21.2%) of the 245 women included in the analysis were diagnosed with BV at study entry. Women with BV were also more likely to be African American ( p < 0.0001) and have lower 25(OH)D concentrations at 22 to 24 weeks' gestation ( p = 0.03). There were no differences in pregnancy outcomes of interest within this group compared with the remaining study subjects. In mixed regression modeling, while race ( p = 0.001) and age ( p = 0.03) were significant predictors of BV prevalence independently, 25(OH)D concentration ( p = 0.81), gestational age ( p = 0.06), and body mass index ( p = 0.87) were not. Conclusion Neither vitamin D deficiency in early pregnancy nor supplementation decreased BV incidence during pregnancy. Pregnancy outcomes (preterm birth and hypertensive disorders of pregnancy) were similar among women with and without BV.

Increased influenza-specific antibody avidity in HIV-infected women compared with HIV-infected men on antiretroviral therapy.

BACKGROUND: It is recommended that HIV-infected individuals receive annual influenza vaccination due to their high susceptibility to influenza infection, especially among women. However, there have been few studies investigating sex-related responses to influenza vaccine in antiretroviral therapy (ART)-treated HIV-infected individuals. METHOD: In this study, 26 aviremic ART-treated HIV-infected individuals and 16 healthy controls were enrolled in the current study. Blood was collected prior to vaccination (D0), on days 7-10 (D7) and on days 14-21 (D14) following administration of the 2013-2014 seasonal influenza vaccine. A series of analyses evaluated the serological and cellular responses following influenza vaccination. RESULTS: Female HIV-infected individuals had increased influenza-specific antibody avidity relative to male HIV-infected individuals, but similar plasma levels of influenza-specific binding antibodies and neutralizing antibodies. Increased cycling B cells and follicular helper CD4 T (Tfh) cells were observed in female HIV-infected individuals pre and postvaccination compared with male HIV-infected individuals, and cycling Tfh cells were directly correlated with influenza-specific antibody avidity. Moreover, plasma testosterone levels were inversely correlated with antibody avidity index. The magnitude of microbial translocation [plasma lipopolysaccharide (LPS)] level was directly correlated with influenza-specific antibody avidity. Circulating 16S rDNA microbiome showed that enrichment of specific species within Proteobacteria was associated with influenza-specific antibody avidity. These results, including differences based on sex and correlations, were only observed in HIV-infected individuals but not in the healthy controls. CONCLUSION: This study demonstrated sex differences in influenza-specific antibody avidity in ART-treated HIV disease, and provides valuable information on vaccination strategy in the ART-treated HIV-infected population.

Vitamin D supplementation decreases immune activation and exhaustion in HIV-1-infected youth.

BACKGROUND: Heightened immune activation and exhaustion drive HIV disease progression and comorbidities. Vitamin D has pleiotropic immunomodulatory effects, but little is known about the effects of supplementation in HIV. Our study investigates changes in immune activation and exhaustion markers after 12 months of supplementation in virologically suppressed HIV-infected youth with vitamin D insufficiency. METHODS: This is a randomized, active-control, double-blind trial investigating with three different vitamin D3 doses (18,000 [standard/active-control dose], 60,000 [moderate dose] and 120,000 IU/month [high dose]) in 8-25-year-old HIV-infected youth on combination antiretroviral therapy with baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations ≤30 ng/ml. Only subjects (n=51) who maintained an undetectable HIV-1 RNA over the 12-month study period were included in this analysis. RESULTS: Baseline serum 25(OH)D concentrations and immune activation/exhaustion markers were not different between groups. By 12 months, 25(OH)D increased significantly within each dosing group with the greatest increase and most sustained concentrations ≥30 ng/ml in the high-dose group. Overall, all measured markers decreased with CD4 activation (CD4+CD38+HLA-DR+), CD8 activation (CD8+CD38+HLA-DR+), CD4 exhaustion (CD4+CD38+HLA-DR+PD1+) and inflammatory monocytes (CD14+CD16+) reaching statistical significance. When analysed separately, there were no significant decreases in the moderate- or standard-dose groups, but CD4 and CD8 activation and inflammatory monocytes decreased significantly in the high-dose group. CONCLUSIONS: Vitamin D supplementation decreased markers of T-cell activation/exhaustion and monocyte activation in HIV-infected youth, with subjects given the highest dose (120,000 IU/month) showing the greatest decreases. These data suggest that high-dose vitamin D supplementation may attenuate immune activation and exhaustion, and serve as adjuvant therapy to antiretroviral therapy in HIV. ClinicalTrials.gov identifier: NCT01523496.

Effects of Vitamin D Supplementation on Bone Mineral Density and Bone Markers in HIV-Infected Youth.

BACKGROUND: Low bone mineral density (BMD) is a significant comorbidity in HIV. However, studies evaluating vitamin D supplementation on bone health in this population are limited. This study investigates changes in bone health parameters after 12 months of supplementation in HIV-infected youth with vitamin D insufficiency. METHODS: This is a randomized, active-control, double-blind trial investigating changes in bone parameters with 3 different vitamin D3 doses [18,000 (standard/control dose), 60,000 (moderate dose), and 120,000 IU/monthly (high dose)] in HIV-infected youth 8-25 years old with baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL. BMD and bone turnover markers were measured at baseline and 12 months. RESULTS: One hundred two subjects enrolled. Over 12 months, serum 25(OH)D concentrations increased with all doses, but the high dose (ie, 120,000 IU/monthly) maintained serum 25(OH)D concentrations in an optimal range (≥30 or ≥20 ng/mL) throughout the study period for more subjects (85% and 93%, respectively) compared with either the moderate (54% and 88%, respectively) or standard dose (63% and 80%, respectively). All dosing groups showed some improvement in BMD; however, only the high-dose arm showed significant decreases in bone turnover markers for both procollagen type 1 aminoterminal propeptide (-3.7 ng/mL; P = 0.001) and Β-CrossLaps (-0.13 ng/mL; P = 0.0005). CONCLUSIONS: High-dose vitamin D supplementation (120,000 IU/mo) given over 12 months decreases bone turnover markers in HIV-infected youth with vitamin D insufficiency, which may represent an early, beneficial effect on bone health. High vitamin D doses are needed to maintain optimal serum 25(OH)D concentrations.

Neurocognitive dysfunction in HIV-infected youth: investigating the relationship with immune activation.

BACKGROUND: HIV-infected individuals are at increased risk of neurocognitive impairment compared to the general population. Studies suggest that, despite combination antiretroviral therapy (cART), HIV infection causes immune activation which results in neural damage; however, few data exist in HIV-infected youth. METHODS: HIV-infected youth 8-26-years-old on cART with virological suppression were prospectively enrolled along with healthy controls. Neurocognitive performance was assessed by age-appropriate Wechsler Intelligence Scales. Soluble and cellular markers of T-lymphocyte and monocyte activation were measured by ELISA and flow cytometry, respectively. RESULTS: 45 HIV-infected subjects and 21 controls were enrolled. Markers of T-cell and monocyte activation were higher in the HIV-infected subjects compared to controls, but proportions of inflammatory and patrolling monocytes were similar. Although there were no significant differences in neurocognitive scores between the HIV-infected and control groups, scores were low-average for four of five testing domains for the HIV-infected subjects and average for all five in the controls, and % of HIV-infected subjects with scores classified as 'low average' or below was higher than in the controls. Variables most associated with neurocognitive performance among HIV-infected subjects included activated CD4+ T-cells (% CD4+CD38+HLA-DR), monocyte activation (soluble CD14), HIV duration, age and sex. CONCLUSIONS: HIV-infected youth on cART with virological suppression show subtle evidence of neurocognitive impairment compared to healthy controls, and increased immune activation appears to play a role. Additional studies are needed to develop strategic interventions beyond cART to potentially improve neurocognitive performance and/or minimize further impairment in this vulnerable population. ClinicalTrials.gov Identifier: NCT01523496.

Arterial stiffness in HIV-infected youth and associations with HIV-related variables.

Children and young adults infected with HIV are at elevated risk for cardiovascular disease (CVD). However, scarce data exist on the utility of non-invasive methods to diagnose subclinical CVD, such as pulse wave velocity (PWV), a non-invasive measure of arterial stiffness. The objectives of this study were to assess the relationship of carotid-femoral PWV with subclinical atherosclerosis measured by carotid intima-media thickness (IMT), compare measurements to healthy controls, and evaluate variables associated with PWV in HIV-infected youth. One hundred and one 8-25 year-old subjects on stable antiretroviral therapy with low-level viremia or an undetectable HIV-1 RNA were enrolled, along with 86 healthy controls similar in age, sex and race. There was no significant difference in PWV between groups (median (Q1, Q3): 5.7 (5.2, 6.3) vs 5.7 (4.9, 6.5) m/s; P = 0.81). Among the HIV-infected subjects, PWV was positively correlated with both internal carotid artery (R = 0.31, P = 0.02) and carotid bulb IMT (R = 0.29, P = 0.01). In multivariable regression, only current alcohol consumption and systolic blood pressure were independently associated with PWV in the HIV-infected group (where current alcohol consumption and higher systolic blood pressure were associated with higher PWV); whereas, age, body mass index, and current marijuana use were associated with PWV in healthy controls. In this study of PWV in HIV-infected youth, measures of arterial stiffness were not different between subjects and controls. However, in HIV-infected youth, there was a significant association between PWV and carotid IMT, as well as between PWV and current alcohol consumption. Thus, PWV may have potential as a useful, non-invasive method to assess CVD risk in HIV-infected youth, but further investigation is needed.

Effects of cholecalciferol supplementation on serum and urinary vitamin D metabolites and binding protein in HIV-infected youth.

Vitamin D insufficiency is widespread in HIV-infected patients. HIV and/or antiretroviral therapy (ART), particularly efavirenz (EFV), may interfere with vitamin D metabolism. However, few data from randomized, controlled trials exist. Here, we investigate changes in vitamin D metabolites and binding protein (VDBP) after 6 months of supplementation in a randomized, active-control, double-blind trial investigating 2 different monthly cholecalciferol (vitamin D3) doses [60,000 (medium) or 120,000 (high) IU/month] vs. a control arm of 18,000 IU/month in 8-25year old HIV-infected youth on ART with HIV-1 RNA <1000 copies/mL and baseline 25-hydroxycholecalciferol (25(OH)D3) ≤30ng/mL. A matched healthy uninfected group was enrolled in a similar parallel study for comparison. Changes after 6 months were analyzed as intent-to-treat within/between groups [control group (low dose) vs. combined supplementation doses (medium+high)]. At 6 months, 55% vs. 82% of subjects in control and supplementation groups, respectively, reached 25(OH)D3 ≥30ng/mL (P=0.01) with no difference between medium and high doses (both 82% ≥30ng/mL). There were few differences for those on EFV vs. no-EFV, except serum VDBP decreased in EFV-treated subjects (both within- and between-groups P≤0.01). There were no significant differences between the HIV-infected vs. healthy uninfected groups. The major finding of the present study is that cholecalciferol supplementation (60,000 or 120,000 IU/month) effectively raises serum 25(OH)D3 in the majority of HIV-infected subjects, regardless of EFV use. Notably, response to supplementation was similar to that of uninfected subjects.

Amino Acid Concentrations in HIV-Infected Youth Compared to Healthy Controls and Associations with CD4 Counts and Inflammation.

Amino acids play critical roles in metabolism, cell function, body composition and immunity, but little data on plasma amino acid concentrations in HIV are available. We evaluated plasma amino acid concentrations and associations with CD4 counts and inflammatory biomarkers in HIV-infected youth. HIV-infected subjects with a high (≥500 cells/mm3) and low (<500 cells/mm3) current CD4+ T cell counts were compared to one another and to a matched healthy control group. Plasma concentrations of 19 amino acids were determined with an amino acid analyzer. Plasma levels of interleukin-6, tumor necrosis factor receptor-I, and soluble vascular cellular adhesion molecule-I were also measured. Seventy-nine HIV-infected subjects (40 and 39 with high and low CD4+ T cell counts, respectively) and 40 controls were included. There were no differences in amino acid concentrations between HIV-infected subjects with high or low CD4+ T cell counts. When combined, the HIV-infected group exhibited significantly lower median plasma concentrations compared to controls for total, essential, branched-chain and sulfur amino acids, as well as for 12 individual amino acids. Glutamate was the only amino acid that was higher in the HIV-infected group. There were no significant correlations between amino acid endpoints and inflammatory biomarkers for either HIV-infected group or controls. Plasma amino acid concentrations were lower in HIV-infected youth compared to healthy controls, regardless of immune status, while glutamate concentrations were elevated. These findings can inform future interventional studies designed to improve metabolic and clinical parameters influenced by amino acid nutriture.

Kallistatin levels in HIV-infected patients and effects of statin therapy.

BACKGROUND: Kallistatin, a serine proteinase inhibitor, has vasodilatory and anti-inflammatory properties and is increased in other inflammatory conditions. We measured kallistatin in HIV for the first time, examined its relationship with inflammation, and determined if statin therapy affected levels. METHODS: Kallistatin levels were measured in subjects from a randomized, double-blinded, placebo-controlled trial. RESULTS: One hundred and thirty-five HIV-infected subjects were included. Kallistatin levels were 28.4 µg/mL at baseline and not affected by rosuvastatin. Levels were correlated with high-sensitivity C-reactive protein (hsCRP), interleukin-6, fibrinogen and insulin resistance. CONCLUSIONS: Kallistatin levels were correlated with some markers of systemic inflammation and should be further explored in the HIV population.

Cardiovascular Disease, Statins, and HIV.

Human immunodeficiency virus (HIV)-infected patients are at an increased risk of serious, non-AIDS-defining comorbidities, even in the setting of viral suppression with combination antiretroviral therapy. This increased risk is due in part to immune dysfunction and heightened inflammation and immune activation associated with chronic HIV infection. Statins have wide-reaching immunomodulatory effects, and their use in the HIV-infected population may be of particular benefit. In this article, we review the pathogenesis of increased inflammation during HIV infection and how it contributes to the risk of cardiovascular disease among HIV-infected individuals. We then we review the immunomodulatory effects of statins and how they may attenuate the risk of cardiovascular disease and other comorbidities in this unique patient population.

Increased Immune Activation and Exhaustion in HIV-infected Youth.

BACKGROUND: Immune activation and exhaustion drive several comorbidities and disease progression in HIV-infected adults; however, they are not well studied in HIV-infected youth. Thus, this study sought to examine levels of immune activation and exhaustion in this population, investigate associated HIV- and non-HIV-related variables and compare results with a matched healthy control group. METHODS: HIV-infected youth 8-25 years of age on stable antiretroviral therapy with an HIV-1 RNA level <1000 copies/mL were enrolled, along with matched healthy controls. We measured T-cell and monocyte immune activation and exhaustion markers in cryopreserved peripheral blood mononuclear cell and plasma samples. RESULTS: A total of 136 subjects (80 HIV+: 66% male; 91% black) were enrolled. Markers of CD4+ and CD8+ T-cell activation were higher in the HIV-infected group versus controls [mean % CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ = 2.2 versus 1.5 (P=0.002) and 4.9 versus 2.2 (P<0.0001), respectively], as were exhausted CD4+ and CD8+ T-cells [mean % CD4+CD38+HLA-DR+PD-1+ and CD8+CD38+HLA-DR+PD-1+ = 1.0 versus 0.5 (P<0.0001) and 1.6 versus 0.7 (P<0.0001), respectively]. There were no differences in proportions of inflammatory or patrolling monocytes between groups (P>0.05); however, soluble CD14 was higher in HIV-infected compared with controls (1.6 versus 1.4 µg/mL; P=0.01). Current CD4 count, low-density lipoprotein cholesterol and age were the variables most associated with CD4+ and CD8+ T-cell activation. CONCLUSIONS: CD4+ and CD8+ T-cell immune activation and exhaustion are higher in HIV-infected youth compared with matched controls, while monocyte subpopulations are not altered despite a high soluble CD14 level. The clinical significance of the increased immune activation and exhaustion should be further explored.