Allison Ross Eckard

Effect of 24 Weeks of Statin Therapy on Systemic and Vascular Inflammation in HIV-Infected Subjects Receiving Antiretroviral Therapy

BACKGROUNDnHuman immunodeficiency virus (HIV)-infected individuals are at increased risk of cardiovascular disease (CVD) due in part to inflammation. Statins decrease inflammation in the general population, but their effect during HIV infection is largely unknown.nnnMETHODSnThis is an ongoing randomized, double-blinded, placebo-controlled trial to evaluate the effect of statin therapy on inflammatory markers during HIV infection. Subjects received rosuvastatin 10 mg daily or placebo for 24 weeks. Subjects were receiving stable (>12 weeks) antiretroviral therapy and had a low-density lipoprotein (LDL) cholesterol level of ≤130 mg/dL and evidence of heightened immune activation or inflammation. This was a prespecified interim analysis.nnnRESULTSnA total of 147 subjects were enrolled (78% were male, 70% were black, and the median age was 47 years). By 24 weeks, LDL cholesterol levels had decreased in the statin group, compared with an increase in the placebo group (-28% vs +3.8%; P < .01). A 10% reduction in the lipoprotein-associated phospholipase A2 (Lp-PLA2) level was seen in the statin group, compared with a 2% reduction in the placebo group (P < .01). In multivariable regression, receipt of statin treatment and having a nadir CD4(+) T-cell count of ≤100 cell/µL were the only statistically significant predictors of a decrease in Lp-PLA2 level. Markers of systemic inflammation did not change significantly between groups.nnnCONCLUSIONSnTwenty-four weeks of rosuvastatin therapy significantly decreased the level of Lp-PLA2, a vascular-specific, inflammatory enzyme that predicts cardiovascular events in the general population. Statins may hold promise as a means of attenuating CVD risk in HIV-infected individuals by decreasing Lp-PLA2 levels.

Metabolic complications and treatment of perinatally HIV-infected children and adolescents

The benefits of long‐term antiretroviral therapy (ART) are recognized all over the world with infected children maturing into adults and HIV infection becoming a chronic illness. However, the improved survival is associated with serious metabolic complications, including lipodystrophy (LD), dyslipidemia, insulin resistance, lactic acidosis and bone loss. In addition, the dyslipidemia mainly seen with protease inhibitors may increase the risk of cardiovascular disease in adulthood and potentially in children as they mature into adults. Nucleoside reverse transcriptase inhibitors, particularly stavudine, zidovudine and didanosine are linked to development of LD and lactic acidosis. Perinatally infected children initiate ART early in life; they require lifelong therapy with multiple drug regimens leading to varying toxicities, all potentially impacting their quality of life. LD has a significant impact on the mental health of older children and adolescents leading to poor self‐image, depression and subsequent poor adherence to therapy. Reduced bone mineral density (BMD) is reported in both adults and children on ART with the potential for children to develop more serious bone complications than adults due to their rapid growth spurts and puberty. The role of vitamin D in HIV‐associated osteopenia and osteoporosis is not clear and needs further study. Most resource‐limited settings are unable to monitor lipid profiles or BMD, exposing infected children and adolescents to on‐going toxicities with unclear long‐term consequences. Improved interventions are urgently needed to prevent and manage these metabolic complications. Longitudinal cohort studies in this area should remain a priority, particularly in resource‐limited settings where the majority of infected children reside.

Risk Factors for Vitamin D Deficiency and Relationship with Cardiac Biomarkers, Inflammation, and Immune Restoration in HIV-Infected Youth

BACKGROUNDnVitamin D deficiency is common in HIV-infected individuals. In adults, traditional and HIV-related factors play a role in vitamin D status, and deficiency appears to impair immune restoration and exacerbate HIV complications, like cardiovascular disease (CVD). This study sought to determine factors contributing to vitamin D status in HIV-infected youth and investigate the relationship with CVD risk, inflammation and immune restoration.nnnMETHODSnHIV-infected subjects (1-25 years old) were enrolled prospectively along with healthy controls that were group-matched by age, sex and race. HIV data were collected for the HIV-infected group, while traditional risk factors, including vitamin D intake, sun exposure, skin pigmentation, physical activity level and body mass index (BMI) were collected for both groups. Fasting lipids, plasma 25-hydroxyvitamin D (25[OH]D), and inflammation markers were measured.nnnRESULTSnIn total, 200 HIV-infected subjects and 50 controls were enrolled. HIV group had 53% male, 95% Black and a mean age of 17.2 ±4.6 years. There was no difference in 25(OH)D between groups; 77% of HIV+ and 74% of controls had 25(OH)D<20 ng/ml. Only Fitzpatrick skin type was independently associated with 25(OH)D. No HIV variables were associated with 25(OH)D, even when HIV sub-populations were examined. Inflammation, CVD risk factors and immune restoration were not independently associated with 25(OH)D.nnnCONCLUSIONSnVitamin D deficiency is common among HIV-infected youth. However, HIV factors, CVD risk, inflammation and immune restoration do not appear to have the same relationship with vitamin D as has been shown in adults. Supplementation trials are needed to determine if increasing 25(OH)D concentrations could better elucidate these relationships.

The Relationship between Vitamin D Status and HIV-Related Complications in HIV-infected Children and Young Adults

Background: In HIV-infected adults, we and others have shown that vitamin D deficiency is independently associated with increased carotid intima-media thickness (cIMT), a surrogate marker for cardiovascular disease (CVD). This study explored for the first time the relationship between vitamin D and CVD risk in HIV-infected youth. Methods: This is a cross-sectional assessment of cIMT, inflammation, metabolic markers and vitamin D status in HIV-infected youth and healthy controls. We measured serum 25-hydroxyvitamin D (25(OH)D), fasting lipids, insulin, glucose, inflammatory markers and cIMT. Results: Thirty HIV-infected subjects and 31 controls were included. Among HIV-infected subjects, median age was 11 years (37% males; 73% black; similar to controls). HIV-infected subjects’ mean (standard deviation) serum 25(OH)D was 24 (35) ng/mL; 70% had 25(OH)D <20 ng/mL (deficient), 23% between 20–30 ng/mL (insufficient) and 7% >30 ng/mL (sufficient); proportions were similar to controls (P = 0.17). After adjusting for season, sex and race, there was no difference in serum 25(OH)D between groups (P = 0.11). Serum 25(OH)D was not significantly correlated with cIMT, inflammatory markers or lipids. Serum 25(OH)D was negatively correlated with body mass index, insulin resistance, HIV duration, and cumulative use of antiretroviral therapy, non- and nucleoside reverse transcriptase inhibitors. Conclusions: Most HIV-infected youth have vitamin D deficiency or insufficiency. Despite no direct association between serum 25(OH)D and cIMT, there were notable associations with some CVD risk factors, particularly inverse correlation with insulin resistance. Studies are needed to determine whether CVD risk, including insulin resistance, could be improved with vitamin D supplementation.

Missed opportunities for prevention of mother-to-child transmission in the United States.

Objective:To describe system failures potentially contributing to perinatal HIV transmission in the state of Georgia, United States, between 2005 and 2012. Design:A retrospective chart review of antenatal and postnatal records of HIV-infected infants between 1 January 2005 and 31 December 2012. Methods:Study participants included all HIV-infected infants referred for specialized management to the Ponce Family and Youth Clinic within Grady Health Systems in Atlanta. Main outcomes included identification of maternal, perinatal, and neonatal risk factors associated with vertical transmission. Results:Twenty-seven cases were identified; 89% of mothers were African–American between 16 and 30 years of age. Seventy-four percent of women knew their HIV status prior to pregnancy, 44% had no prenatal care, and 52% did not receive combination antiretroviral therapy during pregnancy or intrapartum zidovudine. HIV-1 RNA near the time of delivery was available in only 10 of 27 mothers, and of those, only three had an undetectable HIV-1 RNA level. Caesarean section was performed in 70% of women. Of the 27 children, the mean gestational age was 37 (SD: 2.9) weeks, with 33% requiring neonatal ICU admission. Fifty-nine percent were men, and only 67% received postnatal zidovudine prophylaxis. Conclusion:Mother-to-child transmission of HIV continues to occur in Georgia at unacceptable levels. Increased education with adherence to existing national guidelines, as well as coordinated efforts between healthcare and public health providers to improve linkage and retention in medical care are urgently needed to prevent further vertical transmission events in Georgia.

Impact of Body Mass Index on Immunogenicity of Pandemic H1N1 Vaccine in Children and Adults

Obesity emerged as a risk factor for morbidity and mortality related to 2009 pandemic influenza A (H1N1) infection. However, few studies examine the immune responses to H1N1 vaccine among children and adults of various body mass indices (BMI). Pooling data from 3 trials of unadjuvanted split-virus H1N1 A/California/07/2009 influenza vaccines, we analyzed serologic responses of participants stratified by BMI grouping. A single vaccine dose produced higher hemagglutination inhibition antibody titers at day 21 in obese compared to nonobese adults, but there were no significant differences in responses to H1N1 vaccine among children or adults of various BMI following 2 doses.

Vitamin D Deficiency and Altered Bone Mineral Metabolism in HIV-infected Individuals

Although patients with HIV infection are living decades longer than before with the advent of combination antiretroviral therapy, they have an increased rate of co-morbidities associated with chronic HIV, such as osteoporosis, cardiovascular disease, and immune dysfunction. Many of these complications are known to be affected by vitamin D status in the general population. Thus, the high rate of vitamin D deficiency among HIV-infected patients is alarming. Many observational and cohort studies have demonstrated that vitamin D deficiency is associated with these HIV-related complications, but randomized, placebo-controlled trials are limited. This paper reviews recent data on vitamin D deficiency in HIV infection.

Safety and Immunogenicity of Full-Dose Trivalent Inactivated Influenza Vaccine (TIV) Compared With Half-Dose TIV Administered to Children 6 Through 35 Months of Age

BACKGROUNDnChildren 6 through 35 months of age are recommended to receive half the dose of influenza vaccine compared with older children and adults.nnnMETHODSnThis was a 6-site, randomized 2:1, double-blind study comparing full-dose (0.5 mL) trivalent inactivated influenza vaccine (TIV) with half-dose (0.25 mL) TIV in children 6 through 35 months of age. Children previously immunized with influenza vaccine (primed cohort) received 1 dose, and those with no previous influenza immunizations (naive cohort) received 2 doses of TIV. Local and systemic adverse events were recorded. Sera were collected before immunization and 1 month after last dose of TIV. Hemagglutination inhibition antibody testing was performed.nnnRESULTSnOf the 243 subjects enrolled (32 primed, 211 naive), data for 232 were available for complete analysis. No significant differences in local or systemic reactions were observed. Few significant differences in immunogenicity to the 3 vaccine antigens were noted. The immune response to H1N1 was significantly higher in the full-dose group among primed subjects. In the naive cohort, the geometric mean titer for all 3 antigens after 2 doses of TIV were significantly higher in the 12 through 35 months compared with the 6 through 11 months age group.nnnCONCLUSIONSnOur study confirms the safety of full-dose TIV given to children 6 through 35 months of age. An increase in antibody responses after full- versus half-dose TIV was not observed, except for H1N1 in the primed group. Larger studies are needed to clarify the potential for improved immunogenicity with higher vaccine doses. Recommending the same dose could simplify the production, storage, and administration of influenza vaccines.

Effects of vitamin D supplementation on carotid intima-media thickness in HIV-infected youth

Allison Ross Eckard, Paolo Raggi, Mary Ann O’Riordan, Julia C. Rosebush, Danielle Labbato, Ann Chahroudi, Joshua H. Ruff, Christopher T. Longenecker, Vin Tangpricha, and Grace A. McComsey Medical University of South Carolina, Charleston, SC, USA; Emory University School of Medicine, Atlanta, GA, USA; Mazankowski Alberta Heart Institute and University of Alberta, Edmonton, Alberta, Canada; Case Western Reserve University and Rainbow Babies & Children’s Hospital, Cleveland, OH, USA

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.