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1.  Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate 
Antiviral therapy  2014;19(6):613-618.
Background
Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biologic activity, and is elevated in persons with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youth treated with combination antiretroviral therapy (cART) containing or not containing TDF.
Methods
A randomized controlled trial in HIV+ youth ages 18–25 years enrolled participants based on cART treatment with TDF (TDF, N=118) or without TDF (no-TDF, N=85) and randomized within those groups to VITD (50,000 IU every four weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group.
Results
At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was +7.7 pg/mL in the TDF/VITD group, compared to −1.7 (no-TDF/VITD, p=0.010); −1.3 (TDF/PL, p=0.006); and +1.1 (no-TDF/PL, p=0.035).
Conclusions
These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youth.
doi:10.3851/IMP2755
PMCID: PMC4135028  PMID: 24535626
2.  Preexposure Prophylaxis for Adolescents and Young Adults at Risk for HIV Infection: Is an Ounce of Prevention Worth a Pound of Cure? 
Human immunodeficiency virus incidence in youth is disproportionately higher than the prevention research and services available to protect this vulnerable population. There are many ethical, legal, and regulatory considerations in ensuring that at-risk youth have unfettered access to safe and effective health-promoting interventions.
An alarming proportion of incident human immunodeficiency virus (HIV) infections worldwide occur in youth. In the United States, 69% of all new infections among youth occurred in young men who have sex with men (YMSM). Recent studies show the promise of preexposure prophylaxis (PrEP) for preventing HIV infection, but research efforts suffer from disproportionately low representation of the youth who are most at risk. Youth-focused research is critical and should include behavioral, community, and biomedical interventions to create a comprehensive HIV prevention package. The many ethical, legal, and regulatory considerations in conducting HIV research among, and in providing care services to, youth must be addressed so that those at high risk and most likely to benefit can have unfettered access to safe and effective health-promoting interventions. YMSM and minority youth are at substantial HIV risk and urgently need effective HIV prevention tools for which the short and long-term benefits and risks have been carefully considered.
doi:10.1093/cid/cis1020
PMCID: PMC3657491  PMID: 23223604
HIV prevention; adolescents and young adults; preexposure prophylaxis; PrEP
3.  NEUROCOGNITIVE FUNCTIONING IN ANTIRETROVIRAL THERAPY-NAÏVE YOUTH WITH BEHAVIORALLY ACQUIRED HIV 
Purpose
Youth living with HIV account for over one-third of new HIV infections and are at high risk of adverse psychosocial, everyday living, and health outcomes. HIV-associated neurocognitive disorders (HAND) are known to affect health outcomes of HIV-infected adults even in the era of combination antiretroviral therapy (cART). Thus, the current study aimed to characterize the prevalence and clinical correlates of HAND in youth living with HIV. Here we report baseline neurocognitive data for behaviorally HIV-infected youth enrolled in a prospective study evaluating strategies of antiretroviral treatment initiation and use.
Methods
Two hundred twenty participants, age 18-24, naïve to treatment (except for prevention of mother to child HIV transmission; n=3), completed a comprehensive neurocognitive, substance use, and behavioral health assessment battery.
Results
64.7% of youth met criteria for HAND (96.4% asymptomatic, 3.5% syndromic), with deficits in episodic memory and fine-motor skills emerging as the most commonly affected ability areas. Multivariable models showed that lower CD4 count, longer time since HIV diagnosis, and high risk alcohol use were uniquely associated with neurocognitive deficits.
Conclusions
Over two-thirds of youth with behaviorally acquired HIV evidence neurocognitive deficits, which have modest associations with more advanced HIV disease as well as other factors. Research is needed to determine the impact of such neuropsychiatric morbidity on mental health and HIV disease treatment outcomes (e.g., non-adherence) and transition to independent living responsibilities in HIV-infected youth, as well as its long-term trajectory and possible responsiveness to cognitive rehabilitation and pharmacotherapy.
doi:10.1016/j.jadohealth.2013.07.006
PMCID: PMC3878875  PMID: 23972941
HIV; Adolescent; Neurocognitive Functioning; Substance Use; HIV-Associated Neurocognitive Disorder (HAND)
4.  Immunogenicity and Safety of the Human Papillomavirus 6, 11, 16, 18 Vaccine in HIV-Infected Young Women 
Among 16- to 23-year-old human immunodeficiency virus–infected young women who were human papillomavirus (HPV) DNA and HPV seronegative at the time of vaccination with the quadrivalent HPV vaccine, immune responses to vaccination were generally robust and the vaccine was well tolerated.
Background
The objective of this study was to determine whether the 3-dose quadrivalent human papillomavirus (HPV) vaccine series (HPV-6, -11, -16, -18) is immunogenic and safe in young women infected with human immunodeficiency virus (HIV).
Methods
We enrolled 99 women aged 16–23 years in a phase 2, open-label, multicenter trial, conducted from 2008 to 2011 by the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Outcome measures were immunogenicity 4 weeks after dose 3, measured by (1) geometric mean titers (GMTs) and (2) seroconversion rates for HPV-6, -11, -16, and -18, among those seronegative and HPV DNA negative for each type. Immune responses were compared to those of a historical comparison group of HIV-negative women (n = 267) using univariate methods. Clinical and laboratory adverse events were assessed after each dose.
Results
The mean age of subjects was 21.4 years; 80% were non-Hispanic black, 69 were not taking antiretroviral therapy (ART), and 30 were taking ART. No differences in GMTs were noted among participants taking ART vs the comparison group, but GMTs were lower in participants not taking ART vs the comparison group for HPV-16 (2393 vs 3892 milli-Merck units per milliliter [mMU/mL], P = .012) and HPV-18 (463 vs 801 mMU/mL, P = .003). Seroconversion rates were 100% for HPV-6, -11, -16, and -18 among participants taking ART. Rates ranged from 92.3% (for HPV-18) to 100.0% (for HPV-6) among participants not taking ART. One severe adverse event (fatigue) was noted.
Conclusions
In a sample of HIV-infected women who were HPV DNA and HPV seronegative, immune responses to HPV vaccination were generally robust and the vaccine was well tolerated.
Clinical Trials Registration
NCT00710593.
doi:10.1093/cid/cit319
PMCID: PMC3739463  PMID: 23667266
immunogenicity; safety; human papillomavirus; vaccine; HIV infected
5.  Exploration of the Effect of Tobacco Smoking on Metabolic Measures in Young People Living with HIV 
AIDS Research and Treatment  2014;2014:740545.
We conducted cross-sectional, multicenter studies in HIV-positive young women and men to assess metabolic and morphologic complications from tobacco smoking in 372 behaviorally infected HIV-positive youth, aged 14–25 years. Measurements included self-reported tobacco use, fasting lipids, glucose, fat distribution, and bone mineral density (BMD; dual-energy X-ray absorptiometry scans). Overall, 144 (38.7%) self-reported smoking tobacco and 69 (47.9%) of these reported smoking greater than five cigarettes per day. Smokers versus nonsmokers had lower mean total cholesterol (146.0 versus 156.1 mg/dL; P < 0.01) and lower mean total body fat percent (24.1% versus 27.2%, P = 0.03). There was no difference between smokers and nonsmokers in fasting glucose or BMD. There appear to be only minimal effects from tobacco smoking on markers of cardiac risk and bone health in this population of HIV-positive youth. While these smokers may not have had sufficient exposure to tobacco to detect changes in the outcome measures, given the long-term risks associated with smoking and HIV, it is critical that we encourage HIV-positive youth smokers to quit before the deleterious effects become apparent.
doi:10.1155/2014/740545
PMCID: PMC4119894  PMID: 25114801
6.  Preventing HIV among Young People: research priorities for the future 
Objective
To review the current state of knowledge on the prevention of sexual transmission of HIV in adolescents and to highlight existing gaps and priority areas for future research.
Background
A disproportionate burden of HIV infections falls on adolescents, a developmental stage marked by unique neural, biological, and social transition. Successful interventions are critical to prevent the spread of HIV in this vulnerable population.
Methods
We summarized the current state of research on HIV prevention in adolescents by providing examples of successful interventions and best practices, and highlighting current research gaps.
Results
Adolescent interventions fall into three main categories: biomedical, behavioral, and structural. The majority of current research has focused on individual behavior change, while promising biomedical and structural interventions have been largely understudied in adolescents. Combination prevention interventions may be particularly valuable to this group.
Conclusions
Adolescents have unique needs with respect to HIV prevention and, thus, interventions should be designed to most effectively reach this population with information and services that will be relevant to them.
doi:10.1097/QAI.0b013e31829871fb
PMCID: PMC3746811  PMID: 23764629
Adolescence; HIV; Prevention
7.  Mortality Trends in the US Perinatal AIDS Collaborative Transmission Study (1986–2004) 
A significant highly active antiretroviral therapy-associated decrease in annual mortality and a prolongation in survival were seen in this US perinatal cohort of human immunodeficiency virus-infected children. Temporal reductions in opportunistic infection (OI)-associated mortality were replaced by non-OI-associated deaths.
(See the Editorial Commentary by Nachman, on pages 1035–6.)
Background. Highly active antiretroviral therapy (HAART) has improved human immunodeficiency virus (HIV)–associated morbidity and mortality. The bimodal mortality distribution in HIV-infected children makes it important to evaluate temporal effects of HAART among a birth cohort with long-term, prospective follow-up.
Methods. Perinatal AIDS Collaborative Transmission Study (PACTS)/PACTS–HIV Follow-up of Perinatally Exposed Children (HOPE) study was a Centers for Disease Control and Prevention–sponsored multicenter, prospective birth cohort study of HIV-exposed uninfected and infected infants from 1985 until 2004. Mortality was evaluated for the no/monotherapy, mono-/dual-therapy, and HAART eras, that is, 1 January 1986 through 31 December 1990, from 1 January 1991 through 31 December 1996, and 1 January 1997 through 31 December 2004.
Results. Among 364 HIV-infected children, 56% were female and 69% black non-Hispanic. Of 98 deaths, 79 (81%) and 61 (62%) occurred in children ≤3 and ≤2 years old, respectively. The median age at death increased significantly across the eras (P < .0001). The average annual mortality rates were 18 (95% confidence interval [CI], 11.6–26.8), 6.9 (95% CI, 5.4–8.8), and 0.8 (95% CI, 0.4–1.5) events per 100 person-years for the no/monotherapy, mono-/dual-therapy and HAART eras, respectively. The corresponding 6-year survival rates for children born in these eras were 57%, 76%, and 91%, respectively (P < .0001). Among children who received HAART in the first 6 months of age, the probability of 6-year survival was 94%. Ten-year survival rates for HAART and non-HAART recipients were 94% and 45% (P < .05). HAART-associated reductions in mortality remained significant after adjustment for confounders (hazard ratio, 0.3; 95% CI, .08–.76). Opportunistic infections (OIs) caused 31.8%, 16.9%, and 9.1% of deaths across the respective eras (P = .051).
Conclusions. A significant decrease in annual mortality and a prolongation in survival were seen in this US perinatal cohort of HIV-infected children. Temporal decreases in OI-associated mortality resulted in relative proportional increases of non–OI-associated deaths.
doi:10.1093/cid/cir641
PMCID: PMC3202314  PMID: 22002982
8.  Association of Higher Plasma Vitamin D Binding Protein and Lower Free Calcitriol Levels with Tenofovir Disoproxil Fumarate Use and Plasma and Intracellular Tenofovir Pharmacokinetics: Cause of a Functional Vitamin D Deficiency? 
Antimicrobial Agents and Chemotherapy  2013;57(11):5619-5628.
Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation.
(The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.)
doi:10.1128/AAC.01096-13
PMCID: PMC3811269  PMID: 24002093
9.  Assessment of Biomarkers of Cardiovascular Risk Among HIV Type 1-Infected Adolescents: Role of Soluble Vascular Cell Adhesion Molecule As an Early Indicator of Endothelial Inflammation 
Abstract
Cardiovascular disease (CVD) biomarkers were examined in a cohort of HIV-infected and HIV-uninfected adolescents who participated in Adolescent Trials Network study 083 utilizing samples from the Reaching for Excellence in Adolescent Care cohort, a longitudinal study of youth infected through adult risk behavior. Nonfasting blood samples from 97 HIV-infected and 81 HIV-uninfected adolescents infected by adult risk behaviors were analyzed for total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglycerides, apolipoprotein A-I, high-sensitivity C-reactive protein (hsCRP), soluble vascular adhesion molecule-1 (sVCAM-1), myeloperoxidase, and neopterin at baseline and 18 months later. Results were analyzed using ANOVA, Wilcoxon signed-rank, and paired t tests. Among infected subjects 67 received antiretroviral therapy and 30 were treatment naive. The HIV-infected and HIV-uninfected subjects were similar in gender, ethnicity, and cardiovascular risk factors such as smoking and obesity. In all groups lipid parameters were within accepted guidelines for cardiovascular risk. Among HIV-infected youth on antiretroviral therapy (ART), HDL and apoprotein A-I were significantly lower when compared to uninfected youth. hsCRP was not elevated and thus not predictive for risk in any group. sVCAM-1 levels were significantly elevated in both HIV-infected groups: 1,435 ng/ml and 1,492 ng/ml in untreated and treated subjects, respectively, and 1,064 ng/ml in the uninfected group (p<0.0001). Across all groups neopterin correlated with sVCAM at 18 months (Spearman correlation coefficient 0.58, p<0.0001). Only 9% of ART-treated subjects fully suppressed virus. Lipid profiles and hsCRP, traditional markers of cardiovascular disease, are not abnormal among HIV-infected youth but elevated sVCAM may be an early marker of atherosclerosis.
doi:10.1089/aid.2012.0086
PMCID: PMC3581064  PMID: 23062187
10.  Mental Health Care among HIV Infected Youth in Medical Care: Disparities and Equalities 
Objectives
Untreated psychiatric illness can be detrimental to the health and well- being of HIV infected youth and young adults. This exploratory study sought to examine the relationships between social and demographic variables and the rates of psychiatric treatment among HIV infected youth and young adults enrolled at clinics specializing in the provision of HIV care.
Setting/Participants
These analyses are from a cross sectional survey of 1706 HIV infected adolescents and young adults (13-26 yrs) engaged in care at treatment sites or affiliates of the Adolescent Medicine Trials Network (ATN) for HIV/AIDS Interventions from 2010-2011.
Design
Among the youth and young adults who reported recent significant mental health symptoms on the Brief Symptom Inventory (BSI), comparisons on demographic variables (including race, ethnicity, language spoken, level of education, sexual orientation, gender identity, household income, living situation, and history of incarceration/detention) were made.
Results
Among the group with symptoms, Black youth were significantly less likely than non-Blacks to have received mental health care (37.4% vs. 48.6%) and psychiatric medications (19.3% vs. 26.9%). In contrast, Latinos were more likely than non-Latinos to report receiving mental health care (52.9% vs. 35.7%).
Conclusion
Although no disparities in care were found based on gender, sexual orientation, Hispanic ethnicity, or income, care providers should be alerted to the potential disparities that exist for Black youth and young adults living with HIV.
doi:10.1177/2325957413488172
PMCID: PMC3883958  PMID: 23695228
Disparities; HIV; mental health care; psychiatric medication; African American
11.  Youth-Specific Considerations in the Development of PrEP, Microbicide and Vaccine Research Trials 
Preventing HIV infection in adolescents and young adults will require a multimodal, targeted approach including individual-directed behavioral risk reduction, community-level structural change, and biomedical interventions to prevent sexual transmission. Trials testing biomedical interventions to prevent HIV transmission will require special attention in this population due to the unique psychosocial as well as physiologic characteristics that differentiate them from older populations. For example, microbicide research will need to consider acceptability, dosing requirements, and co-infection rates that are unique to this population. Pre-exposure prophylaxis studies also will need to consider potential unique psychosocial issues such as sexual disinhibition and acceptability as well as unique pharmacokinetic parameters of antiretroviral agents. Vaccine trials also face unique issues with this population, including attitudes towards vaccines, risks related to false-positive HIV tests related to vaccine, and different immune responses based on more robust immunity. In this paper, we will discuss issues around implementing each of these biomedical prevention modalities in trials among adolescents and young adults to help to guide future successful research targeting this population.
doi:10.1097/QAI.0b013e3181e3a922
PMCID: PMC2912697  PMID: 20571421
Adolescents; youth; biomedical HIV prevention; vaccines; PrEP; microbicides
12.  Prevalence and Risk Factors for HPV in HIV-Positive Young Women Receiving Their First HPV Vaccination 
Background
The objectives of this study were to describe the prevalence and risk factors for HPV infection among HIV-infected young women receiving their first quadrivalent HPV (HPV-6, -11, -16, -18) vaccine dose.
Methods
We recruited 16-23 year-old women from 14 sites for an HPV vaccine trial. At the first visit they completed a questionnaire and were tested for cervicovaginal HPV DNA (41 types) and HPV serology (4 vaccine types). Factors associated with any HPV, type-specific HPV, and high-risk (cancer-associated) HPV infection were identified using univariate and multivariable logistic regression.
Results
The mean age of participants (N=99) was 21.4 years, 30.3% were on antiretroviral therapy, 74.7% were positive for > 1 HPV DNA type, 53.5% for > 1 high-risk type, 12.1% for HPV-16, and 5.1% for HPV-18. Most were HPV DNA negative and seronegative for HPV-16 (55.6%) and HPV-18 (73.7%); 45.5% were HPV DNA and seronegative for both HPV-16 and -18. Three variables were associated with high-risk HPV DNA in multivariable analysis: non-Hispanic Black vs. Hispanic ethnicity (AOR 7.06, 95% CI 1.63-30.5), HIV viral load > 400 vs. < 400 copies/mL (AOR 3.47, 95% CI 1.28-9.43), and frequency of vaginal sex in the past 90 days (AOR 5.82, 95% CI 1.30-26.11 for > 6 vs. 0 times).
Conclusions
The prevalence of > 1 HPV type was high in these young women, demonstrating the importance of vaccinating prior to sexual initiation. However, most were HPV DNA negative and seronegative for high-risk, vaccine-type HPV infection, supporting vaccination of sexually experienced HIV-positive young women.
doi:10.1097/QAI.0b013e3182676fe3
PMCID: PMC3480995  PMID: 22820809
human papillomavirus; vaccine; epidemiology; women; HIV
13.  Low Bone Mass in Behaviorally HIV-Infected Young Men on Antiretroviral Therapy: Adolescent Trials Network Study 021B 
We report evidence of low bone mass in behaviorally human immunodeficiency virus (HIV)–infected young men on antiretroviral therapy with a relatively recent diagnosis of HIV infection, compared with seronegative controls.
Background. Peak bone mass is achieved in adolescence/early adulthood and is the key determinant of bone mass in adulthood. We evaluated the association of bone mass with human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) during this critical period among behaviorally HIV–infected young men and seronegative controls.
Methods. HIV-positive men (N = 199) and HIV-negative controls (N = 53), ages 14–25 years, were studied at 15 Adolescent Trials Network for HIV/AIDS Interventions sites. HIV-positive participants were recruited on the basis of ART status: ART-naive (N = 105) or on a regimen containing a nonnucleoside reverse transcriptase inhibitor (NNRTI; N = 52) or protease inhibitor (PI; N = 42). Bone mineral density (BMD) and content (BMC) and body composition were measured by dual-energy X-ray absorptiometry (DXA). Results were compared across groups by linear modeling. Bone results were adjusted for race, body mass index (BMI), and type of DXA (Hologic/Lunar).
Results. The HIV-positive and HIV-negative groups had comparable median age (21 years) and racial/ethnic distribution. Median times since HIV diagnosis were 1.3, 1.9, and 2.2 years in the ART-naive, NNRTI, and PI groups, respectively (P = .01). Total and regional fat were significantly lower in the ART-naive group compared with seronegative controls. Mean BMD and Z scores were generally lower among HIV-positive participants on ART, particularly in the PI group. Average Z scores for the spine were below zero in all 4 groups, including controls.
Conclusions. Young men on ART with a relatively recent diagnosis of HIV infection have lower bone mass than controls. Longitudinal studies are required to determine the impact of impaired accrual or actual loss of bone during adolescence on subsequent fracture risk.
doi:10.1093/cid/cis455
PMCID: PMC3491777  PMID: 22573848
14.  Comprehension of a simplified assent form in a vaccine trial for adolescents 
Journal of medical ethics  2013;39(6):410-412.
Introduction
Future HIV vaccine efficacy trials with adolescents will need to ensure that participants comprehend study concepts in order to confer true informed assent. A Hepatitis B vaccine trial with adolescents offers valuable opportunity to test youth understanding of vaccine trial requirements in general.
Methods
Youth reviewed a simplified assent form with study investigators and then completed a comprehension questionnaire. Once enrolled, all youth were tested for HIV and confirmed to be HIV-negative.
Results
123 youth completed the questionnaire (mean age=15 years; 63% male; 70% Hispanic). Overall, only 69 (56%) youth answered all six questions correctly.
Conclusions
Youth enrolled in a Hepatitis B vaccine trial demonstrated variable comprehension of the study design and various methodological concepts, such as treatment group masking.
doi:10.1136/medethics-2012-101286
PMCID: PMC3655100  PMID: 23349510
15.  Vitamin D3 Decreases Parathyroid Hormone in HIV-Infected Youth Being Treated With Tenofovir: A Randomized, Placebo-Controlled Trial 
In this randomized, double-blind, placebo-controlled trial of human immunodeficiency virus–infected youths aged 18–25, vitamin D3, 50000 IU once monthly for 3 months decreased parathyroid hormone in participants treated with tenofovir-containing antiretroviral regimens but not in those participants whose regimens did not contain tenofovir.
Background. The study goal was to determine the effect of vitamin D (VITD) supplementation on tubular reabsorption of phosphate (TRP), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and C-telopeptide (CTX) in youth infected with human immunodeficiency virus (HIV) receiving and not receiving combination antiretroviral therapy (cART) containing tenofovir disoproxil fumarate (TDF).
Methods. This randomized, double-blind, placebo-controlled multicenter trial enrolled HIV-infected youth 18–25 years based on stable treatment with cART containing TDF (n = 118) or no TDF (noTDF; n = 85), and randomized within those groups to vitamin D3, 50 000 IU (n = 102) or placebo (n = 101), administered at 0, 4, and 8 weeks. Outcomes included change in TRP, PTH, BAP, and CTX from baseline to week 12 by TDF/noTDF; and VITD/placebo.
Results. At baseline, VITD and placebo groups were similar except those on TDF had lower TRP and higher PTH and CTX. At week 12, 95% in the VITD group had sufficient serum 25-hydroxy vitamin D (25-OHD; ≥20 ng/mL), increased from 48% at baseline, without change in placebo (P < .001). PTH decreased in the TDF group receiving VITD (P = .031) but not in the noTDF group receiving VITD, or either placebo group. The decrease in PTH with VITD in those on TDF occurred with insufficient and sufficient baseline 25-OHD (mean PTH change, −7.9 and −6.2 pg/mL; P = .031 and .053, respectively).
Conclusions. In youth on TDF, vitamin D3 supplementation decreased PTH, regardless of baseline 25-OHD concentration.
Clinical Trials Registration. NCT00490412.
doi:10.1093/cid/cir968
PMCID: PMC3297650  PMID: 22267714
17.  An Assessment of the Feasibility and Acceptability of a Friendship-Based Social Network Recruitment Strategy to Screen At-Risk African American and Hispanic/Latina Young Women for HIV Infection 
JAMA pediatrics  2013;167(3):289-296.
Objectives
To examine the feasibility and acceptability of a friendship-based network recruitment strategy for identifying undiagnosed human immunodeficiency virus (HIV) infection within young women’s same-sex friendship networks and to determine factors that facilitated and hindered index recruiters (IRs) in recruiting female friendship network members (FNMs) as well as factors that facilitated and hindered FNMs in undergoing HIV screening.
Design
A cross-sectional study design that incorporated dual incentives for IRs and their female FNMs.
Setting
The IRs were recruited through 3 Adolescent Trials Network for HIV/AIDS Interventions sites within their Adolescent Medicine Trials Units. Data were collected from January 1, 2009, through June 30, 2010.
Participants
The IRs self-identifying as HIV positive, negative, or status unknown were enrolled to recruit FNMs to undergo HIV screening.
Main Outcome Measures
Self-reports of HIV risk and facilitators and barriers to network recruitment and HIV screening were assessed using an audio-computer-assisted self-interview. Participants were identified as HIV negative or positive on the basis of an OraQuick HIV test with confirmatory enzyme-linked immunosorbent assay and/or Western blot tests.
Results
Nearly all (156 [98.1%]) eligible IRs agreed to participate and most (78.4%) recruited 1 or more FNMs. Of the 381 FNMs, most (342 [89.8%]) agreed to HIV screening. Although a high acceptance of HIV screening was achieved, the HIV prevalence was low (0.26%).
Conclusion
Our findings provide compelling evidence to suggest that use of a female friendship network approach is a feasible and acceptable means for engaging at-risk young women in HIV screening, as shown by their high rates of agreement to undergo HIV screening.
doi:10.1001/2013.jamapediatrics.398
PMCID: PMC3596427  PMID: 23338776
18.  Randomized Trial to Determine Safety and Immunogenicity of Two Strategies for Hepatitis B Vaccination in Healthy Urban Adolescents in the United States 
Background
Multiple studies have shown excellent response rates after hepatitis B immunization in youth; however, one previous study conducted in urban youth demonstrated poor responses.
Methods
Urban youth, ages 12-17 years, at participating Adolescent Medicine Trials Network for HIV/AIDS Interventions Clinical/Research (ATN) sites were randomized to receive either two doses of Recombivax HB (10mcg hepatitis B surface antigen) or Twinrix (20mcg hepatitis B surface antigen and 720 EL.U hepatitis A antigen) at 0 and 24 weeks. Safety data were collected and antibody measures performed at 0, 28 and 76 weeks.
Results
123 subjects were enrolled and 102 had week 28 serum samples available for antibody measure. A positive response (serum antibody ≥ 10mIU/mL) to hepatitis B antigen was documented in 41/47 (87.2%; 95% confidence interval (CI) 74.3%-95.2%) Recombivax HB recipients and in 52/55 (94.6%; 95% CI 84.9%-98.9%) Twinrix recipients (p=.295). In an adjusted analysis, those identified as Hispanic ethnicity (N=86) were more likely to have a positive response (odds ratio 7.38, 95% confidence interval 1.56-34.95; p=0.0018); whereas those who identified as not heterosexual (N=9) were less likely to respond (odds ratio=0.12, 95%CI, 0.02-0.74). The majority of youth in the Twinrix arm were hepatitis A antibody positive at baseline (26/51; 51%); however, 24/25 hepatitis A antibody negative youth responded to the hepatitis A component. Both vaccines were safe.
Conclusions
Response rate to two doses of Recombivax HB in urban youth is lower than previous studies suggest. The factors associated with diminished response are not known.
doi:10.1097/INF.0b013e3181d285c7
PMCID: PMC3274492  PMID: 20173677
Adolescents; hepatitis B; Vaccination; Immunogenicity
19.  Impaired Generation of Hepatitis B Virus-specific Memory B Cells in HIV Infected Individuals Following Vaccination 
Vaccine  2010;28(21):3672-3678.
Hepatitis B-specific memory B cell (HSMBC) frequencies were measured following hepatitis B vaccination in 15 HIV uninfected and 12 HIV infected adolescents. HSMBC were detected at significantly lower frequencies in HIV infected than in HIV uninfected individuals. The detection of HBsAb >10 mIU/ml at study week 28 was strongly associated with the detection of HSMBC and a direct correlation between HBsAb titers and HSMBC frequencies was observed. In HIV uninfected individuals, antibody titers >1000 mIU/ml were associated with higher HSMC frequencies. Lower HSMBC frequencies, reduced memory B cell (MBC) proliferation, and altered B cell phenotypes were measured in viremic HIV infected individuals compared with aviremic HIV infected or HIV uninfected individuals.
doi:10.1016/j.vaccine.2010.03.022
PMCID: PMC2862082  PMID: 20356567
HIV; hepatitis B vaccines; memory B cells
20.  OBESITY AND DYSLIPIDEMIA IN BEHAVIORALLY HIV-INFECTED YOUNG WOMEN: ADOLESCENT TRIALS NETWORK (ATN) STUDY 021 
Background
The goal of this study was to determine the nature and prevalence of abnormalities in lipids, glucose metabolism, and body composition in behaviorally HIV-infected young women and their relationship to different classes of antiretroviral therapy (ART) regimens.
Methods
We conducted a cross-sectional multicenter study in behaviorally infected women ages 12-24 years (HIVpos; N=173) and seronegative controls (HIVneg; N=61). HIVpos women were categorized as ART-naïve (N=85), on a non-nucleoside reverse transcriptase inhibitor-containing regimen (NNRTI; N=33), on a protease inhibitor-containing regimen (PI; N=36), or on a non-NNRTI/non-PI containing regimen (N=19). Measurements included fasting lipids; glucose and insulin before and 2 hours after an oral glucose challenge; high-sensitivity C-reactive protein (hsCRP); anthropometry; fat distribution (dual energy X-ray absorptiometry); and ART and medical histories. Race-adjusted results were compared across groups and within HIVpos groups.
Results
The median age was 20 (range 14-24) years. 77% of HIVpos were African American, 35% smoked cigarettes, and 32% reported exercising regularly. More than 40% had a BMI ≥25 kg/m2. Triglycerides; total, HDL, and non-HDL cholesterol; and hsCRP differed significantly among groups, with higher levels most common among those on ART. Indices of glucose metabolism did not differ among groups. In general, cholesterol, hsCRP, and indices of glucose metabolism worsened as BMI increased.
Conclusions
Obesity, dyslipidemia, and inflammation were prominent in HIV-infected adolescent women and, coupled with other risk factors, may accelerate the lifetime risk of cardiovascular disease and other adverse events. These results underscore the need for a multifaceted approach to addressing risk reduction in this population.
doi:10.1086/648728
PMCID: PMC2939739  PMID: 19947855
adolescent; women; obesity; dyslipidemia; inflammation
21.  Clear and independent associations of several HLA-DRB1 alleles with differential antibody responses to hepatitis B vaccination in youth 
Human Genetics  2009;126(5):685-696.
To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV+) youth and 80 HIV-1 seronegatives (HIV−) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration ≥ 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10–1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). These immunogenetic relationships were all independent of non-genetic factors, including HIV-1 infection status and immunodeficiency. Alternative analyses confined to HIV+ youth or Hispanic youth led to similar findings. In contrast, analyses of more than 80 non-coding, single nucleotide polymorphisms within and beyond the three HLA class II genes revealed no clear associations. Overall, several HLA-DRB1 alleles were major predictors of differential Ab responses to hepatitis B vaccination in youth, suggesting that T-helper cell-dependent pathways mediated through HLA class II antigen presentation are critical to effective immune response to recombinant vaccines.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-009-0720-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-009-0720-z
PMCID: PMC2771141  PMID: 19597844
22.  Pharmacokinetics of Antiretroviral Regimens Containing Tenofovir Disoproxil Fumarate and Atazanavir-Ritonavir in Adolescents and Young Adults with Human Immunodeficiency Virus Infection▿ †  
The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects ≥18 to <25 years old receiving (≥28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC0-24), maximum concentration of drug in serum (Cmax), concentration at 24 h postdose (C24), and total apparent oral clearance (CL/F) values were 35,971 ng·hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC0-24, Cmax, C24, and CL/F values were 2,762 ng·hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P ≤ 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir Cmax and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.
doi:10.1128/AAC.00761-07
PMCID: PMC2224775  PMID: 18025112
23.  Human Immunodeficiency Virus Type 1 Controllers but Not Noncontrollers Maintain CD4 T Cells Coexpressing Three Cytokines▿  
Journal of Virology  2007;81(21):12071-12076.
Here, we evaluate the cytokine coexpression profiles of human immunodeficiency virus (HIV)-specific CD4 T cells for the expression of the cytokines gamma interferon (IFN-γ), interleukin-2, and tumor necrosis factor alpha. In controllers, CD4 T cells producing three or two cytokines (triple producers and double producers, respectively) represented >50% of the total response. In contrast, in noncontrollers ∼75% of responding cells produced only one cytokine (single producers), mostly IFN-γ. Cells producing three cytokines were functionally superior to those producing single cytokines and showed an inverse correlation (P < 0.001) with viral load. These results demonstrate a strong association between the maintenance of highly functional CD4 T cells producing three cytokines and control of HIV-1.
doi:10.1128/JVI.01261-07
PMCID: PMC2168799  PMID: 17728221

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