Background

Although health disparity research has investigated social structural, cultural, or psychological factors, the interrelations among these factors deserve greater attention.

Purpose

This study aims to examine cancer screening emotions and their relations to screening fatalism as determinants of breast cancer screening among women from diverse socioeconomic and ethnic backgrounds.

Methods

An integrative conceptual framework was used to test the multivariate relations among socioeconomic status, age, screening fatalism, screening emotions, and clinical breast exam compliance among 281 Latino and Anglo women, using multi-group structural equation causal modeling.

Results

Screening emotions and screening fatalism had a negative, direct influence on clinical breast exam compliance for both ethnic groups. Still, ethnicity moderated the indirect effect of screening fatalism on clinical breast exam compliance through screening emotions.

Conclusions

Integrative conceptual frameworks and multivariate methods may shed light on the complex relations among factors influencing health behaviors relevant to disparities. Future research and intervention must recognize this complexity when working with diverse populations.

Introduction

Examine psychological functioning and beliefs about medicine in adolescents with HIV-1 on HAART in a community-based directly observed therapy (DOT) pilot feasibility study.

Methods

Youth with behaviorally-acquired HIV (n=20; 65% female; median age 21 years) with adherence problems, received once-daily DOT. Youth were assessed at baseline, week 12 (post-DOT) and week 24 (follow-up).

Results

Baseline to week 12 comparisons: 55% of youth reported clinical depressive symptoms compared to 27% at week 12 with sustained improvements at week 24. Substance use: Borderline clinical range (Tscore=68), with clinical but statistically non-significant improvement (Tscore=61). Hopelessness scores reflected optimism for the future. Coping strategies showed significantly decreased Cognitive Avoidance (p=0.02), Emotional Discharge (p=0.004), and Acceptance/Resignation (“nothing I can do,” p=0.004); Positive Reappraisal and Seeking Support emerged. Aside from depressive symptoms, week 12 improvements were not sustained at week 24. DOT adherence was predicted by higher baseline depression (p=0.05), Beliefs About Medicine (p=0.006) and Perceived Threat of illness scores (p=0.03).

Discussion

Youth with behaviorally-acquired HIV and adherence problems who participated in a community-based DOT intervention reported clinically improved depressive symptoms, and temporarily reduced substance use and negative coping strategies. Depressive symptoms, Beliefs About Medicine and viewing HIV as a threat predicted better DOT adherence.

Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C24) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (Cmax) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.

Background

HIV-infected youth are at risk of hepatitis B (HBV) infection and should be vaccinated. Previous reports suggest reduced response to standard HBV vaccine regimens.

Methods

HIV-infected youth, age 12 to <25 years, were randomly assigned to one of three treatment arms: Arm 1: Engerix B®, 20 mcg HBsAg; Arm 2: Engerix B®, 40 mcg; and Arm 3: Twinrix®, 20mcg HBsAg combined with 720 ELU hepatitis A antigen. Vaccines were administered at weeks 0, 4 and 24.

Results

Characteristics of evaluable patients (n=336) at entry were similar in the study arms. At enrollment, median CD4+ T-cell count was 460 cells/mm3 (IQR: 305 to 668); 13% were < 200 cells/mm3. Among Engerix B®, 20 mcg recipients, 60.4% responded to vaccine (HBsAb ≥ 10 IU/mL at week 28). Improved vaccine response was seen in recipients of Engerix B®, 40 mcg, (73.2%, vs. Arm 1, p=0.04) and Twinrix® (75.4%, vs. Arm 1, p=0.02). In multivariate analysis, only baseline CD4+ T-cell count and study arm were independent predictors of vaccine response.

Conclusions

In HIV-infected youth, a three dose vaccination regimen with Engerix B®, 40 mcg, or Twinrix® and higher baseline CD4+ T-cell counts were independently associated with improved vaccine response.

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.

The aim of this research was to examine the relation of perceptions of healthcare mistreatment and related emotions to continuity of cancer screening care among women who reported healthcare mistreatment. The structure of relations among cultural beliefs about healthcare professionals, perceptions of mistreatment, mistreatment-related emotions, and continuity of screening was investigated. Participants included 313 Anglo and Latino American women of varying demographic characteristics from Southern California who were recruited using multistage stratified sampling. Structural equation modeling confirmed the relation of perceptions of mistreatment to continuity of care for both Anglo and Latino American women, with ethnicity moderating this association. For Anglo Americans, greater perceptions of mistreatment were negatively related to continuity of screening. However, for Latinas the relation was indirect, through mistreatment-related anger. While greater perceptions of mistreatment were associated with higher levels of anger for both ethnic groups, anger was negatively related to continuity of care for Latino but not for Anglo women. Furthermore, cultural beliefs about professionals were indirectly related to continuity of screening through perceptions of mistreatment and/or mistreatment-related anger. These findings highlight the importance of the role of cultural and psychological factors in research and interventions aimed at improving patient-professional relations with culturally diverse women.

To illustrate the implementation of a bottom-up approach to the study of culture in health disparities, this article describes the development of a cultural cancer screening scale (CCSS) using mixed methodologies. The aim was to identify cultural factors relevant to breast and cervical cancer screening, develop an instrument to assess them and examine its preliminary psychometric properties among Latin American (Latino) and non-Latino White (Anglo) women in Southern California. Seventy-eight Latino and Anglo women participated in semi-structured interviews, which were content coded based on Triandis' methods for the analysis of subjective culture. Based on the emerging cultural elements, items relevant to cancer screening were developed and pilot tested with 161 participants. After the instrument was refined, 314 Latino and Anglo women from various socioeconomic backgrounds completed the CCSS and data were factor analyzed resulting in five cultural factors: cancer screening fatalism, negative beliefs about health professionals, catastrophic disease expectations, symptomatic deterrents and sociocultural deterrents. The instrument demonstrated measurement equivalence, adequate reliability and predictive validity. The research and the CCSS are discussed in terms of implications for the study of culture in relation to health disparities and the development of evidence-based interventions with culturally diverse populations and their health professionals.

Abstract

Adherence to medications is critical to optimizing HIV care and is a major challenge in youth. The utility of directly observed therapy (DOT) to improve adherence in youth with HIV remains undefined and prompted this pilot study. Four U.S. sites were selected for this 24-week cooperative group study to assess feasibility and to identify the logistics of providing DOT to HIV-infected youth with demonstrated adherence problems. Once-a-day DOT was provided by DOT facilitators at the participant's choice of a community-based location and DOT tapered over 12 weeks to self-administered therapy based on ongoing adherence assessments. Twenty participants, median age 21 years and median CD4 227 cells/μl, were enrolled. Participants chose their homes for 82% of DOT visits. Compliance with recommended DOT visits was (median) 91%, 91%, and 83% at weeks 4, 8, and 12, respectively. Six participants completed >90% of the study-specified DOT visits and successfully progressed to self-administered therapy (DOT success); only half sustained >90% medication adherence 12 weeks after discontinuing DOT. Participants considered DOT successes were more likely to have higher baseline depression scores (p = 0.046). Via exit surveys participants reported that meeting with the facilitator was easy, DOT increased their motivation to take medications, they felt sad when DOT ended, and 100% would recommend DOT to a friend. In conclusion, this study shows that while community-based DOT is safe, feasible, and as per participant feedback, acceptable to youth, DOT is not for all and the benefits appear short-lived. Depressed youth appear to be one subgroup that would benefit from this intervention. Study findings should help inform the design of larger community-based DOT intervention studies in youth.

Background

The world is facing a novel H1N1 pandemic. A pandemic scare with a similar virus in 1976 resulted in the vaccination of nearly 45 million persons. We hypothesized that prior receipt of the 1976 “swine flu” vaccine would enhance immune responses to the 2009 novel H1N1 strain.

Methods

A prospective, volunteer sample of employees 55 years of age and older at a children’s cancer hospital in August of 2009 was assessed for antibody responses to the 2009 pandemic H1N1 influenza virus and the 2008-2009 seasonal H1N1 influenza virus.

Results

Antibody responses by hemagglutination-inhibition assay were high against both the seasonal (89.7% had a titer considered seroprotective) and pandemic (88.8% had a seroprotective titer) H1N1 viruses. These antibodies were effective at neutralizing the seasonal H1N1 virus in 68.1% of participants (titer ≥ 40), but only 18.1% had detectable neutralizing titers against the pandemic H1N1. Of 116 participants, 46 (39.7%) received the 1976 “swine flu” vaccine. Receipt of this vaccine significantly enhanced neutralization responses as 8 of 46 (17.4%) vaccine recipients had titers ≥ 160 compared to only 3 of 70 (4.3%) who did not receive the vaccine (P = 0.018 by chi-squared test).

Conclusions

In this cohort, persons 55 years and older had evidence of robust immunity to the 2008-2009 seasonal H1N1 virus. These antibodies were cross-reactive but non-neutralizing against the 2009 pandemic H1N1 strain. Receipt of a vaccine to a related virus significantly enhanced the neutralization capacity of these responses, suggesting homologous vaccination against the 2009 pandemic H1N1 would have a similar effect.

Background

New strains of methicillin-resistant Staphylococcus aureus (MRSA) which frequently carry the Panton–Valentine leukocidin (PVL) genes have been recognized to cause invasive infections in otherwise healthy children and adults. However, the epidemiology of PVL-positive MRSA infections has not been described in children or adults with cancer.

Procedure

The epidemiology of MRSA infections in patients with cancer was retrospectively studied from 2000 to 2007. Molecular typing was performed by polymerase chain reaction (PCR) for the detection of the PVL genes. Staphylococcus cassette chromosome (SCC) mec and spa typing was performed on all PVL-positive isolates.

Results

A total of 88 MRSA isolates from clinically distinct infectious episodes were collected from 88 patients with cancer during the 8-year study period. Infections were predominant in the skin and soft tissues (SSTI; P =0.0003). PVL-positive isolates, bearing the type IV SCCmec element, encoding the gene for methicillin resistance, increased significantly during this period (P =0.043) and comprised 35 of 88 (40%) MRSA isolates. Of these 35 isolates, 32 belonged to spa type 8 and were USA300 genotype. Patients infected with PVL-positive strains did not have more SSTI (P =0.166) or bacteremia (P =0.510) as compared to patients with PVL-negative strains. A greater percentage of PVL-positive isolates were susceptible to ciprofloxacin (P =0.006).

Conclusions

PVL-positive MRSA infections are not associated with a higher morbidity as compared to PVL-negative MRSA infections in children with cancer.

Abstract

The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) infections, in particular with Panton-Valentine leukocidin (PVL)-positive strains, has not been well characterized in children and young adults with HIV infection. It is not known if PVL-positive strains of MRSA cause an increased morbidity in this population compared to PVL-negative strains. The purpose of this study was to retrospectively analyze the epidemiology of PVL-positive and PVL-negative MRSA infections in children and young adults with HIV from 2000 to 2007. Molecular typing was performed by polymerase chain reaction (PCR) for detection of the PVL genes. Staphylococcus Cassette Chromosome (SCC) mec and spa typing were performed on all PVL-positive isolates. The number of HIV patients with MRSA infection increased significantly between 2000 and 2007 (p = 0.0015). Twenty seven (87%) of the 31 MRSA isolates were from skin and soft tissue infections (SSTI). Clindamycin resistance was observed in 19% of the MRSA isolates. PVL-positive isolates bearing the type IV SCC mec element comprised 16 of 31 (52%) MRSA isolates. All the PVL-positive isolates belonged to the USA300 pulsed-field type. There was no difference in the mean CD4 count and HIV viral load between patients with PVL-positive and PVL-negative MRSA infections. PVL-positive MRSA infections were associated with more SSTI (p = 0.043) but not with increased morbidity or a higher risk of complications compared to PVL-negative MRSA infections in children and young adults with HIV.

Background

The etiology, clinical course and outcome of fever and neutropenia (FN) in children with cancer using the current FN guidelines and diagnostic resources in the United States have not been well described.

Patients and Methods

Medical records of one randomly selected FN episode per patient during 2004–2005 at a pediatric oncology center were reviewed. Patients were managed as per institutional FN guidelines and blood cultures collected in continuously-read BACTEC™ bottles.

Results

Of 337 FN episodes, infection was proven in 86 (25%) and probable in 75 (22%). 177 episodes (53%) were judged fever of unknown origin (FUO). Bacteremia accounted for most (41) of the proven bacterial episodes, with viridans streptococci (13), Pseudomonas spp (6) and E. coli (6) the most frequently isolated organisms. The median time to positivity of blood cultures was 12 hrs (range 5.4 – 143.7) with 93% positive within 24 hours of incubation. Viral pathogens were identified in 29 (34%) episodes. Compared to other patients, those with FUO had shorter median duration of fever (0.5 vs. 2.0 days; p<0.0001) and hospitalization (3 vs. 6 days; p<0.0001), longer median duration since last chemotherapy (6.0 vs. 4.0 days; p=0.01) and were less likely to have a diagnosis of acute myelogenous leukemia (AML) (11% vs 22%; p=0.009) or develop a clinical complication (5.1% vs 24.4%; p<0.0001).

Conclusion

Despite currently available diagnostic resources, the majority of patients with FN have FUO marked by a low rate of clinical complications and no infection-related mortality. Emergence of viridans streptococci as the most common blood isolate has affected FN treatment recommendations. Study findings will help further development of strategies for risk stratified management of fever with neutropenia in pediatric patients.

Purpose

To obtain input from adolescents with HIV-1 infection to inform the design of a community-based modified directly observed therapy (MDOT) antiretroviral adherence intervention.

Methods

Pediatric AIDS Clinical Trials Group (PACTG) protocol 1036A conducted three focus groups with 17 adolescents aged 17 to 22 years (10 females, 65% African-American) from three geographically distinct US PACTG sites. Focus group sessions were scripted, audio-taped, and transcribed verbatim. A coding dictionary was developed and validated; Ethnograph v5.08 was used to summarize coded data across and within the three sites. Prevalent themes were identified via frequencies and are reported as percents.

Results

Adolescents specified: the MDOT provider should be familiar to the participant and empathic; the MDOT location should be mutually agreed upon, flexible, and private; and participant and provider communication should be bidirectional, preferably by phone. Ideally the MDOT program should be continued until adolescents independently demonstrate adherence and include a weaning phase as a test of skill-acquisition. The most commonly endorsed barrier to the proposed program was MDOT would be an invasion of privacy. Initially, following introduction to the purpose of the focus group, all but one adolescent expressed MDOT could benefit someone other than themselves; however, at conclusion of the focus group discussion, a significant shift in openness to the intervention occurred whereby 11 participants indicated they would consider participation in a MDOT program if offered.

Conclusions

Focus group feedback clarified the feasibility, logistics, and patient concerns about the design and implementation of a proposed MDOT intervention for adolescents with HIV-1 infection who struggle with medication adherence

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.

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.

Zidovudine (ZDV) and lamivudine (3TC) metabolism to triphosphates (TP) is necessary for antiviral activity. The aims of this study were to compare ZDV-TP and 3TC-TP concentrations in adolescents receiving twice daily (BID) and once daily (QD) regimens and to determine the metabolite concentrations of ZDV and 3TC during chronic therapy on a QD regimen. Human immunodeficiency virus-infected patients (12 to 24 years) taking ZDV (600 mg/day) and 3TC (300 mg/day) as part of a highly active antiretroviral therapy regimen received QD and BID regimens of ZDV and 3TC for 7 to 14 days in a crossover design. Serial blood samples were obtained over 24 h on the QD regimen. Intracellular mono-, di-, and triphosphates for ZDV and 3TC were measured. The median ratio of BID/QD for ZDV-TP predose concentrations was 1.28 (95% confidence interval [CI] = 1.00 to 2.45) and for 3TC-TP was 1.12 (95% CI = 0.81 to 1.96). The typical population estimated half-lives (± the standard error of the mean) were 9.1 ± 0.859 h for ZDV-TP and 17.7 ± 2.8 h for 3TC-TP. Most patients had detectable levels of the TP of ZDV (24 of 27) and 3TC (24 of 25) 24 h after dosing, and half-lives on a QD regimen were similar to previously reported values when the drugs were given BID. Lower, but not significantly different, concentrations of ZDV-TP were demonstrated in the QD regimen compared to the BID regimen (P = 0.056). Although findings were similar between the BID and QD groups, the lower concentrations of ZDV and the number of patients below the level of detection after 24 h suggests that ZDV should continue to be administered BID.

The pharmacologic variability of nucleoside reverse transcriptase inhibitors such as lamivudine (3TC) includes not only systemic pharmacokinetic variability but also interindividual differences in cellular transport and metabolism. A modeling strategy linking laboratory studies of intracellular 3TC disposition with clinical studies in adolescent patients is described. Data from ex vivo laboratory experiments using peripheral blood mononuclear cells (PBMCs) from uninfected human subjects were first used to determine a model and population parameter estimates for 3TC cellular metabolism. Clinical study data from human immunodeficiency virus type 1-infected adolescents were then used in a Bayesian population analysis, together with the prior information from the ex vivo analysis, to develop a population model for 3TC systemic kinetics and cellular kinetics in PBMCs from patients during chronic therapy. The laboratory results demonstrate that the phosphorylation of 3TC is saturable under clinically relevant concentrations, that there is a rapid equilibrium between 3TC monophosphate and diphosphate and between 3TC diphosphate and triphosphate, and that 3TC triphosphate is recycled to 3TC monophosphate through a 3TC metabolite that remains to be definitively characterized. The resulting population model shows substantial interindividual variability in the cellular kinetics of 3TC with population coefficients of variation for model parameters ranging from 47 to 87%. This two-step ex vivo/clinical modeling approach using Bayesian population modeling of 3TC that links laboratory and clinical data has potential application for other drugs whose intracellular pharmacology is a major determinant of activity and/or toxicity.

Caspofungin is a parenteral antifungal that inhibits beta-1,3-d-glucan synthesis. Although licensed for adult use, the appropriate caspofungin dosing regimen in pediatric patients is not yet known. We therefore investigated the pharmacokinetics and safety of caspofungin in pediatric patients. Thirty-nine children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) with neutropenia were administered caspofungin using either a weight-based regimen (1 mg/kg of body weight/day) or a body surface area regimen (50 mg/m2/day or 70 mg/m2/day). Plasma samples for caspofungin profiles were collected on days 1 and 4. These results were compared to those from adults treated with either 50 or 70 mg/day for mucosal candidiasis. In children receiving 1 mg/kg/day (maximum, 50 mg/day), the area under the concentration-time curve over 24 h (AUC0-24) was significantly smaller (46% after multiple doses) than that observed in adults receiving 50 mg/day (P < 0.001). In children and adolescents receiving 50 mg/m2/day (maximum, 70 mg/day), the AUC0-24 following multiple doses was similar to that for the exposure in adults receiving 50 mg/day. The AUC0-24 and concentration trough (at 24 h) in pediatric patients receiving the 50-mg/m2 daily regimen were consistent across the range of ages. Caspofungin was generally well tolerated in this study. None of the patients developed a serious drug-related adverse event or were discontinued for toxicity. These results demonstrate that caspofungin at 1 mg/kg/day in pediatric patients is suboptimal. Caspofungin administration at 50 mg/m2/day provides a comparable exposure to that of adult patients treated with 50 mg/day.

Emtricitabine (FTC; Emtriva), a potent deoxycytidine nucleoside reverse transcriptase inhibitor, has recently been approved by the U.S. Food and Drug Administration for the treatment of human immunodeficiency virus (HIV) infection. In adults, FTC has demonstrated linear kinetics over a wide dose range, and FTC 200 mg once a day (QD) is the recommended therapeutic dose. A phase I open-label trial was conducted in children to identify an FTC dosing regimen that would provide comparable plasma exposure to that observed in adults at 200 mg QD. Two single oral doses of FTC (60 and 120 mg/m2, up to a maximum of 200 mg, in solutions) were evaluated in HIV-infected children aged <18 years old. Children ≥6 years old also received a third dose of ∼120 mg/m2 in capsules. A total of 25 children (two <2 years old, eight 2 to 5 years old, eight 6 to 12 years old, and seven 13 to 17 years old) received at least two doses of FTC. Single escalating oral doses of FTC were well tolerated and produced dose-proportional plasma drug concentrations in children. The FTC pharmacokinetics was comparable between adults and children 22 months to 17 years of age. The capsule formulation provided ∼20% higher plasma FTC exposure than the solution formulation. Using plasma area under the concentration-time curve (AUC) data at the 120-mg/m2 dose, it is projected (based on dose proportionality) that a 6-mg/kg dose (up to a maximum of 200 mg) of FTC would produce plasma AUCs in children comparable to those in adults given a 200-mg dose (i.e., median of ∼10 h·μg/ml). This pediatric FTC dose is being evaluated in long-term phase II therapeutic trials in HIV-infected children.

Abstract

Treatment failure and drug resistance create obstacles to long-term management of HIV-1 infection. Nearly 60% of infected persons fail their first highly active antiretroviral therapy (HAART) regimen, partially because of nonadherence, requiring a switch to a second regimen to prevent drug resistance. Among HIV-infected youth, a group with rising infection rates, treatment switch is often delayed; virologic and immunologic consequences of this delay are unknown. We conducted a retrospective, longitudinal study of drug resistance outcomes of initial HAART in U.S. youth enrolled between 1999–2001 in a multicenter, observational study and experiencing delayed switch in their first nonsuppressive treatment regimen for up to 3 years. HIV-1 genotyping was performed on plasma samples collected longitudinally, and changes in drug resistance mutations, CD4+ T cell numbers and viral replication capacity were assessed. Forty-four percent (n = 18) of youth in the parent study experiencing virologic nonsuppression were maintained on their initial HAART regimen for a median of 144 weeks. Drug resistance was detected in 61% (11/18) of subjects during the study. Subjects on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens developed more (8/10) drug resistance mutations than those on protease-inhibitor (PI) regimens (2/7) (p = 0.058). Subjects developing NNRTI-resistance (NNRTI-R), showed a trend toward lower CD4+ T cell gains (median: −6 cells/mm3 per year) than those without detectable NNRTI-R (median: +149 cells/mm3 per year) (p = 0.16). HIV-1–infected youth maintained on initial nonsuppressive NNRTI-based HAART regimens are more likely to develop drug-resistant viremia than with PI-based HAART. This finding may have implications for initial treatment regimens and transmission risk in HIV-infected youth, a group with rising infection rates.