Lauren V. Wood

Safety, Pharmacokinetics, and Pharmacodynamics of Cyclodextrin Itraconazole in Pediatric Patients with Oropharyngeal Candidiasis

ABSTRACT The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4+-cell count, 128/μl) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (Cmax), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0-24), the concentration in plasma at the end of the dosing interval (predose) (Cmin), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 ± 0.53 μg/ml, 6.80 ± 7.4 μg · h/ml, 0.192 ± 0.06 μg/ml, and 56.48 ± 44 h, respectively, for the QD regimen and 1.340 ± 0.75 μg/ml, 23.04 ± 14.5 μg · h/ml, 0.782 ± 0.19 μg/ml, and 104.22 ± 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 ± 0.9 and 3.53 ± 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxyitraconazole/AUC of ITRA) at day 15 were 1.96 ± 0.1 for the QD regimen and 1.29 ± 0.2 for the BID regimen, respectively (P < 0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 ± 0.8 at baseline to 2.8 ± 0.7 at the end of therapy (P < 0.001), demonstrating antifungal efficacy in this setting. The relationships among Cmax, Cmin, AUC0-12, Cmax/MIC, Cmin/MIC, AUC0-12/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P, <0.01 to <0.05). All patients with fluconazole-resistant isolates responded to treatment with CD-ITRA; however, there was no clear correlation between the MIC of ITRA and response to therapy. In conclusion, CD-ITRA was well tolerated and efficacious for the treatment of OPC in HIV-infected pediatric patients. Pharmacodynamic modeling revealed significant correlations between plasma drug concentrations and antifungal efficacy. Based on this documented safety and efficacy, a dosage of 2.5 mg/kg BID can be recommended for the treatment of OPC in pediatric patients ≥5 years old.

A Phase I/II Study of the Protease Inhibitor Ritonavir in Children With Human Immunodeficiency Virus Infection

Background. Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects. Methods. HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m2 given every 12 hours) were evaluated in two age groups (≤2 years, >2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks. Results. A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m2 for the 24-week period. Conclusions. The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

A Phase I/II Study of the Protease Inhibitor Indinavir in Children With HIV Infection

Background. Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose. Methods. Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and ≥12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks. Results. Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy. Conclusions. Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

Could Human Papillomaviruses Be Spread through Blood

ABSTRACT The human papillomaviruses (HPVs) are epitheliotropic viruses that require the environment of a differentiating squamous epithelium for their life cycle. HPV infection through abrasion of the skin or sexual intercourse causes benign warts and sometimes cancer. HPV DNA detected in the blood has been interpreted as having originated from metastasized cancer cells. The present study examined HPV DNA in banked, frozen peripheral blood mononuclear cells (PBMCs) from 57 U.S. human immunodeficiency virus (HIV)-infected pediatric patients collected between 1987 and 1996 and in fresh PBMCs from 19 healthy blood donors collected in 2002 to 2003. Eight patients and three blood donors were positive mostly for two subgroups of the HPV type 16 genome. The HPV genome detected in all 11 PBMC samples existed as an episomal form, albeit at a low DNA copy number. Among the eight patients, seven acquired HIV from transfusion (three associated with hemophilia) and one acquired HIV through vertical transmission; this patient also had received a transfusion before sampling. Our data suggest that PBMCs may be HPV carriers and might spread the virus through blood.

Protective effect of CCR5 Δ32 heterozygosity is restricted by SDF-1 genotype in children with HIV-1 infection

ObjectiveTo determine the influences on pediatric AIDS of a heterozygous 32 base pair deletion in the CC-chemokine receptor 5 gene (CCR5 wt/Δ32) and a common polymorphism in the 3′ untranslated region of stromal cell-derived factor-1β gene transcript (SDF1-3′A). DesignThe rate of HIV-1 disease progression and viral burden were compared according to the CCR5 and SDF-1 genotypes in 127 (58 Caucasians, 60 African-Americans and nine Hispanics) perinatally HIV-1-infected children. ResultsRegardless of ethnic background, the CCR5 wt/Δ32 genotype was associated with a delayed onset of AIDS-defining infectious complications during the first 5 years of infection [relative hazard (RH) = 0.22; 95% confidence interval (CI), 0.012–1.02; P = 0.053]. Similarly, CCR5 wt/Δ32 conferred an early protection against severe immune suppression and HIV-1 encephalopathy, but only in those without SDF1-3′A (RH = 0; 95% CI, 0–0.70; P = 0.020, and RH = 0; 95% CI, 0–0.71; P = 0.021, respectively). When examined before 5 years of age (n = 81), the children with CCR5 wt/Δ32 had significantly lower levels of cell-associated HIV-1 DNA than wild-type homozygotes (P = 0.016, adjusted by race), while SDF1-3′A carriers had relatively higher levels (P = 0.047, adjusted by race). Although the disease-retarding effect of CCR5 wt/Δ32 subsequently disappeared, time to death was still significantly delayed in the CCR5 Δ32 heterozygotes without SDF1-3′A (RH = 0; 95% CI, 0–0.53; P = 0.008). ConclusionIn pediatric AIDS, the protective effect of CCR5 wt/Δ32 is more pronounced in early years of infection and appears to be abrogated by the SDF1-3′A genotype.

Long-term Virologic and Immunologic Responses in Human Immunodeficiency Virus Type 1-Infected Children Treated with Indinavir, Zidovudine, and Lamivudine

Virologic and immunologic responses were examined for 33 human immunodeficiency virus (HIV)-infected children who participated for > or = 96 weeks in a phase 1/2 protocol of 16 weeks of indinavir monotherapy, followed by the addition of zidovudine and lamivudine. At week 96, a median increase of 199 CD4+ T cells/microL and a median decrease of 0.74 log(10) HIV RNA copies/mL were observed. The relationship between control of viral replication and CD4) T cell count was examined. Patients were categorized into 3 response groups on the basis of duration and extent of control of viral replication. Of 21 children with a transient decrease in virus load of > or = 0.7 log(10) HIV RNA copies/mL from baseline, 7 experienced sustained increases in CD4+, CD4+ CD45RA+, and CD4+ CD45RO+ T cell counts. CD4+ CD45RA+ (naive) T cells were the major contributor to CD4+ T cell expansion. Continued long-term immunologic benefit may be experienced by a subset of children, despite only transient virologic suppression.

A comparison of adherence assessment methods utilized in the United States: perspectives of researchers, HIV-infected children, and their caregivers.

This study sought to elucidate methodological issues in adherence research by comparing multiple methods of assessing adherence to antiretroviral medication. From 2003 to 2004, 24 youths with vertically infected HIV disease (mean age = 14.0 years; range, 8-18) and their caregivers participated in a 6-month study. These children were all on highly active antiretroviral therapy (HAART) and were relatively healthy (mean CD4 absolute count = 711.8 +/- 604.5). Adherence was assessed with the Medication Event Monitoring System (MEMS), pill counts, and interviews. Patients and caregivers completed the Perceptions of Adherence Study Participation (PASP) questionnaire. MEMS provided the most detailed adherence information, and good reliability was indicated by significant correlations with medical markers. Pill counts provided similar adherence rates, while patients and caregivers reported nearly perfect adherence in interviews. Problems were experienced with each method: MEMS were expensive, had cap malfunctions, and lack a consistent guiding principle for data interpretation. With pill counts, families forgot to bring all medication bottles to clinic, and interviews were compromised by social desirability and difficulty reaching families by telephone. Most patients and caregivers believed study participation improved the childs adherence, although PASP ratings were unrelated to adherence at the study endpoint. While MEMS may be most reliable, pill counts offer comparable data and are less costly, while interviews seemed least accurate in this study. Most participants reported positive perceptions of their research experience. A consensus among researchers is needed for defining and measuring adherence, and specific recommendations are offered for achieving this goal.

Esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors.

Background. Littleis known about the epidemiology and clinical features of esophageal candidiasis (EC) in pediatric AIDS. We therefore investigated the clinical presentation and risk factors of EC in a large prospectively monitored population of HIV-infected children at the National Cancer Institute. Patients and methods. We reviewed the records of all HIV-infected children (N = 448) followed between 1987 and 1995 for a history of esophageal candidiasis to characterize the epidemiology, clinical features, therapeutic interventions and outcome of esophageal candidiasis. To understand further the risk factors for EC in pediatric AIDS, we then performed a matched case-control analysis of 25 patients for whom control cases were available. Results. There were 51 episodes of EC documented in 36 patients with 23 male and 13 female patients (0.2 to 17 years; median CD4, count 11/&mgr;l), representing a frequency of EC of 8.0%. Concurrent oropharyngeal candidiasis (OPC) was the most common clinical presentation of EC (94%); other signs and symptoms included odynophagia (80%), retrosternal pain (57%), fever (29%), nausea/vomiting (24%), drooling (12%), dehydration (12%), hoarseness (6%) and upper gastrointestinal bleeding (6%). The causative organism documented in 36 episodes (18 from OPC, 17 from endoscopic biopsy and 1 from autopsy) was Candida albicans in all cases. Patients received treatment for EC with amphotericin B (63%), fluconazole (29%), ketoconazole (4%) or itraconazole (1%). A clinical response was documented in all 45 evaluable episodes. In 6 other cases, EC was a final event without contributing to the cause of death. By a conditional logistic regression model for matched data, the best predictor of EC was the presence of prior OPC (P < 0.0001), followed by CD4 count and CD4 percentage (P = 0.0002) and use of antibacterial antibiotics (P = 0.0013). The risks associated with low CD4 count were independent of that of prior OPC. Conclusion. EC in pediatric AIDS is a debilitating infection, which develops in the setting of prior OPC, low CD4 counts and previous antibiotics.

Prospective Study Evaluating Na18F PET/CT in Predicting Clinical Outcomes and Survival in Advanced Prostate Cancer

This prospective pilot study evaluated the ability of Na18F PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. Methods: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent Na18F PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. Results: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P = 0.014) and 12 mo (P = 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P = 0.0147) and 6–12 mo (P = 0.0053); SUV change at 6 mo and overall survival (P = 0.018); number of lesions on Na18F PET/CT and clinical impression at baseline (P < 0.0001), 6 mo (P = 0.0078), and 12 mo (P = 0.0029); and number of lesions on Na18F PET/CT per patient at baseline and overall survival (P = 0.017). In an exploratory analysis, paired 99mTc-methylene diphosphonate bone scans (99mTc-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on Na18F PET/CT (n = 57) were classified on 99mTc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on Na18F PET/CT than on 99mTc-BS. Conclusion: The baseline number of malignant lesions and changes in SUV on follow-up Na18F PET/CT significantly correlate with clinical impression and overall survival. Na18F PET/CT detects more bone metastases earlier than 99mTc-BS and enhances detection of new bone disease in high-risk patients.

The Antiretroviral Regimen Complexity Index. A novel method of quantifying regimen complexity.

Background:Individuals with HIV disease often must adhere to complex medication regimens. To date, regimen complexity has not been examined in the literature using standardized procedures incorporating all important elements of antiretroviral (ARV) regimens. Objective:This article presents a novel method of quantifying regimen complexity using objective criteria addressing the factors that may complicate adherence to ARV regimens. Methods:Part 1 of this article describes the development of the Antiretroviral Regimen Complexity (ARC) Index scoring system. Based on input from pediatric and adult patients, caregivers of pediatric patients, and health care professionals, this comprehensive system includes the number of medications, dosing schedules, administration methods, special instructions, and required preparations associated with ARV regimens. Weights are applied for each of these factors to produce an overall score representing the regimens level of complexity. Part 2 of this article presents reliability and validity data for the system. Results:The ARC Index demonstrates excellent test-retest and interrater reliability as well as strong construct and discriminant validity. An on-line version of this system minimizes computation errors. Conclusions:Although modifications may be necessary for patients requiring nonstandard dosing instructions, preliminary evidence supports the utility of this measure as a reliable and valid indicator of the complexity of antiretroviral treatment regimens.