Terence Fenton

COMBINATION THERAPY WITH EFAVIRENZ, NELFINAVIR, AND NUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS IN CHILDREN INFECTED WITH HUMAN IMMUNODEFICIENCY VIRUS TYPE 1

BACKGROUND Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.

Psychiatric Comorbidity in Childhood Post Traumatic Stress Disorder.

OBJECTIVE The purpose of this study was to examine the psychiatric comorbidity between children presenting with Post Traumatic Stress Disorder (PTSD) and traumatized children not developing this disorder. DESIGN One-hundred and seventeen severely maltreated children were examined for evidence of PTSD. Analyses probed for diagnostic relationship, between PTSD and other formal diagnoses on The Diagnostic Interview for Children and Adolescents, Revised Version (DICA-CR). PARTICIPANTS All children presented before a juvenile/family court due to severe child maltreatment and psychological trauma. These children had been ordered removed from parental custody due to the trauma suffered by the child. For the purposes of analyses, this entire group of maltreated and traumatized children were dichotomized into a PTSD group and a non-PTSD group. Thirty-five percent (41 of 117) of the children met strict DICA criteria for PTSD. MEASUREMENTS The children were examined by means of a structured clinical interview. The Diagnostic Interview for Children and Adolescents, revised version (DICA-Child-R), along with a more general psychiatric interview. The DICA-Child-R responses provided the only determination of whether the children met formal PTSD criteria. Data gathering on the sample also included a comprehensive review of risk factors for the development of PTSD, including demographics, and type(s) of trauma suffered. RESULTS Findings revealed that the PTSD diagnosis was significantly correlated with: 1. Attention Deficit Hyperactivity Disorder (ADHD) 2. Other anxiety disorders 3. Brief Psychotic Disorder or Psychotic Disorder NOS 4. The presence of suicidal ideation 5. A trend toward mood disorders. There were no differences between the two samples on measures of age, race, and family income. CONCLUSIONS Pediatric PTSD is a severe psychiatric disorder. In this study, PTSD was statistically related to other formal psychiatric diagnoses. The investigators attended to the issues relating to true comorbidity versus inaccurate diagnosis secondary to symptom overlap between different conditions. Applying strict criteria, the results suggest that the presence of PTSD in children confers a substantial likelihood of other formal diagnosis. Moreover, the symptom of suicidal ideation was overrepresented among PTSD subjects. Given these additional conditions, more extensive evaluation and specialized, multi-modal treatment should be considered in children presenting with PTSD.

Maternal Toxemia Is Associated With Reduced Incidence of Germinal Matrix Hemorrhage in Premature Babies

To evaluate prenatal and perinatal risk factors for development of germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH), we conducted a prospective epidemiologic study of 449 babies whose birth weight was less than 1501 grams. This study permitted us to test our previously generated hypothesis that babies born to mothers with preeclampsia were at substantially reduced risk of developing GMH-IVH. Seventy-two (16%) of the babies in this population developed GMH-IVH. One (2.5%) of the 40 mothers with a diagnosis of preeclampsia and 71 (17.4%) of 409 mothers without preeclampsia gave birth to babies who developed GMH-IVH. GMH-IVH was seen in 6/107 (5.6%) of babies born to women with hypertension including 4/69 (5.8%) of babies born to women with pregnancy-induced hypertension, compared to 66/352 (18.8%) of babies born to mothers who did not have hypertension. Only 7.3% (8/108) of babies born to women who had proteinuria had GMH-IVH, compared to 18.3% (64/350) of babies whose mothers did not have proteinuria. GMH-IVH was seen in 5/89 (5.6%) of babies whose mothers had both hypertension and proteinuria, whereas 63/332 (19%) of babies born to mothers who lacked both factors, developed GMH-IVH. In stepwise logistic regression analysis, these significant findings were not explained by the presence of labor, postnatal acidemia, need for intubation, antenatal administration of steroids, birth weight, or gestational age. In addition, we found that maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia. We postulate that the association of preeclampsia and GVH-IVH may be related to prostaglandin effects. Reduced maternal, placental, and umbilical prostaglandin I2 (PGI2) values are characteristic of women with preeclampsia. Thus, babies born to mothers with preeclampsia may have a physiologic state similar to those having received indomethacin, a cyclooxygenase blocker that causes diminished PGI2 levels and an effective GMH-IVH prophylactic agent. We conclude that early third-trimester maternal preeclampsia/toxemia is associated with reduced risk of GMH-IVH in the preterm newborn. (J Child Neurol 1992;7:70-76).

Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion

Tolerance to opioid-induced sedation has been reported in neonates sedated with fentanyl by continuous infusion while undergoing extracorporeal membrane oxygenation. We undertook a prospective analysis of eight newborn infants sedated with fentanyl during extracorporeal membrane oxygenation therapy for respiratory failure. We recorded daily mean fentanyl infusion rate, measured serial plasma fentanyl concentrations, and documented the occurrence of spontaneous motor activity or respiratory effort. Mean fentanyl infusion rate increased steadily during the period of infusion from a mean of 9.2 +/- 1.9 (SEM) micrograms/kg per hour on day 1 to a mean of 21.9 +/- 4.5 micrograms/kg per hour by day 6. Mean plasma fentanyl concentrations increased steadily during the period of fentanyl infusion from 3.1 +/- 1.1 (SEM) ng/ml on day 1 to 13.9 +/- 3.2 ng/ml on day 6. All infants exhibited movement in response to gentle tactile stimulation throughout the period of infusion, and seven of eight infants manifested spontaneous movement of the extremities and eye opening. Our results indicate that when fentanyl is used for sedation in neonates, the plasma concentrations required for satisfactory sedation steadily escalate, possibly indicating the rapid development of tolerance to the sedating effects of fentanyl.

CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children

Background:Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. Methods:In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. Results:NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). Conclusions:The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Optimization and Limitations of Use of Cryopreserved Peripheral Blood Mononuclear Cells for Functional and Phenotypic T-Cell Characterization

ABSTRACT The goals of this study were to optimize processing methods of cryopreserved peripheral blood mononuclear cells (PBMC) for immunological assays, identify acceptance parameters for the use of cryopreserved PBMC for functional and phenotypic assays, and to define limitations of the information obtainable with cryopreserved PBMC. Blood samples from 104 volunteers (49 human immunodeficiency virus-infected and 55 uninfected) were used to assess lymphocyte proliferation in response to tetanus, candida, and pokeweed-mitogen stimulation and to enumerate CD4+ and CD8+ T cells and T-cell subpopulations by flow cytometry. We determined that slowly diluting the thawed PBMC significantly improved viable cell recovery, whereas the use of benzonase improved cell recovery only sometimes. Cell storage in liquid nitrogen for up to 15 months did not affect cell viability, recovery, or the results of lymphocyte proliferation assays (LPA) and flow cytometry assays. Storage at −70°C for ≤3 weeks versus storage in liquid nitrogen before shipment on dry ice did not affect cell viability, recovery, or flow cytometric results. Storage at −70°C was associated with slightly higher LPA results with pokeweed-mitogen but not with microbial antigens. Cell viability of 75% was the acceptance parameter for LPA. No other acceptance parameters were found for LPA or flow cytometry assay results for cryopreserved PBMC. Under optimized conditions, LPA and flow cytometry assay results for cryopreserved and fresh PBMC were highly correlated, with the exception of phenotypic assays that used CD45RO or CD62L markers, which seemed labile to freezing and thawing.

Maternal and child posttraumatic stress disorder in cases of child maltreatment

The purpose of this study was to examine the rates of posttraumatic stress disorder (PTSD) among a sample of severely maltreated children and their mothers, and to investigate the age of onset of documented maltreatment in these children. The sample consisted of 109 pairs of women and their children who were before a juvenile/family court due to maltreatment of sufficient severity to warrant removal of the child from parental custody. Children were examined using the PTSD Section of the Diagnostic Interview for Children and Adolescents, Revised 6th Version (DICA-6-R). The PTSD Module of the Structured Clinical Interview for DSM-III-R (SCID) was administered to all mothers. Clinical psychiatric interviews were also administered to all children and mothers. From the sample of 109 cases, 15.6% of the mothers met SCID criteria for a current presentation of PTSD, while 36.7% had a past history of PTSD. Of the 109 evaluated children, 35.8% met current DICA criteria for PTSD. Posttraumatic stress disorder is significantly overrepresented in the children of mothers diagnosed with PTSD (p = .001). The average age of maltreatment onset was 46.4 months among the children diagnosed as PTSD, and was 61.3 months in the group of seriously maltreated children who did not develop PTSD (p = .038). The onset of maltreatment is significantly earlier among children whose mothers meet PTSD criteria than among other maltreated children (p = .025). Intergenerational transmission of violence and developmental effects of traumatic experiences upon the young child are discussed.

Immunogenicity, safety, and predictors of response after a pneumococcal conjugate and pneumococcal polysaccharide vaccine series in human immunodeficiency virus-infected children receiving highly active antiretroviral therapy

Background: The immunogenicity and safety of 2 doses of pneumococcal conjugate vaccine (PCV) and 1 dose of pneumococcal polysaccharide vaccine (PPV) were evaluated in human immunodeficiency virus (HIV)-infected children receiving highly active antiretroviral therapy (HAART). Methods: Children 2 to <19 years, receiving stable HAART for ≥3–6 months, with HIV RNA PCR <30,000–60,000 copies/mL, received 2 doses of PCV and 1 dose of PPV at sequential 8-week intervals. Antibodies to pneumococcal serotypes (STs) 1 (PPV only) and 6B, 14, 19F, and 23F (PCV and PPV) were measured by ELISA. Results: Two hundred sixty-three subjects were enrolled, of whom 225 met criteria for inclusion in the primary dataset. Antibody concentrations were low at entry, despite previous PPV in 75%. After vaccination, 76%–96% had concentrations ≥0.5 &mgr;g/mL and 62–88% ≥1.0 &mgr;g/mL to the 5 STs (geometric mean concentrations [GMCs] = 1.44–4.25 &mgr;g/mL). Incremental gains in antibody concentration occurred with each vaccine dose. Predictors of response included higher antibody concentration at entry, higher immune stratum (based on nadir CD4% before HAART and CD4% at screening), lower entry viral RNA, longer duration of the entry HAART regimen, and age <7 years. Response was more consistently related to screening CD4% than nadir CD4%. Seven percent had vaccine-related grade 3 events, most of which were local reactions. Conclusions: Two PCVs and 1 PPV were immunogenic and safe in HIV-infected children 2 to <19 years who were receiving HAART. Responses were suggestive of functional immune reconstitution. Immunologic status based on nadir and, especially, current CD4% and control of HIV viremia were independent determinants of response.

Persistence of Pediatric Post Traumatic Stress Disorder after 2 Years.

One-hundred and fifty-six children were randomly evaluated at an inner-city juvenile/family court. These children were removed from their parents custody subsequent to a finding of severe child maltreatment. From our original sample of 156 children, 62 met strict criteria for Post Traumatic Stress Disorder (PTSD). Fifty-two of these 62 were successfully recruited and participated in the 2 year re-examination. Each PTSD diagnosis was conferred by the Diagnostic Interview for Children and Adolescents (DICA). From our sample of 52 PTSD children re-examined after 2 years, 17 (32.7%) retained the full PTSD diagnosis, while 67.3% did not meet criteria.

Recombinant CD4-IgG2 in Human Immunodeficiency Virus Type 1—Infected Children: Phase 1/2 Study

The use of recombinant CD4-IgG2 in pediatric human immunodeficiency virus type 1 (HIV-1) infection was evaluated by single and multidose intravenous infusions in 18 children in a phase 1/2 study. The study drug was well tolerated, and dose proportionality was observed in terms of area under time-concentration curve and peak serum concentration. Acute decreases of >0.7 log(10) copies/mL in serum HIV-1 RNA concentration were seen in 4 of the 6 children treated with 4 weekly 10 mg/kg doses. At 14 days after treatment, 3 children had sustained reductions in serum HIV-1 RNA; the other children had rebounded to baseline levels or above. By 28 days after therapy, the peak HIV-1 cellular infectious units was reduced in all 6 children, including the 2 who had experienced an earlier transient increase in values. Thus, recombinant CD4-IgG2 treatment of HIV-1-infected children appears to be well tolerated and capable of reducing HIV-1 burden.