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Biomedical subjects

Stephen A Spector

Publications and source records attributed to Stephen A Spector.

At least 19 recordsLinked to original sources
PubMed2006

Impact of pregnancy on abacavir pharmacokinetics.

OBJECTIVE: To describe abacavir pharmacokinetics during pregnancy and postpartum; physiological changes during pregnancy are known to affect antiretroviral drug disposition. DESIGN: The Pediatric AIDS Clinical Trials Group P1026s study is an on-going, prospective, non-blinded pharmacokinetic study of pregnant women receiving one or more antiretroviral drugs for routine clinical care, including a cohort receiving abacavir 300 mg twice daily. METHODS: Serial plasma samples (predose, 1, 2, 4, and 6 h postdose) obtained antepartum (30-36 weeks of gestation) and again postpartum (6-12 weeks after delivery) were assayed for abacavir concentration by reversed-phase high-performance liquid chromatography. RESULTS: Antepartum evaluations were available for 25 women [mean age, 28.6 years (SD, 6); mean third-trimester weight 92 kg (SD, 35.4); and race/ethnicity 52% black, 28% Hispanic, 16% white, 4% Asian], with geometric mean abacavir area under the concentration-time curve (AUC) of 5.9 mg.h/l [90% confidence interval (CI), 5.2-6.8] and maximum plasma concentration (Cmax) of 1.9 mg/l (90% CI, 1.6-2.2). Seventeen women completed postpartum sampling, and the ratios of antepartum to postpartum AUC and Cmax were 1.04 (90% CI, 0.91-1.18) and 0.79 (90% CI, 0.65-0.98), respectively. CONCLUSIONS: Abacavir AUC during pregnancy was similar to that at 6-12 weeks postpartum and to that for non-pregnant historical controls (5.8 mg.h/l). Consequently, pregnancy does not appear to affect overall abacavir exposure significantly or to necessitate dose adjustments.

Adult↗
PubMed2006

Perinatal HIV counseling and rapid testing in Tijuana, Baja California, Mexico: seroprevalence and correlates of HIV infection.

OBJECTIVE: To evaluate the acceptance of counseling and rapid HIV testing and to determine the associated risk factors for HIV infection in pregnant women in Baja California, Mexico. METHODS: Pregnant women attending Tijuana General Hospital who consented to participate in the study had blood drawn for a rapid HIV test (Determine HIV-1/2; Abbott Diagnostics, North Chicago, IL). A confirmatory enzyme immunoassay and Western blot were performed and demographic and risk factor data were obtained. RESULTS: From March to November 2003, 1529 (92.5%) of 1653 women who sought prenatal care and 1068 (95.2%) of 1122 women in labor consented to participate. HIV seroprevalence was significantly higher among women screened during labor (12/1068, 1.12%) compared with those seeking prenatal care (5/1529, 0.33%). HIV-infected women were significantly more likely to use injection drugs (12% vs. 1%, P = 0.02), "other" drugs, including methamphetamine, marijuana, and cocaine (65% vs. 6%, P < 0.001), to have more sex partners (3.6 vs. 2.6, P = 0.0002), to not have received prenatal care (41% vs. 13%, P = 0.03), and to have a spouse/partner who used injection drugs (36% vs. 4%, P < 0.001) or "other" drugs (73% vs. 23%, P < 0.001). In multivariate regression analysis, use of methamphetamine (adjusted odds ratio, 17.8, 95% CI, 5.6-56) was independently associated with the risk of HIV infection. CONCLUSIONS: These findings indicate a wide acceptance of HIV counseling and testing and document a higher HIV seroprevalence among pregnant women delivering at Tijuana General Hospital than current established estimates in Mexico.

Adult↗
PubMed2006

Association of CD4+ T-lymphocyte counts and new thymic emigrants in HIV-infected children during successful highly active antiretroviral therapy.

BACKGROUND: In a cohort of children receiving highly active antiretroviral therapy (HAART) with sustained plasma HIV-1 RNA < 50 copies/mL, children who reached undetectable RNA after week 8 (slow responders, median: week 20) had higher HIV-1 intracellular DNA (HIV-1 DNA) and equal or greater CD4+ T-lymphocyte counts compared with children who reached undetectable plasma HIV-1 RNA by week 8 (rapid responders) throughout HAART. OBJECTIVE: To determine whether levels of T-cell receptor excision circles (TRECs) could explain the apparent inconsistency between the quantity of HIV-1 DNA and CD4+ T-lymphocyte counts in HIV-1-infected children receiving HAART with sustained virologic suppression. METHODS: T-cell receptor excision circles and HIV-1 DNA and plasma HIV-1 RNA were quantified longitudinally by PCR in 31 children (median age, 5.6 years) with sustained undetectable plasma HIV-1 RNA for >104 weeks of HAART. RESULTS: There was a positive correlation between TREC and HIV-1 DNA during HAART, notably at weeks 48 and 80 (P < .004). During the early stage of HAART, TREC levels positively correlated with CD4+ T-lymphocyte percentages (P < .02) and naive CD4+ T-lymphocyte counts (P < .001) and percentages (P = .05). Median TREC levels were consistently equal or higher in slow responders compared with rapid responders (P < .001) despite slow responders having consistently greater quantities of HIV-1 DNA. CONCLUSION: To maintain adequate levels of CD4+ T-lymphocytes, children with high HIV-1 DNA maintain high levels of TREC while receiving HAART. Thus, a thymic control mechanism is required to maintain new CD4+ T lymphocytes in the presence of persistent virus. CLINICAL IMPLICATIONS: The TREC level is a useful marker of thymic function in HIV-infected children.

Adolescent↗
PubMed2005

The C terminus of HIV-1 Tat modulates the extent of CD178-mediated apoptosis of T cells.

HIV infection and the progression to AIDS are characterized by the depletion of CD4(+) T cells through apoptosis of the uninfected bystander cells and the direct killing of HIV-infected cells. This is mediated in part by the human immunodeficiency virus, type 1 Tat protein, which is secreted by virally infected cells and taken up by uninfected cells and CD178 gene expression, which is critically involved in T cell apoptosis. The differing ability of HIV strains to induce death of infected and uninfected cells may play a role in the clinical and biological differences displayed by HIV strains. We chemically synthesized the 86-residue truncated short variant of Tat and its full-length form. We show that the trans-activation ability of Tat at the long terminal repeat does not correlate with T cell apoptosis but that the ability of Tat to up-regulate CD178 mRNA expression and induce apoptosis in T cells is critically dependent on the C terminus of Tat. Moreover, the greater 86-residue Tat-induced apoptosis is via the extrinsic pathway of CD95-CD178.

Apoptosis↗
PubMed2005

Genetic polymorphisms in CX3CR1 predict HIV-1 disease progression in children independently of CD4+ lymphocyte count and HIV-1 RNA load.

BACKGROUND: The impact of CX3CR1 polymorphisms on human immunodeficiency virus type 1 (HIV-1) pathogenesis is controversial, with conflicting reports of their role in disease progression in HIV-1-infected adults. METHODS: A cohort of 1055 HIV-1-infected children were genotyped for 2 CX3CR1 polymorphisms, V/I249 and T/M280, and their impact on HIV-1-related disease progression, including central nervous system (CNS) impairment, was evaluated. RESULTS: Children with the CX3CR1 I/I249 genotype experienced more-rapid disease progression (I/I249 vs. V/V249: relative hazard [RH], 2.19 [95% confidence interval {CI}, 1.30-3.68], P=.003; I/I249 vs. V/I249: RH, 1.77 [95% CI, 1.00-3.14], P=.05) and a trend toward more CNS impairment (I/I249 vs. V/V249: RH, 2.19 [95% CI, 1.00-4.78], P=.049; I/I249 vs. V/I249: RH, 2.02 [95% CI, 0.85-4.83], P=.11). Children with the V249-T280 haplotype experienced significantly less disease progression (RH, 0.42 [95% CI, 0.24-0.73]; P=.002) and CNS impairment (RH, 0.39 [95% CI, 0.39-0.22]; P=.001). Of note, these effects remained significant after CD4+ lymphocyte count and plasma HIV-1 RNA load at baseline were adjusted for and in a longitudinal, multivariate analysis. CONCLUSIONS: CX3CR1 genotypes and haplotypes impact HIV-1 disease progression independently of CD4+ lymphocyte count and plasma HIV-1 RNA load, suggesting that the fundamental role of CX3CR1 in the alteration of disease progression might be the recruitment of immunomodulatory cells responsible for the control of HIV-1.

CD4 Lymphocyte Count↗
PubMed2005

An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children.

OBJECTIVE: The multidrug-resistance transporter gene (MDR1) encoding for P-glycoprotein (P-gp) and genes encoding for isoenzymes of cytochrome P450 (CYP) have an important role in transport and metabolism of antiretroviral agents. This research examined the impact of single nucleotide polymorphisms (SNP) of MDR1 and CYP genes on nelfinavir and efavirenz pharmacokinetics and the response to highly active antiretroviral therapy (HAART) in HIV-1 infected children. METHODS: Seventy-one HIV-1-infected children from PACTG 382 receiving nelfinavir, efavirenz and one or two nucleoside reverse transcriptase inhibitors had genomic DNA from PBMC evaluated for MDR1 and CYP SNP by real-time PCR. Plasma drug concentrations, CD4 lymphocyte counts and HIV-1 RNA were measured during HAART. RESULTS: The frequencies of C/C, C/T and T/T genotypes in the MDR1-3435-C-->T polymorphisms were 44% (n = 31), 46% (n = 33) and 10% (n = 7), respectively. Ninety-one percent of children with the C/T genotype reached plasma HIV-1 RNA < 400 copies/ml by week 8 compared to 59% of children with the C/C genotype (P = 0.01). Children with the C/T genotypes had higher 8 h postdose concentration (P = 0.02) and lower clearance rate (P = 0.04) for nelfinavir compared to those with the C/C genotype. The seven children with the T/T genotype had nelfinavir pharmacokinetics and virologic response similar to those with the C/C genotype. No compensatory polymorphisms were observed between MDR1 and CYP genotypes. CONCLUSIONS: HIV-1 infected children with the MDR1-3435-C/T genotype had more rapid virologic responses to HAART at week 8 with higher plasma nelfinavir concentrations compared to those with the C/C genotype. These findings suggest that P-gp may play an important role in the pharmacokinetics and virologic response to HAART containing nelfinavir.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Myelomeningocele in an infant with intrauterine exposure to efavirenz.

We report a case of myelomeningocele in an infant whose mother was exposed to efavirenz during the first 16 weeks of pregnancy. Although the true risk for myelomeningocele with the use of efavirenz early in pregnancy is still unknown, the findings in humans are consistent with those observed in primates and suggest that efavirenz is a potent teratogen. Thus, we suggest that efavirenz only be prescribed for women of childbearing potential when no other comparable antiretroviral options are available.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Hospital and outpatient health services utilization among HIV-infected children in care 2000-2001.

BACKGROUND: The aging of the pediatric HIV cohort and advances in antiretroviral therapy for children may have resulted in recent changes in patterns of healthcare utilization. OBJECTIVES: The objectives of this study were to examine inpatient and outpatient HIV-related health service utilization in a multistate sample of HIV-infected children, and to assess sociodemographic and clinical correlates of utilization. DESIGN: Cohort study of pediatric patients with HIV. Demographic, clinical, and resource utilization data were collected from medical records for 2000 and 2001. SETTING: This study was conducted at 4 U.S. HIV primary pediatric and specialty care sites in different geographic regions. PATIENTS: Three hundred three HIV-positive children with at least one outpatient visit or CD4 test in either 2000 or 2001 were studied. MAIN OUTCOME MEASURES: Mean outcome measures were number of hospital admissions, mean length of hospital stay, and number of outpatient clinic/office visits. RESULTS: Hospitalization rates decreased significantly from 39.2 (95% confidence interval [CI], 28.4-50.1) to 25.3 (95% CI, 16.4-34.3) admissions per 100 patients between 2000 and 2001. Hospitalizations were higher among patients with greater immunosuppression, those 2 years and under, and those with AIDS, but were not significantly related to receipt of highly active antiretroviral therapy. Mean outpatient visits did not change significantly between 2000 and 2001 from 9.09 (95% CI, 8.3-9.9) to 9.06 (95% CI, 8.4-9.7) visits per child per year. Children 2 years and under, those on highly active antiretroviral therapy, those with AIDS, and those with Medicaid had significantly higher outpatient utilization. Those with higher HIV-1 RNA had higher outpatient utilization than those with less advanced disease. CONCLUSION: Inpatient utilization significantly decreased between 2000 and 2001, but outpatient utilization did not change over time. Compared with prior studies, utilization rates appear to be declining over time. Unlike adults, racial/ethnic or gender disparities in healthcare utilization are less pronounced for HIV-infected children.

AIDS-Related Opportunistic Infections↗
PubMed2005

Immunologic function and virologic suppression among children with perinatally acquired HIV Infection on highly active antiretroviral therapy.

BACKGROUND: The goal of highly active antiretroviral therapy (HAART) has been to stabilize and reconstitute immune function and suppress viral replication to the greatest degree possible. Suppression of HIV viral replication has been associated with improved long-term and short-term prognosis. Limited data are available on the level of virologic suppression and immune function of pediatric patients followed in clinical settings in the HAART era. OBJECTIVE: The objective of this study was to assess the level of virologic suppression and immune function in a cohort of children with perinatally acquired HIV infection followed at dedicated HIV specialty care sites. RESEARCH DESIGN: This study comprised a cohort study of HIV-infected children and adolescents. SUBJECTS: Study subjects consisted of 263 HIV-positive children ( 25; only 4.2% had CD4 <15%. Overall, 12.5% of patients had either CD4% <15 or severely decreased absolute CD4 counts (adjusted for age). A total of 4.6% of patients had HIV-1 RNAs >100,000 cpm and severe immunosuppression. Patients who were less likely to achieve virologic suppression to <400 cpm included those with CD4 count <200 cells/mm(3) (odds ratio [OR], 0.06; 95% confidence interval [CI], 0.007-0.46), those with AIDS (OR, 0.5; 95% CI, 0.28-0.94), and those with moderate (OR, 0.42; 95% CI, 0.22-0.79), or severe immunologic suppression (OR, 0.14; 95% CI, 0.046-0.43) based on CD4%. CONCLUSION: In this multisite, pediatric cohort, the rate of near-complete virologic suppression (<50 or <400 cpm) was low. However, the majority of patients have near-normal CD4 counts and viral loads <15,000 cpm. Follow up will be critical to assess the implications of ongoing low-level viral replication with near-normal CD4 values.

Adolescent↗
PubMed2004

Decrease in hospitalization and mortality rates among children with perinatally acquired HIV type 1 infection receiving highly active antiretroviral therapy.

BACKGROUND: The impact of highly active antiretroviral therapy (HAART) on human immunodeficiency virus type 1 (HIV-1) disease progression in perinatally infected children is not well documented. This study aims to identify the effect of evolving antiretroviral therapy on the immunologic and virologic status of and hospitalization and mortality rates among perinatally infected children. METHODS: Children receiving outpatient care during 1994-2001 at 3 HIV clinics in southern California were observed longitudinally for CD4+ cell percentage, plasma HIV-1 RNA load, antiretroviral treatment, Pneumocystis jiroveci pneumonia (PCP) prophylaxis, and rate of hospital admissions. RESULTS: A total of 129 children were observed during the study period; 51% were girls, and 40.3% were Hispanic, 29.5% were African American, and 27.1% were white. The mean CD4+ cell percentage increased from 22.5% in 1994 to 31.2% in 2001 (P<.01), and the mean plasma HIV-1 RNA load decreased from 4.53 log10 copies/mL in 1996 to 3.27 log10 copies/mL in 2001 (P<.001). The use of HAART increased from 0% in 1994 to 93% in 2001 (P<.01), whereas the use of PCP prophylaxis decreased from 55% to 16% during this time (P<.001). The hospitalization rate decreased from 6.49 to 0.60 admissions per 100 person-years during 1994-2001 (P<.001). Acquired immunodeficiency syndrome-associated hospital admission rates decreased from 15.6% in 1994 to 0% in 2001 (P<.0001). Similarly, the admission rate for patients with Centers for Disease Control and Prevention category B decreased from 29.7% in 1994 to 5.9% in 2001 (P<.0001). Logistic regression analysis showed that CD4+ cell percentage and viral load were independently associated with risk of hospitalization. Survival was significantly longer for those who received HAART. CONCLUSIONS: HIV-1-associated mortality and hospitalization rates decreased significantly between 1994 and 2001 in perinatally infected children. This correlated with an increase in CD4+ cell percentage and a decrease in HIV-1 RNA load concurrently with the expanded use of HAART.

AIDS-Related Opportunistic Infections↗
PubMed2004

Virologic and immunologic outcomes after 24 weeks in HIV type 1-infected adolescents receiving highly active antiretroviral therapy.

BACKGROUND: Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. METHODS: We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. RESULTS: Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. CONCLUSIONS: Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.

Adolescent↗
PubMed2004

Longitudinal analysis of lymphocyte ratios and HIV-1 intracellular DNA levels in children.

The associations between human immunodeficiency virus type 1 (HIV-1) intracellular DNA and immunological markers were analyzed longitudinally for children with sustained, undetectable RNA levels while receiving highly active antiretroviral therapy (HAART) for >2 years. When DNA levels reached a plateau at week 104 of therapy, in contrast to findings for adults, there was no correlation between the CD4(+) : CD8(+) ratio and DNA levels (r=-0.02; P=.95), and naive CD4(+)CD45RA(+) lymphocytes predominated. These data suggest that the increased proportion of naive lymphocytes found in children are less susceptible to HIV-1 infection than are the memory lymphocytes that dominate immune reconstitution in adults.

Adolescent↗
PubMed2004

Prevalence of chemokine and chemokine receptor polymorphisms in seroprevalent children with symptomatic HIV-1 infection in the United States.

Several chemokines and chemokine receptors are involved in HIV-1 infection, disease progression, and transmission. We studied the prevalence of genetic variations in CCR2, SDF1, and the CCR5 gene and its promoter region at positions 59029, 59353, and 59356 in a seroprevalent cohort of 1057 children with symptomatic HIV-1 infection in the United States. The percentage of children with the CCR5-wt/Delta32 genotype was significantly higher for white, non-Hispanic children (15%) than for Hispanic (6%) or black, non-Hispanic children (4%). For the CCR5-59029-G/A, CCR5-59353-T/C, and CCR5-59356-C/T polymorphisms, there were significant or marginally significant differences in genotype frequencies across race/ethnicity groups. For the CCR2-wt/64I polymorphism, both black, non-Hispanic and Hispanic children had a higher frequency of the CCR2-wt/64I genotype (24% and 21%, respectively) and CCR2-64I/64I genotype (4% and 3%, respectively) than white, non-Hispanic children (14% and 2%, respectively). For the SDF1-3'-G/A polymorphism, black, non-Hispanic children had a lower combined frequency of the SDF1-3'-G/A and SDF1-3'-A/A genotypes (15%) than did Hispanic children (33%) and white, non-Hispanic children (37%). These analyses show that the distribution of chemokine receptor and chemokine genetic polymorphisms varies significantly across race/ethnicity subgroups of HIV-1-infected children in the United States.

Chemokines↗
PubMed2004

Lack of protective effects of interleukin-4 -589-C/T polymorphism against HIV-1-related disease progression and central nervous system impairment, in children.

The interleukin (IL)-4 -589-C/T polymorphism has been reported to protect against human immunodeficiency virus type 1 (HIV-1)-related disease progression in white adults. In the present study, the effect of the IL-4 -589 polymorphism on HIV-1-related disease progression was evaluated in a seroprevalent cohort of 1043 children. The IL-4 -589-T allele was more prevalent in Hispanic and in black, non-Hispanic children, compared with white, non-Hispanic children. We found that the IL-4 -589-C/T polymorphism does not affect the risk of HIV-1-related disease progression or central nervous system impairment in children, and this did not differ by race/ethnicity. Our findings suggest that the IL-4 -589-C/T polymorphism is not an important determinant of HIV-1 disease progression in children.

AIDS Dementia Complex↗
PubMed2004

Relationship of plasma HIV-1 RNA dynamics to baseline factors and virological responses to highly active antiretroviral therapy in adolescents (aged 12-22 years) infected through high-risk behavior.

We characterized the viral dynamics of human immunodeficiency virus (HIV) type 1-infected adolescents receiving highly active antiretroviral therapy regimens (lamivudine [3TC]/zidovudine [ZDV]/efavirenz [EFV], 3TC/ZDV/nelfinavir [NFV], or other regimens) and studied the relationship of viral dynamics with baseline factors and virological responses. Viral decay rates for 115 evaluable subjects were estimated from a viral dynamic model. Viral dynamics in HIV-1-infected individuals aged 12-22 years were similar to those of HIV-1-infected adults and infants. Individuals who received 3TC/ZDV/EFV had a more rapid phase 1 viral decay rate than those who received 3TC/ZDV/NFV or other regimens. Phase 1 viral decay rates were positively correlated with baseline RNA levels and week 1 virus load reductions. Our findings indicate that the 3TC/ZDV/EFV regimen may be more potent than 3TC/ZDV/NFV or other regimens and that early viral dynamics or week 1 virus load reduction measurements may be useful in evaluating the potency of antiretroviral regimens.

Acquired Immunodeficiency Syndrome↗