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Biomedical subjects

L M Frenkel

Publications and source records attributed to L M Frenkel.

At least 19 recordsLinked to original sources
PubMed2006

Human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis: viral load and muscle tone are correlated.

Human T-lymphotropic virus type 1 (HTLV-1) infections are associated with varying degrees of HTLV-1 viral load and spasticity. Increased viral load is associated with higher risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The authors performed a cross-sectional study of 24 people with HAM/TSP in Lima, Perú, to determine if higher HTLV-1 viral load was correlated with increased muscle tone, measured with a device providing quantitative spasticity assessment (QSA). Median HTLV-1 viral load was 17.0 copies/100 peripheral blood mononuclear cells and QSA value was 39.9 Newton-meters/radian. HTLV-1 viral load was significantly correlated with QSA value (Spearman rho = .48, P = .02), suggesting viral load may play a role in expression of symptomatic neurologic disease. Longitudinal studies are needed to determine if treatments that reduce viral load will reduce muscle tone.

Cross-Sectional Studies↗
PubMed2004

Growth velocity assessment in paediatric AIDS: smoothing, penalized quantile regression and the definition of growth failure.

The analysis of growth records in paediatric anti-HIV clinical trials plays an important role in trial evaluation. Growth failure may be a manifestation of progressive disease or treatment toxicity, and is commonly specified as a major trial outcome event indicating poor treatment performance. Despite new therapeutic advances against HIV proliferation in infected patients, accurate monitoring and interpretation of somatic growth in paediatric AIDS remains clinically important, in light of uncertainties regarding relationship between viral load reductions and achievement of favourable somatic growth profiles. Our aim in this paper is to construct a criterion for growth failure that discriminates patients whose risk of death subsequent to growth failure is elevated to a clinically significant degree. To construct the criterion, individual growth curves and velocities are modelled using loess smoothing, penalized likelihood quantile regressions are fit to model age-specific growth velocity distributions for gender-stratified cohorts, and proportional hazards model selection is conducted to identify features of velocity series that are informative on the survival distribution. The resulting growth-failure criterion is expected to be useful for disease staging in resource-limited medical environments where T-cell counts and viral load measures are unavailable.

Adolescent↗
PubMed2001

Human immunodeficiency virus type 1 (HIV-1) gp120-specific antibodies in neonates receiving an HIV-1 recombinant gp120 vaccine.

Infants born to human immunodeficiency virus type 1 (HIV-1)-infected mothers were immunized at birth and at ages 4, 12, and 20 weeks with low-, medium-, or high-dose recombinant gp120 vaccine with MF59 adjuvant (HIV-1(SF-2); n=52) or with MF59 alone as a placebo (n=9). An accelerated schedule (birth and ages 2, 8, and 20 weeks) was used for an additional 10 infants receiving the defined optimal dose and for 3 infants receiving placebo. At 24 weeks, anti-gp120 ELISA titers were greater for vaccine-immunized than for placebo-immunized infants on both schedules, and 87% of vaccinees had a vaccine-induced antibody response. At 12 weeks, antibody titers of infants on the accelerated vaccine schedule exceeded those of infants receiving placebo (4949 vs. 551; P=.01), and 63% of the vaccinees met the response criteria. Thus, an accelerated schedule of gp120 vaccinations generated an antibody response to HIV-1 envelope distinct from transplacental maternal antibody by age 12 weeks. These results provide support for further studies of vaccine strategies to prevent mother-to-infant HIV-1 transmission.

AIDS Vaccines↗
PubMed2001

Simple, sensitive, and specific detection of human immunodeficiency virus type 1 subtype B DNA in dried blood samples for diagnosis in infants in the field.

The detection of virus is used to diagnose human immunodeficiency virus type 1 (HIV-1) infection in infants due to the persistence of maternal antibodies for a year or more. An HIV-1 DNA PCR assay with simple specimen collection and processing was developed and evaluated. Whole blood was collected on filter paper that lysed cells and bound the DNA, eliminating specimen centrifugation and extraction procedures. The DNA remained bound to the filter paper during PCR amplification. Assays of copy number standards showed reproducible detection of 5 to 10 copies of HIV-1 in 5 microl of whole blood. The sensitivity of the assay did not decrease after storage of the standards on filter paper for 3 months at room temperature or after incubation at 37 or 45 degrees C for 20 h. The primers used for nested PCR of the HIV-1 pol gene amplified templates from a reference panel of multiple HIV-1 subtypes but did not amplify a subtype A or a subtype C virus from children living in Seattle. The assay had a sensitivity of 98.4% and a specificity of 98.3% for testing of 122 specimens from 35 HIV-1-infected and 16 uninfected children and 43 seronegative adults living in Washington. The assay had a sensitivity of 99% and a specificity of 100% for testing of 102 HIV-1-positive (as determined by enzyme immunoassay) Peruvian women and 6 seropositive and 34 seronegative infants. This assay, with adsorption of whole blood to filter paper and no specimen processing, provides a practical, economical, sensitive, and specific method for the diagnosis of HIV-1 subtype B infection in infants.

Adolescent↗
PubMed2001

Natural history of neonatal herpes simplex virus infections in the acyclovir era.

OBJECTIVE: During the 2 decades in which effective antiviral therapies have been available for neonatal herpes simplex virus (HSV) disease, changes have been documented not only in the outcomes of infected infants, but also in the natural history of the disease itself. Numerous studies previously have reported that early institution of antiviral therapy is beneficial to the outcome of the disease. The objective of this study was to provide an update of neonatal HSV disease to identify means by which future improvements in the management of HSV-infected neonates can be made. DESIGN/METHODS: Neonates enrolled in 2 studies of parenteral acyclovir for the treatment of neonatal HSV disease provided the data source. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted the studies between 1981 and 1997. A total of 186 patients are summarized, all of whom were treated with acyclovir. Demographic and clinical characteristics of these patients are reported. RESULTS: Comparisons between patients treated in the periods between 1981-1988 and 1989-1997 according to extent of disease revealed that the mean time between the onset of disease symptoms and initiation of therapy has not changed significantly from the early 1980s to the late 1990s. Of all patients evaluated, 40% had fetal scalp monitors during the delivery process. A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease). Among patients with CNS disease, mortality was associated with prematurity. Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy. Mortality was also associated with lethargy at initiation of antiviral therapy for patients with disseminated disease. Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated). For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy. CONCLUSION: Data presented in the current comparison of neonatal HSV disease over the 2 periods (1981-1988 vs 1989-1997) demonstrate that no progress has been made in decreasing the interval between onset of HSV symptoms and initiation of antiviral therapy. Additional strides in the improvement of disease outcome may occur only if the interval between onset of symptoms and initiation of therapy is shortened. The means by which this will be accomplished lie in increased consideration of neonatal HSV infections in acutely ill infants. Specific data and recommendations to facilitate this goal are contained within.

Acyclovir↗
PubMed2000

Oral ganciclovir in children: pharmacokinetics, safety, tolerance, and antiviral effects. The Pediatric AIDS Clinical Trials Group.

The pharmacokinetics, safety, tolerance, and antiviral effects of ganciclovir (Gcv) administered orally were evaluated in 36 children infected with cytomegalovirus (CMV) who were severely immunocompromised by infection with human immunodeficiency virus type 1. In this dose-escalation study, 30 mg/kg of Gcv administered every 8 h produced serum levels similar to the dose (1 g/8 h) effective for maintenance treatment of CMV retinitis in adults. In older children, serum Gcv concentrations were similar after the administration of capsules and suspension. All doses (10-50 mg/kg/8 h) studied were safe and, except for the volume of suspension or number of pills, were well tolerated. Oral Gcv was associated with a decrease in the detection of CMV by culture or polymerase chain reaction. CMV disease occurred in 3 children during the study: one developed Gcv resistance, another had harbored resistant virus at study entry, and a third had wild-type CMV

Acquired Immunodeficiency Syndrome↗
PubMed2000

Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children. Pediatric AIDS Clinical Trials Group Protocol 144 Study Team.

The effect of food on didanosine bioavailability and interpatient pharmacokinetic variability was examined in children infected with human immunodeficiency virus type 1 (HIV-1). Didanosine pharmacokinetics were determined during fasting and fed conditions in HIV-infected children enrolled in the Pediatric AIDS Clinical Trials Group Protocol 144 randomized to receive didanosine at 50 mg/m2 or 150 mg/m2 orally every 12 hr. Pharmacokinetic parameters from patients in the low (n = 39) and high (n = 38) dosing groups were not significantly different, but intersubject variability was substantial. The fraction absorbed was higher while fasting than with food (0.27+/-0.13 versus 0.19+/-0.09, p < 0.0001); the zero order absorption rate was faster (0.48+/-0.31 versus 0.76+/-0.72 hr, p = 0.003); and the plasma half-life was shorter (0.93+/-0.43 versus 1.39+/-0.65 hr, p < 0.0001). The lower fraction absorbed with food was offset by the absorption rate becoming rate limiting for elimination, resulting in similar areas under the concentration-time curves (normalized to 100 mg/m2) when fasted (853.9+/-465.8 microg/liter-hr) versus fed (796.3+/-367.5 microg/liter x hr). Oral clearances during fasting (152.5+/-81.7 liters/hr/m2) and fed states (163.6+/-99.3 liters/hr/m2) were similar, but these values in children are substantially higher than previously reported for adults. The systemic exposure (i.e., AUC) of didanosine was highly variable in children but similar in the presence and absence of food. Administration of didanosine with food in children may be permissible if total systemic exposure rather than maximum plasma concentration is sufficient for antiretroviral activity. The higher oral clearance and substantial pharmacokinetic variability suggest the need to reexamine current didanosine dose recommendations for HIV-infected children.

Administration, Oral↗
PubMed2000

Lymphoproliferative responses to recombinant HIV-1 envelope antigens in neonates and infants receiving gp120 vaccines. AIDS Clinical Trial Group 230 Collaborators.

Children of mothers infected with human immunodeficiency virus type 1 (HIV-1) were immunized at birth and at 1, 3, and 5 months with 1 of 3 doses of recombinant gp120 vaccines prepared from SF-2 or MN strains of HIV-1. A total of 126 children were not infected; 21 received adjuvant only. Vaccine recipients developed lymphoproliferative responses on >/=2 occasions, responding more often to homologous HIV-1 antigens than did adjuvant recipients (56% vs. 14%; P<.001). Responses were appreciated after 2 immunizations and were maintained for >84 weeks after the last immunization. An accelerated immunization schedule (birth, 2 weeks, 2 months, and 5 months) with the lowest dose of the SF-2 vaccine produced responses in all 11 vaccinees by 4 weeks. Responses to heterologous envelope antigens were also detected. Immune responses to vaccination are achievable at an age when some infection (perinatal or breast milk exposure related) may be prevented.

AIDS Vaccines↗
PubMed2000

Sensitive method for detection of human herpesviruses 6 and 7 in saliva collected in field studies.

To facilitate studies of the epidemiology and natural history of human herpesviruses 6 and 7 in infants, a practical method for collecting and quantifying the DNA of these viruses was developed. Saliva was collected using small strips of filter paper, and virus was detected using a real-time quantitative fluorescent-probe PCR assay. The sensitivity and specificity of this method even after prolonged drying of the specimens compared favorably to those of our traditional method of collecting and assaying saliva.

DNA, Viral↗
PubMed1999

HIV-1 dynamics in children.

HIV-1-infected children have higher plasma viral loads and progress to disease more quickly than infected adults. To gain insight into the accelerated pathogenesis of HIV-1 in children, viral dynamics were measured following the initiation of highly active antiretroviral therapy (HAART) and compared with those reported for adults. A biphasic decline in plasma HIV-1 RNA was observed, with a rapid decrease during the first 1 to 2 weeks of therapy (phase I) followed by a slower decline (phase II). The phase I and II decay rates were not significantly different among children of different ages, pretherapy plasma HIV-1 RNA levels, or CD4 cell counts. Estimated phase I decay rates were similar to those previously reported in adults with a mean of 0.43 days(-1) and a half-life of 1.6 days. The phase II decay rates were slower in children compared with adults with a mean of 0.016 days(-1) versus 0.066 days(-1), and a half-life of 43.3 versus 14.1 days, respectively (p < .05). The mean time required to reach viral levels below detection thresholds was also longer in these children compared with that in adults. These data suggest that HIV-1 dynamics may be different in children, and that these differences may necessitate different treatment strategies.

Adolescent↗
PubMed1999

The effects of zidovudine in the subset of infants infected with human immunodeficiency virus type-1 (Pediatric AIDS Clinical Trials Group Protocol 076).

OBJECTIVE: To describe the effect of zidovudine on human immunodeficiency virus type 1 (HIV-1) and on the course of disease in infants who became infected while they and their mothers received zidovudine preventive therapy or placebo in Pediatric AIDS Clinical Trials Group Protocol 076. STUDY DESIGN: Observational substudy of a multicenter, randomized, double-blind, placebo-controlled trial. METHODS: We compared the progression of disease, timing of HIV-1 transmission, and the plasma HIV-1 RNA level in infected infants of mother-infant pairs who were randomly assigned to receive zidovudine (n = 14) or placebo (n = 43). The development of genotypic zidovudine resistance was assessed among infected infants in the zidovudine treatment group. RESULTS: In this limited study, zidovudine therapy during pregnancy and labor and in the neonatal period for 6 weeks failed to have a major effect on rapid progression of disease, timing of transmission, and viral replication in HIV-infected infants. When the zidovudine treatment regimen failed to prevent maternal-infant transmission of HIV-1, resistance to zidovudine did not develop during study treatment. CONCLUSIONS: Our study supports the safety of zidovudine use in pregnancy and in the newborn period but demonstrates the continued need for more potent antiretroviral treatment of the infected infant.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Advances in antiviral therapy.

Multiple agents for the treatment and prevention of viral illnesses have been developed during the past few years. While in many cases this has been in direct response to the human immunodeficiency virus type 1 epidemic, a number of new antiviral agents are relevant to the practice of general pediatrics. This article reviews recent advances in the therapy of some common and a few unusual viral illnesses of children. The indication and efficacy of the newly developed agents valacyclovir, famciclovir, cidofovir, oral and intraocular ganciclovir, adefovir, respiratory syncytial virus immune globulin, palivizumab, and imiquimod are discussed, as well new uses of acyclovir, lamivudine, and ribavirin. Many of the antivirals discussed, including valacyclovir and cidofovir, have not yet been studied in children, but they hold promise for improving the treatment of pediatric viral infections.

Antiviral Agents↗
PubMed1999

Pharmacokinetics of dapsone administered daily and weekly in human immunodeficiency virus-infected children.

Although dapsone is a commonly used alternative agent for prophylaxis against Pneumocystis carinii pneumonia in children intolerant to trimethoprim-sulfamethoxazole, there are few data that describe dapsone pharmacokinetics in children. We studied dapsone pharmacokinetics in 30 children (median age, 2.8 years; age range, 0. 3 to 12 years) receiving a new proprietary liquid preparation by three dosing regimens (1 mg/kg of body weight daily, 2 mg/kg daily, or 4 mg/kg weekly). Dosing of children with 2 mg/kg daily or 4 mg/kg weekly resulted in peak concentrations equivalent to those reached in adults receiving 100-mg tablets daily. For the entire population, the median half-life was 22.2 h (range, 7.1 to 40.3 h), the median oral clearance was 0.0365 liter/kg/h (range, 0.0104 to 0.1021 liter/kg/h), and the median oral apparent volume of distribution was 1.13 liters/kg (range, 0.50 to 2.32 liters/kg). The median dapsone oral clearance was significantly increased in those infants less than 2 years of age compared to the oral clearance in those over 2 years of age (0.0484 versus 0.0278 liter/kg/h; P = 0.011). These data suggest that absorption of this liquid preparation is adequate and that the concentrations in the sera of children receiving 2 mg/kg daily or 4 mg/kg weekly are equivalent to those seen in adults receiving standard dapsone dosing. Dapsone oral clearance appears to be increased in children under 2 years of age.

Adolescent↗
PubMed1998

Pediatric AIDS prognosis using somatic growth velocity.

OBJECTIVE: To describe the natural history of somatic growth in HIV infection by constructing age-specific growth velocity norms and to assess specific prognostic information available using these norms. DESIGN: Observations on 1338 HIV-infected children aged 3 months to 15 years who participated in one of four US clinical trials of pediatric anti-HIV therapies were pooled; baseline growth velocity data were obtained using the first 6 months of observation for each child. METHODS: Distributions of physical growth velocities in HIV-infected children in the Pediatric AIDS Clinical Trials Group were computed. Statistical smoothing of growth histories was employed to derive velocity estimates, and quantile regression analysis of growth velocities was performed to allow comparisons of growth rates in age- and gender-heterogeneous cohorts in the context of HIV infection. The quantile regressions provide corrected z-scores for growth velocity that appropriately compare HIV-infected children with one another for the purpose of distinguishing more from less favorable prognoses. RESULTS: Consistent deficits in growth velocity amongst HIV-infected children were revealed when compared with the Fels Institute velocity standards. Approximately 33% of height (and 20% of weight) age- and sex-corrected velocity measurements obtained in the first 6 months of clinical trial participation lay beneath the corresponding third percentiles of the Fels reference distributions, which are commonly regarded as critical indicators of growth failure. Proportional hazards regression tests indicated that both weight and height velocity contributed significant information on the risk of death among children with AIDS after adjusting for antiretroviral therapy received, CD4 cell counts, and age at trial enrollment. Comparing subjects who differ in initial weight velocity by one age- and sex-corrected SD, the relative hazard of death was 0.63 (95% confidence interval, 0.55-0.72; P < or = 0.0001) in favor of the child with greater weight velocity, controlling for antiretroviral therapy received, age and CD4 cell count at baseline. The analogous hazard ratio for height velocity was 0.68 (95% confidence interval, 0.57-0.79; P < or = 0.0001). CONCLUSIONS: Suitably normalized growth velocities are informative and inexpensive criteria for pediatric AIDS prognosis; the growth velocity distributions presented will be useful for comparing growth effects of new therapeutic strategies to those of single and combination antiretrovirals employed for maintenance of pediatric HIV infection in the mid-1990s.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Genetic evaluation of suspected cases of transient HIV-1 infection of infants.

Detection of human immunodeficiency virus-type 1 (HIV-1) on only one or a few occasions in infants born to infected mothers has been interpreted to indicate that infection may be transient rather than persistent. Forty-two cases of suspected transient HIV-1 viremia among 1562 perinatally exposed seroreverting infants and one mother were reanalyzed. HIV-1 env sequences were not found in specimens from 20; in specimens from 6, somatic genetic analysis revealed that specimens were mistakenly attributed to an infant; and in specimens from 17, phylogenetic analysis failed to demonstrate the expected linkage between the infant's and the mother's virus. These findings argue that transient HIV-1 infection, if it exists, will only rarely be satisfactorily documented.

DNA, Viral↗
PubMed1998

Maternal syphilis and vertical perinatal transmission of human immunodeficiency virus type-1 infection.

OBJECTIVES: To identify risk factors for vertical HIV transmission that may provide opportunities for the prevention of future pediatric HIV infection. STUDY DESIGN: A prospective cohort of 44 pregnant HIV(+) women and their 53 offspring was followed between July 1989 and July 1996. RESULTS: Secondary and latent maternal syphilis infection was diagnosed in four pregnancies with VDRL titers > or = 1:128. Concurrent maternal syphilis infection was associated with 100% vertical HIV transmission (4/4), compared to 21% (3/14) deliveries that occurred in 13 women with only a history of treated sypillis (P = 0.01) and 14% (5/35) deliveries in women with no history of syphilis (P = 0.0015). Among non-Zidovudine exposed pregnancies, 100% (3/3) patients with concurrent syphilis transmitted HIV to their infants vs. 0% (0/8) patients with only a history of syphilis (P = 0.006). A history of treated syphilis did not increase subsequent transmission risk compared to women with no history of syphilis (3/14 vs. 5/35, P = 0.41). One patient delivered twice during the study and received Zidovudine prophylaxis during both pregnancies. Her first pregnancy VDRL titer was > or = 1:128, during which she delivered an HIV infected child. Following successful treatment for syphilis (VDRL titer, 1:1), she conceived again and delivered an uninfected infant 11 months later. Additional risk factors significantly associated with vertical HIV transmission were prematurity and low birth weight. Variables studied but not statistically-related to HIV transmission included: other sexually transmitted diseases, maternal age, race, intravenous drug or cocaine use, prenatal care, route of delivery, duration of HIV(+) status, and CD4 count. CONCLUSION: Among HIV(+) women, concurrent syphilis infection, but not a history of syphilis, is significantly associated with vertical perinatal HIV transmission. Frequent screening and prompt treatment of syphilis in non-pregnant HIV(+) women may help prevent subsequent HIV infected pregnancies.

Adult↗
PubMed1998

Maternal viral genotypic zidovudine resistance and infrequent failure of zidovudine therapy to prevent perinatal transmission of human immunodeficiency virus type 1 in pediatric AIDS Clinical Trials Group Protocol 076.

Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic zidovudine resistance at entry, if zidovudine resistance developed on study, and the role of zidovudine resistance in vertical transmission of HIV-1 despite zidovudine therapy. Low and high levels of genotypic resistance were assessed by differential hybridization, oligoligation, or direct sequencing of plasma HIV-1 RNA for codons K70R and T215Y/F. None of the women had high-level genotypic resistance to zidovudine at study entry or delivery. For low-level zidovudine resistance, the 95% confidence intervals were 0.3%-6.8% for baseline prevalence and 0.3%-14% for delivery incidence. Low-level zidovudine resistance, adjusted for plasma viral RNA level at delivery, was not strongly associated with an increase in vertical transmission risk (odds ratio, 4.8; 95% confidence interval, 0.2-131; P = .35).

Clinical Protocols↗