Pamela Boyer

The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: Phase I Acquired Immunodeficiency Syndrome Clinical Trials Group study (protocol 082)

OBJECTIVES: We measured the pharmacokinetics and safety of zidovudine in pregnant women infected with human immunodeficiency virus and their offspring. STUDY DESIGN: Asymptomatic human immunodeficiency virus-infected women with uncomplicated singleton gestations (28 to 36 weeks) underwent parenteral and oral zidovudine treatment during pregnancy and labor. Maternal and neonatal drug levels were measured at delivery and sequentially for 48 hours. Infants were followed up for 18 months. RESULTS: The total body clearance (26.3 ± 10.1 ml/min/kg), mean terminal elimination phase zidovudine half-life (1.3 ± 0.2 hours), and urinary zidovudine recovery were similar to values in nonpregnant adults. Essentially equivalent zidovudine levels in the mother and neonate at delivery implied little, if any, fetal zidovudine metabolism. The half-life of zidovudine in the neonates was tenfold that of the mother. No significant adverse effects were noted in the infant at birth or on follow-up. CONCLUSIONS: In both mothers and infants the drug appeared safe and well tolerated with no significant hematologic abnormalities.

Incidence of premature birth and neonatal respiratory disease in infants of HIV-positive mothers

OBJECTIVE We sought to determine the prematurity rate in infants of HIV-positive mothers and to characterize the incidence and severity of neonatal respiratory disease in this population. STUDY DESIGN From 1990 to 1994, 600 live-born infants of HIV-infected mothers were enrolled prenatally (73%) or postnatally (27%) from five U.S. centers. Logistic regression was used to determine the association of HIV status in the infant with prematurity (< or = 37 weeks), low birth weight (< or = 2.5 kg), and very low birth weight (< or = 1.5 kg) rates. The incidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia, meconium aspiration syndrome, and neonatal pneumonia was compared with anticipated rates for gestational age and birth weight. RESULTS Very high rates of prematurity (19%), low birth weight (18.3%), and very low birth weight (3.3%) were found in the infants of HIV-positive mothers; and HIV infection in the infant was associated with younger gestational age. The overall incidence of RDS was 3% (17/600), which coincided with the anticipated rate, after adjusting for prematurity and birth weight. Only five infants (all < or = 1.5 kg) had bronchopulmonary dysplasia, and none required assisted ventilation beyond 14 days. Three term infants had mild meconium aspiration syndrome, and there were no cases of documented neonatal pneumonia. CONCLUSION Infants born to HIV-positive mothers exhibited high prematurity and low birth weight rates, and the odds of prematurity were higher in infants who were infected with HIV. Despite the high incidence of prematurity and perinatal risk of this population, incidence and severity of neonatal respiratory disease were not higher than would be expected from available neonatal data in populations not exposed to HIV.

Immunologic activation during pregnancy: serial measurement of lymphocyte phenotype and serum activation molecules in HIV-infected and uninfected women

Immunologic alterations occur during pregnancy, but the effect of pregnancy on HIV infection is controversial. We characterized some of the immunologic alterations with potential to influence HIV disease in 99 infected and 46 uninfected women during pregnancy and up to 6 months post-partum. Immunophenotyping to quantitate the major lymphocyte subsets and determine expression of activation and adhesion molecules on T cells was performed using 3-color staining and laser flow cytometry. Serum neopterin, beta 2-microglobulin, and tumor necrosis factor-alpha (TNF alpha) were quantitated using commercial immunoassays. HIV + pregnant women were compared to uninfected pregnant subjects and to reference ranges established on healthy, HIV-seronegative non-pregnant female controls. Both CD4 and CD8 T cell subsets were increased in HIV-negative pregnant women compared to non-pregnant controls. In HIV-infected pregnant women, CD4 T cells were low and CD8 cells were elevated compared to HIV-negative pregnant and non-pregnant women. Levels of subsets were stable during pregnancy and postpartum in both groups of women. Evidence of peripheral immune activation was found during the later stages of pregnancy. Increases in HLA-DR and CD38 activation antigens on CD8 cells, serum neopterin and beta-2-microglobulin were seen during pregnancy in HIV-negative women. These correlates of immune activation were increased in HIV-infected pregnant women and increased further during pregnancy, paralleling changes seen in uninfected pregnant women. These immunologic alterations may directly or indirectly enhance viral replication, impacting the long-term course of HIV disease.

Maternal and perinatal factors related to maternal-infant transmission of HIV-1 in the P2C2 HIV study : The role of EBV shedding

The association of maternal and perinatal factors with mother-infant transmission of HIV-1 was examined in a prospective multicenter cohort of singleton live births to 508 HIV-1-infected women with children of known HIV-1 infection status (91 [18%] HIV-1-infected, 417 [82%] uninfected). From multivariate logistic regression, independent predictors of HIV-1 transmission included maternal CD4 percentage (CD4%) (odds ratio [OR] per 10% increase in CD4% = 0.70; p = .003), ruptured membranes <24 hours (OR = 3.15; p = .02), and maternal bleeding (OR = 2.90; p = .03), whereas maternal zidovudine (ZDV) use was marginally associated (OR = 0.60; p = .08). The associations of maternal urinary cytomegalovirus (CMV) shedding, oropharyngeal Epstein-Barr virus (EBV) shedding, and serology profiles during pregnancy with HIV-1 transmission were examined in the subset of mothers in whom the CMV and EBV measurements were available. Maternal EBV seropositivity, CMV shedding, and CMV seropositivity were 100% (279 of 279), 7% (16 of 229), and 92% (270 of 274), respectively. These rates did not differ between transmitting and nontransmitting mothers. In univariate analyses, maternal EBV shedding was higher among transmitting than nontransmitting mothers (40 of 49 [82%] compared with 154 of 226 [68%]; p = .06) and was independently associated with transmission in multivariate logistic analyses adjusting for CD4%, ruptured membranes, and ZDV use, with an OR of 2.45 (95% confidence interval (CI), 1.03-5.84; p = .04). This permits the conclusion that EBV shedding is associated with maternal-infant HIV-1 transmission, independent of CD4%.

Decreased CD8 Cell-Mediated Viral Suppression and Other Immunologic Characteristics of Women Who Transmit Human Immunodeficiency Virus to Their Infants

CD8 T cell function, lymphocyte surface phenotype, serum markers of immunologic activation, and viral burden were assessed in 75 human immunodeficiency virus (HIV)-infected pregnant women, including 9 who transmitted infection to their infants. Serial studies during and after pregnancy showed no significant differences in levels of cell-surface or serum activation molecules in transmitting compared to nontransmitting mothers, with the exception of a postpartum increase in tumor necrosis factor alpha in transmitting women. The transmitting women had a median plasma viral load of 65,516 RNA copies/mL at delivery versus 5139 in nontransmitting women. During the third trimester, the CD8 cells of 81% of the nontransmitting and 44% of the transmitting mothers suppressed HIV production in vitro by >50%. Women with <50% suppression had a 3.4 times greater risk of transmitting HIV to their infants. CD8 suppression and viral load were interrelated, but when either CD4 percent or AZT use was controlled for, suppression was still significant.

A PHASE I STUDY OF ACTIVE SPECIFIC INTRALYMPHATIC IMMUNOTHERAPY (ASILI)

Twenty‐one patients with advanced malignancies who had exhausted or refused conventional modalities of treatment were entered in a Phase I toxicology trial of active specific intralymphatic immunotherapy (ASILI). The patients were immunized with 1 × 107 to 1.2 × 108 viable autochthonous or allogeneic irradiated tumor cells intralymphatically each month and received no other antineoplastic treatment. To date, 274 intralymphatic injections have been performed and except for one case of bacterial lymphangitis, no adverse side effects have been observed. ASILI did not significantly alter peripheral blood lymphocyte counts, absolute E‐rosette forming cell levels, or EA‐rosette forming cell levels. PHA reactivity of peripheral blood lymphocytes increased slightly in all but one patient tested. Seven out of nine patients who had not had delayed hypersensitivity to recall antigens developed positive reactions following ASILI. Sixteen out of twenty patients tested also developed reactivity to their immunizing cells after treatment. Objective regression (greater than 50% reduction of tumor mass) was observed in five out of nineteen evaluable patients. Six patients showed stabilization of tumor growth and eight patients continued to progress under treatment.

Regional intralymphatic infusion (ILI) of irradiated tumor cells with evidence of distant effects.

A case of canine lymphoma with radiographically‐documented involvement of the para‐aortic nodes is reported. Intralymphatic infusions (ILI) of cultured irradiated autochthonous tumor cells to remote lymph node bearing areas were associated with a dramatic initial shrinkage of the para‐aortic lymphadenop‐athies. Three ILI timing schedules were used consecutively during a course of 10 treatments, allowing a comparison of responses in the same animal. The reported case suggests that a normal lymph node can be effectively “stimulated” by the same agent approximately every 3 weeks. A possible schedule for intralymphatic infusion is proposed for further investigation.

Intralymphatic infusion of autochthonous tumor cells in canine lymphoma

Abstract The feasibility of repeated intralymphatic injections of cellular materials was investigated in dogs having spontaneous lymphomas. Forty-two administrations of enzymatically-modified irradiated autochthonous tumor cell preparations were performed with minimal difficulty and negligible deleterious side effects, indicating that the intralymphatic route of administration and these methods of cell vaccine preparation may be safely used for further pre-clinical investigations. Although the number of animals treated thus far is insufficient to realistically evaluate the immunotherapeutic potential of this method, all treated tumor-bearing dogs demonstrated marked reduction in tumor volume and significant clinical improvement.

Intralymphatic immunization: Current status

Abstract A progress report and the research plan for a new method of antitumor immunization using the intralymphatic route are presented. A total of 205 intralymphatic infusions of intact cellular vaccines have been performed in normal and tumor-bearing dogs. In vitro and in vivo experiments on normal dogs demonstrated that intralymphatic immunization produces a more rapid and more intense cytotoxic cellular immune response compared to the subcutaneous route. Experiments in tumor-bearing dogs showed reduction or stabilization of tumor mass after intralymphatic infusion of irradiated malignant cells. These data indicate that intralymphatic immunization may be the method of choice for stimulating strong cellular immune responses to weakly immunogenic materials.

Phase 1 trial of active specific intralymphatic immunotherapy in patients with advanced cancer

28 patients with advanced malignancies of various histologic types have been treated with active specific intralymphatic immunotherapy to determine the toxicity and effect of such treatment. Patients received monthly intralymphatic infusions of 5-10 x 107 viable irradiated autochthonous or allogeneic cells at 2 peripheral sites per treatment. 118 treatments (227 infusions) have been performed. Duration of treatment was 2 to 12 months. No other antitumor treatment was given to any of the patients during this time. Hematologic, immunologic, auto-immune and other clinical parameters were monitored during this time. No toxicity has been observed in any patient. Conversion to positive delayed hypersensitivity to tumor cell suspension skin tests was seen in 17 out of 19 evaluable patients. Non specific skin tests became positive in 8 out of 10 patients. Serial measurements of lymphocyte response to mitogen and B and T cell enumeration showed that 4 out of 5 patients who presented with abnormally low values were restored to normal levels. Patients who were initially normal remained normal. Of the 28 patients, 19 are available for evaluation of tumor response. 8 showed objective response (42%) and two patients currently have no evidence of disease with no further treatment. Of the patients receiving autochthonous vaccine via this route, 66% showed objective response, while 30% of those receiving allogeneic vaccine showed objective response. Tumor stabilization for three to seven months occurred in three other cases. Additional details will be presented.