Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.

BACKGROUND: Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. METHOD: HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. RESULTS: Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. CONCLUSION: NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.

Pharmacokinetics of oral zidovudine administered during labour: a preliminary study.

OBJECTIVES: The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent mother-to-child transmission in HIV-infected pregnant women. METHODS: ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery. RESULTS: In cohort 1 (n=6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n=4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption. CONCLUSIONS: While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.

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.

Effect of protease inhibitors combined with standard antiretroviral therapy on linear growth and weight gain in human immunodeficiency virus type 1-infected children.

Children with HIV-1 infection and poor growth have a significant increase in the risk of death. We studied the effects of protease inhibitors on the height and weight of 27 HIV-1-infected children and found that in our small pilot study, protease inhibitor therapy had a positive effect on the heights of HIV-1-infected children. Accelerated height velocity was sustained for at least 18 to 20 months.

Perinatal transmission of major, minor, and multiple maternal human immunodeficiency virus type 1 variants in utero and intrapartum.

Previous studies have provided conflicting data on the presence of selective pressures in the transmission of a homogeneous maternal viral subpopulation to the infant. Therefore, the purpose of this study was to definitively characterize the human immunodeficiency virus type 1 (HIV-1) quasispecies transmitted in utero and intrapartum. HIV-1 envelope gene diversity from peripheral blood mononuclear cells and plasma was measured during gestation and at delivery in mothers who did and did not transmit HIV perinatally by using a DNA heteroduplex mobility assay. Children were defined as infected in utero or intrapartum based on the timing of the first detection of HIV. Untreated transmitting mothers (n = 19) had significantly lower HIV-1 quasispecies diversity at delivery than untreated nontransmittting mothers (n = 18) (median Shannon entropy, 0.711 [0.642 to 0.816] versus 0.853 [0.762 to 0.925], P = 0.005). Eight mothers transmitted a single major env variant to their infants in utero, and one mother transmitted a single major env variant intrapartum. Four mothers transmitted multiple HIV-1 env variants to their infants in utero, and two mothers transmitted multiple env variants intrapartum. The remaining six intrapartum- and two in utero-infected infants had a homogeneous HIV-1 env quasispecies which did not comigrate with their mothers' bands at their first positive time point. In conclusion, in utero transmitters were more likely to transmit single or multiple major maternal viral variants. In contrast, intrapartum transmitters were more likely to transmit minor HIV-1 variants. These data indicate that different selective pressures, depending on the timing of transmission, may be involved in determining the pattern of maternal HIV-1 variant transmission.

Recovery of replication-competent virus from CD4 T cell reservoirs and change in coreceptor use in human immunodeficiency virus type 1-infected children responding to highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) suppresses plasma viremia in most patients with human immunodeficiency virus (HIV) infection. Prospective study of HIV-infected children (n=27) shows that, in 8 of 12 who responded to HAART (>/=0.5 log reduction in plasma HIV RNA), HAART restricted the number of coreceptors used by the predominant HIV isolate (mean number of coreceptors used at baseline was 4, vs. 1 coreceptor used at 6 months after treatment). This decrease was most striking in 6 of 8 children whose HIV coreceptor tropism changed from X4-tropic at baseline to R5-tropic. In 6 of 10 children tested, with plasma HIV RNA levels of <50 copies/mL, R5-tropic virus was isolated from CD4 T cell reservoirs. All the responding children had a significant increase in naive CD4 T cells (P<.05). These results show that persistent HIV T cell reservoirs are present in children and that HAART may influence the number and type of coreceptors used by the predominant virus isolate.

Pneumococcal and influenza immunization and human immunodeficiency virus load in children.

OBJECTIVE: HIV-infected children receiving influenza vaccine, pneumococcal vaccine and both vaccines concurrently were studied to examine the effect of immunization on plasma HIV viral load. METHODS: Thirteen children received immunizations: pneumococcal vaccine, 5; pneumococcal and influenza vaccines, 7; and influenza vaccine, 1. Most patients (12 of 13) were receiving combination reverse transcriptase inhibitor antiretroviral therapy without protease inhibitors at the time of immunization. Baseline plasma HIV RNA was determined 1 month prior (11 of 13), 2 weeks prior (12 of 13) and on the day of immunization (12 of 13). Plasma HIV RNA was assayed at 2 weeks (11 of 13), 4 weeks (12 of 13) and 3 months (5 of 13) after immunization. T cell activation markers (HLA-DR+, CD38+ and CD45RO+, CD28+) were examined for both CD4+ and CD8+ lymphocytes on the day of immunization and 2 weeks after immunization for 11 children. RESULTS: Only one child developed a >0.5-log increase in viral load at any time after immunization. There was no correlation between an increase in viral load and antibody response to pneumococcal vaccine. At least one activation marker increased (> 10%) for two children receiving pneumococcal vaccine and two children receiving pneumococcal and influenza vaccines. One of these children experienced an increase in viral load. CONCLUSION: Immunization with pneumococcal and influenza vaccines, alone or in combination, is rarely associated with a significant increase in HIV plasma RNA in children receiving combination antiretroviral therapy.

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.

Diagnosis of HIV infection in children.

Many advances have been made in the area of HIV diagnostics. Commercially available virologic assays are sensitive and specific for the early detection of HIV in perinatal infection. The timing of the transmission of HIV from mother to child (in utero, at the time of birth, or postnatally by breast-feeding) is a critical consideration in the appropriate diagnosis of infants. Several algorithms can be used to define early infection and the potential timing of acquisition of infection that combine different assays and timing of specimens. The use of virologic assays, including HIV DNA PCR and HIV RNA detection methods and culture, can define and rule out infection in infants less than 18 months of age. Serologic diagnostic methods, including HIV ELISA, immunofluorescence, and western blot assays, can be used to diagnose infants more than 18 months of age, when transplacental antibody has disappeared in uninfected HIV-exposed infants. The challenge of the early and accurate diagnosis of perinatally HIV-exposed infants is the use of new assays to detect different HIV subtype infections that are prevalent in developing countries. Rapid, simple, and inexpensive serologic and virologic assays are being developed for worldwide use.

Use of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin in HIV type 1-infected children (Pediatric AIDS clinical trials group protocol 273).

The clinical, immunologic, and virologic effects and the pharmacokinetics of human immunodeficiency virus (HIV) human hyperimmune immunoglobulin (HIVIG) were assessed in 30 HIV-infected children aged 2-11 years. All had moderately advanced disease with an immune complex-dissociated (ICD) p24 antigen >70 pg/mL and were on stable antiviral therapy. Three groups of 10 children received 6 monthly infusions of 200, 400, or 800 mg/kg of HIVIG, and serial immunologic and virologic assays were performed. HIVIG doses as high as 800 mg/kg were safe and well tolerated. The half-life of HIVIG, determined by serial p24 antibody titers, was 13-16 days, the volume of distribution was 102-113 mL/kg, and clearance was 5.6-6.0 mL/kg/day. Plasma ICD p24 decreased during the infusions, but CD4 cell levels, plasma RNA copy number, cellular virus, immunoglobulin levels, and neutralizing antibody titers were minimally affected by the infusions. Clinical status did not change during the 6-month infusion and 3-month follow-up periods.

Alterations in cardiac and pulmonary function in pediatric rapid human immunodeficiency virus type 1 disease progressors. Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted Human Immunodeficiency Virus Study Group.

OBJECTIVE: Infants with human immunodeficiency virus type 1 (HIV-1) can be divided into rapid progressors (RPs) and non-rapid progressors (non-RPs) based on symptoms and immunologic status, but detailed information about cardiac and pulmonary function in RP and non-RP children needs to be adequately described. METHODOLOGY: Cardiac, pulmonary, and immunologic data and HIV-1 RNA burden were periodically measured in 3 groups: group I, 205 vertically infected children enrolled from 1990 to 1994 and followed through 1996; group II, a prospectively studied cohort enrolled at birth that included 93 infected (group IIa); and 463 noninfected infants (group IIb). RESULTS: Mean respiratory rates were generally higher in group IIa RP than non-RP children throughout the period of follow-up, achieving statistical signifance at 1 month, 12 months, 24 months, 30 months, and 48 months of follow-up. Non-RP and group IIb (HIV-uninfected children) had similar mean respiratory rates from birth to 5 years of age. Significant differences in mean respiratory rates were found between group I RP and non-RP at 7 age intervals over the first 6 years of life. Mean respiratory rates were higher in RP than in non-RP at <1 year, 2.0 years, 2.5 years, 3.0 years, 3. 5 years, 4.0 years, and 6.0 years of age. Mean heart rates in group IIa RP, non-RP, and group IIb differed at every age. Rapid progressors had higher mean heart rates than non-RP at all ages through 24 months. Mean heart rates at 30 months through 60 months of age were similar for RP and non-RP children. Non-RP children had higher mean heart rates than did group IIb at 8 months, 24 months, 36 months, 42 months, 48 months, 54 months, and 60 months of age. In group I, RP had higher mean heart rates than non-RP at 2.0 years, 2.5 years, 3.0 years, and 4.0 years of age. After 4 years of age, the non-RP and RP had similar mean heart rates. Mean fractional shortening differed between the 3 group II subsets (RP, non-RP, and IIb) at 4, 8, 12, 16, and 20 months of age. Although mean fractional shortening was lower in RP than in non-RP in group II at all time points between 1 and 20 months, the mean fractional shortening was significantly lower in RP only at 8 months when restricting the statistical comparisons to the 2 HIV-infected groups (RP and non-RP). Mean fractional shortening increased in the first 8 months of life followed by a gradual decline through 5 years of age among group IIb children. No significant differences among the 3 groups in mean fractional shortening were detected after 20 months of age. In group I, differences between RP and non-RP in mean fractional shortening were detected at 1.5, 2.0, 2.5, and 3.0 years of age. After 3 years of age, group means for fractional shortening in RP and non-RP did not differ. Because of the limited data from the first months of the group I patients, it could not be determined whether this group experienced the gradual early rise in mean fractional shortening seen in the group II infants. In group IIa, RP had more clinical (eg, oxygen saturation <96%) and chest radiographic abnormalities (eg, cardiomegaly) at 18 months of life. RP also had significantly higher 5-year cumulative mortality than non-RP, higher HIV-1 viral burdens than non-RP, and lower CD8(+) T-cell counts. CONCLUSIONS: Rapid disease progression in HIV-1- infected infants is associated with significant alterations in heart and lung function: increased respiratory rate, increased heart rate, and decreased fractional shortening. The same children exhibited the anticipated significantly increased 5-year cumulative mortality, increased serum HIV-1 RNA load, and decreased CD8(+) (cytotoxic) T-cell counts. Measurements of cardiopulmonary function in HIV-1-infected children seem to be useful in the total assessment of HIV-1 disease progression.

Treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate.

An open-label study was conducted of nelfinavir mesylate, given with reverse transcriptase inhibitors to human immunodeficiency virus 1 (HIV-1)-infected infants and children 3 months to 13 years of age. Doses of nelfinavir mesylate of 20-30 mg/kg yielded drug exposures comparable to those seen in adults. The drug was well tolerated; mild diarrhea was the primary toxic effect observed. Seventy-one percent (39) of the 55 evaluable subjects had an initial decrease in plasma HIV-1 RNA, of at least 0.7 log10 copies/mL; suppression of plasma HIV-1 RNA levels to < 400 copies/mL was observed in 15. Children who began taking at least one new reverse transcriptase inhibitor near the time when nelfinavir mesylate was started, and those with a > or = 24% proportion of CD4 lymphocytes, had a greater chance of achieving and maintaining a decline in plasma HIV-1 RNA to < 400 copies/mL. Suppression of viremia was achieved in children as young as 3 months of age.

Primary HIV infection of infants: the effects of somatic growth on lymphocyte and virus dynamics.

Acute HIV infection is characterized by the appearance of high concentrations of virus in the peripheral blood. In adults, this high-level viremia spontaneously abates after several weeks. In contrast, after perinatal infection of infants, blood virus levels remain high for many months, during which the concentration of circulating CD4+ lymphocytes remains well above normal values for adults. Here we suggest an explanation for these differences, based on developmental factors including somatic growth and immunological ontogeny. Flow cytometric analysis revealed that at birth the thymus contains elevated levels of mature T lymphocytes, compared to the thymus after 3 months of age. A mathematical model is proposed incorporating immunological and virological data from longitudinally evaluated infants who acquired infection at the time of birth. This model explains the pattern of high-level viremia in infants as resulting from the replication of HIV within the progressively expanding lymphoid cell mass.

Treatment of mucocutaneous herpes simplex virus infections unresponsive to acyclovir with topical foscarnet cream in AIDS patients: a phase I/II study.

The efficacy and toxicity of foscarnet cream for the treatment of mucocutaneous herpes simplex virus lesions or lesions that were clinically unresponsive to systemic acyclovir treatment (median, 30.5 days) in AIDS patients were studied in a phase I/II, open-label, nonrandomized multicenter trial. In the study, 20 patients with advanced stages of AIDS were treated with foscarnet 1% cream five times a day for a mean duration of 34.5 days. Response of index lesions (n = 20) was judged to be completely healed (8 lesions), excellent (4 lesions), or good (1 lesion) in 65% of lesions. The median time to first negative herpes simplex virus culture of index lesion was 8 days. Among 15 patients with pain at baseline, 11 had complete resolution of pain and 2 had at least a 50% reduction. Clinical adverse events included skin ulceration (4 patients), application site reactions (3 patients), fever (3 patients), and headache (3 patients). Five (25%) patients developed new lesions due to herpes simplex virus at sites other than those being treated topically while enrolled in the study. Topical foscarnet 1% cream appears to be a safe and effective treatment for acyclovir-unresponsive mucocutaneous herpes simplex virus infection in AIDS patients.

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.

Natural history of primary Epstein-Barr virus infection in children of mothers infected with human immunodeficiency virus type 1.

The natural history of Epstein-Barr virus (EBV) infection in 556 infants born to 517 human immunodeficiency virus (HIV) type 1-infected mothers was studied in a prospective, multicenter, cohort study. HIV-1-infected children had a cumulative EBV infection rate similar to HIV-1-uninfected children at age 3 years (77.8% vs. 84. 9%) but had more frequent oropharyngeal EBV shedding (50.4% vs. 28. 2%; P<.001). The probability of shedding decreased with longer time from EBV seroconversion and was similar to that of HIV-1-uninfected children 3 years after seroconversion. HIV-1-infected children identified as rapid progressors shed EBV more frequently than nonrapid progressors (69.4% vs.41.0%; P=.01). HIV-1-infected children with EBV infection had higher mean CD8 cell counts. EBV infection did not have an independent effect on mean CD4 cell counts, percent CD4, IgG levels, HIV-1 RNA levels, lymphadenopathy, hepatomegaly, or splenomegaly. Early EBV infection is common in children born to HIV-1-infected mothers. Children with rapidly progressive HIV-1 disease have more frequent EBV shedding.

The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1--a meta-analysis of 15 prospective cohort studies.

BACKGROUND: To evaluate the relation between elective cesarean section and vertical transmission of human immunodeficiency virus type 1 (HIV-1), we performed a meta-analysis using data on individual patients from 15 prospective cohort studies. METHODS: North American and European studies of at least 100 mother-child pairs were included in the meta-analysis. Uniform definitions of modes of delivery were used. Elective cesarean sections were defined as those performed before onset of labor and rupture of membranes. Multivariate logistic-regression analysis was used to adjust for other factors known to be associated with vertical transmission. RESULTS: The primary analysis included data on 8533 mother-child pairs. After adjustment for receipt of antiretroviral therapy, maternal stage of disease, and infant birth weight, the likelihood of vertical transmission of HIV-1 was decreased by approximately 50 percent with elective cesarean section, as compared with other modes of delivery (adjusted odds ratio, 0.43; 95 percent confidence interval, 0.33 to 0.56). The results were similar when the study population was limited to those with rupture of membranes shortly before delivery. The likelihood of transmission was reduced by approximately 87 percent with both elective cesarean section and receipt of antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, as compared with other modes of delivery and the absence of therapy (adjusted odds ratio, 0.13; 95 percent confidence interval, 0.09 to 0.19). Among mother-child pairs receiving antiretroviral therapy during the prenatal, intrapartum, and neonatal periods, rates of vertical transmission were 2.0 percent among the 196 mothers who underwent elective cesarean section and 7.3 percent among the 1255 mothers with other modes of delivery. CONCLUSIONS: The results of this meta-analysis suggest that elective cesarean section reduces the risk of transmission of HIV-1 from mother to child independently of the effects of treatment with zidovudine.

Early prognostic indicators in primary perinatal human immunodeficiency virus type 1 infection: importance of viral RNA and the timing of transmission on long-term outcome.

The time of perinatal human immunodeficiency virus type 1 (HIV-1) transmission and the pattern of early plasma viremia as predictors of disease progression were evaluated in infected infants followed from birth. Cox proportional hazards modeling demonstrated that a 1-log higher HIV-1 RNA copy number at birth was associated with a 40% increase in the relative hazard (RH) of developing CDC class A or B symptoms (P = .004), a 60% increase in developing AIDS (P = .01), and an 80% increase in the of risk death (P = .023) over the follow-up period of up to 8 years. The peak HIV-1 RNA copy number for infants during primary viremia was also predictive of progression to AIDS (RH, 9.9; 95% confidence interval [95% CI], 1.8-54.1; P = .008) and death (RH, 6.9; 95% CI, 1.1-43.8; P = .04). The results indicate that high levels of HIV-1 RNA at birth and during primary viremia are associated with early onset of symptoms and rapid disease progression to AIDS and death in perinatally infected children.