RESUMO
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.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Lamivudina/uso terapêutico , Nelfinavir/efeitos adversos , Nelfinavir/farmacocinética , Zidovudina/uso terapêutico , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade , Análise Química do Sangue , Contagem de Linfócito CD4 , Cromatografia Líquida de Alta Pressão , Feminino , Sangue Fetal/química , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/uso terapêutico , Humanos , Nelfinavir/administração & dosagem , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , RNA Viral/sangue , Carga ViralRESUMO
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.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Zidovudina/administração & dosagem , Administração Oral , Adulto , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Estudos de Coortes , Feminino , Infecções por HIV/transmissão , Humanos , Lactente , Recém-Nascido , Trabalho de Parto/efeitos dos fármacos , Gravidez , Zidovudina/farmacocinéticaRESUMO
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.
Assuntos
Estatura/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Transtornos do Crescimento/prevenção & controle , Infecções por HIV/tratamento farmacológico , Inibidores de Proteases/farmacologia , Adolescente , Fármacos Anti-HIV/uso terapêutico , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Transtornos do Crescimento/etiologia , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Lactente , Masculino , Projetos Piloto , Inibidores de Proteases/uso terapêutico , Estudos Retrospectivos , Carga ViralRESUMO
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.
Assuntos
Variação Genética , Infecções por HIV/transmissão , HIV-1/genética , Transmissão Vertical de Doenças Infecciosas , Complicações Infecciosas na Gravidez/virologia , Evolução Molecular , Feminino , Doenças Fetais/virologia , Produtos do Gene env/genética , Genes env , Infecções por HIV/virologia , HIV-1/classificação , Análise Heteroduplex , Humanos , Recém-Nascido , Leucócitos Mononucleares/virologia , Reação em Cadeia da Polimerase , Gravidez , RNA Viral/sangueRESUMO
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.
Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/virologia , HIV-1 , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Replicação Viral , Adolescente , Diferenciação Celular , Criança , Técnicas de Cocultura , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Imunofenotipagem , Lactente , Lamivudina/administração & dosagem , Lamivudina/uso terapêutico , Leucócitos Mononucleares/virologia , Masculino , Nelfinavir/administração & dosagem , Nelfinavir/uso terapêutico , Estudos Prospectivos , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/uso terapêutico , Estavudina/administração & dosagem , Estavudina/uso terapêutico , Carga Viral , Zidovudina/administração & dosagem , Zidovudina/uso terapêuticoRESUMO
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.
Assuntos
Infecções por HIV/diagnóstico , Reação em Cadeia da Polimerase , Criança , DNA Viral/análise , Doenças Fetais/virologia , HIV/genética , Proteína do Núcleo p24 do HIV , Infecções por HIV/transmissão , Humanos , Transmissão Vertical de Doenças Infecciosas , Reação em Cadeia da Polimerase/métodos , Sensibilidade e EspecificidadeRESUMO
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.
Assuntos
Anticorpos Anti-HIV/imunologia , Infecções por HIV/terapia , HIV-1/fisiologia , Imunização Passiva , Imunoglobulinas Intravenosas/uso terapêutico , Células Cultivadas , Criança , Pré-Escolar , Feminino , Proteína do Núcleo p24 do HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Imunoglobulinas/sangue , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/farmacocinética , Leucócitos Mononucleares , Contagem de Linfócitos , Masculino , Testes de Neutralização , RNA Viral/sangue , Subpopulações de Linfócitos T/imunologia , Resultado do TratamentoRESUMO
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.
Assuntos
Infecções por HIV/imunologia , Adulto , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/sangue , Infecções por HIV/transmissão , Humanos , Lactente , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Contagem de Linfócitos , Linfócitos/virologia , Modelos Imunológicos , Carga Viral , Viremia/imunologia , Replicação ViralRESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Soropositividade para HIV/imunologia , Soropositividade para HIV/transmissão , Transmissão Vertical de Doenças Infecciosas , Terceiro Trimestre da Gravidez/imunologia , Complexo CD3/isolamento & purificação , Antígenos CD4/isolamento & purificação , Relação CD4-CD8 , Linfócitos T CD4-Positivos/virologia , Feminino , Proteína do Núcleo p24 do HIV/sangue , Soropositividade para HIV/virologia , Humanos , Neopterina/sangue , Gravidez , RNA Viral/sangue , Fator de Necrose Tumoral alfa/análise , Microglobulina beta-2/análiseAssuntos
Inibidores da Protease de HIV/uso terapêutico , Síndrome de Emaciação por Infecção pelo HIV/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Estatura , Síndrome de Emaciação por Infecção pelo HIV/metabolismo , HIV-1 , Humanos , Masculino , Inibidores da Transcriptase Reversa/uso terapêutico , Resultado do Tratamento , Aumento de PesoRESUMO
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.
Assuntos
Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1 , RNA Viral/sangue , Carga Viral , Síndrome da Imunodeficiência Adquirida/fisiopatologia , Síndrome da Imunodeficiência Adquirida/virologia , Idade de Início , Fármacos Anti-HIV/uso terapêutico , Criança , Pré-Escolar , Seguimentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Prognóstico , Estudos Prospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Fatores de Tempo , Zidovudina/uso terapêuticoRESUMO
Human immunodeficiency virus type 1 (HIV-1) RNA levels in plasma are currently widely used clinically for prognostication and in monitoring antiretroviral therapy. Accurate and reproducible results are critical for patient management. To determine the effects of specimen collection and handling procedures on quantitative measurement of HIV-1 RNA, we compared anticoagulants and sample processing times. Whole blood was collected from 20 HIV-1-infected patients in EDTA, acid citrate dextrose (ACD), and heparin tubes, aliquoted, and stored at room temperature. Plasma was separated from whole-blood aliquots prepared at < or =1, 3, 6, 24, and 48 h postcollection and then stored at -70 degrees C until use. HIV-1 RNA levels were determined by the AMPLICOR HIV-1 MONITOR assay. Heparinized plasma samples, which were pretreated with heparinase prior to analysis, had the lowest baseline HIV-1 RNA levels. In the first 6 h, HIV-1 RNA levels decreased by 10, 20, and 31% in EDTA, ACD, and heparin tubes, respectively. From 6 to 48 h postcollection, HIV-1 RNA levels decreased in all anticoagulants, albeit at a slower, more consistent rate. Our results indicate that EDTA should be the anticoagulant of choice for plasma HIV-1 RNA measurement by reverse transcriptase PCR, but ACD tubes are acceptable if the plasma is separated within 6 h of blood collection. Caution must be applied in the interpretation of absolute HIV-1 RNA copy number values obtained with suboptimal specimen collection and processing procedures.
Assuntos
Coleta de Amostras Sanguíneas , HIV-1/genética , Reação em Cadeia da Polimerase , RNA Viral/sangue , Adolescente , Adulto , Anticoagulantes/farmacologia , Criança , Pré-Escolar , HumanosRESUMO
Apoptosis continues to be controversial in human immunodeficiency virus (HIV)-induced pathogenesis. To investigate whether apoptosis occurs with HIV exposure with or without subsequent infection, levels of apoptosis were measured in cord blood lymphocytes (CBL) from seven newborns delivered to HIV-infected mothers and seven normal, unexposed newborns. Live cells were costained with antibodies to cell surface markers and the DNA dye 7-amino actinomycin D to immunophenotype apoptotic CBL subsets. Apoptosis was measured in fresh and cultured CBL in the presence and absence of CD3 T-cell receptor stimulation. Compared to the CD4+ CBL from HIV-unexposed newborns, CD4+ CBL from six HIV-exposed, noninfected newborns demonstrated significantly greater apoptosis after overnight culture even in the absence of CD3 stimulation. Compared to HIV-unexposed controls, CD8+ CBL from the six HIV-exposed newborns also demonstrated increased levels of apoptosis after overnight culture without stimulation. The one HIV-infected newborn in this study showed the highest levels of CD4+ and CD8+ apoptotic CBL. The data suggest that levels of apoptosis are increased in infants in association with HIV infection. Furthermore, CD4+ and CD8+ cord blood lymphocytes from HIV-exposed infants behaved differently than T lymphocytes from either normal, unexposed infants or an HIV-infected infant. These results suggest that exposure to HIV or HIV-induced factors increases the levels of apoptosis in CBL.
Assuntos
Apoptose/imunologia , Sangue Fetal/imunologia , Infecções por HIV/sangue , Infecções por HIV/congênito , Linfócitos T/imunologia , Linfócitos T/patologia , Adulto , Feminino , Infecções por HIV/imunologia , Humanos , Recém-Nascido , Transmissão Vertical de Doenças InfecciosasRESUMO
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.
Assuntos
Infecções por HIV/complicações , Infecções por HIV/imunologia , Complicações Infecciosas na Gravidez/imunologia , Gravidez/imunologia , Biopterinas/análogos & derivados , Biopterinas/sangue , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Ativação Linfocitária , Neopterina , Fenótipo , Período Pós-Parto/imunologia , Subpopulações de Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Microglobulina beta-2/biossínteseRESUMO
To gain insight into the protective effects of the three components of the zidovudine regimen used in AIDS Clinical Trial Group (ACTG) 076 on mother-to-infant transmission of human immunodeficiency virus (HIV) type 1, 188 zidovudine-treated women and their untreated infants from five HIV-1 obstetric centers were retrospectively studied. The overall rate of mother-to-infant transmission was 12.3% (95% confidence interval [CI], 7.9%-18.0%). When the 38 women with <200 CD4 cells/microL were excluded, the mother-to-infant transmission rate was 8.8% (95% CI, 4.6%-14.8%). This rate compares favorably with the 8.3% transmission in the zidovudine arm of the ACTG 076 study. Apart from low (<200/microL) maternal CD4 cells (P = .016), no factors, including the duration of zidovudine therapy during gestation and intravenous administration of zidovudine during labor, affected the rate of mother-to-infant transmission. These findings suggest that antenatal oral zidovudine may be as effective as antenatal oral plus intravenous zidovudine during labor and the three-component ACTG 076 regimen in decreasing mother-to-infant HIV-1 transmission.
Assuntos
Síndrome da Imunodeficiência Adquirida/prevenção & controle , Fármacos Anti-HIV/uso terapêutico , HIV-1 , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Zidovudina/uso terapêutico , Adulto , Contagem de Linfócito CD4 , Feminino , Humanos , Gravidez , Estudos RetrospectivosRESUMO
The rate of development of disease varies considerably among human immunodeficiency virus type 1 (HIV-1)-infected children. The reasons for these observed differences are not clearly understood but most probably depend on the dynamic interplay between the HIV-1 quasispecies virus population and the immune constraints imposed by the host. To study the relationship between disease progression and genetic diversity, we analyzed the evolution of viral sequences within six perinatally infected children by examining proviral sequences spanning the C2 through V5 regions of the viral envelope gene by PCR of blood samples obtained at sequential visits. PCR product DNAs from four sample time points per child were cloned, and 10 to 13 clones from each sample were sequenced. Greater genetic distances relative to the time of infection were found for children with low virion-associated RNA burdens and slow progression to disease relative to those found for children with high virion-associated RNA burdens and rapid progression to disease. The greater branch lengths observed in the phylogenetic reconstructions correlated with a higher accumulation rate of nonsynonymous base substitutions per potential nonsynonymous site, consistent with positive selection for change rather than a difference in replication kinetics. Viral sequences from children with slow progression to disease also showed a tendency to form clusters that associated with different sampling times. These progressive shifts in the viral population were not found in viral sequences from children with rapid progression to disease. Therefore, despite the HIV-1 quasispecies being a diverse, rapidly evolving, and competing population of genetic variants, different rates of genetic evolution could be found under different selective constraints. These data suggest that the evolutionary dynamics exhibited by the HIV-1 quasispecies virus populations are compatible with a Darwinian system evolving under the constraints of natural selection.
Assuntos
Genes env , Infecções por HIV/virologia , HIV-1/genética , Sequência de Aminoácidos , Sequência de Bases , Linhagem Celular Transformada , Criança , Pré-Escolar , DNA Viral , Progressão da Doença , Evolução Molecular , Feminino , Variação Genética , Proteína gp120 do Envelope de HIV/genética , Infecções por HIV/sangue , HIV-1/classificação , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Fragmentos de Peptídeos/genética , Fenótipo , Filogenia , Homologia de Sequência de AminoácidosRESUMO
OBJECTIVES: To review recent advances and current understanding of risk factors associated with perinatal HIV-1 transmission, the critical gaps in our knowledge, and current and future approaches to prevention of transmission. FACTORS INFLUENCING MOTHER-TO-CHILD TRANSMISSION: Perinatal HIV transmission is multifactorial and all potential risk factors must be considered in the context of the timing of transmission in utero, at birth or after birth by breastfeeding. Major factors that have been associated with increased transmission include a high maternal virus load, decreased CD4+ count, lack of HIV neutralizing antibody, advanced clinical disease, primary infection, first-born twins, and obstetric factors including chorioamnionitis, mode of delivery and more than 4 h of ruptured membranes. There are still significant gaps in our knowledge to explain the known variables in transmission, including the fact that 70-80% of infants born of HIV-infected mothers escape infection. APPROACHES TO REDUCE PERINATAL HIV-1 INFECTION: One of the major advances in prevention of perinatal transmission was the AIDS Clinical Trials Group 076 trial, which showed that antiretroviral therapy with zidovudine given to the mother during pregnancy and delivery, and to the infant, reduced transmission by 70%. Current approaches to further reduce transmission and provide practical application worldwide are discussed, including combined potent antivirals, local approaches and immune-based therapy given to the mother and/or infant. CONCLUSIONS: There is reason for optimism for the potential to further reduce perinatal transmission to a level of less than 2%. The challenge will be to increase education and awareness worldwide in order to translate scientific advances into practical approaches that will be applicable in both industrialized and non-industrialized countries.
Assuntos
Infecções por HIV/transmissão , HIV-1 , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Ensaios Clínicos como Assunto , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/virologia , Fatores de RiscoRESUMO
The current dosage of zidovudine for children is 180 mg/m2 every 6 h. To investigate whether a lower dosage was equally effective, human immunodeficiency virus (HIV)-infected children (3 months to 12 years) with mild to moderate symptoms were randomly assigned to receive either high-dose (180 mg/m2/dose) or low-dose (90 mg/m2/dose) zidovudine (double-blind). Treatments were compared with respect to neuropsychologic function, survival, clinical and laboratory evidence of disease progression, and safety and tolerance. Four hundred twenty-six HIV-infected children were enrolled; median time for receipt of study drug was 35 months. Zidovudine in either dose was well tolerated, with no difference in efficacy or tolerance by treatment group using any clinical or laboratory parameter. In children with mild to moderate disease, a reduction of zidovudine to 90 mg/m2/dose will result in substantial cost savings and should be the recommended dose.
Assuntos
Antivirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Zidovudina/administração & dosagem , Complexo AIDS Demência/tratamento farmacológico , Complexo AIDS Demência/mortalidade , Complexo AIDS Demência/psicologia , Antivirais/efeitos adversos , Criança , Pré-Escolar , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Feminino , Proteína do Núcleo p24 do HIV/sangue , Infecções por HIV/mortalidade , Infecções por HIV/psicologia , Humanos , Lactente , Fígado/fisiopatologia , Masculino , Testes Neuropsicológicos , Zidovudina/efeitos adversosRESUMO
The presence of human immunodeficiency virus (HIV) in cervicovaginal secretions (CVS) may be a risk factor for perinatal transmission. CVS of 25 women were evaluated for HIV and HIV mucosal antibodies; 16 infants had gastric aspirates cultured. Maternal plasma HIV was measured by quantitative RNA polymerase chain reaction. Seven women (28%), 4 of 19 pregnant and 3 of 7 nonpregnant, had HIV in CVS. Two of 4 HIV-infected neonates had positive gastric aspirate cultures. The 4 pregnant women with HIV in CVS did not transmit infection. HIV-specific secretory IgA was present in CVS of 10 (42%) of 24 women (in 3 cases concurrent with virus). Plasma HIV RNA levels at delivery were higher among transmitters (mean, 68,921 copies/mL) than nontransmitters (mean, 9457 copies/mL). Intermittent HIV shedding in CVS occurred despite mucosal antibodies and did not necessarily correlate with maternal plasma HIV RNA copy number. The presence of HIV in newborn gastric aspirates may be a risk factor for perinatal infection.