RESUMO
PURPOSE: Antiretrovirals (ARVs) are life-saving drugs used for the treatment and prevention of HIV infection and antiviral drugs (AVs) for the treatment of chronic HBV infection. ARVs have proven highly effective in reducing perinatal HIV transmission, however the risk of birth defects from prenatal exposure to ARVs/AVs is an ongoing concern. The Antiretroviral Pregnancy Registry (APR), an international, prospective exposure-registration cohort study, monitors ARV and AV use in pregnancy for early signals of teratogenicity. This communication reports results of 30-years' experience of ARV/AV exposure during pregnancy and lessons learned through continuous quality improvement. METHODS AND RESULTS: Birth defect prevalence is estimated and compared to internal and external groups. Statistical inference is based on exact methods for binomial proportions. Between 2006 and 2023, cumulative enrollment more than tripled from 6893 to 25 960 pregnancies and ARVs/AVs monitored increased from 29 to 222. Through January 2023, there were 21 636 live births and 631 outcomes with birth defects, for overall prevalence of 2.9/100 live births (95% CI 2.7, 3.2). The birth defect prevalence was 3.0% (95% CI 2.7%, 3.3%) among first trimester exposures and 2.8% (95% CI 2.5%, 3.2%) among second/third trimester exposures (prevalence ratio 1.04 [95% CI 0.89, 1.21]). CONCLUSIONS: Birth defect prevalence is not statistically significantly different between first trimester ARV/AV pregnancy exposures compared to second/third trimester exposures and is also not different from two population-based surveillance systems: 2.72/100 live births reported in the Metropolitan Atlanta Congenital Defects Program (MACDP); and 4.17/100 live births from the Texas Birth Defects Registry (TBDR).
Assuntos
Anormalidades Induzidas por Medicamentos , Infecções por HIV , Complicações Infecciosas na Gravidez , Sistema de Registros , Humanos , Gravidez , Feminino , Estudos Prospectivos , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/epidemiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Adulto , Prevalência , Recém-Nascido , Antirretrovirais/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Adulto Jovem , Anormalidades Congênitas/epidemiologia , Estudos de CoortesAssuntos
Infecções por HIV/tratamento farmacológico , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Proteção da Criança , Crianças Órfãs , Pré-Escolar , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos , Recém-Nascido , Bem-Estar Materno , GravidezRESUMO
As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.
Assuntos
Feto/imunologia , Tolerância Imunológica , Isoantígenos/imunologia , Linfonodos/imunologia , Troca Materno-Fetal , Linfócitos T Reguladores/imunologia , Adolescente , Células Apresentadoras de Antígenos/imunologia , Células Cultivadas , Criança , Quimerismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Humanos , Linfonodos/citologia , Ativação Linfocitária , Gravidez , Tolerância a Antígenos Próprios , Timo/imunologia , Fatores de Crescimento Transformadores/genética , Fatores de Crescimento Transformadores/metabolismo , Fatores de Necrose Tumoral/genética , Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: Protease inhibitor (PI)-based combination antiretroviral therapy is often indicated for treatment of maternal HIV disease, but little is known about PI pharmacokinetics during pregnancy. Increased cytochrome P450 activity may affect the disposition of PI and decrease drug exposure. METHODS: Steady-state PI pharmacokinetics, measured by the area under the plasma concentration versus time curve (AUC(tau)), were evaluated in women on stable antiretroviral regimens containing nelfinavir (n = 9) or indinavir (n = 4) with or without ritonavir (n = 2) during the second and third trimesters of pregnancy and postpartum. Cytochrome P450 activity was assessed by measuring the urine 6 beta-hydroxycortisol to cortisol ratio (6 beta-OHF/F). RESULTS: AUC(tau) in women on indinavir alone decreased and 6 beta-OHF/F ratios increased during pregnancy compared with postpartum control values (n = 2). Nelfinavir results demonstrated no clear change and were highly variable. CONCLUSIONS: The results for indinavir suggest that metabolic induction occurs during pregnancy, which apparently resolves spontaneously postpartum. This may warrant dosage adjustment during pregnancy. This induction is offset by concomitant use of ritonavir. Nelfinavir results were variable and, therefore, the impact of pregnancy on nelfinavir disposition was not fully determined.
Assuntos
Infecções por HIV/sangue , Inibidores da Protease de HIV/sangue , HIV-1 , Hidrocortisona/análogos & derivados , Complicações Infecciosas na Gravidez/sangue , Adulto , Feminino , Idade Gestacional , Infecções por HIV/urina , Infecções por HIV/virologia , Humanos , Hidrocortisona/urina , Indinavir/sangue , Nelfinavir/sangue , Gravidez , Complicações Infecciosas na Gravidez/urina , Complicações Infecciosas na Gravidez/virologia , Carga ViralRESUMO
The adaptive immune response of human CD8 T cells to invading pathogens involves the differentiation of naive cells into memory and effector cells. However, the lineage relationship between memory and effector cells and the differentiation of CD8 T cells into distinct subsets of effector cell subpopulations are subjects of considerable debate. CD7 identifies three populations of CD8 T cells: CD7 high (CD7(high)), low (CD7(low)), and negative (CD7(neg)) that translate into subsets with distinct functional properties. The CD7(high) subset contains naive and memory cells and the CD7(low) and CD7(neg) subsets contain effector cells. The effector cells can functionally be divided into cytokine-secreting effector CD8 T cells and lytic effector CD8 T cells. These data provide a model of human CD8 T cell differentiation in which specialized distinct subpopulations can be identified by expression of CD7.