700 research outputs found

    Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States

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    "These recommendations update the February 4,2002, guidelines developed by the Public Health Service for the use of zidovudine (ZDV) to reduce the risk for perinatal human immunodeficiency virus type 1 (HIV-1) transmission. This report provides healthcare providers with information for discussion with HIV-1-infected pregnant women to enable such women to make an informed decision regarding the use of antiretroviral drugs during pregnancy and use of elective cesarean delivery to reduce perinatal HIV-1 transmission. Various circumstances that commonly occur in clinical practice are presented, and the factors influencing treatment considerations are highlighted in this report. The Perinatal HIV Guidelines Working Group recognizes that strategies to prevent perinatal transmission and concepts related to management of HIV disease in pregnant women are rapidly evolving and will continually review new data and provide regular updates to the guidelines. The most recent information is available from the HIV/AIDS Treatment Information Service (available at http.//www.hivatis.org). In February 1994, the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 documented that ZDV chemoprophylaxis could reduce perinatal HIV-1 transmission by nearly 70%. Epidemiologic data have since confirmed the efficacy of ZDV for reduction of perinatal transmission and have extended this efficacy to children of women with advanced disease, low CD4+ T-lymphocyte counts, and prior ZDV therapy. Additionally, substantial advances have been made in the understanding of the pathogenesis of HIV-1 infection and in the treatment and monitoring of persons with HIV-1 disease. These advances have resulted in changes in standard antiretroviral therapy for HIV-1-infected adults. More aggressive combination drug regimens that maximally suppress viral replication are now recommended. Although considerations associated with pregnancy may affect decisions regarding timing and choice of therapy pregnancy is not a reason to defer standard therapy. Use of antiretroviral drugs in pregnancy requires unique considerations, including the possible need to alter dosage as a result of physiologic changes associated with pregnancy the potential for adverse short- or long-term effects on the fetus and newborn, and the effectiveness of the drugs in reducing the risk for perinatal transmission. Data to address many of these considerations are not yet available. Therefore, offering antiretroviral therapy to HIV-1-infected women during pregnancy, whether primarily for HIV-1 infection, for reduction of perinatal transmission, or for both purposes, should be accompanied by a discussion of the known and unknown short- and long-term benefits and risks of such therapy to infected women and their infants. Standard antiretroviral therapy should be discussed with and offered to HIV-1-infected pregnant women. Additionally, to prevent perinatal transmission, ZDV chemoprophylaxis should be incorporated into the antiretroviral regimen." - p. 1prepared by Lynne M. Mofenson."The material in this report originated in the National Center for HIV, STD, and TB Prevention, Harold W. Jaffe, M.D., Director; Division of HIV/AIDS Prevention--Surveillance and Epidemiology, Robert S. Janssen, M.D., Director. " - p. 1Includes bibliographical references (p. 32-38).Centers for Disease Control and Prevention. U.S. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions To Reduce Perinatal HIV-1 Transmission in the United States. MMWR 2002;51(No. RR-18).12489844Infectious DiseaseTreatment and InterventionSupersede

    Mucosal Herpes Immunity and Immunopathology to Ocular and Genital Herpes Simplex Virus Infections

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    Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 & HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed

    Use and safety of antiretrovirals in pregnancy: filling the gap between regulatory recommendation and clinical practice

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    Antiretroviral therapy (ART) contributed enormously to the reduction of HIV vertical transmission rate whilst treating maternal disease. Nowadays the proportion of women living with HIV (WLWH) knowing their HIV status and conceiving whilst being on effective combination of antiretroviral agents (ARVs) has stabilized at high level. However, early treatment initiation means prolonged infants in utero exposure to ARVs and consequent potential toxic effect to the developing embryo (i.e. congenital anomalies) and adverse pregnancy outcomes (including stillbirths and preterm delivery). Aim of this thesis was to evaluate safe and effective use of ARVs in pregnant WLWH, to evaluate pregnancy outcomes - with a main focus on detection of congenital anomalies (CAs), and to assess whether early exposure to combinations of ARV was associated with increased risk for CAs. Furthermore, a gap-analysis evaluating real-world use of ARVs and regulatory recommendation for the safe and effective use of ARV agents was conducted. I used data from the National Surveillance of HIV in Pregnancy and Childhood (NSHPC), an ongoing surveillance study of all pregnancies in WLWH and their infants across the UK/Ireland. The analysis included data on pregnancies reported to the NSHPC from 2008 to 2018. For the gap-analysis, I have assessed publicly available data from the European Medicines Agency through their website as source for regulatory recommendations, while the NSHPC was the data source for the real-world use of ARV agents. This thesis identified three main findings: an increased earlier use in pregnancy and from before conception of combinations of ARV (34.5%, 412/1,194 of pregnancies in 2008 started ART prior conception vs 80.6%, 478/593 in 2018) and a wider range of available ARV combinations for pregnant WLWH in the UK between 2008-2018. A gap between real-world use of ART and regulatory/clinical recommendations for pregnant WLWH, with regulatory recommendation “catching up” with real-world use of ARVs and only in recent years timely amended their guidelines whenever a safety signal from the real-world evidence has been detected. No evidence of increased risk of CAs in infants with in utero exposure to ART with an overall CA prevalence of 2.03% (95%CI 1.77-2.31, 227 CA/111,197 liveborn infants) nor of any particular patterns of CAs affecting the same organs/systems by the rule of three

    Antiretroviral drug resistant HIV-1 in women and children living in Honduras

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    Antiretroviral therapy (ART) in HIV infected pregnant women contributes to the prevention of HIV transmission to the newborn. However, as ART can also induce HIV drug resistance during suboptimal levels of virological suppression a major concern is the subsequent risk for transmitted drug resistant (TDR) virus to the child. In Honduras and Belize, like in many other countries around the world, mono-therapy was used to prevent mother-to-child transmission of HIV-1 (MTCT) until relatively recently when it was changed to a more effective combination antiretroviral therapy (cART). Prior to this study there was no information about antiretroviral drug resistance in HIV-1 infected women and children in Honduras and Belize, and limited data other from parts of Latin America. The first aim (Paper I) was to evaluate the prevalence of drug resistance in HIV-1 infected infants born in Honduras and Belize between 2001 to 2004, before cART was implemented for prevention of MTCT. Genotypic resistance was performed by sequencing of the HIV pol region and was successfully in dried blood spots from 66 HIV-1-infected infants (55 from Honduras and 11 from Belize). Mutations associated with antiretroviral drug resistance were detected in sequences from 13% of the Honduran infants and 27% of Belizean infants. Thus the study documented, for first time, the presence of drug resistance in HIV-1 infected Honduran and Belizean infants. Resistance probably was transmitted from the mothers since none of the infants had received antiretroviral drugs as prophylaxis or therapy. The second aim (Paper II) was to evaluate antiretroviral drug resistance in pregnant HIV-1-infected women in Honduras and risk for MTCT subsequent to ART prophylaxis. In addition, we investigated changes in immune activation during pregnancy by evaluating LPS levels. A total of 50 mother-child pairs and 95 HIV-negative pregnant women were enrolled. The presence of antiretroviral drug resistance was monitored in samples drawn during pregnancy and shortly after delivery. Twenty-nine women (58%) were treatment-naïve at study entry and started antiretroviral prophylaxis against MTCT during pregnancy while 21 women were already identified as HIV-1 infected and on ART at study entry. Antiretroviral drug resistance was detected in 20% of the samples obtained from the mothers at baseline; 10% among treatment-naïve patients and 29% among treatment-experienced patients. Furthermore, despite ART prophylaxis 22 of 50 (44%) women were viremic. No MTCT were observed, but still the high prevalence of resistance and viremia indicated that there was a significant risk for MTCT. The LPS levels declined between pregnancy and after delivery in the HIV-1 infected women indicates that pregnancy might influence the LPS levels, a novel finding that merits further investigation. This study demonstrated for the first time a high prevalence of antiretroviral drug resistance and viremia in pregnant Honduran women, which could limit the effectiveness of antiretroviral prophylaxis against MTCT. Taken together the studies indicate that there is a need for improvements of prevention against MTCT in Belize and Honduras. This includes better access to monitoring of plasma HIV-1 RNA levels and antiretroviral drug resistance testing

    Prevention of mother to child transmission of hepatitis B

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    Hepatitis B virus (HBV) is a major cause of morbidity and mortality worldwide with a high prevalence in resource limited settings (RLS) like the Thailand-Myanmar border (6.2%). In these settings the main route of transmission is from mother to child (MTCT). Chronic HBV infection can progress into liver failure, liver cirrhosis and liver cancer which lead to death in 25% of the perinatally infected patients. There is no curative treatment for HBV and the main target to stop the HBV epidemic is preventing MTCT. The current strategy for preventing MTCT is by vaccination, a birth dose vaccine followed by three additional vaccinations later in life, combined with the administration of hepatitis B immunoglobulins (HBIG) after birth. In RLS these strategies are challenging due to home deliveries, people living far away from clinics, absence of a cold chain and presence of out-of-pocket expenditure. Moreover, even with perfect administration of HBIG, birth dose and three vaccinations, MTCT can still occur in 8-32% of the cases. An additional way of preventing HBV transmission is by maternal treatment with Tenofovir Disoproxil Fumarate (TDF), that reduces the HBV DNA load to a minimum at the time of delivery. TDF after rapid diagnostic test is a cost-effective option in a RLS if given at the correct time and dosage. Focusing on the wellbeing of mothers and children would not only support HBV elimination but also contribute to strengthening maternal and child health and achieving the health component of the Sustainable Development Goals in the wider context

    Étude du goulot d’étranglement dans la transmission mère-enfant du virus de l’hépatite C

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    La transmission mère-enfant (TME) du virus de l’hépatite C (VHC) est la première cause d’acquisition de l’infection chez les enfants des pays développés. Celle-ci prend place dans <10% des cas. Toutefois, dans le cas d’une coinfection maternelle avec le virus de l’immunodéficience de type 1 (VIH-1), ce taux est accru alors qu’il n’existe aucune intervention préventive de la TME du VHC. Le VHC arbore une diversité importante qui est le résultat d’une réplication exempte de mécanisme de correction. Il est donc retrouvé chez son hôte sous la forme d’un spectre de virions génétiquement apparentés mais différents qu’on appelle quasiespèce. Lorsque le VHC est transmis entre adultes, seulement un nombre limité de variantes sont responsables de l’infection, c’est ce qu’on appelle un goulot d’étranglement génétique. L’existence d’un tel profil de transmission lors de la TME du VHC restait, jusqu’à maintenant, à confirmer. En se basant sur la détection par RT-PCR de la virémie à la naissance, la TME du VHC est réputée prendre place in utero et peripartum, une dynamique de transmission qui reste à démontrer. Ici, nous rapportons une analyse longitudinale de la TME du VHC par séquençage de nouvelle génération chez 5 paires mère-enfant dont 3 mères sont également coinfectées avec le VIH-1. L’analyse de l’identité des variantes virales basée sur la séquence nucléotidique des régions hypervariables 1-2 de la glycoprotéine E2 (positions 1491-1787 de l’isolat H77) révèle qu’un nombre limité de variantes virales sont transmises de la mère à l’enfant lorsque la mère est seulement infectée par le VHC (n = 1-4 variantes transmises). Dans le cas de la coinfection maternelle avec le VIH-1, ce nombre est toutefois drastiquement plus important (n = 111-118). La détection de variantes retrouvées chez la mère au deuxième trimestre et l’enfant mais non détectées subséquemment chez la mère témoigne que la TME du VHC peut prendre place aussi tôt que lors du deuxième trimestre de grossesse. Finalement, nous montrons que la dynamique d’infection chez l’enfant implique une augmentation transitoire de la virémie concomitante avec une perte de diversité de la quasiespèce. Dans l’ensemble ces résultats sont les premiers à démontrer directement l’existence d’un goulot d’étranglement lors de la TME du VHC. Celui-ci serait moins restringent dans le cas de la coinfection maternelle avec le VIH-1. Cette transmission peut prendre place aussi tôt que lors du deuxième trimestre de grossesse et il semblerait qu’un spectre limité de variantes soit responsable pour l’établissement de l’essentiel de la production virale chez le jeune enfant.Mother-to-child transmission (MTCT) of hepatitis C virus (HCV) represents the first cause of infection in children of developed countries. MTCT of HCV may take place in <10% when the mother is solely infected with HCV. However, maternal coinfection with type 1 human immunodeficiency virus (HIV-1) leads to a drastic increase of this rate. Besides, there is no mean of prevention of MTCT of HCV. HCV replication leads to a prominent variability due to the absence of correction mechanism of its RNA-dependent RNA polymerase. Consequently, it is retrieved in its host as a swarm of genetically closely related but different variants named quasispecies. When HCV transmission occurs between adults, only a very limited number of variants are responsible for the infection. This phenomenon is called a genetic bottleneck and whether it exists during MTCT of HCV is to confirm. Based on the detection by RT-PCR of HCV’s RNA at birth, MTCT is believed to take place both in utero and peripartum. Nevertheless, such dynamics of MTCT of HCV have never been demonstrated directly. Here we report, using next generation sequencing, a longitudinal analysis of MTCT of HCV in 5 mother-child pairs, in 3 cases the mother was also infected with HIV-1. Identity analysis based on nucleotide sequence of the glycoprotein E2 hypervariable regions 1-2 (positions 1491-1787 of the isolate H77) reveals that a tight genetic bottleneck exists during MTCT of HCV (n= 1-4 variants transmitted) when the mother is only infected with HCV. However, in the case of maternal coinfection with HIV-1, this number is radically increased (n = 111-118). Also, the detection of variants shared between mother and child that are only present at the 2nd trimester of pregnancy in the mother but not found after suggest that MTCT of HCV can take place as early as the 2nd trimester of gestation. Lastly, we show that the dynamics of the establishment of the infection in the young child involve a transitional increase of the viremia concomitant with reduced diversity of HCV quasispecies. Together, these results show the first direct evidence of a genetic bottleneck occurring during MTCT of HCV. This bottleneck appears to be much less constricted when the mother is coinfected with HIV-1 and HCV. It appears possible that the MTCT can take place as early as the second trimester of pregnancy and that a limited number of variants may be responsible for the essential of the viral production during early childhood

    Immunology of the genital tract - a review

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    The objective of this work was to systematically review and discuss recent studies and articles dealing with the subject of the immunology of female genital tract mucosal tissue. The emphasis hereby lies on the evaluation of studies concerning the basics of female reproductive immunology, research on immunology of the most important genital infections and vaccination strategies, immunologic principles at the fetomaternal interface during normal pregnancy and its complications as well as on immunologic data on infertility and immunocontraception. It is now established that the mucosal immune system is a distinct and separate component of the host`s immune apparatus and differs from the lymphoid tissues in peripheral sites. Furthermore, despite some common features, the female genital tract mucosal system displays some distinct characteristics which outlines its special role. Analysis of the female genital tract indicates that the key cells of the innate and adaptive immune systems are present and functionally responsive to antigens; however, there is a certain degree of compartmentalization within the tract. The identification of TLRs in the fallopian tubes, uterus, cervix, and vagina and the presence of ECs, macrophages, DCs, NK cells, and neutrophils throughout the reproductive tract along with their responsiveness to selected PAMPs indicate that the female reproductive tract has evolved to meet the challenges of STDs, while at the same time supporting an immunologically distinct fetal placental unit. To meet these diverse challenges, innate and adaptive immune system in the female genital tract are precisely regulated not only by a network of cytokines and chemokines, but also by the sex hormones estrogen and progesterone. Understanding the specialty of the genital tract immune system is of critical importance, because STDs are and will be a major worldwide health problem. Despite extensive efforts, only limited success has been achieved in dealing with a growing list of STDs. The role of immune factors in the control of genital viral and bacterial infections appears complex and needs further studying, also with respect to creating vaccines. Despite the recognition that innate immunity as the first line of defense and adaptive immunity, especially Th1 immune responses, play a critical role in preventing infection and in limiting viral replication, factors such as antimicrobials and TLRs that contribute to the mucosal response in the female genital tract have only recently begun to receive attention. Further studies are also needed to elucidate the relationship between mucosal immunity, the hormonal environment, and response to pathogen challenge. More data must be collected on the mechanisms of immune evasion by several pathogens such as HSV, N. gonorrheae or Chlamydia. While considerable information can be obtained from animal experiments, important differences in the physiology of reproduction and the immune sytem result in the need for studies in humans. Further knowledge on female tract immunology will also impact on immunological approaches to contraception, immunological infertility and the immunological aspects of pregnancy. This does not only involve new options for diagnostics but also for treatment of pregnancy complications such as preeclampsia, preterm birth and early pregnancy loss as well as for infertility. Pregnancy involves maternal tolerance of the semiallogenic histoincompatible fetus and is characterized by the enhancement of the innate immune system and suppression of the adaptive immune response, probably with progesterone as the important regulator. In opposite to normal pregnancy, improper immune responses and an unbalanced cytokine network may characterize implantation failures, pregnancy loss and obstetric complications. These are the presence of elevated Th1/Th2 cell ratios, high concentrations of Th1 cytokines, elevated NK cell cytotoxicity and levels, and emergence of various autoantibodies. These immunological approaches needs to be investigated and evaluated further with respect to widening of treatment options by modification of immune responses
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