María Isabel González-Tomé

Opportunistic infections and organ‐specific diseases in HIV‐1‐infected children: a cohort study (1990–2006)

Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV infection in children, but there are few studies in the literature about the incidence of clinical manifestations after HAART in this population, compared with adults. The aim of this study was to describe the influence of the widespread use of HAART on the development of opportunistic infections and organ‐specific diseases in HIV‐infected children.

High Drug Resistance Prevalence among Vertically HIV-Infected Patients Transferred from Pediatric Care to Adult Units in Spain

Background Antiretroviral treatment (ART) has contributed to increased life expectancy of HIV-1 infected children. In developed countries, an increasing number of children reaching adulthood are transferred to adult units. The objectives were to describe the demographic and clinical features, ART history, antiviral drug resistance and drug susceptibility in HIV-1 perinatally infected adolescents transferred to adult care units in Spain from the Madrid Cohort of HIV-1 infected children. Methods Clinical, virological and immunological features of HIV-1 vertically infected patients in the Madrid Cohort of HIV-infected children were analyzed at the time of transfer. Pol sequences from each patient were recovered before transfer. Resistance mutations according to the InternationaI AIDS Society 2011 list were identified and interpreted using the Stanford algorithm. Results were compared to the non-transferred HIV-1 infected pediatric cohort from Madrid. Results One hundred twelve infected patients were transferred to adult units between 1997 and 2011. They were mainly perinatally infected (93.7%), with a mean nadir CD4+-T-cells count of 10% and presented moderate or severe clinical symptoms (75%). By the time of transfer, the mean age was 18.9 years, the mean CD4+T-cells count was 627.5 cells/ml, 64.2% presented more than 350 CD4+T-cells/ml and 47.3% had ≤200 RNA-copies/ml. Most (97.3%) were ART experienced receiving Highly Active ART (HAART) (84.8%). Resistance prevalence among pretreated was 50.9%, 76.9% and 36.5% for Protease Inhibitors (PI), Nucleoside Reverse Transcriptase Inhibitors (NRTI) and Non-NRTI (NNRTI), respectively. Resistance mutations were significantly higher among transferred patients compared to non-transferred for the PI+NRTI combination (19% vs. 8.4%). Triple resistance was similar to non-transferred pediatric patients (17.3% vs. 17.6%). Conclusion Despite a good immunological and virological control before transfer, we found high levels of resistance to PI, NRTI and triple drug resistance in HIV-1 infected adolescents transferred to adult units.

Guía de la Sociedad Española de Infectología Pediátrica para el diagnóstico y tratamiento de la toxoplasmosis congénita

Congenital toxoplasmosis is the result of transplacental fetal infection by Toxoplasma gondii after the primary maternal infection. The severity of the disease depends on the gestational age at transmission. First trimester infections are more severe, but less frequent, than third trimester infections. Acute maternal infection is diagnosed by seroconversion or by the detection of IgM antibodies and a low IgG avidity test. In these cases, spiramycin should be initiated to prevent transmission to the fetus. For identification of fetal infection, polymerase chain reaction (PCR) testing of amniotic fluid after 18 weeks gestation should be performed. If fetal infection is confirmed, the mothers should be treated with pyrimethamine, sulfadiazine and folinic acid. Most infants infected in utero are born with no obvious signs of toxoplasmosis, but up to 80% developed learning and visual disabilities later in life. Neonatal diagnosis with IgM/IgA antibodies or blood/cerebrospinal fluid PCR may be difficult because false-negative results frequently occur. In these cases diagnosis is possible by demonstrating a rise in IgG titers during follow-up or by the detection of antibodies beyond one year of age. Early treatment with pyrimethamine and sulfadiazine may improve the ophthalmologic and neurological outcome. Congenital toxoplasmosis is a preventable disease. Pre-pregnancy screening and appropriate counseling regarding prevention measures in seronegative women may prevent fetal infection.

Etravirine-based highly active antiretroviral therapy in HIV-1-infected paediatric patients

We evaluated the efficacy, safety and tolerability of etravirine in paediatric patients vertically infected with HIV‐1.

Exposición a antirretrovirales y crecimiento en una cohorte de niños no infectados, hijos de madre con VIH positivo

INTRODUCTION Recent reports show that Antiretroviral Treatment (ART) during pregnancy does not affect somatic growth of children born to HIV-infected mothers, are reassuring. The aim of this study is to perform an anthropometric analysis of the uninfected children followed in the Spanish FIPSE cohort during their first 18 months of life, and to describe the possible risk factors during pregnancy that may influence low birth weight. METHODS The FIPSE cohort includes 8 public hospitals in Madrid, and prospectively follows children born to HIV-infected women at these hospitals. We collected data on 601 uninfected children, following standardised protocols, during their first 2 years of life. A P value<0.05 was considered statistically significant. Data from the Pablo Orbegozo Foundation were used to compare the means of our population with the standard weight, longitude an occipitofrontal circumference (OFC) of the Spanish population during the first 18 months of life. RESULTS The mean weight was 2766g (+/-590), and 2967g (+/-427) when premature neonates were excluded. The proportion of Intrauterine Growth Restriction among non- premature neonates was 19.8% (95% CI: 16.3-23.8). Children born to mothers that used illicit drugs weighed less: 2752g (+/-325) vs. 3002g (+/ 435), P<0.001, as did children born to mothers who smoked during pregnancy: 2842g (+/-363) vs. 3018g (+/-444), P>0.001. Maternal anaemia did not influence the low birth weight of the children when premature neonates were excluded. We found no statistically significant differences depending on the ART received during pregnancy. Children born to mothers who had CD4 > 500 cell /mm were heavier (2834g +/-503) than those whose mothers had CD4 of less than 200 cell/mm (2565g +/-702), P=0.008. These differences disappeared when premature neonates were excluded. Children born to mothers with undetectable viral load were heavier (2866g +/-532 vs. 2704g +/-588, P=0.005), but these differences also disappeared when the prematures were excluded from the analysis. Mean weight, length, and OFC of our population at birth (excluding premature neonates) were lower than the Spanish standards. (z for weight=-0.83; z for length =-1.02; z for OFC=-1.00), but these differences are not statistically significant and disappear at 18 months of age (z for weight=-0.08; z for height=-0.32; z for OFC=-0.31). The type of ART did not have any significant influence. DISCUSSION There is a very significant difference between the weight of the children born to mothers addicted to illicit drugs and the rest of the children. Similarly, the weight of the children born to smoking mothers is significantly lower. There was no association between maternal anaemia and the type of ART. The children of our population have lower weights, length and OFC at birth, but this may due to the high number of scheduled caesarean births, practised at 38 weeks of pregnancy (54.5%). Our children catch-up with anthropometric measurements during the first and second year of life, and these are similar to Spanish standards at 18 months old.

Recomendaciones CEVIHP/SEIP/AEP/PNS respecto al tratamiento antirretroviral en niños y adolescentes infectados por el VIH

Objetivo Efectuar una puesta al dia de las recomendaciones sobre tratamiento antirretroviral (TAR) en ninos y adolescentes infectados por el virus de la inmunodeficiencia humana (VIH). Metodos Estas recomendaciones se han consensuado por un comite del Plan Nacional sobre el Sida (PNS) y la Asociacion Espanola de Pediatria (AEP). Para ello se han revisado los resultados de farmacocinetica, eficacia y seguridad de los estudios recientes pediatricos. Se han definido tres niveles de evidencia segun la procedencia de datos: nivel A, estudios aleatorizados y controlados; nivel B, estudios de cohortes o de casocontrol, y nivel C, estudios descriptivos y opinion de expertos. Resultados La decision de inicio del TAR debe ser individualizada y discutida con la familia, con informacion del riesgo de progresion segun la edad, CD4 y la carga viral, de las complicaciones asociadas al TAR y la dificultad de adherencia. Existe una tendencia mas conservadora para iniciar el TAR y para continuacion con pautas simplificadas y de menor toxicidad. El objetivo del TAR es la maxima y mas duradera supresion de la replicacion viral, lo que no siempre es posible, aun existiendo una mejoria inmunologica y clinica. Son de eleccion combinaciones de al menos tres farmacos, en infeccion aguda y cronica. Deben incluirse inhibidores de la transcriptasa inversa, dos analogos de nucleosidos (ITIAN) mas uno no nucleosidos (ITINN) o 2 ITIAN mas un inhibidor de la proteasa (IP). Se recomienda iniciar el TAR en pacientes sintomaticos, y salvo excepciones, en el primer ano de vida. A partir del ano, en ninos asintomaticos el inicio de TAR se basara en los CD4, sobre todo porcentaje, variable con la edad. Las opciones terapeuticas en caso de fracaso del TAR son limitadas por seleccion de resistencias cruzadas. Se debe identificar la causa del fracaso. Ocasionalmente existe progression inmunologica y/o clinica, y esta indicado un cambio terapeutico, con al menos dos farmacos nuevos o activos para elevar los CD4 a niveles de menor riesgo. Se debe realizar una monitorizacion regular de adherencia y toxicidad. Tambien se discuten aspectos de profilaxis postexposicion y de coinfeccion con el virus de la hepatitis C (VHS) y hepatitis B (VHB). Conclusiones En pediatria existe un mayor nivel de evidencia respecto al efecto del TAR en la evolucion de la enfermedad y su toxicidad, lo que ha conducido a una actitud mas conservadora, y a terapias mas individualizadas. La sintomatologia y los CD4 son los determinantes fundamentales para el inicio o cambio de TAR.

Short Communication: Evaluation of the Effect of Enfuvirtide in 11 HIV-1 Vertically Infected Pediatric Patients Outside Clinical Trials

The effect of enfuvirtide (ENF) in 11 HIV-1 heavily antiretroviral-experienced children and adolescents enrolled in the HIV-1 Paediatric Spanish cohort was further investigated. Patients who received ENF with novel drugs (etravirine, darunavir, and/or tipranavir) reached and maintained undetectable plasma HIV-1 RNA levels and showed immunological recovery within the first 3 months of therapy that was maintained during the follow-up. Viremia was not fully suppressed in patients who did not combine ENF with novel drugs but interestingly, immunological benefit was observed in half of these patients. Therefore, ENF showed a greater and more stable efficacy when administrated with novel drugs.

Enfermedad de Chagas. Prevención de la infección en el recién nacido

Maria Isabel Gonzalez-Tomea, Pablo Rojoa y Maria Flores-Chavezb, en colaboracion con la Sociedad de Infectologia Pediatrica aSeccion de Inmunodeficiencias. Departamento de Pediatria. Hospital 12 de Octubre. Madrid. Espana. bServicio de Parasitologia. Centro Nacional de Microbiologia. Instituto de Salud Carlos III. Madrid. Espana. maribelgt@hotmail.com; projo.hdoc@salud.madrid.org; mflores@isciii.es Vacunas y otras medidas preventivas

Prevention and treatment of fetal cytomegalovirus infection with cytomegalovirus hyperimmune globulin: a multicenter study in Madrid

Abstract Introduction: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection. Materials and methods: A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009–2015, CMV-HIG (Cytotect® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy. Results: Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks (interquartile range: 38–40) and two children (5.5%) were premature (born at 28 and 34 weeks’ gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while two (9.5%) had a mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women were included in the PG and 19 in the TG. In the PG 7/17 (41%) fetuses were infected, one pregnancy was terminated due to abnormalities in cordocentesis and one showed a mild hearing loss at 12 months of age. In the TG, 18/19 children (95%) were diagnosed with cCMV, while the remaining neonate had negative urine CMV at birth. Eight out of the 19 fetuses (42.1%) showed CMV related abnormalities in the fetal US before HIG treatment. Complete clinical assessment in the neonatal period and at 12 months of age was available in 16 and 15 children, respectively. At birth 50% were symptomatic and at 12 months of age, 4/15 (26.7%) showed a hearing loss and 3/15 (20%) neurologic impairment. Fetuses with abnormalities in ultrasonography before HIG presented a high risk of sequelae (odds ratios: 60; 95%CI: 3–1185; p = .007). Discussion: Prophylactic HIG administration in pregnant women after CMV primary infection seems not to reduce significantly the rate of congenital infection, but is safe and it could have a favorable effect on the symptoms and sequelae of infected fetuses. The risk of long-term sequelae in fetuses without US abnormalities before HIG is low, so it could be an option in infected fetuses with normal imaging. On the other hand, the risk of sequelae among infected fetuses with abnormalities in fetal ultrasonography before HIG despite treatment is high.

Pregnancy outcomes in perinatally HIV-infected young women in Madrid, Spain: 2000-2015

Background An increasing number of perinatally HIV-infected women (PHIV) are reaching adulthood and becoming pregnant. Most PHIV women have been exposed to a high number of antiretroviral regimens, and they may have difficulties to achieve viral suppression. Psychosocial problems are not uncommon and could be an important barrier for treatment adherence. The effects of chronic HIV infection and long-term exposure to antiretroviral treatment of PHIV women cause concerns on the developing fetus. The aims of this study were to describe the prevention of mother-to-child transmission strategies in PHIV women and the infant outcomes in the Madrid Cohort of HIV-infected mother-infant pairs. Methods All PHIV pregnant women registered in the Cohort that gave birth from 2000 to 2015 were included in the study. Results Twenty-eight pregnancies in twenty-two perinatally infected women were registered. Most women were Caucasian and heavily treatment-experienced. Nine cases (32.1%) were at high risk of HIV mother-to-child transmission. Maternal HIV-1 viral load was detectable close to delivery in four women (14.3%). The management of these cases was described, and the treatment strategies were discussed. None of the newborns acquired HIV infection. Eight infants (28.6%) were small for gestational age. Conclusions This study included a large series of pregnancies among PHIV women attended according to a youth-centered care model. The challenges in the management of this population by health-care providers were described. Specific strategies to minimize perinatal transmission risks should be addressed in future collaborative studies.