María Luisa Navarro

Immunogenicity and reactogenicity of primary immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B vaccine coadministered with two doses of a meningococcal C-tetanus toxoid conjugate vaccine.

Background: This study evaluated the concurrent use of meningococcal C tetanus conjugate (MenC-TT) vaccine (NeisVac-C) with DTaP-based combinations, according to 2 vaccination schedules, one of which included hepatitis B vaccination at birth (Trial DTaP-HBV-IPV/Hib-097). Methods: Healthy infants were randomized to receive either DTaP-HBV-IPV/Hib (Infanrix hexa) at 2, 4, and 6 months (N = 115) or HBV at birth followed by DTaP-HBV-IPV/Hib at 2 and 6 months and DTaP-IPV/Hib (Infanrix-IPV Hib) at 4 months (N = 115). In both groups 2 doses of MenC-TT conjugate were coadministered at 2 and 4 months, and compared with 3 doses of MenC-CRM197 conjugate (Meningitec) coadministered at 2, 4, and 6 months with DTaP-HBV-IPV/Hib (N = 120). Antibody concentrations were measured at 2, 6 and 7 months. Solicited local and general symptoms, unsolicited symptoms, and serious adverse events (SAEs) were recorded. Results: All MenC-TT recipients had seroprotective concentrations of anti-PRP antibodies (≥0.15 μg/mL) 1 month after the third vaccine dose and all had SBA-MenC titers ≥1:8 after the second dose of MenC-TT. These responses were noninferior to those seen after 3 doses of DTaP-HBV-IPV/Hib and MenC-CRM. Anti-PRP antibody GMCs were significantly higher in MenC-TT than MenC-CRM vaccinees (7.9, 7.3, 3.8 μg/mL, respectively). Immune responses to all other coadministered antigens were unimpaired, with seroprotection/seropositivity rates ≥98.1% in MenC-TT vaccinees. All schedules studied were well tolerated, with no differences in reactogenicity between the study groups. Conclusions: Coadministration of DTaP-HBV-IPV/Hib or DTaP-IPV/Hib with 2 doses of MenC-TT conjugate vaccine is safe, well tolerated, and immunogenic, with no impairment of the response to the coadministered antigens.

Prospective study of renal function in HIV-infected pediatric patients receiving tenofovir-containing HAART regimens

Aim:To describe the impact of tenofovir disoproxil fumarate (TDF) use on renal function in HIV-infected pediatric patients. Design:It is a prospective, multicenter study. The setting consisted of five third-level pediatric hospitals in Spain. The study was conducted on patients aged 18 years and younger who had received TDF for at least 6 months. The intervention was based on the study of renal function parameters by urine and serum analyses. The main outcome measures were renal function results following at least 6 months of TDF therapy. Results:Forty patients were included (32 were white and 26 were diagnosed with AIDS). Median (range) duration of TDF treatment was 77 months (16–143). There were no significant changes in the estimated creatinine clearance. Urine osmolality was abnormal in eight of 37 patients, a decrease in tubular phosphate absorption was documented in 28 of 38 patients, and 33 of 37 patients had proteinuria. A statistically significant decrease in serum phosphate and potassium concentrations was observed during treatment (P = 0.005 and P = 0.003, respectively), as well as a significant relationship between final phosphate concentration and tubular phosphate absorption (P = 0.010). A negative correlation was found between phosphate concentration and time on TDF. Conclusions:TDF use showed a significant association with renal tubular dysfunction in HIV-infected pediatric patients. Periodic assessment of tubular function may be advisable in the follow-up of this population.

Immunogenicity and reactogenicity of primary immunization with a novel combined Haemophilus influenzae Type b and Neisseria meningitidis Serogroup C-tetanus toxoid conjugate vaccine coadministered with a Diphtheria-tetanus-acellular Pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months.

Background: This phase II study evaluated the immunogenicity and reactogenicity of primary vaccination with a novel Hib-MenC conjugate vaccine (GlaxoSmithKline [GSK] Biologicals) coadministered with DTPa-HBV-IPV (GSK Biologicals) at 2, 4 and 6 months. Methods: Healthy infants were randomized to receive Hib-MenC coadministered with DTPa-HBV-IPV (N = 117) or MenC-CRM (Wyeth) coadministered with DTPa-HBV-IPV/Hib (GSK Biologicals; N = 120) at 2, 4 and 6 months. Antibody concentrations were measured before vaccination and after doses 2 and 3. Solicited local and general symptoms, unsolicited symptoms and serious adverse events (SAEs) were recorded. Results: All subjects in the Hib-MenC group had seroprotective titers of anti-PRP antibodies (≥0.15 μg/mL) and SBA-MenC titers (≥1:8) 1 month after the third dose. These responses were noninferior to those seen in the control group, in which a 99.1% seroprotection rate was observed for both Hib and MenC. At that time, anti-PRP and SBA-MenC GMTs were significantly higher in the Hib-MenC group (12.8 μg/mL and 2467.1 μg/mL, respectively) than in the control group (3.8 μg/mL and 1833.7 μg/mL). High seroprotection rates were already observed after the second dose of Hib-MenC; 96.4% and 100% of subjects were seroprotected to Hib and MenC, respectively. Immune responses to coadministered antigens were unimpaired; seroprotection/vaccine response rates ≥96.5% were recorded postdose 3 in the Hib-MenC group. No differences in reactogenicity were seen between the 2 study groups. Conclusions: Coadministration of a Hib-MenC conjugate vaccine with DTPa-HBV-IPV is well tolerated and immunogenic, and does not impair the immune response to any of the coadministered antigens.

Salvage lopinavir-ritonavir therapy in human immunodeficiency virus-infected children.

Objective: To study the control of viral replication in human immunodeficiency virus (HIV)-infected children on different salvage therapies. Design and Setting: A retrospective observational study in 120 HIV-infected children was conducted. The children were divided into 3 groups according to their salvage therapies: (1) children receiving first line highly active antiretroviral therapy (HAART); (2) protease inhibitor-experienced children receiving second line HAART; (3) protease inhibitor-experienced children receiving HAART including lopinavir-ritonavir (LPV/r). The outcome variables examined were time to achieve viral load (VL) ≤400 copies/mL, success in achieving VL ≤400 copies/mL and time to virologic failure (VL >400 copies/mL). Methods: VL (HIV-RNA copies/mL) was quantified with reverse transcription-polymerase chain reaction molecular assay. For each protocol, survival analyses were conducted to determine the probability of achieving VL ≤400 copies/mL and rebound of VL. Results: VL ≤400 copies/mL was achieved by 52.4% of children receiving first line HAART, 48.3% receiving second line HAART and 71.5% receiving HAART including LPV/r. Children receiving HAART including LPV/r reached VL ≤400 copies/mL in a shorter time than children receiving second line HAART (P = 0.017), but quite similar to children receiving first line HAART. In terms of adjusted relative risk, children receiving HAART including LPV/r were 3.36 [95% confidence interval (95% CI), 1.59, 7.07] more likely to achieve VL ≤400 copies/mL than children receiving a different second line HAART. VL rebound occurred in 68.2% children receiving first line HAART, 73.4% receiving second line HAART and 32.4% receiving HAART including LPV/r. Children receiving HAART that includes LPV/r has less incidence of VL rebound (P=0.013) and 3.29 (95% CI 1.04, 10.3) times less risk to achieve a VL rebound than children receiving a different second line HAART. Conclusions: HAART that includes LPV/r is able to control HIV replication more efficiently than other classic salvage antiretroviral therapies.

Trends in drug resistance prevalence in HIV-1-infected children in Madrid: 1993 to 2010 analysis.

Background: Drug resistance mutations compromise antiretroviral treatment (ART) effectiveness in HIV-1–infected children. Trends in drug resistance prevalence have not been previously evaluated in HIV-infected children in Spain. Methods: HIV-1 variants, drug resistance prevalence dynamics and drug susceptibility were analyzed from 1993 to 2010 in HIV-infected children with available pol sequence, sample or drug resistance profile. HIV-1 variants were characterized by phylogenetic analysis. Resistance mutations in pretreated and naive patients were identified according to International AIDS Society-2010 and the World Health Organization list, respectively. Results: In 232 patients, genotypic resistance profiles (n = 11) or pol sequences (n = 128) were recovered or newly generated from infected samples (n = 93). Patients were mainly in care at pediatric units (63%), were mostly Europeans (84%), with moderate AIDS symptoms (65%), on ART (91%) and infected by HIV-1 subtype B (89%). Transmitted major drug resistance mutations were selected in 6 (13.6%) of the 44 ART-naive children: 4.8%, 9.3% and 11.6%, for protease inhibitors, nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors, respectively. Overall resistance prevalence was higher (71.8%) among ART-exposed children: 39.9%, 66.5% and 35.3% for protease inhibitors, nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors, respectively. Resistance prevalence among ART-exposed children was higher in 2009 to 2010 relative to 1993 to1999 for nonnucleoside reverse transcriptase inhibitors (42% versus 6%; P = 0.006), protease inhibitors (39% versus 13%; P = 0.004) and nucleoside reverse transcriptase inhibitors (63% versus 44%; P = NS). Susceptibility to each drug in resistant viruses was predicted. The rate of non-B infections increased in the last years, mainly caused by recombinant viruses. Conclusions: The increasing resistance prevalence among the HIV-infected pediatric population in Spain highlights the importance of specific drug resistance and drug susceptibility surveillance in long-term pretreated children to optimize treatment regimens.

Interferon-γ release assay for the diagnosis of tuberculosis in children

Aims To compare the QuantiFERON-TB GOLD In Tube test (QTF) and the tuberculin skin test (TST) in children. Methods A prospective study was carried out in nine hospitals in Madrid, Spain. TST and QTF were performed in immigrants, tuberculosis (TB) contacts and patients with TB disease (TBD). Results 459 children were included. Disagreement between the tests was more frequently observed among latent tuberculosis infection (LTBI) cases (54%; 38/70) than in non-infected or TBD cases (0.8%; 3/369) (p<0.01). There were more BCG-vaccinated children among LTBI cases with negative QTF (76%) than among LTBI cases with positive QTF (40%) (p<0.001). Agreement between tests in BCG-vaccinated children was lower than in non-vaccinated cases (p<0.05). Tests in TB exposed patients showed better agreement than in non-exposed children (p<0.05). Conclusions Agreement of both tests was excellent in TBD cases, non-vaccinated children and non-infected patients. A significant number of QTF negative results were observed among LTBI cases, especially in BCG-vaccinated children. Agreement was better in exposed children.

Cardiovascular biomarkers in vertically HIV-infected children without metabolic abnormalities

Early cardiovascular disease is a major concern for ART-suppressed vertically HIV-infected children; however, evidence is lacking regarding specific preventive measures. In this study, a complete panel of biomarkers was determined together with carotid intima-media thickness (IMT), in a cohort of 64 HIV-infected children and 30 controls. Mean age of participants was 14.1±5 years. HIV-infected patients showed normal lipid profile, with only slightly higher triglycerides, and no differences between groups were found regarding IMT. HIV-infected patients displayed higher levels of soluble CD14 (sCD14) and soluble vascular cell adhesion molecule-1 (sVCAM) (all p<0.05). However, levels of C-reactive protein, interleukin-6, myeloperoxidase, monocyte chemoattractant protein-1, P-selectin and tissue plasminogen activator were similar between groups. Vertically HIV-infected subjects on ART with no significant metabolic disturbances displayed increased sCD14 and sVCAM but not up-regulation of proinflammatory pathways. Larger studies are warranted to assess the impact of a strict metabolic control on cardiovascular risk and to define specific cardiovascular disease preventive strategies in this population.

HIV-Infected Adolescents: Relationship Between Atazanavir Plasma Levels and Bilirubin Concentrations

The use of atazanavir (ATV) in adolescents infected with human immunodeficiency virus was analyzed in this study. ATV morning plasma concentrations were determined during regular visits to the outpatient department. Results showed that bilirubin levels were higher among patients with higher ATV plasma concentrations (p = .018). Monitoring plasma levels of ATV could avoid toxicity in these patients.

Implementation of occult hepatitis screening in the Spanish cohort of HIV-infected pediatric patients.

Regular screening methods may miss the diagnosis of occult hepatitis B infection and seronegative hepatitis C virus infection in immunocompromised patients. A cross-sectional study within a Spanish cohort of HIV-infected children yielded 6 of 254 (2.4%) possible occult hepatitis B infection cases and 2 of 254 (0.8%) seronegative hepatitis C virus–infected patients. Implementation of occult hepatitis screening in the routine care of these children may be warranted.

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.