María José Mellado

Establishment and replenishment of the viral reservoir in perinatally HIV-1-infected children initiating very early antiretroviral therapy

Initiation of combined antiretroviral therapy within the first 12 weeks of life in vertically human immunodeficiency virus type 1-infected children favors the establishment of low-level proviral reservoirs. Nevertheless, treatment discontinuation in these patients may lead to rapid and irreversible expansion of reservoir size.

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.

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.

Internationally adopted children: What vaccines should they receive?

It is of paramount importance to know the vaccination status in internationally adopted children, so that they can be correctly immunized. This study ascertains the seroprotection rate for vaccine-preventable diseases and the validity of the immunization cards in 637 adopted children. The absence of the immunization card (13% of children) correlated with a poor global vaccine protection. Children with immunization records (87%) had a better global seroprotection but the information obtained from the card did not accurately predict seroprotection for each particular antigen. The best variable to predict the status of seroprotection was the country of origin. The highest rate of protection was found in children from Eastern Europe and, in descending order, India, Latin America, China and Africa. General recommendations for immunization of internationally adopted children are difficult to establish. Actions for vaccination have to be mainly implemented on the basis of the existence of the immunization card and of the country of origin.

Impact of Highly Active Antiretroviral Therapy (HAART) on AIDS and Death in a Cohort of Vertically HIV Type 1-Infected Children: 1980–2006

We evaluated the population effectiveness of highly active antiretroviral therapy (HAART) on the risk of AIDS and death in a multicenter cohort of 346 HIV-1 vertically infected children born between 1980 and 2006 in the Comunidad Autónoma de Madrid (CAM), Spain. Risks of AIDS and death in patients with the same duration of HIV infection were compared in different calendar periods [CP1: 1980-1989, CP2: 1990-1993 (reference), CP3: 1994-1996, CP4: 1997-1998, CP5: 1999-2006] through cumulative incidence curves and Cox proportional hazards models, allowing for late entry, that included the calendar period as the time-dependent covariate and adjusting for gender and mothers transmission category. The median follow-up was 11.8 years [interquartile range (IQR), 6.3-15.9]. Median CD4+ T cell percentage increased up to 26.5 in CP5 (IQR, 19.5-36.7) while the viral load decreased (median log(10) copies/ml in CP5, 3.66; IQR, 3.07-4.22). Multivariate analysis showed significant reduction in the risk of death since 1997 onward [CP4: adjusted hazard ratios (AHR), 0.29; 95% confidence interval (CI), 0.12-0.69; CP5: AHR, 0.06; 95% CI, 0.03-0.15]. Reduction in progression to AIDS reached borderline significance in CP4 (AHR, 0.49; 95% CI, 0.23-1.05) and was more marked in the last period (CP5: AHR, 0.30; 95% CI, 0.16-0.59). The reductions in the incidence of AIDS and death observed since 1996 were largely attributable to HAART.

Withdrawal of Pneumocystis jirovecii prophylaxis in HIV-infected children under highly active antiretroviral therapy.

Objective:In HIV-infected adults Pneumocystis jirovecii pneumonia (PCP) prophylaxis can be safely withdrawn after immune reconstitution due to the introduction of highly active antiretroviral therapy (HAART). With regard to children only a small amount of data has been published. The present study investigated whether the withdrawal of PCP prophylaxis after immune reconstitution is safe in HIV-infected children. Methods:A retrospective analysis at 10 European centers belonging to the Pediatric European Network on the treatment of AIDS (PENTA) using a standardized questionnaire. Results:A total of 113 questionnaires were received. In 82 children the indication for PCP prophylaxis was provided following Centers for Disease Control (CDC) guidelines (72 primary and 10 secondary). Prophylaxis was withdrawn after the CD4 cell count increased above the age-related CDC thresholds. The observation period off prophylaxis was 335 years (300 years for primary and 35 years for secondary prophylaxis) and the median time per patient off prophylaxis was 4.1 years (range, 0.3–7.7 years). No episode of PCP occurred during the study period. In comparison with the incidence rate from historical data before the introduction of PCP prophylaxis and HAART, this was a significant reduction (P < 0.05). Conclusions:The increase in CD4 cell count provides functional reconstitution of the immune system in children. Our data suggests that the risk of developing a PCP after immune reconstitution is sufficiently low to withdraw PCP prophylaxis.

Pandemic H1N1 influenza-associated hospitalizations in children in Madrid, Spain.

Please cite this paper as: del Rosal et al. (2011) Pandemic H1N1 influenza‐associated hospitalizations in children in Madrid, Spain. Influenza and Other Respiratory Viruses 5(6), e544–e551.

Optimizing interpretation of the tuberculin test using an interferon-gamma release assay as a reference standard.

The interferon-gamma release assays have greater specificity than the tuberculin skin test (TST), and at least equal sensitivity. We analyzed the sensitivity and specificity of the TST in immunocompetent children considering QuantiFERON as the referent standard. A TST cut-off point of ≥5 mm indicates excellent sensitivity (100%) and specificity (93%) in children without Bacillus Calmette-Guérin. In Bacillus Calmette-Guérin-vaccinated children, the TST cut-off point of ≥10 mm had poorer specificity (86%), and a cut-off point of ≥15 mm resulted in reduced sensitivity (60%).

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.