Low thymic output, peripheral homeostasis deregulation, and hastened regulatory T cells differentiation in children with 22q11.2 deletion syndrome.

OBJECTIVE: To perform an extensive analysis of the immune status of asymptomatic children with the 22q11.2 deletion syndrome, with special emphasis on the regulatory T cells (Treg) population. STUDY DESIGN: Analysis of thymic function, frequency and absolute counts of immune subsets, and phenotype of Treg were performed in 10 asymptomatic children bearing the 22q11.2 deletion and compared with 12 age-matched, healthy children. RESULTS: Children with 22q11.2 deletion syndrome showed a curtailed thymic output, lower T-cell levels, and a homeostatic deregulation in the CD4 T-cell compartment, characterized by a greater proliferative history in the naïve CD4 T-cell subset. Treg numbers were markedly reduced in children with 22q11.2 deletion syndrome, and remaining Treg showed mostly an activated phenotype. CONCLUSIONS: Reduced thymic output in children with 22q11.2 deletion syndrome could be related with an increased proliferation in the naïve CD4 T-cell compartment and the consequent Treg activation to ensure that T-cell expansion remains under control. Deregulated peripheral homeostasis and loss of suppressive capacity by Treg could compromise the integrity of T-cell immunity during adulthood and play a relevant role in the increased incidence of autoimmune diseases reported in patients with the 22q11.2 deletion syndrome.

A new tool for the paediatric HIV research: general data from the Cohort of the Spanish Paediatric HIV Network (CoRISpe).

There are approximately from 1,100 to 1,200 HIV-infected children in a follow-up in Spain. In 2008 an open, multicentral, retrospective and prospective Cohort of the Spanish Paediatric HIV Network (CoRISpe) was founded. The CoRISpe is divided into the node 1 and node 2 representing geographically almost the whole territory of Spain. Since 2008 seventy-five hospitals have been participating in the CoRISpe. All the retrospective data of the HIV-infected children have been kept in the CoRISpe since 1995 and prospective data since 2008. In this article we are going to present the notion of CoRISpe, its role, the structure, how the CoRISpe works and the process how a child is transferred from Paediatric to Adults Units. The main objective of the CoRISpe is to contribute to furthering scientific knowledge on paediatric HIV infection by providing demographic, sociopsychological, clinical and laboratory data from HIV-infected paediatric patients. Its aim is to enable high-quality research studies on HIV-infected children.

Predictive factors of virological success to salvage regimens containing protease inhibitors in HIV-1 infected children.

BACKGROUND: The impact of HIV drug resistance mutations in salvage therapy has been widely investigated in adults. By contrast, data available of predictive value of resistance mutations in pediatric population is scarce. METHODS: A multicenter, retrospective, observational study was conducted in children who received rescue salvage antiretroviral therapy after virologic failure. CD4 counts and viral load were determined at baseline and 6 months after rescue intervention. Genotypic HIV-1 resistance test and virtual phenotype were assessed at baseline. RESULTS: A total of 33 children met the inclusion criteria and were included in the analysis. The median viral load (VL) and median percentage of CD4+ at baseline was 4.0 HIV-RNA log copies/ml and 23.0% respectively. The median duration that children were taking the new rescue regimen was 24.3 weeks (23.8-30.6). Overall, 47% of the 33 children achieved virological response at 24 weeks. When we compared the group of children who achieved virological response with those who did not, we found out that mean number of PI related mutations among the group of responders was 3.8 vs. 5.4 (p = 0.115). Moreover, the mean number of susceptible drugs according to virtual phenotype clinical cut-off for maximal virologic response was 1.7 vs. 0.8 and mean number of susceptible drugs according to virtual phenotype cut-off for minimal virlologic response was 2.7 vs. 1.3 (p < 0.01 in all cases). Eighteen children were rescued with a regimen containing a boosted-PI and virological response was significantly higher in those subjects compared with the others (61.1% vs. 28.6%, p < 0.01). CONCLUSION: Salvage treatment containing ritonavir boosted-PIs in children with virological failure was very efficient. The use of new tools as virtual phenotype could help to improve virologic success in pediatric population.

Virological phenotype switches under salvage therapy with lopinavir-ritonavir in heavily pretreated HIV-1 vertically infected children.

OBJECTIVE: To investigate the effects of salvage therapy with lopinavir-ritonavir on HIV-1 phenotype in heavily antiretroviral experienced HIV-infected children. DESIGN: Twenty antiretroviral experienced HIV-infected children were studied during a mean of time of 16.1 months from initiation of the treatment with lopinavir-ritonavir. METHODS: Besides CD4 T cells, viral load and clinical status, we analyzed 91 serial viral isolates to study the phenotype, and biological clones derived from co-cultivation techniques. RESULTS: We observed an increase in CD4 T cells, a statistically significant decrease in viral load and clinical benefits from 3 months after treatment. Ninety per cent of children had SI/X4 bulk isolates in peripheral blood mononuclear cells at study entry. The viral phenotype changed to non syncitium-inducing (NSI)/R5 in 94% of the children after a mean of 5.7 months (95% confidence interval, 2.1-9.3 months) of salvage therapy. The remaining 10% of children had NSI/R5 isolates at entry and at all follow-up study. Similar results were found at the clonal level. Thus, at study entry in PBMC of three children with bulk syncitium-inducing (SI) phenotype, we recovered 65 biologic clones, 56 being SI and nine NSI. After salvage therapy bulk isolates changed to NSI and of 40 biologic clones recovered only five were SI and the rest were NSI. CONCLUSIONS: Our data suggest that lopinavir-ritonavir salvage therapy led not only to a viral load decrease but also to a phenotypic change. X4 virus appeared to be preferentially suppressed. Shifts in co-receptor usage may thereby contribute to the clinical efficacy of anti-HIV drugs in vertically infected infants.

Extensive implementation of highly active antiretroviral therapy shows great effect on survival and surrogate markers in vertically HIV-infected children.

We performed a retrospective observational study of 253 children vertically infected with human immunodeficiency virus (1994-2001) to assess the effectiveness of antiretroviral therapies (ARTs) on survival and surrogate markers at the population level. Children were divided into 3 groups according to the ART protocols used during the follow-up period: calendar period (CP) 1 (1994-1996) received combined therapy with 2 nucleoside reverse transcriptase inhibitors (NRTIs); CP2 (1997-1998) received implementation of highly active ART (HAART) with 3 drugs (NRTIs, protease inhibitors, and non-NRTIs); and CP3 (1999-2001) received extensive HAART. The children in the CP3 group had statistically significant longer survival periods, lower virus load (VL), highest undetectable VL proportion, and highest CD4+ T cell counts. HAART is effective at the population level at decreasing VL, increasing CD4+ T cells, and increasing the survival in a higher percentage of HIV-infected children.

Potent and sustained antiviral response of raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and adolescents.

BACKGROUND: There are pediatric patients receiving many highly active antiretroviral therapy (HAART) regimens entailing drug resistance mutations that complicate HAART effective therapies. METHODS: This was a multicenter retrospective study of 19 multidrug-resistant children and adolescents enrolled from July 2007 to October 2009. Patients were nonresponders because no reduction in HIV type 1 (HIV-1) RNA to undetectable levels was observed during their previous antiretroviral treatment history. The long-term effectiveness of raltegravir (RAL)-based salvage therapy was assessed through a longitudinal analysis of immunologic, virologic, and clinical status of the patients. RESULTS: Median age was 16.0 (15.0-18.0) years. At baseline, median HIV-1 RNA was 10,000 (4.0 log10 copies/mL) (interquartile range [IQR]: 4300-83,000), and median CD4T-cell count was 329 (18.2% cells/µL) (IQR: 175-452). The backbone regimen included at least 1 fully active drug in 17/19 (89%) patients. Median follow-up with HAART including RAL was 80.1 weeks (IQR: 49.4-96.4): 16/19 (84%) exposed for >120 weeks and 6/19 (32%) >100 weeks. After RAL-based therapy, 4/19 (21%) patients achieved HIV-1 RNA <400 copies and 13/17 (68%) reached HIV-1 RNA <50 copies: 6 (32%) within the first month and 7 (37%) within the first 4 months. CD4+ T-cell recovery (70% to 90% of the baseline values) was observed in 17/19 (89%) patients. No deaths, AIDS-defining illnesses, or symptoms of severe intolerance were recorded. Only 2 patients experienced mild-moderate short-term skin rash. Two (11%) patients had sustained and optimum adherence to HAART. No patients showed resistance mutations to RAL after follow-up. CONCLUSIONS: We observed a sustained antiviral response and improved immunologic indices in multidrug-resistant pediatric patients, most of whom had received RAL as part of salvage regimens with at least 1 fully active drugs.

Positive virological outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children: a prospective cohort study.

BACKGROUND: Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected patient. OBJECTIVE: To analyse virological response to lopinavir/ritonavir therapy in previously protease inhibitor (PI)-experienced HIV-1-infected children. MATERIALS AND METHODS: Sixty-seven HIV-1-children on lopinavir/ritonavir were studied in a multicentre prospective cohort observational study. The outcome variables were undetectable viral load (uVL; VL < or =400 copies/mL) and virological failure after uVL with a rebound of VL >400 copies/mL. VL and genotype of HIV-1-isolates were measured using standard assays. RESULTS: 83.5% of children had a 1 log10 VL decrease including 65.6% who reached uVL. Children with >2 changes of antiretroviral therapy (ART) or >5 drugs needed a median time of 3-4 months higher than children with < or =2 changes of ART or < or =5 drugs previous to lopinavir/ritonavir, to reach those values, and the relative proportions (RP) were 2.2 (P =0.038) and 1.9 (P=0.050), respectively. Children with CD4+>15% (P=0.122), VL < or =30,000 (P < 0.001) copies/mL, and age >12 years (P=0.096) achieved an earlier control of VL during the follow-up. The children with virological failure or rebound of VL had higher baseline VL and lower CD4+ T-lymphocytes/mm3 and had taken a greater number of drugs previous to lopinavir/ritonavir. HIV-children with a new nucleoside reverse transcriptase inhibitor (NRTI), or protease inhibitor (PI) or PI plus non-nucleoside reverse transcriptase inhibitors (NNRTI) in the current regimen had a better virological response than children without these new drugs. Also, children with <6 protease mutations had an RP of 2.31 of achieving uVL. CONCLUSIONS: Highly active antiretroviral therapy (HAART) including lopinavir/ritonavir induces beneficial effects in terms of virological outcome responses, and it is an effective option for salvage therapy in PI-experienced HIV-1-infected children.