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This study aimed to analyse the long-term effect of direct-acting antivirals (DAAs) in vertically acquired HIV/HCV-coinfected youths. We performed a multicentre, longitudinal and observational study within the Spanish Cohort of HIV-infected children and adolescents and vertically HIV-infected patients transferred to Adult Units (CoRISpe-FARO). We included HIV/HCV-coinfected youths (n = 24) that received DAAs between 2015 and 2017 with successful sustained viral response (SVR) with a subsequent follow-up of at least three years. Long-term evolution in liver disease severity and haematologic markers, lipid and immune profiles after SVR were assessed. Study times were the start date of DAAs treatment (baseline, T0) and 1, 2, 3, 4 and 5 years after SVR (T1, T2, T3, T4 and T5, respectively). We observed global improvements in liver function data that persist over time and a favourable haematologic and immune outcome at the long-term including a constant augment in leucocytes, neutrophils, neutrophils to lymphocytes ratio (NLR) and CD4/CD8 ratio over-time. Regarding the lipid profile, we found a significant increase in total cholesterol T2, total cholesterol/high-density lipoprotein (HDL) ratio at T4, triglycerides at T5, low-density lipoprotein (LDL) over time, and a decrease in HDL in all patients but with marked higher levels in the subgroup receiving anti-HIV Protease Inhibitor (PI)-based regimens. Comparisons of vertically HIV/HCV-coinfected youths after SVR at 3-year follow-up and a control group of vertically HIV-monoinfected youths never infected by HCV showed no significant differences in most variables analysed, suggesting a possible normalization in all parameters., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: To determine by multi-omic analysis changes in metabolites, lipids, and proteins as a consequence of transient viral rebound (tVR) in children with perinatally acquired HIV-1 (PHIV)., Methods: Plasma samples from children with PHIV and with tVR (first episode of transient RNA-HIV viral load >20 copies/ml followed by suppression) on the time-point immediately before (pre-tVR) and after (post-tVR) the tVR were assessed. Multi-omic analyses were performed using nLC-Orbitrap, GC-qTOF-MS, and LC-qTOF-MS., Results: Comparing pre- and post-tVR time-points, HIV-1 children with tVR (n = 5) showed a trend to a decrease in ratio CD4/CD8 (p = 0.08) but no significant differences were observed in plasma metabolites, lipids, or proteins. Post-tVR condition was compared with a reference group of children with PHIV with persistent viral control (n = 9), paired by sex, age, and time under antiretroviral treatment. A total of 10 proteins, 8 metabolites, and 2 lipids showed significant differences (p < 0.05): serotransferrin, clusterin, kininogen-1, succinic acid, threonine, 2-hydroxyisovaleric acid, methionine, 2-hydroxyglutaric, triacylglyceride 50:0 (TG50:0), and diacylglyceride 34:1 (DG34:1) were upregulated while alpha-2-macroglobulin, apolipoprotein A-II, carboxylic ester hydrolase, apolipoprotein D, coagulation factor IX, peptidase inhibitor 16, SAA2-SAA4 readthrough, oleic acid, palmitoleic acid, and D-sucrose downregulated on post-tVR time-point compared to the reference group. Ratio CD4/CD8 correlated with apolipoprotein A-II, DG34:1, and methionine (p = 0.004; ρ = 0.71, p = 0.016; ρ = -0.63; and p = 0.032; ρ = -0.57, respectively). Nadir CD4+ correlated inversely with kininogen-1 (p = 0.022; ρ = -0.60) and positively with D-sucrose (p = 0.001; ρ = 0.77)., Conclusions: tVR followed by suppression implies changes in soluble proteins, lipids, and metabolites that correlate with immunological parameters, mainly ratio CD4/CD8, that decreased after tVR. These distinct soluble biomarkers could be considered potential biomarkers of immune progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Objective: Late presenters (LP) for HIV care are associated with higher morbidity and mortality rates. Our aim was to describe the characteristics associated with LP among adolescents in Spain. Identification of particular features may help in the design of strategies for improvement., Methods: Late-presenting adolescents diagnosed at 12-19 years of age and enrolled in the Spanish paediatric and adult HIV/AIDS cohorts (CoRIS-CoRISpe) from 2004 to 2019 were selected. LP were defined as those presenting with CD4 count <350 cells/mm 3 or an AIDS-defining event in the 6 months following HIV diagnosis. Confirmed low CD4 count in the next 3 months and before antiretroviral treatment initiation defined confirmed LP (cLP)., Results: Of 410 adolescents newly diagnosed with HIV, 303 (73.9%) had available data for assessing late presentation. Of these, 34.7% were LP and 23.7% were cLP. The median CD4 count for cLP was 235 cells/mm 3 (interquartile range 122-285). In a multivariable analysis, adolescents at the highest risk of late presentation were early adolescents (age 12-14 years; odds ratio [OR] 6.50; 95% confidence interval [CI] 2.61-18.2), middle adolescents (age 15-17 years; OR 1.85; 95% CI 0.92-3.59), and adolescents born abroad (OR 1.71; 95% CI 0.97-3.00), particularly those of African origin (OR 3.08; 95% CI 1.38-6.79)., Conclusions: One-quarter of adolescents presented late for HIV care in Spain. Early adolescents, middle adolescents, and those born abroad presented a sevenfold, twofold, and twofold higher risk of being cLP, respectively. Enhancing the awareness of HIV risk and the access to care, especially for younger and foreign adolescents, could help reduce late presentation and tackle the adolescent HIV epidemic., (© 2022 British HIV Association.)

Background: Although integrase inhibitor (INI)-based regimens are now the first-line choice for all people living with HIV, experience among children and adolescents is still scarce. We describe the characteristics and outcomes of a paediatric/adolescent cohort on INI-based ART., Methods: Retrospective analysis of HIV-infected patients below 18 years of age who started an INI-based regimen from 2007 to 2019, enrolled in the Spanish National Adult (CoRIS) and Paediatric (CoRISpe) cohorts. Resistance mutations were identified by the Stanford HIV Drug Resistance Database., Results: Overall, 318 INI-based regimens were implemented in 288 patients [53.8% female; median age at start of 14.3 years (IQR 12.0-16.3)]. Most were born in Spain (69.1%), vertically infected (87.7%) and treatment-experienced (92.7%). The most frequently prescribed INI was dolutegravir (134; 42.1%), followed by raltegravir (110; 34.6%) and elvitegravir (73; 23.0%). The median exposure was 2.0 years (IQR 1.1-3.0). The main reasons to start an INI-based therapy were treatment simplification (54.4%) and virological failure (34.3%). In total, 103 (32.4%) patients interrupted their regimen: 14.5% for simplification and 8.5% due to virological failure. Most subjects who received dolutegravir (85.8%) and elvitegravir (83.6%) did not interrupt their regimen and maintained undetectable viral load. There were only five virological failures with dolutegravir and three with elvitegravir. There were no interruptions related to adverse events. Seven patients with virological failure presented major resistance mutations to INIs; none of them were on dolutegravir., Conclusions: INI-based regimens were effective and safe for HIV treatment in children and adolescents. Dolutegravir and elvitegravir presented an excellent profile, and most patients achieved and maintained viral suppression., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Immune abnormalities have been described among youth with vertically acquired HIV (YWVH) despite antiretroviral treatment (ART). The CD4/CD8 ratio could be a useful prognostic marker. We assess immune activation and senescence in a cohort of YWVH in comparison to youth without vertically acquired HIV., Methods: YWVH under suppressive ART were included and compared to a group of HIV-negative donors (HD) matched by age and sex, from September 2019 to September 2020. Subset distribution and expression of activation, maturation, senescence and exhaustion markers on T and NK cells were studied on peripheral blood mononuclear cells by multiparametric flow cytometry., Results: Thirty-two YWVH (median age: 24.4 years (interquartile range: 22.5 to 28.3 years)) were included. Among YWVH, CD4- and CD8-T cells showed high levels of activation (HLA-DR/CD38), IL-7 receptor expression (CD127) and exhaustion (TIM-3). Regarding NK cells, YWVH showed increased levels of activation and exhaustion markers compared to HD. Strong inverted correlations were observed between T-cell activation (HLA-DR/CD38), senescence (CD57) and exhaustion (TIGIT, PD-1) levels with the CD4/CD8 ratio among YWVH. HLA-DR, CD69, NKG2D and NKG2A expression levels on NK cells also correlated with the CD4/CD8 ratio. Age at ART initiation was directly associated with higher frequency of CD16 high NK-cell subsets, exhaustion T-cell levels (CD57, TIM3) and NK cells activation levels., Conclusions: Immunological changes associated with vertically acquired HIV, characterized by increased activation and exhaustion levels in innate and adaptive immune components, are only partially restored by ART. The CD4/CD8 ratio can be a useful marker of disease progression for routine clinical practice., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Objectives: We analysed the prevalence of M184V/I and/or K65R/E/N mutations archived in proviral DNA (pDNA) in youths with perinatal HIV, virological control and who previously carried these resistance mutations in historic plasma samples., Methods: We included vertically HIV-infected youths/young adults aged ≥10 years in the Madrid Cohort of HIV-1 Infected Children and Adolescents, exposed to lamivudine and/or emtricitabine, with M184V/I and/or K65R/E/N in historic plasma samples, on antiretroviral therapy (ART), virologically suppressed (HIV-1 RNA <50 copies/mL), and with available PBMCs in the Spanish HIV BioBank. Genomic DNA was extracted from PBMCs and HIV-1 RT gene was amplified and sequenced for resistance testing by Stanford HIV Resistance tool., Results: Among the 225 patients under follow-up in the study cohort, 13 (5.8%) met selection criteria, and RT sequences were recovered in 12 (92.3%) of them. All but one were Spaniards, carrying subtype B, with a median age at PBMCs sampling of 21.3 years (IQR: 15.6-23.1) with 4 years (IQR 2.1-6.5) of suppressed viral load (VL). Nine (75%) youths did not present M184V/I in pDNA after at least 1 year of viral suppression. In December 2019, the remaining three subjects carrying M184V/I in pDNA maintained suppressed viraemia, and two still used emtricitabine in ART., Conclusions: The prevalence of resistance mutations to lamivudine and emtricitabine in pDNA in a cohort of youths perinatally infected with HIV who remain with undetectable VL, previously lamivudine and/or emtricitabine experienced, was infrequent. Our results indicate that ART including lamivudine or emtricitabine may also be safe and successful in youths with perinatal HIV with previous experience of and resistances to these drugs detected in plasma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Introduction and Aim: Perinatal transmission of human immunodeficiency virus (PHIV) is considered a chronic disease that has highlighted several cognitive deficits. From birth to early adulthood, cognition is known to play a fundamental role. However, although neurocognitive processes associated with PHIV have been extensively described by psychometric testing, data is scarce on neural activity from functional magnetic resonance imaging (fMRI) which provides in vivo physiological information., Subjects and Methods: We studied described impaired cognitive processes using fMRI on a group of PHIV adolescents with good immunovirological indications and healthy matched controls. Psychological status and neurocognitive functions were also assessed., Results: There were no significant differences between HIV+ and HIV- groups, either on neurocognitive testing nor in fMRI activity for phonological fluency tasks. Prolonged duration of cART was positively associated with greater brain activity in left inferior frontal gyrus (LIFG) which could indicate functional compensation., Conclusions: These results suggest that neural activity through fMRI in PHIV adolescents with good daily functioning and good immunovirological control may be similar to their peers.

The aim of this transversal study was to describe the virological and immunological features of HIV-infected youths transferred from pediatric to adult care units since 1997 vs. the non-transferred patients from the Madrid Cohort of HIV-infected children and adolescents in Spain. We included 106 non-transferred and 184 transferred patients under clinical follow-up in 17 public hospitals in Madrid by the end of December 2017. Virological and immunological outcomes were compared in transferred vs. non-transferred patients. ART drug resistance mutations and HIV-variants were analyzed in all subjects with available resistance pol genotypes and/or genotypic resistance profiles. Among the study cohort, 133 (72.3%) of 184 transferred and 75 (70.7%) of 106 non-transferred patients had available resistance genotypes. Most (88.9%) of transferred had ART experience at sampling. A third (33.3%) had had a triple-class experience. Acquired drug resistance (ADR) prevalence was significantly higher in pretreated transferred than non-transferred patients (71.8% vs. 44%; p = 0.0009), mainly to NRTI (72.8% vs. 31.1%; p < 0.0001) and PI (29.1% vs. 12%; p = 0.0262). HIV-1 non-B variants were less frequent in transferred vs. non-transferred (6.9% vs. 32%; p < 0.0001). In conclusion, the frequent resistant genotypes found in transferred youths justifies the reinforcement of HIV resistance monitoring after the transition to avoid future therapeutic failures.

Direct-acting antivirals (DAAs) for HCV treatment have improved tolerance and efficacy among adults, but experience in vertical transmission is scarce. In our vertically HIV/HCV co-infected youth cohort of 58 patients, DAA achieved excellent rates of cure among naïve and pretreated individuals. Treating vertically infected seems important as 29.6% displayed advanced fibrosis at treatment initiation., (© 2020 John Wiley & Sons Ltd.)

Background: Combination antiretroviral therapy (cART) is associated with marked immune reconstitution. Although a long term viral suppression is achievable, not all children however, attain complete immunological recovery due to persistent immune activation. We use CD4/CD8 ratio like a marker of immune reconstitution., Methods: Perinatal HIV-infected children who underwent a first-line cART, achieved viral suppression in the first year and maintained it for more than 5 years, with no viral rebound were included. Logistic models were applied to estimate the prognostic factors, clinical characteristics at cART start, of a lower CD4/CD8 ratio at the last visit., Results: 146 HIV-infected children were included: 77% Caucasian, 45% male and 28% CDC C. Median age at cART initiation was 2.3 years (IQR: 0.5-6.2). 42 (30%) children received mono-dual therapy previously to cART. Time of undetectable viral load was 9.5 years (IQR: 7.8, 12.5). 33% of the children not achieved CD4/CD8 ratio >1. Univariate analysis showed an association between CD4/CD8 <1 with lower CD4 nadir and baseline CD4; older age at diagnosis and at cART initiation; and a previous exposure to mono-dual therapy. Multivariate analysis also revealed relationship between CD4/CD8 <1 and lower CD4 nadir (OR: 1.002, CI 95% 1.000-1.004) as well as previous exposure to mono-dual therapy (OR: 0.16, CI 95% 0.003-0.720)., Conclusions: CD4/CD8 >1 was not achieved in 33% of the children. Lower CD4 nadir and previous exposure to suboptimal therapy, before initiating cART, are factors showing independently association with a worse immune recovery (CD4/CD8 < 1)., Competing Interests: The authors have declared that no competing interests exist.

Background: The expanded use of long-term antiretroviral treatments in infected children may exacerbate the problem of drug resistance mutations selection, which can compromise treatment efficiency., Objective: We describe the temporal trends of HIV drug resistance mutations and the HIV-1 variants during 23 years (1993 to March 2016) in the Madrid cohort of HIV-infected children and adolescents., Methods: We selected patients with at least one available HIV-1 pol sequence/genotypic resistance profile, establishing different groups according to the sampling year of first resistance data. We determined the prevalence of transmitted drug resistance mutations or acquired drug resistance mutations (DRM), the drug susceptibility among resistant viruses and HIV-1 variants characterized by phylogeny across time., Results: A total of 245 pediatric patients were selected, being mainly female, Spanish native, perinatally infected and carrying HIV-1 subtype B. At first sampling, most pediatric patients were on antiretroviral therapy and heavily pretreated. During 1993 to 2016, transmitted drug resistance mutations was found in 13 (26%) of 50 naive children [non-nucleoside reverse transcriptase inhibitors (NNRTI), 14.6%; nucleoside reverse transcriptase inhibitors (NRTI), 10.4%; protease inhibitors, 8.7%]. DRM appeared in 139 (73.2%) of 190 pretreated patients (NRTI, 64.5%; NNRTI, 36%; protease inhibitors, 35.1%). DRM to NNRTI was higher in last 5 years. Non-B variants infected 14.5% of children and adolescents of the Madrid Cohort, being mainly intersubtype recombinants (76.5%), including complex unique recombinant strains. They caused 3.4% infections before 2000, rising to 85.7% during 2011 to 2016., Conclusions: Periodic surveillance resistance and molecular epidemiology studies in long-term pretreated HIV-infected pediatric populations are required to optimize treatment regimens. Results will permit a better understanding of long-time dynamics of viral resistance and HIV-1 variants in Spain.

Background: The most-used protease-inhibitor in children is Lopinavir-ritonavir (LPV/r), which provides durable suppression of viral load and increases CD4+T-counts. This study describes the virological outcome of the HIV-1-infected paediatric population exposed to LPV/r during 15 years in Spain., Methodology: Patients from the Madrid Cohort of HIV-1-infected-children and adolescents exposed to LPV/r as different line therapy during 2000-2014 were selected. The baseline epidemiological-clinical features, viral suppression, changes in CD4+T-CD8+T cell counts and drug susceptibility were recorded before and during LPV/r exposure. Drug resistance mutations (DRM) were identified in viruses from samples collected until 2011. We predicted drug susceptibility to 19 antiretrovirals among those carrying DRM using the Stanford's HIVdb Algorithm., Results: A total of 199 (37.3%) of the 534 patients from the cohort were exposed to LPV/r during 2000-2014 in first (group 1), second (group 2) or more line-therapies (group 3). Patients were mainly Spaniards (81.9%), perinatally infected (96.5%) with subtype-B (65.3%) and HIV-diagnosed before year 2000 (67.8%). The mean age at first LPV/r exposure was 9.7 years. After protease-inhibitor exposure, viral suppression was higher in groups 1 and 2 than in group 3. Viral suppression occurred in 87.5%, 68.6% and 64.8% patients from groups 1, 2 and 3, respectively. Among the 64 patients with available resistance data during LPV/r treatment, 27(42.3%) carried DRM to protease-inhibitor, 28 (58.3%) to reverse-transcriptase-inhibitors and 21 (43.7%) to non-reverse-transcriptase-inhibitors. Darunavir/ritonavir, atazanavir-ritonavir and tipranavir/ritonavir presented the highest susceptibility and nelfinavir the lowest., Conclusions: A better lymphocyte recovering occurred when protease-inhibitor was taken as part of a first-line regimen and a higher number of patients reached viral suppression. The least compromised antiretrovirals for rescue antiretroviral regimens, according to DRM in the LPV/r-exposed-paediatric cohort, were mainly the new protease inhibitors.

We evaluated the evolution over time of once-daily antiretroviral therapy in HIV-infected children and its relationship with adherence. An increase on the prevalence of once-daily antiretroviral therapy was observed over time (from 0.9% in 2002 to 44.2% in 2011). There was no difference in adherence regarding once-daily or BID regimens in 2011. Adherence was related to age and pill burden.

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.

Introduction: The number of children of immigrant origin in the last few years has increased the cohort of HIV-infected children in the Community of Madrid. The objectives of the study were to evaluate the epidemiological and clinical characteristics of the new diagnosed children and describe the different subtypes of HIV-1., Patients and Methods: The new diagnosed children were analysed from the year 1997, divided into 3 periods: P1 (1997-2000), P2 (2001-2004), P3 (2005-2009). The regions and countries of origin, the clinical, immune and viral characteristics, as well as the response to treatment were analysed. The subtypes of HIV-1 were evaluated by phylogenetic analysis of protease genes and reverse transcriptase., Results: We identified 141 new diagnoses of HIV infection, the percentage of immigrant origin in P1 was (22.5%), P2 (50%) and P3 (68%). The origin had changed from Latin America in P1 to sub-Saharan Africa in P3. There were no differences between Spanish and immigrant children in the age at diagnosis, the CDC clinical stage A/B/C, viral load, percentage of CD4 at diagnosis and actual. Better viral response was more likely in immigrants after the first regimen of HAART (Highly active antiretroviral treatment) independently of the treatment received. A total of 66 subtypes were obtained, 24% were subtypes non-B (56% recombinants forms). All subtypes of Spanish children (43) and Latin American (5) were subtypes B, and all the children from sub-Saharan Africa (14) were subtypes non-B., Conclusion: There were no differences between immigrants and Spanish children infected by HIV, except the different subtypes of HIV-1., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)