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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 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.

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.

Background: Higher plasma concentration of neurofilament light (pNfL) is associated with neurodegeneration. However, to our knowledge, up to now, there are no data in HIV patients with infection due to vertical transmission. This is the first study to report pNfL in a cohort of HIV perinatally infected (PHIV) young adults compared with non-HIV (HIV-) controls.Methods: Thirty-three PHIV patients and 25 age-matched HIV- were recruited to this cross-sectional study. Plasma NfL concentrations were compared between both groups. In a subgroup of 48 participants (25 PHIV patients and 23 HIV-), brain volumes through magnetic resonance imaging (MRI) and neuropsychological testing (NT), were also conducted and compared with pNfL values.Plasma NfL concentration was measured using Single Molecule Array (Simoa) immunoassay.NT included fluid intelligence and processing speed through the WAIS-IV Coding subtest, and the Stroop Test.ResultsFifty-eight participants were included, median age 20.7 years [IQR 17.8-23.4]. 100% of the patients were under antiretroviral treatment (cART) and 85% had viral load 50 copies/ml.With regard to brain volumes and NT, in the PHIV group, lower white matter volumes and lower score in the coding subtest were associated with higher pNfL values. ConclusionsMost PHIV adolescents under cART have similar levels of pNfL than HIV-. As reported in adults, those with HIV-RNA >50 copies/ml showed higher values and lower white matter volumes that may imply an ongoing CNS injury. Plasma NfL could be a feasible biomarker of CNS injury in PHIV patients with unsuppressed viral load.

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 CD16high 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.

Introduction After the introduction of combination antiretroviral treatment, (ART) mortality in HIV-infected patients has dramatically decreased. However, it is still high in patients at risk, as adolescents transitioning to adult care (AC) without virological control. The aim of this study was to characterize mortality and comorbidities of perinatally infected HIV (PHIV) patients after transition to AC. Methods A multicenter retrospective study from patients included in the CoRISpe-FARO Spanish cohort was conducted. PHIV patients who died after transition to AC between 2009 and 2019 were included. Clinical, immunovirologic characteristics, treatments received, comorbidities and causes of death were described. Results Among 401 PHIV patients, 14 died (3.5%). All were Spanish, 11/14 (78.6%) women. The median age at diagnosis was 1.5 years (interquartile range [IQR] 0.5-3.9), at transfer to AC was 18 years [16.1-19.9] and at death was 25.8 years [23.6-27.1]. In pediatric units [pediatric care (PC)], CD4+ nadir was 85 cells/μL [IQR 9.7-248.5] and 6/14 patients were classified as C-clinical stage. During AC, all patients were on C-clinical stage and CD4+ nadir dropped to 11.5 cells/μL [4.5-43.3]. cART adherence was extremely poor: in PC, 8/14 patients registered voluntary treatment interruptions; only one had undetectable VL at transition. In AC, 12/14 patients stopped treatment 2 or more periods of time. All deaths were related to advanced HIV disease. Mental health disorders were observed in 7/14 (50%). Main complications described: recurrent bacterial infections (57.1%), wasting syndrome (42.9%), esophageal candidiasis (28.6%) and Pneumocystis jirovecii pneumonia (28.6%). Four women had 11 pregnancies; 5 children were born (none infected). Conclusions Young adults PHIV infected who transition to AC without virologic suppression or proven ability to adhere to ART are at high risk of mortality. Mortality was noted as a consequence of advanced HIV disease, frequent mental health problems and poor adherence to ART.

Background Sleep quality (SQ) data in human immunodeficiency virus (HIV) pediatric population are scarce. Our main objective was to assess SQ in our cohort and to determine the impact of antiretroviral therapy (ART) on sleep in a cohort of HIV-infected adolescents on cART. Materials and Methods The SQ was assessed through the Pittsburgh Sleep Quality Index (PSQI). Neuropsychiatric symptoms (NS) were recorded using an auto-administered questionnaire. To determine the antiretroviral (ARV) impact of efavirenz (EFV) on SQ, patients on EFV versus protease inhibitors-based regimens were compared. Results Forty-six patients were evaluated (median age: 16 years, interquartile range [IQR]: 10.8, 17)). Age at the start of ART: 1.3 years (0.4, 5.2); 23.9% showed acquired immunodeficiency syndrome (AIDS) category. Median CD4 at baseline was 656 (550, 808) cells/mm3; 91.3% had viral load Conclusions Sleep complaints and NS are common among our cohort of HIV adolescents on long-term cART and interestingly, not only in those who were receiving EFV.

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 Assessing the role of HIV and non-HIV related factors is essential for a better understanding of the neurocognitive outcomes in perinatally HIV-infected (PHIV+) young people. The aim of our study was to assess cognition and quality of life (QoL) of a PHIV+ cohort of young people and to compare it with a control group. Methods Thirty PHIV+ and 30 HIV(−) healthy young adults matched by age, sex and socioeconomic status completed a protocol that included neurocognitive tests, a psychosocial semi-structured interview and a QoL questionnaire (PedsQL). Neurocognitive domain-specific and domain-general (NPZ-5) Z-scores were calculated. CDC AIDS-defining category C or not C (PHIV+/C, PHIV+/noC) was considered to evaluate differences within the PHIV+ group. Univariate and multivariate analysis were performed. Results Sixty patients were included; 67% were female; median age (IQR) 19 years (18–21). Regarding PHIV+ young people, 27% showed CDC C category (none encephalopathy), 93% were on ART and 77% had undetectable viral load. No differences regarding occupation were found, although the HIV(−) group repeated less grades (p = 0.028) and had a higher education level (p = 0.021). No differences were found between PHIV+/noC and HIV(−) participants. However, the PHIV+/C group showed poorer performance than PHIV+/noC (NPZ-5, p = 0.037) and HIV(−) subjects (crystallised intelligence, p = 0.025; intelligence quotient, p = 0.016). Higher nadir CD4+ T-cell count was related to better Z-score in memory (p = 0.007) and NPZ-5 (p = 0.025). Earlier and longer exposure to ART resulted in better performance in memory (p = 0.004) and executive functions (p = 0.015), respectively. Conclusions No significant differences were found in the neurocognitive profile nor QoL between PHIV+/noC and HIV(−) adolescents; however, PHIV+/C participants obtained lower scores. The use of longer and earlier ART seems to have a beneficial effect.

Studies investigating health-related quality of life (HRQoL) in youth with perinatally acquired HIV (PHIV+) are scarce. This study aimed to compare HRQoL of PHIV+ to sociodemographic-matched youth not living with HIV (HIV−), Spanish general youth population, and to explore associations between sociodemographic variables, drug consumption, and HRQoL. PHIV+ youth were randomly selected from CoRISpe database (Cohort of the Spanish Pediatric HIV Network). HRQoL was evaluated by SF-12v2. Thirty-nine PHIV+ youth (mean age: 23.36 years, SD = 3.83) and thirty-nine HIV− youth (mean age: 22.97 years, SD = 3.80) participated in this study. PHIV+ obtained lower scores in SF-12 physical health subscale (PCS) than HIV− (P = 0.001) and Spanish general youth population (P = 0.006). PHIV+ had lower scores on the mental health subscale (MCS) than the Spanish general youth population (P

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.

Background Thymic function has been mainly analyzed with surrogate peripheral markers affected by peripheral T-cell expansion, making it difficult to assess the role of thymic failure in human immunodeficiency virus (HIV) disease progression. The assay of signal-joint/DβJβ T-cell rearrangement excision circles (sj/β-TREC ratio) overcomes this limitation but has only been assayed in small cohorts. Thus, the aim of this study was to determine the role of thymic function, measured by the sj/β-TREC ratio, on CD4 T-cell maintenance in prospective HIV cohorts that include patients with a wide age range and different immunological phenotypes. Methods Seven hundred seventy-four patients including typical progressors, long-term nonprogressors (LTNPs), and vertically HIV-infected subjects were analyzed. Thymic function was quantified in peripheral blood samples using the sj/β-TREC ratio. Associations between thymic function and CD4 T-cell dynamics and combination antiretroviral therapy (cART) onset were analyzed using linear, logistic, and Cox proportional hazard models. Results Thymic function failure (sj/β-TREC ratio

[Objective] To characterize children, adolescents and young adults infected with HIV/hepatitis C virus (HCV) vertically or before age of 18 years and living in Europe regarding mode of acquisition, HCV genotype, clinical status and treatment., [Design] Retrospective, cross-sectional study using pooled data from 11 European paediatric HIV cohorts., [Methods] Patients aged more than 18 months and less than 25 years, with HIV/HCV acquired vertically or in childhood, were included. Anonymized individual patient data were collected using a standard protocol and modified HIV Cohorts Data Exchange Protocol., [Results] Of 229 patients included, 142 (62%) had vertically acquired infection. Median age at last follow-up was 16.2 years. Most children had HCV genotype 1 (101/184, 55%) or 3 (57/184, 31%). One-fifth (46/214) had a previous AIDS diagnosis (data missing on prior AIDS diagnoses for 15). At their last clinic visit, 70% (145/208) had no/mild immunosuppression (Centers for Disease Control and Prevention stage 1), and 131 of 179 on antiretroviral therapy had undetectable HIV RNA (assay thresholds varied from, [Conclusion] The high proportion of patients with progressive liver disease underscores the need for close monitoring and earlier and more effective HCV treatment., This work was supported by funding from the EU Seventh Framework Programme (FP7/2007–2013) under EuroCoord grant agreement [no. 260694] and additional funding from Janssen.

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

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.

Maraviroc (MVC) is not approved for HIV-1-infected paediatric patients. This is the first assessment of the use of MVC-based salvage therapy in vertically HIV-1-infected paediatric patients in clinical settings. The results suggest that MVC-based salvage therapy is useful in children and adolescents with extensive resistance profile leading to maintained virological suppression in up to 88% of the patients with CCR5-tropic virus. The likelihood of treatment success might increase when MVC is combined with other active drugs.

Drug resistance mutations affect antiretroviral therapy (ART) effectiveness in HIV-1-infected children, compromising long-term therapy. HIV-1 variants and drug resistance mutations were identified in HIV-infected children from Madrid, Spain.Patients from the Madrid cohort of HIV-infected children (1993-2009) with available pol sequences or infected samples stored at the Spanish HIV-1 BioBank were selected. Specimens were used to perform new pol sequences when not available. HIV-1 variants were characterized by phylogenetic analysis. Resistance mutations were identified according to the International AIDS Society-USA list (2009).In 198 patients, pol sequences were recovered from routine resistance testing (n = 98) or newly performed using stored plasma, lymphocytes or DNA (n = 100). Patients were mostly Europeans (90%), with moderate to severe AIDS symptoms (65%), on ART (85%) when the specimen was sequenced and infected by subtype B (90%). Among the 19 HIV-1 non-B variants found, 58% were recombinants (8CRF02_AG, 1CRF08_BC, 1CRF12_BF and 1CRF13_cpx) and the rest were 'pure' non-B subtypes (1A2, 2C, 2D, 1F1, 1G and 1H). Transmitted drug resistance (TDR) mutations were detected in 13% of naive children; 4%, 7% and 10% for protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), respectively. Global resistance prevalence was higher (66%) among ART-exposed children; 37% for PIs, 54% for NRTIs and 35% for NNRTIs.HIV-1 non-B variants infected 10% of the cohort during 1993-2009. Resistant viruses were present in 26.5% and 66% of naive and pretreated children, respectively. Our data suggest that TDR prevalence in children could be higher than that reported in adults in Spain. The provided data will help to improve clinical management of HIV-infected children in Spain.

Background Licensing data for paediatric dosing is often sparse and subsequent studies may result in changes to recommended doses. We measured the extent and consequences of off-label antiretroviral (ARV) use in an HIV-infected paediatric cohort. Methods In this multicentre cohort study involving 318 HIV-infected children and adolescents from the Madrid Cohort, all off-label prescriptions from March 1988 to March 2012 were recorded from the clinical records. The reasons for prescribing ARV off-label, the side effects and the consequences of incorrect dosing of ARVs are discussed. Results Among the 318 patients of the cohort, 221 (69%) received off-label ARVs according to EMA licensing at the time of prescription, representing 23% (540) of the 2,353 prescribed ARVs. The main reason for starting an off-label drug was treatment failure. Adverse events led to treatment discontinuation in 12% of the prescriptions. Problems taking the drug led to withdrawal in 5%, more likely when formulation was not suitable for age ( PConclusions Off-label use of ARVs was common in our HIV-1 paediatric patients. Adverse events were common but rarely led to withdrawal. Suitable formulation is important in younger children. Pharmacokinetic studies are needed as frequent incorrect dosing may occur when prescribing off-label and underdosing may lead to treatment failure.

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.

El paciente infectado por VIH presenta, en nuestro entorno, una mayor esperanza de vida con practicamente ausencia de episodios definitorios de SIDA. La cuestion es si esta mayor esperanza de vida esta libre de enfermedades concomitantes o si van a aparecer otras nuevas. La enfermedad hepatica es un buen ejemplo de este cambio epidemiologico. El paciente infectado por VIH presenta un riesgo de afectacion hepatica a traves, tanto de la accion directa del virus como del efecto de los farmacos antirretrovirales. Por otra parte, las tasas de infeccion de VHB y VHC son considerablemente mas altas en estos pacientes, al compartir la mayor parte de las vias de transmision. Los pacientes infectados por el VIH pueden presentar coinfecciones por virus hepatotropos serologicamente silentes: la infeccion VHB oculta y la infeccion por VHC seronegativa, que no se diagnostican con los metodos habituales. Estas entidades suponen un aumento del riesgo de reactivacion de la enfermedad, progresion y evolucion a dano hepatico cronico y grave, sobre todo en los ninos que adquieren el virus precozmente. La inclusion rutinaria del cribado de hepatitis ocultas seria una herramienta util para identificar a los pacientes con riesgo de descompensacion hepatica, de especial interes en los ninos que viven con el VIH, ya que se enfrentan a una perspectiva de coinfeccion, y riesgo de dano hepatico, de por vida. A traves de este estudio transversal en la cohorte nacional de pacientes VIH pediatricos (CoRISPe) se abordo la prevalencia de coinfeccion por VHB y VHC, asi como la coinfeccion por hepatitis ocultas. De forma secundaria, se realizo una valoracion no invasiva de la fibrosis hepatica a traves de marcadores bioquimicos (ALT/AST ratio, APRI index, FIB-4 score). Se incluyo un total de 254 pacientes. Tres (1.2%) presentaron una VHB cronica y 13 (5%) una infeccion cronica por VHC. Seis ninos se consideraron probables casos de infeccion VHB oculta, 2 con anti-HBc aislado y 4 con un patron serologico anti-HBc+/anti-HBs+, a pesar de la negatividad de la PCR a VHB en plasma. Dos pacientes (0.8%) presentaron infeccion VHC seronegativa. No se realizaron biopsias hepaticas en este estudio por razones eticas. La evaluacion no invasiva de la fibrosis hepatica fue patologica en los 3 y en 7 de los 13 con infecciones por VHB y VHC, respectivamente, advirtiendo de una posible fibrosis subyacente. Una paciente infectado por VHC mostro alteracion simultanea de los tres marcadores incluidos en el estudio. Cinco de los 6 casos de probable VHB oculta mostraron ALT/AST ratios alteradas pero con normalidad en el APRI y FIB-4 score. Los dos casos de infeccion VHC seronegativa presentaron valores anormales. En los ninos infectados por VIH sin coinfeccion por virus hepatotropos, el 77% mostro ALT/AST ratios elevadas mientras que el 5.7% presento valores anormales de APRI. Solo un paciente mostro un FIB-4 score elevado. En ausencia de datos mas amplios sobre coinfeccion en poblacion pediatrica infectada por el VIH, la prevalencia de VHB y VHC en CoRISPe es similar a lo descrito previamente. Aunque la tasa de coinfeccion por hepatitis ocultas en esta cohorte fue baja (3.1%) parece razonable la inclusion de tecnicas de diagnostico molecular que aumenten la sensibilidad en el diagnostico de las hepatitis ocultas. Se necesitan mas datos para evaluar la idoneidad del uso de los scores bioquimicos para valoracion de fibrosis hepatica en esta poblacion pediatrica, con el objetivo de aumentar la sensibilidad y especificidad, y correlacionar los resultados con la biopsia hepatica, que sigue siendo la tecnica de referencia. HIV-infected patients can now enjoy a longer life expectancy with almost no AIDS defining episodes if diagnosed promptly, as is the case for most vertically infected children in our setting. The question is whether this longer life expectancy is free of comorbidities or whether other medical conditions will appear. Liver disease is a good example of this epidemiological change. A worse outcome of liver disease is expected through both the direct action of the virus and the effect of the antiretroviral drugs. Moreover, HIV itself is considered a risk factor that contributes to increased MTCT of the hepatitis virus. Furthermore, the infection rates of HBV and HCV are considerably higher in patients living with HIV, as they share most of the transmission routes. HIV-infected patients prone to uncommon variations of hepatotropic coinfections which are serologically silent, namely, occult hepatitis B infection and seronegative HCV infection. These entities bring an increased risk of disease reactivation, progression and evolution to chronic and severe liver damage, especially in children who acquire the virus early in life. Current regular screening methods may miss the diagnosis of these coinfections in immunocompromised patients. The inclusion of screening for OBI and seronegative hepatitis C in routine HIV patient monitoring would be a useful tool to identify those patients at risk of hepatic decompensation. In HIV-infected children who face the prospect of a lifetime coinfection, this possibility would be of particular interest, and highly beneficial, as it would become possible to anticipate secondary clinical conditions and future complications. This is a cross-sectional study among the Spanish cohort of HIV-infected children (CoRISPe) in order to assess the prevalence of HBV and HCV infection and occult hepatitis as well. Secondarily noninvasive liver fibrosis assessment through biochemical serum markers was made. A total of 254 patients were included in this study. Three (1.2%) and 13 (5%) patients respectively had serological markers compatible with overt cHBV and cHCV infection. Two patients showed spontaneous clearance of HCV infection. Six children were considered probable OBI cases, 2 presenting with anti-HBc alone and 4 with an anti-HBc+/anti-HBs+ serological pattern, although blood HBV DNA testing was negative in all cases. Two patients (0.8%) had seronegative HCV infection. Noninvasive assessment of liver fibrosis was pathological in all 3 with overt cHBV and in 7 out of 13 with overt cHCV, warning of a possible underlying fibrosis. One HCV-infected patient showed simultaneous alteration of the three scores included in the study. Five out of 6 probable OBI cases appeared to have altered ALT/AST ratio but APRI index and FIB-4 scores were normal in all patients with occult hepatitis. Both cases of seronegative HCV infection showed abnormal scores values. Among HIV-monoinfected children, 77% showed raised ALT/AST ratios, while 5.7% presented APRI abnormal values. Just one patient showed FIB-4 score abnormality. The HBV and HCV prevalence coinfection rates in this cohort appear to be in keeping with previously published data, in the absence of wider prevalence coinfection data for the HIV-infected pediatric population. The global rate of occult hepatitis coinfection cases detected in this cohort was low (3.1%). However, molecular diagnosis assays are indicated to increase the sensitivity of detection and minimize the risk of under-diagnosis and its clinical implications in adulthood. Further research is needed to assess the suitability of using biochemical scores in these populations in order to approach good levels of sensitivity and specificity, and to correlate this method to liver fibrosis assessed by imaging and/or biopsy.

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 to 1999 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.

Background: Effective therapies have increased life expectancy of human immunodeficiency virus (HIV)-infected pediatric patients. We investigated the underlying causes of death, mortality, and acquired immune deficiency syndrome (AIDS) rates in HIV-infected pediatric patients in Madrid, Spain. Methods: We studied a multicenter cohort of 478 HIV-infected pediatric patients in Madrid. Mortality and AIDS incidence rates, causes of death, CD4 + T-cell, and HIV RNA were analyzed during calendar periods (CPs): pre-HAART (highly active antiretroviral therapy) (CP1: 1982-1996) and post-HAART era (CP2: 1997-2009). Results: During 5690 person-years of follow-up 157 (32.8%) deaths occurred. Median age at death increased (CP1: 3.2 years [1.0-6.3] vs. CP2: 7.7 years [3.1-11.4]; P < 0.01). Mortality and AIDS rates decreased 10.6-fold (95% confidence intervals [CI]: 6.9-16.7) and 6.9-fold (95% CI: 5.0-9.6), respectively, between CPs. Nevertheless, mortality was 10.4-fold (95% CI: 5.8-18.8; P < 0.001) higher than in age-similar general population in late-CP2. In all, 169 causes of death were reported. Multiple causes were reported in 16 of 151 (10.6%) patients. In 81.1% (137/169), the causes were AIDS-defining, 11.8% (20/169) HIV-related, and 7.1% (12/169) non-HIV-related. Infections were the leading causes (60.8%, 101/166); from 1999 to 2007 the risk of death from infections was 115.9 times (95% CI: 42.0-265.8; P < 0.001) higher than in the age-similar general population. Comorbidity was reported in 66.9% (101/151) of patients. Median HIV-1 RNA at death decreased (CP1: 5.9 [5.0-6.3]; CP2: 5.3 [4.2-5.8]; P < 0.01). Conclusions: Despite decline in mortality and AIDS rates, it is important to monitor all causes of death as prolonged survival might allow underlying comorbidity to become more clinically relevant.

Fosamprenavir (FPV) efficacy in human immunodeficiency virus (HIV)-infected pediatric patients is still being evaluated in ongoing clinical trials. The long-term efficacy and safety of FPV boosted with ritonavir (FPV/r) was evaluated in 20 antiretroviral-naive and antiretroviral-experienced HIV-vertically infected pediatric patients. Analyses of CD4(+) T-cells, HIV-ribonucleic acid (RNA), and clinical status were performed during a median of 180 weeks. Initially, median HIV-RNA was 4.6 log(10) in naive and 4.4 log(10) in pretreated patients. Median CD4(+) T-cell was 17% and 31%, respectively. After FPV/r treatment, 18 of 20 patients achieved undetectable HIV-RNA and 4 of 20 experienced adverse events. To date, FPV/r treatment has shown sustained antiviral response and immunologic improvement in our 20 patients.