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Although antiretroviral therapy (ART) is effective in suppressing viral replication, HIV-1 persists in reservoirs and rebounds after ART has been stopped. However, a very few people (eg, elite and post-treatment controllers) are able to maintain viral loads below detection limits without ART, constituting a realistic model for long-term HIV remission. Here, we describe the HIV control mechanisms of an individual who showed exceptional post-treatment control for longer than 15 years.We report the case of a Hispanic woman aged 59 years with sexually acquired acute HIV infection, who was included in an immune-mediated primary HIV infection trial involving a short course of ciclosporine A, interleukin-2, granulocyte macrophage colony-stimulating factor, and pegylated interferon alfa, followed by analytical treatment interruption. We did the following viral assays: total and integrated HIV-1 DNA in CD4 T cells and rectal tissue, quantitative viral outgrowth assay, HIV-1 infectivity in peripheral blood mononuclear cells and CD4 T-cell cultures and viral inhibitory activity by natural killer (NK) and CD8 T cells. NK and T-cell phenotypes were determined by flow cytometry. HLA, killer cell immunoglobulin-like receptors, Δ32CCR5, and NKG2C alleles were genotyped.After ART and immunomodulatory treatment, the person maintained undetectable plasma viral load for 15 years. HIV-1 subtype was CFR_02AG, CCR5-tropic. We found progressive reductions in viral reservoir during the 15-year treatment interruption: total HIV DNA (from 4573·50 copies per 10We described long-term remission in a woman aged 59 years who was treated during primary HIV infection and has maintained undetectable viral load for 15 years without ART. Replication-competent HIV-1 was isolated. NKG2C-memory-like NK cells and γδ T cells were associated with the control viral replication. Strategies promoting these cells could bring about long-term HIV remission.Fondo Europeo para el Desarrollo Regional (FEDER), SPANISH AIDS Research Network (RIS), Fondo de Investigación Sanitaria (FIS), HIVACAT, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CERCA Programme/Generalitat de Catalunya, la Caixa Foundation, and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC).For the Spanish translation of the abstract see Supplementary Materials section.

Cholesterol efflux (CE) capacity has been inversely associated with atherosclerosis and may provide an insight on inflammation occurring in human immunodeficiency virus (HIV) individuals. We address this by studying CE in HIV patients at different stages of HIV disease progression. In this cross-sectional study, CE from ApoB-depleted plasma, lipids levels, viral load (VL), CD4+/CD8+ T-cells, high-sensitive C-reactive protein (hsCRP), and lipoprotein (a) were evaluated in untreated HIV-infected patients (UHIVs; n = 43), elite controllers (ECs; n = 8), HIV-exposed seronegative individuals (HESNs; n = 32), and healthy controls (HCs; n = 14). Among UHIVs, those with CD4+

Introduction Peripheral blood mononuclear cells (PBMCs) are frequently used for genomic analyses, but several factors can affect the yield and integrity of nucleic acids, including the methods of cell collection and isolation. The goal of this work was to analyze the utility of systematic isolation of different immune cell subsets by immunomagnetic separation and the RNA integrity after isolated cells from samples of HIV-infected patients. Methods PBMC from Healthy Controls (HC, n = 15), Elite Controllers (EC, n = 15), Viremic Controllers (VC, n = 15), Viremic Progressors (VP, n = 15) and HIV-infected patients on therapy (ART, n = 15) were isolated by Ficoll-Paque density gradient centrifugation. Subsets were separated with monoclonal antibodies (CD56, CD14, CD4, and CD8) conjugated to microbeads. We evaluated the yield and purity of each subset isolated from PBMCs under resting and activated conditions; LPS, anti-CD3/CD28 and anti-CD16 were used to activate monocytes, PBMC, T cells and NK cells, respectively. The quality of extracted RNA was tested by 2100 Bioanalyzer. Results In resting conditions, the average yield of CD14 + (monocytes) was decreased (p = 0.021) in HIV + patients compared with healthy controls. CD56 + (Natural Killer-NKs; p = 0.03) and CD8 + (Cytotoxic T lymphocytes-CTL p = 0.001) cells were increased in HIV + patients after 72 h of activation. The purity assay detected significant differences in CD14 + (p ≤ 0.001) and CD8 + (p = 0.034) subpopulations when comparing PBMC isolated either from healthy controls or HIV + patients. The number of activated cells in HIV + presented differences in CD8 subset (p = 0.003). Finally, similar quantities of high quality RNA were extracted from immune cells subsets obtained by our method. Specifically, we show that Bioanalyzer electrophenograms reveal optimal RIN values in HIV positive and negative patients in resting condition (EC:8;HC:6.5;VC:8.80;VP:8;HAART:7.5) and activated condition (EC:9;HC:6.7;VC:8.2;VP:7.2;HAART:8.6). Conclusion This method allowed us to obtain a sufficient quantity of different isolated immune cell subsets from HIV–infected individuals at different disease stages. Moreover, the assessed qualities of nucleic acids allow us to perform subsequent molecular studies, such as microRNA profiling.

The work reports the design and synthesis of a chimeric peptide that is composed of the peptide sequences of two entry inhibitors which target different sites of HIV-1 gp41. The chimeric peptide offers the advantage of targeting two gp41 regions simultaneously: the fusion peptide and the loop both of which are membrane active and participate in the membrane fusion process. We therefore use lipid raft-like liposomes as a tool to specifically direct the chimeric inhibitor peptide to the membrane domains where the HIV-1 envelope protein is located. Moreover, the liposomes that mimic the viral membrane composition protect the chimeric peptide against proteolytic digestion thereby increasing the stability of the peptide. The described liposome preparations are suitable nanosystems for managing hydrophobic entry-inhibitor peptides as putative therapeutics.

Background: A slower progression of AIDS and increased survival in GBV-C positive individuals, compared with GBV-C negative individuals has been demonstrated; while the loss of GBV-C viremia was closely associated with a rise in mortality and increased progression of AIDS. Following on from the previous reported studies that support the thesis that GBV-C E2 interferes with HIV-1 entry, in this work we try to determine the role of the GBV-C E1 protein in HIV-1 inhibition. Methods: The present work involves the construction of several overlapping peptide libraries scanning the GBV-C E1 protein and the evaluation of their anti-HIV activity. Results: Specifically, an 18-mer synthetic peptide from the GBV-C E1 protein, E1(139-156), showed similar antiviral activity against HIVs from viruses from clades A, B, C, D and AE. Competitive ELISA using specific gp41-targeting mAbs, fluorescence resonance energy transfer as well as haemolysis assays demonstrated that this E1 peptide sequence interacts with the highly conserved N-terminal region of the HIV-1 gp41 (the fusion peptide) which is essential for viral entry. Conclusions: We have defined a novel peptide lead compound and described the inhibitory role of a highly conserved fragment of the E1 protein. General Significance: The results together allow us to consider the non-pathogenic E1 GBV-C protein as an attractive source of peptides for the development of novel anti-HIV therapies.

To evaluate the course of left-sided infective endocarditis (LsIE) in patients with liver cirrhosis (LC) analyzing its influence on mortality and the impact of surgery.Prospective cohort study, conducted from 1984 to 2013 in 26 Spanish hospitals.A total of 3.136 patients with LsIE were enrolled and 308 had LC: 151 Child-Pugh A, 103 B, 34 C and 20 were excluded because of unknown stage. Mortality was significantly higher in the patients with LsIE and LC (42.5% vs. 28.4%; p0.01) and this condition was in general an independent worse factor for outcome (HR 1.51, 95% CI: 1.23-1.85; p0.001). However, patients in stage A had similar mortality to patients without cirrhosis (31.8% vs. 28.4% p = NS) and in this stage heart surgery had a protective effect (28% in operated patients vs. 60% in non-operated when it was indicated). Mortality was significantly higher in stages B (52.4%) and C (52.9%) and the prognosis was better for patients in stage B who underwent surgery immediately (mortality 50%) compared to those where surgery was delayed (58%) or not performed (74%). Only one patient in stage C underwent surgery.Patients with liver cirrhosis and infective endocarditis have a poorer prognosis only in stages B and C. Early surgery must be performed in stages A and although in selected patients in stage B when indicated.

In this update, antiretroviral therapy (ART) is recommended for all patients infected by type 1 human immunodeficiency virus (HIV-1). The strength and grade of the recommendation vary depending on the CD4+ T-lymphocyte count, the presence of opportunistic infections or comorbid conditions, age, and the efforts to prevent the transmission of HIV. The objective of ART is to achieve an undetectable plasma viral load (PVL). Initial ART should comprise three drugs, namely, two nucleoside reverse transcriptase inhibitors (NRTI) and one drug from another family. Three of the recommended regimens, all of which have an integrase strand transfer inhibitor (INSTI) as the third drug, are considered a preferred regimen; a further seven regimens, which are based on an INSTI, an non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor boosted with ritonavir (PI/r), are considered alternatives. The reasons and criteria for switching ART are presented both for patients with an undetectable PVL and for patients who experience virological failure, in which case the rescue regimen should include three (or at least two) drugs that are fully active against HIV. The specific criteria for ART in special situations (acute infection, HIV-2 infection, pregnancy) and comorbid conditions (tuberculosis and other opportunistic infections, kidney disease, liver disease, and cancer) are updated. (C) 2015 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinics. All rights reserved.

Triple combination regimens consisting of lopinavir/ritonavir (LPV/r) plus 2 nucleoside/nucleotide analogs continue to be a valid option in initial antiretroviral therapy. Other protease inhibitors boosted with ritonavir (and in future with cobicistat) have been introduced, as well as other non-nucleoside analogs (rilpivirin) and 3 integrase inhibitors. None of the new regimens have shown superiority over LPV/r or comparisons are lacking. Therefore, regimens including LPV/r continue to be recommended as initial first-line or alternative strategies in most treatment guidelines. Dual combinations with LPV/r (plus raltegravir or lamivudine) are described in another article and can provide a similar response rate to triple combinations, better tolerance, and an improved cost-efficacy ratio, both for initial therapy and in simplification strategies. In contrast, LPV/r or darunavir/r monotherapy does not seem an acceptable option in treatment-naive patients and is becoming increasingly less acceptable in simplification strategies.

Initial treatment with dolutegravir offers higher efficacy than treatment with efavirenz, darunavir/ritonavir and even with raltegravir in patients with a high viral load. Like ritonavir-boosted protease inhibitors, dolutegravir will probably have a high genetic barrier to resistance and prior genetic testing will not be required in integrase inhibitor-naive patients. The drug is well tolerated and associated with few treatment discontinuations. It can be administered once daily and the tablet size is small. A fixed-dose combination tablet containing dolutegravir, abacavir and lamivudine will soon be available. Dolutegravir has few interactions with commonly-used drugs. It does not require pharmacological boosting and has no food or time of day restrictions. Because of these characteristics, dolutegravir has a unique profile and is the ideal drug for most HIV-infected patients.

Background To investigate the safety and immunogenicity of a modified vaccinia virus Ankara vector expressing HIV-1 antigens from clade B (MVA-B), a phase-I, doubled-blind placebo-controlled trial was performed. Methods 30 HIV-uninfected volunteers at low risk of HIV-1 infection were randomly allocated to receive 3 intramuscular injections (1 × 108 pfu/dose) of MVA-B (n = 24) or placebo (n = 6) at weeks 0, 4 and 16. All volunteers were followed 48 weeks. Primary end-points were adverse events and immunogenicity. Results A total of 169 adverse events were reported, 164 of grade 1–2, and 5 of grade 3 (none related to vaccination). Overall 75% of the volunteers showed positive ELISPOT responses at any time point. The magnitude (median) of the total responses induced was 288 SFC/106 PBMC at week 18. Antibody responses against Env were observed in 95% and 72% of vaccinees at week 18 and 48, respectively. HIV-1 neutralizing antibodies were detected in 33% of volunteers. Conclusions MVA-B was safe, well tolerated and elicited strong and durable T-cell and antibody responses in 75% and 95% of volunteers, respectively. These data support further exploration of MVA-B as an HIV-1 vaccine candidate. Clinical Trials.gov identifier: NCT00679497.

Antecedentes La duracion del tratamiento antibiotico endovenoso de la endocarditis infecciosa (EI) oscila entre 2 y 6 semanas. Aunque varios estudios indican que el tratamiento antibiotico a domicilio endovenoso (TADE) es seguro para el tratamiento domiciliario de la EI sobre valvula nativa no complicada por estreptococos del grupo viridans (EGV) la experiencia en Espana con TADE en la EI es limitada y los datos sobre otros tipos de endocarditis y TADE son escasos en todo el mundo. Metodos Estudio unicentrico, prospectivo, de una cohorte de todos los pacientes con EI admitidos en el programa TADE en el Hospital Clinico de Barcelona entre enero de 1997 y diciembre de 2006. Resultados Durante el periodo de estudio se diagnosticaron 392 episodios consecutivos de EI en pacientes no consumidores de drogas, de los cuales 73 episodios (19%) fueron admitidos en el programa de TADE: 42 EI sobre valvula nativa, 23 EI sobre valvula protesica y 8 EI sobre cable de marcapasos. El porcentaje de inclusion en la TADE fue mayor para la EI por EGV o Streptococcus bovis (S. bovis) (32%) que para el resto de etiologias (14%; p < 0,001). Doce pacientes (16%) fueron reingresados debido a las complicaciones de los cuales tres fallecieron (4%). El uso de glucopeptidos fue el unico factor predictor de reingreso hospitalario (OR [intervalo de confianza del 95%] 4,5 [1,2; 16,8] p = 0,026). No se observaron diferencias entre las EI por EGV y S. bovis y las EI estafilococicas (Staphylococcus aureus y estafilococos coagulasa-negativos) incluidas en el TADE. Los pacientes incluidos estuvieron una mediana de 17 dias en tratamiento domiciliario (rango intercuartilico de 11 a 26,5), lo que permitio un ahorro de 1.466 dias de estancia hospitalaria. Conclusiones Estos datos sugieren que la TADE en la EI es una estrategia terapeutica segura y eficaz en el tratamiento domiciliario de pacientes seleccionados con EI por EGV y otras etiologias, aunque los pacientes que reciben glucopeptidos precisan un mayor control clinico

This study provides a detailed description and characterization of the preparation of individualized lots of autologous heat inactivated HIV-1 virions used as immunogen in a clinical trial designed to test an autologous dendritic-cell-based therapeutic HIV-1 vaccine (Clinical Trial DCV-2, NCT00402142). For each participant, ex vivo isolation and expansion of primary virus were performed by co-culturing CD4-enriched PBMCs from the HIV-1-infected patient with PBMC from HIV-seronegative unrelated healthy volunteer donors. The viral supernatants were heat-inactivated and concentrated to obtain 1 mL of autologous immunogen, which was used to load autologous dendritic cells of each patient. High sequence homology was found between the inactivated virus immunogen and the HIV-1 circulating in plasma at the time of HIV-1 isolation. Immunogens contained up to 10⁹ HIV-1 RNA copies/mL showed considerably reduced infectivity after heat inactivation (median of 5.6 log₁₀), and were free of specified adventitious agents. The production of individualized lots of immunogen based on autologous inactivated HIV-1 virus fulfilling clinical-grade good manufacturing practice proved to be feasible, consistent with predetermined specifications, and safe for use in a clinical trial designed to test autologous dendritic cell-based therapeutic HIV-1 vaccine.

Lymphoid tissue is the main reservoir of HIV-1 in infected individuals. In this study the COBAS® TaqMan® HIV-1 test was evaluated for use with the High Pure System (HPS), for quantifying HIV-1 RNA in infected cells and lymphoid tissue specimens. Serial dilutions of 8E5–LAV1 infected T-cells into SUP-T1 cells and 44 tonsil specimens were examined. Some modifications of the test were required, such as the removal of residual DNA and the HIV-1 RNA output copies were adjusted to the sample input and expressed as HIV-1 RNA copies/μg of total RNA. The Roche COBAS® TaqMan HIV-1® (HPS) test proved to be a robust, sensitive, specific and reproducible method for quantifying HIV-1 RNA in infected cells and lymphoid tissue. Linearity and reproducibility were observed in serial dilutions of 8E5–LAV1 infected T-cells (R2 > 0.86). High reproducibility was found in clinical tonsil specimens (Wilcoxon test p > 0.05). rDNase I treatment was essential to avoid false positives caused by residual HIV-1 DNA, mainly in tonsil specimens obtained from infected patients receiving effective antiretroviral treatment. Probit analysis determined the limit of detection as 22 HIV-1 RNA copies/μg of total RNA. The Roche COBAS® TaqMan® HIV-1 (HPS) test thereby proved to be a helpful tool for measuring the HIV-1 viral load in infected cells and lymphoid tissue reservoirs.

Being able to recruit high-risk volunteers who are also willing to consider future participation in vaccine trials are critical features of vaccine preparedness studies. We described data from two cohorts of injection- and non-injection drug users in Barcelona, Spain [Red Cross centre] and in San Francisco, USA, [UFO-VAX study] at high risk of HIV/HCV infection to assess behaviour risk exposure and willingness to participate in future preventive HIV vaccine trials. We successfully identified drug-using populations that would be eligible for future HIV vaccine efficacy trials, based on reported levels of risk during screening and high levels of willingness to participate. In both groups, Red Cross and UFO-VAX respectively, HCV infection was highly prevalent at baseline (41% and 34%), HIV baseline seroprevalence was 4.2% and 1.5%, and high levels of willingness were seen (83% and 78%).

Objective: HIV treatment failure is commonly associated with drug resistance and the selection of a new regimen is often guided by genotypic resistance testing. The interpretation of complex genotypic data poses a major challenge. We have developed artificial neural network (ANN) models that predict virological response to therapy from HIV genotype and other clinical information. Here we compare the accuracy of ANN with alternative modelling methodologies, random forests (RF) and support vector machines (SVM). Methods: Data from 1204 treatment change episodes (TCEs) were identified from the HIV Resistance Response Database Initiative (RDI) database and partitioned at random into a training set of 1154 and a test set of 50. The training set was then partitioned using an L-cross (L=10 in this study) validation scheme for training individual computational models. Seventy six input variables were used for training the models: 55 baseline genotype mutations; the 14 potential drugs in the new treatment regimen; four treatment history variables; baseline viral load; CD4 count and time to follow-up viral load. The output variable was follow-up viral load. Performance was evaluated in terms of the correlations and absolute differences between the individual models' predictions and the actual @DVL values. Results: The correlations (r^2) between predicted and actual @DVL varied from 0.318 to 0.546 for ANN, 0.590 to 0.751 for RF and 0.300 to 0.720 for SVM. The mean absolute differences varied from 0.677 to 0.903 for ANN, 0.494 to 0.644 for RF and 0.500 to 0.790 for SVM. ANN models were significantly inferior to RF and SVM models. The predictions of the ANN, RF and SVM committees all correlated highly significantly with the actual @DVL of the independent test TCEs, producing r^2 values of 0.689, 0.707 and 0.620, respectively. The mean absolute differences were 0.543, 0.600 and 0.607log"1"0copies/ml for ANN, RF and SVM, respectively. There were no statistically significant differences between the three committees. Combining the committees' outputs improved correlations between predicted and actual virological responses. The combination of all three committees gave a correlation of r^2=0.728. The mean absolute differences followed a similar pattern. Conclusions: RF and SVM models can produce predictions of virological response to HIV treatment that are comparable in accuracy to a committee of ANN models. Combining the predictions of different models improves their accuracy somewhat. This approach has potential as a future clinical tool and a combination of ANN and RF models is being taken forward for clinical evaluation.

Resumen La infeccion por el virus de la Inmunodeficiencia Humana tipo 1 (VIH-1) fue descrita en el ano 1981 y rapidamente se convirtio en una pandemia y la causa mas frecuente de mortalidad en el segmento hetario entre 20 y 40 anos. La introduccion del tratamiento antiretroviral de alta eficacia (HAART) en 1996 ha supuesto una drastica reduccion de la mortalidad y que la mayoria de pacientes infectados tengan una esperanza de vida que se aproxima a la de la poblacion general de similar edad y sexo y con buena calidad de vida. Por el contrario, las medidas para prevenir nuevas infecciones no han funcionado bien y ademas, se estima que en Europa Occidental para cada dos pacientes infectados conocidos hay uno (33%) que lo desconoce. Este 33% de personas infectadas que lo desconocen contribuyen a un exceso de nuevas transmisiones (60–70% del total) y ademas no se beneficiaran, o lo haran con retraso, de los tratamientos HAART. Para el diagnostico precoz, en USA se recomiendan los tests de despistaje de forma universal cada vez que una persona entre en contacto con el sistema sanitario. En Europa, iniciativas como “HIV in Europe” o “HIV en Espana 2009” apoyan una politica de despistaje basada en la presencia de enfermedades o situaciones indicadoras en las que la prevalencia de infeccion por el VIH-1 se estima superior al 1%.

La disciplina de enfermedades infecciosas es reconocida como especialidad clinica en la practica totalidad de los paises de la Union Europea, asi como en los EE. UU., Canada y la mayoria de los paises hispanoamericanos. Aunque los planes de formacion en los distintos paises europeos son heterogeneos, la Seccion de Enfermedades Infecciosas de la Union Europea de Especialidades Medicas (UEMS) trabaja para su armonizacion. El European Board in Infectious Diseases, que data de 1998, recomienda una duracion total del periodo de especializacion de 6 anos, similar al de otras especialidades medicas (2 anos de formacion troncal y 4 de formacion especializada). La actividad asistencial en enfermedades infecciosas en los hospitales de los distintos paises se asemeja, en cuanto a cartera de servicios, a la que existe en los centros espanoles. En este articulo se revisan los programas formativos, la actividad asistencial y la actividad cientifica en la disciplina de enfermedades infecciosas en los distintos paises.

Integrase inhibitors are a new therapeutic modality against HIV. Raltegravir is the first integrase inhibitor to have been approved by the health authorities for human use. This drug acts by inhibiting the HIV enzyme that catalyzes integration of the virus inside the genome of the host cell. In the host cell, there is no homologue to viral integrase and consequently the potential toxicity of this drug is probably low. The results of safety studies in animal models have shown that the recommended dose in humans is lower than the dose below which no secondary effects are observed. Studies of genotoxicity and carcinogenicity, as well as of fertility and embryo development, have been negative to date. During clinical trials, raltegravir has been shown to have a very good safety profile, with few adverse effects, which were mild-to-moderate and similar to those of the comparator. The most notable were diarrhea, nausea and headache. The lipid profile of raltegravir was better than that of efavirenz. In view of the above, the risk-benefit ratio for raltegravir is positive.

Raltegravir is the first in a new class of antiretroviral treatments called integrase inhibitors, which work by preventing HIV from inserting its genetic material into the DNA of the human chromosome. Phase I-III studies have shown this drug to have potent antiretroviral action, which is more rapid than that of protease inhibitors. The dose selected in efficacy studies is 400 mg every 12 h. However, due to the favorable pharmacokinetic profile of raltegravir, the possibility of administration of 600 to 800 mg once daily is under study. Given that this drug is not metabolized by the cytochrome P450 system, the potential for pharmacological interactions is low. Moreover, because humans lack a cellular homologue for HIV integrase, raltegravir has a low potential for toxicity. Raltegravir has an intermediate genetic barrier and consequently there may be cross-resistance across the integrase inhibitor class. For all these reasons, raltegravir is an attractive option in treatment-naive and pretreated patients and in those receiving simplification regimens.

Objetivo Evaluar mediadores inflamatorios (proteina C reactiva [PCR], interleucina-1 beta [IL-1β], IL-6 y factor de necrosis tumoral alfa [TNF-α]) como predictores de bacteriemia en el anciano con sindrome de respuesta inflamatoria sistemica (SRIS). Metodo Se cursaron hemocultivos y mediadores al ingreso y al cuarto dia. Resultados Se incluyeron 82 pacientes, el 34% de ellos con hemocultivos positivos. Los valores de TNF-α y de IL-6 al ingreso fueron superiores en pacientes con hemocultivos positivos (84,5 frente a 28,5 pg/ml [p = 0,001] y 192,5 frente a 113 [p = 0,017], respectivamente). Los valores de TNF-α al cuarto dia fueron superiores en los pacientes con hemocultivos positivos (50,5 frente a 30 [p = 0,017]). Conclusiones Los valores elevados de TNF-α e IL-6 al ingreso y TNF-α al cuarto dia se correlacionaron con bacteriemia.

Background The use of HAART combining 2 nucleoside analogues reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor (PI) or 2 NRTIs + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) has shown comparable efficacy. The study was designed to compare long term (2 years) effectiveness of two antiretroviral (ARV) treatment strategies in patients not previously treated: starting with a nelfinavir based HAART switching to nevirapine in case of failure or side effects or the reverse sequence. Methods This multicenter, randomized, open label clinical trial enrolled ARV-naive HIV patients with CD4 counts below 500 cells/mm3. They were randomly assigned to start ddI + d4T + nelfinavir (switching to ZDV + 3TC + NEV in case of failure or toxicity) (PI-NEV arm) or ddI + d4T + nevirapine, switching to ZDV + 3TC + NFV in case of failure or toxicity (NEV-PI arm). The primary study endpoint was the Kaplan-Meier estimates of the time to failure after switching to second regimen if necessary (considering failure as two consecutive plasma HIV-1 RNA determinations above 200 copies/mL, death, a new category C event or toxicity leading to treatment discontinuation of the second regimen) after a minimum follow-up of two years. Results A total of 137 patients were evaluable (67 and 70 in the PI-NEV and NEV-PI arms respectively). Baseline characteristics did not differ among groups. Kaplan-Meier estimates of time to failure did not show differences between the two arms neither in the on-treatment (OT) analysis (log rank test, p = 0.81) nor in the intent-to-treat (ITT) analysis (p = 0.58). At 24 months, the estimated proportion of patients free of failure were 72% and 66% respectively in the PI-NEV and NEV-PI arms OT analysis (p = 0.54) and 73% and 64% in the PI-NEV and NEV-PI arms in the ITT analysis (p = 0.49). The difference in the median in CD4+ lymphocyte count at 24 months was not significantly different in the two groups: 393 and307 CD4 cells/mm3 in the PI-NEV and NEV-PI arms respectively (p = 0.167). The incidence of adverse events (AEs) in the two arms was very similar: 50 (75%) in the PI-NEV and 54 (70%) in the NEV-PI group, as it was for grade 3-4 AEs leading to drug switching. Conclusion At two years both treatments strategies (PI-NEV vs NEV-PI) had a high and comparable efficacy and were generally well tolerated.

Objetivo En 1995 se creo un servicio de hospitalizacion a domicilio especializado en enfermedades infecciosas con la finalidad de mejorar la calidad de vida, reducir la estancia hospitalaria de los pacientes que precisan antibioterapia parenteral prolongada y mejorar el control del paciente al alta con vigilancia clinico-analitica. Revisamos la experiencia de dicho servicio entre 1995 y 2002 a partir de datos recogidos prospectivamente. Metodos Analisis del numero de pacientes incluidos por ano, el numero de pacientes con infeccion por el virus de la inmunodeficiencia humana (VIH), el diagnostico de enfermedad infecciosa, el servicio de origen, el tratamiento antimicrobiano administrado, el destino al alta y el motivo de reingreso hospitalario. Resultados El numero de pacientes incluidos cada ano durante el periodo de 1995 a 2002 fue: 52, 55, 77, 232, 213, 321, 280 y 219, respectivamente. El porcentaje de pacientes con infeccion por el VIH incluidos en el programa paso del 90% en el ano 1995 al 23% en el 2002. La causa principal de inclusion en el programa ha cambiado desde la sustitucion del hospital de dia para administracion de tratamiento, a la consecucion de un alta hospitalaria precoz. Mientras que la infeccion por citomegalovirus (CMV) fue el proceso tratado con mayor frecuencia durante el periodo 1995-1998, en los anos siguientes fueron las infecciones bacterianas el diagnostico de inclusion mas frecuente. En 148 episodios la autoadministracion y las bombas de infusion portatiles fueron utilizadas para administrar los antimicrobianos. La autoadministracion se asocio a un mayor riesgo de complicaciones (24% frente a 12%; odds ratio [OR]: 2,3; intervalo de confianza del 95% [IC 95%]: 1,5-3,6; p Conclusiones El porcentaje de pacientes con infeccion por el VIH incluidos en el programa ha disminuido progresivamente desde 1996 probablemente en relacion con la introduccion de la terapia antirretroviral de alta eficacia y un mejor control de las infecciones oportunistas. Las infecciones bacterianas son actualmente las infecciones mas frecuentes atendidas en este servicio. El alta hospitalaria precoz es el principal motivo de inclusion en el programa.

Introducción. La necesidad de recursos sanitarios de la población inmigrante ha aumentado en los últimos años. El estudio de los problemas de salud y la vulnerabilidad social planteados durante el ingreso hospitalario de estos pacientes ayudaría a mejorar su cuidado. Pacientes y métodos. Estudio caso-control realizado en el Hospital Clínic de Barcelona. Se incluyeron pacientes inmigrantes ingresados con patología infecciosa de octubre de 2002 a septiembre de 2003. Los casos fueron apareados por edad, sexo e infección por virus de la inmunodeficiencia humana (VIH). Se evaluaron variables clínicas (visitas a Urgencias, días y número de ingresos, cantidad de procedimientos y fármacos, diagnóstico etiológico y control post alta) y de vulnerabilidad social (utilización de trabajo social, tarjeta sanitaria, cuidador de referencia, consumo de tóxicos, barrera idiomática y alta de enfermería). Resultados. Se estudiaron 102 pacientes (51 casos y 51 controles, todos varones). El 56% estaban infectados por VIH en ambos grupos. El número de procedimientos diagnósticos o terapéuticos fue mayor en el grupo de inmigrantes (p = 0,02), se llegó en menor proporción a un diagnóstico etiológico (el 82% frente al 98%, p = 0,021) y el número de visitas post alta fue inferior (el 55% frente al 77%, p = 0,04). Los pacientes inmigrantes tuvieron unos índices de vulnerabilidad social mayores que la población autóctona y en un 35% de ellos existía una barrera idiomática. Un menor número tenían tarjeta sanitaria (el 63% frente al 94%, p < 0,0001) y un número mayor tuvieron necesidad de traslado a un centro sociosanitario (el 16% frente al 2%, p = 0,01). Discusión La vulnerabilidad social de los pacientes inmigrantes influye en una menor obtención del diagnóstico etiológico, mayor número de procedimientos durante la hospitalización y un menor seguimiento posterior al alta.

A polymerase chain reaction (PCR)-based test for Pneumocystis jiroveci (formerly Pneumocystis carinii f. sp. hominis) might be an alternative to histologic diagnoses of P. jiroveci pneumonia (PCP). However, previously developed nested PCR methods tend to have low specificities (high false-positive rates). In this study, nested and quantitative real-time PCR methods for the amplification of the P. jiroveci DHPS (dihydropteroate synthase) gene were evaluated in a variety of stored clinical samples from Spain, South Africa, and Brazil. The sensitivities of both assays were high, ranging from 62.5% to 100% depending on the type of specimen. In a subset of 71 microscopically confirmed PCP cases and 70 negative cases, the sensitivities and specificities were 94% and 81% for nested PCR and 94% and 96% for real-time PCR, respectively. Real-time PCR has a statistically significantly better specificity than nested PCR (P = .015) and is likely to generate fewer false positives.

The chronic infection by the hepatits C virus represents a serious sanitary problem affecting 1-3% of the world-wide population. It is transmitted by sexual route, vertical route and mainly after blood exposure by percutanea route. While HIV shares similar routes of transmission, the co-infection HCV-HIV is very frequent and the chronic hepatopathy and complications associated with its clinical course are an important cause of morbi-mortality in this population. The gold standard of the treatment for the HCV, has been the interferon and later the combination therapy of interferon plus ribavirine. Currently, the combination of ribavirine and a new pegilated formulation of the interferon has become the standard in the treatment reaching rates of sustained viral response around 40-80%.

OBJECTIVE: This consensus document is an update of antiretroviral therapy (ART) recommendations for adult patients infected with the human immunodeficiency virus (HIV). METHODS: To formulate these recommendations, a panel composed of members of the Grupo de Estudio de Sida (GESIDA; AIDS Study Group) and the Plan Nacional sobre el Sida (PNS; Spanish AIDS Plan) reviewed the advances in current understanding of the pathophysiology of HIV, the safety and efficacy findings from clinical trials, and the results from cohort and pharmacokinetic studies published in biomedical journals or presented at scientific meetings over the last years. Three levels of evidence were defined according to the source of the data: randomized studies (level A), cohort or case-control studies (level B), and expert opinion (level C). The decision to recommend, consider or not recommend ART was established in each of these situations. RESULTS: ART consisting of at least three drugs is currently the initial treatment of choice for chronic HIV infection. These regimens should include 2 NRTI + 1 NNRTI or 2 NRTI + 1 PI. Initiation of ART is recommended in patients with symptomatic HIV infection. In asymptomatic patients, initiation of ART is recommended on the basis of CD4+ lymphocyte counts per L and plasma viral load, as follows: 1) Therapy should be started in patients with CD4+ counts of 350 cells/µL. The initial objective of ART is to achieve an undetectable viral load. Adherence to therapy plays an essential role in maintaining the antiviral response. Because of the development of cross resistance, therapeutic options are limited when ART fails. Genotype studies are useful in these cases. Toxicity is a limiting factor in the use of ART, although the benefits outweigh the risks. In addition, the criteria for the use of ART are discussed in situations of acute infection, pregnancy, and post-exposure prophylaxis, and in the management of co-infection of HIV with HCV or HBV. CONCLUSIONS: CD4+ lymphocyte count is the most important reference factor for initiating ART in asymptomatic patients. The large number of available drugs, the increased sensitivity of tests to monitor viral load, and the possibility to determine viral resistance is leading to a more individualized approach to therapy.

Objetivo Efectuar una puesta al dia de las recomendaciones sobre el tratamiento antirretroviral (TAR) para los adultos infectados por el virus de la inmunodeficiencia humana (VIH). Metodos Estas recomendaciones se han consensuado por un comite del Grupo de Estudio de Sida (GESIDA) y del Plan Nacional sobre el Sida (PNS). Para ello se han revisado los avances en la fisiopatologia del VIH, los resultados de eficacia y seguridad de ensayos clinicos, estudios de cohortes y de farmacocinetica, publicados en revistas biomedicas o presentados en congresos en los ultimos anos. Se han definido tres niveles de evidencia segun la procedencia de los datos: estudios aleatorizados (nivel A), de cohortes o de caso-control (nivel B), u opinion de expertos (nivel C). En cada una de las situaciones se ha establecido recomendar, considerar o no recomendar el TAR. Resultados En el momento actual, el TAR con combinaciones de al menos tres farmacos constituye el tratamiento de inicio de eleccion de la infeccion cronica por el VIH. Estas pautas deben incluir dos inhibidores de la transcriptasa inversa analogos de nucleosidos (ITIAN) mas un no nucleosido (ITINN) o dos ITIAN mas un inhibidor de la proteasa (IP). En los pacientes con una infeccion por VIH sintomatica se recomienda iniciar TAR. En los pacientes asintomaticos el inicio de TAR se basara en la cifra de linfocitos CD4+/μl y en la carga viral plasmatica (CVP): a) en pacientes con linfocitos CD4+ 350 cel./μl se puede diferir el inicio del TAR. El objetivo del TAR inicial es lograr una CVP indetectable. La adherencia al TAR tiene un papel fundamental en la duracion de la respuesta antiviral. Las opciones terapeuticas en los fracasos del TAR son limitadas por la aparicion de resistencias cruzadas. Los estudios genotipicos en estos casos son de utilidad. La toxicidad es un factor limitante del TAR, aunque los beneficios superan los posibles perjuicios. Tambien se discuten los criterios de TAR de la infeccion aguda, embarazo y profilaxis postexposicion, y el manejo de la coinfeccion por el VIH y los virus de la hepatitis C y B (VHC y VHB). Conclusiones La cifra de linfocitos CD4+ es el factor de referencia mas importante para iniciar el TAR en pacientes asintomaticos. Por otra parte, el numero considerable de farmacos disponibles, los metodos de monitorizacion mas sensibles (CVP), y la posibilidad de determinar las resistencias hacen que las estrategias terapeuticas sean mucho mas individualizadas.

Objetivo Efectuar una puesta al dia de las recomendaciones sobre el tratamiento antirretroviral (TAR) para los adultos infectados por el virus de la inmunodeficiencia humana (VIH). Metodos Estas recomendaciones se han consensuado por un comite del Grupo de Estudio de Sida (GESIDA) y del Plan Nacional sobre el Sida (PNS). Para ello, se han revisado los avances en la fisiopatologia del VIH, los resultados de eficacia y seguridad de ensayos clinicos, estudios de cohortes y de farmacocinetica, publicados en revistas biomedicas o presentados en congresos en los ultimos anos. Se han definido tres niveles de evidencia segun la procedencia de los datos: estudios aleatorizados (nivel A), de cohortes o de caso-control (nivel B) u opinion de expertos (nivel C). En cada una de las situaciones se ha establecido recomendar, considerar o no recomendar el TAR. Resultados En el momento actual, el TAR con combinaciones de al menos 3 farmacos constituye el tratamiento de eleccion de la infeccion cronica por el VIH. En los pacientes con una infeccion por VIH sintomatica se recomienda iniciar el TAR. En los pacientes asintomaticos el inicio de TAR se basara en la cifra de linfocitos CD4+/μl y en la carga viral plasmatica (CVP): a) en pacientes con linfocitos CD4+ 350 cel./μl se puede diferir el inicio del TAR. El objetivo del TAR es lograr una CVP indetectable. La adherencia al TAR tiene un papel en la durabilidad de la respuesta antiviral. Las opciones terapeuticas en los fracasos del TAR son limitadas por la aparicion de resistencias cruzadas. Los estudios genotipicos en estos casos son de utilidad. La toxicidad es un factor limitante del TAR. Tambien se discuten los criterios de TAR de la infeccion aguda, embarazo y profilaxis postexposicion, y el manejo de la coinfeccion por el VIH y los virus de las hepatitis B y C (VHC y VHB). Conclusiones En la actualidad existe una actitud mas conservadora para iniciar el TAR que en recomendaciones previas. La cifra de linfocitos CD4+ es el factor de referencia mas importante para iniciar el TAR en pacientes asintomaticos. Por otra parte, el numero considerable de farmacos disponibles, los metodos de monitorizacion mas sensibles (CVP) y la posibilidad de determinar las resistencias hacen que las estrategias terapeuticas sean mucho mas individualizadas.

Introduccion El calculo de la adherencia al tratamiento antirretroviral constituye un dato de gran utilidad en el seguimiento de los pacientes con infeccion por virus de la inmunodeficiencia humana (VIH). Se han propuesto varios metodos para calcular la adherencia, pero cada uno de ellos presenta ciertas dificultades de aplicacion. Pacientes y metodos Se han evaluado, de forma prospectiva, tres metodos para el calculo de la adherencia: el recuento de la medicacion sobrante (RMS), la entrevista estructurada (EN) y el registro de dispensacion de medicacion desde el servicio de farmacia (DM). Se ha considerado el RMS como metodo patron y se ha evaluado la sensibilidad y la especificidad de los otros dos metodos con respecto a este. Resultados Los tres metodos se han podido aplicar a 69 casos. De estos, el porcentaje de pacientes que ha tomado el 95% o mas de las dosis prescritas ha sido del 72,5% (RMS), el 85,5% (EN) y el 81,2% (DM). Si se considera el RMS como el metodo patron, la concordancia con DM ha sido del 75,1% y con EN del 73,2%. La sensibilidad de DM y EN ha sido del 52,6 y 42,1%, respectivamente. Los pacientes con una adherencia _ 90% (RMS) presentaron una probabilidad de alcanzar una buena respuesta virologica 1,29 veces mayor (intervalo de confianza [IC] del 95%: 1,04-1,62; p _ 0,0138). Conclusion Aunque la concordancia entre los metodos es aceptable, DM y EN sobrestiman la adherencia respecto a RMS. Debido a que no se dispone de un metodo ideal para medir la adherencia es importante combinar varios metodos para realizar una medicion lo mas aproximada posible a los datos reales.

Objective To evaluate the resistance and mortality rates of multidrug-resistant tuberculosis (MDR-TB) in human immunodeficiency virus type 1 (HIV-1)-infected patients in a 1000-bed teaching hospital in inner-city Barcelona. Methods A total of 311 patients, recruited between July 1991 and July 1993, had either tuberculosis (TB) with HIV (group A), TB without HIV (group B), or TB without HIV and previous exposure to antituberculosis drugs (group C). Mycobacterium tuberculosis was isolated radiometrically or using Lowenstein-Jensen media with p-nitro-a-acetylamino-B-hidroxypropiphenone (NAP) testing. Antibiograms to isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin were performed by the critical proportions method with only one strain per patient. Results Of 197 strains of M. tuberculosis isolated in group A, six (3%) were resistant to one agent and seven (3.5%) were multiresistant vs five (5.7%) and three (3.4%) of 88 strains, respectively, in group B, and three (11.5%) and seven (26.9%) of 26 strains, respectively, in group C. Conclusions The primary resistance rate of M. tuberculosis in Spain remains relatively low in both HIV-infected and non-HIV-infected patients in contrast to a nearly 30% or higher resistance rate among patients previously exposed to antituberculosis agents.

We estimated the cumulative probability of AIDS in a cohort of 191 HIV-positive patients with pulmonary or pleural tuberculosis, as well as the role of age, sex, district of residence, risk group, alcoholism, homelessness, prison history, site of tuberculosis, radiology, tuberculin skin test and lymphocyte subsets as predictive factors for AIDS development. The 1 year cumulative probability of AIDS for all patients was 27.7% (95% Cl:21.7–35.0) and 38.6% (95% Cl:31.5–46.7) at 2 years. In the univariate analysis (Kaplan Meier method) the following categories were associated with a higher probability of AIDS: older age group (P = 0.014), exclusively homosexual risk group (P = 0.005), radiology without cavitary pattern (P < 0.001), negative tuberculin skin test (P < 0.001), low CD4 percentage (P = 0.068) and low CD4–CD8 ratio (P = 0.002). At the multivariate level (Cox method), older age group (risk ratio = 24.45, 95% Cl = 2.1–286.1), radiology without cavitary pattern (risk ratio = 15.68, 95% Cl = 1.1–211.0), and low CD4–CD8 ratio (risk ratio = 50.77, 95% Cl = 3.9–645.0) were associated with a higher probability of AIDS. A positive tuberculin skin test had a protective effect (risk ratio = 0.009, 95% Cl = 0.01-0.61). Findings from this cohort study suggest that pulmonary and/or pleural tuberculosis in HIV infected patients should be seriously considered as criteria for AIDS when a negative tuberculin skin test and/or low T4T8 ratio is present, especially in older people without cavitary radiologic pattern.

The routine clinical assessment of lipodystrophy in HIV-1-infected patients is hindered by the absence of easy and reliable methods to measure regional fat. We used sonography to measure subcutaneous fat thickness at three reference skin points (periumbilical, brachial, and malar) and intra-abdominal fat thickness in HIV-1-infected patients with and without lipodystrophy and in healthy controls. Patients without lipodystrophy had less subcutaneous fat than uninfected controls. Sonographic assessment of subcutaneous malar and brachial fat in patients with lipodystrophy was more sensitive and specific than that of intra-abdominal fat in the diagnosis of abnormal fat distribution.