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Coinfecció pel VIH/VHC; Sistema immunitari; Teràpia amb interferó Coinfección por VIH/VHC; Sistema inmunitario; Terapia con interferón HIV/HCV coinfection; Immune system; Interferon therapy Objective To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients. Methods We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE). Results HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR

Opportunistic infections continue to be a cause of morbidity and mortality in HIV-infected patients. They often arise because of severe immunosuppression resulting from poor adherence to antiretroviral therapy, failure of antiretroviral therapy, or unawareness of HIV infection by patients whose first clinical manifestation of AIDS is an opportunistic infection. The present article is an executive summary of the document that updates the previous recommendations on the prevention and treatment of opportunistic infections in HIV-infected patients, namely, infections by parasites, fungi, viruses, mycobacteria, and bacteria, as well as imported infections. The article also addresses immune reconstitution inflammatory syndrome. This document is intended for all professionals who work in clinical practice in the field of HIV infection. (C) 2016 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

Introduction: The prevalence of HIV-1 non-B variants is increasing in Spain, showing a higher number of transmitted drug resistance mutations (TDR) since 2002. This study presents the features of non-B infected patients enrolled in the cohort of antiretroviral treatment (ART) naive HIV-infected patients included in the Research Network on HIV/AIDS (CoRIS). Methods: The study includes a selected group of HIV-1 non-B-infected subjects from 670 subjects with pol sequence's collected from 2004 to 2008 in the CoRIS cohort. Epidemiological-clinical-virological data were analyzed since cohort entry until October 2011, considering the presence or absence of treatment failure (TF). Results: Eighty two non-B infected subjects with known HIV-1 variants were selected from 2004 to 2008 in the CoRIS cohort, being mainly female, immigrants, infected by recombinant viruses, and by heterosexual route. They had an intermediate TDR rate (9.4%), a high rate of TF (25.6%), of losses to follow-up (35%), of coinfections (32.9%), and baseline CD4+ counts >= 350 cells/mm(3) (61.8%). Non-B subjects with TF showed higher rates of heterosexual infection (85.7% vs. 69.5%, p

The importance of the metabolic disorders and their impact on patients with HIV infection requires an individualized study and continuous updating. HIV patients have the same cardiovascular risk factors as the general population. The HIV infection per se increases the cardiovascular risk, and metabolic disorders caused by some antiretroviral drugs are added risk factors. For this reason, the choice of drugs with a good metabolic profile is essential. The most common metabolic disorders of HIV infected-patients (insulin resistance, diabetes, hyperlipidemia or osteopenia), as well as other factors of cardiovascular risk, such as hypertension, should also be dealt with according to guidelines similar to the general population, as well as insisting on steps to healthier lifestyles. The aim of this document is to provide a query tool for all professionals who treat HIV-patients and who may present or display any metabolic disorders listed in this document. (C) 2014 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

HIV-2 and HTLV-1 infections are globally less frequent than those produced by HIV-1, the classical AIDS agent. In Spain and up to the end of 2014, a total of 310 cases of HIV-2, 274 of HTLV-1, and 776 of HTLV-2 infections had been reported. No cases of HTLV-3 or HTLV-4 infections have been identified so far in Spain. Most persons infected with HIV-2 or HTLV-1 acknowledge epidemiological risk factors for contagion, such as originating from or living in endemic regions and/or having had sexual partners from those areas. However, risk factors could not be recognized in up to 20-25% of carriers in Spain. Thus, it seems worth keeping a high level of clinical suspicion in order to identify earlier these neglected human retroviral infections, since diagnostic procedures and antiviral treatment are specific for each of these agents. In this article we summarize the major contributions reported at the meeting of the Spanish Group for HIV-2/HTLV held in Madrid in December 2014

Rates of spontaneous mutation critically determine the genetic diversity and evolution of RNA viruses. Although these rates have been characterized in vitro and in cell culture models, they have seldom been determined in vivo for human viruses. Here, we use the intrapatient frequency of premature stop codons to quantify the HIV-1 genome-wide rate of spontaneous mutation in DNA sequences from peripheral blood mononuclear cells. This reveals an extremely high mutation rate of (4.1 +/- 1.7) x 10(-3) per base per cell, the highest reported for any biological entity. Sequencing of plasma-derived sequences yielded a mutation frequency 44 times lower, indicating that a large fraction of viral genomes are lethally mutated and fail to reach plasma. We show that the HIV-1 reverse transcriptase contributes only 2% of mutations, whereas 98% result from editing by host cytidine deaminases of the A3 family. Hypermutated viral sequences are less abundant in patients showing rapid disease progression compared to normal progressors, highlighting the antiviral role of A3 proteins. However, the amount of A3-mediated editing varies broadly, and we find that low-edited sequences are more abundant among rapid progressors, suggesting that suboptimal A3 activity might enhance HIV-1 genetic diversity and pathogenesis.

Osteopenia, osteoporosis, and low bone mineral density are frequent in patients with HIV. We assessed the 96 week loss of bone mineral density associated with a nucleoside or nucleotide reverse transcriptase inhibitor (NtRTI)-sparing regimen. Antiretroviral-naive adults with HIV were enrolled in 78 clinical sites in 15 European countries into a randomised (1:1), open-label, non-inferiority trial (NEAT001/ANRS143) assessing the efficacy and safety of darunavir (800 mg once per day) and ritonavir (100 mg once per day) plus either raltegravir (400 mg twice per day; NtRTI-sparing regimen) or tenofovir (245 mg once per day) and emtricitabine (200 mg once per day; standard regimen). For this bone-health substudy, 20 of the original sites in six countries participated, and any patient enrolled at one of these sites who met the following criteria was eligible: plasma viral loads greater than 1000 HIV RNA copies per mL and CD4 cell counts of fewer than 500 cells per μL, except in those with symptomatic HIV infection. Exclusion criteria included treatment for malignant disease, testing positive for hepatitis B virus surface antigen, pregnancy, creatinine clearance less than 60 mL per min, treatment for osteoporosis, systemic steroids, or oestrogen-replacement therapy. The two primary endpoints were the mean percentage changes in lumbar spine and total hip bone mineral density at week 48, assessed by dual energy x-ray absorptiometry (DXA) scans. We did the analysis with an intention-to-treat-exposed approach with antiretroviral modifications ignored. The parent trial is registered with ClinicalTrials.gov, number NCT01066962, and is closed to new participants. Between Aug 2, 2010, and April 18, 2011, we recruited 146 patients to the substudy, 70 assigned to the NtRTI-sparing regimen and 76 to the standard regimen. DXA data were available for 129, 121 and 107 patients at baseline, 48 and 96 weeks respectively. At week 48, the mean percentage loss in bone mineral density in the lumbar spine was greater in the standard group than in the NtRTI-sparing group (mean percentage change -2.49% vs -1.00%, mean percentage difference -1.49, 95% CI -2.94 to -0.04; p=0.046). Total hip bone mineral density loss was similarly greater at week 48 in the standard group than in the NtRTI-sparing group (mean percentage change -3.30% vs -0.73%; mean percentage difference -2.57, 95% CI -3.75 to -1.35; p

Material y metodos Estudiamos pacientes con infeccion por el virus de la inmunodeficiencia humana (VIH) que desarrollaron un linfoma no Hodgkin desde enero de 1985 a octubre de 2001. Resultados Cuarenta y cuatro pacientes (36 varones y 8 mujeres; mediana de edad de 34 anos). Linfoma de Burkitt el 34% de los casos, linfoma difuso de celula grande B el 29,5%. Diagnostico de sida previo en 20 casos (45%). Indice pronostico internacional (IPI) 0-1 en 19 pacientes (43%), IPI 2 en 12 (27%) y superior a 3 en 13 (30%). Recibieron quimioterapia el 64% de los pacientes, radioterapia el 2% y ambas el 11%. Alcanzaron criterios de remision completa 13 pacientes (29%), hubo respuesta parcial en dos (4%) y estabilizacion en uno (2%). Nueve (20%) pacientes siguen vivos (5 sin enfermedad), 22 (50%) fallecieron por el linfoma no Hodgkin, 5 (11%) fallecieron por toxicidad del tratamiento y 8 por otras causas. La mediana de supervivencia fue de tres meses, proyectada al ano del 24% y a los dos anos del 14%. En el analisis univariante de factores pronostico resultaron significativos el IPI 0-1 frente al 2-5 (p = 0,000), el performance status igual o inferior a 2 (p = 0,021) y la ausencia de sintomas B (p = 0,012). En el analisis multivariante mantiene la significacion el IPI 0-1 (p = 0,000). Conclusiones La poblacion VIH con linfoma no Hodgkin tiene multiples factores de mal pronostico. La supervivencia es escasa y la toxicidad de la quimioterapia elevada. Los pacientes con IPI bajo definen un subgrupo de mejor pronostico.

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 varies with clinical circumstances, number of CD4 cells, comorbid conditions and prevention of transmission of HIV. The objective of ART is to achieve an undetectable plasma viral load. Initial ART should always comprise a combination of 3 drugs, including 2 nucleoside reverse transcriptase inhibitors and a third drug from a different family (non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor). This update presents the causes and criteria for switching ART in patients with undetectable plasma viral load and in cases of virological failure. An update is also provided for the specific criteria for ART in special situations (acute infection, HIV-2 infection, and pregnancy) and with comorbid conditions (tuberculosis or other opportunistic infections, kidney disease, liver disease, and cancer). (C) 2014 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in human immunodeficiency virus (HIV)-infected patients. Renal function should be monitored in all HIV-infected patients. The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glycosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir, or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document provides indications for renal biopsy and advises on the optimal time for referral of a patient to the nephrologist. The indications for and evaluation and management of dialysis and renal transplantation are also addressed.

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 varies with clinical circumstances, number of CD4 cells, comorbid conditions and prevention of transmission of HIV. The objective of ART is to achieve an undetectable plasma viral load. Initial ART should always comprise a combination of 3 drugs, including 2 nucleoside reverse transcriptase inhibitors and a third drug from a different family (non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or integrase inhibitor). This update presents the causes and criteria for switching ART in patients with undetectable plasma viral load and in cases of virological failure. An update is also provided for the specific criteria for ART in special situations (acute infection, HIV-2 infection, and pregnancy) and with comorbid conditions (tuberculosis or other opportunistic infections, kidney disease, liver disease, and cancer). (C) 2014 Elsevier Espana, S.L.U. and Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. All rights reserved.

Background: The aim of this study was to assess the short-term and long-term consequences of stopping antiretroviral therapy (ART) in patients with preserved immune function. Methods: This was a randomized 144-week follow-up CD4(+) T-cell-count-guided treatment-interruption trial. HIV-1-infected adults with plasma HIV-1 RNA< 50 copies/ml, CD4(+) T-cell count > 500 cells/ml and nadir CD4(+) T-cell count > 100 cells/ml were randomized to continuous treatment (CT) or treatment interruption (TI) until CD4(+) T-cell count decreased to < 350 cells/mu l. The primary end points were AIDS-defining illnesses, death, CD4(+) T-cell count < 200 cells/ml, or virological failure after restarting ART. Results: A total of 106 patients were included, 50 in the CT arm and 56 in the TI arm. A trend to a higher rate of primary end points was observed in the TI group (26.8% versus 14%, difference 12.8%, 95% CI -2.3, 27.8; P= 0.105). In addition, 10 patients presented clinical events related with HIV rebound, including 8 cases of thrombocytopaenia. The CD4(+) T-cell count significantly decreased in the TI group (even in patients with persistently high CD4(+) T-cell counts and no clinical events) versus the CT group (median change -408 cells/mu l versus -21.5 cells/mu l; P< 0.001), whereas a significant increase in CD8(+) T-cell count was observed (256 cells/mu l versus -59 cells/mu l; P< 0.001). The time to ART re-initiation was significantly associated with nadir and baseline CD4(+) T-cell counts. Conclusions: Discontinuation of ART in patients with preserved immune function is followed by significant immunological impairment even in those with no clinical events, and may be associated with an increased risk of HIV-related complications. Hence, patients who stop ART voluntarily should be closely monitored, regardless of their CD4(+) T-cell count.

Background Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. Results The cross-sectional study carried out with >200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. Conclusions Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations., This study was supported in part by grants of the Spanish Ministery of Science and Innovation (BIO2010/15532), Fundación para la Investigación y Prevención del SIDA en España (FIPSE) (grant 36771/08), Fondo de Investigación Sanitaria (through the “Red Temática de Investigación Cooperativa en SIDA” RD06/006), and an institutional grant from the Fundación Ramón Areces. Work at the AIDS Research Institute IrsiCaixa was supported by the European Commission FP7 under the “Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN), through integrated project 223131 (to J.M.P), and the Spanish Ministery of Science and Innovation (grant BFU2010-15194 to M.A.M). Researchers at Hospital Carlos III were also funded through the CHAIN network.

To determine the clinical, epidemiological and prognostic factors of HIV-infected patients with influenza A H1N1 admitted to hospital.

More than 15 years after the introduction of highly active antiretroviral therapy, HIV/HAART-associated lipodystrophy syndrome still shadows the indisputable efficacy of antiretroviral therapy. Several issues related to this complication (prevalence, diagnosis, pathogenesis, prevention, or clinical management) have not been completely clarified. However, in the last years, substantial progress has been made in elucidating some of these basic aspects. This includes a better knowledge of the pathogenic mechanisms underlying HIV/HAART-associated lipodystrophy syndrome such as genetic host determinants, the impact of HIV infection per se, as well as the contribution of antiretroviral therapy. In regard to treatment, we have learned that certain drugs are especially prone to cause HIV/HAART-associated lipodystrophy syndrome (i.e. thymidine analogues). Pharmacological interventions to treat this condition have yielded mostly disappointing results, and the only intervention which offers an immediate aesthetical improvement for patients with HIV/HAART-associated lipodystrophy syndrome is plastic surgery. Even under the most favorable conditions (ideal host genetic make-up, and the timely initiation of HIV therapy with less toxic drugs), current data show that HIV/HAART-associated lipodystrophy syndrome is a complication of HIV infection and/or antiretroviral treatment that we are unable to avoid. In the context of HIV-1-infected patients under long-term antiretroviral therapy, fat toxicity is still the dark side of the rainbow.

Toxoplasmic encephalitis is associated with high mortality and morbidity and still presents a notable incidence in our setting. Neither the clinical symptoms nor radiological features are diagnostic of this disease; however, because of its frequency and clinical importance, specific treatment is begun whenever toxoplasmosis is suspected. In patients with negative serology, or who are receiving adequate prophylaxis, or who do not respond to 2 weeks of treatment, or who present radiological lesions suggestive of another illness, diagnosis should not be delayed, and brain biopsy should be considered as soon as possible. In these cases, SPECT with 201TI (sensitivity and specificity over 90-95% for lymphoma) and/or the PCR technique to detect T. gondii (sensitivity 50-65% and specificity 95-100%) or Epstein-Barr virus (sensitivity 70-80% and specificity 95% for lymphoma) can be very useful. The treatment of choice is pyrimethamine (100 mg the first day followed by 50 mg/day) and sulphadiazine (1-1.5 g/6 h) during 6-8 weeks. If the patient is allergic to sulfadiazine and cannot be desensitized the regimen of choice is pyrimethamine and clindamycin (600 mg/6 h), with similar efficacy. Clinical experience with other therapeutic alternatives is limited. Pyrimethamine can be associated with clarithromycin (0.5-1 g/12 h), azithromycin (1-1.5 g/day) atovaquone (750 mg/6 h), dapsone (100 mg/day) or doxycyclin (200 mg/12 h). Cotrimoxazole or clindamycin can be administered intravenously to patients who cannot receive enteral treatment. The toxicity of these therapeutic regimens is significant and treatment has to be suspended in 10-40% of cases. The interactions that can be produced with other drugs used to treat HIV-infected patients are generally of little clinical relevance.

We studied by Echocardiographic-Doppler 114 consecutive intravenous drugs addicts (IVDA); 91 were positive human immunodeficiency virus (HIV+) and 23 negatives. We classified them in five groups; beginning the negative HIV as group 0, and groups I to IV stratified according the Central Disease Control (CDC) classification. We compared the cardiac abnormalities founded between themselves and a control group presumed healthy persons of similar age. The cardiac cavities dimensions showed a statistic significant increased left ventricular end-systolic and diastolic diameters, right ventricular diameter, posterior wall and interventricular septum thickness and aortic root diameter compared with the control group; but all were in the normal range for age. The left ventricular fractional shortening was statistically different from control group related the other groups, and the group IV related other. The existence and severity of pericardial effusions were directly related to the illness stage. We founded moderate pericardial effusions in 25% patients in the 0 to III groups, increasing until 50% in the group IV. The presence of valvular vegetations, nearly 30% in our series, ought to the IVDA. We did not found relationship between the severity of valvular incompetence and the illness stage. We recorded a excellent correlation between the ratio T4/T8 lymphocytes with the progress of illness and the existence and severity of cardiac abnormalities.