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Background Aseptic prosthetic loosening (APL) and prosthetic joint infections (PJI) are frequent complications of hip and knee implants. Polymorphisms of cytokines and nitric oxide (NO), key inflammatory molecules in APL and PJI pathogenesis, could explain individual susceptibility to these complications. Methods Three cytokines (IL-1-a, IL-1-β, TNF-α) and two nitric oxide synthase (NOS2, NOS3) genes polymorphisms were genotyped in 77 APL and 117 PJI patients and 145 controls with aseptic hip or knee implants lasting > 16 years. Plasma cytokines and nitrate-nitrite (NOx) levels were measured. Results The TT genotype and T allele of the (+3954C/T, exon 5, rs1143634) IL-1β polymorphism were more frequent in APL patients compared to controls (p=0.03 and p=0.02, respectively). No genotypic associations in PJI patients were observed. S. epidermidis was their most frequently isolated microorganism (39.3%). Plasma IL-6, TNF-α and NOx were significantly different between APL and controls (p< 0.0001). Plasma IL-1β and IL-6 were significantly higher in APL T allele carriers vs. non-carriers (p< 0.03). Knee implant (HR 2.488, 95% CI 1.307-4.739, p=0.005), male gender (HR 2.252, 95% CI 1.121-4.525, p=0.023), carriages of the TT genotype of the (+3954C/T) IL-1β polymorphism (HR 3.704, 95% CI 1.274-10.753, p=0.016) and AA genotype of the (exon 22) NOS2 polymorphism (HR 3.509, 95% CI 1.266-9.709, p=0.016) were independently associated with a shorter implant survival by Cox regression. Conclusion Genotyping of IL-1β (+3954C/T, exon 5, rs1143634) and NOS2 (exon 22) polymorphisms could be useful as predictors of early hip or knee APL. Disclosures All Authors: No reported disclosures.

Primary responses in sepsis-mediated inflammation are regulated by pro-inflammatory cytokines. Variations in the cytokine genes might modify their transcription or expression, plasma cytokines levels and response to sepsis. Activation protein-1 (AP-1) and NF-κB regulate cytokines gene expression in sepsis. A total of 90 severely septic and 91 non-infected patients were prospectively studied. IL-1α (–889 C/T), IL-1β (+3954 C/T), IL-6 (–174 G/C), TNF-α (–238 G/A), TNF-α (–308G/A), IL-8 (–251A/T) and IL-10 (–1082 G/A) SNPs, plasma IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, IFN-γ, TNF-α and monocyte chemoattractant protein 1 (MCP-1) levels, and AP-1 and NF-κB gene expression by neutrophils were assessed. A allele carriers of TNF-α (–238 G/A) SNP were less frequent among septic patients. IL-6, IL-8, IL-10, TNF-α and MCP-1 levels were higher, and AP-1 and NF-κB gene expressions lower in septic patients. Sepsis was independently associated with higher fibrinogen, neutrophils counts and IL-8 levels, lower prothrombin, absence of the variant A allele of the TNF-α (–238 G/A) SNP, and haemodynamic failure. Death was independently associated with a higher APACHE II score, higher IL-8 levels, and the diagnosis of sepsis. TNF-a (–238 G/A) SNP could protect against sepsis development. Higher IL-8 levels are predictive of sepsis and mortality.

Long term liver fibrosis (LF) changes and their best -monitoring non-invasive tools after effective anti-HCV DAA therapy are little- known. Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs) are pivotal in liver inflammation repair .Their plasma levels might assess long term LF changes after therapy. Overall 374 HCV-infected adult patients, 214 HCV-HIV coinfected, were followed-up for 24 months after starting DAA. LF was assessed by transient elastometry (TE), biochemical indexes (APRI, Forns, FIB-4) and, in 61 individuals, by MMPs and TIMP-1 plasma levels. Several MMPs and TIMP-1 SNPs were genotyped in 319 patients.TE was better than biochemical indexes for early and long-term LF monitoring. MMPs-2,-8,-9 and-TIMP-1 levels and TE displayed parallel decreasing curves although only TIMP-1 correlated with TE (P=0.006) and biochemical indexes (PMMP-2 (-1306 C/T) variant TT genotype associated with higher degrees of fibrosis LF regression extends 24 months after therapy. TE and TIMP1 are the most reliable LF-monitoring tools. LF courses were similar in mono- and coinfected patients, DAA regimens type did not influence fibrosis course.

Long term liver fibrosis (LF) changes and their best -monitoring non-invasive markers (NILFM) after effective anti-HCV DAA therapy are little- known. Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs) are pivotal in liver inflammation repair. Their plasma levels might assess long-term LF changes after therapy. Overall 374 HCV-infected adult patients, 214 HCV-HIV coinfected, were followed-up for 24 months after starting DAA. LF was assessed by transient elastometry (TE), biochemical indexes (APRI, Forns, FIB-4) and, in 61 individuals, by MMPs and TIMP-1 plasma levels. Several MMPs and TIMP-1 SNPs were genotyped in 319 patients. TE was better than biochemical indexes for early and long-term LF monitoring. MMPs-2,-8,-9 and-TIMP-1 levels and TE displayed parallel declining curves although only TIMP-1 correlated with TE (P = 0.006) and biochemical indexes (P MMP-2 (-1306 C/T) variant TT genotype associated with higher values of NILFM NILFM decline extends 24 months after therapy. TE and TIMP1 are reliable LF-monitoring tools. NILFM courses were similar in mono-and coinfected patients, DAA regimens type did not influence NILFM course.

ObjectivesWe compared 48 week effectiveness and safety of first-line antiretroviral regimens.MethodsWe analysed HIV treatment-naive adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) starting the most commonly used antiretroviral regimens from 2014 to 2018. We used multivariable regression models to assess the impact of initial regimen on: (i) viral suppression (VS) (viral load 0.4 and >1); (iv) CD4 percentage normalization (>29%); (v) multiple T-cell marker recovery (MTMR: CD4 > 500 cells/mm3 plus CD4 percentage >29% plus CD4/CD8 > 1); (vi) lipid, creatinine and transaminase changes; and (vii) discontinuations due to adverse events (AE).ResultsAmong 3945 individuals analysed, the most frequently prescribed regimens were ABC/3TC/DTG (34.0%), TAF/FTC/EVG/CBT (17.2%), TDF/FTC + DTG (11.9%), TDF/FTC/EVG/CBT (11.7%), TDF/FTC/RPV (11.5%), TDF/FTC + bDRV (8.3%) and TDF/FTC + RAL (5.3%). At 48 weeks, 89.7% of individuals achieved VS with no significant differences by initial regimen. CD4 mean increase was 257.8 (249.3; 266.2) cells/mm3, and it was lower with TAF/FTC/EVG/CBT and TDF/FTC/RPV compared with ABC/3TC/DTG. CD4 percentage normalization was less likely with TAF/FTC/EVG/CBT, and MTMR was less likely with TAF/FTC/EVG/CBT and TDF/FTC + RAL. The proportion of discontinuations due to AE was higher with TDF/FTC + bDRV (9.7%), followed by TDF/FTC/EVG/CBT (9.5%) and TDF/FTC + DTG (7.9%). Compared with ABC/3TC/DTG, cholesterol and LDL mean increases were higher with TAF/FTC/EVG/CBT and lower with TDF/FTC + DTG, TDF/FTC/RPV and TDF/FTC + RAL. Higher mean increases in triglycerides were significantly associated with TAF/FTC/EVG/CBT. Regimens containing DTG showed higher creatinine increases.ConclusionsThe significantly greater immunological response and safety of some combinations may be useful for making decisions when initiating treatment.

© The Author(s) 2020., [Background]: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS)., [Methods]: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014–2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL), [Results]: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL, [Conclusions]: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads., The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I+D+i and cofnanced by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER)”.

ObjectivesTo assess the attitudes and opinions about generic antiretroviral drugs (ARVs) and single-tablet regimen (STR) de-simplification among physicians prescribing HIV treatment in the cohort of the Spanish HIV/AIDS Research Network (CoRIS).MethodsAn online questionnaire with 27 structured questions was sent to all physicians (n = 199) who prescribed ARVs among the 45 centres participating in the cohort.ResultsA total of 169 (84.9%) physicians answered the questionnaire. Only 4.1% of the physicians would never prescribe generic ARVs, but 53.3% would not prescribe them if the number of pills per day increased and 89.3% would not prescribe them if the number of doses per day increased. However, 84.0% of the physicians agreed to prescribe generic ARVs if doing so would decrease costs for the public healthcare system. The percentages of physicians stating that generic ARVs (compared with branded ones) would be associated with worse adherence, more adverse effects or more probability of virological failure, provided that the number of pills and doses per day would not change, were low: 0.6%, 7.7% and 3.6%, respectively. However, these percentages were much higher if the generic ARV entailed breaking an STR: 63.9%, 18.9% and 42.0%, respectively. Most physicians stated that they needed more information about the effectiveness and safety of generic ARVs and the price difference compared with their branded equivalents.ConclusionsAlthough most physicians were confident about prescribing generic ARVs, the majority had strong concerns about de-simplifying STR, and they also needed more information about generic drugs.

[Objectives]: The aim of this study was to evaluate adherence to the recommendations of the Spanish guidelines for the initial assessment of patients with HIV infection in the multicentre Cohort of the Spanish HIV/AIDS Network (CoRIS) during the years 2004–2017., [Methods]: We calculated the percentage of patients who had each of 11 clinical and analytical recommended examinations performed in their initial evaluation. We evaluated the factors associated with not performing each examination with multivariable logistic regression models., [Results]: We included 13 612 patients in the study. In the initial assessment, CD4 count and viral load were determined in more than 98.0% of the patients. Serologies for hepatitis A, B and C and syphilis were determined in 55.8%, 66.4%, 89.8% and 81.7% of the patients, respectively. Total cholesterol and creatinine were determined in 78.7% and 78.9% of the patients, respectively. The lowest proportions of examinations were observed for blood pressure, smoking status and latent tuberculosis screening, which were performed in 43.2%, 50.6% and 53.9% of the patients, respectively. Injecting drug users and heterosexual patients (compared to men who have sex with men) and patients with a lower educational level had a higher risk of having an incomplete initial assessment for a substantial number of examinations. Latent tuberculosis screening was less likely in patients with CD4 counts < 200 cells/µL., [Conclusions]: The initial assessment of HIV‐infected patients is suboptimal for the evaluation of cardiovascular risk, smoking status, screening of syphilis and viral hepatitis, and diagnosis of latent tuberculosis: adherence to the guidelines was low for these examinations., The RIS cohort (CoRIS) is supported by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/ 0017/0018 and RD16/0002/0006) as part of the Plan Nacional I+D+i and cofinanced by ISCIII-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER).

Author(s): Perez-Is, Laura; Ocana, Marcos G; Montes, A Hugo; Carton, Jose A; Alvarez, Victoria; Meana, Alvaro; Fierer, Joshua; Valle-Garay, Eulalia; Asensi, Victor | Abstract: BACKGROUND:Osteomyelitis is a bone infection, most often caused by Staphylococcus aureus, in which neutrophils play a key role. Cathepsin G (CTSG) is a bactericidal serine protease stored in the neutrophil azurophilic granules. CTSG regulates inflammation, activating matrix metalloproteinases (MMPs), and coagulation. Lactoferrin (LF), a neutrophil glycoprotein, increases CTSG catalytic activity and induces inflammation. The aim of this study was to analyze a potential association between a CTSG gene polymorphism (Asn125Ser or N125S, rs45567233), that modifies CTSG activity, and could affect susceptibility to, or outcome of, bacterial osteomyelitis. METHODS:CTSG N125S polymorphism was genotyped in 329 osteomyelitis patients and 415 controls), Blood coagulation parameters, serum CTSG activity, LF, MMP-1, MMP-13, and soluble receptor activator for nuclear factor κ B ligand (sRANKL) levels were assessed in carriers of the different CTSG genotypes. RESULTS:CTSG N125S (AG) genotype was significantly more frequent among osteomyelitis patients than controls (15.5% vs. 9.4%, p = 0.014). CTSG N125S variant G allele (AG +GG) was also more frequent among osteomyelitis patients (8.1% vs. 4.7%, p = 0.01). Serum CTSG activity and LF levels were significantly higher in osteomyelitis patients carrying the G allele compared to those with the AA genotype, (pl0.04). Serum MMP-1 was lower in the G allele carriers (p = 0.01). There was no association between these genotypes and clinical characteristics of osteomyelitis, or coagulation parameters, MMP-13, and sRANKL serum levels. CONCLUSIONS:Differences in the CTSG gene might enhance osteomyelitis susceptibility by increasing CTSG activity and LF levels.

[EN]: [Introduction]: Our aims were to investigate the adherence to national guidelines of initial antiretroviral therapy (ART) in the Spanish multicenter CoRIS cohort during the years 2010–2015, to identify the reasons for the prescription of nonrecommended treatments, and to explore the role of institutional constraints to guideline compliance. [Methods]: ART regimens were classified as recommended, alternative or nonrecommended according to the guidelines. Physicians were asked the reasons for prescribing nonrecommended regimens. Factors associated with the prescription of non recommended regimens were assessed using multivariable logistic regression. [Results]: During the study period, 586 (10.7%) of 5479 patients who started ART were given a regimen not recommended in the guidelines. The most frequent reasons for prescribing nonrecommended regimens were: enrolment in clinical trials (43.3%), comorbidities and/or interactions (10.2%), pregnancy (8.7%), and cost (7.7%). Among 37 participating centers, 16 (43%), treating 3561 patients, reported limitations related with the cost of ART, and 20 (54%), treating 1365 patients, reported restrictions for prescribing at least one recommended antiretroviral. In multivariable analysis, a higher risk of receiving nonrecommended regimens was associated with male gender, HIV acquisition by heterosexual transmission, low viral loads, initiation of treatment during the years 2011 to 2015, and initiation of treatment in a center with restricted access to at least one antiretroviral drug. [Conclusions]: Compliance to clinical guidelines was high. A high proportion of centres reported cost limitations for ART or restricted access to at least one recommended antiretroviral drug, with a significant impact on the choice of initial regimens., [ES]: [Introducción]: Nuestros objetivos fueron investigar la adecuación del tratamiento antirretroviral (TAR) inicial a las guías nacionales en la cohorte multicéntrica española CoRIS durante los años 2010-2015, identificar las razones para la prescripción de pautas no recomendadas y estudiar la influencia de limitaciones institucionales en el cumplimiento de las guías. [Métodos]: Se clasificaron las pautas de TAR en recomendadas, alternativas o no recomendadas según las guías de GeSIDA/Plan Nacional sobre el sida. Se preguntaron las razones para haber prescrito pautas no recomendadas a los médicos prescriptores. Se evaluaron los factores asociados a la prescripción de pautas no recomendadas mediante regresión logística multivariable. [Resultados]: Durante el periodo de estudio 586 (10,7%) de 5.479 pacientes que iniciaron TAR recibieron una pauta no recomendada. Las razones más frecuentes para prescribir pautas no recomendadas fueron: participación en ensayo clínico (43,3%), comorbilidades y/o interacciones (10,2%), embarazo (8,7%) y coste (7,7%). Entre los 37 centros participantes 16 (43%), que incluían 3.561 pacientes, referían limitaciones en el coste del TAR y 20 (54%), que incluían 1.365 pacientes, referían restricciones para la prescripción de al menos un fármaco recomendado. En el análisis multivariable el riesgo de recibir una pauta no recomendada se asoció a ser varón, adquisición del VIH por vía heterosexual, carga viral baja, inicio del tratamiento durante los años 2011 a 2015 e inicio del tratamiento en un centro con acceso restringido al menos a un antirretroviral. [Conclusiones]: El cumplimiento de las guías de TAR fue elevado. Una alta proporción de centros refirieron limitaciones de coste para el TAR o acceso restringido al menos a uno de los fármacos antirretrovirales recomendados; esto último influyó en la elección de pautas no recomendadas.

The objective of this study was to investigate the long-term impact of low-level viremia (LLV) on all-cause mortality, AIDS and non-AIDS events (NAEs), and virological failure in patients receiving antiretroviral therapy (ART).We analyzed ART-naive adults from the cohort of the Spanish AIDS Research Network (CoRIS) who initiated ART from 2004 to 2015 and achieved plasma viral load (VL) below 50 copies per milliliter. LLV50-199 was defined as 2 consecutive VL between 50 and 199 copies per milliliter, and LLV200-499 as 2 consecutive VL between 50 and 499 copies per milliliter with at least one between 200 and 499 copies per milliliter. Multivariable Cox models were used to estimate the association of LLV with AIDS events/death, non-AIDS events, and virological failure.Of 5986 patients included, 237 (4.0%) experienced LLV50-199 and 168 (2.8%) developed LLV200-499. One hundred seventy-one patients died or developed an AIDS event, 245 had any serious NAE and 280 had virological failure. LLV200-499 was strongly associated with a higher risk of both AIDS events/death [adjusted hazard ratio (aHR), 2.89; 95% confidence interval (CI), 1.41 to 5.92] and virological failure (aHR, 3.25; 95% CI: 1.77 to 5.99), whereas no differences were observed between LLV50-199 and no LLV neither for AIDS events/death (aHR, 1.84; 95% CI: 0.89 to 3.82) nor virological failure (aHR, 1.42; 95% CI: 0.78 to 2.58). LLV was not associated with the occurrence of any serious NAE.In this cohort, LLV200-499 was strongly associated with AIDS events/death and virological failure, but not with any serious NAE. Therefore, vigorous treatment should be implemented in patients with more than 200 copies per milliliter.

Objectives The aim of the study was to study the factors associated with immunological recovery in HIV-infected patients with suppressed viral load. Methods Nadir and current CD4 cell counts were recorded in 821 patients, as well as many demographic, epidemiological, lifestyle, clinical, therapeutic, genetic, laboratory, liver fibrosis and viral hepatitis parameters. Results The median age of the patients was 44.4 years [interquartile range (IQR) 40.3–48.0 years], the median time since HIV diagnosis was 15.3 years (IQR 10.5–18.9 years), the median time of suppressed viral load was 7.0 years (IQR 4.0–10.0 years) and the median time on the current antiretroviral regimen was 2.8 years (IQR 1.4–4.7 years). The median nadir and current CD4 counts were 193.0 (IQR 84.0–301.0) and 522.0 (IQR 361.0–760) cells/μL, respectively, separated by a median period of 10.2 years (IQR 5.9–12.9 years). The median CD4 count gain during follow-up was 317.0 (IQR 173.0–508.0) cells/μL. Many variables were associated with CD4 cell gains in univariate analyses, including age, gender, epidemiology, prior clinical conditions, fibrosis stage, transient elastometry, aspartate aminotransferase (AST), nadir CD4 count and hepatitis B and C virus infections and genotypes, as well as the durations of follow-up since nadir CD4 count, overall antiretroviral treatment, current antiretroviral regimen, protease inhibitor therapy and suppression of viral load. Multivariate analysis revealed that longer duration of HIV suppression (P < 0.0001), more advanced clinical Centers for Disease Control and Prevention (CDC) stages (P < 0.0001), younger age (P = 0.0003), hepatitis C virus genotypes 1 and 4 (P = 0.003), sexual acquisition of HIV (P = 0.004), and lower transient elastometry values (P = 0.03) were independent predictors of CD4 cell gains. Overall, the model accounted for 14.2% of the variability in CD4 count. Conclusions In addition to the duration of HIV suppression, HIV-related diseases, HIV epidemiology, age, hepatitis C virus genotypes, and liver fibrosis were independently associated with long-term immunological recovery.

Cohorte de la Red de InvestigacioÂn en Sida (CoRIS)., [Objetives] Outcomes of people living with HIV (PLWH) developing non-AIDS events (NAEs) remain poorly defined. We aimed to classify NAEs according to severity, and to describe clinical outcomes and prognostic factors after NAE occurrence using data from CoRIS, a large Spanish HIV cohort from 2004 to 2013., [Design] Prospective multicenter cohort study., [Methods] Using a multistate approach we estimated 3 transition probabilities: from alive and NAE-free to alive and NAE-experienced (“NAE development”); from alive and NAE-experienced to death (“Death after NAE”); and from alive and NAE-free to death (“Death without NAE”). We analyzed the effect of different covariates, including demographic, immunologic and virologic data, on death or NAE development, based on estimates of hazard ratios (HR). We focused on the transition “Death after NAE”., [Results] 8,789 PLWH were followed-up until death, cohort censoring or loss to follow-up. 792 first incident NAEs occurred in 9.01% PLWH (incidence rate 28.76; 95% confidence interval [CI], 26.80–30.84, per 1000 patient-years). 112 (14.14%) NAE-experienced PLWH and 240 (2.73%) NAE-free PLWH died. Adjusted HR for the transition “Death after NAE” was 12.1 (95%CI, 4.90–29.89). There was a graded increase in the adjusted HRs for mortality according to NAE severity category: HR (95%CI), 4.02 (2.45–6.57) for intermediate-severity; and 9.85 (5.45–17.81) for serious NAEs compared to low-severity NAEs. Male sex (HR 2.04; 95% CI, 1.11–3.84), age>50 years (1.78, 1.08–2.94), hepatitis C-coinfection (2.52, 1.38–4.61), lower CD4 cell count at cohort entry (HR 2.49; 95%CI 1.20–5.14 for CD4 cell count below 200 and HR 2.16; 95%CI 1.01–4.66 for CD4 cell count between 200–350, both compared to CD4 cell count higher than 500) and concomitant CD4, [Conclusion] NAEs, including low-severity events, increase prominently the risk for mortality in PLWH. Prognostic factors differ between NAE-experienced and NAE-free persons. These findings should be taken into account in the clinical management of PLWH developing NAEs and may permit more targeted prevention efforts., This work was supported by the RD12/0017/0023 and RD 16/0025/0038 projects as part of the Plan Nacional R + D + I and cofinanced by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER), FIS (PI08/893), FIS (PI13/02256), FIS (PI16/01740), FISABIO UGP-14-197, Contrato de Intensificación de la Actividad Investigadora INT 14/00207, Contrato Predoctotal FISABIO 2015 (UGP-15-152) and Contrato Río Hortega (CM15/00187).

Objectives The aim of the study was to assess the adequacy of initial antiretroviral therapy (ART), in terms of its timing and the choice of regimens, according to the Spanish national treatment guidelines [Spanish AIDS Study Group−National Plan for AIDS (GeSIDA-PNS) Guidelines] for treatment-naive HIV-infected patients. Methods A prospective cohort study of HIV-positive ART-naive subjects attending 27 centres in Spain from 2004 to 2010 was carried out. Regimens were classified as recommended, alternative or nonrecommended according to the guidelines. Delayed start of treatment was defined as starting treatment later than 12 months after the patient had fulfilled the treatment criteria. Multivariate logistic and Cox regression analyses were performed. Results A total of 6225 ART-naive patients were included in the study. Of 4516 patients who started treatment, 91.5% started with a recommended or alternative treatment. The use of a nonrecommended treatment was associated with a CD4 count > 500 cells/μL [odds ratio (OR) 2.03; 95% confidence interval (CI) 1.14–3.59], hepatitis B (OR 2.23; 95% CI 1.50–3.33), treatment in a hospital with 5 log HIV-1 RNA copies/ml. The use of a nonrecommended regimen was significantly associated with mortality [hazard ratio (HR) 1.61; 95% CI 1.03–2.52; P = 0.035] and lack of virological response. Conclusions Compliance with the recommendations of Spanish national guidelines was high with respect to the timing and choice of initial ART. The use of nonrecommended regimens was associated with a lack of virological response and higher mortality.

Objectives The objective of the study was to analyse key HIV-related outcomes in migrants originating from Latin America and the Spanish-speaking Caribbean (LAC) or sub-Saharan Africa (SSA) living in Spain compared with native Spaniards (NSP). Methods The Cohort of the Spanish AIDS Research Network (CoRIS) is an open, prospective, multicentre cohort of antiretroviral-naive patients representing 13 of the 17 Spanish regions. The study period was 2004–2010. Multivariate logistic or Fine and Gray regression models were fitted as appropriate to estimate the adjusted effect of region of origin on the different outcomes. Results Of the 6811 subjects in CoRIS, 6278 were NSP (74.2%), LAC (19.4%) or SSA (6.4%). For these patients, the follow-up time was 15870 person-years. Compared with NSP, SSA and LAC under 35 years of age had a higher risk of delayed diagnosis [odds ratio (OR) 2.0 (95% confidence interval (CI) 1.5–2.8) and OR 1.7 (95% CI 1.4–2.1), respectively], as did LAC aged 35–50 years [OR 1.3 (95% CI 1.0–1.6)]. There were no major differences in time to antiretroviral therapy (ART) requirement or initiation. SSA exhibited a poorer immunological and virological response [OR 0.8 (95% CI 0.7–1.0) and OR 0.7 (95% CI 0.6–0.9), respectively], while no difference was found for LAC. SSA and LAC showed an increased risk of AIDS for ages between 35 and 50 years [OR 2.0 (95% CI 1.1–3.7) and OR 1.6 (95% CI 1.1–2.4), respectively], which was attributable to a higher incidence of tuberculosis. However, no statistically significant differences were observed in mortality. Conclusions Migrants experience a disproportionate diagnostic delay, but no meaningful inequalities were identified regarding initiation of treatment after diagnosis. A poorer virological and immunological response was observed in SSA. Migrants had an increased risk of AIDS, which was mainly attributable to tuberculosis.

Objectives To compare causes of death (CoDs) from two independent sources: National Basic Death File (NBDF) and deaths reported to the Spanish HIV Research cohort [Cohort de adultos con infeccion por VIH de la Red de Investigacion en SIDA CoRIS)] and compare the two coding algorithms: International Classification of Diseases, 10th revision (ICD-10) and revised version of Coding Causes of Death in HIV (revised CoDe). Methods Between 2004 and 2008, CoDs were obtained from the cohort records (free text, multiple causes) and also from NBDF (ICD-10). CoDs from CoRIS were coded according to ICD-10 and revised CoDe by a panel. Deaths were compared by 13 disease groups: HIV/AIDS, liver diseases, malignancies, infections, cardiovascular, blood disorders, pulmonary, central nervous system, drug use, external, suicide, other causes and ill defined. Results There were 160 deaths. Concordance for the 13 groups was observed in 111 (69%) cases for the two sources and in 115 (72%) cases for the two coding algorithms. According to revised CoDe, the commonest CoDs were HIV/AIDS (53%), non-AIDS malignancies (11%) and liver related (9%), these percentages were similar, 57, 10 and 8%, respectively, for NBDF (coded as ICD-10). When using ICD-10 to code deaths in CoRIS, wherein HIV infection was known in everyone, the proportion of non-AIDS malignancies was 13%, liver-related accounted for 3%, while HIV/AIDS reached 70% due to liver-related, infections and ill-defined causes being coded as HIV/AIDS. Conclusion There is substantial variation in CoDs in HIV-infected persons according to sources and algorithms. ICD-10 in patients known to be HIV-positive overestimates HIV/AIDS-related deaths at the expense of underestimating liver-related diseases, infections and ill defined causes. CoDe seems as the best option for cohort studies.

SUMMARY. The role of exposure to antiretrovirals (ARV) and serum matrix metalloproteases (MMPs) on liver fibrosis (LF) progression in human immunodeficiency virus (HIV) mono or HIV‐ hepatitis C virus (HCV) coinfection is unclear. Thus, 213 Caucasian adult HIV-infected patients were studied, 111 of whom had HCV-coinfection and 68 were HCVmonoinfected. Patients with ethanol consumption >50 g/ day, hepatitis B coinfection, non-infective liver diseases or HAART adherence

Background The aim of this study was to estimate the persistence of the most commonly used first-line combined antiretroviral regimens (cART) in HIV-infected adults in the CoRIS cohort. Methods CoRIS is an open prospective multicentre cohort of HIV-infected adults naive to cART at entry. Patients enrolled between January 2008 and June 2010 were included. The main outcome was treatment persistence, defined as time from cART initiation to first treatment change (TC). Cox models taking into account competing risks to estimate sub-hazard ratios (sHR) were performed. Results Of 1,512 patients, 919 (60.8%) initiated cART with the backbone tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) plus efavirenz (EFV), 252 (16.7%) plus lopinavir/ritonavir (LPV/r), 129 (8.5%) plus atazanavir/ritonavir (ATV/r), 110 (7.3%) plus darunavir/ritonavir (DRV/r) and 102 (6.7%) plus nevirapine (NVP). Among 414 patients who switched therapy, reason for switching was available for 393. The most frequent reasons were toxicity (40%), simplification (14%) and treatment failure/resistance (13%). In multivariate analyses, there were significant differences in the risk of TC according to initial cART regimen ( PConclusions Switching from initial cART regimens is frequent, toxicity being the main reason for it. The significantly greater persistence of some combinations may be useful for making decisions when initiating cART.

Background The aim of this study was to analyse associations between educational level and delayed HIV diagnosis (DD), late initiation of combined antiretroviral therapy (cART), overall and in subjects with timely HIV diagnosis, virological and immunological responses to cART, and mortality from HIV diagnosis and cART initiation. Methods This was a multicentre cohort study of HIV-positive treatment-naive subjects in Spain between 2004–2009. Logistic and Cox regression analyses were used. Results Of 4,549 subjects, 44.5% had low education level (LOW), 34.4% medium education level (MED) and 21.1% high education level (HIG). In men, DD was more common in MED (OR 1.3 [95% CI 1.0, 1.7]) or LOW [OR 1.8 (95% CI 1.4, 2.3)] compared to HIG. In women, the opposite was observed; women with HIG were 40% more likely to have DD than those with LOW (OR 1.4 [95% CI 0.8, 2.5]). In individuals with timely HIV diagnoses, percentages of late cART initiators were similar (LOW 9.5%, MED 11.4% and HIG 7.0%; P=0.114). Immunological (LOW 68%, MED 76% and HIG 84%) and virological (LOW 76%, MED 83% and HIG 86%) responses to cART increased significantly with educational level; these increases remained significant in multivariate analyses. Mortality for LOW subjects was higher than for HIG, from HIV diagnosis (hazard ratio [HR] 2.3 [95% CI 1.1, 4.9]) and from cART initiation (HR 1.8 [95% CI 0.8, 3.9]). Conclusions We found important differences by educational level in diagnosis delay, virological and immunological responses to cART and mortality in a country with universal health care. Women with high educational level are at higher risk of having delayed HIV diagnoses. Educational level should be taken into account when designing HIV testing and clinical management strategies.

Objective: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in extracellular matrix remodelling and adipocyte differentiation and are inhibited by antiretrovirals. MMPs and TIMPs and their single nucleotide polymorphisms (SNPs) might contribute to the HAART-related lipodystrophic syndrome pathogenesis. Design and setting: Cross-sectional study in a university-based outpatient clinic. Patients and methods: Two hundred and sixteen HIV-infected patients on extended HAART were studied. Serum MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4) were measured by ELISA microarrays. MMP1 (� 16071G/2G) SNP was also genotyped. Lipodystrophic syndrome was diagnosed by a clinical scale validated by fat dual energy X-ray absorptiometry. Results: Eighty-two patients (38.0%) showed lipodystrophic syndrome, mostly lipoatrophy. The 2G/2G MMP1 SNP genotype was more frequent among lipodystrophic syndrome patients (41.3 vs. 20.5%, odds ratio, 2.73; 95% confidence interval, 1.41‐ 5.29; x 2 ¼9.62, P ¼0.002 for HIV-infected patients with and without lipodystrophic syndrome respectively). Carriers of this genotype had higher serum levels of MMP1 compared with those with the 1G/1G (P ¼0.02). Higher MMP1 (P ¼0.022) and lower TIMP4 (P ¼0.038) serum levels were observed while comparing HIV patients with and without lipodystrophic syndrome. MMP1 2G carriage (P ¼0.0008), TIMP4 lower serum levels (P ¼0.02), treatment with stavudine (P

Resumen Fundamento y objetivo Describir las caracteristicas de pacientes adultos con infeccion por el virus de la inmunodeficiencia humana (VIH) segun su edad al momento de la inclusion en la Cohorte de la Red de Investigacion en Sida (CoRIS). Pacientes y metodos Analisis de una cohorte abierta, prospectiva, multicentrica de adultos con infeccion por el VIH sin tratamiento antirretroviral previo, atendidos por primera vez entre enero de 2004 y noviembre de 2008, en 28 hospitales espanoles (CoRIS). Se analizaron sus caracteristicas en la primera visita y la distribucion de las enfermedades definitorias de sida (EDS) a lo largo de la vida, segun la edad al momento de la inclusion. El retraso diagnostico se definio como pacientes con diagnostico de sida o cifra de CD4+ inferior a 200 cel/μl durante el ano posterior al diagnostico de la infeccion por el VIH. Resultados Participaron 4.418 personas; el 30,4% con 30 anos o menos, el 60,6% de entre 31 y 50 anos y el 8,9% de mayores de 50 anos. El 31,6% de los pacientes eran inmigrantes (el 44,1% entre los jovenes), el 79,6% correspondia a transmision sexual y el 15,2% tenia diagnostico de sida en la primera visita (el 28,1% entre los mayores de 50 anos). El 34,6% de los pacientes tenia retraso diagnostico (el 53,3% en los mayores de 50 anos). La distribucion de las EDS vario con la edad: las tuberculosis son mas frecuentes en jovenes y la neumonia por Pneumocystis jiroveci , la leucoencefalopatia multifocal progresiva, la encefalopatia por VIH, la neumonia recurrente y el linfoma cerebral primario son mas frecuentes en los mayores. Conclusiones Las caracteristicas inmunologicas y las EDS varian con la edad. El porcentaje de personas con retraso diagnostico es inaceptablemente alto, lo que indica que deben disenarse intervenciones dirigidas a efectuar un diagnostico mas precoz.

The prevalence of injection drug use decreased from 67.3% in 1997 to 14.5% in 2006 among Spanish patients infected with human immunodeficiency virus (HIV). A parallel decrease in the prevalence of coinfection with hepatitis C virus was observed, from 73.8% in 1997 to 19.8% in 2006. This steady decrease in the prevalence of coinfection among Spanish patients was caused by a change in transmission routes of HIV infection.

Neutrophils (PMN), potent phagocytes, are the first line of the host immune defence against microorganisms, especially bacteria. Their half-life is very short and they are eliminated through apoptosis. Delayed neutrophil apoptosis is a characteristic feature of human osteomyelitis arising from Gram-negative or Gram-positive bacterial infection. The aim of this study was to investigate the modulation of apoptosis during infection of the human neutrophils by Staphylococcus aureus or Escherichia coli, the most common isolate in osteomyelitis. Analysis of host cells by flow cytometry using propidium iodide or annexin V labelling revealed an apoptosis inhibition after bacterial infection or treatment with LPS or LTA. We detected the secretion of cytokines such as IL-6, TNF-alpha and IL-1 beta by infected neutrophils. The addition of monoclonal antibodies to each cytokine abolished the protection against apoptosis. The anti-apoptotic Bcl-x(L) protein expression was increased and the pro-apoptotic Bax-alpha protein expression was decreased. These results identify a novel apoptotic effect in bacteria-infected cells that is mainly dependent on auto-production of cytokines and is correlated with Bax-alpha/Bcl-x(L) ratio. This may be a mechanism through which to resolve bacterial osteomyelitis infection.

Purpose: To evaluate the impact of acquired and inherited factors on the development of lipodystrophic syndrome in patients on highly active antiretroviral therapy. Methods: Two hundred forty-three human immunodeficiency virus-infected Caucasians on highly active antiretroviral therapy were prospectively followed-up for 3 years. Eleven were naIve and 232 were on antiretrovirals (mean, 93.0 months ± 43.8 months). Lipodystrophic syndrome was diagnosed clinically with a lipodystrophy severity grading scale. Polymorphisms of cytokines (IL-1β, IL-6, TNF-α), TLR4, and NOS genes were genotyped. Results: Ninety (37%) patients developed lipodystrophic syndrome. The polymorphic T allele of the (+3954C/T) polymorphism of IL-1β was less frequent in patients with lipodystrophic syndrome compared with those without (17.8% vs. 27.0%, P = 0.03). Factors significantly associated with lipodystrophic syndrome were time on stavudine (P < 0.001), use of stavudine (P = 0.001), absence of the T allele of the (+3954C/T) IL-1β polymorphism (P = 0.02), acquired immune deficiency syndrome diagnosis (P = 0.005), nadir levels of CD4 (P = 0.003), and time on highly active antiretroviral therapy (P = 0.003). Of these factors, only the time on stavudine (hazard ratio [95% confidence intervals] 1.007 [1.001–1.013]), use of stavudine (1.678 [1.048–2.68]), and absence of the T allele of the IL-1β (+3954C/T) polymorphism (0.569 [0.347–0.931]) were significantly associated with lipodystrophic syndrome by Cox regression. Conclusions: Genotyping of the (+3954C/T) polymorphism of IL-1β could be useful in patients starting highly active antiretroviral therapy, especially in potential users of stavudine, to predict their risk of developing lipodystrophic syndrome.

Background The relationship between host microRNAs (miRNA), viral control and immune response has not yet been elucidated in the field of HIV. The aim of this study was to assess the differential miRNA profile in CD8+ T-cells between HIV-infected individuals who differ in terms of viral replication control and immune response. Methods miRNA profile from resting and CD3/CD28-stimulated CD8+ T-cells from uninfected individuals (HIV-, n = 11), Elite Controllers (EC, n = 15), Viremic Controllers (VC, n = 15), Viremic Progressors (VP, n = 13) and HIV-infected patients on therapy (ART, n = 14) was assessed using Affymetrix miRNA 3.1 arrays. After background correction, quantile normalization and median polish summarization, normalized data were fit to a linear model. The analysis comprised: resting samples between groups; stimulated samples between groups; and stimulated versus resting samples within each group. Enrichment analyses of the putative target genes were perfomed using bioinformatic algorithms. Results A downregulated miRNA pattern was observed when resting samples from all infected groups were compared to HIV-. A miRNA downregulation was also observed when stimulated samples from EC, ART and HIV- groups were compared to VP, being hsa-miR-4492 the most downregulated. Although a preferential miRNA downregulation was observed when stimulated samples were compared to the respective resting samples, VP presented a differential miRNA expression pattern. In fact, hsa-miR-155 and hsa-miR-181a were downregulated in VP whereas in the other groups, either an upregulation or no differences were observed after stimulation, respectively. Overall, functional enrichment analysis revealed that the predicted target genes were involved in signal transduction pathways, metabolic regulation, apoptosis, and immune response. Conclusions Resting CD8+ T-cells do not exhibit a differential miRNA expression between HIV-infected individuals but they do differ from non-infected individuals. Moreover, a specific miRNA pattern is present in stimulated CD8+ T-cells from VP which could reflect a detrimental pattern in terms of CD8+ T-cell immune response.

Cytokines generate nitric oxide (NO) in osteoblasts and neutrophils through the induction of NO synthase isoforms, endothelial (NOS3) and inducible (NOS2), thereby producing bone loss. In osteomyelitis (OM), a chronic infection of the bone, homozygosity for the NOS3 (27-bp repeat, intron 4 polymorphism) 4 allele was significantly more frequent among the 80 patients than in 300 healthy controls ( p = 0.044). No significant differences were found for other polymorphisms of the NOS genes such as NOS3 , the promoter (−786T/C), and the missense change (E298D) in exon 7, and for NOS2 , the G/A substitution at position 37498 in exon 22, the (CCTTT) n , and (TAAA) n micro-satellites and the −954G/C in the promoter. Serum NO levels were significantly higher only in the OM patients homozygous for the NOS3 (27-bp repeat, intron 4 polymorphism) 4 allele, compared to controls. In the presence of bacteria or bacterial products, the neutrophils of these patients produced more NO. However, immunolabelling of osteoblasts for NOS3 in biopsy tissues did not correlate with the carriage of a determined NOS polymorphism but with the presence of bone inflammation. This is the first report of an association between a NOS3 polymorphism and the risk of developing OM.

Pharmacogenetics refers to the effect of single nucleotide polymorphisms (SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction (HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus (HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1 (MDR1) 3435C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity.

Summary Matrix metalloproteases (MMPs) are increased in different infections due to their role in controlling immune responses and are regulated by tissue inhibitors (TIMPs). Different MMP promoter single nucleotide polymorphisms (SNPs) induce changes in MMP genes, mRNA and protein expression. Gender might also modify MMP plasma levels. In order to determine the weight of these variables on MMP secretion we studied MMP-1, -2, -3, -8, -9, -10, -13 and TIMP-1, -2, -4 plasma levels in 90 patients with severe bacterial sepsis, 102 with anti-retroviral (ARV)-treated HIV monoinfection, 111 with ARV-treated HIV–hepatitis C virus (HCV) co-infection and 86 non-infected controls (45 stroke and 41 trauma patients). MMP-1(-1607 1G/2G), MMP-3(-1612 5A/6A), MMP-8(-799C/T), MMP-9(-1562 C/T) and MMP-13(-77A/G) SNPs were genotyped. MMP-3 plasma levels were significantly higher in men than in women in each diagnostic group, and MMP-3 SNP allele 6A carriers also had higher levels than allele 5A carriers, an effect that was magnified by sepsis. Independent predictors of higher MMP-3 levels were male gender (P = 0·0001), MMP-3(-1612 5A/6A) SNP (P = 0·001), higher levels of TIMP-4 (P = 0·004) and MMP-8 (P = 0·006) and lower levels of MMP-1 (P = 0·03) by multivariate analysis. No strong associations with gender or SNPs were observed for other MMPs or TIMPs. In conclusion, male gender and MMP-3(-1612 5A/6A) 6A allele carriage increased MMP-3 plasma levels significantly, especially in patients with severe bacterial sepsis. This confounding gender effect needs to be addressed when evaluating MMP-3 plasma levels in any infectious or non-infectious condition.

Summary Osteomyelitis is a bone infection caused mostly by Staphylococcus aureus but also by Gram-negative bacteria. Toll-like receptors (TLRs), after recognizing microbial products, induce a signal in neutrophils, leading to NF-κB activation and transcription of pro-inflammatory genes. Polymorphisms in TLR2 (Arg753Gln) and TLR4 (Asp299Gly, Thr399Ile) genes are associated with bacterial infections, we therefore studied these polymorphisms in osteomyelitis patients. Homozygotes for the TLR4 (Asp299Gly) polymorphism were significantly more frequent among the 80 osteomyelitis patients than in the 155 healthy controls (3/80, 3·8%versus 0/155, 0%; P = 0·038). Carriers of one or two G alleles of this tlr4 polymorphism were more likely to have Gram-negative, haematogenous and/or chronic osteomyelitis than those without this mutation (P

Salmonella strains are facultative intracellular pathogens that produce marked cytopathology during infection of host cells. Different forms of cytopathic effects have been associated with the virulence systems encoded by the two Salmonella pathogenicity islands (SPI-1 and SPI-2) and the spv locus. We used Salmonella enterica serovar Dublin to investigate the induction of cytopathology during infection of the human macrophage-like cell line THP-1. Analysis of host cells by flow cytometry using a fluorescent terminal deoxynucleotidyltransferase dUTP-biotin nick end labeling (TUNEL) assay revealed that 70% of THP-1 cells showed DNA fragmentation after 4 h of infection, increasing to greater than 90% by 5.5 h. Moreover, the results showed that gentamicin-killed or chloramphenicol-treated bacteria did not induce DNA fragmentation. Serovar Dublin strains with mutations in SPI-1, SPI-2, or spvB induced these cytopathic effects similar to wild-type bacteria. In contrast, a mutation in the phoP regulatory gene abolished DNA fragmentation in the TUNEL assay. Caspase-3 activation was detected during Salmonella infection of THP-1 cells, but caspase-8 and caspase-9 activities were not found. However, inhibition of caspase-3 did not block Salmonella -induced DNA fragmentation. These results identify a previously undetected apoptotic effect in Salmonella -infected cells that is dependent on phoP gene function.

As osteomyelitis (OM) induces the synthesis of inflammatory cytokines and IL-1 mediates bone resorption by osteoclasts we determined if there is an association between certain common polymorphisms of the genes encoding proinflammatory cytokines (IL-1 alpha and beta, IL-6, TNF-alpha) and OM in adults. The IL-1 alpha (-889) TT genotype was significantly more frequent among 52 OM patients than in 109 healthy controls (13/52, [25.0%] vs. 9/109, [8.3%], P = 0.0081, chi(2) = 7.01, OR = 3.7, 95% CI, 1.35-10.34). Patients who were homozygous for the T allele were younger than the rest of the OM patients (mean age 35.7 +/- 11.5 vs. 58.1 +/- 18.6 years, P = 0.001). IL-1 beta TT (+3953) polymorphism was also more frequent in OM patients (P = 0.014, chi(2) = 5.12, OR = 5.1, 95% CI, 1.21-52.14), but IL-1 beta is in linkage disequilibrium with the IL-1 alpha *T (P < 0.001). Route of infection, chronicity of the infection, type of microorganism isolated, and frequency of relapses were similar in patients with and without the IL-1 alpha TT genotype. There were no associations between OM and polymorphisms of other cytokines genes. IL-1 alpha serum levels were significantly increased in all the OM patients independently of their IL-1 genotype compared to the controls (P = 0.021). Although IL-1 alpha serum levels were not significantly higher in patients with the IL-1 alpha (-889) polymorphism, this does not exclude a difference in production of IL-1 alpha by osteoclasts or other inflammatory cells at the site of infection.

Current clinical guidelines consider regimens consisting of either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir and a nucleoside reverse transcriptase inhibitor (NRTI) backbone among their recommended and alternative first-line antiretroviral regimens. However, these guidelines are based on limited evidence from randomized clinical trials and clinical experience.We compared these regimens with respect to clinical, immunologic, and virologic outcomes using data from prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States in the HIV-CAUSAL Collaboration, 2004-2013. Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started a lopinavir or an atazanavir regimen. We estimated the 'intention-to-treat' effect for atazanavir vs lopinavir regimens on each of the outcomes.A total of 6668 individuals started a lopinavir regimen (213 deaths, 457 AIDS-defining illnesses or deaths), and 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths). The adjusted intention-to-treat hazard ratios for atazanavir vs lopinavir regimens were 0.70 (95% confidence interval [CI], .53-.91) for death, 0.67 (95% CI, .55-.82) for AIDS-defining illness or death, and 0.91 (95% CI, .84-.99) for virologic failure at 12 months. The mean 12-month increase in CD4 count was 8.15 (95% CI, -.13 to 16.43) cells/?L higher in the atazanavir group. Estimates differed by NRTI backbone.Our estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a greater 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for atazanavir compared with lopinavir regimens.? The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

OBJECTIVES: We aim to describe rates and risk factors of Hepatitis C Virus (HCV) diagnoses, follow-up HCV testing and HCV seroconversion from 2004-2011 in a cohort of HIV-positive persons in Spain. METHODS: CoRIS is a multicentre, open and prospective cohort recruiting adult HIV-positive patients naïve to antiretroviral therapy. We analysed patients with at least one negative and one follow-up HCV serology. Incidence Rates (IR) were calculated and multivariate Poisson regression was used to estimate adjusted Rates Ratios (aIRR). RESULTS: Of 2112 subjects, 53 HCV diagnoses were observed, IR = 0.93/100 py (95%CI: 0.7-1.2). IR increased from 0.88 in 2004-05 to 1.36 in 2010-11 (aIRR = 1.55; 95%CI: 0.37-6.55). In men who have sex with men (MSM) from 0.76 to 1.10 (aIRR = 1.45; 95%CI: 0.31-6.82); in heterosexual (HTX) subjects from 1.19 to 1.28 (aIRR = 1.08; 95%CI: 0.11-10.24). HCV seroconversion rates decreased from 1.77 to 0.65 (aIRR = 0.37; 95%CI: 0.12-1.11); in MSM from 1.06 to 0.49 (aIRR = 0.46; 95%CI: 0.09-2.31); in HTX from 2.55 to 0.59 (aIRR = 0.23; 95%CI: 0.06-0.98). HCV infection risk was higher for injecting drug users (IDU) compared to HTX (aIRR = 9.63;95%CI: 2.9-32.2); among MSM, for subjects aged 40-50 compared to 30 or less (IRR = 3.21; 95%CI: 1.7-6.2); and among HTX, for female sex (aIRR = 2.35; 95%CI: 1.03-5.34) and

BACKGROUND Successful combined antiretroviral therapy (cART) does not always result in complete CD4 T-cell recovery despite the effective control of HIV replication. Because telomere dysregulation can lead to an abnormal cell proliferation, we hypothesized that the lack of CD4 recovery may be related to telomere defects; We thus evaluated the association between telomere length (TL) and CD4 T-cell recovery 48 weeks after cART initiation in virologically suppressed patients, and its possible relationship to oxidative stress (OS) and nitrosative stress (NOx) markers. METHODS We studied HIV-infected patients on stable cART who achieved a viral load

To describe tuberculosis (TB) incidence, risk factors, clinical presentation, disease management and outcomes in human immunodeficiency virus (HIV) infected patients from the CoRIS cohort, Spain, 2004-2010.Open multicentre cohort of antiretroviral treatment (ART) naïve patients at entry. Incidence and risk factors were evaluated using multivariate Poisson regression.Among 6811 patients, 271 were eligible for the study and 198 for the estimation of the incidence rate; TB incidence ranged from 12.1 to 14.1/1000 person-years. TB was associated with low education level (rate ratio [RR] 2.65, 95%CI 1.73-4.07), being sub-Saharan African (RR 3.14, 95%CI 1.81-5.45), heterosexual (RR 2.01, 95%CI 1.22-3.29) or an injecting drug user (RR 2.11, 95%CI 1.20-3.69), not undergoing ART (RR 3.33, 95%CI 2.22-4.76), CD4200 cells/mm(3) (RR 5.20, 95%CI 3.25-8.33) and log-viral load of 4-5 (RR 5.44, 95%CI 3.28-9.02) or5 (RR 13.10, 95%CI 8.27-20.76). Overall, 87% were new cases and 13% were previously treated cases; 175 (65%) were bacteriologically confirmed. Drug susceptibility testing was performed in 146 (83%) patients: resistance to first-line drugs was 11.1% in new and 36.4% in previously treated cases. Standard anti-tuberculosis treatment with four or three drugs was prescribed in respectively 55% and 36% of cases. Treatment default was 11%, and was higher among previously treated cases; 80% received ART during anti-tuberculosis treatment, 80% of new and 50% of previously treated cases were cured or completed treatment, and 18 (6.6%) died.TB incidence in HIV-infected patients remains high. Interventions should include early HIV diagnosis and access to ART, enhanced bacteriological confirmation, wider use of four-drug regimens and reduction in treatment default.

Nitric oxide (NO) influences susceptibility to infection and hemodynamic failure (HF) in sepsis. NOS3 and NOS2 SNPs might modify plasma nitrite/nitrate (NOx) levels, sepsis development, hemodynamics and survival.90 severely septic and 91 non-infected ICU patients were prospectively studied. NOS3 (E298D), NOS3 (-786 T/C), NOS3 (27 bp-VNTR), and NOS2A (exon 22) SNPs and plasma NOx levels were assessed.21 patients (11.6%) died, 7 with sepsis. TT homozygotes and T allele carriers of NOS3 (E298D) and AG carriers of the NOS2A (exon 22) SNPs were more frequent among septic compared to non-infected ICU patients (p 0.05). Plasma NOx was higher in septic, especially in septic with hemodynamic failure (HF) or fatal outcome (p 0.006). Plasma NOx was higher in carriers of the T allele of the NOS3 (E298D) SNP (p = 0.006). Sepsis independently associated with HF, increased NOx, peripheral neutrophils, and fibrinogen levels, decreased prothrombin and the presence of the NOS3 (E298D) and NOS2A (exon 22) SNPs. A low APACHE II score was the only variable associated with sepsis survival. NOx was independently associated with sepsis, HF, decreased neutrophils and higher APACHE.NOS3 (E298D) and NOS2A (exon 22) SNPs, individually and in combination, and plasma NOx, associated with sepsis development. NOx associated with HF and fatal outcome.

We report a rare case of a male patient without known immunodeficiency consecutively diagnosed with visceral leishmaniasis, brain abscess and cavitating pneumonia in the 3rd decade of life. Chronic granulomatous disease (CGD) was diagnosed by a nitroblue tetrazolium test. A p47-phox mutation of the NADPH oxidase of the leukocytes was suspected by immunoblotting and confirmed by DNA analysis. The patient was homozygous for this mutation while his mother and sister were heterozygous asymptomatic carriers. After the CGD diagnosis the patient started a chronic prophylactic regimen with subcutaneous interferon-gamma (0.05 mg/m2 of body surface/three times a week), and oral trimethoprim-sulfamethoxazole and itraconazole (both at 5 mg/kg/day) with no subsequent infections after 12 months of follow-up.

A relationship between obesity and intestinal bacterial translocation has been reported. Very little information is available with respect to the involvement of the bacterial translocation mechanistic pathway in HIV-1/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS). We determined whether lipopolysaccharide (LPS)-binding protein (LBP), cluster of differentiation 14 (CD14), myeloid differentiation protein 2 (MD2) and toll-like receptor 4 (TLR4) single-nucleotide polymorphisms and LPS, LBP and soluble CD14 (sCD14) plasma levels are involved in HALS.This cross-sectional multicentre study involved 558 treated HIV-1-infected patients, 240 with overt HALS and 318 without HALS. Anthropometric, clinical, immunovirological and metabolic variables were determined. Polymorphisms were assessed by genotyping. Plasma levels were determined by ELISA in 163 patients (81 with HALS and 82 without HALS) whose stored plasma samples were available. Student's t-test, one-way ANOVA, two-way repeated measures ANOVA, the χ(2) test and Pearson and Spearman correlation analyses were carried out for statistical analysis.LBP rs2232582 T→C polymorphism was significantly associated with HALS (P = 0.01 and P = 0.048 for genotype and allele analyses, respectively). Plasma levels of LPS (P = 0.009) and LBP (P 0.001) were significantly higher and sCD14 significantly lower (P 0.001) in patients with HALS compared with subjects without HALS. LPS levels were independently predicted by triglycerides (P 0.001) and hepatitis C virus (P = 0.038), LBP levels by HALS (P 0.001) and sCD14 levels by age (P = 0.008), current HIV-1 viral load (P = 0.001) and protease inhibitor use (P = 0.018).HALS is associated with LBP polymorphism and with higher bacterial translocation.

Matrix-metalloproteases (MMPs) and their tissue-inhibitors (TIMPs), modulated by different single nucleotide polymorphisms (SNPs), are critical in sepsis development. Ninety ICU severely septic and 91 ICU uninfected patients were prospectively studied. MMP-1 (−1607 1G/2G), MMP-3 (−1612 5A/6A), MMP-8 (−799 C/T), MMP-9 (−1562 C/T) and MMP-13 (−77A/G) SNPs were genotyped. Plasma MMPs (-1, -2, -3, -8, -9, -10, -13) and TIMPs (-1,-2,-4) were measured. AA homozygotes and A allele carriers of MMP-13 (−77 A/G) and 1G2G carriers of the MMP-1 (−1607 1G/2G) SNPs frequencies were different between septic and uninfected patients (p < 0.05), as well as plasma MMP-3, -8, -9 -10 and TIMP-2 levels (p < 0.04). No differences in MMPs levels among MMP-13 or MMP-1 SNPs genotypes carriers were observed. The area under the ROC curve for MMP-8 in the diagnosis of sepsis was 0.87 (95% CI 0.82–0.92) and that of CRP was 0.98 (0.94–0.998), whereas the area of MMP-9 in the detection of non-septic state was 0.73 (0.65–0.80), p < 0.0001 for all curves. Sepsis associated with increased MMP-8 and decreased MMP-9 levels in multivariate analysis (p < 0.0002). We report for the first time an association between MMP-13 and MMP-1 SNPs and sepsis. An independent association of MMP-8 and MMP-9 levels with sepsis was also observed.

Bacillus subtilis is a ubiquitous soil bacterium used for measuring the beta-lysin activity and in other bioassays. We observed a complete bactericidal effect of ADP on B. subtilis at concentrations of 50-100 microM at pH values5.5, which disappeared at pH values above 6. The effect was also found for acetic acid at concentrations17.4 microM and similar pH values. ATP, adenosine, and HCl were not bactericidal. We used BCECF-AM, a pH-sensitive probe, and found that the killing of B. subtilis was due to a change in the intracellular pH caused by the passage across the cell membrane of these weak organic acids when incubated with B. subtilis at pH values near the pK. More experiments are needed to determine the biological meaning of these in vitro findings.

Background. Coagulation and fibrinolysis are important in infections and systemic inflammatory response syndrome. Polymorphisms in plasminogen activator inhibitor-1 (PAI-1, SERPINE1) and tissue plasminogen activator (tPA, PLAT), such as PAI-1 (-675 4G/5G deletion/insertion) and tPA (Alu insertion/deletion [I/D]), are associated with strokes, myocardial infarctions, bacterial infections and septic shock severity, and trauma. Osteomyelitis is a mostly posttraumatic, Staphylococcal bone infection. Patients and methods. tPA Alu (I/D) (rs4646972) and PAI-1 (4G/5G) (rs1799889) polymorphisms were studied by DNA amplification with polymerase chain reaction in 261 patients with osteomyelitis and in 299 matched blood donors. Plasma PAI-1/tPA complex was assessed by enzyme-linked immuosorbent assay. Results. II homozygotes (37.9% vs 19.1%) and I allele carriers (56.3% vs 46.3%) for the tPA Alu (I/D) polymorphism were significantly more frequent in osteomyelitis patients compared to controls (P< .001). II genotype carrier osteomyelitis patients had lower PAI-1/tPA complex levels compared to those with theD allele (P ≤.04). There was no association between these genotypes and chronicity of osteomyelitis, post-traumatic etiology, or with a specific bacterial etiology. PAI-1 (4G/4G) homozygotes were not significantly different between osteomyelitis patients and controls (P= .1). Conclusions. We report for the first time to our knowledge an association between the tPA Alu (I/D) polymorphism and susceptibility to bacterial osteomyelitis, perhaps by fibrinolysis dysfunction.

AIM To investigate the relationships among diverse metalloproteases (MMPs) and their tissue inhibitors (TIMPs) and non-alcoholic liver fibrosis in human immunodeficiency virus (HIV)-infected patients. METHODS Single nucleotide polymorphisms (SNPs) in MMPs, TNF-α and CCR5 genes, and serum levels of MMPs and TIMPs were determined in HIV-infected individuals with/out hepatitis C virus (HCV) coinfection. A total of 158 patients were included, 57 of whom were HCV-coinfected. All patients drank < 50 g ethanol/day. Diverse SNPs (MMP-1 -1607 1G/2G, MMP-8 -799C/T, MMP-9 -1562 C/T, MMP-13 -77A/G, TNF-α -308 G/A, CCR5-∆32), and serum levels of MMPs (2, 3, 8, 9 and 10) and TIMPs (1, 2 and 4) were assessed. Liver fibrosis was determined by transient elastometry, although other non-invasive markers of fibrosis were also considered. Significant liver fibrosis (F ≥ 2) was defined by a transient elastometry value ≥ 7.1 kPa. RESULTS A total of 34 patients (21.5%) had liver fibrosis ≥ F2. MMP-2 and TIMP-2 serum levels were higher in patients with liver fibrosis ≥ F2 (P = 0.02 and P = 0.03, respectively) and correlated positively with transient elastometry values (P = 0.02 and P = 0.0009, respectively), whereas MMP-9 values were negatively correlated with transient elastometry measurements (P = 0.01). Multivariate analyses showed that high levels of MMP-2 (OR = 2.397; 95%CI: 1.191-4.827, P = 0.014) were independently associated with liver fibrosis ≥ F2 in the patients as a whole. MMP-2 (OR = 7.179; 95%CI: 1.210-42.581, P = 0.03) and male gender (OR = 10.040; 95%CI: 1.621-62.11, P = 0.013) were also independent predictors of fibrosis ≥ F2 in the HCV-infected subgroup. Likewise, MMP-2, TIMP-2 and MMP-9 were independently associated with transient elastometry values and other non-invasive markers of liver fibrosis. None of the six SNPs evaluated had any significant association with liver fibrosis ≥ F2. CONCLUSION Certain MMPs and TIMPs, particularly MMP-2, seems to be associated with non-alcoholic liver fibrosis in HIV-infected patients with/without HCV coinfection.

The age of 50 has been considered as a cut-off to discriminate older subjects within HIV-infected people according to the Centers for Disease Control and Prevention (CDC). However, the International AIDS Society (IAS) mentions 60 years of age and the Department of Health and Human Services (DHHS) makes no consideration. We aimed to establish an age cut-off that could differentiate response to highly active antiretroviral therapy (HAART) and, therefore, help to define advanced age in HIV-infected patients. CoRIS is an open, prospective, multicenter cohort of HIV adults naive to HAART at entry (January 2004 to October 2009). Survival, immunological response (IR) (CD4 increase of more than 100 cell/ml), and virological response (VR) (HIV RNA less than 50 copies/ml) were compared among 5-year age intervals at start of HAART using Cox proportional hazards models, stratified by hospital and adjusted for potential confounders. Among 5514 patients, 2726 began HAART. During follow-up, 2164 (79.4%) patients experienced an IR, 1686 (61.8%) a VR, and 54 (1.9%) died. Compared with patients aged

HIV-1 group M is classified into 9 subtypes, as well as recombinants favored by coinfection and superinfection events with different variants. Although HIV-1 subtype B is predominant in Europe, intersubtype recombinants are increasing in prevalence and complexity. In this study, phylogenetic analyses of pol sequences were performed to detect the HIV-1 circulating and unique recombinant forms (CRFs and URFs, respectively) in a Spanish cohort of antiretroviral treatment-naïve HIV-infected patients included in the Research Network on HIV/AIDS (CoRIS). Bootscanning and other methods were used to define complex recombinants not assigned to any subtype or CRF. A total of 670 available HIV-1 pol sequences from different patients were collected, of which 588 (87.8%) were assigned to HIV-1 subtype B and 82 (12.2%) to HIV-1 non-B variants. Recombinants caused the majority (71.9%) of HIV-1 non-B infections and were found in 8.8% of CoRIS patients. Eleven URFs (accounting for 13.4% of HIV-1 non-B infections), presenting complex mosaic patterns, were detected. Among them, 10 harbored subtype B fragments. Four of the 11 URFs were found in Spanish natives. A cluster of three B/CRF02_AG recombinants was detected. We conclude that complex variants, including unique recombinant forms, are being introduced into Spain through both immigrants and natives. An increase in the frequency of mosaic viruses, reflecting the increasing heterogeneity of the HIV epidemic in our country, is expected.