Orthopalladated imidazolones and thiazolones: synthesis, photophysical properties and photochemical reactivity.

The reaction of Pd(OAc)2 with (Z)-5-arylidene-4-(4H)-imidazolones (2a-e) and (Z)-4-arylidene-5(4H)-thiazolones (3a-e) in trifluoroacetic acid results in the corresponding orthopalladated dinuclear complexes (4a-e, imidazolones; 11a-d, thiazolones) with trifluoroacetate bridges through regioselective C-H activation at the ortho position of the 4-arylidene group. Compound 4e, which contains an imidazolone substituted at 2- and 4-positions of the arylidene ring with methoxide groups and exhibits strong push-pull charge transfer, is an excellent precursor for the synthesis of fluorescent complexes with green yellowish emission and remarkable quantum yields. Breaking the bridging system with pyridine yields the mononuclear complex 5e (ΦF = 5%), while metathesis of trifluoroacetate ligands with chloride leads to the dinuclear complex 6e, also a precursor of fluorescent complexes by breaking the chloride bridging system with pyridine (7e, ΦF = 7%), or by substitution of chloride ligands with pyridine (8e, ΦF = 15%) or acetylacetonate (9e, ΦF = 2%). In addition to notable photophysical properties, dinuclear complexes 4 and 11 also exhibit significant photochemical reactivity. Thus, irradiation of orthopalladates 4a-c and 11a-c in CH2Cl2 with blue light (465 nm) proceeds via [2 + 2] photocycloaddition of the CC double bonds of imidazolone and thiazolone ligands, yielding the corresponding cyclobutane-bridging diaminotruxillic derivatives 10a-c and 12a-c, respectively.

Life expectancy of people with HIV on antiretroviral therapy in Spain.

OBJECTIVE: To estimate life expectancy of people with HIV (PWH) and describe causes of death. DESIGN: Antiretroviral therapy (ART)-naive adults from the CoRIS cohort starting ART in 2004-2019. METHODS: We calculated life expectancy at age 40 for men and women according to their ART initiation period, and stratified by transmission category, CD4 + cell count and AIDS diagnosis. We estimated life expectancy in 10-year age bands using life tables constructed from mortality rates, estimated through Poisson models. RESULTS: Life expectancy increased from 65.8 [95% confidence interval (CI) 65.0-66.6] in 2004-2008 to 72.9 (72.2-73.7) in 2014-2019 in men [general population comparators (GPC): 79.1 and 81.2 years, respectively] and from 65.8 (65.0-66.6) to 72.5 (71.8-73.3) in women (GPC: 84.9 and 86.4, respectively). Non-AIDS-related deaths accounted for 68% of deaths among men and 78% among women. Life expectancy was longer when starting ART with higher CD4 + cell counts and without AIDS. For men acquiring HIV through sex with men, starting ART in 2014-2019 without AIDS, life expectancy was 75.0 (74.2-75.7) with CD4 + cell count less than 200 cells/µl, rising to 78.1 (77.5-78.8) with CD4 + cell count at least 350 cells/µl. Corresponding figures were 70.1 (69.4-70.9) and 76.0 (75.3-76.7) for men acquiring HIV heterosexually (HTX) and 61.5 (60.7-62.3) and 69.0 (68.2-69.8) for those acquiring HIV through injection drug use (IDU). For women starting ART from 2014 without AIDS, life expectancy increased from 71.7 (71.0-72.4) to 77.3 (76.7-77.9) among HTX and from 63.7 (62.9-64.5) to 70.7 (70.0-71.5) among IDU. CONCLUSION: Our findings confirm the progressive improvement of life expectancy in PWH in Spain over the last decades, supporting the insurability of PWH on suppressive ART in our current setting and time.

Cardiovascular events in delayed presentation of HIV: the prospective PISCIS cohort study.

Objectives: People with HIV (PWH) have a higher cardiovascular risk than the general population. It remains unclear, however, whether the risk of cardiovascular disease (CVD) is higher in late HIV presenters (LP; CD4 ≤ 350 cells/µL at HIV diagnosis) compared to PWH diagnosed early. We aimed to assess the rates of incident cardiovascular events (CVEs) following ART initiation among LP compared to non-LP. Methods: From the prospective, multicentre PISCIS cohort, we included all adult people with HIV (PWH) initiating antiretroviral therapy (ART) between 2005 and 2019 without prior CVE. Additional data were extracted from public health registries. The primary outcome was the incidence of first CVE (ischemic heart disease, congestive heart failure, cerebrovascular, or peripheral vascular disease). The secondary outcome was all-cause mortality after the first CVE. We used Poisson regression. Results: We included 3,317 PWH [26 589.1 person/years (PY)]: 1761 LP and 1556 non-LP. Overall, 163 (4.9%) experienced a CVE [IR 6.1/1000PY (95%CI: 5.3-7.1)]: 105 (6.0%) LP vs. 58 (3.7%) non-LP. No differences were observed in the multivariate analysis adjusting for age, transmission mode, comorbidities, and calendar time, regardless of CD4 at ART initiation [aIRR 0.92 (0.62-1.36) and 0.84 (0.56-1.26) in LP with CD4 count <200 and 200- ≤ 350 cells/µL, respectively, compared to non-LP]. Overall mortality was 8.5% in LP versus 2.3% in non-LP (p < 0.001). Mortality after the CVE was 31/163 (19.0%), with no differences between groups [aMRR 1.24 (0.45-3.44)]. Women vs. MSM and individuals with chronic lung and liver disease experienced particularly high mortality after the CVE [aMRR 5.89 (1.35-25.60), 5.06 (1.61-15.91), and 3.49 (1.08-11.26), respectively]. Sensitivity analyses including only PWH surviving the first 2 years yielded similar results. Conclusion: CVD remains a common cause of morbidity and mortality among PWH. LP without prior CVD did not exhibit an increased long-term risk of CVE compared with non-LP. Identifying traditional cardiovascular risk factors is essential for CVD risk reduction in this population.

Fluorescence Amplification of Unsaturated Oxazolones Using Palladium: Photophysical and Computational Studies.

Weakly fluorescent (Z)-4-arylidene-5-(4H)-oxazolones (1), ΦPL < 0.1%, containing a variety of conjugated aromatic fragments and/or charged arylidene moieties, have been orthopalladated by reaction with Pd(OAc)2. The resulting dinuclear complexes (2) have the oxazolone ligands bonded as a C^N-chelate, restricting intramolecular motions involving the oxazolone. From 2, a variety of mononuclear derivatives, such as [Pd(C^N-oxazolone)(O2CCF3)(py)] (3), [Pd(C^N-oxazolone)(py)2](ClO4) (4), [Pd(C^N-oxazolone)(Cl)(py)] (5), and [Pd(C^N-oxazolone)(X)(NHC)] (6, 7), have been prepared and fully characterized. Most of complexes 3-6 are strongly fluorescent in solution in the range of wavelengths from green to yellow, with values of ΦPL up to 28% (4h), which are among the highest values of quantum yield ever reported for organometallic Pd complexes with bidentate ligands. This means that the introduction of the Pd in the oxazolone scaffold produces in some cases an amplification of the fluorescence of several orders of magnitude from the free ligand 1 to complexes 3-6. Systematic variations of the substituents of the oxazolones and the ancillary ligands show that the wavelength of emission is tuned by the nature of the oxazolone, while the quantum yield is deeply influenced by the change of ligands. TD-DFT studies of complexes 3-6 show a direct correlation between the participation of the Pd orbitals in the HOMO and the loss of emission through non-radiative pathways. This model allows the understanding of the amplification of the fluorescence and the future rational design of new organopalladium systems with improved properties.

Synthesis of Bis(amino acids) Containing the Styryl-cyclobutane Core by Photosensitized [2+2]-Cross-cycloaddition of Allylidene-5(4H)-oxazolones.

The irradiation of 2-aryl-4-(E-3'-aryl-allylidene)-5(4H)-oxazolones 1 with blue light (456 nm) in the presence of [Ru(bpy)3](BF4)2 (bpy = 2,2'-bipyridine, 5% mol) gives the unstable cyclobutane-bis(oxazolones) 2 by [2+2]-photocycloaddition of two oxazolones 1. Each oxazolone contributes to the formation of 2 with a different C=C bond, one of them reacting through the exocyclic C=C bond, while the other does so through the styryl group. Treatment of unstable cyclobutanes 2 with NaOMe/MeOH produces the oxazolone ring opening reaction, affording stable styryl-cyclobutane bis(amino acids) 3. The reaction starts with formation of the T1 excited state of the photosensitizer 3[Ru*(bpy)3]2+, which reacts with S0 of oxazolones 1 through energy transfer to give the oxazolone T1 state 3(oxa*)-1, which is the reactive species and was characterized by transient absorption spectroscopy. Measurement of the half-life of 3(oxa*)-1 for 1a, 1b and 1d shows large values for 1a and 1b (10-12 µs), while that of 1d is shorter (726 ns). Density functional theory (DFT) modeling displays strong structural differences in the T1 states of the three oxazolones. Moreover, study of the spin density of T1 state 3(oxa*)-1 provides clues to understanding the different reactivity of 4-allylidene-oxazolones described here with respect to the previously reported 4-arylidene-oxazolones.

Luminescence and Palladium: The Odd Couple.

The synthesis, photophysical properties, and applications of highly fluorescent and phosphorescent palladium complexes are reviewed, covering the period 2018-2022. Despite the fact that the Pd atom appears closely related with an efficient quenching of the fluorescence of different molecules, different synthetic strategies have been recently optimized to achieve the preservation and even the amplification of the luminescent properties of several fluorophores after Pd incorporation. Beyond classical methodologies such as orthopalladation or the use of highly emissive ligands as porphyrins and related systems (for instance, biladiene), new concepts such as AIE (Aggregation Induced Emission) in metallacages or in coordination-driven supramolecular compounds (CDS) by restriction of intramolecular motions (RIM), or complexes showing TADF (Thermally Activated Delayed Fluorescence), are here described and analysed. Without pretending to be comprehensive, selected examples of applications in areas such as the fabrication of lighting devices, biological markers, photodynamic therapy, or oxygen sensing are also here reported.

Obesity-Related Single-Nucleotide Polymorphisms and Weight Gain Following First-Line Antiretroviral Therapy.

BACKGROUND: We studied the association of obesity-related single-nucleotide polymorphisms (OR-SNPs) with weight gain after antiretroviral therapy (ART) in people with human immunodeficiency virus (HIV; PWH). METHODS: Participants were ART-naive PWH from the Spanish HIV Research Cohort who started ART from 2014 onward and had blood/DNA deposited in the cohort Biobank. The primary outcome was change in weight at 96 weeks after starting ART. We genotyped 14 OR-SNPs from a meta-analysis of genome-wide association studies of body mass index (BMI) loci. Changes over time in weight and BMI were studied using adjusted linear mixed models. RESULTS: A total of 1021 PWH were included. The mean weight gain over 96 weeks was 2.90 (95% confidence interval, 2.54-3.26) kg. Factors associated with higher weight gain were female sex, birth in sub-Saharan Africa, prior AIDS, CD4+ <200 cells/µL, HIV-RNA >100 000 copies/mL, negative hepatitis C virus serology, and use of tenofovir alafenamide. A significant association was found between ZC3H4 rs3810291 GG genotype and BCDIN3D/FAIM2 rs7138803 GG genotype polymorphisms and weight and BMI increase. The estimated adjusted mean (standard error [SE]) of weight gain was 4.26 (0.56) kg in ZC3H4 rs3810291 GG carriers and 2.66 (0.19) kg in AA/AG carriers (P = .007). Likewise the estimated weight gain at 96 weeks was 3.35 (0.29) kg in BCDIN3D/FAIM2 rs7138803 GG carriers and 2.51 (0.24) kg in AG/AA carriers (P = .020). CONCLUSIONS: Genetic factors may play a role in weight gain after ART initiation. Further work is needed to replicate our findings and understand how the identified SNPs lead to higher weight gain in this context.

Mortality and immunovirological outcomes in patients with advanced HIV disease on their first antiretroviral treatment: differential impact of antiretroviral regimens.

OBJECTIVES: To assess the clinical and immunovirological outcomes among naive patients with advanced HIV presentation starting an antiretroviral regimen in real-life settings. METHODS: This was a multicentre, prospective cohort study. We included all treatment-naive adults with advanced HIV disease (CD4+ T cell count < 200 cells/mm3or presence of an AIDS-defining illness) who started therapy between 2010 and 2020. The main outcomes were mortality, virological effectiveness (percentage of patients with viral load of ≤50 copies/mL) and immune restoration (percentage of patients with CD4+ T cell count above 350 cells/mm3). Competing risk analysis and Cox proportional models were performed. A propensity score-matching procedure was applied to assess the impact of the antiretroviral regimen. RESULTS: We included 1594 patients with advanced HIV disease [median CD4+T cell count of 81 cells/mm3and 371 (23.3%) with AIDS-defining illness] and with a median follow-up of 4.44 years. The most common ART used was an integrase strand transfer inhibitor (InSTI) regimen (46.9%), followed by PI (35.7%) and NNRTI (17.4%), with adjusted mortality rates at 3 years of 3.1% (95% CI 1.8%-4.3%), 4.7% (95% CI 2.2%-7.1%) and 7.6% (95% CI 5.4%-9.7%) (P = 0.001), respectively. Factors associated with increased mortality included older age and history of injection drug use, whilst treatment with an InSTI regimen was a protective factor [HR 0.5 (95% CI 0.3-0.9)]. A sensitivity analysis with propensity score procedure confirms these results. Patients who started an InSTI achieved viral suppression and CD4+ T cell count above 350 cells/mm3significantly earlier. CONCLUSIONS: In this large real-life prospective cohort study, a significant lower mortality, earlier viral suppression and earlier immune reconstitution were observed among patients with advanced HIV disease treated with InSTIs.

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.

The risk of COVID-19 death is much greater and age-dependent with type I IFN autoantibodies.

SARS-CoV-2 infection fatality rate (IFR) doubles with every five years of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-ß are found in ~20% of deceased patients across age groups. In the general population, they are found in ~1% of individuals aged 20-70 years and in >4% of those >70 years old. With a sample of 1,261 deceased patients and 34,159 uninfected individuals, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to non-carriers. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRD was 17.0[95% CI:11.7-24.7] for individuals under 70 years old and 5.8[4.5-7.4] for individuals aged 70 and over, whereas, for autoantibodies neutralizing both molecules, the RRD was 188.3[44.8-774.4] and 7.2[5.0-10.3], respectively. IFRs increased with age, from 0.17%[0.12-0.31] for individuals <40 years old to 26.7%[20.3-35.2] for those ≥80 years old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84%[0.31-8.28] to 40.5%[27.82-61.20] for the same two age groups, for autoantibodies neutralizing both molecules. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, particularly those neutralizing both IFN-α2 and -ω. Remarkably, IFR increases with age, whereas RRD decreases with age. Autoimmunity to type I IFNs appears to be second only to age among common predictors of COVID-19 death.

Reactivity of (Z)-4-Aryliden-5(4H)-thiazolones: [2 + 2]-Photocycloaddition, Ring-Opening Reactions, and Influence of the Lewis Acid BF3.

The irradiation of (Z)-2-phenyl-4-aryliden-5(4H)-thiazolones 2 with blue light (465 nm) in CH2Cl2 solution promotes [2 + 2]-photocycloaddition of the exocyclic C═C bonds and the formation of the dispirocyclobutanes 3. This reaction takes place with high stereoselectivity, given that the ε-isomer (1,3 head-to-tail syn coupling) is formed in more than 90% yield in most of the cases. However, irradiation of 5(4H)-thiazolones 2 with blue light (456 nm) in dry MeOH in the presence of BF3·OEt2 leads to the monospirocyclobutanes 4 with full stereoselectivity, also affording the ε-isomer. A ring-opening reaction of only one of the thiazolone rings appears to have taken place in 4 upon methanolysis, leading to the corresponding ester and thioamide groups. The treatment of free 4-aryliden-5(4H)-thiazolones 2 with a base in alcohol (NaOR/ROH) also produces a ring-opening reaction of the heterocycle by methanolysis, although, under these reaction conditions, further intramolecular S-attack at the exocyclic C(H)═C bond and cyclization is observed, forming the dihydrothiazoles 5 or 6 as mixtures of cis (RS/SR)- and trans (RR/SS)-isomers with high diastereomeric excess. trans-(RR/SS)-Dihydrothiazoles 6 can be isolated as pure diastereoisomers by column chromatography. Surprisingly, dihydrothiazoles 5 can also be obtained by the treatment of 4-aryliden-5(4H)-thiazolones 2 with BF3·OEt2 in methanol in the absence of a base.

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-ß. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-ß do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

Epigenome-wide association study of COVID-19 severity with respiratory failure.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Fluorescent Orthopalladated Complexes of 4-Aryliden-5(4H)-oxazolones from the Kaede Protein: Synthesis and Characterization.

The goal of the work reported here was to amplify the fluorescent properties of 4-aryliden-5(4H)-oxazolones by suppression of the hula-twist non-radiative deactivation pathway. This aim was achieved by simultaneous bonding of a Pd center to the N atom of the heterocycle and the ortho carbon of the arylidene ring. Two different 4-((Z)-arylidene)-2-((E)-styryl)-5(4H)-oxazolones, the structures of which are closely related to the chromophore of the Kaede protein and substituted at the 2- and 4-positions of the arylidene ring (1a OMe; 1b F), were used as starting materials. Oxazolones 1a and 1b were reacted with Pd(OAc)2 to give the corresponding dinuclear orthometalated palladium derivates 2a and 2b by regioselective C-H activation of the ortho-position of the arylidene ring. Reaction of 2a (2b) with LiCl promoted the metathesis of the bridging carboxylate by chloride ligands to afford dinuclear 3a (3b). Mononuclear complexes containing the orthopalladated oxazolone and a variety of ancillary ligands (acetylacetonate (4a, 4b), hydroxyquinolinate (5a), aminoquinoline (6a), bipyridine (7a), phenanthroline (8a)) were prepared from 3a or 3b through metathesis of anionic ligands or substitution of neutral weakly bonded ligands. All species were fully characterized and the X-ray determination of the molecular structure of 7a was carried out. This structure has strongly distorted ligands due to intramolecular interactions. Fluorescence measurements showed an increase in the quantum yield (QY) by up to one order of magnitude on comparing the free oxazolone (QY < 1%) with the palladated oxazolone (QY = 12% for 6a). This fact shows that the coordination of the oxazolone to the palladium efficiently suppresses the hula-twist deactivation pathway.

Effectiveness and safety of first-line antiretroviral regimens in clinical practice: a multicentre cohort study.

OBJECTIVES: We compared 48 week effectiveness and safety of first-line antiretroviral regimens. METHODS: We 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 <50 copies/mL); (ii) change in CD4 cell count; (iii) CD4/CD8 normalization (>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). RESULTS: Among 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. CONCLUSIONS: The significantly greater immunological response and safety of some combinations may be useful for making decisions when initiating treatment.

Profilaxis preexposición al VIH en España: situación política y administrativa / HIV pre-exposure prophylaxis (PrEP) in Spain: political and administrative situation

Este estudio se ha centrado en las actuaciones a nivel político y administrativo que se han realizado en España en relación con la implementación de la profilaxis preexposición (PrEP) al VIH. Se ha analizado todo tipo de iniciativas formales por parte de los actores políticos y administrativos implicados. Las fuentes utilizadas son las fuentes oficiales públicas. Hasta febrero de 2018, la PrEP no ha sido implementada. La decisión depende de los niveles estatal y autonómico. El Ministerio de Sanidad y algunas Comunidades Autónomas trabajan en diversas intervenciones sin establecer un calendario de implementación. Los partidos políticos por su parte han promovido escasas iniciativas relacionadas con la implementación de la PrEP. En el terreno jurídico, se han producido vaivenes legales relacionados con la extensión de la patente. El papel de los órganos intergubernamentales e interdepartamentales es vital para la implementación de la PrEP

This study focuses on actions at the political and administrative level in Spain in relation to the implementation of pre-exposure prophylaxis (PrEP). We analysed a whole range of different formal initiatives taken by the political and administrative actors involved. The information was obtained from official public data sources. As of February 2018, PrEP had not been implemented. The decision is dependent on both state and regional governments. The Ministry of Health and some Autonomous Regions are working on different interventions, but without providing an implementation timetable. The political parties have kept a very low profile in terms of initiatives related to the implementation of PrEP. From a legal point of view, proceedings are passing back and forth with the extension of the patent. The role of intergovernmental and interdepartmental institutions is very important for the implementation of PrEP in Spain

Genetic variation in CCR2 and CXCL12 genes impacts on CD4 restoration in patients initiating cART with advanced immunesupression.

OBJECTIVE: We investigated the association of genetic polymorphisms in chemokine and chemokine receptor genes with poor immunological recovery in HIV patients starting combined antiretroviral therapy (cART) with low CD4 T-cell counts. METHODS: A case-control study was conducted in 412 HIV-infected patients starting cART with CD4 T-cell count <200 cells/µL and successful viral control for two years. CD4 count increase below 200 cells/µL after two years on cART was used to define INR (immunological non-responder) patients. Polymorphisms in CXCL12, CCL5 and CCR2 genes were genotyped using sequenom's MassARRAY platform. RESULTS: Thirty two percent (134/412) of patients were classified as INR. After adjusting by age, route of HIV infection, length of infection before cART and viral hepatitis coinfection, CCR2 rs1799864-AG genotype was significantly associated with INR status (OR [95% CI]: 1.80 [1.04-3.11]; p = 0.04), and CXCL12 rs1801157-TT genotype showed a trend (OR [95% CI]: 2.47 [0.96-6.35]; p = 0.06). CONCLUSIONS: CCR2 rs1799864-AG or CXCL12 rs1801157-TT genotypes influence on the probability of poor CD4 recovery in the population of HIV patients starting cART with low CD4 counts. Genotyping of these polymorphisms could be used to estimate the risk of poor CD4 restoration, mainly in patients who are diagnosed late in the course of infection.

Surveillance of transmitted drug resistance to integrase inhibitors in Spain: implications for clinical practice.

BACKGROUND: Integrase strand-transfer inhibitors (INSTIs) constitute at present one of the pillars of first-line ART. OBJECTIVES: To study the prevalence of and the trend in transmitted drug resistance (TDR) to INSTIs in ART-naive patients in Spain. METHODS: During the period 2012-17, 1109 patients from CoRIS were analysed. The Stanford algorithm v8.7 was used to evaluate TDR and transmission of clinically relevant resistance. To describe individual mutations/polymorphisms, the most recent IAS list (for INSTIs) and the 2009 WHO list update (for the backbone NRTIs used in combination with INSTIs in first-line treatment) were used. RESULTS: Clinically relevant resistance to the INSTI class was 0.2%: T66I, 0.1%, resistance to elvitegravir and intermediate resistance to raltegravir; and G163K, 0.1%, intermediate resistance to raltegravir and elvitegravir. No clinical resistance to dolutegravir or bictegravir was observed. The prevalence of INSTI TDR following the IAS-USA INSTI mutation list was 2.6%, with no trend towards changes in the prevalence throughout the study period. The overall prevalence of NRTI WHO mutations was 4.3%, whereas clinically relevant resistance to tenofovir, abacavir and emtricitabine/lamivudine was 1.7%, 1.9% and 0.7%, respectively. CONCLUSIONS: Given the low prevalence of clinically relevant resistance to INSTIs and first-line NRTIs in Spain, it is very unlikely that a newly diagnosed patient will present with clinical resistance to a first-line INSTI-based regimen. These patients may not benefit from INSTI and NRTI baseline resistance testing.

HIV pre-exposure prophylaxis (PrEP) in Spain: political and administrative situation. / Profilaxis preexposición al VIH en España: situación política y administrativa.

This study focuses on actions at the political and administrative level in Spain in relation to the implementation of pre-exposure prophylaxis (PrEP). We analysed a whole range of different formal initiatives taken by the political and administrative actors involved. The information was obtained from official public data sources. As of February 2018, PrEP had not been implemented. The decision is dependent on both state and regional governments. The Ministry of Health and some Autonomous Regions are working on different interventions, but without providing an implementation timetable. The political parties have kept a very low profile in terms of initiatives related to the implementation of PrEP. From a legal point of view, proceedings are passing back and forth with the extension of the patent. The role of intergovernmental and interdepartmental institutions is very important for the implementation of PrEP in Spain.

Increased frequencies of Th17 cells and IL17a-producing regulatory T-cells preceding the immunodiscordant response to antiretroviral treatment.

BACKGROUND: Despite the fact that antiretroviral therapy (cART) suppresses HIV-viremia, an adequate CD4 T-cell recovery is not always achieved (immunodiscordant response to cART). IL17a-producing CD4 T-cells (Th17) constitutes an important subset involved in the preservation of mucosal surfaces integrity, which depletion has been associated with disease progression in HIV-infection. However, whether Th17 frequency at cART initiation is associated with a poor CD4 T-cell recovery has not been yet explored. Our aim was to explore whether the Th17 cells and other IL17a-producing T-cell subsets at cART initiation were associated with a subsequent immunodiscordant response to cART. METHODS: We selected pre-cART samples of antiretroviral-naïve subjects with and without a low CD4 recovery after cART (LR-subjects and HR-subjects, respectively). Peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycine, and the production of several cytokines including IL17a was analyzed by flow cytometry. RESULTS: A trend to higher Th17 (p = 0.05) and increased frequencies of IL17a-producing Treg (p = 0.011) was found in LR-subjects before cART onset. Despite increased frequencies of both Treg and Th17 in LR-subject at cART initiation, no alteration of Treg/Th17 ratio was observed. While polifunctional profile of CD4 T-cells was not different, frequencies of CD4 T-cells producing cytokine-combinations including IL17a were increased in LR-subjects. CONCLUSION: Increased frequencies of Th17, IL17a-producing Treg and CD4 T-cells producing specific IL17a-containing combinations of cytokines, precede the immunodiscordant response to cART, suggesting a potential contribution of these subsets in such anomalous response to cART.