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Various immune checkpoint proteins have been linked to cirrhosis. This study aimed to explore the association between plasma levels of these proteins measured one year after successful HCV treatment and persistently liver stiffness (defined as liver stiffness measurement (LSM) ≥ 12.5 kPa) five years after HCV treatment in people with HIV (PWH). We conducted a retrospective study involving 39 patients with HIV/HCV-coinfection who had advanced fibrosis or cirrhosis and achieved sustained virologic response (SVR). Plasma samples were obtained one year after treatment, and levels of immune checkpoints along with inflammatory biomarkers were evaluated using a Luminex 200 TM analyzer. Statistical analyses were performed using Generalized Linear Models (GLMs) with a gamma distribution. Spearman correlation tests were used to analyze the correlation between significant immune checkpoints and inflammatory biomarkers. Although LSM values showed a decreasing trend over the years following successful HCV treatment, this trend was not statistically significant due to substantial variability among PWH. Persistently high liver stiffness was observed in 61.5% of patients five years after HCV treatment. Elevated plasma levels of soluble BTLA, PD-1, and TIM-3 one year after HCV treatment were associated with persistently liver stiffness five years later. These significant immune checkpoints were found to correlate with inflammatory biomarkers in PWH with persistently high liver stiffness. In conclusion, increased plasma concentrations of immune checkpoints one year after successful HCV therapy were linked to persistently high liver stiffness five years later, particularly BTLA, PD-1, and TIM-3. This suggests a potential immunopathological mechanism in ongoing liver stiffness post-HCV eradication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Martín-Escolano, Virseda-Berdices, Berenguer, González-García, Brochado-Kith, Fernández-Rodríguez, Díez, Hontañon, Resino and Jiménez-Sousa.)

Introduction: We analyzed epidemiological, clinical characteristics, and the response to treatment in people living with HIV (PLHIV) who recently acquired hepatitis C (RAHC) in a multicentre study in Madrid (Spain)., Methods: Multicenter, ambispective, observational study of RAHC in men who have sex with men (MSM) infected with HIV. Clinical, epidemiological, and RAHC evolution were recorded prospectively in 2019 and 2020 and retrospectively in 2017 and 2018. In patients who received HCV treatment, sustained virological response (SVR) was provided 12 weeks after the end of treatment in an intention to treat analysis (ITT): all treated patients were included; and in analysis per-protocol (PP): missing patients were excluded., Results: Overall, 133 patients were included. Median (IQR) age was 40 (34.3-46.1) years, 90.9% had at least one previous sexual transmission disease (STD), and 33.6% had previously hepatitis C. More than half of the prospective sample included patients using chemsex related drugs (57.3%), 45.7% of them intravenously. The most prevalent genotype was G1a (66.2%), followed by G4 (11.3%). Ten of 90 patients evaluated for spontaneous cure (11%) cured the infection spontaneously, and 119 had treatment after a median time of 1.8 (0.7-4.6) months: sustained virological response (SVR) was achieved in 90.7% in the ITT and 94.7% in the PP analysis, with no differences regarding the direct-acting antiviral agents (DAA) combination used., Conclusions: MSM infected by HIV with a RAHC were exposed to high-risk sexual behavior. Spontaneous cure rate was low, while SVR after treatment was achieved by more than 90%., (Copyright © 2023 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

We studied the association of mitochondrial DNA (mtDNA) haplogroups with weight and body mass index (BMI) gain at 96 weeks in 1019 treatment-naive persons with HIV (PWH) who initiated first-line antiretroviral therapy (ART) since 2014. The mean increase in weight and BMI over the study period was 2.90 kg and 0.98 kg/m2, respectively. We found a significant adjusted association between the major UK mtDNA haplogroup and lower weight and BMI increase at 96 weeks after ART initiation. Our findings reveal a potential role for mitochondrial genetics in the complex phenomenon of weight gain after initial ART in PWH., Competing Interests: Potential conflicts of interest. J. B. reports honoraria for advice or public speaking from Gilead, Glaxo Smith Kline (GSK), Janssen, Merck Sharp & Dohme (MSD), ViiV Healthcare; and grants from Gilead, MSD, and ViiV Healthcare. I. J. reports honoraria for advice or public speaking from Gilead and ViiV Healthcare; grants from MSD; and support for attending meetings and/or travel from Gilead. J. C. L. reports honoraria for advice or public speaking from Gilead, MSD, and ViiV Healthcare; grants from ViiV Healthcare; and support for attending meetings and/or travel from ViiV Healthcare and MSD. P. D. reports honoraria for advice or public speaking from Gilead, MSD, Janssen, and ViiV Healthcare. A. P.-M. reports honoraria for public speaking and support for attending meetings and/or travel from Gilead, MSD, Jannsen, and ViiV Healthcare. S. M. reports honoraria for advice or public speaking from Gilead, GSK, Janssen, MSD, and ViiV Healthcare; and grants from Gilead, MSD, and ViiV Healthcare. M. L. M. reports honoraria for advice or public speaking from AbbVie, BMS, Gilead, Jannsen, and ViiV Healthcare; and support for attending meetings and/or travel from ViiV Healthcare and Janssen. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Combination antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection in people with HIV (PWH). However, a chronic state of immune activation and inflammation is maintained despite achieving HIV suppression and satisfactory immunological recovery. We aimed to determine whether the plasma metabolomic profile of PWH on long-term suppressive ART and immunologically recovered approximates the normality by comparison with healthy controls with similar age and gender., Methods: We carried out a cross-sectional study in 17 PWH on long-term ART (HIV-RNA <50 copies/mL, CD4 + ≥500 cells/mm 3 , and CD4 + /CD8 + ≥1) and 19 healthy controls with similar age and gender. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and Generalized Linear Models (GLM) with a gamma distribution (log-link). Significance levels (p-value) were corrected for multiple testing (q-value)., Results: PCA and PLS-DA analyses found no relevant differences between groups. Adjusted GLM showed 14 significant features (q-value<0.20), of which only three could be identified: lysophosphatidylcholine (LysoPC) (22:6) (q-value=0.148), lysophosphatidylethanolamine (LysoPE) (22:6) (q-value=0.050) and hydroperoxy-octadecatrienoic acid (HpOTrE)/dihydroperoxy-octadecatrienoic acid (DiHOTrE)/epoxy-octadecadienoic acid (EpODE) (q-value=0.136). These significant identified metabolites were directly correlated to plasma inflammatory biomarkers in PWH and negatively correlated in healthy controls., Conclusion: PWH on long-term ART have a metabolomic profile that is almost normal compared to healthy controls. Nevertheless, residual metabolic alterations linked to inflammatory biomarkers persist, which could favor the development of age-related comorbidities among this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Virseda-Berdices, Martín-Escolano, Berenguer, González-García, Brochado-Kith, Rojo, Fernández-Rodríguez, Pérez-Latorre, Hontañón, Barbas, Resino and Jiménez-Sousa.)

Interleukin 7 receptor (IL7R) is vital in the adaptive immune response against human immunodeficiency viruses (HIV). We assessed IL7RA polymorphisms (SNPs) in antiretroviral therapy (ART)-naïve HIV patients for their association with spontaneous HIV infection control. We conducted a retrospective cohort study involving 667 ART-naïve patients categorized by HIV progression (ordinal variable): 150 rapid progressors, 334 moderate/typical progressors, 86 long-term nonprogressors elite controllers (LTNPs-EC), and 97 LTNPs-non-EC. We genotyped three IL7RA SNPs using Agena Bioscience's MassARRAY platform. The association between IL7RA SNPs and spontaneous HIV infection control was evaluated using ordinal logistic regression. Individuals carrying the rs10491434 G allele have a higher likelihood of spontaneous HIV infection control (adjusted odds ratio [aOR] = 1.33; p = 0.023). Moreover, the IL7RA GCT haplotype, consisting of three specific SNPs (rs6897932, rs987106, and rs10491434), demonstrated an association with the control of untreated HIV infection (aOR = 1.34; p = 0.050). Remarkably, the rs10491434 SNP and the IL7RA GCT haplotype exhibited similar aOR values, suggesting that rs10491434 may be primarily responsible for the observed effect of the haplotype. IL7RA rs10491434 G allele is associated with a higher likelihood of spontaneous HIV infection control, indicating its significant role in the pathogenesis of HIV, possibly influencing infection course and viral replication control., (© 2023 Wiley Periodicals LLC.)

Hepatic steatosis is a common condition found in the liver of hepatitis C virus (HCV)-infected patients, contributing to more severe forms of liver disease. In addition, the human immunodeficiency virus (HIV) may accelerate this process. Alternatively, several immune checkpoint proteins have been reported to be upregulated and correlated with disease progression during HCV and HIV infections. In steatosis, a detrimental immune system activation has been established; however, the role of the immune checkpoints has not been addressed so far. Thus, this study aimed to evaluate the association between plasma immune checkpoint proteins at baseline (before antiviral therapy) with hepatic steatosis index (HSI) increase at the end of follow-up (∼ five years after sustained virologic response (SVR)). We performed a multicenter retrospective study in 62 patients coinfected with HIV/HCV who started antiviral therapy. Immune checkpoint proteins were analyzed at baseline using a Luminex 200TM analyzer. The statistical association analysis was carried out using Generalized Linear Models (GLM) and Partial Least Squares Discriminant Analysis (PLS-DA). Fifty-three percent of the patients showed HSI increase from baseline to the end of follow-up. Higher immune checkpoint protein levels of BTLA, CD137(4-1BB), CD80, GITR, LAG-3, and PD-L1 before HCV therapy were associated with a long-term increase in HSI after successful HCV therapy, suggesting a potential predictive role for early detection of progression towards steatosis in HIV/HCV-coinfected patients., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

IRF5-TNPO3 polymorphisms have previously been related to immune response, and TNPO3 plays a role in human immunodeficiency virus (HIV)-1 infection after nuclear import. Therefore, we analyzed the genetic association between IRF5-TNPO3 polymorphisms and the HIV elite control in long-term nonprogressors (LTNPs). We performed a retrospective cohort study on 183 LTNPs, who were antiretroviral therapy-naïve with CD4 +  ≥ 500 cells/mm 3 , viral load ≤10 000 copies/mL, and asymptomatic over 10 years after HIV seroconversion. The primary outcome variable was HIV elite control (undetectable viral load in at least 90% of the measurements for at least 1 year). Seven IRF5-TNPO3 polymorphisms were genotyped using Agena Bioscience's MassARRAY platform. We found a significant association between specific IRF5-TNPO3 genotypes and HIV elite control: rs2004640 TT (aOR = 2.05; p = 0.041), rs10954213 AA (aOR = 1.95; p = 0.035), rs2280714 TT (aOR = 2.02; p = 0.031), and rs10279821 CC (aOR = 2.12; p = 0.017). We also found a significant association between IRF5-TNPO3 haplotype TATC composed of the favorable significant polymorphisms (rs2004640, rs10954213, rs2280714, and rs10279821) and the HIV elite control (aOR = 1.59; p = 0.048). IRF5-TNPO3 rs2004640, rs10954213, rs2280714, and rs10279821 polymorphisms were related to HIV elite control in LTNPs. Our data provide new knowledge about the impact of IRF5-TNPO3 polymorphisms on HIV pathogenesis to understand the phenomenon of natural HIV control., (© 2023 Wiley Periodicals LLC.)

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., Competing Interests: Potential conflicts of interest. J. B. reports honoraria for advice or public speaking from Gilead Sciences, Inc, GSK, Janssen Pharmaceuticals, MSD, and ViiV Healthcare; grants from Gilead Sciences, Inc, MSD, and ViiV Healthcare; and support for attending meetings and/or travel from MSD, ViiV Healthcare, and Janssen Pharmaceuticals. I. J. reports honoraria for advice or public speaking from GILEAD, and ViiV Healthcare; honoraria for performing statistical analyses from Fundación Investigación Biomédica Hospital Gregorio Marañón and grants from MSD. J. G.-G. reports honoraria for advice or public speaking from Gilead Sciences, Inc, Janssen Pharmaceuticals, MSD, and ViiV Healthcare; grants or contracts from MSD, ViiV Healthcare, and Gilead Sciences, Inc; support for attending meetings and/or travel from Gilead Sciences, Inc (paid to author); and participation on a DSMB or advisory board for ViiV Healthcare and Janssen-Cilag, S.A. D. D. reports honoraria for public speaking from Gilead Sciences, Inc, Janssen Pharmaceuticals, and ViiV Healthcare (some of this payment was made to author's institution); support for attending meetings and/or travel from Gilead Sciences, Inc; and plays a role in the Spanish AIDS Society and Spanish HIV/AIDS Research Network of Excellence. J. O. reports honoraria for advice or public speaking from Gilead Sciences, Inc, Janssen Pharmaceuticals, MSD, ViiV Healthcare, Pfizer, and GSK; grants from Gilead Sciences, Inc, MSD, and ViiV Healthcare, including consulting fees from Janssen, ViiV, MSD, Gilead Sciences, Inc, and Pfizer; and support for attending meetings and/or travel from Gilead Sciences, Inc, and ViiV. P. D. reports honoraria for advice or public speaking or grants and participation on a DSMB or advisory board from AbbVie, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Inc, GSK, MSD, Janssen Pharmaceuticals, Pfizer, Theratechnologies, and ViiV Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with advanced cirrhosis are at high risk of developing clinically significant portal hypertension (CSPH). We analyzed the gene expression profile of peripheral blood mononuclear cells (PBMCs) from HIV/HCV coinfected patients to identify a gene expression signature of advanced cirrhosis with high risk for CSPH., Methods: We conducted a cross-sectional study on 68 patients. Liver stiffness measurement (LSM) was used to stratify patients into < 12.5 kPa (no cirrhosis, n = 19), 12.5 - 24.9 kPa (cirrhosis, n = 20), and ≥ 25 kPa (advanced cirrhosis with high risk for CSPH, n = 29). Besides, we further evaluated LSM < 25 kPa (n = 39) vs. ≥ 25 kPa (n = 29). Total RNA was extracted from PBMCs, and poly(A) RNA sequencing was performed. Two significant differentially expressed (SDE) transcripts were validated by quantitative PCR in a different cohort (n = 46)., Results: We found 60 SDE transcripts between patients with LSM < 12.5 kPa and ≥ 25 kPa. Partial least squares discriminant analysis showed that those 60 SDE transcripts collectively discriminated LSM ≥ 25 kPa, with an area under the receiver operating characteristic curve (AUROC) of 0.84. Eight genes had an AUROC ≥ 0.75 for LSM ≥ 25 kPa: five were positively associated with LSM values (SCAMP1, ABHD17B, GPR146, GTF2A1, and TMEM64), while three were inversely associated (ZFHX2-AS1, MDK, and STAG3L2). We validated the two SDE transcripts with the highest discrimination capacity in a different cohort, finding significant differences between < 25 kPa and ≥ 25 kPa (MDK (p = 0.006) and STAG3L2 (p = 0.021))., Conclusions: A gene expression signature of 60 transcripts was associated with advanced cirrhosis with high risk for CSPH in HIV/HCV coinfected patients., Competing Interests: Competing interests The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The standard algorithm for diagnosing hepatitis C virus (HCV) infection has two steps, an HCV antibody test for screening and a nucleic acid amplification test (NAAT) for confirmation. However, the HCV core antigen (HCVcAg) detection assay is an alternative for one-step diagnosis. We aimed to evaluate the diagnostic performance of the Abbott ARCHITECT HCV Ag assay to detect active hepatitis C in serum/plasma in people living with HIV/AIDS (PLWHA), through a systematic review and meta-analysis. PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library were searched until 20 September 2022 (PROSPERO, CRD42022348351). We included studies evaluating Abbott ARCHITECT HCV Ag assay (index assay) versus NAATs (reference test) in PLWHA coinfected with HCV who did not receive antiviral treatment for HCV. Meta-analysis was performed with the MIDAS module using Stata and random-effects models. The QUADAS-2 tool evaluated the risk of bias. The bivariate analysis was conducted on 11 studies with 2,407 samples. Pooled sensitivity was 0.95 (95% CI = 0.92 to 0.97), specificity 0.97 (95% CI = 0.93 to 0.99), positive likelihood ratio 37.76 (95% CI = 12.84 to 111.02), and negative likelihood ratio 0.06 (95% CI = 0.04 to 0.09). The area under the curve was 0.97 (95% CI = 0.20 to 1.00). For low prevalence (≤5%), the posttest probability that an individual with a positive test was a true positive ranged from 4% to 67%, whereas, at high prevalence (≥10%), the posttest probability was between 81% and 87%, indicating that a confirmatory test should be necessary, particularly with prevalence values of ≤1%. Regardless of prevalence, the probability that an individual with a negative test was a false negative was close to zero, indicating that the individual was not infected with HCV. In conclusion, the accuracy of the Abbott ARCHITECT HCV Ag assay was very good for HCV screening in serum/plasma samples from PLWHA. The clinical utility to confirm HCV infection was acceptable in high-prevalence settings (≥10%) but poor in low-prevalence settings (≤1%). Furthermore, it was excellent in excluding active HCV infection.

Objectives: The current study aimed to assess the impact of HIV on the production of anti-HCV antibodies in HCV-infected individuals with advanced HCV-related cirrhosis before and 36 weeks after the sustained virological response (SVR) induced by direct-acting antivirals (DAAs) therapy., Methods: Prospective study on 62 patients (50 HIV/HCV-coinfected and 12 HCV-monoinfected). Plasma anti-E2 and HCV-nAbs were determined respectively by ELISA and microneutralization assays., Results: At baseline, the HCV-group had higher anti-E2 levels against Gt1a (p = 0.012), Gt1b (p = 0.023), and Gt4a (p = 0.005) than the HIV/HCV-group. After SVR, anti-E2 titers against Gt1a (p < 0.001), Gt1b (p = 0.001), and Gt4a (p = 0.042) were also higher in the HCV-group than HIV/HCV-group. At 36 weeks post-SVR, plasma anti-E2 titers decreased between 1.3 and 1.9-fold in the HIV/HCV-group (p < 0.001) and between 1.5 and 1.8-fold in the HCV-group (p ≤ 0.001). At baseline, the HCV-group had higher titers of HCV-nAbs against Gt1a (p = 0.022), Gt1b (p = 0.002), Gt2a (p < 0.001), and Gt4a (p < 0.001) than the HIV/HCV-group. After SVR, HCV-nAbs titers against Gt1a (p = 0.014), Gt1b (p < 0.001), Gt2a (p = 0.002), and Gt4a (p = 0.004) were also higher in the HCV-group. At 36 weeks post-SVR, HCV-nAbs decreased between 2.6 and 4.1-fold in the HIV/HCV-group (p < 0.001) and between 1.9 and 4.0-fold in the HCV-group (p ≤ 0.001)., Conclusions: HIV/HCV-coinfected patients produced lower levels of broad-spectrum anti-HCV antibodies than HCV-monoinfected patients., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Although a wide variety of topical microbicides provide promising in vitro and in vivo efficacy, most of them failed to prevent sexual transmission of human immunodeficiency virus type 1 (HIV-1) in human clinical trials. In vitro, ex vivo, and in vivo models must be optimized, considering the knowledge acquired from unsuccessful and successful clinical trials to improve the current gaps and the preclinical development protocols. To date, dendrimers are the only nanotool that has advanced to human clinical trials as topical microbicides to prevent HIV-1 transmission. This fact demonstrates the importance and the potential of these molecules as microbicides. Polyanionic dendrimers are highly branched nanocompounds with potent activity against HIV-1 that disturb HIV-1 entry. Herein, the most significant advancements in topical microbicide development, trying to mimic the real-life conditions as closely as possible, are discussed. This review also provides the preclinical assays that anionic dendrimers have passed as microbicides because they can improve current antiviral treatments' efficacy. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicine., (© 2022 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Masip, Rallón, Yeregui, Olona, Resino, Benito, Viladés, García-Pardo, Alcamí, Ruiz-Mateos, Gómez-Bertomeu, Vargas, Navarro, Oteo, Pineda, Martí, Alba, Vidal, Peraire and Rull.)

Human immunodeficiency virus-1 (HIV-1) elite controllers are heterogeneous due to different immunovirological features. We aimed to identify plasma biomarkers associated with loss of spontaneous HIV-1 control in long-term elite controllers (HIV-LTECs). We performed a retrospective study in 60 HIV-LTECs [36 true-LTECs and 24 LTECs losing control (LTECs-LC)]. We selected a plasma sample from true-LTECs (towards the middle of the follow-up period) and two samples from LTECs-LC (one far from the loss of control and another close to loss of control). Plasma biomarkers were evaluated using multiplex immunoassays. The partial least squares-discriminant analysis provided the variable importance in projection (VIP), and the adjusted Generalized Linear Model provided the adjusted arithmetic mean ratio (aAMR). At the moment of the first LTECs-LC samples, the only plasma biomarker with a VIP≥1.5 was sTNF-R1, which showed higher values in LTECs-LC than true-LTECs [aAMR=1.62 (95%CI=1.20-2.19); p=0.001]. After a median of 3.9 (IQR=4.5) years of follow-up from the first sample, we also had access to a second plasma sample from 10 LTECs-LC patients. At the moment of this second LTECs-LC sample, the only plasma biomarker with VIP≥1.5 was also sTNF-R1, which showed higher values in LTECs-LC than true-LTECs [aAMR=1.93 (95%CI=1.41-2.65); p<0.001]. The difference between the first and second samples of LTECs-LC was significant (Δx= 6.58 (95%=0.3; 12.88); p=0.040). In conclusion, high plasma values of sTNF-R1 appear to discriminate HIV-LTECs that lose the natural control of HIV-1, helping to define a specific phenotype that may be useful for the clinical management of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sepúlveda-Crespo, Rallón, Muñoz-Gómez, Brochado-Kith, Jiménez, Muñoz-Fernández, Benito and Resino.)

Background: A better understanding of the evolution of cirrhosis after hepatitis C virus (HCV) clearance is essential since the reversal of liver injury may not happen. We aimed to assess the evolution of plasma metabolites after direct-acting antivirals (DAAs) therapy and their association with liver disease scores in HIV/HCV-coinfected patients with advanced HCV-related cirrhosis., Methods: We performed a prospective study in 49 cirrhotic patients who started DAAs therapy. Data and samples were collected at baseline and 36 weeks after SVR. Metabolomics analysis was carried out using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. Inflammation-related biomarkers were analyzed using ProcartaPlex Immunoassays., Results: At 36 weeks after SVR, patients experienced significant decrease in taurocholic acid, 2,3-butanediol, and LPC(18:0); while several phosphatidylcholines (LPC(16:1), LPC(18:1), LPC(20:4), and PC(16:0/9:0(CHO))/PC(16:0/9:0(COH)), 2-keto-n-caproic acid/2-keto-isocaproic acid and N-methyl alanine increased, compared to baseline. The plasma decrease in taurocholic acid was associated with a reduction in Child-Turcotte-Pugh (CTP) (AMR=3.39; q-value=0.006) and liver stiffness measurement (LSM) (AMR=1.06; q-value<0.001), the plasma increase in LPC(20:4) was related to a reduction in LSM (AMR=0.98; q-value=0.027), and the rise of plasma 2-keto-n-caproic acid/2-keto-isocaproic acid was associated with a reduction in CTP (AMR=0.35; q-value=0.004). Finally, plasma changes in taurocholic acid were directly associated with inflammation-related biomarkers, while changes in LPC(20:4) were inversely associated., Conclusions: Plasma metabolomic profile changed after HCV clearance with all oral-DAAs in HIV/HCV-coinfected with advanced HCV-related cirrhosis. Changes in plasma levels of LPC (20: 4), 2-keto-n-caproic acid/2-keto-isocaproic acid, and taurocholic acid were related to improvements in cirrhosis scores and inflammatory status of patients., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Gender-specific consequences after HCV eradication are unexplored. MicroRNAs (miRNAs) play a crucial role in the immune response against viral infections. However, few have highlighted miRNA role in sex-biased disease or therapy response. We aim to assess gender differences reflected in the miRNA expression of HIV/HCV-coinfected patients who achieve sustained virological response (SVR) with direct acting antivirals (DAAs). We conducted a prospective study of miRNA expression in PBMCs from 28 chronic HIV/HCV-coinfected patients (HIV/HCV) at baseline and after achieving SVR with DAAs. Sixteen HIV-monoinfected patients (HIV) and 36 healthy controls (HC) were used as controls. Identification of significant differentially expressed (SDE) miRNAs was performed with generalized linear model and mixed GLMs. We also explored putative dysregulated biological pathways. At baseline, the HIV/HCV patients showed differences in the miRNA profile concerning the HIV group (165 and 102 SDE miRNAs for males and females, respectively). Gender-stratified analysis of HIV/HCV group at baseline versus at SVR achievement showed higher differences in males (80 SDE miRNAs) than in females (55 SDE miRNAs). After SVR, HIV/HCV group showed similar values to HIV individuals, especially in females (1 SDE miRNA). However, ten miRNAs in males remained dysregulated, which were mainly involved in cancer, fatty acid, and inflammatory pathways. Taken together, our results show gender-biased dysregulation in the miRNA expression profile of PBMCs after HCV eradication with DAAs. These differences were normalized in females, while miRNA profile and their target-related pathways in males lack of normalization, which may be related to a high-risk of developing liver-related complications., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objectives: We aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and factors associated with seropositivity and asymptomatic coronavirus disease 2019 (COVID-19) among people with HIV (PWH)., Methods: This was a cross-sectional study carried out within the cohort of the Spanish HIV Research Network. Participants were consecutive PWH with plasma collected from 1st April to 30th September 2020. We determined SARS-CoV-2 antibodies (Abs) in plasma. Illness severity (NIH criteria) was assessed by a review of medical records and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes mellitus, non-AIDS-related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, nucleoside/nucleotide reverse transcriptase inhibitor (N [t]RTI) backbone, type of third antiretroviral drug, and month of sample collection., Results: Of 1076 PWH (88.0% males, median age 43 years, 97.7% on antiretroviral therapy, median CD4+ 688 cells/mm 3 , 91.4% undetectable HIV viral load), SARS-CoV-2 Abs were detected in 91 PWH, a seroprevalence of 8.5% (95%CI 6.9-10.3%). Forty-five infections (45.0%) were asymptomatic. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American countries versus Spain (adjusted odds ratio (aOR) 2.30, 95%CI 1.41-3.76, p 0.001), and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) versus tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR 0.49, 95%CI 0.26-0.94, p 0.031)., Conclusions: Many SARS-CoV-2 infections among PWH were asymptomatic, and birth in Latin American countries increased the risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggests that TDF/FTC may prevent SARS-CoV-2 infection among PWH., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Little is known about the effects of eradication of hepatitis C virus (HCV) on bone mineral density (BMD) and biomarkers of bone remodeling in human immunodeficiency virus (HIV)/HCV-coinfected patients., Methods: We prospectively assessed standardized BMD (sBMD) at the lumbar spine and femoral neck, World Health Organization BMD categories at both sites, and plasma concentrations of soluble receptor activator of NF-κβ ligand (sRANKL), and osteoprotegerin (OPG) at baseline (the date of initiation of anti-HCV therapy) and at 96 weeks., Results: A total of 238 patients were included. The median age was 49.5 years, 76.5% were males, 48.3% had cirrhosis, 98.3% were on antiretroviral therapy, median CD4+ cell count was 527 cells/μL, and 86.6% had HIV-1 RNA <50 copies/mL. The prevalence of osteoporosis at baseline at the lumbar spine (LS) and femoral neck (FN) was 17.6% and 7.2%, respectively. Anti-HCV therapy comprised pegylated interferon (peg-IFN) and ribavirin (RBV) plus 1 direct-acting antiviral in 53.4%, peg-IFN/RBV in 34.5%, and sofosbuvir/RBV in 12.2%. A total of 145 (60.9%) patients achieved sustained virologic response (SVR). No significant effect of SVR was observed on sBMD for the interaction between time and SVR either in the LS (P = .801) or the FN (P = .911). Likewise, no significant effect of SVR was observed in plasma levels of sRANKL (P = .205), OPG (P = .249), or sRANKL/OPG ratio (P = .123) for the interaction between time and SVR. No significant correlation was found between fibrosis by transient elastography, and LS and FN sBMD, at baseline and week 96., Conclusions: SVR was not associated with significant changes in BMD nor biomarkers of bone remodeling in HIV/HCV-coinfected persons., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The burden of human immunodeficiency virus (HIV) infection in people who use drugs (PWUD) is significant. We aimed to screen HIV infection among PWUD and describe their retention in HIV care. Besides, we also screen for hepatitis C virus (HCV) infection among HIV-seropositive PWUD and describe their linkage to care., Methods: We conducted a prospective study in 529 PWUD who visited the "Cañada Real Galiana" (Madrid, Spain). The study period was from June 1, 2017, to May 31, 2018. HIV diagnosis was performed with a rapid antibody screening test at the point-of-care (POC) and HCV diagnosis with immunoassay and PCR tests on dried blood spot (DBS) in a central laboratory. Positive PWUD were referred to the hospital. We used the Chi-square or Fisher's exact tests, as appropriate, to compare rates between groups., Results: Thirty-five (6.6%) participants were positive HIV antibodies, but 34 reported previous HIV diagnoses, and 27 (76%) had prior antiretroviral therapy. Among patients with a positive HIV antibody test, we also found a higher prevalence of homeless (P < 0.001) and injection drug use (PWID) (P < 0.001), and more decades of drug use (P = 0.002). All participants received HIV test results at the POC. Of the 35 HIV positives, 28 (80%) were retained in HIV medical care at the end of the HIV screening study (2018), and only 22 (62.9%) at the end of 2020. Moreover, 12/35 (34.3%) were positive for the HCV RNA test. Of the latter, 10/12 (83.3%) were contacted to deliver the HCV results test (delivery time of 19 days), 5/12 (41.7%) had an appointment and were attended at the hospital and started HCV therapy, and only 4/12 (33.3%) cleared HCV., Conclusions: We found almost no new HIV-infected PWUD, but their cascade of HIV care was low and remains a challenge in this population at risk. The high frequency of active hepatitis C in HIV-infected PWUD reflects the need for HCV screening and reinforcing the link to care., (© 2021. The Author(s).)

Objective: To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients., Methods: We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE)., Results: HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR < 0.05), one linked to Epstein-Barr virus infection and another related to p53 signaling. For HIV/HCV-f vs. HIV-mono group, we found 44 SDE genes that revealed 31 enriched pathways (FDR < 0.05) related to inflammation, cancer/cell cycle alteration, viral and bacterial infection, and comorbidities associated with HIV/HCV-coinfection. Five genes were overrepresented in most pathways (JUN, NFKBIA, PIK3R2, CDC42, and STAT3)., Conclusion: HIV/HCV-coinfected patients who eradicated hepatitis C with IFN-based therapy showed profound gene expression changes after achieving sustained virological response. The altered pathways were related to inflammation and liver-related complications, such as non-alcoholic fatty liver disease and hepatocellular carcinoma, underscoring the need for active surveillance for these patients.

Background: HIV/AIDS progression is linked to vitamin D, which is regulated by several key cytochromes P450 (CYP). Single nucleotide polymorphisms (SNPs) in CYP genes influence vitamin D metabolism and serum levels. The objective of this study was to evaluate the association between CYP SNPs and the clinical AIDS progression in antiretroviral treatment (ART)-naïve HIV-infected patients., Methods: We performed a retrospective study in 661 ART-naïve HIV-infected patients who were stratified by their AIDS progression pattern [181 long-term nonprogressors (LTNPs), 332 moderate progressors, and 148 rapid progressors (RPs)]. Four CYP SNPs (CYP2R1 rs10500804, CYP2R1 rs1993116, CYP27B1 rs10877012, and CYP24A1 rs6013897) were genotyped using Agena Bioscience's MassARRAY platform. Correction for multiple testing was performed using the false discovery rate (Benjamini-Hochberg procedure)., Results: The adjusted regression showed a significant association only for CYP27B1 rs10877012 SNP. When analyzing all HIV patients, the rs10877012 T allele was protective against AIDS progression (ordinal outcome) under the dominant [adjusted odds ratio (aOR) = 0.69; P = 0.021) and additive (aOR) = 0.75; P = 0.025] inheritance models. When analyzing LTNPs versus RPs, the rs10877012 T allele also showed a significant protective association under the dominant (aOR = 0.45; P = 0.004) and additive (aOR = 0.54; P = 0.008) inheritance models. P values remained significant after correcting by multiple comparisons only for the comparison of LTNPs versus RPs (extreme phenotypes)., Conclusions: The CYP27B1 rs10877012 T allele was linked to non-AIDS progression in ART-naïve HIV-infected patients. The rs10877012 SNP seems to have an impact on the clinical AIDS progression, possibly modifying vitamin D levels, which could be relevant for the pathogenesis of HIV infection.

Objective: To explore the differences in peripheral blood markers between HIV well controlled patients on long-term suppressive antiretroviral therapy (HIV-group) and age-matched healthy controls, to evaluate the benefits of virological suppression in those patients., Methods: We performed a case-control study in 22 individuals in the HIV-group and 14 in the healthy control-group. RNA-seq analysis was performed from peripheral blood mononuclear cells. Peripheral blood T-cell subsets were evaluated by flow cytometry and plasma biomarkers by immunoassays. All P values were corrected by the false discovery rate (q values)., Results: Only the serine/arginine repetitive matrix 4 gene, which is involved in alternative RNA splicing events, was differentially expressed between HIV and healthy control groups (q value ≤0.05 and fold-change ≥2). However, 147 differentially expressed genes were found with a more relaxed threshold (P value ≤0.05 and fold-change ≥1.5), of which 67 genes with values of variable importance in projection at least one were selected for pathway analysis. We found that six ribosomal genes represented significant ribosome-related pathways, all of them downregulated in the HIV-group, which may be a strategy to facilitate viral production. T cells subset and plasma biomarkers did not show significant differences after false discovery rate correction (q value >0.05), but a noncorrected analysis showed higher values of regulatory CD4 T cells (CD4CD25CD127), MCP-1, and sVEGF-R1 in the HIV-group (P value ≤0.05)., Conclusion: T-cell subsets, plasma biomarkers, and gene expression were close to normalization in HIV-infected patients on long-term suppressive combination antiretroviral therapy compared with healthy controls. However, residual alterations remain, mainly at the gene expression, which still reveals the impact of HIV infection in these patients.

Introduction: HIV-controllers have the ability to spontaneously maintain viraemia at low or undetectable levels in the absence of antiretroviral treatment. Furthermore, HIV-controllers seem to have a superior capacity to spontaneously clear hepatitis C virus (HCV) compared to non HIV-controllers. Some of these subjects eventually lose HIV-controller status (transient controllers), whereas some HIV-controllers show a persistent natural HIV control (persistent controllers). We aimed to analyse whether persistent controllers have superior capacity to spontaneously clear HCV compared to transient controllers., Methods: We recruited HIV-controllers from January 1981 up to October 2016 with available antibodies to HCV (anti-HCV) data (n = 744). Factors associated with HIV spontaneous control in relation to HCV status were analysed in persistent and transient HIV-controllers with anti-HCV positive (n = 202 and n = 138 respectively) in comparison with 1700 HCV positive non HIV-controllers recruited from January 1981 up to March 2018, bivariate and multivariate analyses, following a logistic regression model, were applied. In addition, the factors related to the loss and time to lose HIV-controller status were explored (n = 744) using Log rank test and Kaplan-Meier curves, in this case the multivariate analysis consisted in a Cox regression model., Results: A higher frequency of HCV spontaneous clearance was found in persistent HIV-controllers (25.5%) compared to non-controllers (10.2%). After adjusting for potential confounders, as sex, age, HIV transmission risk, CD4 + T-cell nadir and time of follow-up, HCV clearance was independently associated with persistent HIV spontaneous control (p = 0.002; OR (95% CI) = 2.573 (1.428 to 4.633)), but not with transient spontaneous control (p = 0.119; 1.589 (0.888 to 2.845)). Furthermore, persistent HIV-controllers were more likely to spontaneously clear the HCV in comparison with transient controllers (p = 0.027; 0.377 (0.159 to 0.893). Finally, not to lose or lengthen the time of losing this control was independently associated with HCV spontaneous clearance (p = 0.010; 0.503 (0.297 to 0.850)., Conclusions: This study shows an association between spontaneous persistent HIV-control and HCV spontaneous clearance. The study findings support the idea of preserved immune mechanisms in persistent HIV control implicated in HCV spontaneous clearance. These results highlight persistent HIV-controllers but not transient controllers as a good model of functional HIV cure., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background & Aims: Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and cirrhosis induce metabolic disorders. Here, we aimed to evaluate the association of plasma metabolites with Child-Turcotte-Pugh (CTP) score and hepatic decompensation in HIV/HCV-coinfected and HCV-monoinfected patients with advanced cirrhosis., Methods: A cross-sectional study was carried out in 62 HIV/HCV-coinfected and 28 HCV-monoinfected patients. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by partial least squares discriminant analysis (PLS-DA) and generalized linear model (GLM) with binomial distribution (to analyse HIV coinfection, high alcohol intake, treatment with statins, previous HCV therapy failure and decompensation) and ordinal logistic regression (OLR) models to analyse different stages of cirrhosis (CTP score)., Results: The statistical analysis identified plasma metabolites associated with HIV coinfection, high alcohol intake, CTP score and hepatic decompensation. Overall, fatty acids, bile acids, aromatic and sulphur amino acids, butyrate derivatives, oxidized phospholipids, energy-related metabolites and bacterial fermentation-related metabolites were increased in more advanced cirrhosis stages; while lysophosphatidylcholines and lysophosphatidylethanolamines, branched-chain amino acids (BCAA) and metabolites of tricarboxylic acid cycle, among others, were decreased in more advanced cirrhosis. Most of the significant metabolites displayed a similar trend after stratifying for HIV/HCV- and HCV-infected patients. Glycolic acid, LPC (16:0) and taurocholic acid had high accuracy for discriminating patients according to decompensated cirrhosis (CTP ≥ 7)., Conclusion: Altered plasma metabolomic profile was associated with advanced stages of cirrhosis in HIV/HCV-coinfected and HCV-monoinfected patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) hijack the host exosomal machinery as an additional mechanism of infection and evasion of the immune system, modifying the small RNA (smRNA) cargo during infection. We characterized the surface epitopes of extracellular vesicles (EVs) from plasma HIV/HCV-coinfected patients and their smRNA cargo profile, by comparing different isolation procedures. Six EVs isolation procedures were compared: ultracentrifugation, and five different polyethylene glycol-based methods (commercial, combined with a column purification step and two custom); and two RNA commercial kits (phenol and non-phenol based) were used. High-throughput sequencing of smRNAs was performed. Exosomal surface epitopes were analyzed by the MACSPlex Exosome Kit. Four miRNAs displayed differences among protocols (hsa-miR-205-5p and hsa-let-7a/b/f-5p). The selection of RNA isolation kit impacted on the detection of miRNAs and other smRNAs, where the phenol-based RNA isolation kit performed acceptably. EVs surface was enriched with HLA-DR/DP/DQ, CD81, and CD8. There were three liver-specific miRNAs overexpressed (let-7a-5p, miR-21-5p and hsa-miR-122-5p), thus, EVs cargo might reflect liver disease evolution. Other smRNAs such as piwi-interacting RNAs were also detected for the first time. Custom polyethylene glycol precipitation-based methods combined with an RNA phenol-based kit yielded the higher number of smRNAs for EVs isolated from plasma HIV/HCV patients.

Background: To assess the effects of eradication of hepatitis C virus (HCV) on cardiovascular risk (CVR) and preclinical atherosclerosis in HIV/HCV-coinfected patients., Setting: Prospective cohort study., Methods: We assessed serum lipids, 10-year Framingham CVR scores, pulse wave velocity, carotid intima-media thickness, and biomarkers of inflammation and endothelial dysfunction (BMKs) at baseline and 96 weeks (wk) after initiation of anti-HCV therapy (Rx) in HIV/HCV-coinfected patients., Results: A total of 237 patients were included. Anti-HCV therapy comprised pegylated interferon and ribavirin plus 1 direct-acting antiviral in 55.2%, pegylated interferon and ribavirin in 33.8%, and all-oral direct-acting antiviral in 11.0%. A total of 147 (62.0%) patients achieved sustained viral response (SVR). Median increases in low-density lipoprotein cholesterol in patients with and without SVR were 14 mg/dL and 0 mg/dL (P = 0.024), respectively. Increases in CVR categories were found in 26.9% of patients with SVR (P = 0.005 vs. baseline) and 8.1% of patients without SVR (P = 0.433). This resulted in a significant interaction between SVR and CVR over time (P < 0.001). No significant effect of SVR was observed for pulse wave velocity (P = 0.446), carotid intima-media thickness (P = 0.320), and BMKs of inflammation and endothelial dysfunction., Conclusions: In coinfected patients, eradication of HCV had no effect on markers of preclinical atherosclerosis and BMKs of inflammation and endothelial dysfunction but was associated with a clinically relevant rise in serum low-density lipoprotein cholesterol. Evaluation of CVR should be an integral part of care after the cure of chronic hepatitis C in patients with HIV.

Objective: There are a lack of consistency among articles in regards to the evolution of peripheral immune biomarkers after HCV therapy. We aimed to detect the most relevant changes in peripheral immune biomarkers among HIV/HCV-coinfected patients who achieved sustained virologic response (SVR) following peg-IFN-α/ribavirin therapy and to evaluate its normalization with respect to an HIV-monoinfected control group., Methods: We performed a prospective cohort study in 99 HIV/HCV-coinfected patients with samples at baseline (HIV/HCV-b-group) and at week 24 after SVR (HIV/HCV-f-group). We also used a control group of 39 HIV-monoinfected patients (HIV-group) negative for HCV and HBV infections, and who had undetectable HIV viral load and CD4 + >500 cells/mm 3 . Peripheral T cell subsets were assessed by flow cytometry and plasma biomarkers by immunoassays., Results: HIV/HCV-coinfected patients had higher values of in IL-10, IL-4, IP-10, IL-8, IL-1β, IL-18, IL-6, IFN-γ, IL-12p70, TNF-α, sVCAM-1, sICAM-1, and sTNFR-1 than HIV control subjects, both at the beginning and at the end of follow-up. Moreover, three biomarkers (CD4 + CD38 + , telomere length, and IL-1RA) were normalized in relation to the control group at the end of follow-up (the HIV/HCV-b group had higher values and the HIV/HCV-f group had similar values as the HIV-group). Additionally, LPS, IL-2, and IL-17A levels were higher in the HIV/HCV-f group than the HIV-group (24 weeks after SVR). During the follow-up, HIV/HCV-coinfected patients had a significant decrease by the end of follow-up in CD8 + CD45RA - CD28 + , CD4 + CD38 + , CD4 + CD25 + CD127 -/low , CD4 + CD25 + CD127 -/low CD45RA - , FABP2, LBP, IP-10, sVCAM1. Only CD4 + CD38 + was normalized., Conclusion: HIV/HCV-patients showed a slight improvement in the overall profile of immune biomarkers after achieving SVR., (Copyright © 2019. Published by Elsevier Ltd.)

Not all HIV-infected patients receiving cART are able to recover optimal CD4-T cell levels despite achieving undetectable viremia. We evaluated the potential association between polymorphisms (SNPs) in cytokines involved in immune response (IL15, IFNγ and IL19) and the failure to achieve optimal CD4 T-cells restoration after cART. For this, we carried out a retrospective study in 412 HIV-infected patients starting cART with CD4<200 cells/μL. These patients were classified as immunological non-responders (INR) if having a CD4 increase (ΔCD4) below 200 cells/μL after two years on successful cART. IL15, IFNγ and IL19 polymorphisms were genotyped using Sequenom's MassARRAY platform. We found 134 INR patients with a median [IQR] ΔCD4 = 133[73-174] cells/μL. In the multivariate analysis adjusted for age, sex, infection route, ethnic origin, hepatitis co-infection and HIV infection length, the AA genotype of the SNP rs2430561 in IFNγ (OR:2.01[1.13-3.56], p = 0.017) and the TT genotype of polymorphism rs2243191 in IL19 (OR:2.58 [1.17-5.68], p = 0.019) showed significant association with the INR status. Our results show that polymorphisms in IFNγ and IL19 genes significantly impacts in the probability of not achieving an optimal immune recovery in HIV-patients starting cART with CD4 T-cells <200 cells/μL. Thus, these SNPs could represent potential predictive markers of the immunodiscordant response., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The main targets for neutralizing anti-hepatitis C virus (HCV) antibodies (HCV-nAbs) are the E1 and E2 envelope glycoproteins. We have studied the characteristics of HCV-nAbs through a retrospective study involving 29 HIV/HCV-coinfected patients who achieved sustained virological response (SVR) with peg-IFNα + ribavirin anti-HCV therapy. Plasma samples at baseline and week 24 after SVR were used to perform neutralization assays against five JFH1-based HCV recombinant viruses coding for E1 and E2 from genotypes 1a (H77), 1b (J4), 2a (JFH1), 3a (S52) and 4a (ED43). At baseline, the majority of plasma samples neutralized 1a, 1b, 2a, and 4a, but not 3a, genotypes. Twenty-four weeks following SVR, most neutralizing titers declined substantially. Furthermore, titers against 3a and 2a were not detected in many patients. Plasma samples with high HCV-nAb titers neutralized all genotypes, and the highest titers at the starting point correlated with the highest titers at week 24 after SVR. In conclusion, high titers of broad-spectrum HCV-nAbs were detected in HIV/HCV-coinfected individuals, however, those titers declined soon after SVR.

Exosome-derived miR-21 was independently associated with CD4 T cell decline in HIV-1-infected elite controllers (OR 0.369, 95% CI 0.137-0.994, p = 0.049). Also, a negative correlation between miR-21 expression and MCP-1 level was found (r = -0.649, p = 0.020), while no correlation between soluble biomarkers or cellular immune activation was found., (Copyright © 2018. Published by Elsevier B.V.)

Background: Mitochondrial DNA (mtDNA) haplogroups have been associated with advanced liver fibrosis and cirrhosis in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Our aim was to determine whether mtDNA haplogroups are associated with liver-related events (LREs) in HIV/HCV-coinfected patients., Methods: We carried out a retrospective cohort study in HIV/HCV-coinfected patients who were potential candidates for therapy with interferon and ribavirin (IFN/Rib) between 2000 and 2009. The primary endpoint was the occurrence of LREs (decompensation or hepatocellular carcinoma). mtDNA genotyping was performed using the Sequenom MassARRAY platform. We used Fine and Gray proportional hazards model to test the association between mtDNA haplogroups and LREs, considering death as a competitive risk., Results: The study population comprised 243 patients, of whom 40 had advanced fibrosis or cirrhosis. After a median follow-up of 7.7 years, 90 patients treated with IFN/Rib achieved sustained viral response (SVR), 18 patients had LREs, and 11 patients died. Patients with haplogroup H had lower cumulative incidence than patients with other haplogroups (p = 0.012). However, patients with haplogroup T had higher cumulative incidence than patients with other haplogroups (p = 0.074). In the multivariate analysis, haplogroup T was associated with an increased hazard of developing LREs [adjusted subhazard ratio (aSHR) = 3.56 (95% CI 1.13;11.30); p = 0.030]; whereas haplogroup H was not associated with lower hazard of LREs [aSHR = 0.36 (95% CI 0.10;1.25); p = 0.105]. When we excluded patients who achieved SVR during follow-up, we obtained similar SHR values., Conclusions: European mitochondrial haplogroups may influence the natural history of chronic hepatitis C.

Interleukin-7 receptor subunit alpha (IL7RA) rs6897932 polymorphism is related to CD4 + recovery after combination antiretroviral therapy (cART), but no studies so far have analyzed its potential impact in patients with very low CD4 + T-cells count. We aimed to analyze the association between IL7RA rs6897932 polymorphism and CD4 + T-cells count restoration in HIV-infected patients starting combination antiretroviral therapy (cART) with CD4 + T-cells count <200 cells/mm 3 . We performed a retrospective study in 411 patients followed for 24 months with a DNA sample available for genotyping. The change in CD4 + T-cells count during the follow-up was considered as the primary outcome. The rs6897932 polymorphism had a minimum allele frequency (MAF) >20% and was in Hardy-Weinberg equilibrium ( p = 0.550). Of 411 patients, 256 carried the CC genotype, while 155 had the CT/TT genotype. The CT/TT genotype was associated with a higher slope of CD4 + T-cells recovery (arithmetic mean ratio; AMR = 1.16; p = 0.016), higher CD4 + T-cells increase (AMR = 1.19; p = 0.004), and higher CD4 + T-cells count at the end of follow-up (AMR = 1.13; p = 0.006). Besides, rs6897932 CT/TT was related to a higher odds of having a value of CD4 + T-cells at the end of follow-up ≥500 CD4 + cells/mm 3 (OR = 2.44; p = 0.006). After multiple testing correction (Benjamini-Hochberg), only the increase of ≥ 400 CD4 + cells/mm 3 lost statistical significance ( p = 0.052). IL7RA rs6897932 CT/TT genotype was related to a better CD4 + T-cells recovery and it could be used to improve the management of HIV-infected patients starting cART with CD4 + T-cells count <200 cells/mm 3 ., Competing Interests: The authors declare no conflict of interest.

In HIV-1/HCV-coinfected patients, chronic HCV infection leads to an increased T-lymphocyte immune activation compared to HIV-monoinfected patients, thereby likely contributing to increase HIV-1 reservoir that is the major barrier for its eradication. Our objective was to evaluate the influence of HCV coinfection in HIV-1 viral reservoir size in resting (r) CD4+ T-cells (CD25-CD69-HLADR-). Multicenter cross-sectional study of 97 cART-treated HIV-1 patients, including 36 patients with HIV and HCV-chronic co-infection without anti-HCV treatment, 32 HIV patients with HCV spontaneous clearance and 29 HIV-monoinfected patients. rCD4+ T-cells were isolated and total DNA was extracted. HIV viral reservoir was measured by Alu-LTR qPCR. Differences between groups were calculated with a generalized linear model. Overall, 63.9% were men, median age of 41 years and Caucasian. Median CD4+ and CD8+ T-lymphocytes were 725 and 858 cells/mm 3 , respectively. CD4+ T nadir cells was 305 cells/mm 3 . Proviral HIV-1 DNA size was significantly increased in chronic HIV/HCV-coinfected compared to HIV-monoinfected patients (206.21 ± 47.38 vs. 87.34 ± 22.46, respectively; P = 0.009), as well as in spontaneously clarified HCV co-infected patients when compared to HIV-monoinfected individuals (136.20 ± 33.20; P = 0.009). HIV-1/HCV co-infected patients showed a larger HIV-1 reservoir size in comparison to HIV-monoinfected individuals. This increase could lead to a greater complexity in the elimination of HIV-1 reservoir in HIV-1/HCV-coinfected individuals, which should be considered in the current strategies for the elimination of HIV-1 reservoir.

Hepatitis E virus (HEV) has emerged as a relevant pathogen for HIV-infected patients. However, there is scarce data on HEV infection in HIV/HCV-coinfected individuals with advanced fibrosis, which seems to increase the risk of HEV infection and worsen the prognosis of liver disease. We aimed to determine the prevalence of anti-HEV antibodies, acute hepatitis E, resolved hepatitis E, and exposure to HEV in HIV/HCV-coinfected patients and to evaluate associations with clinical and epidemiological characteristics. We performed a cross-sectional study on 198 HIV/HCV-coinfected patients, 30 healthy controls and 36 HIV-monoinfected patients. We found a low concordance between techniques used for detection of anti-HEV antibodies (ELISA versus Immunoblot), particularly in HIV/HCV-coinfected patients. HIV/HCV-coinfected patients showed the highest prevalence of IgG against HEV, resolved hepatitis E, and exposure to HEV (19.2%, 17.2%, and 22.2% respectively). However, we did not find any samples positive for HEV-RNA nor significant differences between groups. Moreover, HIV/HCV-coinfected patients with CD4 T-cells <350 cells/mm 3 had higher prevalence for anti-HEV IgG antibodies, resolved hepatitis E, and exposure to HEV than healthy controls or those with CD4 T-cells ≥ 350 cells/mm 3 (p = 0.034, p = 0.035, and p = 0.053; respectively). In conclusion, HIV/HCV-coinfected patients in Spain have a high prevalence for IgG anti-HEV antibodies, resolved hepatitis E, and exposure to HEV; particularly patients with CD4+T-cells <350 cells/mm 3 .

Background: TNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients., Methods: A cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (F ≥ 3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4 ≥ 3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2)., Results: Patients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4 ≥ 3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR) = 0.30 (p = 0.025), aOR = 0.20 (p = 0.014), and aOR = 0.34 (p = 0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR) = 0.76 (p = 0.003) and aAMR = 0.72 (p = 0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aOR = 0.39 (p = 0.030)] and lower levels of APRI [aAMR = 0.77 (p = 0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4 ≥ 3.25 [aOR = 3.72 (p = 0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (p = 0.002 and p = 0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (p = 0.004, p = 0.007, p = 0.020 and p = 0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (p = 0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (p = 0.029, p = 0.040, p = 0.022 and p = 0.024, respectively)., Conclusions: Genetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The mitochondrial DNA (mtDNA) seems to influence in a large number of diseases, including HIV infection. Moreover, there is a substantial inter-individual variability in the CD4+ recovery in HIV-infected patients on combination antiretroviral therapy (cART). Our study aimed to analyze the association between mtDNA haplogroups and CD4+ recovery in HIV-infected patients on cART., Methods: This is a retrospective study of 324 naïve cART patients with CD4+ < 200 cells/mm 3 , who were followed-up during 24 months after initiating cART. All patients had undetectable HIV viral load during the follow-up. Besides, we included 141 healthy controls. MtDNA genotyping was performed by using Sequenom's MassARRAY platform. The primary outcome variable was the slope of CD4+ recovery. Patients were stratified into two groups by the median slope value of CD4+ (9.65 CD4+ cells/mm 3 /month). Logistic regression analyses were performed to calculate the odds of CD4+ recovery according to mtDNA haplogroups., Results: Our study included European HIV-infected patients within the N macro-cluster. The baseline values of CD4+ T-cells were similar between groups of patients stratified by the P50th of the slope of CD4+ T-cells recovery. Patients in the low CD4+ T-cells recovery group were older (p = 0.001), but this variable was included in the multivariate models. When we analyzed the frequencies of mtDNA haplogroups, no significant differences between HIV-infected individuals and healthy controls were found. We did not find any significant association between mtDNA haplogroups and the slope of CD4+ T-cells recovery by linear regression analysis. However, Patients carrying haplogroup H had a higher odds of having a better CD4+ recovery (> 9.65 CD4+ cells/mm 3 /month) than patients without haplogroup H (p = 0.032). The adjusted logistic regression showed that patients carrying haplogroup H had a higher likelihood of achieving a CD4+ recovery > 9.65 CD4+ cells/mm 3 /month [adjusted odds ratio (aOR) = 1.75 (95% CI = 1.04; 2.95); p = 0.035]., Conclusions: European mitochondrial haplogroup H was associated with the improved CD4+ recovery in HIV-infected patients starting cART with CD4+ < 200 cells/mm 3 .

Chronic infections are a major factor in the development of pulmonary embolism (PE). We aimed to evaluate the trends of PE-related hospitalizations and PE-related deaths in people living with HIV (PLWH) during the era of combination antiretroviral therapy (cART) through a retrospective study in Spain. Data were collected from the Minimum Basic Data Set (MBDS) between 1997 and 2013. The study period was fragmented into four calendar periods (1997-1999, 2000-2003, 2004-2007, and 2008-2013). The rate of PE-related hospitalizations remained stable in PLWH (P = 0.361). HIV-monoinfected patients had a higher incidence than HIV/HCV-coinfected patients during all follow-up [(98.7 (95%CI = 92.2; 105.1); P < 0.001], but PE incidence decreased in HIV-monoinfected patients (P < 0.001) and increased in HIV/HCV-coinfected patients (P < 0.001). Concretely, the rate of PE-related hospitalizations decreased significantly in patients monoinfected with HIV [from 203.6 (95%CI = 175.7; 231.6) events per 100,000 patient-years in 1997-1999 to 74.3 (95%CI = 66.1; 82.3) in 2008-2013; P < 0.001], while patients coinfected with HIV/HCV had a significant increase [from 16.3 (95%CI = 11; 21.6) in 1997-1999 to 53.3 (95%CI = 45.9; 60.6) in 2008-2013; P < 0.001]. The mortality rate of PE-related hospitalizations showed a similar trend as PE incidence. In conclusion, the epidemiological trends of PE in PLWH changed during the cART era, with decreases in incidence and mortality in HIV-monoinfected and increases in both variables in patients coinfected with HIV/HCV.

Background: Interferon alpha (IFN-α) can potently reduce human immunodeficiency virus type 1 (HIV-1) replication in tissue culture and animal models, but may also modulate residual viral reservoirs that persist despite suppressive antiretroviral combination therapy. However, mechanisms leading to viral reservoir reduction during IFN-α treatment are unclear., Methods: We analyzed HIV-1 gag DNA levels in CD4 T cells by digital droplet polymerase chain reaction and CD8 T-cell and natural killer (NK) cell phenotypes by flow cytometry in a cohort of antiretroviral therapy-treated HIV-1/hepatitis C virus-coinfected patients (n = 67) undergoing treatment for hepatitis C infection with pegylated IFN-α and ribavirin for an average of 11 months., Results: We observed that IFN-α treatment induced a significant decrease in CD4 T-cell counts (P < .0001), in CD4 T-cell-associated HIV-1 DNA copies (P = .002) and in HIV-1 DNA copies per microliter of blood (P < .0001) in our study patients. Notably, HIV-1 DNA levels were unrelated to HIV-1-specific CD8 T-cell responses. In contrast, proportions of total NK cells, CD56brightCD16- NK cells, and CD56brightCD16+ NK cells were significantly correlated with reduced levels of CD4 T-cell-associated HIV-1 DNA during IFN-α treatment, especially when coexpressing the activation markers NKG2D and NKp30., Conclusions: These data suggest that the reduction of viral reservoir cells during treatment with IFN-α is primarily attributable to antiviral activities of NK cells.

Objectives: Immune dysregulation is a hallmark of HIV and hepatitis C virus (HCV) infections. We aimed to evaluate the relationship between liver stiffness measurement (LSM) and biomarkers of T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy in HIV/HCV-coinfected patients., Design: Cross-sectional study., Methods: We studied 238 HIV/HCV-coinfected patients, 32 healthy controls, and 39 HIV-monoinfected patients. Patients were stratified according to LSM into four groups: less than 12.5, 12.5-25, 25-40, and more than 40 kPa. T-cell subsets were measured using flow cytometry and plasma biomarkers using immunoassays., Results: HIV/HCV-coinfected patients had higher biomarker levels of immune activation in peripheral blood [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (soluble CD14), inflammation [IL-1b, IL-6, IL-8, IL-18, IFN-γ-inducible protein 10 (IP-10)] endothelial dysfunction [soluble vascular cell adhesion molecule 1 (sVCAM1), soluble intercellular cell adhesion molecule 1 (sICAM1), and soluble tumor necrosis factor receptor 1 (sTNFR1)], and coagulopathy (plasminogen activator inhibitor-1)] than healthy controls and HIV-monoinfected patients. Moreover, in HIV/HCV-coinfected patients, a direct relationship between LSM and immune activation [T-cell activation (CD8CD38 bacterial translocation (lipopolysaccharide), inflammation (IL-8, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] was found. Subsequently, patients were stratified into different fibrosis stages, finding that patients with cirrhosis who had LSM at least 40 kPa showed higher biomarker values of immune activation [T-cell activation (CD4CD38 and CD8CD38), bacterial translocation (lipopolysaccharide), inflammation (IL-8, IL-6, IP-10), endothelial dysfunction (sVCAM1, sICAM1, and sTNFR1), and coagulopathy (D-dimer)] than patients from the other three groups (<12.5, 12.5-25, and 25-40 kPa)., Conclusion: T-cell activation, bacterial translocation, inflammation, endothelial dysfunction, and coagulopathy increased with the severity of liver fibrosis in HIV/HCV-coinfected patients, particularly in patients who had LSM at least 40 kPa.

People living with human immunodeficiency virus (HIV) infection typically have hypovitaminosis D, which is linked to a large number of pathologies, including immune disorders and infectious diseases. Vitamin D (VitD) is a key regulator of host defense against infections by activating genes and pathways that enhance innate and adaptive immunity. VitD mediates its biological effects by binding to the Vitamin D receptor (VDR), and activating and regulating multiple cellular pathways. Single nucleotide polymorphisms in genes from those pathways have been associated with protection from HIV-1 infection. High levels of VitD and VDR expression are also associated with natural resistance to HIV-1 infection. Conversely, VitD deficiency is linked to more inflammation and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients. VitD supplementation and restoration to normal values in HIV-infected patients may improve immunologic recovery during combination antiretroviral therapy, reduce levels of inflammation and immune activation, and increase immunity against pathogens. Additionally, VitD may protect against the development of immune reconstitution inflammatory syndrome events, pulmonary tuberculosis, and mortality among HIV-infected patients. In summary, this review suggests that VitD deficiency may contribute to the pathogenesis of HIV infection. Also, VitD supplementation seems to reverse some alterations of the immune system, supporting the use of VitD supplementation as prophylaxis, especially in individuals with more severe VitD deficiency.

Background: Chronic infections may be a triggering factor as well as a risk factor of deep venous thrombosis (DVT). The purpose of this study was to analyze the epidemiological trends of hospital admissions related to DVT in human immunodeficiency virus (HIV)-infected patients during the combination antiretroviral therapy (cART) era, in relation to hepatitis C virus (HCV) serological status., Methods: We performed a retrospective study using the Spanish Minimum Basic Data Set. We selected HIV-infected subjects over 15years old with a hospital admission and DVT diagnosis (ICD-9-CM codes: 453.4x and 453.8x) between 1997 and 2013. Patients were classified according to HCV serology. We estimated the incidence (events per 100,000 patient-years) in four calendar periods (1997-1999, 2000-2003, 2004-2007, and 2008-2013)., Results: Overall, the incidence of DVT-related hospitalizations had a significant upward trend in all HIV-infected patients (P<0.001), with significant differences between 1997-1999 and 2008-2013 [49.5 vs. 88.1 (P<0.001)]. Moreover, the incidence was higher in HIV-monoinfected patients than in HIV/HCV-coinfected patients during the entire follow-up (P<0.001). However, the incidence had a significant downward trend in HIV-monoinfected patients (P=0.002) and a significant upward trend in HIV/HCV-coinfected patients (P<0.001). Specifically, the incidence of DVT-related hospitalizations in HIV-monoinfected patients significantly decreased from 1997-1999 to 2008-2013 [142.7 vs. 103.1 (P=0.006)], whereas in HIV/HCV-coinfected patients, the incidence increased from 8.4 (1997-1999) to 70.7 (2008-2013) (P<0.001)., Conclusions: Our findings suggest that DVT is an emerging health problem among HIV-infected patients, with increasing incidence during the first 17years after the introduction of cART, particularly in HIV/HCV-coinfected patients., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Both hepatitis C virus (HCV) infection and human immunodeficiency virus (HIV) infection are underdiagnosed, particularly in low-income countries and in difficult-to-access populations. Our aim was to develop and evaluate a methodology for the detection of HCV and HIV infection based on capillary dry blood spot (DBS) samples taken under real-world conditions. We carried out a cross-sectional study of 139 individuals (31 healthy controls, 68 HCV-monoinfected patients, and 40 HCV/HIV-coinfected patients). ELISA was used for anti-HCV and anti-HIV antibody detection; and SYBR Green RT-PCR was used for HCV-RNA detection. The HIV serological analysis revealed 100% sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The HCV serological analysis revealed a sensitivity of 92.6%, specificity of 100%, PPV of 100%, and NPV of 79.5%. Finally, the HCV-RNA detection test revealed a detection limit of 5 copies/µl with an efficiency of 100% and sensitivity of 99.1%, specificity of 100%, PPV of 100%, and NPV of 96.9%. In conclusion, our methodology was able to detect both HCV infection and HIV infection from the same DBS sample with good diagnostic performance. Screening for HCV and HIV using DBS might be a key strategy in the implementation of national programs for the control of both infections.

The adenosine deaminase acting on RNA (ADAR1) gene is an interferon-stimulated gene involved in liver injury protection. Our aim was to analyze the association of polymorphisms within this gene with the severity of liver disease in European HIV/HCV-coinfected patients. We performed a cross-sectional study in 220 patients that underwent a liver biopsy. Five SNPs in the ADAR1 gene (rs1127326, rs1127317, rs1127314, rs1127313, rs2229857) were genotyped by GoldenGate assay. The outcome variables were fibrosis stage and necroinflammatory activity grade by METAVIR-score, aspartate aminotransferase to platelet ratio index (APRI), FIB-4 index, and fibrosis progression rate (FPR). In multivariate analysis, fibrosis progression rate (FPR) (aAMRs = 0.97) decreased in a dose-dependent manner with the presence of rs2229857&#95;T, rs1127313&#95;G, rs1127314&#95;G and rs1127317&#95;G; while rs1127326&#95;T allele had only significant associations with FIB-4 (aAMRs ≤ 0.63) and FPR (aAMRs ≤ 0.97). Moreover, carriers of rs2229857&#95;T, rs1127314&#95;G, rs1127317&#95;G, and rs1127326&#95;T alleles were protected against advanced fibrosis (F ≥ 3) (adjusted ORs (aORs) ≤ 0.44), APRI ≥ 1.5 (aORs ≤ 0.33), and FPR ≥ 0.075 (aORs ≤ 0.45). rs1127313&#95;G carriers showed lower odds of having F ≥ 3 (aORs = 0.39), FIB4 ≥ 3.25 (aOR = 0.22) and FPR ≥ 0.075 (aORs = 0.44). In conclusion, ADAR1 polymorphisms protected against severe liver disease in HIV/HCV-coinfected patients. These results could be used to improve therapeutic decision-making in clinical practice.

Background: Our aim was to determine whether α-chain of the IL-7 receptor (IL7RA) polymorphisms (rs10491434, rs6897932 and rs987106) are associated with the clinical pattern of AIDS progression in ART-naïve HIV-infected patients., Materials and Methods: We carried out a cross-sectional study in 673 HIV-infected patients who were classified into three groups according to the clinical pattern of AIDS progression (188 long-term nonprogressors (LTNPs), 334 moderate progressors (MPs) and 151 rapid progressors (RPs)). Additionally, 134 healthy blood donors participated as a Control-group. We selected three IL7RA polymorphisms located at three regulatory regions [rs6897932 (exon 6), rs987106 (intronic region) and rs10491434 (3'UTR)]. DNA genotyping was performed using Sequenom's MassARRAY platform., Results: The Control-group and all HIV-infected patients had similar age and percentage of males. LTNP-group was older at HIV diagnosis and at the inclusion in the study and had higher percentage of intravenous drug users (IDU) (P < 0·001). Besides, LTNP-group had lower proportion of male patients and homosexual HIV transmission than MP and RP groups (P < 0·001). Moreover, similar values of allelic, genotypic and haplotype frequencies for IL7RA polymorphisms were found between healthy controls and HIV-infected patients (P > 0·05), and among different subgroups of HIV patients according to AIDS progression (LTNPs, MPs and RPs) (P > 0·05). The adjusted logistic regression did not show any significant association between IL7RA polymorphisms and AIDS progression., Conclusions: IL7RA polymorphisms (rs6897932, rs987106 and rs10491434) were not associated with AIDS progression in Spanish population. Therefore, IL7RA polymorphisms do not seem to help us to understand HIV pathogenesis in untreated HIV-infected patients with different clinical evolution., (© 2017 Stichting European Society for Clinical Investigation Journal Foundation.)

Unprotected heterosexual intercourse is the first route for sustaining the global spread of human immunodeficiency virus type 1 (HIV-1), being responsible for 80% of new HIV-1 infections in the world. The presence of inflammation in the female reproductive tract and the presence of semen increases the risk of heterosexual HIV-1 transmission. This state-of-the-art research based on an innovative nanotechnology design was focused on a toxicological study of the limitation of the activity of the novel H 2 O-soluble anionic carbosilane dendrimer G2-S16 in the adult cervical and foreskin epithelia. The G2-S16 dendrimer did not cause any irritation or inflammation in the vaginal epithelium, proving that this dendrimer is a safe nanocompound for vaginal application to control viral transmission. It was shown that no significant differences were found in mortality, sublethal or teratogenic effects when the zebra fish embryos were treated with G2-S16. In short, G2-S16 seems to be an ideal candidate for the development of a topical microbicide against HIV-1 infection and the next step is try in clinical trials, because of its great in vivo biocompatibility, as well as its ability to halt HIV-1 infection in the presence of semen.

The incidence of stroke in human immunodeficiency virus (HIV)-infected individuals has been well analyzed in recent epidemiological studies. However, little is known about the specific contribution of hepatitis C virus (HCV) infection to stroke among HIV-infected individuals. The aims of this study were to analyze trends in the incidence rates of stroke in HIV-infected individuals during the combination antiretroviral (cART) era in Spain and to categorize them by the presence or absence of HCV coinfection. We analyzed hospital discharges with a diagnosis of stroke in Spain according to ICD-9-CM during 1997-2013. The study period was divided into four calendar periods (1997-1999, 2000-2003, 2004-2007, and 2008-2013). Patients were classified according to HCV serology. The number of HIV-infected patients was estimated based on data from the National Centre of Epidemiology. We calculated incidence rates (events per 10,000 patient-years) and in-hospital case fatality rates (CFR). The incidence of hemorrhagic stroke (HS) decreased in HIV-monoinfected patients (15.8 [1997-1999] to 6.5 [2008-2013]; P<0.001) and increased in HIV/HCV-coinfected patients (1.3 [1997-1999] to 5.5 [2008-2013]; P<0.001). The incidence of ischemic stroke (IS) decreased in HIV-monoinfected patients (27.4 [1997-1999] to 21.7 [2008-2013]; P = 0.005) and increased in HIV/HCV-coinfected patients (1.8 [1997-1999] to 11.9 [2008-2013]; P<0.001). The CFR was 3.3 times higher for HS than for IS for the whole study period. The CFR of HS in HIV-monoinfected patients decreased significantly (47.4% [1997-1999] to 30.6% [2008-2013]; P = 0.010) but did not change significantly among HIV/HCV-coinfected patients (41.4% [1997-1999] to 44.7% [2008-2013]; P = 0.784). The CFR of IS in the whole HIV-infected population decreased significantly (14.6% [1997-1999] to 10.9% [2008-2013]; P = 0.034), although no significant differences were found when each group was analyzed separately. In conclusion, after the introduction of cART, HS and IS rates decreased in HIV-monoinfected individuals, but increased steadily in HIV/HCV-coinfected individuals.

The mechanisms involved in the chronic hepatitis C progression are incompletely understood. The aim was to analyze the association between 2'5'oligoadenylate synthetase 1,2 and 3 (OAS1-3) and myxovirus resistance proteins 1 (Mx1) polymorphisms and severity of liver disease in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. We performed a cross-sectional study in 219 patients that underwent a liver biopsy. DNA genotyping for Mx1 (rs469390), OAS1 (rs2285934), OAS2 (rs1293762) and OAS3 (rs2010604) was performed by using GoldenGate assay. The outcome variables ion liver biopsy were: (i) significant fibrosis (F ≥ 2); (ii) moderate activity grade (A ≥ 2). Additive model of inheritance for genetic association test was used. The likelihood of having significant fibrosis (F ≥ 2) was lower in patients carrying OAS2 rs1293762 A allele [adjusted odds ratio (aOR) = 0.51; p = 0.040]. Besides, the likelihood of having moderate activity grade (A ≥ 2) was higher in patients carrying Mx1 rs464397 C allele (aOR = 1.63; p = 0.028) and Mx1 rs469390 G allele (aOR = 1.97; p = 0.005), while it was lower in patients carrying OAS1 rs2285934 A allele (aOR = 0.64; p = 0.039) and OAS2 rs1293762 A allele (aOR = 0.41; p = 0.009). In conclusion, Mx1 and OAS1-2 polymorphisms were associated with the severity of liver disease in HIV/HCV-coinfected patients, suggesting a significant role in the progression of hepatic fibrosis., Competing Interests: The authors declare no competing financial interests.

The pathogenic mechanisms of the accelerated progression of liver injury in HIV/HCV coinfection are incompletely understood. The progression of liver disease is variable between individuals having similar risk factors, suggesting that genetic background is an important contributor. The aim of this review is to give a summary of all single nucleotide polymorphisms associated with the severity of liver disease in patients coinfected with HIV and HCV reported in the literature. Therefore, a systematic search for articles published was made, 17 of which were selected for this review. In summary, a large number of single nucleotide polymorphisms have been associated with the severity of liver disease in HIV/HCV-coinfected patients. These genes are involved in different biological processes, including seven that correspond to cytokine genes (IFNL3-4, CXCL9-11, IL15, TNF), two to receptor genes (IL7R, TLR8), and three are genes related to metabolism (PNPLA3, FTO, GSTM1). In addition, two combinations of polymorphisms (cirrhosis risk score and mitochondrial haplogroups) have also been related to severity of liver disease in HIV/HCV-coinfected patients. Although determinants other than genetics, such as environmental and viral factors, may be implicated in liver disease progression, information about genetic variation might be useful in clinical practice, allowing prioritization of patients with a genetic background that predispose to a worse evolution of HCV-related liver disease.

Purpose: The aim of this study was to estimate trends of incidence of hospital admissions and in-hospital mortality (IHM) in HIV-infected patients with COPD in the combination antiretroviral therapy (cART) era in Spain (1997-2012)., Methods: A retrospective study with data from nationwide population-based COPD diagnoses in the Spanish Minimum Basic Data Set (MBDS) was performed. We established groups according to their HIV and HCV infections: 1) HIV-uninfected patients; 2) HIV-infected patients (with or without HCV coinfection)., Results: 1,580,207 patients discharge with a COPD diagnosis were included in the study, 8902 of them were HIV-infected patients (5000 HIV-monoinfected patients and 3902 HIV/HCV-coinfected patients). The HIV-infected patients had higher incidence rates of hospital admissions for COPD than the HIV-uninfected patients during the study period. The HIV-monoinfected patients had higher rates of hospitalizations for COPD than the HIV/HCV-coinfected patients in the early-period cART (1997-1999), but these rates decreased in the first group and increased in the second, being even similar in both groups in the late-period cART (2004-2011). On the other hand, the HIV-infected patients with COPD had higher IHM than the HIV-uninfected patients with COPD. The mortality rates were higher in the HIV-monoinfected patients with COPD than in the HIV/HCV-coinfected patients with COPD in the early-period cART; however, in the late-period cART, the mortality rates trends seems higher in the HIV/HCV group. The likelihood of death in HIV/HCV-coinfected patients with COPD was similar to than in HIV-monoinfected patients with COPD., Conclusions: Incidence of hospital admissions for COPD and IHM have decreased among HIV-monoinfected individuals but have increased steadily among HIV/HCV-coinfected individuals in the cART era., Competing Interests: Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: This study was partly funded by URJC-Banco Santander to the Grupo de Excelencia Investigadora ITPSE (Grant N°30VCPIGI03). There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.