Incidence of Diabetes Mellitus and Associated Factors in the Era of Antiretroviral Drugs With a Low Metabolic Toxicity Profile.

Objective: The incidence of type 2 diabetes mellitus (T2DM) has risen dramatically. Among people living with HIV (PLHIV), chronic disease (now >15 cases/1000 in the general population worldwide) and long-term exposure to antiretroviral therapy (ART) can alter metabolic processes early, favoring insulin resistance and T2DM. We retrospectively studied the incidence of T2DM and associated factors in the Cohort of the Spanish AIDS Research Network, a prospective cohort of PLHIV enrolled at diagnosis and before initiation of ART. Methods: PLHIV were aged >18 years and ART naive at inclusion. The incidence of new diagnoses of T2DM after initiation of ART (per 1000 person-years) was calculated. Predictors of a diagnosis of T2DM were identified by a Cox proportional hazards model adjusted for statistically significant and clinically relevant variables. Results: Cumulative incidence was 5.9 (95% CI, 5.1-6.7) per 1000 person-years, increasing significantly in persons aged >50 years to 14.4 (95% CI, 10.4-19.3). Median time to diagnosis of T2DM was 27 months. Only age and higher education were significant. Interestingly, higher education was associated with a 33% reduction in the incidence of T2DM. Having received tenofovir disoproxil fumarate + (lamivudine or emtricitabine) + rilpivirine was almost significant as a protective factor (hazard ratio, 0.49; 95% CI, .24-1.01; P = .05). Conclusions: The incidence of T2DM in PLHIV in Spain was high, especially in persons aged >50 years. Age was the factor most closely associated with onset, and educational level was the factor most associated with reduced risk. We highlight the lack of association between HIV-related factors and T2DM and show that, within nonnucleoside reverse transcriptase inhibitors, rilpivirine could prove more benign for metabolic comorbidities.

The HIV-1 reservoir landscape in persistent elite controllers and transient elite controllers.

BACKGROUNDPersistent controllers (PCs) maintain antiretroviral-free HIV-1 control indefinitely over time, while transient controllers (TCs) eventually lose virological control. It is essential to characterize the quality of the HIV reservoir in terms of these phenotypes in order to identify the factors that lead to HIV progression and to open new avenues toward an HIV cure.METHODSThe characterization of HIV-1 reservoir from peripheral blood mononuclear cells was performed using next-generation sequencing techniques, such as full-length individual and matched integration site proviral sequencing (FLIP-Seq; MIP-Seq).RESULTSPCs and TCs, before losing virological control, presented significantly lower total, intact, and defective proviruses compared with those of participants on antiretroviral therapy (ART). No differences were found in total and defective proviruses between PCs and TCs. However, intact provirus levels were lower in PCs compared with TCs; indeed the intact/defective HIV-DNA ratio was significantly higher in TCs. Clonally expanded intact proviruses were found only in PCs and located in centromeric satellite DNA or zinc-finger genes, both associated with heterochromatin features. In contrast, sampled intact proviruses were located in permissive genic euchromatic positions in TCs.CONCLUSIONSThese results suggest the need for, and can give guidance to, the design of future research to identify a distinct proviral landscape that may be associated with the persistent control of HIV-1 without ART.FUNDINGInstituto de Salud Carlos III (FI17/00186, FI19/00083, MV20/00057, PI18/01532, PI19/01127 and PI22/01796), Gilead Fellowships (GLD22/00147). NIH grants AI155171, AI116228, AI078799, HL134539, DA047034, MH134823, amfAR ARCHE and the Bill and Melinda Gates Foundation.

Rat hepatitis E virus (Rocahepevirus ratti) in people living with HIV.

Rat hepatitis E virus (ratHEV; species Rocahepevirus ratti) is considered a newly emerging cause of acute hepatitis of zoonotic origin. ratHEV infection of people living with HIV (PLWH) might portend a worse, as with hepatitis E virus (HEV; species Paslahepevirus balayani), and consequently this group may constitute a high-risk population. We aimed to evaluate the prevalence of ratHEV by measuring viral RNA and specific IgG antibodies in a large Spanish cohort of PLWH. Multicentre study conducted in Spain evaluating PLWHIV included in the Spanish AIDS Research Network (CoRIS). Patients were evaluated for ratHEV infection using PCR at baseline and anti-ratHEV IgG by dot blot analysis to evaluate exposure to ratHEV strains. Patients with detectable ratHEV RNA were followed-up to evaluate persistence of viremia and IgG seroconversion. Eight-hundred and forty-two individuals were tested. A total of 9 individuals showed specific IgG antibodies against ratHEV, supposing a prevalence of 1.1 (95% CI; 0.5%-2.1%). Of these, only one was reactive to HEV IgG antibodies by ELISA. One sample was positive for ratHEV RNA (prevalence of infection: 0.1%; 95% CI: 0.08%-0.7%). The case was a man who had sex with men exhibiting a slightly increased alanine transaminase level (49 IU/L) as only biochemical alteration. In the follow-up, the patients showed undetectable ratHEV RNA and seroconversion to specific ratHEV IgG antibodies. Our study shows that ratHEV is geographical broadly distributed in Spain, representing a potential zoonotic threat.

Transmitted drug resistance to antiretroviral drugs in Spain during the period 2019-2021.

To evaluate the prevalence of transmitted drug resistance (TDR) to nucleoside and nonnucleoside reverse transcriptase inhibitors (NRTI, NNRTI), protease inhibitors (PI), and integrase strand transfer inhibitors (INSTI) in Spain during the period 2019-2021, as well as to evaluate transmitted clinically relevant resistance (TCRR) to antiretroviral drugs. Reverse transcriptase (RT), protease (Pro), and Integrase (IN) sequences from 1824 PLWH (people living with HIV) were studied. To evaluate TDR we investigated the prevalence of surveillance drug resistance mutations (SDRM). To evaluate TCRR (any resistance level ≥ 3), and for HIV subtyping we used the Stanford v.9.4.1 HIVDB Algorithm and an in-depth phylogenetic analysis. The prevalence of NRTI SDRMs was 3.8% (95% CI, 2.8%-4.6%), 6.1% (95% CI, 5.0%-7.3%) for NNRTI, 0.9% (95% CI, 0.5%-1.4%) for PI, and 0.2% (95% CI, 0.0%-0.9%) for INSTI. The prevalence of TCRR to NRTI was 2.1% (95% CI, 1.5%-2.9%), 11.8% for NNRTI, (95% CI, 10.3%-13.5%), 0.2% (95% CI, 0.1%-0.6%) for PI, and 2.5% (95% CI, 1.5%-4.1%) for INSTI. Most of the patients were infected by subtype B (79.8%), while the majority of non-Bs were CRF02_AG (n = 109, 6%). The prevalence of INSTI and PI resistance in Spain during the period 2019-2021 is low, while NRTI resistance is moderate, and NNRTI resistance is the highest. Our results support the use of integrase inhibitors as first-line treatment in Spain. Our findings highlight the importance of ongoing surveillance of TDR to antiretroviral drugs in PLWH particularly with regard to first-line antiretroviral therapy.

Decay kinetics of HIV-1-RNA in seminal plasma with dolutegravir/lamivudine versus dolutegravir plus emtricitabine/tenofovir alafenamide in treatment-naive people living with HIV.

BACKGROUND: This was a substudy of a Phase IV, randomized clinical trial (ClinicalTrials.gov identifier: NCT04295460) aiming to compare the activity of dolutegravir/lamivudine versus dolutegravir plus tenofovir alafenamide/emtricitabine (DTG + TAF/FTC) in the male genital tract. METHODS: Participants were asymptomatic adults without sexually transmitted diseases, treatment-naive people living with HIV (PLWH), with CD4+ T cell counts >200 cells/mm3 and plasma HIV-1-RNA levels >5000 and <500 000 copies/mL, randomized (1:1) to DTG + TAF/FTC or dolutegravir/lamivudine. Blood plasma (BP) and seminal plasma (SP) were collected at baseline and Weeks 4, 8, 12 and 24. HIV-1-RNA was measured in BP and SP using the Cobas 6800 system (Roche Diagnostics) with a lower detection limit of 20 copies/mL. The primary efficacy endpoint was the proportion of subjects with undetectable SP HIV-1-RNA at Week 12 by intention-to-treat analysis. RESULTS: Fifteen participants in the DTG + TAF/FTC and 16 in the dolutegravir/lamivudine arms were analysed, with basal SP viral load of 4.81 (4.30-5.43) and 4.76 (4.09-5.23), P = 0.469, respectively. At Week 12, only one participant in each treatment arm had a detectable SP HIV-1-RNA (DTG + TAF/FTC, 141 copies/mL; dolutegravir/lamivudine, 61 copies/mL). Based on the estimated means, there was no significant difference in the decay of HIV-1-RNA in both BP and SP over time between the two arms of treatment (F = 0.452, P = 0.662, and F = 1.147, P = 0.185, respectively). CONCLUSIONS: After 12 weeks of treatment, there were no differences in the percentage of undetectable SP HIV-1-RNA in naive PLWH who started dolutegravir/lamivudine compared with DTG + TAF/FTC.

Cardiometabolic Parameters 3 Years After Switch to Dolutegravir/Lamivudine vs Maintenance of Tenofovir Alafenamide-Based Regimens.

Background: Cardiometabolic outcomes were investigated 3 years after switching to the 2-drug regimen dolutegravir/lamivudine (DTG/3TC) vs continuing 3-/4-drug tenofovir alafenamide (TAF)-based regimens in a multicenter phase 3 noninferiority study based on an open-label randomized design. Method: Adults with virologically suppressed HIV-1 switched to once-daily DTG/3TC (n = 369) or continued TAF-based regimens (n = 372). Cardiometabolic health parameters were assessed through week 144 via mixed-model repeated measures or logistic regression analyses, adjusting for baseline variables. Results: At week 144, 13% (42/316) of the DTG/3TC group and 12% (37/303) of the TAF-based regimen group had ≥10% weight gain from baseline (adjusted odds ratio, 1.11; 95% CI, .68-1.80). Adjusted change from baseline in serum leptin, a surrogate marker of adiposity, was similar between groups (treatment ratio, 1.00; 95% CI, .89-1.13). The lipid profile generally favored DTG/3TC in the baseline boosted subgroup. Adjusted odds revealed no clinically meaningful differences between groups: homeostatic model assessment of insulin resistance ≥2 (adjusted odds ratio, 0.79; 95% CI, .50-1.26), metabolic syndrome (International Diabetes Federation criteria, 0.99; .59-1.68), hepatic fibrosis (fibrosis-4 index score ≥1.45, 1.39; .63-3.06), and coronary artery disease risk (Framingham risk score ≥10%, 0.92; .56-1.49). Baseline variables and characteristics associated with odds of each cardiometabolic parameter outcome were consistent with known risk factors, including age, sex, race, and some disease characteristics. Conclusions: Cardiometabolic health 3 years after switching to DTG/3TC was comparable to that for individuals continuing TAF-based regimens, further supporting DTG/3TC as a robust switch option with a stable metabolic profile. Trial registration: ClinicalTrials.gov NCT03446573.

Toll-like receptor agonists enhance HIV-specific T cell response mediated by plasmacytoid dendritic cells in diverse HIV-1 disease progression phenotypes.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors. METHODS: pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed. FINDINGS: pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC. INTERPRETATION: These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies. FUNDING: This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, "a way to make Europe") and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).

Humoral and cellular immunity to SARS-COV-2 after vaccination with mRNA vaccines in PLWH with discordant immune response. Influence of the vaccine administered.

Background: Data on SARS-CoV-2 mRNA vaccine immunogenicity in people living with human immunodeficiency virus (PLWH) and discordant immune response (DIR) are currently limited. Therefore, we compare the immunogenicity of these vaccines in DIR and immunological responders (IR). Methods: A prospective cohort that enrolled 89 participants. Finally, 22 IR and 24 DIR were analyzed before vaccination (T0), one (T1) and six months (T2) after receiving BNT162b2 or mRNA-1273 vaccine. Additionally, 10 IR and 16 DIR were evaluated after a third dose (T3). Anti-S-RBD IgG, neutralizing antibodies (nAb), neutralization activity, and specific memory B cells were quantified. Furthermore, specific CD4+ and CD8+ responses were determined by intracellular cytokine staining and polyfunctionality indexes (Pindex). Results: At T1, all participants developed anti-S-RBD. 100% IR developed nAb compared to 83.3% DIR. Spike-specific B cells were detected in all IR and 21/24 DIR. Memory CD4+ T cells responded in 5/9 IR and 7/9 DIR, mainly based on the expression of IFN-γ and TNF-α, with a higher Pindex in DIR. Memory CD8+ T cells responded in only four participants in each group. At T2, anti-S-RBD and nAb titers were higher in DIR than in IR. In both groups, there was an increase in specific B memory cells, higher in DIR. Six IR and five DIR maintained a specific memory CD4+ response. Memory CD8+ response was preserved in IR but was lost in DIR. In a multivariate linear regression analysis, receiving mRNA-1273 instead of BNT162b2 played a prominent role in the results. Conclusions: Our data suggest that PLWH with DIR can mount an immune response similar to those with higher CD4+, provided they receive the mRNA-1273 vaccine instead of others less immunogenic.

Prevalence of non-alcoholic fatty liver disease in a multicentre cohort of people living with HIV in Spain.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most important liver comorbidities in people living with HIV (PLWH). Factors that could lead to a higher prevalence of NAFLD or ease the onset of fibrosis are unclear. METHODS: Cohort study of the Spanish HIV Research Network, which comprehends 46 hospitals and more than 15,000 PLWH. Primary objectives were to assess NAFLD prevalence and liver fibrosis according to hepatic steatosis index (HSI) and NAFLD fibrosis score, respectively. Factors associated with both were analysed. RESULTS: A total of 4798 PLWH were included of whom 1461 (30.5%) showed an HSI>36; these patients had higher risk for significant fibrosis (OR 1.91; 95%CI 1.11-3.28). Factors associated with NAFLD were body mass index (OR 2.05; 95%CI 1.94-2.16) and diabetes (OR 4.68; 95%CI 2.17-10.08), while exposure to integrase strand transfer inhibitors showed a lower risk (OR 0.78; 95%CI 0.62-0.97). In patients with HSI>36, being female (OR 7.33; 95%CI 1.34-40), age (OR 1.22; 95%CI 1.11-1.34), body mass index (OR 1.35; 95%CI 1.18-1.54) and exposure to thymidine analogues (OR 75.4, 95%CI 6.9-823.5) were associated with a higher risk of significant fibrosis. However, exposure to non-nucleoside reverse transcriptase inhibitors (OR 0.12, 95%CI 0.02-0.89) and time of exposure to protease inhibitors (OR 0.97, 95%CI 0.95-1) showed a lower risk. CONCLUSION: NAFLD prevalence was high in our cohort. Patients exposed to INSTI showed a lower risk of NAFLD. In patients with hepatic steatosis, exposure to thymidine analogues had 75-fold more risk of significant fibrosis while exposure to NNRTIs reduced this risk.

Anti-CD4 autoantibodies in immunological nonresponder people with HIV: cause of CD4 + T-cell depletion?

OBJECTIVE: We aimed to evaluate the anti-CD4 IgG role in the poor immune recovery of immunological nonresponder people with HIV (INR). DESIGN: INR display low CD4 + T-cell increase despite long-term undetectable viremia. Among other factors, autologous anti-CD4 IgG-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells has been proposed to cause CD4 + T-cell depletion. METHODS: Plasma anti-CD4 IgG levels were quantified and purified by chromatography columns for the subsequent use in a coculture of CD4 + T and NK cells. We analyzed NK cell degranulation markers (CD107a, perforin and granzyme B) and IFN-γ release, and CD4 + T-cell death. Binding affinity of anti-CD4 IgG for CD4 + T cells was also assessed. RESULTS: A total of 168 individuals were enrolled (INR, 56; immunological responders, 40; treatment-naive, 39; and healthy controls, 33). The highest anti-CD4 IgG levels were found in treatment-naive people with HIV (PWH), followed by participants on treatment. There were no correlations between anti-CD4 IgG levels and CD4 + T-cell counts. In a 15-participant subgroup (naive, immunological responders, and INR), anti-CD4 IgG induced a slight NK-cell expression of degranulation markers and IFN-γ; however, the percentage of CD4 + T-cell death was negligible. Consistently, no significant changes in NK cell polyfunctionality were observed. In addition, purified anti-CD4 IgG showed scarce binding affinity for CD4 + T cells. These results were similar in all analyzed participant groups. CONCLUSION: Our results suggest that autologous anti-CD4 IgG neither trigger CD4 + T-cell death by ADCC nor are responsible for CD4 + lymphocyte depletion in INR.

Shorter Time to Discontinuation Due to Treatment Failure in People Living with HIV Switched to Dolutegravir Plus Either Rilpivirine or Lamivudine Compared with Integrase Inhibitor-Based Triple Therapy in a Large Spanish Cohort.

INTRODUCTION: Standard therapy for HIV treatment has consisted of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug regimens (2DR) has been considered for selected patients in part to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase inhibitor (INSTI)-based three-drug regimens (3DR) versus 2DR of dolutegravir (DTG) + rilpivirine (RPV) or DTG + lamivudine (3TC). METHODS: All patients in the Spanish VACH cohort switching to INSTI-based 3DR or a 2DR consisting of DTG + RPV or DTG + 3TC between May 2, 2016 and May 15, 2019 were included. Kaplan-Meier curves and Cox proportional hazard models were used to assess time to/risk of discontinuation due to treatment failure (TF) (defined as virologic failure [VF], immunologic failure, or disease progression) and adverse events (AEs). Three secondary analyses were performed: (1) in restricting the analysis to patients who were virologically suppressed (HIV RNA < 50 copies/mL) at switch; (2) matched analysis (2:1, matched by age, sex, number of previous VFs, and line of regimen), and (3) using VF as the primary endpoint in all patients. RESULTS: Overall, 5047 3DR and 617 2DR patients were analyzed. Baseline characteristics differed between groups; 2DR patients were older, more treatment experienced, and more likely to be virologically suppressed at switch. Time to discontinuation due to TF was significantly shorter for 2DR (P = 0.002). The hazard ratio (HR) for discontinuation due to TF on 2DR vs 3DR was 2.33 (P = 0.003). No difference was observed for time to discontinuation (P = 0.908) or risk of discontinuation due to AEs (HR = 0.80; P = 0.488). Results were qualitatively similar in virologically suppressed patients, matched analysis, and for VF. CONCLUSION: In the real world, the risks of discontinuation due to TF and VF were more than two times higher in patients switching to DTG-based 2DR than INSTI-based 3DR, with no difference in discontinuation due to AEs.

People living with HIV (PLHIV) need lifelong treatment to prevent progression to AIDS. Standard HIV treatments use three different drugs in combination, but these can potentially cause unwanted side effects. Treatments using just two drugs have been developed. These aim to reduce side effects and treat HIV effectively. This study included 5664 participants in Spain who were split into two groups: 5047 participants switched from their old treatment to a three-drug regimen (3DR), and 617 participants switched to a two-drug regimen (2DR). The researchers measured how long it took for the participants to stop taking their treatment because it was not working, or it caused too many side effects. At the end of the study, more than 70% of participants in either group were still taking the same treatment. Of the 30% of participants who stopped treatment because it stopped working, those taking a 2DR stopped sooner than those taking a 3DR. This difference started to appear at about 18 months and got bigger until the study ended, which was 3 years after starting treatment. Participants taking a 2DR were twice as likely to stop treatment because it was not working than those taking a 3DR. There was no difference between the groups for how long it took for participants to stop their treatment because of side effects. These results show that for some PLHIV, the 2DR stopped working sooner than 3DR, without the benefit of fewer side effects.

Immunological and inflammatory changes after simplifying to dual therapy in virologically suppressed HIV-infected patients through week 96 in a randomized trial.

OBJECTIVES: To evaluate whether simplification of antiretroviral treatment to dual therapy (DT) negatively impacts immune recovery (IR), immune activation and inflammation (IA/I), and HIV reservoir. METHODS: An open-label, single-centre, randomized controlled trial conducted in adult virologically suppressed HIV-infected patients on triple therapy (TT) with elvitegravir-cobicistat, emtricitabine and tenofovir alafenamide or dolutegravir (DTG), abacavir, and lamivudine (3TC). Participants were randomized to continue TT or switch to DTG, or darunavir/cobicistat (DRVc) plus 3TC. IR was assessed by CD4+/CD8+ ratio at 48 and 96 weeks. Changes in immune activation, proliferation, exhaustion, senescence, and apoptosis in CD4+ and CD8+ T cells, plasma sCD14, hsCRP, D-dimers, ß2-microglobulin, IL-6, TNF-α and IP-10 levels, cell-associated HIV-DNA (CA-DNA), and unspliced HIV-RNA (usRNA) were also analysed. RESULTS: One hundred and fifty-one participants were enrolled. Fourteen patients did not complete the follow up. In the ITT and PP analysis, the IR was similar between the treatment arms. In the ITT analysis, the median increase in CD4+/CD8+ ratio was 0.10, 0.04, and 0.07 at week 48, and 0.09, 0.05, and 0.08 at week 96 for TT, DTG/3TC, and DRVc/3TC, respectively. After adjusting for confounding factors, the slopes of changes in CD4+/CD8+ ratio over time were independent of treatment (F = 1.699; p = 0.436) and related only to baseline values (F = 756.871; p = 0.000). There were no differences in IA/I, CA-DNA, or usRNA between treatment arms. DISCUSSION: Both IR and IA/I, CA-DNA, and usRNA were similar in the three treatment groups, regardless of maintaining TT or simplifying to DTG/3TC or DRVc/3TC in virologically suppressed HIV-infected patients.

Incidence Rate and Risk Factors for Anal Squamous Cell Carcinoma in a Cohort of People Living With HIV from 2004 to 2017: Implementation of a Screening Program.

BACKGROUND: Anal squamous cell carcinoma is rare, in general, but considerably higher in HIV-infected men who have sex with men. There is no consensus on the screening of at-risk populations. OBJECTIVE: This study aimed to determine the incidence rates of anal squamous cell carcinoma and the efficacy of a screening program. DESIGN: This is a cohort study (SeVIHanal/NCT03713229). SETTING: This study was conducted at an HIV outpatient clinic in Seville, Spain. PATIENTS: From 2004 to 2017, all patients with at least 1 follow-up visit were analyzed (follow-up group), including a subgroup of men who have sex with men who participated in a specialized program for screening and treating anal neoplasia (SCAN group) from 2011 onward. MAIN OUTCOME MEASURES: The primary outcome measure was the incidence rate of anal squamous cell carcinoma. RESULTS: Of the 3878 people living with HIV included in the follow-up group, 897 were transferred to the SCAN group; 1584 (41%) were men who have sex with men. Total follow-up was 29,228 person-years with an overall incidence rate for anal squamous cell carcinoma of 68.4/100,000 person-years (95% CI, 46.7-97.4). The changes in the incidence rate/100,000 person-years (95% CI) over time was 20.7 (3.40-80.5) for 2004 to 2006, 37.3 (13.4-87.3) for 2007 to 2010, and 97.8 (63.8-144.9) for 2011 to 2017 (p < 0.001). The strongest impact on the incidence of anal squamous cell carcinoma was made by the lack of immune restoration (adjusted incidence rate ratio (95% CI): 6.59 (4.24-10); p < 0.001), the Centers for Disease Control and Prevention category C (adjusted incidence rate ratio (95% CI): 7.49 (5.69-9.85); p < 0.001), and non-men who have sex with men (adjusted incidence rate ratio (95% CI): 0.07 (0.05-0.10); p < 0.001) in a Poisson analysis. From 2010 to 2017, incidence rates (95% CI) of anal squamous cell carcinoma within the SCAN group and the men who have sex with men of the follow-up group were 95.7 (39.6-202) and 201 (101-386)/100,000 person-years (adjusted incidence rate ratio (95% CI): 0.30 (0.23-0.39); p<0.001). The incidence rate ratio (95% CI) including non-men who have sex with men in the follow-up group was 0.87 (0.69-1.11); p = 0.269. LIMITATIONS: Adherence to the visits could not be quantified. CONCLUSION: Incidence rates of anal squamous cell carcinoma in people living with HIV increased significantly from 2004 to 2017, especially in men who have sex with men who were not being screened. Participation in the SCAN program significantly reduced the incidence of anal squamous cell carcinoma in men who have sex with men, in whom focus should be placed, especially on those presenting with Centers for Disease Control and Prevention category C and advanced immune suppression. See Video Abstract at http://links.lww.com/DCR/B734. TASA DE INCIDENCIA Y FACTORES DE RIESGO DEL CARCINOMA ANAL A CLULAS ESCAMOSAS EN UNA COHORTE DE PERSONAS QUE VIVEN CON EL VIH DE A IMPLEMENTACIN DE UN PROGRAMA DE DETECCIN: ANTECEDENTES:El carcinoma anal a células escamosas es generalmente raro, pero considerablemente más alto en hombres infectados por el VIH que tienen relaciones sexuales con hombres. No hay consenso sobre el cribado de poblaciones en riesgo.OBJETIVO:Este estudio tuvo como objetivo determinar las tasas de incidencia del carcinoma anal a células escamosas y la eficacia de un programa de detección.DISEÑO:Estudio de cohorte (SeVIHanal / NCT03713229).AJUSTE:Clínica ambulatoria de VIH en Sevilla, España.PACIENTES:De 2004 a 2017, se analizaron todos los pacientes con al menos una visita de seguimiento (grupo F / U), incluido un subgrupo de hombres que tenían relaciones sexuales con hombres que participaron en un programa especializado de cribado y tratamiento de neoplasias anales (SCAN-group) a partir de 2011.PRINCIPALES MEDIDAS DE RESULTADO:Tasas de incidencia del carcinoma anal a células escamosas.RESULTADOS:De las 3878 personas que viven con el VIH incluidas en el grupo F / U, 897 fueron transferidas al grupo SCAN, 1584 (41%) eran hombres que tenían relaciones sexuales con hombres. El seguimiento total fue de 29228 personas-año con una tasa de incidencia general de carcinoma anal a células escamosas de 68,4 / 100000 personas-año [intervalo de confianza del 95%: 46,7-97,4]. El cambio en las tasas de incidencia / 100000 personas-año (intervalo de confianza del 95%) a lo largo del tiempo fue 20,7 (3,40-80,5) para 2004-2006, 37,3 (13,4-87,3) para 2007-2010 y 97,8 (63,8-144,9) para 2011-2017, p <0,001. El impacto más fuerte en la incidencia del carcinoma a células escamosas anal fue la falta de restauración inmunológica [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 6,59 (4,24-10); p <0,001], categoría C de los Centros de Control de Enfermedades [índice de tasa de incidencia ajustado (intervalo de confianza del 95%): 7,49 (5,69-9,85); p <0,001] y no hombres que tenían relaciones sexuales con hombres [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,07 (0,05-0,10); p <0,001] en el análisis de Poisson. Desde 2010-2017, las tasas de incidencia (intervalo de confianza del 95%) de carcinoma anal a células escamosas dentro del grupo SCAN y los hombres que tienen relaciones sexuales con hombres del grupo F / U fueron 95,7 (39,6-202) y 201 (101- 386) / 100000 personas-año [razón de tasa de incidencia ajustada (intervalo de confianza del 95%): 0,30 (0,23-0,39); p <0,001]. La razón de la tasa de incidencia (intervalo de confianza del 95%), incluidos los no hombres que tenían relaciones sexuales con hombres en F / U, fue de 0,87 [0,69-1,11); p = 0,269].LIMITACIONES:No se pudo cuantificar la adherencia a las visitas.CONCLUSIÓNES:La tasa de incidencia del carcinoma anal a células escamosas en personas que viven con el VIH aumentó significativamente de 2004 a 2017, especialmente en hombres que tenían relaciones sexuales con hombres que no se someten a pruebas de detección. La participación en el programa SCAN redujo significativamente la incidencia de carcinoma anal a células escamosas en hombres que tenían relaciones sexuales con hombres, en quienes se debe prestar una especial atención, sobre todo en aquellos que se presentan en la categoría C de los Centros de Control de Enfermedades con inmunodeficiencia avanzada. Consulte Video Resumen en http://links.lww.com/DCR/B734.

eGFR-EPI changes among HIV patients who switch from F/TDF to F/TAF while maintaining the same third agent in the Spanish VACH cohort.

Background: Evidence from clinical practice on the effects of switching from emtricitabine/tenofovir disoproxil fumarate (F/TDF) to emtricitabine/tenofovir alafenamide (F/TAF)-based triple-therapy (TT) regimens on renal parameters is limited.Objective: This retrospective analysis evaluated the effects on renal function of switching from F/TDF to F/TAF-based TT regimens with no change in third agent among people living with HIV (PLWH).Methods: Data were from a multicenter Spanish PLWH cohort. Patients with a baseline estimated glomerular filtration rate (eGFR-EPI) measurement, ≥1 follow-up measurement, ≥30 days treatment with F/TAF, and who switched from F/TDF to F/TAF with no change in third agent were included. Multivariate mixed linear models were used to evaluate change from baseline over time in eGFR-EPI. eGFR-EPI changes before and after switch were analyzed in a matched patient subgroup.Results: Overall, 340 patients were included. Mean (95% CI) eGFR-EPI in patients with baseline eGFR-EPI <90 ml/min/1.73m2 (n = 125) was 79.6 (78.0; 81.2) ml/min/1.73m2 at baseline and 81.3 (79.9; 82.7) ml/min/1.73m2 at 12 months after switch. In the patient-matched subgroup (n = 175), median annual eGFR-EPI declined -4.24 ml/min/1.73m2 while on F/TDF and increased +0.93 ml/min/1.73m2 after switch to F/TAF (P < 0.0001). In patients with baseline eGFR-EPI <90 ml/min/1.73m2, median annual eGFR-EPI increased +4.19 mL/min/1.73m2 after switch (P < 0.0001).Conclusion: Switching from F/TDF to F/TAF-based TT regimens while maintaining the same third agent numerically improved eGFR-EPI in PLWH with baseline eGFR-EPI <90 mL/min/1.73m2. eGFR-EPI improved significantly when comparing progression while on F/TDF vs progression after switch, confirming beneficial renal effects of switching to F/TAF in a clinical practice setting.

Dendritic cell deficiencies persist seven months after SARS-CoV-2 infection.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity components. Dendritic cells (DCs) play a key role in the defense against viral infections, for instance plasmacytoid DCs (pDCs), have the capacity to produce vast amounts of interferon-alpha (IFN-α). In COVID-19 there is a deficit in DC numbers and IFN-α production, which has been associated with disease severity. In this work, we described that in addition to the DC deficiency, several DC activation and homing markers were altered in acute COVID-19 patients, which were associated with multiple inflammatory markers. Remarkably, previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+ myeloid DCs and pDCs seven months after SARS-CoV-2 infection. Moreover, the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients, while no restoration of integrin ß7 and indoleamine 2,3-dyoxigenase (IDO) levels were observed. These findings contribute to a better understanding of the immunological sequelae of COVID-19.

Real world effectiveness of standard of care triple therapy versus two-drug combinations for treatment of people living with HIV.

BACKGROUND: Since 1996, the standard of care (SOC) therapy for HIV treatment has consisted of a backbone of two nucleoside analogue reverse transcriptase inhibitors (NRTI) paired with a third agent. Use of two-drug combinations (2DC) has been considered for selected patients to avoid toxicities associated with the use of NRTIs. This study aimed to compare the real-world outcomes of integrase strand transfer inhibitor (INSTI)-containing triple therapy (TT) to dolutegravir- (DTG) and/or boosted protease inhibitor (bPI)-based 2DC in a large Spanish cohort of HIV patients. METHODS: A retrospective analysis was performed using data from the VACH cohort, a prospective multicentre Spanish cohort of adult HIV patients. All treatment experienced patients initiating a TT of an INSTI combined with two NRTIs or a 2DC-containing DTG and/or a bPI between 01/01/2012 and 01/06/2017 were included. The unit of analysis was patient-regimens. The overall sample analysis was complemented with two sub-analyses. The first sub-analysis focused on patients treated with a backbone plus DTG compared to those treated with DTG+ one other antiretroviral. The second sub-analysis focused on patients with HIV RNA<50 copies/mL at baseline, irrespective of the regimen used. The following endpoints were assessed: time to discontinuation for any reason, time to switch due to virologic failure, and time to switch due to toxicity (reasons for discontinuation according to clinician report in the database). Time-to-event analyses were conducted using Kaplan-Meier survival curves and Cox regression models. RESULTS: Overall 7,481 patients were included in the analysis, contributing to 9,243 patient-regimens. Patient characteristics at baseline differed among groups, with the 2DC group being significantly older and having a higher proportion of women, a longer time on ART and a higher number of previous virologic failures. Median (95% Confidence Interval [C.I.]) time to switch was 2.5 years (2.3, 2.7) in 2DC group versus 2.9 years (2.7, 3.0) in TT. Adjusted hazard ratios (95% C.I.) for discontinuation due to any reason, virologic failure and toxicity in the 2DC vs TT group were 1.29 (1.15; 1.44), 2.06 (1.54; 2.77) and 1.18 (0.94; 1.48), respectively. Results were consistent in the two sub-analyses. CONCLUSION: In this analysis, time to discontinuation and probability of remaining free of virologic failure were significantly higher in patients on INSTI-based TT compared to DTG- and/or bPI-containing 2DC, with no differences in toxicity.

Repeated Pulses of Methyl-Prednisolone in Adults Hospitalized With COVID-19 Pneumonia and Acute Respiratory Distress Syndrome: A Preliminary Before-After Study (CortiCOVID Study).

Introduction: The use of systemic corticosteroids in severely ill patients with coronavirus disease 2019 (COVID-19) is controversial. We aimed to evaluate the efficacy and safety of corticosteroid pulses in patients with COVID-19 pneumonia. Methods: A quasi-experimental study, before and after, was performed in a tertiary referral hospital, including admitted patients showing COVID-19-associated pneumonia. The standard treatment protocol included targeted COVID-19 antiviral therapy from 23rd March 2020, and additionally pulses of methylprednisolone from 30th March 2020. The primary outcome was a composite endpoint combining oro-tracheal intubation (OTI) and death within 7 days. Results: A total of 24 patients were included. Standard of care (SOC) (before intervention) was prescribed in 14 patients, while 10 received SOC plus pulses of methylprednisolone (after intervention). The median age of patients was 64.5 years and 83.3% of the patients were men. The primary composite endpoint occurred in 13 patients (92.9%) who received SOC vs. 2 patients (20%) that received pulses of methylprednisolone (odds ratio, 0.02; 95% confidence interval, 0.001 to 0.25; p = 0.019). Length of hospitalization in survivors was shorter in the corticosteroids group (median, 14.5 [8.5-21.8] days vs. 29 [23-31] days, p = 0.003). There were no differences in the development of infections between both groups. There were 3 deaths, none of them in the corticosteroids group. Conclusions: In patients with severe pneumonia due to COVID-19, the administration of methylprednisolone pulses was associated with a lower rate of OTI and/or death and a shorter hospitalization episode.

Introducción: El uso de corticosteroides sistémicos en pacientes gravemente enfermos por enfermedad coronavírica de 2019 (covid-19) es controvertido. Nuestro objetivo fue evaluar la eficacia y la seguridad de los pulsos de corticoesteroides en los pacientes con neumonía por covid-19. Métodos: Se realizó un ensayo cuasiexperimental, tipo antes y después, en un hospital terciario de referencia que incluyó a pacientes ingresados por neumonía asociada a covid-19. El protocolo de tratamiento estándar incluía un tratamiento antiviral dirigido contra el virus de la covid-19 desde el 23 de marzo de 2020 y añadió pulsos de metilprednisolona desde el 30 de marzo de 2020. El resultado primario fue un criterio combinado compuesto por la intubación orotraqueal y el fallecimiento durante los siguientes siete días. Resultados: Se incluyó un total de 24 pacientes. El protocolo de tratamiento (antes de la intervención) se prescribió en 14 pacientes, mientras que 10 recibieron el protocolo de tratamiento además de los pulsos de metilprednisolona (después de la intervención). La edad media de los pacientes fue de 64,5 años y el 83,3% de los pacientes eran hombres. El resultado combinado primario tuvo lugar en 13 pacientes (92,9%) que recibieron el protocolo de tratamiento frente a 2 pacientes (20%) que recibieron los pulsos de metilprednisolona (odds ratio = 0,02; intervalo de confianza del 95% = 0,001-0,25; p = 0,019). La duración de la hospitalización en los supervivientes fue más corta en el grupo que recibió corticoesteroides (media = 14,5 [8,5-21,8] días frente a 29 [23-31] días, p = 0,003). No hubo diferencias en el desarrollo de infecciones entre ambos grupos. Hubo tres fallecimientos, ninguno de ellos en el grupo que recibió corticoesteroides. Conclusiones: En los pacientes con neumonía grave por covid-19, la administración de pulsos de metilprednisolona se asoció a unas tasas menores de intubación orotraqueal y/o muerte y a episodios de hospitalización más cortos.

Modulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C Virus.

The activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (intracellular interleukin-1α [IL-1α], IL-1ß, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-10 production) in three monocyte subsets (classical, intermediate, and nonclassical) were evaluated by flow cytometry before and at the end of treatment. Cell-associated HIV DNA levels were assayed by droplet digital PCR. After HCV clearance, there was a significant increase in classical monocyte and decreases in intermediate and nonclassical monocyte levels. The levels of the activation markers CD49d, CD40, and CX3CR1 were decreased after treatment in the monocyte subsets, reaching the levels in HIV-monoinfected patients. After lipopolysaccharide (LPS) stimulation, although polyfunctionality significantly decreased in intermediate and nonclassical monocytes, some combinations, such as the IL-1α- (IL-1α-negative) IL-1ß- IL-6+ (IL-6-producing) IL-8- TNF-α- IL-10- combination, were remarkably increased at the end of treatment compared to the control group. Cell-associated HIV DNA levels correlated with activation markers before but not after treatment. HCV clearance after DAA treatment in patients on cART exerts an anti-inflammatory profile on monocyte subsets, activation phenotypes, and polyfunctionality. However, there is not a complete normalization compared with HIV-monoinfected patients.