Switching from a protease inhibitor-based regimen to a dolutegravir-based regimen : a randomized clinical trial to determine the effect on peripheral blood and ileum biopsies from antiretroviral therapy-suppressed human immunodeficiency virus-infected individuals

Background: Optimization of combination antiretroviral therapy (cART) can impact the human immunodeficiency virus (HIV) reservoir. We evaluated the effect on the HIV reservoir in peripheral blood and ileum biopsies in patients switching from boosted protease inhibitor (PI/r)-based therapy to dolutegravir (DTG)-based therapy. Methods: Impact of Integrase-inhibitor DOlutegravir On the viral Reservoir (INDOOR) is a phase 4 open-label clinical trial that randomly included 42 HIV type 1-infected individuals on effective cART: 20 who switched from PI/r-based to DTG-based cART (switch group), and 22 who remained in PI/r-based regimens (control group). We analyzed blood and ileum biopsies to quantify episomal, total, and integrated HIV DNA, cell-associated HIV RNA, residual plasma viremia, T-cell subsets, cell activation, and inflammation markers. Results: There were no related adverse events or treatment discontinuations due to drug intolerance. The HIV reservoir was consistently larger in ileal than in peripheral CD4(+) T cells in both groups (P <.01). Residual viremia in plasma decreased in the switch group (P =.03). However, we did not observe significant longitudinal changes in low-level viral replication, total and integrated HIV reservoir, HIV transcription, T-cell maturation subsets, immunoactivation markers, inflammatory soluble proteins, or cellular markers of latently infected cells. Conclusions: The INDOOR study is the first evaluation of changes in HIV reservoir size in ileum biopsies and in peripheral blood in individuals switched from PI/r- to DTG-based cART. Although this switch was safe and well tolerated, it had no impact on a large array of immunological and inflammatory markers or on HIV reservoir markers in peripheral or in ileal CD4(+) T cells

Exploratory study of an oral screening dysplasia program for HIV-infected men who have sex with men

Dysplasia; Screening; HIV-infectedDisplasia; Cribado; Infectado por el VIHDisplàsia; Cribratge; Infectat pel VIHBackground: HIV-infected men who have sex with men (MSM) are at high risk to develop human papilloma virus (HPV)-related oropharyngeal cancer. The aim of our study was to assess the usefulness of a pilot oral dysplasia screening program and its correlation with an anal dysplasia screening program. Methods: This was a prospective study with HIV-infected MSM. Oral and anal screenings were performed based on HPV determination, liquid cytology, direct and microscopy oral examinations, high-resolution anoscopy and biopsies, if necessary. Results: A total of 103 patients were included. The mean age of the patients was 44.6 years, 55.3% were smokers, and 57.3% had a history of previous anal high-grade squamous intraepithelial lesions (HSILs). The prevalence of oral HPV infections was 14% (9% HPV-high risk), the prevalence of abnormal cytology was 25.2%, and in 4.8% of the patients, oral examinations showed suspicious HSILs. Oral microscopy did not detect additional lesions that visual inspection. Five oral biopsies were performed and the results were normal. No risk factors for oral HPV infections were identified. The prevalence of anal HPV infections was 88.3% (76.7% HPV-high risk), 52.9% of the patients had altered cytology, and in 45.6% anoscopy showed changes suggestive of HSILs. Seventy-two anal biopsies were performed, detecting 25 cases of HSILs (24.3%). A poor correlation was observed between oral and anal HPV infections (κ = 0.037). Conclusions: The prevalence of oral HPV infections, abnormal cytology and lesions in HIV-infected MSM was low, and their correlation with anal HPV-related lesions was slight. These results confirm the current barriers to oral dysplasia screening techniques.Study funded by program MISP of MSD (Merck HPV Investigator Study Program). MISP project code 58237

COVID-19 Follow-App. Mobile App-Based Monitoring of COVID-19 Patients after Hospital Discharge: A Single-Center, Open-Label, Randomized Clinical Trial

COVID-19; App; PneumoniaCOVID-19; App; PneumòniaCOVID-19; App; NeumoníaIntroduction: In the midst of a pandemic, apps can be used to provide close follow-up, ensure that patients are monitored at home, avoid excessive pressure on medical facilities, prevent the movement of people (both patients and health professionals), and reduce the risk of infection. Objective: To adapt and validate the use of a smartphone application for outpatient follow-up of COVID-19 patients after hospital discharge. Methods: We conducted an open-label clinical trial at Hospital Universitari Vall d’Hebron in Barcelona, Spain. Patients were randomly assigned in a 1:1 ratio to be followed by the Farmalarm app or by their primary care center. The primary endpoint was the reduction in the need for in-person return visits. Results: From 31 March to 4 May 2020, 150 patients were enrolled in the study at hospital discharge: 74 patients were randomized to the experimental group, and 76 to the control group. All patients in the control group and all except for six in the experimental group completed the study. During hospitalization, before study inclusion, all but 4 (97.3%) had viral pneumonia, 91 (60.7%) required supplemental oxygen, and 16 (10.7%) required intensive care unit (ICU) admission. COVID-19–related return visits to the emergency department were significantly higher in the control group (7.9% vs. 0%; p = 0.028) in the per-protocol analysis. Telephone consultations with the emergency department were performed by 12 (15.8%) patients in the control group and 0 (0%) in the experimental group (p < 0.001). Satisfaction with outpatient monitoring was rated higher by the experimental group (5 vs. 4 points; p < 0.001). Conclusions: Following COVID-19 hospital discharge, home follow-up via a mobile app was effective in reducing in-person return visits without undermining patient satisfaction or perception of health, compared with standard follow-up

Impact of very early antiretroviral therapy during acute HIV infection on long-term immunovirological outcomes

Acute HIV infection; Antiretroviral treatment; Immune recoveryInfección aguda por VIH; Tratamiento antirretroviral; Recuperación inmunitariaInfecció aguda per VIH; Tractament antiretroviral; Recuperació immunitàriaObjectives We aimed to determine if starting antiretroviral therapy (ART) in the first 30 days after acquiring HIV infection has an impact on immunovirological response. Methods Observational, ambispective study including 147 patients with confirmed acute HIV infection (January/1995-August/2022). ART was defined as very early (≤30 days after the estimated date of infection), early (31-180 days), and late (>180 days). We compared time to viral suppression (viral load [VL] <50 copies/ml) and immune recovery (IR) (CD4+/CD8+ ratio ≥1) according to the timing and type of ART using survival analysis. Results ART was started in 140 (95.2%) patients. ART was very early in 24 (17.1%), early in 77 (55.0%), and late in 39 (27.9%) cases. Integrase strand transfer inhibitor (INSTI)-based regimens were the most used in both the overall population (65%) and the very early ART group (23/24, 95.8%). Median HIV VL and CD4+/CD8+ ratio pre-ART were higher in the very early ART group (P <0.05). Patients in the very early and early ART groups and treated with INSTI-based regimens achieved IR earlier (P <0.05). Factors associated with faster IR were the CD4+/CD8+ ratio pre-ART (hazard ratio: 9.3, 95% CI: 3.1-27.8, P <0.001) and INSTI-based regimens (hazard ratio: 2.4, 95% CI: 1.3-4.2, P = 0.003). Conclusions The strongest predictors of IR in patients who start ART during AHI are the CD4+/CD8+ ratio pre-ART and INSTI-based ART regimens.This work was founded by Instituto de Salud Carlos III (Acción Estratégica en Salud) and Fondo Europeo de Desarrollo Regional (FEDER) through grant PI20/00823. The study was also supported by the Spanish Network for AIDS Research (RIS) through the Instituto de Salud Carlos III – Red Temática de Investigación Cooperativa en Sida (RD06/006, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional R+D+I and by ISCIII Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER). For this project, PS has received a grant from the Catalan Society of Infectious Diseases and Clinical Microbiology (SCMIMC) funded by ViiV Healthcare. MJB is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CPII22/00005). The funders had no role in the study design, data collection, and interpretation, or the decision to submit the work for publication

Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations

CD4+ T cell; HIV-1; Latent reservoirCélula T CD4 +; VIH-1; Reservorio latenteCèl·lula T CD4 +; VIH-1; Reservori latentLatency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.This study was supported by the American National Institutes of Health (grant R21AI118411 to MJB), the Spanish Secretariat of Science and Innovation and FEDER funds (grant SAF2015-67334-R [MINECO/FEDER]), a unrestricted research grant from Bristol-Myers Squibb S.A.U (PfC-2015 AI424-564) to MJB, the Spanish "Ministerio de Economia y Competitividad, Instituto de Salud Carlos III"(ISCIII, PI17/01470) to M.G, a research grant from Gilead Sciences (GLD17-00204) to M. B, GeSIDA and the Spanish AIDS network "Red Tematica Cooperativa de Investigacion en SIDA" (RD16/0025/0007) to ER. The Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179) to MJB. The "Pla estrategic de recerca i innovacioen salut" (PERIS), from the Catalan Government to MG

Switching From a Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen : A Randomized Clinical Trial to Determine the Effect on Peripheral Blood and Ileum Biopsies From Antiretroviral Therapy-suppressed Human Immunodeficiency Virus-infected Individuals

Optimization of combination antiretroviral therapy (cART) can impact the human immunodeficiency virus (HIV) reservoir. We evaluated the effect on the HIV reservoir in peripheral blood and ileum biopsies in patients switching from boosted protease inhibitor (PI/r)-based therapy to dolutegravir (DTG)-based therapy. Impact of Integrase-inhibitor DOlutegravir On the viral Reservoir (INDOOR) is a phase 4 open-label clinical trial that randomly included 42 HIV type 1-infected individuals on effective cART: 20 who switched from PI/r-based to DTG-based cART (switch group), and 22 who remained in PI/r-based regimens (control group). We analyzed blood and ileum biopsies to quantify episomal, total, and integrated HIV DNA, cell-associated HIV RNA, residual plasma viremia, T-cell subsets, cell activation, and inflammation markers. There were no related adverse events or treatment discontinuations due to drug intolerance. The HIV reservoir was consistently larger in ileal than in peripheral CD4 + T cells in both groups (P <.01). Residual viremia in plasma decreased in the switch group (P =.03). However, we did not observe significant longitudinal changes in low-level viral replication, total and integrated HIV reservoir, HIV transcription, T-cell maturation subsets, immunoactivation markers, inflammatory soluble proteins, or cellular markers of latently infected cells. The INDOOR study is the first evaluation of changes in HIV reservoir size in ileum biopsies and in peripheral blood in individuals switched from PI/r- to DTG-based cART. Although this switch was safe and well tolerated, it had no impact on a large array of immunological and inflammatory markers or on HIV reservoir markers in peripheral or in ileal CD4 + T cells. EudraCT 2014-004331-39. INDOOR evaluated the effect of switching from boosted protease inhibitor- to dolutegravir-based antiretroviral therapy on the HIV reservoir in peripheral blood and ileum. Residual plasma viremia and soluble CD14 levels decreased, but low-level HIV replication, the HIV reservoir, and immune activation remained unaffected

Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab

Rituximab; Viral reactivation; CD20Rituximab; Reactivació viral; CD20Rituximab; Reactivación viral; CD20The identification of exclusive markers to target HIV-reservoir cells will represent a significant advance in the search for therapies to cure HIV. Here, we identify the B lymphocyte antigen CD20 as a marker for HIV-infected cells in vitro and in vivo. The CD20 molecule is dimly expressed in a subpopulation of CD4-positive (CD4+) T lymphocytes from blood, with high levels of cell activation and heterogeneous memory phenotypes. In lymph node samples from infected patients, CD20 is present in productively HIV-infected cells, and ex vivo viral infection selectively upregulates the expression of CD20 during early infection. In samples from patients on antiretroviral therapy (ART) this subpopulation is significantly enriched in HIV transcripts, and the anti-CD20 monoclonal antibody Rituximab induces cell killing, which reduces the pool of HIV-expressing cells when combined with latency reversal agents. We provide a tool for targeting this active HIV-reservoir after viral reactivation in patients while on ART.This study was supported by the American National Institutes of Health (grant R21AI118411 to M.B.), the Spanish Secretariat of Science and Innovation and FEDER funds (grant SAF2015-67334-R [MINECO/FEDER]), the Spanish "Ministerio de Economia y Competitividad, Instituto de Salud Carlos III" (ISCIII, PI17/01470), GeSIDA and the Spanish AIDS network Red Tematica Cooperativa de Investigacion en SIDA (RD16/0025/0007). M.B. is supported by the Miguel Servet program funded by the Spanish Health Institute Carlos III (CP17/00179). M.G. is supported by the "Pla estrategic de recerca i innovacio en salut" (PERIS), from the Catalan Government

Switching From a Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen : A Randomized Clinical Trial to Determine the Effect on Peripheral Blood and Ileum Biopsies From Antiretroviral Therapy-suppressed Human Immunodeficiency Virus-infected Individuals

Optimization of combination antiretroviral therapy (cART) can impact the human immunodeficiency virus (HIV) reservoir. We evaluated the effect on the HIV reservoir in peripheral blood and ileum biopsies in patients switching from boosted protease inhibitor (PI/r)-based therapy to dolutegravir (DTG)-based therapy. Impact of Integrase-inhibitor DOlutegravir On the viral Reservoir (INDOOR) is a phase 4 open-label clinical trial that randomly included 42 HIV type 1-infected individuals on effective cART: 20 who switched from PI/r-based to DTG-based cART (switch group), and 22 who remained in PI/r-based regimens (control group). We analyzed blood and ileum biopsies to quantify episomal, total, and integrated HIV DNA, cell-associated HIV RNA, residual plasma viremia, T-cell subsets, cell activation, and inflammation markers. There were no related adverse events or treatment discontinuations due to drug intolerance. The HIV reservoir was consistently larger in ileal than in peripheral CD4 + T cells in both groups (P <.01). Residual viremia in plasma decreased in the switch group (P =.03). However, we did not observe significant longitudinal changes in low-level viral replication, total and integrated HIV reservoir, HIV transcription, T-cell maturation subsets, immunoactivation markers, inflammatory soluble proteins, or cellular markers of latently infected cells. The INDOOR study is the first evaluation of changes in HIV reservoir size in ileum biopsies and in peripheral blood in individuals switched from PI/r- to DTG-based cART. Although this switch was safe and well tolerated, it had no impact on a large array of immunological and inflammatory markers or on HIV reservoir markers in peripheral or in ileal CD4 + T cells. EudraCT 2014-004331-39. INDOOR evaluated the effect of switching from boosted protease inhibitor- to dolutegravir-based antiretroviral therapy on the HIV reservoir in peripheral blood and ileum. Residual plasma viremia and soluble CD14 levels decreased, but low-level HIV replication, the HIV reservoir, and immune activation remained unaffected

Discovering HIV related information by means of association rules and machine learning

Acquired immunodeficiency syndrome (AIDS) is still one of the main health problems worldwide. It is therefore essential to keep making progress in improving the prognosis and quality of life of affected patients. One way to advance along this pathway is to uncover connections between other disorders associated with HIV/AIDS-so that they can be anticipated and possibly mitigated. We propose to achieve this by using Association Rules (ARs). They allow us to represent the dependencies between a number of diseases and other specific diseases. However, classical techniques systematically generate every AR meeting some minimal conditions on data frequency, hence generating a vast amount of uninteresting ARs, which need to be filtered out. The lack of manually annotated ARs has favored unsupervised filtering, even though they produce limited results. In this paper, we propose a semi-supervised system, able to identify relevant ARs among HIV-related diseases with a minimal amount of annotated training data. Our system has been able to extract a good number of relationships between HIV-related diseases that have been previously detected in the literature but are scattered and are often little known. Furthermore, a number of plausible new relationships have shown up which deserve further investigation by qualified medical experts