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1.
Clin Infect Dis ; 2024 Apr 26.
Article En | MEDLINE | ID: mdl-38663013

BACKGROUND: Mortality among people with HIV declined with the introduction of combination antiretroviral therapy. We investigated trends over time in all-cause and cause-specific mortality in people with HIV from 1999-2020. METHODS: Data were collected from the D:A:D cohort from 1999 through January 2015 and RESPOND from October 2017 through 2020. Age-standardized all-cause and cause-specific mortality rates, classified using Coding Causes of Death in HIV (CoDe), were calculated. Poisson regression models were used to assess mortality trends over time. RESULTS: Among 55716 participants followed for a median of 6 years (IQR 3-11), 5263 participants died (crude mortality rate [MR] 13.7/1000 PYFU; 95%CI 13.4-14.1). Changing patterns of mortality were observed with AIDS as the most common cause of death between 1999- 2009 (n = 952, MR 4.2/1000 PYFU; 95%CI 4.0-4.5) and non-AIDS defining malignancy (NADM) from 2010 -2020 (n = 444, MR 2.8/1000 PYFU; 95%CI 2.5-3.1). In multivariable analysis, all-cause mortality declined over time (adjusted mortality rate ratio [aMRR] 0.97 per year; 95%CI 0.96, 0.98), mostly from 1999 through 2010 (aMRR 0.96 per year; 95%CI 0.95-0.97), and with no decline shown from 2011 through 2020 (aMRR 1·00 per year; 95%CI 0·96-1·05). Mortality due all known causes except NADM also declined over the entire follow-up period. CONCLUSION: Mortality among people with HIV in the D:A:D and/or RESPOND cohorts decreased between 1999 and 2009 and was stable over the period from 2010 through 2020. The decline in mortality rates was not fully explained by improvements in immunologic-virologic status or other risk factors.

2.
BMC Infect Dis ; 24(1): 221, 2024 Feb 19.
Article En | MEDLINE | ID: mdl-38373940

OBJECTIVE: This study aimed to assess weight gain associated with treatment switching to INSTI-based regimens in people living with HIV (PLWH) and to determine whether it is accompanied by worsening features of hypertension, dyslipidemia, or hyperglycemia. METHODS: In this two-center retrospective observational study, we assessed weight gain and metabolic features in PLWH who switched to an INSTI-based regimen (study group) as compared to patients who remained on a non-INSTI regimen (control group) over a 24-month follow-up period. RESULTS: One-hundred seventy-four PLWH were included in the study group, and 175 were included in the control group. The study group gained 2.51 kg ± 0.31 (mean ± standard deviation) over the 2 years of follow-up, while the control group gained 1.1 ± 0.31 kg over the same time course (p < 0.001). INSTI treatment, Caucasian origin, and lower BMI were risk factors associated with excessive weight gain during the 2 years of follow-up. Among metabolic parameters, only glucose levels increased after initiating INSTI-based regimens, although limited to males of African origin (p = 0.009). CONCLUSIONS: We observed a mild weight gain after switching to INSTI-based regimens, with no major impact on metabolic parameters over 2 years of follow-up. Longer follow-up might be needed to observe the adverse metabolic effects of INSTI-based regimens. The impact on weight gain should be discussed with every patient before the treatment switch to ensure a balanced diet and physical activity to prevent excessive weight gain that might hamper compliance with ART.


HIV Infections , HIV Integrase Inhibitors , Metabolic Syndrome , Male , Humans , HIV Infections/drug therapy , HIV Infections/complications , HIV Integrase Inhibitors/therapeutic use , Metabolic Syndrome/complications , Weight Gain , Integrases/therapeutic use
3.
Pediatr Allergy Immunol ; 34(12): e14061, 2023 Dec.
Article En | MEDLINE | ID: mdl-38146117

BACKGROUND: Accumulating evidence suggests that food-induced anaphylaxis (FIA) may induce different psychological disorders (PDs). In this study, we aimed to further evaluate the effect of FIA, specifically when occurring in early life, on subsequent PDs development. METHODS: We conducted a population-based, retrospective, matched-cohort study of pediatric patients (age ≤ 18 years) treated at the "Clalit" healthcare organization during the period 2001-2021. Children diagnosed with FIA were propensity score-matched with patients without any allergies (controls) of similar demographic parameters. Associations between FIA and different PDs were examined by multivariable regression models. RESULTS: The cohorts comprised 545 FIA patients and 4514 controls. Most patients were <3 years old [87.6% of controls (N = 3955) and 87.3% of the FIA cohort (N = 476)]. In this age group, the major food allergens were cow's milk (N = 258; 54.2%), eggs (N = 60; 12.6%), and peanuts (N = 20; 4.2%). The multivariable regression model identified an association between FIA and any PDs (p < .001), sleeping disorders (p < .001), and eating disorders (p = .050). Kaplan-Meier curves revealed that patients who experienced FIA before 3 years of age had an increased cumulative risk over the follow-up time of developing any PDs, sleeping disorders, and eating disorders. CONCLUSION: FIA during the first 3 years of life increases the risk of later developing eating and sleeping disorders, which can last into adulthood. Further attention should be focused on accurately diagnosing these children.


Anaphylaxis , Feeding and Eating Disorders , Food Hypersensitivity , Milk Hypersensitivity , Female , Animals , Cattle , Humans , Child , Adolescent , Child, Preschool , Anaphylaxis/epidemiology , Anaphylaxis/etiology , Retrospective Studies , Cohort Studies , Allergens , Feeding and Eating Disorders/epidemiology , Feeding and Eating Disorders/complications , Milk Hypersensitivity/diagnosis
4.
Viruses ; 15(12)2023 12 15.
Article En | MEDLINE | ID: mdl-38140680

Despite the progress in contemporary antiretroviral therapy (ART) and the continuous changes in treatment guidelines, virological failure (VF) is still an ongoing concern. The goal of this study was to assess factors related to VF after first-line ART. A longitudinal cohort retrospective study of individuals on first-line ART diagnosed with HIV-1 in 2010-2018 and followed-up for a median of two years was conducted. Demographics, baseline and longitudinal CD4 counts, treatment regimens, adherence and VF were recorded. The Cox proportional hazards regression and mixed models were used. A cohort of 1130 patients were included. Overall, 80% were males and 62% were Israeli-born individuals. Compared to individuals diagnosed in 2010-2014, when treatment was initiated according to CD4 levels, those diagnosed in 2015-2018 were older and had lower baseline CD4 counts. VF was recorded in 66 (5.8%) patients. Diagnosis with CD4 <200 cells/mmᶟ with AIDS-defining conditions (HR = 2.75, 95%CI:1.52-4.97, p < 0.001) and non-integrase strand transfer inhibitor regimens (non-INSTI, HR = 1.80, 95%CI:1.01-3.24, p = 0.047) increased VF risk. No impact of baseline resistance was observed. We concluded that the early detection of HIV-1 infection and usage of INSTI-based regimens are recommended to reduce VF.


Anti-HIV Agents , HIV Infections , HIV Seropositivity , HIV-1 , Male , Humans , Female , Anti-HIV Agents/therapeutic use , Israel/epidemiology , Retrospective Studies , HIV Infections/diagnosis , HIV Infections/drug therapy , HIV Infections/epidemiology , Anti-Retroviral Agents/therapeutic use , Viral Load
5.
Immunotherapy ; 15(16): 1389-1400, 2023 11.
Article En | MEDLINE | ID: mdl-37694383

Background: Despite their life-threatening potential, medical team mistakes during subcutaneous immunotherapy are rarely discussed. Real data are missing, and a survey study estimated that dosing errors are responsible for 25% of systemic reactions during immunotherapy. To minimize errors, we modified our safety precautions and compared the rates of systemic allergic reactions before and after the change. Methods: Our retrospective comparative cohort study compared systemic allergic reaction rates during 2012-2015 and 2016-2019, after a second check of the injected allergen/s by another nurse/physician was added to the treatment protocol. Results: The rate of systemic allergic reaction per injection was reduced from 0.93 to 0.71%; p = 0.023. Conclusion: A second check prior to injection is beneficial and can reduce the allergic reaction rate during immunotherapy.


Many people suffer from allergies to dust or pollen, and they might suffer from a running nose when they come into contact with the allergens. This reaction is called hayfever or allergic rhinitis. Immunotherapy is a treatment which can help to treat patients with allergic rhinitis. During treatment, the patients receive injections of small amounts of dust or pollen, and with time become less allergic. The injections themselves might cause allergic reactions such as rash, hives, swelling or trouble breathing. Sometimes these allergic reactions are related to mistakes made by the medical team. In our study we changed safety instruction to add a second check of the materials and amounts before the injections were given to the patient. This was checked by two different nurses. We compared the number of allergic reactions to the shots before and after the change. We found that the number of allergic reactions was 9.3 for 1000 injections before and 7.1 for 1000 injections after the change. We think that a second check of the materials and amounts before giving the injections is helpful and can prevent some of the allergic reactions.


Allergens , Rhinitis, Allergic , Humans , Allergens/therapeutic use , Cohort Studies , Retrospective Studies , Injections, Subcutaneous , Desensitization, Immunologic/adverse effects , Desensitization, Immunologic/methods , Rhinitis, Allergic/therapy
7.
Clin Exp Med ; 23(7): 2931-2939, 2023 Nov.
Article En | MEDLINE | ID: mdl-37103650

The aim of this review is to provide a comprehensive overview about the link between viruses and celiac disease. A systematic search on PubMed, Embase, and Scopus was conducted on March 07, 2023. The reviewers independently selected the articles and chose which articles to include. The review is a textual systemic review, and all relevant articles were included based on title and abstract. If there was a disagreement between the reviewers, they came to a consensus during deliberation sessions. A total of 178 articles were selected for the review and read in full; only part of them was retained. We found studies between celiac disease and 12 different viruses. Some of the studies were done only on small groups. Most studies were on pediatric population. Evidence for an association was found with several viruses (trigger or protective). It seems that only a part of the viruses could induce the disease. Several points are important to keep in mind: firstly, simple mimicry or that the virus induces a high level of TGA is not sufficient to promote the disease. Secondly, inflammatory background is necessary to induce CD with virus. Thirdly, IFN type 1 seems to have an important role. Some of the viruses are potential or known triggers like enteroviruses, rotaviruses, reoviruses, and influenza. Further studies are needed to better understand the role of viruses in celiac disease to better treat and prevent the disease.


Celiac Disease , Viruses , Child , Humans , Celiac Disease/epidemiology
8.
Isr Med Assoc J ; 24(10): 649-653, 2022 Oct.
Article En | MEDLINE | ID: mdl-36309860

BACKGROUND: Contact dermatitis is an inflammatory skin disorder characterized by an erythematous pruritic rash. The disorder can be either irritant or allergic. Allergic contact dermatitis is diagnosed by patch testing along with patient history. OBJECTIVES: To review the results of patch tests conducted thought 2 years and to present real-life data characterizing clinical features and comparing prevalent local allergens to the ones common worldwide. METHODS: The retrospective cohort included 517 participants (384 females and 133 males) who underwent patch testing during a 2-year period. For each patient, clinical and demographic data were collected, and statistical analysis was conducted. RESULTS: We found that 261 patients had a positive test for at least one allergen. More females tested positive than males (52.9% vs. 43.6%). Test indications other than dermatitis were associated with a negative result. Hands, head, and neck were the most prevalent body parts affected. Patients with a background of atopic dermatitis had a higher rate of contact sensitization (69 vs. 43). Patients with a specific suspected offending allergen had significantly higher contact sensitizations. The most common allergen was nickel. CONCLUSIONS: Patch testing should be conducted in patients with relevant dermatological findings accompanied by taking a thorough medical history. Clinicians should be updated on emerging allergens and exposure trends.


Dermatitis, Allergic Contact , Male , Female , Humans , Patch Tests/methods , Retrospective Studies , Dermatitis, Allergic Contact/diagnosis , Dermatitis, Allergic Contact/epidemiology , Allergens , Nickel
9.
AIDS Res Ther ; 19(1): 38, 2022 08 06.
Article En | MEDLINE | ID: mdl-35933352

INTRODUCTION: Data on safety and effectiveness of RPV from the real-world setting as well as comparisons with other NNRTIs such as efavirenz (EFV) remain scarce. METHODS: Participants of EuroSIDA were included if they had started a RPV- or an EFV-containing regimen over November 2011-December 2017. Statistical testing was conducted using non-parametric Mann-Whitney U test and Chi-square test. A logistic regression model was used to compare participants' characteristics by treatment group. Kaplan-Meier analysis was used to estimate the cumulative risk of virological failure (VF, two consecutive values > 50 copies/mL). RESULTS: 1,355 PLWH who started a RPV-based regimen (11% ART-naïve), as well as 333 initiating an EFV-containing regimen were included. Participants who started RPV differed from those starting EFV for demographics (age, geographical region) and immune-virological profiles (CD4 count, HIV RNA). The cumulative risk of VF for the RPV-based group was 4.5% (95% CI 3.3-5.7%) by 2 years from starting treatment (71 total VF events). Five out of 15 (33%) with resistance data available in the RPV group showed resistance-associated mutations vs. 3/13 (23%) among those in the EFV group. Discontinuations due to intolerance/toxicity were reported for 73 (15%) of RPV- vs. 45 (30%) of EFV-treated participants (p = 0.0001). The main difference was for toxicity of central nervous system (CNS, 3% vs. 22%, p < 0.001). CONCLUSION: Our estimates of VF > 50 copies/mL and resistance in participants treated with RPV were similar to those reported by other studies. RPV safety profile was favourable with less frequent discontinuation due to toxicity than EFV (especially for CNS).


Anti-HIV Agents , HIV Infections , HIV-1 , Anti-HIV Agents/adverse effects , HIV Infections/drug therapy , HIV-1/genetics , Humans , Rilpivirine/therapeutic use , Treatment Outcome , Viral Load
10.
Discoveries (Craiova) ; 10(4): e158, 2022.
Article En | MEDLINE | ID: mdl-37457644

BACKGROUND: Treatment of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) remains a significant challenge in the face of increased worldwide morbidity and mortality. The acute illness caused by SARS-CoV-2 is initiated by a viral phase, followed by an inflammatory phase. Numerous anti-inflammatory and anti-viral therapies, with a relatively minor clinical effect, have been applied. Developing a safe and efficient direct anti-viral treatment is essential as it can block disease progression before significant complications ensue and potentially prevent transmission. AIM: The present phase 1 study aimed to determine the safety of Codivir, a newly developed anti-viral agent, and to preliminarily assess its anti-viral activity in patients infected by COVID-19. METHODS: In vitro studies were conducted to determine the direct anti-viral effect of Codivir using an immunofluorescence-based assay and to assess its cytotoxic effect by tetrazolium assay (MTT). In a phase I clinical trial, Codivir was administered for ten days in 12 patients who were followed for its safety. Patients were followed for clinical manifestations during administration. Sequential nasal viral PCR titers (Cycle Threshold, CT) were determined preceding and during treatment. RESULTS: In vitro, Codivir showed activity against SARS-CoV-2 with 90% viral replication suppression and minimal cytotoxicity. The anti-viral activity was demonstrated at the early stages of infection, post-entry of the virus in the cell. Codivir was safe in all 12 patients in phase I clinical trial and significantly suppressed viral replication in 5/7 fully assessed patients, with an anti-viral effect noted as early as three days. SUMMARY: The present study's data support the safety of Codivir administration in humans and suggest its significant anti-COVID-19 effect. These results support the testing of the drug in more extensive controlled trials in patients with SARS-CoV-2.

11.
Ann Allergy Asthma Immunol ; 128(2): 206-212, 2022 02.
Article En | MEDLINE | ID: mdl-34737038

BACKGROUND: The prevalence of sesame allergy is increasing; strict avoidance is the mainstay of therapy. Lately, sesame oral immunotherapy was presented as an alternative treatment, with a high rate of success. Therefore, data on the natural history and the clinical characteristics of patients with persistent sesame allergy are important for the management of patients with sesame allergy. OBJECTIVE: To describe the natural history of patients with sesame allergy and the clinical characteristics of patients with spontaneous resolution of sesame allergy compared with patients with persistent sesame allergy. METHODS: In our retrospective study, electronic health records of patients with sesame allergy diagnosis were reviewed for demographic and clinical data. Statistical analysis of clinical characteristics of patients with spontaneous resolution compared with persistent sesame allergy was performed. RESULTS: A total of 190 patients with sesame allergy were followed for 3.86 ±4.43 years. Of these patients, 61 (32.1%) had spontaneous resolution of sesame allergy. Patients with mild, early (before the age of 10 months) first sesame allergic reaction, with smaller than 7-mm skin prick test and without concomitant tree nut allergy had better resolution rate (56.1%). CONCLUSION: Sesame allergy spontaneously resolved in approximately one-third of our patients and in more than half of the patients with mild first reaction (grade 1) at a young age (<10 months), with small skin prick test (<7 mm) and no concomitant tree nut allergy. Larger prospective studies with longer follow-up period are needed to better characterize the sesame allergic patients with persistent allergy who may need oral immunotherapy.


Food Hypersensitivity , Nut Hypersensitivity , Sesamum , Allergens , Humans , Infant , Prospective Studies , Retrospective Studies , Skin Tests
12.
Acta Neurol Belg ; 122(2): 417-422, 2022 Apr.
Article En | MEDLINE | ID: mdl-34114141

The prevalence of vascular diseases in HIV (human immunodeficiency virus)-infected individuals has been comprehensively investigated. However, their incidence of ischemic cerebrovascular events has not been thoroughly examined. Our aim was to examine the rate of ischemic stroke or TIA (transient ischemic attack) in a defined HIV population and to find the risk factors that are characteristic in this population. A case-controlled retrospective cohort study of HIV patients followed up at Kaplan Medical Center between 2009 and 2017 was performed. The study included 300 patients who had been compared to a matched age and gender group. The data were collected by reviewing patients' files and imaging studies. The first goal was to compare the incidence of ischemic cerebrovascular events in both groups. Secondary endpoints were to characterize the types of cerebrovascular events and risk factors in the study group versus the general population. There were more ischemic stroke cases in the study group vs. the control group. After adjusting for vascular risk factors in a multivariate analysis, the odds ratio for a cerebrovascular accident in the HIV patient group was 2.29 (p = 0.057). Notably, in the comparative group, the vascular risk factors' rate (hyperlipidemia, IHD and smoking) was higher than in the HIV group. In this study, ischemic cerebrovascular events were more common in HIV-infected patients than in the control group, in spite of the fact that they had fewer vascular risk factors.


HIV Infections , Ischemic Attack, Transient , Ischemic Stroke , Stroke , Cohort Studies , HIV Infections/complications , HIV Infections/epidemiology , Humans , Incidence , Ischemic Attack, Transient/diagnostic imaging , Ischemic Attack, Transient/epidemiology , Ischemic Stroke/diagnostic imaging , Ischemic Stroke/epidemiology , Ischemic Stroke/etiology , Retrospective Studies , Risk Factors , Stroke/diagnostic imaging , Stroke/epidemiology , Stroke/etiology
13.
PLoS One ; 16(10): e0259271, 2021.
Article En | MEDLINE | ID: mdl-34714873

AIM: Combined antiretroviral treatment (cART) traditionally consists of three antiretroviral medications, while two-drug regimens (2DR), historically used infrequently, recently been suggested to be non-inferior to three-drug regimens, is emerging as a potential treatment option and is currently a recommended option for treatment initiation in many guidelines. PURPOSE: Characterize the indications and clinical efficacy of 2DR use at a real-life setting in a nation-wide survey. METHODS: A cross-sectional survey of Israeli patients treated by 2DR until July 2019, included demographic, immunologic, virologic, genotypic and biochemical/metabolic parameters at diagnosis, ART initiation, 2DR initiation and following 24, 48, 96 and 144 weeks of 2DR treatment. RESULTS: 176 patients were included in the study. In contrast to historical data implicating ART resistance and adverse effects as the major reasons leading to 2DR switching, treatment simplification was the main reason leading to 2DR treatment in 2019. 2DR that included INSTI and PI were more commonly used in cases of drug resistance, while a combination of INSTI and NNRTI was used in all other 2DR indications. A switch to 2DR induced a mean CD4 T cell increase from 599 cells/µl at treatment initiation to 680 cells/µl at 96 weeks of treatment p<0.001 and viral suppression improvement from 73.9% at initiation to 87.0% at 48 weeks of treatment (p = 0.004). PI and INSTI 2DR was inferior in suppressing viral levels compared to other 2DRs but used for subset of more complex patients. CONCLUSIONS: 2DR in a large-scale real-life nation-wide survey proved to be safe and effective. Most 2DRs, other than PI and INSTI, were similarly effective in suppressing HIV viremia and in elevating CD4 T cell counts.


Anti-HIV Agents/therapeutic use , HIV Infections/drug therapy , Adolescent , Adult , Aged , Anti-HIV Agents/administration & dosage , Antiretroviral Therapy, Highly Active/statistics & numerical data , Child , Child, Preschool , Female , HIV Infections/blood , HIV Infections/virology , Health Surveys , Humans , Infant , Israel , Lymphocyte Count , Male , Middle Aged , Viral Load
14.
Lancet HIV ; 8(11): e711-e722, 2021 11.
Article En | MEDLINE | ID: mdl-34555326

BACKGROUND: Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use. METHODS: The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline. RESULTS: 14 703 people were included in this study, of whom 7863 (53·5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1·27, 95% CI 1·17-1·38), raltegravir (1·37, 1·20-1·56), and tenofovir alafenamide (1·38, 1·22-1·35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2·10, 1·91-2·31 for underweight vs healthy weight) and Black ethnicity (1·61, 1·47-1·76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0·97, 0·96-0·98 per 100 cells per µL increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1·21, 95% CI 1·19-1·32) and tenofovir alafenamide without dolutegravir (1·33, 1·15-1·53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1·79, 1·52-2·11, and 1·70, 1·44-2·01, respectively). INTERPRETATION: Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension. FUNDING: The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.


Anti-Retroviral Agents/adverse effects , HIV Infections/drug therapy , HIV-1/drug effects , Weight Gain , Adult , Anti-Retroviral Agents/therapeutic use , Australia/epidemiology , Body Mass Index , Cohort Studies , Europe/epidemiology , Female , HIV Infections/epidemiology , Humans , Male , Middle Aged , Prospective Studies
15.
Oncogene ; 40(22): 3815-3825, 2021 06.
Article En | MEDLINE | ID: mdl-33958722

The integration of viral DNA into the host genome is mediated by viral integrase, resulting in the accumulation of double-strand breaks. Integrase-derived peptides (INS and INR) increase the number of integration events, leading to escalated genomic instability that induces apoptosis. CD24 is a surface protein expressed mostly in cancer cells and is very rarely found in normal cells. Here, we propose a novel targeted cancer therapeutic platform based on the lentiviral integrase, stimulated by integrase-derived peptides, that are specifically delivered to cancerous cells via CD24 antigen-antibody targeting. INS and INR were synthesized and humanized and anti-CD24 antibodies were fused to the lentivirus envelope. The activity, permeability, stability, solubility, and toxicity of these components were analyzed. Cell death was measured by fluorescent microscopy and enzymatic assays and potency were tested in vitro and in vivo. Lentivirus particles, containing non-functional DNA led to massive cell death (40-70%). Raltegravir, an antiretroviral drug, inhibited the induction of apoptosis. In vivo, single and repeated administrations of INS/INR were well tolerated without any adverse effects. Tumor development in nude mice was significantly inhibited (by 50%) as compared to the vehicle arm. In summary, a novel and generic therapeutic platform for selective cancer cell eradication with excellent efficacy and safety are presented.


CD24 Antigen/biosynthesis , Integrases/pharmacology , Lentivirus/enzymology , Neoplasms/therapy , Oncolytic Virotherapy/methods , Peptide Fragments/pharmacology , Animals , Antibodies, Monoclonal/immunology , Apoptosis/drug effects , CD24 Antigen/immunology , Cell Line, Tumor , Humans , Integrases/chemistry , Lentivirus/genetics , Lentivirus/immunology , Mice , Mice, Nude , Neoplasms/genetics , Neoplasms/metabolism , Neoplasms/virology , Peptide Fragments/chemistry , Tissue Distribution , Xenograft Model Antitumor Assays
16.
Viruses ; 14(1)2021 12 31.
Article En | MEDLINE | ID: mdl-35062274

Despite the low prevalence of HIV-1 in Israel, continuous waves of immigration may have impacted the local epidemic. We characterized all people diagnosed with HIV-1 in Israel in 2010-2018. The demographics and clinical data of all individuals (n = 3639) newly diagnosed with HIV-1 were retrieved. Subtypes, transmitted drug-resistance mutations (TDRM), and phylogenetic relations, were determined in >50% of them. In 39.1%, HIV-1 transmission was through heterosexual contact; 34.3% were men who have sex with men (MSM); and 10.4% were people who inject drugs. Many (>65%) were immigrants. Israeli-born individuals were mostly (78.3%) MSM, whereas only 9% of those born in Sub-Saharan Africa (SSA), Eastern Europe and Central Asia (EEU/CA), were MSM. The proportion of individuals from SSA decreased through the years 2010-2018 (21.1% in 2010-2012; 16.8% in 2016-2018) whereas those from EEU/CA increased significantly (21% in 2010-2012; 27.8% in 2016-2018, p < 0.001). TDRM were identified in 12.1%; 3.7, 3.3 and 6.6% had protease inhibitors (PI), nucleotide reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) TDRM, respectively, with the overall proportion remaining stable in the studied years. None had integrase TDRM. Subtype B was present in 43.9%, subtype A in 25.2% (A6 in 22.8 and A1 in 2.4%) and subtype C in 17.1% of individuals. Most MSM had subtype B. Subtype C carriers formed small clusters (with one unexpected MSM cluster), A1 formed a cluster mainly of locally-born patients with NNRTI mutations, and A6 formed a looser cluster of individuals mainly from EEU. Israelis, <50 years old, carrying A1, had the highest risk for having TDRM. In conclusion, an increase in immigrants from EEU/CA and a decrease in those from SSA characterized the HIV-1 epidemic in 2010-2018. Baseline resistance testing should still be recommended to identify TDRM, and improve surveillance and care.


Drug Resistance, Viral/genetics , HIV Infections/epidemiology , HIV Infections/transmission , HIV-1/genetics , Adult , Anti-HIV Agents/therapeutic use , Asia , Cross-Sectional Studies , Europe , Europe, Eastern , Female , HIV Seropositivity , HIV-1/classification , Humans , Israel/epidemiology , Male , Middle Aged , Mutation , Phylogeny , Reverse Transcriptase Inhibitors , Sexual Behavior , Sexual and Gender Minorities
17.
Transpl Infect Dis ; 21(6): e13171, 2019 Dec.
Article En | MEDLINE | ID: mdl-31518477

Human immunodeficiency virus (HIV) infection was traditionally considered an absolute contraindication for kidney transplantation. After the introduction of ART, several studies have demonstrated comparable patient and graft outcomes between HIV-negative and HIV-positive kidney recipients. The US Congress passed the HIV Organ Policy Equity (HOPE) Act in 2013, which permits research in the area of HIV-positive to HIV-positive transplantation. HIV-infected living donation is also permitted under the HOPE Act. However, there is a concern regarding the safety of kidney donation in an HIV-infected person, given the risk of renal disease associated with HIV infection. We report here the case of successful kidney transplantation from HIV-positive living donor to HIV-positive recipient performed in our center on July 2012. To the best of our knowledge, this is the earliest case done in this medical context to be reported in the literature, therefore, potentially carrying several important messages to the transplantation community. In the present case, the living-donor kidney transplant was performed between a married couple infected with same strain of HIV-1, both on effective ART with efficiently suppressed viral replication and satisfactory pre-transplantation immune status.


AIDS-Associated Nephropathy/surgery , Acute Kidney Injury/surgery , HIV Seropositivity/diagnosis , Kidney Transplantation/methods , Living Donors , AIDS-Associated Nephropathy/complications , AIDS-Associated Nephropathy/immunology , AIDS-Associated Nephropathy/virology , Acute Kidney Injury/etiology , Anti-HIV Agents/administration & dosage , Follow-Up Studies , HIV Seropositivity/drug therapy , HIV Seropositivity/virology , HIV-1/isolation & purification , Humans , Kidney Transplantation/legislation & jurisprudence , Male , Middle Aged , Preoperative Care/methods , Spouses , Tissue and Organ Procurement/legislation & jurisprudence , Treatment Outcome , Viral Load/drug effects , Virus Replication/drug effects
18.
AIDS ; 33(13): 2013-2024, 2019 11 01.
Article En | MEDLINE | ID: mdl-31335807

OBJECTIVE: To assess the use of two-drug antiretroviral regimens (2DR) and virologic and immunologic outcomes compared with three-drug regimens (3DR) in the EuroSIDA cohort. DESIGN: Multicentre, prospective cohort study. METHODS: Logistic regression was used to analyse the uptake and outcomes among HIV-positive individuals who started or switched to a 2DR compared with those on a 3DR. Virologic outcomes were assessed on-treatment as the proportion of individuals with controlled viral load (<400 copies/ml), or with a composite modified FDA snapshot endpoint (mFDA), with mFDA success defined as controlled viral load at 6 months or 12 months for individuals with a known viral load, no regimen changes, AIDS or death. Immunologic response was defined as a 100 cells/µl or a 25% increase in CD4 cell counts from baseline. RESULTS: Between 1 July 2010 and 31 December 2016, 423 individuals started or switched to a 2DR (eight antiretroviral-naive) and 4347 started a 3DR (566 naive). Individuals on 2DR tended to have suppressed viral load, higher CD4 cell counts and more comorbidities at baseline compared with those on 3DR. There were no differences in the proportions of individuals who obtained on-treatment or mFDA success, and no significant differences in the adjusted odds ratios for mFDA success or immunologic responses between the 2DR and 3DR groups at 6 months or 12 months. CONCLUSION: In routine clinical practice, 2DR were largely used for virologically suppressed individuals with higher cumulative exposure to antiretrovirals and comorbidities. Virologic and immunologic outcomes were similar among those on 2DR or 3DR, although confounding by indication cannot be fully excluded due to the observational nature of the study.


Anti-HIV Agents/administration & dosage , HIV Infections/drug therapy , Adult , Antiretroviral Therapy, Highly Active/methods , Argentina , CD4 Lymphocyte Count , Drug Therapy, Combination , Europe , Female , Humans , Israel , Logistic Models , Male , Middle Aged , Prospective Studies , Treatment Outcome , Viral Load/drug effects
19.
Medicine (Baltimore) ; 96(18): e6812, 2017 May.
Article En | MEDLINE | ID: mdl-28471983

To evaluate hospitalization rates and causes among human immunodeficiency virus (HIV) patients in the late highly active antiretroviral therapy (HAART) era. Data during the years 2000 to 2012 were obtained from hospital/clinical charts. Hospitalizations were defined as a ≥24 hours hospital admission. Obstetric admissions were excluded. Causes of hospitalizations were defined as acquired immune deficiency syndrome (AIDS)-defining illnesses, AIDS-related diseases (HAART adverse events, metabolic complications and non-AIDS-defining tumors/infections), and non-HIV-related diseases. Hospitalization rates are presented as admissions per 100 patient years. The number of HIV patients (58% males) in our center increased from 521 in 2000 to 1169 in 2012. 1676 hospital admissions (in 557 patients) were observed during the years of the study. The mean number of admissions per hospitalized patient was 3 ±â€Š3.39. Hospitalization rates of HIV patients declined significantly (18.4/100 in 2000, 9/100 patient years in 2012; P = .0001), but it was higher than the rates reported in the Israeli general population (X8.76 in 2000, X6.04 in 2012). Furthermore, hospitalizations for AIDS-defining illness declined (from 46.9% to 16.1%) whereas non-HIV-related hospitalizations increased (from 31.3% to 60.1%). Lower cluster of differentiation 4 (CD4) cell counts and older age, at the time of HIV diagnosis, were associated with higher rates of admissions (especially for AIDS-defining illnesses) and mortality. Hospitalization rates of HIV patients, especially for AIDS-defining illness, continue to decline in the late HAART era despite the increasing age of the patients, though it is still higher than that of the general population. Low CD4 cell counts and older age, at the time of HIV diagnosis, are associated with readmissions and mortality.


HIV Infections/epidemiology , HIV Infections/therapy , Hospitalization/trends , Adult , Age Factors , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Female , Hospitalization/statistics & numerical data , Humans , Israel , Male , Medication Adherence , Middle Aged , Retrospective Studies
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