Trends in mortality in people with HIV from 1999 to 2020: a multi-cohort collaboration.

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.

The effect of a treatment switch to integrase Strand transfer inhibitor-based regimens on weight gain and other metabolic syndrome-related conditions.

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.

Food-induced anaphylaxis during infancy is associated with later sleeping and eating disorders.

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.

Characteristics of patients with spontaneous resolution of sesame allergy.

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.

Observational cohort study of rilpivirine (RPV) utilization in Europe.

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).

Patch Testing in an Allergy Clinic: Real-world Experience.

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.

In sickness and in health: Living HIV positive kidney donation from a wife to her husband, with 7 years' post-transplant follow-up.

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.

Anti-BLyS Treatment of 36 Israeli Systemic Lupus Erythematosus Patients.

BACKGROUND: Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment. OBJECTIVES: To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers. METHODS: We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response. RESULTS: The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%). CONCLUSIONS: Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

HIV-associated neurocognitive disorders (HAND).

Neurocognitive impairment still occurs in the era of HAART, though its onset appears to be delayed and its severity reduced, while HIV-infected individuals live longer with the infection. HAND defines three categories of disorders according to standardized measures of dysfunction: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). The pathogenic mechanisms underlying HAND involve host and virus characterizations and interactions and seem to depend heavily on the overall condition of the immune system. Since there are insufficient data at this point to determine the best therapeutic approach, and since HAART apparently is not sufficient to prevent or reverse HAND, therapy with a combination of drugs with high CPE should be considered while adjunctive and alternative therapies are being explored.

Type I interferon signature in systemic lupus erythematosus.

Type I interferons (IFN) are primarily regarded as an inhibitor of viral replication. However, type I IFN, mainly IFNalpha, plays a major role in activation of both the innate and adaptive immune systems. Systemic lupus erythematosus (SLE) is a chronic, multi-systemic, inflammatory autoimmune disease with undefined etiology. SLE is characterized by dysregulation of both the innate and the adaptive immune systems. An increased expression of type I IFN-regulated genes, termed IFN signature, has been reported in patients with SLE. We review here the role of IFNalpha in the pathogenesis and course of SLE and the possible role of IFNalpha inhibition as a novel treatment for lupus patients.

BLyS levels in sera of patients with systemic lupus erythematosus: clinical and serological correlation.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by disturbance of the innate and adaptive immune systems with the production of autoantibodies by stimulated B lymphocytes. The BLyS protein (B lymphocyte stimulator) is secreted mainly by monocytes and activated T cells and is responsible for the proliferation, maturation and survival of B cells. OBJECTIVES: To study sera BLyS level and its clinical significance in Israeli lupus patients overtime. METHODS: The study population included 41 lupus patients (8 males, 33 females; mean age 35.56 +/- 15.35 years) and 50 healthy controls. The patients were followed for 5.02 +/- 1.95 years. We tested 221 lupus sera (mean 5.4 samples/patient) and 50 normal sera for BLyS levels by a capture ELISA. Disease activity was determined by the SLEDAI score. RESULTS: Sera BLyS levels were significantly higher in SLE patients than in controls (3.37 +/- 3.73 vs. 0.32 +/- 0.96 ng/ml, P < 0.05). BLyS levels were high in at least one sera sample in 80.5% of the patients but were normal in all sera in the control group. There was no correlation between sera BLyS and anti-ds-DNA autoantibody levels. BLyS levels fluctuated over time in sera of lupus patients with no significant correlation to disease activity. CONCLUSIONS: Most of our lupus patients had high sera BLyS levels, suggesting a role for BLyS in the pathogenesis and course of SLE. Our results support the current novel approach of targeting BLyS (neutralization by antibodies or soluble receptors) in the treatment of active lupus patients.

[Situations in which the primary care physician should suspect the presence of HIV-1 infection].

We are living in an era in which AIDS is no longer a terminal disease. It has become a chronic treatable disease. HIV-1 patients are mostly treated in specialized clinics by specialists in cLinical immunology or infectious diseases. In Israel, there are seven authorized centers for the diagnosis and treatment of HIV/AIDS. The primary caregiver for patients (family physician or internist) has to know the risk factors, risk groups and cLinical situations which are highly related to HIV-1 infection. These situations obligate a high clinical suspicion for early detection and diagnosis of HIV-1 infection. Early diagnosis has high clinical, prognostic and even epidemiological value. In this review, we highlight the main clinical situations in which the primary care physician should conduct an HIV-1 test as part of the clinical and Laboratory workup performed on the patient.

[Demographic and clinical characterizations of newly diagnosed patients with HIV/AIDS above fifty years of age].

BACKGROUND: Major changes happened in the last decade in the HIV/AIDS pandemic. The disease is no longer limited to young age. Due to the effectiveness of HAART (Highly Active Anti-Retroviral Therapy) as well as new diagnosis in older age groups, many patients in AIDS centers are above 50 years of age. AIM: To determine the prevalence, demographics and clinical characteristics of newly diagnosed HIV/AIDS patients older than 50 years compared to younger newly diagnosed patients. METHODS: Retrospective single center analysis of the demographics and clinical characterizations of 62 newly diagnosed HIV/AIDS patients over 50 years of age. RESULTS: The average age at diagnosis of the whole cohort was 39+/-16 years. There was a gradual increase in the age at diagnosis over the years, as well as the percent of patients above the age of 50 diagnosed with the disease. In comparison to younger patients, in the older group there were more males compared to females and less patients who acquired the HIV/AIDS in unprotected homosexual sex. Furthermore, CD4 cells counts were lower and viral load leveLs were higher at diagnosis in the older group. Despite good adherence, patients above the age of 50 don't achieve adequate immunological response and many are left with significant immunodeficiency (CD4<200). CONCLUSION: The prevaLence of patients above the age of 50 Living with HIV/AIDS in Israel is rising. Programs aimed at prevention, education and screening for this unique group are mandatory. An AIDS center should adopt new programs and routines to cope with the increasing number of patients over the age of 50 Living with HIV/AIDS.

[HIV post exposure prophylaxis therapy - the experience of two major AIDS centers].

BACKGROUND: During recent years, the use of antiretroviral therapy expanded beyond the treatment of HIV-infected patients. Since the outset of the HIV epidemic, antiretroviral drugs were also used for post-exposure prevention of HIV infection in health workers and implemented after possible exposure during sex. In this study, we summarize the cases from the AIDS center in the Kaplan Medical Center and the Sheba Medical Center after possible exposure to HIV (occupational or sexual). AIM: The study aims to validate the different types of potential exposures to HIV encountered, the treatment and outcomes. METHODS: All the data regarding attendance at the AIDS Center in the Kaplan Medical Center during the years 2008-2010 for any possible HIV exposure (occupational or sexual) and for sexual exposure in the Sheba Medical Center AIDS Clinic during the years 2003-2008 was collected retrospectively. RESULTS: During the years of the study, 448 patients attended the Kaplan Medical Center for consultation after a potential exposure to HIV; 314 of the cases were because of occupational exposure, however, only in 11 (3.5%) of the cases, post exposure prophylaxis (PEP) treatment was advised. In the other 134 patients who attended for non-occupational potential exposure to HIV (18 cases of needle stick or sharp object injury and 116 of sexual exposure), for 46 (40%) of these cases, PEP was recommended. No evidence of HIV infection was found for any of the 448 patients who attended the clinic for possible exposure to HIV, regardless of the consultation that they received. In the Sheba Medical Center, during the years 2003-2008, 175 patients attended for consuLtation after potential sexual exposure to HIV. The medical staff of the clinic decided, after risk assessment, to recommend PEP to 140 (80%) of the cases. Similarly, in this case, no evidence of HIV infection was found (regardless of whether PEP was given or not). DISCUSSION: In potential occupational exposure to HIV it is possible, in most cases, to assess the risk for infection sufficiently so that only a few cases will need PEP. In potential sexual exposure to HIV, there are many cases where data regarding the potential source of infection is partial or missing, making the risk assessment more difficult. This may be the reason for the high percentage of patients in this situation who received PEP. From the data in this study, our cohort support PEP as being effective and safe.

Viruses and celiac disease: what do we know ?

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.

Modification of allergen subcutaneous immunotherapy safety precautions and systemic allergic reaction rate reduction.

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.

Factors Associated with Virological Failure in First-Line Antiretroviral Therapy in Patients Diagnosed with HIV-1 between 2010 and 2018 in Israel.

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.

Novel biological treatments for systemic lupus erythematosus: current and future modalities.

Current treatments for systemic lupus erythematosus (SLE) are effective in reducing morbidity and mortality but are not specific and have severe adverse effects. Based on understanding of the different dysregulated immunological pathways involved in SLE pathogenesis, specific targeted therapies were developed. This review presents the current and the near-future novel biological immune targeted treatments, such as B cell-targeted therapy, cytokine blockade, peptide-based treatments and other novel treatments for SLE.