Diagnosis and Risk Factors of Prediabetes and Diabetes in People Living with HIV- Evaluation of Clinical and Microbiome Parameters.

Diabetes is more common among people living with HIV (PLWH), as compared with healthy individuals. In a prospective multicenter study (N = 248), we identified normoglycemic (48.7%), prediabetic (44.4%) and diabetic (6.9%) PLWH. HbA1c and fasting blood glucose (FBG) sensitivity in defining dysglycemia was 96.8%, while addition of oral glucose tolerance test led to reclassification of only 4 patients. Inclusion of 93 additional PLWH with known DM enabled identification of multiple independent predictors of dysglycemia or diabetes: older age, higher BMI, Ethiopian origin, HIV duration, lower integrase inhibitor exposure and advanced disease at diagnosis. Shotgun metagenomic microbiome analysis revealed 4 species that were significantly expanded with hyperglycemia/hyperinsulinemia, and 2 species that were differentially more prevalent in prediabetic/diabetic PLWH. Collectively, we uncover multiple potential host and microbiome predictors of altered glycemic status in PLWH, while demonstrating that FBG and HbA1C likely suffice for diabetes screening. These potential diabetic predictors merit future prospective validation.

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.

Use of contraindicated antiretroviral drugs in people with HIV/HCV coinfections receiving HCV treatment with direct-acting antivirals-Results from the EuroSIDA study.

OBJECTIVES: Our objective was to determine whether antiretroviral drugs (ARVs) were used according to the European AIDS Clinical Society (EACS) guidelines for people with HIV/hepatitis C virus (HCV) coinfection treated with direct-acting antivirals (DAAs) between 30 November 2014 and 31 December 2019 in the pan-European EuroSIDA study. METHODS: At each publication date of the EACS guidelines, plus 3 and 6 months, we calculated the number of people receiving DAAs with potential and actual ARV contraindications ('red shading' in the EACS guidelines). We used logistic regression to investigate factors associated with using contraindicated ARVs. RESULTS: Among 1406 people starting DAAs, the median age was 51 years, 75% were male, 57% reported injected drug use as an HIV risk, and 76% were from western Europe. Of 1624 treatment episodes, 609 (37.5%) occurred while the patient was receiving ARVs with potential contraindications; among them, 38 (6.2%; 95% confidence interval [CI] 4.3-8.2) involved a contraindicated ARV (18 non-nucleoside reverse transcriptase inhibitors), 16 involved protease inhibitors, and four involved integrase strand transfer inhibitors. The adjusted odds of receiving a contraindicated ARV were higher (3.25; 95% CI 1.40-7.57) among participants from east/central east Europe (vs. south) and lower (0.22; 95% CI 0.08-0.65) for 2015-2018 guidelines (vs. 2014). In total, 29 of the 32 (90.6%) patients receiving a contraindicated ARV and 441 of the 461 (95.7%) with potential ARV contraindications experienced a sustained virological response ≥12 weeks after stopping treatment (SVR12; p = 0.55). CONCLUSION: In this large heterogenous European cohort, more than one-third of people with HIV/HCV coinfection received DAAs with potential ARV contraindications, but few received a contraindicated ARV. Use of contraindicated ARVs declined over time, corresponding to the increased availability of ARV therapy regimens without interactions with DAA across Europe. Participants who received a contraindicated DAA and ARV combination still had a high rate of SVR12.

Endophthalmitis panorama in the Jerusalem area.

PURPOSE: The spectrum of microbial infections and the pattern of their susceptibility are variable among communities. Researching these data will lead to the establishment of the most appropriate national management strategies. The purpose of this study was to analyze the epidemiological, clinical, microbial spectrum and antibiotic susceptibility of endophthalmitis cases in a tertiary referral center in Jerusalem. METHODS: Retrospective review of medical charts of patients presenting with endophthalmitis over a 12-year period. RESULTS: A total of 74 eyes of 70 patients (males 56%) were included. Mean age ± SD at presentation was 60 ± 19.5 years. Exogenous endophthalmitis accounted for 78% of cases, of which 62% followed an intraocular surgery, 21% occurred after intravitreal injections, 10% followed infectious keratitis and 7% were posttraumatic. Endogenous cases were predominantly observed in diabetic patients. Microbial isolates were identified in 44 samples. Of them, gram-positive bacteria were the predominant microorganisms detected in 33 samples (75%); Staphylococcus epidermidis and Enterococcus faecalis were the most commonly detected pathogens. Mean presenting ± SD LogMAR visual acuity (VA) was 2.38 ± 1.21 and it improved at last follow-up to 1.7 ± 1.37 (p = 0.004, paired t test). Cases secondary to gram-positive microbes were associated with improved VA during the follow-up while cases secondary to gram-negative microbes was correlated with poor final VA (p = 0.046, r2 = 0.4). There was no evidence of bacterial resistance in the antibiograms for either vancomycin, ceftazidime, ceftriaxone or amikacin. CONCLUSIONS: Intraocular surgery remains the most common event preceding endophthalmitis with coagulase-negative staphylococci being the most frequently detected microorganisms. The microbial spectrum of endophthalmitis is similar to that in the western world.

False-positive galactomannan antigen testing in pulmonary nocardiosis.

Early diagnosis of invasive aspergillosis (IA) is facilitated by detection of galactomannan (GM) in serum and bronchoalveolar lavage fluid (BALF) using an enzyme-linked immunosorbent assay (ELISA). Although accurate, false positive results have been reported with these tests in numerous contexts. We report for the first time the occurrence of false positive GM ELISA due to nocardiosis, initially in a clinical sample of BALF from a patient with pulmonary nocardiosis, and subsequently corroborated by in vitro reactivity of 26% of tested isolates. Since patients at risk for IA are also at risk for nocardiosis, this finding has important clinical implications. LAY SUMMARY: Early diagnosis of aspergillosis has been facilitated by the routine use of antibody-based detection of galactomannan in various bodily fluids. We report for the first time the occurrence of false positive results of this assay in the context of nocardiosis.

Case Report of Increased Exposure to Antiretrovirals following Sleeve Gastrectomy.

Bariatric surgery is increasingly performed in morbidly obese HIV patients. Limited data exist regarding antiretroviral drug exposure after bariatric surgery. We report a case of a morbidly obese HIV patient who underwent sleeve gastrectomy. Abacavir, lamivudine, and dolutegravir therapeutic drug monitoring was performed at several time points pre- and postsurgery. Significantly increased levels were measured, particularly for abacavir, whose levels increased ∼12-fold. Several mechanistic explanations for these findings are discussed.

Limited awareness of the effective timing of HIV post-exposure prophylaxis among people with high-risk exposure to HIV.

The effectiveness of post-exposure prophylaxis (PEP), a major strategy in the battle against HIV, depends on awareness of this modality and its proper timing among high-risk groups. While general awareness of PEP is improving, recently estimated to be 36-47% among men who have sex with men (MSM), PEP implementation remains disappointingly low and may be driven by limited awareness of effective PEP timing window. The level of detailed understanding of PEP timing and effectiveness among populations at risk has not been prospectively assessed to date. We prospectively evaluated, for the first time, actionable awareness regarding effective timing of PEP among a large cohort of individuals tested for HIV following unprotected sexual intercourse. Four hundred participants were assessed between December 2014 and February 2016. Overall awareness of the option of PEP was 60% and was significantly higher among male members of the LGBTQ community (75·5% as compared to 52·6% among heterosexual males) and those undergoing past HIV testing (67·1%). However, only 24% of individuals at risk were aware as to the proper timing of effective PEP treatment, thereby leading, in the majority of cases, to missing the window of opportunity for PEP treatment. This study highlights the lack of knowledge as to the specific requirements needed for effective PEP timing. Expanded advertising, better targeting of the heterosexual population, training of family physicians in the field of gender, sexuality, and LGBTQ medicine, may improve effective PEP availability, thereby reducing HIV transmission.

Breast Implant Q Fever as a Source of In-Hospital Transmission.

Herein, we describe the first case of mammary implant infection caused by Coxiella burnetii, resulting in delayed diagnosis and treatment and an in-hospital cross-transmission of Q fever to medical personnel.

Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015.

BACKGROUND: Direct comparisons between countries in core HIV care parameters are often hampered by differences in data collection. AIM: Within the EuroSIDA study, we compared levels of antiretroviral treatment (ART) coverage and virological suppression (HIV RNA < 500 copies/mL) across Europe and explored temporal trends. METHODS: In three cross-sectional analyses in 2004-05, 2009-10 and 2014-15, we assessed country-specific percentages of ART coverage and virological suppression among those on ART. Temporal changes were analysed using logistic regression. RESULTS: Overall, the percentage of people on ART increased from 2004-05 (67.8%) to 2014-15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004-05, 87.7% in 2014-15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014-15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe (as defined in this study), patients in other regions were less likely to be virologically suppressed in 2014-15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13-0.21) in Eastern Europe. CONCLUSIONS: Despite overall improvements over a decade, we found persistent disparities in country-specific estimates of ART coverage and virological suppression. Underlying reasons for this variation warrant further analysis to identify a best practice and benchmark HIV care across EuroSIDA.

The gut microbiome in human immunodeficiency virus infection.

HIV/AIDS causes severe dysfunction of the immune system through CD4+ T cell depletion, leading to dysregulation of both the adaptive and innate immune arms. A primary target for viral infection is the gastrointestinal tract, which is a reservoir of CD4+ T cells. In addition to being a major immune hub, the human gastrointestinal tract harbors trillions of commensal microorganisms, the microbiota, which have recently been shown to play critical roles in health. Alterations in the composition and function of microbiota have been implicated in a variety of 'multi-factorial' disorders, including infectious, autoimmune, metabolic, and neoplastic disorders. It is widely accepted that, in addition to its direct role in altering the gastrointestinal CD4+ T cell compartment, HIV infection is characterized by gut microbiota compositional and functional changes. Herein, we review such alterations and discuss their potential local and systemic effects on the HIV-positive host, as well as potential roles of novel microbiota-targeting treatments in modulating HIV progression and associated adverse systemic manifestations.

Pregnancy-associated listeriosis: clinical characteristics and geospatial analysis of a 10-year period in Israel.

BACKGROUND: Listeria monocytogenes is a foodborne pathogen that causes life-threatening infections in elderly, immunocompromised, and pregnant women. In pregnancy it may cause fetal loss or a preterm delivery, and the neonate is prone to neonatal sepsis and death. METHODS: We created a cohort of all L. monocytogenes cases during 10 years (1998-2007) in Israel, by a comprehensive review of cases in hospitals throughout the country and cases reported to the Ministry of Health. RESULTS: One hundred sixty-six pregnancy-related listeriosis cases were identified, resulting in a yearly incidence of 5-25 cases per 100 000 births. Presentation associated with fetal demise was more common in the second trimester (55.3%), and preterm labor (52.3%) and abnormal fetal heart rate monitoring (22.2%) were more common in the third trimester (P = .001). Fetal viability was low in the second trimester (29.2%) and much higher (95.3%) in the third trimester. Each additional week of pregnancy increased the survival chance by 33% (odds ratio, 1.331 [95% confidence interval, 1.189-1.489]). A single case of maternal mortality was identified. Listeria monocytogenes serotype 4b was more common in pregnancy-related than in non-pregnancy-related cases (79.5% vs 61.3%, P = .011). Pulsed-field gel electrophoresis analysis suggested that 1 pulsotype is responsible for 35.7% of the pregnancy cases between 2001 and 2007. This clone is closely related to the Italian gastroenteritis-associated HPB2262 and the invasive US Scott A L. monocytogenes strains. CONCLUSIONS: Our survey emphasizes the high rate of pregnancy-related listeriosis in Israel and shows that specific clones might account for this.

Human CRM1 augments production of infectious human and feline immunodeficiency viruses from murine cells.

Productive replication of human immunodeficiency virus type 1 (HIV-1) occurs efficiently only in humans. The posttranscriptional stages of the HIV-1 life cycle proceed poorly in mouse cells, with a resulting defect in viral assembly and release. Previous work has shown that the presence of human chromosome 2 increases HIV-1 production in mouse cells. Recent studies have shown that human chromosome region maintenance 1 (hCRM1) stimulates Gag release from rodent cells. Here we report that expressions of hCRM1 in murine cells resulted in marked increases in the production of infectious HIV-1 and feline immunodeficiency virus (FIV). HIV-1 production was also increased by hSRp40, and a combination of hCRM1 and hSRp40 resulted in a more-than-additive effect on HIV-1 release. In contrast, the overexpression of mouse CRM1 (mCRM1) minimally affected HIV-1 and FIV production and did not antagonize hCRM1. In the presence of hCRM1 there were large increases in the amounts of released capsid, which paralleled the increases in the infectious titers. Consistent with this finding, the ratios of unspliced to spliced HIV-1 mRNAs in mouse cells expressing hCRM1 and SRp40 became similar to those of human cells. Furthermore, imaging of intron-containing FIV RNA showed that hCRM1 increased RNA export to the cytoplasm.By testing chimeras between mCRM1 and hCRM1 and comparing those sequences to feline CRM1, we mapped the functional domain to HEAT (Huntingtin, elongation factor 3, protein phosphatase 2A, and the yeast kinase TOR1) repeats 4A to 9A and a triple point mutant in repeat 9A, which showed a loss of function. Structural analysis suggested that this region of hCRM1 may serve as a binding site for viral or cellular factors to facilitate lentiviral RNA nuclear export.

Two pandemics intertwined around one patient: Interstitial pneumonia as the first presentation of HIV/AIDS, be it Pneumocystis jirovecii, cytomegalovirus, SARS-CoV2 or all?-A case report.

Concerns have been mounting regarding the underdiagnosis of HIV among respiratory co-infections associated with the COVID-19 pandemic. The delay in recognizing HIV/AIDS may be attributed to the similarities in clinical, laboratory (lymphopenia) and imaging presentations, which are typical for advanced AIDS but could also be indicative of a COVID-19 infection. Herein, we present a case of a 38-year-old ultraorthodox Jew with a late diagnosis of AIDS in the context of COVID-19 infection. This occurred after several months of recurrent respiratory infections compounded by SARS-COV 2 infection, during which no HIV testing was conducted. As a result, a cascade of various opportunistic infections ensued, leading to an extended hospitalization period, ultimately culminating in the patient's demise despite receiving optimal treatment.

Viral and Bacterial Respiratory Pathogens during the COVID-19 Pandemic in Israel.

BACKGROUND: previous worldwide reports indicated a substantial short-term reduction in various respiratory infections during the early phase of the SARS-CoV-2 pandemic. AIMS: exploring the long-term impact of the COVID-19 pandemic on respiratory pathogens. METHODS: retrospective analysis of bacterial and viral positivity rate in respiratory samples, between 1 January 2017-30 June 2022 in a tertiary hospital in Jerusalem, Israel. RESULTS: A decline in overall respiratory tests and positivity rate was observed in the first months of the pandemic. Respiratory isolations of Hemophilus influenza and Streptococcus pneumoniae were insignificantly affected and returned to their monthly average by November 2020, despite a parallel surge in COVID-19 activity, while Mycoplasma pneumoniae was almost eliminated from the respiratory pathogens scene. Each viral pathogen acted differently, with adenovirus affected only for few months. Human-metapneumovirus and respiratory-syncytial-virus had reduced activity for approximately a year, and influenza A virus resurged in November 2021 with the elimination of Influenza-B. CONCLUSIONS: After an immediate decline in non-SARS-CoV-2 respiratory infections, each pathogen has a different pattern during a 2-year follow-up. These patterns might be influenced by intrinsic factors of each pathogen and different risk reduction behaviors of the population. Since some of these measures will remain in the following years, we cannot predict the timing of return to pre-COVID-19 normalcy.

Enterococci in Diabetic Foot Infections: Prevalence, Clinical Characteristics, and Outcomes.

Background: Diabetic foot infections (DFIs) are frequently polymicrobial, yet the relevance of each isolated pathogen, remains ill-defined. Specifically, the prevalence and pathogenicity of enterococcal DFIs and the impact of targeted antienterococcal treatment remain elusive. Methods: We collected demographic, clinical, and outcome-related data on patients admitted with DFIs to the Hadassah Medical Center diabetic foot unit between 2014 and 2019. The primary outcome was a composite of in-hospital death or major amputation. Secondary outcomes included any amputation, major amputation, length of stay (LOS), and 1-year major amputation or mortality rate. Results: Enterococci were isolated in 35% of 537 eligible DFI case patients, who were notable for a higher prevalence of peripheral vascular disease, increased levels of C-reactive protein, and higher Wagner scores. Infection in enterococci-positive individuals was mostly polymicrobial (96.8% vs 61.0% in non-enterococci-infected patients; P < .001). Enterococci-infected patients were more likely to undergo amputation (72.3% vs 50.1%; P < .001) and had longer hospital stays (median LOS, 22.5 vs 17 days; P < .001), but the primary end point of major amputation or in-hospital death did not differ between groups (25.5% vs 21.0%; P = .26). Appropriate antienterococcal antibiotics were used in 78.1% of enterococci-infected patients and, compared with results in untreated patients, were associated with a trend toward a lower rate of major amputations (20.4% vs 34.1%; P = .06) but longer hospitalization (median LOS, 24 vs 18 days; P = .07). Conclusions: Enterococci are common in DFIs and associated with higher rates of amputation and longer hospitalization. A reduction in major amputation rates with appropriate enterococci treatment is suggested retrospectively, meriting validation by future prospective studies.

The Relationship between Body Mass Index and In-Hospital Mortality in Bacteremic Sepsis.

BACKGROUND: The association between Body Mass Index (BMI) and clinical outcomes following sepsis continues to be debated. We aimed to investigate the relationship between BMI and in-hospital clinical course and mortality in patients hospitalized with bacteremic sepsis using real-world data. METHODS: A sampled cohort of patients hospitalized with bacteremic sepsis between October 2015 and December 2016 was identified in the National Inpatient Sample (NIS) database. In-hospital mortality and length of stay were defined as the relevant outcomes. Patients were divided into 6 BMI (kg/m2) subgroups; (1) underweight ≤ 19, (2) normal-weight 20-25, (3) over-weight 26-30, (4) obese I 31-35, (5) obese II 36-39, and (6) obese stage III ≥ 40. A multivariable logistic regression model was used to find predictors of mortality, and a linear regression model was used to find predictors of an extended length of stay (LOS). RESULTS: An estimated total of 90,760 hospitalizations for bacteremic sepsis across the U.S. were analyzed. The data showed a reverse-J-shaped relationship between BMI and study population outcomes, with the underweight patients (BMI ≤ 19 kg/m2) suffering from higher mortality and longer LOS as did the normal-weight patients (BMI 20-25 kg/m2) when compared to the higher BMI groups. The seemingly protective effect of a higher BMI diminished in the highest BMI group (BMI ≥ 40 kg/m2). In the multivariable regression model, BMI subgroups of ≤19 kg/m2 and ≥40 kg/m2 were found to be independent predictors of mortality. CONCLUSIONS: A reverse-J-shaped relationship between BMI and mortality was documented, confirming the "obesity paradox" in the real-world setting in patients hospitalized for sepsis and bacteremia.

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.

HIV/AIDS profile and realities at a regional antiretroviral therapy clinic in Jerusalem: 12 years analysis.

The diagnosis of HIV, quality of follow-up, and treatment among immigrants are greatly influenced by cultural factors and access to the healthcare system. Israel, an immigrant-based society, features 3 cardinal HIV-positive patient groups, namely non-immigrant Israelis, legal immigrants (mainly from Ethiopia), and illegal African work-immigrants. While the first 2 groups are covered by a national health insurance, the latter group depends on an unstructured system of antiretroviral therapy (ART) supply. In the early 1990s, a national mentoring programme was implemented for legal immigrants. The programme involves community-based Ethiopian mentors who follow HIV-positive Ethiopians. In this retrospective cohort study we reviewed the files of HIV-positive patients diagnosed between 1995 and 2007, focusing on comparison between HIV-positive non-immigrant populations with both legal Ethiopian immigrants and the often overlooked illegal immigrants. Our results point to a substantial rate of loss to follow-up among the illegal immigrants. When comparing non-immigrants to legal immigrants, both feature similar adherence to follow-up, exposure and response to ART, despite profound cultural differences. Our results suggest that ethnic-related obstacles in HIV diagnosis and treatment may be overcome by 'cultural mediators', yet, addressing the silent mass of HIV-positive illegal work-immigrants, who are deprived of such programme benefits, poses a major challenge to Western health authorities.