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.

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.

Incidence and risk factors for suicide, death due to substance use, and violent/accidental death in people with HIV.

OBJECTIVE: Deaths due to suicide, substance use and violence/accident may reflect similar risk factors and overlap in their classification. This study aimed to investigate incidence and risk factors of mortality among people with HIV (PWH) due to these three related causes. DESIGN: Prospectively collected data from PWH at least 18 years old and under active follow-up in the EuroSIDA study from 2007 to 2019 were analysed. METHODS: Cause-specific Cox regression analysis was used to assess risk factors. RESULTS: A total of 17 881 participants were included, comprising 149 327 person-years of follow-up (PYFU). Forty participants died by suicide {incidence rate [IR] [95% confidence interval (CI)]: 0.3/1000 PYFU (0.2, 0.4)} 93 from substance use [IR (95% CI): 0.6/1000 PYFU (0.5, 0.8)], and 57 by violence/accident [IR (95% CI): 0.4/1000 PYFU (0.3, 0.5)]. An AIDS diagnosis within the last 12 months was associated with nine-fold increased risk of suicide vs. no history of AIDS [adjusted hazard ratio (aHR): 9.06; 95% CI: 2.07, 39.7]. Male gender was associated with double the risk of violent/accidental death (aHR: 2.28; 95% CI: 1.09, 4.78). PWH in Eastern Europe and those who acquired HIV by injection drug use (IDU) demonstrated a greater risk of death due to substance use or violence/accident. CONCLUSIONS: The association between a recent diagnosis of AIDS and suicide highlights a critical period for intervention. HIV infection acquired through IDU demonstrated an expected relationship with death due to substance use and violent/accidental deaths. Increased risk of death due to substance use and violence/accident in Eastern Europe demands investigation into specific differences that may drive that association.

High-CBD Extract (CBD-X) Downregulates Cytokine Storm Systemically and Locally in Inflamed Lungs.

Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperinflammation. They are often detrimental, and worsen the severity of COVID-19 and other infectious or inflammatory diseases. Cannabinoids are known to have anti-inflammatory effects but their possible therapeutic value on cytokine storms has not been fully elucidated. In vivo and ex vivo studies were carried out to investigate the effects of high-THC and high-CBD extracts on cytokine production in immune cells. Significant differences between the extracts were observed. Subsequent experiments focusing on a specific high CBD extract (CBD-X) showed significant reductions in pro-inflammatory cytokines in human-derived PBMCs, neutrophils and T cells. In vivo mouse studies, using a systemically inflamed mouse model, showed reductions in pro-inflammatory cytokines TNFα and IL-1ß and a concurrent increase in the anti-inflammatory cytokine IL-10 in response to CBD-X extract treatment. Lung inflammation, as in severe COVID-19 disease, is characterized by increased T-cell homing to the lungs. Our investigation revealed that CBD-X extract impaired T-cell migration induced by the chemoattractant SDF1. In addition, the phosphorylation levels of T cell receptor (TCR) signaling proteins Lck and Zap70 were significantly reduced, demonstrating an inhibitory effect on the early events downstream to TCR activation. In a lung inflamed mouse model, we observed a reduction in leukocytes including neutrophil migration to the lungs and decreased levels of IL-1ß, MCP-1, IL-6 and TNFα, in response to the administration of the high-CBD extract. The results presented in this work offer that certain high-CBD extract has a high potential in the management of pathological conditions, in which the secretion of cytokines is dysregulated, as it is in severe COVID-19 disease or other infectious or inflammatory diseases.

Long term dual antiretroviral therapy: A real life retrospective countrywide Israeli study.

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.

The Immunopathology of COVID-19 and the Cannabis Paradigm.

Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. Recently, the therapeutic potential of phytocannabinoids, the unique active compounds of the cannabis plant, has been discovered in the area of immunology. Phytocannabinoids are a group of terpenophenolic compounds which biological functions are conveyed by their interactions with the endocannabinoid system in humans. Here, we explore the anti-inflammatory function of cannabinoids in relation to inflammatory events that happen during severe COVID-19 disease, and how cannabinoids might help to prevent the progression from mild to severe disease.

Medical personnel knowledge and stigmatic attitude toward HIV patients in a high-income country.

Negative attitudes of health care workers (HCW) toward people living with HIV (PLWH) impact patients' care, quality-of-life, therapy adherence, and retention in care. Few publications address stigma and discrimination among HCWs in high income countries. This study aims to provide a better understanding of HCW knowledge and attitudes toward caring for PLWH, how this relates to discriminatory tendencies and professional contacts, and proposes effective strategies to reduce negative attitudes and stigmas among health care providers in a tertiary hospital in Israel. Of 321 health care personnel who responded to an electronic questionnaire, HCWs had a good level of general knowledge regarding HIV. A lack of knowledge was noted regarding antiretroviral therapy influences, HIV transmission from mother to child, and HIV risks and transmission. Cultural diversity was also noted. This study supports the need to implement a training program for HCWs on HIV-related stigma-reduction.

Quantitative ultrasonometry: An alternative and easy method to evaluate bone quality in people living with human immunodeficiency virus.

BACKGROUND: HIV infection and antiretroviral therapy (ART) are associated with bone mineral loss. DXA is the gold standard method to evaluate the status of bone mineral density (BMD). However, it is not always readily available. An easy method is needed to evaluate bone quality in those infected with HIV. OBJECTIVE: To evaluate portable quantitative ultrasonometry (QUS) as an alternative technique to provide information about bone density, bone strength, and the bone turnover markers in HIV-infected people. METHODS: A total of 69 men took part (34 HIV-infected men were matched with 35 non-HIV-infected men) in the study. Bone mineral status was assessed by the Achilles quantitative ultrasonometer at the calcaneal heel. The HIV status was recorded for all HIV-infected patients. Calcium-regulating hormones and bone turnover markers were assessed in all participants. RESULTS: The mean age was 47.8±7.8 years and 49.1±6.00 years for the HIV-infected and non-infected population, respectively. The bone quality expressed as Stiffness index (SI) was reduced in HIV-infected patients. Bone turnover markers were higher in the HIV-infected patients, P1NP (ng/mL) was 48.0±14.3 vs 41.1±15.2 (P=0.057), and the (CTx)) (ng/mL) was 0.41±0.18 vs 0.29±0.11 (P=0.002). CONCLUSIONS: QUS is easy to use. Hence, QUS could be used as alternative method for screening of HIV patients for altered bone status.

A Population-Structured HIV Epidemic in Israel: Roles of Risk and Ethnicity.

BACKGROUND: HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning. METHODS: We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998-2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods. RESULTS: Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes. CONCLUSIONS: Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission.

Successful desensitization protocol for hypersensitivity reaction probably caused by dabrafenib in a patient with metastatic melanoma.

Vemurafenib and dabrafenib are both orally bioavailable small molecule agents that block mitogen activated protein kinase signalling in patients with melanoma and BRAF(V600E) mutation. Generalized hypersensitivity reactions to vemurafenib or dabrafenib have not been described. Continuing vemurafenib or dabrafenib therapy despite hypersensitivity reaction is especially important in patients with melanoma and BRAF(V600E) mutation, in whom this mutation plays a critical role in tumour growth. Desensitization protocols to overcome hypersensitivity reactions by gradual reintroduction of small amounts of the offending drug up to full therapeutic doses are available for many anti-cancer agents, including vemurafenib but, to the best of our knowledge, have not been reported for dabrafenib. We describe a patient with metastatic melanoma who developed Type I hypersensitivity reaction to vemurafenib and to subsequent treatment with dabrafenib, and who was successfully treated by drug desensitization which allowed safe prolonged continuation of dabrafenib. The development of hypersensitivity reactions for both dabrafenib and vemurafinib in the current case could be because these drugs have a similar chemical structure and cause a cross-reactivity. However, hypersensitivity reaction to a non-medicinal ingredient shared by the two drugs is also possible. Oral desensitization appears to be an option for patients with hypersensitivity Type I to dabrafenib. This approach may permit clinicians to safely administer dabrafenib to patients who experience hypersensitivity reactions to this life-prolonging medication.

Alpha-1 adrenergic antagonists induced severe rhinitis in patients with benign prostatic hyperplasia.

The standard gold care medications for benign prostatic hyperplasia (BPH) are the alpha-1-adrenergic antagonists, they are an effective medications and are generally well tolerated. However, at this time, no data have been published concerning the development of severe rhinorrhea with a great impact on quality of life in patients treated with alpha-1-adrenergic antagonists. We report two men with BPH treated with two different alpha-adrenergic antagonists; alfuzosin and doxazocin. The naranjo quality scale documented a probable adverse drug reaction (score 7) between rhinorrhea and treatment with alpha-1-adrenergic antagonists. In conclusion we reported that alpha-1-adrenergic antagonists are able to induce rhinorrhea in patients with BPH.

Comparable long-term efficacy of Lopinavir/Ritonavir and similar drug-resistance profiles in different HIV-1 subtypes.

BACKGROUND: Analysis of potentially different impact of Lopinavir/Ritonavir (LPV/r) on non-B subtypes is confounded by dissimilarities in the conditions existing in different countries. We retrospectively compared its impact on populations infected with subtypes B and C in Israel, where patients infected with different subtypes receive the same treatment. METHODS: Clinical and demographic data were reported by physicians. Resistance was tested after treatment failure. Statistical analyses were conducted using SPSS. RESULTS: 607 LPV/r treated patients (365 male) were included. 139 had HIV subtype B, 391 C, and 77 other subtypes. At study end 429 (71%) were receiving LPV/r. No significant differences in PI treatment history and in median viral-load (VL) at treatment initiation and termination existed between subtypes. MSM discontinued LPV/r more often than others even when the virologic outcome was good (p = 0.001). VL was below detection level in 81% of patients for whom LPV/r was first PI and in 67% when it was second (P = 0.001). Median VL decrease from baseline was 1.9±0.1 logs and was not significantly associated with subtype. Median CD4 increase was: 162 and 92cells/µl, respectively, for patients receiving LPV/r as first and second PI (P = 0.001), and 175 and 98, respectively, for subtypes B and C (P<0.001). Only 52 (22%) of 237 patients genotyped while under LPV/r were fully resistant to the drug; 12(5%) were partially resistant. In48%, population sequencing did not reveal resistance to any drug notwithstanding the virologic failure. No difference was found in the rates of resistance development between B and C (p = 0.16). CONCLUSIONS: Treatment with LPV/r appeared efficient and tolerable in both subtypes, B and C, but CD4 recovery was significantly better in virologically suppressed subtype-B patients. In both subtypes, LPV/r was more beneficial when given as first PI. Mostly, reasons other than resistance development caused discontinuation of treatment.

[Crucial risk factors for renal function deterioration of HIV-infected patients at the AIDS Clinic in Rambam Hospital].

BACKGROUND: Since the introduction of new and efficient antiretroviraL treatment (ART), mortality and morbidity due to HIV infections have been greatly reduced. However, there is a growing incidence of chronic diseases, such as cardiovascular, metabolic, bone and renal diseases. OBJECTIVES: To examine the impact of HIV infection on renal functions over time and to define risk factors which contribute to the change in renal functions. METHODS: We screened 600 out of the 800 patients who are registered in the Institute for Immunology, Allergy and AIDS at the Rambam Medical Center, Haifa. We collected data from the typed and computerized medical fites of the patients. Finally, for 136 patients under surveillance between the years 2005-2010 there was sufficient data to meet the inclusion and exclusion criteria. We followed the renal function, presented by the estimated glomerular filtration rate (eGFR) and quantified the change in GFR each year. Then, we determined the risk factors contributing to the change in renal function, by using a multi-variant model. RESULTS: We found an average yearly decline of 4.83 mt/ min/1.73 m2 body surface area during the period 2005- 2010. We also found that co-infection with HCV and treatment by the antiretrovirat drug Tenofovir are significantly associated with the decline in renal function among our patients [p=0. 0.14 and 0.045 respectively). CONCLUSIONS: There is a persistent decline in renal function, overtime, in HIV patients. This decline is significantly higher than the change observed in age- and sex-matched healthy general populations. Co-infection with HCV and treatment by the antiretroviral drug Tenofovir are substantial risk factors for eGFR.

[Fertility and HIV: equal opportunity for everyone].

Highly active antiretroviral treatment (HAART), the increase in life expectancy and improved HIV viral detection methods, have all led to a change in attitude towards fertility in people living with HIV. There is now acknowledgment of the fundamental rights of HIV patients to parenthood and growing implementation of assisted fertility in this group. The aims of fertility treatment are prevention of infection in HIV-discordant couples, and treatment for fertility problems, identical to the general population. We review the influence of HIV on the reproduction systems of males and females, conditions requiring fertility intervention, various methods that are possible and describe the optional treatment existing in Israel for patients with viral infection, and specifically HIV.

Transmission patterns of HIV-subtypes A/AE versus B: inferring risk-behavior trends and treatment-efficacy limitations from viral genotypic data obtained prior to and during antiretroviral therapy.

BACKGROUND: HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE versus B reflected differences in patient behavior and drug-treatment history. METHODS: Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks. RESULTS: 318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype. CONCLUSIONS: While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older versus newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation.

Vitamin D status in young HIV infected women of various ethnic origins: incidence of vitamin D deficiency and possible impact on bone density.

BACKGROUND: Decreased bone mineral density (BMD) was reported in HIV infected patients. Mechanisms leading to this decrease are poorly understood. AIMS: To assess factors relating to BMD in young HIV infected Israeli women of Ethiopian and Caucasian origin. PATIENTS AND METHODS: 75 young HIV infected women aged 34.5 ± 8.5 followed up at the Institute of Allergy, Clinical Immunology & AIDS filled a questionnaire about sun exposure, daily calcium intake and dress habits. Data about HIV status and treatment regimens were collected from the patients' charts. Serum hydroxyvitamin D [25(OH)D] levels, bone turnover markers and bone densitometry were evaluated. RESULTS: 28 (65%) of Ethiopians and 2 (6.25%) of Caucasians had 25(OH)D serum levels <10 ng/ml (vitamin D deficiency), p = 0.001. 21 (67.7%) Ethiopians and 16 (39%) Caucasians avoided sun exposure, p = 0.019. Mean daily calcium intake was 491 ± 268.6 mg and 279 ± 252.6 mg, respectively, p = 0.001. Z scores < -1 found at Lumbar spine in 26 (89.7%), at Femoral neck in 20 (69%) at Total hip in 17 (58.6%) of vitamin D deficient patients compared to 20 (48.8%), 17 (41.5%), 9 (22%), in patients with 25(OH)D > 10 ng/ml, p < 0.01, <0.03, <0.001, respectively. Significantly more Ethiopian than Caucasian women covered their face (32.3% and 9.5%, p = 0.003) and hands (58.1% and 30.9%, p = 0.03). There was no difference in bone turnover markers levels. CONCLUSION: Poorer vitamin D status was observed in Ethiopian women might be one of the important factors related to lower BMD in this group.

[Outcome of treatment with peg-interferon and ribavirin in HIV-HCV co-infected patients: "real life" single center experience].

BACKGROUND AND AIM: Recently, with the emergence of highly effective antiretroviral treatment (ART), chronic liver disease has become the leading cause of morbidity and mortality in co-infected HIV-HCV (Human immunodeficiency virus-Hepatitis C virus) patients. The overall SVR rate in this population remains unsatisfactory. The aim of this study was to evaluate the response to therapy in HIV-HCV co-infected patients in a single center. PATIENTS AND METHODS: Consecutive HIV-HCV co-infected patients were evaluated in the liver clinic between 2003 -2010. Liver needle biopsy was conducted in 100% of the patients. The patients were treated by a multidisciplinary team consisting of immunologists, hepatologists, social workers and nurses and a close follow-up was conducted. The 48 weeks duration of peg-interferon and ribavirin combination was used for all genotypes according to recent guidelines. Weight-adjusted ribavirin doses were applied. Treatment was initiated after stabilization of HIV parameters and successful weaning from drug and alcohol addiction. RESULTS: A total of 86 out of 143 HIV- HCV co-infected patients, were evaluated; 39 completed treatment. Of those 31 (77%) achieved SVR. Out of 22 genotype 1 patients, 18 (82%) achieved SVR. Six patients had spontaneous viral clearance and 8 are still receiving treatment. In 17 non-one genotype patients, the SVR rate was 76.4% (13 of 17 patients); 6 patients were defined as relapsers and non-responders. Overall adherence to the treatment was high. CONCLUSION: Measures, such as the use of a multidisciplinary approach, high adherence of physicians to the guidelines, weight-based ribavirin dose, and selecting patients who are ready to start therapy, can significantly improve the SVR rate in this difficult-to-treat patient population.