Hypersensitivity reactions, hepatotoxicity, and other discontinuations in persons receiving integrase strand transfer inhibitors: results from the EuroSIDA study.

Background: Hypersensitivity reaction (HSR) and hepatotoxicity are rare, but potentially serious side-effects of antiretroviral use.Objective: To investigate discontinuations due to HSR, hepatotoxicity or other reasons among users of dolutegravir (DTG) vs. raltegravir (RAL) or elvitegravir (EVG) in the EuroSIDA cohort.Methods: We compared individuals ≥18 years and starting combination antiretroviral therapy (ART, ≥3 drugs) with DTG vs. RAL or EVG, with or without abacavir (ABC), between January 16, 2014 and January 23, 2019. Discontinuations due to serious adverse events (SAEs) were independently reviewed.Results: Altogether 4366 individuals started 5116 ART regimens including DTG, RAL, or EVG, contributing 9180 person-years of follow-up (PYFU), with median follow-up 1.6 (interquartile range 0.7-2.8) years per treatment episode. Of these, 3074 (60.1%) used DTG (1738 with ABC, 1336 without) and 2042 (39.9%) RAL or EVG (286 with ABC, 1756 without). 1261 (24.6%) INSTI episodes were discontinued, 649 of the DTG-containing regimens (discontinuation rate 115, 95% CI 106-124/1000 PYFU) and 612 RAL or EVG-containing regimens (173, CI 160-188/1000 PYFU). After independent review, there were five HSR discontinuations, two for DTG (one with and one without ABC, discontinuation rate 0.35, CI 0.04-1.28/1000 PYFU), and three for RAL or EVG without ABC (0.85, CI 0.18-2.48/1000 PYFU). There was one hepatotoxicity discontinuation on DTG with ABC (discontinuation rate 0.18, CI 0.00-0.99/1000 PYFU).Conclusion: During 5 years of observations in the EuroSIDA cohort independently reviewed discontinuations due to HSR or hepatotoxicity were very rare, indicating a low rate of SAEs.

Ensuring HIV care to undocumented migrants in Israel: a public-private partnership case study.

BACKGROUND: Undocumented migrants in Israel, mostly originating from HIV endemic countries, are not covered by Israel's universal healthcare coverage. We initiated a Public-Private Partnership (PPP) to handle this public health and humanitarian challenge. The PPP venture included the Ministry of Health (MoH), pharmaceutical companies, pharmacies, and specialized HIV clinics, the Israeli HIV Medical Society (from the Israel Medical Association), and non-governmental organizations. This study describes the national policy process in conceptualizing and implementing access to HIV services for undocumented migrants through a PPP, and analyzes the preliminary results. METHODS: This case study describes the process of creating a temporary Public-Private Partnership to provide HIV care for undocumented migrants based on institutional records of the Department of Tuberculosis and AIDS (DTA) and memories and reflections from partners. This case was analyzed according to the OECD-DAC criteria for development assistance (relevance, effectiveness, efficiency, sustainability and impact). Demographic and serological data of patients referred between 2014 to 2018 were collected to monitor progress. and analyze preliminary medical and biological outcomes. Ethical approval was obtained from the Ministry of Health. RESULTS: Creating a policy to extend HIV care to undocumented migrants was a 15 year process that confronted several challenges within Israeli and international discourse, particularly concerning governmental response to the migration crisis. The use of a PPP model involving numerous stakeholders provided a solid, local feasibility demonstration that extending HIV care as a matter of policy would have positive implications for public health in Israel. During the first 2 years of the program (2014-2015), the MoH funded medical follow-up and the pharmaceutical companies provided antiretroviral treatment (ART) free of charge for only 100 patients at any given time, in addition to ART provided by the MoH for pregnant women. Since 2016, the MoH has fully covered this service and integrated it within the Israeli health system; this constitutes the major success of the PPP program. As of December 2018, the national program has monitored 350 patients and treated 316 (90.3%). The most prevalent disease present upon referral was Tuberculosis. CONCLUSIONS: To our knowledge, this study documents the first example of a successful PPP with government partnership in a high-income country to address undocumented migrants' lack of access to health services in general and HIV care in particular. In light of the intensification of North-South migration, this Israeli case study could be useful for other countries facing similar challenges. It also has lessons within Israel, as the country grapples with other health problems among uninsured communities.

Evaluation of a benchtop HIV ultradeep pyrosequencing drug resistance assay in the clinical laboratory.

Detection of low-abundance drug resistance mutations (DRMs) of HIV-1 is an evolving approach in clinical practice. Ultradeep pyrosequencing has shown to be effective in detecting such mutations. The lack of a standardized commercially based assay limits the wide use of this method in clinical settings. 454 Life Sciences (Roche) is developing an HIV ultradeep pyrosequencing assay for their benchtop sequencer. We assessed the prototype plate in the clinical laboratory. Plasma samples genotyped by the standardized TruGene kit were retrospectively tested by this assay. Drug-treated subjects failing therapy and drug-naive patients were included. DRM analysis was based on the International AIDS Society USA DRM list and the Stanford algorithm. The prototype assay detected all of the DRMs detected by TruGene and additional 50 low-abundance DRMs. Several patients had low-abundance D67N, K70R, and M184V reverse transcriptase inhibitor mutations that persisted long after discontinuation of the drug that elicited these mutations. Additional patient harbored low-abundance V32I major protease inhibitor mutation, which under darunavir selection evolved later to be detected by TruGene. Stanford analysis suggested that some of the low-abundance DRMs were likely to affect the resistance burden in these subjects. The prototype assay performs at least as well as TruGene and has the advantage of detecting low-abundance drug resistance mutations undetected by TruGene. Its ease of use and lab-scale platform will likely facilitate its use in the clinical laboratory. The extent to which the detection of low-abundance DRMs will affect patient management is still unknown, but it is hoped that use of such an assay in clinical practice will help resolve this important question.

Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata.

BACKGROUND: This study compared the incidence of fatal and nonfatal AIDS and non-AIDS events in HIV-positive individuals with a CD4 cell count more than 350  cells/µl among viral load strata: low (<500  copies/ml), intermediate (500-9999.9  copies/ml) and high (≥ 10000  copies/ml). METHODS: Individuals contributed person-years at risk if their most recent CD4 cell count was more than 350  cells/µl. Follow-up was censored if their CD4 cell count dropped below 350  cells/µl. Poisson regression analysis investigated the relationship between viraemia and the incidence of AIDS and non-AIDS events. RESULTS: Three hundred and fifty-four AIDS events occurred during 51 732  person-years of follow-up (PYFU), crude incidence rate of AIDS across the three strata was 0.53, 0.90 and 2.12 per 100 PYFU, respectively. After adjustment, a higher rate of AIDS was observed in individuals with moderate [incidence rate ratio (IRR) 1.44, 1.02-2.05, P = 0.03] and high viraemia had a higher rate (IRR 3.91, 2.89-5.89, P < 0.0001) compared with low viraemia. Five hundred and seventy-two non-AIDS events occurred during 43 784 PYFU, the crude incidence rates were 1.28, 1.52, and 1.38 per 100 PYFU, respectively. After adjustment, particularly for age, region of Europe and starting combination antiretroviral therapy, there was a 61% (IRR 1.61, 1.21-2.14, P = 0.001) and 66% (IRR 1.66, 1.17-2.32, P = 0.004) higher rate of non-AIDS in individuals with intermediate and high viraemia compared with low viraemia. CONCLUSION: In individuals with a CD4 cell count more than 350  cells/µl, an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment and no differences were observed between intermediate and high viraemia.

Current hemoglobin levels are more predictive of disease progression than hemoglobin measured at baseline in patients receiving antiretroviral treatment for HIV type 1 infection.

The role of hemoglobin levels as an independent prognostic marker of progression to AIDS and/or death in HIV-infected patients starting combination antiretroviral therapy (cART) was investigated. A total of 2,579 patients from the EuroSIDA cohort with hemoglobin, CD4 cell count, and HIV RNA viral load measured 6 months prior to starting cART was included in the analyses. Anemia was defined as mild (

An investigation of the practice of unsafe sex yet repeated HIV testing.

RATIONALE: A purportedly heterogeneous group of people, who come to take tests at the Human Immunodeficiency Virus (HIV) Test-ing Clinic, includes young males and females who lead a normative lifestyle with no unique characteristics. Within this population, we have observed one distinct subgroup of predominantly male individuals, who return from time to time to take the HIV tests. They tend to partake in many occasional sexual encounters with numerous partners, and despite their obvious knowledge of the risks involved, they attest to not using condoms during sexual intercourse. The aim of this preliminary study was to investigate the patterns of their risky behavior in conjunction with their test taking conduct. METHODS: Ten self-referred volunteering subjects were recruited. EXCLUSION CRITERIA: HIV-positive, drug and/or alcohol abusers, mentally ill, men who have sex with men (MSM) and minors. The study was carried-out using semi-structured interviews (40-90 min each). The interviews were recorded, transcribed and content analyzed. FINDINGS: Data analysis showed several possible explanations for risky sexual behavior, such as applying of a variety of risk management mechanisms, refraining from impulse control behaviors, and self-destruction motives. The reasons for undergoing HIV testing were most frequently related to specific events, high-risk in nature, and not part of a routine behavioral practice. CONCLUSIONS: Our findings might suggest that within this population group, the prevailing primary preventive interventions would not satisfy the purpose of decreasing levels and frequency of risk-taking behaviors. In the opinion of the authors, there are two strategies that could be employed, simultaneously or separately. An indirect approach entails the increase and enhancement in utilizing widely spread media, e.g., feature films and television programs, to convey issues related to curbing risk-behavior. Direct emphasis should be put on secondary preventive measures, by encouraging frequent test-taking conduct, preferably accompanied by counseling, in order to decrease the risk of further transmitting the virus.

Viral load of the human immunodeficiency virus could be an independent risk factor for endothelial dysfunction.

BACKGROUND: Recent reports of myocardial infarction in young persons infected with human immunodeficiency virus (HIV) who are receiving protease inhibitor therapy have raised concerns about premature coronary artery disease in this population. However, endothelial dysfunction, hypercoagulability, hypertriglyceridemia, and abnormal coronary artery pathology have been observed in association with HIV infection prior to the availability of protease inhibitor therapy. HYPOTHESIS: The study was undertaken to determine the association between endothelial function, viral load, CD4+ count, and other well-established risk factors for atherosclerosis. METHODS: This prospective, case-controlled study compared viral (HIV) load and the CD4+ T-lymphocyte count and endothelial function in 24 HIV-positive carriers. Brachial artery diameter, HIV viral load, and CD4 count were measured. RESULTS: We found that viral load correlated inversely with endothelial function; the higher the viral load, the worse the endothelial dysfunction (p < 0.005). CONCLUSION: High viral load appears to be associated with endothelial dysfunction in patients with HIV. This preliminary observation supports the infectious theory that viruses may play an important role in the pathogenesis of atherosclerosis.

Overexpression of a novel lymphocyte population, positive for an intracellular CD14-like antigen, in patients positive for human immunodeficiency virus type 1.

CD14, originally recognized as a lipopolysaccharide (LPS) receptor, has recently been implicated in the process of T-cell suppression and apoptosis. Its soluble form has been shown to bind, in vitro, to human T cells, a process that may carry a negative signal onto these cells. We recently described a novel lymphocyte population in human peripheral blood, a population that expresses an intracellular CD14-like antigen. This novel T-cell population, composed mainly of CD8 cells and of very few CD4 cells, was found to be greatly enhanced in asymptomatic, untreated human immunodeficiency virus (HIV)-positive individuals. In the present study, we further characterized this cell population and found that it differed from other CD8 subpopulations associated with HIV infection such as CD8/CD38. In addition, we followed HIV patients under conditions of highly active antiretroviral therapy (HAART) and observed two groups of patients: patients in whom the CD14-like positive-testing T cells returned to normal within 1 to 3 months, and patients in whom it did not, in spite of a significant plasma HIV-RNA viral load decrease. Thus, this new CD14-like positive-testing lymphocyte population may represent an interesting and important component of the cellular events associated with HIV infection. On the basis of its modulation following HAART, we speculate that it may be used, in the future, as a drug-monitoring cellular marker in antiretroviral treatment.

Characterization of new monoclonal antibodies that discriminate between soluble and membrane CD4 and compete with human anti-CD4 autoimmune sera.

In this report we present results on immunization of hu-CD4 C57Black/6J transgenic mice with HIV-1 gp120(451) complexed with its receptor protein, CD4. In addition to development of anti-gp120 antibodies, these mice also produced two anti-CD4 monoclonal antibodies, designated T6 and T9. Both these antibodies recognize soluble CD4 but not membrane associated CD4. Their corresponding epitopes map to the D3-D4 domains of CD4. These characteristics are very similar to the HIV related anti-CD4 autoimmunity found in 10-15% of HIV-1 infected people. Therefore, 208 HIV-1 positive patients were screened for anti-CD4 humoral response of which 27 were found positive (13%). Sixteen of these patients were then tested for their ability to compete with the T6 and T9 anti-CD4 monoclonal antibodies. In such experiments saturating amounts of either T6 or T9 antibodies were able to prevent 20-80% of the human serum binding to immobilized soluble CD4 in competitive ELISA tests. The T6 and T9 antibodies therefore help to define distinct CD4 epitopes associated with clinical anti-CD4 autoimmunity.

An intracellular antigen that reacts with MO2, a monoclonal antibody to CD14, is expressed by human lymphocytes.

CD14, a lipopolysaccharide (LPS) receptor, is present on the surface membrane of phagocytic leukocytes; it is also present in a soluble form in serum. Recently published results confer to this molecule novel functions that are linked to T-cell activation and to apoptosis. We report here that we have defined and characterized a novel lymphocyte population in human peripheral blood, a population that expresses an intracellular antigen detectable with MO2, a monoclonal antibody directed against the human CD14 molecule. This population is composed primarily of CD8-positive T-cells. We found surprisingly that this novel MO2-positive population of lymphocytes was greatly enhanced in asymptomatic, untreated HIV-positive individuals.

Prevalence and clinical features of dementia associated with the antiphospholipid syndrome and circulating anticoagulants.

The increasing prevalence with age of antiphospholipid antibodies (aPL), of dementia and of stroke complicates the study of a causal relationship between antiphospholipid syndrome (APS) and dementia. Prolonged aPTT due to circulating anticoagulants (CAC) may serve as a more specific laboratory marker of APS. In a hospital-based study, we examined all patients with CAC and included 23 who fulfilled standard criteria for primary APS. These patients were assessed for dementia, vascular brain disease, autoimmune disease activity and dementia risk factors. Among CAC-positive APS patients, 13 of the 23 (56%) were demented and these were significantly older (mean age+/-S.E., 68+/-3 years) than the nondemented APS group (n=10, 51+/-4 years; p<0.01, Student's t-test). The demented patients had significantly more pathology on computerized brain tomography (CT) and electroencephalography (EEG) studies but six of them had no clinical or CT evidence of vascular brain disease. Erythrocyte sedimentation rate was significantly lower in the dementia group, in which there was also a significant negative correlation between levels of aPL and age. CAC-positive APS patients seem to be at risk for developing dementia with age, suggesting a pathogenic role for prolonged exposure to elevated aPL.

Antibody dependent cell mediated cytotoxicity and phagocytosis of senescent erythrocytes by autologous peripheral blood mononuclear cells.

Human red blood cells (RBCs) have a life span of 120 days in circulation, after which they are removed primarily by resident macrophages. Autoimmune antibodies are commonly found on effete RBCs and appear to contribute to their removal from the circulation. In this article, we focused on senescent erythrocytes and studied their removal, in comparison to young RBCs, in two RBC-depletion in vitro assays: antibody dependent cell mediated cytotoxicity (ADCC) and erythrophagocytosis. The results were determined prior to and following the addition of anti-D antibodies to the systems. Old (O-RBC) and young (Y-RBC) erythrocytes were separated by differential centrifugation. When incubated with autologous peripheral blood mononuclear cells as attacking cells, both anti-D treated O-RBCs and anti-D treated Y-RBCs were phagocytized and underwent contact lysis. However, O-RBCs had a significantly higher tendency to be phagocytized (p = 0.05) and a higher predisposition to undergo lysis (p = 0.043) than did Y-RBCs. When incubated with attacking cells without anti-D antibodies, O-RBCs were phagocytized while Y-RBCs were not phagocytized at all (p = 0.046). No contact lysis of either source of target cells occurred when incubated with attacking cells alone without anti-D sera. These in vitro results suggest that ADCC may serve as an additional pathway of elimination of senescent erythrocyte in addition to the classical phagocytosis pathway.