Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.

Background The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years. Guideline highlights The 2019 Guidelines were extended with a new section focusing on drug-drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment-na€ ıve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two-drug regimen with dolutegravir and lamivudine, and a three-drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10-year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management. Treatment of resistant tuberculosis (TB) was streamlined with the World Health

Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.

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Introduction Although weight gain has been reported with the use of integrase strand transfer inhibitors (InSTI), concurrent use of tenofovir alafenamide (TAF) has been implicated in recent studies. This study examined weight changes in people living with HIV (PLWH) who switched from tenofovir disoproxil fumarate (TDF) to TAF, to clarify the relative contribution to weight gain of core agents versus TDF to TAF switch. Methods Antiretroviral‐experienced, virologically suppressed PLWH in the U.S. OPERA cohort were included if they switched from TDF to TAF (5NOV2015‐28FEB2019) and either maintained all other antiretrovirals or switched from a non‐InSTI to an InSTI. Linear mixed models were used to assess weight changes before/after the switch to TAF (restricted cubic splines on time) and rates of change over time (linear splines on time, based on the shape of the weight change curves). Changes in weight on TDF or TAF were assessed among those who maintained other antiretrovirals (overall, by core class), and those who maintained an InSTI or switched to an InSTI (by core agent). All models were adjusted for age, sex, race, (age‐sex, race‐sex interactions), BMI, CD4 cell count, endocrine disorders and concurrent medications that could affect weight. Results A total of 6908 PLWH were included, with 5479 maintaining all other antiretrovirals (boosted protease inhibitor: 746, non‐nucleoside reverse transcriptase inhibitor: 1452, InSTI: 3281) and 1429 switching from a non‐InSTI to an InSTI (elvitegravir/cobicistat: 1120, dolutegravir: 174, bictegravir: 129). In adjusted models, modest weight gain was observed over time on TDF for most (0.24 to 0.71 kg/year); raltegravir was the exception with weight loss. Switching to TAF was associated with early, pronounced weight gain for all (1.80 to 4.47 kg/year). This effect with TAF switch was observed both in PLWH maintaining other antiretrovirals and those switching to an InSTI, regardless of which InSTI agent was used. Weight gain tended to slow down or plateau approximately nine months after switch to TAF. Conclusions In this large, diverse U.S. cohort of PLWH, switching from TDF to TAF was associated with pronounced weight gain immediately after switch, regardless of the core class or core agent, suggesting an independent effect of TAF on weight gain.

Background Coronavirus disease 2019 (COVID-19), caused by novel coronavirus SARS-CoV-2, has to date affected over 13.3 million globally. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Objectives Here, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and non-severe COVID-19. Methods An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with non-severe disease (not requiring intensive care), general medical in-patients without COVID-19 and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. Results We show that routine clinical blood parameters including increased MPV and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit admission. Strikingly, agonist-induced ADP release was dramatically higher in COVID-19 patients compared with non-COVID-19 hospitalized patients and circulating levels of PF4, sP-selectin and TPO were also significantly elevated in COVID-19. Conclusion Distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and non-severe COVID-19. Moreover, we have determined that COVID-19 patients possess hyperactive circulating platelets. These data suggest that abnormal platelet reactivity may contribute to hypercoagulability in COVID-19. Further investigation of platelet function in COVID-19 may provide additional insights into the aetiology of thrombotic risk in this disease and may contribute to the optimisation of thrombosis prevention and treatment strategies.

Word count: 247 (max 250) ObjectivesWhilst cognitive impairment is frequently reported in HIV-positive individuals and has historically been associated with poorer functional outcomes, the associations between cognitive impairment and patient-reported outcome measures (PROMs) in contemporary cohorts are unclear. MethodsWe tested cognitive function using a computerised battery (

Three‐drug combination antiretroviral therapy (ART) became available in 1996, dramatically improving the prognosis of people living with HIV. The clinical benefits of ART are due to the sustained viral load suppression and CD4 T cell gains. Major drawbacks of the first ART regimens were adverse events, and high pill burden, which led to the reduction of drug adherence resulting in frequent treatment discontinuations and the development of drug resistance. Due to increased viral potency of new antiretroviral drugs consideration of a two‐drug combination therapy repositioning occurred in an effort to reduce adverse events, drug‐drug interactions and cost, while maintaining a sustained antiviral effect. Various combinations of two‐drug regimens have been studied, and non‐inferiority compared to a three‐drug regimen has been shown only for some of them. In addition, a two‐drug combination regimen may not be suitable for every patient, especially those who are pregnant, those with tuberculosis or coexisting HBV infection. Furthermore no information has been generated concerning the secondary transmission of HIV from patients who have undetectable plasma viral load on two‐drug regimens. Additional studies of two‐drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation. While there is no urgent need to routinely switch patients to two‐drug combination therapy, due to the availability of drug combinations without significant toxicities, dual regimens represent a suitable option that deserve long‐term evaluation before being introduced to clinical practice.