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Background Which components of the immune response to SARS-CoV-2 vaccination best protect against subsequent infection remains unclear. We explored SARS-CoV-2 specific antibody and B-cell responses post 3rd dose vaccine and their relationship to subsequent SARS-CoV-2 infection. Methods In a multicentre prospective cohort, adult subjects provided samples before and 14 days (d14) post 3rd dose vaccine with Pfizer-BioNTech 162b2. At 18-22 weeks post vaccine, subjects self-reported SARS-CoV-2 infection (confirmed by PCR or antigen test). We used electrochemiluminescence assays to quantify antibodies to SARS-CoV-2 spike subunit 1 (S1), subunit 2 (S2) and receptor-binding domain (RBD) in plasma (reported in WHO IU/mL). In a subset of subjects, we assessed SARS-CoV-2 specific differentiated B-cell (plasma cell) and memory B-cell responses from peripheral blood mononuclear cells. Unstimulated plasma cells, and memory B cells stimulated with R848 and IL2, were seeded on plates coated with RBD or full Spike antigen and antigen-specific responses measured by ELISpot (Mabtech ELISpot, Sweden). We compared between group differences by Wilcoxon signed rank or Mann–Whitney tests. Data are median [IQR] unless specified. Results Of 133 subjects (age 43 [32-50], 81.2% female (table 1), 77 subjects in the B-cell subgroup (table 2)), 47 (35.3%) reported SARS-CoV-2 infection post 3rd vaccine. Antibody titres, plasma cell and memory B-cell responses all increased significantly at d14 post 3rd vaccine (Table 1 & 2, all P< 0.001). Although d14 antibody titres did not differ in those with and without subsequent infection (table 1), those reporting subsequent infection had significantly lower d14 RBD-specific plasma cells and a lower proportion of RBD-specific memory B-cells (Figure 1a-b, both P< 0.05). Similar results were observed with full-spike-specific memory B-cell responses (Figure 1d). The differences persisted when the non-infected group was restricted only to those reporting a confirmed close contact (n=26). Conclusion Infection following 3rd dose vaccine is associated with lower d14 circulating and memory B cell responses, but not antibody titres, suggesting B-cell responses better predict protection against subsequent SARS-CoV-2 infection. Disclosures All Authors: No reported disclosures.

Both obesity and HIV infection are characterized by a state of chronic inflammation associated with increased morbidity and mortality. This review aims to assess the available literature on immune dysregulation in obesity and people with HIV infection (PWH).A systematic review of peer-reviewed literature.We conducted a systematic literature search of PubMed, Embase, Scopus, and international conference abstracts for articles on the epidemiology of obesity in the general population and in PWH and the pathogenesis of obesity with a focus on inflammation and immune activation.Of the 631 articles selected after title review, 490 met the inclusion criteria and 90 were included in the final selection. The selected studies highlight the increasing prevalence of obesity in PWH and a substantial role for antiretroviral treatment (ART) in its development. Pathogenesis of obesity and its associated inflammation derives from disturbances in adipose tissue (AT) immune function, focused on T-cell and macrophage function, with a switch to pro-inflammatory immune phenotype and resulting increases in pro-inflammatory chemokines, which contribute to the development of metabolic syndrome. Although dysregulation of these pathways is seen in both obesity and HIV, there remains a lack of human studies on AT inflammation in HIV.Obesity is an emerging comorbidity in PWH, with a substantial overlap in immune dysregulation patterns seen in both conditions. How this immune dysfunction impacts on development of metabolic complications for both obesity and HIV infection, and whether targeting of AT-derived inflammation will improve outcomes in PWH requires further study.

Background We aimed to describe the clinical presentation of individuals presenting with prolonged recovery from coronavirus disease 2019 (COVID-19), known as long COVID. Methods This was an analysis within a multicenter, prospective cohort study of individuals with a confirmed diagnosis of COVID-19 and persistent symptoms >4 weeks from onset of acute symptoms. We performed a multiple correspondence analysis (MCA) on the most common self-reported symptoms and hierarchical clustering on the results of the MCA to identify symptom clusters. Results Two hundred thirty-three individuals were included in the analysis; the median age of the cohort was 43 (interquartile range [IQR], 36–54) years, 74% were women, and 77.3% reported a mild initial illness. MCA and hierarchical clustering revealed 3 clusters. Cluster 1 had predominantly pain symptoms with a higher proportion of joint pain, myalgia, and headache; cluster 2 had a preponderance of cardiovascular symptoms with prominent chest pain, shortness of breath, and palpitations; and cluster 3 had significantly fewer symptoms than the other clusters (2 [IQR, 2–3] symptoms per individual in cluster 3 vs 6 [IQR, 5–7] and 4 [IQR, 3–5] in clusters 1 and 2, respectively; P Conclusions Clusters of symptoms are evident in long COVID patients that are associated with functional impairments and may point to distinct underlying pathophysiologic mechanisms of disease.

The aims of the study were to describe the prevalence of obesity in the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) cohort, to identify demographic, clinical and HIV-specific factors associated with obesity, and to characterize the association between obesity and sociodemographic, clinical and HIV-specific factors and quality of life (QoL).A cross-sectional analysis was carried out of baseline data from the three groups ["older" people with HIV infection (PWH) aged ≥ 50 years, "younger" PWH aged50 years and HIV-negative controls aged ≥ 50 years] within the POPPY cohort. Obesity was defined as a body mass index (BMI) 30 kg/mA total of 1361 subjects were included in the study, of whom 335 (24.6%) were obese. The prevalence of obesity was higher in controls (22.3%) than in older (16.8%) and younger (14.2%) PWH, with no differences between the two groups of PWH. Factors associated with obesity were older age, female gender, black African ethnicity and alcohol consumption. Recreational drug use and a higher current CD4 T-cell count (in PWH) were associated with lower and higher odds of being obese, respectively. The presence of obesity was associated with worse physical health QoL scores, higher odds of having cardiovascular disease, type 2 diabetes and hypertension, but lower odds of having osteopenia/osteoporosis, irrespective of HIV status.Despite a lower prevalence of obesity in PWH, specific subgroups (women, people of black African origin and older people) were more likely to be obese, and negative health consequences of obesity were evident, regardless of HIV status. Whether targeted preventive strategies can reduce the burden of obesity and its complications in PWH remains to be determined.

Monitoring systems have been developed during the COVID-19 pandemic enabling clinicians to remotely monitor physiological measures including pulse oxygen saturation (SpOA remote monitoring system was used to monitor 209 patients diagnosed with COVID-19 in the period following hospital discharge. This system consisted of a patient-facing app paired with a Bluetooth-enabled pulse oximeter (measuring SpOOver the 10-day monitoring period, mean SpOResults indicate that SpO

Measurement of quantitative antibody responses are increasingly important in evaluating the immune response to infection and vaccination. In this study we describe the validation of a quantitative, multiplex serologic assay utilising an electrochemiluminescence platform, which measures IgG against the receptor binding domain (RBD), spike S1 and S2 subunits and nucleocapsid antigens of SARS-CoV-2. The assay displayed a sensitivity ranging from 73-91% and specificity from 90 to 96% in detecting previous infection with SARS-CoV-2 depending on antigenic target and time since infection, and this assay highly correlated with commercially available assays. The within-plate coefficient of variation ranged from 3.8-3.9% and the inter-plate coefficient of variation from 11-13% for each antigen.

Objectives Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. Trial design This trial is a phase 2, open label, two-stage, multicentre, randomised trial. Participants Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent’s University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 μgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. Intervention and comparator Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose – 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose – 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose – 4mg/kg, infused over 60 minutes). Main outcomes The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. Randomisation Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. Blinding This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. Numbers to be randomised In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. Trial Status The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent’s University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. Trial registration COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. Full protocol The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

BackgroundWhole-genome sequencing (WGS) of SARS-CoV-2 laboratory-confirmed cases can provide insights into viral transmission and genetic diversity at a population level. However, less is known about the impact of non-pharmaceutical interventions (NPIs), including ‘lockdowns’, on circulating SARS-CoV-2 lineages and variants of concern, the relative contribution of travel to re-emergence of pandemic waves within communities or how different lineages and variants contribute to disease severity.MethodsWe have conducted an analysis within a prospective, multicentre observational study of individuals attending four hospitals in the South-East of Ireland with COVID-19. Samples underwent WGS from which lineages and variants were assigned, lineage frequency was plotted over time and phylogenetic analysis was employed to determine the origin of variants detected post-lockdown. Univariate and multivariate analyses assessed relationships between viral lineage/variant and COVID-19 disease severity.ResultsWe analysed 225 genome sequences across two SARS-CoV-2 waves, 134 (59.6%) from wave 1 (March to June) and 91 (40.4%) from wave 2 (July to December), representing 15.2% of COVID-19 admissions to these hospitals during the sampling periods. Four variants (B.1.1.162, B1.1.70, B.1.1.267 and B.1.1) comprised 68% of variants detected during wave 1. Of these variants, only a single B.1.1.70 sequence was detected in wave 2, while the B.1.177 lineage emerged and contributed to 82.3% of lineages detected. Phylogenetic analysis suggested multiple introductions of wave 2 variants from outside Ireland. We found no consistent association between SARS-CoV-2 lineages and disease severity.ConclusionsThese data suggest elimination of common SARS-CoV-2 lineages from hospitalised cases associated with effective NPIs and that importation of new viral variants through travel was a significant contributor to the re-emergence of the pandemic in the second wave in Ireland. Our findings highlight the importance of genomic surveillance in identifying circulating viral genetic diversity and variants of concern and, also, modelling the disease burden of SARS-CoV-2.

Background Healthcare workers are encouraged annually to get vaccinated against influenza. This year in view of COVID-19 pandemic, attitudes of HCWs towards vaccination are particularly important. A cross-sectional study was completed to understand how to best encourage and facilitate the vaccination of HCWs based on the previous years’ findings. Methods An online survey was disseminated to all hospital staff via electronic channels. The clinical audit sphinx software was used for data collection and analysis. Results The total number of responses was n = 728, almost double the rate from 2018 (N = 393). A total of 78% (N = 551) of participants were vaccinated last year. A total of 94% (N = 677) of participants reported their intention to be vaccinated this year. The main barriers listed were being unable to find time (32%, N = 36), side effects (30%, N = 33) and thinking that it does not work (21%, N = 23). The most popular suggestions for how to increase uptake were more mobile immunisation clinics (72%, N = 517) and more information on the vaccine (50%, N = 360). A total of 82% of participants (N = 590) agreed that healthcare workers should be vaccinated, with 56% (N = 405) agreeing that it should be mandatory. Of the participants who were not vaccinated last year (N = 159), 40% (N = 63) agreed that COVID-19 had changed their opinion on influenza immunisation with a further 11% (N = 18) strongly agreeing. Discussion In light of the increasing number of survey participants, more staff were interested in flu vaccination this year than ever before. The COVID-19 pandemic has had some influence on staff’s likelihood to be vaccinated. Feasibility of immunisation and education posed the largest barriers to HCW vaccination.

BackgroundAlthough reports suggest that most individuals with COVID-19 develop detectable antibodies post infection, the kinetics, durability, and relative differences between IgM and IgG responses beyond the first few weeks after symptom onset remain poorly understood.MethodsWithin a large, well-phenotyped, diverse, prospective cohort of subjects with and without SARS-CoV-2 PCR-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity and specificity, relationship with disease severity and mapped the kinetics of antibody responses over time using generalised additive models.ResultsWe analysed 1,001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1-47.1%) early (80% after 10 days. IgM positivity increased earlier than IgG-targeted assays but positivity peaked between day 32 and 38 post onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analysed, with more rapid decline observed with IgM. Early (ConclusionsThis study suggests that post-infectious antibody responses in those with confirmed COVID-19 begin to decline relatively early post infection and suggests a potential role for higher IgM levels early in infection predicting subsequent disease severity.

We describe the expansion and adaptation of a frailty response team to assess older people in their usual place of residence. The team had commenced a weekend service to a limited area in February 2020. As a consequence of demand related to the COVID-19 pandemic, we expanded it and adapted the model of care to provide a 7-day service to our entire catchment area. Five hundred and ninety two patient reviews have been completed in the first 105 days of operation with 43 patients transferred to hospital for further investigation or management following assessment.

Hydroxychloroquine has attracted considerable interest as a potential therapy for COVID-19 infection due to its immunomodulatory effects and reported efficiency in clearing upper airways of the virus. Recent data have also suggested the treatment of COVID-19 patients with hydroxychloroquine and azithromycin to cure the associated infection. The objective of this trial is to assess the efficacy of standard of care (SOC) plus hydroxychloroquine monotherapy or SOC plus a combination of hydroxychloroquine and azithromycin in subjects with non-critical, SARS-CoV-2 PCR-positive infection not requiring immediate resuscitation or ventilation but who have evidence of clinical decline compared to SOC alone.

COVID-19, an illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, has spread rapidly worldwide, resulting in significant mortality and placing major strain on healthcare systems. Although the clinical course is variable, 1 in 5 patients will require hospitalisation for management with older age and the presence of comorbidities increasing the risk of more severe disease [1–3]. The median time from first onset of symptoms to development of acute respiratory distress syndrome in those who progress to severe disease is estimated to be 8.0 days [4]. Currently, there is an increased pressure on acute hospital-based care and a corresponding demand for novel solutions to address this. One approach is to utilise telemedicine to facilitate efficient and safe discharge from acute hospitals. Due to the highly contagious nature of SARS-CoV-2, routine or urgent clinical follow-up is difficult within the primary care, or community setting. Hence, the ability to remotely monitor symptoms and vital signs in mild to moderate cases may be one mechanism to alleviate the pressures on healthcare systems, and we present here some initial data on one such approach., Remote monitoring of oxygen saturation in cases of COVID-19 pneumonia may facilitate discharge relieving burden on bed demand and allowing safe follow up for this disease in which the sequelae are unknown.

Background Pneumococcal and influenza vaccination rates have been suboptimal in studies of immunosuppressed patients. We aimed to assess barriers to and increase rates of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and influenza vaccination in this group. Methods In 2017, Rheumatology outpatients completed an anonymous questionnaire recording vaccination knowledge, status and barriers. Simultaneously, a low-cost multifaceted quality improvement (QI) intervention was performed. All outpatients on oral steroids, immunosuppressant conventional synthetic disease modifying antirheumatic drugs (csDMARDs) or biologics (bDMARDs) were included in the study. In 2018, post-intervention, the clinic was re-assessed. Demographics, diagnosis, medications, smart phone access and willingness to use this for vaccination reminders were assessed for independent vaccination predictors using binary logistic regression analysis. Results 425 patients were included (72.6% rheumatoid arthritis, 74% women, 45.6% ≥60 years old). From 2017-2018, vaccination rates increased for PPSV23 {41.0% to 47.2% (p = 0.29)} and influenza {61.8% to 62.1% (p = 0.95)}. The most common reason for non-vaccination was lack of awareness. Following the intervention, this decreased for influenza (36.7% to 34.2%) and PPSV23 (82.1% to 76.4%). General Practitioners performed most vaccinations, only 3.6% were delivered in hospital. Significant predictors of PPSV23 vaccination were older age {≥80 years had an OR 41.66 (95% CI 3.69-469.8, P = 0.003), compared to ≤ 39 years}, bDMARD use (OR 2.80, 95% CI 1.24-6.32, P = 0.013) and adequate influenza vaccination (OR 9.01, 95% CI 4.40-18.42, P < 0.001). Up to date PPSV23 vaccination (OR 8.93, 95% CI 4.39-18.17, P < 0.001) predicted influenza vaccination. Conclusion PPSV23 and influenza vaccination rates were suboptimal and increased marginally. Point-of-care vaccination may be more effective. Disclosures K. Murray: None. C. Low: None. F. Young: None. A. O'Rourke: None. I. Callanan: None. E. Feeney: None. D. Veale: None.

Background: Although reports suggest that most individuals with COVID-19 develop detectable antibodies post infection, the kinetics, durability, and relative differences between IgM and IgG responses beyond the first few weeks after symptom onset remain poorly understood. Methods: Within a large, well-phenotyped, diverse, prospective cohort of subjects with and without SARS-CoV-2 PCR-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity and specificity, relationship with disease severity and mapped the kinetics of antibody seropositivity and antibody levels over time using generalised additive models. Findings: We analysed 1,001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1-47.1%) early ( 80% after 10 days. IgM positivity increased earlier than IgG-targeted assays but positivity peaked between day 32 and 38 post onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analysed, with more rapid decline observed with IgM. Early (

We investigated the real-world effectiveness of interferon-free regimens for the treatment of patients with compensated cirrhosis infected with hepatitis C virus (HCV).Using the Irish national HCV treatment registry, the effectiveness and safety of interferon-free regimens for HCV-infected patients treated between April 2015 and August 2016, was determined.A SVR12 was achieved in 86% of subjects treated with sofosbuvir/ledipasvir ± ribavirin (SOF/LDV±RBV), 93% treated with paritaprevir, ombitasvir and ritonavir combined with dasabuvir ± ribavirin (3D±RBV) and 89% treated with sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV). The discontinuation rate was 5% and the on-treatment mortality rate was 1%.The availability of interferon-free regimens represents a significant breakthrough for the treatment of HCV infection. Treatments options, with high SVR12 rates, are now available for patients with compensated cirrhosis who were unsuitable for treatment with interferon-based regimens. Data obtained from studies conducted in real world practice provide robust information fundamental for input into future economic evaluations for agents used for the treatment of HCV infection.

Pneumococcal and influenza vaccination rates have been suboptimal in studies of immunosuppressed patients. We aimed to assess barriers to and increase rates of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and influenza vaccination in this group. The primary endpoint was a statistically significant increase in adequate PPSV23 and influenza vaccination.In 2017, rheumatology outpatients completed an anonymous questionnaire recording vaccination knowledge, status, and barriers. Simultaneously, a low-cost multifaceted quality improvement (QI) intervention was performed. All outpatients on oral steroids, immunosuppressant conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or biologics disease-modifying antirheumatic drugs (bDMARDs) were included in the study. In 2018, post-intervention, the clinic was re-assessed. Demographics, diagnosis, medications, smart phone access, and willingness to use this for vaccination reminders were assessed for independent vaccination predictors using binary logistic regression analysis.Four hundred twenty-five patients were included (72.6% rheumatoid arthritis, 74% women, 45.6% ≥ 60 years old). From 2017 to 2018, PPSV23 vaccination rates changed from 41.0 to 47.2% (P = 0.29) and influenza from 61.8 to 62.1% (P = 0.95). The most common reason for non-vaccination was lack of awareness. Following the intervention, this changed for influenza (36.7 to 34.2%) and PPSV23 (82.1 to 76.4%). General practitioners performed most vaccinations, only 3.6% were delivered in the hospital. Significant predictors of PPSV23 vaccination were older age {≥ 80 years had an OR 41.66 (95% CI 3.69-469.8, P = 0.003), compared with ≤ 39 years}, bDMARD use (OR 2.80, 95% CI 1.24-6.32, P = 0.013), and adequate influenza vaccination (OR 9.01, 95% CI 4.40-18.42, P 0.001). Up-to-date PPSV23 vaccination (OR 8.93, 95% CI 4.39-18.17, P 0.001) predicted influenza vaccination.PPSV23 and influenza vaccination rates were suboptimal. The intervention did not cause a statistically significant change in vaccination rates. Point-of-care vaccination may be more effective.Key Points• Low vaccination rates amongst immunosuppressed inflammatory arthritis outpatients• Less than 5% of vaccinations occurred in hospital• There was no statistically significant difference in the rates of adequate PPSV23 (41.0 to 47.2%) or influenza (61.8 to 62.1%) vaccination following our intervention.

Background: Disease-related immune dysfunction and medications cause immunosuppression in inflammatory arthritis (IA)(1). EULAR and Centers for Disease Control (CDC) recommend influenza and 23-valent pneumococcal polysaccharide (PPSV23) vaccination. Previous studies show suboptimal coverage. Objectives: To increase influenza (annual) and PPSV23 (5 yearly) vaccination in immunosuppressed IA patients through a multifaceted quality improvement intervention. Methods: Between April and September 2017, IA patients completed an anonymous paper 23 question worksheet recording demographics, medical history, medications, vaccination knowledge, status and barriers. All patients on oral steroids, bDMARDs or immunosuppressant cDMARDs were included. Simultaneously, we introduced staff education sessions, point-of-care paper “Arthritis and Infection Worksheets” and “Vaccination Advice Letters”. In 2018, the clinic was re-assessed. Results: 163 patients met inclusion criteria in 2017 and 262 in 2018. Patients were typical of an IA clinic (74% women, 45.4%≥60 years old, 72.7% had RA, 61.1% on cDMARDs, 53.6% on methotrexate, 46.6% on bDMARDs, 23.1% on cDMARD plus bDMARD). In 2017, 104 (65.4%) knew of the increased infectious risk of IA. In 2018, 168 (65.6%) were aware. Awareness of infection risk with medications increased from 111 (69.8%) to 172 (66.9%). Table 1 shows vaccination rates. PPSV23 rates increased from 41.0% to 47.2% (P value=0.29. Pearson Chi squared), and influenza from 61.8% to 62.1% (P value=0.95, Pearson Chi squared). Vaccination awareness was higher for influenza (Table 2). Most patients were informed of requirements and vaccinated by general practitioners (GPs), with Conclusion: This study shows suboptimal vaccination awareness and uptake. Our interventions increased PPSV23 and influenza vaccination rates. There is debate about who is responsible for vaccinations. Guidelines advocate specialists sharing responsibility with GPs. 57% of rheumatologists considered GPs responsible (2). Perhaps, we should take a more active approach. References [1] Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis & Rheumatism.2002;46(9):2287-93 [2] McCarthy EM, Azeez MA, Fitzpatrick FM, Donnelly S. Knowledge, attitudes, and clinical practice of rheumatologists in vaccination of the at-risk rheumatology patient population. JCR: Journal of Clinical Rheumatology. 2012;18(5):237-41 Disclosure of Interests: Kieran Murray Grant/research support from: Newman Research Fellowship (Abbvie), Francis Young: None declared, Candice Low: None declared, Anna O’Rourke: None declared, Ian Callanan: None declared, Eoin Feeney: None declared, Douglas Veale: None declared

BACKGROUND: Coinfection with human immunodeficiency virus (HIV) accelerates hepatitis C virus (HCV)–related liver fibrosis. Macrophages are triggered during both viral infections and are critical in liver inflammation/fibrogenesis. Liver fibrosis strongly associates with serum soluble CD163 (sCD163, a macrophage activation marker); comprehensive evaluation in HIV/HCV coinfection is lacking. METHODS: We retrospectively analyzed sCD163 (enzyme-linked immunosorbent assay) and hepatic CD163 (immunofluorescent CD163/CD68 costaining) in patients infected with HIV/HCV, HCV, or HIV, pre– and post–antiviral therapy. RESULTS: sCD163 was significantly higher in HIV/HCV compared to either monoinfection, and decreased following successful antiviral therapy, although did not fully normalize. In HIV/HCV, sCD163 was associated with necroinflammation, Ishak fibrosis scores, and noninvasive fibrosis scores. We observed a novel trend whereby sCD163 levels progressively increase with increasing Ishak fibrosis score, peaking at stage 4, above which levels plateaued. Periportal CD163(+) macrophage frequency was also higher with increasing fibrosis score. When stratified by fibrosis stage, sCD163 levels were higher in HIV/HCV than HCV but only in individuals with mild to moderate fibrosis. CONCLUSIONS: In HIV/HCV, increasing sCD163 levels accompanied periportal CD163(+) macrophage enrichment in mild to moderate fibrosis, but not in established cirrhosis, suggesting that sCD163 is a dynamic biomarker of fibrogenesis rather than accumulated fibrosis. Our findings implicate HIV-related macrophage activation in accelerated fibrosis progression in HIV/HCV coinfection.

Objectives Monocyte activation, endothelial dysfunction and platelet activation all potentially contribute to the increased risk of cardiovascular disease (CVD) reported in those with HIV-1 infection. To date, no study has examined how initiation of antiretroviral therapy (ART) affects markers of all three processes. We aimed to compare markers of monocyte, endothelial and platelet function between untreated HIV-positive subjects and HIV-negative controls and to examine the early effects of ART initiation on these markers. Methods We measured monocyte [soluble CD14 (sCD14) and sCD163], endothelial [von Willebrand factor (vWF), intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1)] and platelet [soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L) and soluble glycoprotein VI (sGPVI)] biomarkers before and at weeks 4 and 12 post ART initiation in HIV-positive and well-matched HIV-negative controls. Results We examined 40 subjects, 25 HIV-positive subjects and 15 controls, with a median age of 34 years [interquartile range (IQR) 31, 40 years], of whom 60% were male and 47.5% Caucasian. Pre-ART, all biomarkers (monocyte, endothelial and platelet) were significantly higher in HIV-positive patients versus controls (all P

A 53-year-old woman was diagnosed with hypopituitarism following an acute presentation with cardiac tamponade and hyponatraemia, having recently been investigated for a pericardial effusion. Secondary hypothyroidism is a rare cause of pericardial effusion and tamponade, but an important differential to consider. Management requires appropriate hormone replacement and, critically, a low threshold for commencing stress dose steroids. Clinical signs classically associated with cardiac tamponade are frequently absent in cases of tamponade due to primary and secondary hypothyroidism, and the relatively volume deplete state of secondary hypoadrenalism in hypopituitarism may further mask an evolving tamponade, as the rise in right atrial pressure is less marked even in the presence of large effusion. Our case demonstrates the importance of a high index of suspicion for cardiac tamponade in this patient cohort, even in the absence of clinical signs, and for measuring both thyroid-stimulating hormone and thyroxine levels when evaluating a pericardial effusion.

The immuno-pathogenic mechanisms of chronic hepatitis C virus (HCV) infection remain to be elucidated and pose a major hurdle in treating or preventing chronic HCV-induced advanced liver diseases such as cirrhosis. Macrophages are a major component of the inflammatory milieu in chronic HCV–induced liver disease, and are generally derived from circulating inflammatory monocytes; however very little is known about their role in liver diseases. To investigate the activation and role of macrophages in chronic HCV–induced liver fibrosis, we utilized a recently developed humanized mouse model with autologous human immune and liver cells, human liver and blood samples and cell culture models of monocyte/macrophage and/or hepatic stellate cell activation. We showed that M2 macrophage activation was associated with liver fibrosis during chronic HCV infection in the livers of both humanized mice and patients, and direct-acting antiviral therapy attenuated M2 macrophage activation and associated liver fibrosis. We demonstrated that supernatant from HCV-infected liver cells activated human monocytes/macrophages with M2-like phenotypes. Importantly, HCV-activated monocytes/macrophages promoted hepatic stellate cell activation. These results suggest a critical role for M2 macrophage induction in chronic HCV-associated immune dysregulation and liver fibrosis.

Objective: No randomized study has prospectively followed subcutaneous adipose tissue mitochondrial DNA (mtDNA) changes when starting thymidine nucleoside reverse transcriptase inhibitors (tNRTIs). Design: The Metabolic Effects of DIfferent CLasses of AntiretroviralS study randomized HIV-positive, treatment-naive male participants to start lopinavir/ritonavir (LPVr) with either zidovudine/lamivudine (ZDV/3TC) or nevirapine (NVP). Methods: Regional body fat was assessed by dual energy x-ray absorptiometry and abdominal computed tomography at months 0, 3, 12, 24 and 36. In a molecular substudy, subcutaneous adipose tissue (SAT) biopsies were taken, with mtDNA quantified by quantitative PCR. Data were analyzed using repeated measures linear regression analyses. Results: Of 50 participants recruited (23 to LPVr/ZDV/3TC), 48 started therapy, and 37 participants (19 on LPVr/ZDV/3TC) enrolled in the substudy. At 36 months, the LPVr/ZDV/3TC group had significantly lower limb fat [6.4 kg (0.26) versus 7.3 kg (0.31), P = 0.017] and a trend toward lower abdominal SAT compared to the LPVr/NVP group [131cm(2) (6.86) versus 146 cm(2) (6.33), P = 0.097]. Over 36 months, mtDNA declined in the LPVr/ZDV/3TC group [mtDNA region 1: -190 (95) copies/cell, P = 0.053, region 2: -269 (106) copies/cell, P = 0.016] but not within the LPVr/NVP group [region 1: +28 (99) copies/cell, P = 0.78, region 2: +51 (111) copies/cell, P = 0.65, between-group difference P < 0.01 for both measurements]. mtDNA was significantly lower in the LPVr/ZDV/3TC group at 36 months. Conclusion: This is the first randomized study to prospectively demonstrate reductions in SAT mtDNA in patients initiating ZDV/3TC-containing antiretroviral therapy (ART) but not in those initiating nucleoside reverse transcriptase inhibitor-sparing ART containing NVP and protease inhibitor. That reductions in SAT mtDNA were also accompanied by lower limb fat suggests that use of ART not containing ZDV/3TC may help prevent development of peripheral lipoatrophy. (c) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Objective The aim of the study was to evaluate the predictive value of clinical and molecular risk factors, including peripheral blood mononuclear cell (PBMC) mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA), for the development of lactic acidosis (LA) and symptomatic hyperlactataemia (SHL). Methods In a substudy of a large multicentre, randomized trial of three antiretroviral regimens, all containing didanosine (ddI) and stavudine (d4T), in antiretroviral-naive, HIV-1-infected patients, patients with LA/SHL (‘cases’) were compared with those without LA/SHL in a univariate analysis, with significant parameters analysed in a multivariate model. In a molecular substudy, PBMC mtDNA and mtRNA from cases and matched controls at baseline and time of event were examined. Results In 911 subjects followed for a median of 192 weeks, 24 cases were identified (14 SHL and 10 LA). In univariate analysis, cases were more likely to be female (P=0.05) and to have a high body mass index (BMI) (P=0.02). In multivariate analyses, only BMI remained an independent predictor of the development of LA/SHL (P=0.03). Between cases and controls there was no significant difference in mtDNA copy number at baseline (389 vs. 411 copies/cell, respectively; P=0.60) or at time of event (329 vs. 474 copies/cell, respectively; P=0.21), in the change in mtDNA copy number from baseline to event (−65 vs. +113 copies/cell, respectively; P=0.12), in mtRNA expression at baseline or time of event, or in the change in mtRNA expression from baseline to event. Conclusion The development of LA/SHL was associated with increased BMI, but PBMC mtDNA and mtRNA did not predict LA/SHL. This demonstrates the ineffectiveness of routine measurement of PBMC mtDNA in patients on ddI and d4T as a means of predicting development of LA/SHL.

Effective highly active antiretroviral therapy (HAART) for human immunodeficiency virus-1 (HIV) infection has led to marked improvement in life-expectancy for those infected with HIV. Despite reductions in the incidence of AIDS with effective treatment, patients continue to experience considerable morbidity and mortality from non-AIDS illness such as premature cardiovascular disease, liver failure and renal failure. These morbidities, particularly premature cardiovascular disease, are thought to be related to a combination of the effects of an ageing HIV-infected population coupled with long-term effects of HIV infection and antiretroviral therapy (ART). One of the principle drivers behind the well documented increase in the risk of cardiovascular disease in HIV-infected patients is dyslipidemia. This review will focus on the clinical presentation of HIV and ART-associated dyslipidemia, what is known of its patho-physiology, including associations with use of specific antiretroviral medications, and suggest screening and management strategies.

Oritavancin is a novel lipoglycopeptide with activity against Gram-positive organisms including streptococci, methicillin-resistant Staphylococcus aureus, vancomycin-resistant S aureus (VRSA), and vancomycin-resistant enterococci (VRE) [1–3]. The US Food and Drug Administration approved oritavancin as a single intravenous dose of 1200 mg for the treatment of acute bacterial skin and skin structure infections on the basis of 2 clinical trials demonstrating noninferiority compared with vancomycin [4, 5]. There are limited options for treatment of serious VRE infections. Monotherapy with daptomycin or tigecycline or linezolid may be sufficient in some cases, but combination therapy is often indicated for severe or complicated infections such as endocarditis. Several antibiotic combinations have been used in isolated case reports with some efficacy, including the following: high-dose ampicillin with an aminoglycoside [6], ampicillin with ceftriaxone or imipenem [7, 8], high-dose daptomycin with ampicillin and gentamicin [9] or with gentamicin and rifampin [10], daptomycin with tigecycline [11, 12], quinupristin-dalfopristin with high-dose ampicillin [13] or doxycycline and rifampin [14], and linezolid with tigecycline [15]. The limited efficacy, limited susceptibility, and extensive toxicities with many of these agents and combinations present barriers to effective treatment. Additional treatment options for VRE endocarditis would be valuable. Although oritavancin has been shown to have in vitro activity against some isolates of VRE, clinical data are lacking. We describe the first use of a prolonged course of oritavancin in the treatment of a serious VRE infection, prosthetic valve endocarditis.

PURPOSE OF REVIEW Coinfection with hepatitis C virus (HCV) and HIV is a significant public health problem worldwide. The broad spectrum antivirals interferon-alpha (IFN) and ribavirin (RBV) have lower sustained virologic response rates in HIV-HCV coinfection compared with HCV monoinfection, with significant associated toxicities and prolonged treatment courses. The recent availability of direct acting antivirals (DAA) has transformed the treatment of HCV, with the opportunity of cure available for most patients with much more tolerable regimens. These regimens are now being studied in HIV-HCV coinfection. RECENT FINDINGS DAA-based regimens for HIV-HCV coinfection have shown excellent efficacy, with cure rates similar to HCV monoinfection. Either in combination with IFN and RBV, or in 'IFN-free' regimens, cure rates of over 90% are the goal for all HIV-HCV-infected individuals. Data are excellent in genotype 1 infection, but further data on genotype 2-6 are required. These regimens have been shown to be cost-effective in HCV monoinfection, and are likely to be cost-effective in HIV-HCV coinfection. Nonetheless they remain expensive. Recent guidelines have identified coinfected patients as a group for prioritization for treatment, regardless of fibrosis stage. Earlier treatment of those likely to transmit HCV is also recommended. SUMMARY With the use of DAA, HCV infection in HIV should be curable for most patients, and HIV-infected patients should be prioritized for treatment. The optimal treatment regimens for some genotypes have yet to be determined. The significant cost of DAA-containing regimens is likely to significantly impair their widespread use for the short to medium term, even in well resourced settings, and those with more advanced liver disease are likely to access them first.

Hepatitis C virus (HCV), a single-stranded RNA virus, infects nearly 180 million people worldwide. The treatment of this chronic infection is currently undergoing one of the greatest ‘sea changes’ experienced in modern medicine in that a disease to which millions of deaths have been attributed globally could be virtually eliminated in our lifetime. This shift is due to the replacement of difficult-to-tolerate, injectable interferon-based therapies, given for up to a year with moderate chances of success, by all oral “direct acting antivirals” (DAA), specifically designed to act against HCV proteins including nonstructural (NS)3/4A (a serine protease), NS5A (a viral protein essential for viral assembly and RNA replication) and NS5B (a RNA dependent RNA polymerase). These new medications have markedly increased cure rates (over 90% in most cases), with far fewer adverse effects and shortened courses of therapy[1–3]. At the heart of this change to a more focused model of treatment has been the use of polymerase chain reaction (PCR)-based technologies (among others) in the understanding of key components of the HCV life-cycle and the design of DAAs. In conjunction with this, there has been on ongoing roll-out and expansion of PCR-based assays in regular clinical use for HCV.

With the emergence of very potent antiretroviral regimens, the major limitation to the success of treatment is now the tolerability of drugs, which can ultimately affect adherence. It is important, therefore, to review the current understanding on antiretroviral drug toxicity, and examine key recent data that can inform the successful avoidance or management of such toxicities.A common theme of recent research has focussed on the genetic predisposition to important immediate side-effects, such as abacavir hypersensitivity, nevirapine hepatotoxicity, efavirenz neurotoxicity and hyperbilirubinemia with atazanavir. Long-term toxicities such as body-composition changes and hyperlipidemia have been more closely linked to thymidine analogues and certain protease inhibitors. The management of these toxicities has also been clarified by studies addressing switching antiretroviral drugs or specific treatments for metabolic syndromes.Recent data emphasize the need for the prevention of antiretroviral toxicity by the avoidance of some drugs in certain genetically predisposed populations or by the avoidance of entire classes if possible. In addition, recent studies emphasize the importance of ongoing research to determine the emergence of additional toxicities, as new drugs emerge and achieve widespread use.

We aimed to determine the contribution of high-density lipoprotein cholesterol (HDL-c) to cardiovascular disease (CVD) risk in a cohort of HIV-infected patients. The contribution of CVD risk factors to the predicted CVD risk was assessed. We estimated the degree of reclassification of CVD risk if HDL-c concentration was increased in all patients by 20 and 40%, respectively. After age, HDL-c contributed most to the overall cardiovascular risk. Increasing HDL-c by 20% and 40% reclassified six and 12 patients to lower CVD risk groups, respectively. In this cohort, HDL-c contributed more to cardiovascular risk than smoking, total cholesterol, systolic blood pressure (SBP) and sex.

ObjectivesFibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid.MethodsTen patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab.ResultsThe ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R2=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (pConclusionsThe ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.

HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection, and liver disease is a leading cause of non-AIDS-related mortality among HIV-infected patients. New insights have revealed multiple mechanisms by which HCV and HIV lead to accelerated disease progression, specifically that HIV infection increases HCV replication, augments HCV-induced hepatic inflammation, increases hepatocyte apoptosis, increases microbial translocation from the gut and leads to an impairment of HCV-specific immune responses. Treatment of HIV with antiretroviral therapy and treatment of HCV have independently been shown to delay the progression of fibrosis and reduce complications from end-stage liver disease among co-infected patients. However, rates of sustained virologic response with PEG-IFN and ribavirin have been significantly inferior among co-infected patients compared with HCV-monoinfected patients, and treatment uptake has remained low given the limited efficacy and tolerability of current HCV regimens. With multiple direct-acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.

BACKGROUND Human immunodeficiency virus (HIV) infection is associated with increased cardiovascular risk and reduced high-density lipoprotein cholesterol (HDL-c). In vitro, HIV impairs monocyte-macrophage cholesterol efflux, a major determinant of circulating HDL-c, by increasing ABCA1 degradation, with compensatory upregulation of ABCA1 messenger RNA (mRNA). METHODS We examined expression of genes involved in cholesterol uptake, metabolism, and efflux in monocytes from 22 HIV-positive subjects on antiretroviral therapy (ART-Treated), 30 untreated HIV-positive subjects (ART-Naive), and 22 HIV-negative controls (HIV-Neg). RESULTS HDL-c was lower and expression of ABCA1 mRNA was higher in ART-Naive subjects than in both ART-Treated and HIV-Neg subjects (both P < .01), with HDL-c inversely correlated with HIV RNA (ρ = -0.52; P < .01). Expression of genes involved in cholesterol uptake (LDLR, CD36), synthesis (HMGCR), and regulation (SREBP2, LXRA) was significantly lower in both ART-Treated and ART-Naive subjects than in HIV-Neg controls. CONCLUSIONS In vivo, increased monocyte ABCA1 expression in untreated HIV-infected patients and normalization of ABCA1 expression with virological suppression by ART supports direct HIV-induced impairment of cholesterol efflux previously demonstrated in vitro. However, decreased expression of cholesterol sensing, uptake, and synthesis genes in both untreated and treated HIV infection suggests that both HIV and ART affect monocyte cholesterol metabolism in a pattern consistent with accumulation of intramonocyte cholesterol.

Background Current or recent use of abacavir for treating human immunodeficiency virus type 1 (HIV-1) infection has been associated with increased rates of myocardial infarction (MI). Given the role of platelet aggregation in thrombus formation in MI and the reversible nature of the abacavir association, we hypothesized that patients treated with abacavir would have increased platelet reactivity. Methods In a prospective study in adult HIV-infected patients, we determined associations between antiretrovirals (ARVs), and in particular the nucleoside reverse transcriptase inhibitor abacavir, and platelet reactivity by measuring time-dependent platelet aggregation in response to agonists: adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), collagen, and epinephrine. Results Of 120 subjects, 40 were ARV-naive and 80 ARV-treated, 40 of whom were receiving abacavir. No consistent differences in platelet reactivity were observed between the ARV-naive and ARV-treated groups. In contrast, within the ARV-treated group, abacavir-treated subjects had consistently higher percentages of platelet aggregation upon exposure to ADP, collagen, and epinephrine (P = .037, P = .022, and P = .032, respectively) and had platelets that were more sensitive to aggregation upon exposure to TRAP (P = .025). Conclusions The consistent increases in platelet reactivity observed in response to a range of agonists provides a plausible underlying mechanism to explain the reversible increased rates of MI observed in abacavir-treated patients.

Insulin resistance (IR) was one of the first metabolic complications reported with highly active antiretroviral therapy for HIV infection. It continues to be of concern despite the introduction of newer antiretrovirals with safer metabolic profiles and is associated with inflammation and the development of diabetes mellitus. As the HIV-infected population ages, the prevalence of IR is likely to rise. Specific antiretrovirals can increase insulin resistance through two principal mechanisms, either directly by interfering with insulin signalling at the cellular level or indirectly as a consequence of defects in lipid metabolism (lipotoxocity) arising from antiretroviral toxicities such as the IR observed in those with HIV-associated lipodystrophy. There is considerable overlap between different antiretrovirals in their propensity to cause IR making it more difficult to attribute development of IR to a particular antiretroviral medication. In addition, in the setting of a generalised epidemic of obesity that exists in many populations worldwide, HIV-infected patients may be more prone to the consequences of antiretroviral-induced insulin resistance and diabetes mellitus. Optimal screening and treatment strategies for IR in treated HIV infection have not been established. In this article we review current opinion on insulin resistance in HIV and identify potential areas for future research.

Nucleoside reverse transcriptase inhibitors (NRTIs) are components of most current antiretroviral (ARV) regimens. Side effects arising from mitochondrial toxicity (MtT) induced by these drugs is a common reason why patients treated with NRTI change or discontinue therapy. These toxicities can be difficult to reverse, and on occasion can be life-threatening. The exact pathogenesis underlying NRTI-induced mitochondrial toxicity remains unclear, and likely differs for specific NRTI drugs. We review mitochondrial physiology, what is known about how NRTI cause MtT, and what areas of pathophysiology remain unclear. Using the example of HIV-associated lipodystrophy (HIVLD) as a model of clinical MtT we discuss management strategies and the potential for these toxicities to impact on future ARV development.

OBJECTIVES: Soluble CD163 (sCD163), a marker of Kupffer cell activation detectable in serum, correlates with inflammation and fibrosis in chronic viral hepatitis, but its role in nonalcoholic fatty liver disease is unknown. We hypothesized that sCD163 would correlate with nonalcoholic fatty liver disease activity and fibrosis. METHODS: Liver biopsies and serum were obtained from 145 obese subjects undergoing gastric bypass surgery. Subjects were divided into four groups based on fibrosis stage and nonalcoholic fatty liver disease activity score (NAS); Group 1: F0, NAS=0; Group 2: F