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Background: Sotrovimab, a monoclonal antibody, is among the approved therapies for coronavirus disease – 2019 (COVID-19). Sotrovimab binds to the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and inhibits virus attachment to human cells. Real-life experience about the effectiveness of Sotrovimab is limited. We aimed to evaluate the efficacy of Sotrovimab in preventing COVID-19 hospitalizations and other patient-related outcomes as well as the appropriateness of use in an academic hospital in Lebanon. Methodology: In this retrospective observational study, we included adult patients with positive test results for SARS-CoV-2 who received intravenous (IV) Sotrovimab at the American University of Beirut Medical Center (AUBMC) from November 2021 through March 2022. The data collected included patient demographics and comorbidities. Primary outcomes were hospitalization, deterioration after 24 hours, and death due to any cause up to 60 days after the Sotrovimab infusion. Secondary outcomes were progression to critical illness and adverse events. Results: A total of 62 subjects received Sotrovimab infusion at our hospital. More than 50% of the patients had a malignancy. About 77% of the cohort belonged to Tier 1 of the National Institutes of Health (NIH) criteria for Sotrovimab use, and 21% of the patients had clinical deterioration 24 hours after Sotrovimab infusion. The percentage of progression to critical disease was 9.7% and the mortality 6.5 %. Conclusion: Sotrovimab is effective against COVID-19 infection and prevents mortality in high-risk patients.

Introduction: Fosfomycin has re-emerged as a possible therapeutic alternative for the treatment of resistant bacterial pathogens. Its main mechanism of action is the inhibition of the initial step of cell wall synthesis and is active against both Gram-positive and Gram-negative bacteria. However, its clinical effectiveness against multidrug resistant bacteria remains largely unknown. Therefore, we aim to evaluate the clinical and microbiological effectiveness of intravenous fosfomycin as well as its safety in a tertiary care teaching hospital in Lebanon. Methodology: This is a retrospective chart review of adult patients who had presented to the hospital and were treated with intravenous fosfomycin for at least 24 hours for any type of infection between 2014 and 2019. Results: Among 31 episodes treated with intravenous fosfomycin, 68% had an overall favorable clinical response. In 84% of the episodes, fosfomycin was administered in combination with other antibiotics, commonly tigecycline. Of those with available cultures at end of therapy, 73% achieved microbiological success. No relapse was documented within 30 days of completion of therapy. In the episodes secondary to resistant pathogens, the rates of favorable clinical outcome and microbiological success at the end of therapy were 71% and 73%, respectively. Fosfomycin resistance developed in two cases and mild adverse events occurred in 65% of the episodes during the course of treatment. Conclusions: Fosfomycin is a safe and effective option in the treatment of multi-drug resistant infections. Nevertheless, careful stewardship is important to maintain its efficacy and to reduce the risk of selection of antimicrobial resistance.

Background: Despite multiple reports of increased incidence of bacterial respiratory tract infections following COVID-19 globally, the microbiology is not fully elucidated. In this study, we describe the incidence and microbiology of bacterial infections and the burden of multidrug resistant organisms (MDROs) in hospitalized COVID-19 patients with community-acquired pneumonia (CAP), non-ventilated hospital acquired pneumonia (NVHAP) or ventilator-associated pneumonia (VAP). To our knowledge, this is the first study that compares the microbiology of VAP and NVHAP in COVID-19 patients.Methods:This is a longitudinal retrospective cohort study conducted at the American University of Beirut Medical Center (AUBMC), a tertiary-care center in Lebanon. Adult patients with confirmed COVID-19 who were hospitalized between March 2020 and September 2021 were included. Only pathogens isolated within 42 days of positive SARS-CoV-2 tests were included. Bacterial isolates identified in hospital-acquired pneumonia (HAP) were divided into 3 groups based on the time of acquiring pneumonia after admission: hospital day 3-14, 15-28 and 29-42.Results:Out of 1674 patients admitted with COVID-19, 159 (9.5%) developed one or more respiratory infections. Overall, Gram-negative bacteria were predominant (83.5%) andS. maltophiliawas the most common pathogen (14.3%).S. aureusandHaemophilusspp. were implicated in most CAPs, whileK. pneumonia,S. maltophilia and E. coliwere the top culprits in HAP during hospital days 3-14, 15-28 and 29-42 respectively. Among 231 isolates obtained, 59 (25.5%) were MDROs, seen in higher proportion in HAP, especially among patients with prolonged hospital stay (> 4 weeks). Non-fermenter Gram-negative bacilli (NFGNB) (OR = 3.521, p-value = 0.000), particularlyS. maltophilia(OR = 3.236, p-value = 0.022), were significantly more implicated in VAP compared to NVHAP.Conclusions:COVID-19 patients hospitalized at AUBMC are at a slightly lower risk for bacterial respiratory infections compared to other studies. The pathogens varied according to the time since hospitalization. The burden of NFGNB and S.maltophiliais particularly high in COVID-19 VAP, indicating the need for further studies targeting these pathogens. A high rate of bacterial resistance was found which has important implications in guiding therapeutic decisions in COVID-19 patients who acquire bacterial infections.

Despite advances in antiretroviral treatment (ART), human immunodeficiency virus (HIV) continues to be a major global public health issue owing to the increased mortality rates related to the prevalent oncogenic viruses among people living with HIV (PLWH). Human papillomavirus (HPV) is the most common sexually transmitted viral disease in both men and women worldwide. High-risk or oncogenic HPV types are associated with the development of HPV-related malignancies, including cervical, penile, and anal cancer, in addition to oral cancers. The incidence of anal squamous cell cancers is increasing among PLWH, necessitating the need for reliable screening methods in this population at risk. In fact, the currently used screening methods, including the Pap smear, are invasive and are neither sensitive nor specific. Investigators are interested in circulatory and tissue micro ribonucleic acids (miRNAs), as these small non-coding RNAs are ideal biomarkers for early detection and prognosis of cancer. Multiple miRNAs are deregulated during HIV and HPV infection and their deregulation contributes to the pathogenesis of disease. Here, we will review the molecular basis of HIV and HPV co-infections and focus on the pathogenesis and epidemiology of anal cancer in PLWH. The limitations of screening for anal cancer and the need for a reliable screening program that involves specific miRNAs with diagnostic and therapeutic values is also discussed.

HIV remains one of the major causes of mortality and morbidity among women of reproductive age; given the risk of vertical transmission to the fetus, timely prevention, monitoring and management are imperative (Melaku et al. [2014]. Causes of death among females-investigating beyond maternal causes: A community-based longitudinal study.

Health systems have improved their abilities to identify, diagnose, treat and, increasingly, achieve viral suppression among people living with HIV (PLHIV). Despite these advances, a higher burden of multimorbidity and poorer health-related quality of life are reported by many PLHIV in comparison to people without HIV. Stigma and discrimination further exacerbate these poor outcomes. A global multidisciplinary group of HIV experts developed a consensus statement identifying key issues that health systems must address in order to move beyond the HIV field’s longtime emphasis on viral suppression to instead deliver integrated, person-centered healthcare for PLHIV throughout their lives.

Vaccines against COVID-19 have demonstrated a remarkable efficacy in decreasing hospitalisations and deaths; however, clinical trials leading to vaccine approvals did not include immunocompromised individuals such as patients receiving antineoplastic therapies. Emerging data suggest that patients on active anti-cancer therapy may have a reduced immune response to COVID-19 vaccination compared to the general population and may be at greater risk of COVID-19 infection as measures to reduce transmission in the community are relaxed. We report preliminary data from the American University of Beirut Medical Center in Lebanon demonstrating relatively low seroconversion rates. Of 36 patients on active anti-cancer therapy who had received two doses of vaccine, 17% were negative for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) anti-spike IgG. These results highlight the importance of maintaining strict precautionary measures against COVID-19 in patients on immunosuppressive treatment. There is an urgent need for active monitoring of immune response post-vaccination in prospective studies involving populations from diverse resource settings.

Background. EGDT (Early Goal Directed Therapy) or some portion of EGDT has been shown to decrease mortality secondary to sepsis and septic shock.Objective. Our study aims to assess the effect of adopting this approach in the emergency department on in-hospital mortality secondary to sepsis/septic shock in Lebanon.Hypothesis. Implementation of the EGDT protocol of sepsis in ED will decrease in-hospital mortality.Methods. Our retrospective study included 290 adult patients presenting to the ED of a tertiary center in Lebanon with severe sepsis and/or septic shock. 145 patients between years 2013 and 2014 who received protocol care were compared to 145 patients treated by standard care between 2010 and 2012. Data from the EHR were retrieved about patients’ demographics, medical comorbidities, and periresuscitation parameters. A multivariate analysis using logistic regression for the outcome in-hospital mortality after adjusting for protocol use and other confounders was done and AOR was obtained for the protocol use. 28-day mortality, ED, and hospital length of stay were compared between the two groups.Results. The most common infection site in the protocol arm was the lower respiratory tract (42.1%), and controls suffered more from UTIs (33.8%). Patients on protocol care had lower in-hospital mortality than that receiving usual care, 31.7% versus 47.6% (p=0.006) with an AOR of 0.429 (p =0.018). Protocol patients received more fluids at 6 and 24 hours (3.8 ± 1.7 L and 6.1 ± 2.1 L) compared to the control group (2.7 ± 2.0 L and 4.9 ± 2.8 L p=Conclusion. EGDT- (Early Goal Directed Therapy-) based sepsis protocol implementation in EDs decreases in-hospital mortality in developing countries. Adopting this approach in facilities with limited resources, ICU capabilities, and prehospital systems may have a pronounced benefit.

Background There are uncertainties about mitigating strategies for swimming-related activities in the context of the COVID-19 pandemic. There is an opportunity to learn from the experience of previous re-openings to better plan the future one. Our objectives are to systematically review the evidence on (1) the association between engaging in swimming-related activities and COVID-19 transmission; and (2) the effects of strategies for preventing COVID-19 transmission during swimming-related activities. Methods We conducted a rapid systematic review. We searched in the L·OVE (Living OVerview of Evidence) platform for COVID-19. The searches covered the period from the inception date of each database until April 19, 2021. We included non-randomized studies for the review on association of COVID-19 transmission and swimming-related activities. We included guidance documents reporting on the strategies for prevention of COVID-19 transmission during swimming-related activities. We also included studies on the efficacy and safety of the strategies. Teams of two reviewers independently assessed article eligibility. For the guidance documents, a single reviewer assessed the eligibility and a second reviewer verified the judgement. Teams of two reviewers extracted data independently. We summarized the findings of included studies narratively. We synthesized information from guidance documents according to the identified topics and subtopics, and presented them in tabular and narrative formats. Results We identified three studies providing very low certainty evidence for the association between engaging in swimming-related activities and COVID-19 transmission. The analysis of 50 eligible guidance documents identified 11 topics: ensuring social distancing, ensuring personal hygiene, using personal protective equipment, eating and drinking, maintaining the pool, managing frequently touched surfaces, ventilation of indoor spaces, screening and management of sickness, delivering first aid, raising awareness, and vaccination. One study assessing the efficacy of strategies to prevent COVID-19 transmission did not find an association between compliance with precautionary restrictions and COVID-19 transmission. Conclusions There are major gaps in the research evidence of relevance to swimming-related activities in the context of the COVID-19 pandemic. However, the synthesis of the identified strategies from guidance documents can inform public health management strategies for swimming-related activities, particularly in future re-opening plans.

Introduction: Infections caused by extensively-drug resistant (XDR) and pan-drug resistant (PDR) Klebsiella pneumoniae represent an emerging threat due to the high associated mortality. This study aimed to characterize two carbapenem resistant K. pneumoniae strains from the same patient, the first being PDR (referred to as IMP 1078b) and the second being XDR (referred to IMP 1078s) isolated from the same patient. Methodology: Antimicrobial susceptibility testing was done for the 2 K. pneumoniae isolates, followed by carbapenem/β-lactamase inhibitor combination assay, and fitness cost against cefepime and meropenem. Then, whole-genome sequence analysis was performed to decipher the molecular mechanisms behind the high level of resistance recorded in both isolates. Finally, qRT-PCR was done for β-lactam resistant genes. Results: This is the first report about a K. pneumoniae isolate harboring 47 antimicrobial resistance genes and having type IV pilli (Yersinia) and the fimbrial adherence determinant Stb (Salmonella) as virulence factors. Further analysis on both isolates are discussed within the article. Conclusion: The co-existence of a high number of antimicrobial resistant (AMR) genes and virulence factor genes may lead to a life threatening invasive and untreatable infection.

Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and is spread person-to-person through close contact. We aimed to investigate the effects of physical distance, face masks, and eye protection on virus transmission in health-care and non-health-care (eg, community) settings. Methods We did a systematic review and meta-analysis to investigate the optimum distance for avoiding person-to-person virus transmission and to assess the use of face masks and eye protection to prevent transmission of viruses. We obtained data for SARS-CoV-2 and the betacoronaviruses that cause severe acute respiratory syndrome, and Middle East respiratory syndrome from 21 standard WHO-specific and COVID-19-specific sources. We searched these data sources from database inception to May 3, 2020, with no restriction by language, for comparative studies and for contextual factors of acceptability, feasibility, resource use, and equity. We screened records, extracted data, and assessed risk of bias in duplicate. We did frequentist and Bayesian meta-analyses and random-effects meta-regressions. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. This study is registered with PROSPERO, CRD42020177047. Findings Our search identified 172 observational studies across 16 countries and six continents, with no randomised controlled trials and 44 relevant comparative studies in health-care and non-health-care settings (n=25 697 patients). Transmission of viruses was lower with physical distancing of 1 m or more, compared with a distance of less than 1 m (n=10 736, pooled adjusted odds ratio [aOR] 0·18, 95% CI 0·09 to 0·38; risk difference [RD] −10·2%, 95% CI −11·5 to −7·5; moderate certainty); protection was increased as distance was lengthened (change in relative risk [RR] 2·02 per m; pinteraction=0·041; moderate certainty). Face mask use could result in a large reduction in risk of infection (n=2647; aOR 0·15, 95% CI 0·07 to 0·34, RD −14·3%, −15·9 to −10·7; low certainty), with stronger associations with N95 or similar respirators compared with disposable surgical masks or similar (eg, reusable 12–16-layer cotton masks; pinteraction=0·090; posterior probability >95%, low certainty). Eye protection also was associated with less infection (n=3713; aOR 0·22, 95% CI 0·12 to 0·39, RD −10·6%, 95% CI −12·5 to −7·7; low certainty). Unadjusted studies and subgroup and sensitivity analyses showed similar findings. Interpretation The findings of this systematic review and meta-analysis support physical distancing of 1 m or more and provide quantitative estimates for models and contact tracing to inform policy. Optimum use of face masks, respirators, and eye protection in public and health-care settings should be informed by these findings and contextual factors. Robust randomised trials are needed to better inform the evidence for these interventions, but this systematic appraisal of currently best available evidence might inform interim guidance. Funding World Health Organization.

Background: Coronavirus disease 2019 (COVID-19) is spread person to person by virus through close contact The optimal person-person distance and use of facemas

While the number of HIV cases in the Middle East and North Africa region is low compared to other regions, recent studies show that incidence is increasing especially among high-risk populations; in particular, little is known about women and HIV in the region. Through semi-structured interviews with sexual healthcare providers and staff at non-governmental organisations, we sought to understand barriers to HIV testing among women in Lebanon. Using snowball sampling, key informants were recruited from greater Beirut (12 physicians, 9 non-governmental organisation staff). Data were analysed using a grounded theory framework. Findings identified barriers to HIV testing among women at each level of an adapted social-ecological model (i.e. social-cultural barriers, policy barriers, interpersonal healthcare provider barriers and intrapersonal barriers). Primary findings include the culture of sex as taboo; lack of sexual health education among women; fear of disclosing HIV testing and diagnosis; financial barriers linked to stigmatising insurance policies; and provider attitudes towards women. Findings can be used to inform HIV-related sexual health interventions at multiple levels for women in Lebanon and the greater region.

We are reporting the case of an 82-year-old Yemeni patient, renal transplant recipient who was admitted to our institution and who subsequently developed disseminated infection with Saprochaete capitata. This pathogenic fungus is rarely reported in patients with solid organ trans-plants. Saprochaete capitata is an emerging fungal pathogen, ubiquitously spread in the environment. This is the second case to our knowledge of infection with Saprochaete capitata in a renal transplant patient. Our patient was treated for multiple nosocomial infections with prolonged antibiotic courses. He succumbed to the infection with Saprochaete capitate after several weeks spent in the intensive care unit.

IntroductionProper strategies to minimise the risk of infection in individuals handling the bodies of deceased persons infected with 2019 novel coronavirus (2019-nCoV) are urgently needed. The objective of this study was to systematically review the literature to scope and assess the effects of specific strategies for the management of the bodies.MethodsWe searched five general, three Chinese and four coronavirus disease (COVID-19)–specific electronic databases. We searched registries of clinical trials, websites of governmental and other relevant organisations, reference lists of the included papers and relevant systematic reviews, and Epistemonikos for relevant systematic reviews. We included guidance documents providing practical advice on the handling of bodies of deceased persons with suspected or confirmed COVID-19. Then, we sought primary evidence of any study design reporting on the efficacy and safety of the identified strategies in coronaviruses. We included evidence relevant to contextual factors (ie, acceptability). A single reviewer extracted data using a pilot-tested form and graded the certainty of the evidence using the GRADE approach. A second reviewer verified the data and assessments.ResultsWe identified one study proposing an uncommon strategy for autopsies for patients with severe acute respiratory syndrome. The study provided very low-certainty evidence that it reduced the risk of transmission. We identified 23 guidance documents providing practical advice on the steps of handling the bodies: preparation, packing, and others and advice related to both the handling of the dead bodies and the use of personal protective equipment by individuals handling them. We did not identify COVID-19 evidence relevant to any of these steps.ConclusionWhile a substantive number of guidance documents propose specific strategies, we identified no study providing direct evidence for the effects of any of those strategies. While this review highlights major research gaps, it allows interested entities to build their own guidance.

Background Migrants may carry with them communicable and non communicable diseases as they move to the host country. Screening migrants may help in improving their health status and in preventing the spread of infections to the host population. Objective To identify and assess the quality of published practice guidelines addressing migrants’ health. Methods We included practice guidelines addressing migrants’ health at the clinical, public health or health systems levels. We searched Medline, Embase, the National Guideline Clearinghouse and the Canadian Medical Association’s Clinical Practice Guidelines Database. Two teams of two reviewers conducted in duplicate and independent manner study selection, data abstraction, assessment of the guideline quality (using the AGREE II instrument), and assessment of the quality of the reporting (using the RIGHT statement). Results Out of 2732 citations captured by the electronic search, we included 24 eligible practice guidelines, all addressing the level of post-arrival to the host country and published between 2011 and 2017. The majority of guidelines (57%) addressed non-communicable diseases, 95% addressed screening, while 52% addressed prevention and treatment respectively. The majority of the guidelines reported their funding sources. 86% used the GRADE approach as part of the development process. The included guidelines scored high on the majority of the items, and low on the following two domains of the AGREE II instrument: rigor of development and applicability. The mean number of the RIGHT checklist items met by the included guidelines was 27, out of a total of 35. Most of the guidelines were based on systematic reviews (95.6%). A minority of the included guidelines (26%) reported considering the values and preferences of the target populations or the costs and resource implications (30%) in the formulation of recommendations. Conclusion We identified 23 practice guidelines addressing migrants’ health, the majority of which addressed screening services. The vast majority of the captured guidelines targeted screening because the population of interest is migrants, meaning that the intention of the guidelines is to deal with additional factors than usual ones, such as prevalence of disease in country of origin, endemic diseases and others. The guidelines suffered limitations on two quality domains (rigor of development and applicability), and have room for improvement of their reporting.

Migrants, defined as individuals who move from their country of origin to another, account for 40% of newly-diagnosed cases of human immunodeficiency virus (HIV) in the European Union/European Economic Area (EU/EEA). Populations at high risk for HIV include migrants, from countries or living in neighbourhoods where HIV is prevalent, and those participating in high risk behaviour. These migrants are at risk of low CD4 counts at diagnosis, increased morbidity, mortality, and onward transmission. The aim of this systematic review is to evaluate the effectiveness and cost-effectiveness of HIV testing strategies in migrant populations and to estimate their effect on testing uptake, mortality, and resource requirements. Following a systematic overview, we included four systematic reviews on the effectiveness of strategies in non-migrant populations and inferred their effect on migrant populations, as well as eight individual studies on cost-effectiveness/resource requirements. We assessed the certainty of our results using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The systematic reviews reported that HIV tests are highly accurate (rapid test >90% sensitivity, Western blot and ELISA >99% sensitivity). A meta-analysis showed that rapid testing approaches improve the access and uptake of testing (risk ratio = 2.95, 95% CI: 1.69 to 5.16), and were associated with a lower incidence of HIV in the middle-aged women subgroup among marginalised populations at a high risk of HIV exposure and HIV related stigma. Economic evidence on rapid counselling and testing identified strategic advantages with rapid tests. In conclusion, community-based rapid testing programmes may have the potential to improve uptake of HIV testing among migrant populations across a range of EU/EEA settings.

Background Urinary tract infections (UTIs) are a frequent cause of morbidity and mortality in hospitalized patients, if not adequately and promptly treated. The optimal treatment duration is controversial and most recommendations are based on clinical experience. Current guidelines recommend 5–14 days of treatment depending on the type and severity of infection and the antibiotic used. With the emergence of multi-drug resistance, shorter durations are increasingly favored. This systematic review of randomized controlled trials (RCTs) aims at providing updated evidence on the effectiveness of short (≤7 days) vs. long (>7 days) antibiotic regimens in hospitalized adult patients. Methods MEDLINE, EMBASE, and CENTRAL were searched to identify relevant RCTs. Trial quality was evaluated using Cochrane’s Risk of Bias Tool. The primary outcome was clinical success. Secondary outcomes included microbiological success, withdrawal due to adverse events (AE), relapse, and reinfection rates. A random-effect meta-analysis was performed using R. Results 8 RCTs conducted between 1995 and 2018 were identified. Trial quality was considered poor in 5, fair in 1 and good in 2 RCTs. Clinical and microbiological success was reported in all studies. Withdrawal due to AE was reported in 5, relapse and reinfection in 3 studies. Overall, there was no difference in clinical success between short and long courses (OR = 0.92, 95% CI 0.66–1.29; 2111 patients) (figure). Similarly, microbiological success was comparable in the two arms (OR = 1.0, 95% CI 0.70–1.43; 2111 patients). There was a higher, but nonsignificant, number of withdrawals due to AE in the long duration arm (OR = 0.78, 95% CI 0.29–2.11; 1890 patients). Patients receiving short courses had a nonsignificant higher rate of relapse (OR = 2.65, 95% CI 0.31–22.39, 175 patients). However, there was no difference in reinfection rates (OR = 1.12, 95% CI 0.26–4.90; 175 patients). A subgroup analysis limited to complicated UTIs showed similar results. Conclusion Based on the limited available evidence, short antibiotic courses appear to be equally effective as longer courses in the management of inpatient UTIs. Further research is needed to determine appropriate antibiotic treatment durations and assess treatment-related development of drug resistance. Disclosures All authors: No reported disclosures.

Beta-lactams are at the cornerstone of therapy in critical care settings, but their clinical efficacy is challenged by the rise in bacterial resistance. Infections with multi-drug resistant organisms are frequent in intensive care units, posing significant therapeutic challenges. The problem is compounded by a dearth in the development of new antibiotics. In addition, critically-ill patients have unique physiologic characteristics that alter the drugs pharmacokinetics and pharmacodynamics. Areas covered: The prolonged infusion of antibiotics (extended infusion [EI] and continuous infusion [CI]) has been the focus of research in the last decade. As beta-lactams have time-dependent killing characteristics that are altered in critically-ill patients, prolonged infusion is an attractive approach to maximize their drug delivery and efficacy. Several studies have compared traditional dosing to EI/CI of beta-lactams with regard to clinical efficacy. Clinical data are primarily composed of retrospective studies and some randomized controlled trials. Several reports show promising results. Expert commentary: Reviewing the currently available evidence, we conclude that EI/CI is probably beneficial in the treatment of critically-ill patients in whom an organism has been identified, particularly those with respiratory infections. Further studies are needed to evaluate the efficacy of EI/CI in the management of infections with resistant organisms.

HIV-infected individuals appear to be at higher risk of cardiovascular disease (CVD) than the general population [1, 2]. The etiology of the increased risk remains unclear. Some data suggest that long-term protease inhibitors use contributes to risk [3–5], whereas others cite more traditional risk factors, such as smoking, dyslipidemia, and advanced age [6–8]. Measurement of carotid intima-media thickness (IMT) is a well-accepted, noninvasive method of monitoring subclinical atherosclerotic formation and progression, and increased IMT correlates with an increased risk of CVD events, such as myocardial infarction and stroke, in the general population [9–12]. Although no studies to date show prediction of CVD events on the basis of IMT values in the HIV-infected population, several studies demonstrate increased IMT in HIV-infected individuals, compared with healthy control persons [8, 13–15], and IMT progresses more rapidly over time in HIV-infected patients [8, 14, 16]. Likewise, data show that HIV infection status, when controlled for other factors, is associated with increased carotid IMT [15, 17]. There is mounting evidence to support the role of inflammation and endothelial activation and dysfunction in the development of plaque formation and progression of atherosclerosis in the general population [18–27]. For example, elevated levels of the proinflammatory cytokines interleukin (IL)-6 and C-reactive protein (CRP) are associated with subclinical atherosclerosis [18] and are independently predictive of future cardiovascular events [19, 20]. In addition, tumor necrosis factor (TNF)–α has been implicated in myocardial dysfunction after acute coronary syndromes, and levels of TNF-α have been shown to be higher in patients at baseline who experience recurrent myocardial infarctions or cardiac death [21, 22]. The effects of TNF-α are mediated by 2 receptors, TNFR-I and TNFR-II; these soluble receptors are stable in plasma, easily measured, and reflect activity of TNF-α. Myeloperoxidase, a peroxidase enzyme found in leukocytes and released when leukocytes are activated, has also been established as an independent predictor of early risk of myocardial infarction in patients presenting with chest pain [23], and myeloperoxidase levels are associated with the presence of coronary artery disease and endothelial dysfunction in the general population [24]. Likewise, levels of 2 circulating adhesion molecules, soluble vascular cell adhesion molecule–1 (sVCAM-1) and soluble intercellular adhesion molecule–1 (sICAM-1), as well as levels of von Willebrand factor antigen (vWF), arise from shedding or proteolytic cleavage from activated endothelial cells and are useful markers for increased activation of endothelial cells in atherosclerosis [25–27]. Few studies have examined the relationship between markers of inflammation and endothelial activation and measurements of carotid IMT. In the general population, the Offspring Cohort of the Framingham Heart Study found an association between inflammatory markers and IMT [28], whereas studies examining the role of chronic inflammation as a cause of the increased CVD risk in patients with type-2 diabetes have produced conflicting results [29–31]. Nevertheless, increased levels of inflammatory markers and evidence of endothelial dysfunction are evident in HIV-infected individuals [32–35] and may be correlated with increased risk of CVD. Even in patients who are receiving antiretroviral therapy (ART), inflammatory cytokine levels do not completely normalize to that of the general population [33], suggesting that there is ongoing inflammation despite an undetectable virus level. To date, no study has comprehensively examined the relationship among inflammatory markers, carotid IMT, and endothelial activation markers in HIV-infected individuals. We hypothesized that inflammatory markers are correlated with both carotid IMT and endothelial activation markers in HIV-infected subjects receiving ART and that both inflammatory and endothelial activation markers are associated with carotid IMT. In this study, we measured plasma levels of proinflammatory cytokines, TNF-α, sTNFR-I and -II, IL-6, high-sensitivity CRP (hsCRP), and myeloperoxidase, and of 3 endothelial activation markers, sICAM-1, sVCAM-1, and vWF, to explore their relationship to carotid IMT in HIV-infected individuals receiving ART with virologic control. As a secondary objective, we examined carotid IMT, inflammatory markers, and endothelial activation markers in ART-treated, HIV-infected subjects, compared with a small convenience sample of healthy control subjects.

Objective: We aim to evaluate the mechanisms of rosiglitazone-induced fat recovery in HIV+ patients with lipoatrophy on thymidine Nucleoside Reverse Transcriptase Inhibitors (NRTI) sparing regimens. Method: Measures of limb fat (DXA), oxidative stress (F2 isoprostanes) and inflammation [High-sensitivity C - reactive protein (hsCRP), soluble Tumor Necrosis Factor Receptors (sTNFR)-I, sTNFR-II, and interleukin (IL)-6] were performed. Gluteal fat mitochondrial DNA (mtDNA) and peroxisome proliferator-activated receptor (PPAR)-γ RNA [expressed as PPAR-γ/Glyceraldehyde 6-Phosphate Dehydrogenase (GAPDH) RNA ratio] were measured by quantitative PCR. Result: 71 patients on thymidine NRTI-sparing regimens were randomized to rosiglitazone vs. placebo for 48 weeks. Duration off thymidine NRTIs was similar between groups. From week 0-48, limb fat increased significantly (p=0.02) more in the rosiglitazone than in the placebo group. Within both groups, F2-isoprostanes, sTNFR-I and sTNFR-II increased significantly (p ≤ 0.003), hsCRP decreased significantly (≤ 0.02), and IL-6 did not change. No differences were seen between groups in any of the inflammation markers. Fat mtDNA (copies/ cell) increased nonsignificantly: +41(p=0.08) and +29(p=0.38) within rosiglitazone and placebo group; respectively. PPAR-γ/ GAPDH ratio did not change within or between groups. Conclusion: Limb fat improvements seen after rosiglitazone were not associated with changes in mtDNA, oxidative or inflammation markers, or PPAR-γ expression. F2 isoprostanes and some of the inflammation markers worsened over time in these subjects on stable ART, regardless of the rosiglitazone assignment. Thus, lipoatrophy can be in part overcome by a separate pathway independent of mitochondrial DNA depletion, such as PPAR-γ.

Rosiglitazone may be useful for the treatment of antiretroviral therapy-associated lipoatrophy, but an association with cardiovascular disease (CVD) has been questioned in diabetics. We evaluated rosiglitazone's effect on surrogate markers of CVD in HIV-infected individuals with lipoatrophy. HIV(+) patients with lipoatrophy on thymidine-sparing regimens were randomized to rosiglitazone vs. placebo for 48 weeks. We serially assessed carotid IMT, fasting metabolic profiles, tumor necrosis factor (TNF)-α, soluble receptors (sTNFRI and II), interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO), and endothelial activation markers [von Willebrand factor (vWF), soluble intercellular cell adhesion molecules-1 (sICAM-1), and vascular cell adhesion molecules-1 (sVCAM-1)]. Seventy-one subjects enrolled: 17% were female and 51%were white. Baseline characteristics were similar between groups except for higher total cholesterol in the placebo group (p = 0.04). At 48 weeks, common carotid artery (CCA) IMT changed significantly (p ≤ 0.05) within but not between the groups (p = 0.36): the median (IQR) increase was 0.10 (0.05, 0.25) mm and 0.15 (0, 0.25) mm in the rosiglitazone and placebo groups, respectively. hsCRP, sTNFRI and II, sVCAM-1, and vWF changed significantly (p ≤ 0.02) within but not between groups. Total cholesterol increased significantly in the rosiglitazone group (p = 0.008). In our study of virologically controlled subjects with lipoatrophy, rosiglitazone did not independently increase carotid IMT, endothelial activation, and inflammatory cytokines.

Thymidine reverse transcriptase inhibitors (tNRTI) are strong inhibitors of PPAR-gamma and clearly implicated as a cause of lipoatrophy. Thiazolidenediaones (TZD), potent PPAR-gamma agonists, would be expected to be beneficial in HIV lipoatrophy, but prior studies have been conflicting. None specifically excluded the use of tNRTIs. We report the first study in individuals treated with tNRTI-sparing regimens using a TZD for treatment of HIV lipoatrophy.This double-blind, placebo-controlled study evaluated limb fat in HIV-infected individuals with lipoatrophy who discontinued tNRTI at least 24 weeks prior to enrollment.Individuals were randomized to rosiglitazone vs. placebo for 48 weeks. Dual energy X-ray absorptiometry (DEXA)-scans and fasting metabolic assessments were serially performed.We enrolled 71 individuals, 17% were female and 51% white. Baseline characteristics were similar between groups except for higher total cholesterol in the placebo group (P = 0.04). At 48 weeks, limb fat (grams) increased significantly (P = 0.02) more in the rosiglitazone than in the placebo group: median (IQR) 448 (138, 1670) vs. 153 (-100, 682), respectively. Of lipids parameters, only total cholesterol increased significantly more in the rosiglitazone group (P = 0.008). Prevalence of metabolic syndrome and total bone mineral density did not change between or within groups.In the absence of tNRTI, rosiglitazone significantly improves lipoatrophy without deleterious effect on bone mineral density. Total cholesterol, but not triglycerides, significantly increased in the rosiglitazone arm. The glitazones may be a promising addition for accelerating fat recovery in individuals who had switched off tNRTI and remain with significant lipoatrophy.

To identify inflammatory pathways that may contribute to the pathogenesis of human immunodeficiency virus (HIV) disease, we explored associations between AIDS or death and different inflammatory markers, including selected soluble tumor necrosis factor superfamily receptors (sTNFRs) and ligands, interleukin (IL)-6, and CD8 T cell activation, in individuals treated with highly active antiretroviral therapy (HAART).A case-control study of subjects in AIDS Clinical Trials Group (ACTG) protocols 384 and 5015, who were matched according to the CD4 cell count and plasma viral load at baseline, was performed using conditional logistic regression.Higher pretreatment concentrations of sTNFR-1, sCD27, sCD40L, and plasma IL-6 were associated with a new AIDS-defining illness or death in separate models adjusted for age, sex, hemoglobin, and the latest CD4 cell counts. In additional models that excluded case patients with opportunistic infections, sTNFR-1, sCD27, and sCD40L were each associated with a new AIDS-defining malignancy or death that developed at a median of 51 weeks after initiation of HAART, by which time the majority of subjects had a CD4 cell count of200 cells/cm(3) and had achieved a plasma viral load of50 copies/mL.These data are compatible with a model in which these soluble inflammatory markers identify pathways that may contribute to the pathogenesis of HIV disease progression, pathways that might not be a direct consequence of ongoing HIV type 1 replication.

Objectives: To assess the association of inflammatory and endothelial activation biomarkers with the presence of lipoatrophy in HIV-infected subjects and to examine the role of HIV, antiretroviral therapy (ART), and metabolic parameters in endothelial activation and inflammation. Design: Prospective, cross-sectional study including 4 groups: HIV+ on ART with HIV-1 RNA

HIV type 1 (HIV-1) elite controllers (ECs) represent a rare group of individuals with an ability to maintain an undetectable HIV-1 viral load overtime in the absence of previous antiretroviral therapy. The mechanisms associated with this paradigm remain not clearly defined. However, loss of virological control, morbidity and mortality persist in these individuals, such as progress to AIDS-defining conditions together with persistent high rate of immune activation. Further insight into potential therapeutic options is therefore warranted. In this review, we discuss recent data on the type of immune responses understood to be associated with chronic virological control, the potential for disease progression and therapeutic options in ECs.