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Abstract Observational studies suggest a reduction in fatal or severe COVID-19 disease with the use of ACE2 inhibitors and statins. We implemented a randomized controlled tree-arm open label trial evaluating the benefits of adding telmisartan (TLM) or atorvastatin (ATV) to lopinavir boosted ritonavir (LPVr) on the SARS-CoV-2 nasopharyngeal viral load in patients with mild / moderate COVID-19 infection in Côte d’Ivoire. RT-PCR positive COVID-19 patients ≥ 18 years, with general or respiratory symptoms for less than 7 days were randomized (1:1:1) to receive LPVr (400 mg/100 mg twice daily), LPVr + TLM (10 mg once daily) or LPVr + ATV (20 mg once daily) for 10 days. The primary endpoint was viro-inflammatory success defined as a composite variable at day 11: Ct ≥ 40 and C-reactive protein

Abstract Introduction People living with HIV (PLWH) live longer and face new health challenges resulting from the confluence of chronic HIV infection and the natural effect of aging and comorbidities. However, there is a dearth of information on the long-term impact of HIV infection on the health and wellbeing of PLWH in sub-Saharan Africa. This research aimed to fill this gap by reporting on physical, functional and social outcomes among PLWH treated at a referral center in Abidjan, Ivory Coast, and comparing them with those of a control group. Methods Body composition, functional capacity, sarcopenia, limitations in daily activities and social participation were assessed among 300 PLWH (aged ≥ 30 years) and 200 uninfected adults of similar age and sex. The associations between these outcomes and participants’ socioeconomic characteristics, HIV history and physical activity level were assessed using generalized additive models adjusted for age and sex. Results The median age was 51 years, and the median antiretroviral therapy duration was 15 years. Compared to controls, PLWH reported higher levels of physical activity (p

Abstract Background The burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH – even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines. In the context of herpes zoster, it is therefore important to assess the immune response to varicella zoster virus vaccination in older PLWH and to determine whether it significantly differs to that of HIV-uninfected healthy adults or younger PLWH. We aim at bridging these knowledge gaps by conducting a multicentric, international, non-randomised clinical study (SHINGR’HIV) with prospective data collection after vaccination with an adjuvant recombinant zoster vaccine (RZV) in two distinct populations: in PLWH on long-term ART (> 10 years) over 50 years of and age/gender matched controls. Methods We will recruit participants from two large established HIV cohorts in Switzerland and in France in addition to age-/gender-matched HIV-uninfected controls. Participants will receive two doses of RZV two months apart. In depth-evaluation of the humoral, cellular, and innate immune responses and safety profile of the RZV will be performed to address the combined effect of aging and potential immune deficiencies due to chronic HIV infection. The primary study outcome will compare the geometric mean titer (GMT) of gE-specific total IgG measured 1 month after the second dose of RZV between different age groups of PLWH and between PLWH and age-/gender-matched HIV-uninfected controls. Discussion The SHINGR’HIV trial will provide robust data on the immunogenicity and safety profile of RZV in older PLWH to support vaccination guidelines in this population. Trial registration ClinicalTrials.gov NCT05575830. Registered on 12 October 2022. Eu Clinical Trial Register (EUCT number 2023-504482-23-00).

Background: Type 2 diabetes mellitus (T2DM) and atrial fibrillation are risk factors for stroke. The potential preventive effects of cardiovascular and antidiabetic treatments on stroke risk in patients with these diseases remain insufficiently documented. Sulfonylureas have also been reported to be associated with stroke. This study aimed to assess the risk of stroke according to the use of drugs (anticoagulants, antiplatelet agents, and oral antidiabetic drugs [OADs]) in patients with T2DM and nonvalvular atrial fibrillation (NVAF). Methods: Patients with a history of T2DM and NVAF were identified from two systematic registries: a registry of patients with stroke and a registry of patients with atrial fibrillation. Patients with stroke were randomly matched to patients without prior stroke events based on age, sex, body mass index, and index date. All treatments administered 12 months before the index date were documented. The associations between anticoagulants, antiplatelet agents, and OADs and stroke were assessed using multivariate conditional logistic models that yielded adjusted odds ratios (aORs) and 95 % confidence intervals, controlling for risk factors identified in the univariate comparison of cases and matched referents. Results: Three-hundred and fifteen patients with stroke with both diabetes and NVAF were matched to 523 referents with both diabetes and NVAF but no history of stroke. The aORs for the use of drugs and stroke were 0.24 [0.15–0.40] for direct oral anticoagulants (DOACs), 0.42 [0.27–0.67] for vitamin K agonists (VKA), 0.80 [0.52–1.24] for antiplatelet agents, and 0.68 [0.45–1.02] for OADs. No significant associations were found between individual OAD use and stroke risk. Similar results were obtained for ischemic stroke. Only VKAs were significantly associated with hemorrhagic stroke (odds ratio = 4.25 [1.16–15.64]). Conclusions: Anticoagulant use was associated with a protective effect against the risk of stroke in patients with diabetes and NVAF, with no increase in the risk of hemorrhagic stroke for DOAC. No increased risk of stroke was observed because of any OAD, including sulfonylureas.

Abstract We evaluated people living with Human Immunodeficiency Virus’ (PLWH) quality of life (QoL) and assessed whether their demographic, disease-related, socioeconomic, or behavioral characteristics were associated with poorer QoL. ANRS CO3 AQUIVIH-NA cohort participants (Nouvelle Aquitaine, France) were recruited to a cross-sectional study (2018–2020) and their QoL assessed (WHOQOL-BREF). We calculated median (Q1, Q3) QoL domain scores and assessed factors associated with poorer median QoL using bivariable and multivariable quartile regression. Of the 965 PLWH included, 98.4% were on antiretroviral therapy, 94.7% were virally-suppressed, 63.5% reported good/very good QoL. Median scores (0–100) were highest for physical (69;Q1, Q3: 56, 81) and environmental (69; 56, 75) QoL and lowest for social (56; 44, 69) and psychological (56; 44, 69) QoL. PLWH with ≥ 3 comorbidities, HIV-related stigma, or income of

Abstract Background To evaluate drug use (alcohol, tobacco, cannabis and other drugs) and its association with mean CD4/CD8 T cell count ratio, a marker of chronic inflammation, in virally suppressed people living with HIV-1 (PLWH) in Nouvelle Aquitaine, France. Methods A multi-centric, cross-sectional analysis was conducted in 2018–19 in the QuAliV study—ANRS CO3 AQUIVIH-NA cohort. Tobacco, alcohol, cannabis, and other drug use (poppers, cocaine, amphetamines, synthetic cathinones, GHB/GBL) were self-reported. CD4 and CD8 T cell counts and viral load measures, ± 2 years of self-report, and other characteristics were abstracted from medical records. Univariable and multivariable linear regression models, adjusted for age, sex, HIV risk group, time since HIV diagnosis, and other drug use were fit for each drug and most recent CD4/CD8 ratio. Results 660 PLWH, aged 54.7 ± 11.2, were included. 47.7% [315/660] had a CD4/CD8 ratio of

Abstract Background Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). Methods This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as “definite,” “probable,” or “possible” using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. Discussion The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. Trial registration ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.

Introduction Aseptic abscess (AA) syndrome is a rare disease whose pathophysiology is unknown. It is often associated with inflammatory bowel disease and characterised by sterile inflammation with collections of neutrophils affecting several organs, especially the spleen. Microbiota are known to influence local and systemic immune responses, and both gut and oral microbiota perturbations have been reported in diseases associated with AA syndrome. However, interactions between these factors have never been studied in AA syndrome. The purpose of this translational case-control study (ABSCESSBIOT) is to investigate gut and/or oral microbiota in patients with AA syndrome compared with healthy controls. Moreover, microbiota associated metabolites quantification and Treg/Th17 balance characterisation will give a mechanistic insight on how microbiota may be involved in the pathophysiology of AA syndrome.Methods and analysis This French multicentre case-control study including 30 French centres (University hospital or regional hospital) aims to prospectively enrol 30 patients with AA syndrome with 30 matched controls and to analyse microbiota profiling (in stools and saliva), microbial metabolites quantification in stools and circulating CD4+ T cell populations.Ethics and dissemination This study protocol was reviewed and approved by an independent French regional review board (n° 2017-A03499-44, Comité de Protection des Personnes Ile de France 1) on 10 October 2022, and declared to the competent French authority (Agence Nationale de Sécurité du Médicament et des produits de santé, France). Oral and written informed consent will be obtained from each included patient and the control participant. Study results will be reported to the scientific community at conferences and in peer-reviewed scientific journals.Trial registration number Clinical Trials web-based platform (NCT05537909).

Objective To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial).Design Open label, randomised clinical trial.Setting CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021.Participants 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms 40.Main outcome measures Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids.Results 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10).Conclusions In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further.Trial registration ClinicalTrials.gov NCT04345991.

Abstract We aimed to estimate the prevalence of depressive disorder in people living with HIV (PLWH) and evaluate its association with non-HIV-specific and HIV-specific factors in PLWH and in PLWH compared to the general population (GP). We used cross-sectional data from the QuAliV study, conducted within the ANRS-CO3 Aquitaine-AQUIVIH-NA cohort of PLWH in Nouvelle-Aquitaine (2018–2020), and a nationally-representative survey in the GP (EHIS-ESPS, 2014–2015), we included all participants aged ≥ 18 years old who had completed the Patient Health Questionnaire-8 (PHQ-8). Depressive disorder was defined as Patient Health Questionnaire-8 score greater or equal to 10. Its association with non-HIV-specific (demographic, socio-economic, behavioral, health status), HIV-specific factors (immuno-viral markers, antiretrovirals, level of perceived HIV-stigma), and HIV-status was assessed using Poisson regression models with robust variance in women and men separately. We included 914 PLWH (683 men/231 women). More than one in five PLWH had depressive disorder. It was strongly associated with being younger and experiencing severe pain in both sexes. Unemployment in women, being single, and lack of family ties in men were also associated with depressive disorder. More than 30% of our sample reported HIV-stigma, with a dose–response relationship between level of perceived HIV-stigma and depressive disorder. The crude prevalence of depressive disorder was 2.49 (95%CI 1.92–3.22) and 4.20 (95%CI 3.48–5.05) times higher in women and men living with HIV respectively compared to GP counterparts and 1.46 (95%CI 1.09–1.95) and 2.45 (95%CI 1.93–3.09) times higher after adjustment for non-HIV specific factors. The adjusted prevalence ratio of depressive disorder was not significantly different in HIV-stigma free women, but remained twice as high in HIV-stigma free men. The prevalence of depressive disorder compared to the GP tended to decrease with age in PLWH. Excess depressive disorder remains a major concern in PLWH. Our findings reaffirm the importance of regular screening. Tackling social inequalities and HIV-stigma should be prioritized to ensure that PLWH achieve good mental as well as physical health outcomes.

Summary: Background: Broad direct-acting antiviral (DAA) access may reduce hepatitis C virus (HCV) incidence through a “treatment as prevention” (TasP) effect. We assessed changes in primary HCV incidence following DAA access among people living with HIV (PLHIV). Methods: We used pooled individual-level data from six cohorts from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC). Follow-up started from the first recorded negative HCV antibody test date and ended at last negative antibody test or estimated infection date. Follow-up was restricted to 2010–2019. We used segmented Poisson regression to model trends across pre-, limited- (i.e., restrictions on access) and broad-DAA access periods. Findings: Overall, 45,942 participants had at least one HCV antibody negative result and follow-up between 2010 and 2019. We observed 2042 incident HCV infections over 248,189 person-years (PY). Pooled incidence decreased from 0.91 per 100 PY in 2015 to 0.41 per 100 PY in 2019. Compared to the average pre-DAA period incidence (0.90 per 100 PY), average incidence was similar during the limited-DAA access period (Incidence rate ratio [IRR] = 0.98; 95%CI = 0.87, 1.11), and 52% lower during the broad-DAA access period (IRR = 0.48; 95%CI = 0.42, 0.52). The average annual decline in HCV incidence was 2% in the pre-DAA period; an additional 9% annual decline in incidence was observed during the limited-DAA access period (IRR = 0.91; 95%CI = 0.82, 1.00) and a further 20% decline in the broad-DAA access period (IRR = 0.80, 95%CI = 0.73, 0.89). Interpretation: Our findings suggest that broad DAA access has a TasP effect on primary HCV incidence among PLHIV. Based on the initial years of DAA availability, the countries in the InCHEHC collaboration are on track to meet the World Health Organization's 80% HCV incidence reduction target for PLHIV by 2030. Funding: This study was funded by the Australian Government National Health and Medical Research Council (Grant number GNT1132902).

Abstract Background Type 2 diabetes (T2D) has been identified as a risk factor for poor oral health, however, a limited number of oral health and T2D characteristics have been studied so far. We sought to assess T2D status, age at diagnosis, duration since diagnosis and treatment in relation to a variety of oral diseases. Methods Cross-sectional data were analyzed from the E3N (Etude Epidémiologique auprès de femmes de l'Education Nationale) cohort study which enrolled 60,590 women. Participants self-reported oral health status, and T2D cases were identified using diabetes-specific questionnaires and drug reimbursement insurance databases. Multivariable-adjusted ORs and 95% CIs were estimated using logistic regression models. Results The mean age (SD) of the women was 70 years (7.2), and 4.7% (n = 2857) had T2D. Compared to women without T2D, women with T2D were more likely to report a poor perceived oral health (OR 1.37 [95% CI 1.18, 1.60]), wearing dental prostheses (1.26 [1.14, 1.39]) and having problems of biting and chewing food (1.19 [1.07, 1.33]). In addition, for women with T2D the age at diagnosis (inversely) and the duration (positively) were associated with the likelihood to report poor oral health. Conclusions For women with T2D, duration and age at diagnosis are associated with wearing prostheses, problems of biting and chewing, periodontitis and gingivitis.

Abstract Aims Heart failure (HF) is increasingly recognized as a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), but the global epidemiology and treatment of HF in T2D are not well defined. This study aimed to examine the global prevalence of HF and the incidence of HF over 3 years of follow‐up in patients with T2D [by presence and absence of co‐existing coronary artery disease (CAD)]. Methods and results DISCOVER was a 3 year, prospective, observational study of T2D patients enrolled at initiation of second‐line glucose‐lowering therapy. Among 14 057 patients with T2D from 36 countries, 289 (2.1%) had a diagnosis of HF at enrolment; median prevalence across countries was 2.0% (inter‐quartile range 1.0–3.1%). Patients with HF at baseline were more likely to be older [HF vs. no HF: 67 ± 12 vs. 57 ± 12 years, standardized difference (StDiff) = 84%] and have longer duration of T2D (8.1 ± 7.2 vs. 5.6 ± 5.2 years, StDiff = 40%), CAD (44% vs. 6%, StDiff = 97%), atrial fibrillation (21% vs. 1%, StDiff = 66%), and kidney disease (23% vs. 4%, StDiff = 55%). Patients with HF were less likely to be on metformin (66% vs. 79%, StDiff = 28%) and thiazolidinediones (5.5% vs. 10.6%, StDiff = 19%) but had similar use of other glucose‐lowering medications. Among 9313 patients with follow‐up data, there were 70 incident cases of HF, which translates to an incidence of 2.6 cases per 1000 person years. Of these incident HF cases, 60% occurred in the absence of pre‐existing or concomitant CAD, and 73% were diagnosed in the outpatient setting. Conclusions In a large, global cohort of patients with T2D, the majority of incident cases of HF occurred in outpatients and in the absence of known CAD. These findings highlight the need for greater awareness of HF risk in patients with T2D.

Abstract Background Antiretroviral therapy has prolonged the lives of those with human immunodeficiency virus (HIV), but the effects of chronic infection on their health-related quality of life (HRQoL) remain a concern. Numerous instruments have been developed to measure HRQoL, yet evidence of their cross-cultural equivalence and continued applicability is limited. We adapted the WHOQOL-HIV BREF to French and assessed its psychometric properties in a sample of community-dwelling adults living with HIV who were mostly virally suppressed. Methods We conducted a cross-sectional study within the ANRS CO3 Aquitaine cohort from July 2018 to May 2019. Five hundred eighty-six participants were consecutively enrolled at their HIV-consultations and completed either a web-based (n = 406) or paper self-administered assessment (n = 180). The means and standard deviations for items and domains were computed and the presence of floor and ceiling effects assessed. We evaluated internal consistency by calculating Cronbach’s alpha coefficients per domain. We assessed construct validity by performing a Confirmatory Factor Analysis (CFA). Concurrent, convergent and discriminant validity were assessed with Pearson’s correlations and known-group validity was assessed according to CD4 cell count, viral load, Centers for Disease Control and Prevention clinical categories for HIV, and hospitalization of more than 48 h within 2 years of the most recent consultation using one-way analysis of variance and independent t-tests. Results Five hundred eighty-six PLWH were included in this analysis. Their median age was 55; 73% were male; 85% were of French descent; 99% were on ART and 93% were virally suppressed. We found floor effects for one and ceiling effects for 11 items. Four of the six domains showed good internal consistency (α range: 0.63–0.79). CFA showed that the WHOQOL-HIV BREF’s six-domain structure produced an acceptable fit (SRMR = 0.059; CFI = 0.834; RMSEA = 0.07; 90% CI: 0.06–0.08). It showed good concurrent, convergent and discriminant validity. There was some evidence of known-group validity. The personal beliefs domain had the highest score (15.04 ± 3.35) and the psychological health domain had the lowest (13.70 ± 2.78). Conclusions The French WHOQOL-HIV BREF has acceptable measurement properties. Its broad conceptualisation of HRQoL, going beyond physical and mental health, may be of particular value in our older, treatment-experienced and virally suppressed population. Trial registration ClinicalTrials.gov NCT03296202 (Archived by WebCite at http://www.webcitation.org/6zgOBArps ).

Abstract Background The risk/benefit ratio of using statins for primary prevention of cardiovascular (CV) events in elderly people has not been established. The main objectives of the present study are to assess the cost-effectiveness of statin cessation and to examine the non-inferiority of statin cessation in terms of mortality in patients aged 75 years and over, treated with statins for primary prevention of CV events. Methods The “Statins in the elderly” (SITE) study is an ongoing 3-year follow-up, open-label comparative multi-centre, randomized clinical trial that is being conducted in two parallel groups in outpatient primary care offices. Participants meeting the following criteria are included: people aged 75 years and older being treated with statins as primary prevention for CV events, who provide informed consent. After randomization, patients in the statin-cessation strategy are instructed to withdraw their treatment. In the comparison strategy, patients continue their statin treatment at the usual dosage. The cost-effectiveness of the statin-cessation strategy compared to continuing statins will be estimated through the incremental cost per quality-adjusted life years (QALYs) gained at 36 months, from the perspective of the French healthcare system. Overall mortality will be the primary clinical endpoint. We assumed that the mortality rate at 3 years will be 15%. The sample size was computed to achieve 90% power in showing the non-inferiority of statin cessation, assuming a non-inferiority margin of 5% of the between-group difference in overall mortality. In total, the SITE study will include 2430 individuals. Discussion There is some debate on the value of statins in people over 75 years old, especially for primary prevention of CV events, due to a lack of evidence of their efficacy in this population, potential compliance-related events, drug-drug interactions and side effects that could impair quality of life. Data from clinical trials guide the initiation of medication therapy for primary or secondary prevention of CV disease but do not define the timing, safety, or risks of discontinuing the agents. The SITE study is one of the first to examine whether treatment cessation is a cost-effective and a safe strategy in people of 75 years and over, formerly treated with statins. Trial registration ClinicalTrials.gov: NCT02547883 . Registered on 11 September 2015.

Abstract Background Among potentially modifiable factors, dairy product consumption has been inconsistently associated with hypertension risk. The objective of this study was to investigate the relation between dairy product consumption and the risk of hypertension among middle-aged women. Methods In a prospective cohort of 40,526 French women, there were 9340 new cases of hypertension after an average 12.2 years of follow up. Consumptions of milk, yogurt, and types of cheese were assessed at baseline using a validated dietary questionnaire. Hazard ratios (HRs) and 95% confidence intervals (95% CI) for hypertension were estimated with multivariate Cox models with age as the time scale. Results The mean dairy consumption was 2.2 + 1.2 servings/day, as cottage cheese (0.2 + 0.2 servings/day), yogurt (0.6 + 0.5 servings/day), milk (0.4 + 0.7 servings/day), and cheese (1.1 + 0.8 servings/day). There was no association between risk of hypertension and total dairy consumption (multivariate HR for the fifth vs. first quintile HR5vs.1 = 0.97 [0.91; 1.04]). There was no association with any specific type of dairy, except for a positive association between processed cheese consumption and hypertension (multivariate HR4vs.1 = 1.12 [1.06; 1.18]; p trend =

Background: The objective is to characterise the economic burden to the healthcare system of people living with HIV (PLWHIV) in France and to help decision makers in identifying risk factors associated with high-cost and high mortality profiles. Design and Method: The study is a retrospective analysis of PLWHIV identified in the French National Health Insurance database (SNDS). All PLWHIV present in the database in 2013 were identified. All healthcare resource consumption from 2008 to 2015 inclusive was documented and costed (for 2013 to 2015) from the perspective of public health insurance. High-cost and high mortality patient profiles were identified by a machine learning algorithm. Results: In 2013, 96,423 PLWHIV were identified in the SNDS database, including 3,373 incident cases. Overall, 3,224 PLWHIV died during the three-year follow-up period (mean annual mortality rate: 1.1%). The mean annual per capita cost incurred by PLWHIV was € 14,223, corresponding to a total management cost of HIV of € 1,370 million in 2013. The largest contribution came from the cost of antiretroviral medication (M€ 870; 63%) followed by hospitalisation (M€ 154; 11%). The costs incurred in the year preceding death were considerably higher. Four specific patient profiles were identified for under/over-expressing these costs, suggesting ways to reduce them. Conclusion: Even though current therapeutic regimens provide excellent virological control in most patients, PLWHIV have excess mortality. Other factors such as comorbidities, lifestyle factors and screening for cancer and cardiovascular disease, need to be targeted in order to lower the mortality and cost associated with HIV infection.

Background: Hypertension is a stronger predictor of hemorrhagic than ischemic strokes in the general population. We aimed to identify whether hypertension or other risk factors, including HIV-related factors, differ in their associations with stroke subtypes in people living with HIV (PLWHIV). Methods: HIV-1-positive individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed from the time of first blood pressure (BP) measurement after 1/1/1999 or study entry until the first of a validated stroke, 6 months after last follow-up or 1/2/2014. Stroke events were centrally validated using standardized criteria. Hypertension was defined as one systolic BP ≥140 mm Hg and/or diastolic BP ≥90 mm Hg. Poisson and Cox proportional hazards regression models determined associations of established cerebro/cardiovascular disease and HIV-related risk factors with stroke and tested whether these differed by stroke subtype. Findings: 590 strokes (83 hemorrhagic, 296 ischemic, 211 unknown) occurred over 339,979 person-years (PYRS) (incidence rate/1000 PYRS 1.74 [95% confidence interval (CI) 1.60–1.88]). Common predictors of both hemorrhagic and ischemic strokes were hypertension (relative hazard 3.55 [95% CI 2.29–5.50] and 2.24 [1.77–2.84] respectively) and older age (1.28 [1.17–1.39] and 1.19 [1.12–1.25]). Male gender (1.62 [1.14–2.31] and 0.60 [0.35–0.91]), previous cardiovascular events (4.03 [2.91–5.57] and 1.44 [0.66–3.16]) and smoking (1.90 [1.41–2.56] and 1.08 [0.68–1.71]) were stronger predictors of ischemic then hemorrhagic strokes, whereas hypertension, hepatitis C (1.32 [0.72–2.40] and 0.46 [0.30–0.70]) and estimated glomerular filtration rate

Abstract Background Although there is evidence for a reduced risk of hypertension associated with fruit and vegetable consumption, the relationship between the total antioxidant capacity of the diet (TAC) and the risk of hypertension has not been previously examined. We aimed to evaluate that association in the large E3N French prospective cohort of women. Methods Dietary TAC was estimated using total radical-trapping ability parameter (TRAP) assay food values; self-reported incident hypertension cases were validated. Cox regression models were adjusted for conventional risk factors, body mass index, physical activity, energy, sodium, magnesium, omega-3 fatty acids, and alcohol. Results After an average 12.7 years of follow up, there were 9350 incident cases of hypertension among 40,576 women. Dietary TAC was inversely associated with the risk of hypertension with a 15% lower risk of hypertension in those in the fifth vs. first quintile (HRQ5 0.85 [CI 95% 0.74; 0.95] p-trend 0.03) An inverse dose-effect relationship was observed for dietary TAC excluding coffee (HRQ5 0.85 [CI 95% 0.74; 0.95], p-trend 0.0008), while for dietary TAC from coffee, only the highest quintile was inversely associated with risk (HRQ5 0.86 [0.75, 0.97], p-trend 0.20). In a fully partitioned model with major dietary TAC contributors, TAC from fruit/vegetables, wine, and miscellaneous sources was inversely associated with risk, while associations with TAC from coffee, tea, and chocolate were not statistically significant. Conclusions In a large prospective cohort, the risk of incident hypertension in women was inversely associated with the antioxidant capacity of the diet, suggesting that promoting a diet naturally rich in antioxidants might help prevent the development of hypertension.

Objective: The endogenous estrogen 17β-estradiol (E2) promotes metabolic homeostasis in premenopausal women. In a mouse model of post-menopausal metabolic syndrome, we reported that estrogens increased energy expenditure, thus preventing estrogen deficiency-induced adiposity. Estrogens' prevention of fat accumulation was associated with increased serum concentrations of fibroblast growth factor 21 (FGF21), suggesting that FGF21 participates in estrogens' promotion of energy expenditure. Methods: We studied the effect of E2 on FGF21 production and the role of FGF21 in E2 stimulation of energy expenditure and prevention of adiposity, using female estrogen receptor (ER)- and FGF21-deficient mice fed a normal chow and a cohort of ovariectomized women from the French E3N prospective cohort study. Results: E2 acting on the hepatocyte ERα increases hepatic expression and production of FGF21 in female mice. In vivo activation of ERα increases the transcription of Fgf21 via an estrogen response element outside the promoter of Fgf21. Treatment with E2 increases oxygen consumption and energy expenditure and prevents whole body fat accumulation in ovariectomized female WT mice. The effect of E2 on energy expenditure is not observed in FGF21-deficient mice. While E2 treatment still prevents fat accumulation in FGF21-deficient mice, this effect is decreased compared to WT mice. In an observational cohort of ovariectomized women, E2 treatment was associated with lower serum FGF21 concentrations, which may reflect a healthier metabolic profile. Conclusions: In female mice, E2 action on the hepatocyte ERα increases Fgf21 transcription and FGF21 production, thus promoting energy expenditure and partially decreasing fat accumulation. Keywords: Estrogen, ERα, FGF21, Menopause, Obesity, Metabolic syndrome

Introduction: The prevalence of type 2 diabetes (T2D) is increasing worldwide. Recent studies have suggested that environmental factors, such as exposure to brominated flame retardants (BFRs), could play a role in the epidemic of T2D. The aim of this study was to analyze the association between the dietary exposure to BFRs (Hexabromocyclododecane (HBCD) and Polybromodiphenylether (PBDE)) and T2D risk in the E3N prospective cohort of French women. Research design and methods: Overall, 71,415 women followed for 19 years were included in the study. We performed Cox regression models to analyze the association between dietary exposure to BFRs and T2D risk. Results: Overall 71,415 women were included and 3667 (5.13%) developed a T2D during follow-up. The mean dietary exposure to HBCD and to PBDE was 0.22 ng/kg body weight (BW)/day and 1.21 ng/kg bw/day, respectively. There was a positive linear association between dietary exposure to HBCD and T2D risk starting from the 2nd quintile group (HR: 1.18; 95% CI: 1.06–1.30) to the 5th quintile group (HR: 1.47; 95% CI: 1.29–1.67) when compared to the 1st quintile group. We also found positive although non-linear associations between dietary exposure to PBDE and T2D risk, with an increased HR only for the 2nd and 4th vs. 1st quintile groups (HR: 1.12; 95% CI: 1.02–1.24, and HR: 1.20; 95% CI: 1.08–1.34, respectively). Conclusion: The findings suggest an association between dietary exposure to BFRs and T2D risk, highlighting the importance of further investigating this association the long-term health effects of endocrine disruptors in the general population. Additional studies are needed to reproduce these findings in other populations and clarify the underlying biological mechanisms. Keywords: Dietary exposure, Brominated flame retardants, Organic persistent pollutants, Endocrine disruptors, Types 2 diabetes, Metabolic disease

Background High body mass index (BMI) and low physical activity are associated with increased risk of hypertension. Few studies have assessed their joint impact or the relation of physical activity and hypertension among individuals within a healthy BMI range. The objective of this study was to investigate the associations between physical activity and hypertension across strata of BMI. Methods and Results We used data from the E3N (Etude Epidémiologique de femmes de la Mutuelle Générale de l´Education) cohort, a French prospective study of women aged 40 to 65 years. We included participants who completed a diet history questionnaire and who did not have prevalent hypertension at baseline, resulting in a total of 41 607 women. Questionnaires assessed time spent undertaking various types of physical activity. Hypertension cases were self‐reported. Cox models were used to calculate hazard ratios (HRs) for physical activity. Associations were assessed over strata of BMI. Among the 41 607 included women, 10 182 cases of hypertension were identified in an average follow‐up time of 14.5 years. Total physical activity was associated with a lower hypertension risk in women within the high‐normal BMI range (BMI, 22.5–24.9) (HRQuartile 1–Quartile 4, 0.89; 95% CI, 0.79–0.99). An inverse relationship was observed between sports (HRsports >2 hours, 0.87; 95% CI, 0.83–0.93), walking (HRwalk >6.5 hours, 0.94; 95% CI, 0.90–1.00), and gardening (HRgardening >2.5 hours, 0.94; 95% CI, 0.89–0.99). Sports were associated with a reduced risk of hypertension in women with a healthy weight, but evidence was weaker in overweight/obese or underweight women. Conclusions Women with a healthy weight were those who could benefit most from practicing sports, and sports provided the largest risk reduction compared with other types of activity.

One of the approaches by which the scientific community is seeking to cure HIV is the use of therapeutic vaccination. Previous studies have highlighted the importance of the virus-specific CD8+ T cell cytotoxic responses for the immune control of HIV and have oriented research on vaccine constructs based on CTL epitopes from circulating HIV-1 strains. The clinical trials with therapeutic vaccines to date have had limited success likely due to (i) a discrepancy between archived CTL epitopes in the viral reservoir and those in circulating viruses before antiretroviral therapy (ART) initiation and (ii) the lack of strong affinity between the selected CTL epitopes and the HLA grooves for presentation to CD8+ cells. To overcome these limitations, we launched the Provir/Latitude 45 study to identify conserved CTL epitopes in archived HIV-1 DNA according to the HLA class I alleles of aviremic patients, most of whom are under ART. The near full-length genomes or Gag, Pol and Nef regions of proviral DNA were sequenced by Sanger and/or Next Generation Sequencing (NGS). The HLA-A and B alleles were defined by NGS or molecular analysis. The TuTuGenetics software, which moves a sliding window of 8 to 10 amino acids through the amino acid alignment, was combined with the Immune Epitope Data Base (IEDB) to automatically calculate the theoretical binding affinity of identified epitopes to the HLA alleles for each individual. We identified 15 conserved epitopes in Pol (11), Gag (3), and Nef (1) according to their potential presentation by the dominant HLA-A and B alleles and now propose to use the corresponding conserved peptides in a multi-epitopic vaccine (HLA-fitted VAC, HFVAC).

BackgroundThe last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality.Methods and findingsWe conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level.ConclusionsSGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention.Trial registrationPROSPERO CRD42016043823.

We proposed a new HIV-1 therapeutic vaccine based on conserved cytotoxic T lymphocyte (CTL) epitopes of archived HIV-1 DNA according to their affinity to the dominant HLA-A and -B alleles of the population investigated. Our proposal (Hla Fitted VAC, HFVAC) was composed of 15 peptides originating from the RT, gag and nef parts of proviral DNA. Our aim was to investigate baseline immune reactivity to the vaccine in HIV-1 chronically infected patients at success of antiretroviral therapy (ART) who would be eligible for a therapeutic vaccine. Forty-one patients were tested. Most of them had been infected with HIV-1 subtype B and all had been receiving successful ART for 2 to 20 years. The predominant HLA-A and -B alleles were those of a Caucasian population. ELISPOT was carried out using the HFVAC peptides. In 22 patients, the PD-1 marker was investigated on CD4+ and CD8+ T cells by flow cytometry in order to evaluate global T cell exhaustion. ELISPOT positivity was 65% overall and 69% in patients exhibiting at least one HLA allele fitting with HFVAC. The percentages of CD4+ and CD8+ T cells expressing PD-1 were high (median values 23.70 and 32.60, respectively), but did not seem to be associated with an impairment of the immune response investigated in vitro. In conclusion, reactivity to HFVAC was high in this ART-treated population with dominant HLA alleles, despite potential cellular exhaustion associated with the PD-1 marker.

Purpose: The relationship between egg and cholesterol intakes, and cardiovascular disease is controversial. Meta-analyses indicate that egg consumption is associated with increased cardiovascular disease and mortality, but reduced incidence of hypertension, a major risk factor for cardiovascular disease. This study aims to investigate the associations between consumption of egg and cholesterol, and hypertension risk in a cohort of French women. Methods: We used data from the E3N cohort study, a French prospective population-based study initiated in 1990. From the women in the study, we included those who completed a detailed diet history questionnaire, and who did not have prevalent hypertension or cardiovascular disease at baseline, resulting in 46,424 women. Hypertension cases were self-reported. Egg and cholesterol intake was estimated from dietary history questionnaires. Cox proportional hazard models with time-updated exposures were used to calculate hazard ratios. Spline regression was used to determine any dose–respondent relationship. Results: During 885,321 person years, 13,161 cases of incident hypertension were identified. Higher cholesterol consumption was associated with an increased risk of hypertension: HRQ1–Q5 = 1.22 [1.14:1.30], with associations similar regarding egg consumption up to seven eggs per week: HR4–7 eggs = 1.14 [1.06:1.18]. Evidence for a non-linear relationship between hypertension and cholesterol intake was observed. Conclusions: Egg and cholesterol intakes were associated with a higher risk of hypertension in French women. These results merit further investigation in other populations.

The Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study has developed predictive risk scores for cardiovascular disease (CVD) and chronic kidney disease (CKD, defined as confirmed estimated glomerular filtration rate [eGFR] ≤ 60 ml/min/1.73 m2) events in HIV-positive people. We hypothesized that participants in D:A:D at high (>5%) predicted risk for both CVD and CKD would be at even greater risk for CVD and CKD events.We included all participants with complete risk factor (covariate) data, baseline eGFR > 60 ml/min/1.73 m2, and a confirmed (>3 months apart) eGFR < 60 ml/min/1.73 m2 thereafter to calculate CVD and CKD risk scores. We calculated CVD and CKD event rates by predicted 5-year CVD and CKD risk groups (≤1%, >1%-5%, >5%) and fitted Poisson models to assess whether CVD and CKD risk group effects were multiplicative. A total of 27,215 participants contributed 202,034 person-years of follow-up: 74% male, median (IQR) age 42 (36, 49) years, median (IQR) baseline year of follow-up 2005 (2004, 2008). D:A:D risk equations predicted 3,560 (13.1%) participants at high CVD risk, 4,996 (18.4%) participants at high CKD risk, and 1,585 (5.8%) participants at both high CKD and high CVD risk. CVD and CKD event rates by predicted risk group were multiplicative. Participants at high CVD risk had a 5.63-fold (95% CI 4.47, 7.09, p < 0.001) increase in CKD events compared to those at low risk; participants at high CKD risk had a 1.31-fold (95% CI 1.09, 1.56, p = 0.005) increase in CVD events compared to those at low risk. Participants' CVD and CKD risk groups had multiplicative predictive effects, with no evidence of an interaction (p = 0.329 and p = 0.291 for CKD and CVD, respectively). The main study limitation is the difference in the ascertainment of the clinically defined CVD endpoints and the laboratory-defined CKD endpoints.We found that people at high predicted risk for both CVD and CKD have substantially greater risks for both CVD and CKD events compared with those at low predicted risk for both outcomes, and compared to those at high predicted risk for only CVD or CKD events. This suggests that CVD and CKD risk in HIV-positive persons should be assessed together. The results further encourage clinicians to prioritise addressing modifiable risks for CVD and CKD in HIV-positive people.

To unravel the complex relationships between cytomegalovirus-induced-, autoimmune-induced responses, microbial translocation and chronic immune activation (CIA) in successfully treated HIV-infected patients and to explore the mediating role of alpha-interferon in these processes.Cross-sectional study nested in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients in South-Western France.Patients initiated antiretroviral therapy between 2005 and 2008 and were treated with sustained virological suppression for at least two years. CIA was defined by the percentage of HLA-DR+/CD38+ among CD8+T-cells. Integrative analyses were performed using structural equation modelling (SEM).The main analysis was performed in 57 HLA-A*0201 positive patients, due to availability of percentages of actin-, vimentin-, lamin-specific CD8+T-cells (HLA-A2-restricted tests) to further characterize autoimmune response. Cytomegalovirus-induced response was assessed by Quantiferon and pp-65 ELISPOT. SEM revealed a direct effect of cytomegalovirus-induced response on CIA (standardized estimate βstd = 0.56, p-value = 0.0004). The effect of autoimmune-induced response on CIA was indirect through alpha-interferon pathway, assessed by expression levels of 5 alpha-interferon-stimulated genes ADAR, ISG15, IFIT1, Mx1 and OAS1 (effect of autoimmune response on alpha-interferon: βstd = 0.36, p-value = 0.0401; effect of alpha-interferon on CIA: βstd = 0.39, p-value = 0.0044). There was no direct effect of autoimmune-induced response on CIA (p-value = 0.3169). Microbial translocation as measured by 16SrDNA and sCD14 in plasma was not associated with CIA. Results were consistent in 142 patients in whom cytomegalovirus and auto-immunity responses were measured by Quantiferon and anti-nuclear antibodies, respectively. All analyses performed in HLA-A*0201 positive patients and in the overall population revealed a significant effect of IFN-α latent variable on CIA.The role of cytomegalovirus-induced response on CIA was confirmed as well as the involvement of alpha-interferon on CIA. The indirect effect of auto-immunity response on CIA revealed through the alpha-interferon pathway requires further investigation to confirm the potential role of auto-immunity for CIA in HIV-infected patients.

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].

Severe non-AIDS bacterial infections (SBI) are the leading cause of hospital admissions among people living with HIV (PLHIV) in industrialized countries. We aimed to estimate the incidence of SBI and their risk factors in a large prospective cohort of PLHIV patients over a 13-year period in France. Patients followed up in the ANRS CO3 Aquitaine cohort between 2000 and 2012 were eligible; SBI was defined as a clinical diagnosis associated with hospitalization of ≥48 hours or death. Survival analysis was conducted to identify risk factors for SBI.Total follow-up duration was 39,256 person-years [PY] (31,370 PY on antiretroviral treatment [ART]). The incidence of SBI decreased from 26.7/1000 PY [95% CI: 22.9-30.5] over the period 2000-2002 to 11.9/1000 PY [10.1-13.8] in 2009-2012 (p 50 copies/mL (Hazard Ratio [HR] = 5.1, 95% Confidence Interval: 4.2-6.2), CD4 count