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With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. 3909 of the 49 731 D:A:D study participants died during the 308 719 person-years of follow-up (crude incidence mortality rate, 12·7 per 1000 person-years [95% CI 12·3–13·1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17·5 in 1999–2000 to 9·1 in 2009–11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5·9 to 2·0), deaths from liver disease (2·7 to 0·9), and cardiovascular disease deaths (1·8 to 0·9). However, non-AIDS cancers increased slightly from 1·6 per 1000 person-years in 1999–2000 to 2·1 in 2009–11 (p=0·58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009–11 vs 1999–2000: 0·92 [0·70–1·22]). However, all-cause (0·72 [0·61–0·83]), liver disease (0·48 [0·32–0·74]), and cardiovascular disease (0·33 [0·20–0·53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999–2000 and 141/627 [22%] in 2009–11) and liver-related (40/256 [16%] in 1999–2000 and 64/627 [10%] in 2009–11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999–2000 to 142/627 [23%] in 2009–11). Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

HIV replication leads to a change in lymphocyte phenotypes that impairs immune protection against opportunistic infections. We examined current HIV replication as an independent risk factor for tuberculosis (TB). We included people living with HIV from 25 European cohorts 1983-2015. Individuals <16 years or with previous TB were excluded. Person-time was calculated from enrolment (baseline) to the date of TB diagnosis or last follow-up information. We used adjusted Poisson regression and general additive regression models. We included 272,548 people with a median follow-up of 5.9 years (interquartile range [IQR] 2.3-10.9). At baseline, the median CD4 cell count was 355 cells/μL (IQR 193-540) and the median HIV-RNA level 22,000 copies/mL (IQR 1,300-103,000). During 1,923,441 person-years of follow-up, 5,956 (2.2%) people developed TB. Overall, TB incidence was 3.1 per 1,000 person-years (95% confidence interval [CI] 3.02-3.18) and was four times higher in patients with HIV-RNA levels of 10,000 compared with levels <400 copies/mL in any CD4 stratum. CD4 and HIV-RNA time-updated analyses showed that the association between HIV-RNA and TB incidence was independent of CD4. The TB incidence rate ratio for people born in TB-endemic countries compared with those born in Europe was 1.8 (95% CI 1.5-2.2). Our results indicate that ongoing HIV replication (suboptimal HIV control) is an important risk factor for TB, independent of CD4 count. Those at highest risk of TB are people from TB-endemic countries. Close monitoring and TB preventive therapy for people with suboptimal HIV control is important.

Despite huge advances in the fight against HIV concerning diagnosis, clinical efficacy of antiretroviral treatments (ART), patient survival and quality of life, there is still no cure. Recent developments in HIV cure research have opened the way for clinical trials which could lead to a temporary or definitive end to ART. However, ethical questions exist about related trial-participation risks. The main goal of the ANRS-APSEC survey was, using Q-methodology, to investigate the viewpoints of people living with HIV (PLWH) and HIV healthcare providers (HHP) regarding motivations for and barriers to participation in HIV Cure-related clinical trials (HCRCT). Thirty-three statements were defined encompassing seven dimensions: treatment and follow-up; risks; benefits; patient-physician relationship; beliefs and attitudes; information; target population. Forty-one PLWH and 41 HHP from five French HIV services were asked to rank-order the statements. Five main viewpoints were elicited from \"the most motivated\" to \"the most reluctant\" vis-à-vis HCRCT participation. All placed importance on the wish to participate in HIV research. This result is in line with the HIV-specific culture of joint mobilization. For some viewpoints, the motivation to participate in/propose HCRCT was primarily conditioned by side-effects and/or by constraints, which overall were more accepted by PLWH than HHP. Some viewpoints placed particular importance on HCRCT recruitment strategies. Finally, some expressed a high acceptance of risks and constraints but emphasized the need for information. HIV cure research clinical trials (HCRCT) constitute a risky yet unavoidable step towards the goal of finding a cure. To improve future HCRCT and informed consent designs, based on PLWH and HHP preferences and expectations, we need greater knowledge about how these populations perceive the risks and the benefits of HCRCT. Our results confirmed the importance of careful, studied HCRCT design, management and communication, to ensure PLWH and HHP acceptability and convergence of their expectations.

The current study aimed at describing the distribution and characteristics of malignancy related deaths in human immunodeficiency virus (HIV) infected patients in 2010 and at comparing them to those obtained in 2000 and 2005. Data were obtained from three national surveys conducted in France in 2010, 2005 and 2000. The underlying cause of death was documented using a standardized questionnaire fulfilled in French hospital wards involved in the management of HIV infection. Among the 728 deaths reported in 2010, 262 were cancer-related (36%). After a significant increase from 28% in 2000 to 33% in 2005 and 36% in 2010, cancers represent the leading cause of mortality in HIV infected patients. The proportion of deaths attributed to non-AIDS/non-hepatitis-related cancers significantly increased from 2000 to 2010 (11% of the deaths in 2000, 17% in 2005 and 22% in 2010, p<0.001), while those attributed to AIDS-defining cancers decreased during the same period (16% in 2000, 13% in 2005 and 9% in 2010, p = 0.024). Particularly, the proportion of respiratory cancers significantly increased from 5% in 2000 to 6% in 2005 and 11% in 2010 (p = 0.004). Lung cancer was the most common cancer-related cause of death in 2010 (instead of non-Hodgkin lymphoma so far) and represented the leading cause of death in people living with HIV overall. Cancer prevention (especially smoking cessation), screening strategies and therapeutic management need to be optimized in HIV-infected patients in order to reduce mortality, particularly in the field of respiratory cancers.

Comparison of changes in body composition, adipokines and inflammatory markers after initial therapy with a nucleos(t)ide reverse transcriptase inhibitor (N(t)RTI)- sparing or containing regimen are scarce. Randomised Clinical Trial. This is the body composition substudy of NEAT 001/ANRS 143, a randomised trial comparing darunavir/ritonavir (DRV/r) plus either raltegravir (RAL) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in 805 ART naïve HIV-infected adults. The primary endpoint was percentage change in limb fat at week 96. Secondary endpoints were associations among these changes and metabolic markers (IL-6, insulin, leptin, adiponectin, FGF-23). 126 subjects (61 DRV/r + RAL and 65 DRV/r + TDF/FTC) were included. The rate of change in BMI between groups for RAL versus TDF/FTC at week 96 was 1.5% per 48-week period (p = 0.015). The rate of change in limb fat mass, trunk fat mass, total body fat and total lean mass was for RAL versus TDF/FTC at week 96 was 2.5% (p = 0.38), 7.3% ((p = 0.021), 4.9% (p = 0.061) and 1.3% (p = 0.12) respectively. Baseline insulin and leptin levels were correlated with baseline limb fat and trunk fat mass [r = 0.31 (p = 0.0043)/r = 0.28 (p = 0.0011) for limb fat, and r = 0.63 (p<0.0001)/r = 0.50(p<0.0001) for trunk fat]. After adjustment, a 10% faster increase in leptin between baseline and week 48 was associated with a more rapid increase in limb fat at week 48 (0.5% per 48 weeks, p<0.001), total body fat mass (0.6% per 48 weeks, p<0.001), and trunk fat mass (0.3% per 48 weeks, p = 0.0026). After week 96 a N(t)RTI sparing regimen of DRV/r + RAL produced a numerically greater percentage increase in body composition variables with only change in trunk fat mass and BMI being significant.

Background. The goal of the current study was to describe the distribution and characteristics of malignancy-related deaths among human immunodeficiency virus (HIV)-infected patients with use of data obtained from a national survey conducted in France in 2005 and to compare with results obtained from a similar survey conducted in 2000. Method. The underlying cause of death was documented using a standardized questionnaire fulfilled in French hospital wards and networks that were involved in the treatment of HIV-infected patients. Results. Among the 1042 deaths reported in 2005 (964 were reported in 2000), 344 were cancer related (34%), which represented a significant increase from 2000 (29% of deaths were cancer related) (P=.02); 134 of the cancer-related deaths were AIDS related and 210 were not AIDS related. Among the cancer-related causes of death, the proportion of hepatitis-related cancers (6% in 2000 vs. 11% in 2005) and non-AIDS/hepatitis-related cancers (38% in 2000 vs 50% in 2005) significantly increased from 2000 to 2005 (P=.03 and P=.01, respectively), compared with the proportion of cancer that was AIDS related and adjusting for age and sex. Among cases involving AIDS, the proportion of non-Hodgkin lymphoma-associated deaths did not change statistically significantly between 2000 and 2005 (11% and 10% of deaths, respectively). Conclusions. In this study, an increasing proportion of lethal non-AIDS-related cancers was demonstrated from 2000 to 2005; meanwhile, the proportion of lethal AIDS-related cancers remained stable among HIV-infected patients. Thus, cancer prophylaxis, early diagnosis, and improved management should be included in the routine long-term follow-up of HIV-infected patients.

Background Nontuberculous mycobacteria (NTM) are environmental organisms associated with a range of infections. Reports of NTM epidemiology are mainly focused on pulmonary infections and isolations, and extrapulmonary infections are less frequently described. Methods We conducted a retrospective study of NTM infections at the Bordeaux University Hospital, France, between January 2002 and December 2013. We used the microbiologic component of the American Thoracic Society/Infectious Diseases Society of America's pulmonary NTM disease criteria to define cases of pulmonary NTM, and patients with isolates from a normally sterile site were classified as having extrapulmonary disease. Results In our setting, 170 patients were included. Pulmonary cases predominated (54.1%), followed by skin and soft tissue infections (22.9%), disseminated cases (10.6%), lymphadenitis (7.7%), bone and joint infections (2.9%) and the remaining 1.8% catheter-related infections. Overall, 16 NTM species were isolated. Mycobacterium avium (31.8%) and M. intracellulare (20%) were the most common species identified, followed by M. marinum (13.5%), M. kansasii (10.6%), M. xenopi (9.4%), rapidly growing mycobacteria (9.4%) and other slowly growing mycobacteria (5.3%). In general, NTM isolates were largely prevalent in people older than 50 (62.4%); patients aged 1-10 year-old exclusively yielded M. avium from lymph nodes, almost cases having being diagnosed after 2007. Among the 121 patients with complete follow-up, 78 (64.5%), 24 (19.8%), and 19 (15.7%) were cured, experienced relapse, or died, respectively. Conclusion In our study, extrapulmonary NTM infections represented almost half of cases, consisting mainly in skin and soft tissue infections. The increase lymphadenitis cases in children after 2007 could be linked to the cessation of mandatory BCG vaccination in France. We observed similar cure rates (64%) between pulmonary and extrapulmonary infections.

To examine the role of antiretroviral drugs (ART), HIV-related and traditional risk factors on the incidence of chronic kidney disease (CKD) in HIV-infected patients. Prospective hospital-based cohort of HIV-infected patients from 2004 to 2012. CKD was defined using MDRD equation as an estimated glomerular filtration rate (eGFR) less than 60 ml/mn/1.73 m(2) at 2 consecutive measurements ≥3 months apart. Poisson regression models were used to study determinants of CKD either measured at baseline or updated. ART exposure was classified as ever or never. We additionally tested the role of tenofovir (TDF), whether or not prescribed concomitantly with a Protease Inhibitor (PI), taking into account the cumulative exposure to the drug. 4,350 patients (74% men) with baseline eGFR>60 ml/mn/1.73 m(2) were followed for a median of 5.8 years. At the end of follow-up, 96% had received ART, one third of them (35%) jointly received TDF and a PI. Average incidence rate of CKD was 0.95% person-years of follow-up. Incidence of CKD was higher among women (IRR = 2.2), older patients (>60 y vs <45 y: IRR = 2.5 and 45-60 y: IRR = 1.7), those with diabetes (IRR = 1.9), high blood pressure (IRR = 1.5), hyperlipidemia (IRR = 1.5), AIDS stage (IRR = 1.4), low baseline eGFR (IRR = 15.8 for 6090 and IRR = 7.1 for 70500/mm(3) (IRR = 2.5), and exposure to TDF (IRR = 2.0). Exposure to TDF was even strongly associated with CKD when co-administered with PIs (IRR = 3.1 vs 1.3 when not, p<0,001). A higher risk of CKD was found when tenofovir exposure was >12 months [IRR = 3.0 with joint PIs vs 1.3 without (p<0.001)]. A vast majority of those developing CKD (76.6%) had a baseline eGFR between 60 and 80 ml/mn/1.73 m(2). In patients with eGFR between 60 and 80 mL/min/1.73 m(2), a thorough control of CKD risk factors is warranted. The use of TDF, especially when co-administered with PIs, should be mentioned as a relative contraindication in presence of at least one of these risk factors.

Clinical relevance of low-frequency HIV-1 variants carrying drug resistance associated mutations (DRMs) is still unclear. We aimed to study the prevalence of low-frequency DRMs, detected by Ultra-Deep Sequencing (UDS) before antiretroviral therapy (ART) and at virological failure (VF), in HIV-1 infected patients experiencing VF on first-line ART. Twenty-nine ART-naive patients followed up in the ANRS-CO3 Aquitaine Cohort, having initiated ART between 2000 and 2009 and experiencing VF (2 plasma viral loads (VL) >500 copies/ml or one VL >1000 copies/ml) were included. Reverse transcriptase and protease DRMs were identified using Sanger sequencing (SS) and UDS at baseline (before ART initiation) and VF. Additional low-frequency variants with PI-, NNRTI- and NRTI-DRMs were found by UDS at baseline and VF, significantly increasing the number of detected DRMs by 1.35 fold (p<0.0001) compared to SS. These low-frequency DRMs modified ARV susceptibility predictions to the prescribed treatment for 1 patient at baseline, in whom low-frequency DRM was found at high frequency at VF, and 6 patients at VF. DRMs found at VF were rarely detected as low-frequency DRMs prior to treatment. The rare low-frequency NNRTI- and NRTI-DRMs detected at baseline that correlated with the prescribed treatment were most often found at high-frequency at VF. Low frequency DRMs detected before ART initiation and at VF in patients experiencing VF on first-line ART can increase the overall burden of resistance to PI, NRTI and NNRTI.

ObjectivesThis work aimed to study the prevalence and risk factors associated with well-being and career satisfaction among French internal medicine physicians and residents.MethodsA total of 1689 French internal medicine physicians or trainees were surveyed to evaluate their workload, well-being and career satisfaction during February 2018.ResultsThe response rate was 620/1689 (37%). The mean age of the participants was 37 years (±12); 49% of the participants were female, 27% worked in the Paris area, 74% worked in a university hospital and 49% were residents. Sixty-six per cent of the responders were satisfied with their work, and 66% would choose the internal medicine specialty again. However, 71% of the responders worked more than 50 hours a week, 21% worked more than 60 hours a week and 70% believed that they did not have enough time for personal/family activities. Twenty-five per cent of the responders had at least one sign of burnout (19% of the physicians in practice and 32% of the residents). Compared with the graduate physicians in practice, the residents worked more hours a week, had more activities at night, spent more time on administrative tasks, had a worse global appreciation of their work and felt that their work was less meaningful. In multivariate analysis, the factors associated with global satisfaction at work were autonomy and meaningful work.ConclusionsFrench internal medicine physicians have a high rate of career satisfaction. However, residents have a higher workload, less time for personal/family activities and feel that their work is less meaningful.