Assessing the psychometric properties of the French WHOQOL-HIV BREF within the ANRS CO3 Aquitaine Cohort's QuAliV ancillary study.

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 ).

Emulating a trial of joint dynamic strategies: An application to monitoring and treatment of HIV-positive individuals.

Decisions about when to start or switch a therapy often depend on the frequency with which individuals are monitored or tested. For example, the optimal time to switch antiretroviral therapy depends on the frequency with which HIV-positive individuals have HIV RNA measured. This paper describes an approach to use observational data for the comparison of joint monitoring and treatment strategies and applies the method to a clinically relevant question in HIV research: when can monitoring frequency be decreased and when should individuals switch from a first-line treatment regimen to a new regimen? We outline the target trial that would compare the dynamic strategies of interest and then describe how to emulate it using data from HIV-positive individuals included in the HIV-CAUSAL Collaboration and the Centers for AIDS Research Network of Integrated Clinical Systems. When, as in our example, few individuals follow the dynamic strategies of interest over long periods of follow-up, we describe how to leverage an additional assumption: no direct effect of monitoring on the outcome of interest. We compare our results with and without the "no direct effect" assumption. We found little differences on survival and AIDS-free survival between strategies where monitoring frequency was decreased at a CD4 threshold of 350 cells/µl compared with 500 cells/µl and where treatment was switched at an HIV-RNA threshold of 1000 copies/ml compared with 200 copies/ml. The "no direct effect" assumption resulted in efficiency improvements for the risk difference estimates ranging from an 7- to 53-fold increase in the effective sample size.

Long-term follow-up of HIV-1 multi-drug-resistant treatment-experienced participants treated with etravirine, raltegravir and boosted darunavir: towards drug-reduced regimen? ANRS CO3 Aquitaine Cohort 2007-2018.

OBJECTIVE: To assess the efficacy of raltegravir, etravirine and darunavir/ritonavir (TRIO regimen) in treatment-experienced patients with human immunodeficiency virus-1 (HIV-1) infection by describing the proportion of patients who experienced virological failure (VF) at Week 24. The secondary objectives were to assess the HIV-1 plasma viral load (pVL) after Week 24, the proportion of patients who were receiving dual therapy or monotherapy at the last visit, and the number of deaths. METHODS: Patients from the ANRS CO3 Aquitaine Cohort who were prescribed the TRIO regimen between February 2007 and September 2018 were classified into two groups based on their pVL at study inclusion: the virological failure group (VFG; pVL >50 copies/mL) and the virologically suppressed group (VSG; pVL <50 copies/mL). The impact of baseline pVL and genotypic susceptibility score (GSS) on VF was analysed. RESULTS: In total, 184 patients were enrolled in this study, with 123 (66.8%) in the VFG and 61 (33.2%) in the VSG. The median length of follow-up was 7.5 (interquartile range 4.1-9.6) years, and 29 (15.8%) patients died. Thirty-seven (25.5%) patients experienced VF at Week 24, including 32/145 (32.7%) in the VFG and 5/47 (10.6%) in the VSG (P<0.01). Resistance-associated mutations were detected in integrase, reverse transcriptase and protease for 7/37 (18.9%), 3/37 (8.1%) and 1/37 (2.7%) patients, respectively. High pVL and GSS at baseline were independently associated with VF. At the last visit, 76/184 (41.3%) patients were still receiving the TRIO regimen, while 55/184 (29.9%) were receiving dual therapy and 1/184 (0.5%) was receiving protease inhibitor monotherapy. Among the 56 patients receiving dual therapy or monotherapy, 51 (96.2%) had pVL <50 copies/mL. CONCLUSION: Despite a high level of mutation resistance at baseline, long-term virological follow-up was favourable and one-third of patients were eligible for drug-reducing strategies.

Incidence of lung and human papilloma virus-associated malignancies in HIV-infected patients.

OBJECTIVE: Cancers represent one of the leading cause of mortality/morbidity in patients with HIV (PWH) in industrialized countries. The objective of our study was to compare incidence of lung and human papilloma virus (HPV)-related cancers among PWH with general population over the 2010-2017 period. DESIGN: Prospective and multicenter cohort study. METHODS: The study included patients with lung and HPV-related cancers from the ANRS CO3 Aquitaine cohort (PWH) and the general population-based cancer registry in Gironde area. We calculated incidence rates for 100 000 person-years and incidence rate ratios (IRR). RESULTS: Among the 3572 PWH, 70 cancers were diagnosed in 68 patients including 35 lung and 35 HPV-related cancers (18 oropharyngeal, 11 anal, 6 cervix). Incidence rates of lung and HPV-related-cancers were 311.1 in PWH and 209.8 in general population for 100 000 person-years, respectively. IRR were significantly increased in PWH for lung 1.8 [1.4-2.2] and HPV-related cancer 1.3 [1.0-1.6] and particularly high for patients between 40 and 49 years old [IRR 4.4 (2.3-8.4) for lung cancer and 3.7 (2.1-6.5) for HPV-related cancer]. CONCLUSION: We emphasized the persistent high risk of lung and HPV-related cancer despite advent of antiretroviral therapies, particularly in the age strata of 40-49 years. Screening procedures should take into account this finding.

Statin use and risk of severe bacterial infection in a population living with HIV: prospective cohort study of the ANRS CO3 Aquitaine Cohort 2000-2018.

OBJECTIVES: Bacterial infections remain one of the main causes of morbidity and death in people living with HIV (PLHIV) in the most recent years. Several studies have demonstrated a protective effect of statins in the primary prevention of bacterial infections in other immunocompromised populations, but this effect remains controversial. The objective of this study was to evaluate the effect of statin use on the occurrence of a first episode of severe bacterial infection (SBI) in PLHIV in the ANRS CO3 Aquitaine cohort between 2000 and 2018. METHODS: All individuals included in the prospective ANRS CO3 Aquitaine cohort who had at least two follow-up visits between 2000 and 2018 were included. The primary endpoint was the occurrence of a first episode of bacterial infection leading to hospitalization of ≥48 hours or death. Statin exposure was updated during follow-up. Marginal Cox structural models were developed to consider the potential indication bias and time-dependent confusion. Numerous sensitivity analyses were carried out. RESULTS: In this study 51 658 person-years were followed. The overall incidence of a first episode of SBI was 12.4/1000 person-years. No effect of statins on the occurrence of SBI was demonstrated when subjects were considered on statins throughout their follow-up after treatment initiation (HR = 0.97; 95%CI: 0.75-1.25). The results were similar for the effect of statins on the risk of pneumonia and for all sensitivity analyses. CONCLUSION: In this large cohort of PLHIV with 18 years of follow-up and a high risk of severe infections, we found no effect of statins on the risk of occurrence of SBI or pneumonia.

A Low Level of Darunavir Resistance-Associated Mutation Emergence in Patients With Virological Failure During Long-term Use of Darunavir in People With HIV. The ANRS CO3 Aquitaine Cohort.

BACKGROUND: Ritonavir-boosted darunavir (DRV/r) is a protease inhibitor (PI) indicated for the treatment of naïve and pretreated HIV-infected patients since 2007. Our study aims to describe DRV/r-treated patients experiencing virological failure (VF) documented with HIV resistance testing. METHODS: Data from patients belonging to the ANRS CO3 Aquitaine Cohort treated with a regimen including DRV/r between February 2007 and December 2015 were analyzed. Baseline characteristics of patients experiencing VF (defined by 2 consecutive plasma viral loads >50 copies/mL) were compared with those without VF. We then described factors associated with VF as emergence of IAS DRV resistance-associated mutations (RAMs). RESULTS: Among the 1458 patients treated at least once with a DRV/r-based regimen, 270 (18.5%) patients experienced VF during follow-up, including 240 with at least 1 genotype resistance test (GRT). DRV RAMs were detected in 29 patients (12%). Among them, 25/29 patients had ≥2 DRV RAMs before DRV/r initiation, all of whom had experienced VF during previous PI treatments. For 18/29, DRV/r was maintained after VF, and controlled viremia was restored after modification of DRV-associated antiretroviral molecules or increased DRV dose. Finally, only 6/29 patients selected new DRV RAMs after DRV/r initiation. All of these experienced previous VFs while on other PIs. CONCLUSIONS: These results highlight the efficacy and robustness of DRV/r, as the emergence of DRV RAMs appeared in <0.4% of patients receiving a DRV/r-based regimen in our large cohort.

Serum suppression of tumorigenicity 2 level is an independent predictor of all-cause mortality in HIV-infected patients.

OBJECTIVE: To evaluate the predictive value of soluble suppression of tumorigenicity 2 (sST2), a decoy receptor of IL-33 involved in several inflammatory and immune diseases, for death in HIV infection. DESIGN: Patients enrolled in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients, who had a plasma sample available in the biobank were systematically eligible. METHODS: sST2, soluble CD14 (sCD14) and IL-6 were measured using Luminex multiplex bead-based technology (R&D Systems) and a Bio-Plex 200 instrument (BioRad). Predictive capacities of sST2, sCD14, IL-6 and of the Veterans Aging Cohort Study clinical score at baseline on overall mortality were compared using multivariable Cox proportional hazards models. RESULTS: During a median follow-up of 7.2 years [interquartile range (IQR): 6.0; 7.9], 93 deaths from all causes (incidence rate 9.9 per 1000 patient-years; 95% confidence interval 7.9-11.9) were reported in 1414 patients. The median sST2 baseline concentration was 22.9 ng/ml (IQR: 17.7; 30.3) and was higher (30.8 ng/ml, IQR: 21.5; 42.1) in patients who died as compared with those who stayed alive (22.6 ng/ml; IQR: 17.5; 29.6) (P < 10). An increased risk of death of 21% for a concentration 10.0 ng/ml higher of sST2 remained after adjustment for sCD14, IL-6 and Veterans Aging Cohort Study score (adjusted hazard ratio: 1.21; P < 10). The predictive capacity of sST2 was confirmed in a validation cohort (n = 386, 31 deaths) with an improved area c-index from 0.804 without sST2 to 0.811 with sST2. CONCLUSION: sST2 is a new valuable biomarker to evaluate the risk of all-cause mortality in HIV disease.

Incidence and Risk Factors for Severe Bacterial Infections in People Living with HIV. ANRS CO3 Aquitaine Cohort, 2000-2012.

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 <0.0001). Factors independently associated to increased risk of SBI were: plasma HIVRNA>50 copies/mL (Hazard Ratio [HR] = 5.1, 95% Confidence Interval: 4.2-6.2), CD4 count <500 cells/mm3 and CD4/CD8 ratio <0.8 (with a dose-response relationship for both markers), history of cancer (HR = 1.4 [1.0-1.9]), AIDS stage (HR = 1.7 [1.3-2.1]) and HCV coinfection (HR = 1.4, [1.1-1.6]). HIV-positive patients with diabetes were more prone to SBI (HR = 1.6 [0.9-2.6]). Incidence of SBI decreased over a 13-year period due to the improvement in the virological and immune status of PLHIV on ART. Risk factors for SBI include low CD4 count and detectable HIV RNA, but also CD4/CD8 ratio, HCV coinfection, history of cancer and diabetes, comorbid conditions that have been frequent among PLHIV in recent years.

Protease inhibitors exposure is not related to lung cancer risk in HIV smoker patients: a nested case-control study.

OBJECTIVE: We aimed at assessing in persons living with HIV with a smoking history an association between lung cancer risk and protease inhibitors exposure, especially ritonavir. DESIGN: A nested case-control study was conducted within the ANRS CO4 FHDH, CO3 Aquitaine and Tenon's Hospital Cohorts. METHODS: Cases and controls were eligible if they were ex-smokers or current smokers at the index date, and had a CD4 cell count reported in the year preceding the index date. Cases were incident cases of lung cancer diagnosed between 1 January 2000 and 31 December 2011. All cancer cases were validated and histological types identified when available. Three controls were randomly selected by incidence density sampling using calendar time as the time axis, with individual matching on cohort, age (± 5 years), route of HIV acquisition, sex and hospital. Analyses were performed using conditional logistic regression adjusted for nadir CD4 cell count and smoking status. Ritonavir and protease inhibitors exposures were represented in separate models using categorical variables (never exposed, ever exposed). Several sensitivity analyses were performed. RESULTS: This study performed in 1447 persons living with HIV with a smoking history (383 lung cancer cases and 1064 control patients) did not evidence any association between lung cancer risk and protease inhibitors exposure including ritonavir. CONCLUSION: These results suggest that the risk of lung cancer is not influenced by pharmacologically induced P450 cytochrome protease inhibitors inhibition among smokers or ex-smokers.

Switch to Rilpivirine/Emtricitabine/Tenofovir Single-Tablet Regimen of Human Immunodeficiency Virus-1 RNA-Suppressed Patients, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales CO3 Aquitaine Cohort, 2012-2014.

Background. The purpose of this study was to assess the efficacy and tolerability of combined antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-1 virologically suppressed patients who switched to rilpivirine (RPV)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) as a single-tablet regimen (STR). Methods. A retrospective multicenter cohort study was performed between September 2012 and February 2014 in Bordeaux University Hospital-affiliated clinics. Patients with a plasma HIV viral load (VL) lower than 50 copies/mL and switching to STR were evaluated at baseline, 3, 6, 9, and 12 months from switch time (M3, M6, M9, M12) for VL and other biological parameters. Change from baseline in CD4 cell counts was evaluated at M6 and M12. Virological failure (VF) was defined as 2 consecutive VL >50 copies/mL. Results. Three hundred four patients were included in the analysis. Single-tablet regimen switch was proposed to 116 patients with adverse events, mostly efavirenz (EFV)-based (n = 59), and to 224 patients for cART simplification. Thirty of 196 patients with available genotype resistance test results displayed virus with ≥1 drug resistance mutation on reverse-transcriptase gene. After 12 months of follow-up, 93.4% (95.5% confidence interval, 89.9-96.2) of patients remained virologically suppressed. There was no significant change in CD4 cell count. During the study period, 5 patients experienced VF, one of them harboring RPV resistance mutation. Clinical cART tolerability improved in 79 patients overall (29.9%) at M6, especially neurological symptoms related to EFV. Fasting serum lipid profiles improved, but a significant estimated glomerular function rate decrease (-11 mL/min/1.73 m(2); P < 10(-4)) was observed. Conclusions. Overall, virologic suppression was maintained in patients after switching to RPV/TDF/ FTC. This STR strategy was associated with improved tolerability.

Association of immune-activation and senescence markers with non-AIDS-defining comorbidities in HIV-suppressed patients.

OBJECTIVES: We studied the link between T-cell activation, differentiation and senescence phenotypes and non-AIDS-related comorbidities in HIV-suppressed patients. DESIGN: Patients included in the ANRS CO3 Aquitaine Cohort were consecutively enrolled in this cross-sectional study between October 2011 and May 2013 called Chronic Immune Activation and Senescence (CIADIS) study. METHODS: We summarized immune markers [CD4 and CD8 activation (DR), differentiation (naive and terminally differentiated memory T cells), and senescence (CD57CD28)] in a weighted immune score by principal component analysis called CIADIS. Previously described Veterans Aging Cohort Study (VACS) index and immune risk profile (IRP) scores were calculated. We used adjusted logistic regression to assess the association between the CIADIS score and the presence of at least three non-AIDS-defining comorbidities. RESULTS: Of 876 patients with an undetectable viral load, 73.4% were men and median age was 50.5 years [interquartile range (IQR) 44.7-56.7 years]. Median CD4 T-cell count was 579/µl (IQR 429-759 cells/µl), and median duration of HIV viral suppression was 5.3 years (IQR 2.3-8.7). The weighted CIADIS score was associated with at least three comorbidities (odds ratio 1.3 for 1 SD more, 95% confidence interval 1.0, 1.6) independently of age, sex, AIDS stage, and the Veterans Aging Cohort Study score. The CIADIS and the immune risk profile scores were significantly associated with at least three comorbidities in adjusted models restricted to patients younger than 60 years. None of the tested scores were associated with at least three comorbidities in patients older than 60 years. CONCLUSIONS: The weighted CIADIS score based on activation, senescence, and differentiation markers might help physicians identifying patients at a higher risk for non-AIDS-related comorbidities.

Incidence and risk factors for thoracic spine pain in the working population: the French Pays de la Loire study.

OBJECTIVE: To examine the incidence and risk factors for incident thoracic spine pain (TSP) in workers representative of a French region's working population. METHODS: In this prospective study, 3,710 workers were assessed in 2002-2005, and 2,332 (62.9%) of them were reassessed in 2007-2010. TSP was assessed by a self-administered Nordic questionnaire at baseline and at followup. At baseline, all participants completed a self-administered questionnaire on personal factors and work exposure. A total of 1,886 subjects (1,124 men and 762 women) without TSP at baseline were eligible for analysis. Associations between incident TSP and risk factors at baseline were analyzed by multivariate logistic regression. RESULTS: The incidence rate of TSP was 5.2 (95% confidence interval [95% CI] 3.9-6.6) per 100 men and 10.0 (95% CI 7.8-12.1) per 100 women. TSP was often associated with low back pain and neck pain. TSP in men was associated with age (odds ratios [ORs] ranging from 2.6 [95% CI 0.95-7.1] at 30-39 years to 6.0 [95% CI 2.1-17.3] at ≥50 years), being tall (OR 2.2 [95% CI 1.2-3.9]), frequent/sustained trunk bending (OR 3.0 [95% CI 1.5-6.1]), lack of recovery period or change in the task (OR 2.0 [95% CI 1.2-3.6]), and driving vehicles (OR 2.8 [95% CI 1.4-5.5]). Being overweight or obese was associated with lower risk (OR 0.5 [95% CI 0.3-0.96]). TSP in women was associated with high perceived physical workload (OR 1.9 [95% CI 1.1-3.3]), after adjustment for confounding variables. CONCLUSION: The risk model of TSP combined personal and work-related organizational and physical factors. Trunk bending appeared to be a strong independent predictor of TSP in this working population.