Immune response to the recombinant herpes zoster vaccine in people living with HIV over 50 years of age compared to non-HIV age-/gender-matched controls (SHINGR'HIV): a multicenter, international, non-randomized clinical trial study protocol.

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).

Changes in incidence of hepatitis C virus reinfection and access to direct-acting antiviral therapies in people with HIV from six countries, 2010-19: an analysis of data from a consortium of prospective cohort studies.

BACKGROUND: Reinfection after successful treatment with direct-acting antivirals is hypothesised to undermine efforts to eliminate hepatitis C virus (HCV) infection among people with HIV. We aimed to assess changes in incidence of HCV reinfection among people with HIV following the introduction of direct-acting antivirals, and the proportion of all incident cases attributable to reinfection. METHODS: We pooled individual-level data on HCV reinfection in people with HIV after spontaneous or treatment-induced clearance of HCV from six cohorts contributing data to the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC) in Australia, Canada, France, the Netherlands, Spain, and Switzerland between Jan 1, 2010, and Dec 31, 2019. Participants were eligible if they had evidence of an HCV infection (HCV antibody or RNA positive test) followed by spontaneous clearance or treatment-induced clearance, with at least one HCV RNA test after clearance enabling measurement of reinfection. We assessed differences in first reinfection incidence between direct-acting antiviral access periods (pre-direct-acting antiviral, limited access [access restricted to people with moderate or severe liver disease and other priority groups], and broad access [access for all patients with chronic HCV]) using Poisson regression. We estimated changes in combined HCV incidence (primary and reinfection) and the relative contribution of infection type by calendar year. FINDINGS: Overall, 6144 people with HIV who were at risk of HCV reinfection (median age 49 years [IQR 42-54]; 4989 [81%] male; 2836 [46%] men who have sex with men; 2360 [38%] people who inject drugs) were followed up for 17 303 person-years and were included in this analysis. The incidence of first HCV reinfection was stable during the period before the introduction of direct-acting antivirals (pre-introduction period; 4·1 cases per 100 person-years, 95% CI 2·8-6·0). Compared with the pre-introduction period, the average incidence of reinfection was 4% lower during the period of limited access (incidence rate ratio [IRR] 0·96, 95% CI 0·78-1·19), and 28% lower during the period of broad access (0·72, 0·60-0·86). Between 2015 and 2019, the proportion of incident HCV infections due to reinfection increased, but combined incidence declined by 34%, from 1·02 cases per 100 person-years (95% CI 0·96-1·07) in 2015 to 0·67 cases per 100 person-years (95% CI 0·59-0·75) in 2019. INTERPRETATION: HCV reinfection incidence and combined incidence declined in people with HIV following direct-acting antiviral introduction, suggesting reinfection has not affected elimination efforts among people with HIV in InCHEHC countries. The proportion of incident HCV cases due to reinfection was highest during periods of broad access to direct-acting antivirals, highlighting the importance of reducing ongoing risks and continuing testing in people at risk. FUNDING: Australian National Health and Medical Research Council.

Time to Treatment Initiation and HIV Viral Suppression in People Diagnosed With HIV-1 During COVID-19 Pandemic in Ex-Aquitaine, France (ANRS CO3 AQUIVIH-NA Cohort-QuAliCOV Study).

OBJECTIVES: The COVID-19 pandemic's impact on initiation and effectiveness of antiretroviral therapy (ART) in people diagnosed with HIV remains unclear. We evaluated critical delays in HIV care in people diagnosed before and during the pandemic in ex-Aquitaine, France. METHODS: We considered adults diagnosed with HIV-1 in 2018-2021 and enrolled in the ANRS CO3 AQUIVIH-NA and followed them until October 10, 2022 for those diagnosed during the pandemic (April 01, 2020-December 31, 2021) and until March 31, 2020 for historical controls. We compared their characteristics at inclusion and the median time between diagnosis and ART initiation, ART initiation and viral suppression, and diagnosis and virologic, suppression (effective management). RESULTS: Eighty-three individuals were diagnosed during the pandemic versus 188 during the prepandemic period. Median follow-up was 549 (interquartile range: 329-713) days. Populations were similar in sex, age, HIV acquisition mode, hospital type, and clinical characteristics at diagnosis; however, fewer were foreign-born during the pandemic (15.7% versus 33.5%, P = 0.003). The probability of ART initiation, therapeutic success, and effective management was higher in people living with HIV (PLWH) diagnosed during the pandemic in adjusted analyses (hazard ratio [HR]: 2.0; 95% CI: 1.5 to 2.7; HR: 1.7; 95% CI: 1.2 to 2.3; HR: 1.8; 95% CI: 1.3 to 2.6, respectively). Those diagnosed during the pandemic were 2.3 (95% CI: 1.2 to 4.1) times more likely to be virologically suppressed within six months of diagnosis compared with historical controls. CONCLUSIONS: Pandemic-related reorganizations may have resulted in newly diagnosed PLWH being prioritized; however, the lower proportion of foreign-born PLWH diagnosed during the pandemic period, likely because of reduced migration and potential delays in diagnosis, may contribute to these preliminary findings.

Factors associated with poorer quality of life in people living with HIV in southwestern France in 2018-2020 (ANRS CO3 AQUIVIH-NA cohort: QuAliV study).

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 < 1500€/month had poorer median adjusted physical, psychological, social, and environmental QoL scores compared to reference groups. While more than half of PLWH reported good/very good QoL, we have not achieved good QoL in 90% of PLWH. Multi-morbidity, HIV-related stigma, and social determinants were consistently and independently associated with poorer QoL. Addressing structural factors in addition to those indirectly related to HIV is required to attain good QoL in all PLWH.

Mechanisms of systemic low-grade inflammation in HIV patients on long-term suppressive antiretroviral therapy: the inflammasome hypothesis.

OBJECTIVE: We aimed to determine the contribution of inflammasome activation in chronic low-grade systemic inflammation observed in patients with HIV (PWH) on long-term suppressive antiretroviral therapy (ART) and to explore mechanisms of such activation. DESIGN: Forty-two PWH on long-term suppressive ART (HIV-RNA < 40 copies/ml) were compared with 10 HIV-negative healthy controls (HC). METHODS: Inflammasome activation was measured by dosing mature interleukin (IL)-1ß and IL-18 cytokines in patient serum. We explored inflammasome pathways through ex vivo stimulation of PWH primary monocytes with inflammasome activators; expression of inflammasome components by transcriptomic analysis; and metabolomics analysis of patient sera. RESULTS: Median (Q1; Q3) age, ART and viral suppression duration in PWH were 54 (48; 60), 15 (9; 20) and 7.5 (5; 12) years, respectively. Higher serum IL-18 was measured in PWH than in HC (61 (42; 77) vs. 36 (27-48 pg/ml), P = 0.009); IL-1ß was detected in 10/42 PWH (0.5 (0.34; 0.80) pg/ml) but not in HC. Monocytes from PWH did not produce more inflammatory cytokines in vitro , but secretion of IL-1ß in response to NOD like receptor family, pyrin domain containing 3 (NLRP3) inflammasome stimulation was higher than in HC. This was not explained at the transcriptional level. We found an oxidative stress molecular profile in PWH sera. CONCLUSION: HIV infection with long-term effective ART is associated with a serum inflammatory signature, including markers of inflammasome activation, and an increased activation of monocytes upon inflammasome stimulation. Other cells should be investigated as sources of inflammatory cytokines in PWH. Oxidative stress might contribute to this chronic low-grade inflammation.

Treatment as prevention effect of direct-acting antivirals on primary hepatitis C virus incidence: Findings from a multinational cohort between 2010 and 2019.

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).

External validation of the PAGE-B score for HCC risk prediction in people living with HIV/HBV coinfection.

BACKGROUND & AIMS: HBV coinfection is common among people living with HIV (PLWH) and is the most important cause of hepatocellular carcinoma (HCC). While risk prediction tools for HCC have been validated in patients with HBV monoinfection, they have not been evaluated in PLWH. Thus, we performed an external validation of PAGE-B in people with HIV/HBV coinfection. METHODS: We included data on PLWH from four European cohorts who were positive for HBsAg and did not have HCC before starting tenofovir. We estimated the predictive performance of PAGE-B for HCC occurrence over 15 years in patients receiving tenofovir-containing antiretroviral therapy. Model discrimination was assessed after multiple imputation using Cox regression with the prognostic index as a covariate, and by calculating Harrell's c-index. Calibration was assessed by comparing our cumulative incidence with the PAGE-B derivation study using Kaplan-Meier curves. RESULTS: In total, 2,963 individuals with HIV/HBV coinfection on tenofovir-containing antiretroviral therapy were included. PAGE-B was <10 in 26.5%, 10-17 in 57.7%, and ≥18 in 15.7% of patients. Within a median follow-up of 9.6 years, HCC occurred in 68 individuals (2.58/1,000 patient-years, 95% CI 2.03-3.27). The regression slope of the prognostic index for developing HCC within 15 years was 0.93 (95% CI 0.61-1.25), and the pooled c-index was 0.77 (range 0.73-0.80), both indicating good model discrimination. The cumulative incidence of HCC was lower in our study compared to the derivation study. A PAGE-B cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. Restricting efforts to individuals with a PAGE-B of ≥10 would spare unnecessary HCC screening in 27% of individuals. CONCLUSIONS: For individuals with HIV/HBV coinfection, PAGE-B is a valid tool to determine the need for HCC screening. IMPACT AND IMPLICATIONS: Chronic HBV infection is the most important cause of hepatocellular carcinoma (HCC) among people living with HIV. Valid risk prediction may enable better targeting of HCC screening efforts to high-risk individuals. We aimed to validate PAGE-B, a risk prediction tool that is based on age, sex, and platelets, in 2,963 individuals with HIV/HBV coinfection who received tenofovir-containing antiretroviral therapy. In the present study, PAGE-B showed good discrimination, adequate calibration, and a cut-off of <10 had a negative predictive value of 99.4% for the development of HCC within 5 years. These results indicate that PAGE-B is a simple and valid risk prediction tool to determine the need for HCC screening among people living with HIV and HBV.

Severe Bacterial Non-AIDS Infections in Persons With Human Immunodeficiency Virus: The Epidemiology and Evolution of Antibiotic Resistance Over an 18-Year Period (2000-2017) in the ANRS CO3 AquiVih-Nouvelle-Aquitaine Cohort.

BACKGROUND: Severe non-AIDS bacterial infections (SBIs) are among the leading causes of hospital admissions among persons with human immunodeficiency virus (PWH) in regions with high antiretroviral therapy coverage. METHODS: This large prospective cohort study of PWH examined the types of infections, bacterial documentation, and evolution of antibiotic resistance among PWH hospitalized with SBIs over an 18-year period. RESULTS: Between 2000 and 2017, 459 PWH had at least 1 SBI with bacterial documentation. Among the 847 SBIs, there were 280 cases of bacteremia, 269 cases of pneumonia, and 240 urinary tract infections. The 1025 isolated bacteria included Enterobacteriaceae (n = 394; mainly Escherichia coli), Staphylococcus aureus (n = 153), and Streptococcus pneumoniae (n = 82). The proportion of S. pneumoniae as the causative agent in pneumonia and bacteremia decreased sharply over time, from 34% to 8% and from 21% to 3%, respectively. The overall antibiotic resistance of S. aureus and S. pneumoniae decreased progressively but it increased for Enterobacteriaceae (from 24% to 48% for amoxicillin-clavulanate, from 4% to 18% for cefotaxime, and from 5% to 27% for ciprofloxacin). Cotrimoxazole prophylaxis was associated with higher nonsusceptibility of S. pneumoniae to amoxicillin and erythromycin, higher nonsusceptibility of Enterobacteriaceae to ß-lactams and fluoroquinolones, and a higher risk of extended-spectrum ß-lactamase-producing Enterobacteriaceae. CONCLUSIONS: The bacterial resistance pattern among PWH between 2014 and 2017 was broadly similar to that in the general population, with the exception of a higher resistance profile of Enterobacteriaceae to fluoroquinolones. The use of cotrimoxazole as prophylaxis was associated with an increased risk of antibiotic resistance.

Tobacco, alcohol, cannabis, and illicit drug use and their association with CD4/CD8 cell count ratio in people with controlled HIV: a cross-sectional study (ANRS CO3 AQUIVIH-NA-QuAliV).

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 < 1. Their mean CD4/CD8 ratio was 1.1 ± 0.6. 35% smoked; ~ 40% were considered to be hazardous drinkers or have alcohol use disorder; 19.9% used cannabis and 11.9% other drugs. Chemsex-associated drug users' CD4/CD8 ratio was on average 0.226 (95% confidence interval [95% CI] - 0.383, - 0.070) lower than that of non-users in univariable analysis (p = 0.005) and 0.165 lower [95% CI - 0.343, 0.012] in multivariable analysis (p = 0.068). CONCLUSIONS: Mean differences in CD4/CD8 ratio were not significantly different in tobacco, alcohol and cannabis users compared to non-users. However, Chemsex-associated drug users may represent a population at risk of chronic inflammation, the specific determinants of which merit further investigation. TRIAL REGISTRATION NUMBER: NCT03296202.

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.

A comprehensive analysis of excess depressive disorder in women and men living with HIV in France compared to the general population.

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.

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.

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 ).

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.

Web-Based Module for the Collection of Electronic Patient-Reported Outcomes in People Living With HIV in Nouvelle Aquitaine, France: Usability Evaluation.

BACKGROUND: Patient-reported outcomes (PROs) can be of great value for both research and chronic disease management. We developed a new module of the ANRS CO3 Aquitaine cohort study's Web-based data capture and visualization solution (APPEGE 2.0) for the collection of electronic PROs among people living with HIV cared for in Nouvelle Aquitaine, France. OBJECTIVE: This study aimed to evaluate the usability of 2 successively developed prototypes of ARPEGE 2.0's electronic PROs module before launching a pilot study, owing to the novelty of the proposed data collection method for our setting and specific characteristics of the target population. METHODS: A total of 2 sequential rounds of empirical, task-based usability evaluations were conducted, involving 8 research staff and then 7 people living with HIV. Evaluators provided written feedback during round 1 and oral feedback during round 2. Evaluators who completed the full set of tasks responded to the System Usability Scale (SUS). We assessed changes in SUS scores between rounds and concluded usability testing when SUS scores reached a ceiling effect, defining good usability a priori as a usability score of 70. RESULTS: Insights were generated regarding the visibility of system status and the match between the system and the real world that improved the module's usability. Research staff evaluators reported mean SUS scores of 65 (SD 18.87) and patient evaluators reported mean SUS scores of 85 (SD 5.4; P=.032). CONCLUSIONS: Software modifications, informed by successive rounds of usability testing, resulted in sufficient gains in usability to undertake piloting. Insights generated during evaluations prompted us to find the appropriate balance between optimal security and ease of use. TRIAL REGISTRATION: ClinicalTrials.gov NCT03296202; https://clinicaltrials.gov/ct2/show/NCT03296202. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/10.2196/resprot.9439.

Integrating Electronic Patient-Reported Outcome Measures into Routine HIV Care and the ANRS CO3 Aquitaine Cohort's Data Capture and Visualization System (QuAliV): Protocol for a Formative Research Study.

BACKGROUND: Effective antiretroviral therapy has greatly reduced HIV-related morbidity and mortality, dramatically changing the demographics of the population of people living with HIV. The majority of people living with HIV in France are well cared for insofar as their HIV infection is concerned but remain at risk for age-associated comorbidities. Their long-term, potentially complex, and growing care needs make the routine, longitudinal assessment of health-related quality of life and other patient-reported outcomes of relevance in the current treatment era. OBJECTIVE: We aim to describe the development of a Web-based electronic patient-reported outcomes system for people living with HIV linked to the ANRS CO3 Aquitaine cohort's data capture and visualization system (ARPEGE) and designed to facilitate the electronic collection of patient-reported data and ultimately promote better patient-physician communication and quality of care (both patient satisfaction and health outcomes). METHODS: Participants who meet the eligibility criteria will be invited to engage with the Web-based electronic patient-reported outcomes system and provided with the information necessary to create a personal patient account. They will then be able to access the electronic patient-reported outcomes system and complete a set of standardized validated questionnaires covering health-related quality of life (World Health Organization's Quality of Life Instrument in HIV infection, named WHOQOL-HIV BREF) and other patient-reported outcomes. The information provided via questionnaires will ultimately be presented in a summary format for clinicians, together with the patient's HIV care history. RESULTS: The prototype of the Web-based electronic patient-reported outcome system will be finalized and the first 2 formative research phases of the study (prototyping and usability testing) will be conducted from December 2017 to May 2018. We describe the sequential processes planned to ensure that the proposed electronic patient-reported outcome system is ready for formal pilot testing, referred to herein as phases 1a and 1b. We also describe the planned pilot-testing designed to evaluate the acceptability and use of the system from the patient's perspective (phase 2). CONCLUSIONS: As the underlying information technology solution, ARPEGE, has being developed in-house, should the feasibility study presented here yield promising results, the panel of services provided via the proposed portal could ultimately be expanded and used to experiment with health-promoting interventions in aging people living with HIV in hospital-based care or adapted for use in other patient populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03296202; https://clinicaltrials.gov/ct2/show/NCT03296202 (Archived by WebCite at http://www.webcitation.org/6zgOBArps). REGISTERED REPORT IDENTIFIER: RR1-10.2196/9439.

HIV-induced immune deficiency is associated with a higher risk of hepatocarcinoma, ANRS CO3 Aquitaine Cohort, France, 1998-2008.

BACKGROUND & AIMS: HIV and viral hepatitis co-infected patients are at high risk for hepatocarcinoma. The contribution of immunodeficiency is not well documented. We aimed at estimating the relationship between the occurrence of hepatocarcinoma and both types of measures of immunodeficiency, current and cumulative (time below a given threshold), to assess their independent effects. METHODS: HIV-infected adults included in the ANRS CO3 Aquitaine Cohort with no history of cancer, ≥ 3 months of follow-up between 1998 and 2008, ≥ 1 CD4+ cell count (CD4+), and documented hepatitis virus status were eligible. Extended Cox proportional hazards models with delayed entry were used to estimate the risk of hepatocarcinoma. Exposure to a CD4+ < 350 or <500 cells/mm(3) (current and cumulative duration) was time-updated. Hepatitis B or C virus co-infection and gender were fixed-effect variables. RESULTS: Sixteen cases of hepatocarcinoma were diagnosed among the 2864 eligible patients, the incidence rate was 0.78 case/1000 person-years (95% Confidence Interval [CI]: 0.40-1.16). Current CD4+ < 350 or < 500 was independently associated with a higher risk of hepatocarcinoma (Hazard Ratio [HR]: 5.0, CI 1.5-16.8, p = 0.009 and HR = 10.3, CI 1.3-82.8, p = 0.029, respectively). The occurrence of hepatocarcinoma was independent of the cumulative exposure to a CD4+ < 350 or < 500 (p = 0.38 or p = 0.80, respectively). CONCLUSIONS: Presenting with CD4+ < 500 was associated with a higher risk of hepatocarcinoma, whereas the cumulative duration with immunodeficiency was not. These results suggest that moving CD4+ count above 500 following antiretroviral therapy initiation is associated with a decreased risk of hepatocarcinoma, regardless of the duration of HIV-induced immunodeficiency.