Cardiac Adverse Events and Remdesivir in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19): A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial.

BACKGROUND: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) receiving remdesivir plus standard of care (SoC) compared to SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. METHODS: This post-hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19 (NCT04315948). Any first AE occurring between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves and Kaplan-Meier estimates were calculated for event rates. RESULTS: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (HR 1.0, 95% CI 0.7-1.5, p = 0.98), even when evaluating serious and non-serious cardiac AEs separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between remdesivir and control groups in the occurrence of different cardiac AE subclasses, including arrhythmic events (HR 1.1, 95% CI: 0.7-1.7, p = 0.68). CONCLUSIONS: Remdesivir treatment was not associated with an increased risk of cardiac AEs, whether serious or not, and regardless of AE severity, compared to control, in patients hospitalized with moderate or severe COVID-19. This is consistent with the results of other randomized controlled trials and meta-analyses.

Decrease in CD4 T-Cell Count and Risk of Severe Morbid Conditions in People With Human Immunodeficiency Virus Infection With Controlled Viral Load After Initiating Combination Antiretroviral Therapy Between 2006 and 2018.

BACKGROUND: A previous study showed an association between CD4 T-cell count decline in people with human immunodeficiency virus infection (PWH) with viral suppression and an increased risk of severe morbid conditions. We aimed to assess the risk of CD4 T-cell count decline (hereafter, CD4 decline), determine associated factors, and evaluate the association of this decline with the risk of severe morbid conditions (cardiovascular disease and cancer) or death. METHODS: From the Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) CO4 French Hospital Database on HIV cohort, we selected PWH >18 years old who had been followed up for ≥2 years after viral suppression following the initiation of combination antiretroviral therapy (cART) between 2006 and 2018. CD4 decline was defined as 2 consecutive relative differences ≥15%. Among participants with such decline, we modeled CD4, CD8, and total lymphocyte counts before and after CD4 decline, using spline regression. The remaining objectives were assessed using Poisson regression, with the association between CD4 decline and the risk of severe morbid conditions or death evaluated during or after 6 months of decline. RESULTS: Among 15 714 participants (75 417 person-years), 181 presented with CD4 decline (incidence rate, 2.4/1000 person-years (95% confidence interval, 2.1-2.8). CD8 and total lymphocyte counts also showed a similar decline. Older current age and lower viral load at treatment initiation were associated with the risk of CD4 decline. The risk of severe morbid conditions or death was 11-fold higher during the first 6 months for participants who presented with CD4 decline versus those who did not (incidence rate ratio, 10.8 [95% confidence interval, 5.1-22.8]), with no significant difference after 6 months. CONCLUSIONS: In PWH with viral suppression, CD4 decline was rare and related to global lymphopenia. It was associated with a higher risk of severe morbid conditions or death during the first 6 months.

Screening HIV Patients at Risk for NAFLD Using MRI-PDFF and Transient Elastography: A European Multicenter Prospective Study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a growing concern in the aging population with human immunodeficiency virus (HIV). Screening for NAFLD is recommended in patients with metabolic risk factors or unexplained transaminitis. This study aimed to prospectively assess the prevalence and associated factors of liver steatosis and advanced fibrosis (AF) in HIV-monoinfected patients at risk of NAFLD. METHODS: We conducted a multicenter study in HIV-monoinfected patients, nonexcessive drinkers with metabolic syndrome, and/or persistently elevated liver enzymes, and/or clinical lipodystrophy. All participants had magnetic resonance imaging proton density fat fraction (MRI-PDFF), Fibroscan/controlled attenuation parameter (CAP), and cytokine and genetic analysis. RESULTS: From March 2014 to November 2015, we enrolled 442 participants and analyzed 402: male (85%); median age, 55 years (interquartile range [IQR], 50-61 years); body mass index, 27.0 kg/m2 (IQR, 23.6-28.7 kg/m2); metabolic syndrome (67%); and CD4 cell count, 630/mm3 (IQR, 510-832/mm3). Overall 257 of 402 (64%) had NAFLD (MRI-PDFF ≥5%). Among them, 11.3% had a liver stiffness ≥9.6 kPa, suggestive of AF. Multivariable analysis identified 7 factors of steatosis: high CD4-cell count (odds ratio [OR], 4.04; 95% confidence interval [CI], 1.92-8.51), high leptin level (OR, 2.12; 95% CI, 1.14-3.93), non-CC PNPLA3s738409 genetic polymorphism (OR, 1.92; 95% CI, 1.11-3.33), low high-density lipoprotein (OR, 1.83; 95% CI, 1.03-3.27), high triglycerides (OR, 1.48; 95% CI, 1.18-1.84), elevated alanine transaminase (OR, 1.23; 95% CI, 1.16-1.31), and hyper ferritinemia (OR, 1.05; 95% CI, 1.03-1.07). Two factors were associated with AF: high body mass index (OR, 1.23 ; 95% CI, 1.07-1.42 ; P = .005, and elevated aspartate aminotransferase (OR, 1.03; 95% CI, 1.01-1.05; P = .001). Using MRI-PDFF as a reference, CAP (best cutoff, 280 dB/m) had good accuracy (area under the receiver operating characteristic curve = 0.86; 95% CI, 0.82-0.90) for the diagnosis of moderate to severe steatosis. CONCLUSIONS: In a large cohort of HIV-moninfected patients at risk of NAFLD, steatosis is present in two-thirds of cases, and around 10% have AF. The CAP technique is accurate for screening steatosis in this population.

Striking differences in weight gain after cART initiation depending on early or advanced presentation: results from the ANRS CO4 FHDH cohort.

BACKGROUND: Many studies have reported weight gain in ART-naive people living with HIV (PWH) initiating an integrase strand-transfer inhibitor-based regimen. We studied the impact of early or advanced presentation and that of individual drugs in PWH initiating combined ART (cART) between 2012 and 2018. METHODS: From the French Hospital Database HIV cohort, we assessed factors associated with a weight gain  ≥10%, weight change after cART initiation or BMI increase  ≥5 kg/m2 up to 30 months. The analyses were conducted overall, and among PWH with early (primary infection or CD4 >350/mm3 and viral load  <100 000 copies/mL, without AIDS) and advanced presentation (AIDS or CD4 <200/mm3, not during primary infection). RESULTS: At 30 months, 34.5% (95% CI: 33.5-35.6) of the 12 773 PWH had a weight gain ≥10%, with 20.9% (95% CI: 19.6-22.2) among the 5794 with early presentation and 63.1% (95% CI: 60.9-65.3) among the 3106 with advanced presentation. Weight gain was 2.8 kg (95% CI: 2.0-3.7) for those with early presentation and 9.7 kg (95% CI: 8.4-11.1) for those with advanced presentation. Most weight gain occurred in the first 12 months. Underweight and obese PWH were at significantly higher risk of a BMI increase  ≥5 kg/m2 than normal-weight PWH. Results differed within classes and by outcome. Raltegravir and dolutegravir were consistently associated with greater weight gain than the other third agents. Tenofovir alafenamide was also associated with higher weight gain than tenofovir disoproxil or abacavir. CONCLUSIONS: After initiating cART, PWH with early presentation exhibited a small weight gain, whereas it was large among those with advanced presentation. The choice of ART should account for the risk of weight gain, especially for PWH who present with advanced disease and/or are obese.

Four days/week antiretroviral maintenance strategy (ANRS 170 QUATUOR): substudies of reservoirs and ultrasensitive drug resistance.

BACKGROUND: In a 4 days/week (4/7 days) maintenance strategy (ANRS-170 QUATUOR trial), the virological impact of an intermittent strategy was assessed by ultrasensitive virological analyses of reservoirs and resistance. METHODS: HIV-1 total DNA, ultra-sensitive plasma viral load (USpVL) and semen VL were measured in the first 121 participants. Sanger and ultra-deep sequencing (UDS) were performed on the HIV-1 genome (Illumina technology) according to the ANRS consensus. A generalized estimation equation with a Poisson distribution was used to compare changes in the proportion of residual viraemia, detectable semen HIV RNA and HIV DNA within and between the two groups over time. RESULTS: The proportion of participants with residual viraemia at Day 0 (D0) and Week 48 (W48) was 16.7% and 25.0% in the 4/7 days group and 22.4% and 29.7% in the 7/7 days group, respectively (+8.3% versus +7.3%, P = 0.971). The proportion of detectable DNA (>40 copies/106 cells) at D0 and W48 was 53.7% and 57.4% in the 4/7 days group and 56.1% and 51.8% in the 7/7 days group, respectively (+3.7% versus -4.3%, P = 0.358). Semen HIV RNA was detectable (≥100 copies/mL) in 2.2% of participants at D0 and 4.5% at W48 in the 4/7 days group versus 6.1% and 9.1% in the 7/7 days group, respectively (+2.3% versus +3.0%, P = 0.743). Emerging resistance at failure was more frequent in the 4/7 days group detected by Sanger sequencing: 3/6 participants versus 1/4 in the 7/7 days group, and similar with the UDS assay: 5/6 versus 4/4, respectively. CONCLUSIONS: These findings support the potency of a 4/7 days maintenance strategy on virological suppression at the reservoirs and emergent resistance level, including minority variants.

Impact of corticosteroids use on midterm sequelae in survivors of COVID-19 admitted to hospital: A prospective cohort study.

An understanding of the midterm sequelae in COVID-19 and their association with corticosteroids use are needed. Between March and July 2020, we evaluated 1227 survivors of COVID-19, 3 months posthospitalization, of whom 213 had received corticosteroids within 7 days of admission. Main outcome was any midterm sequelae (oxygen therapy, shortness of breath, one major clinical sign, two minor clinical signs or three minor symptoms). Association between corticosteroids use and midterm sequelae was assessed using inverse propensity-score weighting models. Our sample included 753 (61%) male patients, and 512 (42%) were older than 65 years. We found a higher rate of sequelae among users than nonusers of corticosteroids (42% vs. 35%, odds ratio [OR] 1.40 [1.16-1.69]). Midterm sequelae were more frequent in users of low-dose corticosteroids than nonusers (64% vs. 51%, OR 1.60 [1.10-2.32]), whereas no association between higher doses (≥20 mg/day equivalent of dexamethasone) and sequelae was evidenced (OR 0.95 [0.56-1.61]). Higher risk of sequelae with corticosteroids use was observed among subjects with propensity score below the 90th percentile. Our study suggest that corticosteroids use during hospitalization for COVID-19 is associated with higher risk of midterm sequelae.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Impact on renal function of daily and on-demand HIV pre-exposure prophylaxis in the ANRS-PREVENIR study.

OBJECTIVES: To assess the impact on the estimated glomerular filtration rate (eGFR) of different tenofovir disoproxil/emtricitabine dosing regimens for HIV pre-exposure prophylaxis (PrEP). PATIENTS AND METHODS: We included in the study individuals with baseline eGFR > 50 mL/min/1.73 m2 who initiated PrEP in the ongoing ANRS-PREVENIR PrEP cohort. We retrospectively classified PrEP users in three groups: 'on-demand' (reported at ≥75% of study visits), 'daily' (≥75% of study visits) or 'switches'. We compared the area under curve (AUC) of the eGFR variation from baseline (ΔeGFR) between groups using analysis of covariance, and assessed factors associated with a negative AUC of ΔeGFR. RESULTS: From May 2017 to October 2020, 1253 PrEP-naïve participants (98% of MSM) were included in the study with a median follow-up of 22 months. 499 (40%), 494 (39%) and 260 (21%) users were in the group daily, on-demand and switches, respectively, for a median number of pills taken per week of 6, 1.7 and 4. The mean AUC of the ΔeGFR was -1.09 mL/min/1.73 m2 in the daily PrEP group, -0.69 mL/min/1.73 m2 in the switches group and +0.18 mL/min/1.73 m2 with on-demand PrEP. In a model adjusted on baseline age and eGFR, the AUC of the ΔeGFR was significantly higher with on-demand PrEP compared to daily PrEP (P = 0.037). Independent factors associated with a negative AUC of ΔeGFR were a daily PrEP regimen, a switches regimen, an age > 40 years and a baseline eGFR≥90 mL/min/1.73 m². CONCLUSIONS: On-demand PrEP dosing had a smaller impact on eGFR evolution than daily PrEP, but the difference was not clinically relevant.

Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial.

BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

Household transmission of SARS-CoV-2 infection in the Paris/Ile-de-France area.

This st udy aims to evaluate the prevalence of SARS-CoV-2 antibodies in locked-down family households to determine viral dynamics and immunity acquisition. COVID-19 individuals and their households in lockdown under the same roof during early spring 2020 were interviewed and tested using rapid immunochromatographic lateral flow antibodies assays (LFA) between July and September 2020. Outcomes were secondary infection rate (SIR) among contacts, household infection rate, and predictors of transmission. We enrolled 87 households including 87 COVID-19 index cases (female 78.2%; median age: 47.0 years, IQR: 42.0-51.5) and 255 contacts (males: 52.9%; median age: 19.0 years, IQR: 11.0-43.5) consisting of their children (42%) or spouses/partners (28.2%). A total of 95/255 contacts were SARS-CoV-2 antibody positive leading to a SIR of 37.3% (95% confidence interval (CI): 31.3-43.5%). Viral transmission was observed in 54 households (62%). SARS-CoV-2 infection was asymptomatic in 33/95 (34.7%) of SARS-CoV-2-positive contacts. Independent predictors of virus transmission from index to contacts were housing surface area < 60 m2 (OR: 5.6 [1.1; 28.2] and a four-member family compared to five (OR: 3.6 [1.2; 10.3]). Households represent a high-risk setting for SARS-CoV-2 transmission through close contact within the family amplified by the number of family members and the housing surface area.

Increased risk of severe COVID-19 in hospitalized patients with SARS-CoV-2 Alpha variant infection: a multicentre matched cohort study.

BACKGROUND: The impact of the variant of concern (VOC) Alpha on the severity of COVID-19 has been debated. We report our analysis in France. METHODS: We conducted an exposed/unexposed cohort study with retrospective data collection, comparing patients infected by VOC Alpha to contemporaneous patients infected by historical lineages. Participants were matched on age (± 2.5 years), sex and region of hospitalization. The primary endpoint was the proportion of hospitalized participants with severe COVID-19, defined as a WHO-scale > 5 or by the need of a non-rebreather mask, occurring up to day 29 after admission. We used a logistic regression model stratified on each matched pair and accounting for factors known to be associated with the severity of the disease. RESULTS: We included 650 pairs of patients hospitalized between Jan 1, 2021, and Feb 28, 2021, in 47 hospitals. Median age was 70 years and 61.3% of participants were male. The proportion of participants with comorbidities was high in both groups (85.0% vs 90%, p = 0.004). Infection by VOC Alpha was associated with a higher odds of severe COVID-19 (41.7% vs 38.5%-aOR = 1.33 95% CI [1.03-1.72]). CONCLUSION: Infection by the VOC Alpha was associated with a higher odds of severe COVID-19.

CD4/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies.

BACKGROUND: A persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH. METHODS: PLWH from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) were included if they achieved virological control (viral load ≤ 500 copies/mL) within 9 months following cART and without previous KS/LNH diagnosis. Cox models were used to identify factors associated with KS or NHL risk, in all participants and those with CD4 ≥ 500/mm3 at virological control. We analyzed the CD4/CD8 ratio, CD4 count and CD8 count as time-dependent variables, using spline transformations. RESULTS: We included 56 708 PLWH, enrolled between 2000 and 2014. At virological control, the median (interquartile range [IQR]) CD4 count, CD8 count, and CD4/CD8 ratio were 414 (296-552)/mm3, 936 (670-1304)/mm3, and 0.43 (0.28-0.65), respectively. Overall, 221 KS and 187 NHL were diagnosed 9 (2-37) and 18 (7-42) months after virological control. Low CD4/CD8 ratios were associated with KS risk (hazard ratio [HR] = 2.02 [95% confidence interval {CI } = 1.23-3.31]) when comparing CD4/CD8 = 0.3 to CD4/CD8 = 1) but not with NHL risk. High CD8 counts were associated with higher NHL risk (HR = 3.14 [95% CI = 1.58-6.22]) when comparing CD8 = 3000/mm3 to CD8 = 1000/mm3). Similar results with increased associations were found in PLWH with CD4 ≥ 500/mm3 at virological control (HR = 3.27 [95% CI = 1.60-6.56] for KS; HR = 5.28 [95% CI = 2.17-12.83] for NHL). CONCLUSIONS: Low CD4/CD8 ratios and high CD8 counts despite effective cART were associated with increased KS/NHL risks respectively, especially when CD4 ≥ 500/mm3.

Use of rilpivirine in HIV-1-infected individuals in routine clinical practice from 2012 to 2017 in France.

OBJECTIVES: We assessed virological outcomes of rilpivirine use in France from 2012 to 2017, in three groups of people living with HIV (PLHIV): (i) antiretroviral (ARV)-naive PLHIV; (ii) ARV-experienced PLHIV switching to rilpivirine while failing therapy; and (iii) ARV-experienced PLHIV switching to rilpivirine while virologically controlled. METHODS: Virological success (VS) was defined as a plasma HIV-1 viral load (VL) <50 copies/mL and virological failure (VF) as two consecutive VL >50 copies/mL or one VL >50 copies/mL followed by a treatment switch prior to the next VL measurement. The cumulative incidence of VS was assessed considering rilpivirine discontinuation, loss to follow-up and death as competing risks, while estimates of cumulative incidence of VF accounted for loss to follow-up and death. RESULTS: Among the 2166 ARV-naive PLHIV initiating rilpivirine, the 4 year cumulative incidence of VS was 91.0% and was associated with baseline VL. Among the 2125 ARV-experienced PLHIV switching to rilpivirine while failing therapy, the 4 year cumulative incidence of VS was 82.5% and was associated with lower VL, higher CD4 and less than three prior ARVs. Among the 11 828 ARV-experienced PLHIV switching to rilpivirine while virologically controlled, the 4 year cumulative incidence of VF was 9.6%. The risk of VF was lower among MSM, for PLHIV with CD4 ≥ 500 cell/mm3, without a prior AIDS event, or with a longer VL suppression at baseline. CONCLUSIONS: Rilpivirine-containing regimens yielded high rates of viral suppression in most participants, while it was ineffective when used outside the marketing authorization in naive participants.

Genetic variation near CXCL12 is associated with susceptibility to HIV-related non-Hodgkin lymphoma.

Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

Pharmacological data of a successful 4-days-a-week regimen in HIV antiretroviral therapy (ANRS 162-4D trial).

INTRODUCTION: Few data are available on plasma concentrations of antiretroviral therapy (ARV) during intermittent treatment. OBJECTIVE: To compare plasma concentrations in OFF vs ON treatment periods at several time points during treatment. METHODS: During a successful 48-week multicenter study (ANRS 162-4D trial) of 4 days with treatment (ON) followed by 3 days without treatment (OFF) in adults treated by two nucleoside analogues and a third agent belonging to a boosted protease-inhibitor (PI, darunavir [DRV], atazanavir [ATV], lopinavir [LPV]) or a non-nucleoside-reverse-transcriptase inhibitor (NNRTI, efavirenz [EFV], etravirine [ETR], rilpivirine [RPV]) conducted in 100 patients (96% success), we determined the plasma concentrations of ARV. Blood samples were collected for analysis at inclusion (W0, 7/7 strategy for all patients), W16 and W40 (ON) and at W4, W8, W12, W24, W32 and W48 (OFF). RESULTS: A total of 866 samples was analysed. Plasma concentrations were not statistically lower after 4 days (ON) vs 7/7 days of treatment except for RPV (-30 ng/mL at 4/7, P = 0.003). Significant lower plasma concentrations were observed for OFF vs ON except for ETR (n = 5, P = 0.062). Overall, 87.1% of ON concentrations (ATV 92.1%, DRV 51.1%, LPV 62.5%, EFV 94.4%, ETR 100% and RPV 94.9%) and 21.8% of OFF concentrations (ATV 1.4%, DRV 0.0%, LPV 0.0%, EFV 16.0%, ETR 92.6% and RPV 39.0%) were above the theoretical limit of efficacy of the molecule. In the OFF period, 85.8% of PI concentrations were under the limit of quantification, while 98.0% of NNRTI concentrations were quantifiable. CONCLUSION: Despite low/undetectable PI/NNRTI plasma concentrations in the OFF period, patients maintained an undetectable viral load. The mechanistic explanation should be investigated.

Addition of Maraviroc Versus Placebo to Standard Antiretroviral Therapy for Initial Treatment of Advanced HIV Infection: A Randomized Trial.

Background: Patients diagnosed with advanced HIV infection have a poor prognosis despite initiation of combined antiretroviral therapy (c-ART). Objective: To assess the benefit of adding maraviroc, an antiretroviral drug with immunologic effects, to standard c-ART for patients with advanced disease at HIV diagnosis. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT01348308). Setting: Clinical sites in France (n = 25), Italy (n = 5), and Spain (n = 20). Participants: 416 HIV-positive, antiretroviral-naive adults with CD4 counts less than 0.200 × 109 cells/L and/or a previous AIDS-defining event (ADE). Intervention: C-ART plus placebo or maraviroc (300 mg twice daily with dose modification) for 72 weeks. Measurements: The primary end point was first occurrence of severe morbidity (new ADE, selected serious infections, serious non-ADE, immune reconstitution inflammatory syndrome, or death). Prespecified secondary outcomes included primary outcome components, biological and pharmacokinetic measures, and adverse events graded 2 or higher. Results: 409 randomly assigned participants (207 in the placebo group and 202 in the maraviroc group) who received more than 1 dose were included in the analysis. During 72 weeks of follow-up, incidence of severe morbidity was 11.1 per 100 person-years in the maraviroc group and 11.2 per 100 person-years in the placebo group (hazard ratio, 0.97 [95% CI, 0.57 to 1.67]). Incidence of adverse events graded 2 or higher was 36.1 versus 41.5 per 100 person-years (incidence rate ratio, 0.87 [CI, 0.65 to 1.15]). Limitations: Sixty-four participants discontinued therapy during follow-up. The study was not designed to evaluate time-dependent outcomes or effect modification. Conclusion: Addition of maraviroc to standard c-ART does not improve clinical outcomes of patients initiating therapy for advanced HIV infection. Primary Funding Source: INSERM-ANRS (French National Agency for Research on AIDS).

Hepatitis C virus (HCV) incidence among men who have sex with men (MSM) living with HIV: results from the French Hospital Database on HIV (ANRS CO4-FHDH) cohort study, 2014 to 2017.

BackgroundDespite the availability of highly effective direct-acting antivirals (DAAs) and the expected treatment as prevention (TasP) effect, transmission of hepatitis C virus (HCV) persists in men who have sex with men (MSM) who engage in high-risk sexual behaviours.AimWe aimed to estimate the incidence of primary HCV infection among MSM living with HIV in France when DAA was readily available.MethodsWe used data from a large French hospital cohort of persons living with HIV (ANRS CO4-FHDH) prospectively collected between 2014 and 2017. HCV incidence rates were calculated using person-time methods for HCV-negative MSM at inclusion who had serological follow-up from 1 January 2014 to 31 December 2017. Sensitivity analyses were performed by varying the main assumptions to assess their impact on the results.ResultsOf 14,273 MSM living with HIV who were initially HCV-seronegative, 330 acquired HCV during follow-up over 45,866 person-years (py), resulting in an overall estimated incidence rate of 0.72/100 py (95% CI: 0.65-0.80). HCV incidence significantly decreased from 0.98/100 py (95% CI: 0.81-1.19) in 2014 to 0.45/100 py (95% CI: 0.35-0.59) in 2017 (54% decrease; 95% CI: 36-67). This trend was confirmed by most of the sensitivity analyses.ConclusionThe primary incidence of HCV was halved for MSM living with HIV between 2014 and 2017. This decrease may be related to unrestricted DAA availability in France for individuals living with HIV. Further interventions, including risk reduction, are needed to reach HCV micro-elimination in MSM living with HIV.

Risk of Severe Bacterial Infection in People Living Human Immunodeficiency Virus Infection in the Combined Antiretroviral Therapy Era.

BACKGROUND: Severe bacterial infections are the first cause of morbidity in people with human immunodeficiency virus (PWH). We aimed to assess their incidence and to analyze their determinants. METHODS: We studied human immunodeficiency virus (HIV)-1-infected individuals aged at least 15 years and prospectively followed between 2006 and 2015 in the French Hospital Database on HIV. The Andersen and Gill model was used to calculate the adjusted hazard ratios (HRs), focusing on heavy alcohol use and neutrophil function-altering comorbidities. RESULTS: Of 25 795 participants, 1414 developed 1883 severe bacterial infections. Between 2006 and 2009 and 2013 and 2015, the incidence fell from 13.2 (95% confidence interval [CI], 12.3-14.1) to 7.1 (95% CI, 6.3-7.8) per 1000 person-years. Heavy alcohol use was associated with an increased risk of severe bacterial infection (HR = 1.3, 95% CI = 1.1-1.7 for 40-80 g/day and HR = 1.6, 95% CI = 1.2-2.1 for >80 g/day), as were diabetes, chronic kidney disease, and end-stage liver disease (HR = 1.2, 95% CI = 1.0-1.4 when 1 comorbidity; HR = 2.3, 95% CI = 1.6-3.4 when more than 1 comorbidity), and nonacquired immune deficiency syndrome-defining malignancy (HR = 2.0; 95% CI, 1.6-2.4). CONCLUSIONS: Heavy alcohol use was associated with an increased risk of severe bacterial infection, as were neutrophil function-altering comorbidities. Controlled-drinking approaches should be promoted and comorbidity management should be strengthened in PWH.

Is the Risk of Myocardial Infarction in People With Human Immunodeficiency Virus (HIV) Associated With Atazanavir or Darunavir? A Nested Case-Control Study Within the French Hospital Database on HIV.

BACKGROUND: The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study has reported an increased risk of cardiovascular diseases in people with human immunodeficiency virus who were exposed to darunavir (DRV) but not to atazanavir (ATV). Our objective was to evaluate associations between ATV or DRV exposures and the risk of myocardial infarction (MI) in a nested case-control study within ANRS-CO4 French Hospital Database on HIV (FHDH). METHODS: Cases were individuals who had a first validated MI between 2006 and 2012. Up to 5 controls were selected at random with replacement among individuals with no history of MI, followed at the time of MI diagnosis, and matched for age and sex. Conditional logistic regression models were used to adjust for potential confounders (MI risk factors and HIV-related parameters) and for cumulative exposure to each antiretroviral drug (ARV). RESULTS: Overall, 408 MI cases and 1250 controls were included: 109 (27%) cases and 288 (23%) controls had been exposed to ATV, and 41 (10%) cases and 107 (9%) controls had been exposed to DRV. There was no significant association between exposure to ATV (adjusted odds ratio [OR] = 1.54; 95% confidence interval [CI], .87-2.73) or DRV (adjusted OR = 0.51; 95% CI, .11-2.32) and the risk of MI. CONCLUSIONS: In FHDH, exposures to ATV or to DRV were not significantly associated with the risk of MI, adjusting for complete ARV history, contrary to the analysis in DAD.

Factors Influencing the Incubation of an Infectious Form of Creutzfeldt-Jakob Disease.

The French epidemics of iatrogenic Creutzfeldt-Jakob disease after growth hormone (GH) treatment provide an opportunity to understand factors governing the inter-human transmission of prions. The present analysis relying on truncated Weibull distribution supports a relationship between host genetics, dose of the at-risk GH, age at treatment onset, and duration of the incubation period.