Publications by authors named "Francois Raffi"

234 Publications

Modeling SARS-CoV-2 viral kinetics and association with mortality in hospitalized patients from the French COVID cohort.

Proc Natl Acad Sci U S A 2021 02;118(8)

Université de Paris, INSERM, IAME, F-75018 Paris, France.

The characterization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics in hospitalized patients and its association with mortality is unknown. We analyzed death and nasopharyngeal viral kinetics in 655 hospitalized patients from the prospective French COVID cohort. The model predicted a median peak viral load that coincided with symptom onset. Patients with age ≥65 y had a smaller loss rate of infected cells, leading to a delayed median time to viral clearance occurring 16 d after symptom onset as compared to 13 d in younger patients ( < 10). In multivariate analysis, the risk factors associated with mortality were age ≥65 y, male gender, and presence of chronic pulmonary disease (hazard ratio [HR] > 2.0). Using a joint model, viral dynamics after hospital admission was an independent predictor of mortality (HR = 1.31, < 10). Finally, we used our model to simulate the effects of effective pharmacological interventions on time to viral clearance and mortality. A treatment able to reduce viral production by 90% upon hospital admission would shorten the time to viral clearance by 2.0 and 2.9 d in patients of age <65 y and ≥65 y, respectively. Assuming that the association between viral dynamics and mortality would remain similar to that observed in our population, this could translate into a reduction of mortality from 19 to 14% in patients of age ≥65 y with risk factors. Our results show that viral dynamics is associated with mortality in hospitalized patients. Strategies aiming to reduce viral load could have an effect on mortality rate in this population.
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http://dx.doi.org/10.1073/pnas.2017962118DOI Listing
February 2021

Evaluation of drug abuse by hair analysis and self-reported use among MSM under PrEP: Results from a French sub-study of the ANRS-IPERGAY trial.

J Acquir Immune Defic Syndr 2020 Dec 23;Publish Ahead of Print. Epub 2020 Dec 23.

Département des Maladies Infectieuses, Hôpital Tenon, AP-HP, Paris, France; INSERM SC10 US19, Villejuif, France; Département de Pharmacologie - Toxicologie, Hôpital Raymond Poincaré, AP-HP, et MassSpecLab, Plateforme de Spectrométrie de Masse, Inserm U-1173, UFR des Sciences de la Santé Simone Veil, Université Paris-Saclay (Versailles Saint-Quentin-en-Yvelines), Garches, France; Département de Pharmacologie - Toxicologie, Hôpital Bichat Claude Bernard, AP-HP, et IAME, INSERM, UMRS1137, Université de Paris, Paris, France Aix Marseille Université, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Marseille, France; ORS PACA, Observatoire régional de la santé Provence-Alpes-Côte d'Azur, Marseille, France; Département des Maladies Infectieuses, Hôpital de l'Archet, Nice, France; Département des Maladies Infectieuses, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France; Département des Maladies Infectieuses, Hôpital G Dron, Centre Hospitalier Universitaire de Tourcoing, Tourcoing, France; Université Paris Sud, Paris, France; Hôtel-Dieu, Département des Maladies Infectieuses, Nantes, France; Sorbonne Université; Département de Maladies Infectieuses, Hôpital Lariboisière Saint-Louis, Paris, France; Université de Paris, Paris, France; INSERM U944, Paris, France.

Abstract.

Background: We used the ANRS-IPERGAY trial in order to qualitatively and quantitatively measure drug use among MSM under PrEP using two different methods, in order to better understand and collectively respond to risky practices.

Method: We included 69 voluntaries of ANRS-IPERGAY trial. We measured drug use by two methods: (1) Drug detection by hair analysis; (2) Reported drug use by self-reported drug consumption.

Results: New Psychoactive Substances (NPS) and conventional drugs were detected in 53/69 (77%) by hair analysis and in 39/69 (57%) by questionnaires. On the 219 hair segments analyzed, the most commonly used drugs were cocaine in 47/69 (68%), MDMA/ecstasy in 31/69 (45%), NPS in 27/69 (39%). On the 1,061 collected questionnaires, the most commonly used drugs were cocaine in 31/69 (45%), MDMA/ecstasy in 29/69 (42%) and NPS in 16/69 (23%). Hair analysis detects more conventional drugs and/or NPS use (p<0.05). Drug use identified by hair was significantly associated with a higher number of sexual partners in the past two months (p≤0.001), more often casual partners (p≤0.001), condomless anal sex (p≤0.005), hardcore sexual practices (p≤0.001), a higher number of STIs and chemsex (p≤0.05).

Conclusion: Self-report drug use by questionnaires remains the reference tool for harm reduction at the individual level due to its feasibility and low cost. However, hair analysis is more sensitive, objectively assessing consumption and is interesting in order to understand uses and to be able to collectively respond to risky practices with adapted messages.
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http://dx.doi.org/10.1097/QAI.0000000000002610DOI Listing
December 2020

Influence of the ARV regimen on the early changes in plasma HIV RNA and immune activation at initiation of antiretroviral therapy in naïve HIV-1-infected patients.

J Acquir Immune Defic Syndr 2020 Dec 17;Publish Ahead of Print. Epub 2020 Dec 17.

Sorbonne Université, Inserm 1135, Centre d'immunologie et des maladies infectieuses, Cimi-Paris, F-75013 Paris, France Univ. Bordeaux, INSERM, BPH, U1219, F-33000 Bordeaux, France IrsiCaixa AIDS Research Institute, Institut de Recerca Germans Trias i Pujol, Germans Trias i Pujol University Hospital, 08916 Badalona, Barcelona, Spain UVIc-UCC, Catalonia, Spain Hanover Medical School, Department for Rheumatology and Immunology, OE 6830, Carl-Neuberg-Str. 1, 30625 Hannover, Germany Immunology of Infection Section, Division of Infectious Diseases, Imperial College, Chelsea & Westminster Hospital Campus, London, United Kingdom Ifi-institut, an der Asklepios-Klinik St Georg, Hamburg, Germany Sorbonne Université, INSERM U1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié Salpêtrière, Service de Maladies Infectieuses et Tropicale, F-75013 Paris, France Pôle de Santé Publique, CHU de Bordeaux, F-33000 Bordeaux, France Department of Infectious Diseases, CHU de Nantes and CIC 1413, INSERM, Nantes, France Sorbonne Université, Inserm 1135, Centre d'immunologie et des maladies infectieuses, Cimi-Paris, AP-HP, Hôpital universitaire Pitié-Salpêtrière, F-75013 Paris, France.

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http://dx.doi.org/10.1097/QAI.0000000000002594DOI Listing
December 2020

High Prevalence and High Rate of Antibiotic Resistance of Mycoplasma genitalium Infections in Men who Have Sex with Men. A Sub-Study of the ANRS Ipergay PrEP Trial.

Clin Infect Dis 2020 Dec 11. Epub 2020 Dec 11.

INSERM UMR 941, Department of Infectious Diseases, University of Paris, Saint-Louis and Lariboisière Hospitals, APHP, Paris, France.

Background: Mycoplasma genitalium (MG) is an emerging pathogen among men who have sex with men (MSM) with raising rates of antibiotic resistance. In this study, we assessed the prevalence and incidence of MG infection in MSM enrolled in the open-label phase of the ANRS IPERGAY trial with on demand TDF/FTC for HIV prevention and the impact of doxycycline post-exposure prophylaxis (PEP).

Methods: 210 subjects were tested at baseline and at 6 months by real-time PCR assays for MG detection in urine samples, oro-pharyngeal and anal swabs. Resistance to azithromycin (AZM), to fluoroquinolones (FQ) and to doxycycline were investigated in the French National Reference Centre of bacterial STI.

Results: The all-site prevalence of MG at baseline was 10.5% [6.3% in urine samples, 4.3% in anal swabs and 0.5% in throat swabs] and remained unchanged at 6 months whether or not PEP was used: 9.9% overall, 10.2% with PEP and 9.6% without. The overall rate of MG resistance (prevalent and incident cases) to AZM and FQ was 67.6% and 9.1%, respectively, with no difference between arms. An in vivo mutation of the MG 16S rRNA which could be associated with tetracycline resistance was observed in 12.5% of specimens tested.

Conclusions: The prevalence of MG infection among MSM on PrEP was high and its incidence was not decreased by doxycycline prophylaxis with a similar high rate of AZM- and FQ-resistance, raising challenging issues for the treatment of this STI and supporting current recommendations to avoid testing or treatment of asymptomatic MG infection.
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http://dx.doi.org/10.1093/cid/ciaa1832DOI Listing
December 2020

Rate of DRESS Syndrome With Raltegravir and Role of the HLA-B*53: 01 Allele.

J Acquir Immune Defic Syndr 2020 Dec;85(4):e77-e80

Infectious Diseases Department, CHU Hôtel Dieu and INSERM UIC 1413 Nantes University, Nantes, France.

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http://dx.doi.org/10.1097/QAI.0000000000002474DOI Listing
December 2020

Evaluation of the acceptability in France of the vaccine against papillomavirus (HPV) among middle and high school students and their parents.

PLoS One 2020 22;15(10):e0234693. Epub 2020 Oct 22.

Center for the Prevention of Infectious and Transmitted Diseases of the UHC of Nantes, Nantes, France.

Background: The pathogenic and oncogenic roles of papillomavirus (HPV) infections have been documented and shown to occur in women as well as in men. While other countries have already extended their vaccination guidelines to include boys, in 2019 the French National Authority for Health validated implementation of HPV vaccination in the 2020 vaccination schedule. There is, however, a climate of distrust in regard to vaccination in France, and there have been few studies to date regarding the acceptability of HPV vaccination in boys in France. The aim of this study was, therefore, to evaluate the acceptability of extending the recommendations for HPV vaccination in men, among middle and high school students and their parents.

Methods: Our study (HPVac) was a prospective, multicenter, departmental, and descriptive survey applied to a sample of male middle and high school students attending schools in the Loire-Atlantique department and their parents. It took place from January 2017 to January 2018.

Results: We analyzed the information obtained from 127 parent questionnaires and 145 children questionnaires. In terms of acceptability, 36.6% (n = 53) of the children and 37.8% (n = 48) of the parents were in favour of being vaccinated or of having their children vaccinated against HPV (51.7% (n = 75) and 50.4% (n = 64), respectively, were undecided). The perception of a risk stemming from HPV infection was positively associated with acceptability of the HPV vaccine. Being against vaccines in general, being discouraged by their parents, parents thinking that their child is not at risk, and the belief that the vaccine is not mandatory were arguments cited and significantly associated with a willingness to be vaccinated.

Conclusion: This study revealed a lack of information among boys and their parents about HPV and its vaccination. It also clearly showed that taking time to discuss the consequences of an infection and the merits of being vaccinated can help parents overcome their reluctance. The children then generally go along with their parent's choice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234693PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580947PMC
November 2020

Switching from boosted PIs to dolutegravir in HIV-infected patients with high cardiovascular risk: 48 week effects on subclinical cardiovascular disease.

J Antimicrob Chemother 2020 Nov;75(11):3334-3343

Hospital Clínic-IDIBAPS, University of Barcelona, Barcelona, Spain.

Background: Switching from boosted PIs to dolutegravir in virologically suppressed HIV-infected patients with high cardiovascular risk significantly decreased total cholesterol and other proatherogenic lipid fractions at 48 weeks. The impact of this strategy on subclinical cardiovascular disease is unknown.

Methods: NEAT022 is a European, multicentre, open-label, randomized, non-inferiority trial. HIV-infected adults aged >50 years or with a Framingham score >10% were eligible if plasma HIV RNA was <50 copies/mL for >24 weeks on a boosted PI-based regimen. Patients were randomized 1:1 to switch from boosted PIs to dolutegravir or to continue on boosted PIs. Common carotid arteries intima-media thickness (CIMT) and pulse wave velocity (PWV) were measured following a standardized protocol in a subgroup of NEAT022 study participants at baseline and at Week 48.

Results: One hundred and fifty-six patients participated in the ultrasonography and arterial stiffness substudies, respectively. In each substudy, population characteristics did not differ between arms and matched those of the main study. At 48 weeks, patients who switched to dolutegravir had lower mean progression of both right (+4 versus +14.6 μm) and left (-6.1 versus +1.6 μm) CIMT and also a smaller increase in mean PWV (+0.18 versus +0.39 m/s) than patients continuing on boosted PIs, although differences were not statistically significant. CIMT trends were consistent across Framingham score, age and country. Inconsistent effects were seen in arterial stiffness.

Conclusions: Relative to continuing on boosted PIs, switching to dolutegravir in virologically suppressed patients with high cardiovascular risk showed consistent favourable although non-significant trends on CIMT progression at 48 weeks.
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http://dx.doi.org/10.1093/jac/dkaa292DOI Listing
November 2020

Assessment of drug-drug interaction in an elderly human immunodeficiency virus population: Comparison of 3 expert databases.

Br J Clin Pharmacol 2020 Jul 21. Epub 2020 Jul 21.

Department of Infectious Diseases, and CIC 1413, INSERM, University Hospital, Nantes, France.

Aims: Polypharmacy increase the risk of drug-drug interactions (DDIs) in the elderly population living with human immunodeficiency virus (HIV). Several expert databases can be used to evaluate DDIs. The aim of the study was to describe actual DDIs between antiretroviral drugs and comedications in an elderly population and to compare grading of the DDIs in 3 databases.

Methods: All treatments of HIV-infected subjects aged 65 years and older were collected in 6 French HIV centres. Summary of Product Characteristic (SPC), French DDI Thesaurus (THES), and Liverpool HIV DDI website (LIV) were used to define each DDI and specific grade. DDIs were classified in yellow flag interaction (undefined grade in SPC and THES or potential weak interaction in LIV), amber flag interaction (to be considered/precaution of use in SPC and THES and potential interaction in LIV) and red flag interaction (not recommended/contraindication in SPC and THES and do not administer/contraindication in LIV).

Results: Among 239 subjects included, 60 (25.1%) had at least 1 DDI for a total of 126 DDIs: 23/126 red flag DDIs were identified in 17 patients. All these 23 DDIs were identified in LIV. THES and SPC missed 6 and 1 red flag DDIs, respectively. Seven of 23 red flag DDIs were identified in the 3 databases concomitantly.

Conclusion: Polypharmacy is frequent in this elderly HIV population leading to DDI in a quarter of the subjects. The discrepancies between databases can be explained by differences in analysis methods. A consensus between databases would be helpful for clinicians.
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http://dx.doi.org/10.1111/bcp.14491DOI Listing
July 2020

Atherosclerotic Cardiovascular Events in Patients Infected With Human Immunodeficiency Virus and Hepatitis C Virus.

Clin Infect Dis 2020 Jul 20. Epub 2020 Jul 20.

Assistance Publique des Hôpitaux de Paris, Hôpitaux de l'Est Parisien, Hôpital Saint-Antoine, Department of Cardiology, Faculty of Medicine, Sorbonne Paris University, Paris, France.

Background: An increased risk of cardiovascular disease (CVD) was reported in patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), without identifying factors associated with atherosclerotic CVD (ASCVD) events.

Methods: HIV-HCV coinfected patients were enrolled in the ANRS CO13 HEPAVIH nationwide cohort. Primary outcome was total ASCVD events. Secondary outcomes were coronary and/or cerebral ASCVD events, and peripheral artery disease (PAD) ASCVD events. Incidences were estimated using the Aalen-Johansen method. Factors associated with ASCVD were identified using cause-specific Cox proportional hazards models.

Results: At baseline, median age of the study population (n=1213) was 45.4 (interquartile range [IQR] 42.1-49.0) years and 70.3% were men. After a median follow-up of 5.1 (IQR 3.9-7.0) years, the incidence was 6.98 (95% confidence interval [CI] 5.19-9.38) per 1000 person-years for total ASCVD events, 4.01 (2.78-6.00) for coronary and/or cerebral events, and 3.17 (2.05-4.92) for PAD ASCVD events. Aging (hazard ratio [HR] 1.06, 95% CI 1.01-1.12), prior CVD (HR 8.48, 95% CI 3.14-22.91), high total cholesterol (HR 1.43, 95% CI 1.11-1.83), high-density lipoprotein cholesterol (HR 0.22, 95% CI 0.08-0.63), statin use (HR 3.31, 95% CI 1.31-8.38), and high alcohol intake (HR 3.18, 95% CI 1.35-7.52) were independently associated with total ASCVD events, while undetectable baseline viral load (HR 0.41, 95%CI 0.18-0.96) with coronary and/or cerebral events.

Conclusion: HIV-HCV coinfected patients experienced a high incidence of ASCVD events. Some traditional cardiovascular risk factors were the main determinants of ASCVD. Controlling cholesterol abnormalities and maintaining undetectable HIV viral load are essential to control cardiovascular risk.
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http://dx.doi.org/10.1093/cid/ciaa1014DOI Listing
July 2020

Previously unreported emergence of A265V substitution in the integrase gene in association with bictegravir virological failure.

Int J Antimicrob Agents 2020 Aug 29;56(2):106039. Epub 2020 May 29.

Infectious Diseases Department, CHU Hôtel Dieu and INSERM CIC 1413 Nantes University, Nantes, France.

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http://dx.doi.org/10.1016/j.ijantimicag.2020.106039DOI Listing
August 2020

Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors.

J Thromb Thrombolysis 2020 Jul;50(1):211-216

Service de Maladies Infectieuses et Tropicales, CHU de Nantes, 44093, Nantes, France.

Coagulopathy in COVID-19 is a burning issue and strategies to prevent thromboembolic events are debated and highly heterogeneous. The objective was to determine incidence and risk factors of venous thromboembolism (VTE) in COVID-19 inpatients receiving thromboprophylaxis. In this retrospective French cohort study, patients hospitalized in medical wards non-ICU with confirmed COVID-19 and adequate thromboprophylaxis were included. A systematic low limb venous duplex ultrasonography was performed at hospital discharge or earlier if deep venous thrombosis (DVT) was clinically suspected. Chest angio-CT scan was performed when pulmonary embolism (PE) was suspected. Of 71 patients, 16 developed VTE (22.5%) and 7 PE (10%) despite adequate thromboprophylaxis. D-dimers at baseline were significantly higher in patients with DVT (p < 0.001). Demographics, comorbidities, disease manifestations, severity score, and other biological parameters, including inflammatory markers, were similar in patients with and without VTE. The negative predictive value of a baseline D-dimer level < 1.0 µg/ml was 90% for VTE and 98% for PE. The positive predictive value for VTE was 44% and 67% for D-dimer level ≥ 1.0 µg/ml and ≥ 3 µg/ml, respectively. The association between D-dimer level and VTE risk increased by taking into account the latest available D-dimer level prior to venous duplex ultrasonography for the patients with monitoring of D-dimer. Despite thromboprophylaxis, the risk of VTE is high in COVID-19 non-ICU inpatients. Increased D-dimer concentrations of more than 1.0 μg/ml predict the risk of venous thromboembolism. D-dimer level-guided aggressive thromboprophylaxis regimens using higher doses of heparin should be evaluated in prospective studies.
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http://dx.doi.org/10.1007/s11239-020-02146-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246965PMC
July 2020

Lopinavir pharmacokinetics in COVID-19 patients.

J Antimicrob Chemother 2020 09;75(9):2702-2704

Department of Infectious Diseases, Hotel-Dieu Hospital - INSERM CIC 1413, Nantes University Hospital, Nantes, France.

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http://dx.doi.org/10.1093/jac/dkaa195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313987PMC
September 2020

Endophthalmitis Cured With Linezolid in an Immunocompetent Farmer Woman: Hazard of a Sweep of a Cow's Tail.

Open Forum Infect Dis 2019 Nov 23;6(11):ofz459. Epub 2019 Oct 23.

Infectious Diseases Department, Hotel-Dieu Hospital and INSERM Clinical Investigation Center, Nantes University Hospital, Nantes, France.

We report the first case of an unexpected exogenous endophthalmitis in a previously healthy woman after a cow's tail's sweep, successfully treated with surgery and linezolid. It is the first case carried out with linezolid to treat endophthalmitis. Therefore, it may challenge the requirement for intravenous antibiotics for long-term treatment.
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http://dx.doi.org/10.1093/ofid/ofz459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194287PMC
November 2019

Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV-1 infection: results from a longitudinal study in the French ANRS Primo cohort.

J Int AIDS Soc 2020 04;23(4):e25485

Inserm, CESP, U1018, Department of Internal Medicine, AP-HP, Bicêtre Hospital, Paris-Saclay University, Le Kremlin-Bicêtre, France.

Introduction: Previous studies have reported better immunovirological characteristics in women compared with men after HIV seroconversion. We investigated whether differences persisted under long-term antiretroviral therapy (ART) in individuals treated since acute and early HIV-1 infection (AHI).

Methods: Data were obtained for 262 women and 1783 men enrolled between 1996 and 2017 in the French multicentre ANRS PRIMO cohort. We modelled the viral response, long-term immune recovery and HIV DNA decay in the 143 women and 1126 men who initiated ART within the first three months of infection.

Results: The participants were mostly white. The mean age was 37 years at AHI diagnosis. Pre-ART viral loads were lower in women than men, 5.2 and 5.6 log copies/mL (p = 0.001). After ART initiation, women more rapidly achieved viral suppression than men (adjusted hazard ratio: 1.33, 95% confidence interval 1.09 to 1.69). They also experienced a faster increase in CD4 T-cell count and CD4:CD8 ratio during the first months of treatment. Sex-related differences in CD4 T-cell counts were more pronounced with increasing age. This led to a sustained mean difference of 99 to 168 CD4 T-cells/µL depending on age between women and men at 150 months of ART. Moreover, CD4:CD8 ratio of women was higher than that of men by 0.31, at 150 months of ART. There was no statistically significant difference between sexes for the levels of HIV DNA over time (mean estimate at the last modelling point: 1.9 log copies/10 PBMCs after 70 months of ART for both sexes).

Conclusions: The high level of immune recovery and decrease in total HIV DNA levels achieved after ART initiation during AHI reinforce the importance of early diagnosis of HIV infection and immediate ART initiation. The immunological benefit of being female increased throughout prolonged ART duration, which may give women additional protection from adverse clinical events and premature ageing.
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http://dx.doi.org/10.1002/jia2.25485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183251PMC
April 2020

Plea for multitargeted interventions for severe COVID-19.

Lancet Infect Dis 2020 10 21;20(10):1122-1123. Epub 2020 Apr 21.

Department of Infectious Diseases, Hotel-Dieu Hospital and INSERM CIC 1413, Nantes University Hospital, Nantes 44093, France. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(20)30312-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172613PMC
October 2020

Correlation between blood telomere length and CD4+ CD8+ T-cell subsets changes 96 weeks after initiation of antiretroviral therapy in HIV-1-positive individuals.

PLoS One 2020 8;15(4):e0230772. Epub 2020 Apr 8.

Hospital La Paz Institute for Health Research, Madrid, Spain.

In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230772PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141657PMC
July 2020

Five-year follow-up of patients enrolled in the NEAT 001/ANRS 143 randomized clinical trial: NEAT 001/ANRS 143 LONG TERM study.

J Antimicrob Chemother 2020 06;75(6):1618-1622

Division of Infectious Diseases, Saint Pierre University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Background: Few long-term data are available in subjects having initiated ART with an NRTI-sparing regimen.

Objectives: Outcomes of subjects enrolled in the NEAT 001/ANRS 143 randomized clinical trial (comparing ritonavir-boosted darunavir + raltegravir versus ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were retrospectively collected, through anonymized electronic case report forms, up to 6 years post-enrolment.

Methods: The last NEAT 001 visit (Week 96) was conducted in 745/805 randomized subjects (363/401 ritonavir-boosted darunavir + raltegravir and 382/404 ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine). Of these, 430 were enrolled in NEAT 001/ANRS 143 LONG TERM (NLT) study (201 raltegravir, 229 tenofovir disoproxil fumarate/emtricitabine), with a median follow-up of 44.4 months.

Results: During NLT follow-up, the proportion of AIDS, non-AIDS events, virological rebound and serious adverse events, discontinuation for virological failure and for adverse events did not differ between groups; discontinuations for virological failure since NEAT 001 inclusion were more frequent in subjects with baseline CD4 <200 cells/mm3 (11.9% versus 5.3%; P = 0.077). At last follow-up, a quarter of subjects (22.2% for ritonavir-boosted darunavir + raltegravir and 29.7% for ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were still receiving their initial regimen. Integrase inhibitor exposure was not associated with weight gain (P = 0.48), while tenofovir disoproxil fumarate exposure was associated with a trend to higher creatinine increase (P = 0.067).

Conclusions: After a median of 5.6 years, subjects initiating ritonavir-boosted darunavir + raltegravir or ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine experienced few serious clinical adverse events. Most discontinuations were for reasons unrelated to adverse events or virological failure.
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http://dx.doi.org/10.1093/jac/dkaa056DOI Listing
June 2020

Factors associated with psoriasis in a French Nationwide HIV cohort: the independent role of HLA-B*57:01.

AIDS 2020 06;34(7):1057-1063

Department of Internal Medicine, Clinical Immunology and Infectious Diseases, Robert Debré Hospital, University Hospital of Reims.

Objective: Psoriasis is a T-cell-mediated inflammatory disease with genetic factors involved in its etiopathogenesis. In non-HIV populations, HLA-B57:01 has been associated with a higher risk of psoriasis. The aim of this study was to investigate demographic and immunovirological characteristics associated with psoriasis, and to assess whether HLA-B57:01 is associated with psoriasis among people living with HIV (PLHIV) followed in a large French multicenter Dat'AIDS cohort.

Methods: All PLHIV followed up from January 2000 to December 2018 with an available result for HLA-B57:01 were included. Logistic regression models were used to identify associations between psoriasis (outcome variable) and explanatory variables.

Results: Among 31 076 PLHIV, the overall prevalence of psoriasis and HLA-B57:01 were 2.25 and 4.73%, respectively and varied according to ethnicity. By multivariate analysis, male gender [OR 1.81 (95% CI 1.46-2.24), P < 10], positive HLA-B57:01 [OR 2.66 (95% CI 2.12-3.33), P < 10], nadir CD4 cell count less than 200 cells/μl [OR 1.41 (95% CI 1.19-1.67), P < 10] and positive HCV serology [OR 1.45 (95% CI 1.20-1.76), P < 10] were significantly associated with a higher risk of psoriasis. Being born in West and Central Africa [OR 0.15 (95% CI 0.10-0.25), P < 10], the Caribbean islands [OR 0.14 (95% CI 0.05-0.45), P = 0.0008] or Latin America [OR 0.31 (95% CI 0.14-0.69), P = 0.004] was associated with a lower risk of psoriasis compared with patients born in mainland France.

Conclusion: PLHIV carrying HLA-B57:01 have around a three-fold increased risk of psoriasis. This association might provide a possible explanation for the observed differences in psoriasis prevalence between ethnic groups.
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http://dx.doi.org/10.1097/QAD.0000000000002519DOI Listing
June 2020

Pharmacovirological analyses of blood and male genital compartment in patients receiving dolutegravir + lamivudine dual therapy as a switch strategy (ANRS 167 LAMIDOL trial).

J Antimicrob Chemother 2020 06;75(6):1611-1617

Université de Paris, INSERM UMR 1137 IAME, F-75018 Paris, France.

Objectives: To describe plasma residual HIV viraemia, cellular HIV reservoir size, blood plasma drug concentrations and their male genital tract penetration during the maintenance dual therapy dolutegravir + lamivudine.

Patients And Methods: ANRS167 LAMIDOL enrolled 104 virologically suppressed patients to switch to dolutegravir + lamivudine. In this pharmacovirological substudy, ultrasensitive plasma viral load (USpVL) and plasma drug concentrations were measured at Day 0 (D0), Week 24 (W24) and W48 of dolutegravir + lamivudine, and HIV-DNA was measured at W-8 and W48. Semen samples were collected at D0 and W24 from 18 participants. Total and unbound blood and seminal plasma drug concentrations were measured using UPLC-MS/MS.

Results: Median HIV-DNA was 2.5 log10 copies/106 PBMC (IQR = 2.2-3.0, n = 100) at W-8 and 2.4 log10 copies/106 PBMC (IQR = 2.1-2.9, n = 100) at W48 (P = 0.17). The proportion of patients with undetected USpVL was 38% (n = 98), 43% (n = 98) and 49% (n = 97) at D0, W24 and W48, respectively (P = 0.08). Total and unbound plasma dolutegravir concentrations were stable between timepoints (P = 0.13) and all total plasma dolutegravir concentrations except one were adequate. Median free fraction of dolutegravir in plasma was 0.21%. Median blood plasma and seminal plasma concentrations of total dolutegravir at 24 h were 1812 ng/mL and 206 ng/mL, respectively. Median seminal plasma/blood plasma total concentration ratios were 11.6% and 2478% for dolutegravir and lamivudine, respectively. HIV-RNA (365 to 475 copies/mL) was detected in seminal plasma of one patient at D0 (5.9%) and of two patients at W24 (11.8%).

Conclusions: These findings add further important information regarding the effectiveness of dolutegravir + lamivudine maintenance dual therapy in terms of plasma residual viraemia, cellular reservoir size and drug penetration in the male genital tract.
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http://dx.doi.org/10.1093/jac/dkaa035DOI Listing
June 2020

Changes in kidney function among men having sex with men starting on demand tenofovir disoproxil fumarate - emtricitabine for HIV pre-exposure prophylaxis.

J Int AIDS Soc 2020 02;23(2):e25420

Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France.

Introduction: Daily pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is associated with a small but statistically significant decrease in estimated glomerular filtration rate (eGFR). We assessed the renal safety of on-demand PrEP with TDF/FTC in HIV-1 uninfected men.

Methods: We used data from the randomized double-blind placebo-controlled ANRS-IPERGAY trial and its open-label extension conducted between February 2012 and June 2016 among HIV-uninfected MSM starting on-demand PrEP. Using linear mixed model, we evaluated the mean eGFR decline from baseline over time and determined risks factors associated with eGFR decline during the study.

Results: During the blind phase, with a median follow-up of 9.4 months, the mean decline slope of eGFR from baseline was -0.88 and -1.53 mL/min/1.73 m per year in the placebo (n = 201) and the TDF/FTC group (n = 198) respectively, with a slope difference of 0.65 mL/min/1.73 m per year (p = 0.27). Including both phases, 389 participants started on-demand TDF/FTC with a median follow-up of 19.2 months and a mean decline of eGFR from baseline of -1.14 mL/min/1.73 m per year (p < 0.001). The slope of eGFR reduction was not significantly different in participants with baseline eGFR ≤ 90 mL/min/1.73 m (p = 0.44), age >40 years (p = 0.24) or hypertension (p = 0.21). There was a dose-response relationship between recent tenofovir exposure and lower eGFR when considering the number of pills taken in the two months prior the visit (eGFR difference of -0.88 mL/min/1.73 m between >15 pills/month vs. ≤15 pills/month, p < 0.01) or plasma tenofovir concentrations at the visit (eGFR difference compared to ≤2 ng/mL: >2 to ≤10ng/mL: -0.98 mL/min/1.73 m , >10 to ≤40ng/mL: -1.28 mL/min/1.73 m , >40 ng/mL: -1.82 mL/min/1.73 m , p < 0.001). Three participants discontinued TDF/FTC for eGFR < 60 mL/min/1.73 m during the OLE phase. No case of Fanconi syndrome was reported.

Conclusions: The renal safety of on-demand PrEP with TDF/FTC was good. The overall reduction and intermittent exposure to TDF/FTC may explain this good renal safety.
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http://dx.doi.org/10.1002/jia2.25420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035456PMC
February 2020

Differences in HIV cure clinical trial preferences of French people living with HIV and physicians in the ANRS-APSEC study: a discrete choice experiment.

J Int AIDS Soc 2020 02;23(2):e25443

INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l'Information Médicale, Aix Marseille Univ, Marseille, France.

Introduction: Despite the advent of HIV cure-related clinical trials (HCRCT) for people living with HIV (PLWH), the risks and uncertainty involved raise ethical issues. Although research has provided insights into the levers and barriers to PLWH and physicians' participation in these trials, no information exists about stakeholders' preferences for HCRCT attributes, about the different ways PLWH and physicians value future HCRCT, or about how personal characteristics affect these preferences. The results from the present study will inform researchers' decisions about the most suitable HCRCT strategies to implement, and help them ensure ethical recruitment and well-designed informed consent.

Methods: Between October 2016 and March 2017, a discrete choice experiment was conducted among 195 virally controlled PLWH and 160 physicians from 24 French HIV centres. Profiles within each group, based on individual characteristics, were obtained using hierarchical clustering. Trade-offs between five HCRCT attributes (trial duration, consultation frequency, moderate (digestive disorders, flu-type syndrome, fatigue) and severe (allergy, infections, risk of cancer) side effects (SE), outcomes) and utilities associated with four HCRCT candidates (latency reactivation, immunotherapy, gene therapy and a combination of latency reactivation and immunotherapy), were estimated using a mixed logit model.

Results: Apart from severe SE - the most decisive attribute in both groups - PLWH and physicians made different trade-offs between HCRCT attributes, the latter being more concerned about outcomes, the former about the burden of participation (consultation frequency and moderate SE). These different trades-offs resulted in differences in preferences regarding the four candidate HCRCT. PLWH significantly preferred immunotherapy, whereas physicians preferred immunotherapy and combined therapy. Despite the heterogeneity of characteristics within the PLWH and physician profiles, results show some homogeneity in trade-offs and utilities regarding HCRCT.

Conclusions: Severe SE, not outcomes, was the most decisive attribute determining future HCRCT participation. Particular attention should be paid to providing clear information, in particular on severe SE, to potential participants. Immunotherapy would appear to be the best HCRCT candidate for both PLWH and physicians. However, if the risk of cancer could be avoided, gene therapy would become the preferred strategy for the latter and the second choice for the former.
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http://dx.doi.org/10.1002/jia2.25443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048214PMC
February 2020

Ludwig's angina: A diagnostic and surgical priority.

Int J Infect Dis 2020 Apr 23;93:160-162. Epub 2020 Jan 23.

Department of Infectious Disease, CHU Hôtel Dieu, Nantes, France; CIC 1413, INSERM, France. Electronic address:

Ludwig's angina has been known for two centuries as a rapidly and frequently fatal progressive gangrenous cellulitis or necrotizing fasciitis of the neck and the floor of the mouth. The management of the usually young patients affected requires a trained team combining medical skills in surgery, antibiotic therapy, and resuscitation. The prognosis is directly related to early surgical debridement and the experience of the team managing these patients. We present four cases of severe necrotizing cervical cellulitis notably associated with concomitant self-medication with non-steroidal anti-inflammatory drugs. Through these cases, we conclude that several surgical steps could be required, combined with broad-spectrum antibiotic therapy. An optimal surgery, draining all collections and excising all necrotic tissues, seems to be a condition needed for antibiotic efficacy and finally healing.
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http://dx.doi.org/10.1016/j.ijid.2020.01.028DOI Listing
April 2020

Nevirapine Use Is Associated with Higher Bone Mineral Density in HIV-1 Positive Subjects on Long-Term Antiretroviral Therapy.

AIDS Res Hum Retroviruses 2020 05 24;36(5):399-405. Epub 2020 Feb 24.

Infectious Diseases Department, University Hospital Hotel-Dieu, and INSERM CIC 1413, University of Nantes, Nantes, France.

We assessed bone mineral density (BMD) in a cohort of human immunodeficiency virus (HIV)-positive patients after a median of 11 years of combination antiretroviral therapy (cART) and evaluated the respective role of HIV infection and antiretroviral drugs (ARVs). A cross-sectional study of 162 participants (131 male) from the ANRS-C08 cohort was performed with bone dual-energy X-ray absorptiometry (DXA) scans and renal assessment. The window of exposure to ARVs was defined as an exposure of more than six cumulative months during the last 3 years before the DXA evaluation to account for a cumulative exposure that could affect bone remodeling. The association with low BMD (Z-score < -2) was assessed by a multiple logistic regression model. The study population was 50 years (median), hepatitis C virus (HCV) (18%), and hepatitis B virus (HBV) (8%) coinfection with HIV-RNA <50 c/mL in 89%, median CD4 of 619/mm. Prevalence of low BMD was 18% in males and 6% in females. The factors associated with a Z-score < -2 in males were uric acid renal loss [adjusted odds ratio (aOR): 6.1; 95% confidence interval (CI): 1.2-31.5;  = .03], HCV coinfection (aOR: 4.0; 95% CI: 1.3-12.2;  = .02), and less frequent window of exposure to nevirapine (NVP) (aOR: 0.1; 95% CI: 0.02-0.6;  = .01). For the full study sample, there was a strong positive association between duration of exposure to NVP and lumbar spine Z-score ( = .004). HIV-positive patients exposed to long-term cART have a high incidence of low BMD. Tenofovir disoproxil fumarate and ritonavir-boosted protease inhibitors did not seem to be associated with increased risk of low BMD, whereas NVP exposure appeared to have an independent positive association.
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http://dx.doi.org/10.1089/AID.2019.0229DOI Listing
May 2020

Long-term Outcome of Patients With Nonoperated Prosthetic Valve Infective Endocarditis: Is Relapse the Main Issue?

Clin Infect Dis 2020 Aug;71(5):1316-1319

Intensive Care and Infectious Disease Unit, Groupe Saint-André, University Hospital, Bordeaux, France.

In nonoperated prosthetic valve endocarditis (PVE), long-term outcome is largely unknown. We report the follow-up of 129 nonoperated patients with PVE alive at discharge. At 1 year, the mortality rate was 24%; relapses and reinfection were rare (5% each). Enterococcal PVE was associated with a higher risk of relapse.
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http://dx.doi.org/10.1093/cid/ciz1177DOI Listing
August 2020

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.

J Infect Dis 2020 02;221(4):516-522

Sorbonne Université, APHP, Hôpital Saint-Antoine, Hôpitaux de l'Est Parisien, Service de Cardiologie, Paris, France.

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.
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http://dx.doi.org/10.1093/infdis/jiz481DOI Listing
February 2020

Early diagnosis and risk factors of acute hepatitis C in high-risk MSM on preexposure prophylaxis.

AIDS 2020 01;34(1):47-52

Infectious Diseases Department Virology Department, APHP-Saint Louis Hospital, Paris INSERM SC10-US19, Villejuif Infectious Diseases Department, Hospices Civils de Lyon, Lyon, France Université de Montréal, Montreal, Québec, Canada Infectious Diseases Department, APHP-Tenon Hospital, Paris Infectious Diseases Department, CHU Hôtel Dieu and INSERM UIC 1413, Nantes University, Nantes Infectious Diseases Department, CHU Nice, Nice Université Paris Sud U944 INSERM, CNRS UMR 7212 Cell Biology of Virus Infection, Institut de Recherche Saint Louis, Université de Paris, Hôpital Saint-Louis, Paris, France.

Background: A high incidence of acute hepatitis C virus (HCV) (AHCV) infection has been reported among at-risk HIV-negative MSM. The optimal strategy for early diagnosis of AHCV in this population is not clearly defined.

Methods: In the ANRS IPERGAY PrEP trial, among high-risk HIV-negative MSM, HCV serology and serum alanine aminotransferase (ALT) were used for screening at enrollment and during follow-up. Behavioral risk factors were compared at baseline between participants who were diagnosed with AHCV during the study compared with those who did not. In participants with a positive HCV serology, we used stored sera to perform the following tests at diagnosis and on previous visits: HCV-antibodies rapid tests, plasma HCV viral load and HCV antigen immunoassay. We evaluated the sensitivity of each test for AHCV diagnosis.

Results: Among 429 enrolled participants, 14 were diagnosed with AHCV infection, with a median follow-up of 2.1 (interquartile range, 1.5-2.8) years. AHCV incidence was 1.40 per 100 person-years (95% confidence interval, 0.74-2.39). Patients with AHCV reported a significantly higher number of sexual acts and/or partners, and more frequent recreational drug use at baseline. At the prior visit before AHCV diagnosis (median of 2 months earlier), sensitivities of HCV RNA and HCV antigen tests were, respectively, 100 and 89%, whereas none of the patients had a positive serology, and only 25% had elevated ALT.

Conclusion: HCV antigen and RNA tests were positive within a median of 2 months before the detection of antibodies and ALT elevation. These tests could be considered for HCV screening in high-risk MSM.
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http://dx.doi.org/10.1097/QAD.0000000000002364DOI Listing
January 2020

On-demand pre-exposure prophylaxis with tenofovir disoproxil fumarate plus emtricitabine among men who have sex with men with less frequent sexual intercourse: a post-hoc analysis of the ANRS IPERGAY trial.

Lancet HIV 2020 02 26;7(2):e113-e120. Epub 2019 Nov 26.

Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France; INSERM UMR 944, Biologie Cellulaire des Infections Virales, Paris, France; Université de Paris, Paris, France.

Background: ANRS IPERGAY found that on-demand pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine was associated with an 86% relative reduction of HIV-1 incidence compared with placebo among men who have sex with men at high risk of HIV. We aimed to investigate whether on-demand PrEP was similarly effective among individuals with lower exposure to HIV risk.

Methods: Participants in the ANRS IPERGAY trial were randomly assigned to receive PrEP (fixed-dose combination of 300 mg tenofovir disoproxil fumarate and 200 mg emtricitabine per pill) or placebo. The primary endpoint was the diagnosis of HIV-1 infection. Pill uptake was assessed by counting returned pills at each follow-up and by estimating tenofovir concentration from frozen plasma samples. Participants were interviewed at each visit to assess the pattern of PrEP use. All participants enrolled in the modified intention-to-treat population of the double-blind phase of the ANRS IPERGAY trial were eligible for this post-hoc analysis. We calculated the total follow-up time for periods of less frequent sexual intercourse with high PrEP adherence (15 pills or fewer per month taken systematically or often during sexual intercourse). To estimate the time of HIV acquisition, fourth-generation HIV-1/2 ELISA assays, plasma HIV-1 RNA assays, and western blot analyses were done with use of frozen samples, and the stage of HIV infection was defined according to Fiebig staging. HIV incidence was compared between the two treatment groups among individuals who had less frequent sexual intercourse with high PrEP adherence. The ANRS IPERGAY trial is registered with ClinicalTrials.gov, NCT01473472.

Findings: 400 participants who were randomly assigned to receive PrEP (n=199) or placebo (n=201) between Feb 22, 2012, and Oct 17, 2014, were included in this analysis. 270 participants had at least one period of less frequent sexual intercourse with high PrEP adherence during the study, representing 134 person-years of follow-up and 31% of the total study follow-up. During these periods, participants in both groups reported a median of 5·0 (IQR 2·0-10·0) episodes of sexual intercourse per month and used a median of 9·5 (6·0-13·0) pills per month. Six HIV-1 infections were diagnosed in the placebo group (HIV incidence of 9·2 per 100 person-years; 95% CI 3·4-20·1) and none were diagnosed in the tenofovir disoproxil fumarate plus emtricitabine arm (HIV incidence of 0 per 100 person-years; 0-5·4; p=0·013), with a relative reduction of HIV incidence of 100% (95% CI 39-100).

Interpretation: A choice between daily or on-demand PrEP regimens could be offered to men who have sex with men who have less frequent sexual intercourse.

Funding: ANRS (France Recherche Nord and Sud Sida-HIV Hépatites), the Canadian HIV Trials Network, Fonds Pierre Bergé (Sidaction), Gilead Sciences, and the Bill & Melinda Gates Foundation.
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http://dx.doi.org/10.1016/S2352-3018(19)30341-8DOI Listing
February 2020

Outcome and prognostic factors of Pneumocystis jirovecii pneumonia in immunocompromised adults: a prospective observational study.

Ann Intensive Care 2019 Nov 27;9(1):131. Epub 2019 Nov 27.

Medical Intensive Care, University Hospital, Nantes, France.

Background: Pneumocystis jirovecii pneumonia (PJP) remains a severe disease associated with high rates of invasive mechanical ventilation (MV) and mortality. The objectives of this study were to assess early risk factors for severe PJP and 90-day mortality, including the broncho-alveolar lavage fluid cytology profiles at diagnosis.

Methods: We prospectively enrolled all patients meeting pre-defined diagnostic criteria for PJP admitted at Nantes university hospital, France, from January 2012 to January 2017. Diagnostic criteria for PJP were typical clinical features with microbiological confirmation of P. jirovecii cysts by direct examination or a positive specific quantitative real-time polymerase chain reaction (PCR) assay. Severe PJP was defined as hypoxemic acute respiratory failure requiring high-flow nasal oxygen with at least 50% FiO, non-invasive ventilation, or MV.

Results: Of 2446 respiratory samples investigated during the study period, 514 from 430 patients were positive for P. jirovecii. Of these 430 patients, 107 met criteria for PJP and were included in the study, 53 (49.5%) patients had severe PJP, including 30 who required MV. All patients were immunocompromised with haematological malignancy ranking first (n = 37, 35%), followed by solid organ transplantation (n = 27, 25%), HIV-infection (n = 21, 20%), systemic diseases (n = 13, 12%), solid tumors (n = 12, 11%) and primary immunodeficiency (n = 6, 8%). By multivariate analysis, factors independently associated with severity were older age (OR, 3.36; 95% CI 1.4-8.5; p < 0.05), a P. jirovecii microscopy-positive result from bronchoalveolar lavage (BAL) (OR, 1.3; 95% CI 1.54-9.3; p < 0.05); and absence of a BAL fluid alveolitis profile (OR, 3.2; 95% CI 1.27-8.8; p < 0.04). The 90-day mortality rate was 27%, increasing to 50% in the severe PJP group. Factors independently associated with 90-day mortality were worse SOFA score on day 1 (OR, 1.05; 95% CI 1.02-1.09; p < 0.001) whereas alveolitis at BAL was protective (OR, 0.79; 95% CI 0.65-0.96; p < 0.05). In the subgroup of HIV-negative patients, similar findings were obtained, then viral co-infection were independently associated with higher 90-day mortality (OR, 1.25; 95% CI 1.02-1.55; p < 0.05).

Conclusions: Older age and P. jirovecii oocysts at microscopic examination of BAL were independently associated with severe PJP. Both initial PJP severity as evaluated by the SOFA score and viral co-infection predicted 90-day mortality. Alveolitis at BAL examination was associated with less severe PJP. The pathophysiological mechanism underlying this observation deserves further investigation.
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http://dx.doi.org/10.1186/s13613-019-0604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881486PMC
November 2019

Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial.

J Antimicrob Chemother 2020 03;75(3):628-639

Chelsea and Westminster NHS Trust, London, UK.

Objectives: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure.

Methods: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression.

Results: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively].

Conclusions: Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.
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http://dx.doi.org/10.1093/jac/dkz479DOI Listing
March 2020