Publications by authors named "Constance Delaugerre"

170 Publications

Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial.

Lancet Infect Dis 2021 Mar 2. Epub 2021 Mar 2.

National Institute of Infectious Diseases Evandro Chagas, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.

Background: In patients co-infected with HIV and tuberculosis, antiretroviral therapy options are limited due to drug-drug interactions with rifampicin. A previous phase 2 trial indicated that raltegravir 400 mg twice a day or efavirenz 600 mg once a day might have similar virological efficacy in patients given rifampicin. In this phase 3 trial, we assessed the non-inferiority of raltegravir to efavirenz.

Methods: We did a multicentre, open-label, non-inferiority, randomised, phase 3 trial at six sites in Côte d'Ivoire, Brazil, France, Mozambique, and Vietnam. We included antiretroviral therapy (ART)-naive adults (aged ≥18 years) with confirmed HIV-1 infection and bacteriologically confirmed or clinically diagnosed tuberculosis who had initiated rifampicin-containing tuberculosis treatment within the past 8 weeks. Using computerised random numbers, we randomly assigned participants (1:1; stratified by country) to receive raltegravir 400 mg twice daily or efavirenz 600 mg once daily, both in combination with tenofovir and lamivudine. The primary outcome was the proportion of patients with virological suppression at week 48 (defined as plasma HIV RNA concentration <50 copies per mL). The prespecified non-inferiority margin was 12%. The primary outcome was assessed in the intention-to-treat population, which included all randomly assigned patients (excluding two patients with HIV-2 infection and one patient with HIV-1 RNA concentration of <50 copies per mL at inclusion), and the on-treatment population, which included all patients in the intention-to-treat population who initiated treatment and were continuing allocated treatment at week 48, and patients who had discontinued allocated treatment due to death or virological failure. Safety was assessed in all patients who received at least one dose of the assigned treatment regimen. This study is registered with ClinicalTrials.gov, NCT02273765.

Findings: Between Sept 28, 2015, and Jan 5, 2018, 460 participants were randomly assigned to raltegravir (n=230) or efavirenz (n=230), of whom 457 patients (230 patients in the raltegravir group; 227 patients in the efavirenz group) were included in the intention-to-treat analysis and 410 (206 patients in the raltegravir group; 204 patients in the efavirenz group) in the on-treatment analysis. At baseline, the median CD4 count was 103 cells per μL and median plasma HIV RNA concentration was 5·5 log copies per mL (IQR 5·0-5·8). 310 (68%) of 457 participants had bacteriologically-confirmed tuberculosis. In the intention-to-treat population, at week 48, 140 (61%) of 230 participants in the raltegravir group and 150 (66%) of 227 patients in the efavirenz had achieved virological suppression (between-group difference -5·2% [95% CI -14·0 to 3·6]), thus raltegravir did not meet the predefined criterion for non-inferiority. The most frequent adverse events were HIV-associated non-AIDS illnesses (eight [3%] of 229 patients in the raltegravir group; 21 [9%] of 230 patients in the efavirenz group) and AIDS-defining illnesses (ten [4%] patients in the raltegravir group; 13 [6%] patients in the efavirenz group). 58 (25%) of 229 patients in raltegravir group and 66 (29%) of 230 patients in the efavirenz group had grade 3 or 4 adverse events. 26 (6%) of 457 patients died during follow-up: 14 in the efavirenz group and 12 in the raltegravir group.

Interpretation: In patients with HIV given tuberculosis treatment, non-inferiority of raltegravir compared with efavirenz was not shown. Raltegravir was well tolerated and could be considered as an option, but only in selected patients.

Funding: National French Agency for AIDS Research, Ministry of Health in Brazil, Merck.

Translations: For the Portuguese and French translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1473-3099(20)30869-0DOI Listing
March 2021

Deep sequencing analysis of M184V/I mutation at the switch and at the time of virological failure of boosted protease inhibitor plus lamivudine or boosted protease inhibitor maintenance strategy (substudy of the ANRS-MOBIDIP trial).

J Antimicrob Chemother 2021 Feb 24. Epub 2021 Feb 24.

TransVIHMI, Institut de Recherche pour le Développement (IRD) - INSERM U1175 University of Montpellier, Montpellier, France.

Background: The ANRS12286/MOBIDIP trial showed that boosted protease inhibitor (bPI) plus lamivudine dual therapy was superior to bPI monotherapy as maintenance treatment in subjects with a history of M184V mutation.

Objectives: We aimed to deep analyse the detection of M184V/I variants at time of switch and at the time of virological failure (VF).

Methods: Ultra-deep sequencing (UDS) was performed on proviral HIV-DNA at inclusion among 265 patients enrolled in the ANRS 12026/MOBIDIP trial, and on plasma from 31 patients experiencing VF. The proportion of M184V/I variants was described and the association between the M184V/I mutation at 1% of threshold and VF was explored with logistic regression models.

Results: M184V and I mutations were detected in HIV-DNA for 173/252 (69%) and 31/252 (12%) of participants, respectively. Longer duration of first-line treatment, higher plasma viral load at first-line treatment failure and higher baseline HIV-DNA load were associated with the archived M184V. M184I mutation was always associated with a STOP codon, suggesting defective virus. The 48 week estimated probability of remaining free from VF was comparable with or without the M184V/I mutation for dual therapy. At failure, M184V and major PI mutations were detected in 1/17 and 5/15 patients in the bPI arm and in 2/2 and 0/3 in the bPI+lamivudine arm, respectively.

Conclusions: Using UDS evidenced that archiving of M184V in HIV-DNA is heterogeneous despite past historical M184V in 96% of cases. The antiviral efficacy of lamivudine-based dual therapy regimens is mainly due to the residual lamivudine activity.
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http://dx.doi.org/10.1093/jac/dkab002DOI Listing
February 2021

Low level of baseline resistance in recently HCV-infected men who have sex with men with high-risk behaviours.

J Glob Antimicrob Resist 2021 Feb 2;24:311-315. Epub 2021 Feb 2.

Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de virologie, F-75013 Paris, France. Electronic address:

Objectives: Presence of baseline hepatitis C virus (HCV) resistance-associated substitutions (RASs) can impair treatment outcome of direct-acting antivirals. We investigated the prevalence of pre-treatment HCV resistance among recently HCV-infected men who have sex with men (MSM) with high risk behaviours, either human immunodeficiency virus (HIV) co-infected or at high risk of HIV acquisition and under pre-exposure prophylaxis (PrEP).

Methods: NS5A and NS3 fragments were deep sequenced on pre-treatment samples of 72 subjects using Illumina MiSeq paired-end sequencing technology. Ultra-deep sequencing data were analysed by SmartGene® platform. RASs mentioned in the literature were analysed and interpreted depending on genotype (GT) at 10% cut-off.

Results: HCV genotyping showed 36 (50.0%) GT1a, 31 (43.1%) GT4d and 5 (6.9%) GT3a infections. Fifty-five patients (76.4%) were co-infected with HIV and 15 (20.8%) received PrEP. In GT1a viruses, NS3 RASs were found in 4/30 viruses (13.3%; S122 G/N, R155 K and I170 V) and Q80 K polymorphism was present in 14/30 viruses (46.7%). No NS3 RASs were detected in GT4d and GT3a viruses. NS5A RASs were detected in 3/36 GT1a viruses (8.3%; Q30E/R, L31 M and H58 L). NS5A subtype-specific polymorphisms L30R and T58 P were found at high frequencies in 31/31 (100%) and 16/31 (51.6%) GT4d viruses, respectively. One RAS M31 L was also observed along with the polymorphisms L30R and T58 P. No NS5A RASs were detected in GT3a viruses.

Conclusion: A low level of RASs to NS3 and NS5A inhibitors in pre-treatment samples was detected in the study population. Our findings reassure the clinical management of HCV infection in this high-risk population.
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http://dx.doi.org/10.1016/j.jgar.2021.01.012DOI Listing
February 2021

SARS-CoV-2 induces human plasmacytoid predendritic cell diversification via UNC93B and IRAK4.

J Exp Med 2021 04;218(4)

Université de Paris, Institut de Recherche Saint-Louis, Institut National de la Santé et de la Recherche Médicale U976, Hôpital Saint-Louis, Paris, France.

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.
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http://dx.doi.org/10.1084/jem.20201387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849819PMC
April 2021

SARS-CoV-2 induces human plasmacytoid pre-dendritic cell diversification via UNC93B and IRAK4.

bioRxiv 2021 Jan 8. Epub 2021 Jan 8.

Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, 75010 Paris, France.

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here, we have isolated primary SARS-CoV-2 viral strains, and studied their interaction with human plasmacytoid pre-dendritic cells (pDC), a key player in antiviral immunity. We show that pDC are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2020.07.10.197343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805442PMC
January 2021

A governmental program to encourage medical students to deliver primary prevention: experiment and evaluation in a French faculty of medicine.

BMC Med Educ 2021 Jan 13;21(1):47. Epub 2021 Jan 13.

Université de Paris, ECEVE UMR 1123, Inserm, F-75010, Paris, France.

Background: A public health student service was set up by the French government in 2018 with the aim of increasing awareness of primary health promotion among the 47,000 students of medicine and other health professions. It is an annual program involving community-based actions on nutrition, physical activity, addiction or sexuality. Our objective was to evaluate its implementation at local level and the different experiences of the stakeholders.

Methods: A quasi-experimental study using process evaluation was performed in a Faculty of Medicine in Paris. Quantitative and qualitative data were collected from medical students who carried out preventive health actions, in the institutions in which the actions took place and from a subsample of beneficiaries.

Results: One hundred and eight actions were carried out by 341 students in 23 educational or social institutions, mostly high schools (n = 12, 52%). Two thirds of the students did not feel sufficiently prepared to deliver preventive health interventions (65.7%, 224/341); however the beneficiaries found that the interventions were good (278/280, 99,2%). Nineteen (83%) of the host institutions agreed to welcome health service students again, of which 9 required some modifications. For students, the reporting of a satisfactory health service experience was associated with the reporting of skills or knowledge acquisition (p < 0.01). Delivering actions in high schools and to a medium-sized number of beneficiaries per week was associated with students' satisfaction. No effect of gender or theme of prevention was observed. For 248/341 (72.7%) students, the public health service program prompts them to address prevention issues in the future.

Conclusion: The public health service undertaken by medical students through the program is a feasible and acceptable means of delivering preventive actions. Reinforcement of training and closer interaction with the host institutions would improve results.
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http://dx.doi.org/10.1186/s12909-020-02472-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805043PMC
January 2021

Online self-sampling kits to screen multipartner MSM for HIV and other STIs: participant characteristics and factors associated with kit use in the first 3 months of the MemoDepistages programme, France, 2018.

Sex Transm Infect 2021 Mar 4;97(2):134-140. Epub 2021 Jan 4.

Sexual Health Unit, Santé publique France, Saint Maurice, France.

Objectives: In 2017, to reduce the proportion of men who have sex with men (MSM) in the undiagnosed HIV population in France (38%), HIV screening is advised each 3 months and STI screening is advised each year in multipartner MSM. Despite the range of testing solutions, over 40% of MSM were not tested for HIV and over 50% for STIs in the past year. Based on international experiments that offer screening solutions via online advertising, the French National Health Agency launched a programme (MemoDepistages) to provide a free self-sampling kit (SSK) for HIV and STIs. This article analyses the sociodemographic and behavioural characteristics of MSM in terms of kit acceptance and sample return.

Methods: Participants were registered for the programme online after ordering an SSK. The study included men aged over 18 years, living in one of the four selected French regions, and willing to disclose their postal and email address; they had health insurance, acknowledged more than one male partner in the past year, indicated a seronegative or unknown HIV status and were not taking medically prescribed pre-exposure prophylaxis drugs. Samples were collected by users and posted directly to the laboratory. Characteristics associated with kit acceptance and sample return were analysed using logistic regression.

Results: Overall, 7158 eligible MSM were offered to participate in the programme, with 3428 ordering the kit (47.9%) and 1948 returning their sample, leading to a return rate of 56.8% and an overall participation rate of 27.2%. Acceptance and return rates were strongly associated with sociodemographic characteristics, mainly education level but not with behavioural characteristics. Non-college graduates had lower acceptance (44.2%) and return rates (47.7%).

Conclusion: The programme rapidly recruited a large number of MSM. It removed geographical inequalities related to screening access.
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http://dx.doi.org/10.1136/sextrans-2020-054790DOI Listing
March 2021

Mortality in relation to hepatitis B virus (HBV) infection status among HIV-HBV co-infected patients in sub-Saharan Africa after immediate initiation of antiretroviral therapy.

J Viral Hepat 2020 Dec 31. Epub 2020 Dec 31.

INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.

It is unknown how past and active hepatitis B virus (HBV) infection affect immunorecovery and mortality in people with HIV who initiate tenofovir-based antiretroviral therapy (ART). Using data collected between 2008 and 2015, we studied people with HIV in sub-Saharan Africa initiating immediate ART in the Temprano randomized control trial. We classified participants into HBV groups at ART initiation: hepatitis B surface antigen (HBsAg)-positive with HBV DNA ≥ 2,000 IU/ml; HBsAg-positive with HBV DNA < 2,000 IU/ml; isolated HBcAb-positive; resolved infection (HBsAb-positive/HBcAb-positive); and HBV non-immune/vaccinated (HBcAb-negative). We compared square-root CD4-cell count increases using mixed-effect, non-linear regression adjusted for age, sex, baseline CD4 cell count, and HIV RNA. We compared all-cause mortality using Bayesian parametric survival regression. Among 879 participants, 24 (2.7%) had HBsAg with high HBV DNA, 76 (8.6%) HBsAg with low HBV DNA, 325 (37.0%) isolated anti-HBcAb, 226 (25.7%) resolved HBV infection and 228 (25.9%) HBV non-immune/vaccinated. We found no significant difference in CD4 cell increases between HBV-infection groups after adjustment (p = 0.16). Participants with HBsAg and high HBV DNA had the highest incidence of all-cause mortality (1.9/100 person-years, 95% Credibile Interval [CrI] = 1.0-3.4). By comparison, incidence rates of mortality were reduced by 57% (95%CrI = -79%, -13%), 60% (95%CrI = -82%, -12%) and 66% (95%CrI = -84%, -23%) in those who had isolated anti-HBcAb-positive, resolved HBV infection and HBV non-immune/vaccinated, respectively. In conclusion, individuals with HIV and past HBV infection or isolated anti-HBcAb-positive serology, much like HBV non-immune/vaccinated, experience lower mortality than those with HBsAg and high HBV DNA. Additional HBV-related management would not be necessary for these individuals.
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http://dx.doi.org/10.1111/jvh.13461DOI 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

Improvement of HIV-associated neurocognitive disorders after antiretroviral therapy intensification: the Neuro+3 study.

J Antimicrob Chemother 2021 Feb;76(3):743-752

APHP Hospital Raymond Poincaré, Paris-Saclay University, Garches, France.

Objectives: Despite the effectiveness of antiretroviral (ARV) therapy to control HIV infection, HIV-associated neurocognitive disorders (HAND) remain frequent. The Neuro+3 study assessed the cognitive improvement associated with ARV intensification based on increased CNS penetration effectiveness (CPE) scoring ≥+3 and total CPE score ≥9.

Methods: Thirty-one patients, aged 18-65 years, with confirmed diagnosis of HAND and effective ARV therapy were included. The cognitive improvement was measured using Frascati three-stage classification and global deficit score (GDS) after 48 and 96 weeks of ARV intensification. Ultrasensitive HIV-RNA, neopterin, soluble CD14, CCL2, CXCL10, IL6, IL8 and NF-L were measured in plasma and cerebrospinal fluid at Day 0 (baseline), Week 48 (W48) and W96.

Results: The intensified ARV was associated with a median (IQR) CPE score increase from 6 (4-7) at baseline to 10 (9-11). From baseline to W96, the median (IQR) GDS decreased from 1.4 (0.8-2.2) to 1.0 (0.6-2.0) (P = 0.009); HAND classification improved from 2 to 1 HIV-associated dementia, 22 to 8 mild neurocognitive disorders, 7 to 17 asymptomatic neurocognitive impairment and 0 to 5 patients without any neurocognitive alterations (P = 0.001). In multivariable linear regression analysis, GDS improvement at W96 was significantly associated with CPE score ≥9 after intensification (P = 0.014), CD4 lymphocyte increase at W48 (P < 0.001) and plasma CXCL10 decrease at W96 (P = 0.001).

Conclusions: In patients with HAND, a significant cognitive improvement was observed after the ARV intensification strategy, with a higher CPE score. Cognitive improvement was more often observed in the case of a switch of two drug classes, arguing for better control of CNS HIV immune activation.
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http://dx.doi.org/10.1093/jac/dkaa473DOI Listing
February 2021

Association of Hepatitis B Core-Related Antigen and Antihepatitis B Core Antibody With Liver Fibrosis Evolution in Human Immunodeficiency Virus-Hepatitis B Virus Coinfected Patients During Treatment With Tenofovir.

Open Forum Infect Dis 2020 Jul 7;7(7):ofaa215. Epub 2020 Jun 7.

Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France.

Background: Quantitative hepatitis B core-related antigen (qHBcrAg) or antihepatitis B core antibody (qAnti-HBc) could be useful in monitoring liver fibrosis evolution during chronic hepatitis B virus (HBV) infection, yet it has not been assessed in human immunodeficiency virus (HIV)-HBV-coinfected patients undergoing treatment with tenofovir (TDF).

Methods: One hundred fifty-four HIV-HBV-infected patients initiating a TDF-containing antiretroviral regimen were prospectively followed. The qHBcrAg and qAnti-HBc and liver fibrosis assessment were collected every 6-12 months during TDF. Hazard ratios (HRs) assessing the association between qHBcrAg/qAnti-HBc and transitions from none/mild/significant fibrosis to advanced fibrosis/cirrhosis (progression) and from advanced fibrosis/cirrhosis to none/mild/significant fibrosis (regression) were estimated using a time-homogeneous Markov model.

Results: At baseline, advanced liver fibrosis/cirrhosis was observed in 40 (26%) patients. During a median follow-up of 48 months (interquartile range, 31-90), 38 transitions of progression (IR = 7/100 person-years) and 34 transitions of regression (IR = 6/100 person-years) were observed. Baseline levels of qHBcrAg and qAnti-HBc were not associated with liver fibrosis progression (adjusted-HR per log U/mL = 1.07, 95% confidence interval [CI] = 0.93-1.24; adjusted-HR per log Paul-Ehrlich-Institute [PEI] U/mL = 0.85, 95% CI = 0.70-1.04, respectively) or regression (adjusted-HR per log U/mL = 1.17, 95% CI = 0.95-1.46; adjusted-HR per log PEI U/mL = 0.97, 95% CI = 0.78-1.22, respectively) after adjusting for age, gender, duration of antiretroviral therapy, protease inhibitor-containing antiretroviral therapy, and CD4/CD8 ratio. Nevertheless, changes from the previous visit of qAnti-HBc levels were associated with liver fibrosis regression (adjusted-HR per log PEIU/mL change = 5.46, 95% CI = 1.56-19.16).

Conclusions: Baseline qHBcrAg and qAnti-HBc levels are not associated with liver fibrosis evolution in TDF-treated HIV-HBV coinfected patients. The link between changes in qAnti-HBc levels during follow-up and liver fibrosis regression merits further study.
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http://dx.doi.org/10.1093/ofid/ofaa215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580158PMC
July 2020

Acute Hepatitis B Infection After a Switch to Long-Acting Cabotegravir and Rilpivirine.

Open Forum Infect Dis 2020 Sep 25;7(9):ofaa367. Epub 2020 Sep 25.

Department of Infectious Diseases, Saint-Louis Hospital, University of Paris Diderot, Paris, France.

Maintenance antiretroviral therapy with combination of two injectable long-acting drugs, cabotegravir and rilpivirine, is a new strategy addressing the challenges of daily adherence to oral pills that has shown non-inferior efficacy to standard of care therapy in patients with suppressed HIV-infection. Patients co-infected with hepatitis B virus (HBV) are not eligible for this dual therapy since it has no activity against HBV, but this strategy should also be restricted to patients with anti-HBs antibodies since people with HIV are still at risk of HBV acquisition due to high risk behavior and since HBV vaccination does not always elicit anti-HBs antibodies, as highlighted in the case report below.
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http://dx.doi.org/10.1093/ofid/ofaa367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518369PMC
September 2020

Performance evaluation of two SARS-CoV-2 IgG/IgM rapid tests (Covid-Presto and NG-Test) and one IgG automated immunoassay (Abbott).

J Clin Virol 2020 11 3;132:104618. Epub 2020 Sep 3.

Université de Paris, INSERM UMR 1137 IAME, Laboratoire de Virologie, AP-HP, Hôpital Bichat-Claude Bernard, F-75018, Paris, France.

The aim of this study was to assess the analytical performances, sensitivity and specificity, of two rapid tests (Covid- Presto® test rapid Covid-19 IgG/IgM and NG-Test® IgM-IgG COVID-19) and one automated immunoassay (Abbott SARS-CoV-2 IgG) for detecting anti- SARS-CoV-2 antibodies. This study was performed with: (i) a positive panel constituted of 88 SARS-CoV-2 specimens collected from patients with a positive SARS-CoV-2 RT-PCR, and (ii) a negative panel of 120 serum samples, all collected before November 2019, including 64 samples with a cross-reactivity panel. Sensitivity of Covid-Presto® test for IgM and IgG was 78.4% and 92.0%, respectively. Sensitivity of NG-Test® for IgM and IgG was 96.6% and 94.9%, respectively. Sensitivity of Abbott IgG assay was 96.5% showing an excellent agreement with the two rapid tests (κ = 0.947 and κ = 0.936 for NGTest ® and Covid-Presto® test, respectively). An excellent agreement was also observed between the two rapid tests (κ = 0.937). Specificity for IgM was 100% and 86.5% for Covid-Presto® test and NG-Test®, respectively. Specificity for IgG was 92.0%, 94.9% and 96.5% for Covid-Presto®, NGTest ®, and Abbott, respectively. Most of the false positive results observed with NG-Test® resulted from samples containing malarial antibodies. In conclusion, performances of these 2 rapid tests are very good and comparable to those obtained with automated immunoassay, except for IgM specificity with the NG-Test®. Thus, isolated IgM should be cautiously interpreted due to the possible false-positive reactions with this test. Finally, before their large use, the rapid tests must be reliably evaluated with adequate and large panel including early seroconversion and possible cross-reactive samples.
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http://dx.doi.org/10.1016/j.jcv.2020.104618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470702PMC
November 2020

Emerging and Reemerging Sexually Transmitted Infections.

N Engl J Med 2020 08;383(8):793-794

Saint-Louis Hospital, Paris, France

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http://dx.doi.org/10.1056/NEJMc2022699DOI Listing
August 2020

Surfaces and equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the emergency department at a university hospital.

Int J Hyg Environ Health 2020 Aug 7;230:113600. Epub 2020 Aug 7.

Université de Paris, Virology Department, Saint-Louis Hospital, AP-HP, INSERM U976, Paris, France. Electronic address:

Objectives: Environmental contamination by patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through respiratory droplets suggests that surfaces and equipment could be a medium of transmission. We aimed to assess the surface and equipment contamination by SARS-COV-2 of an emergency department (ED) during the coronavirus infectious disease-2019 (COVID-19) outbreak.

Methods: We performed multiple samples from different sites in ED patients care and non-patient care areas with sterile premoistened swabs and used real-time reverse transcriptase polymerase chain reaction (RT-PCR) to detect the presence of SARS-CoV-2 ribonucleic acid (RNA). We also sampled the personal protective equipment (PPE) from health care workers (HCWs).

Results: Among the 192 total samples, 10 (5.2%) were positive. In patient care areas, 5/46 (10.9%) of the surfaces directly in contact with COVID-19 patients revealed the presence of SARS-CoV-2 RNA, and 4/56 (7.1%) of the surfaces that were not directly in contact with COVID-19 patients were positive. SARS-CoV-2 RNA was present only in the patients' examination and monitoring rooms. Before decontamination SARS-CoV-2 RNA was present on the saturation clip, the scuff for blood pressure measurement, the stretcher, the plastic screens between patients and the floor. After decontamination, SARS-CoV-2 RNA remained on the scuff, the stretcher and the trolleys. All samples from non-patient care areas or staff working rooms were negative. Only one sample from the PPE of the HCWs was positive.

Conclusions: Our findings suggest that surfaces and equipment contamination by SARS-CoV-2 RNA in an ED during the COVID-19 outbreak is low and concerns exclusively patients' examination and monitoring rooms, preserving non-patient care areas.
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http://dx.doi.org/10.1016/j.ijheh.2020.113600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413114PMC
August 2020

Correlation of serum hepatitis B core-related antigen with hepatitis B virus total intrahepatic DNA and covalently closed circular-DNA viral load in HIV-hepatitis B coinfection.

AIDS 2020 11;34(13):1943-1949

APHP, Hôpital Saint-Antoine, Service de Maladies Infectieuses et Tropicales, Paris.

Objective: To assess whether quantified hepatitis B core-related antigen (qHBcrAg) is a surrogate marker of intrahepatic replication in HIV and hepatitis B virus (HBV) coinfection.

Design: Cross-sectional study of 31 HIV-HBV-infected patients (total liver biopsies, n = 38) from a well defined cohort.

Methods: Spearman's rank correlation coefficients were calculated between qHBcrAg and intrahepatic markers of HBV replication [total intrahepatic-DNA, covalently closed circular (ccc) DNA, cccDNA : total intrahepatic-DNA ratio].

Results: At biopsy, 22 (71.0%) patients were hepatitis B 'e' antigen (HBeAg)-positive, 22 (71.0%) had detectable plasma HBV-DNA, and 17 (54.8%) were treated with tenofovir. Median levels (interquartile range) of intrahepatic markers were as follows: HBV cccDNA (n = 34), 0.26 copies/cell (0.4-2.89); total intrahepatic-DNA (n = 38), 2.38 copies/cell (0.58-207.9), and cccDNA : total intrahepatic-DNA ratio (n = 34), 0.05 (interquartile range = 0.01-0.12). There was a significantly strong correlation between qHBcrAg and cccDNA in all patients (Rho = 0.65, P < 0.001), while a moderate correlation was observed between qHBcrAg and total intrahepatic-DNA (Rho = 0.57, P < 0.001) or cccDNA : total intrahepatic-DNA ratio (Rho = -0.45, P = 0.01). Similar findings were observed for HBeAg-positive patients and those with detectable HBV-DNA, with the exception of qHBcrAg and cccDNA or cccDNA : total intrahepatic-DNA ratio. In contrast, no significant correlation between qHBcrAg and any intrahepatic marker was observed in HBeAg-negative patients or those with undetectable HBV-DNA. No significant difference was observed in median qHBcrAg levels across liver fibrosis stages (P = 0.5).

Conclusion: qHBcrAg is a potential surrogate marker of cccDNA in HIV-HBV coinfected patients, yet might be less useful with undetectable serum HBV-DNA or HBeAg-negative status. Whether qHBcrAg provides further clinical utility compared with other serological markers remains debatable.
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http://dx.doi.org/10.1097/QAD.0000000000002659DOI Listing
November 2020

Multicenter comparison of the Cobas 6800 system with the RealStar RT-PCR kit for the detection of SARS-CoV-2.

J Clin Virol 2020 Sep 31;130:104573. Epub 2020 Jul 31.

Université de Paris, Département des Agents Infectieux, Service de Virologie, Hôpital Saint-Louis, Paris, France; INSERM UMR 944, Université de Paris, Paris, France. Electronic address:

Background: RT-PCR testing is crucial in the diagnostic of SARS-CoV-2 infection. The use of reliable and comparable PCR assays is a cornerstone to allow use of different PCR assays depending on the local equipment. In this work, we provide a comparison of the Cobas® (Roche) and the RealStar® assay (Altona).

Methods: Assessment of the two assays was performed prospectively in three reference Parisians hospitals, using 170 clinical samples. They were tested with the Cobas® assay, selected to obtain a distribution of cycle threshold (Ct) as large as possible, and tested with the RealStar assay with three largely available extraction platforms: QIAsymphony (Qiagen), MagNAPure (Roche) and NucliSENS-easyMag (BioMérieux).

Results: Overall, the agreement (positive for at least one gene) was 76 %. This rate differed considerably depending on the Cobas Ct values for gene E: below 35 (n = 91), the concordance was 99 %. Regarding the positive Ct values, linear regression analysis showed a coefficient of determination (R) of 0.88 and the Deming regression line revealed a strong correlation with a slope of 1.023 and an intercept of -3.9. Bland-Altman analysis showed that the mean difference (Cobas® minus RealStar®) was + 3.3 Ct, with a SD of + 2.3 Ct.

Conclusions: In this comparison, both RealStar® and Cobas® assays provided comparable qualitative results and a high correlation when both tests were positive. Discrepancies exist after 35 Ct and varied depending on the extraction system used for the RealStar® assay, probably due to a low viral load close to the detection limit of both assays.
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http://dx.doi.org/10.1016/j.jcv.2020.104573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836314PMC
September 2020

Evaluation of the COVID-19 IgG/IgM Rapid Test from Orient Gene Biotech.

J Clin Microbiol 2020 07 23;58(8). Epub 2020 Jul 23.

Université de Paris, Département des Agents Infectieux, Service de Virologie, Hôpital Saint-Louis, Paris, France.

While the coronavirus disease 2019 (COVID-19) pandemic has peaked in many countries already, the current challenge is to assess population immunity on a large scale. Many serological tests are available and require urgent independent validation. Here, we report performance characteristics of Orient Gene Biotech COVID-19 IgG/IgM Rapid Test Cassette (OG) and compare it to Abbott SARS-CoV-2 IgG immunoassay (ASIA). Patients ( = 102) with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase PCR (RT-PCR) were tested. The patients were asymptomatic ( = 2) or had mild ( = 37) or severe symptoms requiring hospitalization in a medical unit ( = 35) or intensive care unit ( = 28). Specificity was evaluated for 42 patients with previous viral and parasitic diseases as well as a high level of rheumatic factor. The sensitivity of OG was 95.8% (95% confidence interval [CI95%], 89.6 to 98.8) for samples collected ≥10 days after the onset of symptoms, which was equivalent to the sensitivity of ASIA of 90.5% (CI95%, 82.8 to 95.6). OG uncovered six false-negative results of ASIA, of which two had only IgM with OG. Specificity was 100% (CI95%, 93.4 to 100) with both tests on samples, including patients infected with endemic coronavirus. Overall, OG performance characteristics indicate that the test is suitable for routine use in clinical laboratories, and its performance is equivalent to that of immunoassay. Testing OG on a larger asymptomatic population may be needed to confirm these results.
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http://dx.doi.org/10.1128/JCM.01233-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383543PMC
July 2020

Difficulties of Identifying the Early HIV Antibody Seroconversion Period Depending on the Confirmatory Assay.

Open Forum Infect Dis 2020 May 21;7(5):ofaa140. Epub 2020 Apr 21.

Laboratoire de Virologie, CHU Saint Louis, Paris, France.

Background: Identification of HIV infection at the early stage is valuable for patient management, for prevention, and for research purposes. In practice, identification of a recent HIV infection at diagnosis proves challenging after HIV antibody seroconversion but can be suspected using Western blots (WBs) or immunoblots (IBs) as confirmatory assays.

Methods: Five commercially available confirmatory assays were compared using 43 samples from recently infected individuals. This included 2 WBs (New LAV Blot I, Biorad, and HIV Blot 2.2, MP Biomedicals), 2 IBs (INNO-LIA HIV I/II, Fujirebio, and RecomLine HIV-1 & HIV-2, Mikrogen Diagnostik), and 1 immunochromatographic single-use assay (Geenius HIV1/2 supplemental assay, Biorad).

Results: Following the manufacturer's recommendations for interpretation, the 2 WBs led to indeterminate results for 30% and 42% of the samples, suggesting recent infection, compared with 2%-7% for the 3 other assays. When interpreted based on the Fiebig classification, concordant stages were observed in 42% of samples, and only 49% were classified as early seroconversion by all 5 assays. For the remaining specimens, the distinction with chronic infection was highly variable depending on the assay (5%-100%).

Conclusions: Clinical laboratories must consider this variability, which must be kept in mind both for initial diagnosis and for multicenter studies for which inclusion criteria refer to serological profiles by confirmatory assays.
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http://dx.doi.org/10.1093/ofid/ofaa140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246347PMC
May 2020

Characterization of viral rebounds on dual etravirine/raltegravir maintenance therapy (ANRS-163 ETRAL trial).

J Antimicrob Chemother 2020 07;75(7):1943-1949

Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, AP-HP, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, laboratoire de virologie, F75013 Paris, France.

Background: The ANRS-163 ETRAL trial, a switch study to an etravirine 200 mg/raltegravir 400 mg twice-daily regimen in 165 patients with HIV-1 infection, showed durable efficacy until Week 96. The aim of this work was to investigate in detail the virological rebounds (VRs), defined as at least one plasma HIV viral load (VL) >50 copies/mL.

Methods: Quantification of HIV-DNA level was assessed at baseline, Week 48 and Week 96 (n = 157). VLs were measured in seminal plasma at Week 48 (n = 26). Genotypic resistance testing by ultra-deep sequencing (UDS) for reverse transcriptase (RT) and integrase regions was performed at baseline and at the time of VR.

Results: In this study, 19 patients experienced VR, with 2 patients having virological failure (VF; two consecutive VLs >50 copies/mL). For the first patient with VF, UDS detected minority resistant variants only in RT (K103N, 9.6%; Y181C, 4.9%) at baseline. Some RT variants became dominant at VF (K101E, 86.3%; Y181C, 100.0%; G190A, 100.0%) and others emerged in integrase (Y143C, 2.4%; Q148R, 6.2%; N155H, 18.8%). For the second patient with VF, neither RT nor integrase mutations were detected at baseline and VF. Median HIV-DNA level was similar at baseline, Week 48 and Week 96 (2.17, 2.06 and 2.11 log10 copies/106 cells, respectively). Only one patient had a detectable seminal HIV VL (505 copies/mL).

Conclusions: The dual etravirine/raltegravir regimen as maintenance therapy was effective and the emergence of mutations in cases of VF was similar to that seen in other dual-regimen studies. No HIV-DNA level modification was evidenced by Week 96.
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http://dx.doi.org/10.1093/jac/dkaa090DOI Listing
July 2020

A Hyper-Glycosylation of HBV Surface Antigen Correlates with HBsAg-Negativity at Immunosuppression-Driven HBV Reactivation in Vivo and Hinders HBsAg Recognition in Vitro.

Viruses 2020 02 23;12(2). Epub 2020 Feb 23.

Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.

Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3-8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of >1 additional NLGSs ( < 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation.
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http://dx.doi.org/10.3390/v12020251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077195PMC
February 2020

Impact of Raltegravir or Efavirenz on Cell-Associated Human Immunodeficiency Virus-1 (HIV-1) Deoxyribonucleic Acid and Systemic Inflammation in HIV-1/Tuberculosis Coinfected Adults Initiating Antiretroviral Therapy.

Open Forum Infect Dis 2020 Feb 11;7(2):ofz549. Epub 2020 Jan 11.

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

Background: In view of the fast viremia decline obtained with integrase inhibitors, we studied the respective effects of initiating efavirenz (EFV) or raltegravir (RAL)-based antiretroviral therapy (ART) regimens on human immunodeficiency virus (HIV)-1 deoxyribonucleic acid (DNA) levels and inflammation biomarkers in the highly inflammatory setting of advanced HIV-1 disease with tuberculosis (TB) coinfection.

Methods: We followed cell-associated HIV-1 DNA, high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), soluble CD14 and D-Dimer levels for 48 weeks after ART initiation in the participants to the ANRS12-180 REFLATE-TB study. This phase II open-label randomized study included ART-naive people with HIV and TB treated with rifampicin to receive RAL 400 mg twice daily (RAL400), RAL 800 mg twice daily (RAL800) or EFV 600 mg QD with tenofovir and lamivudine.

Results: In 146 participants, the median (interquartile range [IQR]) week (W)0 HIV-1 DNA level was 4.7 (IQR, 4.3-5.1) log copies/10 CD4, and the reduction by W48 was -0.8 log copies/10 CD4 on EFV, -0.9 on RAL400, and -1.0 on RAL800 ( = .74). Baseline median (IQR) hsCRP, IL-6, sCD14, and D-Dimer levels were 6.9 (IQR, 3.3-15.6) mg/L, 7.3 (IQR, 3.5-12.3) pg/mL, 3221 (IQR, 2383-4130) ng/mL, and 975 (IQR, 535-1970) ng/mL. All biomarker levels decreased over the study: the overall W0-W48 mean (95% confidence interval) fold-change on ART was 0.37 (IQR, 0.28-0.48) for hsCRP, 0.42 (IQR, 0.35-0.51) for IL-6, 0.51 (IQR, 0.47-0.56) for sCD14, and 0.39 (IQR, 0.32-0.47) for D-Dimers. There were no differences in biomarker reduction across treatment arms.

Conclusions: In participants with HIV and TB, EFV, RAL400, or RAL800 effectively and equally reduced inflammation and HIV-1 DNA levels.
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http://dx.doi.org/10.1093/ofid/ofz549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019658PMC
February 2020

Characterization of HIV-1 diversity in various compartments at the time of primary infection by ultradeep sequencing.

Sci Rep 2020 02 12;10(1):2409. Epub 2020 Feb 12.

AP-HP, Hôpital Saint-Louis, Virologie, Paris, France.

We used next-generation sequencing to evaluate the quantity and genetic diversity of the HIV envelope gene in various compartments in eight patients with acute infection. Plasma (PL) and seminal fluid (SF) were available for all patients, whole blood (WB) for seven, non-spermatozoid cells (NSC) for four, and saliva (SAL) for three. Median HIV-1 RNA was 6.2 log copies/mL [IQR: 5.5-6.95] in PL, 4.9 log copies/mL [IQR: 4.25-5.29] in SF, and 4.9 log copies/mL [IQR: 4.46-5.09] in SAL. Median HIV-1 DNA was 4.1 log copies/10 PBMCs [IQR: 3.15-4.15] in WB and 2.6 log copies /10 Cells [IQR: 2.23-2.75] in NSC. The median overall diversity per patient varied from 0.0005 to 0.0232, suggesting very low diversity, confirmed by the clonal aspect of most of the phylogenetic trees. One single haplotype was present in all compartments for five patients in the earliest stage of infection. Evidence of higher diversity was established for two patients in PL and WB, suggesting compartmentalization. Our study shows low diversity of the env gene in the first stages of infection followed by the rapid establishment of cellular reservoirs of the virus. Such clonality could be exploited in the search for early patient-specific therapeutic solutions.
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http://dx.doi.org/10.1038/s41598-020-59234-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016127PMC
February 2020

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

Ann Intern Med 2020 03 11;172(5):297-305. Epub 2020 Feb 11.

INSERM, Sorbonne Université, Institut Pierre Louis d'épidémiologie et de Santé Publique (IPLESP), Paris, France (L.A., R.L., L.B., D.C.).

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).
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http://dx.doi.org/10.7326/M19-2133DOI Listing
March 2020

Kinetics of Hepatitis B Core-Related Antigen and Anti-Hepatitis B Core Antibody and Their Association With Serological Response in Human Immunodeficiency Virus-Hepatitis B Coinfection.

J Infect Dis 2020 05;221(11):1826-1837

Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France.

Background: The aim of the current study was to describe the kinetics of quantified hepatitis B core-related antigen (qHBcrAg) and quantified anti-hepatitis B core antibody (qAnti-HBc) during tenofovir (TDF) treatment and assess their ability to predict hepatitis B e antigen (HBeAg) seroclearance in patients coinfected with human immunodeficiency virus (HIV) and hepatitis B virus.

Methods: Serum qHBcrAg, qAnti-HBc, and hepatitis B virus DNA were obtained at TDF initiation and every 6-12 months. The on-treatment kinetics of qHBcrAg (ΔqHBcrAg) and qAnti-HBc (ΔqAnti-HBc) were estimated using mixed-effect linear regression. Hazard ratios (HRs) assessing the association between markers and HBeAg seroclearance were calculated using proportional hazards regression, and the sensitivity (Se) and specificity (Sp) of marker levels in predicting HBeAg seroclearance were assessed using time-dependent receiving operating characteristic curves.

Results: During a median of 4.6 years, the cumulative incidences of hepatitis B surface antigen and HBeAg seroclearance were 3.2% (n = 5 of 158) and 27.4% (n = 26 of 95), respectively. ΔqHBcrAg was biphasic in HBeAg-positive patients (-0.051 and -0.011 log10 U/mL/mo during ≤18 and >18 months, respectively) and monophasic in HBeAg-negative patients. ΔqAnti-HBc was monophasic regardless of HBeAg status. In HBeAg-positive patients, baseline qHBcrAg and qAnti-HBc levels were associated with HBeAg seroclearance (adjusted HR, 0.48/log10 U/mL [95% confidence interval, .33-.70] and unadjusted HR, 1.49/log10 Paul Ehrlich Institute units/mL [1.08-2.07], respectively). Cutoffs with the highest accuracy in predicting HBeAg seroclearance at 36 months were qHBcrAg <6.5 log10 U/mL at month 24 (Se, 1; Sp, 0.58) and baseline qAnti-HBc ≥4.1 log10 Paul Ehrlich Institute units/mL (Se, 0.42; Sp, 0.81).

Conclusions: In coinfected patients undergoing TDF, qHBcrAg/qAnti-HBc could be of use in monitoring HBeAg seroclearance.
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http://dx.doi.org/10.1093/infdis/jiaa013DOI Listing
May 2020

A Genome-Wide CRISPR-Cas9 Screen Identifies the Dolichol-Phosphate Mannose Synthase Complex as a Host Dependency Factor for Dengue Virus Infection.

J Virol 2020 03 17;94(7). Epub 2020 Mar 17.

INSERM U944, CNRS UMR 7212, Genomes & Cell Biology of Disease Unit, Institut de Recherche Saint-Louis, Université de Paris, Hôpital Saint-Louis, Paris, France

Dengue virus (DENV) is a mosquito-borne flavivirus responsible for dengue disease, a major human health concern for which no specific therapies are available. Like other viruses, DENV relies heavily on the host cellular machinery for productive infection. In this study, we performed a genome-wide CRISPR-Cas9 screen using haploid HAP1 cells to identify host genes important for DENV infection. We identified DPM1 and -3, two subunits of the endoplasmic reticulum (ER) resident dolichol-phosphate mannose synthase (DPMS) complex, as host dependency factors for DENV and other related flaviviruses, such as Zika virus (ZIKV). The DPMS complex catalyzes the synthesis of dolichol-phosphate mannose (DPM), which serves as mannosyl donor in pathways leading to N-glycosylation, glycosylphosphatidylinositol (GPI) anchor biosynthesis, and C- or O-mannosylation of proteins in the ER lumen. Mutation in the DXD motif of DPM1, which is essential for its catalytic activity, abolished DPMS-mediated DENV infection. Similarly, genetic ablation of ALG3, a mannosyltransferase that transfers mannose to lipid-linked oligosaccharide (LLO), rendered cells poorly susceptible to DENV. We also established that in cells deficient for DPMS activity, viral RNA amplification is hampered and truncated oligosaccharides are transferred to the viral prM and E glycoproteins, affecting their proper folding. Overall, our study provides new insights into the host-dependent mechanisms of DENV infection and supports current therapeutic approaches using glycosylation inhibitors to treat DENV infection. Dengue disease, which is caused by dengue virus (DENV), has emerged as the most important mosquito-borne viral disease in humans and is a major global health concern. DENV encodes only few proteins and relies on the host cell machinery to accomplish its life cycle. The identification of the host factors important for DENV infection is needed to propose new targets for antiviral intervention. Using a genome-wide CRISPR-Cas9 screen, we identified DPM1 and -3, two subunits of the DPMS complex, as important host factors for the replication of DENV as well as other related viruses such as Zika virus. We established that DPMS complex plays dual roles during viral infection, both regulating viral RNA replication and promoting viral structural glycoprotein folding/stability. These results provide insights into the host molecules exploited by DENV and other flaviviruses to facilitate their life cycle.
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http://dx.doi.org/10.1128/JVI.01751-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081898PMC
March 2020

Prevalence and Incidence of Human Papillomavirus Infection in Men Having Sex With Men Enrolled in a Pre-exposure Prophylaxis Study: A Sub-study of the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales "Intervention Préventive de l'Exposition aux Risques avec et pour les hommes Gays" Trial.

Clin Infect Dis 2021 Jan;72(1):41-49

Institut National de la Santé et de la Recherche Médicale, Unité 944, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7212, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.

Background: Human papillomavirus (HPV) infection is more frequent in men having sex with men (MSM) who are living with human immunodeficiency virus (HIV) than in MSM without HIV. There are currently no data regarding HPV infections in preexposure prophylaxis (PrEP)-using MSM.

Methods: MSM living without HIV who were enrolled in the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales "Intervention Préventive de l'Exposition aux Risques avec et pour les hommes Gays" PrEP study were prospectively enrolled. Anal, penile, and oral samples were collected at baseline and every 6 months for HPV detection and genotyping. Anal swabs for cytology were obtained at baseline and at 24 months.

Results: We enrolled 162 participants. The prevalences of any HPV genotypes at baseline were 92%, 32%, and 12% at the anal, penile, and oral sites, respectively. High-risk (HR) HPV genotypes were observed in 84%, 25%, and 10% of anal, penile, and oral baseline samples, respectively. Nonavalent HPV vaccine genotypes were observed in 77%, 22%, and 6% of anal, penile, and oral baseline samples, respectively. Multiple infections were observed in 76%, 17%, and 3% of cases at the anal, penile, and oral sites, respectively. The most frequent HR genotypes were HPV 53, 51, and 16 in anal samples; HPV 33, 39, and 73 in penile samples; and HPV 66 in oral samples. The incidence of any HPV genotype at the anal site was 86.2/1000 person-months and the incidence of HR-HPV genotypes was 72.3/1000 person-months. The baseline cytology was normal in 32% of cases and was classified as atypical squamous cells of undetermined significance, low-grade squamous intra-epithelial lesion, high-grade squamous intra-epithelial lesion (HSIL), and atypical squamous cells that cannot exclude HSIL in 23%, 40%, 5%, and 1% of cases, respectively.

Conclusions: PrEP users have a similar risk of HPV infection as MSM living with HIV and the risk is much higher than that previously reported in MSM living without HIV.
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http://dx.doi.org/10.1093/cid/ciaa002DOI Listing
January 2021