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Natural hazards, due to climate change, are particularly damaging in urban areas because of interdependencies of their networks. So, urban resilience has to face up to climate risks. The most impacting phenomenon is the urban heat island (UHI) effect. The storage capacity of heat is depending on shapes of buildings, public spaces, spatial organization, transport or even industrial activities. So, adaptive strategies for improving urban climate could be possible in different ways. In the framework of the French project Resilis, this study characterises urban vulnerability and resilience in terms of energy needs of buildings and outside urban comfort according to the IPCC carbon dioxide emission scenarios B2 and A2 for the period 2050–2100 for 10 French cities. The evolutions of four climate indicators in terms of heating and cooling needs and number of hours when the temperature is above 28 °C are then obtained for each city to analyse climate risks and their impacts in urban environment.

Apolipoprotein E (apoE) is associated with the two hallmarks of Alzheimer's disease: Aβ deposits and neurofibrillary tangles. ApoE synthesis was detected in astrocytes byin situhybridization but was not detected in neurons. Nevertheless, different studies on apoE immunoreactivity reported the presence of apoE in neurons of Alzheimer, control, and necrosis pontisubicular brains. In this study, we addressed the question of potential synthesis of apoE in neurons and its possible involvement in or in response to pathological conditions. To this purpose, we have studied human neuronal cell lines (SY 5Y and Kelly cells) originating from neuroblastoma. Using monoclonal and polyclonal antibodies, a 32-kDa band was detected in SY 5Y and Kelly cells, before and after NGF differentiation. Two-dimensional gel electrophoresis analysis showed a typical profile of apoE spots resolved to the exact isoelectric points. By reverse transcription-polymerase chain reaction experiments, we demonstrated the presence of apoE mRNA in these cell lines. SY 5Y cells synthesized the apoE3 variant, whereas Kelly cells expressed both apoE3 and apoE4 isoforms, corroborating the two-dimensional gel results. These results suggested that apoE synthesis could occur in human neuronal cell lines under certain conditions.

Background: Second-generation integrase strand transfer inhibitors (InSTIs) have a high barrier to resistance and potent antiretroviral activity. They are recommended as first- or second-line (FL and SL) options in two- and three-drug regimens (2DR and 3DR) in international treatment guidelines. However, there are limited real-world data on emerging resistance at the time of virological failure (VF) with these regimens., Objectives: The Virostar-1 study objective is to analyse the emergence of resistance-associated mutations (RAMs) over 3 years with DTG-based 2DRs and DTG- or bictegravir (BIC)-based 3DRs in people living with HIV (PLWH) experiencing a VF (FL or SL)., Methods: Retrospective analysis of genotypic resistance detected at the time of a FL or SL VF with BIC/FTC/TAF, DTG/ABC/3TC, DTG/3TC and DTG/RPV between 2019 and 2022 was conducted from a French multicentre database. VF was defined as two consecutive HIV-1 plasma viral loads > 50 c/mL. Sanger assays were performed at VF within standard clinical care. Resistance mutations were reported using the ANRS algorithm. Selection biases prevent group comparisons., Results: During the period, N = 5986 PLWH were followed either in FL or SL. The VF rate was overall low: BIC/FTC/TAF, 6.8%; DTG/ABC/3TC, 7.5%; DTG/3TC, 5.1%; and DTG/RPV, 2.1%. Some emergent InSTI or NRTI RAMs were detected with BIC/FTC/TAF 4%, DTG/ABC/3TC 8.5%, DTG/3TC 18% and 39% emergent NNRTI RAMs with DTG/RPV. However, a complete absence of dual resistance against NRTIs and InSTIs was observed., Conclusions: We detected rare emergent InSTI RAMs and few emergent NRTI RAMs in PLWH failing DTG- or BIC-based regimens in FL or SL. The observed rates of emergent RAMs at VF were 4% with BIC/FTC/TAF, 8.5% with DTG/ABC/3TC, 18% with DTG/3TC and 39% with DTG/RPV., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: We aimed to determine how non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance profiles have changed over the last decade in people living with HIV (PLWHIV) experiencing virological failure on all antiretroviral treatments, including different NNRTIs., Materials and Methods: We analysed the use of the different NNRTIs in PLWHIV treated with antiretroviral drugs at an academic centre and the HIV NNRTI resistance profiles observed in cases of virological failure over the last 10 years (2014-23). We used the latest ANRS-MIE algorithm (v33; https://hivfrenchresistance.org/) to analyse the resistance mutation profiles of the HIV reverse transcriptase sequences., Results: During this period, the frequency of NNRTI use remained high, fluctuating slightly between 43.5% (n = 1782/4094) and 39.9% (n = 1758/4421). The use of efavirenz (10.8%-1.5%), nevirapine (7.0%-1.2%), and etravirine (11.0%-1.1%) decreased, whereas the use of rilpivirine (14.7%-26.3%) and doravirine (available from 2018, rising to 9.7% in 2023) increased. These trends were statistically significant for etravirine (P = 0.033) and rilpivirine (P < 0.001). Resistance rates for efavirenz, nevirapine and rilpivirine remained above 15% (efavirenz: 17.3%-16.6%, nevirapine: 16.9%-15.4% and rilpivirine: 17.6%-16.1%). This reflects significant cross-resistance between these three NNRTIs. By contrast, resistance rates were lower for etravirine (7.8%-6.0%) and doravirine (4.9%-4.6%), probably due to differences in their resistance profiles and higher genetic barriers to resistance., Conclusions: The NNRTI class of antiretroviral drugs remains widely used. Changes in the usage of drugs from this class have not altered the ecology of NNRTI resistance in antiretroviral drug-treated PLWHIV with virological failure during the studied period., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: We assessed the kinetics of the clearance of integrase strand transfer inhibitors resistance mutations (INSTIs-RMs) and associated factors from people living with HIV (PWH) displaying suppressed viral replication after virological failure (VF) on an INSTI regimen., Patients and Methods: We included PWH with HIV-RNA viral loads ≤20 copies/mL for at least 5 years in whom INSTIs-RM had been identified at least once in a prior RNA resistance genotyping test. HIV DNAs were sequenced by Sanger sequencing (SS) and ultra-deep sequencing (UDS; detection threshold: 5%) every year over the preceding 5 years., Results: We included 39 PWH in the study. Most (95%) had experienced VF on a raltegravir-containing regimen. The past INSTIs-RMs were not detected in the peripheral blood mononuclear cells of 35 of the 39 (90%) PWH by SS at the end of follow-up. In a longitudinal analysis (2017-21) based on UDS, the previously detected INSTIs-RMs were not detected in 29 of the 35 (83%) PWH. In multivariable analysis, the duration of viral replication and the level of HIV-RNA during prior VF were significantly associated with the persistence of INSTIs-RM, with odds ratios of 1.05 per week of replication (95% CI, 1.00-1.11; P  = 0.024) and 8.26 per log 10 copies/mL (95% CI, 1.46-46.59; P  = 0.017)., Conclusions: We observed a clear trend towards the clearance of archived INSTIs-RM after a long period of virological control leading to changes in the resistance profile in cellular DNA, raising the possibility of studies assessing the recycling of INSTI classes even in the presence of a history of resistance., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

The goal of this study is to test a novel device and methodology based on the "Pebble" platform and real-time quantitative colorimetric loop-mediated isothermal amplification (qcLAMP) during SARS-CoV-2 detection using crude samples and extracted RNA. The new method employs an inexpensive lightweight device aimed toward rapid point-of-care testing. An extensive evaluation was performed consisting of 1,693 clinical samples across five independent clinical testing centers. Positive colorimetric results were observed within 20 minutes of testing. At a 20-minute time-to-positive cut-off, the specificity is 98.5% with a diagnostic accuracy of 91.9%, compared to qPCR assays. Our findings indicate that the SARS-CoV-2 qcLAMP diagnostic assay in conjunction with the Pebble device is ideal for point-of-care/near-patient testing.IMPORTANCEHere, we describe our analyses and validation of a novel real-time quantitative colorimetric loop-mediated isothermal amplification (qcLAMP) device, available under the name "Pebble" and associated SARS-CoV-2 diagnostic qcLAMP assay for clinical diagnostic use. The analyses were performed in five independent testing sites across Europe using clinical samples from the associated clinical sites and support the use of "pebble" and associated kit in the diagnostic environment.

Background: Neutralizing antibodies targeting the SARS-CoV-2 Spike protein reduce COVID-19-related risk of hospitalization, particularly in high-risk individuals. The COCOPREV-R study aimed to evaluate and compare clinical outcomes in high-risk SARS-CoV-2 patients treated with dual monoclonal antibody therapies and to identify associated virological factors., Methods: The COCOPREV-R study retrospectively collected real-world data from high-risk patients receiving Bamlanivimab/Etesevimab or Casirivimab/Imdevimab dual monoclonal antibody therapies (22 February 2021 to 15 June 2021)., Results: The study included 1004 patients with COVID-19, of whom 691 received Bamlanivimab/Etesevimab and 313 received Casirivimab/Imdevimab. The alpha variant represented 90.1% of those for whom data were available. The risk of hospitalization within 30 days was lower with Bamlanivimab/Etesevimab (12.7%, CI 95% [9.9-16.3%]) compared to Casirivimab/Imdevimab (28.4%, CI 95% [22.7-35.1%) ( p < 0.001). The 30-day mortality rates were comparable between both groups ( p = 0.982). Analysis of SARS-CoV-2 PCR negativity showed no difference between the two treatment groups (95.2% [93.0-96.9%] and 93.5% [89.1-96.6%] until day 30, p = 0.851 for Bamlanivimab/Etesevimab and Casirivimab/Imdevimab, respectively). Among persistently positive samples with available sequencing results ( n = 43), Spike protein changes occurred only in Bamlanivimab/Etesevimab (42.9%) vs. Casirivimab/Imdevimab (0.0%) groups. Q493R (25.0%) and E484K (12.5%) were the most common mutations selected by Bamlanivimab/Etesevimab in follow-up samples. Other factors (immunodepression, comorbidities, and age) did not appear to be associated with the occurrence of Spike protein mutations., Conclusions: A higher rate of hospitalization was seen with Casirivimab/Imdevimab (RONAPREVE ® ) in comparison with Bamlanivimab/Etesevimab treatment, but with the emergence of Spike mutations only in the Bamlanivimab/Etesevimab group.

Background: Immune checkpoint inhibitors (ICIs) have been a major advance in cancer management. However, we still lack prospective real-world data regarding their usage in people with HIV infection (PWH)., Methods: The ANRS CO24 OncoVIHAC study (NCT03354936) is an ongoing prospective observational cohort study in France of PWH with cancer treated with ICI. We assessed the incidence of grade ≥3 immune-related adverse events (irAEs). All grade ≥3 irAEs were reviewed by an event review., Results: Between January 17, 2018, and December 05, 2023, 150 participants were recruited from 33 sites and 140 were included in this analysis. At the data cut-off date of December 05, 2023, the median follow-up was 9.2 months (IQR: 3.9-18.3), with a total of 126.2 person-years.Median age was 59 years (IQR: 54-64) and 111 (79.3%) were men. Median time since HIV diagnosis was 25 years (12-31), the median duration on antiretroviral (ARV) was 19.5 years (7.7-25.4), and the CD4 nadir was 117/µL (51-240). ICI regimens comprised anti-programmed cell death protein-1 (PD-1) for 111 (79.3%) participants, anti-programmed death-ligand 1 for 25 (17.9%), a combination of anti-PD-1 and anti-cytotoxic T-lymphocyte associated protein 4 for 3 (2.1%), and anti-PD-1 along with anti-vascular endothelial growth factor receptor for 1 (0.7%). The most frequent cancers were lung (n=65), head/neck (n=15), melanoma (n=12), liver (n=11) and Hodgkin's lymphoma (n=9).During follow-up, a total of 34 grade ≥3 irAEs occurred in 20 participants, leading to an incidence rate of 26.9 per 100 person-years. The Kaplan-Meier estimates of the proportion of participants with at least one episode of grade ≥3 irAEs were 13.8% at 6 months, 15.0% at 12 months and 18.7% at 18 months. One treatment-related death due to myocarditis was reported (0.7%). Multivariable analysis of cumulative incidence showed that participants with time since HIV diagnosis >17 years (incidence rate ratio (IRR)=4.66, p=0.002), with CD4<200 cells/µL (IRR=4.39, p<0.0001), with positive cytomegalovirus (CMV) serology (IRR=2.76, p=0.034), with history of cancer surgery (IRR=3.44, p=0.001) had a higher risk of incidence of grade ≥3 irAEs., Conclusion: This study showed that the incidence of a first episode of grade ≥3 irAE was 15.0% (95% CI: 9.6% to 22.9%) at 1 year and the cumulative incidence of all severe irAE episodes was 26.9 per 100 person-years. Low CD4 count, positive CMV serology, history of cancer surgery and a longer time since HIV diagnosis were associated with the occurrence of severe irAEs., Competing Interests: Competing interests: DC received personal fees from Pfizer for a lecture outside of the submitted work. A-GM and CK received consulting fees from Gilead Sciences, Merck, and ViiV. J-PS received grant from MSD avenir and personal fees from Roche, MSD, AZ, Novartis, leopharma, PFO, Lilly, Gilead, Daichy-sakyo, and Pfizer for lectures, presentations, speakers bureaus, manuscript writing or educational events outside of the submitted work. OL reports paid expert testimony and consultancy fees from BMS France, MSD; consultancy fees from Boehringer, AbbVie. BA reports research grant from MSD avenir, and consulting fees or honoraria from Novartis, AstraZeneca, BMS, MSD, Astellas, and Sanofi. MV received consulting fees from Gilead Sciences. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Doravirine is the latest NNRTI to be approved for the treatment of HIV-1 and has a different resistance profile from first-generation NNRTIs. Our aim was to investigate the virological efficacy of antiretroviral treatment including doravirine in people living with HIV-1 (PLWHIV), the factors associated with virological failure (VF) and those associated with the emergence of reverse transcriptase (RT) mutations in the case of VF., Methods: A retrospective national survey of PLWHIV who were either naive or experienced on antiretroviral treatment including doravirine was conducted. VF was defined as two consecutive plasma viral loads (VLs) of ≥50 copies/mL or one VL of ≥200 copies/mL. Genotypic resistance tests were interpreted using the Stanford (v9.4.1) and ANRS (v33) algorithms., Results: Of the 589 PLWHIV treated with a doravirine-containing regimen, 8.5% were naive and 91.5% had prior antiretroviral experience; 56.9% were infected with HIV-1 B subtype. Overall, 88.3% and 85.1% of participants were virologically controlled at Month (M)3 and M6 of doravirine treatment, respectively. In multivariable analysis, CRF02&#95;AG subtype, higher zenith plasma HIV-1 RNA VL, doravirine initiation in the context of failure and baseline V179D mutation presence were associated with VF. Among 88 PLWHIV who experienced virological failure at M6, 15.9% had a median of 2 (IQR 1-3) HIV RT mutations. In multivariable analysis, the only factor associated with the occurrence of mutations was a genotypic sensitivity score that was not fully sensitive., Conclusions: This study is one of the largest to characterize the virological efficacy of doravirine-containing regimens in clinical practice and to identify factors associated with VF or emergence of resistance mutations that should be considered in clinical management., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Resistance associated mutations (RAMs) are archived in the HIV reservoir and can re-emerge with an inappropriate ART use limiting treatment options. However, recent studies, using ultra-deep sequencing (UDS), showed a decrease of quasispecies harbouring RAMs, suggesting that recycling some antiretrovirals could be considered. The aim of this study was to characterize, in HIV treated PLWHIV, the M184V mutation decrease kinetics in proviral DNA and associated factors of M184V mutation clearance over time., Methods: UDS was performed on HIV-DNA from blood cells at different time points to quantify the percentage of M184V positive quasispecies. The sequence reads were analysed with a minimum coverage set at 50 and an ambiguity filter at 5% or 2%., Results: At 2.5 years after the first time point, the M184V lost was observed in 50% of PLWHIV. Moreover, univariate analyses highlight that a higher nadir CD4 count and a lower zenith HIV1 RNA viral load were correlated with a faster clearance of the mutation. In multivariate analysis, a higher zenith was negatively associated with the M184V clearance at the 5% threshold. Interestingly, lamivudine/emtricitabine presence in the ART therapy regiment during the 5 years was not associated with the persistence of the M184V., Conclusions: Our study provides new information concerning the clearance speed of M184V mutation over time in PLWHIV with fully suppressed viremia, opens the discussion about the duration needed to consider a lamivudine/emtricitabine recycling and reinforces the association of the nadir and zenith values with the M184V mutation clearance., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: High-risk patients, often immunocompromised and not responding to vaccine, continue to experience severe coronavirus disease 2019 (COVID-19) and death. Monoclonal antibodies (mAbs) were shown to be effective to prevent severe COVID-19 for these patients. Nevertheless, concerns about the emergence of resistance mutations were raised., Methods: We conducted a multicentric prospective cohort study, including 264 patients with mild to moderate COVID-19 at high risk for progression to severe COVID-19 and treated early with casirivimab/imdevimab, sotrovimab, or tixagevimab/cilgavimab. We sequenced the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome during follow-up and searched for emerging spike mutations., Results: Immunocompromised patients have a 6-fold increased risk of developing mutations, which are associated with a prolonged duration of viral clearance but no clinical worsening. Emerging P337S/R/L/H, E340D/K/A/Q/V/G, and K356T/R substitutions in patients treated with sotrovimab are associated with higher viral RNA loads for up to 14 days post-treatment initiation. Tixagevimab/cilgavimab is associated with a 5-fold increased risk of developing mutations. R346K/I/T/S and K444R/N/M substitutions associated with tixagevimab/cilgavimab have been identified in multiple SARS-CoV-2 lineages, including BQ.1 and XBB., Conclusions: The probability of emerging mutations arising in response to mAbs is significant, emphasizing the crucial need to investigate these mutations thoroughly and assess their impact on patients and the evolutionary trajectory of SARS-CoV-2., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection lasts longer in immunocompromised hosts than in immunocompetent patients. Prolonged infection is associated with a higher probability of selection for novel SARS-CoV-2 mutations, particularly in the spike protein, a critical target for vaccines and therapeutics., Methods: From December 2020 to September 2022, respiratory samples from 444 immunocompromised patients and 234 health care workers positive for SARS-CoV-2, diagnosed at 2 hospitals in Paris, France, were analyzed using whole-genome sequencing using Nanopore technology. Custom scripts were developed to assess the SARS-CoV-2 genetic diversity between the 2 groups and within the host., Results: Most infections were SARS-CoV-2 Delta or Omicron lineages. Viral genetic diversity was significantly higher in infections of immunocompromised patients than those of controls. Minor mutations were identified in viruses sequenced from immunocompromised individuals, which became signature mutations for newer SARS-CoV-2 variants as the epidemic progressed. Two patients were coinfected with Delta and Omicron variants. The follow-up of immunocompromised patients revealed that the SARS-CoV-2 genome evolution differed in the upper and lower respiratory tracts., Conclusions: This study found that SARS-CoV-2 infection in immunocompromised patients is associated with higher genetic diversity, which could lead to the emergence of new SARS-CoV-2 variants with possible immune evasion or different virulence characteristics., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Initiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population., Methods: Forty adolescents perinatally infected with HIV on suppressive ART for >5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested., Results: CA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-α was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study., Conclusions: Low CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gärtner, Domínguez-Rodríguez, Heaney, Gkouleli, Grant, Dorgham, Sauce, Soulie, Busby, O’Sullivan, Spyer, Botha, Muñoz-Fernandez, Tagarro, Cotugno, Huggett, Klein, Palma, Rojo Conejo, Foster, Giaquinto, Rossi, Persaud, De Rossi, Marcelin and Nastouli.)

Objectives: We aimed to characterize and compare the viral loads (VL) of the Omicron BA.1 and BA.2 lineages and the Delta variant in nasopharyngeal samples from newly diagnosed COVID-19 patients and their kinetics over time., Patients and Methods: The kinetics of the VL were measured on the CT data from 215 SARS-CoV-2 positive patients who presented at least two positive PCRs a day apart and were screened for SARS-CoV-2 viral lineages., Results: We observed no significant difference in median CT value during the first diagnostic test between the Delta variant and the two Omicron lineages. However, the kinetics of CT decreases for the BA.1 and BA.2 lineage were significantly lengthier in time than the kinetics for the Delta variant. The BA.2 lineage presented lower median CT value (-2 CT) (inversely proportional to the VL) than the BA.1 lineage., Conclusions: BA.2 Omicron lineage presented higher VL than BA.1 Omicron lineage at diagnostic. Omicron BA.1 and BA.2 lineages have more prolonged replication than the Delta variant., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objectives: To assess whether antiretroviral therapy (ART) prescriptions differ between naive and virally suppressed HIV patients born in France (PBFs) and in Sub-Saharan Africa (PBSSAs)., Setting: Observational single-center study., Methods: We included all PBFs and PBSSAs who entered into care at Pitié-Salpêtrière Hospital, Paris, France, from 01/01/2000 to 31/12/2018, with plasma HIV-RNA>200 copies/mL. We first compared the initial ART in naive PBFs and PBSSAs. Second, we compared the last-prescribed ART (including drug-reduced ART: daily 2-drug regimens, daily 1-drug regimens and intermittent 3-drug regimens) in virally suppressed PBFs and PBSSAs, by focusing on patients in care in 2018 with HIV-RNA <50 copies for at least 24 months. A univariable and multivariable logistic regression model was used to assess the impact of geographical origin on ART prescriptions., Results: A total of 1944 naive patients were included (915 PBSSAs and 1029 PBFs). PBSSAs were more frequently women, hepatitis B coinfected, with a lower pretherapeutic CD4 T-cell count, and most had tuberculosis at HIV diagnosis. After adjustment for confounders, PBSSAs were more likely to receive a first-line protease inhibitor-based regimen (OR 1.61, 95% CI: 1.31 to 1.98), and less likely to receive an integrase inhibitor-based regimen (OR 0.61, 95% CI: 0.42 to 0.88). Of the 968 virally suppressed patients (431 PBSSAs and 537 PBFs), PBSSAs were less likely to receive drug-reduced ART, including 2-drug regimens and intermittent three-drug regimens (OR 0.48, 95% CI: 0.36 to 0.65)., Conclusions: Differences in ART prescriptions between PBSSAs and PBFs were not only explained by different clinical and virologic situations. Personal motivations of doctors in choosing ART according to country of birth need to be explored., Competing Interests: R.P., L.C., S.S., C.S., R.T., M.A.V., L.S., V.P., and C.K. have received travel grants and honoraria from Gilead, ViiV Healthcare, and Merck. AGM has received travel and research grants and honoraria from Gilead, ViiV Healthcare, Theratechnologies and Merck. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To assess humoral responses to SARS-CoV-2 Delta-variant in people with HIV (PWH) after BNT162b2-vaccination., Design: Multicenter cohort study of PWH with CD4 + cell count less than 500 cells/μl and viral load less than 50 copies/ml on stable antiretroviral therapy for at least 3 months., Methods: Anti-SARS-CoV-2 receptor-binding-domain IgG antibodies (anti-RBD IgG) were quantified and neutralization capacity was evaluated by ELISA/GenScript and virus-neutralization-test against the D614G-strain, beta and delta variants before vaccination (day 0) and 1 month after complete schedule (M1)., Results: We enrolled 97 PWH, 85 received two vaccine shots. The seroconversion rate for anti-RBD IgG was 97% [95% confidence interval (CI) 90-100%] at M1. Median (IQR) anti-RBD IgG titer was 0.97 (0.97-5.3) BAU/ml at D0 and 1219 (602-1929) at M1. Neutralization capacity improved between D0 (15%; 50% CI 8-23%) and M1 (94%; 95% CI 87-98%) ( P  < 0.0001). At M1, NAbs against the D614G strain, beta and delta variants were present in 82, 77, and 84% PWH, respectively. The seroconversion rate and median anti-RBD-IgG level were 91% and 852 BAU/ml, respectively, in PWH with CD4 + cell count less than 250 ( n  = 13) and 98% and 1270 BAU/ml for CD4 + greater than 250 ( n  = 64) ( P  = 0.3994). NAbs were present in 73% of PWH with CD4 + less than 250 and 97% of those with CD4 + cell count greater than 250 ( P  = 0.0130). NAbs against beta variant were elicited in 50% in PWH with CD4 + cell count less than 250 and in 81% of those with CD4 + cell count greater than 250 ( P  = 0.0292). CD4 + and CD8 + T-cell counts were unchanged, whereas CD19 + B-cell counts decreased after vaccination(208 ± 124 at D0 vs. 188 ± 112 at M1, P  < 0.01). No notable adverse effects or COVID-19 cases were reported., Conclusion: Seroconversion rates were high, with delta-neutralization rates similar to those for the D61G strain, after a two-dose BNT162b2 vaccination in PWH., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We aimed to characterize the evolution of humoral immune response up to 1 year after SARS-CoV-2 infection in healthcare workers (HCWs) during the first wave of COVID-19 in Paris., Methods: Serum samples from 92 HCWs were tested at month 0 (M0), M6, and M12 after SARS-CoV-2 infection for IgG targeting the nucleocapsid (N), IgG targeting the receptor-binding domain (RBD) of spike (S) protein, IgA targeting S, and anti-RBD neutralizing antibodies. After M6, 46 HCWs received a single dose of COVID-19 vaccine., Results: We observed a significant decrease in all SARS-CoV-2 immunologic markers at M6 post-infection: median decreases were 0.26 log binding antibody units/mL (M0: 1.9 (interquartile range (IQR) 1.47-2.27); M6: 1.64 (IQR 1.22-1.92)) for anti-RBD IgG; 4.10 (index) (M0: 4.94 (IQR 2.72-6.82); M6: 0.84 (IQR 0.25-1.55)) for anti-N IgG; 0.64 (index) (M0: 2.50 (IQR 1.18-4.62); M6: 1.86 (IQR 0.85-3.54)) for anti-S IgA; and 24.4% (M0: 66.4 (IQR 39.7-82.5); M6: 42.0 (IQR 16.8-68.8)) inhibition activity for the RBD neutralizing antibodies. Between M6 and M12, anti-RBD IgG level, anti-S IgA index, and anti-RBD neutralizing activity significantly increased among COVID-19 vaccinated HCWs, whereas they remained stable among unvaccinated HCWs. Anti-N IgG index significantly decreased between M6 and M12 among both vaccinated (median: 0.73 (IQR 0.23-1.11) at M6 and 0.52 (IQR 0.20-0.73) at M12) and unvaccinated HCWs (median: 0.79 (IQR 0.21-4.67) at M6 and 0.34 (IQR 0.24-2.78) at M12)., Discussion: A steady decline in the anti-N IgG response was observed during the first year after SARS-CoV-2 infection among HCWs, whereas the anti-RBD IgG and the anti-S IgA responses remained stable and could be enhanced by COVID-19 vaccination., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

There are concerns about neutralizing antibodies' (NAbs') potency against severe acute respiratory syndrome coronavirus 2 variants. Despite decreased NAb titers elicited by BNT162b2 vaccine against VOC202012/01 and 501Y.V2 strains, 28/29 healthcare workers (HCWs) had an NAb titer ≥1:10. In contrast, 6 months after coronavirus disease 2019 mild forms, only 9/15 (60%) of HCWs displayed detectable NAbs against 501Y.V2 strain., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: We aimed to assess the kinetics of drug-resistant viral variants (DRVs) harboring the M184V mutation in proviral DNA of long-term virally suppressed patients, and factors associated with DRV persistence., Methods: Human immunodeficiency virus (HIV) DNA from blood cells stored in 2016 and 2019 was sequenced using Sanger and ultradeep sequencing (SS and UDS; detection threshold 1%) in antiretroviral therapy (ART)-treated patients with HIV RNA < 50 copies/mL for at least 5 years, with past M184V mutation documented in HIV RNA., Results: Among 79 patients, by combining SS and UDS, M184V was found to be absent in 26/79 (33%) patients and persistent in 53/79 (67%). M184V-positive patients had a longer history of ART, lower CD4 nadir, and higher pretherapeutic HIV RNA. Among 37 patients with viral sequences assessed by UDS, the proportion of M184V-positive DRVs significantly decreased between 2016 and 2019 (40% vs 14%, P = .005). The persistence of M184V was associated with duration and level of HIV RNA replication under lamivudine/emtricitabine (3TC/FTC; P = .0009 and P = .009, respectively)., Conclusions: While it decreased over time in HIV DNA, M184V mutation was more frequently persistent in HIV DNA of more treatment-experienced patients with longer past replication under 3TC/FTC., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Little is known about patients who forego healthcare, although it is an important provider of unfavorable health-related outcomes. Forgoing healthcare characterizes situations in which people do not initiate or interrupt a care process, even though they perceive the need for it, whether or not this need is medically proven. The aims of this study were to assess the prevalence and the determinants of patients who forego healthcare. The second aim was to compare the characteristics of patients who gave up healthcare during the French lockdown due to COVID-19., Methods: We conducted two multicenter cross-sectional studies in 2017 and 2020 carried out in French patients presenting to the emergency departments. Patients who gave their consent to participate were interviewed with a standardized questionnaire. It consisted of two parts: epidemiological characteristics and health care refusal. A third part concerning the renunciation of care during the COVID-19 period was added to the second study period., Results: A total of 1878 patients had completed the questionnaire during the interview with the physicians, 900 during the first period in 2017 (47.9%) and 978 (52.1%) during the second period. A total of 401/1878 patients reported not seeking care in the last 12 months (21.4% [95%CI: 19.5-23.3%]). In 2020, patients forewent care more during the confinement period than outside with different characteristics of the foregoing care populations., Conclusion: Forgoing care is common in a universal health care system such as France's and increased during the pandemic. Key public health messages targeted at the reasons for not seeking care must now be disseminated in order to combat this., (© 2022. The Author(s).)

Background: Severely ill patients with SARS-CoV-2 have an increased risk of venous thromboembolism (VTE) i.e., deep vein thrombosis and pulmonary embolism. However, the VTE risk in patients with mild and moderate COVID-19, hospitalized or managed at home, remain uncertain. The aims of this study were to assess the rate and the risk factors symptomatic VTE, in patients with mild and moderate COVID-19 and to compare them to a cohort of similar patients without COVID-19., Methods: Patients presenting to the emergency department (ED) of participating centers for confirmed or probable mild or moderate COVID-19 and not having acute VTE were included. This COVID-19 cohort was retrospectively compared to a prospective cohort of similar ED patients using propensity score matching. The main outcome was the rate of symptomatic VTE within the 28 days after ED presentation., Results: A total of 2292 patients were included in the COVID-19 cohort. The 28-day incidence of symptomatic VTE was 1.3% (n = 29/2292, 95%CI: 0.9 to 1.8), 2.3% (n = 20/866, 95%CI: 1.5 to 3.5) in moderate COVID-19 patients and 0.6% (n = 9/1426; 95%CI: 0.3 to 1.2) in mild COVID-19 patients managed as outpatients. An age over 65 years and hospitalization were independent risk factors of VTE. After adjustment, patients in the COVID-19 cohort had an absolute increase in over symptomatic VTE risk of +1.69% (95%CI, 0.88 to 2.51) versus patients in the comparison cohort (n = 1539)., Conclusions: Patients with moderate COVID-19 presenting to the ED had a high risk of subsequent VTE., Trial Registration: Ethics committee of the CHU of Angers (N°2020/87)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The Hospitalization or Outpatient Management of Patients With SARS-CoV-2 Infection (HOME-CoV) rule is a checklist of eligibility criteria for home treatment of patients with COVID-19, defined using a Delphi method., Research Question: Is the HOME-CoV rule reliable for identifying a subgroup of COVID-19 patients with a low risk of adverse outcomes who can be treated at home safely?, Study Design and Methods: We aimed to validate the HOME-CoV rule in a prospective, multicenter study before and after trial of patients with probable or confirmed COVID-19 who sought treatment at the ED of 34 hospitals. The main outcome was an adverse evolution, that is, invasive ventilation or death, occurring within the 7 days after patient admission. The performance of the rule was assessed by the false-negative rate. The impact of the rule implementation was assessed by the absolute differences in the rate of patients who required invasive ventilation or who died and in the rate of patients treated at home, between an observational and an interventional period after implementation of the HOME-CoV rule, with propensity score adjustment., Results: Among 3,000 prospectively enrolled patients, 1,239 (41.3%) demonstrated a negative HOME-CoV rule finding. The false-negative rate of the HOME-CoV rule was 4 in 1,239 (0.32%; 95% CI, 0.13%-0.84%), and its area under the receiver operating characteristic curve was 80.9 (95% CI, 76.5-85.2). On the adjusted populations, 25 of 1,274 patients (1.95%) experienced an adverse evolution during the observational period vs 12 of 1,274 patients (0.95%) during the interventional period: -1.00 (95% CI, -1.86 to -0.15). During the observational period, 858 patients (67.35%) were treated at home vs 871 patients (68.37%) during the interventional period: -1.02 (95% CI, -4.46 to 2.26)., Interpretation: A large proportion of patients treated in the ED with probable or confirmed COVID-19 have a negative HOME-CoV rule finding and can be treated safely at home with a very low risk of complications., Trial Registry: ClinicalTrials.gov; No.: NCT04338841; URL: www.clinicaltrials.gov., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: APOBEC3 editing activity contributes to sequences variation and viral diversification. We aimed to characterize virological and clinical factors associated with G-to-A mutations and stop codons in the HIV-1 reservoir, markers of APOBEC3 footprints, in order to better understand HIV-1 diversity among virologically suppressed HIV-1-infected patients., Methods: Immuno-virological and clinical factors were compared between 92 patients harbouring G-to-A mutations and stop codons (APOBEC+) in the reverse transcriptase gene and 92 patients without G-to-A mutations (APOBEC-) and stop codons in their DNA genotypes., Results: Patients were predominantly men (74.5%) and were mostly infected by B-subtype (69.0%), with 44.1% and 55.9% in APOBEC+ and APOBEC- groups, respectively. At time of HIV DNA genotypes, the total cell-associated HIV-1 DNA load was 2.34 log10 copies/106 cells (IQR 1.85-2.67) and 33.2% of them had a detectable ultrasensitive plasma viral load. Hypermutated sequences were identified in 28.2% of the APOBEC+ group. The median total cell-associated HIV-1 DNA level was significantly lower in APOBEC+ than APOBEC- group: 2.13 log10 copies/106 cells (IQR 1.60-2.60) versus 2.52 log10 copies/106 cells (IQR 2.19-2.71) (P < 0.001), respectively. Presence of G-to-A mutations and stop codon was independently associated with HIV-1 subtype non-B (P = 0.017)., Conclusions: These results show an independent association between the presence of G-to-A mutations and stop codons with HIV-1 subtype non-B and low proviral DNA that could be explained by the APOBEC3 footprints and restriction of DNA synthesis and integration. However, further investigations are needed to study the contribution of Vif amino acid variability among HIV-1 subtypes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To assess in real life whether two-drug regimens (2-DRs) given 4-5 days a week in virally suppressed patients can maintain viral suppression over 48 and 96 weeks., Methods: This observational single-centre study enrolled all patients who initiated an intermittent 2-DR between 01/01/2016 and 30/06/2019. The primary outcome was the rate of virological failure (VF), defined as confirmed plasma viral load (pVL) ≥50 copies/mL or single pVL ≥50 copies/mL followed by ART change at week 48 (W48) and W96. Secondary outcomes were the 2-DR intermittent strategy success rate (pVL <50 copies/mL with no ART change), change in CD4 count, CD4/CD8 ratio and rate of residual viraemia., Results: Eighty-five patients were included; 67/85 (79%) were men, median age = 57 years (IQR = 50-63), CD4 nadir = 233 cells/mm3 (110-327), ART duration = 21 years (13-24), duration of virological suppression = 6.5 years (3.7-10.8) and CD4 count = 658 cells/mm3 (519-867). Intermittent 2-DRs consisted of integrase strand transfer inhibitor (INSTI)/NNRTI (58%), INSTI/NRTI (13%), two NRTIs (11%), PI/NRTI (7%) and other combinations (11%). The median follow-up was 90 weeks (IQR = 64-111). Overall, four VFs occurred, leading to a virological success rate of 98.8% (95% CI = 93.6-100) at W48 and 95.3% (95% CI = 88.4-98.7) at W96. Resuming the same 2-DR 7 days a week led to viral resuppression in three patients, whereas the M184V mutation emerged in one patient, leading to ART modification. There was no significant change in the CD4 count or residual viraemia rate, but a small increase in the CD4/CD8 ratio (P = 0.009) occurred over the study period., Conclusions: This observational study shows the potential for intermittent 2-DRs to maintain a high virological success rate, which should be assessed in larger prospective randomized studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To describe clinical, biological, radiological presentation and W4 status in COVID-19 elderly patients., Patients and Methods: All patients ≥ 70 years with confirmed SARS-CoV-2 infection and hospitalized in the Infectious Diseases department of the Pitié-Salpêtrière hospital, Paris, France, from March 1st to April 15th 2020 were included. The primary outcome was death four weeks after hospital admission. Data on demographics, clinical features, laboratory tests, CT-scan findings, therapeutic management and complications were collected., Results: All in all, 100 patients were analyzed, including 49 patients ≥ 80 years. Seventy percent had ≥2 comorbidities. Respiratory features were often severe as 48% needed oxygen support upon admission. Twenty-eight out of 43 patients (65%) with a CT-scan had mild to severe parenchymal impairment, and 38/43 (88%) had bilateral impairment. Thirty-two patients presented respiratory distress requiring oxygen support ≥ 6 liters/minute. Twenty-four deaths occurred, including 21 during hospitalization in our unit, 2 among the 8 patients transferred to ICU, and one at home after discharge from hospital, leading to a global mortality rate of 24% at W4. Age, acute renal failure and respiratory distress were associated with mortality at W4., Conclusion: A substantial proportion of elderly COVID-19 patients with several comorbidities and severe clinical features survived, a finding that could provide arguments against transferring the most fragile patients to ICU., (© 2021 Elsevier Masson SAS. All rights reserved.)

Background: Little is known about HIV-1 integrase inhibitor resistance in the CNS., Objectives: This study aimed to evaluate integrase inhibitor resistance in CSF, as a marker of the CNS, and compare it with the resistance in plasma., Methods: HIV integrase was sequenced both in plasma and CSF for 59 HIV-1 patients. The clinical and biological data were collected from clinical routine care., Results: Among the 59 HIV-1 patients, 32 (54.2%) were under antiretroviral (ARV) treatment. The median (IQR) HIV-1 RNA in the plasma of viraemic patients was 5.32 (3.85-5.80) and 3.59 (2.16-4.50) log10 copies/mL versus 4.79 (3.56-5.25) and 3.80 (2.68-4.33) log10 copies/mL in the CSF of ARV-naive and ARV-treated patients, respectively. The patients were mainly infected with non-B subtypes (72.2%) with the most prevalent recombinant form being CRF02&#95;AG (42.4%). The HIV-1 integrase sequences from CSF presented resistance mutations for 9/27 (33.3%) and 8/32 (25.0%) for ARV-naive (L74I, n = 3; L74I/M, n = 1; T97A, n = 1; E157Q, n = 4) and ARV-treated (L74I, n = 6; L74M, n = 1; T97A, n = 1; N155H, n = 1) patients, respectively. Integrase inhibitor resistance mutations in CSF were similar to those in plasma, except for 1/59 patients., Conclusions: This work shows similar integrase inhibitor resistance profiles in the CNS and plasma in a population of HIV-1 viraemic patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Etravirine/raltegravir dual therapy has been shown to be highly effective as a twice-daily (q12h) regimen in suppressed HIV-infected patients enrolled in the ANRS-163 study., Objectives: As a once-daily (q24h) regimen is easier for daily life, we aimed to evaluate the capacity of etravirine/raltegravir (400/800 mg) q24h to maintain viral suppression in patients on etravirine/raltegravir q12h., Methods: Patients on a suppressive etravirine/raltegravir q12h regimen for at least 96 weeks were switched to etravirine/raltegravir q24h in this prospective, multicentre, open-label, single-arm study. Primary outcome was the rate of virological failure (VF: confirmed pVL >50 copies/mL, single pVL >400 copies/mL or single pVL >50 copies/mL with ART change) at Week 48 (W48). Secondary outcomes included treatment strategy success rate (no VF and no treatment discontinuation), regimen tolerability, plasma drug concentrations and resistance profile in the case of VF., Results: A total of 111 patients were enrolled, with a median (IQR) age of 57 years (52-62), CD4 count of 710 cells/mm3 (501-919) and viral suppression for 7.9 years (5.9-10.7). Two patients experienced viral rebound at W24 and W48, leading to a VF rate of 2.0% (95% CI 0.5-7.8) at W48, associated with INSTI resistance in one case. Both had past NNRTI mutations. Ten patients discontinued treatment for adverse events (n = 2), investigator or patient decisions (n = 3), lost to follow-up (n = 3), death (n = 1) or pregnancy (n = 1). Overall, the strategy success rate was 89% (95% CI 81.5-93.6) at W48. In a subgroup of 64 patients, median (IQR) plasma C24h concentrations were 401 ng/mL (280-603) for etravirine and 62 ng/mL (31-140) for raltegravir., Conclusions: Switching patients virally suppressed on etravirine/raltegravir q12h to the same regimen but given q24h was highly effective in maintaining virological suppression in HIV-infected patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Most studies about HIV-1 molecular evolution have shown the lack of viral evolution on effective antiretroviral therapy (ART), although controversial results have been documented. We therefore aimed to look for evidence of HIV-1 evolution in patients who initiated ART at the time of primary HIV-1 infection (PHI)., Design: We included retrospectively 20 patients diagnosed at PHI, treated at the time of acute infection and with subsequent effective long-term suppressive ART (HIV viral load <20 copies/ml during at least 5 years without any blips)., Methods: Longitudinal blood samples were deep sequenced using Illumina Miseq. Drug-resistance-associated mutations were retained at 2% cutoff and interpreted using the latest Agence Nationale de Recherches sur le Sida et les Hépatites Virales resistance algorithm. Viral evolution was established when temporal structure on maximum-likelihood phylogenetic tree and significant change over time of HIV-1 genetic diversity measured as the average pairwise distance was observed., Results: Emergences or disappearances of drug-resistance-associated mutations were detected in the blood cells during follow-up despite sustained virological control. In all patients, tree topologies showed an absence of segregation between sequences and blood viral populations from all time-points were intermingled. Comparison of the average pairwise distance showed the absence of significant viral diversity at the time of primary infection and afterwards during 5 years of full virological control under ART., Conclusion: Despite a slight variation of minority resistance-associated mutation variants, there was no clear evidence of viral evolution during a prolonged period of time in this population of highly controlled adult patients treated at time of PHI.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Inspired by the antiviral activity of known pyrazole-based HIV inhibitors, we screened our in-house library of pyrazole-based compounds to evaluate their in cellulo activity against HIV-1 replication. Two hits with very similar structures appeared from single and multiple-round infection assays to be non-toxic and active in a dose-dependent manner. Chemical expansion of their series allowed an in-depth and consistent structure-activity-relationship study (SAR) to be built. Further ADME evaluation led to the selection of 4-amino-3-cyano-1-(2-benzyloxyphenyl)-1 H -pyrazole-5-carboxylate with an advantageous pharmacokinetic profile. Finally, examination of its mode of action revealed that this compound does not belong to the three main classes of anti-HIV drugs, a feature of prime interest in the context of viral resistance., (This journal is © The Royal Society of Chemistry 2020.)

Objectives: Doravirine, a novel NNRTI, selects for specific mutations in vitro, including mutations at reverse transcriptase (RT) positions 106, 108, 188, 227, 230 and 234. The aim of this study was to examine the prevalence of doravirine-associated resistance mutations in HIV-1-infected antiretroviral-experienced patients., Methods: Doravirine-associated resistance mutations identified in vitro or in vivo were studied in a set of 9199 HIV-1 RT sequences from HIV-1 antiretroviral-experienced patients, including 381 NNRTI-failing patients in France and Italy between 2012 and 2017. The following mutations were considered as resistance mutations: V106A/M, V108I, Y188L, G190S, F227C/L/V, M230I/L, L234I, P236L, K103N + Y181C, K103N + P225H and K103N + L100I., Results: The frequencies of doravirine-associated resistance mutations (total dataset versus NNRTI-failing patients) were: V106A/M, 0.8% versus 2.6%; V108I, 3.3% versus 9.2%; Y188L, 1.2% versus 2.6%; G190S, 0.3% versus 2.1%; F227C/L/V, 0.5% versus 1.8%; M230I/L, 2.8% versus 0%; L234I, 0.1% versus 0.5%; K103N + Y181C, 3.9% versus 3.9%; K103N + P225H, 2.9% versus 4.7%; and K103N + L100I, 1.7% versus 3.9%, with a significantly higher proportion of these mutations in the NNRTI-failing group (P < 0.05), except for M230I/L and K103N + Y181C. The overall prevalence of sequences with at least one doravirine-associated resistance mutation was 12.2% and 34.9% in the total dataset and NNRTI-failing patients (P < 0.001), respectively. In comparison, the prevalence of the common NNRTI mutations V90I, K101E/P, K103N/S, E138A/G/K/Q/R/S, Y181C/I/V and G190A/E/S/Q were higher (8.9%, 7.9%, 28.6%, 12.6%, 14.2% and 8.9%, respectively)., Conclusions: These results suggest that doravirine resistance in antiretroviral-experienced patients generally and specifically among NNRTI-failing patients is lower than resistance to other NNRTIs currently used, confirming its distinguishing resistance pattern., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Objective: The ANRS163-ETRAL study showed that etravirine 200 mg/raltegravir 400 mg twice-daily dual therapy was highly effective in the treatment of human immunodeficiency virus (HIV)-infected patients older than 45 years, with virologic and therapeutic success rates at week 48 of 99.4% and 94.5%, respectively. The objective of this study was to determine whether a clinically significant pharmacokinetic interaction between etravirine and raltegravir exists by assessing steady-state total and unbound etravirine, raltegravir, and inactive raltegravir-glucuronide concentrations 12 hours after last intake (C 12h ) in blood plasma (BP) and seminal plasma (SP)., Design: Pharmacokinetic analysis of data from the ANRS163-ETRAL study., Patients: One hundred forty-six HIV-1-infected patients (of the 165 patients included in the ANRS-163 ETRAL study) who were receiving etravirine 200 mg and raltegravir 400 mg twice daily., Measurements and Main Results: Blood was collected from all 146 patients at weeks 2-4, 12, 24, and 48, and semen was collected from 21 patients at week 48. The extent of BP and SP protein binding was determined by using ultrafiltration assay. Total and unbound etravirine, raltegravir, and raltegravir-glucuronide C 12h were determined by ultra high performance liquid chromatography coupled with tandem mass spectrometry and interpreted by using the in vitro calculated protein-bound 95% inhibitory concentration (PBIC 95 ) for wild-type (WT) HIV: etravirine (116 ng/ml) and raltegravir (15 ng/ml). Median (interquartile range [IQR]) total BP etravirine C 12h (536 ng/ml [376-719]) and raltegravir (278 ng/ml [97-690]) were adequate in 99% and 96% of patients, respectively. Median (IQR) SP:BP C 12h ratio and BP unbound fraction were etravirine 0.3 (0.2-0.5) and < 1%, respectively, raltegravir 1.8 (1.3-3.3) and 12%, respectively, and raltegravir-glucuronide 12.0 (6.5-17.7) and > 99%, respectively. The BP raltegravir metabolic ratio (raltegravir glucuronide:raltegravir ratio) was 1.7, suggesting only weak induction of raltegravir glucuronidation by etravirine. Only three patients had etravirine and raltegravir C 12h < PBIC 95 simultaneously., Conclusion: No clinically significant pharmacokinetic interaction between etravirine and raltegravir was detected. Total etravirine and raltegravir BP concentrations were adequate in most patients, favoring virologic efficacy and confirming good treatment adherence (> 95%), despite twice-daily administration. The long half-life of etravirine and higher unbound fraction SP of raltegravir (57%) ensured adequate concentrations of dual therapy in genital compartments. Our results indicate that etravirine and raltegravir have good, complementary pharmacokinetic profiles, suggesting that they could be used in a dual-treatment strategy., (© 2019 Pharmacotherapy Publications, Inc.)