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

High rates of sexually transmitted infections (STIs) have been reported among pre-exposure prophylaxis (PrEP) users. We wished to assess the incidence and risk factors for recurrent STIs.The ANRS IPERGAY trial was a prospective study investigating PrEP among MSM and transgender women in outpatient clinics in France and Canada. In all, 429 participants were enrolled, offered up to 4 years of PrEP and screened for bacterial STIs (syphilis, chlamydia and gonorrhea) at baseline and every 6 months.STIs incidence was calculated yearly. Cox proportional hazards model regression was used to explore associations between participants characteristics at baseline and recurrent STI during follow-up.Over a median follow-up of 23 months, bacterial STI incidence was 75, 33, 13, 32 and 30 per 100 person-years for all STIs, rectal STIs, syphilis, gonorrhea and chlamydia, respectively. STI incidence significantly increased from the first year to the fourth year of the study (55 vs. 90 per 100 person-years, P 0.001). During the study period, 167 participants (39%) presented with more than one bacterial STIs which accounted for 86% of all STIs. Baseline risk factors associated with recurrent STIs in a multivariate analysis were an STI at baseline [hazards ratio: 1.48 (95% confidence interval (CI): 1.06-2.07), P = 0.02], more than eight sexual partners in prior 2 months [hazards ratio: 1.72 (95% CI: 1.21-2.43), P = 0.002] and the use of gamma-hydroxybutyrate [hazards ratio: 1.66 (95% CI: 1.16-2.38), P = 0.005].STI incidence was high and increased over time. Most STIs were concentrated in a high-risk group that should be targeted for future interventions.

Objectives We assessed the virologic efficacy of switching to co-formulated elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate (E/C/F/TDF) in patients with controlled HIV infection. Methods We conducted a retrospective multicenter observational cohort study including adult patients with controlled HIV-1 infection on any stable antiretroviral (ART) regimen, who switched to E/C/F/TDF. Success was measured by the proportion of patients with plasma viral load Results 382 patients with HIV RNA 3 and 24.6% of the patients had a history of previous virological failure. The reasons for switching were simplification (67.0%) and tolerance issues (22.0%). At week 48, 314 (82.0% [95% CI 78.4–86.0]) patients had HIV RNA Conclusion In our cohort, switching well-suppressed patients to E/C/F/TDF resulted in few virologic failures and was well tolerated. However, resistance to integrase inhibitors emerged in patients with virological failure.

Summary Background In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and tenofovir disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov , number NCT02842086 . Findings Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07–0·31]) and 15 in participants who had received emtricitabine and tenofovir disoproxil fumarate (0·30 infections per 100 person-years [0·17–0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and tenofovir disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78–82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and tenofovir disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p Interpretation Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. Funding Gilead Sciences.

Background Understanding the natural history of anal high-risk human papillomavirus (hrHPV) infection is key for designing anal cancer prevention programs but has not been systematically characterized. Methods We reanalyzed data from 34 studies including 16 164 individuals in 6 risk groups defined by human immunodeficiency virus (HIV) status, sex, and male sexuality: men who have sex with men (MSM) and people with HIV (MSMWH), HIV-negative MSM, women with HIV (WWH), HIV-negative women, men who have sex with women (MSW) with HIV (MSWWH), and HIV-negative MSW. We used Markov models to estimate incidence and clearance of 13 hrHPV types and their determinants. Results Human papillomavirus (HPV) 16 had the highest incidence-clearance ratio of the hrHPV types. MSMWH had the highest hrHPV incidence (eg, 15.5% newly HPV-16 infected within 2 years), followed by HIV-negative MSM (7.5%), WWH (6.6%), HIV-negative women (2.9%), MSWWH (1.7%), and HIV-negative MSW (0.7%). Determinants of HPV-16 incidence included HIV status and number of sexual partners for MSM, women, and MSW, and anal sex behavior for MSM only. HPV-16 clearance was lower for people with HIV (PWH) and lower for prevalent than incident infection. Among MSM, increasing age was associated with lower clearance of prevalent, but not incident, HPV-16 infection. Conclusions This robust and unifying analysis of anal hrHPV natural history is essential to designing and predicting the impact of HPV vaccination and HPV-based screening programs on anal cancer prevention, particularly in MSM and PWH. Importantly, it demonstrates the higher carcinogenic potential of longstanding anal prevalent hrHPV infection than more recent incident infection.

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

Summary Background Islatravir is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1 infection. We aimed to assess the efficacy and safety of islatravir-based regimens for the treatment of HIV-1. Methods We did a phase 2b, randomised, double-blind, comparator-controlled, dose-ranging trial at 24 clinics or hospitals in four countries (Chile, France, the UK, and the USA). Treatment-naive adults (≥18 years) with plasma HIV-1 RNA concentrations of at least 1000 copies per mL, CD4 T-cell counts of at least 200 cells per mL, and a calculated creatinine clearance of at least 50 mL/min (all within 60 days before study treatment) were eligible for inclusion. Participants were randomly assigned (1:1:1:1) with a block size of four via an interactive voice and web response system to receive oral treatment with one of three doses of islatravir (0·25 mg, 0·75 mg, or 2·25 mg) plus doravirine (100 mg) and lamivudine (300 mg) or to doravirine (100 mg) plus lamivudine (300 mg) plus tenofovir disoproxil fumarate (TDF; 300 mg) once daily with placebo (part 1). Treatment groups were stratified according to screening HIV-1 RNA concentration (≤100 000 copies per mL or >100 000 copies per mL). After at least 24 weeks of treatment, participants taking islatravir who achieved an HIV-1 RNA concentration lower than 50 copies per mL switched to a two-drug regimen of islatravir and doravirine (part 2). All participants and study investigators were masked to treatment in part 1; in part 2, the islatravir dose was masked to all participants and investigators, but the other drugs were given open label. The primary efficacy outcomes were the proportions of participants with an HIV-1 RNA concentration lower than 50 copies per mL at weeks 24 and 48 (US Food and Drug Administration snapshot approach). The primary safety outcomes were the number of participants experiencing adverse events and the number of participants discontinuing study drug owing to adverse events. All participants who received at least one dose of any study drug were included in the analyses. This trial is ongoing, but closed to enrolment of new participants; herein, we report study findings through 48 weeks of treatment. This trial is registered with ClinicalTrials.gov , NCT03272347 . Findings Between Nov 27, 2017, and April 25, 2019, 121 participants (mean age 31 years [SD 10·9], 112 [93%] male, 92 [76%] white, 27 [22%] with HIV-1 RNA concentration >100 000 copies per mL) were randomly assigned: 29 to the 0·25 mg, 30 to the 0·75 mg, and 31 to the 2·25 mg islatravir groups, and 31 to the doravirine, lamivudine, and TDF group. At week 24, 26 (90%) of 29 participants in the 0·25 mg islatravir group, 30 (100%) of 30 in the 0·75 mg islatravir group, and 27 (87%) of 31 in the 2·25 mg islatravir group achieved HIV-1 RNA concentrations lower than 50 copies per mL compared with 27 (87%) of 31 in the doravirine plus lamivudine plus TDF group (difference 2·8%, 95% CI –14·9 to 20·4, for the 0·25 mg islatravir group; 12·9%, –1·6 to 27·5, for the 0·75 mg islatravir group; and 0·3%, –17·9 to 18·5, for the 2·25 mg islatravir group). At week 48, these data were 26 (90%) of 29 in the 0·25 mg islatravir group, 27 (90%) of 30 in the 0·75 mg islatravir group, and 24 (77%) of 31 in the 2·25 mg islatravir group compared with 26 (84%) of 31 in the doravirine plus lamivudine plus TDF group (difference 6·1%, 95% CI –12·4 to 24·4, for the 0·25 mg islatravir group; 6·2%, –12·2 to 24·6, for the 0·75 mg islatravir group; and –6·1%, –27·1 to 14·8, for the 2·75 mg islatravir group). 66 (73%) of participants in the islatravir groups combined and 24 (77%) of those in the doravirine plus lamivudine plus TDF group reported at least one adverse event. Two participants in the 2·25 mg islatravir group and one participant in the doravirine plus lamivudine plus TDF group discontinued owing to an adverse event. No deaths were reported up to week 48. Interpretation Treatment regimens containing islatravir and doravirine showed antiviral efficacy and were well tolerated regardless of dose. Doravirine in combination with islatravir has the potential to be a potent two-drug regimen that warrants further clinical development. Funding Merck, Sharp, & Dohme Corp, a subsidiary of Merck & Co., Inc.

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.

Objectives Tetracyclines are widely used for the treatment of bacterial sexually transmitted infections (STIs) and recently have been used successfully for post-exposure prophylaxis of STIs in MSM. We investigated the in vitro and in vivo development of tetracycline resistance in Chlamydia trachomatis and Mycoplasma genitalium and evaluated 16S rRNA mutations associated with acquired resistance in other bacteria. Methods In vitro selection of resistant mutants of reference strains of C. trachomatis and M. genitalium was undertaken by serial passage in medium containing subinhibitory concentrations of tetracycline or doxycycline, respectively. The 16S rRNA gene of the two microorganisms was amplified and sequenced at different passages, as were those of 43 C. trachomatis- and 106 M. genitalium-positive specimens collected in France from 2013 to 2019. Results No tetracycline- or doxycycline-resistant strains of C. trachomatis and M. genitalium, respectively, were obtained after 30 serial passages. The tetracycline and doxycycline MICs were unchanged and analysis of the 16S rRNA gene, the molecular target of tetracyclines, of C. trachomatis and M. genitalium revealed no mutation. No mutation in the 16S rRNA gene was detected in C. trachomatis-positive specimens. However, six M. genitalium-positive specimens harboured a mutation potentially associated with tetracycline resistance without known prior tetracycline treatment for patients. Conclusions Tetracyclines did not select in vitro-resistant mutants of C. trachomatis or M. genitalium. However, 16S rRNA mutations either responsible for or associated with tetracycline resistance in other bacteria, including mycoplasma species, were identified in several M. genitalium-positive specimens.

International audience; Objectives: The increasing incidence of fluoroquinolones (FQ) resistance may lower its efficacy in preventing UTI following transrectal ultrasound-guided prostate biopsy (TRUS-PB). We assessed the efficacy and safety of FQ and fosfomycin-trometamol (FT) in patients undergoing TRUS-PB.Methods: A prospective observational study was conducted between April 2017 and June 2019 and enrolled men undergoing TRUS-PB and receiving a single-dose of FQ (FQ-arm) or FT (FT-arm) for UTI prophylaxis per physician's choice. The primary efficacy endpoint was self-reported TRUS-PB UTI. We assessed baseline factors associated with UTI with logistic regression.Results: A total of 222 men were enrolled, 141/222 (64%) received FQ, and 81/222 (36%) FT. The median age was 67.6 years [IQR, 61.4-72.1] and the Charlson score was 3 [IQR, 3-5]. The overall incidence of self-reported TRUS-PB UTI was 12% (24/197, (95%CI, 8%-17%)): 15% (17/116, (95% CI, 10%-17%)) in FQ-arm, versus 9% (7/81, 95% CI (5%-13%)) in FT-arm (RR = 0.55 (95% CI, 0.22-1.40), p-value = 0.209). No baseline characteristic was significantly associated with TRUS-PB UTI. Safety was similar between the arms: the rate of the reported adverse event was 31% (36/116, (95% CI, 25%-37%) in the FQ-arm versus 36% (28/81, (95% CI, 28%-41%)) in the FT-arm (RR = 1.17 (95% CI, 0.64-2.15), p = 0.602).Conclusions: TRUS-PB UTI prophylaxis with FT and FQ has similar efficacy and safety. A randomized comparison of these two antibiotics is warranted.

Background: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. Methods: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA

Introduction The optimal management of men who have sex with men (MSM) requires active involvement of family physicians (FP). We assessed knowledge and practices of Parisian FPs related to the management of MSM for sexually transmitted infections (STIs) and pre-exposure prophylaxis for HIV (PrEP). Method We conducted an observational prospective study between June 20 and July 31, 2017, with a sample of FPs practicing in Paris. The questionnaire posted via the Google Form website included 42 questions on sexual health management of MSM patients. A statistical analysis was then performed. Results One hundred and four FPs took part in the study. The median age was 34 and 68% were women. Overall, 86.5% of FPs had already heard about PrEP, but only 36% of them were familiar with the indication for therapy and 77.9% of FPs declared to be willing to renew PrEP prescription. Overall, 89.4% of respondents declared to be willing to attend additional training on sexual health of MSM patients, including 73% on PrEP. Conclusion FPs have an important role in the management of MSM patients. They showed strong interest in PrEP despite limited knowledge of indications and methods of administration. They declared to be willing to attend additional training for further involvement.

In high-income countries, causes of death in people living with HIV (PLHIV) have changed. Three French national surveys from 2000 to 2010 showed a decrease in AIDS-related and an increase in non-AIDS-related deaths. Deaths notified in PLHIV followed between January 1, 2011 and December 31, 2015 in 1 of 13 participating hospitals northeast of Paris area were described. Risk factors for death were assessed, using a multivariable logistic regression model. Of 14,403 individuals, 295 died. Median age at death was 52 years (interquartile range = 47-60) and 77% were men. Sixty-seven individuals (23%) died from non-AIDS-defining nonviral hepatitis-related (NaNH) malignancy, 40 (14%) from AIDS, 34 (12%) from cardiovascular disease (CVD), 33 (11%) from non-AIDS infection, 21 (7%) from liver disease, and 12 (4%) from suicide. Men and women born in sub-Saharan Africa had a lower adjusted odds ratio (aOR) of dying than men having sex with men (MSM) born in France (0.70, 95% confidence interval = 0.45-1.09; and 0.45, 0.28-0.73, respectively). Risk factors for death were older age (aOR = 2.26, 1.36-3.77 for 40-49 years and 2.91, 1.75-4.84 for50 years vs. 18-39 years), male intravenous drug users (IVDU) transmission (2.24, 1.42-3.54 vs. MSM born in France), AIDS (2.75, 2.10-3.59), antiretroviral therapy initiation in earlier periods, time since HIV diagnosis1 year, low CD4 cell count nadir, hepatitis B virus and/or hepatitis C virus coinfection (1.69, 1.23-2.30), and psychiatric disorders (1.73, 1.27-2.38). Our study confirms the increasing frequency of non-AIDS-related deaths, mainly NaNH malignancies and CVD, in PLHIV, justifying overall and in some specific populations (psychiatric and IVDU) prevention and screening.

International audience; Background: Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor.Methods: In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort.Results: A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log10 copies per milliliter in the fostemsavir group and 0.17 log10 copies in the placebo group (P

Doravirine is a novel, non-nucleoside reverse transcriptase inhibitor that has shown non-inferior efficacy to ritonavir-boosted darunavir, with a superior lipid profile, in adults with HIV who were treatment naive at week 48 in the phase 3 DRIVE-FORWARD trial. Here we present the 96-week data for the study.This randomised, controlled, double-blind, multicentre, non-inferiority, phase 3 study was undertaken at 125 clinical centres in 15 countries. Eligible participants were adults (aged ≥18 years) infected with HIV-1 who were naive to antiretroviral therapy, with a plasma HIV-1 RNA concentration of 1000 copies per mL or higher at screening, and no known resistance to any of the study drugs. Participants were randomly assigned (1:1) using an interactive voice and web response system, stratified by baseline HIV-1 RNA concentration and background nucleoside reverse transcriptase inhibitor therapy, to doravirine (100 mg per day) or ritonavir-boosted darunavir (100 mg ritonavir and 800 mg darunavir per day), both with investigator-selected nucleoside reverse transcriptase inhibitors: emtricitabine and tenofovir disoproxil fumarate or abacavir and lamivudine. Participants and investigators were masked to treatment assignment until week 96. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here we report the key secondary efficacy endpoint of the proportion of participants who achieved this concentration by week 96, assessed in all participants who received at least one dose of any study drug, regardless of whether it was their randomly assigned treatment. We used a US Food and Drug Administration snapshot approach and a margin of 10 percentage points to define the non-inferiority of doravirine to ritonavir-boosted darunavir at 96 weeks. Key safety endpoints were change in fasting serum lipid concentrations, the incidence of adverse events, and time to discontinuation due to an adverse event, assessed in all participants who received at least one dose of any study medication. This study is registered with ClinicalTrials.gov, NCT02275780, and is closed to accrual.Between Dec 1, 2014, and Oct 20, 2015, 1027 individuals were screened, of whom 769 participants were randomly assigned to doravirine (n=385) or ritonavir-boosted darunavir (n=384), and 383 in both groups were given at least one dose of their allocated treatment. Most participants were male (645 [84%] of 766) and white (560 [73%]), with a mean age of 35·2 years (SD 10·6). 292 participants in the doravirine group and 273 in the darunavir group completed 96 weeks of treatment. At week 96, a higher proportion of the doravirine group (277 [73%] of 383) achieved an HIV-1 RNA concentration of less than 50 copies per mL than did of the darunavir group (248 [66%] of 383; difference 7·1%, 95% CI 0·5-13·7). Responses were similar regardless of baseline characteristics. Treatment-emergent resistance to any study drug occurred in two (1%) of 383 participants in the doravirine group and one (1%) of 383 in the ritonavir-boosted darunavir group. Significant differences were seen between treatment groups in mean changes from baseline in LDL cholesterol (-14·6 mg/dL, 95% CI -18·2 to -11·0) and non-HDL cholesterol (-18·4 mg/dL, -22·5 to -14·3). Frequencies of adverse events were similar between groups. No significant treatment difference (log-rank nominal p=0·063) through week 96 was observed in time to discontinuation due to an adverse event. The most common adverse events (week 0-96) were diarrhoea (65 [17%] in the doravirine group vs 91 [24%] in the ritonavir-boosted darunavir group), nausea (45 [12%] vs 52 [14%]), headache (57 [15%] vs 46 [12%]), and upper respiratory tract infection (51 [13%] vs 30 [8%]). Two participants, one in each group, died during treatment; neither death was considered to be related to study medication.These results through 96 weeks support the efficacy and safety results reported previously for doravirine at 48 weeks, supporting the use of doravirine for the long-term treatment of adults with previously untreated HIV-1 infection.Merck.

People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52 weeks in PWH.This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420 mg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24 weeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART.Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined.Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP.Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events.NCT02833844.http://links.lww.com/QAD/C441.

International audience; BackgroundThere are few data available regarding the use of on-demand pre-exposure prophylaxis (PrEP) for HIV prevention. We aimed to assess PrEP effectiveness, adherence, and safety in adults using daily or on-demand PrEP.MethodsWe conducted a prospective observational cohort study (ANRS PREVENIR) at 26 sites in the Paris region, France. We enrolled HIV-negative adults (aged ≥18 years) at high risk of HIV infection who were starting or continuing PrEP. PrEP was prescribed as a fixed-dose combination of tenofovir disoproxil and emtricitabine (245 mg and 200 mg, respectively, per pill). PrEP could be prescribed as a daily regimen with one pill per day or, in men who have sex with men (MSM) or in transgender women who have sex with men, as an on-demand regimen following the IPERGAY dosing recommendation. At enrolment and every 3 months thereafter, participants were tested for HIV and provided information regarding the PrEP dosing regimen used. Adherence to PrEP was assessed by self-report and by tenofovir diphosphate concentrations in dried blood spots. The primary outcome of HIV-1 incidence was assessed using Poisson regression among participants who started PrEP. This study is registered with ClinicalTrials.gov, NCT03113123, and EudraCT, 2016A0157744.FindingsBetween May 3, 2017, and May 2, 2019, 3082 people were assessed for eligibility and 3065 participants were enrolled. 3056 (99·7%) of 3065 participants reported using PrEP and were included in the analyses. The median age was 36 years (IQR 29–43), 1344 (44·0%) of 3056 participants were PrEP-naive, and 3016 (98·7%) were MSM. At enrolment, 1540 (50·5%) of 3049 participants opted for daily PrEP dosing and 1509 (49·5%) opted for on-demand PrEP dosing; these proportions remained stable during follow-up. Median follow-up was 22·1 months (IQR 15·9–29·7) and incidence of study discontinuation was 17·6 participants (95% CI 16·5–18·7) per 100 person-years. At the data cutoff on Sept 30, 2020, there had been six HIV-1 seroconversions (three participants using daily PrEP and three using on-demand PrEP; all were MSM) over 5623 person-years. Overall HIV-1 incidence was 1·1 cases (95% CI 0·4–2·3) per 1000 person-years, and did not differ between participants using daily PrEP and those using on-demand PrEP (incidence rate ratio 1·00, 95% CI 0·13–7·49; p=0·99). Four participants (two using daily PrEP and two using on-demand PrEP) discontinued PrEP due to treatment-related adverse events (nausea [n=2], vomiting and diarrhoea [n=1], and lumbar pain [n=1]).InterpretationIn this study, which enrolled mainly MSM, HIV-1 incidence on PrEP was low and did not differ between participants using daily PrEP and those using on-demand PrEP. On-demand PrEP therefore represents a valid alternative to daily PrEP for MSM, providing greater choice in HIV prevention.FundingANRS/Maladies Infectieuses Emergentes, Gilead Sciences, SIDACTION, and Région Ile de France.TranslationFor the French translation of the abstract see Supplementary Materials section.; ANRS/Maladies Infectieuses Emergentes, Gilead Sciences, SIDACTION, and Région Ile de France.

ObjectivesWe aimed to assess among men who have sex with men (MSM) risk factors for HIV infection, to identify those who require urgent pre-exposure prophylaxis (PrEP) prescription.MethodsAll participants enrolled in the placebo arm of the ANRS IPERGAY trial, or infected between screening and day 0, were included. Baseline characteristics were described and HIV incidence rate ratios (RRs) were estimated with their 95% CIs.Results203 MSM were included with a median follow-up of 9 months. During the study period, 16 participants acquired HIV infection while not receiving tenofovir disoproxil and emtricitabin (TDF/FTC) over 212.4 person-years (PYs) of follow-up (incidence rate 7.5/100 PYs, 95% CI: 4.3 to 12.2). Being enrolled in Paris was associated with a significant increased risk of HIV infection (RR: 4.1; 95% CI: 1.1 to 28.3). A high number of sexual partners in prior 2 months (≥10 vs <5) and of condomless receptive anal sex episodes in prior 12 months (>5 vs ConclusionsMSM who have frequent condomless receptive anal sex and multiple partners, or use recreational drugs should be targeted in priority for PrEP prescription especially if they live in an area with a high prevalence of HIV infection.

Summary Background The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding European Union Commission, French Ministry of Health, Domaine d'interet majeur One Health Ile-de-France, REACTing, Fonds Erasme-COVID-Universite Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation For the French translation of the abstract see Supplementary Materials section.

Background Tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is a reliable pharmacokinetics biomarker of adherence to tenofovir disoproxil fumarate (TDF). We aimed to use DBSs to estimate pill intake among participants using on-demand pre-exposure prophylaxis (PrEP) and to identify predictive factors associated with higher TFV-DP concentrations. Methods DBSs were collected at the last study visit of the open-label phase of the ANRS IPERGAY study, assessing on-demand oral TDF/emtricitabine for PrEP among MSM and transgender female participants. We quantified TFV-DP in DBSs centrally. We assessed correlation between pill count and TFV-DP concentration by Spearman correlation and explored associations between participant demographics, sexual behaviour and PrEP use during sexual intercourse (SI) with TFV-DP concentrations by univariate and multivariate logistic regression models. Results The median age of the 245 participants included in this study was 40 years, with a median body weight of 73 kg. Median (IQR) TFV-DP concentration reached 517 (128–868) fmol/punch, corresponding to an estimated intake of 8–12 tablets per month (2–3 doses per week). Only 39% of participants had a TFV-DP concentration above 700 fmol/punch. TFV-DP concentrations were moderately correlated with pill count (r: 0.59; P This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record [Estimated pill intake with on-demand PrEP with oral TDF/FTC using TFV-DP concentration in dried blood spots in the ANRS IPERGAY trial. Journal of Antimicrobial Chemotherapy (2021)] is available online at: https://doi.org/10.1093/jac/dkab253. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

Background: Antiretroviral treatment (ART) reduces HIV infectiousness but the effect of early ART on sexual behaviour is unclear. Methods: We assessed, within the START randomized trial that enrolled HIV-positive adults with CD4+ cell count greater than 500 cells/μl, the effect of early (immediate) versus deferred ART on: condomless sex with HIV-serodifferent partners (CLS-D); all condomless sex (CLS); HIV transmission-risk sex (CLS-D-HIV risk, defined as CLS-D and: not on ART or started ART

Background Tenofovir alafenamide is associated with less renal and bone toxicity than tenofovir disoproxil fumarate and might improve the long-term safety of antiretroviral therapy. We aimed to investigate the effect on bone mineral density of switching from a regimen containing tenofovir disoproxil fumarate to one containing tenofovir alafenamide in participants aged 60 years and older. Methods We did a prospective, open-label, multicentre, randomised trial in 36 European centres. Participants were virologically suppressed (HIV-1 RNA

Background Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is a once-daily, single-tablet regimen for treatment of HIV-1 infection. The efficacy/safety of switching to D/C/F/TAF versus continuing boosted protease inhibitor (bPI) + emtricitabine/tenofovir disoproxil fumarate (control) were demonstrated in a phase 3, randomized study (EMERALD) of treatment-experienced, virologically suppressed adults through week 48. The objective of this analysis was to evaluate EMERALD outcomes across subgroups of patients based on demographic characteristics, prior treatment experience, and baseline antiretroviral regimen. Methods EMERALD patients were virologically suppressed (viral load [VL] 50 years), gender, race (black/non-black), prior number of antiretrovirals used (4/5/6/7/> 7), prior VF (0/≥ 1), baseline bPI (darunavir/atazanavir or lopinavir), and baseline boosting agent (ritonavir/cobicistat). Results Among 1141 patients in the D/C/F/TAF (n = 763) and control (n = 378) arms, virologic rebound rates (2.5% and 2.1%, respectively) were similar, and this was consistent across all subgroups. Virologic response rates ranged from 91 to 97% (D/C/F/TAF) and 89 to 99% (control) across all subgroups, with differences between treatment arms of 0 and 6%. Adverse event rates were low in both arms and across subgroups. Improvements in renal and bone parameters were observed with D/C/F/TAF across demographic subgroups. Conclusions For treatment-experienced, virologically suppressed patients, switching to D/C/F/TAF was highly effective and safe, regardless of demographic characteristics, prior treatment experience, or pre-switch bPI. Trial registration ClinicalTrials.gov Identifier: NCT02269917. Registered 21 October 2014. https://clinicaltrials.gov/ct2/show/NCT02269917

The clinical trial ANRS-IPERGAY investigated the efficacy of sexual activity-based (i.e. on demand) HIV pre-exposure prophylaxis (PrEP). Using a qualitative method, we analysed the role of adherence as one of the main elements for PrEP effectiveness and its associated determinants. Data were collected in various French ANRS-IPERGAY sites during the double-blind (2012-2014) and open-label study (2015-2016) phases, through two individual interviews per participant, collective interviews and focus groups. A total of 83 participants participated in the present study. Our analysis included 32 individual interviews (with 16 participants), 13 collective interviews (

Background Human Norovirus (HuNoV) has recently been identified as a major cause of diarrhea among kidney transplant recipients (KTR). Data regarding risk factors associated with the occurrence of HuNoV infection, and its long-term impact on kidney function are lacking. Methods We conducted a retrospective case-control study including all KTR with a diagnosis of HuNoV diarrhea. Each case was matched to a single control according to age and date of transplantation, randomly selected among our KTR cohort and who did not develop HuNoV infection. Risk factors associated with HuNoV infection were identified using conditional logistic regression, and survival was estimated using Kaplan-Meier estimator. Results From January 2012 to April 2018, 72 cases of NoV diarrhea were identified among 985 new KT, leading to a prevalence of HuNoV infection of 7.3%. Median time between kidney transplantation and diagnosis was 46.5 months (Inter Quartile Range [IQR]:17.8–81.5), and the median duration of symptoms 40 days (IQR: 15–66.2). Following diagnosis, 93% of the cases had a reduction of immunosuppression. During follow-up, de novo Donor Specific Antibody (DSA) were observed in 8 (9%) cases but none of the controls (p = 0.01). Acute rejection episodes were significantly more frequent among cases (13.8% versus 4.2% in controls; p = 0,03), but there was no difference in serum creatinine level at last follow-up between the two groups (p = 0.08). Pre-transplant diabetes and lymphopenia below 1000/mm3 were identified as risks factors for HuNoV infection in multivariate analysis. Conclusion HuNoV infection is a late-onset and prolonged infection among KTR. The current management, based on the reduction of immunosuppressive treatment, is responsible for the appearance of de novo DSA and an increase in acute rejection episodes.

International audience; Background: Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods: In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual.Findings: Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2·5%, 90% credible interval [CrI] -17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45).Interpretation: Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19.Funding: The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.

Background: The ability of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) to maintain virologic suppression in participants with M184V and/or M184I resistance mutations from historical genotypic reports when switching from a tenofovir disoproxil fumarate-based or abacavir (ABC)-based regimen was investigated. Setting: Phase IIIb, 48-week, open-label, single-arm, multicenter, clinical trial (NCT02616029). Methods: Virologically suppressed adults with HIV and documented M184V/I on historical genotypic records switched to E/C/F/TAF from a tenofovir disoproxil fumarate-based or ABC-based regimen. The primary end point was HIV-1 RNA of = 50 copies per milliliter (week 12); confirmatory HIV-1 RNA was

Risk perception is one of the several important factors impacting sexual health behaviours. This study investigated the evolution of HIV risk perception on pre-exposure prophylaxis adherence and condom use in men who have sex with men at high risk of HIV and associated factors. Group-based trajectory modelling helped in identifying patterns of risk perception, pre-exposure prophylaxis adherence and condom use over time. The association between the former and the latter two dimensions was then investigated. An estimated 61 per cent ( p

In this placebo-controlled phase II randomized clinical trial, we evaluated the safety and immunogenicity of a therapeutic prime-boost vaccine strategy using a recombinant DNA vaccine (GTU-MultiHIV B clade) followed by a boost vaccination with a lipopeptide vaccine (HIV-LIPO-5) in HIV-infected patients on combined antiretroviral therapy. We show here that this prime-boost strategy is well tolerated, consistently with previous studies in HIV-1-infected individuals and healthy volunteers who received each vaccine component individually., In this placebo-controlled phase II randomized clinical trial, 103 human immunodeficiency virus type 1 (HIV-1)-infected patients under cART (combined antiretroviral treatment) were randomized 2:1 to receive either 3 doses of DNA GTU-MultiHIV B (coding for Rev, Nef, Tat, Gag, and gp160) at week 0 (W0), W4, and W12, followed by 2 doses of LIPO-5 vaccine containing long peptides from Gag, Pol, and Nef at W20 and W24, or placebo. Analytical treatment interruption (ATI) was performed between W36 to W48. At W28, vaccinees experienced an increase in functional CD4+ T-cell responses (P

International audience; Pre-Exposure Prophylaxis (PrEP) is changing the landscape of HIV prevention, and may bring changes in sexual behaviors. The double-blind phase (DBP) and open-label extension (OLE) study of the ANRS-IPERGAY trial allowed us to assess changes in sexual behavior of men who have sex with men (MSM) taking sexual activity-based (i.e., on-demand) PrEP. Generalized Estimating Equation (GEE) models found a significant decrease in the number of sexual partners (Coefficient [CI95%], p value; - 0.37[- 0.70 to - 0.04], p = 0.03) between the DBP and OLE as well as in the number of sexual relations (- 0.25 [- 0.49 to 0.00], 0.04). GEE estimates also showed that respondents' most recent sexual relation was less likely to have been with an unknown casual partner during the OLE than during the DBP (Odds Ratio [CI95%], p value: 0.75[0.62-0.92], 0.005). Furthermore, they showed an increase in the proportion of condomless anal sex in the OLE (1.32[1.04-1.67], 0.02), a decrease in the proportion of 'suboptimal PrEP adherence' over time (0.75[0.58-0.97], p = 0.03), a decrease in PrEP only use (0.73[0.55-0.96], 0.03) and in both PrEP and condom use over time (0.70[0.51-0.95], 0.02) and finally, a decrease in alcohol consumption between the DBP and OLE (0.74[0.61-0.90], 0.002). We observed both protective and risky behaviors in terms of HIV and STI risk after on-demand PrEP uptake in the OLE phase. Our findings are consistent with results from previous PrEP trials.

BACKGROUND In the primary analysis of the DRIVE-SHIFT trial, switching to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintained suppression of HIV-1 through week 48. Here, we present long-term efficacy and safety outcomes through week 144 of the DRIVE-SHIFT trial. METHODS This phase 3, randomized, open-label trial evaluated switching from a stable antiretroviral regimen to once-daily DOR/3TC/TDF in adults with HIV-1 suppressed for ≥6 months and no previous virologic failure. Participants switched at day 1 [immediate switch group (ISG); n = 447] or week 24 [delayed switch group (DSG); n = 209]. Nine ISG participants who completed week 48 but did not enter extension-1 were excluded from week 144 efficacy analyses. RESULTS At week 144, HIV-1 RNA

Importance Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices. Objective To evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV. Evidence Review New evidence was collected since the previous International Antiviral (formerly AIDS) Society–USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations. Findings From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic. Conclusion and Relevance Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.

BACKGROUND We used the Agence nationale de Recherches sur le sida et les hepatites virales (ANRS)-IPERGAY trial to qualitatively and quantitatively measure drug use among men who have sex with men under preexposure prophylaxis using 2 different methods, to better understand and collectively respond to risky practices. METHOD We included 69 volunteers of the ANRS-IPERGAY trial. We measured drug use by 2 methods: (1) drug detection by hair analysis and (2) reported drug use by self-reported drug consumption. RESULTS New psychoactive substances (NPS) and conventional drugs were detected in 53 of the 69 (77%) volunteers by hair analysis and in 39 of the 69 (57%) volunteers by questionnaires. On the 219 hair segments analyzed, the most commonly used drugs were cocaine in 47 of the 69 (68%), 3,4-methylenedioxymethamphetamine/ecstasy in 31 of the 69 (45%), and NPS in 27 of the 69 (39%). On the 1061 collected questionnaires, the most commonly used drugs were cocaine in 31 of the 69 (45%), 3,4-methylenedioxymethamphetamine/ecstasy in 29 of the 69 (42%), and NPS in 16 of the 69 (23%). Hair analysis detects more conventional drugs and/or NPS use (P < 0.05). Drug use identified by hair was significantly associated with a higher number of sexual partners in the past 2 months (P ≤ 0.001), more often casual partners (P ≤ 0.001), condomless anal sex (P ≤ 0.005), hardcore sexual practices (P ≤ 0.001), a higher number of sexually transmitted infections, and chemsex (P ≤ 0.05). CONCLUSIONS Self-report drug use by questionnaires remains the reference tool for harm reduction at the individual level because of its feasibility and low cost. However, hair analysis is more sensitive, objectively assessing consumption, and interesting to understand uses and to be able to collectively respond to risky practices with adapted messages.

Background Mycoplasma genitalium (MG) is an emerging pathogen among men who have sex with men (MSM) with raising rates of antibiotic resistance. This study assessed the prevalence and incidence of MG infection in MSM enrolled in the open-label phase of the ANRS IPERGAY trial with on-demand tenofovir disoproxil fumarate/emtricitabine for human immunodeficiency virus 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 and oropharyngeal and anal swabs. Resistance to azithromycin (AZM), to fluoroquinolones (FQs), and to doxycycline was investigated in the French National Reference Center of Bacterial Sexually Transmitted Infections (STIs). Results The all-site prevalence of MG at baseline was 10.5% (6.3% in urine samples, 4.3% in anal swabs, 0.5% in throat swabs) and remained unchanged at 6 months whether or not PEP was used: 9.9% overall, 10.2% with PEP, 9.6% without. The overall rate of MG resistance (prevalent and incident cases) to AZM and FQs 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 pre-exposure prophylaxis 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.

Recent clinical trial data showed that injectable long-acting antiretroviral treatment (LA-ART) every four or eight weeks could become an alternative option for HIV treatment or prevention. The purpose of our study was to explore perceptions and potential users' points of views of this new mode of administration through individuals' therapeutic itinerary and their singular history with ART. Between 2018 and 2019, a qualitative study was conducted in two University Hospitals in Paris, France. In-depth interviews were conducted with 15 virologically controlled People Living with HIV (PLWH) and 13 men on pre-exposure prophylaxis (PrEP) for at least six months. Interviews, focused on the daily experience with ART, were recorded, transcribed, and analyzed using thematic content analysis. Collected discourses were organized around three emergent concerns: social, material and experimental. Each of these concerns was perceived as ambivalent, balanced by skepticism and hope. It revealed the complexity of each individual's relationship to their HIV treatment or PrEP, leading to balance the injectable LA-ART popularity reported within clinical trials. This new mode of administration may be a suitable alternative for some PLWH and PrEP users, a "simplification" compared to the oral route. It opens a window for "customizable" ART-treatment according to individuals' lives.

We assessed the coverage of sex acts by event-driven pre-exposure prophylaxis (ED-PrEP) over a 2-month period in 54 participants in the open label phase of the ANRS Ipergay trial. Participants received an electronic monitoring system device to record bottle openings. Self-questionnaires collected daily information on PrEP intake and sexual behavior. Intake was also estimated through returned pill counts. Full coverage of sex acts was defined as at least one pill taken both within 24 h before and within 48 h following sex. There was a strong correlation (r = − 0.92) between the number of bottle openings and returned pill counts. During the study, 42 participants (78%) practiced ED-PrEP and 12 (22%) daily PrEP with bottle openings at least 5 days/week whatever their sexual activity. Out of the 154 reported receptive anal sex acts, 81% were condomless: among them, PrEP coverage was hight: 97% among those practicing daily PrEP and 82% among those using ED-PrEP.

BackgroundObligate anaerobes usually account for less than 10% of bacteria recovered from blood cultures (BC). The relevance of routine use of the anaerobic bottle is under debate. The aim of this study was to evaluate the utility of anaerobic bottles for the diagnosis of bloodstream infections (BSI).MethodsWe conducted a 6-month, retrospective, monocentric study in a tertiary hospital. All positive BC were grouped into a single episode of bacteremia when drawn within 7 consecutive days. Bacteremia were classified into contaminants and BSI. Charts of patients with BSI due to obligate anaerobes were studied.ResultsA total of 19,739 blood cultures were collected, 2341 of which (11.9%) were positive. Anaerobic bottles were positive in 1528 (65.3%) of all positive BC but were positive alone (aerobic bottles negative) in 369 (15.8%). Overall 1081 episodes of bacteremia were identified, of which 209 (19.3%) had positive anaerobic bottles alone. The majority 126/209 (60.3%) were contaminants and 83 (39.7%) were BSI. BSI due to facultative anaerobes, obligate aerobes and obligate anaerobes were identified in 67 (80.7%), 3 (3.6%) and 13 (15.7%) of these 83 episodes, respectively. BSI due to obligate anaerobic bacteria were reported in 9 patients with gastro-intestinal disease, in 3 with febrile neutropenia and in 1 burned patient.ConclusionsAnaerobic bottles contributed to the diagnosis of a significant number of episodes of bacteremia. Isolated bacteria were mostly contaminants and non-obligate anaerobic pathogens. Rare BSI due to obligate anaerobes were reported mainly in patients with gastro-intestinal disorders and during febrile neutropenia.

International audience; The ANRS-PREVENIR (2017-2020) prospective cohort study aims to reduce the number of new HIV infections in the "Ile-de-France" region in France, by enrolling individuals at high risk of HIV infection and proposing daily and on-demand pre-exposure prophylaxis (PrEP). The qualitative component of the ANRS-PREVENIR study aimed to investigate social and relational evolutions associated with PrEP use in men who have sex with men (MSM). In 2018, 12 focus groups with MSM (n = 68) were conducted by a social sciences researcher in Paris. A thematic analysis was performed. Results showed that stigma concerning PrEP use is a complex issue, with various kinds of stigmatization being practiced, sometimes even by the wider MSM population and PrEP users themselves. All types of stigma identified were expressed in forms of verbal abuse which made PrEP use taboo. Inside the wider MSM population a PrEP-user "community" was identified which shared a certain complicity in terms of values and a positive attitude towards PrEP. The emergence of new intragroup and intergroup social norms should be taken into account by policy makers to promote a more positive image of PrEP users.

The authors report interim results of the WHO Solidarity trial of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with Covid-19. Effects on overall mortality, initiation of ventilation, and duration of hospital stay are compared. Background World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). Methods We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. Results At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. Conclusions These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ; ClinicalTrials.gov number, .)

International audience; Background: Interpretation of the increase in certain inflammatory markers in virally suppressed HIV-infected individuals must rely on an appropriate uninfected control group well characterized for non-HIV-related factors that contribute to chronic inflammation, e.g. smoking, alcohol consumption, or being overweight. We compared the inflammatory profiles of HIV-infected participants under long-term antiretroviral therapy (ART) with those of two HIV-uninfected groups with contrasting health behaviours. Methods: We studied 150 HIV-infected participants (42 women, 108 men) under long-term ART (median, 6 years) followed in the ANRS PRIMO cohort since acute/early HIV-1 infection (AHI) diagnosis. Sex and age-matched controls were sampled from i) the ANRS IPERGAY pre-exposure prophylaxis trial among men at high risk for HIV infection and with high frequencies of non-HIV factors of inflammation ii) the ANRS COHVAC cohort of volunteers in vaccine trials with a low-risk profile for HIV infection. We measured the plasma levels of ten inflammatory markers. Findings: After adjusting for smoking, alcohol use and body mass index, both HIV-infected men and women had higher levels of sCD14, sCD163, sTNFRII and I-FABP than their high-risk IPERGAY and low-risk COHVAC counterparts. Hierarchical clustering showed a subset of 15 PRIMO participants to have an inflammatory profile similar to that of most HIV-negative participants. These participants already had favourable markers at AHI diagnosis. Interpretation: Long-term ART, even when initiated at a low level of immunodeficiency, fails to normalize monocyte/macrophage activation and gut epithelial dysfunction. Persistent inflammation under treatment may be related to an increased inflammatory profile since AHI. Funding: ANRS and Paris-Saclay University.

International audience; Objective: This study aimed to identify situational and behavioral factors associated with condomless anal sex without on-demand PrEP in the open-label extension (OLE) study of the ANRS-IPERGAY trial.Methods: Univariable and multivariable modified Poisson regressions with a generalized estimating equation (GEE) were used. The attributable risk percentage for each explanatory variable and for condomless anal sex without PrEP was calculated.Results: In the OLE, 19% of anal intercourses were unprotected (i.e. no PrEP or condom). Of these, 85% were attributable to sexual intercourse with main partners and 47% with HIV-negative partners. The following factors were positively associated with condomless anal sex without PrEP: a depressive episode in the previous 12 months [aR (95% CI), P-value: 1.49 (1.02--2.17), 0.039], a higher number of sexual intercourses during the previous 4 weeks [1.01 [1.002--1.02], 0.014], and sexual intercourses under the influence of alcohol [1.45 (1.10--1.92), 0.008]. By contrast, condomless anal sex without PrEP was less frequent during sexual intercourses with known casual, unknown casual and multiple partners [0.20 (0.14--0.30)

Background Dexamethasone is standard of care for the treatment of patients with COVID-19 requiring oxygen. The objective is to assess the clinical benefit of adding remdesivir to dexamethasone. Patients and methods A retrospective cohort study of hospitalized patients with COVID-19 pneumonia requesting low-flow oxygen who received dexamethasone. Patients admitted to infectious diseases wards also received remdesivir. Primary outcome was duration of hospitalization after oxygen initiation. Secondary outcomes were in-hospital death, and death and/or transfer to the intensive care unit. To handle potential confounding by indication bias, outcome comparison was performed on propensity score-matched populations. Propensity score was estimated by a multivariable logistic model including prognostic covariates; then 1:1 matching was performed without replacement, using the nearest neighbor algorithm with a caliper of 0.10 fold the standard deviation of the propensity score as the maximal distance. Balance after matching was checked on standardized mean differences. Results From August 15th 2020, to February 28th, 2021, 325 patients were included, 101 of whom received remdesivir. At admission median time from symptoms onset was 7 days, median age: 68 years, male sex; 61%, >1 comorbidity: 58.5%. Overall 180 patients matched on propensity score were analyzed, 90 each received remdesivir plus dexamethasone or dexamethasone alone. Median duration of hospitalization was 9 (IQR: 7–13) and 9 (IQR: 5–18) days with and without remdesivir, respectively (p = 0.37). In-hospital death rates and rates of transfer to the intensive care unit or death were 8.9 and 17.8% (HR: 0.46, 95% CI: 0.21–1.02, p = 0.06) and 20.0 and 35.6% with and without remdesivir, respectively (HR: 0.45, 95% CI: 0.23–0.89, p = 0.015). Conclusion In hospitalized patients with COVID-19 pneumonia receiving low-flow oxygen and dexamethasone, the addition of remdesivir was not associated with shorter hospitalization or lower in-hospital mortality but may have reduced the combined outcome of death and transfer to the intensive care unit.

Supplemental Digital Content is Available in the Text., Background: Raltegravir 1200mg (2×600mg tablets) once daily (QD) demonstrated noninferior efficacy and similar safety to raltegravir 400mg twice daily (BID) at week 48 of the ONCEMRK trial. Here, we report the week 96 results from this study. Methods: ONCEMRK is a phase 3, multicenter, double-blind, noninferiority trial comparing raltegravir 1200mg QD with raltegravir 400mg BID in treatment-naive HIV-1–infected adults. Participants were assigned (2:1) to raltegravir 2×600mg QD or 400mg BID, both with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) for 96 weeks. Randomization was stratified by screening HIV-1 RNA and hepatitis B/C status. Efficacy was assessed as the proportion of participants with HIV-1 RNA 260 cells/mm3 from baseline in both groups. Resistance to raltegravir was infrequent, occurring in 0.8% of each treatment group through week 96. Adverse event rates were similar for the 2 regimens. Conclusions: In HIV-1–infected treatment-naive adults receiving FTC/TDF, raltegravir 1200mg QD demonstrated noninferior efficacy to raltegravir 400mg BID that was durable to week 96, with a safety profile similar to raltegravir 400mg BID.

Preexposure prophylaxis of HIV with antiretroviral drugs is a prevention tool available in France since 2016, combined with the prevention methods already used (condoms, post-exposure treatment, rapid treatment of diagnosed HIV infections, etc.). It is targeted at populations at high risk of HIV infection, especially men who have sex with men, for whom traditional prevention methods are insufficient. We collected clinical research data, which resulted in the launch of preexposure prophylaxis in the United States and then elsewhere in the world, safety, tolerability and cost data, as well as ongoing research data (new molecules/methods of administration). We also provided an update of its use in France.

Background In the ANRS 165 DARULIGHT study (NCT02384967) carried out in HIV-infected patients, the use of a darunavir/ritonavir-containing regimen with a switch to a reduced dose of darunavir maintained virological efficacy (≤50 copies/mL) for 48 weeks with a good safety profile. Objectives To assess the total and unbound blood plasma pharmacokinetics of darunavir and associated antiretrovirals, and their penetration into semen before and after dose reduction. Patients and methods Patients receiving a darunavir/ritonavir (800/100 mg q24h)-containing regimen for >6 months with plasma HIV-RNA ≤50 copies/mL for >12 months were switched to 400/100 mg darunavir/ritonavir q24h at week 0. A 24 h intensive pharmacokinetic blood sampling and a trough seminal sampling were performed before (week 0) and after (week 12) dose reduction. Individual pharmacokinetic parameter estimates were obtained using non-linear mixed-effect modelling for darunavir/ritonavir in blood plasma and used to test for bioequivalence, whereas darunavir/ritonavir in seminal plasma and NRTIs were analysed using a non-compartmental approach. Results and conclusions Fifteen patients completed the intensive pharmacokinetic analysis. There was no significant decrease in total and unbound darunavir blood plasma exposure despite a 50% decrease in darunavir daily dose from 800 to 400 mg (AUC0-24 = 65 563 versus 52 518 ng·h/mL; P = 0.25). A decrease in apparent oral clearance (CL/F) of both darunavir and ritonavir at week 12 suggests a modification of the initial darunavir/ritonavir daily dose balance (800/100 to 400/100 mg), in favour of a reduced inducer effect of darunavir on cytochrome P450 and efflux transporters compared with the standard dose.

International audience; Objectives:To assess whether low-dose ritonavir-boosted darunavir (darunavir/r) in combination with two NRTIs could maintain virological suppression in patients on a standard regimen of darunavir/r + two NRTIs.Design:A multicentre, Phase II, non-comparative, single-arm, open-label study.Setting:Tertiary care hospitals in France.Subjects:One hundred HIV-1-infected adults with no darunavir or NRTI resistance-associated mutations (RAMs) and a plasma HIV RNA level ≤50 copies/mL for ≥12 months on once-daily darunavir/r (800/100 mg) + two NRTIs for ≥6 months were switched to darunavir/r 400/100 mg with the same NRTIs.Primary outcome measure:Proportion of patients with treatment success: plasma HIV RNA level ≤50 copies/mL up to 48 weeks without any change in the study regimen, in a modified ITT (mITT) analysis.Results:At baseline, most patients were male (78%), with a median age of 43 years, median duration of HIV RNA ≤50 copies/mL of 35 months and median CD4 T cell count of 633 cells/mm3. Seventy-six percent received tenofovir/emtricitabine and 24% abacavir/lamivudine. Five patients were excluded from the mITT analysis. The rate of treatment success through to week 48 was 91.6% (87/95; 95% CI 84.1%-96.3%). No RAM was detected in three amplifiable genotypes. A total of 212 adverse events (AEs) occurred in 64 patients (64%); 9 AEs were serious, none leading to treatment discontinuation.Conclusions:In HIV-infected patients well suppressed with darunavir/r (800/100 mg) and two NRTIs, a reduction of the darunavir dose to 400 mg/day maintained virological efficacy and was safe over 48 weeks.

Despite their high global incidence, sexually transmitted infections (STIs) remain a neglected area of research. Increased rates of STIs have been reported in particular among men who have sex with men (MSM) probably because of the advances in the treatment and prophylaxis of human immunodeficiency virus (HIV) infection with a decrease in condom use. A recent report among MSM showed that the use of postexposure prophylaxis with doxycycline could dramatically reduce the incidence of chlamydia and syphilis but not of gonorrhea. The long-term consequences of this strategy are yet unknown, especially the risk of selection and dissemination of syphilis and chlamydia strains with doxycycline resistance, which has not been reported yet.

International audience; BACKGROUND:Tobacco smoking is common in people living with HIV, but high-quality evidence on interventions for smoking cessation is not available in this population. We aimed to assess the efficacy and safety of varenicline with counselling to aid smoking cessation in people living with HIV.METHODS:The ANRS 144 Inter-ACTIV randomised, parallel, double-blind, multicentre, placebo-controlled phase 3 trial was done at 30 clinical hospital sites in France. People living with HIV who had smoked at least ten cigarettes per day for 1 year or longer, were motivated to stop smoking, were not dependent on another psychoactive substance, and had no history of depression or suicide attempt were eligible. Using a computer-generated randomisation sequence, we allocated (1:1) the patients to receive either varenicline titrated to two 0·5 mg doses twice daily or placebo twice daily for 12 weeks, plus face-to-face counselling. Patients and investigators were masked to treatment group allocation. Patients who were not abstinent at week 24 were offered open-label varenicline for 12 additional weeks. The primary outcome was the proportion of smokers continuously abstinent from week 9 to week 48. Smoking status was confirmed by carbon monoxide in exhaled air. Primary analyses were done in both the intention-to-treat (ITT) population and modified ITT (mITT) population, which comprised all patients who took at least one tablet of their assigned study treatment. The safety analyses were done in the mITT population. The trial is registered at ClinicalTrials.gov, number NCT00918307. The trial status is complete.FINDINGS:From Oct 26, 2009, to Dec 20, 2012, of 303 patients assessed for eligibility, 248 patients were randomly assigned to the varenicline group (n=123) or the placebo group (n=125). After randomisation, one participant initially assigned to the placebo group was excluded from the ITT analysis for a regulatory reason (no French health-care coverage). 102 patients in the varenicline group and 111 patients in the placebo group received at least one dose of their assigned treatment and were included in the mITT analysis. In the ITT analysis, varenicline was associated with a higher proportion of patients achieving continuous abstinence over the study period (week 9-48): 18 (15%, 95% CI 8-21) of 123 in the varenicline group versus eight (6%, 2-11) of 124 in the placebo group, adjusted odds ratio (OR) 2·5 (95% CI 1·0-6·1; p=0·041). In the mITT analysis, varenicline was also associated with higher continuous abstinence: 18 (18%, 95% CI 10-25) of 102 versus eight (7%, 2-12) of 111 in the placebo group (adjusted OR 2·7, 95% CI 1·1-6·5; p=0·029). The incidence of depression was 2·4 per 100 person-years (95% CI 0·6-9·5; two [2%] of 102) in the varenicline group and 12·4 per 100 person-years (95% CI 6·9-22·5; 11 [10%] of 111) in the placebo group. 14 (7%) of 213 participants had 18 cardiovascular events: six (6%) of 102 people in the varenicline group and eight (7%) of 111 people in the placebo group.INTERPRETATION:Varenicline is safe and efficacious for smoking cessation in people living with HIV and should be recommended as the standard of care.FUNDING:The French National Institute for Health and Medical Research (INSERM)-French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Pfizer.

Background To investigate metabolic changes associated with second-line antiretroviral therapy (ART) following virological failure of first-line ART. Methods SECOND-LINE was an open-label randomized controlled trial. Participants were randomized 1:1 to receive ritonavir-boosted lopinavir (LPV/r) with 2–3 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTI group) or raltegravir (RAL group). 210 participants had a dual energy X-ray absorptiometry (DXA)-scan at baseline, week 48 and 96. We categorized participants according to second-line ART backbone: thymidine analogue (ta-NRTI) + lamivudine/emtricitabine (3[F]TC; ta-NRTI group); tenofovir (TDF)+3(F)TC (TDF group); TDF+ta-NRTI ±3(F)TC (TDF+ta-NRTI group); RAL. Changes in fasted total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, TC/HDL-cholesterol ratio, triglycerides and glucose from baseline to week 96 were examined. We explored the association between metabolic and DXA-assessed soft-tissue changes. Linear regression methods were used. Results We analysed 454 participants. Participants in RAL group had greater TC increases, TC (adjusted mean difference [aMD]=0.65, 95% CI 0.33, 0.96), LDL-c (aMD=0.38, 95% CI 0.15, 0.61) and glucose (aMD=0.47, 95% CI -0.01, 0.92) compared to TDF group, and had greater increases in TC (aMD=0.65, 95% CI 0.28, 1.03), HDL-c (aMD=0.12, 95% CI 0.02, 0.23) and LDL-c (aMD=0.41, 95% CI 0.13, 0.69) compared to TDF+ta-NRTI group. TC/HDL ratio and triglycerides increased in all groups without significant differences between groups. A 1 kg increase in trunk fat mass was associated with an increase in TC. Conclusions We observed metabolic changes of limited clinical significance in the relatively young population enrolled in this study. However, the metabolic changes observed may have greater clinical significance in older people living with HIV or those with other concomitant cardiovascular risks.

Daclatasvir (DCV) is a potent, pangenotypic, hepatitis C virus (HCV) non-structural protein 5A inhibitor with low potential for drug interactions with antiretroviral therapy (ART). We evaluated the safety and efficacy of DCV plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in HIV-1/HCV genotype-1-coinfected patients. AI444043 (NCT01471574), an open-label, Phase III, single-arm, response-guided treatment (RGT) study included 301 patients. They received DCV doses of 30, 60 or 90 mg once daily (depending on concomitant ART), plus weight-based RBV (