Susceptibility to lenacapavir, fostemsavir and broadly neutralizing antibodies in French primary HIV-1 infected patients in 2020-2023.

Surveillance studies of Transmitted Drug Resistance (TDR) are crucial in tracking the evolution of HIV epidemiology. Our aim was to investigate TDR to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), as well as to new drugs: lenacapavir, fostemsavir. Predictive sensitivity was evaluated for maraviroc and broadly neutralizing antibodies (bNAbs) (zinlirvimab and teropavimab). Between 2020 and 2023, 85 people with HIV (PWH) were diagnosed with primary HIV-1 infection (PHI). Pol and env sequences were analyzed and TDR was characterized according to the French ANRS algorithm. The genotypic-based prediction of bNAbs sensitivity was based on HIV env amino acid signatures I108, I201, F353 for teropavimab and N325, N332, H330 for zinlirvimab. TDR to NRTIs, NNRTIs, PIs and INIs was evidenced in 8.2%, 12.9%, 4.7%, and 5.9% strains, respectively. Ten viruses were CXCR4/dual mix. All viruses were susceptible to lenacapavir (100%) and 52% harbored resistance to fostemsavir. The genotypic profile was associated with a predictive positive value (PPV) > 83% of susceptibility to both teropavimab and zinlirvimab for 23 viruses (31%), while 22 (29%) had a PPV between 62% and 75%, suggesting reduced susceptibility to both bNAbs as soon as primary infection. The surveillance of TDR evidenced at the time of PHI is important with regard to new strategies for HIV patients with virological failure and global implementation of PrEP using NRTI, INI such as recently approved injectable cabotegravir, and future long-acting drugs such as lenacapavir and bNAbs.

Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial.

BACKGROUND: Lenacapavir is a long-acting HIV-1 capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1. METHODS: This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults living with multidrug-resistant HIV-1. Following a 2-week oral lenacapavir loading phase, participants received subcutaneous lenacapavir every 26 weeks with an OBR. HIV-1 RNA, CD4 cell counts, and adverse events were assessed over 104 weeks. One participant did not enter the extension phase. RESULTS: At Week 104, 44 of 71 participants (62%, 95% CI 50; 73) had HIV-1 RNA <50 copies/mL via US Food & Drug Administration (FDA) snapshot algorithm. When missing data (including discontinuations) were excluded, 44 of 54 participants (82%) had HIV-1 RNA <50 copies/mL at Week 104, mean CD4 cell count increased by 122 cells/µL (95% CI 80; 165), and the proportion of participants with CD4 cell count <200 cells/µL decreased from 64% (46 of 72) at Baseline to 29% (16 of 55). Fourteen participants had treatment-emergent lenacapavir resistance; seven resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use. There were no Grade 4 or serious treatment-related adverse events. One participant discontinued study drug due to an injection site reaction. CONCLUSIONS: Treatment with subcutaneous lenacapavir in combination with an OBR was well tolerated and resulted in a high rate of virological suppression over 104 weeks. Lenacapavir represents an important treatment option in people with multidrug-resistant HIV-1.

Prevalence and Risk Factors of Cytomegalovirus Among Men Having Sex With Men Enrolled in a Pre-Exposure Prophylaxis Study.

Risk factors for cytomegalovirus (CMV) acquisition in men having sex with men remain unclear. Seroprevalence, incidence, risk factors and shedding of CMV were analyzed among participants enrolled in the HIV pre-exposure prophylaxis IPERGAY-ANRS trial. Among the 417 participants tested, 382 were seropositive at baseline (prevalence of 91.6%; 95%CI[88.5-94.1]) and 10/35 seroconverted during the study (incidence of 17.1 per 100 person-years; 95%CI[8.2-31.3]). A high number of sexual partners was independently associated with CMV seroprevalence. Shedding among CMV-seroconverters was reported for 6/9 and 2/9 at the oral and anal levels, respectively. Our data supports transmission of CMV during sexual contacts. Study part of the ANRS-IPERGAY Clinical trial: ClinicalTrials.gov number, NCT01473472.

Impact of vaccination with third generation modified vaccinia Ankara and sexual behaviour on mpox incidence in men who have sex with men: analysis among participants of the ANRS-174 DOXYVAC trial.

Background: Mpox was first reported in France on May 19 and third-generation live Modified Vaccinia Ankara (MVA-BN) vaccination of multiple-partner men who have sex with men (MSM) was recommended as of July 11, 2022. We assessed the impact of vaccination and of sexual behavior adopted during the epidemic period on mpox incidence in the ANRS-174-DOXYVAC trial enrolling MSM on HIV pre-exposure prophylaxis (PrEP) with history of sexually-transmitted infections (STI) in the previous year. Methods: We compared pre-epidemic socio-behavioral characteristics and change in sexual behaviors after the onset of the epidemic of participants with mpox and mpox-free. Then we compared incidence rates of mpox per 1000 person-months (p-m) between May 9-July 10 (before vaccination of MSM, period-1) and July 11-September 20 2022 (after vaccination launch, period-2) and explored factors explaining the period effect using Poisson regression model. Findings: 472 MSM had data before and after May 9, 2022. Twenty percent had received smallpox vaccine during childhood. Mpox occurred in 77/472 participants (incidence 49.3 per 1000 p-m (95% CI 38.9-61.6)). MVA-BN vaccination roll-out was rapid, with 86% (341/398) of eligible participants having received at least one dose by September 20, 2022. Sexual behavior significantly changed before and after May 9, with a decrease in the proportion of mpox-free participants with >10 partners during last 3 months (45% vs 38%, p = 0.0035). Mpox incidence was 67.4 per 1000 p-m (95% CI 51.6-86.6) in period-1, and 24.4 per 1000 p-m (95% CI 13.9-39.6) in period-2, with an incidence rate ratio of 0.36 (95% CI 0.21-0.63). In multivariable Poisson regression model, only MVA-BN vaccination in 2022 remained significantly associated with mpox incidence, with a 99% risk reduction (95% CI 96.6-99.7). Interpretation: In MSM on PrEP enrolled in the ANRS-174-DOXYVAC trial, rapid roll-out of MVA-BN vaccination was associated with a strong reduction in mpox incidence. Funding: ANRS Maladies Infectieuses Emergentes (ANRS/MIE).

New Insights Into the Therapeutic Management of Varicella Zoster Virus Meningitis: A Series of 123 Polymerase Chain Reaction-Confirmed Cases.

Background: Varicella zoster virus (VZV) can reactivate and cause meningitis, but few studies have distinguished it from meningoencephalitis regarding treatment recommendations.The objective of this study was to assess the outcomes of a large series of patients with VZV meningitis according to their therapeutic management. Methods: We conducted a bicentric retrospective cohort study, in Paris, France, including all adult patients with a cerebrospinal fluid sample positive for VZV by polymerase chain reaction between April 2014 and June 2022. We distinguished meningitis from encephalitis according to the International Encephalitis Consortium criteria. Unfavorable outcome was defined as mortality or functional sequelae defined by a loss of 2 points on the modified Rankin Scale. Results: We included 123 patients with meningitis. Among them, 14% received no antivirals, while 20% were treated with oral valacyclovir alone, 41% with a short course of intravenous (IV) acyclovir before switch to valacyclovir, and 25% with a long course of IV acyclovir. Outcomes were favorable regardless of antiviral regimen. In multivariate analysis, only age, underlying immunosuppression, and cranial radiculitis appear to be predictive factors for longer IV therapy, based on the Akaike information criterion. Conclusions: In this study, patients with VZV meningitis had a good outcome, with no evidence of any impact of the treatment strategy. However, further studies are needed to support the possibility of milder treatment in immunocompetent patients, avoiding cost and side effects of IV acyclovir.

HIV-1 infection kinetics, drug resistance, and long-term safety of pre-exposure prophylaxis with emtricitabine plus tenofovir alafenamide (DISCOVER): week 144 open-label extension of a randomised, controlled, phase 3 trial.

BACKGROUND: Data characterising the long-term use and safety of emtricitabine plus tenofovir disoproxil fumarate as daily oral pre-exposure prophylaxis (PrEP) are scarce and there are uncertainties regarding the value of routine HIV-1 RNA testing during oral PrEP follow-up. METHODS: The DISCOVER trial was a randomised, controlled, phase 3 trial in which cisgender men and transgender women aged 18 years and older with a high likelihood of acquiring HIV were recruited from 94 clinics in Europe and North America and randomly assigned to receive either emtricitabine plus tenofovir disoproxil fumarate (200/25 mg) tablets daily, with matched placebo tablets, or emtricitabine plus tenofovir alafenamide (200/300 mg) tablets daily, with matched placebo tablets, for at least 96 weeks. After completion of the trial, participants were offered enrolment in this 48-week open-label extension study of emtricitabine plus tenofovir alafenamide. In participants diagnosed with HIV during the randomised and open-label phases of the study, we characterised HIV-1 test results and measured HIV-1 RNA viral load retrospectively when available. Adherence based on tenofovir diphosphate concentrations in dried blood spots and genotypic resistance were assessed in participants diagnosed with HIV. Safety assessments included adverse events, laboratory parameters, and, in a subset of participants, bone mineral density. HIV-1 incidence in participants initially randomly assigned to receive emtricitabine plus tenofovir alafenamide was estimated using a Poisson distribution. Changes from baseline in safety endpoints were described in participants assigned to received emtricitabine plus tenofovir alafenamide and in those who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase. This trial is registered with ClinicalTrials.gov, NCT02842086, and is ongoing. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5399 participants were enrolled and randomly assigned in DISCOVER. 2699 were assigned to receive emtricitabine plus tenofovir disoproxil fumarate and 2700 were assigned to receive emtricitabine plus tenofovir alafenamide, of whom 2693 and 2694, respectively, received at least one dose of study drug. 2115 (79%) assigned to emtricitabine plus tenofovir disoproxil fumarate switched to emtricitabine plus tenofovir alafenamide in the open-label phase, and 2070 (77%) continued with emtricitabine plus tenofovir alafenamide in the open-label phase. As of data cutoff (Dec 10, 2020), after 15 817 person-years of follow-up, 27 new HIV-1 diagnoses were observed across the total study period, with three occurring during the open-label phase. In participants who were initially assigned to emtricitabine plus tenofovir alafenamide, the incidence was 0·13 per 100 person-years (95% CI 0·061-0·23; ten of 2670). Stored plasma samples were available for 23 of 27 participants, including 22 with incident infection. In four (17%) of 23 participants, retrospective testing detected HIV-1 RNA before serological HIV-1 test positivity; one was a suspected baseline infection. Of the three incident cases, all three were non-adherent to PrEP and none developed drug resistance. Among participants taking emtricitabine plus tenofovir alafenamide for up to 144 weeks, markers of glomerular filtration and proximal renal tubule dysfunction (ß2-microglobulin to creatinine ratio and retinol-binding protein to creatinine ratio) improved or remained stable at 144 weeks compared with baseline, bone mineral density in hip and lumbar spine increased or remained stable from baseline to week 144 (n=191), cholesterol and glucose concentrations remained stable, and median bodyweight increased by less than 1 kg per year. In participants who switched from emtricitabine plus tenofovir disoproxil fumarate during the open-label phase (2115 [79%] of 2693), markers of glomerular filtration and proximal renal tubule dysfunction improved or remained stable, bone mineral density increased, cholesterol concentrations increased, glucose concentrations were similar, and median bodyweight increased more compared with those who remained on emtricitabine and tenofovir alafenamide. INTERPRETATION: Routine HIV-1 RNA testing for follow-up of individuals on daily oral PrEP provides modest additional clinical benefit. Long-term use of emtricitabine and tenofovir alafenamide as daily oral PrEP is safe and well tolerated and can be an especially appropriate choice for people with bone or renal morbidities. FUNDING: Gilead Sciences.

Emergence of Extensively Drug-Resistant Neisseria gonorrhoeae, France, 2023.

Since 2022, Europe has had 4 cases of extensively drug-resistant Neisseria gonorrhoeae, sequence type 16406, that is resistant to ceftriaxone and highly resistant to azithromycin. We report 2 new cases from France in 2023 involving strains genetically related to the 4 cases from Europe as well as isolates from Cambodia.

Effectiveness of integrating HIV prevention within sexual reproductive health services with or without peer support among adolescents and young adults in rural KwaZulu-Natal, South Africa (Isisekelo Sempilo): 2 × 2 factorial, open-label, randomised controlled trial.

BACKGROUND: Approximately 200 000 South Africans acquired HIV in 2021 despite the availability of universal HIV test and treat and pre-exposure prophylaxis (PrEP). The aim of this study was to test the effectiveness of sexual and reproductive health services or peer support, or both, on the uptake of serostatus neutral HIV services or reduction of sexually transmissible HIV. METHODS: We did an open-label, 2 × 2 randomised factorial trial among young people in a mostly rural area of KwaZulu-Natal, South Africa. Inclusion criteria included being aged 16-29 years, living in the mapped geographical areas that were accessible to the area-based peer navigators, being willing and able to provide informed consent, and being willing to provide a dried blood spot for anonymous HIV testing and HIV viral load measurement at 12 months. Participants were randomly allocated by computer-generated algorithm to one of four groups: those in the standard-of-care group were referred to youth-friendly services for differentiated HIV prevention (condoms, universal HIV test and treat with antiretroviral therapy, and PrEP if eligible); those in the sexual and reproductive health services group received baseline self-collected specimens for sexually transmitted infection (STI) testing and referral to integrated sexual and reproductive health and HIV prevention services; those in the peer support group were referred to peer navigators for health promotion, condom provision, and facilitation of attendance for differentiated HIV prevention services; and those in the final group received a combination of sexual and reproductive health services and peer support. Coprimary outcomes were linkage to clinical services within 60 days of enrolment, proportion of participants who had sexually transmissible HIV at 12 months after enrolment, and proportion of sampled individuals who consented to participation and gave a dried blood spot for HIV testing at 12 months. Logistic regression was used for analyses, and adjusted for age, sex, and rural or peri-urban area of residence. This study is registered with ClinicalTrials.gov (NCT04532307) and is closed. FINDINGS: Between March 2, 2020, and July 7, 2022, 1743 (75·7%) of 2301 eligible individuals were enrolled and followed up. 12-month dried blood spots were collected from 1168 participants (67·0%). The median age of the participants was 21 years (IQR 18-25), 51·4% were female, and 51·1% had secondary level education. Baseline characteristics and 12-month outcome ascertainment were similar between groups. 755 (43·3%) linked to services by 60 days. 430 (49·8%) of 863 who were in the sexual reproductive health services group were linked to care compared with 325 (36·9%) of 880 who were not in the sexual and reproductive health services group (adjusted odds ratio [aOR] 1·68; 95% CI 1·39-2·04); peer support had no effect: 385 (43·5%) of 858 compared with 370 (43·1%) of 885 (1·02, 0·84-1·23). At 12 months, 227 (19%) tested ELISA-positive for HIV, of whom 41 (18%) had viral loads of 400 copies per mL; overall prevalence of transmissible HIV was 3·5%. 22 (3·7%) of 578 participants in the sexual and reproductive health services group had transmissible HIV compared with 19 (3·3%) of 590 not in the sexual and reproductive health services group (aOR 1·12; 95% CI 0·60-2·11). The findings were also non-significant for peer support: 21 (3·3%) of 565 compared with 20 (3·3%) of 603 (aOR 1·03; 95% CI 0·55-1·94). There were no serious adverse events or deaths during the study. INTERPRETATION: This study provides evidence that STI testing and sexual and reproductive health services create demand for serostatus neutral HIV prevention in adolescents and young adults in Africa. STI testing and integration of HIV and sexual health has the potential to reach those at risk and tackle unmet sexual health needs. FUNDING: US National Institute of Health, Bill & Melinda Gates Foundation, and 3ie.

HIV Pre-Exposure Prophylaxis.

Pre-exposure prophylaxis (PrEP) of human immunodeficiency virus (HIV) represents the most significant breakthrough in the HIV prevention field over the past decade. PrEP is an effective strategy in preventing the transmission of HIV across all populations, providing high adherence. The current PrEP options include oral daily and on-demand tenofovir-based regimens, long-acting injections of cabotegravir, and a 1-month dapivirine vaginal ring. As a component of a multifaceted prevention approach, extensive deployment of PrEP holds the promise to significantly reduce the global HIV epidemic. Nonetheless, barriers still exist in terms of uptake, adherence, and persistence, while disparities in PrEP accessibility remain a concern.

Low cabotegravir trough concentrations without oral lead-in in patients with HIV-1 switching to long-acting cabotegravir and rilpivirine.

In a cohort of 72 consecutive virologically-suppressed patients with HIV-1 switching to long-acting cabotegravir and rilpivirine, we observed low cabotegravir trough concentrations 1 and 3 months after the first injection, with a significant association with no oral lead-in at 1 month [odds ratio (OR) = 6.3 [95% confidence interval (CI) 1.7-29.5], P = 0.01] and three months (OR = 5.6 [95% CI 1.3-29.7], P = 0.03), and with high BMI at 1 month (OR = 1.3 [95% CI 1.1-1.6], P = 0.007).

Prescriptions of generic antiretroviral drugs in three healthcare centers in the Paris area, France.

In a retrospective study conducted in three hospitals in Paris, generic antiretroviral accounted for 30.2% of all prescriptions. Tenofovir disoproxil/emtricitabine (TDF/FTC) was the most prescribed generic ART (82.3% of generic prescriptions). Generic ART (gART) was more likely to be prescribed to women, to patients less than 50 years, and with recent HIV diagnosis less than 3 years. Physicians prescribed more gART if they were men, older than 55 years or worked at a university teaching hospital.

Switch to fixed-dose doravirine (100 mg) with islatravir (0·75 mg) once daily in virologically suppressed adults with HIV-1 on antiretroviral therapy: 48-week results of a phase 3, randomised, open-label, non-inferiority trial.

BACKGROUND: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen with high antiviral potency, favourable safety and tolerability, and low propensity for resistance. We report week 48 results from a phase 3 trial evaluating switch from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·75 mg). METHODS: This phase 3, multicentre, randomised, active-controlled, open-label, non-inferiority trial was conducted at 77 research, community, and hospital-based clinics in 15 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation schedule to switch to doravirine (100 mg) and islatravir (0·75 mg) or to continue their baseline ART regimen. Block randomisation was based on a block size of four, and randomisation was stratified by baseline regimen (ie, protease inhibitor, integrase inhibitor, or other). Participants in the doravirine and islatravir group were instructed to take one tablet at approximately the same time each day, and participants in the baseline ART group continued to take the medication according to the locally approved label. HIV-1 RNA and safety evaluations were done at baseline and weeks 4, 12, 24, 36, and 48. CD4 cell counts were measured at baseline, week 24, and week 48. The primary endpoint was proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug) using the US Food and Drug Administration snapshot approach and prespecified non-inferiority margin of 4%. This study is registered with ClinicalTrials.gov (NCT04223778) and is completed. FINDINGS: Between Feb 18 and Oct 2, 2020, 740 individuals were screened for eligibility, of whom 672 (90·8%) participants (249 [37·1%] women and 423 [62·9%] men; median CD4 count of 678 cells per µL [IQR 496-868]) were randomly assigned to doravirine (100 mg) and islatravir (0·75 mg; n=336) or to continue baseline ART (n=336). The last follow-up visit occurred on Sept 8, 2021. At week 48, zero of 336 participants in the doravirine and islatravir group versus five (1·5%) of 336 participants in the baseline ART group had greater than or equal to 50 HIV-1 RNA copies per mL (difference -1·5, 95% CI -3·4 to -0·3). The per-protocol analysis showed consistent results. Headache was the most common adverse event in both groups (35 [10·4%] of 336 participants in the doravirine and islatravir group, 16 [4·8%] of 336 in the baseline ART group), infection rates were similar (113 [33·6%] in both groups), and discontinuations due to adverse events were low (seven [2·1%] vs one [0·3%]). 66 (19·6%) of 336 participants had treatment-related adverse events in the doravirine and islatravir group compared with 30 (8·9%) of 336 in the baseline ART group. In the islatravir and doravirine group, CD4 cell counts (mean change -30·3 cells per µL) and total lymphocyte counts (mean change -0·26 × 109/L) were decreased at 48 weeks. INTERPRETATION: Switching to single-tablet doravirine (100 mg) and islatravir (0·75 mg) maintained viral suppression up to week 48 and was non-inferior to antiretroviral combinations used in clinical practice for adults with HIV-1; however, decreases in CD4 cell and total lymphocyte counts do not support further development of once-daily doravirine (100 mg) and islatravir (0·75 mg). FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

Doxycycline prophylaxis and meningococcal group B vaccine to prevent bacterial sexually transmitted infections in France (ANRS 174 DOXYVAC): a multicentre, open-label, randomised trial with a 2 × 2 factorial design.

BACKGROUND: Increased rates of sexually transmitted infections (STIs) are reported among men who have sex with men (MSM) and new interventions are needed. We aimed to assess whether post-exposure prophylaxis (PEP) with doxycycline could reduce the incidence of chlamydia or syphilis (or both) and whether the meningococcal group B vaccine (4CMenB) could reduce the incidence of gonorrhoea in this population. METHODS: ANRS 174 DOXYVAC is a multicentre, open-label, randomised trial with a 2 × 2 factorial design conducted at ten hospital sites in Paris, France. Eligible participants were MSM aged 18 years or older, HIV negative, had a history of bacterial STIs within the 12 months before enrolment, and who were already included in the ANRS PREVENIR study (a cohort of MSM using pre-exposure prophylaxis with tenofovir and emtricitabine for HIV prevention). Participants were randomly assigned (2:1) to doxycycline PEP (two pills of 100 mg each orally within 72 h after condomless sex, with no more than three doses of 200 mg per week) or no PEP groups and were also randomly assigned (1:1) to the 4CMenB vaccine (GlaxoSmithKline, Paris, France; two intramuscular injections at enrolment and at 2 months) or no vaccine groups, using a computer-generated randomisation list with a permuted fixed block size of four. Follow-up occurred for at least 12 months (with visits every 3 months) up to 24 months. The coprimary outcomes were the risk of a first episode of chlamydia or syphilis (or both) after the enrolment visit at baseline for the doxycycline intervention and the risk of a first episode of gonorrhoea starting at month 3 (ie, 1 month after the second vaccine dose) for the vaccine intervention, analysed in the modified intention-to-treat population (defined as all randomly assigned participants who had at least one follow-up visit). This trial is registered with ClinicalTrials.gov, NCT04597424 (ongoing). FINDINGS: Between Jan 19, 2021, and Sept 19, 2022, 556 participants were randomly assigned. 545 (98%) participants were included in the modified intention-to-treat analysis for the doxycycline PEP and no PEP groups and 544 (98%) were included for the 4CMenB vaccine and no vaccine groups. The median follow-up was 14 months (IQR 9-18). The median age was 40 years (34-48) and all 545 participants were male. There was no interaction between the two interventions (p≥0·1) for the primary outcome. The incidence of a first episode of chlamydia or syphilis (or both) was 8·8 per 100 person-years (35 events in 362 participants) in the doxycycline PEP group and 53·2 per 100 person-years (80 events in 183 participants) in the no PEP group (adjusted hazard ratio [aHR] 0·17 [95% CI 0·12-0·26]; p<0·0001). The incidence of a first episode of gonorrhoea, starting from month 3 was 58·3 per 100 person-years (103 events in 274 participants) in the 4CmenB vaccine group and 77·1 per 100 person-years (122 events in 270 participants) in the no vaccine group (aHR 0·78 [95% CI 0·60-1·01]; p=0·061). There were no deaths during the study. One drug-related serious adverse event (fixed-drug eruption) occurred in the doxycycline PEP group. Six (2%) participants in the doxycycline group discontinued doxycycline PEP because of gastrointestinal adverse events. INTERPRETATION: Doxycycline PEP strongly reduced the incidence of chlamydia and syphilis in MSM, but we did not show efficacy of the 4CmenB vaccine for gonorrhoea. Doxycycline PEP should be assessed in other populations, such as heterosexual men and women, and its effect on antimicrobial resistance carefully monitored. FUNDING: ANRS Maladies Infectieuses Emergentes. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Incidence and Predictors of Tuberculosis-associated IRIS in People With HIV Treated for Tuberculosis: Findings From Reflate TB2 Randomized Trial.

Background: After antiretroviral therapy (ART) initiation, people with HIV (PWH) treated for tuberculosis (TB) may develop TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Integrase inhibitors, by providing a faster HIV-RNA decline than efavirenz, might increase the risk for this complication. We sought to assess incidence and determinants of TB-IRIS in PWH with TB on raltegravir- or efavirenz-based ART. Methods: We conducted a secondary analysis of the Reflate TB 2 trial, which randomized ART-naive PWH on standard TB treatment, to receive raltegravir- or efavirenz-based ART. The primary objective was to evaluate the incidence of TB-IRIS. Incidence rate ratio comparing TB-IRIS incidence in each arm was calculated. Kaplan-Meier curves were used to compare TB-IRIS-free survival probabilities by ART arm. Cox regression models were fitted to analyze baseline characteristics associated with TB-IRIS. Results: Of 460 trial participants, 453 from Brazil, Côte d'Ivoire, Mozambique, and Vietnam were included in this analysis. Baseline characteristics were median age 35 years (interquartile range [IQR], 29-43), 40% female, 69% pulmonary TB only, median CD4, 102 (IQR, 38-239) cells/mm³, and median HIV RNA, 5.5 (IQR, 5.0-5.8) log copies/mL. Forty-eight participants developed TB-IRIS (incidence rate, 24.7/100 PY), 19 cases in the raltegravir arm and 29 in the efavirenz arm (incidence rate ratio 0.62, 95% confidence interval .35-1.10). Factors associated with TB-IRIS were: CD4 ≤ 100 cells/µL, HIV RNA ≥500 000 copies/mL, and extrapulmonary/disseminated TB. Conclusions: We did not demonstrate that raltegravir-based ART increased the incidence of TB-IRIS compared with efavirenz-based ART. Low CD4 counts, high HIV RNA, and extrapulmonary/disseminated TB at ART initiation were associated with TB-IRIS.

Harm reduction and multidisciplinary consultations for gay, bisexual, and other men who have sex with men practising chemsex based in a French infectious disease unit: patients' characteristics and perceptions.

BACKGROUND: Chemsex, a type of sexualised drug use, is expanding among gay, bisexual, and other men who have sex with men (GBMSM), with physical and mental health risks. Health-seeking behaviours of GBMSM practising chemsex is not clear. METHODS: Harm reduction (HR) consultations for GBMSM engaging in chemsex and seeking comprehensive services including HR were offered in a Parisian infectious disease unit. From December 2021 to January 2022, HR consultation patients completed an online survey on their consumption, health, used services, and perspective on consultations. We generated descriptive statistics, and tested (χ 2 ) the relationship between reporting a specialised follow-up and perceived usefulness of intervention. RESULTS: Of 172 patients, a total of 96 GBMSM (55.2%) completed the survey. Most ever consumed substance was 3-methylmethcathinone (3MMC; 92/96; 95.8%). Before consultations, about half consumed at least once a week (50/96; 52%), most reported negative impacts of chemsex on their social (60/96, 62.5%), professional (56/96, 58.3%), intimate (53/96; 55.21%), or sexual life (52/96; 54.17%). Also, more than two-thirds (n =57; 69.38%) had received a follow-up in specialised services: one-third had been followed in addictology (28/96, 29.2%) and/or psychotherapy (32/96, 33.3%), and one-fourth (24/96, 25.0%) had used emergency services. After consultations, three-quarters perceived the intervention as useful (n =74; 77.08%); we found no significant relationship with receiving a specialised follow-up; and most were satisfied with professionals' listening (90/96; 93.8%), and reported reduced risks (80/96; 83.3%). DISCUSSION: Multidisciplinary HR, preventive, diagnostical, and therapeutic sexological and psychiatric interventions are greatly needed among GBMSM practising chemsex. HR interventions accessible in services already attended by GBMSM are a valuable option.

Sexual behaviour and STIs among MSM living with HIV in the PrEP era: the French ANRS PRIMO cohort study.

INTRODUCTION: In a context of declining condom use and high sexually transmitted infection (STI) incidence, the diffusion of "treatment as prevention" (Tasp) and more recently pre-exposure prophylaxis (PrEP) may have changed the sexual behaviour of newly diagnosed men who have sex with men (MSM) with HIV. METHODS: Six hundred and nine MSM were enrolled and followed annually between 2014 and 2021 in the ANRS PRIMO Cohort (ClinicalTrials.gov:NCT03148964) from the time of HIV seroconversion. We studied changes over calendar time in sexual behaviour before and after HIV diagnosis. Factors associated with inconsistent condom use (ICU) after HIV diagnosis, PrEP use by partner(s) and bacterial STI acquisition were studied in random-effects models. RESULTS: In the 6 months preceding HIV diagnosis, the number of sexual partners decreased from a median of 10 (IQR: 4-19) in 2014 to 6 (3-11) in 2021. After HIV diagnosis, ICU increased from 57.1% (16/28) of visits in 2014 up to 84.2% (229/272) in 2020-2021. Up to 25% (63/229) of MSM with HIV in recent years reported the use of PrEP by their partner(s) as the reason for ICU; these MSM were less frequently in a stable relationship, had a higher number of sexual partners and higher education level than those who did not report the use of PrEP by their partner(s). STI incidence after HIV diagnosis increased between 2014 and 2016 and remained high afterwards. STI risk was no longer associated with PrEP use by partners after adjustment for the number of partners and calendar period. ICU, age below 35 years, not being in a stable relationship, higher number of sexual partners were independently associated with an increased risk of STI. CONCLUSIONS: Implementation of TasP and more recently PrEP has led to major changes in the sexual behaviour of MSM with HIV. ICU has become overwhelmingly prevalent, PrEP use by the partner increasingly being the reported reason for ICU, behind TasP, which remains the main reason. Characteristics of MSM at the time of diagnosis of HIV have changed, with fewer number of sexual partners today than in 2014, which must lead to broaden the indications for PrEP prescription. STIs incidence remains high in MSM with HIV and requires improvements in screening and prevention methods such as pre- or post-exposition antibiotics or vaccines.

Filling in the Gaps: Updates on Doxycycline Prophylaxis for Bacterial Sexually Transmitted Infections.

Over the past two decades, cases of sexually transmitted infections (STIs) due to syphilis, gonorrhea, and chlamydia have been rising in the United States, disproportionately among gay, bisexual, and other men who have sex with men (MSM), as well as racial and ethnic minorities of all genders. In this review, we address updates about the evidence on doxycycline post-exposure prophylaxis (doxy-PEP) for prevention of bacterial STIs, including efficacy, safety, antimicrobial resistance (AMR), acceptability, modeling population impact, and evolving guidelines for use. Equitable implementation of doxy-PEP will require evaluation of who is offered and initiates it, understanding patterns of use and longer-term STI incidence and AMR, provider training, and tailored community education.

Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy.

OBJECTIVE: To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. DESIGN: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. METHODS: A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. RESULTS: At OLE Week 96, participants who switched to B/F/TAF ( N  = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. CONCLUSION: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

Failure of bamlanivimab with selection of E484K mutation in an allogeneic stem cell transplant recipient with nosocomial SARS-CoV-2 infection.

We report the case of an allogeneic stem cell transplant recipient with nosocomial acquisition of SARS-CoV-2 infection who received antispike neutralizing monoclonal antibody bamlanivimab 2 days after diagnosis of SARS-CoV-2 infection but progressed to severe COVID-19 pneumonia and died with the selection of E484K/Q resistance mutations to bamlanivimab.