Background: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen containing two potent antiretrovirals with complementary mechanisms of action and resistance profiles. We aimed to evaluate the efficacy and safety of switching from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (025 mg) in virologically suppressed adults living with HIV-1. Methods: This phase 3, randomised, active-controlled, open-label, non-inferiority trial was conducted at 53 research, community, and hospital-based clinics in eight countries: Australia, Canada, Colombia, Japan, South Africa, Switzerland, the UK, and the USA. Adults (aged >= 18 years) with a viral load of fewer than 50 copies of HIV-1 RNA per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, with no history of treatment failure, known resistance to doravirine, or active hepatitis B infection, were randomly assigned (2:1) according to a computer-generated randomisation schedule (block size three) to receive oral doravirine (100 mg) and islatravir (025 mg) once daily or to continue baseline ART for 48 weeks. Randomisation was stratified by the anchor antiretroviral drug class (integrase strand-transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor, or protease inhibitor) in the baseline regimen. The primary endpoint (assessed in all treated participants) was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 (analysed according to the US Food and Drug Administration snapshot approach); non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The safety analysis population included all randomly assigned participants who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT05631093, and is ongoing but closed to enrolment. Findings: Between Feb 20 and Oct 24, 2023, 614 individuals were screened for eligibility, of whom 553 were randomly assigned to receive doravirine and islatravir (n=368) or baseline ART (n=185). 551 participants received at least one dose of allocated medication: 366 in the doravirine and islatravir group and 185 in the baseline ART group. Of these 551 participants, 332 (60%) were assigned male and 219 (40%) were assigned female at birth, and the median age was 51 years (IQR 41-59); 250 (45%) identified as Black or African American and 80 (15%) identified as Hispanic, Latino, or Latina. Doravirine and islatravir showed non-inferiority at week 48, with viral loads of 50 copies per mL or higher in five (14%) of 366 participants versus nine (49%) of 185 participants on baseline ART (difference -36% [multiplicity-adjusted 95% CI -78 to -08]). Treatment-related adverse events were more common with doravirine and islatravir (44 [120%] of 366 participants) than with baseline ART (nine [49%] of 185 participants; difference 72 [95% CI 22 to 116]). Rates were similar in the doravirine and islatravir group and the baseline ART group for any adverse event (795% [291 of 366 participants] vs 838% [155 of 185 participants]; difference -43 [-107 to 28]), serious adverse events (63% [23] vs 49% [nine]; 14 [-32 to 52]), and discontinuation due to adverse events (05% [two] vs 22% [four]; -16 [-49 to 02]). One death occurred (in the baseline ART group) and was not considered treatment-related. No participants discontinued treatment as a result of protocol-specified declines in CD4 cell or total lymphocyte counts. Interpretation: Doravirine and islatravir is efficacious and well tolerated and would represent the first non-INSTI-based, two-drug regimen for HIV-1 treatment. With increasing concern over the potential development of widespread INSTI resistance, this once-daily, oral, single-tablet regimen could be a potential option for people living with HIV-1 requiring a change to their antiretroviral regimen. The safety and efficacy findings support the ongoing development of islatravir, a drug with long-acting potential.

BACKGROUND:Single-tablet regimens (STRs) revolutionised HIV-1 treatment, improving adherence and clinical outcomes; however, many people cannot take these due to resistance, contraindications, or drug-drug interactions, instead relying on complex multi-tablet regimens. Novel STRs are therefore needed. We aimed to evaluate the efficacy and safety of a novel STR, bictegravir-lenacapavir, in people with HIV-1. METHODS:ARTISTRY-1 was a randomised, open-label, active-controlled, non-inferiority phase 3 trial conducted at hospitals and clinics across 15 countries that enrolled people with HIV-1 with virological suppression on complex regimens. Participants were randomly assigned (using interactive technology, 2:1, stratified by geographical region) to switch to once-daily oral bictegravir-lenacapavir 75 mg/50 mg STR or continued complex regimen. The primary outcome was the proportion of participants with an HIV-1 RNA viral load of 50 copies per mL or higher at week 48 (US Food and Drug Administration Snapshot algorithm), assessed in all randomly assigned participants who received any dose of assigned treatment. This trial (active; enrolment complete) was registered with ClinicalTrials.gov (NCT05502341). FINDINGS:Between Jan 29 and Sept 26, 2024, 729 participants were screened; 557 were randomly assigned and treated (bictegravir-lenacapavir n=371; complex regimen n=186). At baseline, median age was 60 years (range 22-84), HIV treatment duration was 28 years (IQR 22-32); participants were taking a median of three antiretroviral pills per day (range 2-11). At week 48, an HIV-1 RNA viral load of 50 copies per mL or higher was observed in three (1%) participants receiving bictegravir-lenacapavir and two (1%) receiving a complex regimen (difference -0·3%; 95·002% CI -2·3 to 1·8), meeting the non-inferiority margin of 4%. No resistance emerged. Adverse event rates were similar between groups. Six (2%) participants discontinued bictegravir-lenacapavir and one (1%) discontinued their complex regimen due to adverse events. There were five deaths in the bictegravir-lenacapavir group, none of which were deemed related to study drug. Participants reported increased treatment satisfaction after switching to bictegravir-lenacapavir. INTERPRETATION:Bictegravir-lenacapavir STR demonstrated non-inferior efficacy to complex regimens, with a similar safety profile and increased treatment satisfaction. Bictegravir-lenacapavir offers new opportunities for HIV-1 treatment optimisation for people taking complex regimens. FUNDING:Gilead Sciences.

Somatic gene mutations (SGMs) that drive clonal haematopoiesis (CH) have been shown to be more prevalent in people with HIV (PWH), potentially contributing to the higher risk of comorbidities in PWH compared to those without HIV. It is unknown whether mosaic chromosomal alterations (mCA), another form of CH, are associated with HIV. We demonstrate, for the first time, a markedly lower prevalence of mosaic chromosomal alterations (mCA), particularly loss of chromosome Y, in PWH compared to participants without HIV - an opposing pattern to SGMs. Our findings that mCA development may be suppressed in HIV infection suggest that the selective pressures driving mCA-related CH differ fundamentally from those driving SGM-related CH.

Phase 2 and Phase 3 studies of DOR/ISL 100/0.75 mg QD demonstrated good antiretroviral activity in adults with HIV-1. However, declines in total lymphocyte and/or CD4+ T-cell counts were observed. Modeling studies predicted that ISL 0.25 mg would achieve efficacy comparable to ISL 0.75 mg with no meaningful declines in total lymphocyte or CD4+ T-cell counts. We studied the safety and efficacy of DOR/ISL 100/0.25 mg in participants who had received DOR/ISL 100/0.75 mg previously.Table 1.Summary of Adverse Events through Week 48Table 2.Virologic Outcomes at Week 48 (FDA Snapshot Approach; Full Analysis Set*) In this phase 3, open-label, single-arm study (NCT05766501), adults with HIV-1 RNA < 200 copies/mL who had tolerated DOR/ISL 100/0.75 mg QD in a previous study (MK8591A-018, 020, or 033) switched to open-label DOR/ISL 100/0.25 mg QD for maintenance therapy. The primary objective was to evaluate the safety and tolerability of DOR/ISL 100/0.25 mg QD through week 96. Secondary objectives included assessment of the antiretroviral activity of DOR/ISL (FDA Snapshot Approach) and changes in total lymphocyte and CD4+ T-cell counts. An interim analysis conducted at week 48 is reported here.Figure 1.Total Lymphocyte Count, Mean Change from Baseline (and 95% CI)Figure 2.CD4+ T-cell Count, Mean Change from Baseline (and 95% CI) 639 participants entered the study: mean age 44.7 (range 20-79) years, 69.3% male, 55.7% white, and 31.5% black/African American. Mean time on DOR/ISL before enrollment was 31.7 (range 17.6-61.9) months. By week 48, adverse events (AE) were reported by 75.4% of participants and were considered drug-related in only 2.2% (Table 1). Serious AEs were reported in 5.6% of participants; none were drug-related. Three participants (0.5%) discontinued treatment due to an AE; none were drug-related. At week 48, HIV-1 RNA was < 50 copies/mL in 598 participants (93.6%) and ≥50 copies/mL in 11 (1.7%) (Table 2). Two participants (0.3%) developed clinically significant viremia (confirmed HIV-1 RNA ≥200 copies/mL); resistance data were not available due to assay failure. Total lymphocyte and CD4+ T-cell counts showed mean increases from baseline of 0.19x109 cells/L (95% CI: 0.15, 0.22) and 74.5 cells/mm3 (95% CI: 59.2, 89.8), respectively, at week 48 (Figures 1 and 2). DOR/ISL 100/0.25 mg QD was generally well tolerated and maintained virologic suppression in a high proportion of participants who had previously received DOR/ISL 100/0.75 mg. Baseline total lymphocyte and CD4+ T-cell counts increased after ISL dose reduction. Cheryl McDonald, MD, Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Merck: Grant/Research Support|Viiv: Grant/Research Support Mark Bloch, MBBS, MMed, Gilead Sciences: Lectures|GSK: Board Member|GSK: Lectures|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Lectures, Support to attend scientific meetings Christopher Bettacchi, MD, Merck: Honoraria|Viiv: Honoraria Margaret Johnson, MD, Merck & Co., Inc.: Grant/Research Support Euna Kim, BA, Merck & Co., Inc.: Stocks/Bonds (Public Company) Uche Nwoke, MS, Merck & Co., Inc.: Stocks/Bonds (Public Company) Michelle C. Fox, MD, Merck & Co., Inc.: Employment|Merck & Co., Inc.: Stocks/Bonds (Public Company) Luisa M. Stamm, MD, PhD, Merck & Co., Inc.: Employment|Merck & Co., Inc.: Stocks/Bonds (Public Company) Mengchun Li, MD, Merck & Co., Inc.: Stocks/Bonds (Public Company) Wayne Greaves, MD, Merck & Co., Inc.: Stocks/Bonds (Public Company)

BACKGROUND:Doravirine and islatravir is an investigational, once-daily, single-tablet regimen containing two potent antiretrovirals with complementary mechanisms of action and resistance profiles. We aimed to evaluate the efficacy and safety of switching from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·25 mg) in virologically suppressed adults living with HIV-1. METHODS:This phase 3, randomised, active-controlled, open-label, non-inferiority trial was conducted at 53 research, community, and hospital-based clinics in eight countries: Australia, Canada, Colombia, Japan, South Africa, Switzerland, the UK, and the USA. Adults (aged ≥18 years) with a viral load of fewer than 50 copies of HIV-1 RNA per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, with no history of treatment failure, known resistance to doravirine, or active hepatitis B infection, were randomly assigned (2:1) according to a computer-generated randomisation schedule (block size three) to receive oral doravirine (100 mg) and islatravir (0·25 mg) once daily or to continue baseline ART for 48 weeks. Randomisation was stratified by the anchor antiretroviral drug class (integrase strand-transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor, or protease inhibitor) in the baseline regimen. The primary endpoint (assessed in all treated participants) was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 (analysed according to the US Food and Drug Administration snapshot approach); non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The safety analysis population included all randomly assigned participants who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT05631093, and is ongoing but closed to enrolment. FINDINGS:Between Feb 20 and Oct 24, 2023, 614 individuals were screened for eligibility, of whom 553 were randomly assigned to receive doravirine and islatravir (n=368) or baseline ART (n=185). 551 participants received at least one dose of allocated medication: 366 in the doravirine and islatravir group and 185 in the baseline ART group. Of these 551 participants, 332 (60%) were assigned male and 219 (40%) were assigned female at birth, and the median age was 51 years (IQR 41-59); 250 (45%) identified as Black or African American and 80 (15%) identified as Hispanic, Latino, or Latina. Doravirine and islatravir showed non-inferiority at week 48, with viral loads of 50 copies per mL or higher in five (1·4%) of 366 participants versus nine (4·9%) of 185 participants on baseline ART (difference -3·6% [multiplicity-adjusted 95% CI -7·8 to -0·8]). Treatment-related adverse events were more common with doravirine and islatravir (44 [12·0%] of 366 participants) than with baseline ART (nine [4·9%] of 185 participants; difference 7·2 [95% CI 2·2 to 11·6]). Rates were similar in the doravirine and islatravir group and the baseline ART group for any adverse event (79·5% [291 of 366 participants] vs 83·8% [155 of 185 participants]; difference -4·3 [-10·7 to 2·8]), serious adverse events (6·3% [23] vs 4·9% [nine]; 1·4 [-3·2 to 5·2]), and discontinuation due to adverse events (0·5% [two] vs 2·2% [four]; -1·6 [-4·9 to 0·2]). One death occurred (in the baseline ART group) and was not considered treatment-related. No participants discontinued treatment as a result of protocol-specified declines in CD4 cell or total lymphocyte counts. INTERPRETATION:Doravirine and islatravir is efficacious and well tolerated and would represent the first non-INSTI-based, two-drug regimen for HIV-1 treatment. With increasing concern over the potential development of widespread INSTI resistance, this once-daily, oral, single-tablet regimen could be a potential option for people living with HIV-1 requiring a change to their antiretroviral regimen. The safety and efficacy findings support the ongoing development of islatravir, a drug with long-acting potential. FUNDING:Merck Sharp & Dohme, a subsidiary of Merck & Co.

BACKGROUND:Although clinical trials and real-world studies demonstrate the efficacy and tolerability of dolutegravir and lamivudine (DTG + 3TC), Australian real-world evidence remains limited despite differences in access to health care and prescribing context. Here, we present the motivations for switching to DTG/3TC (a fixed-dose, single-tablet regimen) and treatment outcomes. METHODS:We performed a retrospective, observational analysis of individuals with HIV with an undetectable viral load (VL; <50 copies/mL) who switched to DTG/3TC during a 24-month inclusion window from 1 December 2020 to 1 December 2022, in nine Australian clinics. Healthcare providers completed an electronic survey using baseline demographics of people with HIV and other clinical information gathered from participant medical records. Data were collected after December 2023 to allow a 12-month follow-up. Primary endpoints were baseline demographics, clinical characteristics, and motivations for switching to DTG/3TC. Secondary endpoints included virologic outcomes and rates and reasons for DTG/3TC discontinuation. RESULTS:Overall, 276 individuals with HIV who switched to DTG/3TC were included. Most were male (97%) and White (76%), with a median (interquartile range) age of 54 (45-61) years. The most common antiretroviral therapy before DTG/3TC switch was abacavir/dolutegravir/lamivudine (54%). The most common reason for switching to DTG/3TC was clinician preference for two-drug regimen (43%). Most individuals (98%) maintained virologic suppression (VL <50 copies/mL), and none experienced virologic failure. Through Month 12, one (<1%) individual discontinued DTG/3TC. CONCLUSIONS:These real-world data support the use of DTG/3TC as a viable treatment strategy in this Australian population of individuals with HIV.

BACKGROUND:Complex antiretroviral therapy (ART) regimens, such as those requiring multiple tablets, several doses per day, or both, can negatively affect quality of life and treatment adherence among people with human immunodeficiency virus (HIV). METHODS:ARTISTRY-1 is a phase 2/3, operationally seamless, randomized, open-label, multicenter, active-controlled study (GS-US-621-6289; NCT05502341). Phase 2 of the study enrolled adults with plasma HIV-1 RNA <50 copies/mL receiving a complex ART regimen for ≥6 months. Efficacy and safety outcomes were evaluated after a switch to bictegravir (BIC) (75-mg) + lenacapavir (LEN) (25- or 50-mg) regimens, compared with continuing on a complex ART regimen through 24 weeks. RESULTS:Overall, 128 participants were assigned randomly to begin BIC 75 mg + LEN 25 mg (n = 51) or BIC 75 mg + LEN 50 mg (n = 52) or continue on their complex ART regimen (n = 25). At week 24, HIV-1 RNA was ≥50 copies/mL in 0 of 51, 1 of 52 (1.9%), and 0 of 25 participants in the 3 groups, respectively. CD4 cell counts and percentages remained stable through week 24; the median change from baseline in CD4 cell count (interquartile range) was 18 (-39 to 70), -16 (-80 to 93), and 42 (-36 to 90) cells/µL, respectively. There were no study discontinuations due to a serious adverse event through week 24. Both BIC + LEN dosing regimens were well tolerated, with similar safety profiles observed between groups. CONCLUSIONS:These data support the continued evaluation of the combination of BIC and LEN to optimize treatment in people with HIV and virologic suppression who are receiving complex ART regimens.

ARTISTRY-1 is a phase 2/3 trial of bictegravir (BIC; 75 mg) plus lenacapavir (LEN; 25 mg or 50 mg) versus complex antiretroviral therapy regimens in 128 virologically suppressed people with HIV-1. At 48 weeks, BIC + LEN (at either LEN dose) was highly effective at maintaining virologic suppression and was well tolerated.

BACKGROUND AND SETTING:People living with HIV, especially gay, bisexual, and other men who have sex with men, are at increased risk of anal cancer. A recent randomized controlled trial showed treating anal high-grade squamous intraepithelial lesions (HSIL) reduces anal cancer incidence, supporting development of screening programs. Given the transition from cytological to HPV testing in cervical cancer screening, HPV testing for anal cancer is worth investigating. However, because of its low specificity, additional biomarkers like the p16/Ki67 dual stain may improve specificity. METHODS:In this multicenter pilot study, people living with HIV aged 35+ years were recruited from sexual health centers and a general practice. Participants underwent digital anorectal examination and anal swab collection for HPV and p16/Ki67 dual stain testing. High-resolution anoscopy (HRA) referrals were based on screening results at baseline and 12 months, with immediate HRA referral for HPV16-positive participants. The primary objective was to assess adherence to the screening program. RESULTS:From October 2019 to July 2021, 136 participants (median age 54 years) were recruited. Overall, 85.3% completed all screening and HRA steps, with 92.8% attending HRA referrals. At baseline, 71.4% had anal high-risk HPV (HRHPV), with 40 testing positive for HPV16. Of those with HRHPV, 42.1% had a positive p16/Ki67 dual stain, whereas 37.9% had unsatisfactory results. Among 37 HRA attendees, 73.0% had composite cytological/histological HSIL. At 12 months, 81.4% tested positive for HRHPV, and 25.9% had composite HSIL. CONCLUSIONS:Adherence to the screening algorithm was 85.3%, with >90% attendance at HRA referrals. Screening identified composite HSIL in 53.1% of participants. Utility of the p16/Ki67 dual stain remains undetermined because of high rates of unsatisfactory samples.

BACKGROUND:Increasing evidence indicates a metabolic etiology for migraines, with ketosis potentially rectifying metabolic and clinical features. We conducted a pilot study to evaluate CER-0001, a ketogenic agent, for migraine prevention without dietary changes. METHODS:This was a 2-part, double-blind, randomised, placebo-controlled study conducted in Australia. Adults with at least a 1-year history of migraine and ≥ 1 prior preventive treatment failure were randomised to either oral CER-0001 (up to 30 g twice a day) or placebo for 12 weeks. The primary endpoint was Month 3 change in Migraine Headache Days from baseline. RESULTS:Part 1 results are presented. 81 participants were randomised and dosed (n = 40 CER-0001, n = 41 placebo), and 61 participants had evaluable efficacy data. No statistically significant difference was observed in the primary endpoint (LSMean difference 0.92 days; p = 0.586). During Month 2, a mean improvement of -2.8 days was observed for CER-0001 (p = 0.056). Withdrawal rates were 45.0% and 53.7% (CER-0001; placebo). The proportion of participants reporting at least one treatment-emergent adverse event was similar between arms (90.0% CER-0001, 82.9% placebo), mostly gastrointestinal (85.0% CER-0001, 70.7% placebo). CONCLUSION:Results suggest positive directional promise over 2-3 months for CER-0001. A new formulation will be used for larger, fully powered phase 2/3 studies. TRIAL REGISTRATION:This study is registered at ClinicalTrials.gov (NCT04437199).

Background In Australia, the incidence of hepatitis C virus (HCV) has declined among gay and bisexual men (GBM) with human immunodeficiency virus (HIV) since 2015 and is low among GBM using HIV preexposure prophylaxis (PrEP). However, ongoing HCV testing and treatment remains necessary to sustain this. To assess the potential utility of sexually transmissible infections (STIs) to inform HCV testing among GBM with HIV and GBM using PrEP, we examined the association between bacterial STI diagnoses and subsequent primary HCV infection.Methods Data were from a national network of 46 clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance. GBM included had >= 1 HCV antibody negative test result and >= 1 subsequent HCV antibody and/or RNA test. Discrete time survival analysis was used to estimate the association between a positive syphilis, rectal chlamydia, and rectal gonorrhea diagnosis in the previous 2 years and a primary HCV diagnosis, defined as a positive HCV antibody or RNA test result.Results Among 6529 GBM with HIV, 92 (1.4%) had an incident HCV infection. A prior positive syphilis diagnosis was associated with an incident HCV diagnosis (adjusted hazard ratio, 1.99 [95% confidence interval, 1.11-3.58]). Among 13 061 GBM prescribed PrEP, 48 (0.4%) had an incident HCV diagnosis. Prior rectal chlamydia (adjusted hazard ratio, 2.75 [95% confidence interval, 1.42-5.32]) and rectal gonorrhea (2.54 [1.28-5.05]) diagnoses were associated with incident HCV.Conclusions Diagnoses of bacterial STIs in the past 2 years was associated with HCV incidence. These findings suggest that STIs might be useful for informing HCV testing decisions and guidelines for GBM with HIV and GBM using PrEP. Sexually transmissible infections (STIs) are a marker of hepatitis C virus (HCV) risk among gay and bisexual men with human immunodeficiency virus (HIV) and those prescribed HIV preexposure prophylaxis in the context of declining HCV incidence. These STIs may be useful for guiding more tailored HCV testing.

Invasive meningococcal disease, caused by the bacterium Neisseria meningitidis, is life-threatening but can be prevented with vaccination. There are effective vaccines against different meningococcal serogroups, including serogroup B. Evidence from immunization programs with the 4-component meningococcal serogroup B vaccine, 4CMenB, over the past decade confirms its effectiveness and positive impact against serogroup B disease in people of all age groups. To assess the performance of serogroup B vaccines in clinical trials, tests are required that take into account the wide diversity of serogroup B strains circulating in the population. In this study, the performance of 4CMenB was evaluated using the enc-hSBA assay, which uses the complement (proteins) present in each vaccinated person's blood and is used to test a large number of N meningitidis strains, thereby determining breadth of immune response, based on the vaccine's killing activity against diverse strains. Using this assay, our results showed breadth of immune response following administration of 4CMenB (2 doses, 2 or 6 months apart) against the 110 serogroup B strains tested that was consistent with its performance in immunization programs, with no additional benefit from administering 3 4CMenB doses over the 6-month period. The safety of 4CMenB was consistent with its known safety profile.Clinical Trial Registration. NCT04502693.

Background Gay and bisexual men (GBM) remain overrepresented among syphilis diagnoses in Australia and globally. The extent to which changes in sexual networks associated with HIV pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) may have influenced fl uenced syphilis transmission among GBM at the population-level is poorly understood. We describe trends in syphilis testing and incidence among GBM in Australia over eleven years spanning widespread uptake of HIV PrEP and TasP. Methods We analysed linked clinical data from GBM aged 16 years or older across a sentinel surveillance network in Australia from January 1, 2012, to December 31, 2022. Individuals with at least two clinic visits and with at least two syphilis tests during the observations period were included in testing and incidence analyses, respectively. Annual rates of testing and infectious syphilis incidence from 2012 to 2022 were disaggregated by HIV status and PrEP use (record of PrEP prescription; retrospectively categorised as ever or never-PrEP user). Cox regression explored associations between demographics, PrEP use and history of bacterial sexually transmissible infections (STIs) and infectious syphilis diagnosis. Findings Among 129,278 GBM (mean age, 34.6 years [SD, 12.2]) included in testing rate analyses, 7.4% were living with HIV at entry and 31.1% were prescribed PrEP at least once during the study period. Overall syphilis testing rate was 114.0/100 person-years (py) and highest among GBM with HIV (168.4/100 py). Syphilis testing increased from 72.8/100 py to 151.8/100 py; driven largely by increases among ever-PrEP users. Among 94,710 GBM included in incidence analyses, there were 14,710 syphilis infections diagnosed over 451,560 person-years (incidence rate = 3.3/100 py). Syphilis incidence was highest among GBM with HIV (6.5/100 py), followed by ever-PrEP users (3.5/100 py) and never-PrEP users (1.4/100 py). From 2012 to 2022, syphilis incidence increased among ever-PrEP users from 1.3/100 py to 5.1/100 py, and fl uctuated between 5.4/100 py and 6.6/100 py among GBM with HIV. In multivariable Cox regression, previous syphilis diagnosis (adjusted hazard ratio [aHR] = 1.98, 95% CI = 1.83-2.14), - 2.14), living with HIV (aHR = 1.83, 95% CI = 1.12-1.25) - 1.25) and recent (past 12 m) prescription of PrEP (aHR = 1.78, 95% CI = 1.61-1.97) - 1.97) were associated with syphilis diagnosis. Interpretation Syphilis trends between GBM with HIV and GBM with evidence of PrEP use have converged over the past decade in Australia. Our fi ndings recommend targeting emergent syphilis control strategies (e.g. doxycycline post-exposure prophylaxis) to GBM with prior syphilis diagnoses, using HIV PrEP or who are living with HIV.

Objective Guidelines recommend annual hepatitis C virus (HCV) testing for gay and bisexual men (GBM) with HIV and GBM prescribed HIV pre-exposure prophylaxis (PrEP). However, there is a limited understanding of HCV testing among GBM. We aimed to examine trends in HCV testing and positivity from 2016 to 2022. Methods Using sentinel surveillance data, we examined the proportion of GBM with at least one test and the proportion with a positive test in each year for HCV antibody testing among GBM with no previous HCV positive test, HCV RNA testing among GBM with a positive antibody test but no previous positive RNA test (naïve RNA testing), and HCV RNA testing among people who had a previous RNA positive test and a subsequent negative test (RNA follow-up testing). Trends were examined using logistic regression from 2016 to 2019 and 2020 to 2022. Results Among GBM with HIV, from 2016 to 2019 antibody testing was stable averaging 55% tested annually. Declines were observed for both naïve HCV RNA testing (75.4%–41.4%: p<0.001) and follow-up HCV RNA testing (70.1%–44.5%: p<0.001). Test positivity declined for HCV antibody tests (2.0%–1.3%: p=0.001), HCV RNA naïve tests (75.4%–41.4%: p<0.001) and HCV RNA follow-up tests (11.3%–3.3%: p=0.001). There were minimal or no significant trends from 2020 to 2022. Among GBM prescribed PrEP, antibody testing declined from 2016 to 2019 (79.4%–69.4%: p<0.001) and was stable from 2020 to 2022. Naïve and follow-up HCV RNA testing was stable with an average of 55% and 60% tested each year, respectively. From 2016–2019, the proportion positive from HCV RNA naïve tests declined (44.1%–27.5%: p<0.046) with no significant change thereafter. Positive follow-up HCV RNA tests fluctuated with no or one new positive test among this group in most years. Conclusion The proportion of GBM with positive HCV tests has declined, however a substantial proportion are not tested annually. A renewed focus on HCV testing, and treatment where required, is warranted to achieve HCV elimination among GBM in Australia.

BACKGROUND:SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS:In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 μg SARS-CoV-2 recombinant spike protein and 50 μg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 μg of NVX-CoV2373 plus 2·5 μg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS:Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION:All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING:Novavax.

Introduction Alors que les traitements en un comprimé unique (STR) constituent aujourd'hui la norme pour le traitement du VIH dans le monde, certaines personnes vivant avec le VIH (PVVIH) prennent un traitement en comprimés multiples (MTR) en raison de résistances archivées, d'une intolérance ou d'interactions médicamenteuses. L'association du bictégravir (BIC), un inhibiteur de l'intégrase, et du lénacapavir (LEN), un inhibiteur de capside et premier de sa classe, pourrait simplifier le traitement des PVVIH en succès virologique (SV) pour lesquelles les STR ne sont pas indiqués. Nous présentons les résultats du critère principal à 24 semaines de l'étude de phase 2 évaluant le changement vers l'association BIC + LEN comparé au maintien du traitement oral en cours (MTO) chez les PVVIH en SV ayant un MTR complexe. Matériels et méthodes ARTISTRY-1 (NCT05502341) est une étude de phase 2/3 multicentrique, randomisée, en ouvert et en cours. Lors de la phase 2, 128 participants (≥ 6 mois avant le dépistage) ont été randomisés selon un rapport 2:2:1 pour recevoir par voie orale en une fois par jour BIC 75 mg + LEN 25 mg ou BIC 75 mg + LEN 50 mg, ou le maintien du MTO. Tous les participants recevant BIC + LEN ont reçu une dose de charge orale de 600 mg de LEN les jours 1 et 2 du traitement. Le critère d'évaluation principal était la proportion de participants avec un ARN du VIH ≥ 50 c/ml (FDA Snapshot) à la semaine 24. Les critères d'évaluation secondaires comprenaient la proportion de participants avec un ARN du VIH < 50 c/ml, la variation par rapport à l'inclusion du nombre de cellules CD4 et la proportion de participants présentant des événements indésirables survenus durant le traitement (EIDT) jusqu'à la semaine 24. Résultats 51 et 52 participants ont reçu respectivement BIC 75 mg + LEN 25 mg ou BIC 75 mg + LEN 50 mg et 25 ont continué leur MTO. A l'inclusion, 19 % des participants étaient des femmes, 31 % étaient noirs et 16 % étaient hispaniques ou latinos ; L'âge médian (Q1, Q3) était de 60 (56, 65) ans et les participants prenaient une médiane (intervalle) de 3 (2 à 9) comprimés par jour. A la semaine 24, l'ARN du VIH-1 était ≥ 50 c/ml chez 0/51 participant du groupe BIC 75 mg + LEN 25 mg, 1/52 (2 %) dans le groupe BIC 75 mg + LEN 50 mg (puis en succès <50 c/ml sans changement du traitement) et 0/25 dans le groupe MTO. Les taux de CD4 étaient comparables dans tous les groupes. Les EIDT les plus courants dans les deux groupes BIC + LEN jusqu'à la semaine 24 étaient la diarrhée (7 %), le COVID-19 (6 %) et la constipation (5 %). Des EIDT liés aux traitements sont survenus respectivement chez 18 %, 6 % et 0 % des participants. Conclusion Le changement de traitement pour BIC + LEN s'est avéré hautement efficace pour maintenir la suppression virologique chez les ayant un MTR complexe, avec des profils de tolérance similaires observés dans les deux groupes BIC + LEN. Ces données soutiennent l'utilisation de l'association de BIC et LEN pour les traitements complexes des PVVIH en SV. Un STR BIC/LEN sera évalué lors de la Phase 3 de l'étudeAucun lien d'intérêt