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Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV.In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (≤100 000 or100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading [600 mg on days 1 and 2, followed by 300 mg on day 8]) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594.Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2·6%, 95% CI -18·4 to 13·2), 85% (45 of 53) for group 2 (-7·1%, -23·4 to 9·3), 85% (44 of 52) for group 3 (-7·2%, -23·5 to 9·1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling).Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs.Gilead Sciences.

BackgroundBaricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19.MethodsIn this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168.FindingsBetween Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012).InterpretationIn hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered.FundingNational Institute of Allergy and Infectious Diseases.

BackgroundWe assessed the efficacy and safety of dolutegravir/lamivudine (DTG/3TC) in a US test-and-treat setting at a secondary 48-week time point of the multicenter, single-arm, phase IIIb STAT study.MethodsParticipants were eligible adults newly diagnosed with human immunodeficiency virus (HIV)-1 and had started once-daily DTG/3TC within 14 days of diagnosis, before laboratory results were available. Antiretroviral therapy (ART) was modified if baseline testing indicated DTG or 3TC resistance, hepatitis B virus (HBV) coinfection, or creatinine clearance ResultsAt Week 48, 82% of all participants regardless of ART (107 of 131; ITT-E missing = failure) and 97% with available data (107 of 110; observed analysis) achieved HIV-1 RNA ConclusionsResults demonstrated high proportions of participants with sustained virologic suppression, no treatment-emergent resistance, and good safety over 48 weeks, supporting first-line use of DTG/3TC in a test-and-treat setting.

Background People with HIV (PWH) who are initiated on guidelines-recommended first-line INSTI-based antiretroviral therapy routinely achieve rapid virologic suppression; however, those with a high baseline (BL) HIV-1 RNA and/or low CD4 count may be more challenging to manage in the short- and long-term. To further characterize long-term outcomes over 5 years in select subgroups, we analyzed results from two studies examining B/F/TAF as initial treatment stratified by BL HIV-1 RNA and/or CD4 count. Methods Adults with HIV were randomized to receive blinded initial treatment with B/F/TAF versus dolutegravir [DTG]/abacavir/lamivudine (Study 1489) or DTG+F/TAF (1490) for 144 weeks (W) of blinded treatment followed by an optional switch to open-label B/F/TAF for 96W. We present virologic response (HIV-1 RNA < 50 c/mL, missing=excluded and missing=failure) and study drug-related adverse events (DRAE) from a pooled analysis of participants originally randomized to B/F/TAF who had BL HIV-1 RNA 100,00-400,000 copies(c)/mL, HIV-1 RNA >400,000 c/mL and/or CD4 count < 200 cells/µL through W240. Results 634 adults (median age 32 years, 89% men, 33% Black/African descent, 24% Hispanic/LatinX) originally randomized to B/F/TAF were included for analysis. At BL, 80 participants had a BL CD4 count < 200 cells/µL and 119 participants had HIV-1 RNA >100,000 c/mL, of whom, 20 had HIV-1 RNA >400,000 c/mL. At W240, virologic suppression was high for the low CD4 count and/or high HIV-1 RNA subgroups (Table). No participant in the final resistance analysis developed virologic resistance to any component of B/F/TAF. Across the subgroups, the most common DRAEs were nausea, headache and diarrhea and there were no serious DRAEs. There was only one discontinuation due to a DRAE in the low CD4 count subgroup, and none in the high HIV-1 RNA subgroup. Conclusion Initial treatment with B/F/TAF was safe and efficacious over 5 years of follow-up in people with a high BL HIV-1 RNA and/or low CD4 count. These outcomes provide additional evidence that B/F/TAF is an effective and durable regimen for a broad range of PWH, including those with advanced disease. Disclosures Moti Ramgopal, MD, FACP, FIDSA, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Speakers Bureau|Janssen: Advisor/Consultant|Janssen: Speakers Bureau|Merck: Advisor/Consultant|Merck: Speakers Bureau|ViiV: Advisor/Consultant|ViiV: Speakers Bureau Axel Baumgarten, MD, AbbVie: Honoraria|Gilead Sciences: Honoraria|Janssen: Honoraria|MSD: Honoraria|ViiV: Honoraria Anton Pozniak, MD, FRCP, Gilead: Grant/Research Support|Gilead: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Merck: Honoraria|theratec: Honoraria|ViiV: Grant/Research Support|ViiV: Honoraria Chloe Orkin, MBChB, FRCP, MD, Gilead Sciences: Honoraria|GSK: Honoraria|Janssen: Honoraria|MSD: Honoraria Juan Manuel Tiraboschi, PhD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|MSD: Advisor/Consultant|MSD: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Debbie P. Hagins, MD, FAPCR, AAHIVS, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Speakers Bureau|Janssen: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Hailin Huang, PhD, Gilead Sciences, Inc.: Employer|Gilead Sciences, Inc.: Stocks/Bonds Kristin Andreatta, MSc, Gilead Sciences, Inc: Employee of Gilead Sciences|Gilead Sciences, Inc: Stocks/Bonds Nathan Unger, PharmD, AAHIVP, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Jason Hindman, PharmD, MBA, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Hal Martin, MD, Gilead Sciences: employee|Gilead Sciences: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Olayemi Osiyemi, MD, Gilead: Advisor/Consultant|gsk: Advisor/Consultant|viiv: Advisor/Consultant.

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.

Objectives Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. Design The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. Methods Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). Results Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. Conclusion These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

BACKGROUND Surgical site infections (SSIs) after left ventricular assist device (LVAD) implantation are associated with high mortality, while surgical prophylaxis is variable. METHODS This retrospective study included adult patients who underwent LVAD implantation at a single center. We compared outcomes in patients who received narrow antimicrobial prophylaxis (cefazolin, vancomycin, or both) to those who received broad antimicrobial prophylaxis (any antimicrobial combination targeting gram-positive and gram-negative organisms not included in the narrow group) at 30-day and 1-year postimplantation. Cox-proportional hazards models and log-rank tests were used for survival analysis. RESULTS Among the 39 and 65 patients comprising narrow and broad groups respectively, there was no difference in rate of SSI at 30 days (6.2% vs. 12.8%, p = .290) and 1 year (16.9% vs. 25.6%, p = .435). Comparing narrow to broad prophylaxis, the risk of mortality (hazard ratio [HR] = 0.44, 95% confidence interval [CI] = 0.15-1.35, logrank p = .14), and composite of mortality and infection was reduced (HR = 0.92, 95% CI = 0.45-1.88, logrank p = .83), but did not reach statistical significance. Most culture positive infections were due to gram-positive bacteria (70%) and the most common organisms were the Staphylococcus spp (47%). There were no significant differences in the rate of SSI at 1-year (p = 1.00) and mortality (p = .33) by device type. CONCLUSIONS The rates of infection and all-cause mortality were not different between patients who received narrow or broad prophylaxis. This highlights an opportunity for institutions to narrow their surgical infection prophylaxis protocols to primarily cover gram-positive organisms.

The prevalence and seroconversion rate of SARS-CoV-2 infection among asymptomatic health care workers in the US is unclear. Our study utilized real-time polymerase chain reaction (RT-PCR) SARS-CoV-2 testing and serological evaluation to detect IgG antibodies specific to SARS-CoV-2 antigens in asymptomatic health care workers. A total of 197 subjects with a mean age of 35 years were recruited into the study. While most (67%) reported prolonged contact with known COVID-19 patients, only 8 (4.2%) tested positive on RT-PCR and 23 (11.7%) had detectable levels of IgG antibody to SARS-CoV-2. Out of 19 subjects with detectable IgG antibody at week 1, 11 (57.9%) lost their antibody response by week 3. No statistically significant difference was found in baseline characteristics or exposure status between subjects with positive and negative results on RT-PCR or antibody positivity. In conclusion, we found a low incidence of PCR positivity for SARS-CoV-2 in a high-risk group. This likely demonstrates the effectiveness of proper personal protective equipment use and low transmission risk in health care settings. The detectable IgG antibody titer was low, and a significant portion of subjects lost their antibody response on repeat testing. This may mean that antibody response in asymptomatic patients is categorically different than in symptomatic hospitalized patients with COVID-19.

Evidence suggests that SARS-CoV-2 viral load is an independent predictor of disease severity and mortality. A 61-year-old woman presented with severe COVID-19 and was treated with casirivimab/imdevimab and remdesivir. Quantitative nasopharyngeal (NP) viral loads were trended throughout the treatment course. Baseline NP viral load was 25,860,901 copies/mL (7.4 log10). Casirivimab/imdevimab was administered, with subsequent reduction in NP viral load to 26,049 copies/mL (4.4 log10) on hospital day 4. A repeat NP viral load on day 7 was 13,113 copies/mL (4.1 log10). Despite uncertainty regarding correlation with reduction in viral load and outcomes, NP viral load may be considered when selecting treatment options and evaluating treatment response in hospitalized patients with early infection.

Patients with multidrug-resistant human immunodeficiency virus type 1 (HIV-1) infection have limited treatment options. Lenacapavir is a first-in-class capsid inhibitor that showed substantial antiviral activity in a phase 1b study.In this phase 3 trial, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to the change in the plasma HIV-1 RNA level between the screening and cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral lenacapavir or placebo in addition to their failing therapy for 14 days; during the maintenance period, starting on day 15, patients in the lenacapavir group received subcutaneous lenacapavir once every 6 months, and those in the placebo group received oral lenacapavir, followed by subcutaneous lenacapavir; both groups also received optimized background therapy. In cohort 2, all the patients received open-label oral lenacapavir with optimized background therapy on days 1 through 14; subcutaneous lenacapavir was then administered once every 6 months starting on day 15. The primary end point was the percentage of patients in cohort 1 who had a decrease of at least 0.5 logA total of 72 patients were enrolled, with 36 in each cohort. In cohort 1, a decrease of at least 0.5 logIn patients with multidrug-resistant HIV-1 infection, those who received lenacapavir had a greater reduction from baseline in viral load than those who received placebo. (Funded by Gilead Sciences; CAPELLA ClinicalTrials.gov number, NCT04150068.).

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

BACKGROUND: Tixagevimab-cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab-cilgavimab versus placebo, in patients receiving remdesivir and other standard care.METHODS: In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg-cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab-cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing.FINDINGS: From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab-cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab-cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97-1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97-1·34]; p=0·13). Mortality was lower in the tixagevimab-cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50-0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab-cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68-1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab-cilgavimab group and 38 (5%) in the placebo group.INTERPRETATION: Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab-cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower.FUNDING: US National Institutes of Health (NIH) and Operation Warp Speed.

Active immunization with the BNT162b2 vaccine (Pfizer-BioNTech) has been a critical mitigation tool against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (Covid-19) pandemic. In light of reports of waning protection occurring 6 months after the primary two-dose vaccine series, data are needed on the safety and efficacy of offering a third (booster) dose in persons 16 years of age or older.In this ongoing, placebo-controlled, randomized, phase 3 trial, we assigned participants who had received two 30-μg doses of the BNT162b2 vaccine at least 6 months earlier to be injected with a third dose of the BNT162b2 vaccine or with placebo. We assessed vaccine safety and efficacy against Covid-19 starting 7 days after the third dose.A total of 5081 participants received a third BNT162b2 dose and 5044 received placebo. The median interval between dose 2 and dose 3 was 10.8 months in the vaccine group and 10.7 months in the placebo group; the median follow-up was 2.5 months. Local and systemic reactogenicity events from the third dose were generally of low grade. No new safety signals were identified, and no cases of myocarditis or pericarditis were reported. Among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated, Covid-19 with onset at least 7 days after dose 3 was observed in 6 participants in the vaccine group and in 123 participants in the placebo group, which corresponded to a relative vaccine efficacy of 95.3% (95% confidence interval, 89.5 to 98.3).A third dose of the BNT162b2 vaccine administered a median of 10.8 months after the second dose provided 95.3% efficacy against Covid-19 as compared with two doses of the BNT162b2 vaccine during a median follow-up of 2.5 months. (Funded by BioNTech and Pfizer; C4591031 ClinicalTrials.gov number, NCT04955626.).

Casirivimab/imdevimab, a cocktail of monoclonal antibodies, is currently approved for emergency use in high-risk ambulatory patients with early COVID-19 to reduce risk of hospitalization and/or death from SARS-CoV-2 infection. In the United States, there is no approved monoclonal antibody therapy for patients hospitalized for complications due to acute SARS-CoV-2 infection. We describe here the use of casirivimab/imdevimab in a 52-year-old fully vaccinated, immunocompromised man admitted to the intensive care unit for acute hypoxemic respiratory failure due to SARS-CoV-2 infection.

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

Surgical site infections (SSI) after left ventricular assist device (LVAD) implantation are associated with high mortality, while surgical prophylaxis is variable. This retrospective study included adult patients who underwent LVAD implantation at a single center. We compared outcomes in patients who received narrow antimicrobial prophylaxis (cefazolin, vancomycin or both) to those who received broad antimicrobial prophylaxis (any antimicrobial combination targeting gram-positive and gram-negative organisms not included in the narrow group) at 30 days and 1 year post-implantation. Cox-proportional hazards models and log-rank tests were used for survival analysis. Among the 39 and 65 patients comprising narrow and broad groups respectively, there was no difference in rate of SSI at 30 days (6.2% vs 12.8%, p = 0.290) and 1 year (16.9% vs 25.6%, p = 0.435). Comparing narrow to broad prophylaxis, the risk of mortality [HR (95% CI): 0.44 (0.15. 1.35), logrank P = 0.14], and composite of mortality and infection was reduced [HR (95% CI): 0.92 (0.45, 1.88), logrank P = 0.83], but did not reach statistical significance. Most culture positive infections were due to gram-positive bacteria (70%) and the most common organisms were the Staphylococcus spp (47%). There were no significant differences in the rate of SSI at 1-year (p=1.00) and mortality (p=0.33) by device type. The rates of infection and all-cause mortality were not different between patients who received narrow or broad prophylaxis. This highlights an opportunity for institutions to narrow their surgical infection prophylaxis protocols to primarily cover gram-positive organisms.

Brucellosis is a zoonotic infection caused by the intracellular gram-negative bacterium Brucella. It is the most common zoonosis worldwide, and its transmission is classically associated with consumption of unpasteurized animal products. However, other mechanisms of transmission include contact of the skin or mucous membranes with infected animal tissue. We present a case of a patient who had more than one possible route of infection.

Background: Rapid molecular diagnostic tests can aid in deescalating antimicrobial therapy prior to final culture and susceptibility reports. Objective: The purpose of this study was to determine whether a new workflow that incorporated pharmacist review of these results reduced time to change in antimicrobial therapy. Methods: This retrospective study analyzed pre- and post-implementation of pharmacist review of positive blood cultures analyzed by rapid diagnostics with clinical recommendations paged to providers. Patients 18 years of age or older initiated on empiric antibiotics were included. The primary outcome was the time to change to targeted antimicrobials. Other outcomes evaluated were rates of Clostridioides difficile (C difficile) infection, inpatient mortality, and intensive care unit and hospital lengths of stay. Results: A total of 199 patients were included, with 98 and 101 patients in the pre- and post-implementation groups, respectively. The median time to change to targeted antimicrobials was significantly reduced with pharmacist intervention from 18.35 to 8.43 hours ( P = 0.042). The groups had similar rates of C difficile infection (1% vs 0%, P = 0.492) and mortality (7.1% vs 5%, P = 0.564). The post-group also had significant reductions in antibiotic days of therapy (10.5 vs 9 days, P = 0.014) and intensive care unit length of stay (3.04 vs 1.44 days, P = 0.046). Median hospital length of stay was similar between the pre- and post-groups (8.5 vs 8 days, P = 0.106), respectively. Conclusion: Incorporating pharmacist review of rapid molecular results of blood cultures decreased time to change to targeted antimicrobials and reduced inpatient antibiotic days of therapy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or novel coronavirus disease 2019 (COVID-19) emerged from China in December 2019 and progressed to become a global pandemic. Our understanding of its pathophysiology and potential management was initially extrapolated from previous epidemics of coronaviruses like SARS and MERS. SARS-CoV-2 is asymptomatic or minimally symptomatic in more than 80% of patients and requires no additional management; however, the remaining patients progress to pneumonia and hypoxemia with ranging severity, including a smaller group that requires intensive care unit admission. To date, there are no approved treatments for SARS-CoV-2, and current management is focused on supplemental oxygen and supportive care. The antiviral medication remdesivir recently received emergency use authorization by the US Food and Drug Administration for patients with severe disease. Multiple clinical trials evaluating different treatment modalities such as antivirals, immunomodulators, convalescent plasma, and monoclonal antibodies, among others, are still ongoing. We believe that patients present with clinical phenotypes that correlate with the spectrum of disease. Each phenotype may benefit from one or multiple interventions. We discuss treatments under evaluation in clinical trials and their potential application based on clinical phenotype presentation.

Background The primary analysis of the STAT study demonstrated the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting through 24 weeks, with therapy adjustments for baseline resistance or hepatitis B virus (HBV) co-infection. Here we present secondary analyses through Week 48 of virologic outcomes in participants by baseline viral load (VL). Methods STAT is a single-arm study of treatment-naive adults with HIV-1 infection who initiated DTG/3TC ≤ 14 days after HIV-1 diagnosis without availability of screening/baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance < 30 mL/min/1.73 m2, then antiretroviral therapy (ART) was potentially adjusted and participants remained on study. Efficacy analyses included proportion of participants with HIV-1 RNA < 50 c/mL regardless of ART regimen at Week 48, among all participants (ITT-E missing = failure analysis) and among participants with available HIV-1 RNA data at Week 48 (observed analysis). Results Of 131 enrolled, DTG/3TC treatment was adjusted in 10 participants, and of those with available data (n=7), all (100%) achieved HIV-1 RNA < 50 c/mL at Week 48. At Week 48, 82% (107/131) of all participants (Figure 1) and 97% (107/110) of those with available data (Figure 2) achieved HIV-1 RNA < 50 c/mL. Of participants with baseline VL ≥ 500,000 c/mL, 89% (17/19) achieved HIV-1 RNA < 50 c/mL at Week 48; the remaining 2 withdrew from study. Of participants with baseline VL ≥ 1,000,000 c/mL, 90% (9/10) achieved HIV-1 RNA < 50 c/mL at Week 48 (Table); the remaining participant withdrew consent. Of the 17 participants with baseline VL ≥ 500,000 c/mL with available data through Week 48, 76% (13/17) achieved virologic suppression by Week 24. One participant with baseline VL ≥ 500,000 c/mL switched from DTG/3TC before the Week 48 assessment. Of the 9 participants with baseline VL ≥ 1,000,000 c/mL with available data through Week 48, most participants (8/9; 89%) were suppressed by Week 24. Figure 1. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: ITT-E missing = failure analysis. Figure 2. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: observed analysis. Table. Viral Load by Study Visit Among Participants with Baseline HIV-1 RNA ≥1,000,000 c/mL Conclusion These data provide evidence for the efficacy and feasibility of using DTG/3TC as a first-line regimen in a test-and-treat setting, including among participants with very high baseline VL. Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Scientific Research Study Investigator, Advisor or Review Panel member)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Tulika Singh, MD MS AAHIVS, Gilead (Grant/Research Support, Advisor or Review Panel member)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Dushyantha Jayaweera, MD, mrcog(uk), face, Gilead (Research Grant or Support)Janssen (Research Grant or Support)viiv (Research Grant or Support) Peter Leone, MD, viiv healthcare (Employee) Jessica Matthews, BS, ViiV Healthcare (Employee) Michael Cupo, Ph.D., GlaxoSmithKline (Employee) Mark Underwood, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kostas Angelis, PhD, GSK (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Deanna Merrill, PharmD, MBA, AAHIVP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christopher T. Nguyen, MD, ViiV Healthcare (Employee) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Andrew Zolopa, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Background Bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) is a guidelines-recommended single-tablet regimen (STR) for people living with HIV-1 (PLWH). Week (W) 48 primary endpoint results of this phase 3 study switching to B/F/TAF from dolutegravir (DTG), abacavir (ABC) and lamivudine (3TC) established the safety and efficacy of B/F/TAF. Here we report outcomes from an open-label (OL) extension of B/F/TAF. Methods Adults virologically suppressed on DTG, ABC, and 3TC were randomized 1:1 to switch to B/F/TAF once daily or continue their current regimen as a STR in a double blind (DB) manner. Unblinding occurred after the W48 primary endpoint, then participants received B/F/TAF in an OL extension while transitioning off the study. All participants who received B/F/TAF in the DB or OL phases are included in analyses. Efficacy was assessed as the proportion with HIV-1 RNA < 50 copies/mL at each study visit using missing=excluded (M=E) analysis, efficacy in in subgroups with pre-existing resistance was assessed using last observation carried forward. Safety was assessed by adverse events (AEs) and laboratory results. Results 563 participants were randomized and treated (282 B/F/TAF, 281 ABC/DTG/3TC); 524 (93%) completed the DB phase and received OL B/F/TAF; a total of 547 participants received B/F/TAF in DB and/or OL phases: 11% women, 21% Black, median age 47 yrs (range 21, 71). The median duration of B/F/TAF was 96 weeks (IQR 49-119). HIV-1 RNA < 50 c/mL was maintained in 99-100% at all timepoints (M=E) through a maximum of 168 weeks, including high efficacy in those with archived resistance (Table 1). No participant developed resistance to B/F/TAF. Study drug-related AEs occurred in 7% on B/F/TAF; most were grade 1; the most common was headache (1.6%). 7 (1%) participants had an AE leading to premature study drug discontinuation, only 1, headache, occurred in the OL phase. Estimated GFR and lipids were mostly stable with slightly increased LDL at W96; weight changes are noted at W48 and W96. (Table 2). Table 1. Table 2. Conclusion Extended follow-up to the study of switching to B/F/TAF from DTG/ABC/3TC, demonstrates continued high rates of virologic suppression with no resistance and excellent safety and tolerability of B/F/TAF through a maximum of 168 weeks for treatment of PLWH. Disclosures Indira Brar, MD, Gilead (Speaker’s Bureau)janssen (Speaker’s Bureau)ViiV (Speaker’s Bureau) Peter Ruane, MD, AbbVie (Consultant, Grant/Research Support, Speaker’s Bureau)Bristol-Myers Squibb (Grant/Research Support)Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Shareholder, Speaker’s Bureau)Idenix (Consultant)Janssen (Grant/Research Support, Speaker’s Bureau)Viiv Healthcare (Grant/Research Support) Douglas Ward, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Merck (Advisor or Review Panel member)Viiv Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Jean-michel Molina, MD, PhD, Bristol-Myers Squibb (Advisor or Review Panel member)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Teva (Advisor or Review Panel member)Viiv Healthcare (Advisor or Review Panel member) Anthony Mills, MD, Gilead (Grant/Research Support, Advisor or Review Panel member)Janssen Pharmaceutica (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Shionogi (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Advisor or Review Panel member) Mezgebe Berhe, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator) Cynthia Brinson, MD, Gilead (Advisor or Review Panel member, Speaker’s Bureau)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Moti Rampogal, MD, Gilead Sciences (Consultant, Research Grant or Support, Speaker’s Bureau)Janssen (Consultant, Research Grant or Support, Speaker’s Bureau)Merck (Consultant, Research Grant or Support)ViiV Healthcare (Consultant, Research Grant or Support, Speaker’s Bureau) Keith Henry, MD, Gilead (Research Grant or Support, Paid to institution)GSK/ViiV (Research Grant or Support, Paid to institution)Janssen (Research Grant or Support, Paid to institution)Merck (Research Grant or Support, Paid to institution) Hailin Huang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Kristen Andreatta, MSc, Gilead Sciences (Employee, Shareholder) Hal Martin, MD, MPH, Gilead Sciences Inc. (Employee, Shareholder)

Summary Background Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. Methods We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of −10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. Findings Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −2·6%, 95% CI −6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference −0·7%, 95% CI −4·3 to 2·9), showing non-inferiority at a −10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. Interpretation The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. Funding ViiV Healthcare.

Background Surgical site infections (SSI) for implantation of left ventricular assist devices (LVADs) are associated with high mortality. Updated guidance from the International Society for Heart and Lung Transplant recommends that SSI prophylaxis regimens target Staphylococcus spp and recommend against broad regimens targeting gram-negatives and fungi. The purpose of this study was to compare outcomes between patients that received broad or narrow antimicrobial prophylaxis regimens after a change in institutional protocol. Methods This single center retrospective study included adult patients who underwent LVAD implantation between January 2015 and September 2019. Patients were excluded if post-surgical care was managed at an outside facility, were treated for an active infection at the time of implantation, or underwent re-implantation within 90 days. The narrow spectrum group consisted of patients that received cefazolin, vancomycin or both, while the broad spectrum group consisted of patients that received an anti-pseudomonal beta-lactam plus vancomycin ± other antibiotics. Data was compared using t-test or Wilcoxon rank sum test, Chi-Square test, or Fisher’s Exact. Cox-proportional hazards models and log-rank tests were used for survival analysis. Results A total of 104 patients were included, with 39 and 65 patients receiving narrow and broad spectrum prophylaxis, respectively. There was no difference in the primary outcome of SSI rate between the narrow and broad antimicrobial prophylaxis groups at 30 days (7.7% vs 7.7%, p=1.00) and 1 year (18.0% vs 18.5%, p=1.00) respectively. Secondary outcomes of time to mortality (HR 0.45, 95% CI 0.15-1.36, logrank P=0.15), time to first infection (HR 0.68, 95% CI 0.26-1.8, logrank P=0.44), or the composite outcome of mortality or infection (HR 0.55, 95% CI 0.24-1.23, logrank P=0.14) were not different between the groups. The majority of infections were due to gram-positive bacteria (73%), most commonly methicillin susceptible S. aureus (36%). Time to Mortality Time to First Infection Composite Outcome (Time to First Infection or Death) Conclusion This study supports the use of narrow spectrum antimicrobial prophylaxis in LVAD implantation. These results highlight an opportunity to improve antibiotic use in LVAD implantation. Disclosures All Authors: No reported disclosures

Numerous risk factors have been linked to invasive candidiasis; however, they are nonspecific and often trigger empiric antifungal therapy in a large number of patients. Identification of more precise predictors could promote judicious use of empiric echinocandins. In this retrospective review, 127 patients with blood cultures positive for Candida spp. were compared to a randomly selected cohort of 134 patients on empiric micafungin for ≥3 days and with blood cultures negative for Candida spp. Factors associated with candidemia included total parenteral nutrition (TPN; 26.0% vs 15.7%, P = 0.040), multifocal Candida colonization (23.6% vs 3.0%, P < 0.001), and positive 1,3-β-d-glucan assay (95.0% vs 35.0%, P < 0.001). Patients without candidemia on empiric micafungin were more likely to receive antibiotic therapy in the previous 10 days (55.9% vs 79.9%, P < 0.001) and to be taking immunosuppressive medications (11.0% vs 30.6%, P < 0.001). Receipt of TPN (odds ratio [OR] = 2.07, 95% confidence interval [CI], 1.02–4.21), severe sepsis (OR = 2.20, 95% CI, 1.00–4.83), and multifocal Candida colonization (OR = 13.87, 95% CI, 4.43–43.37) were independently associated with candidemia in the multivariable logistic regression model. Therefore, the absence of these risk factors, especially in conjunction with a negative 1,3-β-d-glucan assay, may be used to recommend de-escalation of empiric micafungin therapy.

Background Rapid diagnostic testing can identify bacterial pathogens and genetic markers of resistance. This information can aid in deescalating antimicrobial therapy based on local patterns prior to the return of final culture and susceptibility reports. In August of 2017 at our institution, pharmacists were incorporated in the review of these rapid diagnostic tests in real time with recommendations for changes to therapy paged to providers. The purpose of this study was to determine whether the inclusion of a pharmacist in this workflow reduces time to change in antimicrobial therapy. Methods This retrospective study over two periods in 2016 and 2018 analyzed the pre- and post-implementation of a workflow incorporating pharmacist review of positive blood cultures analyzed by rapid molecular assay. Patients were included if they were at least 18 years of age and were initiated on empiric antibiotics prior to test results. Patients were excluded if transitioned to hospice within 24 hours of test results, discharged prior to test results, if more than one infectious process or organism was identified, or if test results were positive for coagulase-negative staphylococci. The primary outcome of the study was the time to change to targeted antimicrobials. Secondary outcomes were rates of Clostridium difficile infection within 3 months and inpatient mortality. Categorical variables were evaluated using chi-squared or Fisher exact tests, and continuous variables were evaluated using Wilcoxon rank-sum tests. Results A total of 199 patients were included, with 98 and 101 patients in the pre- and post-implementation groups, respectively. The median time to change to targeted antimicrobials was significantly reduced with pharmacist intervention from 18.35 to 8.43 hours (P = 0.042). The groups had similar rates of C. difficile infection (1% vs. 0%, P = 0.492) and mortality (7.1% vs. 5%, P = 0.564). The post-group also had significant reductions in antibiotic days of therapy (10.5 vs. 9 days, P = 0.014) and intensive-care unit length of stay (3.04 vs. 1.44 days, P = 0.046). Conclusion Incorporating pharmacist review of rapid molecular results of blood cultures decreased time to change in antimicrobial regimen and reduced antibiotic days of therapy. Disclosures All authors: No reported disclosures.

Tularemia is a zoonotic disease caused by Francisella tularensis that can be transmitted to humans when they handle rabbits, receive tick bites, consume contaminated water, or inhale aerosolized particles. We present the case of a 51-year-old white man with rheumatoid arthritis who was taking immunosuppressive medications and presented with tularemia. Our patient acquired the typhoidal form of tularemia, which is a severe systemic illness that manifests with fevers, headaches, myalgias, vomiting, diarrhea, and neurological symptoms, due to his immunocompromised state. The diagnosis was made through biopsy of a pulmonary nodule found incidentally on computed tomography scan.

Background Infections due to extended spectrum β-lactamase (ESBL) producing bacteria are problematic due to the association with worse outcomes and limited treatment options. Carbapenems (CBPs) remain the drugs of choice for these infections due to evidence of a mortality benefit and the mixed clinical efficacy associated with piperacillin/tazobactam (PTZ) despite often reported in vitro activity. While definitive treatment for these infections has been well-defined, evidence for appropriate empiric therapy remains inconclusive. Rapid molecular assays capable of identifying ESBL markers may aid in switching to appropriate definitive therapy sooner and spare empiric carbapenem use. Methods This multicenter retrospective study at 9 sites at Baylor Scott & White Health included patients with a positive blood culture with ESBL-producing bacteria identified by rapid molecular assay from January 1, 2014 to September 22, 2017 and were empirically prescribed either PTZ or a CBP. Patients were excluded if they continued PTZ for more than 24H after identification or did not receive a CBP for definitive therapy. Categorical data were analyzed using the Fisher’s exact test and continuous data were evaluated using the t-test and Wilcoxon rank-sum test. Results 117 patients met inclusion criteria of which 66 and 51 received empiric PTZ or CBPs, respectively. Baseline characteristics were similar between the groups, including suspected source of bacteremia, prior hospital stay, prior antibiotic therapy, history of positive non-blood ESBL culture, ICU admission, and time to ESBL identification. There was no difference in hospital mortality (3 vs. 7.8%, P = 0.4), hospital length of stay (6.1 vs. 5.9%, P = 0.88), ICU length of stay (4.7 vs. 3.3%, P = 0.39) or recurrent ESBL bacteremia (7.6 vs. 7.8%, P = 0.99) between those that received PTZ or a CBP for initial treatment, respectively. Conclusion This study in patients with ESBL bacteremia showed similar outcomes when treated empirically with PTZ or a CBP. In the era of rapid molecular assays, these results suggest that empiric PTZ use and avoidance of empiric CBP therapy in the first 24H of infection can be considered until a microbiological diagnosis is confirmed. Disclosures All authors: No reported disclosures.

Background Ibalizumab (IBA), a humanized monoclonal antibody, is the first CD4-directed post-attachment HIV-1 inhibitor. It was approved by the FDA in March 2018 based on results from the pivotal Phase 3 TMB-301 clinical study. The TMB-311 expanded access protocol Cohort 2 enrolled treatment-experienced patients with multidrug-resistant (MDR) HIV-1 infection to further evaluate the efficacy, safety and tolerability of IBA in combination with an optimized background regimen (OBR). Here, we report the results through 48 weeks of treatment in these patients. Methods Major eligibility criteria included HIV-1 viral load (VL) >1000 copies/mL, resistance to ≥1 antiretroviral (ARV) medication from three different ARV classes and full viral sensitivity to ≥1 ARV agent. Treatment started with IBA 2000 mg intravenously (IV) on Day 0 and then 800 mg IV (maintenance) every 2 weeks thereafter. OBR with ≥1 fully active agent also started at Day 0. Results Cohort 2 enrolled 38 patients with a median age of 53 years, mostly male (87%) and white (53%). At Baseline, median VL was 4.7 log10 copies/mL, CD4 cell count was 26 cells/mm3 and overall susceptibility score of 1. A ≥0.5 log10 decrease in VL from Baseline was achieved in 28 of 37 patients (76%) at Day 7. Of 24 patients who completed the Week 24 visit, 11 (46%) had HIV-1 RNA levels Conclusion Results from Cohort 2 patients of TMB-311 (IBA + OBR) demonstrate durable viral suppression in this difficult-to-treat patient population and with a safety profile consistent with pivotal Phase 3 study of IBA. Disclosures All authors: No reported disclosures.

Background Surgical site infections in neurosurgery occur in up to 10% of procedures. The American Society of Health-System Pharmacists guidelines promote antimicrobial prophylaxis (AP) for up to 24 hours from neurosurgery using cefazolin while the Neurocritical Care Society guidelines promote single pre-procedural dose of AP for extraventricular drain (EVD) monitoring. Despite these guidelines, practice variation exists with often longer antimicrobial exposure and subsequent complications. Methods This retrospective study included patients admitted to Baylor University Medical Center from January 1, 2014 to September 20, 2017 and underwent cranial or spinal neurosurgery requiring AP. This study excluded patients with basilar skull fracture, presence of cerebrospinal fluid leak, penetrating trauma, meningitis, and patients receiving antibiotics for documented or suspected infection unrelated to neurosurgery. Patients who received AP for up to 24H (short course) were compared with patients who received AP for greater than 24H (long course) at 90 days. Data were analyzed using the Fisher exact test, Student’s t-test and Wilcoxon rank-sum tests as applicable. Results A total of 183 patients were included with 90 and 93 patients receiving short or long courses of AP, respectively. Baseline characteristics were similar for the groups. Patients in the short course AP group received a mean antibiotic duration of 16.9 ± 4.3H while those in the long course AP group received 72.2 ± 50.9H (P < 0.001). The mean number of antimicrobials prescribed was 1.1 vs. 1.8 (P < 0.001) in the short vs. long groups, respectively. At 90 days, there were no significant differences in the rate of surgical site infections (1.1% vs. 2.1%, P = 0.99), development of multi-drug-resistant infections (2.2% vs. 2.2%, P = 0.99), and Clostridium difficile infection (0% vs. 1.1%, P = 0.99) in the short vs. long groups, respectively. Conclusion The rate of surgical site infections was not significantly different in patients that received short vs. long durations of antimicrobial prophylaxis. These results highlight an opportunity to improve antibiotic use and promote principles of antimicrobial stewardship in neurosurgery. Disclosures All authors: No reported disclosures.

Infection control process measures provide actionable and measurable indicators for performance improvement.To determine the relationship between the measurement and feedback of selected infection control process measures and compliance with infection control practices.We measured selected infection control process measures (hand hygiene, femoral catheter use as a proportion of all central venous catheter (CVC) days and proportion of head of bed elevations) in the medical respiratory intensive care unit (ICU) (MRICU) and the surgical trauma ICU (STICU). All data were collected by trained infection control practitioners. Baseline data were obtained April through June 2004. Baseline hand hygiene data were obtained from May to June. Follow-up observations were obtained from July 2004 through March 2005. Both baseline and follow-up observations were reported to the units' leadership. The data were reviewed for improvement in compliance with process measures. Differences in proportions were analyzed for statistical significance by the chi(2) test.There was a statistically significant improvement in the head of bed elevation rates: 54.9% versus 98.4% (P.001) for the MRICU and 46.5% versus 77.2% (P.001) for the STICU, respectively. There was also a statistically significant decline in femoral catheter rates in both ICUs: 17.8% versus 10% (P = .001) in the MRICU and 8.4% versus 3% (P.001) in the STICU, respectively. There was no significant improvement in hand hygiene rates in either ICU: 31.8% versus 39.3% (P = .1) in the MRICU and 50% versus 50.3% (P = .9) in the STICU, respectively.Feedback of process measures lowered the use of femoral catheters and improved the proportion of elevated head of beds in 2 ICUs, but there was no significant improvement in hand hygiene.

The impact of nosocomial infections, including associated mortality, morbidity, and attributable cost is well documented. Infection control practices, such as handwashing and use of gloves and gowns, have proven to be effective. Because many nosocomial infections result from cross transmission, primarily via the hands of health care workers (HCWs), handwashing remains the single most important means to prevent the transmission of nosocomial pathogens. Although most HCWs are aware of the rationale for infection control practices, compliance is generally poor. HCWs have cited various reasons for noncompliance, including insufficient time, inaccessible supplies, and lack of knowledge. Little is known about the factors that motivate HCWs to comply with infection control practices. The purpose of this study was 3-fold. First, it was to assess HCWs’ perceptions of adherence to infection control practices including isolation guidelines and hand hygiene using an antiseptic soap or an alcoholbased hand sanitizer product. Additionally, we sought to measure motivational factors for compliance. Last, we sought to assess beliefs regarding the etiology and prevention of nosocomial infections.

Purpose: Gastrointestinal bleeding is an important complication of hospitalization with a significant morbidity and mortality. Stress ulcer prophylaxis has been used for this reason. Coagulopathy and mechanical ventilation for more than 48 hours have been identified as risk factors for clinically significant bleeding from stress ulcers. Significant bleeding in the absence of these risk factors is rare. Stress ulcer prophylaxis tends to be overused, particularly in low risk patients who may not benefit from prophylaxis. We conducted a retrospective study to assess whether stress ulcer prophylaxis is appropriately initiated in a community teaching hospital setting.