Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial

IMPORTANCE Preventive interventions are needed to protect residents and staff of skilled nursing and assisted living facilities from COVID-19 during outbreaks in their facilities. Bamlanivimab, a neutralizing monoclonal antibody against SARS-CoV-2, may confer rapid protection from SARS-CoV-2 infection and COVID-19. OBJECTIVE To determine the effect of bamlanivimab on the incidence of COVID-19 among residents and staff of skilled nursing and assisted living facilities. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, single-dose, phase 3 trial that enrolled residents and staff of 74 skilled nursing and assisted living facilities in the United States with at least 1 confirmed SARS-CoV-2 index case. A total of 1175 participants enrolled in the study from August 2 to November 20, 2020. Database lock was triggered on January 13, 2021, when all participants reached study day 57. INTERVENTIONS Participants were randomized to receive a single intravenous infusion of bamlanivimab, 4200mg (n = 588), or placebo (n = 587). MAIN OUTCOMES AND MEASURES The primary outcomewas incidence of COVID-19, defined as the detection of SARS-CoV-2 by reverse transcriptase–polymerase chain reaction and mild or worse disease severity within 21 days of detection, within 8 weeks of randomization. Key secondary outcomes included incidence of moderate or worse COVID-19 severity and incidence of SARS-CoV-2 infection. RESULTS The prevention population comprised a total of 966 participants (666 staff and 300 residents) who were negative at baseline for SARS-CoV-2 infection and serology (mean age, 53.0 [range, 18-104] years; 722 [74.7%] women). Bamlanivimab significantly reduced the incidence of COVID-19 in the prevention population compared with placebo (8.5%vs 15.2%; odds ratio, 0.43 [95%CI, 0.28-0.68]; P < .001; absolute risk difference, −6.6 [95%CI, −10.7 to −2.6] percentage points). Five deaths attributed to COVID-19 were reported by day 57; all occurred in the placebo group. Among 1175 participants who received study product (safety population), the rate of participants with adverse events was 20.1% in the bamlanivimab group and 18.9% in the placebo group. The most common adverse events were urinary tract infection (reported by 12 participants [2%] who received bamlanivimab and 14 [2.4%] who received placebo) and hypertension (reported by 7 participants [1.2%] who received bamlanivimab and 10 [1.7%] who received placebo). CONCLUSIONS AND RELEVANCE Among residents and staff in skilled nursing and assisted living facilities, treatment during August-November 2020 with bamlanivimab monotherapy reduced the incidence of COVID-19 infection. Further research is needed to assess preventive efficacy with current patterns of viral strains with combination monoclonal antibody therapy

Optical imaging of the peri-tumoral inflammatory response in breast cancer

<p>Abstract</p> <p>Purpose</p> <p>Peri-tumoral inflammation is a common tumor response that plays a central role in tumor invasion and metastasis, and inflammatory cell recruitment is essential to this process. The purpose of this study was to determine whether injected fluorescently-labeled monocytes accumulate within murine breast tumors and are visible with optical imaging.</p> <p>Materials and methods</p> <p>Murine monocytes were labeled with the fluorescent dye DiD and subsequently injected intravenously into 6 transgenic MMTV-PymT tumor-bearing mice and 6 FVB/n control mice without tumors. Optical imaging (OI) was performed before and after cell injection. Ratios of post-injection to pre-injection fluorescent signal intensity of the tumors (MMTV-PymT mice) and mammary tissue (FVB/n controls) were calculated and statistically compared.</p> <p>Results</p> <p>MMTV-PymT breast tumors had an average post/pre signal intensity ratio of 1.8+/- 0.2 (range 1.1-2.7). Control mammary tissue had an average post/pre signal intensity ratio of 1.1 +/- 0.1 (range, 0.4 to 1.4). The p-value for the difference between the ratios was less than 0.05. Confocal fluorescence microscopy confirmed the presence of DiD-labeled cells within the breast tumors.</p> <p>Conclusion</p> <p>Murine monocytes accumulate at the site of breast cancer development in this transgenic model, providing evidence that peri-tumoral inflammatory cell recruitment can be evaluated non-invasively using optical imaging.</p

Impact of the HIV-1 env Genetic Context outside HR1–HR2 on Resistance to the Fusion Inhibitor Enfuvirtide and Viral Infectivity in Clinical Isolates

Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drug's target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1–HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1–HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1–HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1–HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy

Community based distribution of oral HIV self-testing kits in Zambia: a cluster-randomised trial nested in four HPTN 071 (PopART) intervention communities

Background The HPTN 071 (PopART) cluster-randomised trial provided door-to-door HIV testing services to a large proportion of individuals residing in 21 intervention communities in Zambia and South Africa from 2014 to 2017 and reached the UNAIDS first 90 target among women in Zambia, yet gaps remained among men and young adults. This cluster-randomised study nested in the HPTN 071 (PopART) trial sought to increase knowledge of HIV status across all groups by offering the choice of oral HIV self-testing in addition to routine door-to-door HIV testing services. Methods We nested this cluster-randomised trial in four HTPN 071 (PopART) intervention communities in northern Zambia. 66 zones (clusters) in these communities were randomly allocated (1:1) to either oral HIV self-testing plus routine door-to-door HIV testing services (HIV self-testing group) or the PopART standard of care of door-to-door HIV testing services alone (non- HIV self-testing group) over a 3-month period. All individuals aged 16 years or older were eligible for HIV testing. Randomisation was achieved by randomly selecting one allocation from a list of 10 000 possible allocations during a public ceremony. In HIV self-testing zones, trained lay-counsellors (known as community HIV care providers) visited households and offered eligible individuals the choice of HIV testing using HIV self-testing or routine door-to-door HIV testing services. For individuals aged 18 years or older whose partner was absent during the household visit, an HIV self-test kit could be left for secondary distribution to the absent partner. The primary outcome was knowledge of HIV status (defined as self-reporting HIV positive to the community HIV care providers or accepting an offer of HIV testing services). Outcomes were measured among households that were first visited, and individuals first enumerated as a household member during the HIV self-testing intervention period. We analysed data at the individual level using population-average logistic regression models, accounting for clustering of outcomes by zone, to estimate the effect of the intervention. This trial is registered with ClinicalTrials.gov, number NCT02994329. Findings Between Feb 1, and April 30, 2017, the community HIV care providers enumerated 13 267 eligible individuals in the HIV self-testing group and 13 706 in the non-HIV self-testing group. After intervention implementation, 9027 (68%) of 13 267 in the HIV self-testing group had knowledge of HIV status compared with 8952 (65%) of 13 706 in the non-HIV self-testing group (adjusted odds ratio 1·30, 95% CI 1·03–1·65; p=0·03). The effect differed by sex (pinteraction=0·01). Among men, knowledge of HIV status was higher in the HIV self-testing group than in the non-HIV self-testing group (3843 [60%] of 6368 vs 3571 [55%] of 6486; adjusted odds ratio 1·31, 95% CI 1·07–1·60; p=0·01). There was no evidence of a between-group difference among female participants. Interpretation Providing a choice of HIV self-testing during delivery of door-to-door HIV testing services increased knowledge of HIV status, driven by an effect among men. Lay counsellors have a vital role to play in adapting HIV self-testing interventions to local context

Projected outcomes of universal testing and treatment in a generalised HIV epidemic in Zambia and South Africa (the HPTN 071 [PopART] trial): a modelling study

Background The long-term impact of universal home-based testing and treatment as part of universal testing and treatment (UTT) on HIV incidence is unknown. We made projections using a detailed individual-based model of the effect of the intervention delivered in the HPTN 071 (PopART) cluster-randomised trial. Methods In this modelling study, we fitted an individual-based model to the HIV epidemic and HIV care cascade in 21 high prevalence communities in Zambia and South Africa that were part of the PopART cluster-randomised trial (intervention period Nov 1, 2013, to Dec 31, 2017). The model represents coverage of home-based testing and counselling by age and sex, delivered as part of the trial, antiretroviral therapy (ART) uptake, and any changes in national guidelines on ART eligibility. In PopART, communities were randomly assigned to one of three arms: arm A received the full PopART intervention for all individuals who tested positive for HIV, arm B received the intervention with ART provided in accordance with national guidelines, and arm C received standard of care. We fitted the model to trial data twice using Approximate Bayesian Computation, once before data unblinding and then again after data unblinding. We compared projections of intervention impact with observed effects, and for four different scenarios of UTT up to Jan 1, 2030 in the study communities. Findings Compared with standard of care, a 51% (95% credible interval 40–60) reduction in HIV incidence is projected if the trial intervention (arms A and B combined) is continued from 2020 to 2030, over and above a declining trend in HIV incidence under standard of care. Interpretation A widespread and continued commitment to UTT via home-based testing and counselling can have a substantial effect on HIV incidence in high prevalence communities. Funding National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial

Background: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. Methods: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18–45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. Findings: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22–30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73–1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06–0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3–2·57]; hazard ratio 0·12 [0·05–0·31]; p<0·0001; risk difference –1·6% [–1·0% to –2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9–1·7); no congenital birth anomalies were reported. Interpretation: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. Funding: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support