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Background We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1–2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. Methods This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18–59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. Findings Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744–2746) for the low-dose group, 2269 (1792–2873) for the medium-dose group, and 2895 (2294–3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85–135) in the low-dose group, 110 (87–140) in the medium-dose group, and 141 (111–179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836–11 815) in the low-dose group, 2338 (593–9226) in the medium-dose group, and 7069 (1361–36 725) in the high-dose group. Interpretation Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. Funding Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Background Sotrovimab, a monoclonal antibody with efficacy against SARS-CoV-2 including certain Omicron variants, has been used in treatment of mild-moderate COVID-19. Limited data exists regarding its use in pregnant women. Methods Electronic medical record review of pregnant COVID-19 patients treated with sotrovimab from 12/30/21-1/31/22 (Yale New Haven Health Hospital System [YNHHS]) was performed. Included were pregnant individuals ≥ 12 years, weighing ≥ 40 kg, with positive SARS-CoV-2 test (within 10 days). Those receiving care outside YNHHS or receiving other SARS-CoV-2 treatment were excluded. We assessed demographics, medical history, and Monoclonal Antibody Screening Score (MASS). Clinical outcomes assessed included emergency department (ED) visit < 24 hours, hospitalization, ICU admission, and/or death within 29 days of sotrovimab. Pregnancy and neonatal outcomes were assessed until 8/15/22. Results Among 22 subjects, median age was 32 years and body mass index was 27 kg/m2. Sixty-three percent were Caucasian, 9% Hispanic, 14% African-American, and 9% Asian. Nine percent had diabetes and sickle cell disease. Five percent had well-controlled HIV. Eighteen percent, 46%, and 36% received sotrovimab in trimester 1, 2, and 3, respectively. No infusion/allergic reactions occurred. MASS values were < 4. Only 12/22 (55%) received complete primary vaccination (46% mRNA-1273; 46% BNT162b2; 8% JNJ-78436735); none received a booster. There were no ICU admissions nor deaths. One subject was hospitalized for post-partum pyelonephritis; another had an ED visit for post-partum vaginal bleeding. Median gestational age at birth was 38.9 weeks. Nine percent had premature labor and premature rupture of membranes, respectively. Median infant birth weight was 3220 g. One neonate required an ICU stay due to prenatally diagnosed omphalocele (before sotrovimab) in a mother with congenital defect history. There were no abortions, fetal loss, or other birth/neurodevelopmental defects. Conclusion Pregnant COVID-19 patients receiving sotrovimab at our center tolerated it well with good clinical outcomes. Pregnancy and neonatal complications did not appear sotrovimab-related. Though a limited sample, our data helps elucidate the safety and tolerability of sotrovimab in pregnant women. Disclosures All Authors: No reported disclosures.

Background Lenacapavir (LEN), a potent first-in-class inhibitor of HIV-1 capsid function, is in development as a long-acting agent for treatment and prevention of HIV-1. Methods CAPELLA is an ongoing, phase 2/3 study in heavily treatment-experienced (HTE) people with HIV-1 (PWH) with multidrug-resistance. 36 participants were randomized (2:1) to add oral LEN or placebo to their failing regimen. At D15, those on oral LEN received subcutaneous (SC) LEN 927 mg (Q6M); those on placebo started the oral LEN lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, optimized background regimen (OBR) at D15. An additional 36 participants started OBR concurrent with LEN (oral lead-in → SC) in a non-randomized cohort. We report the Week (W) 52 efficacy and safety results from both cohorts. Results Of 72 participants enrolled, 25% were female, 38% Black, median age 52 years, 64% had CD4 < 200 cells/µL, 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI), and 53% had OBR with 1 or no fully active agents. At W52, 78% (56/72) achieved VL< 50 c/mL and 82% (59/72) achieved VL< 200 c/mL via FDA Snapshot algorithm. CD4 count increased by a median 84 cells/µL (Q1 to Q3: 21 to 153) and the proportion of participants with CD4 count ≥200 cells/ul increased from 36% at baseline to 68% at W52. Ten participants had emergent LEN resistance (8 previously reported); 4 of 10 subsequently suppressed. The median (range) duration of follow up on LEN was 71 (13–111) weeks. One participant discontinued due to injection site nodule (Grade 1). The most common injection site reaction (ISR) was swelling (28% [20/72] and 17% [12/70] after the 1st and 2nd SC doses, respectively). Most ISRs were mild or moderate. The most common AEs (excluding injection site reactions) were nausea and diarrhea (14% each). Conclusion In HTE PWH, subcutaneous LEN was well tolerated and in combination with OBR led to high and sustained rate of virologic suppression at W52. These results support the potential role for LEN for treatment of multi-drug resistant HIV-1 infection. Disclosures Sorana Segal-Maurer, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|JANSSEN THERAPEUTICS: Honoraria|ViiV: Honoraria Benoit Trottier, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Jason Brunetta, M.D., Gilead Canada: Advisor/Consultant|Gilead Canada: Honoraria|Gilead Canada: Conference Attendance Sponsorship|Viiv Canada: Advisor/Consultant Hui Wang, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Nicolas A. Margot, MA, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Hadas Dvory-Sobol, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Martin S Rhee, MD, Gilead Sciences: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Jean-Michel Molina, MD; PhD, GIlead: Board Member|GIlead: Grant/Research Support|Merck: Board Member|Merck: Expert Testimony|ViiV: Board Member.

Objectives Effective and safe COVID‐19 vaccines have been developed and have resulted in decreased incidence and severity of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and can decrease secondary transmission. However, there are concerns about dampened immune responses to COVID‐19 vaccination among immunocompromised patients, including people living with HIV (PLWH), which may blunt the vaccine's efficacy and durability of protection. This study aimed to assess the qualitative SARS‐CoV‐2 vaccine immunogenicity among PLWH after vaccination. Methods We conducted targeted COVID‐19 vaccination (all received BNT162b2 vaccine) of PLWH (aged ≥ 55 years per state guidelines) at Yale New Haven Health System and established a longitudinal survey to assess their qualitative antibody responses at 3 weeks after the first vaccination (and prior to receipt of the second dose of the COVID‐19 vaccine) (visit 1) and at 2–3 weeks after the second vaccination (visit 2) but excluded patients with prior COVID‐19 infection. Our goal was to assess vaccine‐induced immunity in the population we studied. Qualitative immunogenicity testing was performed using Healgen COVID‐19 anti‐Spike IgG/IgM rapid testing. Poisson regression with robust standard errors was used to determine factors associated with a positive IgG response. Results At visit 1, 45 of 78 subjects (57.7%) tested positive for SARS‐CoV‐2 anti‐Spike IgG after the first dose of COVID‐19 vaccine. Thirty‐nine subjects returned for visit 2. Of these, 38 had positive IgG (97.5%), including 20 of 21 subjects (95.2%) with an initial negative anti‐Spike IgG. Our bivariate analysis suggested that participants on an antiretroviral regimen containing integrase strand transfer inhibitors [relative risk (RR) = 1.81, 95% confidence interval (CI): 0.92–3.56, p = 0.085] were more likely to seroconvert after the first dose of the COVID‐19 vaccine, while those with a CD4 count

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

Background: Human Immunodeficiency Virus (HIV) infection continues to have a profound humanitarian and public health impact in western and central Africa, a region that risks being left behind in the global response to ending the AIDS epidemic. In Liberia, where the health system is being rebuilt following protracted civil wars and an Ebola virus disease outbreak, the Resilient and Responsive Health System (RRHS) is assisting with quality HIV services delivery through support from PEPFAR and HRSA but gaps remain across the cascade of care from diagnosis to viral load suppression. Objective: To highlight gaps in HIV service delivery in Liberia, identify opportunities and offer recommendations for improving the quality of service delivery. Methods: A narrative review of relevant literature was conducted following a search of all local and online databases known to the authors. Findings: Antiretroviral therapy (ART) has transformed the HIV response in Liberia by averting deaths, improving quality of life, and preventing new HIV infections but critical gaps remain. These include weak HIV prevention and testing strategies; suboptimal ART initiation and retention in care; low viral load testing volumes, commodity supply chain disruptions and a HIV workforce built on non-physician healthcare workers. In the context of the prevailing socioeconomic, heath system and programmatic challenges, these will impact achievement of the UNAIDS targets of 95-95-95 by 2030 and ending the epidemic. Conclusion: Combination prevention approaches are necessary to reach the most at risk populations, while a robust health workforce operating through facilities and communities will be needed to reach people with undiagnosed HIV earlier to provide efficient and effective services to ensure that people know their HIV status, receive and sustain ART to achieve viral suppression to maintain a long and healthy life within the framework of overall health system strengthening, achieving universal health coverage and the sustainable development goal.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ∼6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

SummaryBackgroundThis study evaluated the safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein candidate vaccine, CoV2 preS dTM.MethodsThis Phase 2, modified double-blind, parallel-group study (NCT04762680) was conducted in adults, including those at increased risk of severe COVID-19. Participants were randomised 1:1:1, stratified by age (18–59/≥60 years), rapid serodiagnostic test (positive/negative) and high-risk medical conditions (yes/no), to receive two injections (day [D]1 and D22) of 5μg, 10μg or 15μg of CoV2 preS dTM antigen with fixed AS03 content. Interim safety and reactogenicity results (to D43) and neutralising antibodies (NAbs) against the D614G variant are presented (primary objectives).FindingsOf 722 participants enrolled and randomised between 24 February and 8 March 2021, 721 received ≥1 injections (5μg, n=240; 10μg, n=239; 15μg, n=242). Four participants reported unsolicited immediate adverse events (AEs), two were vaccine-related (investigator assessment). Five participants reported seven vaccine-related medically-attended AEs. No vaccine-related serious AEs and no AEs of special interest were reported. Solicited reactions (local and systemic) were reported at similar frequencies between study groups; these were mostly mild to moderate and transient, with higher frequency and intensity post-injection 2 than post-injection 1. In SARS-CoV-2 naïve participants at D36, 96·9%, 97.0% and 97·6% of participants had ≥4-fold-rise in NAb titres from baseline in the 5μg-, 10μg- and 15μg-dose groups, respectively. NAb titres increased with antigen dose in younger (GMTs: 2954, 3951 and 5142 for 5μg-, 10μg- and 15μg-dose groups) but not older adults (GMTs: 1628, 1393 and 1736, respectively). NAb titres in non-naïve adults after one injection were higher than titres after two injections in naïve adults.InterpretationTwo injections of CoV2 preS dTM-AS03 demonstrated acceptable safety and reactogenicity, and robust immunogenicity in SARS-CoV-2 naïve and non-naïve adults. These results informed antigen dose selection for progression to Phase 3 evaluation of primary and booster vaccination.

The 5-year Resilient and Responsive Health Systems (RRHS)-Liberia Initiative, funded by PEPFAR via HRSA, launched in 2017 and was designed to support the implementation of Liberia's National Health Workforce Program as a means to improving HIV-related health outcomes. The COVID-19 pandemic, arrived in Liberia just five years after Ebola and during RRHS-Liberia's fourth year, impacted educational programs and threatened the project's continued work. This paper presents the challenges that the COVID-19 pandemic posed to the RRHS partners, as well as adaptations they made to maintain progress towards project goals: 1) contributing to Liberia's 95-95-95 HIV targets via direct service delivery, and 2) building a resilient and responsive health workforce in Liberia via instruction and training. Direct health service impacts included decreased patient volumes and understaffing; adaptations included development of and trainings on safety protocols, provision of telehealth services, and community health worker involvement. Instruction and training impacts included suspension of in-person teaching and learning; adaptations included utilization of multiple online learning and virtual conferencing tools, and increasing clinical didactics in lieu of bedside mentorship. The RRHS team recommends that these adaptations be continued with significant investment in technology, IT support, and training, as well as close coordination among partner institutions. Ultimately, the RRHS Liberia consortium and its partners made significant strides in response to ensuring ongoing education during the pandemic, an experience that will inform continued service delivery, teaching, and learning in Liberia.

The incidence of syphilis has increasing recently, largely attributable to improved screening that may result in the diagnosis of chronic untreated infections. These patients can develop severe or subtle neurologic symptoms that can be missed and, therefore, detected accidentally while a patient is evaluated for other mimicking neurological infections. A 58-year-old man with diabetes presented with 2 days of aphasia, headache, chills and confusion. He had an MRI brain with evidence of a prior cerebrovascular accident. Subsequently, he developed a fever and thoracic dermatomal rash consistent with herpes zoster. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed a lymphocytic pleocytosis, a reactive Venereal Disease Research Laboratory test and positive varicella-zoster virus (VZV) PCR. He was suspected to have both late neurosyphilis and acute meningoencephalitis from VZV. This paper will discuss how to approach the diagnosis of late neurosyphilis and possible associations with herpesvirus central nervous system infections.

There have been remarkable advances in drug development for the treatment of HIV-1 infection. From the co-formulation of combination antiretroviral therapy (cART) into single-tablet regimens to the development of long-acting antiretroviral (ARV) drug formulations, the treatment of HIV has and will become much more tolerable and less complicated for patients. In addition, and appropriately, there is a focus on reducing short- and long-term toxicities of treatment while maintaining robust efficacy. One of such approaches includes 2-drug regimen constructs that contain and retain effective ARV compounds while excluding components that have relatively unfavorable toxicity profiles. The first-ever 2-drug regimen approved for the treatment of HIV-1 infection for treatment-naive people living with HIV (PLWH), consisting of the integrase inhibitor dolutegravir (DTG) and the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (3TC), is reviewed in this paper. The chemical composition and properties, pharmacokinetic and pharmacodynamics profile, and clinical trial data on efficacy and safety of DTG/3TC are presented. An expert opinion aims to highlight important considerations for the use of DTG/3TC in the context of existing and emerging ARV options.

We present a case of a patient who had a history of severe coronavirus disease (COVID-19) 4 months prior to this current presentation and, after a long asymptomatic period, subsequently tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) by a RNA PCR assay, after several interval negative SARS-CoV-2 RNA tests. We present this potential case of SARS-CoV-2 reinfection in order to incite discussion around differentiating persistent infection with intermittent viral shedding and reinfection, as well as to discuss evolving knowledge and approaches to the clinical management, follow-up molecular testing and treatment of COVID-19 reinfection.

As the Coronavirus-2019 (COVID-19) pandemic continues, multiple therapies are rapidly being tested for efficacy in clinical trials. Clinical trials should be racially and ethnically representative of the population that will eventually benefit from these medications. There are multiple potential barriers to racial and ethnic minority enrollment in clinical trials, one of which could be that inclusion and exclusion criteria select for certain racial or ethnic groups disproportionately. In this observational cohort study at a single health care system, we examined if there were differences in eligibility for treatment with remdesivir based on clinical trial criteria for racial and ethnic minorities compared to non-Hispanic Whites. 201 electronic medical record charts were reviewed manually. Self-identified Whites were older than other racial or ethnic groups. At the time of presentation, Black, Latinx, and White participants met inclusion criteria for remdesivir at similar rates (72%, 80%, and 73% respectively), exclusion criteria at similar rates (43%, 38% and 49% for Black, Latinx and White participants respectively). In this study, there was no difference in eligibility for remdesivir based on race or ethnicity alone.

Background: In DISCOVER, a multinational randomized controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate demonstrated noninferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. Here, we report outcomes analysed after all participants had completed 96 weeks of follow up. Methods: Adult cisgender men and transgender women who have sex with men with a high risk of acquiring HIV were randomly assigned (1:1) to either of two study arms. This trial is registered with ClinicalTrials.gov, NCT02842086. Findings: 5,387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2,694) or emtricitabine and tenofovir disoproxil fumarate (n=2,693), contributing 10,081 person-years (PY) of follow-up. There were eight HIV infections in emtricitabine and tenofovir alafenamide users (0·16 infections/100 PY [95% CI 0·07–0·31]), and 15 in emtricitabine and tenofovir disoproxil fumarate users (0·30 infections/100 PY [0·17–0·49]). Emtricitabine and tenofovir alafenamide was noninferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the infection rate ratio (IRR) was less than the prespecified noninferiority margin of 1·62 (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78% to 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 arms (21 per 100 PYs for rectal gonorrhea and 28 per 100 PY for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to demonstrate superiority over emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarkers. There was more weight gain among emtricitabine and tenofovir alafenamide users (median weight gain 1·7 kg vs. 0·5 kg, p

Respiratory viruses can be transmitted through contact, droplet and airborne routes. Viruses that are not naturally airborne may be aerosolised during medical procedures and transmitted to healthcare workers. Most resource-limited healthcare settings lack complex air handling systems to filter air and create pressure gradients that are necessary for minimising viral transmission. This review explores the association between ventilation and the transmission of respiratory viruses like SAR-CoV-2. When used appropriately, both natural and mechanical ventilation can decrease the concentration of viral aerosols, thereby reducing transmission. Although mechanical ventilation systems are more efficient, installation and maintenance costs limit their use in resource-limited settings, whereas the prevailing climate conditions make natural ventilation less desirable. Cost-effective hybrid systems of natural and mechanical ventilation may overcome these limitations.

Highlights • PrEP implementation in primary care has been slow. • Primary care providers equally favor training all vs. having a PrEP specialist. • Efforts to promote knowledge of clinical guidelines may enhance PrEP implementation., Primary care physicians (PCPs) are critical for promoting HIV prevention by prescribing pre-exposure prophylaxis (PrEP). Yet, there are limited data regarding PCP’s preferred approaches for PrEP implementation. In 2015, we conducted an online survey of PCPs’ PrEP prescribing and implementation. Participants were general internists recruited from a national professional organization. We examined provider and practice characteristics and perceived implementation barriers and facilitators associated with preferred models for PrEP implementation. Among 240 participants, the majority (85%) favored integrating PrEP into primary care, either by training all providers (“all trained”) (42%) or having an onsite PrEP specialist (“on-site specialist”) (43%). Only 15% preferred referring patients out of the practice to a specialist (“refer out”). Compared to those who preferred to “refer out,” participants who preferred the “all trained” model were more likely to spend most of their time delivering direct patient care and to practice in the Northeast. Compared to participants who preferred the “refer out” or on-site specialist” models, PCPs preferring the all trained model were less likely to perceive lack of clinic PrEP guidelines/protocols as a barrier to PrEP. Most PCPs favored integrating PrEP into primary care by either training all providers or having an on-site specialist. Time devoted to clinical care and geography may influence preferences for PrEP implementation. Establishing clinic-specific PrEP protocols may promote on-site PrEP implementation. Future studies should focus on evaluating the effectiveness of different PrEP implementation models on PrEP delivery.

Much progress has been made in the development of antiretroviral therapies (ARTs) for HIV-1 infection. Beginning a little over a decade ago, single tablet combination regimens (STRs) became available, and subsequently, newer STR formulations with improved safety profiles have emerged. Recently, there is a growing interest in regimen simplification with the primary goal of further reducing long-term toxicities of ART and improving medication adherence. Dolutegravir/rilpivirine (DTG/RPV) was approved by the US Food and Drug Administration (FDA) as the first dual antiretroviral STR for the maintenance therapy of HIV-1 infection. Following an extensive review of all published papers on RPV and DTG, administered alone and in combination, extracted from databases including PubMed, Google scholar, and EMBASE, as well as drug package inserts and conference abstracts and proceedings, this review discusses the chemical properties and composition, pharmacodynamics and pharmacokinetic properties, clinical trial efficacy and safety data, as well as important drug-drug interactions associated with DTG/RPV. An expert opinion section discusses ideal candidates for DTG/RPV in the context of available but limited data and in comparison to currently available and emerging ART alternatives.

Pre-exposure prophylaxis (PrEP) is effective in preventing HIV acquisition among men who have sex with men (MSM). However, little is known about unhealthy substance use among MSM initiating PrEP in real-world settings. Unhealthy substance use is a risk factor for HIV acquisition and non-adherence to treatment, and may also impact PrEP use. MSM who were prescribed PrEP from 2015 to 2017 at clinics in Providence, Rhode Island and New Haven, Connecticut were recruited to participate in a prospective observational study. Structured clinical assessments were used to assess demographics, HIV risk behaviors, and unhealthy alcohol (alcohol use disorders identification test [AUDIT]-C scores ≥ 4) and drug use (use of any drugs in the past 3 months). Bivariate and multivariate analyses were performed to determine demographics and behaviors associated with unhealthy alcohol and drug use. Among 172 MSM initiating PrEP, 64% were white and 40% were 25–34 years old. Participants reported a median of 3 (IQR 2–7) sexual partners in the last 3 months; 20% reported an HIV positive partner. Unhealthy alcohol and any drug use were reported by 54 and 57%, respectively, and 76% reported at least one of the two. The majority of drug use reported was marijuana and poppers (41 and 26% of participants, respectively). Relative to those without unhealthy alcohol use, unhealthy alcohol use was independently associated with any drug use (adjusted odds ratio [AOR] = 2.57, 95% CI 1.32–5.01). Frequent drug use was associated with younger age (< 25 years, AOR 4.27, 95% CI 1.51–12.09). Unhealthy alcohol use is common among MSM taking PrEP. Drug use other than marijuana and poppers was uncommon among our cohort. Further efforts may be needed to understand the influence of unhealthy alcohol and other substance use on PrEP outcomes and to engage MSM who use drugs for PrEP.

Women involved in the criminal justice system (WICJ) are at high risk of acquiring HIV and would benefit from HIV pre-exposure prophylaxis (PrEP) but there are no studies in this population to inform PrEP implementation programs. We conducted a cross-sectional survey of HIV-uninfected, cis-gender women on probation, parole and/or recently released from prison/jail to assess PrEP awareness, eligibility, potential barriers to uptake, and the PrEP care continuum. The 125 WICJ surveyed reported high rates of HIV risk behaviors including recent transactional sex (22.4%) and unsafe injection practices (14.4%). Despite 33% (n = 42) meeting eligibility criteria for PrEP, only 25% were aware of PrEP and one person was currently using it. Just 16.7% of those who were PrEP eligible perceived they were at risk for HIV. Following a brief explanation of PrEP, 90% said they would try it if recommended by their physician. Compared to those not PrEP eligible (n = 83), PrEP eligible women were less likely to be stably housed or have a primary care provider, and were more likely to be violence-exposed, charged with drug possession, have lifetime substance use, or living with Hepatitis C infection. WICJ frequently engage in HIV risk behaviors that make them eligible for PrEP. Uptake may be limited by lack of PrEP awareness or underestimation of personal HIV risk. WICJ report receptiveness to PrEP and represent an important population for targeted PrEP implementation programs.

Treatments for hepatitis C virus (HCV) infection have advanced rapidly in the last decade. Pegylated interferon alpha 2a (PEG-IFN alpha 2a) alone, in combination with ribavirin and with or without direct acting antivirals (DAAs) is modestly effective in the treatment of chronic HCV infection. Areas covered: The review describes the chemistry, pharmacokinetic and pharmacodynamic properties, clinical efficacy, safety and drug-drug interaction profiles of PEG-IFN alpha 2a. Expert opinion: Despite the availability of DAAs and its formidable toxicity profile, PEG-IFN alpha 2a retains a role for the treatment of acute HCV and chronic HCV infection in resource limited settings and for end-stage renal disease patients and others who cannot access DAAs or are DAA-ineligible. Knowledge of pharmacogenetic profiles which favor successful treatment outcomes with IFN-based therapies may allow for selection of best candidates for the regimen.

Introduction. Acute kidney injury (AKI) requiring renal replacement therapy is associated with high mortality. The study assessed the impact of the introduction of hemodialysis (HD) on outcomes of patients with AKI in Rwanda. Methods. A single center retrospective study that evaluated the clinical profile and survival outcomes of patients with AKI requiring HD [AKI-D] at a tertiary hospital in Rwanda. Data was collected on patients who received HD for AKI from September 2014 to December 2016. Patient demographics, comorbidities, clinical presentation, laboratory tests, and mortality were reviewed and analyzed. Predictors of mortality were assessed using age and gender adjusted multivariate analyses. Results. Of the 82 eligible patients, median age was 38 years (IQR 28–57 years). Males comprised 51% of the cohort. Infectious diseases including malaria, pneumonia, and sepsis (35.1%) and pregnancy-related conditions (26.9%) were the most frequent comorbidities. Pulmonary oedema (54.9%) and uremic encephalopathy (50%) were top indications for HD. Mortality was 34.1%. On multivariate analysis, receipt of P=0.026) and hyperkalemia (OR = 3.23, 95% CI 1.040–10.065, P=0.043) were associated with mortality. Conclusion. The availability of acute hemodialysis in Rwanda has resulted in improved patient survival and persistent hyperkalemia predicted higher mortality.

Background Black and Hispanic/Latinx gay and other men who have sex with men (MSM), transgender women (TGW), transgender men (TGM), and gender nonbinary individuals (GNB) have been historically underrepresented in HIV prevention trials despite being disproportionately affected by the disease. Therefore, studies of pre-exposure prophylaxis (PrEP), a highly effective intervention for reducing HIV incidence, should include these individuals, and doing so would promote generalizability of the findings. Methods PURPOSE 2 (GS-US-528-9023) will evaluate a twice-yearly long-acting subcutaneous, first in class capsid inhibitor, lenacapavir, for PrEP in MSM, TGW, TGM, and GNB in the US, Brazil, Peru, and South Africa. The study team adopted a multifactorial approach to address historic underrepresentation. This included a literature review to assess successful evidence-based approaches for increasing enrollment of Black and Hispanic/ LatinX MSM, TG, and GNB individuals. We engaged with community and patient advocates as well as key stakeholders to solicit feedback prior to protocol development. Results We established a trial-specific Global Community Advisory Group and implemented their recommendations for site selection, investigator and staff diversity, and strong linkage with community-based organizations. We recruited new community-based research sites and principal investigators (PIs) to mirror historically underrepresented populations and emphasized mentorship of junior sub-Is by seasoned PIs to support enrollment and retention. We developed required trainings for all study and site staff on good participatory practices for PrEP, anti-racism and transgender cultural humility. We established recruitment goals of 50% Black and 20% Hispanic/LatinX MSM in the US, and 20% TGW study-wide. Our strategy to ensure achievement of these overall goals involves nuanced site-specific recruitment goals considering site capacity, local demographics, and HIV incidence data. We will review metrics weekly during enrollment and make any necessary adjustments. Conclusion Using novel approaches, we have carefully chosen with whom, where, and how we will collaborate to increase the diversity, equity, and inclusion in the PURPOSE 2 trial. Disclosures Michelle Cespedes, MD, MS, Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support)GlaxoSmithKline (Scientific Research Study Investigator, Research Grant or Support) Jill Blumenthal, MD, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator) Karam Mounzer, MD, Epividian (Advisor or Review Panel member)Gilead Sciences Inc. (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker’s Bureau)Janssen (Consultant, Research Grant or Support, Speaker’s Bureau)Merck (Research Grant or Support, Speaker’s Bureau)ViiV Healthcare (Consultant, Speaker’s Bureau) Moti Ramgopal, MD FACP 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) Ayana Elliott, DNP, APRN, FNP-C, NEA-BC, Gilead Sciences Inc. (Employee, Shareholder) A.C. Demidont, MD, Gilead Sciences Inc. (Employee, Shareholder) C. Chauncey Watson, MD, Gilead Sciences Inc. (Employee, Shareholder) Christoph C. Carter, MD, Gilead Sciences Inc. (Employee, Shareholder) Alex Kintu, MD, ScD, Gilead Sciences Inc. (Employee, Shareholder) Moupali Das, MD, Gilead Sciences Inc. (Employee, Shareholder) Jared Baeten, MD, PHD, Gilead Sciences Inc. (Employee, Shareholder) Onyema Ogbuagu, MD, Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Research Grant or Support, Other Financial or Material Support)ViiV Healthcare (Advisor or Review Panel member)

A 30-year-old woman living with HIV was diagnosed with genotype 2b hepatitis C virus (HCV) infection during the second trimester of her pregnancy. She had achieved virologic suppression on an HIV protease inhibitor-based regimen and had recurrent genital herpes simplex virus infection managed with antivirals. Given the risk of perinatal transmission of HCV and to avoid performing a caesarean section, after multidisciplinary consultations and consideration of the limited data on safety on HCV direct-acting antivirals (DAAs) in pregnancy, she consented to and was successfully treated with a 6-week lead-in course of sofosbuvir (SOF) alone followed by a 6-week course of SOF and velpatasvir postpartum. This resulted in cure of her HCV infection. The neonate tested negative for HCV at birth and was healthy without birth defects 2 years postdelivery. Our case highlights a successful HCV treatment approach in a pregnant woman with newer DAAs.

The gradual accumulation of mitochondrial DNA (mtDNA) mutations is implicated in aging and may contribute to the accelerated aging phenotype seen with tobacco smoking and HIV infection. mtDNA mutations are thought to arise from oxidative damage; however, recent reports implicate polymerase γ errors during mtDNA replication. Investigations of somatic mtDNA mutations have been hampered by technical challenges in measuring low‐frequency mutations. We use primer ID‐based next‐generation sequencing to quantify both somatic and heteroplasmic blood mtDNA point mutations within the D‐loop, in 164 women and girls aged 2–72 years, of whom 35% were smokers and 56% were HIV‐positive. Somatic mutations and the occurrence of heteroplasmic mutations increased with age. While transitions are theorized to result from polymerase γ errors, transversions are believed to arise from DNA oxidative damage. In our study, both transition and transversion mutations were associated with age. However, transition somatic mutations were more prevalent than transversions, and no heteroplasmic transversions were observed. We also measured elevated somatic mutations, but not heteroplasmy, in association with high peak HIV viremia. Conversely, heteroplasmy was higher among smokers, but somatic mutations were not, suggesting that smoking promotes the expansion of preexisting mutations rather than de novo mutations. Taken together, our results are consistent with blood mtDNA mutations increasing with age, inferring a greater contribution of polymerase γ errors in mtDNA mutagenesis. We further suggest that smoking and HIV infection both contribute to the accumulation of mtDNA mutations, though in different ways.