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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 IC 50 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. Here, the authors identify and validate the emergence of a SARS-CoV-2 resistance mutation to Remdesivir, associated with virological recrudesce in an immunocompromised patient with persistent COVID-19.

Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of human immunodeficiency virus (HIV) infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear. In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF). The primary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with the background HIV incidence in the screened population. The secondary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with that in the F/TDF group. Among 3265 participants who were included in the modified intention-to-treat analysis, HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77). The background HIV incidence in the screened population (4634 participants) was 2.37 per 100 person-years (95% CI, 1.65 to 3.42). The incidence of HIV infection in the lenacapavir group was significantly lower than both the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P = 0.002). No safety concerns were identified. A total of 26 of 2183 participants (1.2%) in the lenacapavir group and 3 of 1088 (0.3%) in the F/TDF group discontinued the trial regimen because of injection-site reactions. The HIV incidence with twice-yearly lenacapavir was significantly lower than the background incidence and the incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 2 ClinicalTrials.gov number, NCT04925752.).

•Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody.•In COVID-19 leronlimab appears to have improved NEWS2 scores compared to placebo.•In COVID-19 leronlimab may be associated with fewer AEs compared to placebo. Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19. The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14). Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%). At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials. ClinicalTrials.gov number, NCT04343651 https://classic.clinicaltrials.gov/ct2/show/NCT04343651

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.

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.

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.

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. 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. 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. 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. Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Mycobacterium marinum is a slow-growing, acid-fast bacillus in the category of non-tuberculous mycobacteria which most commonly cause skin and soft tissue infections in patients, particularly those with aquatic exposure. Classically, M. marinum skin and soft tissue infections clinically manifest with formation of nodular or sporotrichoid extremity lesions, or deeper space infections such as tenosynovitis and osteomyelitis. Disseminated disease may occur in immunocompromised hosts. M. marinum is a slow-growing organism that is challenging to culture, as it typically requires 5–14 days (yet may take up to several weeks) with low temperatures of approximately 30°C to yield growth. In terms of treatment, further data are needed to elucidate the optimal regimen and duration for M. marinum infections. Combination therapy with clarithromycin and ethambutol is recommended for treatment of skin and soft tissue infections, with addition of rifampicin for deeper space infections. Surgery may be needed in addition to medical management.

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 <5 sessions of HD (OR = 4.01, 95% CI 1.185–13.61, 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.

Black and Hispanic/Latinx cisgender men who have sex with men (MSM), transgender women, transgender men, and gender nonbinary (TGNB) individuals have been historically underrepresented in HIV pre-exposure prophylaxis (PrEP) clinical trials. There is an urgent need for ongoing engagement with communities that have been the most impacted by HIV and diverse representation in clinical trials. Here we describe strategic approaches undertaken in the PURPOSE 2 trial to optimize engagement of underrepresented individuals. PURPOSE 2 is an ongoing Phase 3 trial evaluating the safety and efficacy of lenacapavir as PrEP in cisgender MSM and TGNB individuals. In PURPOSE 2, we used a multipronged approach aimed at enriching participation of underrepresented individuals. We conducted a review to identify evidence-informed recommendations from literature, engaged with stakeholders, and established the Global Community Advisory and Accountability Group (GCAG) to represent the needs of the community. Insights from stakeholders and GCAG members resulted in an expansion of the study population to include transgender men, gender nonbinary persons, and adolescents, and evaluation of population-specific outcomes. Feedback from stakeholders and GCAG members also informed investigator and site selection; these were selected based on prior experience working with persons from diverse racial, ethnic and gender identities, and estimates of local HIV incidence. Site selection was also expanded to include community-based clinics with services tailored towards Black, Hispanic/Latinx, and TGNB populations. We established a study-wide recruitment goal of 50% Black MSM and 20% Hispanic/Latinx MSM in US sites and 20% transgender women globally. Site-specific recruitment goals were also developed based on local demographics and HIV incidence. Mandatory trainings included Good Participatory Practice guidelines, gender inclusivity, and antiracism. While further work is needed to achieve equitable representation, the strategies we describe may serve as a framework for future clinical trials. Clinical Trial Number: NCT04925752.