Remdesivir in Hospitalized Covid-19 Patients: Individual Patient Data Meta-Analysis

Background: The interpretation of the evidence from randomized clinical trials (RCTs) on remdesivir for hospitalized patients with coronavirus disease 2019 (COVID-19) is conflicting. We conducted a systematic review and individual patient data meta-analysis (IPDMA) of RCTs to assess the benefit and harm of remdesivir compared to placebo or usual care in hospitalized patients and whether treatment effects differed between prespecified subgroups. Method(s): We systematically searched electronic databases and registries through April 11th 2022 and contacted authors of eligible trials to share individual patient data. The primary outcome was all-cause mortality at day 28. We used multivariable hierarchical regression adjusting for respiratory support, age, and enrollment period to investigate effect modifiers. The study was registered in PROSPERO (CRD42021257134). Result(s): Out of nine eligible RCTs, eight provided individual data for 10480 hospitalized COVID-19 patients (99% of global IPD) recruited between February 2020 and April 2021. Within 28 days of randomization, 662 of 5317 patients (12.5%) assigned to remdesivir and 706 of 5005 (14.1%) assigned to no remdesivir died (adjusted odds ratio [aOR] 0.88;95% confidence interval [CI], 0.78-1.00;p=0.045). We found evidence for a credible subgroup effect according to respiratory support at baseline (interaction p=0.019). Of those ventilated including high-flow oxygen, 253/844 (30.0%) assigned to remdesivir died versus 241/846 (28.5%) assigned to no remdesivir (aOR 1.10 [0.88-1.38];low certainty evidence). Of those receiving no or low flow oxygen, 409/4473 (9.1%) assigned to remdesivir died versus 465/4159 (11.2%) assigned to no remdesivir (aOR 0.80 [0.70-0.93];high certainty evidence). There was no credible subgroup effect with respect to time to start of remdesivir after symptom onset, age, presence of comorbidities, enrollment period or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events. Table 1 summarizes the findings according to GRADE (Grading of Recommendations, Assessment, Development and Evaluations). Conclusion(s): This IPDMA, summarizing the evidence of 99% patients ever randomized on the topic, demonstrated that remdesivir reduced mortality in hospitalized COVID-19 patients requiring no or conventional oxygen support, but patients requiring more respiratory support may not benefit. These findings may inform clinical guidelines, especially due to increasing resistance to current monoclonal antibodies.

Clinical Outcomes of Hospitalized COVID-19 Patients Treated with Remdesivir-NEAT ID 909REM Study

Background. There are few real-world data on the use of remdesivir (RDV) looking at timing of initiation in relation to symptom onset and severity of presenting disease. Methods. We conducted multi-country retrospective study of clinical practice and use of RDV in COVID-19 patients. De-identified medical records data were entered into an e-CRF. Primary endpoints were all-cause mortality at day 28 and hospitalization duration. We assessed time from symptom onset to RDV start and re-admission. We included adults with PCR-confirmed symptomatic COVID-19 who were hospitalized after Aug 31, 2020 and received at least 1 dose of RDV. Descriptive analyses were conducted. Kaplan-Meier methods were used to calculate the mortality rate, LogRank test to compare groups defined by severity of disease. Competing risk regression with discharge and death as competing events was used to estimate duration of hospitalization, and Gray's test to compare the groups. Results. 448 patients in 5 countries (12 sites) were included. Demographics are summarized (table) by 3 disease severity groups at baseline: no supplemental oxygen (NSO), low flow oxygen ≤6 L/min (LFO), and high-flow oxygen > 6L/min (HFO). No demographic differences were found between groups except for the higher percentage of cancer/chemotherapy patients in NSO group. Corticosteroids use was HFO 73.6%, LFO 62.7%, NSO 58.0%. Mortality rate was significantly lower in NSO, and LFO groups compared with HFO (6.2%, 10.2%, 23.6%, respectively;Fig1). Median duration of hospitalization was 9 (95%CI 8-10), 9 (8-9), 13 (10-15) days, respectively (Fig2). Median time from first symptom to RDV start was 7 days in all 3 groups. Patients started RDV on day 1 of hospitalization in HFO and LFO and day 2 on NSO groups. And received a 5 day course (median). Readmission within 28-days of discharge was < 5% and similar across all 3 groups. Conclusion. In this real-world cohort of COVID-19 positive hospitalized patients, RDV use was consistent across countries. RDV was started within a median of 7 days from symptom within 2 days of admission and given for a median of 5 days. Higher mortality rate and duration of hospitalization was seen in the HFO group and similar rates seen in the LFO and NSO groups. Readmission was consistently low across all 3 groups.

Olfactory and gustatory dysfunctions in COVID-19 outpatients: A prospective cohort study.

OBJECTIVES: To describe the characteristics, evolution and risk factors for long-term persistence of olfactory and gustatory dysfunctions (OGD) in COVID-19 outpatients. PATIENTS AND METHODS: We conducted a prospective study in SARS-CoV-2 infected outpatients with OGD. Weekly phone interviews were set up starting from COVID-19 onset symptoms and over the course of 60 days, using standardized questionnaires that included a detailed description of general symptoms and OGD. The primary outcome was the proportion of patients with complete recovery of OGD at D30. Rate and time to recovery of OGD, as well as risk factors for late recovery (>30 days), were evaluated using Cox regression models. RESULTS: Ninety-eight outpatients were included. The median time to onset of OGD after first COVID-19 symptoms was 2 days (IQR 0-4). The 30-day recovery rate from OGD was 67.5% (95% CI 57.1-75.4) and the estimated median time of OGD recovery was 20 days (95% CI 13-26). Risk factors for late recovery of OGD were a complete loss of smell or taste at diagnosis (HR=0.26, 95% CI 0.12-0.56, P=0.0005) and age over 40 years (HR=0.56, 95% CI 0.36-0.89, P=0.01). CONCLUSIONS: COVID-19 patients with complete loss of smell or taste and over age 40 are more likely to develop persistent OGD and should rapidly receive sensorial rehabilitation.

Prevalence and factors associated with symptom persistence: a prospective study of 429 mild COVID-19 outpatients

Introduction. Persistent symptoms have recently emerged as a clinical issue in COVID-19. We aimed to assess the prevalence and risk factors in symptomatic non-hospitalized individuals with mild COVID-19. Methods. We performed a prospective cohort study of symptomatic COVID-19 outpatients, from March to May 2020, with weekly phone calls from clinical onset until day 30 and up to day 60 in case of persistent symptoms. The main outcomes were the proportion of patients with complete recovery at day 30 and day 60 and factors associated with persistent symptoms. Results. We enrolled 429 individuals mostly women (72.5%) and healthcare workers (72.5%), with a median age of 41.6 years [IQR 30-51.5]. Symptoms included: cough (69.7%), asthenia (68.8%), anosmia (64.8%), headaches (64.6%), myalgia (62.7%), gastrointestinal symptoms (61.8%), fever (61.5%), and ageusia (60.8%). Mean duration of disease was 27 days (95%CI: 25-29). The rate of persistent symptoms was 46.8% at day 30 and 6.5% at day 60 consisting in asthenia (32.6%), anosmia (32.6%), and ageusia (30.4%). The probability of complete recovery was 56.3% (95%CI: 51.7-61.1) at day 30 and 85.6% (95%CI: 81.2-89.4) at day 60. Factors associated with persistent symptoms were age >40 (HR 0.61), female sex (HR 0.70), low cycle threshold (HR 0.78), and ageusia (HR 0.59). Conclusions. COVID-19 — even in its mild presentation — led to persistent symptoms (up to one month) in nearly half of individuals. Identification of risk factors such as age, gender, ageusia and viral load is crucial for clinical management and argues for the development of antiviral agents.

Incidence of HIV infection with daily or on-demand oral prep with TDF/FTC in france

Background: On-demand PrEP with TDF/FTC has been recommended as an alternative to daily PrEP for MSM by EACS, WHO and IAS-USA guidelines, but has not been endorsed yet by CDC due to limited real-world experience. Methods: The ANRS Prevenir study is an ongoing prospective cohort study enrolling individuals at high risk for HIV infection on PrEP. MSM could opt for either daily or on-demand PrEP with TDF/FTC. At baseline, month 1 and every 3 months thereafter, subjects were tested for HIV using a 4th generation combined ELISA assay and other STIs and creatinine plasma levels were monitored. At each visit participants provided information regarding sexual behaviour, dosing regimen and drug adherence. Our main objective was to assess the overall HIV incidence in the study and per dosing regimen, as well as incidence of bacterial STIs (including syphilis, gonorrhoea, chlamydia and Mycoplasma genitalium) and viral hepatitis. Safety and study retention were also assessed. This analysis uses data accumulated up to September 30, 2020. Results: From May 3rd 2017 to March 2nd 2019, 3067 subjects were enrolled across 22 sites in the Paris region, 44% being PrEP naive. Median age was 36 years (IQR: 29-43), 98.5% were MSM. At enrolment, PrEP was used daily and on demand by 50.5% and 49.5% of participants, respectively. Median number of partners in the last 3 months was 10 (5-20) and median number of condomless sex events in the prior 4 weeks was 2 (0-5). Median follow-up lasted 22 months and accumulated 5633 person-years (PY) with an overall HIV incidence in the cohort of 0.11 (95% CI: 0.04-0.23) per 100 PY. Six participants (3 daily, 3 on demand) acquired HIV-infection during the study period (P=0.99). Condom use at last sexual intercourse was 19.6%. Overall STIs incidence was 73 (95% CI: 70.7-75.5) per 100 PY which remained stable during follow-up except during the COVID-19 lockdown when it dropped to 32.4 per 100 PY (P<10-4). HCV incidence was 0.69 per 100 PY. Incidence of participants lost to follow-up was 10.3/100 PY and 19 subjects (0.6%) discontinued PrEP for drug-related adverse events (gastrointestinal: 12, e-GFR < 70 ml/mn: 4, other: 3). Conclusion: In this PrEP cohort, enrolling mainly MSM at high risk of HIVacquisition in Paris, HIV incidence was low whether participants used daily or on demand PrEP. There was a high incidence of bacterial STIs and HCV infection despite a drop in STIs incidence during the COVID-19 lockdown.