Inappropriate sinus tachycardia (IST) is a common observation in patients with post-COVID-19 syndrome (PCS) but has not yet been fully described to date. To investigate the prevalence and the ...mechanisms underlying IST in a prospective population of PCS patients. Consecutive patients admitted to the PCS Unit between June and December 2020 with a resting sinus rhythm rate ≥ 100 bpm were prospectively enrolled in this study and further examined by an orthostatic test, 2D echocardiography, 24-h ECG monitoring (heart rate variability was a surrogate for cardiac autonomic activity), quality-of-life and exercise capacity testing, and blood sampling. To assess cardiac autonomic function, a 2:1:1 comparative sub-analysis was conducted against both fully recovered patients with previous SARS-CoV-2 infection and individuals without prior SARS-CoV-2 infection. Among 200 PCS patients, 40 (20%) fulfilled the diagnostic criteria for IST (average age of 40.1 ± 10 years, 85% women, 83% mild COVID-19). No underlying structural heart disease, pro-inflammatory state, myocyte injury, or hypoxia were identified. IST was accompanied by a decrease in most heart rate variability parameters, especially those related to cardiovagal tone: pNN50 (cases 3.2 ± 3 vs. recovered 10.5 ± 8 vs. non-infected 17.3 ± 10; p < 0.001) and HF band (246 ± 179 vs. 463 ± 295 vs. 1048 ± 570, respectively; p < 0.001). IST is prevalent condition among PCS patients. Cardiac autonomic nervous system imbalance with decreased parasympathetic activity may explain this phenomenon.
Scarce data are available on what variables affect the risk of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the development of symptomatic COVID-19, and, ...particularly, the relationship with viral load. We aimed to analyse data from linked index cases of COVID-19 and their contacts to explore factors associated with transmission of SARS-CoV-2.
In this cohort study, patients were recruited as part of a randomised controlled trial done between March 17 and April 28, 2020, that aimed to assess if hydroxychloroquine reduced transmission of SARS-CoV-2. Patients with COVID-19 and their contacts were identified by use of the electronic registry of the Epidemiological Surveillance Emergency Service of Catalonia (Spain). Patients with COVID-19 included in our analysis were aged 18 years or older, not hospitalised, had quantitative PCR results available at baseline, had mild symptom onset within 5 days before enrolment, and had no reported symptoms of SARS-CoV-2 infections in their accommodation or workplace within the 14 days before enrolment. Contacts included were adults with a recent history of exposure and absence of COVID-19-like symptoms within the 7 days preceding enrolment. Viral load of contacts, measured by quantitative PCR from a nasopharyngeal swab, was assessed at enrolment, at day 14, and whenever the participant reported COVID-19-like symptoms. We assessed risk of transmission and developing symptomatic disease and incubation dynamics using regression analysis. We assessed the relationship of viral load and characteristics of cases (age, sex, number of days from reported symptom onset, and presence or absence of fever, cough, dyspnoea, rhinitis, and anosmia) and associations between risk of transmission and characteristics of the index case and contacts.
We identified 314 patients with COVID-19, with 282 (90%) having at least one contact (753 contacts in total), resulting in 282 clusters. 90 (32%) of 282 clusters had at least one transmission event. The secondary attack rate was 17% (125 of 753 contacts), with a variation from 12% when the index case had a viral load lower than 1 × 106 copies per mL to 24% when the index case had a viral load of 1 × 1010 copies per mL or higher (adjusted odds ratio per log10 increase in viral load 1·3, 95% CI 1·1–1·5). Increased risk of transmission was also associated with household contact (3·0, 1·59–5·65) and age of the contact (per year: 1·02, 1·01–1·04). 449 contacts had a positive PCR result at baseline. 28 (6%) of 449 contacts had symptoms at the first visit. Of 421 contacts who were asymptomatic at the first visit, 181 (43%) developed symptomatic COVID-19, with a variation from approximately 38% in contacts with an initial viral load lower than 1 × 107 copies per mL to greater than 66% for those with an initial viral load of 1 × 1010 copies per mL or higher (hazard ratio per log10 increase in viral load 1·12, 95% CI 1·05–1·20; p=0·0006). Time to onset of symptomatic disease decreased from a median of 7 days (IQR 5–10) for individuals with an initial viral load lower than 1 × 107 copies per mL to 6 days (4–8) for those with an initial viral load between 1 × 107 and 1 × 109 copies per mL, and 5 days (3–8) for those with an initial viral load higher than 1 × 109 copies per mL.
In our study, the viral load of index cases was a leading driver of SARS-CoV-2 transmission. The risk of symptomatic COVID-19 was strongly associated with the viral load of contacts at baseline and shortened the incubation time of COVID-19 in a dose-dependent manner.
YoMeCorono, Generalitat de Catalunya.
For the Catalan translation of the abstract see Supplementary Materials section.
Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of ...HIV-1 viral suppression through 96 weeks.
In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir–lamivudine 600–300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir–lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir–lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir–lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352.
Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% 95% CI −5·8 to 11·5 vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% −4·8 to 12·2 vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 84% of 4360 injections) or moderate (673 15% of 4360 injections) in intensity and rarely resulted in discontinuation (two <1% of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related.
The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated.
ViiV Healthcare and Janssen R&D.
IMPORTANCE: A key factor in assessing the effectiveness and cost-effectiveness of antiretroviral therapy (ART) as a prevention strategy is the absolute risk of HIV transmission through condomless sex ...with suppressed HIV-1 RNA viral load for both anal and vaginal sex. OBJECTIVE: To evaluate the rate of within-couple HIV transmission (heterosexual and men who have sex with men MSM) during periods of sex without condoms and when the HIV-positive partner had HIV-1 RNA load less than 200 copies/mL. DESIGN, SETTING, AND PARTICIPANTS: The prospective, observational PARTNER (Partners of People on ART—A New Evaluation of the Risks) study was conducted at 75 clinical sites in 14 European countries and enrolled 1166 HIV serodifferent couples (HIV-positive partner taking suppressive ART) who reported condomless sex (September 2010 to May 2014). Eligibility criteria for inclusion of couple-years of follow-up were condomless sex and HIV-1 RNA load less than 200 copies/mL. Anonymized phylogenetic analysis compared couples’ HIV-1 polymerase and envelope sequences if an HIV-negative partner became infected to determine phylogenetically linked transmissions. EXPOSURES: Condomless sexual activity with an HIV-positive partner taking virally suppressive ART. MAIN OUTCOMES AND MEASURES: Risk of within-couple HIV transmission to the HIV-negative partner RESULTS: Among 1166 enrolled couples, 888 (mean age, 42 years IQR, 35-48; 548 heterosexual 61.7% and 340 MSM 38.3%) provided 1238 eligible couple-years of follow-up (median follow-up, 1.3 years IQR, 0.8-2.0). At baseline, couples reported condomless sex for a median of 2 years (IQR, 0.5-6.3). Condomless sex with other partners was reported by 108 HIV-negative MSM (33%) and 21 heterosexuals (4%). During follow-up, couples reported condomless sex a median of 37 times per year (IQR, 15-71), with MSM couples reporting approximately 22 000 condomless sex acts and heterosexuals approximately 36 000. Although 11 HIV-negative partners became HIV-positive (10 MSM; 1 heterosexual; 8 reported condomless sex with other partners), no phylogenetically linked transmissions occurred over eligible couple-years of follow-up, giving a rate of within-couple HIV transmission of zero, with an upper 95% confidence limit of 0.30/100 couple-years of follow-up. The upper 95% confidence limit for condomless anal sex was 0.71 per 100 couple-years of follow-up. CONCLUSIONS AND RELEVANCE: Among serodifferent heterosexual and MSM couples in which the HIV-positive partner was using suppressive ART and who reported condomless sex, during median follow-up of 1.3 years per couple, there were no documented cases of within-couple HIV transmission (upper 95% confidence limit, 0.30/100 couple-years of follow-up). Additional longer-term follow-up is necessary to provide more precise estimates of risk.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, is considered a zoonotic pathogen mainly transmitted human to human. Few reports indicate that pets ...may be exposed to the virus. The present report describes a cat suffering from severe respiratory distress and thrombocytopenia living with a family with several members affected by COVID-19. Clinical signs of the cat prompted humanitarian euthanasia and a detailed postmortem investigation to assess whether a COVID-19–like disease was causing the condition. Necropsy results showed the animal suffered from feline hypertrophic cardiomyopathy and severe pulmonary edema and thrombosis. SARS-CoV-2 RNA was only detected in nasal swab, nasal turbinates, and mesenteric lymph node, but no evidence of histopathological lesions compatible with a viral infection were detected. The cat seroconverted against SARS-CoV-2, further evidencing a productive infection in this animal. We conclude that the animal had a subclinical SARS-CoV-2 infection concomitant to an unrelated cardiomyopathy that led to euthanasia.
The banning of mass-gathering indoor events to prevent SARS-CoV-2 spread has had an important effect on local economies. Despite growing evidence on the suitability of antigen-detecting rapid ...diagnostic tests (Ag-RDT) for mass screening at the event entry, this strategy has not been assessed under controlled conditions. We aimed to assess the effectiveness of a prevention strategy during a live indoor concert.
We designed a randomised controlled open-label trial to assess the effectiveness of a comprehensive preventive intervention for a mass-gathering indoor event (a live concert) based on systematic same-day screening of attendees with Ag-RDTs, use of facial masks, and adequate air ventilation. The event took place in the Sala Apolo, Barcelona, Spain. Adults aged 18–59 years with a negative result in an Ag-RDT from a nasopharyngeal swab collected immediately before entering the event were randomised 1:1 (block randomisation stratified by age and gender) to either attend the indoor event for 5 hours or go home. Nasopharyngeal specimens used for Ag-RDT screening were analysed by real-time reverse-transcriptase PCR (RT-PCR) and cell culture (Vero E6 cells). 8 days after the event, a nasopharyngeal swab was collected and analysed by Ag-RDT, RT-PCR, and a transcription-mediated amplification test (TMA). The primary outcome was the difference in incidence of RT-PCR-confirmed SARS-CoV-2 infection at 8 days between the control and the intervention groups, assessed in all participants who were randomly assigned, attended the event, and had a valid result for the SARS-CoV-2 test done at follow-up. The trial is registered at ClinicalTrials.gov, NCT04668625.
Participant enrollment took place during the morning of the day of the concert, Dec 12, 2020. Of the 1140 people who responded to the call and were deemed eligible, 1047 were randomly assigned to either enter the music event (experimental group) or continue with normal life (control group). Of the 523 randomly assigned to the experimental group, 465 were included in the analysis of the primary outcome (51 did not enter the event and eight did not take part in the follow-up assessment), and of the 524 randomly assigned to the control group, 495 were included in the final analysis (29 did not take part in the follow-up). At baseline, 15 (3%) of 495 individuals in the control group and 13 (3%) of 465 in the experimental group tested positive on TMA despite a negative Ag-RDT result. The RT-PCR test was positive in one case in each group and cell viral culture was negative in all cases. 8 days after the event, two (<1%) individuals in the control arm had a positive Ag-RDT and PCR result, whereas no Ag-RDT nor RT-PCR positive results were found in the intervention arm. The Bayesian estimate for the incidence between the experimental and control groups was –0·15% (95% CI –0·72 to 0·44).
Our study provides preliminary evidence on the safety of indoor mass-gathering events during a COVID-19 outbreak under a comprehensive preventive intervention. The data could help restart cultural activities halted during COVID-19, which might have important sociocultural and economic implications.
Primavera Sound Group and the #YoMeCorono Initiative.
For the Spanish translation of the abstract see Supplementary Materials section.
Summary Background Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor (NNRTI). In FLAMINGO, we compared ...dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy. Methods In this multicentre, open-label, phase 3b, non-inferiority study, HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were randomly assigned (1:1) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily, with investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100 000 or >100 000 copies per mL) and nucleoside reverse transcriptase inhibitor (NRTI) selection. The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL (Food and Drug Administration FDA snapshot algorithm) at week 48 with a 12% non-inferiority margin. This trial is registered with ClinicalTrials.gov , NCT01449929. Findings Recruitment began on Oct 31, 2011, and was completed on May 24, 2012, in 64 research centres in nine countries worldwide. Of 595 patients screened, 484 patients were included in the analysis (242 in each group). At week 48, 217 (90%) patients receiving dolutegravir and 200 (83%) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL (adjusted difference 7·1%, 95% CI 0·9–13·2), non-inferiority and on pre-specified secondary analysis dolutegravir was superior (p=0·025). Confirmed virological failure occurred in two (<1%) patients in each group; we recorded no treatment-emergent resistance in either group. Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir (four 2% patients) than for darunavir plus ritonavir (ten 4% patients) and contributed to the difference in response rates. The most commonly reported (≥10%) adverse events were diarrhoea (dolutegravir 41 17% patients vs darunavir plus ritonavir 70 29% patients), nausea (39 16% vs 43 18%), and headache (37 15% vs 24 10%). Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher (11 2% vs 36 7%; p=0·0001). Interpretation Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir. Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected, treatment-naive patients. Funding ViiV Healthcare and Shionogi & Co.
An elevated activity of retrotransposons is increasingly recognized to be implicated in a wide range of neurodegenerative and neurodevelopmental diseases. Down syndrome (DS) is the most common ...genetic disorder associated with intellectual disability and a genetic form of Alzheimer's disease. For this reason, we hypothesized that treatment with reverse transcriptase inhibitors could ameliorate DS phenotypes. In this proof of concept study, we treated trisomic (Ts65Dn) mice, a model of DS, with lamivudine, a reverse transcriptase inhibitor. We detected a significant improvement of neurobehavioural phenotypes, and a complete rescue of the hippocampal‐dependent recognition memory upon treatment with lamivudine. Despite clinical studies in patients with DS are warranted, this study lays the groundwork for a novel and actionable therapeutic approach.
PDF
