RESUMEN
BACKGROUND: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR). OBJECTIVE: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19. DESIGN: Observational cohort study. SETTING: Multicenter health care system in Boston, Massachusetts. PARTICIPANTS: Ambulatory adults with acute COVID-19 with and without use of N-R. INTERVENTION: Receipt of 5 days of N-R treatment versus no COVID-19 therapy. MEASUREMENTS: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL. RESULTS: Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected. LIMITATIONS: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission. CONCLUSION: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus. PRIMARY FUNDING SOURCE: National Institutes of Health.
Asunto(s)
COVID-19 , SARS-CoV-2 , Adulto , Humanos , Ritonavir/uso terapéutico , Tratamiento Farmacológico de COVID-19RESUMEN
Importance: Urinary tract infection (UTI) is the second most common infection leading to hospitalization and is often associated with gram-negative multidrug-resistant organisms (MDROs). Clinicians overuse extended-spectrum antibiotics although most patients are at low risk for MDRO infection. Safe strategies to limit overuse of empiric antibiotics are needed. Objective: To evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO risk estimates could reduce use of empiric extended-spectrum antibiotics for treatment of UTI. Design, Setting, and Participants: Cluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time and risk-based CPOE prompts; 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in noncritically ill adults (≥18 years) hospitalized with UTI with an 18-month baseline (April 1, 2017-September 30, 2018) and 15-month intervention period (April 1, 2019-June 30, 2020). Interventions: CPOE prompts recommending empiric standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics who have low estimated absolute risk (<10%) of MDRO UTI, coupled with feedback and education. Main Outcomes and Measures: The primary outcome was empiric (first 3 days of hospitalization) extended-spectrum antibiotic days of therapy. Secondary outcomes included empiric vancomycin and antipseudomonal days of therapy. Safety outcomes included days to intensive care unit (ICU) transfer and hospital length of stay. Outcomes were assessed using generalized linear mixed-effect models to assess differences between the baseline and intervention periods. Results: Among 127â¯403 adult patients (71â¯991 baseline and 55â¯412 intervention period) admitted with UTI in 59 hospitals, the mean (SD) age was 69.4 (17.9) years, 30.5% were male, and the median Elixhauser Comorbidity Index count was 4 (IQR, 2-5). Compared with routine stewardship, the group using CPOE prompts had a 17.4% (95% CI, 11.2%-23.2%) reduction in empiric extended-spectrum days of therapy (rate ratio, 0.83 [95% CI, 0.77-0.89]; P < .001). The safety outcomes of mean days to ICU transfer (6.6 vs 7.0 days) and hospital length of stay (6.3 vs 6.5 days) did not differ significantly between the routine and intervention groups, respectively. Conclusions and Relevance: Compared with routine stewardship, CPOE prompts providing real-time recommendations for standard-spectrum antibiotics for patients with low MDRO risk coupled with feedback and education significantly reduced empiric extended-spectrum antibiotic use among noncritically ill adults admitted with UTI without changing hospital length of stay or days to ICU transfers. Trial Registration: ClinicalTrials.gov Identifier: NCT03697096.
Asunto(s)
Antibacterianos , Programas de Optimización del Uso de los Antimicrobianos , Sistemas de Entrada de Órdenes Médicas , Infecciones Urinarias , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Hospitales Comunitarios , Tiempo de Internación , Infecciones Urinarias/tratamiento farmacológico , Anciano de 80 o más AñosRESUMEN
Importance: Pneumonia is the most common infection requiring hospitalization and is a major reason for overuse of extended-spectrum antibiotics. Despite low risk of multidrug-resistant organism (MDRO) infection, clinical uncertainty often drives initial antibiotic selection. Strategies to limit empiric antibiotic overuse for patients with pneumonia are needed. Objective: To evaluate whether computerized provider order entry (CPOE) prompts providing patient- and pathogen-specific MDRO infection risk estimates could reduce empiric extended-spectrum antibiotics for non-critically ill patients admitted with pneumonia. Design, Setting, and Participants: Cluster-randomized trial in 59 US community hospitals comparing the effect of a CPOE stewardship bundle (education, feedback, and real-time MDRO risk-based CPOE prompts; n = 29 hospitals) vs routine stewardship (n = 30 hospitals) on antibiotic selection during the first 3 hospital days (empiric period) in non-critically ill adults (≥18 years) hospitalized with pneumonia. There was an 18-month baseline period from April 1, 2017, to September 30, 2018, and a 15-month intervention period from April 1, 2019, to June 30, 2020. Intervention: CPOE prompts recommending standard-spectrum antibiotics in patients ordered to receive extended-spectrum antibiotics during the empiric period who have low estimated absolute risk (<10%) of MDRO pneumonia, coupled with feedback and education. Main Outcomes and Measures: The primary outcome was empiric (first 3 days of hospitalization) extended-spectrum antibiotic days of therapy. Secondary outcomes included empiric vancomycin and antipseudomonal days of therapy and safety outcomes included days to intensive care unit (ICU) transfer and hospital length of stay. Outcomes compared differences between baseline and intervention periods across strategies. Results: Among 59 hospitals with 96â¯451 (51â¯671 in the baseline period and 44â¯780 in the intervention period) adult patients admitted with pneumonia, the mean (SD) age of patients was 68.1 (17.0) years, 48.1% were men, and the median (IQR) Elixhauser comorbidity count was 4 (2-6). Compared with routine stewardship, the group using CPOE prompts had a 28.4% reduction in empiric extended-spectrum days of therapy (rate ratio, 0.72 [95% CI, 0.66-0.78]; P < .001). Safety outcomes of mean days to ICU transfer (6.5 vs 7.1 days) and hospital length of stay (6.8 vs 7.1 days) did not differ significantly between the routine and CPOE intervention groups. Conclusions and Relevance: Empiric extended-spectrum antibiotic use was significantly lower among adults admitted with pneumonia to non-ICU settings in hospitals using education, feedback, and CPOE prompts recommending standard-spectrum antibiotics for patients at low risk of MDRO infection, compared with routine stewardship practices. Hospital length of stay and days to ICU transfer were unchanged. Trial Registration: ClinicalTrials.gov Identifier: NCT03697070.
Asunto(s)
Antibacterianos , Programas de Optimización del Uso de los Antimicrobianos , Neumonía , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Hospitalización , Sistemas de Entrada de Órdenes Médicas , Neumonía/tratamiento farmacológico , Neumonía Bacteriana/tratamiento farmacológico , Estados Unidos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Antiretroviral treatment improves health related quality of life (HRQoL) of people with human immunodeficiency virus (PWH). However, one third initiating first-line treatment experience virological failure and the determinants of HRQoL in this key population are unknown. Our study aims to identify determinants of among PWH failing antiretroviral treatment in sub-Saharan Africa. METHODS: We analysed data from a cohort of PWH having virological failure (> 1,000 copies/mL) on first-line ART in South Africa and Uganda. We measured HRQoL using the EuroQOL EQ-5D-3L and used a two-part regression model to obtain by-country analyses for South Africa and Uganda. The first part identifies risk factors that were associated with the likelihood of participants reporting perfect health (utility = 1) versus non-perfect health (utility < 1). The second part identifies risk factors that were associated with the EQ-5 L-3L utility scores for participants reporting non-perfect health. We performed sensitivity analyses to compare the results between the two-part model using tobit models and ordinary least squares regression. RESULTS: In both countries, males were more likely to report perfect health and participants with at least one comorbidity were less likely to report perfect health. In South Africa, participants with side effects and in Uganda those with opportunistic infections were also less likely to report perfect health. In Uganda, participants with 100% ART adherence were more likely to report perfect health. In South Africa, high HIV viral load, experiencing ART side effects, and the presence of opportunistic infections were each associated with lower HRQoL, whereas participants with 100% ART adherence reported higher HRQoL. In Uganda participants with lower CD4 count had lower HRQoL. CONCLUSION: Markers of advanced disease (opportunistic infection, high viral load, low CD4), side effects, comorbidities and lack of ART adherence negatively impacted HRQoL for PWH experiencing virological failure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02787499.
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Infecciones por VIH , Infecciones Oportunistas , Masculino , Humanos , VIH , Calidad de Vida , Sudáfrica/epidemiología , Antirretrovirales , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiologíaRESUMEN
BACKGROUND: Despite the advent of safe and effective coronavirus disease 2019 vaccines, pervasive inequities in global vaccination persist. METHODS: We projected health benefits and donor costs of delivering vaccines for up to 60% of the population in 91 low- and middle-income countries (LMICs). We modeled a highly contagious (Re at model start, 1.7), low-virulence (infection fatality ratio [IFR], 0.32%) "Omicron-like" variant and a similarly contagious "severe" variant (IFR, 0.59%) over 360 days, accounting for country-specific age structure and healthcare capacity. Costs included vaccination startup (US$630 million) and per-person procurement and delivery (US$12.46/person vaccinated). RESULTS: In the Omicron-like scenario, increasing current vaccination coverage to achieve at least 15% in each of the 91 LMICs would prevent 11 million new infections and 120 000 deaths, at a cost of US$0.95 billion, for an incremental cost-effectiveness ratio (ICER) of US$670/year of life saved (YLS). Increases in vaccination coverage to 60% would additionally prevent up to 68 million infections and 160 000 deaths, with ICERs Asunto(s)
COVID-19
, Países en Desarrollo
, Humanos
, Análisis Costo-Beneficio
, COVID-19/prevención & control
, Vacunas contra la COVID-19
, Vacunación
RESUMEN
The impact of coronavirus disease 2019 vaccination on viral characteristics of breakthrough infections is unknown. In this prospective cohort study, incidence of severe acute respiratory syndrome coronavirus 2 infection decreased following vaccination. Although asymptomatic positive tests were observed following vaccination, the higher cycle thresholds, repeat negative tests, and inability to culture virus raise questions about their clinical significance.
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COVID-19 , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19 , Personal de Salud , Humanos , Incidencia , Estudios Prospectivos , SARS-CoV-2 , VacunaciónRESUMEN
OBJECTIVES: HIV virological failure remains a major threat to programme success in sub-Saharan Africa. While HIV drug resistance (HIVDR) and inadequate adherence are the main drivers of virological failure, the individual, clinical and health system characteristics that lead to poor outcomes are not well understood. The objective of this paper is to identify those characteristics among people failing first-line antiretroviral therapy (ART). METHODS: We enrolled a cohort of adults in HIV care experiencing virological failure on first-line ART at five sites and used standard statistical methods to characterize them with a focus on three domains: individual/demographic, clinical, and health system, and compared each by country of enrolment. RESULTS: Of 840 participants, 51% were women, the median duration on ART was 3.2 years [interquartile range (IQR) 1.1, 6.4 years] and the median CD4 cell count prior to failure was 281 cells/µL (IQR 121, 457 cells/µL). More than half of participants [53%; 95% confidence interval (CI) 49-56%] stated that they had > 90% adherence and 75% (95% CI 72-77%) took their ART on time all or most of the time. Conversely, the vast majority (90%; 95% CI 86-92%) with a completed genotypic drug resistance test had any HIV drug resistance. This population had high health system use, reporting a median of 3 (IQR 2.6) health care visits and a median of 1 (IQR 1.1) hospitalization in the preceding 6 months. CONCLUSIONS: Patients failing first-line ART in sub-Saharan Africa generally report high rates of adherence to ART, have extremely high rates of HIV drug resistance and utilize significant health care resources. Health systems interventions to promptly detect and manage treatment failure will be a prerequisite to establishing control of the HIV epidemic.
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Fármacos Anti-VIH , Infecciones por VIH , Adulto , Recuento de Linfocito CD4 , Farmacorresistencia Viral , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Sudáfrica/epidemiología , Insuficiencia del Tratamiento , Uganda/epidemiología , Carga ViralRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality. In high-income settings, the presence of cardiovascular disease among people with COPD increases mortality and complicates longitudinal disease management. An estimated 26 million people are living with COPD in sub-Saharan Africa, where risk factors for co-occurring pulmonary and cardiovascular disease may differ from high-income settings but remain uncharacterized. As non-communicable diseases have become the leading cause of death in sub-Saharan Africa, defining multimorbidity in this setting is critical to inform the required scale-up of existing healthcare infrastructure. METHODS: We measured lung function and carotid intima media thickness (cIMT) among participants in the UGANDAC Study. Study participants were over 40 years old and equally divided into people living with HIV (PLWH) and an age- and sex-similar, HIV-uninfected control population. We fit multivariable linear regression models to characterize the relationship between lung function (forced expiratory volume in one second, FEV1) and pre-clinical atherosclerosis (cIMT), and evaluated for effect modification by age, sex, smoking history, HIV, and socioeconomic status. RESULTS: Of 265 participants, median age was 52 years, 125 (47%) were women, and 140 (53%) were PLWH. Most participants who met criteria for COPD were PLWH (13/17, 76%). Median cIMT was 0.67 mm (IQR: 0.60 to 0.74), which did not differ by HIV serostatus. In models adjusted for age, sex, socioeconomic status, smoking, and HIV, lower FEV1 was associated with increased cIMT (ß = 0.006 per 200 mL FEV1 decrease; 95% CI 0.002 to 0.011, p = 0.01). There was no evidence that age, sex, HIV serostatus, smoking, or socioeconomic status modified the relationship between FEV1 and cIMT. CONCLUSIONS: Impaired lung function was associated with increased cIMT, a measure of pre-clinical atherosclerosis, among adults with and without HIV in rural Uganda. Future work should explore how co-occurring lung and cardiovascular disease might share risk factors and contribute to health outcomes in sub-Saharan Africa.
Asunto(s)
Aterosclerosis/complicaciones , Aterosclerosis/epidemiología , Enfermedades Pulmonares Obstructivas/complicaciones , Enfermedades Pulmonares Obstructivas/epidemiología , Pulmón/fisiopatología , Adulto , Anciano , Aterosclerosis/fisiopatología , Arterias Carótidas/diagnóstico por imagen , Estudios de Cohortes , Estudios Transversales , Femenino , Volumen Espiratorio Forzado , Infecciones por VIH/epidemiología , Humanos , Enfermedades Pulmonares Obstructivas/fisiopatología , Masculino , Persona de Mediana Edad , Multimorbilidad , Pruebas de Función Respiratoria , Factores de Riesgo , Fumar/epidemiología , Espirometría , Uganda/epidemiologíaRESUMEN
BACKGROUND: Virologic failure in HIV predicts the development of drug resistance and mortality. Genotypic resistance testing (GRT), which is the standard of care after virologic failure in high-income settings, is rarely implemented in sub-Saharan Africa. OBJECTIVE: To estimate the effectiveness of GRT for improving virologic suppression rates among people with HIV in sub-Saharan Africa for whom first-line therapy fails. DESIGN: Pragmatic, unblinded, randomized controlled trial. (ClinicalTrials.gov: NCT02787499). SETTING: Ambulatory HIV clinics in the public sector in Uganda and South Africa. PATIENTS: Adults receiving first-line antiretroviral therapy with a recent HIV RNA viral load of 1000 copies/mL or higher. INTERVENTION: Participants were randomly assigned to receive standard of care (SOC), including adherence counseling sessions and repeated viral load testing, or immediate GRT. MEASUREMENTS: The primary outcome of interest was achievement of an HIV RNA viral load below 200 copies/mL 9 months after enrollment. RESULTS: The trial enrolled 840 persons, divided equally between countries. Approximately half (51%) were women. Most (72%) were receiving a regimen of tenofovir, emtricitabine, and efavirenz at enrollment. The rate of virologic suppression did not differ 9 months after enrollment between the GRT group (63% [263 of 417]) and SOC group (61% [256 of 423]; odds ratio [OR], 1.11 [95% CI, 0.83 to 1.49]; P = 0.46). Among participants with persistent failure (HIV RNA viral load ≥1000 copies/mL) at 9 months, the prevalence of drug resistance was higher in the SOC group (76% [78 of 103] vs. 59% [48 of 82]; OR, 2.30 [CI, 1.22 to 4.35]; P = 0.014). Other secondary outcomes, including 9-month survival and retention in care, were similar between groups. LIMITATION: Participants were receiving nonnucleoside reverse transcriptase inhibitor-based therapy at enrollment, limiting the generalizability of the findings. CONCLUSION: The addition of GRT to routine care after first-line virologic failure in Uganda and South Africa did not improve rates of resuppression. PRIMARY FUNDING SOURCE: The President's Emergency Plan for AIDS Relief and the National Institute of Allergy and Infectious Diseases.
Asunto(s)
Terapia Antirretroviral Altamente Activa , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Adulto , Alquinos/uso terapéutico , Benzoxazinas/uso terapéutico , Ciclopropanos/uso terapéutico , Emtricitabina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sudáfrica , Tenofovir/uso terapéutico , Uganda , Carga ViralRESUMEN
BACKGROUND: Weeks after issuing social distancing orders to suppress severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and reduce growth in cases of severe coronavirus disease 2019 (COVID-19), all US states and the District of Columbia partially or fully relaxed these measures. METHODS: We identified all statewide social distancing measures that were implemented and/or relaxed in the United States between 10 March and 15 July 2020, triangulating data from state government and third-party sources. Using segmented linear regression, we estimated the extent to which relaxation of social distancing affected epidemic control, as indicated by the time-varying, state-specific effective reproduction number (Rt). RESULTS: In the 8 weeks prior to relaxation, mean Rt declined by 0.012 units per day (95% confidence interval [CI], -.013 to -.012), and 46/51 jurisdictions achieved Rtâ <â 1.0 by the date of relaxation. After relaxation of social distancing, Rt reversed course and began increasing by 0.007 units per day (95% CI, .006-.007), reaching a mean Rt of 1.16. Eight weeks later, the mean Rt was 1.16 and only 9/51 jurisdictions were maintaining an Rt < 1.0. Parallel models showed similar reversals in the growth of COVID-19 cases and deaths. Indicators often used to motivate relaxation at the time of relaxation (eg, test positivity rate <5%) predicted greater postrelaxation epidemic growth. CONCLUSIONS: We detected an immediate and significant reversal in SARS-CoV-2 epidemic suppression after relaxation of social distancing measures across the United States. Premature relaxation of social distancing measures undermined the country's ability to control the disease burden associated with COVID-19.
Asunto(s)
COVID-19 , Número Básico de Reproducción , District of Columbia , Humanos , Distanciamiento Físico , SARS-CoV-2 , Estados Unidos/epidemiologíaRESUMEN
[This corrects the article DOI: 10.1371/journal.pmed.1003244.].
RESUMEN
BACKGROUND: Social distancing measures to address the US coronavirus disease 2019 (COVID-19) epidemic may have notable health and social impacts. METHODS AND FINDINGS: We conducted a longitudinal pretest-posttest comparison group study to estimate the change in COVID-19 case growth before versus after implementation of statewide social distancing measures in the US. The primary exposure was time before (14 days prior to, and through 3 days after) versus after (beginning 4 days after, to up to 21 days after) implementation of the first statewide social distancing measures. Statewide restrictions on internal movement were examined as a secondary exposure. The primary outcome was the COVID-19 case growth rate. The secondary outcome was the COVID-19-attributed mortality growth rate. All states initiated social distancing measures between March 10 and March 25, 2020. The mean daily COVID-19 case growth rate decreased beginning 4 days after implementation of the first statewide social distancing measures, by 0.9% per day (95% CI -1.4% to -0.4%; P < 0.001). We did not observe a statistically significant difference in the mean daily case growth rate before versus after implementation of statewide restrictions on internal movement (0.1% per day; 95% CI -0.04% to 0.3%; P = 0.14), but there is substantial difficulty in disentangling the unique associations with statewide restrictions on internal movement from the unique associations with the first social distancing measures. Beginning 7 days after social distancing, the COVID-19-attributed mortality growth rate decreased by 2.0% per day (95% CI -3.0% to -0.9%; P < 0.001). Our analysis is susceptible to potential bias resulting from the aggregate nature of the ecological data, potential confounding by contemporaneous changes (e.g., increases in testing), and potential underestimation of social distancing due to spillover effects from neighboring states. CONCLUSIONS: Statewide social distancing measures were associated with a decrease in the COVID-19 case growth rate that was statistically significant. Statewide social distancing measures were also associated with a decrease in the COVID-19-attributed mortality growth rate beginning 7 days after implementation, although this decrease was no longer statistically significant by 10 days.
Asunto(s)
Betacoronavirus/aislamiento & purificación , Control de Enfermedades Transmisibles , Infecciones por Coronavirus , Transmisión de Enfermedad Infecciosa , Pandemias , Neumonía Viral , Aislamiento Social , COVID-19 , Control de Enfermedades Transmisibles/métodos , Control de Enfermedades Transmisibles/organización & administración , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/transmisión , Transmisión de Enfermedad Infecciosa/prevención & control , Transmisión de Enfermedad Infecciosa/estadística & datos numéricos , Humanos , Estudios Longitudinales , Mortalidad , Pandemias/prevención & control , Neumonía Viral/epidemiología , Neumonía Viral/prevención & control , Neumonía Viral/transmisión , SARS-CoV-2 , Factores de Tiempo , Estados Unidos/epidemiologíaAsunto(s)
COVID-19 , SARS-CoV-2 , Cultivo de Virus , Esparcimiento de Virus , Animales , COVID-19/virología , Chlorocebus aethiops , Humanos , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus , Células Vero , Cultivo de Virus/métodos , Esparcimiento de Virus/fisiologíaRESUMEN
Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the immune defects that predispose an individual to persistent coronavirus disease 2019 (COVID-19) remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median times to nasal viral RNA and culture clearance in individuals with severe immunosuppression due to hematologic malignancy or transplant (S-HT) were 72 and 40 days, respectively, both of which were significantly longer than clearance rates in individuals with severe immunosuppression due to autoimmunity or B cell deficiency (S-A), individuals with nonsevere immunodeficiency, and nonimmunocompromised groups (P < 0.01). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing resistance against therapeutic monoclonal antibodies. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral responses, whereas only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across distinct immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Estudios Prospectivos , Cinética , Terapia de InmunosupresiónRESUMEN
OBJECTIVE: This study aimed to evaluate the 9-month cost and health-related quality of life (HRQOL) outcomes of resistance versus viral load testing strategies to manage virological failure in low-middle income countries. METHODS: We analyzed secondary outcomes from the REVAMP clinical trial: a pragmatic, open label, parallel-arm randomized trial investigating resistance versus viral load testing for individuals failing first-line treatment in South Africa and Uganda. We collected resource data, valued according to local cost data and used the 3-level version of EQ-5D to measure HRQOL at baseline and 9 months. We applied seemingly unrelated regression equations to account for the correlation between cost and HRQOL. We conducted intention-to-treat analyses with multiple imputation using chained equations for missing data and performed sensitivity analyses using complete cases. RESULTS: For South Africa, resistance testing and opportunistic infections were associated with statistically significantly higher total costs, and virological suppression was associated with lower total cost. Higher baseline utility, higher cluster of differentiation 4 (CD4) count, and virological suppression were associated with better HRQOL. For Uganda, resistance testing and switching to second-line treatment were associated with higher total cost, and higher CD4 was associated with lower total cost. Higher baseline utility, higher CD4 count, and virological suppression were associated with better HRQOL. Sensitivity analyses of the complete-case analysis confirmed the overall results. CONCLUSION: Resistance testing showed no cost or HRQOL advantage in South Africa or Uganda over the 9-month REVAMP clinical trial.
Asunto(s)
Fármacos Anti-VIH , Humanos , Fármacos Anti-VIH/uso terapéutico , Calidad de Vida , SudáfricaRESUMEN
Objective: To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound. Design: Observational cohort study. Setting: Multicenter healthcare system in Boston, Massachusetts. Participants: We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir. Exposures: Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy. Main Outcome and Measures: The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log10 copies/milliliter after a prior reduction in viral load to <4.0 log10 copies/milliliter. Results: Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvir-ritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene. Conclusions and Relevance: Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.
RESUMEN
Despite vaccination and antiviral therapies, immunocompromised individuals are at risk for prolonged SARS-CoV-2 infection, but the immune defects that predispose to persistent COVID-19 remain incompletely understood. In this study, we performed detailed viro-immunologic analyses of a prospective cohort of participants with COVID-19. The median time to nasal viral RNA and culture clearance in the severe hematologic malignancy/transplant group (S-HT) were 72 and 40 days, respectively, which were significantly longer than clearance rates in the severe autoimmune/B-cell deficient (S-A), non-severe, and non-immunocompromised groups (P<0.001). Participants who were severely immunocompromised had greater SARS-CoV-2 evolution and a higher risk of developing antiviral treatment resistance. Both S-HT and S-A participants had diminished SARS-CoV-2-specific humoral, while only the S-HT group had reduced T cell-mediated responses. This highlights the varied risk of persistent COVID-19 across immunosuppressive conditions and suggests that suppression of both B and T cell responses results in the highest contributing risk of persistent infection.
RESUMEN
Isolation guidelines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are largely derived from data collected prior to the emergence of the delta variant. We followed a cohort of ambulatory patients with postvaccination breakthrough SARS-CoV-2 infections with longitudinal collection of nasal swabs for SARS-CoV-2 viral load quantification, whole-genome sequencing, and viral culture. All delta variant infections in our cohort were symptomatic, compared with 64% of non-delta variant infections. Symptomatic delta variant breakthrough infections were characterized by higher initial viral load, longer duration of virologic shedding by PCR, greater likelihood of replication-competent virus at early stages of infection, and longer duration of culturable virus compared with non-delta variants. The duration of time since vaccination was also correlated with both duration of PCR positivity and duration of detection of replication-competent virus. Nonetheless, no individuals with symptomatic delta variant infections had replication-competent virus by day 10 after symptom onset or 24 hours after resolution of symptoms. These data support US CDC isolation guidelines as of November 2021, which recommend isolation for 10 days or until symptom resolution and reinforce the importance of prompt testing and isolation among symptomatic individuals with delta breakthrough infections. Additional data are needed to evaluate these relationships among asymptomatic and more severe delta variant breakthrough infections.
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Vacunas contra la COVID-19/administración & dosificación , COVID-19/genética , COVID-19/metabolismo , SARS-CoV-2/fisiología , Replicación Viral , Esparcimiento de Virus/fisiología , Adulto , COVID-19/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Protective immunity against SARS-CoV-2 infection after COVID-19 vaccination may differ by variant. We enrolled vaccinated (n = 39) and unvaccinated (n = 11) individuals with acute, symptomatic SARS-CoV-2 Delta or Omicron infection and performed SARS-CoV-2 viral load quantification, whole-genome sequencing, and variant-specific antibody characterization at the time of acute illness and convalescence. Viral load at the time of infection was inversely correlated with antibody binding and neutralizing antibody responses. Across all variants tested, convalescent neutralization titers in unvaccinated individuals were markedly lower than in vaccinated individuals. Increases in antibody titers and neutralizing activity occurred at convalescence in a variant-specific manner. For example, among individuals infected with the Delta variant, neutralizing antibody responses were weakest against BA.2, whereas infection with Omicron BA.1 variant generated a broader response against all tested variants, including BA.2.
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Vacunas contra el SIDA , COVID-19 , Vacunas contra la Influenza , Vacunas contra Papillomavirus , Vacunas contra Virus Sincitial Respiratorio , Vacunas contra el SIDAS , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BCG , COVID-19/prevención & control , Vacunas contra la COVID-19 , Convalecencia , Vacuna contra Difteria, Tétanos y Tos Ferina , Humanos , Vacuna contra el Sarampión-Parotiditis-Rubéola , Pruebas de Neutralización , SARS-CoV-2RESUMEN
Clinical features of SARS-CoV-2 Omicron variant infection, including incubation period and transmission rates, distinguish this variant from preceding variants. However, whether the duration of shedding of viable virus differs between omicron and previous variants is not well understood. To characterize how variant and vaccination status impact shedding of viable virus, we serially sampled symptomatic outpatients newly diagnosed with COVID-19. Anterior nasal swabs were tested for viral load, sequencing, and viral culture. Time to PCR conversion was similar between individuals infected with the Delta and the Omicron variant. Time to culture conversion was also similar, with a median time to culture conversion of 6 days (interquartile range 4-8 days) in both groups. There were also no differences in time to PCR or culture conversion by vaccination status.