RESUMEN
Cryptococcosis is a fungal infection that is becoming increasingly prevalent worldwide, particularly among individuals with compromised immune systems, such as HIV patients. Amphotericin B (AmB) is the first-line treatment mainly combined with flucytosine. The scarcity and the prohibitive cost of this regimen urge the use of fluconazole as an alternative, leading to increased rates of treatment failure and relapses. Therefore, there is a critical need for efficient and cost-effective therapy to enhance the efficacy of AmB. In this study, we evaluated the efficacy of the HIV protease inhibitors (PIs) to synergize the activity of AmB in the treatment of cryptococcosis. Five PIs (ritonavir, atazanavir, saquinavir, lopinavir, and nelfinavir) were found to synergistically potentiate the killing activity of AmB against Cryptococcus strains with Æ©FICI ranging between 0.09 and 0.5 against 20 clinical isolates. This synergistic activity was further confirmed in a time-kill assay, where different AmB/PIs combinations exhibited fungicidal activity within 24 hrs. Additionally, PIs in combination with AmB exhibited an extended post-antifungal effect on treated cryptococcal cells for approximately 10 hrs compared to 4 hours with AmB alone. This promising activity against cryptococcal cells did not exhibit increased cytotoxicity towards treated kidney cells, ruling out the risk of drug combination-induced nephrotoxicity. Finally, we evaluated the efficacy of AmB/PIs combinations in the Caenorhabditis elegans model of cryptococcosis, where these combinations significantly reduced the fungal burden of the treated nematodes by approximately 2.44 Log10 CFU (92.4%) compared to the untreated worms and 1.40 Log10 ((39.4%) compared to AmB alone. The cost-effectiveness and accessibility of PIs in resource-limited geographical areas compared to other antifungal agents, such as flucytosine, make them an appealing choice for combination therapy.
Asunto(s)
Anfotericina B , Antifúngicos , Criptococosis , Sinergismo Farmacológico , Inhibidores de la Proteasa del VIH , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/farmacología , Animales , Criptococosis/tratamiento farmacológico , Humanos , Caenorhabditis elegans/microbiología , Caenorhabditis elegans/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Cryptococcus neoformans/efectos de los fármacos , Quimioterapia Combinada , Ritonavir/uso terapéutico , Ritonavir/farmacología , Cryptococcus/efectos de los fármacosRESUMEN
BACKGROUND: The effect of nirmatrelvir/ritonavir on preventing post-COVID condition (PCC) in the BA4, BA5, and XBB Omicron predominant periods is not well understood. The purpose of this study was to assess how nirmatrelvir/ritonavir treatment affected both PCC and health-related quality of life. METHODS: This retrospective cohort study enrolled 2,524 adults aged 18 years and older who were eligible for nirmatrelvir/ritonavir between July 14 to November 14, 2022. All outcomes were observed from the patient's first visit to the primary health clinic, 1 week, 1 month, 3 months, and 6 months after testing positive for COVID-19. The primary outcome was the presence of PCC. Secondary outcomes included the effects on health-related quality of life, such as walking, bathing and dressing, activities, cause adverse emotions or signs that prevent individuals from leading normal lives over a 180-day observation period. RESULTS: There were no significant differences observed between the nirmatrelvir/ritonavir and those not administered (control group) in terms of PCC symptoms at 3 months (OR 0.71 95% CI 0.31, 1.64) and 6 months (OR 1.30 95% CI 0.76, 2.21). At 3 months, the use of nirmatrelvir/ritonavir was associated with a 26% reduction in symptoms causing negative emotions (OR 0.74 95% CI 0.60, 0.92) and an increased likelihood of symptoms limiting walking (OR 1.58 95% CI 1.10, 2.27). However, there were no significant differences between the nirmatrelvir/ritonavir and the control group in terms of the impact of PCC on health-related quality of life at 6 months. CONCLUSIONS: Our study indicates that the administration of nirmatrelvir/ritonavir does not significantly reduce PCC after 3 months and 6 months in a population with high vaccination coverage.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Calidad de Vida , Ritonavir , Humanos , Ritonavir/uso terapéutico , Masculino , Femenino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Malasia/epidemiología , COVID-19/prevención & control , SARS-CoV-2 , Anciano , Antivirales/uso terapéuticoRESUMEN
PURPOSE: Paxlovid is effective in reducing COVID-19 hospitalization and mortality. This study characterized Paxlovid use and evaluated racial/ethnic disparities over time among community-dwelling adults at high risk of progression to severe COVID-19 disease. METHODS: This retrospective cohort study used the National COVID Cohort Collaborative (N3C) data and included individuals aged 18 years or older diagnosed with COVID-19 between January 2022 and December 2023. The study cohort included nonhospitalized individuals who were at high risk of COVID-19 progression, and selected the first COVID-19 episode in each quarter, including reinfection episodes. Paxlovid use was defined as receiving Paxlovid within ±5 days of a COVID-19 diagnosis. We used descriptive statistics to characterize Paxlovid use overall and by calendar quarter and race/ethnicity. We used a generalized estimating equations (GEE) models to quantify the association of race/ethnicity with Paxlovid use controlling for age, gender, and clinical characteristics. RESULTS: Among 1 264 215 individuals at high risk of disease progression (1 404 607 episodes), Paxlovid use increased from 1.2% in January-March 2022 to 35.1% in October-December 2023. Paxlovid use was more common among non-Hispanic White individuals (23.9%) than non-Hispanic Black (16.5%) and Latinx/e (16.7%) patients. After adjusting age, gender, and clinical characteristics, Paxlovid use was less likely among non-Hispanic Black (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.68-0.70) and Latinx/e (OR 0.72, CI 0.71-0.73) patients than non-Hispanic White patients. CONCLUSIONS: Among a large, diverse cohort of community-dwelling individuals with COVID-19, nearly two out of three eligible individuals did not receive Paxlovid, and minoritized racial/ethnic groups were less likely to use Paxlovid than their non-Hispanic White individuals.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Combinación de Medicamentos , Ritonavir , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto , Anciano , Ritonavir/uso terapéutico , COVID-19/epidemiología , Estudios de Cohortes , Lopinavir/uso terapéutico , Índice de Severidad de la Enfermedad , Progresión de la Enfermedad , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton's tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.
Asunto(s)
Anticuerpos Neutralizantes , Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Linfoma , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Anticuerpos Neutralizantes/uso terapéutico , Persona de Mediana Edad , Femenino , Antivirales/uso terapéutico , SARS-CoV-2/inmunología , Linfoma/tratamiento farmacológico , Linfoma/complicaciones , COVID-19/inmunología , COVID-19/complicaciones , Ritonavir/uso terapéutico , Anciano , Estudios Prospectivos , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Resultado del Tratamiento , Combinación de Medicamentos , Recurrencia , Lopinavir/uso terapéutico , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/uso terapéuticoRESUMEN
BACKGROUND: Molnupiravir and nirmatrelvir-ritonavir are orally administered pharmacotherapies for mild to moderate COVID-19. However, the effectiveness of these drugs among very old (≥80 years), hospitalised patients remains unclear, limiting the risk-benefit assessment of these antivirals in this specific group. This study investigates the effectiveness of these antivirals in reducing mortality among this group of hospitalised patients with COVID-19. METHODS: Using a territory-wide public healthcare database in Hong Kong, a target trial emulation study was conducted with data from 13 642 eligible participants for the molnupiravir trial and 9553 for the nirmatrelvir-ritonavir trial. The primary outcome was all-cause mortality. Immortal time and confounding bias was minimised using cloning-censoring-weighting approach. Mortality odds ratios were estimated by pooled logistic regression after adjusting confounding biases by stabilised inverse probability weights. RESULTS: Both molnupiravir (HR: 0.895, 95% CI: 0.826-0.970) and nirmatrelvir-ritonavir (HR: 0.804, 95% CI: 0.678-0.955) demonstrated moderate mortality risk reduction among oldest-old hospitalised patients. No significant interaction was observed between oral antiviral treatment and vaccination status. The 28-day risk of mortality was lower in initiators than non-initiators for both molnupiravir (risk difference: -1.09%, 95% CI: -2.29, 0.11) and nirmatrelvir-ritonavir (risk difference: -1.71%, 95% CI: -3.30, -0.16) trials. The effectiveness of these medications was observed regardless of the patients' prior vaccination status. CONCLUSIONS: Molnupiravir and nirmatrelvir-ritonavir are moderately effective in reducing mortality risk among hospitalised oldest-old patients with COVID-19, regardless of their vaccination status.
Asunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , Hospitalización , SARS-CoV-2 , Humanos , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Masculino , Femenino , Anciano de 80 o más Años , Hospitalización/estadística & datos numéricos , Hong Kong/epidemiología , Administración Oral , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , COVID-19/mortalidad , COVID-19/epidemiología , Hidroxilaminas/administración & dosificación , Hidroxilaminas/uso terapéutico , Resultado del Tratamiento , Citidina/análogos & derivados , Citidina/administración & dosificación , Citidina/uso terapéutico , Leucina/análogos & derivadosAsunto(s)
Ritonavir , Tacrolimus , Humanos , Ritonavir/administración & dosificación , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Tacrolimus/sangre , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Masculino , Inhibidores de la Proteasa del VIH/administración & dosificación , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Persona de Mediana Edad , Quimioterapia Combinada , Trasplante de RiñónAsunto(s)
Tratamiento Farmacológico de COVID-19 , Hospitalización , Enfermedades Reumáticas , Ritonavir , Humanos , Ritonavir/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Reumáticas/complicaciones , COVID-19/prevención & control , COVID-19/mortalidad , Masculino , SARS-CoV-2 , Femenino , Persona de Mediana Edad , Quimioterapia CombinadaRESUMEN
BACKGROUND: The clinical benefit of coronavirus disease 2019 (COVID-19) treatments against new circulating variants remains unclear. We sought to describe characteristics and clinical outcomes of highest risk patients with COVID-19 receiving early COVID-19 treatments in Scotland. METHODS: Retrospective cohort study of non-hospitalized patients diagnosed with COVID-19 from December 1, 2021-October 25, 2022, using Scottish administrative health data. We included adult patients who met ≥ 1 of the National Health Service highest risk criteria for early COVID-19 treatment and received outpatient treatment with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or no early COVID-19 treatment. Index date was defined as the earliest of COVID-19 diagnosis or early COVID-19 treatment. Baseline characteristics and acute clinical outcomes in the 28 days following index were reported. Values of ≤ 5 were suppressed. RESULTS: In total, 2548 patients were included (492: sotrovimab, 276: nirmatrelvir/ritonavir, 71: molnupiravir, and 1709: eligible highest risk untreated). Patients aged ≥ 75 years accounted for 6.9% (n = 34/492), 21.0% (n = 58/276), 16.9% (n = 12/71) and 13.2% (n = 225/1709) of the cohorts, respectively. Advanced renal disease was reported in 6.7% (n = 33/492) of sotrovimab-treated and 4.7% (n = 81/1709) of untreated patients, and ≤ 5 nirmatrelvir/ritonavir-treated and molnupiravir-treated patients. All-cause hospitalizations were experienced by 5.3% (n = 25/476) of sotrovimab-treated patients, 6.9% (n = 12/175) of nirmatrelvir/ritonavir-treated patients, ≤ 5 (suppressed number) molnupiravir-treated patients and 13.3% (n = 216/1622) of untreated patients. There were no deaths in the treated cohorts; mortality was 4.3% (n = 70/1622) among untreated patients. CONCLUSIONS: Sotrovimab was often used by patients who were aged < 75 years. Among patients receiving early COVID-19 treatment, proportions of 28-day all-cause hospitalization and death were low.
Asunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Progresión de la Enfermedad , SARS-CoV-2 , Humanos , Antivirales/uso terapéutico , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Anciano , SARS-CoV-2/efectos de los fármacos , COVID-19/mortalidad , Adulto , Resultado del Tratamiento , Escocia/epidemiología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Ritonavir/uso terapéutico , Anciano de 80 o más Años , Citidina/análogos & derivados , HidroxilaminasRESUMEN
BACKGROUND: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis. METHODS: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline. RESULTS: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group). CONCLUSIONS: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.).
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Profilaxis Posexposición , Ritonavir , SARS-CoV-2 , Humanos , Ritonavir/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/administración & dosificación , Método Doble Ciego , Masculino , Femenino , Adulto , Persona de Mediana Edad , COVID-19/prevención & control , Administración Oral , Indazoles/efectos adversos , Indazoles/uso terapéutico , Combinación de Medicamentos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , Indoles/efectos adversos , Indoles/uso terapéutico , Indoles/administración & dosificación , Adulto Joven , Quimioterapia Combinada , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
OBJECTIVES: This study seeks to identify demographic and clinical factors prompting clinician prescribing of nirmatrelvir/ritonavir to pediatric patients for management of coronavirus disease 2019 (COVID-19) infection. METHODS: Patients aged 12 to 17 years with a COVID-19 infection and nirmatrelvir/ritonavir prescription during an outpatient clinical encounter within a PEDSnet-affiliated institution between January 2022 and August 2023 were identified using electronic health record data. A multivariate logistic regression analysis was used to estimate odds of nirmatrelvir/ritonavir prescription after adjusting for various factors. RESULTS: A total of 20 959 patients aged 12 to 17 years were diagnosed with a COVID-19 infection on the basis of an electronic health record-documented positive polymerase chain reaction or antigen test or diagnosis during an outpatient clinical visit. Of these patients, 408 received a nirmatrelvir/ritonavir prescription within 5 days of diagnosis. Higher odds of nirmatrelvir/ritonavir treatment were associated with having chronic or complex chronic disease (chronic: odds ratio [OR] 2.50 [95% confidence interval (CI) 1.83-3.38]; complex chronic: OR 2.21 [95% CI 1.58-3.08]). Among patients with chronic disease, each additional body system conferred 1.18 times higher odds of treatment (95% CI 1.10-1.26). Compared with non-Hispanic white patients, Hispanic patients (OR 0.61 [95% CI 0.44-0.83]) had lower odds of treatment. CONCLUSIONS: Children with chronic conditions are more likely than those without to receive nirmatrelvir/ritonavir prescriptions. However, nirmatrelvir/ritonavir prescribing to children with chronic conditions remains infrequent. Pediatric data concerning nirmatrelvir/ritonavir safety and effectiveness in preventing severe disease and hospitalization are critical optimizing clinical decision-making and use among children.
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Tratamiento Farmacológico de COVID-19 , Pautas de la Práctica en Medicina , Ritonavir , Humanos , Ritonavir/uso terapéutico , Niño , Femenino , Masculino , Adolescente , Pautas de la Práctica en Medicina/estadística & datos numéricos , Combinación de Medicamentos , COVID-19/epidemiología , SARS-CoV-2 , Antivirales/uso terapéutico , Lopinavir/uso terapéutico , Estudios RetrospectivosRESUMEN
BACKGROUND: The efficacy, effectiveness, and safety of the approved nirmatrelvir/ritonavir regimen for treatment of laboratory-confirmed mild/moderately severe COVID-19 remains unclear. METHODS: We systematically identified randomized controlled trials (RCTs) and real-world studies (RWS; observational studies) of the efficacy/effectiveness and/or safety of the approved nirmatrelvir/ritonavir regimen for COVID-19. We pooled appropriate data (adjusted estimates for RWS) using an inverse variance, random-effects model. We calculated statistical heterogeneity using the I 2 statistic. Results are presented as relative risk (RR) with associated 95% CI. We further assessed risk of bias/study quality and conducted trial sequential analysis of the evidence from RCTs. RESULTS: We included 4 RCTs (4,070 persons) and 16 RWS (1,925,047 persons) of adults (aged ≥18 years). One and 3 RCTs were of low and unclear risk of bias, respectively. The RWS were of good quality. Nirmatrelvir/ritonavir significantly decreased COVID-19 hospitalization compared with placebo/no treatment (RR = 0.17; 95% CI, 0.10-0.31; I 2 = 77.2%; 2 RCTs, 3,542 persons), but there was no significant difference for decrease of worsening severity (RR = 0.82; 95% CI, 0.66-1.01; I 2 = 47.5%; 3 RCTs, 1,824 persons), viral clearance (RR = 1.19; 95% CI, 0.93-1.51; I 2 = 82%; 2 RCTs, 528 persons), adverse events (RR = 1.41; 95% CI, 0.92-2.14; I 2 = 70.6%; 4 RCTs, 4,070 persons), serious adverse events (RR = 0.82; 95% CI, 0.41-1.62; I 2 = 0%; 3 RCTs, 3,806 persons), and all-cause mortality (RR = 0.27; 95% CI, 0.04-1.70; I 2 = 49.9%; 3 RCTs, 3,806 persons), although trial sequential analysis suggested that the current total sample sizes for these outcomes were not large enough for conclusions to be drawn. Real-world studies also showed significantly decreased COVID-19 hospitalization (RR = 0.48; 95% CI, 0.37-0.60; I 2 = 95.0%; 11 RWS, 1,421,398 persons) and all-cause mortality (RR = 0.24; 95% CI, 0.14-0.34; I 2 = 65%; 7 RWS, 286,131 persons) for nirmatrelvir/ritonavir compared with no treatment. CONCLUSIONS: Nirmatrelvir/ritonavir appears to be promising for preventing hospitalization and potentially decreasing all-cause mortality for persons with mild/moderately severe COVID-19, but the evidence is weak. More studies are needed.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Ritonavir , SARS-CoV-2 , Humanos , Ritonavir/uso terapéutico , Antivirales/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Quimioterapia Combinada , COVID-19/mortalidad , Indazoles/uso terapéuticoRESUMEN
Despite emerging evidence indicating that molecular SARS-CoV-2 tests performed on saliva have diagnostic sensitivity and specificity comparable to those observed with nasopharyngeal swabs (NPSs), most in vivo follow-up studies on the efficacy of drugs against SARS-CoV-2 have been performed on NPSs, not considering saliva as a possible alternative matrix. For this reason, in this study, we used, in parallel, saliva and NPS samples for the detection of SARS-CoV-2 by real-time RT-PCR in patients receiving Tixagevimab/Cilgavimab, Nirmatrelvir/Ritonavir, or Sotrovimab as a treatment against SARS-CoV-2. Our results showed a good correlation between the NPS and saliva samples for each drug; moreover, comparable changes in the cycle threshold (Ct) levels in saliva and NPSs were observed both 7 days and 30 days after treatment, thus confirming that the saliva represents a good matrix for in vivo follow-up studies verifying the effectiveness of treatments against SARS-CoV-2.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Nasofaringe , Ritonavir , SARS-CoV-2 , Saliva , Sensibilidad y Especificidad , Humanos , Saliva/virología , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/virología , Ritonavir/uso terapéutico , Nasofaringe/virología , Estudios de Seguimiento , Antivirales/uso terapéutico , Resultado del Tratamiento , Anticuerpos Monoclonales Humanizados/uso terapéutico , Combinación de Medicamentos , Lopinavir/uso terapéutico , Femenino , Masculino , Prueba de Ácido Nucleico para COVID-19/métodos , Persona de Mediana EdadRESUMEN
BACKGROUND: Patients with Hematological Malignancies (HM) are at a high risk of mortality from Coronavirus disease 2019 (COVID-19). The available antivirals were different between China and other countries. In China, azvudine was obtained for emergency use to treat adult COVID-19 patients with moderate symptoms in July 2022. While nirmatrelvir-ritonavir was well-known and used in many countries. The purpose of the present study was to assess whether there was any difference in the efficacy and safety of the two drugs. METHODS: This study was a prospective observational study of patients with HM who developed COVID-19. Patients were divided into three treatment groups: nirmatrelvir-ritonavir, azvudine, and observation. Treatment outcomes, first nucleic acid test negative time, hospitalization time, and the conversion rate of mild or moderate disease to severe disease were recorded. RESULTS: First nucleic acid test negative time (23.5 days vs. 34 days, p = 0.015), hospitalization time (p = 0.015), and conversion rate (31.8 % vs. 8 %, p = 0.046) were statistically different between the nirmatrelvir-ritonavir and observation groups. First nucleic acid test negative time (20 days vs. 34 days, p = 0.009) and hospitalization time (p = 0.026) were statistically different between the azvudine and observation groups. ECOG score and liver disease were significantly associated with the conversion rate from mild or moderate disease to severe disease using multivariate analysis (p < 0.05). CONCLUSIONS: The authors found no significant differences existed in outcome measures between patients with HM and COVID-19 who were treated with nirmatrelvir-ritonavir or azvudine.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Neoplasias Hematológicas , Ritonavir , Humanos , Masculino , Ritonavir/uso terapéutico , Persona de Mediana Edad , Antivirales/uso terapéutico , Femenino , Estudios Prospectivos , Neoplasias Hematológicas/tratamiento farmacológico , Resultado del Tratamiento , Adulto , Anciano , SARS-CoV-2 , COVID-19RESUMEN
Nirmatrelvir (PF-07321332), a first-in-class inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro), was developed by Pfizer under intense pressure during the pandemic to treat COVID-19. A weakness of nirmatrelvir is its limited metabolic stability, which led to the development of a combination therapy (paxlovid), involving coadministration of nirmatrelvir with the cytochrome P450 inhibitor ritonavir. However, limitations in tolerability of the ritonavir component reduce the scope of paxlovid. In response to these limitations, researchers at Pfizer have now developed the second-generation Mpro inhibitor PF-07817883 (ibuzatrelvir). Structurally related to nirmatrelvir, including with the presence of a trifluoromethyl group, albeit located differently, ibuzatrelvir manifests enhanced oral bioavailability, so it does not require coadministration with ritonavir. The development of ibuzatrelvir is an important milestone, because it is expected to enhance the treatment of COVID-19 without the drawbacks associated with ritonavir. Given the success of paxlovid in treating COVID-19, it is likely that ibuzatrelvir will be granted approval as an improved drug for treatment of COVID-19 infections, so complementing vaccination efforts and improving pandemic preparedness. The development of nirmatrelvir and ibuzatrelvir dramatically highlights the power of appropriately resourced modern medicinal chemistry to very rapidly enable the development of breakthrough medicines. Consideration of how analogous approaches can be used to develop similarly breakthrough medicines for infectious diseases such as tuberculosis and malaria is worthwhile.
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Antivirales , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/efectos de los fármacos , Antivirales/uso terapéutico , Antivirales/farmacología , Ritonavir/uso terapéutico , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Indazoles/uso terapéutico , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
In adults requiring protease inhibitor (PI)-based antiretroviral therapy (ART), replacing rifampicin with rifabutin is a preferred option, but there is lack of evidence to guide rifabutin dosing in children, especially with PIs. We aimed to characterize the population pharmacokinetics of rifabutin and 25-O-desacetyl rifabutin (des-rifabutin) in children and optimize its dose. We included children from three age cohorts: (i) <1-year-old cohort and (ii) 1- to 3-year-old cohort, who were ART naïve and received 15- to 20-mg/kg/day rifabutin for 2 weeks followed by lopinavir/ritonavir (LPV/r)-based ART with 5.0- or 2.5 mg/kg/day rifabutin, respectively, while the (iii) >3-year-old cohort was ART-experienced and received 2.5-mg/kg/day rifabutin with LPV/r-based ART. Non-linear mixed-effects modeling was used to interpret the data. Monte Carlo simulations were performed to evaluate the study doses and optimize dosing using harmonized weight bands. Twenty-eight children were included, with a median age of 10 (range 0.67-15.0) years, a median weight of 11 (range 4.5-45) kg, and a median weight-for-age z score of -3.33 (range -5.15 to -1.32). A two-compartment disposition model, scaled allometrically by weight, was developed for rifabutin and des-rifabutin. LPV/r increased rifabutin bioavailability by 158% (95% confidence interval: 93.2%-246.0%) and reduced des-rifabutin clearance by 76.6% (74.4%-78.3%). Severely underweight children showed 26% (17.9%-33.7%) lower bioavailability. Compared to adult exposures, simulations resulted in higher median steady-state rifabutin and des-rifabutin exposures in 6-20 kg during tuberculosis-only treatment with 20 mg/kg/day. During LPV/r co-treatment, the 2.5-mg/kg/day dose achieved similar exposures to adults, while the 5-mg/kg/day dose resulted in higher exposures in children >7 kg. All study doses maintained a median Cmax of <900 µg/L. The suggested weight-band dosing matches adult exposures consistently across weights and simplifies dosing.
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Infecciones por VIH , Lopinavir , Rifabutina , Ritonavir , Humanos , Rifabutina/farmacocinética , Rifabutina/uso terapéutico , Lopinavir/uso terapéutico , Lopinavir/farmacocinética , Ritonavir/uso terapéutico , Ritonavir/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Preescolar , Masculino , Femenino , Lactante , Tuberculosis/tratamiento farmacológico , Niño , Coinfección/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/farmacocinética , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéuticoRESUMEN
OBJECTIVE: To describe characteristics and acute clinical outcomes for patients with COVID-19 treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated patients at highest risk per National Health Service (NHS) criteria. METHODS: Retrospective study of non-hospitalized patients between 1 December 2021 and 31 May 2022, using data from the Discover-NOW dataset (North-West London). Included patients were aged ≥12 years and treated with sotrovimab, nirmatrelvir/ritonavir or molnupiravir, or untreated but expected to be eligible for early treatment per NHS highest-risk criteria. COVID-19-related and all-cause hospitalizations were reported for 28 days from COVID-19 diagnosis (index). Subgroup analyses were conducted in patients with advanced renal disease, those aged 18-64 and ≥65 years, and by period of Omicron BA.1, BA.2 and BA.5 (post-hoc exploratory) predominance. RESULTS: Overall, 1503 treated and 4044 eligible high-risk untreated patients were included. A high proportion of patients on sotrovimab had advanced renal disease (29.3%), ≥3 high-risk comorbidities (47.6%) and were aged ≥65 years (36.9%). Five of 696 (0.7%) patients on sotrovimab, <5/337 (0.3-1.2%) on nirmatrelvir/ritonavir, 10/470 (2.1%) on molnupiravir and 114/4044 (2.8%) untreated patients were hospitalized with COVID-19. Similar results were observed across all subgroups. The proportion of patients dying within 28 days of the index period was similarly low across all cohorts (<2%). CONCLUSION: Patients receiving sotrovimab appeared to show evidence of multiple high-risk comorbidities. Low hospitalization rates were observed for all treated cohorts across subgroups and periods of predominant variants of concern. These results require confirmation with comparative effectiveness analyses adjusting for differences in underlying patient characteristics.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Progresión de la Enfermedad , SARS-CoV-2 , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Masculino , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Femenino , Adulto , Anciano , COVID-19/epidemiología , SARS-CoV-2/aislamiento & purificación , Adolescente , Adulto Joven , Inglaterra/epidemiología , Hospitalización/estadística & datos numéricos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Resultado del Tratamiento , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Betacoronavirus , Administración Oral , Citidina/análogos & derivados , HidroxilaminasRESUMEN
Among immunocompromised hosts, leukemia patients, and hematopoietic cell transplant recipients are particularly vulnerable, facing challenges in balancing coronavirus disease 2019 (COVID-19) management with their underlying conditions. In this How I Treat article, we discuss how we approach severe acute respiratory syndrome coronavirus 2 infections in daily clinical practice, considering the existing body of literature and for topics where the available data are not sufficient to provide adequate guidance, we provide our opinion based on our clinical expertise and experience. Diagnostic approaches include nasopharyngeal swabs for polymerase chain reaction testing and chest computed tomography scans for symptomatic patients at risk of disease progression. Preventive measures involve strict infection control protocols and prioritizing vaccination for both patients and their families. Decisions regarding chemotherapy or hematopoietic cell transplantation in leukemia patients with COVID-19 require careful consideration of factors such as COVID-19 severity and treatment urgency. Treatment protocols include early initiation of antiviral therapy, with nirmatrelvir/ritonavir or remdesivir. For cases of prolonged viral shedding, distinguishing between viable and non-viable viruses remains challenging but is crucial for determining contagiousness and guiding management decisions. Overall, individualized approaches considering immune status, clinical presentation, and viral kinetics are essential for effectively managing COVID-19 in leukemia patients.
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Adenosina Monofosfato , Alanina , Antivirales , COVID-19 , Trasplante de Células Madre Hematopoyéticas , Huésped Inmunocomprometido , Leucemia , SARS-CoV-2 , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , COVID-19/complicaciones , Antivirales/uso terapéutico , Leucemia/complicaciones , Leucemia/terapia , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Ritonavir/uso terapéutico , Receptores de Trasplantes , Lopinavir/uso terapéutico , Esparcimiento de Virus , Combinación de MedicamentosRESUMEN
PURPOSE: Immunocompromised individuals, such as those diagnosed with cancer, are at a significantly higher risk for severe illness and mortality when infected with SARS-CoV-2 (COVID-19) than the general population. Two oral antiviral treatments are approved for COVID-19: Paxlovid® (nirmatrelvir/ritonavir) and Lagevrio® (molnupiravir). There is a paucity of data regarding the benefit from these antivirals among immunocompromised patients with cancer, and recent studies have questioned their efficacy among vaccinated patients, even those with risk factors for severe COVID-19. METHODS: We evaluated the efficacy and safety of nirmatrelvir/ritonavir and molnupiravir in preventing severe illness and death using our database of 457 patients with cancer and COVID-19 from Brown University-affiliated hospitals. RESULTS: Sixty-seven patients received nirmatrelvir/ritonavir or molnupiravir and were compared to 45 concurrent controls who received no antiviral treatment despite being eligible to receive it. Administration of nirmatrelvir/ritonavir or molnupiravir was associated with improved survival and lower 90-day all-cause and COVID-19-attributed mortality (p < 0.05) and with lower peak O2 requirements (ordinal odds ratio [OR] 1.52, 95% confidence interval [CI] 0.92-2.56). CONCLUSION: Acknowledging the small size of our sample as a limitation, we concluded that early antiviral treatment might be beneficial to immunocompromised individuals, particularly those with cancer, when infected with SARS-CoV-2. Larger-scale, well-stratified studies are needed in this patient population.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Neoplasias , Ritonavir , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Masculino , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Femenino , Persona de Mediana Edad , Anciano , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Administración Oral , Citidina/análogos & derivados , Citidina/uso terapéutico , Citidina/administración & dosificación , Hidroxilaminas/uso terapéutico , Hidroxilaminas/administración & dosificación , COVID-19 , Adulto , Huésped Inmunocomprometido , Leucina/análogos & derivados , Leucina/uso terapéutico , Anciano de 80 o más Años , SARS-CoV-2 , Estudios RetrospectivosRESUMEN
GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled (n = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (-12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171's maximum plasma concentration (Cmax), area under the concentration-time curve up to the last quantifiable time (AUC0-t), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171's peak time (Tmax) and elimination half-life (T1/2). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic.Clinical TrialsRegistered at ClinicalTrials.gov (NCT06106113).
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Inhibidores del Citocromo P-450 CYP3A , Hígado , Inhibidores de Proteasas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Área Bajo la Curva , China , Tratamiento Farmacológico de COVID-19 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Pueblos del Este de Asia , Hígado/efectos de los fármacos , Hepatopatías , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/farmacocinética , Ritonavir/efectos adversos , Ritonavir/farmacocinéticaRESUMEN
(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.