RESUMEN
OBJECTIVES: Effectiveness of nirmatrelvir/ritonavir (NR) in kidney transplant recipients (KTRs) infected COVID-19 for more than 5 days has not been evaluated. METHODS: In this multicenter retrospective study, 85 KTRs with COVID-19 were enrolled, including 50 moderate, 21 severe, and 14 critical patients. RESULTS: The median time from onset to starting NR treatment was 14 (IQR, 11-19) days. Before NR treatment, 96.5% patients reduced use of antimetabolites. They also stopped using calcineurin inhibitors (CNI) 12-24 hours before NR treatment, with CNI concentrations well-controlled during NR treatment. The use of intravenous corticosteroids increased with COVID-19 severity. The median time to reach viral negative conversion was 5 (IQR, 4-8) days for all patients. For moderate and severe COVID-19 patients, they had a low rate of ICU admission (1.4%), exacerbation requiring upgraded oxygen therapy (5.6%), and dialysis (2.8%); no intubation and mechanical ventilation, and no deaths were observed. Patients with critical COVID-19 had a low mortality rate (7.1%). CONCLUSIONS: A regimen including NR for clearing SARS-CoV-2 along with reducing immunosuppressants and using intravenous corticosteroids is associated with lower rates of exacerbation and mortality in KTRs who have moderate to critical SARS-CoV-2 infection and the virus still present after 5 days.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Trasplante de Riñón , Ritonavir , Humanos , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Anciano , COVID-19/mortalidad , COVID-19/complicaciones , SARS-CoV-2 , Combinación de Medicamentos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Resultado del Tratamiento , Lopinavir/uso terapéutico , Lopinavir/administración & dosificación , Adulto , Receptores de Trasplantes/estadística & datos numéricos , Hospitalización/estadística & datos numéricosAsunto(s)
Tratamiento Farmacológico de COVID-19 , Hospitalización , Ritonavir , Humanos , Ritonavir/administración & dosificación , Hospitalización/estadística & datos numéricos , Combinación de Medicamentos , Adulto , Masculino , Vacunas contra la COVID-19/administración & dosificación , Persona de Mediana Edad , COVID-19/prevención & control , Femenino , Anciano , Antivirales/administración & dosificación , Resultado del TratamientoAsunto(s)
Antivirales , Tratamiento Farmacológico de COVID-19 , Combinación de Medicamentos , Hospitalización , Huésped Inmunocomprometido , Ritonavir , Humanos , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Hospitalización/estadística & datos numéricos , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Citidina/análogos & derivados , Citidina/uso terapéutico , Hidroxilaminas/uso terapéutico , Leucina/análogos & derivados , Leucina/uso terapéutico , Prolina/análogos & derivados , Prolina/uso terapéutico , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , COVID-19/prevención & control , Lactamas , NitrilosRESUMEN
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.
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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 & derivadosRESUMEN
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 RetrospectivosAsunto(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 RiñónRESUMEN
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.).
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Profilaxis Posexposición , SARS-CoV-2 , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Administración Oral , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , COVID-19/prevención & control , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Indazoles/efectos adversos , Indazoles/uso terapéutico , Indoles/efectos adversos , Indoles/uso terapéutico , Indoles/administración & dosificación , Lactamas , Leucina , Nitrilos , Prolina , Ritonavir/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/administración & dosificaciónRESUMEN
OBJECTIVES: To describe the management of haematological patients experiencing prolonged SARS-CoV-2 viral shedding, as the optimal management strategy for this condition remains undetermined. METHODS: We conducted a retrospective evaluation of our prospectively followed cohort of haematological patients treated with remdesivir for more than 10 days. Starting January 2023, upon COVID-19 diagnosis, the treatment strategy was based on symptoms and PCR cycle threshold (Ct) as follows: (i) when Ct was 25 or less or if the patient had symptoms, a course of remdesivir for at least 10 days, nirmatrelvir/ritonavir for 5 days (whenever possible) and convalescent plasma was administered; and (ii) when the patient was asymptomatic and had a PCR Ct of more than 25, when possible, a course of 5 days of nirmatrelvir/ritonavir was administered. The patient was considered to have achieved viral clearance and, thus, remdesivir was stopped, in either of these cases: (i) PCR negativity, or (ii) subgenomic RNA negativity. RESULTS: From January to November 2023, 18 patients benefited from a safe extended remdesivir administration, resulting in detection of SARS-CoV-2 viral clearance in a median time of 3.5 weeks (IQR 2.6-3.9) (min-max 1.6-8.0). No clinical or biological side effects were detected. No patient died or needed further treatment for their COVID-19 episode. CONCLUSIONS: The extended course of remdesivir, combined with other active therapies for COVID-19 infection, was well tolerated. Cure and virus negativity were obtained in all these high-risk patients.
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Adenosina Monofosfato , Alanina , Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Neoplasias Hematológicas , Ritonavir , SARS-CoV-2 , Esparcimiento de Virus , Humanos , Alanina/análogos & derivados , Alanina/uso terapéutico , Alanina/administración & dosificación , Alanina/efectos adversos , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Adenosina Monofosfato/efectos adversos , Adenosina Monofosfato/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , Estudios Retrospectivos , SARS-CoV-2/efectos de los fármacos , Anciano , Ritonavir/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/administración & dosificación , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/tratamiento farmacológico , Esparcimiento de Virus/efectos de los fármacos , Adulto , Resultado del Tratamiento , Combinación de Medicamentos , Inmunización Pasiva , Sueroterapia para COVID-19RESUMEN
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
Importance: There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC). Objective: To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms. Design, Setting, and Participants: This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration. Interventions: Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days. Main Outcomes and Measures: Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline. Results: Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade. Conclusions and Relevance: The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC. Trial Registration: ClinicalTrials.gov Identifier: NCT05576662.
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Síndrome Post Agudo de COVID-19 , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Femenino , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Persona de Mediana Edad , COVID-19/complicaciones , Adulto , Método Doble Ciego , Antivirales/uso terapéutico , Antivirales/efectos adversos , Resultado del Tratamiento , Índice de Severidad de la EnfermedadRESUMEN
In a pivotal trial (EPIC-HR), a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days of symptoms onset), decreased hospitalization and death by 89.1% and nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis in a trial, and frequent viral rebound has been observed in subsequent cohorts. We develop a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulates viral loads from this and another clinical trial (PLATCOV). Our results suggest that nirmatrelvir's in vivo potency is significantly lower than in vitro assays predict. According to our model, a maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of treatment to 10 days for Omicron variant infection in vaccinated individuals, rather than increasing dose or dosing frequency, is predicted to lower the incidence of viral rebound significantly.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Ritonavir , SARS-CoV-2 , Carga Viral , Humanos , SARS-CoV-2/efectos de los fármacos , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , COVID-19/prevención & control , COVID-19/virología , COVID-19/inmunología , Carga Viral/efectos de los fármacos , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Antivirales/farmacología , Indazoles/farmacología , Modelos Teóricos , Profilaxis Posexposición/métodos , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
The Japanese package insert (J-PI) for nirmatrelvir/ritonavir (N/r) (specially approved pharmaceutical) includes numerous warnings about drug interactions. However, discrepancies in the information on drug interaction are reported between J-PI and foreign databases. This study aimed to evaluate various information sources on N/r drug interactions. We categorized and compared information on N/r drug interactions from the J-PI, prescribing information from foreign regulatory agencies, guidance from the National Institutes of Health and University Health Network, the Ontario coronavirus disease 2019 (COVID-19) Science Advisory Table, University of Liverpool, Lexicomp, and the Japanese Society of Pharmaceutical Health Care and Sciences (JSPHCS). We assessed information quantity, missing data in J-PI, predicted change of the area under the blood concentration-time curve (AUC) for nirmatrelvir or co-administered drugs, and the information source consistency. From these information sources, we compiled a dataset with 115 contraindications and 203 precautions for N/r co-administration, and 51 contraindications are missing in J-PI. Among them, at least 12 drugs have large predicted AUC changes with N/r (AUC ≥5-fold or <1/5 of the baseline value). Nine of these 12 drugs are included as contraindications in Lexicomp and the JSPHCS. The consistency among the information sources is low. Information in the J-PI alone may be insufficient and Lexicomp or the JSPHCS guidelines should be useful because of their large amounts of information and wide coverage of drugs with large AUC changes. Due to low source consistency, multiple sources are needed for clinical management.
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Combinación de Medicamentos , Interacciones Farmacológicas , Ritonavir , Ritonavir/administración & dosificación , Humanos , Tratamiento Farmacológico de COVID-19 , Lopinavir , Área Bajo la Curva , Japón , IndazolesRESUMEN
This systematic review and meta-analysis aimed to compare the effectiveness and safety of azvudine versus nirmatrelvir/ritonavir (Paxlovid) in treating coronavirus disease 2019 (COVID-19). The researchers conducted searches on PubMed, Cochrane Library, Web of Science, medRxiv, and Google Scholar until January 2024. The Cochrane risk of bias tool was utilised to evaluate the quality of the included studies, and data analysis was performed using Comprehensive Meta-Analysis software. Thirteen studies, including 4949 patients, were analysed. The meta-analysis results showed no significant difference between the azvudine and Paxlovid groups in terms of mortality rate (odds rate [OR] = 0.84, 95% confidence interval [CI]: 0.59-1.21), negative polymerase chain reaction (PCR) conversion time (standard mean difference [SMD] = 1.52, 95% CI: -1.07-4.11), and hospital stay (SMD = -0.39, 95% CI: -1.12-0.33). However, a significant difference was observed between the two groups in terms of intensive care unit admission (OR = 0.42, 95% CI: 0.23-0.75) and the need for mechanical ventilation (OR = 0.61, 95% CI: 0.44-0.86) in favour of azvudine. The incidence of adverse events in the azvudine group was significantly lower (OR = 0.66, 95% CI: 0.43-0.99). The certainty of evidence was rated as low and moderate. Azvudine and Paxlovid demonstrated similar effectiveness in reducing mortality rates, negative PCR conversion time and hospital stay. However, azvudine showed better effectiveness in improving other outcomes. Regarding the level of certainty of evidence, further research is needed to validate or challenge these results.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Combinación de Medicamentos , Ritonavir , SARS-CoV-2 , Humanos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , SARS-CoV-2/efectos de los fármacos , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , COVID-19/mortalidad , COVID-19/virología , Lopinavir/uso terapéutico , Lopinavir/efectos adversos , Lopinavir/administración & dosificación , Resultado del TratamientoRESUMEN
OBJECTIVES: This study aimed to determine the association of early use of oral antiviral drugs (including nirmatrelvir-ritonavir and molnupiravir) with the risk of post COVID-19 condition (PCC) and compare the possible efficacy of nirmatrelvir-ritonavir and molnupiravir. METHODS: PubMed, Web of Science, Embase, Cochrane, MedRxiv, and Psycinfo were searched from inception until November 1, 2023. We included studies that assessed the effect of oral antiviral drugs on the incidence of PCC. Pairwise and network meta-analyses were conducted using a random-effects model. Risk ratios (RRs) for oral antiviral drugs were calculated with a confidence interval (CI). RESULTS: Nine observational studies containing 866,066 patients were included. Nirmatrelvir-ritonavir and molnupiravir were evaluated in eight and two studies respectively, with both drugs evaluated in one study. Pair-wise meta-analysis showed that early oral antiviral drugs reduced PCC risk (RR 0.77, 95% CI 0.68-0.88). Network meta-analysis showed that nirmatrelvir-ritonavir may perform better than molnupiravir (surface under the cumulative ranking curve: 95.5% vs. 31.6%) at reducing PCC risk. CONCLUSIONS: Early use of oral antiviral drugs may potentially protect against developing PCC in non-hospitalized patients with COVID-19. These findings support the standardized administration of oral antiviral drugs in patients during the acute phase of COVID-19 according to the guidelines.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Metaanálisis en Red , Ritonavir , SARS-CoV-2 , Humanos , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Administración Oral , COVID-19/epidemiología , Combinación de Medicamentos , Hidroxilaminas/uso terapéutico , Hidroxilaminas/administración & dosificación , Síndrome Post Agudo de COVID-19 , Lactamas , Citidina/análogos & derivados , Nitrilos , Prolina , LeucinaRESUMEN
BACKGROUNDS: The effectiveness of oral antiviral therapy including nirmatrelvir plus ritonavir and molnupiravir in managing COVID-19 among individuals with pre-existing lung cancer was unclear. Therefore, this study was conducted to evaluate the usefulness of antiviral agents in the management of COVID-19 among patients with lung cancer. METHODS: Utilizing data from the TriNetX - a global health research network, a retrospective cohort study was conducted involving 2484 patients diagnosed with both lung cancer and COVID-19. Propensity score matching (PSM) was employed to create well-balanced cohorts. The study assessed the primary outcome of all-cause hospitalization or mortality within a 30-day follow-up. RESULTS: After PSM, the oral antiviral group exhibited a significantly lower risk of the primary composite outcome compared to the control group (6.1 % vs. 9.9 %; HR: 0.60; 95 % CI: 0.45-0.80). This association was consistent across various subgroups according to age, sex, vaccine status, type of oral antiviral agent, and lung cancer characteristics. Additionally, the oral antiviral group showed a lower risk of all-cause hospitalization (HR: 0.73; 95 % CI: 0.54-0.99) and a significantly lower risk of mortality (HR: 0.16; 95 % CI: 0.06-0.41). CONCLUSION: The study suggests a favorable impact of oral antiviral therapy on the outcomes of COVID-19 in individuals with lung cancer and support the potential utility of oral antiviral agents in improving outcomes in this vulnerable population.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Neoplasias Pulmonares , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Femenino , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Administración Oral , Hospitalización/estadística & datos numéricos , COVID-19/mortalidad , Hidroxilaminas/uso terapéutico , Hidroxilaminas/administración & dosificación , Resultado del Tratamiento , Combinación de Medicamentos , Citidina/análogos & derivadosRESUMEN
BACKGROUND: Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches. METHODS: This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per µL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants. FINDINGS: Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group. INTERPRETATION: The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen. FUNDING: ANRS MIE.
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , VIH-2 , Ritonavir , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , Adulto , Masculino , Femenino , VIH-2/efectos de los fármacos , Tenofovir/uso terapéutico , Tenofovir/efectos adversos , Proyectos Piloto , Recuento de Linfocito CD4 , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificación , Emtricitabina/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Resultado del Tratamiento , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/efectos adversos , Lopinavir/uso terapéutico , Lopinavir/efectos adversos , Lopinavir/administración & dosificación , Raltegravir Potásico/uso terapéutico , Raltegravir Potásico/efectos adversos , Raltegravir Potásico/administración & dosificación , Lamivudine/uso terapéutico , Lamivudine/administración & dosificación , Lamivudine/efectos adversos , Carga Viral/efectos de los fármacos , Terapia Antirretroviral Altamente Activa , Persona de Mediana Edad , Zidovudina/uso terapéutico , Zidovudina/efectos adversos , Zidovudina/administración & dosificación , Quimioterapia Combinada , VIH-1/efectos de los fármacosRESUMEN
BACKGROUND: Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV. METHODS: D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872. FINDINGS: 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per µL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects. INTERPRETATION: In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines. FUNDING: UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.
Asunto(s)
Darunavir , Infecciones por VIH , VIH-1 , Compuestos Heterocíclicos con 3 Anillos , Oxazinas , Piperazinas , Piridonas , Inhibidores de la Transcriptasa Inversa , Ritonavir , Carga Viral , Humanos , Darunavir/uso terapéutico , Darunavir/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Femenino , Adulto , Masculino , VIH-1/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Carga Viral/efectos de los fármacos , Persona de Mediana Edad , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Nivel de Atención , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Quimioterapia Combinada , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificación , Resultado del Tratamiento , Terapia Antirretroviral Altamente Activa , Tenofovir/uso terapéutico , Tenofovir/administración & dosificación , Recuento de Linfocito CD4 , Insuficiencia del Tratamiento , Lamivudine/uso terapéutico , Lamivudine/administración & dosificaciónRESUMEN
BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.
Asunto(s)
Carbamazepina , Darunavir , Interacciones Farmacológicas , Infecciones por VIH , Humanos , Darunavir/uso terapéutico , Darunavir/farmacocinética , Masculino , Persona de Mediana Edad , Carbamazepina/uso terapéutico , Carbamazepina/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Neuralgia del Trigémino/tratamiento farmacológico , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/administración & dosificación , Piridonas/farmacocinética , Piridonas/uso terapéutico , Piridonas/sangre , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Piperazinas/uso terapéutico , Piperazinas/farmacocinética , Oxazinas/uso terapéutico , Oxazinas/farmacocinética , Relación Dosis-Respuesta a Droga , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Monitoreo de Drogas/métodosRESUMEN
OBJECTIVES: To establish a population pharmacokinetics (PopPK) model of nirmatrelvir in Chinese COVID-19 patients and provide reference for refining the dosing strategy of nirmatrelvir in patients confirmed to be infected with SARS-CoV-2. METHODS: A total of 80 blood samples were obtained from 35 mild to moderate COVID-19 patients who were orally administered nirmatrelvir/ritonavir tablets. The PopPK model of nirmatrelvir was developed using a nonlinear mixed effects modelling approach. The stability and prediction of the final model were assessed through a combination of goodness-of-fit and bootstrap method. The exposure of nirmatrelvir across various clinical scenarios was simulated using Monte Carlo simulations. RESULTS: The pharmacokinetics of nirmatrelvir was well characterised by a one-compartment model with first-order absorption, and with creatinine clearance (Ccr) as the significant covariate. Typical population parameter estimates of apparent clearance and distribution volume for a patient with a Ccr of 95.5 mL·min-1were 3.45 L·h-1 and 48.71 L, respectively. The bootstrap and visual predictive check procedures demonstrated satisfactory predictive performance and robustness of the final model. CONCLUSION: The final model was capable of offering an early prediction of drug concentration ranges for different nirmatrelvir dosing regimens and optimise the dose regimen of nirmatrelvir in individuals with confirmed SARS-CoV-2 infection.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Monitoreo de Drogas , Ritonavir , SARS-CoV-2 , Humanos , Masculino , Persona de Mediana Edad , Femenino , Adulto , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Antivirales/farmacocinética , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Anciano , China , Combinación de Medicamentos , Método de Montecarlo , Adulto Joven , COVID-19 , Pueblos del Este de AsiaRESUMEN
Quantitative systems pharmacology (QSP) has been an important tool to project safety and efficacy of novel or repurposed therapies for the SARS-CoV-2 virus. Here, we present a QSP modeling framework to predict response to antiviral therapeutics with three mechanisms of action (MoA): cell entry inhibitors, anti-replicatives, and neutralizing biologics. We parameterized three distinct model structures describing virus-host interaction by fitting to published viral kinetics data of untreated COVID-19 patients. The models were used to test theoretical behaviors and map therapeutic design criteria of the different MoAs, identifying the most rapid and robust antiviral activity from neutralizing biologic and anti-replicative MoAs. We found good agreement between model predictions and clinical viral load reduction observed with anti-replicative nirmatrelvir/ritonavir (Paxlovid®) and neutralizing biologics bamlanivimab and casirivimab/imdevimab (REGEN-COV®), building confidence in the modeling framework to inform a dose selection. Finally, the model was applied to predict antiviral response with ensovibep, a novel DARPin therapeutic designed as a neutralizing biologic. We developed a new in silico measure of antiviral activity, area under the curve (AUC) of free spike protein concentration, as a metric with larger dynamic range than viral load reduction. By benchmarking to bamlanivimab predictions, we justified dose levels of 75, 225, and 600 mg ensovibep to be administered intravenously in a Phase 2 clinical investigation. Upon trial completion, we found model predictions to be in good agreement with the observed patient data. These results demonstrate the utility of this modeling framework to guide the development of novel antiviral therapeutics.