RESUMEN
INTRODUCTION: Lurbinectedin is FDA approved for treatment of metastatic small cell lung cancer (SCLC) following progression on or after platinum-based chemotherapy. Prostatic small cell or neuroendocrine carcinoma (SC/NEPC) behaves like SCLC; however, no safety or efficacy data for lurbinectedin in SC/NEPC exists. PATIENTS AND METHODS: All SC/NEPC patients treated with lurbinectedin across 4 academic oncology centers were identified. Baseline patient data and lurbinectedin outcomes including radiographic responses (complete response [CR], partial response [PR], stable disease [SD], progressive disease [PD]), progression free survival (PFS), overall survival (OS), and treatment-related adverse events (trAEs) were described. Clinical benefit rate (CBR) included CR, PR, or SD on imaging. Descriptive statistics were performed. RESULTS: At first lurbinectedin dose, all 18 patients had metastatic disease. Median age was 63.5 (Range: 53-84), number of prior systemic therapies was 4 (Range: 2-7), and lurbinectedin cycles completed was 5 (Range: 1-10). ADT was administered during lurbinectedin treatment in 9/18 patients. CBR was 9/16 (56%). The most common trAEs were fatigue and anemia. Median OS and PFS were 6.01 (0.23-16.69) and 3.35 (0.16-7.79) months. CONCLUSIONS: Lurbinectedin showed modest but significant clinical benefit in some patients with SC/NEPC and demonstrated an acceptable toxicity profile with no hospitalizations from trAEs. SC/NEPC is an aggressive disease with a poor prognosis for which more treatment options are needed. Evidence for subsequent treatments after platinum-based chemotherapy is lacking. Lurbinectedin is an active treatment option for SC/NEPC; however, larger confirmatory studies are needed.
Asunto(s)
Carbolinas , Carcinoma Neuroendocrino , Compuestos Heterocíclicos de 4 o más Anillos , Neoplasias de la Próstata , Humanos , Masculino , Carbolinas/administración & dosificación , Carbolinas/uso terapéutico , Carbolinas/efectos adversos , Anciano , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/patología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Persona de Mediana Edad , Anciano de 80 o más Años , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Resultado del Tratamiento , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Estudios Retrospectivos , Supervivencia sin ProgresiónRESUMEN
INTRODUCTION: Pharmacotherapy against hepatitis C virus (HCV) infection has tremendously improved since the advent of interferon (IFN)-free direct-acting antivirals (DAAs). Additionally, fixed-dose pangenotypic DAAs, which are safe, potent, easy for use, and can cover a wide spectrum of patients, have been recommended by professional guidelines for DAA-naïve and DAA-experienced patients with HCV. AREAS COVERED: We review the pharmacokinetics, pharmacodynamics, and potential drug-drug interactions (DDIs) of fixed-dose pangenotypic DAA regimens, including glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). Additionally, we summarize the efficacy and safety of these regimens in clinical trials as well as real-world studies for treating different populations. Lastly, we discuss unmet medical needs in managing HCV in the era of fixed-dose pangenotypic DAAs. EXPERT OPINION: Protease inhibitors (PIs), including GLE and VOX, are prone to have more frequent DDIs, compared to the non-structural (NS) 5A and 5B inhibitors. These regimens are generally well tolerated and can be applied to different populations, except for the contraindicated use of PI-containing DAA regimens in decompensated cirrhosis. Using the first-line GLE/PIB and SOF/VEL can eradicate HCV in more than 95% of DAA-naïve patients across different populations. The viral cure usually exceeds 95% when using the rescue SOF/VEL/VOX regimen for prior DAA failures.
Asunto(s)
Antivirales , Interacciones Farmacológicas , Humanos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/farmacocinética , Antivirales/farmacología , Antivirales/administración & dosificación , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Combinación de Medicamentos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Bencimidazoles/uso terapéutico , Bencimidazoles/farmacología , Sulfonamidas/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Pirrolidinas/uso terapéuticoRESUMEN
PURPOSE: This study aims to comprehensively assess the safety of Asenapine by conducting an comprehensive statistical analysis of adverse event reports in the FAERS database, with a particular focus on potential adverse reactions related to its use in the treatment of psychiatric disorders. METHODS: Event reports from the first quarter of 2009 to the third quarter of 2023 were collected and analyzed. Detailed examinations of gender, age, reporter identity, and other aspects were conducted to reveal the fundamental characteristics of Asenapine-related adverse events. Signal mining techniques were employed to systematically evaluate various adverse reactions associated with Asenapine. RESULTS: The study found that adverse event reports involving Asenapine were more common among female patients, with the age group mainly distributed between 18 and 45 years. Physicians were the primary reporters of adverse events, and psychiatric disorders, neurological disorders, and gastrointestinal disorders were the most common areas affected by adverse reactions. In addition to known adverse reactions, potential risks not mentioned in the drug label were identified, such as anosognosia, attentional drift, and psychogenic compensation disorder. CONCLUSION: Asenapine carries the risk of various adverse reactions alongside its therapeutic effects. In clinical practice, physicians should closely monitor the occurrence of neurological disorders, psychiatric disorders, and gastrointestinal system disorders.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Antipsicóticos , Bases de Datos Factuales , Dibenzocicloheptenos , Trastornos Mentales , Humanos , Femenino , Masculino , Persona de Mediana Edad , Antipsicóticos/efectos adversos , Trastornos Mentales/tratamiento farmacológico , Trastornos Mentales/inducido químicamente , Adulto , Adolescente , Adulto Joven , Enfermedades del Sistema Nervioso/inducido químicamente , Anciano , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversosRESUMEN
INTRODUCTION: Rapid initiation of ART after HIV diagnosis is recommended for individual and public health benefits. However, certain clinical and ART-related considerations hinder immediate initiation of therapy. METHODS: An open-label, single-arm, single-centre 48-week prospective clinical trial involving ART-naïve HIV-diagnosed adults who started bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) within a week from the first hospital visit, before the availability of baseline laboratory and genotype results. The primary aim was to determine the proportion of people with at least one condition that would hinder immediate initiation of any recommended ART regimen other than BIC/FTC/TAF. Clinicaltrials.gov: NCT04416906. RESULTS: We included 100 participants: 79% men, 64% from Latin America, median age 32 years. According to European AIDS Clinical Society (EACS) and US Department of Health and Human Services 2023 guidelines, 11% (95%CI 6; 19) of participants had at least one condition that made any ART different from BIC/FTC/TAF less appropriate for a rapid ART strategy. Seventy-nine percent of the people started BIC/FTC/TAF within the first 48 hours of their first hospital visit. There were 16 early discontinuations (11 lost to follow-up). By week 48, 92% (95%CI 86; 98) of the participants of the ITT population with observed data achieved viral suppression. Eight grade 3-4 adverse events (AEs), five serious AEs and six ART-related AEs were identified. Adherence remained high. CONCLUSIONS: BIC/FTC/TAF is an optimal treatment for rapid initiation of ART. However, additional strategies to improve retention in care must be implemented.
Asunto(s)
Alanina , Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , Masculino , Adulto , Estudios Prospectivos , Femenino , Tenofovir/uso terapéutico , Tenofovir/administración & dosificación , Tenofovir/análogos & derivados , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Piridonas/administración & dosificación , Alanina/uso terapéutico , Alanina/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Piperazinas/administración & dosificación , Amidas/administración & dosificación , Amidas/uso terapéutico , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/administración & dosificación , Adenina/efectos adversos , Combinación de Medicamentos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Persona de Mediana Edad , Adulto Joven , Carga Viral/efectos de los fármacosRESUMEN
OBJECTIVE: This systematic review provides an update on outcomes for patients with spinal muscular atrophy (SMA) type 1 to 4 treated with approved therapeutics, including the most recent, risdiplam, for an observation period of up to 48 months. METHODS: A systematic literature search was conducted in July 2023 in four databases. Selected publications were assessed for internal validity and risk of bias by two authors and relevant data were extracted into standardised tables. Results were summarised narratively as substantial heterogeneity of studies prevents meaningful quantitative analysis. RESULTS: Twenty observational studies and one RCT were included in the analysis, fifteen studies on nusinersen, one on onasemnogene abeparvovec and two on risdiplam. Evidence supports the effectiveness of the therapies in motor function improvement for up to 48 months of follow-up in the SMA types specified in their respective indications. Better results were observed with earlier treatment initiation and higher baseline function. Whilst motor improvement was consistently observed, regardless of SMA type or treatment used, we noted no significant improvements in respiratory and nutritional outcomes. Quality of life endpoints were rarely investigated. Adverse events were common but seldom classified as treatment-related except for post-lumbar puncture syndrome, which was frequently reported across nusinersen studies. CONCLUSION: The treatment of SMA with the new therapies changes the disease phenotype with changes in motor function far exceeding any improvement in respiratory and nutritional function. Questions persist on long-term efficacy, potential regressions, impact on quality of life and social functioning, therapy duration, and discontinuation indicators.
Asunto(s)
Oligonucleótidos , Humanos , Oligonucleótidos/administración & dosificación , Oligonucleótidos/uso terapéutico , Oligonucleótidos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Atrofias Musculares Espinales de la Infancia/tratamiento farmacológico , Atrofia Muscular Espinal/tratamiento farmacológico , Quimioterapia Combinada , Compuestos Azo , Productos Biológicos , Pirimidinas , Proteínas Recombinantes de FusiónRESUMEN
PURPOSE: While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. PATIENTS AND METHODS: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. RESULTS: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0-ND]. The objective response rate was 60% (6/10 confirmed partial responses). CONCLUSIONS: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well tolerated and demonstrated intriguing clinical activity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carbolinas , Doxorrubicina , Compuestos Heterocíclicos de 4 o más Anillos , Sarcoma , Humanos , Masculino , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Persona de Mediana Edad , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carbolinas/administración & dosificación , Carbolinas/efectos adversos , Carbolinas/uso terapéutico , Anciano , Adulto , Sarcoma/tratamiento farmacológico , Sarcoma/patología , Sarcoma/mortalidad , Dosis Máxima Tolerada , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Resultado del Tratamiento , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: The use of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) is based on the results of robust clinical trials. OBJECTIVES: To assess the effectiveness and safety of BIC/FTC/TAF in treatment-naïve (TN) and treatment-experienced (TE) people with HIV using available real-world cohort studies. METHODS: Systematic review and meta-analysis of publications and communications identified via Boolean search in Medline, PubMed and Embase, and conference abstracts reporting retrospective real-world use of BIC/FTC/TAF, published until 31 January 2024. The primary endpoint was the proportion of TN and TE people with HIV with viral load (VL)â<â50â copies/mL at 48â weeks while on treatment. RESULTS: Of the 38 identified publications and conference abstracts, for the present analysis we included 12 publications (comprising 792 TN and 6732 TE individuals). For the three publications including 507 TN participants reporting the primary outcome, VL suppression was 97% [95% confidence intervals (CI): 89-100]. For the nine publications including 4946 TE participants reporting the primary outcome, VL suppression was 95% (95% CI: 94-96), with suppression >93% in all studies. Total discontinuations at 48â weeks in TE individuals were 3% (95% CI: 2-5), 1% (95% CI: 0-2) due to side effects. A total of four publications with 151 TE individuals with previous presence of M184V substitution were identified, reporting a suppression rate at 48â weeks of 95% (95% CI: 88-100). CONCLUSIONS: Real-world studies demonstrate low discontinuation rates and high rates of virologic suppression in individuals treated with BIC/FTC/TAF, both TN and TE with and without previous detection of M184V substitution.
Asunto(s)
Alanina , Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos , Tenofovir , Carga Viral , Humanos , Infecciones por VIH/tratamiento farmacológico , Tenofovir/uso terapéutico , Tenofovir/administración & dosificación , Tenofovir/análogos & derivados , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Alanina/uso terapéutico , Carga Viral/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Combinación de Medicamentos , Amidas/uso terapéutico , Piperazinas , Piridonas , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/efectos adversos , Adenina/administración & dosificación , Resultado del Tratamiento , VIH-1/efectos de los fármacos , VIH-1/genética , Estudios RetrospectivosRESUMEN
OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive, and longitudinal study. All human immunodeficiency virus (HIV) patients over 18â¯years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (p=.001). Persistence with DGT/3TC was 1237â¯days (IC95% 1216-1258) and persistence with BIC/FTC/TAF was 986â¯days [(IC95% 950-1021); p<.001]. The difference was remained after adjusting for covariates with the cox regression model [HR=8.2 (IC95% 1.03-64.9), p=.047]. The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study, patients have a high persistence. Patients on DTG/3TC treatment are more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF is tolerability/toxicity.
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Lamivudine , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , Estudios Retrospectivos , Masculino , Piridonas/uso terapéutico , Femenino , Lamivudine/uso terapéutico , Piperazinas/uso terapéutico , Oxazinas/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Adulto , Persona de Mediana Edad , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/uso terapéutico , Tenofovir/uso terapéutico , Alanina/uso terapéutico , Alanina/análogos & derivados , Estudios Longitudinales , Combinación de Medicamentos , Amidas/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Adenina/análogos & derivados , Adenina/uso terapéuticoRESUMEN
Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.
Asunto(s)
Antivirales , Hepacivirus , Sofosbuvir , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , África Central , África Occidental , Ácidos Aminoisobutíricos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Bencimidazoles/uso terapéutico , Bencimidazoles/efectos adversos , Benzopiranos , Carbamatos/uso terapéutico , Ciclopropanos/uso terapéutico , Ciclopropanos/efectos adversos , Quimioterapia Combinada , Estudios de Factibilidad , Fluorenos/uso terapéutico , Fluorenos/efectos adversos , Genotipo , Hepacivirus/genética , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Prolina/uso terapéutico , Quinoxalinas , Ribavirina/uso terapéutico , Ribavirina/efectos adversos , Sofosbuvir/uso terapéutico , Sofosbuvir/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017.
Asunto(s)
Pirimidinas , Humanos , Masculino , Femenino , Adulto , Niño , Adolescente , Adulto Joven , Persona de Mediana Edad , Preescolar , Pirimidinas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Atrofia Muscular Espinal/tratamiento farmacológico , Resultado del Tratamiento , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos AzoRESUMEN
BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.
Asunto(s)
Adenina , Alanina , Amidas , Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Compuestos Heterocíclicos de 4 o más Anillos , Piperazinas , Piridonas , Tenofovir , Tenofovir/análogos & derivados , Humanos , Emtricitabina/farmacocinética , Emtricitabina/administración & dosificación , Emtricitabina/uso terapéutico , Emtricitabina/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Tenofovir/farmacocinética , Tenofovir/administración & dosificación , Tenofovir/efectos adversos , Tenofovir/uso terapéutico , Niño , Masculino , Femenino , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Preescolar , Alanina/farmacocinética , Alanina/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Amidas/farmacocinética , Adolescente , Piridonas/farmacocinética , Piridonas/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/farmacocinética , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/efectos adversos , Adenina/administración & dosificación , Adenina/uso terapéutico , Tailandia , Estados Unidos , Sudáfrica , Combinación de Medicamentos , Uganda , Carga Viral/efectos de los fármacosRESUMEN
This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.
Asunto(s)
Carbolinas , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Compuestos Heterocíclicos de 4 o más Anillos , Itraconazol , Neoplasias , Humanos , Itraconazol/farmacocinética , Itraconazol/administración & dosificación , Itraconazol/efectos adversos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Neoplasias/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacología , Carbolinas/farmacocinética , Carbolinas/administración & dosificación , Carbolinas/efectos adversos , Adulto , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Área Bajo la Curva , Antineoplásicos/farmacocinética , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificaciónRESUMEN
BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.
Asunto(s)
Antivirales , Carbamatos , Combinación de Medicamentos , Hepatitis C Crónica , Compuestos Heterocíclicos de 4 o más Anillos , Sofosbuvir , Humanos , Sofosbuvir/uso terapéutico , Sofosbuvir/farmacocinética , Sofosbuvir/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Niño , Carbamatos/uso terapéutico , Carbamatos/farmacocinética , Carbamatos/efectos adversos , Carbamatos/administración & dosificación , Masculino , Preescolar , Femenino , Antivirales/uso terapéutico , Antivirales/farmacocinética , Antivirales/administración & dosificación , Antivirales/efectos adversos , Adolescente , Hepatitis C Crónica/tratamiento farmacológico , Resultado del Tratamiento , Hepacivirus/genética , Hepacivirus/efectos de los fármacos , Respuesta Virológica Sostenida , Genotipo , Bencimidazoles , BenzopiranosRESUMEN
OBJECTIVES: To assess the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) among people poorly represented in clinical trials and potentially at higher risk of suboptimal response to ART. METHODS: Observational cohort study on persons with HIV (PWH) enrolled in ICONA who started BIC/FTC/TAF as initial therapy or as switching regimen while virologically suppressed. Primary endpoint was time to treatment failure (TF): new AIDS/death or virological failure (VF) or discontinuation for toxicity/failure. Secondary endpoints were time to treatment discontinuation for toxicity (TDT) and to VF. Groups of interest were those aged >50â years, female sex, and advanced HIV disease at first ART start. Probability of the events overall and according to groups and adjusted HR for every endpoint were calculated by Kaplan-Meier curves and Cox regression models. RESULTS: Nine hundred and thirty-three ART-naive and 1655 ART-experienced PWH initiated BIC/FTC/TAF. Over a median follow-up of 69.8â weeks, 89 (9.6%) PWH at their first regimen experienced TF. PWH aged >50â years had 1.83-fold (95% CI: 1.19-2.83) higher risk of TF; PWH with advanced HIV disease had 2.21-fold (95% CI: 1.53-3.82) higher risk; there were no differences in TF according to sex.Over a median follow-up of 146.3â weeks, 109 (6.6%) out of 1655 switching PWH experienced TF; no differences were found in the risk of TF, TDT and VF according to groups of interest. CONCLUSIONS: Overall, BIC/FTC/TAF is well tolerated and virologically effective in the real-world scenario for ART-naive and -experienced PWH. Older ART-naive PWH and those with advanced HIV disease may respond less well as the burden of diseases might compromise treatment efficacy.
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos de 4 o más Anillos , Piridonas , Tenofovir , Humanos , Infecciones por VIH/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Tenofovir/uso terapéutico , Tenofovir/análogos & derivados , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificación , Estudios de Cohortes , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Adulto , Piridonas/uso terapéutico , Resultado del Tratamiento , Alanina/uso terapéutico , Amidas/uso terapéutico , Piperazinas/uso terapéutico , Piperazinas/administración & dosificación , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/administración & dosificación , Adenina/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Carga Viral/efectos de los fármacos , Combinación de Medicamentos , Sustitución de MedicamentosRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of 96âweeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. DESIGN: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144âweeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. METHODS: A pooled analysis evaluated viral suppression (HIV-1 RNA <50âcopies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. RESULTS: At OLE Week 96, participants who switched to B/F/TAF ( N â=â519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. CONCLUSION: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , VIH-1 , Oxazinas , Piperazinas , Tenofovir , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Adenina/análogos & derivados , Adenina/uso terapéutico , Adenina/efectos adversos , Alanina/uso terapéutico , Amidas/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Recuento de Linfocito CD4 , Método Doble Ciego , Sustitución de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Emtricitabina/uso terapéutico , Emtricitabina/administración & dosificación , Emtricitabina/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Piridonas , Tenofovir/uso terapéutico , Tenofovir/efectos adversos , Tenofovir/administración & dosificación , Tenofovir/análogos & derivados , Resultado del Tratamiento , Carga ViralRESUMEN
BACKGROUND AND AIMS: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. METHODS: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). RESULTS: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. CONCLUSION: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.
Asunto(s)
Carbolinas , Compuestos Heterocíclicos de 4 o más Anillos , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Femenino , Anciano , Carbolinas/uso terapéutico , Persona de Mediana Edad , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Australia , Antineoplásicos/uso terapéutico , Anciano de 80 o más Años , Supervivencia sin Progresión , Resultado del Tratamiento , AdultoRESUMEN
This single-arm, multi-center clinical trial aimed to evaluate the safety, tolerability, DLT, recommended dose (RD), preliminary efficacy, and pharmacokinetics (PK) characteristics of lurbinectedin, a selective inhibitor of oncogenic transcription, in Chinese patients with advanced solid tumors, including relapsed SCLC. Patients with advanced solid tumors were recruited in the dose-escalation stage and received lurbinectedin in a 3 + 3 design (two cohorts: 2.5 mg/m2 and 3.2 mg/m2, IV, q3wk). The RD was expanded in the following dose-expansion stage, including relapsed SCLC patients after first-line platinum-based chemotherapy. The primary endpoints included safety profile, tolerability, DLT, RD, and preliminary efficacy profile, while the secondary endpoints included PK characteristics. In the dose-escalation stage, ten patients were included, while one patient had DLT in the 3.2 mg/m2 cohort, which was also the RD for the dose-expansion stage. At cutoff (May 31, 2022), 22 SCLC patients were treated in the ongoing dose-expansion stage, and the median follow-up was 8.1 months (range 3.0-11.7). The most common grade ≥ 3 treatment-related adverse events (TRAEs) included neutropenia (77.3%), leukopenia (63.6%), thrombocytopenia (40.9%), anemia (18.2%), and ALT increased (18.2%). The most common severe adverse events (SAEs) included neutropenia (27.3%), leukopenia (22.7%), thrombocytopenia (18.2%), and vomiting (9.1%). No treatment-related deaths occurred. The Independent Review Committee (IRC)-assessed ORR was 45.5% (95% CI 26.9-65.3). Lurbinectedin at the RD (3.2 mg/m2) showed manageable safety and acceptable tolerability in Chinese patients with advanced solid tumors, and demonstrates promising efficacy in Chinese patients with SCLC as second-line therapy.Trial registration: This study was registered with ClinicalTrials.gov NCT04638491, 20/11/2020.
Asunto(s)
Anemia , Carbolinas , Compuestos Heterocíclicos de 4 o más Anillos , Neoplasias Pulmonares , Neutropenia , Carcinoma Pulmonar de Células Pequeñas , Trombocitopenia , Humanos , Anemia/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carbolinas/efectos adversos , China , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Neoplasias Pulmonares/patología , Neutropenia/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Trombocitopenia/etiologíaRESUMEN
BACKGROUND: Sofosbuvir/Velpatasvir (Epclusa, ECS) is the first pan-genotype direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, and Danoprevir (DNV) is the first DAA developed by a Chinese local enterprise, which is suitable for combined use with other drugs to treat genotype 1b chronic hepatitis C. However, previous reports have never compared the real-world data of ECS and DNV. PATIENTS AND METHODS: 178 chronic hepatitis C patients were retrospectively recruited, and 94cases were accepted with Sofosbuvir/Velpatasvir ± Ribavirin (ECS group), and others (n = 84 treated with DNV combination therapy (DNV group). The HCV genotype, virological response, adverse effects and some laboratory biochemical indexes were contrasted between above two groups in the real world study. RESULTS: DNV group had significantly lower level of alpha-fetoprotein (AFP), lower rates of decompensated cirrhosis ( P < 0.05). ECS group possessed more 6a (31.91% vs.13.10%) while DNV group was provided with more 1b (48.81% vs. 22.34%) patients. Significantly poor liver function was detected in ECS group at 4-week treatment (ALT and AST) and 12-week follow-up (AST) (all P < 0.05). The SVR12 undetectable rates of both groups were 100%, and no serious event was observed during the treatment and follow-up in both groups. CONCLUSION: In this retrospective real-world study, the efficacy of DNV combined therapy is similar to Sofosbuvir/Velpatasvir ± Ribavirin for chronic HCV infection, and the safety is comparable. DNV based therapy is a promising regimen for chronic hepatitis C.
Asunto(s)
Bencimidazoles , Benzopiranos , Carbamatos , Ciclopropanos , Combinación de Medicamentos , Hepatitis C Crónica , Hepatitis C , Isoindoles , Lactamas Macrocíclicas , Prolina , Sulfonamidas , Humanos , Antivirales/efectos adversos , China , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/genética , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Cirrosis Hepática/tratamiento farmacológico , Prolina/análogos & derivados , Estudios Retrospectivos , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: We evaluated the effectiveness and safety of pan-genotypic regimens, glecaprevir/pibrentasvir (GLE/PIB), sofosbuvir/velpatasvir (SOF/VEL), and sofosbuvir/daclatasvir (SOF/DCV) and other direct-acting antivirals (DAA) regimens for the treatment of hepatitis C virus (HCV)-infected adolescents (12-18 years), older children (6-11 years), and young children (3-5 years). The purpose of this systematic review and meta-analysis was to inform the World Health Organization (WHO) guidelines. METHODS: We included clinical trials and observational studies published up to August 11, 2021, that evaluated DAA regimens in HCV-infected adolescents, older children, and young children. We searched MEDLINE, EMBASE, and CENTRAL databases and key conference abstracts. Sustained virological response 12 weeks after the end of treatment (SVR12), adverse events (AEs), and treatment discontinuation were the outcomes evaluated. Risk of bias was assessed using a modified version of the ROBINS-I tool. Data were pooled using random-effects models, and certainty of the evidence was assessed using the GRADE approach. RESULTS: A total of 49 studies including 1882 adolescents, 436 older children, and 166 young children were considered. The SVR12 was 100% (95% Confidence Interval: 96-100), 96% (90-100), and 96% (83-100) for GLE/PIB in adolescents, older, and young children, respectively; 95% (90-99), 93% (86-98), and 83% (70-93), for SOF/VEL, respectively; and 100% (97-100) and 100% (94-100) for SOF/DCV in adolescent and older children, respectively. There was a clear trend towards a higher rate of any reported AE from adolescents (50%), older children (53%), to young children (72%). Serious AEs and treatment discontinuations were uncommon in adolescents and older children (<1%) but slightly higher in young children (3%). CONCLUSIONS: All three pan-genotypic DAA regimens were highly effective and well-tolerated and are now recommended by the WHO for use in adults, adolescents, and children down to 3 years, which will simplify procurement and supply chain management. The evidence was based largely on single-arm non-randomized controlled studies. Moreover, there were also missing data regarding key variables such as route of HCV acquisition, presence or absence of cirrhosis, or HIV co-infection that precluded evaluation of the impact of these factors on outcomes. PROSPERO RECORD: CRD42020146752.
Asunto(s)
Antivirales , Hepatitis C Crónica , Pirrolidinas , Respuesta Virológica Sostenida , Humanos , Niño , Adolescente , Hepatitis C Crónica/tratamiento farmacológico , Antivirales/uso terapéutico , Antivirales/efectos adversos , Pirrolidinas/uso terapéutico , Pirrolidinas/efectos adversos , Hepacivirus/genética , Hepacivirus/efectos de los fármacos , Bencimidazoles/uso terapéutico , Bencimidazoles/efectos adversos , Preescolar , Carbamatos/uso terapéutico , Carbamatos/efectos adversos , Sulfonamidas/uso terapéutico , Sulfonamidas/efectos adversos , Sofosbuvir/uso terapéutico , Sofosbuvir/efectos adversos , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Combinación de Medicamentos , Valina/análogos & derivados , Imidazoles/uso terapéutico , Imidazoles/efectos adversos , Ciclopropanos/uso terapéutico , QuinoxalinasRESUMEN
BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with human immunodeficiency virus (HIV)-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400 mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among men who have sex with men (MSM) who have been diagnosed with HIV. METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV (400 mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50â copies/mL) at 48 weeks per US Food and Drug Administration Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression, and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (P < .001), respectively, discontinued treatment because of adverse effects, death, or lost to follow-up. The median increase of CD4 count was 181 and 223â cells/µL (P = .020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < .001). CONCLUSIONS: BIC/FTC/TAF was more efficacious and safer than EFV (400 mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.