RESUMEN
Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis patients with chronic HCV infection, who had been undergoing hemodialysis for a duration of 0.5-20 years. Blood samples were collected before dose (0) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, and 12.0 h after dose. Dialysate samples were also collected before dose (0) and 1.0, 2.0, 3.0, and 4.0 h after dose. Plasma and dialysate samples were quantified for SOF and its metabolite, GS-331007, and VEL concentrations using a fully validated LCMS technique. In addition, a preliminary efficacy study was conducted using the proposed SOF/VEL dose reduction regimen in all patients. No differences in SOF/VEL PK parameters between on- and off-dialysis studies. On the contrary, GS-331007 exhibited a 30% reduction in the area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24h) on dialysis days compared with non-dialysis days (AUC0-24h ratio 0.68 vs. 1.04, respectively). The dialysis clearance of SOF and GS-331007 was 9.35 (8.72-15.11) and 8.89 (8.52-14.07) mL/min, respectively. Subsequently, an alternate-day regimen of SOF/VEL (400/100 mg) was administered for 12 weeks, resulting in an undetectable plasma HCV viral load without side effects. Further clinical studies are warranted to validate the efficacy and safety of our proposed dose reduction regimen.
Asunto(s)
Antivirales , Carbamatos , Esquema de Medicación , Combinación de Medicamentos , Hepatitis C Crónica , Compuestos Heterocíclicos de 4 o más Anillos , Diálisis Renal , Sofosbuvir , Humanos , Sofosbuvir/farmacocinética , Sofosbuvir/administración & dosificación , Carbamatos/farmacocinética , Carbamatos/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Antivirales/farmacocinética , Antivirales/administración & dosificación , Estudios Prospectivos , Anciano , Adulto , Resultado del Tratamiento , Hepacivirus/efectos de los fármacos , Hepacivirus/aislamiento & purificación , Bencimidazoles , BenzopiranosRESUMEN
Sofosbuvir (SOF) is a P-glycoprotein (P-gp) substrate, and carvedilol (CAR) is an inhibitor of P-gp, suggesting that it may affect the oral pharmacokinetics and safety of SOF. The current study investigated the pharmacokinetic interaction of CAR with SOF and its metabolite, GS-331007, and the possible consequent toxicities in rats. To assess the pharmacokinetics of SOF and GS-331007, rats were divided into three groups; all received a single oral dose of SOF preceded with saline (SAL), verapamil (VER) as a standard P-gp inhibitor, or CAR, respectively. The serosal, plasma, and hepatic tissue contents of SOF and GS-331007 were assessed using LC-MS/MS. Renal and hepatic toxicities were assessed using biochemical and histopathological tests. Serosal and plasma concentrations of SOF and GS-331007 were increased in the presence of CAR, suggesting a significant inhibitory effect of CAR on intestinal P-gp. Simultaneously, the pharmacokinetic profile of SOF showed a significant increase in the Cmax, AUC(0-t), AUC (0-∞), t1/2, and a reduction in its apparent oral clearance. While the pharmacokinetic profile of GS-331007 was not significantly affected. However, this notable elevation in drug oral bioavailability was corroborated by a significant alteration in renal functions. Hence, further clinical investigations are recommended to ensure the safety and dosing of CAR/SOF combination.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Carvedilol , Interacciones Farmacológicas , Sofosbuvir , Carvedilol/farmacocinética , Carvedilol/farmacología , Carvedilol/administración & dosificación , Animales , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Masculino , Ratas , Sofosbuvir/farmacocinética , Sofosbuvir/farmacología , Sofosbuvir/administración & dosificación , Ratas Sprague-Dawley , Verapamilo/farmacocinética , Verapamilo/farmacología , Carbazoles/farmacocinética , Carbazoles/administración & dosificación , Carbazoles/farmacología , Área Bajo la Curva , Propanolaminas/farmacocinética , Propanolaminas/administración & dosificación , Propanolaminas/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Antivirales/farmacocinética , Antivirales/administración & dosificación , Antivirales/farmacología , Riñón/metabolismo , Riñón/efectos de los fármacos , Administración OralRESUMEN
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
BACKGROUND: There exist many barriers to hepatitis C virus (HCV) treatment for those with substance use disorder (SUD) or who lack access to routine medical care. A hospital-based telehealth program was developed to provide treatment opportunities for hospitalized patients living with HCV. METHODS: This single site prospective cohort study conducted from July 2022 to March 2023 aimed to measure linkage to care with an HCV clinician and initiation of HCV treatment in hospitalized patients. Patients were assessed in-person by a social worker then seen via telehealth by a clinician who prescribed either glecaprevir/pibrentasvir or sofosbuvir/velpatasvir. Treatment was initiated with pharmacist assistance. The team conducted in-person and/or telephonic outreach during and after hospitalization. Cure was confirmed by sustained virologic response at 12 weeks (SVR12) post-treatment. RESULTS: A total of 25 patients were enrolled and completed telehealth visits. All patients had a history of SUD and 18 (72 %) were unstably housed. Nineteen patients (76 %) initiated treatment, and 14 (56 %) successfully completed treatment. Twelve patients (48 %) completed post-treatment labs, including two who prematurely discontinued treatment. Eleven patients (44 %) achieved confirmed cure with SVR12. CONCLUSION: A hospital-based, multidisciplinary telehealth program can be an innovative care model to successfully treat HCV in a difficult-to-treat patient populations.
Asunto(s)
Antivirales , Sofosbuvir , Respuesta Virológica Sostenida , Telemedicina , Humanos , Masculino , Antivirales/uso terapéutico , Antivirales/administración & dosificación , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Sofosbuvir/administración & dosificación , Adulto , Quinoxalinas/administración & dosificación , Quinoxalinas/uso terapéutico , Combinación de Medicamentos , Sulfonamidas/administración & dosificación , Carbamatos/administración & dosificación , Pirrolidinas/administración & dosificación , Hepatitis C/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Bencimidazoles/uso terapéutico , Bencimidazoles/administración & dosificación , Estudios de Cohortes , Hospitalización/estadística & datos numéricos , Hepatitis C Crónica/tratamiento farmacológico , Anciano , Lactamas MacrocíclicasRESUMEN
Silymarin is proclaimed to be a blend of flavonolignans or phytochemicals. An era of new generation of direct-acting antivirals (DAAs) has commenced to have facet effect in swaying of the hepatitis C virus (HCV). Nonetheless, this therapy has serious side effects that jeopardize its efficacy. This study is aimed at probing the effects of ribavirin (RBV) and sofosbuvir (SOF) along with silymarin as an adjunct therapy on hematological parameters and markers of obscured oxidative stress. The effect of DAAs along with silymarin was also examined on variable sex hormone level and liver function markers such as alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and bilirubin. The study was followed to determine viral load and viral genotypes. A total of 30 patients were randomly divided into two equal groups comprising the control group (n = 15) and treatment group (n = 15). The control group was solely administered with DAAs (SOF and RBV; 400 mg/800 mg each/day). Conversely, the treatment group was dispensed with DAAs, but with adjunct therapy of silymarin (400 mg/day) along with DAAs (400/800 mg/day) over period of 8 weeks. Sampling of blood was performed at pre- and posttreatment levels for the evaluation of different propound parameters. Our data showed that silymarin adjunct therapy enhances the efficiency of DAAs. A decrease in menace level of liver markers such as ALT, ALP, AST, and bilirubin was observed (p > 0.05). The adjunct therapy concurrently also demonstrated an ameliorative effect on hematological indices and oxidative markers, for instance, SOD, TAS, GSH, GSSG, and MDA (p < 0.05), diminishing latent viral load. The silymarin administration was also found to revamp the fluster level of sex hormones. Our outcomes provide evidence that systematic administration of silymarin effectively remits deviant levels of hematological, serological, hormonal, and antioxidant markers. This demonstrates a possibly unique role of silymarin in mitigating hepatitis C.
Asunto(s)
Antioxidantes/administración & dosificación , Antivirales/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Fitoquímicos/administración & dosificación , Fitoterapia/métodos , Ribavirina/administración & dosificación , Silimarina/administración & dosificación , Sofosbuvir/administración & dosificación , Adolescente , Adulto , Estudios de Casos y Controles , Quimioterapia Combinada/métodos , Femenino , Genotipo , Hepatitis C Crónica/metabolismo , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Resultado del Tratamiento , Carga Viral , Adulto JovenRESUMEN
BACKGROUND: For patients with hepatitis C virus (HCV)-related decompensated cirrhosis, poor prognosis was documented due to the development of portal hypertension-related complications and hepatocellular carcinoma. Sofosbuvir-based direct-acting antiviral agents (DAAs) has revolutionized the treatment landscape of HCV, particularly in this subpopulation. To date, real-world efficacy, tolerability, and safety profiles for Taiwanese HCV-related decompensated cirrhosis treated by DAAs have not been reported. METHODS: Between December 2015 and June 2020, 50 consecutive HCV-related Child-Turcotte-Pugh (CTP) classes B or C cirrhotics treated by sofosbuvir-based DAAs (with daclatasvir: 7, with ledipasvir: 32, with velpatasvir: 10, with ledipasvir then shifted to velpatasvir: 1) were enrolled. Forty-seven (94%) patients used DAAs in combination with low-dose ribavirin. SVR12 was defined by undetectable HCV RNA (<15 IU/mL) at treatment end and 12 weeks after the completion of therapy. RESULTS: The mean age of the enrolled patients was 68.1 ± 11.2 years, 18% of the patients were CTP class C, and the baseline HCV RNA level was 5.42 ± 1.2 log10 IU/mL. The genotype distribution was as follows: 1a: 3; 1b: 34; 2: 9; 6: 3; and one patient with an unclassified HCV genotype. After DAAs treatment, the rates of undetectable HCV RNA at week 4 and at the end of the treatment were 88.9% and 98.0%, respectively. Subjective adverse events were reported by 42.0% of the patients, but they were generally mild and could be relieved by medications. One patient did not finish therapy due to sepsis with multiple organ dysfunction. The overall SVR12 rate was 96.0% (CTP class B: 97.6%, CTP class C: 88.9%). A significant improvement in hepatic functional reserve was noted after successful antiviral therapy. CONCLUSION: For patients with HCV-related decompensated cirrhosis, which has been considered a contraindication for interferon-based therapy, sofosbuvir-based all-oral DAAs provided high treatment efficacy, acceptable safety, and good tolerability.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Seguridad , Sofosbuvir/administración & dosificación , Resultado del Tratamiento , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Respuesta Virológica Sostenida , TaiwánRESUMEN
INTRODUCTION: The conventional interferon therapy of hepatitis C virus has been substituted substantially with sofosbuvir and daclatasvir due to constraints in efficacy and tolerability. This study aimed diagnostically to monitor the effectiveness and side effects of direct-acting antivirals in the management of HCV infections. METHODOLOGY: This prospective study was conducted on HCV-infected patients treated with sofosbuvir and daclatasvir. Different serological, biochemical, hematological, and molecular techniques were used for the assessment of patients. Only treatment-naive patients aged ≥ 18 to 75 years received 12 weeks of treatment. The primary endpoint was a sustained virologic response with undetectable HCV RNA in the patients' serum at the end of the treatment. RESULTS: We identified 229 cases of confirmed HCV infections by PCR, 94.3% of which had genotype 3. The study population comprised 66% females and 34% males with a median age of 42.2 ± 10.6 SD. Ninety-three percent of the patients accomplished SVR at week 12. The combined therapy of SOF/DAC achieved the highest efficacy rate (92.6%) among the different HCV genotype 3 patients. A statistically significant relationship was observed between low baseline viral load (p < 0.001; 95% CI = 1.2-3.1) and HCV genotype 3 with minor side effects, including lethargy, headache, nausea, insomnia, diarrhea, and fever. CONCLUSIONS: HCV-infected patients can be treated well with an interferon-free SOF/DAC regimen, tolerated with generally mild adverse effects with a higher SVR.
Asunto(s)
Antivirales/administración & dosificación , Carbamatos/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Pirrolidinas/administración & dosificación , Sofosbuvir/administración & dosificación , Valina/análogos & derivados , Adulto , Anciano , Antivirales/efectos adversos , Carbamatos/efectos adversos , Quimioterapia Combinada , Femenino , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/genética , Humanos , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Pirrolidinas/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Valina/administración & dosificación , Valina/efectos adversosRESUMEN
OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3âmonths post-LT, and ≥3âmonths post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3âmonths post-LT, and ≥3âmonths post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3âmonths after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.
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Antivirales/administración & dosificación , Carcinoma Hepatocelular/cirugía , Hepatitis C Crónica/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Anciano , Bencimidazoles/administración & dosificación , Carbamatos/administración & dosificación , Carcinoma Hepatocelular/virología , Esquema de Medicación , Combinación de Medicamentos , Femenino , Fluorenos/administración & dosificación , Hepatitis C Crónica/complicaciones , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Neoplasias Hepáticas/virología , Masculino , Persona de Mediana Edad , Pirrolidinas/administración & dosificación , Quinoxalinas/administración & dosificación , Estudios Retrospectivos , Sofosbuvir/administración & dosificación , Sulfonamidas/administración & dosificación , Respuesta Virológica SostenidaAsunto(s)
Antivirales/uso terapéutico , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Infecciones por VIH , Hepacivirus , Hepatitis C Crónica , Infecciones por Parvoviridae , Sofosbuvir/administración & dosificación , Adulto , Coinfección/diagnóstico , Coinfección/tratamiento farmacológico , Coinfección/inmunología , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Humanos , Inmunocompetencia , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/etiología , Pruebas de Función Hepática/métodos , Infecciones por Parvoviridae/sangre , Infecciones por Parvoviridae/diagnóstico , Pruebas Serológicas/métodos , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
Hepatitis C virus (HCV) has a high rate of genetic variability, with eight genotypes and 91 subtypes. The genetic diversity of HCV genotype 6 (HCV-6) is the highest with 31 subtypes, and this genotype is prevalent in Southeast Asia. In this study, we investigated 160 individuals with chronic hepatitis C in Yunnan Province, China. Using reverse transcription (RT)-PCR and Sanger sequencing, 147 cases were successfully amplified and genotyped as 3b (4.9%), 3a (19.73%), 6n (12.24%), 1b (7.48%), 2a (6.12%), 6a (2.04%), 1a (0.68%), 6v (0.68%), and 6xa (0.68%), with eight sequences remaining unclassified. Subsequently, the eight nearly full-length genomes were successfully amplified and analyzed. The eight complete coding sequences formed a phylogenetic group that was distinct from the previously assigned HCV-6 subtypes and clustered with two previously unnamed HCV-6 sequences. Furthermore, Simplot analysis showed no recombination and the p-distance was more than 15% in comparison to the 6a to 6xi subtypes. Taken together, we identified a new HCV-6 subtype, 6xj, which originated approximately in 1775 according to Bayesian analyses. Moreover, all eight individuals received follow-up assessments at 44 weeks from the beginning of their 12-week treatments of sofosbuvir/velpatasvir (after-treatment week 32). One case relapsed at after-treatment week 32. Next-generation sequencing (NGS) was conducted and showed that the treatment failure case had two suspected antiviral resistance mutations, NS5A V28M (a change of V to M at position 28) and NS5B A442V, compared with the baseline. Overall, this newly identified 6xj subtype further confirmed the high diversity of the HCV-6 genotype. The newly identified resistance-associated amino acid substitutions may help inform future clinical treatments. IMPORTANCE This study investigated the genetic diversity of hepatitis C virus (HCV), particularly in relation to genotype 6, which is prevalent in Yunnan, China, and is often difficult to treat successfully. We identified a new HCV-6 subtype, 6xj, which is an ancient strain. Moreover, all eight individuals with the novel subtype received follow-up assessments at 44 weeks from the beginning of their treatments. One case relapsed after 8 months of withdrawal. NGS was conducted and showed that the isolate from the treatment failure case had two suspected antiviral resistance mutations, NS5A V28M and NS5B A442V, compared with the baseline. Overall, this newly identified 6xj subtype further confirmed the high diversity of the HCV-6 genotype. The newly identified resistance-associated amino acid substitutions may help inform future clinical treatments. We believe that our study makes a significant contribution to the literature based on the results described above.
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Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Adulto , Carbamatos/administración & dosificación , China , Combinación de Medicamentos , Evolución Molecular , Femenino , Genotipo , Hepacivirus/clasificación , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Filogenia , Sofosbuvir/administración & dosificación , Adulto JovenRESUMEN
INTRODUCTION: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. METHODS: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). RESULTS: Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. DISCUSSION: Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.
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Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Fallo Renal Crónico/terapia , Sofosbuvir/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Esquema de Medicación , Femenino , Fluorenos/administración & dosificación , Hepatitis C/complicaciones , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Sofosbuvir/administración & dosificación , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. APPROACH AND RESULTS: We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. CONCLUSIONS: This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.
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Antivirales/administración & dosificación , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , 2-Naftilamina/administración & dosificación , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anilidas/administración & dosificación , Bencimidazoles/administración & dosificación , Benzofuranos/administración & dosificación , Ciclopropanos/administración & dosificación , Combinación de Medicamentos , Quimioterapia Combinada/métodos , Femenino , Fluorenos/administración & dosificación , Estudios de Seguimiento , Técnicas de Genotipaje , Hepacivirus/genética , Hepatitis C Crónica/sangre , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/virología , Humanos , Imidazoles/administración & dosificación , Lactamas Macrocíclicas/administración & dosificación , Masculino , Persona de Mediana Edad , Prolina/administración & dosificación , Prolina/análogos & derivados , Quinoxalinas/administración & dosificación , ARN Viral/sangre , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Sulfonamidas/administración & dosificación , Respuesta Virológica Sostenida , Resultado del Tratamiento , Uracilo/administración & dosificación , Uracilo/análogos & derivados , Valina/administración & dosificación , Adulto JovenRESUMEN
ABSTRACT: We present the efficacy and safety of 12 weeks of therapy with a fixed dose of ledipasvir/sofosbuvir in 2 teenagers with HIV/hepatitis C virus coinfection. Patient 1 presented with compensated cirrhosis, whereas patient 2 had evidence of previous hepatitis B virus infection. Both patients achieved a sustained virologic response 12 weeks after the end of treatment. No serious adverse effects were reported.
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Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Adolescente , Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Esquema de Medicación , Quimioterapia Combinada , Fluorenos/administración & dosificación , Genotipo , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología , Masculino , Sofosbuvir/administración & dosificación , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
BACKGROUND: Sofosbuvir (SOF)/daclatasvir (DCV) is the direct-acting antiviral regimen of choice in many low- and middle-income countries for curative treatment of chronic hepatitis C virus (HCV) infection in adults, but data on the use of DCV in children are lacking. We performed a population pharmacokinetic (PK) analysis to predict DCV exposure in children treated with available adult formulations. METHODS: DCV concentration data from HCV-infected adolescents receiving SOF/DCV [400/60 mg, once daily (OD)] who participated in a PK study in Egypt were used for model development. PK parameters were estimated using a population approach. Monte Carlo simulations were run for virtual children weighing 10 to <35 kg receiving 60 or 30 mg OD, and DCV exposures were compared with adults ranges. RESULTS: Seventeen HCV-infected adolescents (13 males) provided 151 DCV concentrations. Median (range) age was 14 (11-18) years and weight 50 (32-63) kg. In these adolescents receiving 60 mg DCV, median (interquartile range) DCV area under the concentration time curve 0 to 24 hours, maximum concentrations, and minimum concentrations were 11,130 (8140-14,690) ng·h/mL, 1030 (790-1220) ng/mL and 130 (110-220) ng/mL, respectively, compared with 10,343 (7661-14,095) ng·h/mL, 1132 (876-1518) ng/mL and 110 (55.7-192) ng/mL predicted in children 10 to <35 kg receiving 30 mg. The proportion of children with DCV exposures above the adult range rapidly increased for children <30 kg using 60 mg OD, similarly for children 10-14 kg using 30 mg. CONCLUSIONS: DCV 30 mg OD was predicted to achieve effective and safe exposures in children 14 to <35 kg, perhaps down to 10 kg. These results should be validated clinically. Low-cost available adult DCV formulations together with approved pediatric doses of SOF would expand global access to HCV treatment for children.
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Antivirales/administración & dosificación , Carbamatos/administración & dosificación , Imidazoles/administración & dosificación , Pirrolidinas/administración & dosificación , Sofosbuvir/administración & dosificación , Valina/análogos & derivados , Adolescente , Adulto , Antivirales/farmacocinética , Carbamatos/farmacocinética , Niño , Relación Dosis-Respuesta a Droga , Egipto , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Imidazoles/farmacocinética , Masculino , Pirrolidinas/farmacocinética , Sofosbuvir/farmacocinética , Resultado del Tratamiento , Valina/administración & dosificación , Valina/farmacocinéticaRESUMEN
This study aimed to investigate the efficacy and safety of sofosbuvir-based therapies for the treatment of cirrhosis from hepatitis C virus (HCV) genotype 2 infection. Data of all consecutive HCV genotype 2 cirrhotic patients who started sofosbuvir-based treatments between January 2015 and March 2017 in eight Italian tertiary hospitals were collected retrospectively. Overall, 273 patients (Child A: 94.5%) were enrolled. In the 194 subjects treated with sofosbuvir/ribavirin, median initial ribavirin dosage was 13.9 mg/kg/day, and therapy duration was 16 weeks. Sustained virological response (SVR) rates were 93.8% in intention-to-treat (ITT) and 95.3% in per-protocol (PP) analyses for the 129 treatment-naïve patients, and 96.9% (ITT) and 98.4% (PP) for the 65 treatment-experienced subjects. Adverse events were reported in 142 patients (73.2%), but only 1.5% discontinued treatment. Eighty-eight subjects with treatment-induced anemia (mild: 34.5%, moderate: 7.7%, severe: 3.1%) had to reduce ribavirin dosage, but SVR rates were comparable to the weight-based dose group, both in ITT (95.4% and 94.3%) and PP (97.7% and 95.2%) analyses, respectively. Moreover, ITT and PP SVR rates were similar between shorter (<20 weeks) (94.1% and 96.0%, respectively) and prolonged (≥20 weeks) regimens (95.7% and 96.7%, respectively). SVR rates in the 79 subjects treated with sofosbuvir/daclatasvir (without ribavirin) were similar (ITT: 96.2%; PP: 97.4%, respectively), without de novo/worsening anemia. In conclusion, in a real-life study centered on genotype 2 patients with well-compensated cirrhosis, sofosbuvir-based regimens were associated with good SVR and tolerability rates, regardless of previous antiviral treatments, without a significant impact of on treatment ribavirin dose reductions.
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Antivirales/administración & dosificación , Carbamatos/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Cirrosis Hepática/tratamiento farmacológico , Pirrolidinas/administración & dosificación , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Valina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/efectos adversos , Carbamatos/efectos adversos , Quimioterapia Combinada , Femenino , Genotipo , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/virología , Humanos , Imidazoles/efectos adversos , Cirrosis Hepática/etiología , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Pirrolidinas/efectos adversos , ARN Viral/genética , Estudios Retrospectivos , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Resultado del Tratamiento , Valina/administración & dosificación , Valina/efectos adversosRESUMEN
ABSTRACT: All-oral direct-acting antiviral therapies are becoming the choice for hepatitis C (HCV) treatment. In this study, we aimed to evaluate the efficacy and safety of ritonavir-boosted danoprevir (DNVr) plus sofosbuvir±ribavirin on HCV genotype 1, 2, 3, or 6 in the real world in China.In this observational, prospective, multicenter cohort, we enrolled a total of 58 patients with HCV genotype 1, 2, 3, or 6 patients from July 2018 to December 2019. All patients were treated with DNVr plus sofosbuvir ± ribavirin for 12âweeks and then followed up for 12âweeks. The primary endpoint was the rate of sustained virologic response at week 12 after the end of treatment (SVR12). The secondary endpoint was virologic response rate at end-of-treatment and adverse event outcome.Of the 58 patients who were enrolled, 5.2% (nâ=â3) had genotype 1a; 43.1% (nâ=â25) had HCV genotype 1b; 17.2% (nâ=â10) had genotype 2a; 5.2% (nâ=â3) had genotype 3a; 8.6% (nâ=â5) had genotype 3b; and 20.7% (nâ=â12) had genotype 6a. The virologic response rate at end-of-treatment was 100% (58/58). The HCV-RNA results of 5 patients were absent at week 12 after treatment. Among the 53 patients, SVR12 rate achieved 100% (53/53) with DNVr plus sofosbuvir ± ribavirin treatment in patients with HCV genotype 1b, 2a, 3, and 6a. For compensated cirrhosis and noncirrhosis patients, SVR12 was 100% with DNVr plus sofosbuvir ± ribavirin treatment. No serious event was observed during the treatment and follow-up. Only 5 patients had mild adverse events.DNVr plus sofosbuvir ± ribavirin for 12âweeks provided 100% SVR12 in a broad patient population and were well tolerated, which may be a promising regimen for CHC treatment.
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Antivirales/administración & dosificación , Ciclopropanos/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Isoindoles/administración & dosificación , Lactamas Macrocíclicas/administración & dosificación , Prolina/análogos & derivados , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Sulfonamidas/administración & dosificación , Adulto , China , Quimioterapia Combinada , Femenino , Genotipo , Hepatitis C Crónica/virología , Humanos , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Prolina/administración & dosificación , Estudios Prospectivos , ARN Viral/efectos de los fármacos , Respuesta Virológica SostenidaAsunto(s)
Ácidos Aminoisobutíricos/administración & dosificación , Bencimidazoles/administración & dosificación , Ciclopropanos/administración & dosificación , Hepatitis C Crónica , Lactamas Macrocíclicas/administración & dosificación , Leucina/análogos & derivados , Cirrosis Hepática , Prolina/análogos & derivados , Pirrolidinas/administración & dosificación , Quinoxalinas/administración & dosificación , Ribavirina/administración & dosificación , Sofosbuvir/administración & dosificación , Sulfonamidas/administración & dosificación , Antivirales/administración & dosificación , Monitoreo de Drogas/métodos , Farmacorresistencia Viral , Femenino , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Leucina/administración & dosificación , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/terapia , Masculino , Administración del Tratamiento Farmacológico , Persona de Mediana Edad , Prolina/administración & dosificación , Respuesta Virológica Sostenida , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. METHODS: Longitudinal samples from 177 patients enrolled in a phase IIIb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. RESULTS: Of 177 patients, 169 (95.5%) were PI-naïve. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. CONCLUSION: Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. LAY SUMMARY: Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. CLINICAL TRIAL NUMBER: NCT03092375.
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Bencimidazoles/farmacología , Resistencia a Medicamentos/inmunología , Pirrolidinas/farmacología , Quinoxalinas/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Sofosbuvir/metabolismo , Sulfonamidas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto , Antivirales/administración & dosificación , Antivirales/metabolismo , Bencimidazoles/uso terapéutico , Combinación de Medicamentos , Femenino , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepatitis C/fisiopatología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pirrolidinas/uso terapéutico , Quinoxalinas/administración & dosificación , Quinoxalinas/uso terapéutico , ARN Polimerasa Dependiente del ARN/farmacología , Sofosbuvir/administración & dosificación , Sulfonamidas/uso terapéutico , Estados Unidos/epidemiología , Proteínas no Estructurales Virales/farmacologíaRESUMEN
The treatment of chronic hepatitis C virus (HCV) infection in chronic hemodialysis patients remains an issue of great concern for nephrologists. In 2008 the kidney disease improving global outcomes working group suggested the use of pegylated interferon in end stage kidney disease patients treated by dialysis. Since then, series and some clinical trials on different direct-acting antiviral agents have shown better efficacy and tolerance than interferon-based regimens. Data on the efficacy, tolerance and the right dose of sofosbuvir in this population are still unclear. We report a case of chronic HCV genotype 1b infection in a 47-year-old patient on maintenance hemodialysis successfully treated by a combination of sofosbuvir and ledipasvir for 12 weeks. Evolution was marked by the complete regression of the hepatic cytolysis, a complete and sustained virologic response with HCV viral load undetectable for a 24 months follow-up period. No adverse reaction was found. The treatment of HCV genotype 1 or 4 infection in patients on maintenance hemodialysis is possible with sofosbuvir based regimens with a good efficacy/safety ratio in the absence of current recommended drugs for patients with eGFR<30ml/min/1.73m2. The prescription of sofosbuvir should be encouraged amongst this population in this setting.
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Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Diálisis Renal , Sofosbuvir/administración & dosificación , Antivirales/efectos adversos , Bencimidazoles/efectos adversos , Fluorenos/efectos adversos , Estudios de Seguimiento , Genotipo , Tasa de Filtración Glomerular , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Sofosbuvir/efectos adversos , Respuesta Virológica SostenidaRESUMEN
BACKGROUND: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV. METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183. FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment. INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality. FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.