RESUMO
We assessed the presence of hepatitis C virus (HCV) RNA in liver explants from 39 patients awaiting liver transplantation who were treated with an interferon-free regimen and had undetectable serum HCV RNA at the time of liver transplantation. Interestingly, HCV RNA was detected in most liver explants (67%). Patients with HCV RNA-positive explants had received shorter courses of treatment, and HCV RNA was undetectable in serum for shorter periods before transplantation compared to patients with HCV RNA-negative explants (P = .014 and P = .013, respectively). Levels of HCV RNA in explants were significantly higher in patients with a relapse of HCV infection than patients who responded to treatment (P = .016), but most patients (85%) with residual HCV-RNA in the explant achieved a sustained virologic response after receiving their liver transplant.
Assuntos
Antivirais/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepatite C/virologia , Transplante de Fígado , Fígado/virologia , RNA Viral/efeitos dos fármacos , Transplantes/virologia , Feminino , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , RNA Viral/sangue , Recidiva , Resposta Viral Sustentada , Listas de EsperaRESUMO
BACKGROUND & AIMS: Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS: In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS: Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS: Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/cirurgia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/efeitos adversos , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Antivirais/efeitos adversos , Antivirais/farmacocinética , Biomarcadores/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/virologia , Farmacorresistência Viral , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/complicações , Hepatite C/diagnóstico , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/virologia , Masculino , Nova Zelândia , Projetos Piloto , Estudos Prospectivos , RNA Viral/sangue , Recidiva , Ribavirina/efeitos adversos , Ribavirina/farmacocinética , Sofosbuvir , Espanha , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/uso terapêutico , Carga ViralRESUMO
BACKGROUND & AIMS: Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward. METHODS: In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation. RESULTS: Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%). CONCLUSIONS: Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/cirurgia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Idoso , Antivirais/efeitos adversos , Biomarcadores/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/virologia , Quimioterapia Combinada , Europa (Continente) , Feminino , Genótipo , Hepacivirus/genética , Hepacivirus/patogenicidade , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite C/mortalidade , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Cirrose Hepática/virologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/virologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Projetos Piloto , RNA Viral/sangue , Recidiva , Ribavirina/efeitos adversos , Sofosbuvir , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêutico , Carga Viral , Listas de EsperaRESUMO
BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Colestase Intra-Hepática/tratamento farmacológico , Fluorenos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/mortalidade , Colestase Intra-Hepática/virologia , Progressão da Doença , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/mortalidade , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Cirrose Hepática/virologia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversos , Sofosbuvir , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêuticoRESUMO
UNLABELLED: Recurrent hepatitis C virus (HCV) infection after liver transplantation (LT) is associated with accelerated progression of liver disease, frequently leading to graft loss and early death. Existing treatment options for severe recurrent HCV infection are limited by suboptimal efficacy, poor tolerability, and numerous drug interactions. We provided sofosbuvir (SOF) and ribavirin (RBV) on a compassionate-use basis to patients with severe recurrent hepatitis C, including those with fibrosing cholestatic hepatitis (FCH) and decompensated cirrhosis who had a life expectancy of 1 year or less. All patients were to receive 24-48 weeks of SOF plus RBV. Investigators could add pegylated interferon to the regimen at their discretion. Data from the first 104 patients who completed or prematurely discontinued treatment by January 1, 2014 are presented. Of the 104 patients analyzed, 52 had an early severe recurrence (diagnosed <12 months after LT) and 52 had cirrhosis (diagnosed >12 months after LT). Twelve patients who underwent retransplantation were excluded from our efficacy analysis. Of the 92 patients assessed, 54 (59%) achieved sustained virological response (SVR) at 12 weeks after the end of treatment, with a higher rate (73%; 35 of 48) in patients with early severe recurrence. Of the 103 patients assessed for clinical outcome, 59 (57%) reported clinical improvement at the last study visit, 23 (22%) were unchanged, 3 (3%) had a worsened clinical status, and 13 (13%) died. Overall, 123 serious adverse events (SAEs) occurred in 49 patients (47%). SAEs associated with hepatic decompensation were the most frequent, with 26 SAEs occurring in 19 patients (18%). CONCLUSION: SOF and RBV provide high rates of SVR in patients with severe recurrent HCV, including patients with early severe recurrence, FCH, and cirrhosis.
Assuntos
Antivirais/uso terapêutico , Ensaios de Uso Compassivo , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/cirurgia , Transplante de Fígado , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Índice de Gravidade de Doença , Sofosbuvir , Falha de Tratamento , Uridina Monofosfato/uso terapêuticoRESUMO
To investigate the pharmacokinetics, safety, and tolerability of GS-9851 (formerly PSI-7851), a new nucleotide analog inhibitor of hepatitis C virus (HCV), we conducted a double-blind, parallel, placebo-controlled, randomized, single-ascending-dose study. Healthy subjects received oral doses of 25 to 800 mg GS-9851. Peak concentrations of GS-9851 in plasma were achieved more rapidly than those of the metabolites GS-566500 (formerly PSI-352707) and GS-331007 (formerly PSI-6206), with time to maximum concentration of drug in plasma (t(max)) values of 1.0 to 1.8 h, 1.5 to 3.0 h, and 3.0 to 6.0 h, respectively. The majority of systemic drug exposure was from the nucleoside GS-331007, with maximum concentration of drug in plasma (C(max)) and area under the concentration-time curve to the last measurable concentration (AUC(0-t)) values at least 7- and 41-fold higher, respectively, than those obtained for GS-9851 after adjusting for differences in molecular weight. The terminal elimination half-life (t(1/2)) of GS-331007 increased with the dose, achieving a t(1/2) of 25.7 h at 800 mg GS-9851. Dose proportionality was not observed for GS-331007. The majority of drug recovered in urine was in the form of GS-331007, with the percentage of this metabolite in urine samples ranging from 57% to 27% with increasing dose. GS-9851 was generally well tolerated, with no maximum tolerated dose identified. In conclusion, GS-9851 and its metabolites demonstrated a favorable pharmacokinetic profile consistent with once-daily dosing, and therefore, further clinical studies evaluating GS-9851 in HCV-infected patients are warranted.
Assuntos
Antivirais/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Nucleotídeos/farmacocinética , RNA Viral/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/sangue , Antivirais/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Meia-Vida , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleotídeos/sangue , Nucleotídeos/farmacologia , Placebos , RNA Viral/biossíntese , Carga Viral/efeitos dos fármacosRESUMO
We conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naïve patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t(1/2)) values of approximately 1 h for GS-9851 and 3 h for GS-566500. Accumulation (21%) was observed only for GS-331007 (formerly PSI-6206) after multiple dosing. GS-331007 was the primary drug-related moiety in the plasma and urine. Increases in the GS-9851, GS-566500, and GS-331007 maximum concentrations in plasma (C(max)) and area under the concentration-time curve (AUC) were less than dose proportional, particularly at the highest doses. The decline in plasma HCV RNA levels was dose dependent, and a mean maximal change from the baseline of -1.95 log(10) IU/ml was obtained for 400 mg GS-9851, compared with -0.090 log(10) IU/ml for the placebo. Most patients had a decrease in HCV RNA of ≥1.0 log(10) IU/ml after 3 days' dosing with 400 mg GS-9851. No virologic resistance was observed. GS-9851 was generally well tolerated, with no notable differences in adverse event frequency across doses. The pharmacokinetic profile observed in this study was similar to that seen in a single-ascending-dose study in healthy subjects.
Assuntos
Antivirais/farmacocinética , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Nucleotídeos/farmacocinética , RNA Viral/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/sangue , Antivirais/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Meia-Vida , Hepacivirus/crescimento & desenvolvimento , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Nucleotídeos/sangue , Nucleotídeos/farmacologia , Placebos , RNA Viral/biossíntese , Carga Viral/efeitos dos fármacosRESUMO
Serotonin plays a key role in the development and maintenance of the pathobiology associated with pulmonary arterial hypertension (PAH). Platelet-driven and locally produced serotonin from lung tissue and arterial endothelial cells induce excessive growth of pulmonary artery smooth muscle cells. The unchecked growth of these cells is a major driver of PAH including the remodeling of pulmonary arteries that dramatically reduces the diameter and flexibility of the arterial lumen. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme for biosynthesis of serotonin and is upregulated in PAH arterial endothelial cells, supporting TPH1 inhibition to treat PAH. Targeting the serotonin pathway via inhibition of peripheral serotonin and local production in diseased tissues, rather than individual receptor-mediated or receptor-independent mechanisms, may result in the ability to halt or reverse pulmonary vascular remodeling. Rodatristat ethyl, a prodrug for rodatristat, a potent, peripheral inhibitor of TPH1, has demonstrated efficacy in monocrotaline and SUGEN hypoxia nonclinical models of PAH and robust dose-dependent reductions of 5-hydroxyindoleacetic acid, the major metabolite of serotonin in plasma and urine of healthy human subjects. ELEVATE 2 (NCT04712669) is a Phase 2b, double-blind, multicenter trial where patients with PAH are randomized to placebo, 300 or 600 mg twice daily of rodatristat ethyl. The trial incorporates endpoints to generate essential clinical efficacy, safety, pharmacokinetic, and pharmacodynamic data needed to evaluate the ability of rodatristat ethyl to ameliorate PAH by halting or reversing pulmonary vascular remodeling through its unique mechanism of TPH1 inhibition. Herein we describe the experimental design highlighting the trial's unique features.
RESUMO
BACKGROUND: In the Phase II SOLAR-1 study, 12 or 24 weeks of ledipasvir/sofosbuvir and ribavirin yielded high sustained virological response rates at 12 weeks (SVR12) in patients with chronic HCV infection and advanced liver disease, including untransplanted patients with decompensated cirrhosis and liver transplant recipients with all stages of liver disease. METHODS: We performed a post hoc analysis using data from this study to investigate associations between baseline characteristics and early on-treatment HCV RNA, and to determine the utility of early virological response (week 2 and 4) to predict SVR12. Serum HCV RNA was quantified using the Roche COBAS® Ampliprep®/Cobas TaqMan HCV Test, Version 2.0 with a lower limit of quantification (LLOQ) of 15 IU/ml. RESULTS: Most patients achieved HCV RNA Assuntos
Antivirais/administração & dosagem
, Hepatite C Crônica/tratamento farmacológico
, Hepatite C Crônica/patologia
, Cirrose Hepática/tratamento farmacológico
, Cirrose Hepática/patologia
, RNA Viral/sangue
, Adulto
, Idoso
, Benzimidazóis/administração & dosagem
, Quimioterapia Combinada
, Feminino
, Fluorenos/administração & dosagem
, Hepacivirus/genética
, Hepatite C Crônica/virologia
, Humanos
, Cirrose Hepática/virologia
, Transplante de Fígado
, Masculino
, Pessoa de Meia-Idade
, RNA Viral/genética
, Estudos Retrospectivos
, Ribavirina/administração & dosagem
, Sofosbuvir
, Uridina Monofosfato/administração & dosagem
, Uridina Monofosfato/análogos & derivados
, Carga Viral
RESUMO
BACKGROUND: Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. METHODS: We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600-1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). FINDINGS: Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70-96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81-100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66-96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60-91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84-98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93-100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91-100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84-100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78-100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86-100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3-98) of two CTP-C patients (12 weeks treatment); and four (80%, 34-99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55-100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56-92) of 18 patients (12 weeks treatment) and 16 (94%, 75-100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir-sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. INTERPRETATION: Ledipasvir-sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. FUNDING: Gilead Sciences.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/classificação , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Quimioterapia Combinada , Feminino , Genótipo , Saúde Global , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/mortalidade , Humanos , Cirrose Hepática/mortalidade , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , RNA Viral , Sofosbuvir , Fatores de Tempo , Resultado do Tratamento , Uridina Monofosfato/uso terapêutico , Carga ViralRESUMO
BACKGROUND: Sofosbuvir (GS-7977) and GS-0938 are nucleotide analogue HCV polymerase inhibitors, with sofosbuvir being a pyrimidine and GS-0938 being a purine. Mathematical modelling has provided important insights for characterizing HCV RNA decline and for estimating the in vivo effectiveness of single direct-acting antiviral agents (DAAs); however it has not been used to characterize viral kinetics with combination DAA therapy. METHODS: We evaluated the antiviral activity of sofosbuvir and GS-0938 given alone and in combination for 14 days in 32 HCV genotype 1 treatment-naive patients (P2938-0212; NUCLEAR study). RESULTS: Viral load declined rapidly in a biphasic manner in all subjects and could be well fitted by assuming that both drugs had a similar and additive level of effectiveness in reducing viral production equal to 99.96%, on average. The model predicted that this level of effectiveness was not reached until 0.6 and 2 days for GS-0938 and sofosbuvir, respectively, and likely represents the time needed to accumulate intracellular triphosphates. Subsequently, both drugs led to a rapid second phase of viral decline with a mean rate of 0.35 d(-1). No effect of IL28B-polymorphism was found on viral kinetic parameters. CONCLUSIONS: Both sofosbuvir and GS-0938 are highly effective at blocking viral production from HCV-infected cells. Both drugs led to a rapid and consistent second phase viral decline and exhibited no breakthroughs or other signs of resistance. From a kinetics perspective, because both drugs were of the same class there was little benefit in combining them, suggesting that future DAA combinations should consider utilizing drugs with different modes of action.