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2.
Lancet Gastroenterol Hepatol ; 5(10): 918-926, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32531259

RESUMO

BACKGROUND: There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. METHODS: This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov, number NCT01958281, and is completed. FINDINGS: This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12-74) of ten patients in cohort 1 and six (60%, 26-88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82-100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. INTERPRETATION: In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4-5 chronic kidney disease who were not on dialysis. FUNDING: Gilead Sciences.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Ensaios Clínicos Controlados não Aleatórios como Assunto/métodos , Insuficiência Renal Crônica/complicações , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Uridina Monofosfato/análogos & derivados , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Quimioterapia Combinada/métodos , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Fluorenos/farmacocinética , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Insuficiência Renal Crônica/classificação , Insuficiência Renal Crônica/fisiopatologia , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Ribavirina/farmacocinética , Segurança , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Sofosbuvir/farmacocinética , Resultado do Tratamento , Estados Unidos/epidemiologia , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/uso terapêutico , Carga Viral/efeitos dos fármacos
3.
Lancet Gastroenterol Hepatol ; 5(9): 809-818, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526210

RESUMO

BACKGROUND: Highly effective direct-acting antiviral drugs provide the opportunity to eliminate hepatitis C virus (HCV) infection, but established pathways can be ineffective. We aimed to examine whether a community pharmacy care pathway increased treatment uptake, treatment completion, and cure rates for people receiving opioid substitution therapy, compared with conventional care. METHODS: This cluster-randomised trial was done in Scottish community pharmacies. Before participants were recruited, pharmacies were randomly assigned (1:1) to refer patients with evidence of HCV antibodies to conventional care or offered them care in the pharmacy (pharmacist-led care). Pharmacies were stratified by location. All pharmacies were trained to offer dried blood spot testing. All eligible participants had received opioid substitution therapy for approximately 3 months, and those eligible to receive treatment in the pharmacist-led care pathway were HCV PCR positive, were infected with HCV genotype 1 or 3, and were willing to have a pharmacist supervise their antiviral drug administration. Neither pharmacists nor patients were masked to treatment allocation. In both groups, assessment blood samples were taken, infection with HCV was confirmed, and daily oral ledipasvir-sofosbuvir (90 mg ledipasivir plus 400 mg sofosbuvir) for 8 weeks for genotype 1 or daily oral sofosbuvir (400 mg) plus oral daclatasvir (60 mg) for 12 weeks for genotype 3 was prescribed by a nurse (conventional care group) or pharmacist (pharmacist-led care group). In the conventional care group, the patient received care at a treatment centre. Once prescribed, medication in both groups was delivered as daily modified directly observed therapy alongside opioid substitution therapy in the participants' pharmacy where treatment was observed on 6 days per week. The primary outcome was the number of patients with sustained virological response 12 weeks after completion of treatment (SVR12) as a proportion of the number of people receiving opioid substitution therapy at participating pharmacies. Participants were monitored at each visit for nausea and fatigue; other adverse events were recorded as free text. Secondary outcomes compared key points on treatment pathway between the two groups. These key points were the proportion of patients having dry blood spot testing, the proportion of patients initiating HCV treatment, the proportion of patients completing the 8 or 12 week HCV course of treatment, and the proportion of patients with sustained virological response at 12 months. This study is registered with ClinicalTrials.gov, NCT02706223. FINDINGS: 56 pharmacies were randomly assigned (28 to each group; one pharmacy withdrew from the conventional care group). The 55 participating pharmacies included 2718 patients receiving opioid substitution therapy (1365 in the pharmacist-led care group and 1353 in the conventional care group). More patients met the primary endpoint of SVR12 in the pharmacist-led care group (98 [7%] of 1365) than in the conventional care group (43 [3%] of 1353; odds ratio 2·375, 95% CI 1·555-3·628, p<0·0001). More users of opioid substitution therapy in the pharmacist-led care group versus the conventional care group agreed to dry blood spot testing (245 [18%] of 1365 vs 145 [11%] of 1353, 2·292, 0·968-5·427, p=0·059); initiated treatment (112 [8%] of 1365 vs 61 [4%] of 1353, 1·889, 1·276-2·789, p=0·0015) and completed treatment (108 [8%] of 1365 vs 58 [4%] of 1353, 1·928, 1·321-2·813, p=0·0007). The data for sustained virological response at 12 months are not reported in this study: patients remain in follow-up for this outcome. No serious adverse events were recorded. INTERPRETATION: Using pharmacists to deliver an HCV care pathway made testing and treatment more accessible for patients, improved engagement, and maintained high treatment success rates. The use of this pathway could be a key part of an integrated and effective approach to HCV elimination at a community level. FUNDING: Partnership between the Scottish Government, Gilead Sciences, and Bristol-Myers Squib.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Tratamento de Substituição de Opiáceos/métodos , Uridina Monofosfato/análogos & derivados , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Feminino , Fluorenos/administração & dosagem , Fluorenos/efeitos adversos , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/epidemiologia , Humanos , Imidazóis/administração & dosagem , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Farmacêuticos/normas , Escócia/epidemiologia , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêutico
4.
PLoS One ; 15(5): e0233446, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433676

RESUMO

BACKGROUND: Hepatitis C virus (HCV) genotype 6 is the commonest cause of chronic hepatitis C infection in much of southeast Asia, but data on the effectiveness of direct-acting antiviral agents (DAAs) against this genotype are limited. We conducted a retrospective cohort study of patients attending the Hospital for Tropical Diseases (HTD), Ho Chi Minh City, Vietnam, to define the effectiveness of DAAs in the treatment of chronic HCV genotype 6 in actual practice. METHODS: We included all patients with genotype 6 infections attending our hospital between March 2016 and October 2017 who received treatment with sofosbuvir-based DAA treatment regimens, and compared their responses with those with genotype 1 infections. RESULTS: 1758 patients (1148 genotype 6, 65.4%; 610 genotype 1, 34.6%) were analyzed. The majority of patients (1480, 84.2%) received sofosbuvir/ledipasvir (SOF/LDV) ± ribavirin (RBV); 278 (15.8%) received sofosbuvir/Daclatasvir (SOF/DCV) ± RBV. The median age of the patients was 57 years, (interquartile range (IQR) 46-64 years) The baseline HCV viral load (log IU/ml) was significantly higher in patients infected with genotype 6 compared with those infected with genotype 1 (6.8, 5.3-6.6 versus 6.3, 5.3-6.5 log10 IU/ml, p = <0.001, Mann Whitney U test). A sustained virological response (SVR), defined as an undetectable viral load measured between 12 and 24 weeks after completing treatment, and indicating cure, was seen in 97.3% (1711/1758) of patients. Treatment failure, defined as HCV viral load ≥15 IU/ml ≥12 weeks after completing treatment appeared to be more frequent in patients infected with genotype 6 virus (3.2%, 37/1148) than in those infected with genotype 1 (1.7%, 10/610), p = 0.050 chi-squared test). We found no evidence that patient's age, gender, liver cirrhosis, diabetes, HBV or HIV coinfection, prior treatment failure with pegylated interferon therapy, body mass index (BMI), aspartate aminotransferase to platelet ratio index (APRI), or fibrosis 4 (FIB-4) index were associated with treatment failure. CONCLUSIONS: Our study suggests that patients with HCV genotype 6 infection in Vietnam may respond less well to treatment with sofosbuvir based DAAs than patients with genotype 1 infections. Further studies are needed to confirm this observation and to define whether it is driven by genotype-specific mutations.


Assuntos
Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/administração & dosagem , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Resultado do Tratamento , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêutico , Vietnã , Carga Viral/efeitos dos fármacos , Carga Viral/genética
5.
Aliment Pharmacol Ther ; 52(1): 168-181, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32441382

RESUMO

BACKGROUND: In England, choice of hepatitis C therapy is determined by national contracts that change with time, facilitating comparisons between different regimens. England has a diverse population with hepatitis C including large proportions of uncommon viral genotypes. AIM: To evaluate efficacy of directly acting anti-viral treatments for hepatitis C in England using real-world data from the national treatment registry. METHODS: Sustained virological response (SVR) rates 12 weeks after treatment completion for patients treated between 2014 and August 2018 who attended for SVR tests were analysed in univariate subgroups using Chi-squared tests. Multivariate models were constructed with clinically relevant variables to determine predictors of SVR and evaluate the impact of treatment regimens. RESULTS: SVR data were available on 14,603 treated patients. The overall SVR rate was 95.59% [95% CI 95.25%-95.91%]. Multivariable regression modelling in patients with genotype 1 infection showed that the odds of SVR with elbasvir/grazoprevir were higher than for those treated with sofosbuvir/ledipasvir (OR 1.891, 95% CI 1.072-3.336, P = 0.028). For genotype 3, we found no significant difference between any of the treatment regimens. Patients who completed at least one third of the planned treatment duration achieved SVR rates in excess of 80%. CONCLUSIONS: All of the currently licensed hepatitis C direct-acting anti-viral regimens had similar efficacy (>95%) in an unselected population. Noncompletion of planned treatment duration still resulted in over 80% SVR rates provided that more than one third of treatment was completed.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/uso terapêutico , Benzimidazóis/uso terapêutico , Benzofuranos/uso terapêutico , Carbamatos/uso terapêutico , Combinação de Medicamentos , Inglaterra , Feminino , Fluorenos/uso terapêutico , Humanos , Imidazóis/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Quinoxalinas/uso terapêutico , Sistema de Registros , Ribavirina/uso terapêutico , Sofosbuvir , Resposta Viral Sustentada , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêutico , Adulto Jovem
6.
Medicine (Baltimore) ; 99(11): e19140, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32176039

RESUMO

Treatment of hepatitis C virus (HCV) infection for patients with human immunodeficiency virus (HIV) has improved with direct acting antivirals. However, outcomes among Black persons treated with ledipasvir/sofosbuvir (LDV/SOF) may be inferior to non-Blacks. We assessed responses to LDV/SOF in a cohort of Black HIV/HCV coinfected persons.Retrospective chart reviews were conducted for Black, genotype 1 (GT1), HIV/HCV coinfected patients treated with LDV/SOF at 3 hospitals in Newark, NJ between January 2014 and July 2016. Data collected included demographics, HCV treatment history, treatment duration, and response.One hundred seventeen HIV/HCV coinfected Black patients started treatment with LDV/SOF but 5 had no follow-up data and 5 prematurely discontinued treatment (1 due to side effects). We included 107 HIV/HCV coinfected patients who completed LDV/SOF at all 3 sites. The study population was 65% male, median age 58 years, 26% had cirrhosis, and 78% had GT1a. Thirty-one percent were treatment experienced but none with prior NS5a treatment. At baseline, median CD4 count was 680 cells/mm, HIV viral load (VL) was <40 copies/mL in 94% and median HCV VL was 2,257,403 IU/mL. Twenty-nine percent of patients changed antiretroviral treatment before LDV/SOF treatment due to drug interactions. Six, 89, and 12 patients completed 8, 12, and 24 weeks of LDV/SOF, respectively. Overall sustained virologic response rate was 93% with 7 relapses.In this real-world cohort of Black, GT1, HIV/HCV coinfected patients, LDV/SOF had high sustained virologic response 12 weeks post completion of treatment rate of 93%. This data supports the overall high efficacy of LDV/SOF in a historically difficult-to-treat patient population.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Coinfecção/tratamento farmacológico , Fluorenos/uso terapêutico , Infecções por HIV/complicações , Hepacivirus/efeitos dos fármacos , Hepatite C/complicações , Uridina Monofosfato/análogos & derivados , Afro-Americanos/estatística & dados numéricos , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Coinfecção/virologia , Feminino , Fluorenos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , New Jersey , Estudos Retrospectivos , Sofosbuvir , Resultado do Tratamento , Uridina Monofosfato/administração & dosagem , Uridina Monofosfato/uso terapêutico
7.
Am J Kidney Dis ; 75(6): 857-867, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32081494

RESUMO

RATIONALE & OBJECTIVE: Less than 4% of patients with kidney failure receive kidney transplants. Although discard rates of hepatitis C virus (HCV)-viremic kidneys are declining, ~39% of HCV-viremic kidneys donated between 2018 and 2019 were discarded. Highly effective antiviral agents are now available to treat chronic HCV infection. Thus, our objective was to examine the cost-effectiveness of transplanting kidneys from HCV-viremic donors into HCV-uninfected recipients. STUDY DESIGN: Markov state transition decision model. Data sources include Medline search results, bibliographies from relevant English language articles, Scientific Registry of Transplant Recipients, and the US Renal Data System. SETTING & POPULATION: US patients receiving maintenance hemodialysis who are on kidney transplant waiting lists. INTERVENTION(S): Transplantation with an HCV-unexposed kidney versus transplantation with an HCV-viremic kidney and HCV treatment. OUTCOMES: Effectiveness measured in quality-adjusted life-years and costs measured in 2018 US dollars. MODEL, PERSPECTIVE, AND TIMEFRAME: We used a health care system perspective with a lifelong time horizon. RESULTS: In the base-case analysis, transplantation with an HCV-viremic kidney was more effective and less costly than transplantation with an HCV-unexposed kidney because of the longer waiting times for HCV-unexposed kidneys, the substantial excess mortality risk while receiving dialysis, and the high efficacy of direct-acting antiviral agents for HCV infection. Transplantation with an HCV-viremic kidney was also preferred in sensitivity analyses of multiple model parameters. The strategy remained cost-effective unless waiting list time for an HCV-viremic kidney exceeded 3.1 years compared with the base-case value of 1.56 year. LIMITATIONS: Estimates of waiting times for patients willing to accept an HCV-viremic kidney were based on data for patients who received HCV-viremic kidney transplants. CONCLUSIONS: Transplanting kidneys from HCV-viremic donors into HCV-uninfected recipients increased quality-adjusted life expectancy and reduced costs compared with a strategy of transplanting kidneys from HCV-unexposed donors.


Assuntos
Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica , Falência Renal Crônica/cirurgia , Transplante de Rim , Complicações Pós-Operatórias , Pirrolidinas/uso terapêutico , Quinoxalinas/uso terapêutico , Sulfonamidas/uso terapêutico , Uridina Monofosfato/análogos & derivados , Adulto , Antivirais/economia , Antivirais/uso terapêutico , Análise Custo-Benefício , Seleção do Doador/economia , Seleção do Doador/métodos , Combinação de Medicamentos , Feminino , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/etiologia , Hepatite C Crônica/virologia , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/economia , Complicações Pós-Operatórias/virologia , Sofosbuvir , Uridina Monofosfato/uso terapêutico , Viremia/diagnóstico , Viremia/etiologia
8.
PLoS One ; 15(2): e0228847, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32053682

RESUMO

The advent of direct-acting antiviral (DAA) therapies has dramatically transformed HCV treatment, with most recent trials demonstrating high efficacy rates (>90%) across all genotypes and special populations, including patients with HIV/HCV coinfection. The efficacy rates of HCV treatment are nearly identical between patients with HCV monofection and patients with HIV/HCV coinfection; however, there are limited studies to compare real-world efficacy with efficacy observed in clinical trials. Using a database from HIV clinics across the United States (US), we identified 432 patients with HIV/HCV coinfection who completed DAA therapy from January 1, 2014 to March 31, 2017 and were assessed for efficacy. Efficacy was evaluated as sustained virologic response (SVR) 12 weeks after DAA completion; furthermore, factors associated with achieving SVR12 were identified. In this analysis, we found DAA therapies to be effective, with 94% of the patients achieving SVR12 and 6% experiencing virologic failure. Baseline variables, including older age, HCV viral load <800K IU/ML, FIB-4 score <1.45, absence of depression, diabetes, substance abuse, and use of DAA regimens without ribavirin were significant predictors of achieving SVR12. Patients with fewer comorbidities, better liver health, and lower HCV viral loads at baseline were more likely to achieve treatment success. Our results were consistent with other real-world studies, supporting the use of HCV therapy in HIV/HCV coinfected patients.


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Adulto , Idoso , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Coinfecção/virologia , Quimioterapia Combinada , Feminino , Fluorenos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepacivirus/metabolismo , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ribavirina/uso terapêutico , Simeprevir/uso terapêutico , Sofosbuvir , Resposta Viral Sustentada , Resultado do Tratamento , Estados Unidos , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêutico , Carga Viral
9.
PLoS One ; 15(2): e0228767, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32045447

RESUMO

INTRODUCTION: Hepatitis C (HCV) infection is a significant health threat, with increasing incidence rates in the setting of the opioid crisis. Many patients miss appointments and cannot initiate treatment. We implemented financial incentives to improve appointment attendance in a primary care-based HCV treatment setting. METHODS: We conducted a systems-level financial incentives intervention at the Adult Primary Care HCV Treatment Program at Boston Medical Center which provides care to many patients with substance use disorders. From April 1 to June 30, 2017, we provided a $15 gift card to patients who attended appointments with an HCV treatment provider. We evaluated the effectiveness of the incentives by 1) conducting a monthly interrupted time series analysis to assess trends in attendance January 2016-September 2017; and 2) comparing the proportion of attended appointments during the intervention to a historical comparison group in the previous year, April 1 to June 30, 2016. RESULTS: 327 visits were scheduled over the study period; 198 during the intervention and 129 during the control period. Of patient visits in the intervention group, 72.7% were attended relative to 61.2% of comparison group visits (p = 0.03). Appointments in the intervention group were more likely to be attended (adjusted odds ratio 1.94, 95% confidence interval 1.16-3.24). Interrupted time series analysis showed that the intervention was associated with an average increase of 15.4 attended visits per 100 appointments scheduled, compared to the period prior to the intervention (p = 0.01). CONCLUSIONS: Implementation of a financial incentive program was associated with improved appointment attendance at a safety-net hospital-based primary care HCV treatment program. A randomized trial to establish efficacy and broader implementation potential is warranted.


Assuntos
Hepatite C/psicologia , Avaliação de Programas e Projetos de Saúde , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Atenção Primária à Saúde , Recompensa , Provedores de Redes de Segurança , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Adulto Jovem
11.
Adv Ther ; 37(1): 457-476, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31808054

RESUMO

INTRODUCTION: The objective of the study was to evaluate the cost-effectiveness of glecaprevir/pibrentasvir versus other direct-acting antivirals (DAAs) for treating chronic hepatitis C virus (HCV) infections in Japan. METHODS: We developed a health state transition model to capture the natural history of HCV. A cost-effectiveness analysis of DAAs from the perspective of a public healthcare payer in Japan with a lifetime horizon over annual cycles was performed. Treatment attributes, baseline demographics, transition probabilities, health-state utilities, and costs data were extracted from publications. Costs and outcomes were discounted at 2% per annum. In the base case we focused on genotype 1 (GT1) treatment-naïve patients without cirrhosis. The scenario analysis examined a pan-genotype treatment in GT1-3 (i.e., portfolio), treatment-naïve, and treatment-experienced patients. The portfolio cost-effectiveness of DAAs was derived by calculating a weighted average of patient segments defined by treatment history, cirrhosis status, and genotype. RESULTS: The base case results indicated that glecaprevir/pibrentasvir was dominant (i.e., generating higher quality-adjusted life years [QALYs] and lower lifetime costs) compared to all other DAAs. The predicted lifetime risk of hepatocellular carcinoma was 3.66% for glecaprevir/pibrentasvir and sofosbuvir/ledipasvir, 4.99% for elbasvir/grazoprevir, and 5.27% for daclatasvir/asunaprevir/beclabuvir. In scenario analysis the glecaprevir/pibrentasvir (GLE/PIB) portfolio dominated the sofosbuvir (SOF)-based portfolio (namely sofosbuvir/ledipasvir in GT1-2 and sofosbuvir + ribavirin in GT3). The base case probabilistic sensitivity analysis (PSA) showed that glecaprevir/pibrentasvir was cost-effective in 93.4% of the simulations for a willingness-to-pay/QALY range of Japanese yen (JPY) 1.6-20 million. The PSA for the portfolio scenario indicated that the GLE/PIB portfolio was cost-effective in 100% of simulations until the willingness-to-pay/QALY reached JPY 5.2 million; this proportion decreased to 69.4% at a willingness-to-pay/QALY of JPY 20 million. Results were also robust in deterministic sensitivity analyses. CONCLUSION: In GT1 treatment-naïve non-cirrhotic patients GLE/PIB was a cost-effective strategy compared to other DAAs. When a pan-genotypic framework was used, the GLE/PIB portfolio dominated the SOF-based portfolio.


Assuntos
Antivirais/economia , Benzimidazóis/economia , Fluorenos/economia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/economia , Quinoxalinas/economia , Sulfonamidas/economia , Uridina Monofosfato/análogos & derivados , Adulto , Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Análise Custo-Benefício , Quimioterapia Combinada , Feminino , Fluorenos/uso terapêutico , Humanos , Japão , Quinoxalinas/uso terapêutico , Ribavirina/economia , Sofosbuvir/economia , Sulfonamidas/uso terapêutico , Uridina Monofosfato/economia , Uridina Monofosfato/uso terapêutico
12.
Curr Drug Saf ; 15(1): 53-60, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31573893

RESUMO

BACKGROUND: Chronic Hepatitis C (CHC) is a common progressive healthcare challenge that leads to liver cirrhosis, liver failure, and hepatocellular carcinoma. The optimum therapy was a combination of pegylated interferon and ribavirin, which was associated with moderate response and severe side effects. Sofosbuvir revolutionized CHC treatment, especially in combination with other antiviral agents. OBJECTIVE: The aim of this study was to compare and evaluate the safety and efficacy of sofosbuvir/ daclatasvir versus sofosbuvir/ledipasvir for the treatment of non-cirrhotic naïve patients with chronic Hepatitis C Virus (HCV) genotype 4 infection for 12 weeks. METHODS: One hundred CHC genotype 4 patients (70 females, 30 males) were recruited from the hepatology clinic at the Beni-Suef general hospital. Patients were randomly allocated into two groups that received a 12 weeks treatment of either sofosbuvir 400 mg/daclatasvir 60 mg or sofosbuvir 400 mg/ledipasvir 90 mg. The sustained virological response 12 weeks post-treatment (SVR12) (HCV RNA < Lower Limit of Quantification (LLOQ)) was determined to evaluate efficacy. The clinical laboratory tests and any reported adverse effects starting from the administration of the first dose till 30 days after the last dose were assessed to evaluate safety. The main outcome measure was the assessment of the safety, efficacy and compliance of sofosbuvir/ daclatasvir versus sofosbuvir/ledipasvir for the treatment of non-cirrhotic naïve CHC genotype 4 patients for 12 weeks. RESULTS: SVR12 was achieved by 98% and 96% of patients receiving sofosbuvir plus ledipasvir and sofosbuvir plus daclatasvir, respectively. The most common adverse events reported were headache, and fatigue. No patients discontinued treatment due to adverse events. CONCLUSION: The findings from this study suggest that the 12 weeks treatment regimens of sofosbuvir plus daclatasvir and sofosbuvir plus ledipasvir were both efficacious and well-tolerated in patients with HCV genotype 4 infection. Impact on Practice: In this paper, we report on the most recent approaches in the treatment of Hepatitis C genotype 4 patients in Egypt. This is significant because this article focuses on comparing the efficacy and tolerability of the most commonly used antiviral drugs in Egypt.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Antivirais/administração & dosagem , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Egito , Feminino , Genótipo , Hepatite C Crônica/sangue , Humanos , Cirrose Hepática , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Resultado do Tratamento
13.
J Formos Med Assoc ; 119(3): 712-719, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31672433

RESUMO

BACKGROUND: Mongolia has the highest prevalence of hepatitis C virus (HCV) infection worldwide. Ledipasvir/sofosbuvir (LDV/SOF) was introduced to Mongolia since 2016 for HCV eradication. It has been reported that HCV resistance-associated substitutions (RASs) would affect the effectiveness of LDV/SOF in western chronic hepatitis C (CHC) patients. We thus investigated the effectiveness of LDV/SOF and the impact of RAS on the treatment outcome in Mongolian CHC patients. METHODS: Patients with genotype (GT) 1b HCV infection were prospectively enrolled in Mongolia and treated with LDV/SOF for 12 weeks. The proportion of pre-treatment NS5A Y93H RAS in viral quasispecies was measured with next-generation sequencing. The endpoint of LDV/SOF effectiveness was sustained virological response at post-treatment week 12 (SVR12). RESULTS: A total of 94 CHC patients were evaluated. The baseline Y93H proportion was <1% in 74 patients, 1-15% in 7, 15-50% in 2, and ≥50% in 11. All patients completed 12-week LDV/SOF treatment and the SVR rate was 90.4%. The rate of failure to achieve SVR12 for patients with Y93H < 1%, 1-15%, and ≥15% were 0%, 14.3%, and 61.5%, respectively (p for trend = 0.001). In univariable analysis, older age, baseline alanine transaminase level <40 U/mL, and a higher proportion of Y93H were associated with treatment failure. In multivariable analysis, only a higher proportion of Y93H was associated with treatment failure (p = 0.022). CONCLUSION: LDV/SOF therapy achieves a high SVR rate in Mongolian CHC GT1b patients without baseline Y93H RAS. A higher proportion of Y93H may severely undermine the effectiveness of LDV/SOF.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Hepatite C Crônica/tratamento farmacológico , Adulto , Idoso , Benzimidazóis/uso terapêutico , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Fluorenos/uso terapêutico , Genótipo , Hepatite C Crônica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mongólia , Sofosbuvir/uso terapêutico , Falha de Tratamento , Resultado do Tratamento , Uridina Monofosfato/análogos & derivados
15.
ASAIO J ; 66(5): 553-558, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31425256

RESUMO

Donor-derived hepatitis C (dd-HCV) infection may increase the risk of renal impairment (RI) among heart transplantation (HT) recipients. Sofosbuvir, an integral component of HCV direct-acting antivirals (DAAs) has also been linked to RI. To date, no study has examined the trends in renal function for HT recipients of dd-HCV infection and assessed safety and efficacy of Sofosbuvir-based DAAs. Between September 2016 and June 2018, 46 HCV-naive patients and one patient with a history of HCV treated pretransplant, underwent HT from HCV-positive donors (follow-up available through October 10, 2018). Patients were treated with Ledipasvir-Sofosbuvir (genotype 1) or Sofosbuvir-Velpatasvir (genotype 3) for 12 or 24 weeks; no dose adjustments were made for renal function. Data on renal function were available for 23 patients who achieved a sustained virologic response at 12 weeks after the treatment (SVR12; cohort A) and 18 patients who completed 1 year of follow-up (cohort B). Treatment of dd-HCV infection was initiated at a median of 6 weeks post-HT. In both cohorts, a nonsignificant reduction in median estimated glomerular filtration rate (eGFR; ml/min/1.73 m) was noted (cohort A: pretransplant eGFR: 62 [interquartile range {IQR}: 1-84] to SVR12 eGFR: 49 [IQR: 37-82]; p = 0.43; cohort B: pretransplant eGFR: 65 [IQR: 54-84] to 1 year post-HT eGFR: 56 [IQR: 39-75]; p = 0.29). Pretreatment renal function had no significant impact on changes in renal function during treatment. All patients tolerated DAAs well with 100% completion rate to the assigned therapy and duration and 100% success at achieving SVR12. In this first and largest reported case series to date of HT recipients with dd-HCV infection, we observed that neither the dd-HCV infection nor its treatment with Sofosbuvir-based DAAs increased the risk of RI. Sofosbuvir-based DAAs appear safe, tolerable, and effective for HCV treatment even in presence of severe RI.


Assuntos
Antivirais/uso terapêutico , Transplante de Coração , Hepatite C/tratamento farmacológico , Hepatite C/etiologia , Nefropatias/epidemiologia , Adulto , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Quimioterapia Combinada/métodos , Feminino , Fluorenos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Doadores de Tecidos , Transplantados , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêutico
16.
Hepatology ; 71(1): 196-213, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211856

RESUMO

Cholangiocarcinoma (CCA) mortality rates are increasing as a result of rising incidence and limited curative treatment(s) for patients with advanced disease. NOTCH pathway reactivation has been reported in biliary malignancies to conflicting degrees, hindering prioritization of key therapeutic targets within the network and identification of candidate responder patients for NOTCH-directed therapies. We analyzed genomic data from 341 patients with CCA and identified NOTCH1 significantly increased in a subgroup characterized by distinct stromal infiltration. Network-wide imbalance of the NOTCH pathway was seen in CCA, including correlation of NOTCH1 with NOTCH3 and NOTCH ligands. Given the diversity of observed NOTCH receptor engagement, γ-secretase modulation was rationalized as a therapeutic option. Indeed, subcutaneous transplantation of sensitive and resistant CCA cell lines pretreated with a γ-secretase inhibitor (GSi) cocktail demonstrated the antineoplastic effects of GSi in a subset of CCA and led to the development of a 225-gene responder signature. This signature was validated in an independent cohort of 119 patients. Further, this signature was enriched in liver tumors initiated by hydrodynamic injections of activated-NOTCH as compared with the AKT-RAS-driven tumors. Candidate GSi-responder patients were characterized by distinct transcriptomes overlapping with previous hepatobiliary metastasis and stemness, unique stromal properties, and dysfunctional intratumoral immune infiltration. Pan-cancer analysis identified 41.9% of cancer types to harbor prospective GSi-responder patients, which was adapted into a 20-gene GSi-sensitivity score metric capable of discriminating nanomolar versus micromolar sensitivity to a cell-permeable GSi (Z-LLNle-CHO) across 60 diverse tumor lines (area under the curve = 1). Conclusion: We have established a GSi-responder signature with evidence across several patient cohorts, as well as in vitro and in vivo models, to enable precision medicine application of NOTCH-directed therapy in CCA as well as prospectively across diverse malignancies.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/etiologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/etiologia , Dibenzazepinas/farmacologia , Dibenzazepinas/uso terapêutico , Fluorenos/farmacologia , Fluorenos/uso terapêutico , Cetonas/farmacologia , Cetonas/uso terapêutico , Receptores Notch/efeitos dos fármacos , Receptores Notch/fisiologia , Linhagem Celular Tumoral , Humanos , Resultado do Tratamento
17.
J Pediatric Infect Dis Soc ; 9(3): 386-389, 2020 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31310312

RESUMO

We assessed the safety and efficacy of a generic form of ledipasvir-sofosbuvir for the treatment of hepatitis C virus infection in Egyptian adolescents and compared the results with those of treatment with the brand-named form. The generic form resulted in a high response rate, significant improvement in liver function, and mild adverse effects. These results are comparable with those of the brand form at a reduced price.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Uridina Monofosfato/análogos & derivados , Adolescente , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Transfusão de Sangue , Criança , Combinação de Medicamentos , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/uso terapêutico , Egito , Feminino , Fluorenos/efeitos adversos , Hepatite C Crônica/terapia , Humanos , Masculino , Estudos Prospectivos , Sofosbuvir , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/uso terapêutico
18.
Acta Biomed ; 91(4): e2020102, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33525212

RESUMO

BACKGROUND: There is no study regarding the use of SOF/LDP in treatment of COVID-19.  Objectives: In this study, the efficacy and safety of SOF/LDP were assessed in treatment of patients with mild to moderate COVID-19. METHODS: Among an open-label randomized clinical trial, 82 patients with mild to moderated COVID-19 were assigned to receive either SOF/LDP 400/100 mg daily plus the standard of care (SOF/LDP group, n=42) or the standard of care alone (control group, n=40) for 10 days. Time to clinical response, rate of clinical response, duration of hospital and ICU stay and 14-day mortality were assessed. RESULTS: Clinical response occurred in 91.46% of patients. Although rates of clinical response were comparable between the groups but it occurred faster in the SOF/LDP group than the control group (2 vs. 4 days respectively, P= 0.02). Supportive cares were provided in the medical wards for most patients but 17.07% of patients were transferred to ICU during the hospitalization course. However, durations of hospital and ICU stay were comparable between the groups.  14--day mortality rate was 7.14% and 7.5% in the SOF/ LDP and control groups respectively. No adverse effects leading to drug discontinuation occurred. Gastrointestinal events (nausea, vomiting and diarrhea) were the most common side effects (15.85%). CONCLUSION: Added to the standard of care, SOF/LDP accelerated time to the clinical response. However, rate of clinical response, duration of hospital and ICU stay and 14-day mortality were not different. No significant adverse event was detected.  More randomized clinical trials with larger sample sizes are needed to confirm the efficacy and safety of SOF/LDP in the treatment of COVID-19.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Sofosbuvir/uso terapêutico , Idoso , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Combinação de Medicamentos , Fluorenos/efeitos adversos , Humanos , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Sofosbuvir/efeitos adversos , Resultado do Tratamento
19.
Ann Parasitol ; 66(4): 561-571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33789028

RESUMO

The purpose of this study was to update efficacy data of Artesunate-Amodiaquine (AS+AQ) and Artemether-Lumefantrine (AL) used as first-line malaria treatment in Côte d'Ivoire since 2005. This was an open-label, randomized trial conducted in patients older than 6 months with uncomplicated P. falciparum malaria at six sentinel sites. The WHO 2009 protocol on surveillance of anti-malaria drug efficacy was used with primary outcomes as ACPR corrected by PCR at day 42. Secondary endpoints were parasite and fever clearance times and safety. From January to July 2016, 712 patients were included in the trial. 353 and 359 patients were randomly assigned respectively to the AS+AQ and AL arm. Day 42 PCR-adjusted ACPR in the per-protocol analysis was 99.4% and 98.8% in AS+AQ and AL arm respectively. Delayed parasite clearance was observed in six patients at Abidjan and Yamousssoukro sites. Both ACTs were well tolerated. Both ACTs remain efficacious for uncomplicated P. falciparum malaria treatment in Côte d'Ivoire. But regarding delayed parasite clearance observed in this study, a close monitoring and supervision for ACT resistance are essential for future malaria treatment and control strategies in Côte d'Ivoire.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Malária , Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Artemisininas/uso terapêutico , Costa do Marfim/epidemiologia , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Fluorenos/uso terapêutico , Humanos , Lactente , Malária/tratamento farmacológico , Malária/epidemiologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Resultado do Tratamento
20.
Biomed Res Int ; 2019: 2301291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815126

RESUMO

Direct-acting antivirals (DAAs) are modern treatments for chronic hepatitis C infection, but majority of available evidence on its treatment effect covers genotypes 1 to 4. Therefore, the efficacy and safety of DAAs for genotypes 5 and 6 need to be analysed. Studies were identified from Medline, Scopus, and CENTRAL and a Chinese database CNKI, from inception until Dec 4, 2018. Clinical trials were included if they enrolled patients with genotypes 5 and/or 6 infection, any type of second-generation DAAs was studied, and sustained virological response was assessed at the 12th week after treatment (SVR12) as outcome measure. Meta-analysis using metaprop statistical program was applied for pooling proportions if data were sufficient (i.e., at least 2 studies). Thirteen studies were included in the analysis. Four studies assessed the efficacy of four DAA regimens in genotype 5 patients, which were mainly sofosbuvir (SOF) plus pegylated-interferon/ribavirin (PR) or other DAAs, with SVR12 ranging from 94.4% to 100%. Twelve studies assessed the efficacy of seven DAA regimens among genotype 6 patients, but only two DAA regimens (i.e., SOF + PR and SOF/ledipasvir) had sufficient data for pooling. The pooled SVR12 rates (95% CI) were 99.6% (92.2 to 100) for SOF + PR and 99.2% (96.5 to 100) for SOF/ledipasvir. No treatment-related serious adverse event was reported, while the nonserious adverse events were comparable to other genotypes. In conclusion, DAAs are effective and may be safe for the treatment of chronic hepatitis C genotypes 5 and 6. However, our evidence is based on noncomparative studies; hence, further larger-scale randomized controlled trials in these genotypes are still required.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Benzimidazóis/uso terapêutico , Bases de Dados Factuais , Quimioterapia Combinada , Fluorenos/uso terapêutico , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Humanos , Interferons , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/uso terapêutico
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