Effectiveness and Safety of Interferon-Free Direct-Acting Antiviral Hepatitis C Virus Therapy in HIV/Hepatitis C Virus Coinfected Individuals: Results From a Pan-European Study.

OBJECTIVES: To investigate the effectiveness, safety, and reasons for premature discontinuation of direct-acting antivirals (DAAs) in a diverse population of HIV/hepatitis C virus (HCV) coinfected individuals in Europe. METHODS: All HIV/HCV coinfected individuals in the EuroSIDA study that started interferon free DAA treatment between January 6, 2014, and January 3, 2018, with ≥12 weeks of follow-up after treatment stop were included in this analysis. Sustained virological response (SVR) was defined as a negative HCV-RNA result ≥12 weeks after stopping treatment (SVR12). Logistic regression was used to explore factors associated with SVR12. RESULTS: 1042 individuals started interferon-free DAA treatment after 1/6/2014 and were included, 862 (82.2%) had a known response to treatment, and 789 [91.5%, 95% confidence interval (CI): 89.7 to 93.4] of which achieved SVR12. There were no differences in SVR12 across regions of Europe (P = 0.84). After adjustment, the odds of achieving SVR12 was lower in individuals that received sofosbuvir/simeprevir ± ribavirin (RBV) [adjusted odds ratio 0.21 (95% CI: 0.08 to 0.53)] or ombitasvir/paritaprevir/dasabuvir ± RBV [adjusted odds ratio 0.46 (95% CI: 0.22 to 1.00)] compared with sofosbuvir/ledipasvir ± RBV. Forty-three (4.6%) individuals had one or more components of their HCV regimen stopped early, most commonly because of toxicity (n = 14); of these 14, 11 were treated with ribavirin. Increased bilirubin was the most common grade 3 or 4 laboratory adverse event (n = 15.3%) and was related to treatment with atazanavir and ribavirin. CONCLUSIONS: Our findings from real-world data on HIV/HCV coinfected individuals across Europe show DAA treatment is well tolerated and that high rates of SVR12 can be achieved in all regions of Europe.

Anti-rod and ring antibodies in patients with chronic hepatitis C using direct-acting antivirals.

Anti-rods and rings (anti-RR) antibody induction is related to the combination of interferon and ribavirin in the treatment of hepatitis C virus (HCV) infection. If the main factor leading to this autoimmune reaction is the combination of these drugs, is not well known, but in vitro studies shows that ribavirin alone can induce rods and rings structures. New direct-acting antivirals (DAAs) permit HCV treatment without needing interferon but may be associated with ribavirin in the most difficult-to-treat patients. The aim of this study is to evaluate the occurrence of anti-RR in patients with chronic HCV infection, before and after 12 weeks of treatment with DAAs, with and without ribavirin. From Jun 2016 to Oct 2017, 52 HCV-infected patients were screened for anti-RR before and after DAA therapy, including sofosbuvir, daclatasvir, simeprevir, and ribavirin. Serum samples were analyzed using indirect immunofluorescence. The anti-RR was present in 11 (21%) of the 52 patients (51.9% male and mean age of 59.1 years) before using DAAs. All of them had been previously treated and previous exposed to interferon/ribavirin, with exposure time to ribavirin associated with the presence of anti-RR. After 12 weeks of DAA treatment, 3 patients (5.7%) developed the antibody in low titers, and two of them (66%) were interferon/ribavirin experienced. Only one of the 29 naïve patients (3.44%) developed anti-RR during the current treatment. Anti-RR was present in patients previously treated with interferon/ribavirin and can emerge after DAA treatment probably at a lower frequency than after interferon/ribavirin treatment.

High success rates for the use of sofosbuvir/ombitasvir/paritaprevir/ritonavir + ribavirin and sofosbuvir/simeprevir/daclatasvir + ribavirin in retreatment of chronic hepatitis C infection after unsuccessful sofosbuvir/daclatasvir therapy: a real-life experience.

The aim of this work was assessment of the efficacy and tolerability of two different regimens for retreatment of hepatitis C virus (HCV) patients who failed to respond to SOF/DCV-based therapy. This prospective study included 104 HCV patients who failed to respond to SOF/DCV-based therapy. Patients were randomly allocated to two groups. Efficacy and tolerability were assessed. The 12-week sustained virological response (SVR12) rates were 96% and 94.4% in groups B and A, respectively, with no significant difference (p = 1.000). Most adverse events reported were mild to moderate, with no deaths during the study. Multi-target direct-acting antiviral (DAA) combinations are efficient for retreatment of HCV patients after failure of SOF/DCV-based therapy in real-world management.ClinicalTrials.gov identifier: NCT02992457.

HEPATITIS C TREATMENT OF RENAL TRANSPLANT AND CHRONIC KIDNEY DISEASE PATIENTS: EFFICACY AND SAFETY OF DIRECT-ACTING ANTIVIRAL REGIMENS CONTAINING SOFOSBUVIR.

BACKGROUND: Direct-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min. OBJECTIVE: To evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients. METHODS: All patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively. CONCLUSION: The direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.

JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study.

BACKGROUND: The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis. METHODS: In this Phase IIa, open-label, multicenter study-OMEGA-3 (NCT02993250)-patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs). RESULTS: Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up. CONCLUSIONS: In HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.

Tratamento da hepatite C em pacientes com doença renal crônica e pós-tranplante renal: eficácia e segurança dos esquemas de antivirais de ação direta contendo sofosbuvir / Hepatitis c treatment of renal transplant and chronic kidney disease patients: efficacy and safety of direct-acting antiviral regimens containing sofosbuvir

ABSTRACT BACKGROUND: Direct-acting antivirals have revolutionized hepatitis C treatment, also for patients with chronic kidney disease (CKD), but some controversy exists regarding the use of sofosbuvir (SOF) in patients with glomerular filtration rate (GFR) <30 mL/min. OBJECTIVE: To evaluate the efficacy and safety of these regimens for hepatitis C treatment of patients with CKD and after renal transplantation, as well as the impact of SOF on renal function in non-dialysis patients. METHODS: All patients with hepatitis C and CKD or renal transplant treated with direct-acting antivirals at a referral center in Brazil between January 2016 and August 2017 were included. Efficacy was evaluated based on viral load (HCV RNA) and a sustained virological response (SVR) consisting of undetectable RNA 12 and/or 24 weeks after the end of treatment (SVR12 and SVR24) was defined as cure. Safety was determined by adverse events and ribavirin, when combined, was administered in escalating doses to all patients with GFR <60 mL/min. The impact of SOF on renal function was determined by the measurement of baseline creatinine during and after the end of treatment and its increase was evaluated using the Acute Kidney Injury Network (AKIN) classification. RESULTS: A total of 241 patients (52.7% females) with a mean age of 60.72±10.47 years were included. The combination of SOF+daclatasvir was the predominant regimen in 75.6% of cases and anemia was present in 28% of patients who used ribavirin (P=0.04). The SVR12 and SVR24 rates were 99.3% and 97.1%, respectively. The treatment was well tolerated and there were no major clinically relevant adverse events, with the most prevalent being asthenia (57.7%), itching (41.1%), headache (40.7%), and irritability (40.2%). Among conservatively treated and renal transplant patients, oscillations of creatinine levels (AKIN I) were observed in 12.5% of cases during treatment and persisted in only 8.5% after the end of treatment. Of these, 2.0% had an initial GFR <30 mL/min and this percentage decreased to 1.1% after SOF use. Only 0.5% and 1.6% of the patients progressed to AKIN II and AKIN III elevation, respectively. CONCLUSION: The direct-acting antivirals were safe and efficacious in CKD patients treated with SOF-containing regimens, with the observation of high SVR rates, good tolerability and few severe adverse events. The combination with ribavirin increased the risk of anemia and the administration of escalating doses seems to be useful in patients with GFR <60 mL/min. In patients with GFR <30 mL/min, SOF had no significant renal impact, with serum creatinine returning to levels close to baseline after treatment.

RESUMO CONTEXTO: Os antivirais de ação direta revolucionaram o tratamento da hepatite C, inclusive para os pacientes com doença renal crônica (DRC), porém ainda há divergências no emprego do sofosbuvir (SOF) quando taxa de filtração glomerular (TFG) <30 mL/min. OBJETIVO: Avaliar a eficácia e segurança desses esquemas no tratamento da hepatite C em pacientes com DRC e pós-transplante renal, além de avaliar o impacto do SOF sobre a função renal dos não-dialíticos. MÉTODOS: Todos os pacientes com hepatite C e DRC ou transplante renal que realizaram tratamento com antivirais de ação direta em centro referenciado do Brasil no período de janeiro/2016 a agosto/2017 foram incluídos. A eficácia foi avaliada por meio da carga viral (HCV-RNA), considerando-se cura uma resposta virológica sustentada (RVS) com resultado indetectável após 12 e/ou 24 semanas do término do tratamento (RVS12 e RVS24). A segurança foi determinada pelos eventos adversos e a ribavirina, quando associada, foi introduzida de forma escalonada em todos os pacientes com TFG <60 mL/min. Para determinação do impacto do SOF sobre a função renal, foram observadas as dosagens de creatinina basal, durante e após término do tratamento com seu incremento avaliado por meio da classificação de AKIN (acute kidney injury network). RESULTADOS: Foram incluídos 241 pacientes, sendo 52,7% do sexo feminino, com média de idade de 60,72±10,47 anos. A associação de SOF+daclatasvir predominou em 75,6% dos casos e anemia esteve presente em 28% dos pacientes que utilizaram ribavirina (P=0,040). As taxas de RVS12 e RVS24 foram de 99,3% e 97,1%. O tratamento foi bem tolerado, com eventos adversos pouco relevantes, sendo os mais prevalentes: astenia (57,7%), prurido (41,1%), cefaleia (40,7%) e irritabilidade (40,2%). Entre os pacientes em tratamento conservador e transplantados renais, os valores de creatinina sofreram oscilações AKIN I em 12,5% dos casos, durante o tratamento, persistindo em apenas 8,5% da amostra após o término, dos quais 2,0% apresentavam TFG <30 mL/min inicialmente, com queda para 1,1% após uso do SOF. Apenas 0,5% e 1,6% evoluíram com elevação AKIN II e AKIN III. CONCLUSÃO: Os antivirais de ação direta foram seguros e eficazes em pacientes com DRC tratados com esquemas contendo SOF, apresentando altas taxas de RVS, boa tolerabilidade e poucos eventos adversos graves. A associação com ribavirina aumentou o risco de anemia, portanto sua introdução de forma escalonada parece ser útil nos pacientes com TFG <60 mL/min. Em pacientes com TFG <30 mL/min o SOF não apresentou impacto renal significativo, com creatinina sérica retornando a valores próximos ao basal após o tratamento.

The benefits of a public pharmacist service in chronic hepattis C treatment: The real-life results of sofosbuvir-based therapy.

BACKGROUND: In Brazil, the sofosbuvir-based therapy was introduced in the public health system (SUS) in 2015 to treat Chronic Hepatitis C (CHC). This drug and other direct-acting antiviral agents (DAAs) represent a major advance in the HCV-infection treatment due to their high effectiveness and tolerability. However, the drug safety profile is limited by significant drug interactions and its use is restricted for their high cost. Pharmacists have the opportunity to improve patient care by monitoring the therapy, recommending strategies to guarantee treatment adherence, effectiveness and safety, preventing complications of the disease, and drug-related problems, thus reducing the cost for patients and payers. OBJECTIVE: This study aimed to assess the results of the one of the first patient group treated with sofosbuvir in Brazil and their opinions about the benefits of clinical pharmacist services in the achievement of the cure for CHC and in the management of their therapy difficulties. METHODS: This cohort study (November 2015-January 2017) enrolled 240 patients followed up by the clinical pharmacists at the University Pharmacy (UPh) of the Federal University of Santa Catarina, Brazil, during the CHC treatment. The therapeutic schemes used were sofosbuvir + daclatasvir or + simeprevir associated or not with ribavirin. At the end of the therapy, the patients provided qualitative feedback about the clinical pharmacist services. RESULTS: The study demonstrated high levels of treatment adherence (99.2% of completion rates) and effectiveness rates (Sustained Virological Response rates) (92.1%). Patients reported high levels of satisfaction with the care provided on account of the good rapport built with their pharmacist, the counseling and education on HCV-infection and on sofosbuvir-based therapy utilization, motivation for adherence, and convenient access to the pharmacist. CONCLUSIONS: The clinical pharmacist services provided by the UPh was beneficial to patients treated for CHC with the sofosbuvir-based therapy.

Estimating Efflux Transporter-Mediated Disposition of Molecules beyond the Rule of Five (bRo5) Using Transporter Gene Knockout Rats.

Transporter gene knockout models are a practical and widely used tool for pharmacokinetic studies in drug discovery. P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are major efflux transporters that control absorption and bioavailability, and are important when determining oral drug disposition. To the best of our knowledge, beyond the rule of five (bRo5) molecules launched on the market to date tend to be substrates for efflux transporters. The purpose of this study is to evaluate in vivo the impact of efflux transporters on the oral absorption process and systemic clearance using rats which lack P-gp and/or Bcrp expression. We administered five bRo5 substrates (asunaprevir, cyclosporine, danoprevir, ledipasvir, and simeprevir) intravenously or orally to wild-type and Mdr1a, Bcrp, and Mdr1a/Bcrp knockout rats, calculated the clearance, oral bioavailability, and absorption rate profile of each substrate, and compared the results. Systemic clearance of the substrates in knockout rats changed within approximately ±40% compared to wild-types, suggesting the efflux transporters do not have a significant influence on clearance in rats. On the other hand, the oral absorption of substrates in the knockout rats, especially those lacking Mdr1a, increased greatly-between 2- and 5-fold more than in wild-types. This suggests that rat efflux transporters, especially P-gp, greatly reduce the oral exposure of these substrates. Moreover, results on the absorption rate-time profile suggest that efflux transporters are constantly active during the absorption period in rats. Transporter knockout rats are a useful in vivo tool for estimating the transporter-mediated disposition of bRo5 molecules in drug discovery.

[QOL Assessment in Chronic Hepatitis C Patients Receiving Ledipasvir/ Sofosbuvir or Simeprevir/Peginterferon/Ribavirin in Clinical Practice].

Recently, a clinical study using a Chronic Liver Disease Questionnaire (CLDQ) showed that ledipasvir/sofosbuvir (LDV/SOF)-treated patients' QOL was more favorable than that of IFN/ribavirin (RBV)-treated patients. However, no study has reported QOL assessment in clinical practice. In this study, we compared the QOL between patients treated with LDV/SOF and those treated with simeprevir (SMV)/peginterferon (Peg-IFN)/RBV to provide QOL information in clinical practice. The subjects were 169 patients with type I chronic hepatitis C or compensated cirrhosis C (Child-Pugh Grade A) who were treated with SMV/Peg-IFN/RBV or LDV/SOF in Hitachi General Hospital. The QOL was assessed ≥2 weeks after the start of administration using the Japanese version of the CLDQ (Kida et al., 2008 version). The total CLDQ score in the LDV/SOF group was significantly higher than in the SMV/Peg-IFN/RBV group (6.59 vs. 6.38, respectively, p=0.007). In particular, the scores for 4 domains (abdominal symptoms, systemic symptoms, activity, and emotional function) in the former were significantly higher than in the latter (p<0.05). Furthermore, the rates of patients scoring 7 (no symptom) on 8 items in the former were significantly higher than in the latter (p<0.05). In clinical practice, LDV/SOF-treated patients' QOL was more favorable than that of those receiving conventional treatment with IFN and RBV. This study may make it possible for health care professionals to provide clinical QOL information on LDV/SOF therapy to patients. Furthermore, QOL information may promote decision-making for treatment, leading to effective treatment.

Efficacy, Safety, and Predictors of Direct-acting antivirals in Hepatitis C Virus Patients with Heterogeneous Liver Diseases.

Safety, efficacy, and predictor factors of sustained-virological-response after 24 weeks of new direct-acting antivirals were evaluated in hepatitis C virus patients with different stages of hepatic disease. 260 patients, median age 60 years, of whom 48.1% cirrhotics, 17.7% liver transplant recipients, and 45.7% naïve were treated with Sofosbuvir+Ribavirine, Sofosbuvir+Simeprevir±Ribavirine, Sofosbuvir+Daclatasvir± Ribavirine, Sofosbuvir+Ledispavir±Ribavirine, Ombitasvir/Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. Therapy outcomes, hematochemical parameters, viral replication, genotype, and resistance-associated-mutations were analyzed retrospectively. Sustained virological response was 90.4% in the whole population, 83.2% in cirrhotics, 85% in patients with previous virological failure, 93.6% in patients >60 years, and 95.6% in liver transplant recipients. SVR24 for each drug regimen was 75% Sofosbuvir+Ribavirine, 80.4% Sofosbuvir+Simeprevir±Ribavirine, 94.3% Sofosbuvir+Daclatasvir±Ribavirine, 98.7% Sofosbuvir+Ledispavir±Ribavirine, 100% Ombitasvir/ Paritaprevir/Ritonavir+Ribavirine and Ombitasvir/Paritaprevir/Ritonavir+Dasabuvir±Ribavirine. The highest sustained virological response rates were obtained with genotype-1b (95.9%). Twenty-five patients, mostly cirrhotics or suffering from severe liver complications, manifested relapse (84%), breakthrough (12%), or non-response (4%). Mild side effects were observed in 41.1% of patients. Model-for-End-Liver- Disease score <10 and alanine aminotransferase ≤20 U/L at week 8 of therapy proved positive predictors of sustained virological response. Direct-acting antiviral therapy is efficacious and safe even in patients with advanced liver disease and/ or previous virological failure; Model-for-End-Liver-Disease <10 and alanine aminotransferase reduction during therapy were found to be reliable predicting markers of sustained-virological-response.

Retreatment of Egyptian Chronic Hepatitis C Patients Not Responding to Pegylated Interferon and Ribavirin Dual Therapy.

In the current study, we aimed to assess the efficacy of different Sofosbuvir (SOF)-based antiviral regimens available in Egypt in the treatment of Pegylated interferon/Ribavirin (PEG-INF/RBV)-experienced chronic hepatitis C virus (HCV) patients. Two hundred fifty-eight patients experienced with PEG-INF/RBV, and 1,283 naive patients were included in the study. The patients received one of the following 3 regimens for 12 weeks; PEG-INF/SOF, Simeprevir/SOF (SIM/SOF), and Daclatasvir/SOF (DCV/SOF). The endpoint was a sustained virological response 12 weeks (SVR12) after the end of the treatment. SVR12, treatment failure, and relapse were assessed. Moreover, predictors of SVR12 were analyzed. The mean age of treatment-experienced and treatment-naive patients was 51.11 ± 5.84 years and 50.04 ± 5.97 years, respectively. Treatment-experienced patients included 132 (51.16%) males and 126 (48.83%) females. Treatment-naive patients included 709 (55.26%) males and 574 (44.73%) females. The SVR12, treatment failure and treatment relapse rates in treatment-experienced versus treatment-naive patients were 91.1% versus 96.8%, 0.8% versus 0.9%, and 8.9% versus 2.7%, respectively. The SIM/SOF regimen provoked a ubiquitous high SVR12 in both treatment-experienced and -naive patients. A SIM/SOF regimen provokes the highest SVR12 in PEG-INF/RBV-experienced chronic HCV patients. Retreatment with PEG-INF/SOF in PEG-INF/RBV-experienced chronic HCV patients has a high probability of treatment failure.

Sofosbuvir-Based Regimens for Chronic Hepatitis C in a Well-Insured U.S. Population: Patient Characteristics, Treatment Adherence, Effectiveness, and Health Care Costs, 2013-2015.

BACKGROUND: Chronic hepatitis C (CHC) is a leading cause of morbidity and mortality and has imposed a high health care burden in the United States. Direct-acting antiviral (DAA) regimens are well tolerated and highly effective for CHC therapy but were initially marketed at a high price. Studies of their real-world use with a nationwide population are limited. OBJECTIVE: To examine patient characteristics, treatment adherence, effectiveness, and health care costs in a large U.S. population with commercial and Medicare supplemental insurance plans who received simeprevir (SIM), sofosbuvir (SOF), or ledipasvir/sofosbuvir (LED/SOF) during the years 2013-2015. METHODS: Patients with at least 1 diagnosis code for CHC and at least 1 claim for SIM, SOF, or LED/SOF prescriptions were selected. The date of the first claim for SIM, SOF, or LED/SOF was defined as the index date. Analyses were stratified by 4 regimens: SOF + SIM ± ribavirin (RBV), SOF + peginterferon alpha-2a or 2b (PEG) + RBV, SOF + RBV, and LED/SOF ± RBV. Adherence was defined by the proportion of days covered (PDC) ≥ 80%. Sustained virologic response (SVR12) was defined as a hepatitis C virus (HCV) RNA load of ≤ 25 IU/mL measured at ≥ 12 weeks following the end of the days supply of the last DAA refill. Health care costs such as DAA drug costs and medical costs (inpatient costs plus outpatient costs) were described. RESULTS: Of 10,808 CHC patients, approximately two thirds were male, and mean age was 55 years. The proportion of patients with compensated cirrhosis among each regimen ranged from 7.4% in LED/SOF ± RBV to 13.8% in SOF + SIM ± RBV, and the proportion of patients with decompensated cirrhosis ranged from 3.9% in LED/SOF ± RBV to 10.7% in SOF + SIM ± RBV. The majority of patients (89.0%) used the newer regimen LED/SOF ± RBV in 2015. Adherence rates were estimated at 80.5%, 81.5%, 85.7%, and 91.4% for SOF + SIM ± RBV (n = 1,761); SOF + PEG + RBV (n = 1,314); SOF + RBV (n = 1,994); and LED/SOF ± RBV (n = 5,739), respectively. Regimen-specific adherence predictors included sex, age group, payer type, health plan, and treatment option with RBV. Being born during 1945-1965, liver disease severity, and Charlson Comorbidity Index levels did not predict adherence in any regimen. Overall SVR12 was 92.6% in 203 patients with available HCV RNA results: 100% (41/41) in SOF + SIM ± RBV; 83.3% (25/30) in SOF + PEG + RBV; 90.6% (29/32) in SOF + RBV; and 93% (93/100) in LED/SOF ± RBV. While the drug costs for these DAA regimens were initially high, they had decreased 18.9% (P < 0.001) during 2013-2015. Medical costs decreased 9.2% (P < 0.001) 1 year after the index dates. CONCLUSIONS: These results indicate that DAA drug costs decreased steadily during 2013-2015 and that 89% of patients on SOF-based DAA regimens took newer, lower-cost regimens with adherence rates above 80%. Available data show that SVR12 rates were close to those obtained in clinical studies. Medical costs also significantly decreased 1 year after the index dates. DISCLOSURES: No outside funding supported this study. All authors are U.S. federal employees of the Centers for Disease Control and Prevention. The authors declare that they have no competing interests. The findings and conclusions in this research are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Cost-effectiveness analysis of Daclatasvir/Sofosbuvir for the treatment of the HCV patients failed after the first line with second generation of DAAs in Italy.

BACKGROUND: Daclatasvir (DCV) combinated with Sofosbuvir (SOF) has shown good efficacy and safety profile for HCV patients. The aim was to evaluate the cost-effectiveness of DCV/SOF regimen versus HCV alternative treatments for patients who failed to achieve the SVR12 after a first DAA treatment from Italian perspective (PITER cohort). METHODS: A Markov model of HCV chronically infected patients was used to develop two scenarios: 1) DCV+ SOF versus Ledipasvir (LDV)+ SOF in Genotype (Gt)1 and Gt4; 2) DCV+ SOF versus no retreatment option in Gt1, Gt3, and Gt4. The percentage of patients who failed the first line with SOF/Simeprevir/Ribavirin (RBV) or SOF/RBV and were retreated or not according to evidences from PITER cohort, were used to populate the model. HCV resources consumption and SVR rates were quantified using PITER data. Transition probabilities and utility rates were derived from the literature. The outcomes were expressed in terms of Quality adjusted life years (QALYs). Probabilistic sensitivity analysis (PSA) was performed considering a cost-effectiveness threshold of € 30,000/QALY. RESULTS: In the base-case analysis, DCV+ SOF represents a cost-effectiveness therapy with ICERs lower than the threshold. The PSA showed robust results, ICERs remain below the threshold in 94% and 99% simulations in Scenario 1 and 2, respectively.

Quality of life of Brazilian chronic hepatitis C patients treated with interferon-free therapies.

Due to the severity of chronic hepatitis C, there are multiple factors that can negatively affect the quality of life of infected patients. The aim of this study was to evaluate changes in the health-related quality of life (HRQoL) in patients under second-generation direct-acting antiviral (DAA) (interferon-free) therapies and to assess treatment effectiveness. This was an observational study conducted in Curitiba (Brazil) using two instruments (a generic and a specific) for measuring the quality of life in patients with chronic hepatitis C, the Short Form-36 (SF-36) and the Chronic Liver Disease Questionnaire (CLDQ) for liver disease evaluation. The study included patients receiving any interferon-free therapy for hepatitis C treatment during 2016 and 2017. Data were collected before, during, and after treatment regarding the two questionnaires, effectiveness and safety. Fifty-six patients fulfilled all eligibility criteria and were included for analysis. Sustained virological response was obtained in 88% of the patients. They were mainly genotype 1, cirrhotic and treated with sofosbuvir combined with daclatasvir or sofosbuvir with simeprevir. Improvement in the quality of life was observed for several domains in both questionnaires (p < 0.05) in the comparison before and after treatment. Patients receiving sofosbuvir with daclatasvir had significantly lower scores compared to the group receiving sofosbuvir with simeprevir. Second-generation DAA therapies were effective and have considerably increased the HRQoL of patients with chronic hepatitis C virus.

Population Pharmacokinetics of AL-335 and Its Two Main Metabolites (ALS-022399, ALS-022227) in Monotherapy and in Combination with Odalasvir and/or Simeprevir.

The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300 L/h (33.9%) and 1910 L/h (30.0%), respectively. ALS-022227 elimination was characterized as a nonlinear process, with typical values of Vmax,ALS-022227 and Km,ALS-022227 estimated to be 84,799 ng/h (14.9%) and 450.2 ng/mL, respectively. AL-335 and ALS-022399 plasma concentrations were increased more than 2-fold in presence of simeprevir and/or odalasvir, while the effect on ALS-022227 plasma concentrations was limited. The effect of simeprevir and/or odalasvir might be explained by their capacity to inhibit P-glycoprotein. Internal evaluation confirmed that the population pharmacokinetic model developed was deemed appropriate to describe the time course of AL-335, ALS-022399, and ALS-022227 plasma concentrations and their associated variability in both healthy and HCV-infected subjects, as well as the interaction effect of simeprevir and/or odalasvir over AL-335 and its metabolites in healthy subjects. This model can be used as a starting point to evaluate drug-drug interaction processes in HCV-infected patients and support the development of a direct-acting antiviral (DAA) combination.

Characterizing the Pharmacokinetic Interaction Between Simeprevir and Odalasvir in Healthy Volunteers Using a Population Modeling Approach.

The aim of this study was to characterize the pharmacokinetic drug-drug interaction (DDI) between simeprevir (NS3/4A protease inhibitor) and odalasvir (NS5A inhibitor) after oral administration to support the design and dose selection of clinical studies with this combination for the treatment of chronic hepatitis C infection (HCV). Simeprevir and odalasvir plasma concentrations from 30 healthy subjects receiving these drugs in monotherapy as well as in combination were pooled and analyzed using a population pharmacokinetic modeling approach. Previous pharmacokinetic models developed to characterize the pharmacokinetics for each drug were used as starting point. The dual effect of simeprevir and odalasvir on their pharmacokinetic parameters was explored. Simulations were performed to assess the impact of the DDI on exposure parameters. In presence of odalasvir, the relative bioavailability of simeprevir increased by 26% and the apparent clearance was reduced following competitive inhibition depending on odalasvir plasma concentrations, with an inhibitory constant (Ki) estimated to be 1610 ng/mL. The apparent odalasvir clearance was reduced by simeprevir plasma concentrations following an Imax model, characterized by a maximum inhibitory effect of 46.7% and an IC50 of 257 ng/mL. Model-based simulations indicated that both Cmax and AUC24h increased for both drugs, when co-administered. The pharmacokinetic model adequately describes the time course of plasma concentrations and their variability when simeprevir and/or odalasvir were orally administered. This model can be used as a first step to predict the exposures of concomitant administration of simeprevir and odalasvir in HCV-infected subjects. Data from study AL355-602 (NCT02512562) were used for this analysis.

Short-Duration AL-335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis.

This open-label, phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct-acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6-12-week oral regimens of 400-800 mg once daily (QD) AL-335 + 50 mg QD/every other day odalasvir ± 75-150 mg QD simeprevir were evaluated in treatment-naïve, HCV genotype (GT)1/3-infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV-RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment-emergent adverse events occurred, one of which (a Mobitz type 1 second-degree atrioventricular block [Wenckebach]) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1-infected patients receiving 3-DAA for 6-8 weeks achieved 100% sustained virologic response 12 weeks and 24 weeks after the end of treatment (sustained virologic response [SVR12/24]). GT1-infected patients receiving 2-DAA or GT3-infected patients receiving 3-DAA had SVR12/24 less than 90%, whether treated for 8 weeks or 12 weeks. Virologic failure was associated with the emergence of generally persistent NS5A and/or transient NS5B resistance-associated substitutions in most patients. Pharmacokinetic characteristics of the three drugs were also elucidated. Conclusions: In treatment-naïve subjects without cirrhosis, AL-335 + odalasvir + simeprevir for 6-8 weeks was generally safe and highly efficacious against HCV GT1. However, inadequate efficacy was observed for the 2-DAA regimen in GT1-infected subjects and the 3-DAA regimen in GT3-infected subjects.

Effectiveness and safety of simeprevir-based regimens for hepatitis C in Italy: The STIly observational study.

The combination of the direct-acting antivirals, simeprevir (SMV) and sofosbuvir (SOF), was the first highly efficacious interferon-free combination for treating patients with hepatitis C virus (HCV), and was widely used in Italy as a result.The aim of this study was to evaluate effectiveness and safety of SMV in Italian patients with HCV genotype (GT) 1 and 4 overall, by treatment regimen [SMV/SOF and SMV/SOF+ribavirin (RBV)], cirrhosis status, and GT (GT1a, GT1b, and GT4).An observational multicenter cohort study was conducted in 46 centers across Italy. Adult HCV + GT1 or GT4 patients, naive or treatment-experienced, with or without cirrhosis, who underwent treatment with a SMV-containing regimen from May to September 2015 were included. The primary endpoint was sustained virologic response (SVR), defined as undetectable serum HCV RNA levels 12 weeks after treatment end (SVR12). The secondary endpoints included duration of treatment, safety and tolerability of each treatment regimen, and SVR by treatment and according to response to previous treatment and fibrosis stage. The association between SVR and a subset of the most clinically relevant variables was investigated by a multivariate logistic regression analysis.A total of 349 HCV-positive patients treated with an SMV-based regimen were enrolled, of whom 342 received SMV/SOF ±â€ŠRBV and were included in this analysis. Most patients (59.4%) were treatment-experienced and had cirrhosis (78.1%). In the group receiving SMV/SOF + RBV, most (63.1%) were treatment-experienced and 82.9% had cirrhosis. Three patients were lost to follow-up; 330 patients receiving SMV/SOF ±â€ŠRBV (96.5%) were treated for 12 weeks. Overall, SVR12 was achieved by 324 patients [94.2%, 95% confidence interval (95% CI) 92-97]. When stratified by treatment and clinical and virologic characteristics, SVR12 was achieved by 77 of 79 [97.5% (95% CI 94.0-100.0)] and 247 of 263 [93.9% (95% CI 91.0-96.8)] patients receiving SMV/SOF and SMV/SOF + RBV, respectively; 132 of 139 (95.0%) naive versus 192/203 (94.6%) treatment-experienced patients; 250 of 267 (93.6%) cirrhotic and 56 of 62 (90.3%) HIV coinfected patients. SMV-based regimens were generally well tolerated. Adverse events leading to treatment discontinuations were not observed.A high proportion of patients treated with SMV/SOF-based regimens achieved SVR12 in this study. A high SVR12 rate was also achieved in patients with cirrhosis, treatment experience, and HUV coinfected patients.

High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma.

BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.

The Observed Effect of Gastric Bypass Surgery on Direct-acting Antiviral Treatment: a Case Report.

Chronic hepatitis C virus (HCV) infection can be cured with treatment using direct-acting antivirals (DAAs). Although these drugs have been widely studied, information about certain special populations is missing. In this case report we describe a treatment-experienced patient with chronic HCV infection genotype 1b, treated with 150 mg/day simeprevir, 400 mg/day sofosbuvir, and 1,000 mg/ day ribavirin for 24 weeks, after a Roux-and-Y gastric bypass. At steady-state a pharmacokinetic curve was recorded of sofosbuvir, GS-331007, and simeprevir. Ribavirin trough plasma concentration (Ctrough) was determined. The simeprevir area under the-concentration time curve (AUClast) and Ctrough were 9.42 h.mg/L and 0.046 mg/L, respectively. Compared to what was described in the literature, simeprevir exposure was low and therefore the simeprevir dose was increased to 300 mg/day. The increased dose of simeprevir was well tolerated and Ctrough was 0.532 mg/L. Sofosbuvir AUClast and Ctrough were 0.63 h.mg/L and 0.0013 mg/L. GS-331007 AUClast and Ctrough were 21.02 h.mg/L and 0.35 mg/L. Ribavirin Ctrough was 2.5 mg/L. Sofosbuvir, GS-331007, and ribavirin exposure were comparable with levels described in literature. The patient achieved a sustained virological response twelve weeks after the completion of treatment.