Interferon-free Regimens Research Articles

Hepatitis C Virus-Infected Patients Receiving Opioid Substitution Therapy Experience Improvement in Patient-Reported Outcomes Following Treatment With Interferon-Free Regimens.

There is a paucity of patient-reported outcomes (PROs) data for people undergoing hepatitis C virus (HCV) treatment who are treated with opioid substitution therapy (OST) for addiction. Patients enrolled in phase 3 clinical trials of sofosbuvir completed 4 PRO instruments-SF-36v2, FACIT-F, CLDQ-HCV, and WPAI-HCV-before, during, and after treatment. A total of 8450 HCV-infected subjects were included; 4.8% (407) were receiving OST. At baseline, OST recipients had significantly (P < .0001) lower PRO scores (by -3.5 to -15.6 on a 0-100 scale). By the end of treatment, subjects receiving pegylated interferon, ribavirin, and sofosbuvir (IFN+RBV+SOF) experienced significant decreases in PROs regardless of OST use. Subjects receiving IFN-free RBV-containing regimens had significant but smaller PRO decreases, again similar in the OST and non-OST groups. Finally, subjects treated with regimens free of both IFN and RBV (IFN/RBV-free) showed improvements in nearly all PROs during treatment, with improvements more pronounced in OST recipients. Achieving a sustained virological response for 12 consecutive weeks after treatment cessation (SVR-12) was associated with improvement of PROs in OST recipients treated with IFN/RBV-free regimens. In contrast, OST recipients who achieved SVR-12 with IFN+RBV+SOF did not have consistent PRO gains after the SVR-12. Receiving IFN-free regimens leads to PRO improvement during treatment and after the SVR-12, regardless of OST status. HCV-infected subjects receiving OST did not experience similar PRO improvements with IFN-containing therapy, suggesting that IFN-based therapy may be less suitable for this vulnerable population.

Economic Evaluation of the Hepatitis C Virus Treatment Extension to Early-Stage Fibrosis Patients: Evidence from the PITER Real-World Cohort

ObjectivesTo conduct a cost-effectiveness analysis of two planning strategies of the second-generation direct-acting antiviral interferon-free regimens for the treatment of chronic hepatitis C virus infection. MethodsA lifetime multicohort model comprised 8125 real-life patients enrolled in the PITER (Italian platform for the study of viral hepatitis) registry, implemented by the ISS (Istituto Superiore di Sanità). Two treatment planning strategies were compared: 1) policy 1—treat all patients regardless of the stage of fibrosis (F0–F4) with second-generation direct-acting antivirals and 2) policy 2—treat patients at F3/F4 stage and those who are prioritized by the scientific guidelines first, and the remaining patients when they reach the F3 stage. Clinical outcomes and costs were evaluated by using a lifetime horizon Markov model and adopting the third-party payer perspective. Health outcomes were expressed in terms of quality-adjusted life-years (QALYs). A sensitivity analysis was run to explore first- and second-order uncertainty and heterogeneity. An expected value of perfect information analysis was also conducted. ResultsPolicy 1 exhibits an incremental cost-effectiveness ratio of €8,775/QALY gained and remains less than €30,000/QALY in 94% of realizations produced by the Monte-Carlo simulation. Such a proportion increases to 97% when adopting a threshold of €40,000/QALY gained. ConclusionsMoving from the urgency criterion to evidence-based escalating strategies when prioritizing the access to new anti–hepatitis C virus treatments is a good investment in health, whose affordability should be explored through context-specific budget impact analyses.

Hepatocellular Carcinoma Occurrence and Recurrence after Antiviral Treatment in HCV-Related Cirrhosis. Are Outcomes Different after Direct Antiviral Agents? A Review.

Hepatitis C virus (HCV) infection is one of the major causes of hepatocellular carcinoma (HCC) worldwide. In the last decades, several studies have showed a lower rate of HCC occurrence or recurrence in patients with HCV-related cirrhosis after interferon-based antiviral therapies compared to untreated controls, even without reaching viral clearance. Unfortunately, interferon regimens could only yield viral clearance in approximately half of the patients. The recent development of new all-oral regimens with direct-acting antivirals (DAAs) has radically improved the cure rate to above 90%. In respect to these findings, many would have thought that interferon-free regimens would decrease the development and recurrence of HCC. Literature data have unexpectedly reported high rates of both the occurrence and recurrence of HCC after therapy with DAAs. However, it is probably too early to express some concerns. More recent data showed that both occurrence and recurrence of HCC are decreased by the DAAs. Interferon-free therapy is definitely not without limits. Together with the initial thoughts of an increased risk of HCC, these may lead to an unwanted restricted access to interferon-free regimens in specific subpopulations. This issue should be settled as soon as possible because millions of hepatitis C patients are and will be using DAAs in the present and future. Our purpose is to review the existing literature and to offer a more precise and rational interpretation of the existing data.

Role of ribavirin in interferon-free therapy for the treatment of hepatitis C virus

Interferon-free regimens achieve sustained virologic response (SVR) rates of over 90%, have generally well-tolerated adverse effects and involve 12-week treatment durations for most patients with chronic hepatitis C, including naive or previously treated patients and patients with or without cirrhosis. However, some of the treatment options recommended by the guidelines require the addition of ribavirin (RBV) or extend the duration of treatment to increase efficacy. The use of RBV is a useful tool in those difficult-to-cure patients such as patients with decompensated or genotype-3-infected cirrhosis and those who have not achieved SVR after treatment with direct-acting antivirals (DAA). Overall, adding RBV to the different combinations causes adverse effects related to a decrease in haemoglobin and involves inconveniences such as its dosage, which requires patients to take several tablets twice daily. However, severe anaemia is rare and easily manageable with a dose reduction. In addition, RBV is teratogenic. In practice, because RBV is inexpensive and well tolerated when combined with an interferon-free regimen, it continues to be a useful tool to optimise the results of some HCV treatment regimens. RBV-free regimens eliminate RBV-related adverse effects related, resulting in better tolerability, improving patient adherence and quality of life and reducing the cost of treatment.

Micro-costing analysis of guideline-based treatment by direct-acting agents: the real-life case of hepatitis C management in Brazil

BackgroundEradication of hepatitis C virus (HCV) using direct-acting agents (DAA) has been associated with a financial burden to health authorities worldwide. We aimed to evaluate the guideline-based treatment costs by DAAs from the perspective of the Brazilian Ministry of Health (BMoH).MethodsThe activity based costing method was used to estimate the cost for monitoring/treatment of genotype-1 (GT1) HCV patients by the following strategies: peg-interferon (PEG-IFN)/ribavirin (RBV) for 48 weeks, PEG-IFN/RBV plus boceprevir (BOC) or telaprevir (TEL) for 48 weeks, and sofosbuvir (SOF) plus daclastavir (DCV) or simeprevir (SIM) for 12 weeks. Costs were reported in United States Dollars without (US$) and with adjustment for purchasing power parity (PPP$). Drug costs were collected at the National Database of Health Prices and an overview of the literature was performed to assess effectiveness of SOF/DCV and SOF/SIM regimens in real-world cohorts.ResultsTreatment costs of GT1-HCV patients were PPP$ 43,176.28 (US$ 24,020.16) for PEG-IFN/RBV, PPP$ 71,196.03 (US$ 39,578.23) for PEG-IFN/RBV/BOC and PPP$ 86,250.33 (US$ 47,946.92) for PEG-IFN/RBV/TEL. Treatment by all-oral interferon-free regimens were the less expensive approach: PPP$ 19,761.72 (US$ 10,985.90) for SOF/DCV and PPP$ 21,590.91 (US$ 12,002.75) for SOF/SIM. The overview reported HCV eradication in up to 98% for SOF/DCV and 96% for SOF/SIM.ConclusionStrategies with all oral interferon-free might lead to lower costs for management of GT1-HCV patients compared to IFN-based regimens in Brazil. This occurred mainly because of high discounts over international DAA prices due to negotiation between BMoH and pharmaceutical industries.

The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: Role of the treatment regimen

Previous studies have reported a high frequency of hepatocellular carcinoma (HCC) occurrence in patients with advanced liver disease, after receipt of interferon (IFN)-free therapy for hepatitis C virus (HCV) infection. Our objective was to verify and account for this phenomenon using data from the Scottish HCV clinical database. We identified HCC-naïve individuals with liver cirrhosis receiving a course of antiviral therapy in Scotland from 1997-2016 resulting in a sustained virologic response. Patients were followed-up from their treatment start date to the earliest of: date of death, date of HCC occurrence, or 31 January 2017. We used Cox regression to compare the risk of HCC occurrence according to treatment regimen after adjusting for relevant co-factors (including: demographic factors; baseline liver disease stage; comorbidities/health behaviours, virology, and previous treatment experience). HCC occurrence was ascertained through both the HCV clinical database and medical chart review. For our main analysis, treatment regimen was defined as IFN-free vs. IFN-containing. A total of 857 patients met the study criteria, of whom 31.7% received an IFN-free regimen. Individuals receiving IFN-free therapy were more likely to be: older; of white ethnicity, Child-Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic; non-genotype 3; and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated with a significantly increased risk of HCC (HR: 2.48; p = 0.021). However, after multivariate adjustment for baseline factors, no significant risk attributable to IFN-free therapy persisted (aHR: 1.15, p = 0.744). These findings suggest that the higher incidence of HCC following sustained virologic response with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se. We examined the risk of liver cancer in 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer.

Treatment of hepatitis C virus infection with direct-acting antiviral drugs is safe and effective in patients with hemoglobinopathies.

Progression of liver fibrosis in patients with hemoglobinopathies is strongly related to the severity of iron overload and the presence of chronic hepatitis C virus (HCV) infection. Effective iron chelation therapy and HCV infection eradication may prevent liver complications. The European Association for the Study of the Liver guidelines recommend interferon-free regimens for the treatment of HCV infection in patients with hemoglobinopathies. However, data regarding the use of direct-acting antiviral drugs (DAAs) in this patient population are few. This observational study evaluated the safety and efficacy of therapy with DAAs in an Italian cohort of patients with hemoglobinopathies, chronic HCV infection and advanced liver fibrosis. Between March 2015 and December 2016, 139 patients received DAAs and completed 12 weeks of follow up after the end of treatment for the evaluation of sustained virological response (12SVR). The 12SVR (93.5%) was comparable with that typically observed in cirrhotic patients without hemoglobinopathies. Three patients died during the period of observation of causes unrelated to DAAs. One patient did not achieve a virological response and five (3.6%) relapsed during 12 weeks of follow-up after the end of therapy. In addition, patients showed significant reductions in serum ferritin at 12 weeks to levels similar to those observed in a control group of 39 patients with thalassemia major without HCV infection, who adhered to chelation therapy and had no overt iron overload. In conclusion, the use of DAAs appears to be safe and effective in patients with hemoglobinopathies and advanced liver disease due to HCV.

Treating Hepatitis C Infection in Patients With Chronic Kidney Disease: Our Options Have Improved Greatly

Chronic hepatitis C infection (HCV) is a common problem in patients with kidney disease (Corouge M. et al. Liver Int (2016); 36:28–33, Fabrizi F. et al. Int. J. Artif. Organs (2017); 0). In the past, treatment of hepatitis C infection was very difficult due to poor efficacy, significant side effects, and the multiple comorbidities that affect patients with advanced kidney disease (Pockros PJ et al. Gastroenterology (2016); 150:1590–1598). Significant recent advances in oral interferon-free treatment regimens allow patients with hepatitis C to be treated effectively with minimal side effects. For patients with genotype 1a, 1b, or 4, there are several recommended oral regimens that achieve virologic cure in greater than 95% of patients, even in patients with severe or end-stage renal disease. For other genotypes, specifically 2, 3, 5, and 6, treatment with direct acting antiviral (DAA) agents that are used in patients with normal renal clearance has significant potential for side effects and is not recommended. Patients who are waiting for a kidney transplant or who have received a kidney transplant and have estimated eGFR greater than 30 ml/min can be treated with multiple regimens in an attempt to cure their hepatitis C (Fabrizi F. et al. Int. J. Artif. Organs (2017); 0). Patients with kidney-related complications due to their chronic hepatitis C infection can also be treated with a significant chance of resolution of the complication (Corouge M. et al. Liver Int (2016); 36:28–33, Kamar N. et al. Clin. Nephrol (2008); 69:149–160). The timing of HCV treatment and kidney transplant depends on the individual transplant centers protocol and the patient’s position on the waiting list for a kidney (Fabrizi F Clin. Liver Dis 2005; 9: 503, viii). USA transplant centers in order to reduce the time on the waiting list have decided to offer HCV-infected patients a kidney from an HCV-positive donor. Treatment of the HCV is then done early after recovery from the transplant surgery. Due to significant advances in developing oral direct acting antiviral agents, we now have safe and effective oral regimens to treat HCV-infected patients with renal disease, including those on hemodialysis, waiting for a kidney transplant, or after a renal transplant. The purpose of this review is to summarize the currently recommended treatment regimens and provide clinicians with guidance in terms of the efficacy and safety of the new direct acting antiviral agents (DAAs) in treating HCV-infected patients who have advanced kidney disease.

Short‐term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct‐acting anti‐viral treatment

With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n=152) or without previous HCC (n=1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. During the follow-up period (median: 17months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P<0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0ng/mL and ≥ 9.0ng/mL groups (cut-off value) respectively (log-rank test: P<0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P=0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.

Daclatasvir and asunaprevir treatment in patients with severe liver fibrosis by hepatitis C virus genotype 1b infection: Real-world data.

In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan: daclatasvir and asunaprevir in chronic hepatitis C patients with severe fibrosis. Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib-4 index≧3.25 and were included in this study. We investigated antiviral effect and factors associated with sustained viral response 12 (SVR12), and the additional effects on serum α-fetoprotein and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P<0.05 was considered as significant levels. Antiviral effect was lower in patients with severe fibrosis at 8 and 12weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P=0.002 and P=0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P=0.008) was seen in patients with severe fibrosis; however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum α-fetoprotein significantly decreased, and serum albumin levels significantly increased as early as 4weeks after the start of treatment. Although the antiviral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective and well-tolerable treatment in these populations.

What Is Beyond ALLY-3 +? A Large Experience of Treatment of HCV Genotype 3-Related Chronic Decompensated Liver Disease by an Interferon-Free Regimen

Introduction: The treatment options for HCV genotype 3 infection is limited in patients with decompensated cirrhosis (DC). Combination of Daclatasvir (DCV; pangenotypic non-structural protein [NS] 5a inhibitor), sofosbuvir (SOF; pangenotypic NS 5b inhibitor) and ribavirin (RBV) in recent phase 3 ALLY 3+ trial showed an overall sustained virological response at week 12 (SVR 12) in 86% of the compensated cirrhotic patients.1 However, the treatment efficacy of DCV-SOF-RBV (interferon free regimen) in DC patients is unknown. Our aim is to assess the efficacy of DCV-SOF-RBV regimen in achieving SVR 12 in patients (treatment naïve) with decompensated cirrhosis. Methods: This prospective study was conducted from 07/2014 to 01/2017 at one of the highly prevalent HCV genotype 3 zone in North India (J&K). All included study subjects were treatment naïve, HCV genotype 3 related with decompensated chronic liver disease. They were treated with interferon free regimen of DCV (60mg)-SOF (400mg)-RBV (600mg/day with potential to dose adjustment to 1000mg/day) for 16 weeks.Table: Table. Virological responseResults: A total of 75 patients met the study criteria and were included in the study. The baseline characteristics of all patients were demonstrated in Table 1. In this study, DCV-SOF-RBV for 16 weeks achieved SVR 12 rates of 82.6% and 85.3% in patients with CTP score up to 10 and CTP score > 10 respectively. The overall SVR 12 rate was 84 % in treatment naive genotype 3 DC patients. The virological response of the study subjects were shown in Table 2.10 patients (13.3%) did not achieve SVR 12 and relapsed. None of the patients showed virological failure. Two patients lost follow up due to complication of CLD. Most common adverse events were insomnia and fatigue and patients were continued in the study without discontinuation of the drug.Table: Table. No Caption available.Conclusion: This is first and largest study primarily focussed on treatment of HCV genotype 3 decompensated cirrhotic patients with an interferon free regimen of DCV-SOF-RBV. Our study showed encouraging result of an overall SVR 12 rate of 84% in treatment naive patients. The regimen was well tolerated with minimal side effects.

The Incidence of Hepatocellular Carcinoma Is not Increased in Individuals with Chronic Hepatitis C After Treatment with Interferon-free Regimens: an ERCHIVES Study

BackgroundSustained virologic response (SVR) after interferon-based treatment for chronic hepatitis C virus (HCV) infection has been strongly linked with decreased incidence of hepatocellular carcinoma (HCC). Surprisingly, several recent studies have reported higher rates of HCC in individuals treated with direct-acting antivirals (DAAs). However, making definitive conclusions has been challenging due to the heterogeneous populations and methodologies of these reports. As such, we sought to investigate whether DAA use is associated with increased rates of incident HCC.MethodsUsing the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, we identified 17,836 patients without a prior diagnosis of HCC and divided them into 3 groups based on treatment: (a) pegylated interferon and ribavirin (IFN) (n = 3,534); (b) DAA-based therapy (n = 5,734); and (c) an untreated control group (n = 8,468). Predictors of HCC were identified using multivariate Cox proportional hazards analysis. HCC-free survival in cirrhotics was assessed by Kaplan–Meier analysis.ResultsSVR was achieved by 66.6% and 96.2% of the IFN and DAA groups, respectively. In our cohort, the incidence rate of HCC was not different between IFN and DAA groups (7.48/1000 vs. 7.92/1000 patient-years of follow-up; P = 0.72). Moreover, DAA treatment was not associated with an increased risk of HCC (HR 1.16; [95% CI: 0.79, 1.71]) compared to IFN treatment. Other risk factors for HCC included older age, alcohol abuse/dependance history, smoking history, HCV genotype 3 infection, proton-pump inhibitor use, AFP > 20, and cirrhosis. Notably, among cirrhotics who achieve SVR, HCC-free survival was not different between IFN and DAA treated groups, and both groups had significantly improved HCC-free survival compared with untreated patients.ConclusionAmong cirrhotic patients with HCV, DAA treatment is associated with a comparable risk of HCC to IFN treatment. Furthermore, the rate of HCC after SVR by any treatment was significantly lower than for those untreated or who failed to achieve SVR. Previously reported increases in HCC associated with DAA treatment appear to be explained by the presence of pre-existing risk factors for HCC.Disclosures R. T. Chung, Gilead: Investigator, Research grant; Abbvie: Investigator, Research grant; Merck: Investigator, Research grant; Janssen: Investigator, Research grant; A. Butt, Merck: Investigator, Grant recipient

Unique Characteristics Associated with Sustained Liver Damage in Chronic Hepatitis C Patients Treated with Direct Acting Antivirals

Background and Aims: Direct-acting antivirals (DAAs) dramatically improve the sustained virological response (SVR) of chronic hepatitis C (CHC) patients. However, continuous liver damage after SVR may be a risk of hepatocellular carcinoma (HCC). We clarified pretreatment characteristics related to sustained liver damage after SVR. Methods: A total of 286 CHC patients were treated with an interferon-free DAA regimen. Among them, 250 patients achieved SVR for 12 weeks after the end of treatment (SVR12); these individuals were classified based on α-fetoprotein (AFP) and alanine transaminase (ALT) levels posttreatment. Baseline characteristics significantly associated with AFP >5 ng/mL and ALT level ≥20 IU/L after SVR were clarified using multivariate analyses. Results: Among the pretreatment factors examined, serum AFP values and the presence of fatty liver (FL) were significantly associated with abnormal AFP (p < 0.0001) and ALT levels 12 weeks after SVR12 (SVR24; p = 0.0109). For 126 patients who showed an increase in baseline AFP level, FL, fibrosis-4 (FIB-4) index, and albumin levels before treatment were related to abnormal AFP at SVR24 (p = 0.0005, 0.0232, and 0.0400 for FL, FIB-4 index, and albumin, respectively). Similarly, for 150 patients with abnormal baseline ALT levels, FL was associated with an ALT level ≥ 30 IU/L after SVR (p = 0.0430). Conclusions: High FIB-4 index, low albumin level, and FL before DAA treatment were associated with a risk of sustained liver damage with AFP and ALT elevation after SVR; patients with these factors should be carefully monitored for emergence of HCC.

Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with or without Ribavirin for Treatment of Hepatitis C Virus Genotype 1: A Systematic Review and Meta-analysis.

Interferon-free regimens are rapidly evolving for patients with chronic hepatitis C virus (HCV) infection. We performed this meta-analysis to investigate the safety and efficacy of a combination regimen (ombitasvir [OBV]/paritaprevir [PTV]/ritonavir [r]±dasabuvir [DSV]) for the treatment of patients with HCV genotype 1infection. A computerized literature search for relevant clinical trials was conducted during May 2017. Data on sustained virological response (SVR), virological relapse, and safety outcomes were extracted and calculated as pooled proportion (PP) or risk ratio (RR) with their 95% confidence interval (CI), using StatsDirect and RevMan software. The final analysis included 13 studies for HCV genotype 1 (3115 patients). The pooled effect estimate showed that 12-week treatment of genotype 1 patients with the OBV/PTV/r regimen achieved a high SVR rate (PP=94%, 95% CI 92-96) that increased to (PP=97%, 95% CI 96-98) upon the addition of DSV. These results were consistent when independent subgroup analyses were conducted based on viral subgenotypes, the presence of cirrhosis, or former treatment failure. Adding ribavirin(RBV) to this regimen was not associated with increased SVR rates (risk ratio=1, 95% CI 0.98-1.02), while it increased the risk of serious adverse events (p=0.02), insomnia (p=0.001), and pruritus (p<0.001). The current meta-analysis showed a high efficacy for the OBV/PTV/r regimen in the treatment of HCV genotype 1 (with DSV) infection, regardless of the presence of cirrhosis or former treatment failure. Adding RBV to this regimen slightly decreased the relapse rate. Future studies with larger sample sizes are required to investigate the efficacy of this regimen in other HCV genotypes and to establish the evidence about the effect of adding RBV to OBV/PTV/r+DSV.

Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation

Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients. Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain. In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p=0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT. Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need. Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need.

Papel de la ribavirina en la terapia libre de interferón frente al virus de la hepatitis C

Interferon-free regimens achieve sustained virologic response (SVR) rates of over 90%, have generally well-tolerated adverse effects and involve 12-week treatment durations for most patients with chronic hepatitis C, including naive or previously treated patients and patients with or without cirrhosis. However, some of the treatment options recommended by the guidelines require the addition of ribavirin (RBV) or extend the duration of treatment to increase efficacy. The use of RBV is a useful tool in those difficult-to-cure patients such as patients with decompensated or genotype-3-infected cirrhosis and those who have not achieved SVR after treatment with direct-acting antivirals (DAA). Overall, adding RBV to the different combinations causes adverse effects related to a decrease in haemoglobin and involves inconveniences such as its dosage, which requires patients to take several tablets twice daily. However, severe anaemia is rare and easily manageable with a dose reduction. In addition, RBV is teratogenic. In practice, because RBV is inexpensive and well tolerated when combined with an interferon-free regimen, it continues to be a useful tool to optimise the results of some HCV treatment regimens. RBV-free regimens eliminate RBV-related adverse effects related, resulting in better tolerability, improving patient adherence and quality of life and reducing the cost of treatment.

Hepatitis C treatment from "response-guided" to "resource-guided" therapy in the transition era from interferon-containing to interferon-free regimens.

Peginterferon/ribavirin has been the standard-of-care for chronic hepatitis C virus (HCV) infections: 48weeks for genotype 1 or 4 (HCV-1/4) and 24weeks for HCV-2/3. Response-guided therapy recommended shorter 24- and 16-week regimens for HCV-1 with lower baseline viral loads (<400000-800000IU/mL) and rapid virological response (RVR, undetectable HCV RNA at week 4) and HCV-2/3 with RVR, respectively; and extending to 72 and 48weeks for HCV-1 slower responders and HCV-2 non-RVR patients, respectively, to improve the efficacy. The progress of directly acting antivirals (DAA), moving from interferon-containing regimens in 2011 to interferon-free regimens in 2013, has greatly improved the treatment success. Interferon-containing regimens include boceprevir or telaprevir or simeprevir or daclatasvir plus peginterferon/ribavirin, 24-48weeks, for HCV-1 or 4. However, adding these DAA has no benefit for HCV-1 with lower baseline viral loads/RVR. Instead, 12-week sofosbuvir plus peginterferon/ribavirin attained sustained virological response rates of >90% for HCV-1/3-6. Interferon-free regimens include two main categories: NS5B nucleotide inhibitor (sofosbuvir)-based regimens and NS3/4A inhibitor/NS5A inhibitor-based regimens (daclatasvir/asunaprevir, paritaprevir/r/ombitasvir/dasabuvir and grazoprevir/elbasvir). About 8-24weeks interferon-free regimens could achieve sustained virological response rates of 82-99% for corresponding HCV genotypes. Although the newly DAA interferon-free regimens have high efficacy and safety, the huge budget impact increases the treatment barriers. The current recommendation should, therefore, base on the availability, indication, and cost-effectiveness in the transition era of DAA. Based on the concept of "resource-guided therapy," peginterferon/ribavirin might be applied for easy-to-treat interferon-eligible patients in resource-constrained areas. Prioritizing patients for interferon-free regimens according to "time-degenerative factors" (age and fibrosis) is justified before the regimens becoming available and affordable.

Non-invasive liver fibrosis assessment and HCV treatment initiation within asystematic screening program in HIV/HCV coinfected patients.

SummaryBackground and aimHepatitis C virus (HCV) therapy should be considered without delay in all patients with significant (SIGFIB) or advanced liver fibrosis (ADVFIB). We aimed to investigate the rates of treatment initiation with interferon-free regimens within a screening program for SIGFIB/ADVFIB in human immunodeficiency virus/HCV coinfected patients (HIV/HCV).MethodsThe FIB-4 was calculated in all HIV/HCV from 2014–2016. HIV/HCV were counselled by the HIV clinic and referred to the Division of Gastroenterology and Hepatology for transient elastography (TE) and evaluation for HCV therapy. Patients were stratified by FIB-4 of </≥1.45 (established cut-off for ruling out ADVFIB) and SIGFIB/ADVFIB were defined by liver stiffness >7.1 kPa/>9.5 kPa, respectively.ResultsAmong 1348 HIV+ patients, 16% (210/1348) had detectable HCV-RNA. One hundred HIV/HCV had a FIB-4 ≥1.45. Among these, 57% (57/100) underwent TE. The majority of these patients had SIGFIB (75%; 43/57) or ADVFIB (37%; 21/57), however, interferon-free treatment was initiated in only 56% (24/43).In addition, fifty-two percent (57/110) of HIV/HCV with FIB-4 <1.45 underwent TE. Interestingly, 40% (23/57) and 18% (10/57) of these patients showed SIGFIB or even ADVFIB, respectively, and 78% (18/23) finally received interferon-free treatment. Overall, only 20% (42/210) of HIV/HCV received interferon-free treatment.ConclusionFIB-4 was not useful for ruling out SIGFIB/ADVFIB in our cohort of HIV/HCV. Treatment was initiated only in a small proportion (20%) of HIV/HCV during the first 2 years of interferon-free treatment availability, although the observed proportion of patients with SIGFIB (assessed by TE) was considerably higher (58%). Thus, it requires the ongoing combined efforts of both HIV and HCV specialists to increase treatment uptake rates in this special population.Electronic supplementary materialThe online version of this article (doi: 10.1007/s00508-017-1231-x) contains supplementary material, which is available to authorized users.

Estimating the cost-effectiveness of daclatasvir\xa0+\xa0sofosbuvir versus sofosbuvir\xa0+\xa0ribavirin for patients with genotype 3 hepatitis C virus

BackgroundAs treatments for chronic hepatitis C are moving away from interferon-containing regimens, the most appropriate allocation of resources to higher cost, interferon-free, direct-acting antiviral (DAA) regimens needs to be assessed. Hepatitis C virus (HCV) genotype 3 is associated with faster disease progression and has fewer treatment options, historically, than other HCV genotypes. This analysis aims to estimate the comparative cost-effectiveness of two recently licenced interferon-free regimens for the treatment of HCV genotype 3.MethodsUtilising a published Markov model and results of a matching-adjusted indirect comparison of recently published clinical trial data (ALLY-3 and VALENCE, respectively), 12 weeks of treatment with daclatasvir + sofosbuvir (DCV + SOF) was compared to 24 weeks of treatment with sofosbuvir + ribavirin (SOF + RBV). UK-specific model inputs were used to inform a cost-utility analysis of these regimens.ResultsIn the base case analysis, DCV + SOF was found to be dominant over SOF + RBV in treatment-naïve patients, patients that had previously been treated, and patients that are intolerant to, or ineligible for, interferon-containing regimens. Given the low rates of treatment currently observed in the UK, DCV + SOF was also compared to no treatment in the interferon-ineligible/intolerant patients, and may be considered cost-effective with an incremental cost-effectiveness ratio of £8817.ConclusionsWhen compared to 24 weeks of SOF + RBV, 12 weeks of treatment with DCV + SOF results in improved quality of life and reduced total costs, and therefore is likely to represent significant clinical and economic value as a treatment option for genotype 3 HCV infection.

Treatment Discontinuation, Adherence, and Real-World Effectiveness Among Patients Treated with Ledipasvir/Sofosbuvir in the United States

IntroductionLedipasvir/sofosbuvir (LDV/SOF) for hepatitis C virus (HCV) treatment provides an oral interferon-free treatment regimen with high rates of sustained virologic response (SVR). This study assessed treatment discontinuation, factors associated with treatment completion, and real-world effectiveness.MethodsPatients with HCV treated with LDV/SOF between October 2014 and June 2015 and enrolled in a large US health plan were identified. Expected treatment duration was calculated based on IDSA/AASLD treatment guidelines and US labels using data for genotype, initial treatment regimen, baseline cirrhosis, and prior treatments. Logistic regression was used to identify factors associated with treatment completion, controlling for patient characteristics.ResultsThe study included 1483 LDV/SOF patients. Mean age was 59.7 years, most were male (63.9%), had commercial insurance (51.9%), and were treatment-naïve (85.6%). Cirrhosis or end stage liver disease was present in 46.1%. Among patients with an expected 8-week treatment regimen, 49.4% were treated for longer. Most patients (99.8%) with expected 12-week treatment durations were adherent to the expected treatment duration. Treatment-experienced patients [odds ratio (OR) 0.124, p < 0.001] and those on Medicare (OR 0.382, p = 0.039) had lower odds of completing the expected treatment regimen, while males were more likely to complete treatment than females (OR 3.235, p = 0.003). SVR12 in patients treated with LDV/SOF was 89.4% (n = 76/85).ConclusionHalf of patients eligible for an 8-week treatment regimen with LDV/SOF were treated longer, while most patients with a 12-week regimen were adherent to the expected treatment duration. Prior HCV treatment, female gender, and Medicare Advantage insurance were associated with lower odds of treatment completion. Overall SVR12 was 89.4%.FundingMerck & Co. Inc.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-017-0163-0) contains supplementary material, which is available to authorized users.