All-oral Interferon-free Regimens Research Articles

Antivirals against HCV infection: the story thus far.

Remarkable scientific breakthroughs have been made in the stride towards the development of potent and tolerable hepatitis C regimens within the last three decades. Earlier approaches involved the use of pegylated interferon alfa and ribavirin as standard-of-care treatment. Treating genotype 1a infection with this regimen which was at that time considered the gold standard for hepatitis C virus therapy was rife with challenges; safety and toxicity issues necessitated a rigorous quest for alternative regimens. Deeper understanding of the pathogenesis of hepatitis C virus ushered in the era of direct acting antiviral agents. These agents have been the subject of intensive research in the last two decades, leading to the development of drug classes such as protease inhibitors (e.g., grazoprevir), NS5A inhibitors (e.g., daclatasvir) and NS5B inhibitors (e.g., sofosbuvir). While many are still under development, several have been approved for hepatitis C therapy. A number of studies investigating the combination of direct acting antiviral agents with or without pegylated interferon and/or ribavirin for the treatment of chronic hepatitis have demonstrated sustained virologic response of > 90%. Given the array of direct acting antiviral agents currently available, the present landscape of hepatitis C therapy is now characterized by a gradual transition to all-oral interferon-free regimens. Despite these milestones, the WHO global target of eliminating hepatitis C as a public health problem by 2030 seems uncertain. In this review, we provide a concise account of the evolution and advancements in the development of anti-HCV regimens.

THU391 - Safety and efficacy of an all-oral interferon-free regimen of seraprevir, an NS3/4A protease inhibitor and sofosbuvir in patients with chronic hepatitis C virus (HCV) genotype 1: an open-label, multicentre, phase 3 trial

THU391 - Safety and efficacy of an all-oral interferon-free regimen of seraprevir, an NS3/4A protease inhibitor and sofosbuvir in patients with chronic hepatitis C virus (HCV) genotype 1: an open-label, multicentre, phase 3 trial

Asymptomatic chronic hepatitis c with F0-1 fibrosis: Wait and monitor

The short-term progression of asymptomatic chronic hepatitis C patients with mild fibrosis isexcellent. Non-invasive test is easy and use to monitor the progression of fibrosis. Interferon regimen isthe treatment for HCV patients, currently direct-acting antiviral drug (DDA) regimens is more effectiveand shorter duration. Many DDA regimens can have sustained viral response (SVR) rates of morethan 90% and safety outcomes. Furthermore, all-oral interferon free regimens are not cost-effectivefor patients with mild fibrosis disease. The HCV treatment should be deferred for a few years and theprogression of fibrosis is regularly monitored. This option is safe until new treatment, which ischeaper, shorter, more effective and more convenient, become available.
 
 Keywords: symptomatic, direct-acting antiviral drug, fibrosis progression, cost

Glecaprevir/pibrentasvir expands reach while reducing cost and duration of hepatitis C virus therapy.

Hepatitis C virus (HCV) treatments have dramatically progressed from poorly tolerated, moderately successful interferon-based therapies to highly effective all-oral interferon-free regimens. While sustained virologic responses have significantly improved with fixed-dose combinations (FDC) of these direct-acting antivirals (DAA), cost remains high and certain populations of patients remain difficult to treat. Glecaprevir (GLE, an NS3/4A protease inhibitor) and pibrentasvir (PIB, NS5A inhibitor) were recently approved as a FDC therapy for HCV, and have expanded reach, reduced cost, and in certain populations, reduced HCV treatment duration. GLE/PIB is effective across all genotypes, and has been shown to be effective in HIV-infected patients, patients with chronic kidney disease, and Child-Pugh A-compensated cirrhosis. GLE/PIB is also effective for a shortened duration of 8weeks in treatment-naive non-cirrhotic patients.

Real world experience with the all-oral interferon free regimen for the treatment of chronic hepatitis c virus infection in the Lebanese population.

The treatment of hepatitis C has dramatically improved since the introduction of the new Direct-Acting Antivirals (DAAs). The aim of this study is to assess the effectiveness and safety of all oral DAAs with or without ribavirin in the treatment of hepatitis C virus (HCV) in treatment naïve and experienced Lebanese population. We reviewed all cases approved for hepatitis C treatment with DAAs according to the Lebanese guidelines for treatment of HCV at the Ministry of Public Health from October 2015 till December 2016. Available data concerning age, sex, mode of transmission, genotype (GT) and subtype, fibrosis stage, previous treatment (if present), new DAAs treatment, and sustained virological response at week 12 (SVR12) were collected. During a period of 15 months (October 2015 to December 2016), 186 patients were treated with DAAs. 57% were male and the mean age was 54.3 years. The source of infection was unknown in 51% of cases and blood transfusion in 35.5% of cases. Genotype 1 was the most predominant genotype (45%), followed by GT4 (34%) and GT3 (12%). 71.6% of patients had advanced fibrosis before starting DAAs and 57% were cirrhotic. 42% of patients were treatment experienced (85% pegylated interferon and ribavirin). Different DAAs regimens were used according to the Lebanese guidelines for treatment of HCV: Ledipasvir/Sofosbuvir (38.7%), Sofosbuvir/Daclatasvir (16.1%), Sofosbuvir/Velpatasvir (1.6%), Sofosbuvir/RBV (7.5%), Ombitasvir/Paritaprevir/Ritonavir (17.5%) and Ombitasvir/Paritaprevir/Ritonavir -Dasabuvir (18.8%). Ribavirin was used in 51.6% of cases. SVR12 was achieved in 93% of patients (relapse in 4%, loss of follow up and/or severe adverse effect in 3%). SVR 12 was achieved in 93%, 96% and 94% of GT1, GT3 and GT4 cases respectively. SVR12 was seen in 91.3% of cirrhotic patients vs. 98.7% of F0-F3 patients. (p = 0.047). There was no difference in SVR12 between treatment naïve and experienced patients. Hepatocellular carcinoma developed in 5 patients (2.9%) during the study period. This is the first real world Lebanese data of HCV treatment with DAAs. The study population was significant for a large number of patients with cirrhotic (50%) and treatment experienced patients (42%). SVR12 was achieved in 93% of patients with no difference between treatment naïve and experienced patients. SVR12 was lower in patients with cirrhosis compared to patients with lower stage of fibrosis (91.3% vs. 98.7%).

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 Role of Direct-acting Antivirals in the Treatment of Children with Chronic Hepatitis C.

In the United States, chronic infection with the hepatitis C virus (HCV) affects an estimated 0.1–2% of the pediatric population, who are consequently at risk for major complications, including cirrhosis, hepatocellular carcinoma, and death. The current standard of treatment for chronic hepatitis C (CHC) in children is pegylated-interferon-alpha (PEG-IFN) in combination with ribavirin. PEG-IFN/ribavirin therapy is approved for children ages 3 and older; however, it is often held from use until adulthood because of its extensive list of potential side effects and high likelihood of causing adverse symptoms. While CHC is usually indolent in children and adolescents, immediately treating and curbing the spread of HCV before adulthood is important, as there can be transmission to other individuals via sexual activity and infected females can later vertically transmit the infection during pregnancy, the latter representing the most common means of transmission for children in the United States. The recent development of direct-acting antivirals has shown promising results in clinical trials for use in children and has dramatically increased the rates of sustained virological response in adults while improving side effect profiles as compared to interferon-based treatments. Given the usually indolent course of CHC in children, significant side effects of the currently-approved PEG-IFN/ribavirin therapy, and likely availability of all-oral interferon-free regimens for children within a few years, deferring treatment in clinically-stable children with CHC in anticipation of upcoming superior treatment modalities may be justified.

Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial

Hepatitis C virus (HCV) genotype 4 accounts for about 13% of global HCV infections. Because interferon-containing treatments for genotype 4 infection have low efficacy and poor tolerability, an unmet need exists for effective all-oral regimens. We examined the efficacy and safety of an all-oral interferon-free regimen of ombitasvir, an NS5A inhibitor, and paritaprevir (ABT-450), an NS3/4A protease inhibitor dosed with ritonavir (ombitasvir plus paritaprevir plus ritonavir), given with or without ribavirin. In this multicentre ongoing phase 2b, randomised, open-label combination trial (PEARL-I), patients were recruited from academic, public, and private hospitals and clinics in France, Hungary, Italy, Poland, Romania, Spain, Turkey, and the USA. Eligible participants were aged 18-70 years with non-cirrhotic, chronic HCV genotype 4 infection (documented ≥6 months before screening) and plasma HCV RNA levels higher than 10,000 IU/mL. Previously untreated (treatment-naive) patients were randomly assigned (1:1) by computer-generated randomisation lists to receive once-daily ombitasvir (25 mg) plus paritaprevir (150 mg) plus ritonavir (100 mg) with or without weight-based ribavirin for 12 weeks. Previously treated (treatment-experienced) patients who had received pegylated interferon plus ribavirin all received the ribavirin-containing regimen. The primary endpoint was a sustained virological response (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01685203. Between Aug 14, 2012, and Nov 19, 2013, 467 patients with HCV infection were screened, of whom 174 were infected with genotype 4. 135 patients were randomly assigned to treatment and received at least one dose of study medication; 86 patients were treatment-naive, of whom 44 received ombitasvir plus paritaprevir plus ritonavir and 42 received ombitasvir plus paritaprevir plus ritonavir with ribavirin, and 49 treatment-experienced patients received the ribavirin-containing regimen. In previously untreated patients, SVR12 rates were 100% (42/42 [95% CI 91·6-100]) in the ribavirin-containing regimen and 90·9% (40/44 [95% CI 78·3-97·5]) in the ribavirin-free regimen. No statistically significant differences in SVR12 rates were noted between the treatment-naive groups (mean difference -9·16% [95% CI -19·61 to 1·29]; p=0·086). All treatment-experienced patients achieved SVR12 (49/49; 100% [95% CI 92·7-100]). In the ribavirin-free group, two (5%) of 42 treatment-naive patients had virological relapse, and one (2%) of 44 had virological breakthrough; no virological failures were recorded in the ribavirin-containing regimen. The most common adverse event was headache (14 [29%] of 49 treatment-experienced patients and 14 [33%] of 42 treatment-naive patients). No adverse event-related discontinuations or dose interruptions of study medications, including ribavirin, were noted, and only four patients (4%) of 91 receiving ribavirin required dose modification for haemoglobin less than 100 g/L or anaemia. An interferon-free regimen of ombitasvir plus paritaprevir plus ritonavir with or without ribavirin achieved high sustained virological response rates at 12 weeks after the end of treatment and was generally well tolerated, with low rates of anaemia and treatment discontinuation in non-cirrhotic previously untreated and previously treated patients with HCV genotype 4 infection. AbbVie.

Management of Hepatitis C in the Indian Context: An Update

Hepatitis C, a leading cause of chronic liver disease globally, is caused by Hepatitis C Virus (HCV), a hepatotropic RNA virus. HCV infection starts with an acute infection, mostly subclinical, which ultimately leads to chronic hepatitis in about 80% of the infected cases. HCV is classified into 6 major genotypes and numerous subtypes. The global prevalence of HCV infection is about 1.6% with a majority of these infections being in adults. There is widespread heterogeneity in the prevalence of different genotypes of HCV in different geographical regions of the world. While genotype 1 is the most common worldwide, different regions of the world report variations in the prevalence of the other genotypes. Genotype 3 is the commonest genotype in India, but there is a wide variation in the distribution of the other genotypes in different parts of the country; genotype 6, a comparatively rarer genotype, has been reported frequently from the northeast part of India. With the introduction of new oral drugs, the Directly Acting Antivirals (DAA), the management protocols of hepatitis C has undergone dramatic transformation, with a paradigm shift towards an all-oral interferon-free regimen. However, developing countries like India still face a challenge with respect to accessibility and affordability of such newer regimens. Furthermore, the differences in genotypic distributions in India, with a higher prevalence of genotype 3, which is more difficult to treat, makes the situation even more challenging. As newer antivirals are being universally used to manage HCV infection, economically weaker countries like India should incorporate these changes in treatment guidelines soon. However, till substantial evidence on the efficacy of the newer regimens is accrued in the Indian population, and issues on cost and accessibility are addressed, it may not yet be prudent enough to altogether discard the existing conventional modes of HCV therapy.

All-oral interferon-free treatments: The end of hepatitis C virus story, the dream and the reality.

The year 2014 marked the beginning of the end of the interferon era and the triumph of the all-oral interferon-free regimens for treatment of hepatitis C virus (HCV) infection. These innovative therapies are safe and yield a cure rate of over 90%. The scientific hepatology community is euphoric about the possibility of elimination and even eradication of HCV infection. However, the current high cost of the new all-oral regimens allows access to treatment only for a restricted number of HCV-infected patients. In addition, many other conditions such as modality of access and delivery of care, inadequate knowledge of HCV epidemiology and political commitments to be undertaken, hamper the fulfillment of the dream to eliminate the virus. Since, such conditions are not impossible to overcome, a global urgent effort must be made to allow a widespread access to the new treatments which will permit in the next years to avoid million of HCV-related deaths.

Hepatitis C in Liver Allograft Recipients: Utility of One-Year Post-Transplantation Biopsy as an Indicator of Antiviral Therapy.

BackgroundAll-oral interferon-free regimens for hepatitis C viral (HCV) infection are highly efficacious; however, high cost is a barrier to applicability. Liver allograft recipients are particularly likely to benefit from therapy as HCV often leads to graft dysfunction and loss. In this study, we aimed to establish the utility of allograft biopsy at 1 year post-transplant as an indicator of treatment.Methods and ResultsAmong 252 liver recipients enrolled, 136 (54%) developed severe disease (fibrosing cholestatic hepatitis (FCH) or fibrosis stage ≥ 2 at 1 year post-transplant). Multivariable analysis revealed younger recipient age and female gender, older donor age and T cell depletive therapy to be independent predictors of severe disease. Recipients with severe disease had higher rate of further graft loss compared to those with mild disease. Patients with mild disease and sustained virologic response (SVR) had the best survival rate, whereas those with severe disease and viremia had the worst survival (96% versus 63% at 5 years).ConclusionIn conclusion, allograft biopsy at 1 year helps identify recipients at high risk of further graft dysfunction and loss. In view of high cost of therapy, treatment should be preferably directed to high-risk patients including those with FCH or fibrosis stage ≥ 2 by 1 year post-transplant.