Increase In Sustained Virological Response Research Articles

Direct-acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment and future perspectives.

There has been a revolution in the treatment of chronic hepatitis C. Several oral regimens combining direct-acting antivirals (DAAs) from different families [NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors (PI)] have been developed. These regimens result in an increase in sustained virological response (SVR) rates to above 90% and reduce the duration of treatment to 12 weeks or less. As of 2016 several regimens will be approved with additive potencies, without cross-resistance and with a good safety profile. Remaining issues will include increasing screening and access to care so that HCV may become the first chronic viral infection eradicated worldwide. This review summarizes results obtained with oral DAA combinations that have been approved and/or have completed phase 3 clinical trials for HCV infection and discusses future perspectives.

Concise review: Interferon-free treatment of hepatitis C virus-associated cirrhosis and liver graft infection.

Chronic hepatitis C is a major reason for development of cirrhosis and hepatocellular carcinoma and a leading cause for liver transplantation. The development of direct-acting antiviral agents lead to (pegylated) interferon-alfa free antiviral therapy regimens with a remarkable increase in sustained virologic response (SVR) rates and opened therapeutic options for patients with advanced cirrhosis and liver graft recipients. This concise review gives an overview about most current prospective trials and cohort analyses for treatment of patients with liver cirrhosis and liver graft recipients. In patients with compensated cirrhosis Child-Pugh-Turcotte (CTP) class A, all approved agents are safe and SVR rates do not significantly differ from patients without cirrhosis in general. In patients with decompensated cirrhosis CTP class B or C, daclastasvir, ledipasvir, velpatasvir, and sofosbuvir are approved, and SVR rates higher than 90% can be achieved. Especially for patients with a model of end stage liver disease score higher than 15 and therefore eligible for liver transplantation, data is scarce. Reported SVR rates in patients with cirrhosis CTP class C are lower compared to patients with a less severe liver disease. In liver transplant recipients with a maximum of CTP class A, SVR rates are comparable to patients without LT. Patients with decompensated graft cirrhosis should be treated on an individual basis.

Allergic sensitization to pegylated interferon-α results in drug eruptions.

The introduction of pegylated interferon (PEG-IFN)-α in the treatment of chronic hepatitis C has led to an increase in sustained virological response. Despite reduced immunogenicity of the pegylated form in comparison with native interferon (IFN)-α, a high frequency of adverse cutaneous reactions has been reported with pegylated IFN-α. Here, we aimed to investigate the immunological mechanisms underlying pegylated IFN-α-induced drug eruptions. Hepatitis C patients suffering from drug eruptions in association with administration of pegylated interferons were enrolled in the study (n=22). Subjects were tested for sensitivity to pegylated IFN-α2a , pegylated IFN-α2b , or ribavirin using intradermal, scratch, and/or patch tests, as well as lymphocyte activation tests (LATs). Skin biopsies obtained from pegylated IFN-α-associated exanthemas, as well as from localized inflammatory skin reactions at pegylated IFN-α injection sites, were analyzed for the expression of relevant chemokines by quantitative real-time PCR and immunohistochemistry. A subset of patients suffering from pegylated IFN-α-associated exanthemas displayed positive intradermal tests to PEG-IFNs but not to conventional IFN (11/22). In selected patients, this observation correlated with the presence of pegylated IFN-specific T cells (3/11). Chemokine profiles of inflammatory skin reactions at the injection sites reflected an IFN-α-signature, whereas lesional skin of exanthemas showed induction of TH2-associated chemokines. Our results indicate that specific sensitizations are one cause of exanthemas under therapy with PEG-IFNs. Clinical proof-of-concept analyses demonstrate that affected patients may benefit from a switch to conventional,nonpegylated drugs, enabling IFN-α therapy continuation without drug-associated skin eruptions.

HCV cure for everyone or which challenges remain?

Following the approval of the first HCV direct-acting antiviral (DAA) in 2011, an unforeseen revolution in the treatment of chronic hepatitis C has taken place. In 2015 several all-oral DAA regimens, combining agents from different families (NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors) are now commercially available. In clinical trials, these regimens result in an increase in sustained virological response (SVR) rates to above 90–95% and reduce the duration of treatment to 12 weeks or less. As these new all-oral therapies are easy to take, with some already available as simple fixed-dose combinations, and are associated with minimal adverse events, increasing numbers of HCV patients appear treatable with these modern regimens. Nevertheless, the questions remain on how far the spectacular treatment trial results can be reproduced in clinical practice and whether more challenging patient populations, including previous non-responders and patients with advanced cirrhosis, will continue to exist even in the era of all-oral DAA therapy.

Optimal IFN-free therapy in treatment-naïve patients with HCV genotype 1 infection.

There has been a revolution in the treatment of chronic hepatitis C. Several oral regimens combining direct-acting antivirals (DAAs) from different families [NS5B nucleotide inhibitors, NS5B non-nucleoside inhibitors, NS5A replication complex inhibitors and NS3/4A protease inhibitors (PI)] are under development. These regimens result in an increase in sustained virological response (SVR) rates to above 90% and reduce the duration of treatment to twelve weeks or less. As of 2015 several regimens will be approved with additive potencies, without cross-resistance and with a good safety profile. Remaining issues will include increasing screening and access to care so that HCV may become the first chronic viral infection eradicated worldwide. This review summarizes results obtained with oral DAAs combinations, that have been approved and/or have completed phase III clinical trials for HCV genotype 1 (HCV-1) treatment-naïve patients.

Telaprevir: Pharmacokinetics and Drug Interactions

Telaprevir is an inhibitor of the HCV NS3/4A protease. When used in combination with pegylated interferon and ribavirin, telaprevir has demonstrated a substantial increase in sustained virological response compared with pegylated interferon and ribavirin used alone. Telaprevir has good oral bioavailability, which is enhanced when administered with food. Telaprevir is extensively metabolized and primarily eliminated via faeces. No dose adjustment of telaprevir is needed in patients with mild to severe renal impairment or mild liver impairment. Telaprevir is a substrate and inhibitor of cytochrome P450 3A and P-glycoprotein and, thus, might interact with coadministered drugs that affect or are affected by these metabolic/transport pathways. This article reviews the pharmacokinetic and drug interaction profile of telaprevir.

Role of growth factors and thrombopoietic agents in the treatment of chronic hepatitis C

Advanced liver disease and interferon-based treatment are both associated with varying degrees of cytopenia in patients with chronic hepatitis C. Growth factors to increase hemoglobin and neutrophils are commonly used in clinical practice, despite the absence of data to indicate benefits in terms of sustained viral response. Thrombocytopenia is observed frequently, is multi-factorial in etiology, and may result in significant limitations on interventional and therapeutic options. A small-molecule thrombopoietin mimetic, eltrombo-pag, has demonstrated a dose-response associated increase in platelet count in a phase 2 study, allowing initiation and completion of a 12-week course of peginterferon plus ribavirin in 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, or 75 mg of eltrombopag daily, respectively, compared with 6% in the placebo arm. Phase 3 studies are currently evaluating whether initiating and maintaining antiviral therapy with eltrombopag will lead to an increase in sustained virologic response in chronic hepatitis C infection.

Optimizing PEG-interferon and ribavirin combination therapy for patients infected with HCV-2 or HCV-3: is the puzzle completed?

Optimizing PEG-interferon and ribavirin combination therapy for patients infected with HCV-2 or HCV-3: is the puzzle completed?