Ivan Gentile

The efficacy and safety of telaprevir – a new protease inhibitor against hepatitis C virus

Importance of the field: Hepatitis C virus (HCV) is the main agent of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in the western world. It affects more than 170 million people worldwide. HCV treatment, based on the combination of Peg-interferon and ribavirin, is effective in about 50% of treated patients. Therefore, there is a need to develop new drugs active against HCV. Areas covered in this review: Data were obtained by searching for all full articles on Medline and abstracts presented at major international congresses on viral hepatitis. What the reader will gain: A review of clinical data about the efficacy and safety of telaprevir (VX-950), the HCV protease inhibitor that is in the most advanced phase of clinical development. Take home message: Telaprevir has an acceptable pharmacokinetic profile and seems to be a potent antiviral drug against HCV, although, owing to a low genetic barrier, resistant variants emerge within a few days when used in monotherapy, thereby decreasing its efficacy. Consequently, telaprevir has been combined with pegylated-interferon and ribavirin in clinical trials. This triple combination is more effective but has a higher rate of adverse events (notably rash) than the standard of care, despite the shorter duration of therapy.

Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review

BackgroundDrug-Induced Hypersensitivity Syndrome (DIHS) is a severe and rare systemic reaction triggered by a drug (usually an antiepileptic drug). We present a case of DISH and we review studies on the clinical features and treatment of DIHS, and on its pathogenesis in which two elements (Herpesvirus infection and the drug) interact with the immune system to trigger such a syndrome that can lead to death in about 20% of cases.Case presentationWe report the case of a 26-year old woman with fever, systemic maculopapular rash, lymphadenopathy, hepatitis and eosinophilic leukocytosis. She had been treated with antibiotics that gave no benefit. She was taking escitalopram and lamotrigine for a bipolar disease 30 days before fever onset. Because the patients general condition deteriorated, betamethasone and acyclovir were started. This treatment resulted in a mild improvement of symptoms. Steroids were rapidly tapered and this was followed with a relapse of fever and a worsening of laboratory parameters. Human herpesvirus 6 (HHV-6) DNA was positive as shown by PCR. Drug-Induced Hypersensitivity Syndrome (DIHS) was diagnosed. Symptoms regressed on prednisone (at a dose of 50 mg/die) that was tapered very slowly. The patient recovered completely.ConclusionsThe search for rare causes of fever led to complete resolution of a very difficult case. As DIHS is a rare disease the most relevant issue is to suspect and include it in differential diagnosis of fevers of unknown origin. Once diagnosed, the therapy is easy (steroidal administration) and often successful. However our case strongly confirms that attention should be paid on the steroidal tapering that should be very slow to avoid a relapse.

A Novel Promising Therapeutic Option Against Hepatitis C Virus: An Oral Nucleotide NS5B Polymerase Inhibitor Sofosbuvir

Hepatitis C virus (HCV) infection is one of the main causes of liver disease worldwide. Its treatment is currently based on the combination of peg-interferon, ribavirin, and, for patients with genotype 1, a protease inhibitor (telaprevir or boceprevir). However, interferon-based combinations are not effective in all patients. Moreover, they are contraindicated in patients who cannot receive interferon (e.g. those with decompensated cirrhosis), and are frequently associated with adverse events. Consequently, there is a need to develop new drugs to treat HCV infection. This review focuses on preclinical and clinical data regarding sofosbuvir (GS-7977), a uridine nucleotide analogue inhibitor of HCV NS5 B polymerase that is effective against HCV genotypes 1,2, 3,4 and 6. Thanks to its excellent pharmacokinetic profile, sofosbuvir can be administered in an oral single daily dose. In vitro it exerts a potent antiviral effect against HCV. Clinical data show that combined with peg-interferon and ribavirin for 12 weeks it yields SVR of about 90% in subjects with HCV genotype 1 and about 100% in patients with HCV genotype 2 or 3. Moreover, sofosbuvir and ribavirin administered for 12 weeks yield similar high SVR rate (84% for genotype 1 and 100% for genotype 2/3 patients) as well as sofosbuvir and daclatasvir (an inhibitor of NS5A) which produce SVR rate of about 100% regardless of genotype or of ribavirin employment. Safety and tolerability of sofosbuvir appear to be excellent. In conclusion, sofosbuvir especially in interferon-free combinations represents a very promising option in the treatment of chronic hepatitis C.

Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world?

About 2% of the world’s population is estimated to be chronically infected with hepatitis C virus (HCV). These chronic carriers are at risk of developing liver cirrhosis and its complications. Successful treatment of HCV infection is associated with improved quality of life and increased survival. Antiviral approaches were formerly based on interferon and therefore all patients with a contraindication to interferon were excluded from treatment (e.g., patients with decompensated disease, severe impairment of other organs). Very recently, interferon-free combinations have become available for genotypes 2 and 3. This review focuses on the most recently reported data on the various interferon-free combinations used (namely, sofosbuvir-based combinations, the ABT-450/ombitasvir/dasabuvir/ribavirin combination, the daclatasvir/asunaprevir combination, and the MK-5172/MK-8742 combination). All these combinations yielded amazing results in terms of efficacy (90–100%), tolerability and safety. If the problem of the high cost is overcome, interferon-free therapies will lead to what has long been a chimera, namely, an HCV-free world.

Homocysteine levels and sustained virological response to pegylated‐interferon α2b plus ribavirin therapy for chronic hepatitis C: a prospective study

Background: Chronic hepatitis C affects about 3% of the worlds population. Pegylated interferon (IFN) α plus ribavirin is the gold standard treatment. Methylenetetrahydrofolate reductase(MTHFR) is a key enzyme in the metabolism of homocysteine. MTHFR gene polymorphisms and high levels of homocysteine are associated with a high degree of steatosis and fibrosis, conditions associated with a low sustained virological response (SVR) rate.

Multiple Sclerosis and Hepatitis C Virus Infection Are Associated with Single Nucleotide Polymorphisms in Interferon Pathway Genes

We have studied 35 single nucleotide polymorphisms (SNPs) in the interferon (IFN) pathway to determine their contribution to multiple sclerosis (MS) and hepatitis C virus (HCV) infection. A total of 182 patients with MS, 103 patients with chronic hepatitis C, and 118 control subjects were enrolled in the study. Of the 35 SNPs studied, 3 were in IFN-alpha receptor (IFNAR-1), 10 in IFN-alpha/beta receptor (IFNAR-2), 9 in Stat1, 5 in Stat2, and 8 in IFN regulatory factor-1 (IRF-1). Compared to controls, Stat1 gene polymorphisms were significantly more frequent in MS patients (rs# 2066802 OR = 7.46, 95% CI = 2.22-25.10; rs# 1547550 OR = 1.69, 95% CI = 1.01-2.81) and in HCV patients (rs# 2066802 OR = 5.95, 95% CI = 1.55-22.81; rs# 1547550 OR = 2.30, 95% CI = 1.24-4.24). Also one IRF-1 gene SNP was associated with MS (rs# 2070721 OR = 2.05, 95% CI = 1.03-4.09), and four IRF-1 gene SNPs were associated with HCV infection (rs# 2070721 OR = 2.59, 95% CI = 1.23-5.43; rs# 2070723 OR = 4.8, 95% CI = 1.26-18.20; rs# 2070728 OR = 9.81, 95% CI = 1.21-79.4; rs# 2070729 OR = 3.6, 95% CI = 1.23-10.48; rs# 839 OR = 4.67, 95%CI = 1.29-16.87). Characteristic nucleotide combinations on single chromosomes (haplotype) generated block structures, including SNPs, that differed between patients and controls. Using a permutation test to detect differences in haplotype distribution between groups, the CCATTGA and the CCGAA haplotypes in the IRF-1 gene were more frequent in MS (p = 0.03) and in HCV patients (p = 0.001) than in controls. In conclusion, our data show that genetic variants in the IRF-1 and Stat1 genes of the IFN pathway are associated with MS and HCV infection.

Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection

Introduction: About 150,000,000 people worldwide are chronically infected with hepatitis C virus (HCV). HCV infection can lead to liver cirrhosis, hepatocellular carcinoma and death. Treatment was based previously only on pegylated interferon combined with other antiviral drugs. Recently, the first interferon-free combination for patients with genotype 2 or 3 was approved in the USA and Europe, and several molecules are in an advanced phase of clinical development. Areas covered: This review focuses on the pharmacokinetics, pharmacodynamics and tolerability of ledipasvir, an inhibitor of HCV nonstructural 5A protein. The authors also highlight the drugs safety and resistance profile. Expert opinion: The pharmacokinetic profile and antiviral activity of ledipasvir are ideal. However, given the high rate of natural and drug-related ledipasvir-resistant HCV mutations, ledipasvir is administered in combination regimens with other antiviral drugs, which resulted in a cure rate up to 100%. While ledipasvir is effective in patients with genotype 1 chronic hepatitis C, its efficacy remains to be established in patients with genotype 4, 5 or 6, in subjects with HIV coinfection, in hemodialyzed and elderly patients and in subjects with decompensated cirrhosis. If the excellent results of combination therapy be confirmed in larger trials, hepatologists will have the possibility to cure most HCV-positive patients in the near future.

Treating chronic hepatitis B: today and tomorrow.

Three hundred and fifty million people worldwide are estimated to be chronically infected with hepatitis B virus. 15-40% of these subjects will develop cirrhosis, liver failure or hepatocellular carcinoma during their life. The treatment of chronic hepatitis B has improved dramatically over the last decade thanks to the advent of nucleoside/nucleotide analogues and the use of pegylated interferons. However, these agents have increased the complexity of the management of hepatitis B. Five drugs have been approved for chronic hepatitis B treatment: standard interferon-alpha 2b, pegylated interferon-alpha 2a, lamivudine, adefovir dipivoxil, and entecavir. A definite course of standard or pegylated interferon is administered to induce hepatitis B virus clearance. Unfortunately, these agents are not effective in all patients and are associated with not negligible side effects. Nucleoside or nucleotide analogues that inhibit hepatitis B virus polymerase induce on-treatment suppression of viral replication but patients tend to relapse after cessation of treatment. Consequently, these analogues, which are well tolerated, should be used for prolonged periods, even indefinitely. However, prolonged treatment is associated with a high rate of resistance. The following anti-hepatitis B virus drugs are currently undergoing clinical testing: telbivudine, emtricitabine, tenofovir disoproxil fumarate, clevudine and thymosin-+/-1. Here we will examine the mechanism of action, efficacy, safety, tolerability and emergence of resistance of agents used to treat chronic hepatitis B. We shall also examine the potential of drugs now being tested and of combination treatment.

Daclatasvir: The First of a New Class of Drugs Targeted Against Hepatitis C Virus NS5A

Hepatitis C virus (HCV) infection affects about 160 million people worldwide. It is treated with pegylatedinterferon (peg-IFN) and ribavirin, and in the case of patients affected by genotype 1, also with a protease inhibitor (telaprevir or boceprevir). Despite a good success rate, IFN-based combinations are contraindicated in several patients (e.g. decompensated cirrhosis, patients with psychiatric disorders, severe heart diseases or autoimmune disorders) and are associated with frequent adverse events that ultimately reduce their use. Numerous oral drugs are in an advanced phase of clinical development, and in some cases, in IFN-free combinations. This review focuses on preclinical and clinical data regarding daclatasvir (BMS-790052), which is a highly selective HCV NS5A replication complex inhibitor effective against HCV genotypes 1, 2, 3 and 4. In vitro data show that daclatasvir exerts a very potent antiviral effect against several HCV genotypes. Its pharmacokinetics is optimal and allows once-a-day oral administration. Its adverse event profile is good. Clinical data regarding its efficacy in combination with peg-IFN, ribavirin or other direct antiviral agents are impressive (rates of sustained virological response range between 60% and 100% in treatment-naïve patients). The only drawback of this drug appears to be a relatively low genetic barrier to resistance. In conclusion, daclatasvir, especially in combinations with other antiviral agents, is a very promising drug for the treatment of chronic hepatitis C.

Myasthenia Gravis During Low-Dose IFN-α Therapy for Chronic Hepatitis C

We describe the case of a 56-year-old man who had high aminotransferase levels and anti-hepatitis C virus (HCV) antibodies. He underwent liver biopsy and biochemical screening to evaluate whether he would benefit from interferon (IFN) treatment. The patient was discharged with a diagnosis of HCV-related active chronic hepatitis, skin porphyria, and type 2 diabetes. On December 5, 1995, he began therapy with recombinant IFN-α at a dose of 3 MIU three times a week. He stopped this therapy in February 1996 because of asthenia, dyplopia, headache, and anxiety. During IFN therapy, he had normal aminotransferase levels and no detectable HCV RNA, a condition that persists to the present. Between March and May 1996, the patient was admitted several times to a neurology clinic, where myasthenia gravis was diagnosed and treatment with pyridostigmine and cyclosporine was initiated. This case and others indicate that caution should be exercised in administering IFN because low doses can be correlated with myasthenia ...