Alberto Enrico Maraolo

The discovery of sofosbuvir: a revolution for therapy of chronic hepatitis C

Introduction: Hepatitis C virus (HCV) infection is a worldwide health problem, whose management has been revolutionized after the availability of sofosbuvir, a direct-acting antiviral (DAAs). Sofosbuvir is a HCV NS5B polymerase inhibitor. Antiviral regimens including sofosbuvir are associated with success rates >90%, even in the case of “difficult-to-treat” patients such as subjects with liver cirrhosis as well as prior null response to IFN and ribavirin. Areas covered: This drug discovery case history focuses on the pre-clinical and clinical development of sofosbuvir. The authors analyze all of the main steps leading to the global approval of sofosbuvir. The paper also highlights the encouraging data from the subsequent trials wherein sofosbuvir was tested in combination with other DAAs (IFN- and often ribavirin-free regimens) and from first real life studies. Expert opinion: Sofosbuvir is a very powerful weapon in the new armamentarium against HCV. Thanks to its valuable features including its pangenotypic activity, once-daily oral administration, its excellent tolerability, and safety profile, it represents the backbone of several effective regimens, in combination with IFN or with other DAAs (IFN-free therapies). Regimens including sofosbuvir have quickly become the touchstone for all the novel anti-HCV treatments.

Vertical hepatitis C virus transmission: Main questions and answers.

Hepatitis C virus (HCV) affects about 3% of the worlds population and peaks in subjects aged over 40 years. Its prevalence in pregnant women is low (1%-2%) in most western countries but drastically increases in women in developing countries or with high risk behaviors for blood-transmitted infections. Here we review clinical, prognostic and therapeutic aspects of HCV infection in pregnant women and their offspring infected through vertical transmission. Pregnancy-related immune weakness does not seem to affect the course of acute hepatitis C but can affect the progression of chronic hepatitis C. In fact, postpartum immune restoration can exacerbate hepatic inflammation, thereby worsening the liver disease, particularly in patients with liver cirrhosis. HCV infection increases the risk of gestational diabetes in patients with excessive weight gain, premature rupture of membrane and caesarean delivery. Only 3%-5% of infants born to HCV-positive mothers have been infected by intrauterine or perinatal transmission. Maternal viral load, human immunodeficiency virus coinfection, prolonged rupture of membranes, fetal exposure to maternal infected blood consequent to vaginal or perineal lacerations and invasive monitoring of fetus increase the risk of viral transmission. Cesarean delivery and breastfeeding increases the transmission risk in HCV/human immunodeficiency virus coinfected women. The consensus is not to offer antiviral therapy to HCV-infected pregnant women because it is based on ribavirin (pregnancy category X) because of its embryocidal and teratogenic effects in animal species. In vertically infected children, chronic C hepatitis is often associated with minimal or mild liver disease and progression to liver cirrhosis and hepatocarcinoma is lower than in adults. Infected children may be treated after the second year of life, given the adverse effects of current antiviral agents.

Limiting the access to direct-acting antivirals against HCV: an ethical dilemma

ABSTRACT Introduction: Hepatitis C virus (HCV) infection affects about 200 million people worldwide and represents a leading cause of liver-related mortality. Eradication of HCV infection, achieved mainly through direct-acting antivirals (DAA), results in a decrease of mortality and an improvement of quality of life. These drugs have a maximal efficacy and an optimal tolerability. However, their high cost precludes a universal access even in wealthy countries. Areas covered: This article deals with the policies adopted for the use of the new anti-HCV drugs, especially in Europe and most of all in Italy, supposedly the developed country with the highest HCV prevalence. The literature search was performed using Pubmed and Web of Science. Moreover, national regulatory institutional websites were consulted. Expert commentary: The current policy of limitation to the access of the DAA presents a series of ethical issues that makes it non-applicable. A ‘treat-all’ strategy should resolve all ethical dilemmas, by virtue of the wide benefits of anti-HCV treatment not only for the advanced stage of infection, but also for the initial stages. A reduction in price of the drugs is the actual condition to achieve such a change.

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

Antimicrobial resistance of bacterial infections is widely acknowledged to be one of the most serious health threats worldwide: its global burden is impressive in terms of morbidity and mortality [1]. In their 2013 report on multidrugresistant (MDR) pathogens, the Center for Disease Control and Prevention classified microorganisms according to their threat level: among gram-negative bacteria (GNB), carbapenem-resistant Enterobacteriaceae (CRE) are ‘a highconsequence antibiotic-resistant threat [...] requiring urgent public attention to identify infections and to limit transmission’, whereas Enterobacteriaceae that produce extendedspectrum β-lactamases (ESBLs) and the MDR Pseudomonas aeruginosa are significant antibiotic-resistant menaces that are not urgent, but may worsen without monitoring and prevention activities [2]. Enterobacteriaceae have been associated with a particularly worrisome increase of resistance to such antibiotic classes as tetracyclines, aminoglycosides, quinolones, and β-lactams, in the latter case through drugmodifying enzymes often linked to mobile gene pools that favor the spread of resistance [3]. Also, P. aeruginosa produces β-lactamases as one of its multiple bacterial resistance strategies; given the paucity of therapeutic options, alternative approaches, namely nonantibiotic agents such as lectin inhibitors or iron chelators, have been proposed [4]. The US FDA has recently approved the use of the anti-GNB antibiotics ceftolozane/tazobactam (TOL/TAZ) and ceftazidime/avibactam (CAZ/AVI). Thus, physicians now have two important weapons with which to manage infections by MDR bacteria, particularly in the case of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) [5]. Here, we examine the data about these two novel antibiotics and discuss their most appropriate clinical use in the light of the approved indications (cUTIs and cIAIs). We also address the issue of potential additional indications in various clinical settings in the case of GNB infection. Obviously, only a wise use of these agents, for example, in the framework of antimicrobial stewardship programs, will prevent the development of resistance and thus preserve these valuable weapons [6]. 2. Features of the new β-lactam/β-lactamase inhibitors

Fecal microbiota transplantation for Clostridium difficile infection: back to the future

Introduction: Clostridium difficile infection (CDI) is a leading cause of diarrhea in the industrialized world. The estimated costs of this infection are impressive: over 3.2 billion dollars annually in the US. The introduction of fecal microbiota transplantation (FMT) to clinical practice can be considered a Copernican Revolution. The rationale of this approach consists of correcting the imbalance of the organisms dwelling in the gut by reintroducing a normal flora. Areas covered: This review focuses on the indication for FMT in CDI; it examines in-depth the most relevant aspects of the techniques used, and the safety and efficacy of this new ‘old’ therapy. Expert Opinion: Authoritative guidelines about the management of CDI strongly recommend FMT for multiple recurrent episodes of infection by C. difficile unresponsive to repeated antibiotic treatment. The cure rates are about 90%, with no serious adverse events having been reported. The main concerns are the long-term outcomes, lack of a standardized procedure for the delivery of donor material, and a cultural barrier to the transplantation of fecal microbiota. A promising solution to some of these problems could be the use of a more acceptable administration route of fecal material, namely, oral capsules.

Efficacy of ultra-short single agent regimen antibiotic chemo-prophylaxis in reducing the risk of meningitis in patients undergoing endoscopic endonasal transsphenoidal surgery.

OBJECTIVES The study aims to evaluate the incidence of infectious complications (namely meningitis) within 30 days after endoscopic endonasal transspheinodal neurosurgery (EETS) in patients receiving an ultra-short peri-operative chemo-prophylaxis regimen with 2 doses of 1st generation cephalosporin or macrolide. PATIENTS AND METHODS We retrospectively analyzed the clinical records of 145 patients who received an ultra-short chemoprophylaxis with two doses of an antibiotic, given 30 min before and 8h after EETS, over a 30-month time-frame. Ninety-seven patients (66.89%) received endovenous cefazolin, a 1st generation cephalosporin, administered at a dosage of 1000 mg, and 48 patients (33.10%) with an history of allergy to various agents, received endovenous clarithromycin at a dosage of 500 mg. RESULTS No case of peri- and post-operative meningitis occurred in patients receiving the 2 doses of antibiotic. Only one patient (0.68%) developed cerebral fluid leakage on the 7th postoperative day, which required the switching to a broad-spectrum antibiotic prophylaxis for one week; this patient received the ultrashort prophylaxis with a macrolide. In addition, 7 patients (4.82%) developed minor infectious complications such as low-grade fever (3 cases, all of them receiving cefazolin), enlarged submandibular and cervical lymphnodes (3 cases, all of them receiving cefazolin), and upper and lower respiratory tract infection (1 case receiving clarithromycin). The cost of this prophylaxis regimen ranged from 7.76 Euro (cefazolin) to 39.54 Euro (clarithromycin). CONCLUSIONS This study suggested that an ultra-short single-antibiotic prophylaxis is a safe, cheap and effective regimen to prevent post-operative meningitis in patients undergoing EETS and who do not require lumbar drainage after surgery. In these patients also the rate of minor infective complications was acceptable when compared with the previous more expensive regimen based on 3rd generation cephalosporin plus aminoglycoside or alone, that could be suitable only for at-risk patients (e.g. smokers, cerebrospinal leak or Cushings diseases).

Nosocomial spontaneous bacterial peritonitis antibiotic treatment in the era of multi-drug resistance pathogens: A systematic review

AIM To systematically review literature upon aetiology of nosocomial spontaneous bacterial peritonitis (N-SBP) given the rising importance of multidrug-resistant (MDR) bacteria. METHODS A literature search was performed on MEDLINE and Google Scholar databases from 2000 to 15th of November 2016, using the following search strategy: “spontaneous” AND “peritonitis”. RESULTS The initial search through electronic databases retrieved 2556 records. After removing duplicates, 1958 records remained. One thousand seven hundred and thirty-five of them were excluded on the basis of the screening of titles and abstract, and the ensuing number of remaining articles was 223. Of these records, after careful evaluation, only 9 were included in the qualitative analysis. The overall proportion of MDR bacteria turned out to be from 22% to 73% of cases across the studies. CONCLUSION N-SBP is caused, in a remarkable proportion, by MDR pathogens. This should prompt a careful re-assessment of guidelines addressing the treatment of this clinical entity.

Beclabuvir for the treatment of hepatitis C

Introduction: About 185,000,000 people worldwide are chronically infected with hepatitis C virus (HCV). Currently, the most successful HCV infection antiviral therapies reduce the chance of progression towards the advanced phases of the hepatopathy (liver cirrhosis, hepatocellular carcinoma and death). Recently, however, several new direct-acting antivirals against HCV are available or are in an advanced phase of clinical development. Areas covered: This review focuses on beclabuvir, an allosteric non-nucleotide inhibitor of HCV polymerase. The article covers its pharmacokinetics, mechanism of action, in addition to its tolerability and safety profile as well as its resistance pattern. Expert opinion: The pharmacokinetic, efficacy and tolerability profile of beclabuvir, as well as its barrier to resistance, are very favorable. In particular, the combination of beclabuvir with asunaprevir and daclatasvir achieves very high rates of viral eradication (about 90%) in patients infected with HCV genotype 1, which is the most common genotype worldwide. Therefore, beclabuvir represents a powerful weapon against HCV infection and has to be considered an optimal option in tailored IFN-free combinations.

The therapeutic potential of new investigational hepatitis C virus translation inhibitors.

ABSTRACT Introduction: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis, hepatocellular carcinoma and liver-related death worldwide. Currently, the anti-HCV armamentarium encompasses several direct-acting antivirals (DAA) that achieve very high response rates and have an excellent tolerability profile. However, they do not represent a final solution for HCV global eradication for at least these two reasons: i) some patients harbour resistant strains to DAAs and cannot benefit from currently available treatments; ii) the cost of these drugs remains very high. Areas covered: This review summarizes pre-clinical and clinical data regarding HCV translation inhibitors, a new class of drugs currently in the pipeline with novel mechanisms of action. Expert opinion: The availability of DAAs resolved most issues related to HCV treatment compared with the previous interferon-based therapies. However, there are some patients that cannot achieve a viral clearance with currently available treatments. Therefore, there is still room for new drugs in this setting, providing that they demonstrate an advantage in terms of efficacy, safety, cost or or simplicity of use. Based on preliminary results, at least for some promising molecules (e.g. miravirsen and RG-101), studies on safety and efficacy on this intriguing class of drugs are needed.

Liver Illness and Psoriatic Patients

Psoriasis is a chronic inflammatory disease of the skin affecting approximately 2% of the worlds population. Systemic treatments, including methotrexate and cyclosporin, are associated with potential hepatotoxicity, due to either direct liver damage or immunosuppression or both immunomediated and a direct liver injury; therefore, treatment of patients with psoriasis poses a therapeutic challenge. The aim of this minireview is to help clinicians in the management of psoriatic patients who develop signs of liver dysfunction. To find relevant articles, a comprehensive search was performed on PubMed, EMBASE, and Cochrane with appropriate combinations of the following keywords being considered: viral hepatitis, nonalcoholic fatty liver disease, psoriasis, hepatotoxicity, drug toxicity, cholestasis, and autoimmune liver diseases.