[ ISSN : 2573-3680 ]
Hepatitis C, DAAs, treatment, antivital, cirrhosis, liver transplant
Hepatitis C Virus infection (HCV) is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350.000 yearly deaths from HCV-related complications.
Hepatitis C Virus infection (HCV) is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350.000 yearly deaths from HCV-related complications [1] and, until recently, its treatment has been far from ideal. Thus, the scientific advances in the field of HCV treatment have been progressing in leaps and bounds and, in fact, numerous new drugs were recently added to the anti-HCV regimens. During the past decade, Interferon (IFN)-based antiviral regimens were the only available therapeutic option for all patients with Chronic Hepatitis C (CHC) [2].
Indeed, such regimens had significant side effects that, in many cases, precluded the completion of the treatment course. Undoubtedly, understanding the steps of HCV life cycle has paved the way for the development of highly effective therapies that target the virus at different steps of this cycle in order to impede it from hepatocyte entry to assembly, replication and virion release.
Since December 2013, the regulatory authorities approved seven new anti-HCV molecules and since then the treatment landscape has been changed drastically. Sofosbuvir (SOF) was the first FDA-approved nucleotide analogue inhibitor of HCV RNA-dependent RNA polymerase in 2013 followed by Simeprevir (SMV) [NS3/4A protease inhibitor], Daclatasvir (DCV) [NS5A replication complex inhibitors], the combination of Ledipasvir (LDV) [NS5A replication complex inhibitor] plus SOF and most recently the combination of Ombitasvir (OBV) [NS5A inhibitor], the ritonavirboosted protease inhibitor Paritaprevir (PTV), and the first non-nucleosidic polymerase inhibitor Dasabuvir (DSV). Of note, only SOF and DCV can be considered Directly Acting Antivirals (DAAs) with pan-genotypic activity [3-5], while all the remaining drugs can exert a genotype-specific activity [6-8]. Historically, Genotype 1 (Gt1) was considered difficult-to-treat. However, with these new DAAs, Gt3 is the new challenging genotype especially in cirrhotic patients who failed previous antiHCV therapy [9]. Currently, few regimens are available for Gt3 CHC and they are all SOF-based ones.
Fortunately, there are some ongoing trials that investigate LDV/SOF, PTV/ritonavir plus the investigational NS5A inhibitor (ABT-530), and the combination of ABT-530 plus ABT-493 for the treatment of such genotype (NCT02243293 and NCT02576314). Recently, the results of the four ASTRAL trials have been revealed. In ASTRAL-3, the new combination of SOF and Velpatasvir (investigational pan-genotypic NS5A inhibitor) was evaluated in Gt3 patients for 12 weeks with Sustained Virologic Response (SVR) rates of 95%. If approved, this combination would be the first all-oral, pan-genotypic, single tablet regimen for CHC [10].
There is no doubt that with the discovery of these new molecules, the rates of SVR have improved tremendously even in patients with cirrhosis. Yet, rates of SVR are still unsatisfactory in patients with decompensated cirrhosis. In the recent SOLAR-1 study [11], the investigators evaluated SOF/LDV combination in conjunction with Ribavirin (RBV) for 12 or 24 weeks in Gt1 and 4 patients that had or had not undergone liver transplantation including those with decompensated liver disease.
Rates of SVR were 60%–75% among patients with severe hepatic impairment. Likewise, Saxena and colleagues have recently revealed that the SOF+SMV with or without RBV can cure up to 73% of patients with Child-Pugh score B/C versus 91% of Child-Pugh A [12]. The investigators of this study, however, would advise against the use of this combination in patients with hyperbilirubinemia or hepatic encephalopathy at baseline.
Another challenge that might face the hepatologist is liver transplant recipients with recurrent CHC. Those patients are always on calcineurin inhibitors (CYP3A4 substrates) and, unfortunately, these drugs have potential drug-drug interactions with SMV and ritonavir-boosted PTV, OBV and DSV combination [6,8] that might require immunosuppressant dose adjustment. On the other hand, SOF and LDV/SOF combination [5,7] lack that clinically relevant drug–drug interactions with CYP3A4 substrates, hence, can be considered as preferable therapeutic choice in those patients. Albeit these new DAAs seem very promising, special patient populations still have unmet needs and patients with severe renal impairment are no exception. Most DAAs are metabolized primarily via the liver and, theoretically, can be used in patients with severe renal disease except SOF that should not be administered to patients with an estimated Glomerular Filtration Rate (eGFR)<30mL/ min/1.73m2 or with end-stage renal disease. Certainly, more data are warranted to conclusively demonstrate the efficacy and safety profiles of these DAAs in that setting of patients.
Even though these new molecules have been hailed internationally as a breakthrough anti-HCV therapy, there is still a worldwide concern over the high cost of those drugs. A 12-week course of SOF, for instance, costs $84,000 in the US, €41,000 in France, £35,000 in the UK and €45,000 in Italy. Not to mention the double price when a patient needs to undergo a 24-week course. Clearly, the various assistance programs are not able to cover the whole cost for all patients and, in fact, some national health systems restrict the reimbursement of these new all-oral regimens for the following groups: patients with advanced fibrosis (Metavir≥F3), intereferon-incapable, patients with extrahepatic manifestations of HCV infection (e.g. cryoglobulinemic syndrome or non-Hodgkin lymphoma) or with solid organ transplant recipients and CHC, with Metavir≥2 [13]. As regards drug resistance, treatment failure of SMV plus SOF is associated with resistance to SMV and other HCV NS3/ 4A protease inhibitors such as PTV. Conversely, SOF resistance-associated variants are uncommon [14]. Another major point of interest, we should acknowledge the fact that those formerly-called “experimental” drugs have been almost always evaluated in a setting of patients with no other significant concomitant disease and only time and real-life data can demonstrate their efficacy and safety in patients with CHC along with other important system involvement. Indeed, more robust evidence from ongoing trials in patients with non- Gt1, decompensated cirrhosis and with end-stage renal disease are eagerly awaited.
To conclude, we are witnessing a revolution of Hepatits C treatment that is IFN, and sometimes, RBV-free. A whole new era in which the treatment paradigm went from daily injections to once-daily pills and from one-year course to as short as 12 or even 8 weeks with much improved safety profile and response rates that are approaching 100% in some cases. Simply, we are living today the future that we always dreamed of in the past, as once said by Physician Sir William Osler “the future is today”.
Pietro Andreone declares the following potential conflict of interest:
1) Research support from Roche, MSD and Gilead Sciences
2) Advisory committees for Roche, MSD, Janssen Cilag, AbbVie, Boehringer Ingelheim, Gilead Sciences and BMS. References
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7. HARVONI (ledipasvir and sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc; 2015.
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11. Charlton M, Everson GT2, Flamm SL3, Kumar P4, Landis C5. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterology. 2015; 149: 649-659.
12. Saxena V, Nyberg L2, Pauly M3, Dasgupta A, Nyberg A2. Safety and Efficacy of Simeprevir/Sofosbuvir in Hepatitis C-Infected Patients With Compensated and Decompensated Cirrhosis. Hepatology. 2015; 62: 715-725.
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Gamal N and Andreone P. Treatment of Chronic Hepatitis C: An Overview. SM J Clin Med. 2015; 1(2): 1007.
The purpose of this statement is none other than to highlight the importance of ethical standards and quality required in basic and applied research currently being done so we can subsequently inform health care professionals of new developments that are taking place in this area.
Ma. Esperanza Rodríguez-van Lier*
Chemotherapy is commonly used in cancer treatment. So far, chemotherapy agents can be categorized into three types: classical chemotherapeutic drugs, molecular target agents and cellular machineries target drugs.
Ziyou Wang1,2 and Zunnan Huang1,2*
Blood transfusion can cause some transfusion adverse reactions. In order to understand the incidence of adverse transfusion reactions, we performed a meta-analysis in Chinese hospitals. Of 809 literatures, seven studies involving a total of 211, 050 patients with blood transfusion treatment were included in this meta-analysis. Meta-analysis showed that the total incidence of adverse reactions was 0.4% [95% CI (0.2, 0.9), P < 0.0001]. Further subgroup analysis showed that the incidence of febrile and allergic reactions was 0.2% [95% CI (0.1, 0.5), P < 0.0001] and 0.2% [95% CI (0.1, 0.3), P < 0.0001], respectively. The common blood components caused adverse reactions were red blood cell, plasama, and platelet in clinical practice.
Yulu Gao1 , Qinyun Li2 , Zongshuai Gao2 , Yunxia Zhu4 , Yanqiu Liao5 , Changtai Zhu2 *# , Yongning Sun3 *#
Background: CT scanning remains one of the most routinely used diagnostic tools in a setting of Interstitial Lung Disease (ILD). New and improved technologies, such as High Resolution Computer Tomography (HRCT) have revolutionized the quality of imaging, leading to a prominent increase in number of incidental findings that may or may not be of any clinical significance. The aim of this study was to evaluate the prevalence of incidental findings on thoracic CT and their clinical significance.
Methods: Retrospective analysis was conducted on a cohort of 84 patients referred to our academic center as cases of ILD. Patients were referred for further evaluation between January 2000 and January 2014 and were followed over the disease course. CT scans were done annually as part of clinical management and patients were screened for any incidental findings. All incidental findings were reviewed, recorded in a clinical database and followed up on subsequent visits.
Results: 25 (30%) patients were found to have incidental findings. Liver abnormalities were found in 12 (14.29 %) patients. 11(13.10 %) patients were reported to have coronary artery calcifications. 5 (5.95 %) and 3 (3.57%) patients had thyroid abnormalities and renal cysts, respectively. A malignant lesion was found in 1 patient each in liver and thyroid abnormality subgroup.
Conclusion: Incidental findings are common on thoracic CT scans providing valuable and unexpected findings which warrant investigation by health care providers to exclude malignant processes.
Sonu Sahni1,2*, Sameer Verma1,2, Reeju S Thomas1 , Barbara Capozzi3 and Arunabh Talwar1,2
We report a case of large cell undifferentiated lung carcinoma in a middle aged patient with previously treated tuberculosis and scarring. 20 pack years of smoking history was noted. He presented with metastasis at multiple sites including trochanter, liver and acute bilateral lateral rectus palsy. Chest radiography showed fibrosis of right upper zone with homogenous opacity. Sputum examination for AFB was negative. Computerized tomography of the thorax showed an irregular heterogeneously enhancing mass involving right upper lobe with cavitation, necrosis along with lymph node involvement and the erosion of the 4th rib with liver metastasis. Radiography of hip joint was suggestive of lesser trochanteric metastasis. MRI brain was suggestive of mass at base of brain in parasellar area. Fine needle aspiration cytology and CT guided biopsy confirmed undifferentiated large cell carcinoma of lung. Tuberculosis and smoking may increase the risk of lung scarring and malignancy and pulmonary scarring may be associated with increased lung carcinoma in ipsilateral lung. Clinician needs to be more sensitive to look for malignancy association particularly in patient with or previously treated for tuberculosis and even more emphasis to be laid if scarring of lung is observed.
Sreenivasa Rao Sudulagunta1 *, Shyamala Krishnaswamy Kothandapani2 , Mahesh Babu Sodalagunta3 , Hadi Khorram2 , Mona Sepehrar4 and Zahra Noroozpour1
Systemic Sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs, pronounced alterations in the microvasculature and frequent cellular and humoral immunity abnormalities. The rheumatic involvement of SSc is polymorphic and can reveal the disease or may appear during the course of its progression. Musculoskeletal involvement is dominated by non specific arthralgia, polyarthritis, and bony resorption especially acro-osteolysis. The diagnosis of these rheumatic manifestations is generally based on x rays examination. Musculoskeletal involvement in SSc is generally relieved with Non Steroidal Anti-Inflammatory Drugs (NSAID) or low dose of corticotherapy. The immunosuppressive therapy is used in corticoid-resistant or corticoid-dependent forms such us méthotrexate. The aim of our review is to presents an overview of the different osteoarticular and muscular involvement in SSc, their diagnosis and management.
Nessrine Akasbi*, Fatima Ezzahra Abourazzak and Taoufik Harzy
Sedigheh Mirhashemi1 , Mohammad Hosein Kalantar Motamedi1 *, Amir Hossein Mirhashemi2 and Hamid Reza Rasouli1
We encountered two autopsy cases of huge cardiomegaly with over 1000g in weight. Histochemical characteristics were examined using conventional staining including HE and Azan stains and immunohistochemical staining using antibodies against Complement Component 9 (CC9), RNA Binding Protein Motif 3(RBM3), Endothelial Type NO Synthase (eNOS) and Hypoxic Inducible Factor1α (HIF1). The reactive area with anti CC9 antibody, which presumed to be a marker of hypoxic change of myocardium, overlapped with eosinophilic area by HE and basophilic one by Azan. Although the reactive area with anti CC9 antibody showed relatively weak in the cytoplasm by anti eNOS antibody and no in the nucleus of cardiocytes with anti RBM3 antibody, outside of the reactive area with anti CC9 antibody there were intensive reactivity with anti eNOS antibody in cytoplasm and in a nucleus with anti RBM3 antibody. Anti HIF1 antibody showed weak reactivity with cytoplasm of endocardial cardiocytes and no with cytoplasm of cardiocytes in another area. The results obtained from the present cases revealed that the hypoxic change was equivalent even though the cause of cardiomegaly was deferred between two cases, and conventional staining such as HE and Azan utilized to detect hypoxic change in the heart and immunohistochemical studies seemed to be a useful tool for clarifying the cascade of hypoxic changes in the myocardium.
Satoshi Furukawa1,2*, Mayumi Kataoka1 , Satomu Morita1,2, Akari Uno2 , Masahito Hitosugi2 , Hiroshi Matsumoto1,3 and Katsuji Nishi1,2
A 45-year-old woman with multiple sclerosis was admitted to our hospital after out of hospital cardio-pulmonary resuscitation. The first ECG showed ventricular fibrillation. Following direct current defibrillation and mechanical reanimation, spontaneous circulation was restored and the ECG unremarkable without any signs of ischemia. Coronary angiography showed unobstructed coronary arteries Figure 1, (Panel A). Left ventriculography revealed apical wall obstruction, suggestive of apical aneurysm (Panel B, supplementary videos). Transthoracic echocardiography and Cardiac Magnetic Resonance Imaging (CMR) eventually lead to the diagnosis of a rare case of Apical Hypertrophic Cardiomyopathy (AHC) with ace of spades-form (Panel C,D). The patient underwent Cardioverter-Defibrillator Implantation (ICD) and amiodarone medical therapy for secondary prophylaxis. Patient’s family history and screening for HCM were unsuspicious.
Wiedemann S# *, Heidrich FM# , Speiser U and Strasser RH
We present the case of a 23-year-old female who was 23 weeks pregnant and presented to the emergency room of our Obstetric Department in nausea and vomiting that had been worsening over the course of 2 months with loss of eight kilograms in clinical presentation compatible with hyperemesis.
Elisa Picardo1*, Marco Mitidieri1, Marco Bozzaro2, Roberto Altieri2, Carlo Carmazzi1 and Saverio Danese1