Approaches and Considerations for the Successful Treatment of HCV Infection

The complexity of the hepatitis C virus (HCV) infection is reflected in its therapy, and great efforts are needed from the patient and the physician to be successful in eliminating the infection. How HCV will progress depends a lot on patient characteristics and social factors, in addition to the timing of initiation, duration, and final results of the therapy. The first treatment approved for patients with chronic hepatitis C was interferon (IFN) which had a sustained viral response (SVR) rate in 20%. Due to side effects, the adherence to this treatment was limited and required a patient-tailored approach with various medical disciplines working together and intervening at the right time to minimize potential obstacles. The introduction of direct-acting antivirals (DAAs) has contributed to the advancement of HCV treatment. However, a major obstacle to wide use of DAAs is their high price which has largely limited access to treatment. Guidelines and recommendations on treatment of hepatitis C have been developed to assist physicians and other health care providers to determine priority. Despite that, the arrival of new oral therapies has been met with enthusiasm as shorter, simpler, safer treatment allows for the possibility of delivering antiviral therapy on a large scale

MANAGEMENT OF SIDE EFFECTS INDUCED BY ANTIVIRAL THERAPY FOR CHRONIC HEPATITIS INFECTION

Dva nova lijeka za liječenje kronične infekcije virusom hepatitisa C genotipa 1 nedavno odobrena u Republici Hrvatskoj, telaprevir i boceprevir, blokiraju HCV NS3/4 proteazu ciljano zaustavljajući proces replikacije samog virusa, značajno su unaprijedili stalan virološki odgovor u liječenju pacijenata s kroničnom HCV infekcijom genotipa 1. Njihovim dodatkom do tada standardnoj dvojnoj terapiji - kombinaciji pegiliranog interferona i ribavirina, nastala je trojna terapija koja postaje novi standard u liječenju kronične HCV infekcije genotipa 1. Nažalost, trojna je terapija praćena širokim spektrom neželjenih popratnih pojava koje za posljedicu imaju smanjenje doziranja lijeka, a u konačnici mogu rezultirati i preranim prestankom uzimanja terapije. Adekvatno anticipiranje pojave neželjenih popratnih pojava trojne terapije, informiranje pacijenata o riziku za razvoj nuspojava, te učinkovito liječenje nus-pojava neophodno je za postizanje sigurnog i učinkovitog ishoda liječenja. Iako nije najčešća nuspojava trojne terapije, anemija se pokazala kao najproblematičnija nuspojava. Učinkovito liječenje anemije sastoji se od pomnog praćenja kompletne krvne slike, opsežnog smanjivanja doza ribavirina, te eventualne primjene eritropoetina, te nadoknade krvi. U pacijenata na trojnoj terapiji, ako je primjena ribavirina prekinuta sedam ili više dana, također trajno treba prekinuti i primjenu blokatora HCV NS3/4 proteaze. Doziranje blokatora HCV proteaze ne smije se smanjivati; blokatori HCV NS3/4 proteaze se ili primjenjuju u punoj dozi ili se njihova primjena u potpunosti prekida. Uspjeh u pridržavanju pacijenta propisanoj terapiji može se poboljšati ako ga se pravodobno pouči da se gotovo sve neželjene popratne pojave trojne terapije kronične infekcije virusom hepatitisa C mogu uspješno liječiti.Recently approved direct-acting antiviral agents (DAA) for the treatment of chronic infection with hepatitis C virus (HCV) genotype 1, protease inhibitors (PI) boceprevir and telaprevir, have substantially increased the rates of sustained virologic response in the treatment of naïve and experienced patients. However, triple therapy came with a burden of a new spectrum of side effects, which may lead to dose reduction and even discontinuation of therapy. Anticipating the adverse events of PIs, informing patients about their risk and manage them appropriately and efficiently is important for safe and successful treatment outcome. Anemia, although not the most common side effect, has emerged as the most significant one. Effective management of anemia includes close monitoring of complete blood count, extensive ribavirin dose reductions, and possible addition of erythropoietin or blood transfusions. In patients on triple therapy, if RBV is stopped for 7 days or more, the PI should also be permanently discontinued. Dose reductions of HCV PIs are not allowed; the HCV PIs are either administered at full dose or discontinued. Successful adherence to treatment can be enhanced by timely informing the patient that most treatment-related adverse effects can be minimized and managed

Hepatitis C–Associated Diabetes Mellitus

Diabetes type 2 mellitus (T2DM) is the most common extrahepatic association of hepatitis C virus (HCV) infection. Substantial research has suggested that insulin resistance (IR) has crucial importance in development of type 2 diabetes in HCV-infected patients. Several pathophysiological mechanisms are proposed, such as direct effect of HCV proteins on inhibition of the insulin-signaling pathway inducing central insulin resistance (IR), while overproduction of inflammatory cytokines and increased lipolysis promote peripheral IR. IR in HCV-infected patients is associated with impaired sustained virologic response (SVR) and higher incidence of hepatocellular carcinoma (HCC). Some, but not all, studies have shown improvements in achieving SVR in patients with interferon/ribavirin (RBV) therapy co-treated with metformin or pioglitazone as well as beneficiary effect on the incidence of hepatocellular carcinoma. Recent studies indicate that response to the new direct-acting antiviral (DAA) treatments is unaffected by insulin resistance thus diminishing importance of IR in the new era of DAA. Additionally, viral eradication by DAAs has been shown to ameliorate insulin resistance, attenuating the risk of new-onset diabetes type 2. However, those metabolic improvements are sustainable long after the treatment remains unclear

Pharmacogenomic Testing in the Era of Patient-Tailored HCV Treatment

Hepatitis C affects approximately 180 million people worldwide, with 3–4 million newly infected each year. Hepatitis C virus (HCV) has been classified into seven different genotype categories, wherein HCV genotype 1 (HCV-1) is the most prevalent. To date, there is still no vaccine available against HCV infection. Until recently, combination therapy of pegylated interferon-a (PegIFN) and ribavirin (RBV) has been the standard of care. Nevertheless, for many patients, particularly those infected with HCV genotype 1 (HCV-1), this treatment has resulted with unsatisfactory treatment response rates and high adverse drug reaction (ADR) rates. Many clinical factors, including pharmacogenetics, influence the treatment response rate. This review focuses on the association between pharmacogenetics and HCV antiviral therapy in patients infected with HCV genotype 1 and other genotypes (GT); patients reinfected with HCV after liver transplantation; and patients coinfected with HCV and human immunodeficiency virus. Data considering triple therapy in HCV-infected patients are also reviewed. Additionally, various genetic polymorphisms, with an emphasis to IL-28B, and their association with pharmacogenetic testing in HCV are discussed

Implementation and Evaluation o of Online Learning at the Faculty of Dental Medicine and Health, Osijek, Croatia – Project Report

This paper presents the report on the project of implementation and evaluation of online learning at the Faculty of Dental Medicine and Health Osijek. The aim of this project was to include online learning in the teaching process at the Faculty of Dental Medicine and Health, and to assess student’s satisfaction with online learning implemented during elective courses in social sciences. Several dislocated study programs were included, where video conferencing equipment was installed and video conference lectures were held during elective courses in social sciences (Health economics, ealth management, Quality control) using Carnet video conferencing system. Lectures were recorded and made available for students to access at different times and locations. An anonymous survey assessing students’ experience and perception of online education was conducted after each course as a part of the regular anonymous course evaluation survey. A large proportion of students were satisfied with the online lectures and agreed that online teaching improves education quality

Drug Treatment of Obesity: From Bench to Bedside

Obesity is a complex metabolic and behavioural disorder associated with increased health risk, including coronary artery disease, congestive heart failure and sudden cardiac death. Effective prevention and treatment strategies for obesity are needed. This unmet need for efficient and safe antiobesity medication resulted in many new therapies at various stages of development. Obesity has become one of the most intensively studied diseases because of the availability of suitable animal and cell culture models of adipocyte differentiation and appetite regulation

Occurrence of Hepatocellular Carcinoma in Patients with Chronic hepatitis C Treated with Direct-Acting Antiviral Therapy

Poznato je kako oboljeli od kronične bolesti jetre učestalije obolijevaju od hepatocelularnog karcinoma. Premda se RNA molekula hepatitis C virusa uspješno eliminira iz cirkulacije direktnodjelujućim antivirusnim lijekovima, HCV RNA može ostati i dalje prisutna u jetrenom tkivu ili perifernim mononuklearnim stanicama te je taj entitet poznat kao okultni HCV. Postoje brojne nedoumice povezane s ponovnom pojavom HCC-a nakon provedenog liječenja DAA terapijom jetrenih stanica kronično zaraženih HCV-om, a jedan od glavnih čimbenika rizika koji dovodi do de novo HCC-a je pojava kroničnosti HCV-a u stanicama jetre. Mnoge studije provedene su s ciljem istraživanja promjena jetrenih stanica inficiranih HCV-om u HCC. Međutim, još uvijek nisu u potpunosti jasni molekularni mehanizmi koji vode do progresije kronične HCV infekcije u HCC i učinak HCV-a na promjenu DNA ploidnosti, što dovodi do ponovnog povratka HCC-a nakon liječenja DAA terapijom. Stoga je cilj ovoga članka razmotriti čimbenike rizika koji bi mogli dovesti do razvoja HCC-a nakon liječenja HCV-a upotrebom DAA terapije, poput uloge ciroze jetre, promjene DNA ploidnosti, reaktivacije virusa hepatitisa B, kao i okultne HCV infekcije.Patients with chronic liver disease are known to be more likely to develop hepatocellular carcinoma (HCC). Although direct-acting antivirals have proven successful in eliminating the hepatitis C virus RNA from blood circulation, the HCV RNA can still remain present in liver tissue or peripheral blood mononuclear cells – a condition known as occult HCV infection. There have been numerous concerns related to the recurrence of HCC after DAA treatment of hepatocytes infected with chronic HCV. One of the major risk factors leading to de novo HCC is the chronicity of HCV in liver cells. Moreover, numerous studies investigated the change of HCV-infected hepatocytes into HCC. However, the molecular mechanisms leading to the progression of chronic HCV infection into HCC, as well as the effect of HCV on the alteration of DNA ploidy that leads to recurrence of HCC after DAA treatment, are still unclear. Therefore, this article examines the risk factors that could lead to the development of HCC after treatment of HCV with DAAs, such as the role of liver cirrhosis, reactivation of hepatitis B virus, alteration of DNA ploidy and occult HCV infection

HCV and Work Ability Assessment

Modifications to work and work ability assessment are required to prevent occupational transmission of hepatitis C virus (HCV). This is usually required in the health care setting, where exposure-prone procedures (EPPs) should not be carried out by infectious carriers of HCV. The risk of an individual surgeon acquiring HCV has been estimated at 0.001–0.032% per annum. Even in an area with a high prevalence of HCV among its population, the risk of acquiring HCV through occupational exposure is low. Rates of viral clearance with treatment of acute HCV infection are considerably higher than treatment of chronic HCV infection. Consequently, it is imperative that health care workers follow universal precautions and promptly report all exposures to blood or body fluid exposures according to their local policy. Health care workers who embark on, or transfer to, a career that requires EPP (exposure-prone procedures and dialysis work) should be assessed to ensure that they are free from infection with HCV. If the HCV antibodies are positive, the health care worker should be tested for HCV RNA PCR. If the HCV RNA PCR is negative on two separate occasions, the health care worker may be permitted to perform EPPs. If the HCV RNA PCR is positive, the health care worker should not be allowed to perform EPPs. Health care workers who already perform EPPs and who believe they may have been exposed to HCV infection should be advised to seek advice from their occupational health department for confidential advice on whether they should be tested

Occurrence of Hepatocellular Carcinoma in Patients with Chronic hepatitis C Treated with Direct-Acting Antiviral Therapy

Poznato je kako oboljeli od kronične bolesti jetre učestalije obolijevaju od hepatocelularnog karcinoma. Premda se RNA molekula hepatitis C virusa uspješno eliminira iz cirkulacije direktnodjelujućim antivirusnim lijekovima, HCV RNA može ostati i dalje prisutna u jetrenom tkivu ili perifernim mononuklearnim stanicama te je taj entitet poznat kao okultni HCV. Postoje brojne nedoumice povezane s ponovnom pojavom HCC-a nakon provedenog liječenja DAA terapijom jetrenih stanica kronično zaraženih HCV-om, a jedan od glavnih čimbenika rizika koji dovodi do de novo HCC-a je pojava kroničnosti HCV-a u stanicama jetre. Mnoge studije provedene su s ciljem istraživanja promjena jetrenih stanica inficiranih HCV-om u HCC. Međutim, još uvijek nisu u potpunosti jasni molekularni mehanizmi koji vode do progresije kronične HCV infekcije u HCC i učinak HCV-a na promjenu DNA ploidnosti, što dovodi do ponovnog povratka HCC-a nakon liječenja DAA terapijom. Stoga je cilj ovoga članka razmotriti čimbenike rizika koji bi mogli dovesti do razvoja HCC-a nakon liječenja HCV-a upotrebom DAA terapije, poput uloge ciroze jetre, promjene DNA ploidnosti, reaktivacije virusa hepatitisa B, kao i okultne HCV infekcije.Patients with chronic liver disease are known to be more likely to develop hepatocellular carcinoma (HCC). Although direct-acting antivirals have proven successful in eliminating the hepatitis C virus RNA from blood circulation, the HCV RNA can still remain present in liver tissue or peripheral blood mononuclear cells – a condition known as occult HCV infection. There have been numerous concerns related to the recurrence of HCC after DAA treatment of hepatocytes infected with chronic HCV. One of the major risk factors leading to de novo HCC is the chronicity of HCV in liver cells. Moreover, numerous studies investigated the change of HCV-infected hepatocytes into HCC. However, the molecular mechanisms leading to the progression of chronic HCV infection into HCC, as well as the effect of HCV on the alteration of DNA ploidy that leads to recurrence of HCC after DAA treatment, are still unclear. Therefore, this article examines the risk factors that could lead to the development of HCC after treatment of HCV with DAAs, such as the role of liver cirrhosis, reactivation of hepatitis B virus, alteration of DNA ploidy and occult HCV infection

Urolithiasis and Osteoporosis: Clinical Relevance and Therapeutic Implications

Several clinical and epidemiological studies revealed increased bone turnover and lower bone mass in patients with urolithiasis. Bone mass loss is particularly evident in idiopathic calcium stone formers. However, pathogenetic mechanisms and factors implicated in bone loss in these patients are still unknown. Dietary calcium restriction, increased intake of salt and animal proteins, vitamin D receptor polymorphisms are likely risk factors, while role of inflammatory cytokines, osteopontin and prostaglandin mediated bone resorption is yet to be determined. Regarding treatment and prevention, it has been proven that calcium supplements and high calcium diet with the addition of potassium alkali have an important role in prevention and treatment of both, urolithiasis and osteoporosis. Thiazide diuretics reduce hypercalciuria in renal tubules, and in addition promote osteoblast differentiation. Finally, bisphosphonates, a commonly used drugs in treatement of osteoporosis, show the potential to inhibit calcium stone formation, whereas a possible protective effect of antioxidants in bone loss and renal injurie needs to be investigated further