Posljednjih je 15 godina standardna terapija u liječenju kroničnog hepatitisa C kombinirana terapija pegiliranim interferonom (PEG-INF) i ribavirinom (RBV) u trajanju od 24 do 48 tjedana, ovisno o genotipu HCV-a. Standardna terapija rezultirala je održivim virološkim odgovorom (engl. sustained virological response, SVR) od 75 do 85% u pacijenata s genotipom 2 i 3, ali samo od 40 do 50% u pacijenata s genotipom 1. Trenutačno postoji brz i kontinuiran razvoj brojnih novih lijekova protiv hepatitis C-virusa (HCV), koji su u žarištu ovog pregleda. Boceprevir i telaprevir, dva inhibitora NS3/4A-proteaze prve generacije, unaprijedili su liječenje HCV-a. Nedavno su registrirani u nekoliko zemalja diljem svijeta u kombinaciji s PEGINF-om i RBV-om za liječenje bolesnika s genotipom 1. Trojna terapija s boceprevirom ili telaprevirom u usporedbi s kombinacijom PEG-INF/RBV poboljšava SVR za 25-31% u prethodno neliječenih bolesnika s genotipm 1, za 40-64% u bolesnika koji su nakon prethodne terapije imali povrat infekcije (“relapser”), za 33-45% u bolesnika koji su tijekom prethodne terapije imali djelomičan odgovor (“partial responders”) i za 34-38% kod bolesnika koji na prethodnu terapiju nisu imali odgovor (“null-responder”). U isto vrijeme primjena individualiziranog liječenja, odnosno liječenja ovisnog o virološkom odgovoru (engl. response-guided therapy, RGT), dovodi do skraćenja trajanja ukupnog liječenja na samo 24 tjedna u 45-55% prethodno neliječenih bolesnika. Postoji međutim nekoliko izazova u korištenju nove trojne kombinacije u bolesnika s genotipom 1, kao što je potreba za brzim rezultatima HCV RNA-testiranja s pomoću osjetljivih kvantitativnih testova, nove i češće nuspojave (anemija i disgeuzija za boceprevir; pruritus, osip i anemija za telaprevir), nove interakcije lijekova i teškoće u suradljivosti bolesnika. Štoviše, učestalost SVR-a još je niska u teško izlječivih podgrupa s genotipom 1, kao null-responderi s cirozom, a od nove terapije nemaju nikakve koristi bolesnici koji ne toleriraju PEG-INF/ RBV ili koji nisu zaraženi genotipom 1. Trenutačno se u liječenju infekcije HCV-om procjenjuje učinkovitost mnogih novih anti- HCV-lijekova, različitih klasa i kombinacija, a rezultati ohrabruju. U nadolazećim godinama očekuju nas novi antivirusni lijekovi s direktnim djelovanjem (engl. direct-acting agent, DAA) s pojednostavnjenim doziranjem i/ili minimalnom toksičnošću, koji će u kombinaciji s drugim lijekovima dovesti do eradikacije virusa u gotovo većine bolesnika s kroničnom infekcijom HCV-om. Novi će agensi omogućiti protokole bez interferona.Over the last 15 years, the standard therapy for the treatment of chronic hepatitis C (HCV) has been the combination of pegylated-interferon-alfa (PEG-IFN) and ribavirin (RBV) administered for 24 to 48 weeks depending on the HCV genotype. Standard therapy resulted in sustained virological response (SVR) rates of 75%-85% in patients with genotypes 2 or 3 but only of 40%-50% in patients with genotype 1. Currently, there are rapid and continuous developments of numerous new agents against hepatitis C virus (HCV), which are the focus of this review. Boceprevir and telaprevir, two firstgeneration NS3/4A HCV protease inhibitors, have revolutionized HCV therapy. They have been recently licensed in several countries around the world to be used in combination with PEGIFN and RBV for the treatment of genotype 1 patients. Boceprevir or telaprevir based triple regimens, compared with the PEG-IFN/RBV combination, improve the SVR rates by 25%-31% in treatment-naive genotype 1 patients, by 40%-64% in prior relapsers, by 33%-45% in prior partial responders and by 24%- 28% in prior null responders. At the same time, the application of response-guided treatment algorithms according to the ontreatment virological response results in shortening of the total therapy duration to only 24 wk in 45%-55% of treatment-naive patients. There are, however, several challenges with the use of the new triple combinations in genotype 1 patients, such as the need for immediate results of HCV RNA testing using sensitive quantitative assays, new and more frequent adverse events (anaemia and dysgeusia for boceprevir; pruritus, rash and anaemia for telaprevir), new drug interactions and increasing difficulties in compliance. However, the SVR rates are still poor in subgroups of genotype 1 patients, which are very difficult to treat, such as null responders with cirrhosis. There is no benefit for patients who cannot tolerate PEGIFN/ RBV or who are infected with non-1 HCV genotype. Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results. New DAA with simplified dosing regimens and/or minimal toxicity which, when used in combination, will lead to viral eradication in almost all CHC patients who undergo treatment are expected in the years ahead. The novel agents in clinical development are paving the way for future interferon-sparing regimens
