Saturday, January 30, 2016

Chronic hepatitis C: This and the new era of treatment.

*Abstract, discussion and conclusion provided below please, click here to review the full text article. 

World J Hepatol. 2016 Jan 18; 8(2): 92–106.
Published online 2016 Jan 18. doi: 10.4254/wjh.v8.i2.92

Chronic hepatitis C: This and the new era of treatment.
Bertino G1, Ardiri A1, Proiti M1, Rigano G1, Frazzetto E1, Demma S1, Ruggeri MI1, Scuderi L1, Malaguarnera G1, Bertino N1, Rapisarda V1, Di Carlo I1, Toro A1,Salomone F1, Malaguarnera M1, Bertino E1, Malaguarnera M1.

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Over the last years it has started a real revolution in the treatment of chronic hepatitis C. This occurred for the availability of direct-acting antiviral agents that allow to reach sustained virologic response in approximately 90% of cases. In the near future further progress will be achieved with the use of pan-genotypic drugs with high efficacy but without side effects.

Boceprevir; Daclatasvir; Dasabuvir; Direct-acting antiviral agents; Faldaprevir; Hepatitis C; Ledipasvir; Nucleoside inhibitors; Ombitasvir; Ritonavir; Simeprevir; Sofosbuvir; Telaprevir

Core tip: This review analyzes the current therapies for chronic hepatitis C and the future challenges of the research. So it tries to give an update on the research of hepatitis C virus (HCV) infection, providing a critical view of the emerging therapies and their impact on the future management of HCV infection. Since novel treatments for HCV infection are highly efficacious but costly, priority should be given to patients with advanced hepatic fibrosis, which is a disease that cannot be deferred.

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Today, it can be anticipated that the future of HCV infection treatment seems very bright after the addition of first-generation HCV PIs as well as SMV and the first-in-kind HCV RNA polymerase inhibitor, ‘‘sofosbuvir’’, in the standard of care (i.e., PEG-IFN/RBV). However, the real success of these drugs is very much dependent on careful monitoring of viral load and resistance, patterns of response to previous treatment, side effects and drug-drug interactions. Moreover, the logical meaning of novel emerging therapies must be to achieve high SVR and thorough clearance of the virus from treated patients. Nevertheless, the triple therapeutic regimens have several limitations. First, concomitant use of PEG-IFN plus RBV is essential to prevent the emergence of viral escape mutants and viral breakthrough during triple therapy. Second, triple therapy becomes less effective in prior null responders to PEG-IFN plus RBV and cannot be administered to patients who are contraindicated for PEG-IFN or RBV. To overcome these limitations, in the near future, many patients will be treated with two or more DAAs with or without IFN-α plus RBV based combination therapies. Currently, the approval of sofosbuvir- and SMV-based IFN-free regimens is an indication in this way. Triple and quadruple treatment regimens including multiple DAAs with or without PEG-IFN and RBV will likely be a suitable option for difficult-to-treat populations and for the prior null responders. All-oral IFN free regimens including drugs with a high genetic barrier to antiviral resistance (e.g., NS5B inhibitors) and high antiviral efficacy (e.g., NS3/4A PIs or NS5A inhibitors) may be a potent option for numerous patients contraindicated for PEG-IFN plus RBV. All oral regimens consisting of daclatasvir plus sofosbuvir once daily presented higher rates of SVR in untreated HCV GT-1, -2 and -3 infected patients and in HCV GT-1 infected patients who had failed previous treatment with PIs. We hope that such combinational treatment strategies will become ‘‘the weapon’’ to treat the majority of HCV infected patients who represent the difficult population (i.e., IL-28 polymorphism, HCV genotypes 1 and 4 subtypes, receipt of RBV, and the emergence of resistant variants) and will be more efficient to access the treatment in the near future. The testing of adenovirus vector based vaccines, which escalate the innate and acquired immune response against the most conserved regions of HCV genome in chimpanzees and humans, may be a promising therapeutic approach against HCV in the near future, although its fate still needs to be exploited fully in diverse HCV populations. One thing must be of special concern is whether the newly developed or being developed DAAs added in triple or quadruple therapies are safer or not than antiretroviral and traditional IFNs. Overall, the achievements in the field of HCV medicines may predict that we are near to complete elimination of HCV disease in the world[140]. The real challenges that our efforts must be directed are: (1) the effectiveness of IFN-free regimens in HCV-3, especially in cirrhotic non-responders; in this setting, combination with PEG-IFN is still possible; (2) the effectiveness of IFN-free regimens in decompensated cirrhosis are scarce in relation to the current correlation data between SVR and clinical outcome (literature confirms that the results of IFN-free regimens are good in compensated cirrhosis even if further clinical development is necessary in certain groups to improve SVR rates); (3) the development of new treatment strategies for patients who show resistance to new drugs; and (4) free-access to care[141]. In fact, many patients with CHC have mild disease and are currently excluded from the interferon-free treatment. In the near future we will inevitably prioritize this category in order to prevent progression to cirrhosis, decompensation and HCC.

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