European Review for Medical and Pharmacological Sciences 2013; 17: 2271-2274
A. GASBARRINI, F.R. PONZIANI, B.E. ANNICHIARICO, M. SICILIANO, A. CRAXÌ1
Gastroenterology Division, Catholic University of the Sacred Heart of Rome, School of Medicine, Rome, Italy 1Gastroenterology Division, University of Palermo, Palermo, Italy
1Gastroenterology Division, University of Palermo, Palermo, Italy
The revolution of hepatitis C virus (HCV) infection treatment started in the early 1990s, with the introduction of interferon (IFN) alpha, but the best results have been achieved in the recent years. Far from the possibility to be preempted by vaccination, hepatitis C is not easy to cure in every patient. The combined therapy with pegylated-IFN (PEG-IFN) plus ribavirin (RBV), which represented the standard of care available up to now, led to suboptimal results and was almost always poorly tolerated, requiring dose reduction or treatment discontinuation. Furthermore, infection recurrence was around the corner, and patients who partially responded or did not respond to treatment had to face the frustrating concept to have no alternative therapeutic option.
The need to improve treatment results, which is particularly heartfelt when special population of patients are considered, such as liver transplant recipients and cirrhotics, pushed the scientific community to struggle for the development of new drugs. The new direct acting antivirals (DAAs) are active on specific viral components and include non-structural 3/4A (NS3/4A) protease inhibitors, nucleoside/ nucleotide analogue and non-nucleoside inhibitors of the HCV RNA-dependent RNA polymerase (RdRp), inhibitors of the HCV non-structural protein 5A (NS5A), and cyclophylin inhibitors1. Telaprevir and Boceprevir are the first NS3/4A protease inhibitors, approved in 2011 for the treatment of genotype 1 patients2,3. However, the first era of DAAs will end soon, more quickly then expected. The clinical experience with Telaprevir and Boceprevir has not produced in facts fully satisfactory results. Up to 86% of genotype 1 non-cirrhotic patients may achieve a sustained virological response (SVR), (SPRINT-2, RESPOND-2, ADVANCE, REALIZE Trials4-7), however, strong efforts due to poor tolerability and adverse events, and 24-48 weeks of treatment are needed. Moreover, the efficacy is lower in patients experienced to treatment. Nevertheless, treatment administration is not simple and requires the intake of a number of daily pills, up to 12, in addition to RBV. Cirrhotic patients have less benefits and experience more life-threatening adverse events8. Data about liver transplanted patients with HCV recurrence clearly show low SVR rates, increased prevalence of acute rejection and interaction with immunosuppressants, the main factor that has made improbable their future use in these patients9-12. Finally, Telaprevir and Boceprevir are not approved for the treatment of genotype 2 and 3 patients, whose standard of care still remains the PEG-IFN plus RBV combination therapy.
For all these reasons, several second generation DAAs are being tested. The most promising news is that HCV treatment is clearly moving toward the burial of PEG-IFN. According to the most recent scientific reports, selected patients (and hopefully every patient in the near future) will benefit of PEG-IFN free regimens, with very good results. Three recent trials, the FISSION13, FUSION and POSITRON14 (Table 1) assessed the rate of SVR at 12 weeks (SVR 12) obtained after the end of treatment with the NS5B polymerase inhibitor Sofosbuvir in genotype 2 or 3 naïve, experienced to treatment or IFN intolerant patients. The results were exciting for genotype 2 patients, with SVR12 rates of at least 93%. In contrast, genotype 3 naïve patients showed more benefit from the combination of PEG-IFN plus RBV, and lower rates of SVR12 have been reported in experienced or IFN-intolerant patients, compared to genotype 2. Preliminary experiences and phase II trials with IFN-free regimens based on DAAs combination showed encouraging results also in genotype 1 naïve and null responder patients. In particular, Sofosbuvir in combination with various DAAs, such as Daclatasvir, Ledipasvir or Simeprevir, plus RBV show excellent SVR rates, close to 100%15-17. However, further data are needed to confirm these results. A recent phase III trial showed that the addition of Sofosbuvir to PEGIFN and RBV for 12 weeks could obtain excellent results in genotype 1, 4, 5 and 6 patients (92% of SVR12 in genotype 1a, 82% in genotype 1b, 96% in genotype 4 and 100% in genotype 5/6 patients; NEUTRINO trial13, Table I). Finally, two NS3/4A protease inhibitors, Simeprevir and Faldaprevir, were also tested in genotype 1 patients in association with PEG-IFN and RBV, with inferior SVR12 rates, 80% and 79-80% respectively, than that obtained with Sofosbuvir (QUEST-1 and STARTVERSO-1 phase II trials18,19.
Table I. Clinical trials assessing the efficacy and safety of Sofosbuvir in the treatment of HCV infection. Pegylated Interferon = PEG-IFN; Ribavirin = RBV; Adverse events = AEs; number of enrolled patients = N).
(Click table to enlarge)
Nevertheless, if data about the efficacy of the new DAAs are exciting, those regarding safety are astounding. The rate of reported adverse events is lower compared to the previous therapeutic regimens; remarkably, Sofosbuvir presents a good profile of tolerability and no hematologic toxicity13, which represented the main limitation of combined PEG-IFN plus RBV therapy and of the first era of DAAs.
What is certain is that, about 20 years after the approval of the first treatment for hepatitis C, we have once again arrived at a starting point. New antiviral drugs, directly acting against the virus particles, are available. Some of them, namely Telaprevir and Boceprevir, disattended the initial promises, revealing low tolerability profiles and limited efficacy according to patients’ genotypes and subsets (e.g. cirrhotics, liver transplanted). New all-oral, IFN-free regimens requiring short treatment duration are on the horizon. Due to the very encouraging results reported so far, the forecast of a future without HCV infection is now credible. It is unknown how much time will it take, but it is reasonable to encourage patients who have a little benefit from the treatments available so far to wait for the new incoming treatments. On the other hand, clinicians have often to deal with the willingness of their patients to be healed. The major limitation of HCV infection treatments disposable so far was the impossibility to offer to every patient the same opportunity to be treated, an opportunity that was extremely dependent on treatment tolerability and on other factors affecting the route through a favorable response. The first months of 2013 have brought great changes, but there is probably still a long way to difficult to treat go before to reach the same efficacy of treatment in every patient with hepatitis C, and what we see is just the tip of a giant iceberg.
Conflict of Interest
The Authors declare that they have no conflict of interests.
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