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Sofosbuvir for the Treatment of Patients with Genotype 2 Or 3 Chronic Hepatitis C Virus Infection Höner Zu Siederdissen & Cornberg

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Sofosbuvir for the Treatment of Patients with Genotype 2 Or 3 Chronic Hepatitis C Virus Infection Höner Zu Siederdissen & Cornberg Review: Clinical Trial Outcomes SOFOSBUVIR FOR THE TREATMENT OF PATIENTS WITH GENOTYPE 2 OR 3 CHRONIC HEPATITIS C VIRUS INFECTION Höner zu Siederdissen & Cornberg 4 Review: Clinical Trial Outcomes Sofosbuvir for the treatment of patients with genotype 2 or 3 chronic hepatitis C virus infection Clin. Invest. Treatment of chronic hepatitis C will dramatically change with the introduction of Christoph Höner zu direct antiviral agents that allow interferon-free treatment schedules. However, most Siederdissen1 & Markus of the currently developed direct antiviral agents focus on genotype 1. Thus, other Cornberg*,1 1 genotypes, especially genotype 3 will become more difficult to treat with interferon-free Hannover Medical School, Department of Gastroenterology, Hepatology & regimens in the near future in comparison with genotype 1. Hepatitis C virus genotype Endocrinology, Carl-Neuberg-Str.1, 3 may convert to the most problematic genotype as not only interferon-free therapies 30625 Hannover, Germany are more challenging but also progression to cirrhosis is faster. Sofosbuvir, a NS5B *Author for correspondence: nucleoside HCV polymerase inhibitor is one of the direct antiviral agents that has pan- Tel.: +49 511 532 6821 genotypic efficacy. Phase III trials investigating sofosbuvir plus ribavirin treatment in Fax: +49 511 532 6820 [email protected] patients with hepatitis C virus genotype 2 and 3 infection have been completed and sofosbuvir was approved by the US FDA and European Medicines Agency. Keywords: direct acting antivirals • HCV genotype 2 • HCV genotype 3 • HCV RNA • hepatitis C virus • pegylated IFNα • ribavirin • sofosbuvir Seven major genotypes (G1–G7) have been mortality, as shown by a large study by van identified for the hepatitis C virus (HCV), der Meer and colleagues [7]. Fortunately, with different distribution across the world successful therapy lowers the increased risk 10.4155/CLI.14.24 [1] . G1 is the most prevalent; however, in of mortality in HCV G3 to the same risk some parts of the world, G2 and G3 have level of the other genotypes [6]. G3 is also significant impact [2]. For example, G2 and linked to higher rates of liver steatosis. Due G3 are common genotypes in some parts of to the correlation with HCV RNA, it is con- Asia, with G3 being the dominant genotype sidered to be virus-induced steatosis. Viral in India and Pakistan and G2 in Taiwan eradication subsequently leads to a decline 4 [3,4]. Thus, the size of the population of the in steatosis [8,9]. affected countries and the seroprevalence of In consideration of the increased mortality HCV G2 and G3 lead to a significant total and faster progression to cirrhosis, a distinct number of HCV G2- and G3-infected peo- urge for treatment exists in HCV G3. Even 2014 ple in need of therapy. Although HCV G2 more so, as successful therapy can negate and G3 are often evaluated together, major most of the detrimental effects. differences exist between their natural course The current standard of care (SOC) and response to treatment. for HCV G2 and G3 infection is based on G3 has a faster progression to cirrhosis pegylated interferon alpha (PEG-IFN) and and patients who failed to achieve sustained ribavirin (RBV) [10] . Different results for virological response (SVR; negative results SVR are described in the literature and sig- for HCV RNA 12 or 24 weeks after end nificant distinctions in favour of HCV G2 of treatment) have an increased mortality are reported; that is, Zeuzem et al., who in comparison with G1 and G2 [5,6]. Infec- reported SVR rates of 93% in HCV G2 tion with HCV G3 even outweighs alcohol and 79% in HCV G3 [11] . A meta-analysis use and diabetes mellitus as a risk factor for by Andriulli et al. confirmed the favourable part of 10.4155/CLI.14.24 © 2014 Future Science Ltd Clin. Invest. (2014) 4(4), 361–371 ISSN 2041-6792 361 Review: Clinical Trial Outcomes Höner zu Siederdissen & Cornberg findings for HCV G2, albeit their study stated lower (DAA). Boceprevir (BOC) and telaprevir (TLV) are SVR rates with an overall SVR rate of 74% for G2 and both HCV protease inhibitors (PI) that still require 68% for G3 [12] . the combination of PEG-IFN and RBV. However, In summary, the natural course of HCV G2 and G3 both PIs are only approved for G1. Nevertheless, some is different, with a faster progression and higher mor- patients with G2 and G3 have been exposed to BOC tality linked to HCV G3. Despite the bigger need for and TLV. The combination of TLV, PEG-IFN and therapy, HCV G3 has lower response rates to current RBV did show an increased antiviral activity in G2 in PEG-IFN/RBV therapy comparison with only PEG-IFN and RBV, whereas no To spare side effects and increase response rates, additional benefit could be observed in G3[24] . several studies compared different treatment durations In comparison, BOC showed some antiviral activity to increase the treatment efficacy. Although a fixed in both, G2 and G3. However, only the dose of 400 duration of 24 weeks has been proposed [13], response- mg t.i.d. has been studied and not the approved dose of guided therapy has been found to have an optimized 800 mg t.i.d. [25]. Based on these data, BOC and TLV risk–benefit ratio. Based on rapid virological response cannot be recommended for non-G1 patients. (RVR; undetectable HCV RNA after 4 weeks of treat- Most of the other DAAs that are currently inves- ment), early virological response (EVR; undetectable tigated in Phase II–III trials have limited efficacy in HCV RNA after 12 weeks of treatment) and risk HCV G2 and G3. Some PIs like simeprevir, asuna- factors for treatment failure, therapy duration varies previr, faldaprevir and MK 5172 showed an effect in between 16 and 48 weeks [10,14]. As mentioned, for both HCV G2, but no effect or only a reduced effect (i.e., genotypes the most important predictor for successful MK 5172 in higher doses) in HCV G3. The NS5A therapy and, therefore, the most important factor for inhibitor daclatasvir as well as the combination of response-guided treatment, is the RVR. RVR can be the PI ABT-450/r and the NS5A inhibitor ABT-267 achieved in 62–78% of G2 and G3 patients, however have been tested successfully in HCV G2 and G3. sensitive assays should be used to test for HCV RNA Though, HCV G2 showed better response rates for [15–18]. Though reduction of treatment to less than 24 both treatment regimens [26–31]. More data for these weeks increased the chance of relapse [18,19], shortening DAA are needed to judge their use in HCV G2 and is an option to spare side effects and costs in selected G3. Non-nucleosides did not show an effect [32]. patients [14] . A treatment duration of 12–16 weeks is However, nucleoside polymerase inhibitors have possible in patients who show RVR defined by HCV pan-genotypic efficacy. Sofosbuvir (SOF, Gilead Sci- RNA negativity with a sensitive HCV assay by week ences) is the most advanced NS5B polymerase inhibi- 4 of therapy [16–17,20]. Though it is important to note tor and will be evaluated in more detail in the following that the dose of RBV should not be given as flat dose section. of 800 mg in response-guided therapy regimens [14] . Besides DAA, host-targeting antivirals may also Several risk factors for poor SVR rates have been iden- play a role in further treatment regimens. The host- tified that should not allow response-guided treatment: targeting antiviral alisporivir, which is a cyclophillin baseline viral load, immunosuppression, advanced cir- A inhibitor has been shown to be effective in HCV rhosis, age, adipositas, and nonadherence to therapy G2 and G3 [33,34]. Of note, alisporivir demonstrated [16,21–23]. The predictive value for IL28b is less for G2 best results in HCV G3 in a trial with HCV/HIV and G3 compared with G1 [23]. However, despite the co-infected patients with G1, G3 and G4 [35]. huge efforts that have been made to understand and optimize the therapy for HCV G2 and G3, the treat- SOF in the treatment of HCV G2 & G3 ment has basically not changed in recent years and the As already mentioned, there is a huge need for new compounds PEG-IFN and RBV, with their specific treatment options in HCV G2 and G3, especially in drawbacks, remained the mainstay of therapy. regard of interferon-free treatment. This need could Considering the higher mortality and the lower potentially be addressed by SOF, a new NS5B-poly- response rates to treatment of HCV G3, a huge need merase inhibitor. NS5B is an HCV RNA dependent exists for new therapies. This is even more important in RNA polymerase and essential for viral replication. hard-to-treat patients, who are defined by a combina- Amazing results have been shown in the first trial, tion of HCV G3, cirrhosis, high baseline viral load, age, which has evaluated the combination of SOF, RBV and adipositas and non-compliance. Furthermore, no treat- PEG-IFN (added for 4–12 weeks) and even SOF and ment options exist for patients who are not eligible for RBV without PEG-IFN. This trial has demonstrated PEG-IFN treatment or who did not respond to SOC. 100% SVR [36]. Monotherapy with SOF has been also A small improvement was achieved in 2011 with tested in ten patients but SVR was only 60%, rendering the approval of the first two direct-acting antivirals RBV still irreplaceable in current HCV therapy. 362 Clin. Invest. (2014) 4(4) future science group Sofosbuvir for the treatment of genotype 2 or 3 chronic HCV infection Review: Clinical Trial Outcomes Table 1.
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