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Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV
Infection 12, 24 weeks GT1/2/3, FDA Approvals Oct 10 thru Dec This Fall
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The FDA is reviewing several new interferon therapies now, expected by Oct 10 is approval for sofosbuvir+ledipapsir from Gilead, and Abbvie's 3D sometime during October thru December, Janssen's Simeprevir+Sofosbuvir, (results for these combinations at EASL: http://www.natap.org/2014/EASL/EASL_86.htm) - and BMS's daclatasvir.
Daclatasvir+sofosbuvir phase 3 studies of started January 2014:
Phase III HIV/HCV Co-Infection Daclatasvir (DCV)+ Sofosbuvir (SOF).......in Treatment-naïve and Treatment-experienced Chronic Hepatitis C (Genotype 1, 2, 3, 4, 5, or 6)
Phase III Daclatasvir + Sofosbuvir in Cirrhotic Subjects and Subjects Post-liver Transplant.......
Phase III Daclatasvir and Sofosbuvir for Genotype 3 Chronic HCV
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Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection - (01/17/14) NEJM
from Jules: essentially all 123 patients with GT1 achieved SVR - essentially 100% (tratment-naive: n=82) of patients with GT1 who received 12 weeks therapy with or without ribavirin had an SVR, there were no virology failures; the 41 previously treated recd 24 weeks essentially had SVR, there was 1 patient whose data was missing on treatment who later had achieved an SVR.
"Among patients with genotype 1 infection, the median age ranged from 54 to 59 years, and most had fibrosis of Metavir stage 2 or higher (on a scale from F0 to F4, with higher stages indicating a greater degree of fibrosis) (Table 1). Of the 41 patients who did not have a response to prior treatment with protease inhibitors, 19 (46%) had NS3 polymorphisms conferring resistance to telaprevir or boceprevir (Tables S2 and S3 in the Supplementary Appendix)."
"None of the previously untreated patients with genotype 1 infection had a virologic breakthrough, and all had an HCV RNA level of less than 25 IU per milliliter at the end of the treatment period (Table 2). After the treatment period, no patient had a virologic relapse. Overall, 164 of 167 patients with genotype 1 infection (98%) had a sustained virologic response at week 12 after treatment, including 84 of 85 patients who received treatment for 24 weeks (all 44 patients who had not received previous treatment and 40 of 41 patients who had received a protease inhibitor) and 80 of 82 patients who received treatment for 12 weeks. Of the 3 patients who were classified as not having a sustained virologic response 12 weeks after treatment, 2 missed the assessment visit at 12 weeks but had a sustained virologic response at week 24 after treatment, and 1 was lost to follow-up (Table 2, and Tables S2 and S4 in the Supplementary Appendix). Rates of sustained virologic response 12 weeks after treatment were similar in subgroups defined according to viral subtype (genotype 1a, 98% [129 of 132 patients]; genotype 1b, 100% [35 of 35 patients]), IL28B genotype (CC, 93% [57 of 61 patients]; non-CC, 98% [147 of 150 patients]), race (white, 97% [170 of 175 patients]; black, 96% [25 of 26 patients]; and other race, 90% [9 of 10 patients]), ribavirin status (ribavirin, 94% [85 of 90 patients]; no ribavirin, 98% [119 of 121 patients]), and history of treatment failure with protease inhibitors (98% [40 of 41 patients]).
......Of 126 patients with previously untreated genotype 1 infection, 120 (95%) had a sustained virologic response at week 24 after treatment (Table 2). Of the 6 patients who were classified as not having a sustained virologic response at week 24 after treatment, 4 missed the assessment visit at week 24 but were classified as having a sustained virologic response at week 36 after treatment, and 1 was lost to follow-up. The remaining patient, whose history included injection-drug use, had a high level of viremia (HCV RNA level, 670,772 IU per milliliter), and viral sequences at week 24 after treatment that differed from the sequences at baseline suggested a new HCV infection. Furthermore, no daclatasvir-resistant or sofosbuvirresistant variants were detected (Fig. S3 in the Supplementary Appendix)."
from Jules: looking at GT2/3 14/14, 100%, in group D had SVR after 24 weeks treatment, and 13/14 in group F. Group B recd SOF for 7 days alone then added DCV.
"All patients infected with genotype 2 or 3 had an undetectable HCV RNA level during the treatment period. One patient with genotype 3 infection who was treated without ribavirin had a detectable HCV RNA level of less than 25 IU per milliliter at weeks 8 and 10, which, per protocol, was defined as a virologic breakthrough (Table 2). However, before the initiation of rescue therapy at week 12, HCV RNA was undetectable; the patient had a sustained virologic response at 24 weeks after rescue therapy (Table S4 in the Supplementary Appendix). Overall, 91% of the patients infected with genotype 2 or 3 had a sustained virologic response 12 weeks after treatment and 93% had a sustained virologic response 24 weeks after treatment (Table 2). Rates of sustained virologic response 12 weeks after treatment were 92% among patients with genotype 2 infection (24 of 26 patients) and 89% among patients with genotype 3 infection (16 of 18).......
Virologic relapse was confirmed in 1 patient with genotype 3 infection who received treatment without ribavirin; adherence to the treatment regimen was documented on the basis of pill counts, as well as plasma concentrations of daclatasvir and major sofosbuvir metabolites that were consistent with those in other patients. Resistance analysis showed a preexisting NS5A-A30K polymorphism, associated with daclatasvir resistance, at baseline and at the time of relapse. No other resistance-associated changes were detected at the time of relapse. Of the available baseline samples, pretreatment polymorphisms, including NS5A-A30K and others known to confer loss of susceptibility to daclatasvir in vitro, were observed in 10 of 123 untreated patients with genotype 1 infection (8%), 3 of 40 patients with genotype 1 infection in whom prior treatment with protease inhibitors had failed (8%), 14 of 23 patients with genotype 2 infection (61%), and 5 of 18 patients with genotype 3 infection (28%) (Table S5 in the Supplementary Appendix). Except for the patient described above, all patients with preexisting daclatasvir resistance variants had a sustained virologic response. With respect to sofosbuvir, no preexisting NS5B-S282T polymorphisms were detected. In the only patient with protocol-defined virologic breakthrough, no baseline daclatasvir or sofosbuvir resistance-associated polymorphisms were detected, and the HCV RNA level at the time of virologic breakthrough was too low (<25 IU per milliliter) for resistance testing; the patient had a sustained virologic response after rescue therapy."
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