February 22, 2014

HCV Genotype 3

Provided by NATAP

Written by Jules Levin

You are asking if Sovaldi (sofosbuvir) is effective for patients with genotype 3 with compensated cirrhosis???

Here is the data below from studies showing 83%+ SVR rates with Sovaldi+Peg/Rbv having better results than Sovaldi+Rbv without Peg/INF. Small phase 2 study in genotype 3 patients with & without cirrhosis have been conducted with daclatasvir+Sovaldi with good SVR rates but a smaller number of patients who were non-cirrhotic & treatment-naive, just starting is a study in genotype 3, here are links to this data......

Bottom lime Sovaldi+Peg/Rbv appears to provide more effective results for patients with cirrhosis & gt3 than Sovaldi+Rbv, and that is FDA approved with 83% SVR but the number of patients in the study is small, see links & pics below.\

ALSO, in development is Gilead's GS-5816 for genotype 3, it's in earlier stage of development, data from early phase 2 studies show it to be potent, studies are ongoing:

AASLD: Deep Sequencing of HCV NS5A From a 3-Day Study of GS-5816 Monotherapy Confirms the Potency of GS-5816 Against Pre-Existing Genotype 1-3 NS5A Resistance-Associated Variants - (11/05/13)

AASLD: GS-5816, a Once-Daily NS5A Inhibitor, Demonstrates Potent Antiviral Activity in Patients With Genotype 1-4 HCV Infection in a 3 Day Monotherapy Study - (11/04/13)

The New HCV Guidelines/Recommendations from AASLD/IDSA were released Feb 1, 2014. Several days after that BMS announced the start of several phase 3 studies of daclatasvir+sofosbuvir (Sovaldi) including a study for genotype 3 patients. The Guidelines for genotype 3 are below and discuss Sofosbuvir+Peg/Rbv and Sofosbuvir+Ribavirin in treatment-naives & prior nonresponders, below are links and pics of the results from studies in genotype 3 patients using sofosvuvir+Peg/Rbv and sofosbuvir+Rbv.

Here is a link to the phase 3 study of daclatasvir+sofosbuvir (IFN/Rbv free): Phase III Daclatasvir and Sofosbuvir for Genotype 3 Chronic HCV

And here is link to the study results from the small phase 2 study conducted with daclatasvir+sofosbuvir in genotypes 1, 2 and 3"

EASL/2012: Potent Viral Suppression With the All-Oral Combination of Daclatasvir (NS5A Inhibitor) and GS-7977 (Nucleotide NS5B Inhibitor), +/- Ribavirin, in Treatment-Naive Patients With Chronic HCV GT1, 2, or 3 (100% SVR gt1, 91% gt2) - (04/19/12)

Here is a link to study of daclatasvir+Sovaldi in patients who failed boceprevir+telaprevir, some patients had more advanced fibrosis:

EASL: Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC) - (04/27/13)

The daclatasvir+Sovaldi (IFN/Rbv free) regimen is not FDA approved, the data from their studies:

HCV1

AASLD: Sofosbuvir in Combination With PegIFN and Ribavirin for 12 Weeks Provides High SVR Rates in HCV-Infected Genotype 2 or 3 Treatment- Experienced Patients with and without Compensated Cirrhosis: Results from the LONESTAR-2 Study - (11/05/13)

The LONESTAR-2 study aimed to:
- Evaluate the efficacy of a 12-week SOF + PEG/RBV regimen in treatment-experienced patients with GT 2 or 3 infection, including those with cirrhosis-

HCV2

AASLD: Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients With HCV Genotype 2 or 3: the VALENCE Trial - (11/04/13)

VALENCE (NCT01682720) is a Phase 3 study conducted in Europe assessing safety and efficacy of SOF+RBV administered for:
- 12 weeks in patients with HCV GT 2
- 24 weeks in patients with HCV GT 3
Treatment-naïve or -experienced patients with HCV GT 2 or 3 were originally randomized 4:1 to receive SOF+RBV for 12 weeks or matching placebo

CONCLUSIONS:
- SOF + RBV for 24 weeks demonstrated SVR rates >90% in treatment-naïve HCV GT 3 patients
- In treatment-experienced HCV GT 3 patients, SVR rates were 60% and 87% in those with and without cirrhosis, respectively
- GT 2 patients had high SVR rates following treatment with SOF+RBV for 12 weeks
- No resistance detected in any patient with relapse SOF+RBV for 12 or 24 weeks was well tolerated
- Safety profile consistent with that of RBV
- No additional adverse events when treatment was extended to 24 weeks

HCV3

These are the recommendations from the new HCV Guidelines for patients who have been previously treated, non responders......

Link to New HCV Guidelines:

New Recommendations for Testing, Managing, and Treating Hepatitis C from AASLD/IDSA Panel. And newer developments in HCV therapy - (01/31/14)

HCV4

The phase 3 FUSION trial compared 12 weeks (n=103) with 16 weeks (n=98) of daily sofosbuvir (400 mg) and weight-based RBV (1000 mg to 1200 mg) in genotype 2 or 3 HCV-infected patients in whom previous PEG/RBV therapy had failed. Of patients, 63% had genotype 3; 34% of all patients had cirrhosis. Because persons who had experienced prior relapses to IFN-based therapy accounted for 75% of patients, the number of patients with a prior nonresponse in the study was limited. The SVR rate for genotype 3 patients in the 12-week arm was 30% (19% among patients with cirrhosis and 37% among those without cirrhosis). Extending therapy to 16 weeks increased the SVR rate among genotype 3 patients to 62% (61% among patients with and 63% in those without cirrhosis).

Based on results from FUSION, the phase 3 multicenter, randomized placebo-controlled VALENCE trial was amended to evaluate the effect of extending sofosbuvir plus RBV therapy to 24 weeks in all patients with HCV genotype 3. As with the FUSION study, most (65%) treatment-experienced patients had relapsed. The SVR12 rates after 24 weeks of therapy for treatment-experienced patients with genotype 3 was 79% (60% among patients with and 87% in those without cirrhosis). The increased efficacy with 24 weeks of sofosbuvir plus RBV therapy across all fibrosis stages combined with a favorable safety and tolerability profile supports the recommendation to use 24 weeks of sofosbuvir plus RBV in all genotype 3 patients despite the minimal number of patients studied to date. The response rate for HCV genotype 3-infected patients with cirrhosis treated for 24 weeks in the VALENCE trial (60%) was similar to that observed after 16 weeks of treatment in the FUSION trial (61%). Although longer treatment duration with a well-tolerated regimen may potentially be more successful in these more difficult-to-treat patients, data remain limited. Either duration of treatment is considered acceptable at this time (see below).

HCV5

Choice of specific regimen may be influenced by previous or anticipated tolerance to PEG or the presence of advanced fibrosis or cirrhosis. For most patients, the ease of administration and tolerability of sofosbuvir plus RBV will outweigh any potential benefit associated with the addition of PEG. However, for HCV genotype 3-infected patients who have cirrhosis, responses to sofosbuvir and RBV alone for 24 weeks were suboptimal.

In the LONESTAR-2 study, adding 12 weeks of PEG to the sofosbuvir and RBV regimen resulted in numerically higher response rates among persons with HCV genotype 3 than those obtained with sofosbuvir and RBV for 24 weeks. Of HCV genotype 3-infected patients with and without cirrhosis, 10 (83%) of 12 achieved SVR. Given the limited number of patients in this demographic in both the VALENCE and LONESTAR-2 studies, these differences in response rates should be interpreted with caution.

HCV6

No HCV protease inhibitors have been approved or are indicated for the treatment of genotype 3 HCV infection. Although PEG/RBV has been the mainstay of treatment of genotype 3 HCV, it is less efficacious and has more adverse effects than the recommended regimens.

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Genotype 3

HCV7

The VALENCE study assessed the efficacy and safety of sofosbuvir (400 mg daily) plus RBV for 24 weeks in 250 treatment-naive (42%) and treatment-experienced (58%) subjects with HCV genotype 3 infection. The overall SVR12 was 84% and was higher among treatment-naive than treatment-experienced patients (93% versus 77%, respectively). These results suggest higher response rates can be achieved with a 24-week duration of sofosbuvir plus RBV than those reported for the 12- or 16-week durations studied in the FISSION (Lawitz, 2013b) (12 weeks, SVR12: 63%), POSITRON, (Jacobson, 2013c) (12 weeks, SVR 12: 61%) and FUSION (12 weeks, SVR12: 30%, 16 weeks, SVR12: 62%) trials. The primary reason for the higher SVR with extended therapy among treatment-naive patients was a reduction in the relapse rate from 40% to 5%. In sub-analysis, response rates were similarly high among those with (n=45) and without (n=100) cirrhosis (92% and 93%, respectively).

HCV8

The combination of sofosbuvir plus PEG/RBV has been evaluated in patients with genotype 3 infection. In 2 phase 2 clinical trials, PROTON and ELECTRON, 38 of 39 (97%) treatment-naive patients with genotype 3 infection achieved SVR with sofosbuvir plus PEG (4 to 12 weeks of therapy)/RBV. (Gane, 2013b) For many patients with genotype 3, the adverse effects and increased monitoring requirements of PEG make this less acceptable than the recommended regimen of sofosbuvir plus weight-based RBV.

HCV9

Although the combination of PEG/RBV is an FDA-approved regimen for HCV genotype 3, its less acceptable adverse effect profile, requirement for more intensive monitoring, and overall lower efficacy make it less desirable than the recommended regimen.

Because of their limited in vitro and in vivo activity against genotype 3, boceprevir, telaprevir, and simeprevir should not be used as therapy for patients with HCV genotype 3 infection.

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