Sofosbuvir (1) – Sovaldi®

• Clinical trials
  • NEUTRINO (N=327) was an open-label, single-arm Phase III trial evaluating a 12-week course of treatment with sofosbuvir in combination with peginterferon alfa-2a and ribavirin in treatment-naïve patients with HCV infection of genotypes 1, 4, 5 or 6; 17% had cirrhosis (N=54); 89% had HCV genotype 1 (N=292) and 11% had HCV genotypes 4, 5 or 6 (N=35).
  • FISSION (N=499; [256 intervention/243 control]) was a randomised, open-label, actively controlled trial comparing a 12-week course of treatment with sofosbuvir and ribavirin was compared with a 24-week course of treatment with peginterferon alfa-2a and ribavirin in treatment-naïve patients with HCV infection of genotype 2 or 3; 28% had genotype 2 (N=140 [73 intervention/67 control]), of whom approximately 18% had cirrhosis (N=25).
  • FUSION (N=201; [103 12 weeks/98 16 weeks]) was a randomised, double-blind Phase III trial investigating a 12- or 16-week course of treatment with sofosbuvir and ribavirin was investigated in patients with HCV infection of genotype 2 or 3 who had not achieved an SVR following previous interferon-containing therapy (relapsers and non-responders); 39 patients with genotype 2 received a 12-week course of treatment in accordance with the marketing authorisation.
  • VALENCE was a Phase III study in which sofosbuvir in combination with ribavirin was used to treat HCV infection of genotype 2 (N=73) or 3 (N=261) in treatment-naïve patients or in patients who had failed to achieve SVR following prior interferon-containing therapy, including patients with compensated cirrhosis.
  • PHOTON-1 was an open-label Phase III clinical trial investigating 12- or 24-week treatment with sofosbuvir and ribavirin in patients with chronic hepatitis C infection of genotype 1, 2 or 3 and HIV-1 co-infection.
  • POSITRON (N=272; [207 intervention/71 placebo]) was a randomised, double-blind, placebo-controlled Phase III trial in which 12-week treatment with sofosbuvir and ribavirin was compared with placebo in HCV patients (genotypes 2 and 3) who were intolerant to interferon and in patients who were unsuitable for or refused interferon therapy; 16% had cirrhosis; 49% had an HCV genotype 3 infection (N=135; [98 intervention/37 placebo]).

a) Treatment-naive patients without cirrhosis with chronic hepatitis C virus (cHCV) infection (genotype 1)

• The G-BA classifies the extent of the additional benefit of sofosbuvir as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• The certainty of the evidence is downgraded to a hint as only a single-arm study was available to demonstrate an adequate response in terms of SVR and to describe the adverse reaction profile of the sofosbuvir-ribavirin-peginterferon regimen.
• Morbidity – sustained virological response (SVR)
  • In the NEUTRINO study, 262 out of 292 HCV genotype 1 patients achieved an SVR (90%). SVR rates in patients without cirrhosis are 93%.
  • Given the magnitude of the SVR rates achieved and taking the study size into account, it is assumed – despite this being a single-arm study – that treatment with a sofosbuvir regimen is equivalent to triple therapy (protease inhibitor plus ribavirin plus peginterferon) is assumed to be equivalent with regard to this endpoint.
• Side effects
  • The side effects recorded in the NEUTRINO study under the sofosbuvir-ribavirin-peginterferon regimen correspond in nature to the side effect profile of a ribavirin-peginterferon regimen.
  • Taking into account the adverse effects of triple therapy, which are both provided with sufficient proof in studies and described in the summary of product characteristics (SmPC), in particular the side effects of treatment with peginterferon, the significant reduction in treatment duration compared with the appropriate comparator therapy is considered relevant in terms of avoiding side effects.
  • In an overall assessment in the sense of an indirect comparison, the G-BA identifies a minor additional benefit in treatment-naïve HCV patients with genotype 1 (with and without cirrhosis) compared with the appropriate comparator therapy, due to the significant avoidance of side effects.

Treatment-naive patients with cirrhosis and chronic hepatitis C virus (cHCV) infection (genotype 1)

• The G-BA classifies the extent of the additional benefit of sofosbuvir as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• The level of certainty is downgraded to a hint as only a single-arm study was available to demonstrate an adequate response in terms of SVR and to describe the side-effect profile of the sofosbuvir-ribavirin-peginterferon regimen.
• Morbidity – sustained virological response (SVR)
  • In the NEUTRINO study, 262 out of 292 HCV genotype 1 patients achieved an SVR (90%). SVR rates in patients with cirrhosis are 80%.
  • Given the magnitude of the SVR rates achieved and taking the study size into account, it is assumed – despite this being a single-arm study – that treatment with a sofosbuvir regimen is equivalent to triple therapy (protease inhibitor plus ribavirin plus peginterferon) is assumed to be equivalent with regard to this endpoint.
• Side effects
  • The side effects recorded in the NEUTRINO study under the sofosbuvir-ribavirin-peginterferon regimen correspond in nature to the side effect profile of a ribavirin-peginterferon regimen.
  • Taking into account the proof of the adverse effects of triple therapy, which is both sufficient in studies and described in the summary of product characteristics (SmPC), in particular the side effects of treatment with peginterferon, the significant reduction in treatment duration compared with the appropriate comparator therapy is considered relevant in terms of avoiding side effects.
  • Taking an overall view in the sense of an indirect comparison, the G-BA identifies a minor additional benefit in treatment-naïve HCV patients with genotype 1 (with and without cirrhosis) compared with the appropriate comparator therapy, due to the significant avoidance of side effects.

Treatment-experienced patients with chronic hepatitis C virus (cHCV) infection (genotype 1)

• There are insufficient data available to assess the additional benefit. Therefore, the additional benefit for treatment-experienced HCV patients with genotype 1 is not proven.

Treatment-naive patients with chronic hepatitis C virus (cHCV) infection (genotype 2)

• For treatment-naive patients with chronic hepatitis C virus (cHCV) infection (genotype 2), there is an indication of considerable additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of sofosbuvir as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease. Compared with the appropriate comparator therapy, there is, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, there is a considerable improvement in the therapy-relevant benefit compared with the appropriate comparator therapy, resulting in particular from a significant improvement in sustained virological response (SVR) and the possibility of an interferon-free regimen, along with the associated significant reduction in side effects.
• Morbidity – sustained virological response (SVR)
  • The population of ‘treatment-naïve HCV patients with genotype 2’ was investigated in a randomised, open-label, actively controlled study (FISSION). The proportion of treatment-naïve patients with genotype 2 who achieved an SVR 24 following 12 weeks’ treatment with sofosbuvir plus ribavirin is significantly higher than after 24 weeks’ treatment with peginterferon alfa plus ribavirin (97.1% versus 76.1% [RR: 1.28 / 95% CI: 1.11–1.47]).
  • Given the clinical relevance of SVR, a considerable additional benefit is observed in this patient group.
• Side effects
  • A qualitative analysis revealed fewer adverse events (AEs) and fewer discontinuations due to AEs in the FISSION study among treatment-naïve HCV patients with genotype 2.
  • A joint analysis of HCV patients with genotypes 2 and 3 from the FISSION study reveals a qualitative clustering of side effects such as flu-like symptoms, depression and fever in the control group, which is consistent with the side effect profile of peginterferon.
  • The interferon-free treatment regimen of sofosbuvir plus ribavirin is considered to offer an advantage over the appropriate comparator therapy, as it has a demonstrably positive effect on the adverse reaction profile.
  • The interferon-free treatment regimen of sofosbuvir plus ribavirin also enables treatment-naïve HCV genotype 2 patients, for whom interferon-containing regimens cannot be used, to receive antiviral treatment.
• Overall assessment
  • For treatment-naïve patients with chronic hepatitis C virus (cHCV) infection (genotype 2), an overall review of the results on mortality, morbidity and side effects provides an indication that sofosbuvir in combination with ribavirin offers considerable additional benefit compared with the appropriate comparator therapy [peginterferon + ribavirin] in terms of the therapeutic effects on morbidity.
  • The results of a randomised controlled trial show that treatment with sofosbuvir plus ribavirin leads to a significant improvement in sustained virological response compared with peginterferon plus ribavirin. Taking into account the severity of the disease and the therapeutic goal in its treatment, this is regarded as a considerable improvement in treatment-related benefit.
  • In the overall assessment of the results of the FISSION study, a considerable additional benefit is identified due to the significant improvement in SVR and the positive impact on side effects resulting from the interferon-free treatment regimen (sofosbuvir plus ribavirin). As an RCT is available, the results on SVR are assessed as robust and are therefore seen as an indication of additional benefit.
  • There are insufficient reliable results available for the relevant patient population to assess health-related quality of life. No deaths occurred in the relevant patient population during the study.

Treatment-experienced patients with chronic hepatitis C virus (cHCV) infection (genotype 2)

• The G-BA classifies the extent of the additional benefit of sofosbuvir as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• The certainty of the evidence has been downgraded to ‘a point of reference’ due to the availability of two single-arm studies for the interferon-free treatment regimen of sofosbuvir plus ribavirin in treatment-experienced HCV patients with genotype 2, and the comparative analysis of the adverse reaction profiles of the interferon--free sofosbuvir regimen on the one hand and the appropriate comparator therapy containing interferon on the other, the hint regarding the certainty of the evidence has been downgraded to ‘indicative’.
• Morbidity – sustained virological response (SVR)
  • In the FUSION study, 32 out of 39 patients (82.1 per cent) with HCV genotype 2 (previously treated) achieved an SVR, whilst in the VALENCE study, 37 out of 41 patients achieved an SVR (90 per cent). SVR rates were 60.0% (FUSION) and 88% (VALENCE) in patients with cirrhosis, and 89.6% (FUSION) and 91% (VALENCE) in patients without cirrhosis.
  • Given the magnitude of the SVR rates achieved and the availability of two studies with similar designs, it is assumed – despite these being single-arm studies – that treatment with a sofosbuvir regimen is equivalent to dual therapy (ribavirin plus peginterferon) with regard to this endpoint.
• Side effects
  • Taking into account the proof of the adverse effects of treatment with peginterferon, which is both sufficient in studies and described in the summary of product characteristics (SmPC), the interferon-free treatment regimen of sofosbuvir plus ribavirin – which is also administered over a comparatively much shorter treatment cycle – is considered to offer an advantage over the appropriate interferon-based comparator therapy, as a positive impact on the side-effect profile is evident.
  • The interferon-free treatment regimen of sofosbuvir plus ribavirin also enables treatment-experienced HCV patients with genotype 2, for whom interferon-containing treatment regimens cannot be used, to receive antiviral treatment.
  • In its overall assessment, in the sense of an indirect comparison, the G-BA identifies a minor additional benefit for treatment-experienced HCV patients with genotype 2 compared with the appropriate comparator therapy, due to the significant reduction in side effects.

Treatment-naive patients with chronic hepatitis C virus (cHCV) infection (genotype 3)

• The G-BA classifies the extent of the additional benefit of sofosbuvir as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition.
• The certainty of the findings has been downgraded to ‘indication’ due to the presence of a single-arm study for the interferon-free treatment regimen of sofosbuvir plus ribavirin in treatment-naïve and treatment-experienced HCV patients with genotype 3, and the comparative analysis of the adverse reaction profiles of the interferon-free sofosbuvir regimen on the one hand and the appropriate comparator therapy containing interferon on the other, the evidence provides a hint of certainty, downgraded to ‘indicative’.
• Morbidity – sustained virological response (SVR)
  • In the VALENCE study, 98 out of 105 (93 per cent) HCV patients with genotype 3 (treatment-naïve) achieved an SVR.
  • Given the magnitude of the SVR rates achieved and taking the study size into account, it is assumed – despite this being a single-arm study – that treatment with a sofosbuvir regimen is equivalent to dual therapy (ribavirin plus peginterferon) with regard to these endpoints.
• Side effects
  • In its overall assessment, in the sense of an indirect comparison, the G-BA identifies a minor additional benefit for the sofosbuvir-ribavirin regimen in treatment-naïve and treatment-experienced HCV patients with genotype 3 compared with the appropriate interferon--containing appropriate comparator therapy, due to the significant reduction in side effects.

Treatment-experienced patients with chronic hepatitis C virus (cHCV) infection (genotype 3)

• The G-BA classifies the extent of the additional benefit of sofosbuvir as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the condition.
• The level of certainty is downgraded to ‘indicative’ due to the presence of a single-arm study for the interferon-free treatment regimen of sofosbuvir plus ribavirin in treatment-naïve and treatment-experienced HCV patients with genotype 3, and the comparative assessment of the adverse reaction profiles of the interferon--free sofosbuvir regimen on the one hand and the appropriate comparator therapy containing interferon on the other, the evidence provides a hint of certainty, downgraded to ‘indicative’.
• Morbidity – sustained virological response (SVR)
  • Given the magnitude of the SVR rates achieved and taking the study size into account, it is assumed – despite this being a single-arm study – that treatment with a sofosbuvir regimen is equivalent to dual therapy (ribavirin plus peginterferon) with regard to these endpoints.
• Side effects
  • Taking into account the proof of the adverse effects of treatment with peginterferon, which has been provided in studies and described in the summary of product characteristics (SmPC), the interferon-free treatment regimen of sofosbuvir plus ribavirin – which, moreover, is administered over a comparatively much shorter treatment cycle in treatment-experienced patients – is considered to offer an advantage over the interferon-based appropriate comparator therapy, as a positive impact on the side-effect profile is evident.
  • Taking an overall view in the sense of an indirect comparison, the G-BA identifies a minor additional benefit for the sofosbuvir-ribavirin regimen in treatment-naïve and treatment-experienced HCV patients with genotype 3 compared with the interferon-containing appropriate comparator therapy, due to the significant reduction in side effects.

Treatment-naive and treatment-experienced patients with chronic hepatitis C virus (cHCV) infection (genotype 3) (sofosbuvir in combination with ribavirin and peginterferon alfa)

• For HCV patients with genotype 3 who were treated with the sofosbuvir-ribavirin-peginterferon regimen, there were insufficient data available to assess the additional benefit. Consequently, the additional benefit of the sofosbuvir-ribavirin-peginterferon regimen in HCV patients with genotype 3 is not proven.

Treatment-naive and treatment-experienced patients with chronic hepatitis C virus (cHCV) infection (genotypes 4, 5 and 6)

• Morbidity – sustained virological response (SVR)
  • In the NEUTRINO study, the SVR rates for genotypes 4, 5 and 6 were 97 per cent (34/35) and 100 per cent (33/33) for genotypes 4, 5 and 6 (without cirrhosis) and 50 per cent (1/2) for genotypes 4, 5 and 6 (with cirrhosis). The number of patients available for these genotypes is very minor [genotype 4 (N=28), genotype 5 (N=1), genotype 6 (N=6)]. No conclusion regarding SVR can be drawn on the basis of this data. The available data are not considered sufficient to assess the additional benefit.

Treatment-naive patients with HIV co-infection and chronic hepatitis C virus (cHCV) infection (genotypes 1 to 6)

• The G-BA classifies the extent of the additional benefit of sofosbuvir as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• The certainty of the findings is downgraded to a hint due to the availability of a single-arm study for the patient group with HCV/HIV co-infection and the comparative analysis of the adverse reaction profiles of the sofosbuvir regimen on the one hand and the appropriate comparator therapy containing interferon on the other.
• Morbidity – sustained virological response (SVR)
  • Given the magnitude of the SVR rates achieved and taking into account the study size (N=168 [genotype 1 (treatment-naïve), genotype 2 (treatment-naïve, treatment-experienced), genotype 3 (treatment-experienced)]) it is assumed, despite this being a single-arm trial, that treatment with a sofosbuvir regimen is equivalent to dual therapy (ribavirin plus peginterferon) with regard to these endpoints.
• Side effects
  • Taking into account the adverse effects of treatment with peginterferon, which are both sufficiently proven in studies and described in the summary of product characteristics (SmPC), the comparatively much shorter treatment cycle of the sofosbuvir-containing regimens, as well as the fact that the interferon-free ‘sofosbuvir plus ribavirin’ regimen, as opposed to dual therapy, is considered to offer an advantage in terms of reducing side effects.
  • In an overall assessment in the sense of an indirect comparison, the G-BA identifies a minor additional benefit for patients with HCV/HIV co-infection compared with the appropriate comparator therapy, due to the significant reduction in side effects.

Treatment-experienced patients with HIV co-infection and chronic hepatitis C virus (cHCV) infection (genotypes 1 to 6)

• The G-BA classifies the extent of the additional benefit of sofosbuvir as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in treating the disease.
• The certainty of the findings is downgraded to ‘hint’ due to the availability of a single-arm study for the patient group with HCV/HIV co-infection and the comparative analysis of the adverse reaction profiles of the sofosbuvir regimen on the one hand and the appropriate comparator therapy containing interferon on the other.
• Morbidity – sustained virological response (SVR)
  • Given the magnitude of the SVR rates achieved and taking into account the study size (N=168 [genotype 1 (treatment-naïve), genotype 2 (treatment-naïve, treatment-experienced), genotype 3 (treatment-experienced)]) it is assumed, despite this being a single-arm trial, that treatment with a sofosbuvir regimen is equivalent to dual therapy (ribavirin plus peginterferon) with regard to these endpoints.
• Side effects
  • Taking into account the adverse effects of treatment with peginterferon, which are both provided with sufficient proof in studies and described in the summary of product characteristics (SmPC), the comparatively much shorter treatment cycle of the sofosbuvir-containing regimens, as well as the interferon-free ‘Sofosbuvir plus Ribavirin’ regimen, as opposed to dual therapy, is considered to offer an advantage in terms of reducing side effects.
  • Taking an overall view in the sense of an indirect comparison, the G-BA concludes that there is a minor additional benefit for patients with HCV/HIV co-infection compared with the appropriate comparator therapy, due to the significant reduction in side effects.

Courtesy translation only, please refer to the German original.