Ledipasvir / Sofosbuvir (3) – Harvoni®

a) Patients with chronic hepatitis C aged between 3 and < 12 years, genotypes 1, 4, 5 or 6

• Hint for a non-quantifiable additional benefit.
• The certainty of the evidence must be regarded as limited due to the single-arm study design (genotypes 1 and 4) or due to the extrapolation of the evidence (genotypes 5 and 6), and must be classified as a hint.
• mortality
  • No deaths were observed in the three studies.
• morbidity
  • A sustained virological response 12 (SVR12) or 24 weeks (SVR24) after the end of treatment was achieved in the patient population of Study 1116 receiving ledipasvir/sofosbuvir in 124 out of 126 (98.4%) patients.
  • In the Kamal 2020 study, 11 out of 11 (100%) patients achieved SVR12, and in the El-Shabrawi 2018 study, 19 out of 20 (95%) patients achieved SVR12; SVR24 was not assessed.
  • Although only single-arm data are available, it can be assumed with a high degree of certainty that these results cannot be achieved with the appropriate comparator therapy, ‘watchful waiting’.
• Health-related quality of life
  • Health-related quality of life was assessed in study 1116 using the PedsQL 4.0 SF15 (Pediatric Quality of Life Inventory 4.0 Short Form 15) at the start of the study and 24 weeks after the end of treatment.
  • For the entire patient population, there was a change of 2.0 points in the total score over the course of the study.
  • Due to the lack of comparative data, the results cannot be adequately interpreted.
• Side effects
  • In Study 1116, one serious adverse event and one adverse event leading to therapy discontinuation occurred.
• Overall assessment / Conclusion
  • Given the available data, it is possible – despite the single-arm study design – to infer an additional benefit of ledipasvir/sofosbuvir in the population of children aged 3 to under 12 years with HCV infection of genotype 1 or 4.
  • The results in the morbidity category relating to sustained virological response (SVR12 and SVR24) cannot, with a high degree of certainty, be achieved with the appropriate comparator therapy of ‘watchful waiting’.
  • There were no deaths, and only one serious adverse event and one adverse event that led to therapy discontinuation. This provides no hint that the potential for harm associated with ledipasvir/sofosbuvir is greater than that of the appropriate comparator therapy.
  • There are therefore no findings on mortality or side effects that call into question the advantage in terms of morbidity.
  • Nor is it assumed that the partial under- and overdosing (in patients weighing ≥ 35 kg and < 17 kg, respectively) leads to an underestimation of the result.
  • The available data on health-related quality of life cannot be adequately interpreted.
  • However, due to the lack of comparative data, it is not possible to quantify the extent of the additional benefit in this population.
  • No data are available for children with genotypes 5 and 6. By analogy with the findings for adult and adolescent patients, and taking into account the EMA’s conclusions, it can be assumed that for children with genotypes 5 or 6, an advantage over the appropriate comparator therapy—a ‘watch-and-wait’ approach—can be expected, particularly on the basis of the response rate.
  • The G-BA therefore also identifies a non-quantifiable additional benefit for children with genotype 5 or 6 infection.

b) Patients with chronic hepatitis C aged 3 to < 12 years, genotype 3 (previously treated patients and/or patients with cirrhosis)

• An additional benefit is therefore not proven for patients aged 3 to < 12 years with chronic hepatitis C infection of genotype 3 (previously treated patients and/or patients with cirrhosis).
• No data suitable for a benefit assessment are available for children with genotype 3 CHC infection (previously treated patients and/or patients with cirrhosis).
• Study 1116, submitted by the pharmaceutical manufacturer, included only two patients with genotype 3 infection; the other studies listed under patient group a) did not include any such patients.
• Overall, the available data are insufficient to demonstrate any additional benefit.
• As no additional benefit has been demonstrated in adult and adolescent patients with genotype 3 either, it is not possible to extrapolate such a benefit to the population of children aged between 3 and 12 years.
• Furthermore, it can be inferred from the current evidence base and the written and oral statements that genotype 3 shows minor response rates and – consequently – requires different treatment regimens; even in adults, treatment with ledipasvir/sofosbuvir should not be regarded as the standard treatment for genotype 3 infection.
• Therefore, even taking into account the EMA’s findings and contrary to the possibility of evidence transfer for genotype 3 identified by the EMA, no advantage of ledipasvir/sofosbuvir over the appropriate comparator therapy can be inferred.

Courtesy translation only, please refer to the German original.