Dolutegravir (4) – Tivicay®

• Clinical trials
  • The ODYSSEY trial is a multicentre, open-label, randomised, controlled trial in which antiretroviral therapy (ART) comprising dolutegravir and two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) was compared with ‘standard of care’ (SOC) therapy.
  • This SOC consisted of a non-dolutegravir-based ART comprising two NRTIs and a boosted protease inhibitor, or a non-nucleoside reverse transcriptase inhibitor, or another integrase inhibitor.

a) Children and adolescents aged 6 to < 18 years with HIV infection (treatment-naïve)

• For treatment-naïve children with HIV aged 6 to < 12 years who have no known or suspected resistance to the class of integrase inhibitors, dolutegravir in combination with other antiretroviral medicinal products—atazanavir plus ritonavir in combination with abacavir plus emtricitabine, or in combination with abacavir plus lamivudine—has been identified as an appropriate comparator therapy.
• For treatment-naïve adolescents with HIV aged 12 to < 18 years who have no known or suspected resistance to the class of integrase inhibitors, rilpivirine in combination with tenofovir alafenamide plus emtricitabine, or in combination with abacavir plus lamivudine, was determined to be the appropriate comparator therapy for dolutegravir in combination with other antiretroviral medicinal products.
• In the ODYSSEY study, 145 out of 157 (92 %) of the treatment-naïve children and adolescents in the control arm received ART based on efavirenz.
• Treatment with regimens containing efavirenz does not constitute an adequate implementation of the appropriate comparator therapy specified by the G-BA for treatment-naive children and adolescents with HIV infection.
• As the majority of treatment-naïve children and adolescents in the ODYSSEY study were treated with regimens containing efavirenz, the study is not suitable for benefit assessment for this patient group, as the appropriate comparator therapy was not implemented.

b) Children and adolescents aged 6 to < 18 years with HIV infection (treatment-experienced)

• Cohort B of the ODYSSEY study comprises treatment-experienced children and adolescents aged < 18 years with HIV-1 infection without integrase inhibitor resistance and a body weight of ≥ 14 kg for whom second-line ART was indicated due to treatment failure.
• Due to the change in dosage specified in the SmPC, corresponding adjustments were made to the dosage of dolutegravir (DTG) in the intervention arm of the ODYSSEY study.
• Consequently, in the ODYSSEY study, only children and adolescents with a body weight of 40 kg or more were dosed in accordance with the current marketing authorisation from the outset.
• Although dosing in accordance with the current marketing authorisation was possible from May 2018 onwards for children and adolescents with a body weight of 20 to < 40 kg, the proportion of the patient population cannot be conclusively assessed.
• Consequently, only a patient population of unknown size from the ODYSSEY study corresponds to the authorised therapeutic indication.
• Given the substantial proportion of the relevant study population that was not treated in accordance with the current summary of product characteristics (SmPC) for dolutegravir, the pharmaceutical manufacturer does not use the ODYSSEY study for the benefit assessment.

• The dossier submitted by the pharmaceutical manufacturer did not contain any data suitable for assessing the additional benefit of dolutegravir in combination with other antiretroviral medicinal products compared with the appropriate comparator therapy for any of the specified patient groups.
• Due to the failure, identified during the IQWiG’s review, to implement the appropriate comparator therapy in treatment-naïve children and adolescents, as well as the fact that the dosage of dolutegravir in treatment-experienced children and adolescents was, in some cases, notin accordance with the package leaflet for treatment-experienced children and adolescents, and taking into account the pharmaceutical manufacturer’s lack of access to detailed patient data, the ODYSSEY study is not suitable for deriving additional benefit.
• Although the ODYSSEY study provides new scientific insights for children and adolescents with HIV aged 6 to < 18 years, the results of the study are not regarded as new evidence in the present therapeutic indication due to the study’s lack of suitability, as identified in the IQWiG review.
• Conclusion
  • The ODYSSEY study is a randomised, controlled trial conducted in children and adolescents aged < 18 years, which, for the first time, generates direct comparative evidence in the present therapeutic indication of HIV infection in this age group.
  • Endpoints relating to morbidity – such as virological failure or response and AIDS-defining events (WHO grades 3 and 4) – as well as health-related quality of life and side effects were recorded.

Courtesy translation only, please refer to the German original.