Doravirin / Lamivudin / Tenofovirdisoproxil (1) – Delstrigo®

• Clinical trials
  • In Study 021, DOR/3TC/TDF was compared with EFV/emtricitabine (FTC)/TDF. In Study 021, a total of 734 patients were randomised in a 1:1 ratio to receive either DOR/3TC/TDF (N = 368) or EFV/FTC/TDF (N = 366).
  • The SINGLE and SPRING-1 studies were randomised, parallel-group trials. The SINGLE study was conducted as a double-blind trial, whilst the SPRING-1 study was partially blinded.
  • In the SINGLE study, DTG + ABC/3TC was compared with EFV/FTC/TDF. In the SINGLE study, a total of 844 patients were randomised in a 1:1 ratio to receive treatment with DTG + ABC/3TC (N = 422) or EFV/FTC/TDF (N = 422).
  • The SPRING-1 study is a dose-finding study of DTG. Only patients from the study arm in which the daily adult dose of 50 mg DTG (N = 51) was administered, in accordance with the SmPC, are included in this benefit assessment. Patients in the comparator arm (N = 52) received EFV.

a) Treatment-naive adult HIV-1 patients whose HIV viruses do not harbour mutations known to be associated with resistance to the NNRTI class of drugs, lamivudine or tenofovir

• An additional benefit is not proven.
• mortality
  • For the endpoint of overall survival, the adjusted indirect comparison showed no statistically significant difference between DOR/3TC/TDF and DTG + 2 NRTI.
  • Consequently, the additional benefit of DOR/3TC/TDF compared with DTG + 2 NRTIs is not proven for the endpoint of mortality.
• Morbidity – AIDS-defining events (CDC Class C)
  • The endpoint ‘AIDS-defining events (CDC Class C)’ consists mainly of opportunistic infections (e.g. pneumonia) and typical tumours (e.g. Kaposi’s sarcoma, lymphomas) that indicate the onset of AIDS.
  • For the endpoint of AIDS-defining events (CDC Class C), the adjusted indirect comparison showed no statistically significant difference between DOR/3TC/TDF and DTG + 2 NRTIs.
• Morbidity – Virological response
  • The validated surrogate parameter ‘virological response (viral load)’ is clinically relevant.
  • For the endpoint ‘virological response’, no statistically significant difference was found between DOR/3TC/TDF and DTG + 2 NRTIs in the adjusted indirect comparison.
• Morbidity – CD4 cell counts
  • The endpoint ‘CD4 cell count’ shows a high potential for bias (breach of the ITT principle) in studies 021 and SPRING-1.
  • Consequently, neither an advantage nor a disadvantage of DOR/3TC/TDF compared with DTG + 2 NRTIs can be inferred for this endpoint.
• morbidity
  • Based on a comprehensive review of the results regarding AIDS-defining illnesses, virological response and CD4 cell count, the additional benefit of DOR/3TC/TDF compared with DTG + 2 NRTIs is not proven for the morbidity endpoint.
• Health-related quality of life
  • Endpoints in the ‘health-related quality of life’ category were not investigated in the 021, SINGLE and SPRING-1 studies.
  • Consequently, the additional benefit of DOR/3TC/TDF compared with DTG + 2 NRTIs for the quality of life endpoint is not proven.
• Side effects
  • For the endpoints of serious adverse events (SAE) and severe adverse events (AEs; Division of AIDS (DAIDS) Grade 3–4), the adjusted indirect comparison revealed no statistically significant difference between DOR/3TC/TDF and DTG + 2 NRTIs.
  • For the endpoint of treatment discontinuation due to AEs, no statistically significant difference was found between DOR/3TC/TDF and DTG + 2 NRTIs in the adjusted indirect comparison.
  • For the endpoint of specific AEs, the pharmaceutical manufacturer submitted incomplete analyses both in the dossier and during the commenting procedure; these were not taken into account in the benefit assessment. Consequently, no statistically significant advantages or disadvantages of DOR/3TC/TDF over DTG + 2 NRTI can be inferred for this endpoint.
  • In the category of side effects, there are no statistically significant differences between DOR/3TC/TDF and DTG + 2 NRTI when viewed as a whole.
• Overall assessment / Conclusion
  • For the benefit assessment of doravirin/lamivudine/tenofovir disoproxil for the treatment of treatment-naïve adult patients infected with HIV-1, an adjusted indirect comparison of DOR/3TC/TDF (Study 021) with dolutegravir (DTG) in combination with 2 NRTIs (Studies SINGLE, SPRING-1) via the bridge comparator efavirenz (EFV).
  • For the endpoint of overall survival, the adjusted indirect comparison showed no statistically significant difference between DOR/3TC/TDF and DTG + 2 NRTIs.
  • In the overall review of the results in the morbidity category relating to AIDS-defining conditions, virological response and CD4 cell count, the additional benefit of DOR/3TC/TDF compared with DTG + 2 NRTIs is not proven.
  • In the ‘side effects’ category, no statistically significant difference was found between the treatment arms in the adjusted indirect comparison.
  • In summary, for treatment-naïve adult patients infected with HIV-1, an overall assessment of the results regarding mortality, morbidity and side effects shows no additional benefit for DOR/3TC/TDF compared with DTG + 2 NRTI.

b) Treatment-experienced adult HIV-1 patients whose HIV viruses do not harbour mutations known to be associated with resistance to the NNRTI class of drugs, lamivudine or tenofovir

• The additional benefit is not proven.
• For this patient population, the pharmaceutical manufacturer did not submit any study that would have been suitable for assessing the additional benefit of DOR/3TC/TDF compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.