Dolutegravir / Lamivudin (1) – Dovato®

• Clinical trials
  • To assess the additional benefit for the patient group of antiretrovirally pre-treated (treatment-experienced) adults, the pharmaceutical manufacturer has submitted the two open-label, parallel, randomised, controlled trials ASPIRE and TANGO.

a) Treatment-naïve adult HIV-1 patients with no known or suspected resistance to the class of integrase inhibitors or lamivudine

• The additional benefit is not proven.
• In summary, based on an overall assessment of the results, there is no additional benefit for DTG/3TC compared with DTG + TDF/FTC in treatment-naïve adult patients infected with HIV-1.
• mortality
  • In the GEMINI-1 and GEMINI-2 studies, no statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
  • Consequently, the additional benefit of DTG/3TC compared with DTG + TDF/FTC for the endpoint of mortality is not proven.
• Morbidity – AIDS-defining events (CDC Class C)
  • For the endpoint of CDC Class AIDS-defining events, the meta-analysis shows no statistically significant difference between the treatment groups.
• Morbidity – Virological response/virological failure
  • For the endpoints virological response and virological failure, the meta-analysis shows no statistically significant difference between the treatment groups in the overall population.
  • For the endpoint of virological response, there is proof of an effect modification by the characteristic of CD4 cell count at baseline. For patients with a CD4 cell count of ≤ 200 cells/mm³ at baseline, there is a statistically significant disadvantage of DTG/3TC compared with DTG + TDF/FTC. For patients with a CD4 cell count > 200 cells/mm³ at baseline, there was no statistically significant difference between the treatment groups.
• Morbidity – CD4 cell counts
  • With regard to CD4 cell counts, the meta-analysis of the two studies, GEMINI-1 and GEMINI-2, showed no statistically significant difference between the treatment arms.
• Morbidity – Health status measured using the EQ-5D VAS
  • No meta-analysis is presented for the health status endpoint, assessed using the EQ-5D VAS, due to heterogeneity and the absence of consistent effects between the GEMINI-1 and GEMINI-2 studies. In the GEMINI-1 study, a statistically significant difference in favour of DTG/3TC was observed; in the GEMINI-2 study, no statistically significant difference was observed between the treatment groups. An additional benefit is therefore not proven for this endpoint.
• quality of life
  • The GEMINI-1 and GEMINI-2 studies did not investigate endpoints in the ‘health-related quality of life’ category.
  • Consequently, additional benefit from DTG/3TC compared with DTG + TDF/FTC for the quality of life endpoint is not proven.
• Side effects
  • For the endpoints, serious adverse events (SAEs), severe adverse events (AEs; Division of AIDS (DAIDS) Grade 3–4) and discontinuation due to AEs, the meta-analysis revealed no statistically significant difference between DTG/3TC and DTG + TDF/FTC.
  • With regard to specific AEs, a statistically significant advantage of DTG/3TC over DTG + TDF/FTC was observed for the endpoints nasopharyngitis (PT), arthralgia (PT) and nausea (PT). Overall, these were non-serious events. For the other specific adverse events, the meta-analysis showed no statistically significant difference between the treatment groups in any case. The advantages regarding specific adverse events are assessed as not constituting a clinically relevant reduction in side effects, taking into account the clinical symptoms and severity of the disease, as well as the nature and frequency of the adverse events.
  • In the category of side effects, there are no clinically relevant differences overall between DTG/3TC and DTG + TDF/FTC.
• Overall assessment / Conclusion
  • For the endpoint of overall survival, no statistically significant difference was observed between DTG/3TC and DTG + TDF/FTC.
  • In the overall review of the results in the ‘morbidity’ category concerning AIDS-defining illnesses, virological response, virological failure, CD4 cell count and health status, the additional benefit of DTG/3TC compared with DTG + TDF/FTC is not proven.
  • In the ‘side effects’ category, the meta-analysis revealed no statistically significant difference between the treatment groups for any of the endpoints: SAE, severe AEs and discontinuation due to AEs.
  • At the level of individual specific adverse events (nasopharyngitis, arthralgia, nausea), a statistically significant difference in favour of DTG/3TC was observed in each case. Overall, these were non-serious events. Taking into account the clinical symptoms and the severity of the disease, as well as the nature and frequency of the adverse events, this advantage is assessed as an irrelevant reduction in side effects and therefore does not lead to the conclusion that there is any additional benefit.
  • In the category of side effects, therefore, there are no differences between DTG/3TC and DTG + TDF/FTC that are relevant to the benefit assessment when viewed as a whole.

b) Treatment-experienced adult HIV-1 patients with no known or suspected resistance to the class of integrase inhibitors or lamivudine

• The additional benefit is not proven.
• In summary, for treatment-experienced adult patients infected with HIV-1, an overall assessment of the results on mortality, morbidity and side effects shows no additional benefit of dolutegravir/lamivudine compared with the appropriate comparator therapy.
• mortality
  • In the ASPIRE and TANGO studies, no statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
  • Consequently, the additional benefit of DTG/3TC compared with continuing existing ART for the endpoint of mortality is not proven.
• Morbidity – AIDS-defining events (CDC Class C) and health status (EQ-5D VAS)
  • For the endpoints AIDS-defining events and health status, the TANGO study showed no statistically significant difference between the treatment arms. No data are available for these endpoints in the ASPIRE study.
• Morbidity – virological response, virological failure and CD4 cell count
  • For the endpoints virological response and CD4 cell count, neither study showed a statistically significant difference between the treatment arms. No results were available from the ASPIRE study regarding virological failure. In the TANGO study, there was no statistically significant difference between the treatment arms.
  • Taking together the results on AIDS-defining illnesses, virological response, virological failure, CD4 cell count and health status, the additional benefit of DTG/3TC compared with continuing existing ART is not proven for the endpoint of morbidity.
• quality of life
  • The ASPIRE and TANGO studies did not investigate endpoints in the health-related quality of life category.
  • Consequently, the additional benefit of DTG/3TC compared with continuing existing ART is not proven for the endpoint of quality of life.
• Side effects
  • In the ASPIRE study, no statistically significant difference was observed between the treatment groups for the endpoints of serious adverse events (SAEs) and discontinuation due to adverse events. No usable data are available for the endpoint ‘severe adverse events’ (AEs; Division of AIDS (DAIDS) Grade 3–4) due to possible multiple reporting. No results are available for the endpoint ‘specific adverse events’.
  • In the TANGO trial, there was no statistically significant difference between the treatment groups for the endpoints of SUE and severe AEs (DAIDS grade 3–4). For the endpoints of discontinuation due to AEs, fatigue (PT) and seasonal allergy (PT), a statistically significant difference was observed in each case to the detriment of DTG/3TC. The events that occurred were predominantly classified as non-serious.
• Overall assessment / Conclusion
  • Overall, no data are available for patients with an indication for switching.
  • For patients without an indication for switching, the ASPIRE and TANGO studies provide results on mortality, morbidity and side effects. Health-related quality of life was not assessed in the studies.
  • The ASPIRE study revealed no significant differences. The TANGO study reveals statistically significant differences to the detriment of dolutegravir/lamivudine for patients without an indication for switching in the endpoints of discontinuation due to adverse events, as well as fatigue (PT) and seasonal allergy (PT).
  • Overall, it is questionable whether, in clinical practice, a switch from the current treatment would be initiated for patients for whom there are no medical reasons to change therapy. A clear distinction between patients with and without an indication for switching cannot be directly applied to the everyday healthcare situation. Furthermore, it is unclear whether the results from the patient subgroup without an indication for switching are generalisable to the overall population of treatment-experienced adults.
  • As the results therefore apply only to a subgroup of this patient group—the relevance of which to everyday healthcare situations is questionable—it is not possible to infer from the data on side effects any additional benefit or less benefit of dolutegravir/lamivudine compared with the appropriate comparator therapy for the general population.

c) Treatment-naïve adolescents with HIV-1 aged 12 years and over who have no known or suspected resistance to the class of integrase inhibitors or lamivudine

• An 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 dolutegravir/lamivudine compared with the appropriate comparator therapy.

d) Treatment-experienced adolescents aged 12 years and over with HIV-1 who have no known or suspected resistance to the class of integrase inhibitors or lamivudine

• An 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 dolutegravir/lamivudine compared with the appropriate comparator therapy.
• Overall, therefore, the additional benefit of DTG/3TC is not proven for treatment-experienced adolescents infected with HIV-1.

Courtesy translation only, please refer to the German original.