Elvitegravir / Cobicistat / Emtricitabin / Tenofovirdisoproxil (1) – Stribild®

• Clinical trials
  • Two randomised controlled trials (GS-US-236-0102 and GS-US-236-0104) were included in the assessment, with randomised treatment durations of 96 weeks and 60 weeks respectively.
  • The GS-US-236-0102 study was a Phase III trial involving 707 randomised patients.
  • The GS-US-236-0104 is a double-blind Phase II registration trial involving 71 randomised patients and having a study duration of 96 weeks, although only the first 60 weeks of treatment were conducted under double-blind, randomised and controlled conditions and were included in the analysis.
  • In both studies, the combination drug EVG/COBI/FTC/TDF was compared directly with the appropriate comparator therapy, efavirenz in combination with emtricitabine plus tenofovir disoproxil (EFV/FTC/TDF).

a) Adult patients who had not previously received antiretroviral therapy

• mortality
  • For the endpoint of all-cause mortality, the result was not statistically significant, neither at 96 weeks nor at 48/60 weeks.
  • No additional benefit or greater harm of EVG/COBI/FTC/TDF compared with EFV/FTC/TDF is not proven for this endpoint.
• morbidity
  • Results on incident AIDS-defining events, virological response and CD4 cell count are available for the assessment of morbidity.
  • The virological endpoints of CD4 cell count and virological response are sufficiently valid surrogate endpoints for the composite endpoint ‘AIDS-defining illnesses/death’.
  • AIDS-defining events
  • The endpoint ‘AIDS-defining events’ (CDC Class C events) consists mainly of opportunistic infections (e.g. pneumonia) and typical tumours (e.g. Kaposi’s sarcoma, lymphomas), which indicate the onset of AIDS.
  • The aim of any antiretroviral therapy is to prevent the occurrence of the events summarised under the endpoint ‘AIDS-defining events’ and thus the onset of AIDS.
  • At the 96-week analysis point, a statistically significant greater number of patients on treatment with EVG/COBI/FTC/TDF experienced an AIDS-defining event than those on treatment with EFV/FTC/TDF (8 patients vs. 1 patient).
  • It is not clear from the documentation provided whether events in patients who had already been diagnosed with AIDS at the start of the study were counted again during the course of the study.
  • The occurrence of AIDS-defining events within the first few months after the start of treatment may not be attributed to insufficient efficacy of the therapy, but may also be due to the advanced stage of immunodeficiency in individual patients at the time treatment began.
  • Of the total of nine AIDS-defining events (CDC-C) that occurred, three events occurred within 16 days of the start of treatment, two whilst on treatment with EVG/COBI/FTC/TDF and one whilst on EFV/FTC/TDF, and could be classified as IRIS cases in the sense described above.
  • Furthermore, one patient on treatment with EVG/COBI/FTC/TDF experienced a drop in CD4 cell count to < 200/µL, which was classified as an AIDS-defining event.
  • However, the statistically significant difference for the endpoint of AIDS-defining events persists even after excluding the aforementioned cases (4 patients in the EVG/COBI/FTC/TDF group versus no patients in the EFV/FTC/TDF group).
  • The total number of events that occurred is, however, minor.
  • Virological response
  • Virological response (time to loss of viral response, TLOVR) is used in the benefit assessment as a sufficiently valid surrogate endpoint for the composite endpoint ‘AIDS-defining illnesses/death’.
  • No statistically significant difference in virological response was observed between the two treatment arms, neither at 96 weeks (GS-US-236-0102) nor at 48 weeks (GS-US-236-0102/GS-US-236-0104).
  • “Virological response (viral load)” is a validated surrogate parameter and is clinically relevant to patients.
  • CD4 cell counts
  • The CD4 count endpoint is of great importance for the diagnosis and treatment planning of HIV infection, as well as for the planning and evaluation of results in studies relating to the indication for HIV infection; it is therefore used in the benefit assessment as a sufficiently valid surrogate endpoint for the combined endpoint ‘AIDS-defining conditions/death’.
  • For the CD4 cell count, a statistically significant difference in favour of EVG/COBI/FTC/TDF was demonstrated in the increase in cell count after 96 weeks (GS-US-236-0102) (30 cells [1, 60]).
  • This positive effect in favour of EVG/COBI/FTC/TDF was also evident in the results of the meta-analysis at 60 weeks.
  • It remains unclear whether the statistically significant difference also represents a clinically relevant difference.
  • Taking into account the results on AIDS-defining illnesses, virological response and CD4 cell count, no clear advantage or disadvantage of EVG/COBI/FTC/TDF is identified with regard to the morbidity criteria for the appropriate comparator therapy.
• quality of life
  • In the GS-US-236-0102 and GS-US-236-0104 studies, no data on health-related quality of life were collected, although the G-BA considers such data to be significant.
• Side effects
  • Serious adverse events occurred at a statistically significantly higher rate after 96 weeks in patients treated with EVG/COBI/FTC/TDF.
  • The pooled data at 48/60 weeks confirmed this finding.
  • A total of 2 patients receiving treatment with EVG/COBI/FTC/TDF were counted in both the AIDS-defining event category and the SAE category.
  • Even when these patients are excluded from the SAE count, a significant result remains (54/348 vs. 33/352; RR 1.66 [1.10; 2.49]; p=0.014).
  • For the endpoint of psychiatric disorders (SOC), a statistically significant difference in favour of EVG/COBI/FTC/TDF compared with EFV/FTC/TDF was observed at the 96-week analysis point.
  • The pooled data at 46/60 weeks confirmed this result.
  • For the endpoint ‘nervous system disorders’ (SOC), a statistically significant difference in favour of EVG/COBI/FTC/TDF compared with EFV/FTC/TDF was observed at the 96-week analysis time point.
  • The pooled data at 46/60 weeks confirmed this result.
  • For the endpoint ‘skin rashes’ (pre-specified set of preferred terms, PT), a statistically significant difference in favour of EVG/COBI/FTC/TDF compared with EFV/FTC/TDF was observed at the 96-week analysis time point.
  • The pooled data at 46/60 weeks confirmed this result.
  • Renal events (pre-specified PT set) occurred at a statistically significant higher rate with EVG/COBI/FTC/TDF treatment at 96 weeks.
  • The pooled data at 46/60 weeks did not confirm this result.
  • No statistically significant difference was observed between the treatment arms in terms of gastrointestinal disorders (SOC), neither at 96 weeks nor at 48/60 weeks.

Treatment-experienced patients in whom HIV-1 does not harbour mutations known to be associated with resistance to any of the three active ingredients in Stribild®

• For pre-treated adult patients whose HIV-1 does not harbour any known mutations associated with resistance to any of the three active ingredients in the combination of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil, additional benefit is not proven.
• For the group of pre-treated patients, no relevant study was available to assess the additional benefit compared with the appropriate comparator therapy.
• An additional benefit of EVG/COBI/FTC/TDF compared with the appropriate comparator therapy (individualised therapy) is therefore not proven for this population.
• The extrapolation of results from treatment-naïve patients to patients who have already received antiretroviral therapy, carried out as part of the marketing authorisation process, is not suitable for assessing additional benefit on the basis of the criteria set out in Section 5(7) of the AM-NutzenV.

Courtesy translation only, please refer to the German original.