Darunavir / Cobicistat / Emtricitabin / Tenofoviralafenamid (1) – Symtuza®

• Clinical trials
  • To assess the additional benefit for the patient group of antiretrovirally pre-treated (treatment-experienced) adults, the pharmaceutical manufacturer has drawn on the open-label, randomised, controlled EMERALD trial.

a) Adults not previously treated with antiretrovirals (treatment-naive)

• The additional benefit is not proven.
• No data were submitted for the patient population of treatment-naive adults to assess the additional benefit of darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy.

b) Adolescents aged 12 years and over who have not previously received antiretroviral treatment (treatment-naïve)

• The additional benefit is not proven.
• No data were submitted to assess the additional benefit of darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy for the patient population of treatment-naive adolescents aged 12 years and over.

c) Adults who have previously received antiretroviral treatment (treatment-experienced)

• The additional benefit is not proven.
• The pharmaceutical manufacturer has cited the open-label, randomised, controlled EMERALD study to assess the additional benefit for the patient group of antiretrovirally pre-treated (treatment-experienced) adults.
• The study included virologically suppressed (HIV-1 ribonucleic acid [RNA] viral load < 50 copies/ml) who had previously been treated for at least 6 consecutive months with a regimen comprising 1 boosted protease inhibitor (bPI) (consisting of darunavir boosted with ritonavir [DRV/r], darunavir boosted with cobicistat [DRV/co], atazanavir boosted with ritonavir [ATV/r], atazanavir boosted with cobicistat [ATV/co] or lopinavir boosted with ritonavir [LPV/r]) and the combination of emtricitabine and tenofovir disoproxil (FTC/TDF) for at least 6 consecutive months.
• The patients (N = 1149) were randomised in a 2:1 ratio to either the DRV/COBI/FTC/TAF arm (N = 766) or the arm continuing their previous therapy (N = 383).
• In the patient population studied, it can be assumed that the vast majority of patients had no medically necessary indication for switching treatment, neither due to virological failure nor due to side effects of their previous therapy.
• Consequently, for these patients, continuing their previous treatment in the control arm of the EMERALD study constitutes the appropriate comparator therapy; the results of the EMERALD study can be used to assess the additional benefit in pre-treated adults without an indication for switching.
• By contrast, no data are available for pre-treated adult patients with an indication for switching. Consequently, it is not possible to assess the additional benefit for these patients.
• mortality
  • No deaths occurred in the EMERALD study. Consequently, the additional benefit of darunavir/cobicistat/emtricitabine/tenofovir alafenamide is not proven compared with continuing the current treatment regimen for the endpoint of mortality.
• Morbidity – AIDS-defining events
  • The pU operationalises the endpoint ‘AIDS-defining events’ as the number of Grade 4 events according to the WHO classification for the severity of clinical manifestations of HIV infection.
  • In the EMERALD study, an adapted version of the WHO classification was used, in which the CD4 cell count was not taken into account when assessing the endpoint ‘AIDS-defining events’.
  • The endpoint ‘AIDS-defining events’ (WHO Class 4 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 to prevent the onset of AIDS.
  • This endpoint therefore enables the assessment of treatment success in terms of preventing AIDS-defining conditions and is thus directly relevant to patients.
  • The occurrence of AIDS-defining events within the first few months of starting treatment may not necessarily be attributed to insufficient efficacy of the treatment, but may also be due to the advanced stage of immunodeficiency in individual patients at the time treatment began.
  • In the EMERALD study, no WHO Class 4 AIDS-defining event occurred.
• Health-related quality of life
  • Endpoints in the health-related quality of life category were not investigated in the EMERALD study. Consequently, additional benefit from darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with continuing the previous treatment for the endpoint of quality of life is not proven.
• Side effects
  • For the endpoints serious adverse events (SAEs), severe (Division of AIDS (DAIDS) Grade 3–4) adverse events (AEs), and discontinuation due to AEs, no statistically significant difference was observed between the treatment groups.
  • For specific AEs, classified by system organ class (SOC) and preferred term (PT), statistically significant differences to the detriment of darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with continuation of previous therapy.
  • However, the extent of the increased harm for these non-serious side effects is no more than minor.
  • For the endpoint‘nervous system disorders’(particularly headaches), a statistically significant difference was observed to the detriment of darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with continuation of previous therapy.
• Overall assessment
  • Overall, no data are available for patients with an indication for switching.
  • For patients without an indication for switching, a statistically significant difference to the detriment of darunavir/cobicistat/emtricitabine/tenofovir alafenamide can be observed in the ‘side effects’ category, particularly for the endpoint ‘nervous system disorders’.
  • It seems questionable whether, in clinical practice, a switch from the current therapy would be initiated for patients for whom there are no medical reasons for a change in treatment.
  • A clear distinction between patients with and without an indication for switching is not directly applicable to the everyday healthcare situation. Furthermore, it is unclear whether the results from the patient group without an indication for switching can be extrapolated to the overall population of treatment-experienced adults.
  • The assessment of additional benefit is therefore carried out for the overall population of treatment-experienced adults.
  • As the statistically significant results therefore apply only to a subgroup of this patient group—whose relevance to everyday healthcare situations is questionable—no additional benefit or less benefit of darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy.
  • In summary, for pre-treated, HIV-1-infected adult patients, an overall assessment of the results regarding mortality, morbidity, quality of life and side effects does not indicate any additional benefit of darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy.

d) Adolescents aged 12 years and over who have previously received antiretroviral therapy (treatment-experienced)

• An additional benefit is not proven
• No data were submitted for the patient population of antiretrovirally pre-treated (treatment-experienced) adolescents aged 12 years and over to assess the additional benefit of darunavir/cobicistat/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.