Bictegravir / Emtricitabin / Tenofoviralafenamid (1) – Biktarvy®

• Clinical trials
  • To assess the additional benefit for the patient group of adults who have not previously received antiretroviral treatment (treatment-naive), the pharmaceutical manufacturer has submitted the two double-blind, parallel, randomised, controlled trials GS-US-1489 (1489) and GS-US-1490 (1490).
  • In the submitted study 1489, bictegravir/emtricitabine/tenofovir alafenamide was compared with the specified appropriate comparator therapy, dolutegravir/abacavir/lamivudine, in study 1489, and with dolutegravir in combination with emtricitabine/tenofovir alafenamide in study 1490.
  • To assess the additional benefit for the patient group of antiretrovirally pre-treated (treatment-experienced) adults, the pharmaceutical manufacturer has submitted the three parallel, randomised, controlled studies GS-US-1844 (double-blind), GS-US-1878 (open-label) and GS-US-1961 (open-label) in the dossier.
  • In the studies, bictegravir/emtricitabine/tenofovir alafenamide was compared in each case with continuation of the patients’ previous treatment.

a) Treatment-naïve adult HIV-1 patients in whom no resistance to the class of integrase inhibitors, emtricitabine or tenofovir has been detected, either currently or in the past

• An additional benefit is not proven.
• In summary, for treatment-naïve adult HIV-1 patients, an overall assessment of the results regarding mortality, morbidity, quality of life and side effects, bictegravir/emtricitabine/tenofoviralafenamide offers no additional benefit compared with the appropriate comparator therapy.
• mortality
  • In studies 1489 and 1490, no statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
  • Consequently, the additional benefit of bictegravir/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy for the endpoint of mortality is not proven.
• Morbidity – AIDS-defining events (CDC Class C)
  • For the endpoint of CDC-class AIDS-defining events, study 1489 showed no statistically significant difference between the treatment groups.
  • No usable data are available for this endpoint in study 1490.
• Morbidity – Virological response/virological failure
  • For the endpoints virological response and virological failure, the meta-analysis at week 96 showed no statistically significant difference between the treatment groups.
• Quality of life – SF-36v2 – Physical Component Summary (PCS)
  • For the PCS of the SF-36v2, the meta-analysis at week 48 shows no statistically significant difference between the treatment groups.
• Side effects
  • Heterogeneity was observed for the SAE endpoint. In Study 1489, there was no statistically significant difference between the treatment groups for SAE. In Study 1490, there was a statistically significant difference to the detriment of bictegravir/emtricitabine/tenofovir alafenamide. As the effect was not consistent across studies, the overall analysis of both studies provides no hint of greater or minor harm from bictegravir/emtricitabine/tenofovir alafenamide for this endpoint.
  • For the endpoints of severe adverse events (AEs; Division of AIDS (DAIDS) Grade 3–4) and discontinuation due to AEs, the meta-analysis showed no statistically significant difference between the treatment groups.
  • At the level of individual events considered relevant in the therapeutic indication for HIV, classified according to the MedDRA System Organ Class (SOC) term, a statistically significant difference was observed for the endpoint ‘gastrointestinal disorders’ (SOC) in favour of bictegravir/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy. This difference is largely attributable to the PT (Preferred Term) ‘Nausea’ contained within this SOC, for which the meta-analysis also shows a statistically significant difference in favour of bictegravir/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy.
  • For the endpoints ‘skin and subcutaneous tissue disorders’ (SOC), ‘nervous system disorders’ (SOC) and ‘psychiatric disorders’ (SOC), the meta-analytical evaluation revealed no statistically significant differences between the study arms.
  • In addition to the events considered relevant in advance, a statistically significant difference in favour of bictegravir/emtricitabine/tenofovir alafenamide.
  • For the endpoints of kidney and urinary tract disorders (SOC) and pain in a limb (PT), the meta-analysis revealed a statistically significant difference in each case to the detriment of bictegravir/emtricitabine/tenofovir alafenamide.
  • Overall, in the ‘Side Effects’ category, neither an advantage nor a disadvantage for bictegravir/emtricitabine/tenofovir alafenamide can be inferred from the statistically significant endpoints.
• Overall assessment
  • The two double-blind, parallel, randomised, controlled studies 1489 and 1490 were submitted for the assessment of the extent of the additional benefit of bictegravir/emtricitabine/tenofovir alafenamide. Results are available on mortality, morbidity, quality of life and side effects.
  • No statistically significant difference was observed between the treatment groups for the endpoint of mortality. In the morbidity category, a statistically significant advantage was observed for the endpoint ‘symptoms measured using the HIV Symptom Index’. For the CD4 cell count endpoint, a meta-analysis revealed a statistically significant difference to the detriment of bictegravir/emtricitabine/tenofovir alafenamide. No clinical relevance can be inferred from these two differences.
  • No statistically significant difference was observed between the treatment groups in terms of health-related quality of life.
  • In the category of side effects, no statistically significant difference was observed between the treatment groups for the SAE endpoint in Study 1489. In Study 1490, a statistically significant difference was observed to the detriment of bictegravir/emtricitabine/tenofovir alafenamide.
  • For the endpoints ‘severe adverse events’ and ‘discontinuation due to adverse events’, the meta-analysis showed no statistically significant difference between the treatment groups in either case.
  • In the ‘Side Effects’ category, at the level of individual events considered relevant, a statistically significant difference was observed in the meta-analysis for the endpoint ‘Gastrointestinal disorders’ (SOC), largely driven by the endpoint ‘Nausea’ (PT), as well as the endpoint ‘infections of the upper respiratory tract, thoracic cavity and mediastinum’ (SOC), a statistically significant difference in favour of bictegravir/emtricitabine/tenofovir alafenamide was found in the meta-analysis for each of these events.
  • For the endpoints ‘Renal and urinary disorders’ (SOC) and ‘Pain in a limb’ (PT), the meta-analysis revealed a statistically significant difference to the detriment of bictegravir/emtricitabine/tenofovir alafenamide.
  • In the category of side effects, no overall advantage or disadvantage for bictegravir/emtricitabine/tenofovir alafenamide can be inferred.
  • In summary, for treatment-naïve adult HIV-1 patients, an overall assessment of the results regarding mortality, morbidity, quality of life and side effects, bictegravir/emtricitabine/tenofovir alafenamide offers no additional benefit compared with the appropriate comparator therapy.

b) Treatment-experienced adult HIV-1 patients in whom no resistance to the class of integrase inhibitors, emtricitabine or tenofovir has been detected, either currently or in the past

• The additional benefit is not proven.
• 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 shows that bictegravir/emtricitabine/tenofovir alafenamide offers no additional benefit compared with the appropriate comparator therapy.
• mortality
  • In the meta-analysis of studies 1844, 1878 and 1961, no statistically significant difference was observed between the treatment groups for the endpoint of overall survival.
• Morbidity – AIDS-defining events (CDC Class C) [similar to Darunavir combination/Elvitegravir combination 2016-01-01_D-206 and D-362 Dolutegravir/Rilpivirin]
  • In the GS-US-1844, GS-US-1878 and GS-US-1961 studies, no AIDS-defining events occurred in any of the treatment arms.
• Morbidity – Virological response/virological failure
  • For the endpoints of virological response and virological failure, the meta-analysis showed no statistically significant difference between the treatment arms.
• Morbidity – CD4 cell counts
  • For CD4 cell counts, no statistically significant difference was observed between the treatment arms in any of the three studies (GS-US-1844, GS-US-1878 and GS-US-1961).
• Morbidity – HIV symptoms measured using the HIV Symptom Index (HIV-SI)
  • For the HIV-SI endpoint, there is heterogeneity in the overall index. In study 1844, a statistically significant difference was observed in favour of bictegravir/emtricitabine/tenofovir alafenamide. In study 1878, no statistically significant difference was observed between the treatment groups. In study 1961, this endpoint was not assessed. As the effects were not consistent across the studies, an overall review of both studies for this endpoint provides no hints of greater or minor harm associated with bictegravir/emtricitabine/tenofovir alafenamide.
• morbidity
  • A review of the results regarding AIDS-defining illnesses, virological response, virological failure and CD4 cell count does not demonstrate any additional benefit of bictegravir/ Emtricitabine/tenofovir alafenamide compared with continuing the previous therapy does not provide proof that this is better than continuing the previous therapy for the endpoint of morbidity.
• Quality of life – SF-36v2 – physical composite score (PCS)
  • For the PCS, the meta-analysis of the GS-US-1844 and GS-US-1878 studies shows a statistically significant difference in favour of bictegravir/emtricitabine/tenofovir alafenamide compared with continuing the existing therapy. The 95% confidence interval (CI) for the standardised mean difference (Hedges’ g) does not lie entirely outside the irrelevance range of −0.2 to 0.2. It cannot therefore be concluded that the effect is clinically relevant. In the GS-US-1961 study, this endpoint was not assessed.
• Side effects
  • For the endpoints, serious adverse events (SAEs), discontinuation due to adverse events (AEs) and severe (Division of AIDS (DAIDS) Grade 3–4) adverse events (AEs), the meta-analysis revealed no statistically significant difference between the treatment groups in any of these cases.
  • At the level of individual events considered relevant in the therapeutic indication for HIV, classified according to the MedDRA System Organ Class (SOC) term, the meta-analysis revealed a statistically significant difference to the detriment of bictegravir/emtricitabine/tenofovir alafenamide compared with continuation of previous therapy.
  • For the endpoint ‘psychiatric disorders’ (SOC), heterogeneity was observed, with a statistically significant difference in favour of bictegravir/emtricitabine/tenofovir alafenamide in study 1844, and statistically significant differences to the detriment of bictegravir/emtricitabine/tenofovir alafenamide in studies 1878 and 1961.
  • There is heterogeneity for the endpoints ‘skin and subcutaneous tissue disorders’ (SOC) and ‘nervous system disorders’ (SOC). For both endpoints, a statistically significant difference to the detriment of bictegravir/emtricitabine/tenofovir alafenamide was observed in study 1878, whilst no statistically significant difference was found in either study 1844 or 1961.
  • In addition to the events previously considered relevant, the meta-analysis reveals a statistically significant difference to the detriment of bictegravir/emtricitabine/tenofovir alafenamide for the endpoint ‘urinary tract infection’ (PT).
  • For this endpoint, there is proof of an effect modification by the characteristic of sex. For women, there is an indication of greater harm from bictegravir/emtricitabine/tenofovir alafenamide compared with continuing their previous therapy for this non-serious side effect. For men, there is no hint for greater or minor harm associated with bictegravir/emtricitabine/tenofovir alafenamide compared with continuing the existing therapy for this endpoint.
• Overall review
  • In the overall review, no data are available for patients with an indication for switching.
  • For patients without an indication for switching, the three studies provide results on mortality, morbidity, quality of life and side effects.
  • For patients without an indication for switching, a statistically significant side effect for the endpoint Urinary Tract Infection (PT) for women, and a statistically significant side effect for the endpoint Gastrointestinal Tract Disorders (SOCemtricitabine/tenofovir alafenamide.
  • Overall, however, 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 is not readily transferable to the everyday healthcare situation. Furthermore, the generalisability of the results from the patient group without an indication for switching to the overall population of treatment-experienced adults is unclear.
  • 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—the relevance of which to the everyday healthcare situation is questionable—no additional benefit or less benefit of bictegravir/emtricitabine/tenofovir alafenamide compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.