Elvitegravir / Cobicistat / Emtricitabin / Tenofoviralafenamid (1) – Genvoya®

• Clinical trials
  • The studies GS-US-292-0102, GS-US-292-0104, GS-US-292-0111 were randomised, active-controlled, multicentre, double-blind trials comparing EVG/COBI/FTC/TAF with EVG/COBI/FTC/TDF.
  • The studies GS-US-236-0102 and GS-US-236-0104 are randomised, actively controlled, multicentre, double-blind studies comparing EFV/FTC/TDF with EVG/COBI/FTC/TDF.
  • 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 study 292-0109.

a) Adults who have not previously received antiretroviral treatment (treatment-naive)

• For adults who have not previously received antiretroviral treatment, an additional benefit over the appropriate comparator therapy is not proven.
• Based on these considerations, the information in the dossier, the results of the benefit assessment and the statements submitted, the G-BA finds that there is insufficient proof to demonstrate either an additional benefit or less benefit of EVG/COBI/FTC/TAF compared with the appropriate comparator therapy.
• mortality
  • For the endpoint of overall mortality, the result was not statistically significant. An additional benefit or greater harm from EVG/COBI/FTC/TAF compared with EFV/FTC/TDF is not proven for this endpoint.
• Morbidity – AIDS-defining events (CDC Class C 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.
  • For the endpoint ‘AIDS-defining events’, the adjusted indirect comparison shows a statistically significant difference to the detriment of EVG/COBI/FTC/TAF.
• Morbidity – Virological response
  • The validated surrogate parameter ‘virological response (viral load)’ is also clinically relevant.
  • For virological response (using both the snapshot algorithm and in the sensitivity analyses), the adjusted indirect comparison showed no statistically significant difference between EVG/COBI/FTC/TAF and EFV/FTC/TDF.
• Morbidity – CD4 cell counts
  • For CD4 cell counts, the adjusted indirect comparison revealed a statistically significant difference in favour of EVG/COBI/FTC/TAF. However, in light of the results for the other endpoints, it remains unclear whether this statistically significant difference also represents a clinically relevant difference.
• morbidity
  • Taking into account the combined results on AIDS-defining conditions, virological response and CD4 cell count, no clear advantage or disadvantage of EVG/COBI/FTC/TAF is identified with regard to the morbidity criteria for the appropriate comparator therapy.
• Health-related quality of life
  • None of the included studies collected data on health-related quality of life, although the G-BA considers such data to be significant.
• Side effects – severe adverse events (SAEs) and severe AEs (Grade 3–4)
  • For the SAE endpoint, the adjusted indirect comparison revealed a statistically significant difference to the detriment of EVG/COBI/FTC/TAF.
  • For the endpoint ‘severe AEs (Grade 3–4)’, the meta-analysis of the studies involving the intervention revealed unexplained heterogeneity without consistent effects. Consequently, no pooled estimate was calculated.
  • In adjusted indirect comparisons, in which only one of the studies 292-0104 and 292-0111 was included in each case, no statistically significant results were found.
• Side effects – discontinuation due to AE
  • For the endpoint ‘withdrawal due to AEs’, the adjusted indirect comparison shows a statistically significant difference in favour of EVG/COBI/FCT/TAF. However, the extent of the effect for this endpoint—which falls under the category of non-serious side effects—is no more than minimal.
• Side effects – nervous system disorders
  • For the endpoint ‘nervous system disorders’, the adjusted indirect comparison shows a statistically significant difference in favour of EVG/COBI/FCT/TAF. However, the extent of the effect for this endpoint, which falls within the category of non-serious/mild side effects, is no more than minimal.
• Side effects – psychiatric disorders
  • For the endpoint ‘psychiatric disorders’, the adjusted indirect comparison reveals a statistically significant difference in favour of EVG/COBI/FCT/TAF.
  • Furthermore, for this endpoint, there is an indication of an effect modification by the characteristic of age. In patients aged ≥ 40 years, a statistically significant difference was observed in favour of EVG/COBI/FCT/TAF. For patients aged < 40 years, the difference between the treatment arms was not statistically significant.
  • However, no age-specific distinction is made in the assessment of the additional benefit.
• Side effects – diseases of the skin and subcutaneous tissue
  • For the endpoint ‘skin and subcutaneous tissue disorders’, the adjusted indirect comparison shows a statistically significant difference in favour of EVG/COBI/FCT/TAF. However, the extent of the effect for this endpoint in the ‘non-serious’ side effects category is no more than minimal.
• Side effects – infections and parasitic diseases (SAE)
  • For the endpoint ‘infections and parasitic diseases’ (SAE), the adjusted indirect comparison shows a statistically significant difference to the detriment of EVG/COBI/FTC/TAF.
• Side effects – gastrointestinal disorders, renal and urinary tract disorders
  • No statistically significant differences were observed between the treatment groups for the above-mentioned endpoints.
• Side effects
  • Overall, the data on side effects do not suggest any additional benefit or less benefit of EVG/COBI/FTC/TAF compared with the appropriate comparator therapy.
• Overall assessment
  • Taking the results on mortality, morbidity, missing quality of life data and side effects into account as a whole, compared with the appropriate comparator therapy (in an adjusted indirect comparison): on the one hand, an increased incidence of the endpoint ‘AIDS-defining events’, albeit with a lower overall event rate; on the other hand, a conversely better recovery from immunodeficiency, as demonstrated by a statistically significant greater increase in CD4 cell count during treatment with the fixed-dose combination EVG/COBI/FTC/TAF, whilst again there was no statistically significant difference in the endpoint of virological response.
  • With regard to side effects, similarly opposing effects can be observed, which is why the overall assessment does not indicate any additional benefit or less benefit for the drug combination EVG/COBI/FTC/TAF.

b) adolescents aged 12 years and over who have not previously received antiretroviral therapy (treatment-naive)

• For adolescents aged 12 years and over who have not previously received antiretroviral therapy, an additional benefit over the appropriate comparator therapy is not proven.
• For this patient group, there are no relevant data available for a comparison of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide with the appropriate comparator therapy of efavirenz in combination with abacavir plus lamivudine.

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

• An additional benefit for the patient population under consideration here is not proven.
• In summary, for pre-treated, HIV-1-infected adult patients, an overall assessment of the results on mortality, morbidity, quality of life and side effects shows no additional benefit of EVG/COBI/FTC/TAF compared with the appropriate comparator therapy.
• mortality
  • For the endpoint of all-cause mortality, the differences at the 48-week analysis time point were not statistically significant, given the overall minor event rate. Additional benefit or greater harm from EVG/COBI/FTC/TAF compared with continuation of the previous therapy is not proven for this endpoint.
• Morbidity – AIDS-defining events (CDC Class C events)
  • For the endpoint of AIDS-defining events, there was no statistically significant difference between the treatment groups.
• Morbidity – Virological response
  • For virological response, the results of the snapshot algorithm show a statistically significant difference in favour of EVG/COBI/FTC/TAF (RR: 1.04 [1.02; 1.07]; p = 0.002).
  • However, the sensitivity analyses yield conflicting results regarding statistical significance, meaning that these analyses cannot support the statistically significant effect presented.
  • However, both the results based on the Snapshot algorithm and the sensitivity analyses (Missing = Failure and Missing = Excluded) may be biased if the proportions of patients with (a value of < 50 HIV-1 RNA copies/ml) and without virological data within the evaluation window, and the proportion of patients who discontinued treatment, differ between the study arms.
  • Consequently, the result regarding virological response obtained using the snapshot algorithm is not robust, and no conclusions regarding additional benefit can be drawn from this endpoint.
• Morbidity – CD4 cell count
  • No statistically significant difference was observed between the treatment arms in terms of the change in CD4 cell count.
• Morbidity – Health status (EQ-5D VAS)
  • No statistically significant difference was observed between the treatment groups.
• morbidity
  • Taking the results as a whole, there is therefore no additional benefit from EVG/COBI/FTC/TAF compared with continuing the previous treatment for the endpoint of morbidity.
• Health-related quality of life – SF-36 – physical summary score
  • There is no statistically significant difference between the treatment groups for the SF-36 physical summary score.
• Health-related quality of life – SF-36 – mental health summary score
  • For the mental health summary score of the SF-36, a statistically significant difference was observed in favour of EVG/COBI/FTC/TAF.
  • As the 95% confidence interval does not lie entirely above the irrelevance threshold of 0.2, the effect is assessed as not clinically relevant.
  • No additional benefit of EVG/COBI/FTC/TAF compared with continuing the previous therapy is not proven for the quality of life category.
• Side effects – SAE and severe AEs (Grade 3–4)
  • For the endpoint SAE and severe AEs (Grade 3–4), there are no statistically significant differences between the treatment groups.
  • However, for the endpoint ‘severe AEs (Grade 3–4)’, there is an indication of an effect modification (p = 0.097) by the characteristic of ethnicity (Caucasian/non-Caucasian).
  • However, no specific distinction is made in the assessment of additional benefit according to ethnicity.
• Side effects – discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AEs’, a statistically significant difference was observed in favour of EVG/COBI/FTC/TAF.
  • As study 292-0109 may have included patients who switched treatment due to side effects, and as it is not possible to estimate how high this proportion actually is, the result for this endpoint cannot be conclusively interpreted.
• Side effects – nervous system disorders
  • For the endpoint ‘disorders of the nervous system’, there is a statistically significant difference to the detriment of EVG/COBI/FTC/TAF.
  • However, for this endpoint, there is proof of an effect modification by the characteristic of sex (p = 0.038).
  • However, a gender-specific distinction is not applied in the assessment of additional benefit.
• Side effects – psychiatric disorders, disorders of the skin and subcutaneous tissue, disorders of the gastrointestinal tract, disorders of the kidney and urinary tract
  • No statistically significant differences were observed between the treatment groups for the above-mentioned endpoints.
• Side effects
  • Overall, the data on side effects do not suggest that EVG/COBI/FTC/TAF offers any greater or less benefit compared with continuing the previous treatment.
• Conclusion
  • In summary, for previously treated, HIV-1-infected adult patients, an overall assessment of the results regarding mortality, morbidity, quality of life and side effects reveals no additional benefit of EVG/COBI/FTC/TAF compared with the appropriate comparator therapy.
  • Thus, no additional benefit of EVG/COBI/FTC/TAF compared with continuing the current therapy can be inferred from the results of study 292-0109, which predominantly included patients without an indication for switching therapy and therefore does not reflect standard clinical practice.
  • Furthermore, no data are available for EVG/COBI/FTC/TAF in comparison with a change of therapy for patients in whom a switch in therapy would have been indicated.

d) antiretrovirally pre-treated (treatment-experienced) adolescents aged 12 years and over

• For antiretrovirally pre-treated adolescents aged 12 years and over, an additional benefit is not proven compared with the appropriate comparator therapy.
• Compared with the appropriate comparator therapy—an individualised antiretroviral regimen based on prior therapy(ies) and taking into account the reason for the change in treatment— in particular treatment failure due to virological failure and any associated development of resistance, or due to side effects, there are no data available for antiretrovirally pre-treated, HIV-1-infected adolescents aged 12 years and over.

Courtesy translation only, please refer to the German original.